Ectopic pregnancy: History, incidence, epidemiology, and risk factors.
Marion Laura L,Meeks George Rodney
Clinical obstetrics and gynecology
Ectopic pregnancy is directly related to tubal infection, and so prevention of chlamydia and gonorrhea must be the watchword to lower its risk and incidence. With accurate determination of very low human chorionic gonadotropin concentrations and sonography, >85% of women are diagnosed before tubal rupture, which has led to medical therapy and laparoscopic surgery with tubal preservation and the potential for future fertility. Today, early intervention saves lives and reduces morbidity, but ectopic pregnancy still accounts for 4% to 10% of pregnancy-related deaths and leads to a high incidence of ectopic site gestations in subsequent pregnancies.
10.1097/GRF.0b013e3182516d7b
Ectopic pregnancy.
Farquhar Cynthia M
Lancet (London, England)
Ectopic pregnancy is an important cause of morbidity and mortality worldwide. Use of transvaginal ultrasonography and quantitative measurement of the beta subunit of human chorionic gonadotropin (beta-hCG) has led to a reduction in the need for diagnostic laparoscopy. Furthermore, with earlier diagnosis, medical therapy with methotrexate can be offered and surgery avoided in some women, though the best regimen remains unclear. In the surgical management of ectopic pregnancy, the benefits of salpingectomy over salpingostomy are uncertain. Although there have been advances in the management of ectopic pregnancy there are still questions to be answered.
10.1016/S0140-6736(05)67103-6
Ectopic pregnancy--United States, 1990-1992.
MMWR. Morbidity and mortality weekly report
Ectopic pregnancy is the leading cause of pregnancy-related death during the first trimester (1). Women who have one ectopic pregnancy are at increased risk for another such pregnancy and for future infertility (2). In the United States, the reported number of hospitalizations for ectopic pregnancy increased from 17,800 in 1970 to 88,400 in 1989 (1). This report summarizes trends in hospitalizations for ectopic pregnancy in the United States during 1990-1992 and presents the incidence of ectopic pregnancy in 1992, based on aggregated inpatient and outpatient data.
Sites of ectopic pregnancy: a 10 year population-based study of 1800 cases.
Bouyer J,Coste J,Fernandez H,Pouly J L,Job-Spira N
Human reproduction (Oxford, England)
BACKGROUND:Several risk factors for ectopic pregnancy (EP) have been identified, but the site of implantation of EP has been little studied. METHODS:A total of 1800 surgically treated EP was registered between January 1992 and December 2001 in the Auvergne EP register and the women concerned were followed up. In this large population-based sample, we studied the distribution of EP sites, immediate complications, determining factors, and subsequent fertility. RESULTS:EP sites were interstitial (2.4%), isthmic (12.0%), ampullary (70.0%), fimbrial (11.1%), ovarian (3.2%) or abdominal (1.3%). No cervical pregnancies were observed. Complications and treatment depended on the site of EP. In multivariate analysis, the only risk factor associated with EP site was current use of an intrauterine device (IUD), which was more frequent in distal EP. The 2 year cumulative rate of subsequent spontaneous intrauterine pregnancy (IUP) increased progressively from interstitial to ovarian EP. Fair concordance (weighted kappa = 0.31) was observed between the sites of two successive EP if they were homolateral. CONCLUSION:In addition to providing an accurate description of the sites of implantation of EP, this study shows that current IUD use 'protects' against interstitial pregnancies, which are the most difficult to manage. It shows that subsequent fertility tends to be higher in women with distal EP.
10.1093/humrep/17.12.3224
Symptomatic patients with an early viable intrauterine pregnancy: HCG curves redefined.
Barnhart Kurt T,Sammel Mary D,Rinaudo Paolo F,Zhou Lan,Hummel Amy C,Guo Wensheng
Obstetrics and gynecology
OBJECTIVE:To analyze the change in serial human chorionic gonadotropin (hCG) levels in women symptomatic with pain or bleeding who presented with nondiagnostic ultrasonography but were ultimately confirmed to have a viable intrauterine pregnancy. METHODS:The rise in serial hCG measures were modeled over time, with the start point defined in 2 ways: by last menstrual period and by date of presentation for care. Both semiparametric (spline) curves and linear random-effects models were explored. The slope and projected increase of hCG were calculated to define 99% of viable intrauterine pregnancies. RESULTS:A total of 287 subjects met inclusion criteria and contributed 861 measurements of hCG. On average, these subjects contributed 3.00 observations and were followed up for 5.25 days. A linear increase in log hCG best described the pattern of rise. Curves derived from last menstrual period and day of presentation do not differ substantially. The median slope for a rise of hCG after 1 day was 1.50, (or a 50% increase); 2.24 after 2 days (or a 124% rise), and 5.00 after 4 days. The fastest rise was 1.81 at 1 day, 3.28 at 2 days, and 10.76 at 4 days. The slowest or minimal rise for a normal viable intrauterine pregnancy was 24% at 1 day and 53% at 2 days. CONCLUSION:These data define the slowest rise in serial hCG values for a potentially viable gestation and will aid in distinguishing a viable early pregnancy from a miscarriage or ectopic pregnancy. The minimal rise in serial hCG values for women with a viable intrauterine pregnancy is "slower" than previously reported, suggesting that intervention to diagnosis and treat an abnormal gestation should be more conservative.
10.1097/01.AOG.0000128174.48843.12
Diagnosis and treatment of ectopic pregnancy.
CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne
Ectopic pregnancy is a life- and fertility-threatening condition that is commonly seen in Canadian emergency departments. Increases in the availability and use of hormonal markers, coupled with advances in formal and emergency ultrasonography have changed the diagnostic approach to the patient in the emergency department with first-trimester bleeding or pain. Ultrasonography should be the initial investigation for symptomatic women in their first trimester; when the results are indeterminate, the serum beta human chorionic gonadotropin (beta-hCG) concentration should be measured. Serial measurement of beta-hCG and progesterone concentrations may be useful when the diagnosis remains unclear. Advances in surgical and medical therapy for ectopic pregnancy have allowed the proliferation of minimally invasive or noninvasive treatment. Guidelines for laparoscopy and for methotrexate therapy are provided.
10.1503/cmaj.050222
Application of redefined human chorionic gonadotropin curves for the diagnosis of women at risk for ectopic pregnancy.
Seeber Beata E,Sammel Mary D,Guo Wensheng,Zhou Lan,Hummel Amy,Barnhart Kurt T
Fertility and sterility
OBJECTIVE:To validate recently characterized curves of hCG rise and fall that are seen in viable and nonviable pregnancies in a population of women who have pregnancies of unknown location. DESIGN:Historical cohort study. SETTING:University hospital. PATIENT(S):One thousand two hundred forty-nine women with symptomatic early pregnancies. INTERVENTION(S):None. MAIN OUTCOME MEASURE(S):Comparison of observed hCG values to predicted hCG values; time to diagnosis of ectopic pregnancy; accuracy of diagnosis. RESULT(S):Of the 1,249 patients included in this study, 196 had ectopic pregnancy (EP); 261, intrauterine pregnancy (IUP); and 792, spontaneous abortion (SAB). By determining the rate of change in hCG values from two consecutive visits and comparing them with a minimal rise of 35% in 2 days (the bound that is defined by the 99.9% confidence interval [CI] for the rise of hCG in an IUP) or a minimal fall of 21%-35% (the bound that is defined by the 90% CI for the fall of hCG in an SAB), we were able to make the diagnosis of EP an average of 2.5 days sooner than by standard clinical practice. Only 12% of patients had an EP go undiagnosed by using these rules, because the curve of rise or fall of their hCG mimicked that of a non-EP gestation. CONCLUSION(S):Recently redefined curves of rise and fall in hCG for IUP and SAB are valid for clinical use on the basis of our application to this large cohort of patients. Using them can shorten the time needed to make the diagnosis of EP. Use of a more conservative cutoff for minimal rise in hCG, one as slow as 35% over 2 days, to characterize a potentially viable gestation would minimize potential interruption of a desired pregnancy.
10.1016/j.fertnstert.2005.12.056
Why are some ectopic pregnancies characterized as pregnancies of unknown location at the initial transvaginal ultrasound examination?
Kirk Emma,Daemen Anneleen,Papageorghiou Aris T,Bottomley Cecilia,Condous George,De Moor Bart,Timmerman Dirk,Bourne Tom
Acta obstetricia et gynecologica Scandinavica
OBJECTIVE:To compare the appearance and behavior of ectopic pregnancies (EPs) initially classified as pregnancies of unknown location (PULs) to those visualized on the initial transvaginal ultrasound scan (TVS). METHODS:An observational study over a four-year period on women undergoing a TVS prior to diagnosis of a tubal EP. Demographic details, presenting symptoms, TVS findings, serum hCG and progesterone levels were recorded at the time of the initial TVS and at the time of diagnosis of the EP in those initially classified as a PUL. RESULTS:411 women with a tubal EP underwent a TVS prior to treatment. In 85.9% (353/411) the EP was visualized on the initial TVS while 14.1%(58/411) were initially classified as PULs. Those initially classified as PULs had significantly lower mean gestational age and mean initial human chorionic gonadotrophin (hCG) levels, and significantly higher mean progesterone level at presentation than those where the EP was visualized on the initial TVS. Of those with a PUL, 60.3% (35/58) had the EP subsequently visualized on TVS. At the time of diagnosis these EPs were significantly smaller (p<0.0001); the appearance of the EPs, serum hCG and progesterone levels at the time of visualization on TVS were not significantly different from those visualized on the initial TVS. CONCLUSION:In women with EPs who are initially classified as PULs, failure of visualization of the EP on the initial TVS is likely to be due to the fact that they are too small and probably too early in the disease process.
10.1080/00016340802443822
MicroRNAs: target recognition and regulatory functions.
Bartel David P
Cell
MicroRNAs (miRNAs) are endogenous approximately 23 nt RNAs that play important gene-regulatory roles in animals and plants by pairing to the mRNAs of protein-coding genes to direct their posttranscriptional repression. This review outlines the current understanding of miRNA target recognition in animals and discusses the widespread impact of miRNAs on both the expression and evolution of protein-coding genes.
10.1016/j.cell.2009.01.002
Current knowledge of the aetiology of human tubal ectopic pregnancy.
Shaw J L V,Dey S K,Critchley H O D,Horne A W
Human reproduction update
BACKGROUND An ectopic pregnancy is a pregnancy which occurs outside of the uterine cavity, and over 98% implant in the Fallopian tube. Tubal ectopic pregnancy remains the most common cause of maternal mortality in the first trimester of pregnancy. The epidemiological risk factors for tubal ectopic pregnancy are well established and include: tubal damage as a result of surgery or infection (particularly Chlamydia trachomatis), smoking and in vitro fertilization. This review appraises the data to date researching the aetiology of tubal ectopic pregnancy. METHODS Scientific literature was searched for studies investigating the underlying aetiology of tubal ectopic pregnancy. RESULTS Existing data addressing the underlying cause of tubal ectopic pregnancy are mostly descriptive. There are currently few good animal models of tubal ectopic pregnancy. There are limited data explaining the link between risk factors and tubal implantation. CONCLUSIONS Current evidence supports the hypothesis that tubal ectopic pregnancy is caused by a combination of retention of the embryo within the Fallopian tube due to impaired embryo-tubal transport and alterations in the tubal environment allowing early implantation to occur. Future studies are needed that address the functional consequences of infection and smoking on Fallopian tube physiology. A greater understanding of the aetiology of tubal ectopic pregnancy is critical for the development of improved preventative measures, the advancement of diagnostic screening methods and the development of novel treatments.
10.1093/humupd/dmp057
Analysis of circulating microRNA biomarkers in plasma and serum using quantitative reverse transcription-PCR (qRT-PCR).
Kroh Evan M,Parkin Rachael K,Mitchell Patrick S,Tewari Muneesh
Methods (San Diego, Calif.)
MicroRNAs (miRNAs) are small (approximately 22 nt) RNAs that play important roles in gene regulatory networks by binding to and repressing the activity of specific target mRNAs. Recent studies have indicated that miRNAs circulate in a stable, cell-free form in the bloodstream and that the abundance of specific miRNAs in plasma or serum can serve as biomarkers of cancer and other diseases. Measurement of circulating miRNAs as biomarkers is associated with some special challenges, including those related to pre-analytic variation and data normalization. We describe here our procedure for qRT-PCR analysis of circulating miRNAs as biomarkers, and discuss relevant issues of sample preparation, experimental design and data analysis.
10.1016/j.ymeth.2010.01.032
Trends in the diagnosis and treatment of ectopic pregnancy in the United States.
Hoover Karen W,Tao Guoyu,Kent Charlotte K
Obstetrics and gynecology
OBJECTIVE:To estimate trends in the rates of diagnosis and treatment of ectopic pregnancy in the United States. METHODS:We analyzed data from a large administrative claims database of more than 200 U.S. commercial health plans, and estimated time trends in the rate and incidence of ectopic pregnancy among girls and women aged 15-44 years by 5-year age groups and by region from 2002 to 2007. We also estimated time trends in the proportion of cases that were treated surgically, either by laparoscopy or laparotomy, or medically with methotrexate. RESULTS:We identified 11,989 ectopic pregnancies during the period from 2002 to 2007. The overall rate of ectopic pregnancy among pregnant girls and women aged 15-44 years during the 6-year study period was 0.64%. We did not observe a trend in the rate of ectopic pregnancy by 5-year age group or by geographic region. The ectopic pregnancy rate increased with age; it was 0.3% among girls and women aged 15-19 years and 1.0% among women aged 35-44 years. Methotrexate treatment increased from 11.1% in 2002 to 35.1% in 2007 (P<.001); the methotrexate failure rate was 14.7% over the 6-year study period. Surgical management with laparotomy decreased over the study period from 40.0% to 33.1% (P<.001). CONCLUSION:We did not find an increasing or decreasing trend in the rate of ectopic pregnancy among U.S. commercially insured women from 2002 to 2007. The use of administrative claims data are likely the most feasible method for estimating the rate and monitoring trends of ectopic pregnancy in the United States.
10.1097/AOG.0b013e3181d0c328
Exosomes: extracellular organelles important in intercellular communication.
Mathivanan Suresh,Ji Hong,Simpson Richard J
Journal of proteomics
In addition to intracellular organelles, eukaryotic cells also contain extracellular organelles that are released, or shed, into the microenvironment. These membranous extracellular organelles include exosomes, shedding microvesicles (SMVs) and apoptotic blebs (ABs), many of which exhibit pleiotropic biological functions. Because extracellular organelle terminology is often confounding, with many preparations reported in the literature being mixtures of extracellular vesicles, there is a growing need to clarify nomenclature and to improve purification strategies in order to discriminate the biochemical and functional activities of these moieties. Exosomes are formed by the inward budding of multivesicular bodies (MVBs) and are released from the cell into the microenvironment following the fusion of MVBs with the plasma membrane (PM). In this review we focus on various strategies for purifying exosomes and discuss their biophysical and biochemical properties. An update on proteomic analysis of exosomes from various cell types and body fluids is provided and host-cell specific proteomic signatures are also discussed. Because the ectodomain of ~42% of exosomal integral membrane proteins are also found in the secretome, these vesicles provide a potential source of serum-based membrane protein biomarkers that are reflective of the host cell. ExoCarta, an exosomal protein and RNA database (http://exocarta.ludwig.edu.au), is described.
10.1016/j.jprot.2010.06.006
Pregnancy of unknown location: a consensus statement of nomenclature, definitions, and outcome.
Barnhart Kurt,van Mello Norah M,Bourne Tom,Kirk Emma,Van Calster Ben,Bottomley Cecilia,Chung Karine,Condous George,Goldstein Steven,Hajenius Petra J,Mol Ben Willem,Molinaro Thomas,O'Flynn O'Brien Katherine L,Husicka Richard,Sammel Mary,Timmerman Dirk
Fertility and sterility
OBJECTIVE:To improve the interpretation of future studies in women who are initially diagnosed with a pregnancy of unknown location (PUL), we propose a consensus statement with definitions of population, target disease, and final outcome. DESIGN:A review of literature and a series of collaborative international meetings were used to develop a consensus for definitions and final outcomes of women initially diagnosed with a PUL. RESULT(S):Global differences were noted in populations studied and in the definitions of outcomes. We propose to define initial ultrasound classification of findings into five categories: definite ectopic pregnancy (EP), probable EP, PUL, probable intrauterine pregnancy (IUP), and definite IUP. Patients with a PUL should be followed and final outcomes should be categorized as visualized EP, visualized IUP, spontaneously resolved PUL, and persisting PUL. Those with the transient condition of a persisting PUL should ultimately be classified as nonvisualized EP, treated persistent PUL, resolved persistent PUL, or histologic IUP. These specific categories can be used to characterize the natural history or location (intrauterine vs. extrauterine) of any early gestation where the initial location is unknown. CONCLUSION(S):Careful definition of populations and classification of outcomes should optimize objective interpretation of research, allow objective assessment of future reproductive prognosis, and hopefully lead to improved clinical care of women initially identified to have a PUL.
10.1016/j.fertnstert.2010.09.006
Clinical factors affecting the accuracy of ultrasonography in symptomatic first-trimester pregnancy.
Barnhart Kurt T,Fay Courtney A,Suescum Maria,Sammel Mary D,Appleby Dina,Shaunik Alka,Dean Anthony J
Obstetrics and gynecology
OBJECTIVE:To evaluate factors associated with accuracy of initial ultrasonography in patients with symptomatic first-trimester pregnancy. METHODS:Ultrasound diagnosis in the emergency department was compared with an ultimate clinical diagnosis in women in need of a gynecologic consult. The sensitivity, specificity, positive predictive values, and accuracy of the initial ultrasound impression were calculated and stratified by criteria of diagnosis, serum human chorionic gonadotropin (hCG) levels, pain, and bleeding. RESULTS:Eighteen hundred eighty women were evaluated. Overall accuracy of initial ultrasound diagnosis was 78%. A probable ultrasound diagnosis of ectopic pregnancy (adnexal mass without the presence of a yolk sac or embryo) resulted in a higher sensitivity (42.1% compared with 13.2%: P<.001) but a lower positive predictive value (82.7% compared with 98%: P<.01) compared with a definite diagnosis. A probable ultrasound diagnosis of intrauterine pregnancy (double decidual sign without yolk sac or embryo) resulted in a higher sensitivity (36.0% compared with 4.0%; P<.001) and lower positive predictive value (58.8% compared with 87.0%; P>.001) compared with a definite diagnosis. The sensitivity (34.3% compared with 75.9%; P<.01) and positive predictive value (80.4% compared with 91.5%; P=.02) were lower for diagnosis of ectopic pregnancy when serum hCG level was less than 2,000 milli-international units/mL. Ultrasonography was less accurate when bleeding was the chief complaint (72.7% compared with 84.8% P<.006) but not substantially altered by pain as a chief complaint (78.0 compared with 77.8% P>.99). CONCLUSION:A substantial number of misdiagnoses can occur when initial ultrasound diagnosis of intrauterine pregnancy or ectopic pregnancy is made without evidence of a yolk sac or embryo, when hCG values are low, or when a patient has significant bleeding. LEVEL OF EVIDENCE:II.
10.1097/AOG.0b013e3182050ed0
Trends in ectopic pregnancy mortality in the United States: 1980-2007.
Creanga Andreea A,Shapiro-Mendoza Carrie K,Bish Connie L,Zane Suzanne,Berg Cynthia J,Callaghan William M
Obstetrics and gynecology
OBJECTIVE:To estimate trends in ectopic pregnancy mortality and examine characteristics of recently hospitalized women who died as a result of ectopic pregnancy in the United States. METHODS:We used 1980-2007 national birth and death certificate data to calculate ectopic pregnancy mortality ratios (deaths per 100,000 live births) overall and stratified by maternal age and race. We performed nonparametric tests for trend to assess changes in ectopic pregnancy mortality over time and calculated projected mortality ratios for 2013-2017. Ectopic pregnancy deaths among hospitalized women were identified from 1998-2007 Nationwide Inpatient Sample data. RESULTS:Between 1980 and 2007, 876 deaths were attributed to ectopic pregnancy. The ectopic pregnancy mortality ratio declined by 56.6%, from 1.15 to 0.50 deaths per 100,000 live births between 1980-1984 and 2003-2007; at the current average annual rate of decline, this ratio will further decrease by 28.5% to 0.36 ectopic pregnancy deaths per 100,000 live births by 2013-2017. The ectopic pregnancy mortality ratio was 6.8 times higher for African Americans than whites and 3.5 times higher for women older than 35 years than those younger than 25 years during 2003-2007. Of the 76 deaths among women hospitalized between 1998 and 2007, 70.5% were tubal pregnancies; salpingectomy was performed in 80.6% of cases. Excessive hemorrhage, shock, or renal failure accompanied 67.4% of ectopic pregnancy deaths among hospitalized women. CONCLUSION:Despite a significant decline in ectopic pregnancy mortality since the 1980s, age disparities, and especially racial disparities, persist. Strategies to ensure timely diagnosis and management of ectopic pregnancies can further reduce related mortality and age and race mortality gaps.
10.1097/AOG.0b013e3182113c10
MicroRNAs in body fluids--the mix of hormones and biomarkers.
Cortez Maria Angelica,Bueso-Ramos Carlos,Ferdin Jana,Lopez-Berestein Gabriel,Sood Anil K,Calin George A
Nature reviews. Clinical oncology
Since the discovery of microRNAs (miRNAs), the study of these small noncoding RNAs has steadily increased and more than 10,000 papers have already been published. The great interest in miRNAs reflects their central role in gene-expression regulation and the implication of miRNA-specific aberrant expression in the pathogenesis of cancer, cardiac, immune-related and other diseases. Another avenue of current research is the study of circulating miRNAs in serum, plasma, and other body fluids--miRNAs may act not only within cells, but also at other sites within the body. The presence of miRNAs in body fluids may represent a gold mine of noninvasive biomarkers in cancer. Since deregulated miRNA expression is an early event in tumorigenesis, measuring circulating miRNA levels may also be useful for early cancer detection, which can contribute greatly to the success of treatment. In this Review, we discuss the role of fluid-expressed miRNAs as reliable cancer biomarkers and treatment-response predictors as well as potential new patient selection criteria for clinical trials. In addition, we explore the concept that miRNAs could function as hormones.
10.1038/nrclinonc.2011.76
Performance of human chorionic gonadotropin curves in women at risk for ectopic pregnancy: exceptions to the rules.
Morse Christopher B,Sammel Mary D,Shaunik Alka,Allen-Taylor Lynne,Oberfoell Nicole L,Takacs Peter,Chung Karine,Barnhart Kurt T
Fertility and sterility
OBJECTIVE:To investigate the accuracy of serial hCG to predict outcome of a pregnancy of unknown location in an ethnically and geographically diverse setting. DESIGN:Multisite cohort study. SETTING:University hospital. PATIENT(S):Women with a pregnancy of unknown location. INTERVENTION(S):None. MAIN OUTCOME MEASURE(S):Patients were followed until diagnosed with ectopic pregnancy (EP), intrauterine pregnancy (IUP), or miscarriage. To predict outcome, observed hCG level was compared with recommended thresholds to assess deviation from defined normal curves. Predicted outcome was compared with standard of care. Sensitivity, specificity, predictive value, and accuracy were calculated, stratified by diagnosis. RESULT(S):The final diagnosis of 1,005 patients included 179 EPs, 259 IUPs, and 567 miscarriages. The optimal balance in sensitivity and specificity used the minimal expected 2-day increase in hCG level of 35%, and the minimal 2-day decrease in hCG level of 36%-47% (depending on the level) achieving 83.2% sensitivity, 70.8% specificity to predict EP. However, 16.8% of EPs and 7.7% of IUPs would be misclassified solely using serial hCG levels. Consideration of a third hCG and early ultrasound decreased IUP misclassification to 2.7%. CONCLUSION(S):Solely using serial hCG values can result in misclassification. Clinical judgment should trump prediction rules and continued surveillance with a third hCG may be prudent, especially when initial values are low or when values are near suggested thresholds.
10.1016/j.fertnstert.2011.10.037
The multifaceted exosome: biogenesis, role in normal and aberrant cellular function, and frontiers for pharmacological and biomarker opportunities.
Pant Saumya,Hilton Holly,Burczynski Michael E
Biochemical pharmacology
Exosomes are bioactive vesicles derived from the cell's endosomal membrane system and secreted into surrounding body fluids. Exosomes contain cell and cell-state specific cargos of protein, mRNA and miRNA. Exosome formation, cargo content, and delivery to surrounding cells is of immense biological interest considering the role that exosomes are believed to play in various pathological conditions. They aid antigen presentation by immune cells and can exhibit either anti-inflammatory or pro-inflammatory properties depending on the parent antigen-presenting cell's conditioning. Viruses can hijack a host cell's exosomal machinery to evade host defense systems aiding in the trans-infection of viruses. Tumor derived exosomes may help establish an oncogenic niche systemically via delivery of protein, mRNA, and miRNA that can aid angiogenesis, cell proliferation, and cell survival. Exosomes have also been implicated in the spread of neurodegenerative diseases. Studies have shown that exosomes are selectively taken up by cells distal from their release. They can reprogram the recipient cells due to their active molecular cargo. Cell-lineage and state-specific exosomes imply that they may therefore harbor body fluid-based biomarkers of unparalleled accuracy, particularly for tissues that are difficult or impossible to access. Exosome-specific membrane proteins provide markers enabling exosome identity and selection, while cell type and cell condition-specific protein, mRNA and miRNA cargo provide a rich potential source of biomarkers. This review serves to provide an overview of the current state of the science in the burgeoning field of exosome biology.
10.1016/j.bcp.2011.12.037
Circulating microRNA miR-323-3p as a biomarker of ectopic pregnancy.
Zhao Zhen,Zhao Qiuhong,Warrick Joshua,Lockwood Christina M,Woodworth Alison,Moley Kelle H,Gronowski Ann M
Clinical chemistry
BACKGROUND:The use of serum human chorionic gonadotropin (hCG) and progesterone to identify patients with ectopic pregnancy (EP) has been shown to have poor clinical utility. Pregnancy-associated circulating microRNAs (miRNAs) have been proposed as potential biomarkers for the diagnosis of pregnancy-associated complications. This proof-of-concept study examined the diagnostic accuracy of various miRNAs to detect EP in an emergency department (ED) setting. METHODS:This study was a retrospective case-control analysis of 89 women who presented to the ED with vaginal bleeding and/or abdominal pain/cramping and received a diagnosis of viable intrauterine pregnancy (VIP), spontaneous abortion (SA), or EP. Serum hCG and progesterone concentrations were measured by immunoassays. The serum concentrations of miRNAs miR-323-3p, miR-517a, miR-519d, and miR-525-3p were measured with TaqMan real-time PCR. Statistical analysis was performed to determine the clinical utility of these biomarkers, both as single markers and as multimarker panels for EP. RESULTS:Concentrations of serum hCG, progesterone, miR-517a, miR-519d, and miR-525-3p were significantly lower in EP and SA cases than in VIP cases (P < 0.01). In contrast, the concentration of miR-323-3p was significantly increased in EP cases, compared with SA and VIP cases (P < 0.01). As a single marker, miR-323-3p had the highest sensitivity of 37.0% (at a fixed specificity of 90%). In comparison, the combined panel of hCG, progesterone, and miR-323-3p yielded the highest sensitivity (77.8%, at a fixed specificity of 90%). A stepwise analysis that used hCG first, added progesterone, and then added miR-323-3p yielded a 96.3% sensitivity and a 72.6% specificity. CONCLUSIONS:Pregnancy-associated miRNAs, especially miR-323-3p, added substantial diagnostic accuracy to a panel including hCG and progesterone for the diagnosis of EP.
10.1373/clinchem.2011.179283
Changes of corneal biomechanics with keratoconus.
Wolffsohn James S,Safeen Saima,Shah Sunil,Laiquzzaman Mohammad
Cornea
PURPOSE:To perform advanced analysis of the corneal deformation response to air pressure in keratoconics compared with age- and sex-matched controls. METHODS:The ocular response analyzer was used to measure the air pressure-corneal deformation relationship of 37 patients with keratoconus and 37 age (mean 36 ± 10 years)- and sex-matched controls with healthy corneas. Four repeat air pressure-corneal deformation profiles were averaged, and 42 separate parameters relating to each element of the profiles were extracted. Corneal topography and pachymetry were performed with the Orbscan II. The severity of the keratoconus was graded based on a single metric derived from anterior corneal curvatures, difference in astigmatism in each meridian, anterior best-fit sphere, and posterior best-fit sphere. RESULTS:Most of the biomechanical characteristics of keratoconic eyes were significantly different from normal eyes (P < 0.001), especially during the initial corneal applanation. With increasing keratoconus severity, the cornea was thinner (r = -0.407, P < 0.001), the speed of corneal concave deformation past applanation was quicker (dive; r2 = -0.314, P = 0.01), and the tear film index was lower (r = -0.319, P = 0.01). The variance in keratoconus severity could be accounted for by the corneal curvature and central corneal thickness (r = 0.80) with biomechanical characteristics contributing an additional 4% (total r = 0.84). The area under the receiver operating characteristic curve was 0.919 ± 0.025 for keratometry alone, 0.965 ± 0.014 with the addition of pachymetry, and 0.972 ± 0.012 combined with ocular response analyzer biomechanical parameters. CONCLUSIONS:Characteristics of the air pressure-corneal deformation profile are more affected by keratoconus than the traditionally extracted corneal hysteresis and corneal resistance factors. These biomechanical metrics slightly improved the detection and severity prediction of keratoconus above traditional keratometric and pachymetric assessment of corneal shape.
10.1097/ICO.0b013e318243e42d
Elevated cord serum manganese level is associated with a neonatal high ponderal index.
Yu XiaoDan,Cao LuLu,Yu XiaoGang
Environmental research
BACKGROUND:The effects of low-level prenatal manganese (Mn) exposure on neonatal growth remain unclear. The level of fetal Mn that may be considered "safe" has never been examined. METHODS:A multicenter study including 1377 mother-infant pairs was conducted from 2008 through 2009 in Shanghai. Mn concentrations were determined for both the cord and maternal serum, as well as neonatal birth weight and birth length. The ponderal index (PI) was calculated as (birth weight g/birth length cm(3))×100, and a ponderal index ≥3.17 was defined as a high ponderal index (HPI). RESULTS:The median serum Mn concentration was 4.0μg/L in the cord blood, and was 2.8μg/L in maternal blood. Of 1377 infants, 135 (9.8%) had a HPI. After adjusting for potential confounders, cord serum Mn was not associated with birth weight. However, there was a linear relationship between the cord serum Mn and the birth length (adjusted ß=-0.5, 95% CI=-0.7 to -0.2, p<0.0001). Additionally, a nonlinear relationship was observed between the cord serum Mn and the ponderal index, and between the cord serum Mn and HPI. The ponderal index and the prevalence of HPI increased with Mn levels above 5.0μg/L (Log Mn ≥0.7). A high level of Mn in the cord (≥5.0μg/L) was associated with a higher ponderal index (adjusted ß=0.2, 95% CI=0.1 to 0.2, p<0.001) and a high risk of HPI (adjusted OR=3.3, 95% CI=1.8-6.0, p<0.001). CONCLUSIONS:Higher prenatal Mn exposure, even at a low level, is associated with a higher prevalence of HPI in a nonlinear pattern. Cord serum Mn levels less than 5.0μg/L may be considered safe with respect to neonatal ponderal index assessment.
10.1016/j.envres.2012.11.002
Direct control of hepatic glucose production by interleukin-13 in mice.
Stanya Kristopher J,Jacobi David,Liu Sihao,Bhargava Prerna,Dai Lingling,Gangl Matthew R,Inouye Karen,Barlow Jillian L,Ji Yewei,Mizgerd Joseph P,Qi Ling,Shi Hang,McKenzie Andrew N J,Lee Chih-Hao
The Journal of clinical investigation
Hyperglycemia is a result of impaired insulin action on glucose production and disposal, and a major target of antidiabetic therapies. The study of insulin-independent regulatory mechanisms of glucose metabolism may identify new strategies to lower blood sugar levels. Here we demonstrate an unexpected metabolic function for IL-13 in the control of hepatic glucose production. IL-13 is a Th2 cytokine known to mediate macrophage alternative activation. Genetic ablation of Il-13 in mice (Il-13-/-) resulted in hyperglycemia, which progressed to hepatic insulin resistance and systemic metabolic dysfunction. In Il-13-/- mice, upregulation of enzymes involved in hepatic gluconeogenesis was a primary event leading to dysregulated glucose metabolism. IL-13 inhibited transcription of gluconeogenic genes by acting directly on hepatocytes through Stat3, a noncanonical downstream effector. Consequently, the ability of IL-13 to suppress glucose production was abolished in liver cells lacking Stat3 or IL-13 receptor α1 (Il-13rα1), which suggests that the IL-13Rα1/Stat3 axis directs IL-13 signaling toward metabolic responses. These findings extend the implication of a Th1/Th2 paradigm in metabolic homeostasis beyond inflammation to direct control of glucose metabolism and suggest that the IL-13/Stat3 pathway may serve as a therapeutic target for glycemic control in insulin resistance and type 2 diabetes.
10.1172/JCI64941
Biomarkers for ectopic pregnancy and pregnancy of unknown location.
Senapati Suneeta,Barnhart Kurt T
Fertility and sterility
Early pregnancy failure is the most common complication of pregnancy, and 1% to 2% of all pregnancies will be ectopic. As one of the leading causes of maternal morbidity and mortality, diagnosing ectopic pregnancy and determining the fate of a pregnancy of unknown location are of great clinical concern. Several serum and plasma biomarkers for ectopic pregnancy have been investigated independently and in combination. The following is a review of the state of biomarker discovery and development for ectopic pregnancy and pregnancy of unknown location.
10.1016/j.fertnstert.2012.11.038
Associations of noniodized salt and thyroid nodule among the Chinese population: a large cross-sectional study.
The American journal of clinical nutrition
BACKGROUND:The controversy that iodized salt may increase the risk of thyroid disorders has arisen in China during the past several years. OBJECTIVE:This study aimed to explore whether iodized salt increased the risk of thyroid nodule among a Chinese population. DESIGN:A cross-sectional study was conducted in Hangzhou, China, in 2010. Iodized salt intake, urinary iodine concentration (UIC), and thyroid nodule (by ultrasonography) were measured in 9412 adults. The associations of iodized salt with thyroid nodule were evaluated by using multiple mixed logistic regression models. RESULTS:The prevalence of thyroid nodule among men and women was 24.1% and 34.7%, respectively. Adults consuming noniodized salt had an increased risk of thyroid nodule (OR: 1.36; 95% CI: 1.01, 1.83). Similarly, compared with moderate salt appetite, mild salt appetite was associated with an increased risk of thyroid nodule among all adults (OR: 1.19; 95% CI: 1.03, 1.37) and among women (OR: 1.23; 95% CI: 1.03, 1.46). Furthermore, those who consumed neither iodized salt nor milk had a higher risk of thyroid nodule (OR: 1.72; 95% CI: 1.21, 2.43) than did those who consumed both iodized salt and milk. In addition, an increased risk of thyroid nodule (OR: 1.25; 95% CI: 1.07, 1.45) was observed among both pooled samples and women with low UIC. CONCLUSIONS:These findings indicate that low iodine intake may increase the risk of thyroid nodule in a Chinese population, particularly in women. Hence, the Universal Salt Iodization program may be indispensable for a coastal Chinese population such as that living in Hangzhou. This trial was registered at clinicaltrials.gov as NCT01838629.
10.3945/ajcn.112.054353
Extracellular microRNAs in urologic malignancies: chances and challenges.
Huang Xiaoyi,Liang Meihua,Dittmar Rachel,Wang Liang
International journal of molecular sciences
Small noncoding RNAs that are 19-23 nucleotides long, known as microRNAs (miRNAs), are involved in almost all biological mechanisms during carcinogenesis. Recent studies show that miRNAs released from live cells are detectable in body fluids and may be taken up by other cells to confer cell-cell communication. These released miRNAs (here referred to as extracellular miRNAs) are often protected by RNA-binding proteins or embedded inside circulating microvesicles. Due to their relative stability, extracellular miRNAs are believed to be promising candidates as biomarkers for diagnosis and prognosis of disease, or even as therapeutic agents for targeted treatment. In this review, we first describe biogenesis and characteristics of these miRNAs. We then summarize recent publications involving extracellular miRNA profiling studies in three representative urologic cancers, including: prostate cancer, bladder cancer, and renal cell carcinoma. We focus on the diagnostic, prognostic, and therapeutic potential of these miRNAs in biological fluids, such as serum, plasma, and urine. Finally, we discuss advantages and challenges of these miRNAs in clinical applications.
10.3390/ijms140714785
Practical guidelines for the supplementation of vitamin D and the treatment of deficits in Central Europe - recommended vitamin D intakes in the general population and groups at risk of vitamin D deficiency.
Płudowski Paweł,Karczmarewicz Elżbieta,Bayer Milan,Carter Graham,Chlebna-Sokół Danuta,Czech-Kowalska Justyna,Dębski Romuald,Decsi Tamas,Dobrzańska Anna,Franek Edward,Głuszko Piotr,Grant William B,Holick Michael F,Yankovskaya Liudmila,Konstantynowicz Jerzy,Książyk Janusz B,Księżopolska-Orłowska Krystyna,Lewiński Andrzej,Litwin Mieczysław,Lohner Szimonetta,Lorenc Roman S,Lukaszkiewicz Jacek,Marcinowska-Suchowierska Ewa,Milewicz Andrzej,Misiorowski Waldemar,Nowicki Michał,Povoroznyuk Vladyslav,Rozentryt Piotr,Rudenka Ema,Shoenfeld Yehuda,Socha Piotr,Solnica Bogdan,Szalecki Mieczysław,Tałałaj Marek,Varbiro Szabolcs,Żmijewski Michał A
Endokrynologia Polska
INTRODUCTION:Adequate Vitamin D intake and its concentration in serum are important for bone health and calcium-phosphate metabolism as well as for optimal function of many organs and tissues. Documented trends in lifestyle, nutritional habits and physical activity appear to be associated with moderate or severe Vitamin D deficits resulting in health problems. Most epidemiological studies suggest that Vitamin D deficiency is prevalent among Central European populations. Concern about this problem led to the organising of a conference focused on overcoming Vitamin D deficiency. METHODS:After reviewing the epidemiological evidence and relevant literature, a Polish multidisciplinary group formulated theses on recommendations for Vitamin D screening and supplementation in the general population. These theses were subsequently sent to Scientific Committee members of the 'Vitamin D - minimum, maximum, optimum' conference for evaluation based on a ten-point scale.With 550 international attendees, the meeting 'Vitamin D - minimum, maximum, optimum' was held on October 19-20, 2012 in Warsaw(Poland). Most recent scientific evidence of both skeletal and non-skeletal effects of Vitamin D as well as the results of panellists' voting were reviewed and discussed during eight plenary sessions and two workshops. RESULTS:Based on many polemical discussions, including post-conference networking, the key opinion leaders established ranges of serum 25-hydroxyVitamin D concentration indicating Vitamin D deficiency [< 20 ng/mL (< 50 nmol/L)], suboptimal status [20-30 ng/mL(50-75 nmol/L)], and target concentration for optimal Vitamin D effects [30-50 ng/mL (75-125 nmol/L)]. General practical guidelines regarding supplementation and updated recommendations for prophylactic Vitamin D intakes in Central European neonates, infants, children and adolescents as well as in adults (including recommendations for pregnant and breastfeeding women and the elderly) were developed. CONCLUSIONS:Improving the Vitamin D status of children, adolescents, adults and the elderly must be included in the priorities of physicians,healthcare professionals and healthcare regulating bodies. The present paper offers elaborated consensus on supplementation guidance and population strategies for Vitamin D in Central Europe.
10.5603/ep.2013.0012
miR-210 inhibits trophoblast invasion and is a serum biomarker for preeclampsia.
Anton Lauren,Olarerin-George Anthony O,Schwartz Nadav,Srinivas Sindhu,Bastek Jamie,Hogenesch John B,Elovitz Michal A
The American journal of pathology
Preeclampsia is characterized by hypertension and proteinuria in pregnant women. Its exact cause is unknown. Preeclampsia increases the risk of maternal and fetal morbidity and mortality. Although delivery, often premature, is the only known cure, early targeted interventions may improve maternal and fetal outcomes. Successful intervention requires a better understanding of the molecular etiology of preeclampsia and the development of accurate methods to predict women at risk. To this end, we tested the role of miR-210, a miRNA up-regulated in preeclamptic placentas, in first-trimester extravillous trophoblasts. miR-210 overexpression reduced trophoblast invasion, a process necessary for uteroplacental perfusion, in an extracellular signal-regulated kinase/mitogen-activated protein kinase-dependent manner. Conversely, miR-210 inhibition promoted invasion. Furthermore, given that the placenta secretes miRNAs into the maternal circulation, we tested if serum expression of miR-210 was associated with the disease. We measured miR-210 expression in two clinical studies: a case-control study and a prospective cohort study. Serum miR-210 expression was significantly associated with a diagnosis of preeclampsia (P = 0.007, area under the receiver operator curves = 0.81) and was predictive of the disease, even months before clinical diagnosis (P < 0.0001, area under the receiver operator curve = 0.89). Hence, we conclude that aberrant expression of miR-210 may contribute to trophoblast function and that miR-210 is a novel predictive serum biomarker for preeclampsia that can help in identifying at-risk women for monitoring and treatment.
10.1016/j.ajpath.2013.07.021
Identification and validation of reference genes for qPCR detection of serum microRNAs in colorectal adenocarcinoma patients.
Zheng Guixi,Wang Haiyan,Zhang Xin,Yang Yongmei,Wang Lili,Du Lutao,Li Wei,Li Juan,Qu Ailin,Liu Yimin,Wang Chuanxin
PloS one
Serum microRNAs (miRNAs) have become a highlighted research hotspot, especially for their great potential as a novel promising non-invasive biomarker in cancer diagnosis. The most frequently used approach for serum miRNAs detection is quantitative real time polymerase chain reaction (qPCR). In order to obtain reliable qPCR data of miRNAs expression, the use of reference genes as endogenous control is undoubtly necessary. However, no systematic evaluation and validation of reference genes for normalizing qPCR analysis of serum miRNAs has been reported in colorectal adenocarcinoma. We firstly profiled pooled serum of colorectal adenocarcinoma, colorectal adenoma and healthy controls and selected a list of 13 miRNAs as candidate reference genes. U6 snRNA (U6) and above-mentioned 13 miRNAs were included in further confirmation by qPCR. As a result, 5 miRNAs (miR-151a-3p, miR-4446-3p, miR-221-3p, miR-93-5p and miR-3184-3p) were not detected in all samples and 2 miRNAs (miR-197-3p and miR-26a-5p) were relatively low with median Cq more than 35, and were excluded from further stability analysis. Then variable stability of other 6 miRNAs (miR-103b, miR-484, miR-16-5p, miR-3615, miR-18a-3p and miR-191-5p) and U6 were evaluated using two algorithms: geNorm and NormFinder which both identified miR-191-5p as the most stably expressed reference gene and selected miR-191-5p and U6 as the most stable pair of reference genes. After validating in an independent large cohorts and selecting miR-92a-3p as target miRNA to evaluate the effect of reference gene, we propose that combination of miR-191-5p and U6 could be used as reference genes for serum microRNAs qPCR data in colorectal adenocarcinoma, colorectal adenoma and healthy controls.
10.1371/journal.pone.0083025
New inflammatory markers in pre-eclampsia: echocardiographic epicardial fat thickness and neutrophil to lymphocyte ratio.
Oylumlu Mustafa,Ozler Ali,Yildiz Abdulkadir,Oylumlu Muhammed,Acet Halit,Polat Nihat,Soydinc Hatice Ender,Yuksel Murat,Ertas Faruk
Clinical and experimental hypertension (New York, N.Y. : 1993)
BACKGROUND:Increased epicardial fat thickness (EFT) has been proposed as a new cardiometabolic risk factor. The neutrophil/lymphocyte ratio (NLR) has predictive and prognostic value in several cardiovascular diseases. The aim of this study was to explore the association between EFT and NLR in patients with pre-eclampsia. METHODS:Hundred and eight pregnant patients with a mean age of 30.6 ± 6.3 years were included in the study. Patients were divided into two groups based on the presence of pre-eclampsia. All participants underwent transthoracic echocardiography imaging, and complete blood counts were measured by an automated hematology analyzer. Statistical analysis was performed using the Chi-square, Mann-Whitney U, correlation and logistic regression tests, and receiver operating characteristic (ROC) analysis. RESULT:The mean EFT value of the pre-eclampsia group was significantly higher than the control group (6.9 ± 0.6 versus 5.6 ± 0.6; p < 0.001), and the NLR value of the pre-eclampsia group was also significantly higher than the control group (7.3 ± 3.5 versus 3.1 ± 1.1; p < 0.001). Multivariate analysis showed that increased levels of NLR and echocardiographic EFT are independent predictors of pre-eclampsia. In the receiver operating characteristic analysis, a level of EFT ≥ 6.2 mm and NLR ≥ 4.1 predicted the presence of pre-eclampsia with 77.8% sensitivity, 79.6% specificity and 83.3% sensitivity, 81.5% specificity, respectively. CONCLUSION:Unlike many other inflammatory markers and bioassays, NLR and echocardiographic EFT are inexpensive and readily available biomarkers that may be useful for risk stratification in patients with pre-eclampsia.
10.3109/10641963.2013.863324
Clinical relevance of circulating cell-free microRNAs in cancer.
Schwarzenbach Heidi,Nishida Naohiro,Calin George A,Pantel Klaus
Nature reviews. Clinical oncology
Efficient patient management relies on early diagnosis of disease and monitoring of treatment. In this regard, much effort has been made to find informative, blood-based biomarkers for patients with cancer. Owing to their attributes-which are specifically modulated by the tumour-circulating cell-free microRNAs found in the peripheral blood of patients with cancer may provide insights into the biology of the tumour and the effects of therapeutic interventions. Moreover, the role of microRNAs in the regulation of different cellular processes points to their clinical utility as blood-based biomarkers and future therapeutic targets. MicroRNAs are optimal biomarkers owing to high stability under storage and handling conditions and their presence in blood, urine and other body fluids. In particular, detection of levels of microRNAs in blood plasma and serum has the potential for an earlier cancer diagnosis and to predict prognosis and response to therapy. This Review article considers the latest developments in the use of circulating microRNAs as prognostic and predictive biomarkers and discusses their utility in personalized medicine.
10.1038/nrclinonc.2014.5
Exosomes provide a protective and enriched source of miRNA for biomarker profiling compared to intracellular and cell-free blood.
Cheng Lesley,Sharples Robyn A,Scicluna Benjamin J,Hill Andrew F
Journal of extracellular vesicles
INTRODUCTION:microRNA (miRNA) are small non-coding RNA species that are transcriptionally processed in the host cell and released extracellularly into the bloodstream. Normally involved in post-transcriptional gene silencing, the deregulation of miRNA has been shown to influence pathogenesis of a number of diseases. BACKGROUND:Next-generation deep sequencing (NGS) has provided the ability to profile miRNA in biological fluids making this approach a viable screening tool to detect miRNA biomarkers. However, collection and handling procedures of blood needs to be greatly improved for miRNA analysis in order to reliably detect differences between healthy and disease patients. Furthermore, ribonucleases present in blood can degrade RNA upon collection rendering extracellular miRNA at risk of degradation. These factors have consequently decreased sensitivity and specificity of miRNA biomarker assays. METHODS:Here, we use NGS to profile miRNA in various blood components and identify differences in profiles within peripheral blood compared to cell-free plasma or serum and extracellular vesicles known as exosomes. We also analyse and compare the miRNA content in exosomes prepared by ultracentrifugation methods and commercial exosome isolation kits including treating samples with RNaseA. CONCLUSION:This study demonstrates that exosomal RNA is protected by RNaseA treatment and that exosomes provide a consistent source of miRNA for disease biomarker detection.
10.3402/jev.v3.23743
Genome-wide miRNA profiling of villus and decidua of recurrent spontaneous abortion patients.
Dong Fulu,Zhang Yuan,Xia Fei,Yang Yi,Xiong Sidong,Jin Liping,Zhang Jinping
Reproduction (Cambridge, England)
MicroRNAs (miRNAs) are non-coding RNA molecules of about 22 nucleotides that involved in post-transcriptional gene regulation. Evidence indicates that miRNAs play essential roles in endometriosis, pre-eclampsia, infertility and other reproductive system diseases. However, whether miRNAs are involved in recurrent spontaneous abortion (RSA) is unclear. In this work, we analysed the miRNA expression profiles in six pairs of villus or decidua from RSA patients and normal pregnancy (NP) women using a human miRNA microarray. Some of the chip results were confirmed by RT-qPCR. In the villi of RSA patients, expression of hsa-miR-184, hsa-miR-187 and hsa-miR-125b-2 was significantly higher, while expression of hsa-miR-520f, hsa-miR-3175 and hsa-miR-4672 was significantly lower, comparing with those of NP control. As well, a total of five miRNAs (hsa-miR-517c, hsa-miR-519a-1, hsa-miR-522, hsa-miR-520h and hsa-miR-184) were upregulated in the decidua of RSA patients. The target genes of these differentially expressed miRNAs were predicted by miRWalk, and we speculate a network of miRNA regulating RSA by target genes function on adhesion, apoptosis and angiogenesis. Our study may help clarify the molecular mechanisms which are involved in the progression of RSA, and provide a reference for future research.
10.1530/REP-14-0095
A gestational profile of placental exosomes in maternal plasma and their effects on endothelial cell migration.
Salomon Carlos,Torres Maria Jose,Kobayashi Miharu,Scholz-Romero Katherin,Sobrevia Luis,Dobierzewska Aneta,Illanes Sebastian E,Mitchell Murray D,Rice Gregory E
PloS one
Studies completed to date provide persuasive evidence that placental cell-derived exosomes play a significant role in intercellular communication pathways that potentially contribute to placentation and development of materno-fetal vascular circulation. The aim of this study was to establish the gestational-age release profile and bioactivity of placental cell-derived exosome in maternal plasma. Plasma samples (n = 20 per pregnant group) were obtained from non-pregnant and pregnant women in the first (FT, 6-12 weeks), second (ST, 22-24 weeks) and third (TT, 32-38 weeks) trimester. The number of exosomes and placental exosome contribution were determined by quantifying immunoreactive exosomal CD63 and placenta-specific marker (PLAP), respectively. The effect of exosomes isolated from FT, ST and TT on endothelial cell migration were established using a real-time, live-cell imaging system (Incucyte). Exosome plasma concentration was more than 50-fold greater in pregnant women than in non-pregnant women (p<0.001). During normal healthy pregnancy, the number of exosomes present in maternal plasma increased significantly with gestational age by more that two-fold (p<0.001). Exosomes isolated from FT, ST and TT increased endothelial cell migration by 1.9±0.1, 1.6±0.2 and 1.3±0.1-fold, respectively compared to the control. Pregnancy is associated with a dramatic increase in the number of exosomes present in plasma and maternal plasma exosomes are bioactive. While the role of placental cell-derived exosome in regulating maternal and/or fetal vascular responses remains to be elucidated, changes in exosome profile may be of clinical utility in the diagnosis of placental dysfunction.
10.1371/journal.pone.0098667
The association of thyroid nodule with non-iodized salt among Chinese children.
Xu Weimin,Chen Zexin,Liu Hui,Huo Liangliang,Huang Yangmei,Jin Xingyi,Deng Jin,Zhu Sujuan,Jin Wen,Zhang Shanchun,Yu Yunxian
PloS one
OBJECTIVE:The controversy that iodized salt may increase the risk of thyroid disorders has been aroused in China during the past decade. Most of studies focused on adult rather than children. We aimed to explore whether iodized salt was associated with an increased risk of thyroid nodule in Chinese children. METHODS:The cross-sectional study was conducted in Hangzhou, China, in 2010. Iodized salt intake, urine iodine concentration (UIC) and thyroid nodule (by ultrasonography) were measured in 3026 children. The associations of iodized salt with thyroid nodule were evaluated using multiple logistic regression models. RESULTS:The prevalence of thyroid nodule was 10.59% among Chinese children. Girls (11.89%) had higher prevalence of thyroid nodule than boys (9.26%). No significant association was observed between type of salt and thyroid nodule in pooled samples, boys and girls, respectively. Similar associations were observed between UIC and thyroid nodule. There was no significant association between milk consumption and thyroid nodule as well. CONCLUSION:The present study indicated that non-iodized salt may not increase the risk of thyroid nodules among Chinese children. Similar associations were observed between milk consumption, UIC and thyroid nodules.
10.1371/journal.pone.0102726
Serum microRNA panel as biomarkers for early diagnosis of colorectal adenocarcinoma.
Zheng G,Du L,Yang X,Zhang X,Wang L,Yang Y,Li J,Wang C
British journal of cancer
BACKGROUND:Currently, none of the available colorectal adenocarcinoma (CAC) testing has been established as a well-accepted diagnosis tool, particularly for the early stage of CAC. The recent discovery of serum microRNA (miRNA) profile has provided a new auxiliary approach for tumour diagnosis. Our study is involved in the global analysis of serum miRNAs during the normal-colorectal adenoma (CA)-CAC sequence. METHODS:Serum samples were collected from 307 CAC patients, 164 CA patients and 226 healthy controls. Differentially expressed serum miRNAs were screened with Miseq sequencing followed by the reverse transcription PCR (RT-qPCR) validation. The miRNA panel was developed with a logistic regression model and validated using an independent cohort. The miRNA levels in CAC patients of different clinical stages and CA patients of different grades were compared. Receiver operating characteristic curves were constructed to evaluate the diagnostic accuracy of the panel. RESULTS:The Miseq sequencing results revealed 15 differentially expressed miRNAs in the intersection of CAC vs CA and CA vs healthy controls according to our criteria. After the selection and validation process via RT-qPCR, we identified a four-miRNA panel (miR-19a-3p, miR-223-3p, miR-92a-3p and miR-422a) with a high diagnostic accuracy of CAC. Even in the low-carcinoembryonic antigen level group, the diagnostic accuracy of this miRNA panel was still acceptable (AUC=0.810). Surprisingly, our results indicated that the miRNA panel could differentiate stage I/II CAC from controls. In addition, this panel could also differentiate CA from CAC (AUC=0.886) and healthy controls (AUC=0.765). CONCLUSIONS:We established a serum four-miRNA panel with considerable clinical value in the early-stage diagnosis of CAC.
10.1038/bjc.2014.489
U6 is not a suitable endogenous control for the quantification of circulating microRNAs.
Xiang Mengqin,Zeng Ying,Yang Ruirui,Xu Haifan,Chen Zhuo,Zhong Jing,Xie Hailong,Xu Yinghui,Zeng Xi
Biochemical and biophysical research communications
Recently, microRNAs have been detected in serum and plasma, and circulating microRNA (miRNA) profiles have now been associated with many diseases such as cancers and heart disease, as well as altered physiological states. Because of their stability and disease resistance, circulation miRNAs appear to be an ideal material for biomarkers of diseases and physiological states in blood. However, the lack of a suitable internal reference gene (internal reference miRNA) has hampered research and application of circulating miRNAs. Currently, U6 and miR-16 are the most common endogenous controls in the research of miRNAs in tissues and cells. We performed microarray-based serum miRNA profiling on the serum of 20 nasopharyngeal carcinoma patients and 20 controls to detect the expressions of U6 and miRNAs. Profiling was followed by real-time quantitative Polymerase Chain Reaction (qPCR) in 80 patients (20 each with gastric cancer, nasopharyngeal carcinoma, colorectal cancer, and breast cancer) and 30 non-cancerous controls. qPCR was also performed to detect miRNAs in serum with repeated freezing and thawing. The results of microarray showed that with the exception of U6, Ct values of miR-16, miR-24, miR-142-3p, miR-19b and miR-192 in serum samples of nasopharyngeal carcinoma were greater than control samples. The results of 110 cases showed large fluctuations in U6 expression. The difference between the greatest and the least levels of expression was 3.29 for delta Ct values, and 1.23 for miR-16. The expressions of U6, miR-16 and miR-24 in serum subjected to different freeze-thaw cycles showed that U6 expression gradually decreased after 1, 2, and 4 cycles of freezing and thawing, while the expression of miR-16 and miR-24 remained relatively stable. Collectively, our results suggested that U6 is unsuitable as an internal reference gene in the research of circulating miRNAs.
10.1016/j.bbrc.2014.10.064
Pregnancy-associated microRNAs in plasma as potential molecular markers of ectopic pregnancy.
Miura Kiyonori,Higashijima Ai,Mishima Hiroyuki,Miura Shoko,Kitajima Michio,Kaneuchi Masanori,Yoshiura Koh-Ichiro,Masuzaki Hideaki
Fertility and sterility
OBJECTIVE:To investigate cell-free pregnancy-associated microRNAs as molecular markers for the diagnosis of ectopic pregnancy. DESIGN:Laboratory study using human plasma samples. SETTING:Research unit in a university hospital. PATIENT(S):Plasma samples from 18 women with ectopic pregnancies (EP group), 12 women with spontaneous abortion (SA group), and 26 normal women with singleton pregnancies (NP group). INTERVENTION(S):Total RNAs containing small RNA molecules extracted from 1.2 mL of plasma. MAIN OUTCOME MEASURE(S):Plasma concentrations of cell-free microRNAs measured by quantitative real-time reverse-transcriptase polymerase chain reaction. RESULT(S):Plasma concentrations of cell-free pregnancy-associated microRNAs (miR-323-3p, miR-515-3p, miR-517a, miR-517c, and miR-518b) and serum concentration of human chorionic gonadotropin (hCG) were confirmed to have statistically significantly different plasma or serum concentrations in women with EP, SA, or NP. There was no statistically significant difference in the plasma concentrations of cell-free miR-21 between the three groups. By correlation coefficient analysis, no relationship was detected between serum hCG levels and plasma cell-free miR-517c, miR-515-3p, miR-517a, miR-518b, miR-323-3p, or miR-21 levels. Plasma concentrations of cell-free miR-517a could distinguish EP/SA from NP, yielding an area under the curve of 0.9654 (95% confidence interval, 0.9172-1.0). Plasma concentrations of cell-free miR-323-3p could distinguish EP from SA, yielding an area under the curve of 0.7454 (95% confidence interval, 0.5558-0.9349). CONCLUSION(S):Cell-free pregnancy-associated microRNAs have potential as molecular markers of ectopic pregnancy.
10.1016/j.fertnstert.2015.01.041
The Relationship between Estimated Glomerular Filtration Rate and Diabetic Retinopathy.
Wu Jingyang,Geng Jin,Liu Limin,Teng Weiping,Liu Lei,Chen Lei
Journal of ophthalmology
Diabetic retinopathy (DR) is the leading cause of visual impairment and blindness in working-aged people. Several studies have suggested that glomerular filtration rate (GFR) was correlated with DR. This is a hospital-based study and the aim of it was to examine the relationship between the GFR and DR in patients with type 2 diabetes mellitus (T2DM). We used CKD-EPI equation to estimate GFR and SPSS 19.0 and EmpowerStats software to assess their relationship. Among the 1613 participants (aged 54.75 ± 12.19 years), 550 (34.1%) patients suffered from DR. The multivariate analysis revealed that the risk factors for DR include age (P < 0.001, OR = 0.940), duration of diabetes (P < 0.001, OR = 1.163), hemoglobin A1c (P = 0.007, OR = 1.224), systolic blood pressure (P < 0.001, OR = 1.032), diastolic blood pressure (P = 0.007, OR = 0.953), high density lipoprotein cholesterol (P = 0.024, OR = 3.884), and eGFR (P = 0.010, OR = 0.973). Through stratified analysis and saturation effect analysis, our data suggests that eGFR of 99.4 mL/min or lower might imply the early stage of DR in diabetic patients. Thus, the evaluation of eGFR has clinical significance for the early diagnosis of DR.
10.1155/2015/326209
Non-HDL-cholesterol to HDL-cholesterol ratio as an independent risk factor for the development of chronic kidney disease.
Zuo P Y,Chen X L,Liu Y W,Zhang R,He X X,Liu C Y
Nutrition, metabolism, and cardiovascular diseases : NMCD
BACKGROUND AND AIMS:Dyslipidemia contributes to the development and progression of renal disease. The objective of this study was to investigate whether an elevated non-HDL-cholesterol to HDL-cholesterol ratio (NonHDLc/HDLc) predicts new-onset chronic kidney disease (CKD). METHODS AND RESULTS:We followed 1891 Chinese adults with normal or near-normal kidney function at baseline who participated in an annual health checkup program for the occurrence of new-onset CKD [defined as an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m(2) (low eGFR) and/or proteinuria (defined as urinary protein ≥1 + on dipstick testing)] or low eGFR. Cox proportional hazards models were used to examine the independent relationship between the plasma NonHDLc/HDLc ratio and new-onset CKD. During a median follow-up period of 2.8 years, 3% (n = 57) of participants developed new-onset CKD. Compared with patients in the lowest tertile, patients with NonHDLc/HDLc ratios in the highest tertile had a 1.45-fold higher risk of new-onset CKD (hazard ratio [HR], 2.45; 95% confidence interval [95% CI], 1.07 to 5.61; P = 0.035) after adjustment for potential confounders. There was a marginally significant association with low eGFR (tertile 3 versus tertile 1: HR, 2.94; 95% CI, 0.98 to 8.82; P = 0.054). CONCLUSIONS:NonHDLc/HDLc ratio is an independent risk factor for the development of CKD. Assessment of NonHDLc/HDLc ratio may help identify high risk groups with chronic kidney disease.
10.1016/j.numecd.2015.03.003
Biological properties of extracellular vesicles and their physiological functions.
Journal of extracellular vesicles
In the past decade, extracellular vesicles (EVs) have been recognized as potent vehicles of intercellular communication, both in prokaryotes and eukaryotes. This is due to their capacity to transfer proteins, lipids and nucleic acids, thereby influencing various physiological and pathological functions of both recipient and parent cells. While intensive investigation has targeted the role of EVs in different pathological processes, for example, in cancer and autoimmune diseases, the EV-mediated maintenance of homeostasis and the regulation of physiological functions have remained less explored. Here, we provide a comprehensive overview of the current understanding of the physiological roles of EVs, which has been written by crowd-sourcing, drawing on the unique EV expertise of academia-based scientists, clinicians and industry based in 27 European countries, the United States and Australia. This review is intended to be of relevance to both researchers already working on EV biology and to newcomers who will encounter this universal cell biological system. Therefore, here we address the molecular contents and functions of EVs in various tissues and body fluids from cell systems to organs. We also review the physiological mechanisms of EVs in bacteria, lower eukaryotes and plants to highlight the functional uniformity of this emerging communication system.
10.3402/jev.v4.27066
The effects of intraoperative cryoprecipitate transfusion on acute renal failure following orthotropic liver transplantation.
Liu Shuang,Wang Xiaoliang,Lu Yuanshan,Li Tao,Gong Zijun,Sheng Tao,Hu Bin,Peng Zhihai,Sun Xing
Hepatology international
PURPOSE:The definition of risk factors associated with acute renal failure (ARF) following orthotropic liver transplantation (OLT) is still controversial. Cryoprecipitate, which can supply fibrinogen and other coagulation factors, is widely used in OLT. However, the effects of intraoperative cryoprecipitate transfusion on ARF following OLT remain unclear. METHODS:In a series of 389 adult patients who received grafts from deceased donors and underwent their first OLT, the clinical correlation between intraoperative cryoprecipitate transfusion and ARF following OLT was retrospectively studied after adjusting for potential confounders. The distribution of ARF and the causes of death within the first year after OLT were also compared separately in patients with and without cryoprecipitate transfusion. RESULTS:The incidence of ARF in patients with cryoprecipitate transfusion was significantly higher than in patients without cryoprecipitate transfusion (15.9 vs. 7.8 %, p = 0.012). A nonlinear relationship between intraoperative cryoprecipitate transfusion and ARF following OLT was observed. The risk of ARF increased with the cryoprecipitate transfusion level up to the turning point (16 U) (adjusted OR 1.1, 95 % CI 1.1-1.2; p < 0.001). When the cryoprecipitate level exceeded 16 U, the level of cryoprecipitate transfusion was not associated with the risk of ARF (OR 0.95, 95 % CI 0.85-1.1; p = 0.319). Deaths within the first year after the operation occurred more frequently in cases with cryoprecipitate transfusion (22.9 vs. 14.2 %, p = 0.029). CONCLUSIONS:These findings suggested that intraoperative cryoprecipitate transfusion is associated with ARF following OLT. Cryoprecipitate transfusion during OLT should be performed carefully until more convincing evidence has been found.
10.1007/s12072-013-9457-9
Placental exosomes in normal and complicated pregnancy.
Mitchell Murray D,Peiris Hassendrini N,Kobayashi Miharu,Koh Yong Q,Duncombe Gregory,Illanes Sebastian E,Rice Gregory E,Salomon Carlos
American journal of obstetrics and gynecology
While there is considerable contemporary interest in elucidating the role of placenta-derived extracellular vesicles in normal and complicated pregnancies and their utility as biomarkers and therapeutic interventions, progress in the field is hindered by a lack of standardized extracellular vesicle taxonomy and isolation protocols. The term "extracellular vesicle" is nonspecific and refers to all membrane-bound vesicles from nanometer to micrometer diameters and of different biogenic origins. To meaningfully ascribe biological function and/or diagnostic and therapeutic utility to extracellular vesicles, and in particular exosomes, greater specificity and vesicle characterization is required. The current literature relating to exosome biology must be interpreted in this context. Exosomes are a subtype of extracellular vesicle that are specifically defined by an endosomal biogenesis and particle size (40-120 nm) and density (1.13-1.19 g/mL(-1)). Exosomes are specifically package with signaling molecules (including protein, messenger RNA, microRNA, and noncoding RNA) and are released by exocytosis into biofluid compartments. Exosomes regulate the activity of both proximal and distal target cells, including translational activity, angiogenesis, proliferation, metabolism, and apoptosis. As such, exosomal signaling represents an integral pathway mediating intercellular communication. During pregnancy, the placenta releases exosomes into the maternal circulation from as early as 6 weeks of gestation. Release is regulated by factors that include both oxygen tension and glucose concentration and correlates with placental mass and perfusion. The concentration of placenta-derived exosomes in maternal plasma increases progressively during gestation. Exosomes isolated from maternal plasma are bioactive in vitro and are incorporated into target cells by endocytosis. While the functional significance of placental exosomes in pregnancy remains to be fully elucidated, available data support a role in normal placental development and maternal immunotolerance. Similarly, the role of exosomes in the etiology and progression of complications of pregnancy remains in a formative stage. Changes in the release of placenta- and nonplacenta-derived exosomes, their concentration in maternal plasma, composition, and bioactivity have been reported in association with pregnancies complicated by gestational diabetes and preeclampsia. The data, however, are confounded by the use of different isolation methodologies and vesicle subpopulations. The application of specific and well-characterized isolation methodologies is requisite to resolving the precise role of exosomes in complications of pregnancies and their ultimate clinical utility.
10.1016/j.ajog.2015.07.001
Gestational hypertension, preeclampsia and intrauterine growth restriction induce dysregulation of cardiovascular and cerebrovascular disease associated microRNAs in maternal whole peripheral blood.
Hromadnikova Ilona,Kotlabova Katerina,Hympanova Lucie,Krofta Ladislav
Thrombosis research
AIMS:To demonstrate that pregnancy-related complications are associated with alterations in cardiovascular and cerebrovascular microRNA expression. Gene expression of 29 microRNAs (miR-1-3p, miR-16-5p, miR-17-5p, miR-20a-5p, miR-20b-5p, miR-21-5p, miR-23a-3p, miR-24-3p, miR-26a-5p, miR-29a-3p, miR-92a-3p, miR-100-5p, miR-103a-3p, miR-122-5p, miR-125b-5p, miR-126-3p, miR-130b-3p, miR-133a-3p, miR-143-3p, miR-145-5p, miR-146a-5p, miR-181a-5p, miR-195-5p, miR-199a-5p, miR-210-3p, miR-221-3p, miR-342-3p, miR-499a-5p, and miR-574-3p) was assessed in maternal whole peripheral blood, compared between groups (39 gestational hypertension, 68 preeclampsia, 33 intrauterine growth restriction and 20 normal pregnancies) and correlated with the severity of the disease with respect to clinical signs, delivery date, and Doppler ultrasound parameters. Initially, selection and validation of endogenous controls for microRNA expression studies in patients affected by pregnancy-related complications have been carried out. RESULTS:The expression profile of microRNAs was different between pregnancy-related complications and controls. The down-regulation of miR-100-5p, miR-125b-5p and miR-199a-5p was a common phenomenon shared between gestational hypertension, preeclampsia, and intrauterine growth restriction. Moreover, IUGR pregnancies induced down-regulation of miR-17-5p, miR-146a-5p, miR-221-3p and miR-574-3p in maternal circulation. Irrespective of the severity of the disease, preeclampsia was associated with the dysregulation of miR-100-5p and miR-125b-5p and IUGR with dysregulation of miR-199a-5p. Preeclampsia requiring termination of gestation before 34 weeks was associated with down-regulation of miR-146a-5p, miR-199a-5p and miR-221-3p. Weak negative correlation between miR-146a-5p and miR-221-3p expression and the pulsatility index in the umbilical artery was found. Additional microRNAs (miR-103a-3p, miR-126-3p, miR-195-5p and miR-499a-5p) showed a trend to down-regulation in appropriate pregnancy-related complications. CONCLUSION:Epigenetic changes are induced by pregnancy-related complications in maternal whole peripheral blood.
10.1016/j.thromres.2015.11.032
Antiphospholipid antibody-induced miR-146a-3p drives trophoblast interleukin-8 secretion through activation of Toll-like receptor 8.
Gysler Stefan M,Mulla Melissa J,Guerra Marta,Brosens Jan J,Salmon Jane E,Chamley Lawrence W,Abrahams Vikki M
Molecular human reproduction
STUDY QUESTION:What is the role of microRNAs (miRs) in antiphospholipid antibody (aPL)-induced trophoblast inflammation? SUMMARY ANSWER:aPL-induced up-regulation of trophoblast miR-146a-3p is mediated by Toll-like receptor 4 (TLR4), and miR-146a-3p in turn drives the cells to secrete interleukin (IL)-8 by activating the RNA sensor, TLR8. WHAT IS KNOWN ALREADY:Obstetric antiphospholipid syndrome (APS) is an autoimmune disorder characterized by circulating aPL and an increased risk of pregnancy complications. We previously showed that aPL recognizing beta2 glycoprotein I (β2GPI) elicit human first trimester trophoblast secretion of IL-8 by activating TLR4. Since some miRs control TLR responses, their regulation in trophoblast cells by aPL and functional role in the aPL-mediated inflammatory response was investigated. miRs can be released from cells via exosomes, and therefore, miR exosome expression was also examined. A panel of miRs was selected based on their involvement with TLR signaling: miR-9; miR-146a-5p and its isomiR, miR-146a-3p; miR-155, miR-210; and Let-7c. Since certain miRs can activate the RNA sensor, TLR8, this was also investigated. STUDY DESIGN, SIZE, DURATION:For in vitro studies, the human first trimester extravillous trophoblast cell line, HTR8 was studied. HTR8 cells transfected to express a TLR8 dominant negative (DN) were also used. Plasma was evaluated from pregnant women who have aPL, either with or without systemic lupus erythematous (SLE) (n = 39); SLE patients without aPL (n = 30); and healthy pregnant controls (n = 20). PARTICIPANTS/MATERIALS, SETTING, METHODS:Trophoblast HTR8 wildtype and TLR8-DN cells were incubated with or without aPL (mouse anti-human β2GPI mAb) for 48-72 h. HTR8 cells were also treated with or without aPL in the presence and the absence of a TLR4 antagonist (lipopolysaccharide from Rhodobacter sphaeroides; LPS-RS), specific miR inhibitors or specific miR mimics. miR expression levels in trophoblast cells, trophoblast-derived exosomes and exosomes isolated from patient plasma were measured by qPCR. Trophoblast IL-8 secretion was measured by ELISA. MAIN RESULTS AND THE ROLE OF CHANCE:aPL significantly increased trophoblast cellular and exosome expression of miR-146a-5p, miR-146a-3p, miR-155 and miR-210. aPL-induced up-regulation of trophoblast miR-146a-5p, miR-146a-3p and miR-210, but not miR-155, was inhibited by the TLR4 antagonist, LPS-RS. While inhibition or overexpression of miR-146a-5p had no effect on aPL-induced trophoblast IL-8 secretion, miR-146a-3p inhibition significantly reduced this response. aPL-induced trophoblast IL-8 secretion was inhibited by the presence of the TLR8-DN. In the absence of aPL, transfection of trophoblast cells with a miR-146a-3p mimic significantly increased IL-8 secretion and this was inhibited by the presence of the TLR8-DN. Patients with aPL and adverse pregnancy outcomes (APOs) expressed significantly higher levels of circulating miR-146a-3p compared with healthy pregnant controls with no pregnancy complications (P < 0.05). LIMITATIONS, REASONS FOR CAUTION:While the enrichment of miR-146a-3p in trophoblast-derived exosomes support the role of this miR acting in a paracrine or endocrine manner through exosome delivery, this has not been demonstrated. However, miR-146a-3p may also exert its pro-inflammatory effect intracellularly within the same trophoblast cell targeted by aPL. WIDER IMPLICATIONS OF THE FINDINGS:These findings provide a novel mechanism of trophoblast inflammation through miRs activating RNA-sensing receptors. Furthermore, circulating exosomal-associated miR-146a-3p in APS patients may serve clinically as a biomarker for related APOs. STUDY FUNDING/COMPETING INTERESTS:This study was supported in part by grants from the American Heart Association (#10GRNT3640032 to V.M.A.), the March of Dimes Foundation (Gene Discovery and Translational Research Grant #6-FY12-255 to V.M.A.), NICHD, NIH (R01HD049446 to V.M.A.), the Gina M. Finzi Memorial Student Summer Fellowship from the Lupus Foundation of America (to S.M.G.), and the Yale University School of Medicine Medical Student Fellowship (to S.M.G.). The authors declare no competing financial interests. TRIAL REGISTRATION NUMBER:N/A.
10.1093/molehr/gaw027
Noninvasive Central Systolic Blood Pressure Is More Strongly Related to Kidney Function Decline Than Peripheral Systolic Blood Pressure in a Chinese Community-Based Population.
Fan Fangfang,Qi Litong,Jia Jia,Xu Xin,Liu Yan,Yang Yang,Qin Xianhui,Li Jianping,Li Haixia,Zhang Yan,Huo Yong
Hypertension (Dallas, Tex. : 1979)
This study aimed to investigate the association of noninvasive central aortic blood pressure with kidney function decline in a Chinese community-based population with normal kidney function at baseline. A total of 3153 Chinese participants from an atherosclerosis cohort were included in our analysis. The primary outcome was renal function decline defined as a drop in estimated glomerular filtration rate (eGFR) category accompanied by a ≥25% drop in eGFR from baseline; or a sustained decline in eGFR of >5 mL/min per 1.73 m(2)/y. The secondary outcomes were rapid eGFR decline (a decline in eGFR of >3 mL/min per 1.73 m(2)/y) and new incidence of chronic kidney disease. Participants were 56.6±8.5 years old, 36.0% were males, and 48.8% had hypertension. Mean (SD) baseline eGFR was 101.2±10.6 mL/min per 1.73 m(2) After a mean 2.35-year follow-up, the incidence of renal function decline, rapid eGFR decline and chronic kidney disease were 7.3%, 19.7%, and 0.7%, respectively. In multivariate logistic-regression analyses, central and peripheral systolic blood pressure (SBP) were both independently associated with all outcomes after adjustment for various confounders. When peripheral SBP was forced into the model with central SBP simultaneously, its significant association with the 3 outcomes all disappeared; however, central SBP was still significantly related with all outcomes even after further adjusting peripheral SBP. In conclusion, central SBP is a stronger predictor compared with peripheral SBP for early kidney function decline in a Chinese community-based population with normal kidney function at baseline.
10.1161/HYPERTENSIONAHA.115.07019
Serum microRNAs as diagnostic markers of endometriosis: a comprehensive array-based analysis.
Cosar Emine,Mamillapalli Ramanaiah,Ersoy Gulcin Sahin,Cho SihYun,Seifer Benjamin,Taylor Hugh S
Fertility and sterility
OBJECTIVE:To investigate serum microRNAs (miRNAs) in women with endometriosis. DESIGN:Case-control study. SETTING:University hospital. PATIENT(S):Women with (n = 24) and without (n = 24) endometriosis. INTERVENTION(S):Serum samples were obtained from surgically diagnosed subjects. MAIN OUTCOME MEASURE(S):miRNA from women with without endometriosis were used for microarray profiling and confirmed by means of quantitative real-time polymerase chain reaction (qRT-PCR). Receiver operating characteristic (ROC) analysis was performed on differentially expressed miRNAs. RESULT(S):miR-3613-5p, miR-6755-3p were down-regulated and miR-125b-5p, miR-150-5p, miR-342-3p, miR-143-3p, miR-145-5p, miR-500a-3p, miR-451a, miR-18a-5p were up-regulated more than 10-fold in the microarray. These results were confirmed with the use of qRT-PCR. Among the differentially expressed miRNAs, miR-125b-5p expression levels had the highest area under the ROC curve (AUC). The maximum AUC score of 1.000 was achieved when combining miR-125b-5p, miR-451a, and miR-3613-5p with the use of a logistic regression model. CONCLUSION(S):We identified several miRNAs in serum that distinguished subjects with endometriosis from those without. miR-125b-5p had the greatest potential as a single diagnostic biomarker. A combination of that miRNA with miR-451a and miR-3613-5p further improved diagnostic performance.
10.1016/j.fertnstert.2016.04.013
The Effects of Serum ANGPTL8/betatrophin on the Risk of Developing the Metabolic Syndrome - A Prospective Study.
Wang Haoyu,Lai Yaxin,Han Cheng,Liu Aihua,Fan Chenling,Wang Hong,Zhang Hongmei,Ding Shuangning,Teng Weiping,Shan Zhongyan
Scientific reports
ANGPTL8/betatrophin is a recently discovered hormone, which mainly synthesized and secreted by liver and adipose tissue, playing a critical role in pancreatic beta cell proliferation. Previous studies have suggested that serum ANGPTL8/betatrophin levels are associated with obesity and diabetes mellitus. Here, we evaluated the prospective association between ANGPTL8/betatrophin and the metabolic syndrome from a community-based cohort of 153 adults without metabolic syndrome. After 3.5-year follow-up, we observed an inverse correlation between the baseline ANGPTL8/betatrophin levels and the incidence of metabolic syndrome, even after multivariate adjustments. In receiver operating characteristic analysis, the area underneath the curve for ANGPTL8/betatrophin was 0.70 in males and 0.86 in females, and the optimal cut-off values were 23.9 ng/mL and 31.1 ng/mL, respectively. This article suggests that ANGPTL8/betatrophin might be useful in predicting newly-onset metabolic syndrome and its progression in clinical setting.
10.1038/srep28431
Exosomal miR-24-3p impedes T-cell function by targeting FGF11 and serves as a potential prognostic biomarker for nasopharyngeal carcinoma.
Ye Shu-Biao,Zhang Han,Cai Ting-Ting,Liu Yi-Na,Ni Jian-Jiao,He Jia,Peng Jing-Yun,Chen Qiu-Yan,Mo Hao-Yuan,Jun-Cui ,Zhang Xiao-Shi,Zeng Yi-Xin,Li Jiang
The Journal of pathology
Recent studies have shown that extracellular microRNAs are not only potential biomarkers but are also involved in cell interactions to regulate the intercommunication between cancer cells and their microenvironments in various types of malignancies. In this study, we isolated exosomes from nasopharyngeal carcinoma (NPC) cell lines and patient sera (T-EXOs), or control NP69 cells and healthy donor sera (HD-EXOs). We found that miR-24-3p was markedly enriched in T-EXOs as compared with HD-EXOs; the serum exosomal miR-24-3p level was correlated with worse disease-free survival of patients (p < 0.05). Knockdown of exosomal miR-24-3p (miR-24-3p-sponge-T-EXOs) by a sponge RNA targeting miR-24-3p restored the T-EXO-mediated (control-sponge-T-EXO) inhibition of T-cell proliferation and Th1 and Th17 differentiation, and the induction of regulatory T cells (Tregs). Mechanistic analyses revealed that administration of exosomal miR-24-3p increased P-ERK, P-STAT1 and P-STAT3 expression while decreasing P-STAT5 expression during T-cell proliferation and differentiation. Moreover, by in vivo and in vitro assessments, we found FGF11 to be a direct target of miR-24-3p. However, both miR-24-3p-sponge-T-EXOs and T-EXOs (control-sponge-T-EXOs) impeded proliferation and Th1 and Th17 differentiation, but induced Treg differentiation, of lenti-shFGF11-transfected T cells. The levels of phosphorylated ERK and STAT proteins were different in lenti-ScshRNA-transfected T cells and lenti-shFGF11-transfected T cells following administration of miR-24-3p-sponge-T-EXO. Interestingly, tumour FGF11 expression was positively correlated with the number of CD4 and CD8 T cells in vivo, and predicted favourable patient DFS (p < 0.05). Additionally, hypoxia increased cellular and exosomal miR-24-3p levels and enhanced the inhibitory effect of T-EXO on T-cell proliferation and differentiation. Collectively, our findings suggest that exosomal miR-24-3p is involved in tumour pathogenesis by mediating T-cell suppression via repression of FGF11, and may serve as a potential prognostic biomarker in NPC. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
10.1002/path.4781
The role of cord blood BDNF in infant cognitive impairment induced by low-level prenatal manganese exposure: LW birth cohort, China.
Yu Xiaodan,Chen Limei,Wang Caifeng,Yang Xin,Gao Yu,Tian Ying
Chemosphere
This study aimed to examine the potential association between low-level prenatal manganese (Mn) exposure and 1-year-old children's neurodevelopment quotient (DQ) by using the Gesell Developmental Inventory (GDI) (motor, adaptive, language, and social domains) and explored the role of brain-derived neurotrophic factor (BDNF) in Mn-induced cognitive impairments. A total of 377 mothers were recruited from a prospective birth cohort in rural northern China. Cord serum concentrations of Mn and BDNF were measured and children's DQ was evaluated. The median serum Mn concentration was 3.4 μg/L. After adjusting for confounding factors, Mn level was significantly associated with gross motor scores (β = -6.0, 95% CI: -11.8 to -0.2, p < 0.05) and personal-social scores (β = -4.2, 95% CI: -8.4 to 0.1, p < 0.05). BDNF level was positively correlated with personal-social score (β = 0.7, 95% CI: 0-1.4, p < 0.05). A significant correlation was found between Mn and BDNF (r = -0.13, 95% CI: -0.23 to -0.03, p < 0.01). Furthermore, the interaction between cord serum Mn and BDNF was significant (p < 0.001). In conclusion, elevated low-level prenatal Mn exposure impaired infant's neurodevelopment, and BDNF plays an important role in cognitive impairment, especially in the personal-social ability.
10.1016/j.chemosphere.2016.07.095
Enhancing outpatient clinics management software by reducing patients' waiting time.
Almomani Iman,AlSarheed Ahlam
Journal of infection and public health
The Kingdom of Saudi Arabia (KSA) gives great attention to improving the quality of services provided by health care sectors including outpatient clinics. One of the main drawbacks in outpatient clinics is long waiting time for patients-which affects the level of patient satisfaction and the quality of services. This article addresses this problem by studying the Outpatient Management Software (OMS) and proposing solutions to reduce waiting times. Many hospitals around the world apply solutions to overcome the problem of long waiting times in outpatient clinics such as hospitals in the USA, China, Sri Lanka, and Taiwan. These clinics have succeeded in reducing wait times by 15%, 78%, 60% and 50%, respectively. Such solutions depend mainly on adding more human resources or changing some business or management policies. The solutions presented in this article reduce waiting times by enhancing the software used to manage outpatient clinics services. Both quantitative and qualitative methods have been used to understand current OMS and examine level of patient's satisfaction. Five main problems that may cause high or unmeasured waiting time have been identified: appointment type, ticket numbering, doctor late arrival, early arriving patient and patients' distribution list. These problems have been mapped to the corresponding OMS components. Solutions to the above problems have been introduced and evaluated analytically or by simulation experiments. Evaluation of the results shows a reduction in patient waiting time. When late doctor arrival issues are solved, this can reduce the clinic service time by up to 20%. However, solutions for early arriving patients reduces 53.3% of vital time, 20% of the clinic time and overall 30.3% of the total waiting time. Finally, well patient-distribution lists make improvements by 54.2%. Improvements introduced to the patients' waiting time will consequently affect patients' satisfaction and improve the quality of health care services.
10.1016/j.jiph.2016.09.005
Does acupuncture have a role in the treatment of threatened miscarriage? Findings from a feasibility randomised trial and semi-structured participant interviews.
BMC pregnancy and childbirth
BACKGROUND:Threatened miscarriage is a common complication of early pregnancy increasing the risk of miscarriage or premature labour. Currently there is limited evidence to recommend any biomedical pharmacological or self-care management, resulting in a 'watchful waiting' approach. The objective of this study was to examine the feasibility of offering acupuncture as a therapeutic treatment for women presenting with threatened miscarriage. METHODS:A mixed methods study involving a randomised controlled trial and semi structured interviews. A pragmatic acupuncture protocol including medical self-care advice was compared to an active control receiving touch intervention and medical self-care advice. Descriptive statistics were used to examine the demographic and baseline characteristics. Endpoints were analysed between groups using a mean t-test and chi-square tests with P < 0.05 considered statistically significant. Dichotomous data was expressed as Risk Ratio with 95 % confidence intervals. Eleven participants were purposively interviewed about their experiences on exiting the trial with interviews analysed using thematic analysis. RESULTS:Forty women were successfully randomised. For women receiving acupuncture there was a statically significant reduction with threatened miscarriage symptoms including bleeding, cramping and back pain compared with the control (p = 0.04). Thematic analysis revealed women were dissatisfied with the medical support and advice received. An overarching theme emerged from the data of 'finding something you can do.' This encompassed the themes: 'they said there was nothing they could do,' 'feeling the benefits' and 'managing while marking time.' CONCLUSION:Acupuncture was a feasible intervention and reduced threatened miscarriage symptoms when compared to a touch intervention. Further research is required to further explore acupuncture use for this common complication and whether it can reduce the incidence of miscarriage. TRIAL REGISTRATION:Australian New Zealand Clinical Trials Registry (ANZCTR), ACTRN12610000850077 . Date of registration 12/10/2010. Retrospectively registered, with first participant enrolled 11/10/2012.
10.1186/s12884-016-1092-8
Predicting first trimester pregnancy outcome: derivation of a multiple marker test.
Fertility and sterility
OBJECTIVE:To predict first trimester pregnancy outcome using biomarkers in a multicenter cohort. DESIGN:Case-control study. SETTING:Three academic centers. PATIENT(S):Women with pain and bleeding in early pregnancy. INTERVENTION(S):Sera from women who were 5-12 weeks' gestational age with ectopic pregnancy (EP), viable intrauterine pregnancy (IUP), and miscarriage/spontaneous abortion (SAB) was analyzed by ELISA and immunoassay for activin A, inhibin A, P, A Disintegrin And Metalloprotease-12, pregnancy-associated plasma protein A (PAPP-A), pregnancy specific B-glycoprotein (SP), placental-like growth factor, vascular endothelial growth factor, glycodelin (Glyc), and hCG. Classification trees were developed to optimize sensitivity/specificity for pregnancy location and viability. MAIN OUTCOME MEASURE(S):Area under receiver operating characteristic curve, sensitivity, specificity, and accuracy of first trimester pregnancy outcome. RESULT(S):In 230 pregnancies, the combination of trees to maximize sensitivity and specificity resulted in 73% specificity (95% confidence interval (CI) 0.65-0.80) and 31% sensitivity (95% CI 0.21-0.43) for viability. Similar methods had 21% sensitivity (95% CI 0.12-0.32) and 33% specificity (95% CI 0.26-0.41) for location. Activin A, Glyc, and A Disintegrin And Metalloprotease-12 definitively classified pregnancy location in 29% of the sample with 100% accuracy for EP. Progesterone and PAPP-A classified the viability in 61% of the sample with 94% accuracy. CONCLUSION(S):Multiple marker panels can distinguish pregnancy location and viability in a subset of women at risk for early pregnancy complications. This strategy of combining markers to maximize sensitivity and specificity results in high accuracy in a subset of subjects. Activin A, ADAM12, and Glyc are the most promising markers for pregnancy location; P and PAPP-A for viability.
10.1016/j.fertnstert.2016.08.044
Thrombin-activated platelet-derived exosomes regulate endothelial cell expression of ICAM-1 via microRNA-223 during the thrombosis-inflammation response.
Li Jiannan,Tan Ming,Xiang Qinqin,Zhou Zhou,Yan Hongbing
Thrombosis research
Platelet activation and endothelial damage play essential roles in atherosclerosis. The pathophysiology of this process is mediated by chemokines and exosomes, two critical players in cell communication. Thrombin-activated platelet-derived exosomes have protective effects on atherosclerosis and endothelial inflammation. To confirm these findings, we isolated exosomes using differential ultracentrifugation and transmission electron microscopy. The exosomes were identified using NanoSight-tracking analysis. Immunofluorescence staining and western blotting were performed to assess exosome uptake and intercellular adhesion molecule-1 (ICAM-1) expression in human umbilical vein endothelial cells (HUVECs). We found that the levels of miR-223, miR-339 and miR-21 were elevated in thrombin-activated platelet exosomes. This finding was verified in our atherosclerosis mouse model. We also found that miR-223 transfection in HUVECs inhibited ICAM-1 expression under TNF-α stimulation. Furthermore, the miR-223 inhibitor blocked the downregulating effects of exosomes on ICAM-1 expression. We examined the key proteins of two classical signaling pathways, MAPK and NF-κB, and found that miR-223 inhibited the phosphorylation of p38, JNK and ERK and blocked the nuclear translocation of NF-κB p65. Our results suggest that thrombin-activated platelet-derived exosomes inhibit ICAM-1 expression during inflammation. MiR-223 may mediate this process via regulation of the NF-κB and MAPK pathways.
10.1016/j.thromres.2017.04.016
MicroRNA-873 is a Potential Serum Biomarker for the Detection of Ectopic Pregnancy.
Lu Qi,Yan Qi,Xu Fengying,Li Yuhong,Zhao Wenxia,Wu Chunzhu,Wang Yudong,Lang Xiao
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology
BACKGROUND:Ectopic pregnancy (EP) refers to the implantation of the zygote outside the uterine cavity. In clinical practice, the diagnosis of EP relies on a combination of ultrasound findings and serum human chorionic gonadotrophin (hCG) measurements. However, the need for serial hCG measurements increases the risk of tubal rupture and death, underscoring the need to identify biomarkers for the early detection of EP. METHODS:The serum concentrations of 21 microRNAs (miRNAs) associated with pregnancy or with known placental expression, as well as serum hCG and progesterone levels were analyzed 36 patients with viable intrauterine pregnancy (VIP), 30 patients with spontaneous abortion (SA), and 34 patients with EP using specific assay kits and reverse transcription PCR. The diagnostic performance of the different serum markers for detecting EP was analyzed by ROC curve analysis. RESULTS:Five miRNAs were differentially expressed between the three groups, of which miR-873 and miR-223 were significantly lower in EP than in VIP and SA patients and did not change significantly according to gestational age, and miR-323 was significantly higher in EP than in VIP and SA. As a single marker, miR-873 had the highest sensitivity for detecting EP at 61.76% (at a fixed specificity of 90%). In comparison, the combination of hCG, progesterone and miR-873 had the highest sensitivity for detecting EP at 79.41% (at a fixed specificity of 90%). CONCLUSION:Although further validation in large-scale prospective studies is necessary, our results suggest that miR-873 could be a valuable noninvasive and stable biomarker for the early detection of EP.
10.1159/000475946
WBC count predicts the risk of new-onset peripheral arterial disease in a Chinese community-based population.
Li Yuxi,Fan Fangfang,Jia Jia,Li Jianping,Huo Yong,Zhang Yan
Hypertension research : official journal of the Japanese Society of Hypertension
This longitudinal cohort study investigated whether peripheral WBC counts could predict peripheral arterial disease (PAD) incidence after a 2.3-year follow-up in a Chinese community-based population without PAD at baseline. A total of 3555 Chinese subjects without fever and PAD at baseline from an atherosclerosis cohort were included in our analysis. The ankle brachial index (ABI) was measured, and PAD was defined as an ABI <0.9. Multivariate regression models were used to evaluate the association of WBC count and new-onset PAD. The mean (±s.d.) baseline WBC count was 6.11±1.54 × 10 l, the mean (±s.d.) ABI was 1.11±0.08 at baseline and the incidence of PAD was 2.7% over 2.3 years. WBC counts were significantly associated with PAD incidence (odds ratio (OR)=1.27, 95% confidence interval (CI): 1.14-1.41, P<0.0001) with every 1 × 10 l increase in WBC count. This relationship remained significant (OR=1.21, 95% CI: 1.08-1.36, P=0.0014) even after adjusting for other variables. The highest WBC quartile group had increased risk when compared with the lowest quartile group (OR=2.14, 95% CI: 1.09-4.22, P=0.027) in a multivariate logistic model. Furthermore, we did not find significant heterogeneity among the analyzed subgroups based on sex (male or female), age (<60 or ⩾60 years old), body mass index (BMI, <25 or ⩾25 kg m), current smoking, current drinking, hypertension, diabetes mellitus, dyslipidemia or cardiovascular disease. In conclusion, elevated WBC counts independently predict the risk of new-onset PAD in a Chinese community-based population, supporting the hypothesis that systemic inflammation plays an important role in PAD development.
10.1038/hr.2017.64
Macrophage function in tissue repair and remodeling requires IL-4 or IL-13 with apoptotic cells.
Bosurgi Lidia,Cao Y Grace,Cabeza-Cabrerizo Mar,Tucci Andrea,Hughes Lindsey D,Kong Yong,Weinstein Jason S,Licona-Limon Paula,Schmid Edward T,Pelorosso Facundo,Gagliani Nicola,Craft Joseph E,Flavell Richard A,Ghosh Sourav,Rothlin Carla V
Science (New York, N.Y.)
Tissue repair is a subset of a broad repertoire of interleukin-4 (IL-4)- and IL-13-dependent host responses during helminth infection. Here we show that IL-4 or IL-13 alone was not sufficient, but IL-4 or IL-13 together with apoptotic cells induced the tissue repair program in macrophages. Genetic ablation of sensors of apoptotic cells impaired the proliferation of tissue-resident macrophages and the induction of anti-inflammatory and tissue repair genes in the lungs after helminth infection or in the gut after induction of colitis. By contrast, the recognition of apoptotic cells was dispensable for cytokine-dependent induction of pattern recognition receptor, cell adhesion, or chemotaxis genes in macrophages. Detection of apoptotic cells can therefore spatially compartmentalize or prevent premature or ectopic activity of pleiotropic, soluble cytokines such as IL-4 or IL-13.
10.1126/science.aai8132
Placental Exosomes as Early Biomarker of Preeclampsia: Potential Role of Exosomal MicroRNAs Across Gestation.
Salomon Carlos,Guanzon Dominic,Scholz-Romero Katherin,Longo Sherri,Correa Paula,Illanes Sebastian E,Rice Gregory E
The Journal of clinical endocrinology and metabolism
Context:There is a need to develop strategies for early prediction of patients who will develop preeclampsia (PE) to establish preventive strategies to reduce the prevalence and severity of the disease and their associated complications. Objective:The objective of this study was to investigate whether exosomes and their microRNA cargo present in maternal circulation can be used as early biomarker for PE. Design, Setting, Patients, and Interventions:A retrospective stratified study design was used to quantify total exosomes and placenta-derived exosomes present in maternal plasma of normal (n = 32 per time point) and PE (n = 15 per time point) pregnancies. Exosomes present in maternal circulation were determined by nanoparticle tracking analysis. An Illumina TruSeq® Small RNA Library Prep Kit was used to construct a small RNA library from exosomal RNA obtained from plasma samples. Results:In presymptomatic women, who subsequently developed PE, the concentration of total exosomes and placenta-derived exosomes in maternal plasma was significantly greater than those observed in controls, throughout pregnancy. The area under the receiver operating characteristic curves for total exosome and placenta-derived exosome concentrations were 0.745 ± 0.094 and 0.829 ± 0.077, respectively. In total, over 300 microRNAs were identified in exosomes across gestation, where hsa-miR-486-1-5p and hsa-miR-486-2-5p were identified as the candidate microRNAs. Conclusions:Although the role of exosomes during PE remains to be fully elucidated, we suggest that the concentration and content of exosomes may be of diagnostic utility for women at risk for developing PE.
10.1210/jc.2017-00672
Cisplatin-resistant lung cancer cell-derived exosomes increase cisplatin resistance of recipient cells in exosomal miR-100-5p-dependent manner.
Qin Xiaobing,Yu Shaorong,Zhou Leilei,Shi Meiqi,Hu Yong,Xu Xiaoyue,Shen Bo,Liu Siwen,Yan Dali,Feng Jifeng
International journal of nanomedicine
Exosomes derived from lung cancer cells confer cisplatin (DDP) resistance to other cancer cells. However, the underlying mechanism is still unknown. A549 resistance to DDP (A549/DDP) was established. Microarray was used to analyze microRNA (miRNA) expression profiles of A549 cells, A549/DDP cells, A549 exosomes, and A549/DDP exosomes. There was a strong correlation of miRNA profiles between exosomes and their maternal cells. A total of 11 miRNAs were significantly upregulated both in A549/DDP cells compared with A549 cells and in exosomes derived from A549/DDP cells in contrast to exosomes from A549 cells. A total of 31 downregulated miRNAs were also observed. miR-100-5p was the most prominent decreased miRNA in DDP-resistant exosomes compared with the corresponding sensitive ones. Downregulated miR-100-5p was proved to be involved in DDP resistance in A549 cells, and mammalian target of rapamycin (mTOR) expression was reverse regulated by miR-100-5p. Exosomes confer recipient cells' resistance to DDP in an exosomal miR-100-5p-dependent manner with mTOR as its potential target both in vitro and in vivo. Exosomes from DDP-resistant lung cancer cells A549 can alter other lung cancer cells' sensitivity to DDP in exosomal miR-100-5p-dependent manner. Our study provides new insights into the molecular mechanism of DDP resistance in lung cancer.
10.2147/IJN.S131516
White blood cell count predicts the odds of kidney function decline in a Chinese community-based population.
Fan Fangfang,Jia Jia,Li Jianping,Huo Yong,Zhang Yan
BMC nephrology
BACKGROUND:Inflammatory processes are very important in the development of kidney disease. Nevertheless, the association between white blood cell (WBC) count and the risk of renal dysfunction has not been well-established, especially in subjects without chronic kidney disease (CKD). Our study investigated the association between WBC count and kidney function decline in a Chinese community-based population with baseline estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m. METHODS:A total of 3768 subjects who were enrolled in an atherosclerosis cohort in Beijing were included in this study. EGFRs were calculated at baseline and follow-up using the CKD-EPI formula. The outcomes of this study were renal function decline (RFD) (a drop in eGFR stage along with a decline in eGFR of 25% or exceeding 5 mL/min/1.73 m/year), rapid eGFR decline (an annual decrease in eGFR exceeding 3 mL/min/1.73 m), and incident CKD (eGFR <60 min/1.73 m at follow-up). Multivariate logistic regression models were used to evaluate the associations between WBC count and each outcome. RESULTS:On average, the subjects were 56.6 ± 8.5 years old, and 35.9% were male. Of the participants, 48.6% had hypertension and 17.4% had diabetes. The mean (SD) WBC count at baseline was 6.1 ± 1.5 × 10/L. The mean (SD) eGFR at baseline was 101.1 ± 10.6 mL/min/1.73 m. After 2.3 years follow-up, the incidence rates of RFD, rapid eGFR decline and new CKD were 7.7, 20.9, and 0.8%, respectively. WBC count was significantly related to RFD, rapid eGFR decline and new CKD in the univariate analyses. Even after adjustment for demographic variables, comorbidities, medications and baseline eGFR, these associations remained. Moreover, similar trends in RFD were observed in nearly all subgroups stratified by each confounding variable. The increase in the odds of RFD associated with each 10/L increase in WBC count was significantly greater in subjects not undergoing treatment with lipid-lowering drugs than those not undergoing this treatment (P-interaction: 0.05). CONCLUSIONS:In conclusion, elevated WBC count served as a predictor of the odds of kidney function decline in this population, which supports the hypothesis that systemic inflammation may serve as a risk factor for CKD development.
10.1186/s12882-017-0608-4
Pregnancy-Related Mortality in the United States, 2011-2013.
Creanga Andreea A,Syverson Carla,Seed Kristi,Callaghan William M
Obstetrics and gynecology
OBJECTIVE:To update national population-level pregnancy-related mortality estimates and examine characteristics and causes of pregnancy-related deaths in the United States during 2011-2013. METHODS:We conducted an observational study using population-based data from the Pregnancy Mortality Surveillance System to calculate pregnancy-related mortality ratios by year, age group, and race-ethnicity groups. We explored 10 cause-of-death categories by pregnancy outcome during 2011-2013 and compared their distribution with those in our earlier reports since 1987. RESULTS:The 2011-2013 pregnancy-related mortality ratio was 17.0 deaths per 100,000 live births. Pregnancy-related mortality ratios increased with maternal age, and racial-ethnic disparities persisted with non-Hispanic black women having a 3.4 times higher mortality ratio than non-Hispanic white women. Among causes of pregnancy-related deaths, the following groups contributed more than 10%: cardiovascular conditions ranked first (15.5%) followed by other medical conditions often reflecting pre-existing illnesses (14.5%), infection (12.7%), hemorrhage (11.4%), and cardiomyopathy (11.0%). Relative to the most recent report of Pregnancy Mortality Surveillance System data for 2006-2010, the distribution of cause-of-death categories did not change considerably. However, compared with serial reports before 2006-2010, the contribution of hemorrhage, hypertensive disorders of pregnancy, and anesthesia complications declined, whereas that of cardiovascular and other medical conditions increased (population-level percentage comparison). CONCLUSION:The pregnancy-related mortality ratio and the distribution of the main causes of pregnancy-related mortality have been relatively stable in recent years.
10.1097/AOG.0000000000002114
Second trimester extracellular microRNAs in maternal blood and fetal growth: An exploratory study.
Rodosthenous Rodosthenis S,Burris Heather H,Sanders Alison P,Just Allan C,Dereix Alexandra E,Svensson Katherine,Solano Maritsa,Téllez-Rojo Martha M,Wright Robert O,Baccarelli Andrea A
Epigenetics
Healthy feto-maternal communication is critical during pregnancy and is orchestrated by the placenta. Dysfunction of the placenta leads to fetal growth complications; however, the underlying biological mechanisms have yet to be fully elucidated. Circulating extracellular microRNAs (exmiRNAs) in the blood have been implicated in cell-to-cell communication. Therefore, exmiRNAs may provide useful biological information about communication between the mother, the fetus, and the placenta during pregnancy. We used logistic regression to determine the association of exmiRNAs with abnormal fetal growth by comparing mothers of infants classified as small-for-gestational age (SGA) (n = 36) and large-for-gestational age (LGA) (n = 13) to appropriate-for-gestational age (AGA), matched by gestational age at delivery and infant sex. In addition, we used linear regression to determine associations between exmiRNAs and birth weight-for-gestational age (BWGA) z-score (n = 100), adjusting for maternal age, body mass index, and parity. We found that higher levels of miR-20b-5p, miR-942-5p, miR-324-3p, miR-223-5p, and miR-127-3p in maternal serum were associated with lower odds for having a SGA vs. AGA infant, and higher levels of miR-661, miR-212-3p, and miR-197-3p were associated with higher odds for having a LGA vs. AGA infant. We also found associations between miR-483-5p, miR-10a-5p, miR-204-5p, miR-202-3p, miR-345-5p, miR-885-5p, miR-127-3p, miR-148b-3p, miR-324-3p, miR-1290, miR-597-5p, miR-139-5p, miR-215-5p, and miR-99b-5p and BWGA z-score. We also found sex-specific associations with exmiRNAs and fetal growth. Our findings suggest that exmiRNAs circulating in maternal blood at second trimester are associated with fetal growth. Validation of our findings may lead to the development of minimally-invasive biomarkers of fetal growth during pregnancy.
10.1080/15592294.2017.1358345
Real-world effectiveness of 8-week treatment with ledipasvir/sofosbuvir in chronic hepatitis C.
Buggisch Peter,Vermehren Johannes,Mauss Stefan,Günther Rainer,Schott Eckart,Pathil Anita,Boeker Klaus,Zimmermann Tim,Teuber Gerlinde,Vornkahl Heike-Pfeiffer,Simon Karl-Georg,Niederau Claus,Wedemeyer Heiner,Zeuzem Stefan
Journal of hepatology
BACKGROUND & AIMS:Ledipasvir/sofosbuvir (LDV/SOF) for 8 to 24 weeks is approved for the treatment of chronic hepatitis C virus infection (HCV). In the ION-3 study, 8 weeks of LDV/SOF was non-inferior to 12 weeks in previously untreated genotype 1 (GT1) patients without cirrhosis. According to the Summary of Product Characteristics (SmPC), 8-week treatment may be considered in naïve non-cirrhotic GT1-patients. However, there are only limited data on the effectiveness of an 8-week regimen of LDV/SOF under real-world conditions. The aim of the present study was to characterise patients receiving 8 weeks of LDV/SOF compared to those receiving 12 weeks of LDV/SOF, and to describe therapeutic outcomes in routine clinical practice. METHODS:The German Hepatitis C-Registry is a large national real-world cohort that analyses effectiveness and safety of antiviral therapies in chronic HCV. This data set is based on 2,404 patients. Treatment with SOF/LDV (without RBV) for 8 or 12 weeks was initiated on or before September 30, 2015. RESULTS:Overall, 84.6% (2,034/2,404) of the safety population (intention-to-treat-1 [ITT1]) and 98.2% (2,029/2,066) of the per protocol (PP) population achieved sustained virological response at week 12 (SVR12). In the 8-week group, 85.1% (824/968) of ITT1 and 98.3% (821/835) of PP patients achieved SVR12, while in the 12-week group, 85.5% (1,210/1,415) of ITT1, and 98.1% (1,208/1,231) of PP patients achieved SVR12. When treated according to the SmPC, 98.7% (739/749) of the patients achieved SVR12 (PP). Relapse was observed in 9.5% (2/21) of cirrhotic patients treated for 8 weeks (PP). CONCLUSIONS:Under real-world conditions a high proportion of eligible patients receiving 8-week LDV/SOF treatment achieved SVR12. Relapse occurred more frequently in patients who did not meet the selection criteria according to the SmPC. LAY SUMMARY:In a large real-world cohort of patients mainly treated by physicians in private practice in Germany, shorter HCV treatment (8-week) resulted in equivalent cure rates to 12-week treatment in genotype 1 HCV-infected patients. Thus, shorter treatment can be recommended in these patients which would substantially reduce costs of therapy. Clinical Trial number: DRKS00009717 (German Clinical Trials Register, DRKS).
10.1016/j.jhep.2017.11.009
Various levels of circulating exosomal total-miRNA and miR-210 hypoxamiR in different forms of pregnancy hypertension.
Biró Orsolya,Alasztics Bálint,Molvarec Attila,Joó József,Nagy Bálint,Rigó János
Pregnancy hypertension
INTRODUCTION:Hypertension is a common complication during pregnancy, affecting 10% of pregnant women worldwide. Several microRNA (miRNA) were shown to be involved in hypertensive disorders of pregnancy. In preeclampsia (PE), placental dysfunction causes the enhanced release of extracellular vesicle-derived miRNAs. The hypoxia-sensitive hsa-mir-210 is the most common PE-associated miRNA, but its exosomal profile has not been investigated. OBJECTIVES:Our aims were to measure exosomal total-miRNA concentration and to perform expression analysis of circulating exosomal hsa-miR-210 in women affected by chronic hypertension (CHT) gestational hypertension (GHT) or PE. MATERIALS AND METHODS:We collected plasma samples from women with CHT, GHT, PE (moderate: mPE and severe: sPE) and from normotensive pregnancies. Exosomal miRNAs were extracted and miRNA concentration was measured. RT-PCR was carried out with hsa-miR-210-3p-specific primers and relative expression was calculated using the comparative Ct method. RESULTS:The total-miRNA concentration was different in the disease subgroups, and was significantly higher in mPE and sPE compared to the other groups. We found a significant difference in the relative exosomal hsa-miR-210-3p expression between all hypertensive groups compared to the normotensive samples, but significant upregulation was only observed in case of mPE and sPE patients. Both the level of total-miRNA and hsa-miR-210 expression was higher in case of severe PE. CONCLUSIONS:The level of circulating exosomal total-miRNA and hsa-miR-210 was elevated in women with PE, and it was higher in the severe form. We showed that hsa-miR-210 is secreted via exosomes, which may have a role in the pathomechanism of the disease.
10.1016/j.preghy.2017.09.002
In Vivo Early Corneal Biomechanical Changes After Corneal Cross-linking in Patients With Progressive Keratoconus.
Vinciguerra Riccardo,Romano Vito,Arbabi Esmaeil M,Brunner Matthias,Willoughby Colin E,Batterbury Mark,Kaye Stephen B
Journal of refractive surgery (Thorofare, N.J. : 1995)
PURPOSE:To report early corneal biomechanical changes after corneal cross-linking (CXL) in patients with keratoconus. METHODS:Thirty-four eyes of 34 patients undergoing CXL for progressive keratoconus were included in this prospective clinical study. Dynamic corneal response (DCR) parameters obtained with the Corvis ST (OCULUS Optikgeräte GmbH; Wetzlar, Germany) were assessed at baseline (day of CXL) and after 1 month of follow-up; conversely, corneal tomography with the Pentacam (OCULUS Optikgeräte GmbH) was assessed at baseline and at 1, 3, and 6 months after CXL. RESULTS:At the last follow-up visit (123.7 ± 69.6 days), all morphological parameters including steepest point (Kmax) and thinnest corneal thickness (ThCT) indicated stabilization of keratoconus (P > .05). Comparative analyses showed a rise of corneal stiffness demonstrated by a significant increase of Stiffness Parameter A1 (SP-A1) and Highest Concavity (SP-HC) and a significant decrease of Inverse Concave Radius (1/R) and Deformation Amplitude Ratio (DA Ratio) (P < .05). There was a significant correlation between the preoperative keratoconus characteristics (Kmax, Belin/Ambrósio final D value [BAD-D], and ThCT) and the DCR parameters (P < .05). Kmax and BAD-D showed a significant positive correlation with DA Ratio, Deflection Amplitude (DefA), and 1/R and a significant negative correlation with SPA1 and SP-HC. ThCT showed a significant positive correlation with SP-A1 and SP-HC and a significant negative correlation with DA Ratio, DefA, and 1/R. CONCLUSIONS:This study suggests that the new DCR parameters of the Corvis ST are able to detect early changes in biomechanics following CXL and those that are measurable before corneal shape modifications take place. Based on these results, the authors suggest the use of these metrics to assess the early efficacy of cross-linking. [J Refract Surg. 2017;33(12):840-846.].
10.3928/1081597X-20170922-02
ACOG Practice Bulletin No. 191: Tubal Ectopic Pregnancy.
Obstetrics and gynecology
Ectopic pregnancy is defined as a pregnancy that occurs outside of the uterine cavity. The most common site of ectopic pregnancy is the fallopian tube. Most cases of tubal ectopic pregnancy that are detected early can be treated successfully either with minimally invasive surgery or with medical management using methotrexate. However, tubal ectopic pregnancy in an unstable patient is a medical emergency that requires prompt surgical intervention. The purpose of this document is to review information on the current understanding of tubal ectopic pregnancy and to provide guidelines for timely diagnosis and management that are consistent with the best available scientific evidence.
10.1097/AOG.0000000000002464
Exosome Theranostics: Biology and Translational Medicine.
Theranostics
Exosomes are common membrane-bound nanovesicles that contain diverse biomolecules, such as lipids, proteins, and nucleic acids. Exosomes are derived from cells through exocytosis, are ingested by target cells, and can transfer biological signals between local or distant cells. Exosome secretion is a constitutive phenomenon that is involved in both physiological and pathological processes and determines both the exosomal surface molecules and the contents. Hence, we can exploit exosomes as biomarkers, vaccines and drug carriers and modify them rationally for therapeutic interventions. However, it is still a challenge to identify, isolate and quantify exosomes accurately, efficiently and selectively. Further studies on exosomes will explore their potential in translational medicine and provide new avenues for the creation of effective clinical diagnostics and therapeutic strategies; the use of exosomes in these applications can be called exosome theranostics. This review describes the fundamental processes of exosome formation and uptake. In addition, the physiological and pathological roles of exosomes in biology are also illustrated with a focus on how exosomes can be exploited or engineered as powerful tools in translational medicine.
10.7150/thno.21945
Optimal use of peri-operative human chorionic gonadotrophin concentrations to identify persistent ectopic pregnancy after laparoscopic salpingostomy: a retrospective cohort study.
Morse Abraham N,Si Wenyue,Qin Shuang,Liang Huiying
Reproductive biomedicine online
The aim of this study was to improve clinical decision-making for the identification of persistent ectopic pregnancy after linear salpingostomy. The study identified 854 laparoscopic salpingostomies performed between 2011 and 2016; 794 had a human chorionic gonadotrophin (HCG) <10 mIU/ml documented in the electronic medical record within 1 month after surgery ('successes'). Sixty (7%) received either methotrexate or repeat surgery for persistent ectopic pregnancy ('failures'). Five hundred and seventeen, including 46 'failures', had two or more immediate post-operative HCG measurements available. The most clinically useful prediction rule was calculated by dividing the difference between the first and second post-operative HCG values by the first post-operative HCG value (i.e. [HCG1 - HCG2]/HCG1). When this ratio exceeded 0.75, it reliably ruled out persistent ectopic with a negative predictive value = 99%. When this ratio was less than 0.2, it identified persistent ectopics with a positive predictive value = 88%. It appears that this simple arithmetic calculation involving two early post-operative HCG values may allow for efficient triage of patients before post-operative day 5. If validated in prospective studies, this could help minimize the risk, inconvenience and expense of requiring several weeks of frequent follow up to rule in/rule out persistent ectopic pregnancy.
10.1016/j.rbmo.2017.12.006
microRNA-1246 Is an Exosomal Biomarker for Aggressive Prostate Cancer.
Bhagirath Divya,Yang Thao Ly,Bucay Nathan,Sekhon Kirandeep,Majid Shahana,Shahryari Varahram,Dahiya Rajvir,Tanaka Yuichiro,Saini Sharanjot
Cancer research
Because of high heterogeneity, molecular characterization of prostate cancer based on biopsy sampling is often challenging. Hence, a minimally invasive method to determine the molecular imprints of a patient's tumor for risk stratification would be advantageous. In this study, we employ a novel, digital amplification-free quantification method using the nCounter technology (NanoString Technologies) to profile exosomal serum miRNAs (ex-miRNA) from aggressive prostate cancer cases, benign prostatic hyperplasia, and disease-free controls. We identified several dysregulated miRNAs, one of which was the tumor suppressor miR-1246. miR-1246 was downregulated in prostate cancer clinical tissues and cell lines and was selectively released into exosomes. Overexpression of miR-1246 in a prostate cancer cell line significantly inhibited xenograft tumor growth and increased apoptosis and decreased proliferation, invasiveness, and migration miR-1246 inhibited N-cadherin and vimentin activities, thereby inhibiting epithelial-mesenchymal transition. Ex-miR-1246 expression correlated with increasing pathologic grade, positive metastasis, and poor prognosis. Our analyses suggest ex-miR-1246 as a promising prostate cancer biomarker with diagnostic potential that can predict disease aggressiveness. Dysregulation of exosomal miRNAs in aggressive prostate cancer leads to alteration of key signaling pathways associated with metastatic prostate cancer. .
10.1158/0008-5472.CAN-17-2069
Automated diabetic retinopathy detection in smartphone-based fundus photography using artificial intelligence.
Rajalakshmi Ramachandran,Subashini Radhakrishnan,Anjana Ranjit Mohan,Mohan Viswanathan
Eye (London, England)
OBJECTIVES:To assess the role of artificial intelligence (AI)-based automated software for detection of diabetic retinopathy (DR) and sight-threatening DR (STDR) by fundus photography taken using a smartphone-based device and validate it against ophthalmologist's grading. METHODS:Three hundred and one patients with type 2 diabetes underwent retinal photography with Remidio 'Fundus on phone' (FOP), a smartphone-based device, at a tertiary care diabetes centre in India. Grading of DR was performed by the ophthalmologists using International Clinical DR (ICDR) classification scale. STDR was defined by the presence of severe non-proliferative DR, proliferative DR or diabetic macular oedema (DME). The retinal photographs were graded using a validated AI DR screening software (EyeArt) designed to identify DR, referable DR (moderate non-proliferative DR or worse and/or DME) or STDR. The sensitivity and specificity of automated grading were assessed and validated against the ophthalmologists' grading. RESULTS:Retinal images of 296 patients were graded. DR was detected by the ophthalmologists in 191 (64.5%) and by the AI software in 203 (68.6%) patients while STDR was detected in 112 (37.8%) and 146 (49.3%) patients, respectively. The AI software showed 95.8% (95% CI 92.9-98.7) sensitivity and 80.2% (95% CI 72.6-87.8) specificity for detecting any DR and 99.1% (95% CI 95.1-99.9) sensitivity and 80.4% (95% CI 73.9-85.9) specificity in detecting STDR with a kappa agreement of k = 0.78 (p < 0.001) and k = 0.75 (p < 0.001), respectively. CONCLUSIONS:Automated AI analysis of FOP smartphone retinal imaging has very high sensitivity for detecting DR and STDR and thus can be an initial tool for mass retinal screening in people with diabetes.
10.1038/s41433-018-0064-9
Smartwatch Algorithm for Automated Detection of Atrial Fibrillation.
Bumgarner Joseph M,Lambert Cameron T,Hussein Ayman A,Cantillon Daniel J,Baranowski Bryan,Wolski Kathy,Lindsay Bruce D,Wazni Oussama M,Tarakji Khaldoun G
Journal of the American College of Cardiology
BACKGROUND:The Kardia Band (KB) is a novel technology that enables patients to record a rhythm strip using an Apple Watch (Apple, Cupertino, California). The band is paired with an app providing automated detection of atrial fibrillation (AF). OBJECTIVES:The purpose of this study was to examine whether the KB could accurately differentiate sinus rhythm (SR) from AF compared with physician-interpreted 12-lead electrocardiograms (ECGs) and KB recordings. METHODS:Consecutive patients with AF presenting for cardioversion (CV) were enrolled. Patients underwent pre-CV ECG along with a KB recording. If CV was performed, a post-CV ECG was obtained along with a KB recording. The KB interpretations were compared to physician-reviewed ECGs. The KB recordings were reviewed by blinded electrophysiologists and compared to ECG interpretations. Sensitivity, specificity, and K coefficient were measured. RESULTS:A total of 100 patients were enrolled (age 68 ± 11 years). Eight patients did not undergo CV as they were found to be in SR. There were 169 simultaneous ECG and KB recordings. Fifty-seven were noninterpretable by the KB. Compared with ECG, the KB interpreted AF with 93% sensitivity, 84% specificity, and a K coefficient of 0.77. Physician interpretation of KB recordings demonstrated 99% sensitivity, 83% specificity, and a K coefficient of 0.83. Of the 57 noninterpretable KB recordings, interpreting electrophysiologists diagnosed AF with 100% sensitivity, 80% specificity, and a K coefficient of 0.74. Among 113 cases where KB and physician readings of the same recording were interpretable, agreement was excellent (K coefficient = 0.88). CONCLUSIONS:The KB algorithm for AF detection supported by physician review can accurately differentiate AF from SR. This technology can help screen patients prior to elective CV and avoid unnecessary procedures.
10.1016/j.jacc.2018.03.003
Association between Growth Hormone-Insulin-Like Growth Factor-1 Axis Gene Polymorphisms and Short Stature in Chinese Children.
Zhang Yanhong,Zhang Mei,Chu Yuntian,Ji Baolan,Shao Qian,Ban Bo
BioMed research international
OBJECTIVE:This study was designed to analyze the association between the growth hormone-insulin-like growth factor-1 (GH-IGF-1) axis gene polymorphisms and short stature in Chinese children. METHODS:181 growth hormone deficiency (GHD) patients and 206 normal stature controls were enrolled to attend this study. Five single-nucleotide polymorphisms in the GH receptor (GHR) and 5 SNPs within the GH-signaling pathway were genotyped by matrix-assisted laser desorption/ionization time of flight mass spectrometry. We conducted an association study between these SNPs and the risk of developing short stature. Linkage disequilibrium analysis was performed using Haploview software and the associations of the SNPs frequencies with short stature were analyzed using tests. RESULTS:No significant difference was found in gender, weight, height, and BMI between the GHD and control groups, except that the age of GHD group was older than the control one. Allele and genotype frequencies were consistent with those expected from Hardy-Weinberg equilibrium. Compared with the controls, heterozygous genotype frequencies (CT) of rs12515480 and rs6873545 of GHR gene were significantly lower. Genotype frequencies of the other 8 SNPs did not show significant difference between these two groups. Considering a dominant model, an OR < 1 was observed for genotypes rs12515480 (OR = 0.532, = 0.019) and rs6873545 (OR = 0.587, = 0.017). CONCLUSIONS:The heterozygous genotypes of rs12515480 and rs6873545 of GHR gene were associated with decreased risk of GHD in Chinese children.
10.1155/2018/7431050
Association between Insulin-Like Growth Factor-1 and Uric Acid in Chinese Children and Adolescents with Idiopathic Short Stature: A Cross-Sectional Study.
Wang Panpan,Ji Baolan,Shao Qian,Zhang Mei,Ban Bo
BioMed research international
OBJECTIVE:The aim of this study was to examine the relationship between insulin-like growth factor-1 (IGF-1) and serum uric acid (UA) in Chinese children and adolescents with idiopathic short stature (ISS). METHODS:A cross-sectional study of 91 Chinese children and adolescents with ISS was performed. Anthropometric measurements and biochemical parameters were tested. The standard deviation score of IGF-1 (IGF-1 SDS) was calculated. RESULTS:A univariate analysis displayed a significant positive correlation between IGF-1 SDS and UA ( = 0.004). In multivariate piecewise linear regression, the levels of IGF-1 SDS increased with the elevation of UA when UA was between 168 mol/L and 301 mol/L ( 0.010, 95% CI 0.004-0.017; = 0.002). The levels of IGF-1 SDS decreased with the elevation of UA when UA was either less than 168 mol/L ( -0.055, 95% CI -0.081--0.028; < 0.001) or more than 301 mol/L ( -0.005, 95% CI -0.013-0.002; = 0.174). CONCLUSIONS:This study demonstrated a nonlinear relationship between IGF-1 and UA levels in Chinese children and adolescents with ISS. This finding suggests that either high or low levels of UA may have an adverse effect on IGF-1, whereas appropriate UA levels have a beneficial effect.
10.1155/2018/4259098
Evaluation of keratoconus progression.
Shajari Mehdi,Steinwender Gernot,Herrmann Kim,Kubiak Kate Barbara,Pavlovic Ivana,Plawetzki Elena,Schmack Ingo,Kohnen Thomas
The British journal of ophthalmology
AIM:To define variables for the evaluation of keratoconus progression and to determine cut-off values. METHODS:In this retrospective cohort study (2010-2016), 265 eyes of 165 patients diagnosed with keratoconus underwent two Scheimpflug measurements (Pentacam) that took place 1 year apart ±3 months. Variables used for keratoconus detection were evaluated for progression and a correlation analysis was performed. By logistic regression analysis, a keratoconus progression index (KPI) was defined. Receiver-operating characteristic curve (ROC) analysis was performed and Youden Index calculated to determine cut-off values. RESULTS:Variables used for keratoconus detection showed a weak correlation with each other (eg, correlation r=0.245 between RPImin and Kmax, p<0.001). Therefore, we used parameters that took several variables into consideration (eg, D-index, index of surface variance, index for height asymmetry, KPI). KPI was defined by logistic regression and consisted of a Pachymin coefficient of -0.78 (p=0.001), a maximum elevation of back surface coefficient of 0.27 and coefficient of corneal curvature at the zone 3 mm away from the thinnest point on the posterior corneal surface of -12.44 (both p<0.001). The two variables with the highest Youden Index in the ROC analysis were D-index and KPI: D-index had a cut-off of 0.4175 (70.6% sensitivity) and Youden Index of 0.606. Cut-off for KPI was -0.78196 (84.7% sensitivity) and a Youden Index of 0.747; both 90% specificity. CONCLUSIONS:Keratoconus progression should be defined by evaluating parameters that consider several corneal changes; we suggest D-index and KPI to detect progression.
10.1136/bjophthalmol-2017-311651
Prevalence of iodine deficiency and associated factors among pregnant women in Ada district, Oromia region, Ethiopia: a cross- sectional study.
BMC pregnancy and childbirth
BACKGROUND:Maternal iodine deficiency (ID) during pregnancy has been recognized as a major cause of abortion, stillbirth, congenital abnormalities, perinatal mortality and irreversible mental retardation. In Ethiopia limited information is available regarding the epidemiology of maternal ID. The purpose of the present study was to assess the prevalence of iodine deficiency and associated factors among pregnant women in Ada district, Oromia region, Ethiopia. METHOD:A community based, cross-sectional study was conducted in rural areas of Ada district, October to November, 2014. Data were collected from 356 pregnant women selected by multistage cluster sampling technique. Presence of goiter was examined by palpation and urinary iodine concentration was measured using inductively-coupled-plasma mass spectrometry. Salt iodine concentration was determined using a digital electronic iodine checker. Statistical analysis was done primarily using binary logistic regression. The outputs of the analysis are presented using adjusted odds ratio (AOR) with the respective 95% confidence intervals (CI). RESULTS:The median urinary iodine concentration (UIC) was 85.7 (interquartile range (IQR): 45.7-136) μg/L. Based on UIC, 77.6% (95% CI: 73.0-82.0%) of the study subjects had insufficient iodine intake (UIC < 150 μg/L). The goiter rate was 20.2% (95% CI: 16.0-24.0%). The median iodine concentration of the household salt samples was 12.2 (IQR: 6.9-23.8) ppm. Of the households, only 39.3% (95% CI: 34.0-44.0%) consumed adequately iodized salt (≥15 ppm). Prevalence of goiter was significantly higher among pregnant women aged 30-44 years (AOR = 2.32 (95% CI: 1.05-5.14)) than among younger women and among illiterate women (AOR = 2.71 (95% CI: 1.54-4.79)). Compared to nulliparous, women with parity of 1, 2 and 3 or more had 2.28 (95% CI: 1.01-5.16), 2.81 (95% CI: 1.17-6.74) and 4.41 (95% CI: 1.58-12.26) times higher risk of goiter. CONCLUSION:Iodine deficiency was a public health problem in the study area. This indicates the need for further strengthening of the existing salt iodization program in order to avail homogenously and adequately iodized salt. Also it is necessary to find ways to provide iodine supplements as needed until universal salt iodization (USI) is fully established.
10.1186/s12884-018-1905-z
A novel U-shaped relationship between BMI and risk of generalized aggressive periodontitis in Chinese: A cross-sectional study.
Li Wenjing,Shi Dong,Song Wenli,Xu Li,Zhang Li,Feng Xianghui,Lu Ruifang,Wang Xiane,Meng Huanxin
Journal of periodontology
BACKGROUND:Association between BMI and periodontitis were controversial. A study indicated that not only overweight or obesity but also underweight was correlated with generalized aggressive periodontitis (GAgP). However, the exact relationship between BMI and GAgP and the optimal BMI value for the lowest risk of GAgP remain unknown. OBJECTIVE:To explore the exact relationship between BMI and GAgP risk, periodontal status and WBC (white blood cell) count and find the optimal BMI value associated with the lowest risk, periodontal status and lowest WBC of GAgP in Chinese. METHODS:300 GAgP patients and 133 healthy controls were recruited. Height and weight of participants were accurately measured to calculate BMI value. Clinical periodontal parameters, including probing depth (PD), attachment loss (AL), and bleeding index (BI) were recorded. WBC was obtained from routine blood examination. Smooth curve fitting and segmented regression model were used to analyze the threshold effect between BMI and variables. The shape of the curve was used to describe the relationships between BMI and GAgP. RESULTS:U-shaped relationships between BMI and risk of GAgP, AL, and WBC count in GAgP patients were observed. The optimal value of BMI for the lowest risk of GAgP and lowest WBC count was 22 kg/m . The risk of GAgP increased by 39% in patients per unit increase of BMI when BMI ranged from 22 to 28 kg/m (adjusted OR = 1.39, 95% CI: 1.17, 1.67) and increased by 18% per unit decrease of BMI when BMI ranged from 22 to 18 kg/m (adjusted OR = 0.82, 95% CI: 0.69, 0.97). The count of WBC increased by 1.12 × 10 /L in patients per unit increase of BMI when BMI ranged from 22 to 28 kg/m (adjusted β = 0.12, 95% CI: 0.01, 0.23) and increased by 0.2 × 10 /L per unit decrease of BMI when BMI ranged from 22 to18 kg/m (adjusted β = -0.2, 95% CI: -0.35, -0.04). CONCLUSION:U-shaped relationships exist between BMI and risk of GAgP, AL, and WBC count in patients with GAgP among Chinese aged below 36 years old with their BMI range from 18 to 28 kg/m ; the optimal BMI value for lowest odds ratio and lowest WBC count of GAgP was 22 kg/m .
10.1002/JPER.18-0064
SMARTphone and social media-based Cardiac Rehabilitation and Secondary Prevention (SMART-CR/SP) for patients with coronary heart disease in China: a randomised controlled trial protocol.
BMJ open
INTRODUCTION:The burden of cardiovascular disease (CVD) is rapidly increasing in developing countries, however access to cardiac rehabilitation and secondary prevention (CR/SP) in these countries is limited. Alternative delivery models that are low-cost and easy to access are urgently needed to address this service gap. The objective of this study is to investigate whether a smartphone and social media-based (WeChat) home CR/SP programme can facilitate risk factor monitoring and modification to improve disease self-management and health outcomes in patients with coronary heart disease (CHD), after percutaneous coronary intervention (PCI) therapy. METHODS AND ANALYSIS:We propose a single-blind, randomised controlled trial of 300 patients post-PCI with follow-up over 12 months. The intervention group will receive a smartphone-based and WeChat-based CR/SP programme providing education and support for risk factor monitoring and modification. SMART-CR/SP incorporates core components of modern CR/SP: physical activity tracking with interactive feedback and goal setting; education modules addressing CHD understanding and self-management; remote blood pressure monitoring and strategies to improve medication adherence. Furthermore, a dedicated data portal and a CR/SP coach will facilitate individualised supervision and counselling. The control group will receive usual care but no formal CR/SP programme. The primary outcome is change in exercise capacity measured by 6 minute walk test distance. Secondary outcomes include knowledge and awareness of CHD, risk factor status, medication adherence, psychological well-being and quality of life, major cardiovascular events, re-hospitalisations and all-cause mortality. To assess the feasibility and patients' acceptance of the intervention, a process evaluation will be performed at the conclusion of the study. ETHICS AND DISSEMINATION:Ethics approval was granted by both the Human Research Ethics Committee of Fudan University Zhongshan Hospital (HREC B2016-058) and Curtin University Human Research Ethics Office (HRE2016-0120). Results will be disseminated via peer-reviewed publications and presentations at conferences. CLINICAL TRIAL REGISTRATION NUMBER:ChiCTR-INR-16009598; Pre-results.
10.1136/bmjopen-2018-021908
Neutrophils and neutrophil-lymphocyte ratio: Inflammatory markers associated with intimal-media thickness of atherosclerosis.
Meng Ling-Bing,Yu Ze-Mou,Guo Peng,Wang Qing-Qing,Qi Ruo-Mei,Shan Meng-Jie,Lv Jian,Gong Tao
Thrombosis research
INTRODUCTION:Cardiac-cerebral vascular diseases (CCVDs) are global health problems due to the characteristic of high mortality. It is found that atherosclerosis (AS), a main cause of CCVDs, is significantly relevant to the change of intimal and media thickness. Neutrophil count (NEU) and neutrophil-lymphocyte ratio (N/L) are recognized possible risk factors for atherosclerosis (AS). However, there are few studies on the separate relationship between carotid intimal thickness, media thickness and NEU, N/L. This study explored the respective effects of NEU and N/L on AS and intimal, media thickness. MATERIALS AND METHODS:The χ, Spearman's rho test, and multiple linear regression were implemented to analyze the relevance between blood parameters and intimal-media thickness. The potential factors, affecting non-depression time (NDT), is identified by univariate Cox regression. ROC curve was performed to determine the ability of blood parameters to predict intimal-media thickness. Immunohistochemistry was implemented. RESULTS AND CONCLUSION:Based on χ, Spearman's rho test and multiple linear regression, NEU is related with intimal thickness (P < 0.05). Furthermore, NEU can predict the intimal thickness through the ROC curve. What's more, N/L is a risk factor of carotid media thickness (P < 0.05) by the Spearman's rho test, and is also correlated with poor NDT (P < 0.05) based on univariate Cox proportional regression analysis. Through ROC curve, N/L can predict the carotid media thickness. The carotid atherosclerotic endarterium is richest in macrophagocytes, and the arrangement of endotheliocytes is disordered. In summary, the increased NEU and N/L respectively have a strong correlation and precise predictability for carotid intimal and media thickness of atherosclerosis.
10.1016/j.thromres.2018.08.002
Insulin-like Growth Factor-I Receptor and Thyroid-Associated Ophthalmopathy.
Endocrine reviews
Thyroid-associated ophthalmopathy (TAO) is a complex disease process presumed to emerge from autoimmunity occurring in the thyroid gland, most frequently in Graves disease (GD). It is disfiguring and potentially blinding, culminating in orbital tissue remodeling and disruption of function of structures adjacent to the eye. There are currently no medical therapies proven capable of altering the clinical outcome of TAO in randomized, placebo-controlled multicenter trials. The orbital fibroblast represents the central target for immune reactivity. Recent identification of fibroblasts that putatively originate in the bone marrow as monocyte progenitors provides a plausible explanation for why antigens, the expressions of which were once considered restricted to the thyroid, are detected in the TAO orbit. These cells, known as fibrocytes, express relatively high levels of functional TSH receptor (TSHR) through which they can be activated by TSH and the GD-specific pathogenic antibodies that underpin thyroid overactivity. Fibrocytes also express insulin-like growth factor I receptor (IGF-IR) with which TSHR forms a physical and functional signaling complex. Notably, inhibition of IGF-IR activity results in the attenuation of signaling initiated at either receptor. Some studies suggest that IGF-IR-activating antibodies are generated in GD, whereas others refute this concept. These observations served as the rationale for implementing a recently completed therapeutic trial of teprotumumab, a monoclonal inhibitory antibody targeting IGF-IR in TAO. Results of that trial in active, moderate to severe disease revealed dramatic and rapid reductions in disease activity and severity. The targeting of IGF-IR with specific biologic agents may represent a paradigm shift in the therapy of TAO.
10.1210/er.2018-00066
Methodological approaches to analyzing IVF data with multiple cycles.
Human reproduction (Oxford, England)
STUDY QUESTION:Which methodological approaches are most appropriate for analyzing IVF data with multiple cycles in the context of a binary outcome? SUMMARY ANSWER:Both mixed effect models and generalized estimating equation (GEE) modeling approaches can account for multiple IVF cycles and may reduce bias over first-cycle only approaches, but CIs were narrowest with cluster-weighted generalized estimating equation models (CWGEE). WHAT IS KNOWN ALREADY:There is a lack of consensus among investigators regarding how to best incorporate data from multiple cycles and whether to present odds or risks in the analysis of IVF data. Failure to account for correlated outcomes within individuals and informative cluster size may lead to invalid CIs and biased estimates. STUDY DESIGN, SIZE, DURATION:The Environment and Reproductive Health (EARTH) Study is an ongoing prospective cohort study of subfertile couples conducted at an academic medical center. This cohort was established in 2004 and follows couples seeking treatment for infertility throughout the course of their treatment and pregnancy. PARTICIPANTS/MATERIALS, SETTING, METHODS:Women aged 18-46 years enrolled in the EARTH Study from 2004 to 2017 who initiated at least one IVF cycle were eligible. Cycle initiation was defined as beginning ovulation induction with the intent to progress through an IVF or ICSI cycle. This analysis included 442 women undergoing 642 cycles who met the study inclusion criteria. We compared the results and interpretations of log-binomial and logistic models restricting to the first cycle, as well as mixed effects models, unweighted GEE models, and CWGEE models including all cycles. This analysis was conducted for two distinct exposures: maternal age at cycle initiation, and maternal preconception urinary concentrations of di(2-ethylhexyl) phthalate (DEHP) metabolites (previously reported to be associated with a decreased probability of live birth). MAIN RESULTS AND THE ROLE OF CHANCE:In general, the CIs were widest for mixed effects models and narrowest for CWGEE models. Further, in models evaluating the sum of urinary concentrations of DEHP metabolites (∑DEHP, available for 91% of women), the point estimates were surprisingly different between the first-cycle and multiple-cycle models. We observed significant associations between maternal age and live birth in all models. However, we observed no associations between ∑DEHP and live birth. LIMITATIONS, REASONS FOR CAUTION:This analysis was limited to an example dataset in which the true effect of any exposure is unknown. While this allows us to observe model performance in the context of real data, future analyses should be conducted within simulated datasets under various assumptions to further evaluate the appropriateness of each approach. In addition, we did not address differential loss to follow-up in our statistical approaches. WIDER IMPLICATIONS OF THE FINDINGS:The use of CWGEE models should be more widely considered in the analysis of IVF data with multiple cycles per woman. The CWGEE approach is computationally simple, addresses non-ignorable (informative) cluster size, and is robust against mis-specification of the underlying covariance structure. Among the methods compared in this analysis, CWGEE models generally yielded the narrowest CIs, possibly indicating the most precise estimates. We also stress the importance of estimating risks rather than odds in the analysis of IVF data. STUDY FUNDING/COMPETING INTEREST(S):The project was funded by Grants (R01ES022955, R01ES009718, and P30ES000002) from the National Institutes of Health. None of the authors has any conflicts of interest to declare.
10.1093/humrep/dey374
Noninvasive central systolic blood pressure, not peripheral systolic blood pressure, independently predicts the progression of carotid intima-media thickness in a Chinese community-based population.
Sun Pengfei,Yang Ying,Cheng Guanliang,Fan Fangfang,Qi Litong,Gao Lan,Han Xiaoning,Jia Jia,Huo Yong,Zhang Yan
Hypertension research : official journal of the Japanese Society of Hypertension
This study aimed to investigate the predictive values of central systolic blood pressure (cSBP) and peripheral systolic blood pressure (pSBP) for the progression of carotid intima-media thickness (cIMT). A total of 953 Chinese participants from an atherosclerosis cohort with complete information, including baseline cSBP, questionnaire information, biochemical examination, baseline, and follow-up carotid ultrasonography quantitative data, were included in this study. A multilinear regression model, adjusted for possible covariates, was used to investigate the predictive values of cSBP and pSBP for rate of cIMT change. The average age of all participants was (52.11 ± 4.74 years). The baseline levels of cSBP, pSBP, max cIMT, and mean cIMT were (132.55 ± 18.18)mmHg, (130.76 ± 15.40)mmHg, (813.52 ± 118.49)µm and (681.11 ± 99.90)µm, respectively Those with hypertension, diabetes and dyslipidemia accounted for 40.71% (388), 18.05% (172), and 70.41% (671), respectively. After 2.3 years of follow-up, the average rates of max and mean cIMT change were 8.70 (-0.49-19.43)% and 2.59 (-4.72-10.81)%, respectively. Per standard deviation increase of cSBP, but not pSBP, was associated with increases of max (for cSBP, β 1.07, 95%CI 0.18-1.96, p = 0.018; for pSBP, β 0.48, 95%CI -0.45-1.41, p = 0.315) and mean (for cSBP, β 0.84%, 95%CI 0.10-1.58, p = 0.027; for pSBP, β 0.59%, 95%CI -0.18-1.37, p = 0.135) cIMT change rate after adjusting for possible covariates. In conclusion, cSBP, but not pSBP, is independently associated with cIMT progression in our community-based Chinese population. cSBP should be considered for the purpose of CVD primary prevention.
10.1038/s41440-018-0175-5
Randomized Delayed-Start Trial of Levodopa in Parkinson's Disease.
Verschuur Constant V M,Suwijn Sven R,Boel Judith A,Post Bart,Bloem Bas R,van Hilten Johannes J,van Laar Teus,Tissingh Gerrit,Munts Alexander G,Deuschl Guenther,Lang Anthony E,Dijkgraaf Marcel G W,de Haan Rob J,de Bie Rob M A,
The New England journal of medicine
BACKGROUND:Levodopa is the main treatment for symptoms of Parkinson's disease. Determining whether levodopa also has a disease-modifying effect could provide guidance as to when in the course of the disease the treatment with this drug should be initiated. METHODS:In a multicenter, double-blind, placebo-controlled, delayed-start trial, we randomly assigned patients with early Parkinson's disease to receive levodopa (100 mg three times per day) in combination with carbidopa (25 mg three times per day) for 80 weeks (early-start group) or placebo for 40 weeks followed by levodopa in combination with carbidopa for 40 weeks (delayed-start group). The primary outcome was the between-group difference in the mean change from baseline to week 80 in the total score on the Unified Parkinson's Disease Rating Scale (UPDRS; scores range from 0 to 176, with higher scores signifying more severe disease). Secondary analyses included the progression of symptoms, as measured by the UPDRS score, between weeks 4 and 40 and the noninferiority of early initiation of treatment to delayed initiation between weeks 44 and 80, with a noninferiority margin of 0.055 points per week. RESULTS:A total of 445 patients were randomly assigned: 222 to the early-start group and 223 to the delayed-start group. The mean (±SD) UPDRS score at baseline was 28.1±11.4 points in the early-start group and 29.3±12.1 points in the delayed-start group. The change in UPDRS score from baseline to week 80 was -1.0±13.1 points and -2.0±13.0 points, respectively (difference, 1.0 point; 95% confidence interval [CI], -1.5 to 3.5; P=0.44); this finding of no significant between-group difference at week 80 implies that levodopa had no disease-modifying effect. Between weeks 4 and 40, the rate of progression of symptoms, as measured in UPDRS points per week, was 0.04±0.23 in the early-start group and 0.06±0.34 in the delayed-start group (difference, -0.02; 95% CI, -0.07 to 0.03). The corresponding rates between weeks 44 and 80 were 0.10±0.25 and 0.03±0.28 (difference, 0.07; two-sided 90% CI, 0.03 to 0.10); the difference in the rate of progression between weeks 44 and 80 did not meet the criterion for noninferiority of early receipt of levodopa to delayed receipt. The rates of dyskinesia and levodopa-related fluctuations in motor response did not differ significantly between the two groups. CONCLUSIONS:Among patients with early Parkinson's disease who were evaluated over the course of 80 weeks, treatment with levodopa in combination with carbidopa had no disease-modifying effect. (Funded by the Netherlands Organization for Health Research and Development and others; LEAP Current Controlled Trials number, ISRCTN30518857 .).
10.1056/NEJMoa1809983
A Randomized Trial of Endometrial Scratching before In Vitro Fertilization.
Lensen Sarah,Osavlyuk Diana,Armstrong Sarah,Stadelmann Caroline,Hennes Aurélie,Napier Emma,Wilkinson Jack,Sadler Lynn,Gupta Devashana,Strandell Annika,Bergh Christina,Vigneswaran Kugajeevan,Teh Wan T,Hamoda Haitham,Webber Lisa,Wakeman Sarah A,Searle Leigh,Bhide Priya,McDowell Simon,Peeraer Karen,Khalaf Yacoub,Farquhar Cynthia
The New England journal of medicine
BACKGROUND:Endometrial scratching (with the use of a pipelle biopsy) is a technique proposed to facilitate embryo implantation and increase the probability of pregnancy in women undergoing in vitro fertilization (IVF). METHODS:We conducted a pragmatic, multicenter, open-label, randomized, controlled trial. Eligible women were undergoing IVF (fresh-embryo or frozen-embryo transfer), with no recent exposure to disruptive intrauterine instrumentation (e.g., hysteroscopy). Participants were randomly assigned in a 1:1 ratio to either endometrial scratching (by pipelle biopsy between day 3 of the cycle preceding the embryo-transfer cycle and day 3 of the embryo-transfer cycle) or no intervention. The primary outcome was live birth. RESULTS:A total of 1364 women underwent randomization. The frequency of live birth was 180 of 690 women (26.1%) in the endometrial-scratch group and 176 of 674 women (26.1%) in the control group (adjusted odds ratio, 1.00; 95% confidence interval, 0.78 to 1.27). There were no significant between-group differences in the rates of ongoing pregnancy, clinical pregnancy, multiple pregnancy, ectopic pregnancy, or miscarriage. The median score for pain from endometrial scratching (on a scale of 0 to 10, with higher scores indicating worse pain) was 3.5 (interquartile range, 1.9 to 6.0). CONCLUSIONS:Endometrial scratching did not result in a higher rate of live birth than no intervention among women undergoing IVF. (Funded by the University of Auckland and others; PIP Australian New Zealand Clinical Trials Registry number, ACTRN12614000626662 .).
10.1056/NEJMoa1808737
Decreased total iron binding capacity upon intensive care unit admission predicts red blood cell transfusion in critically ill patients.
Imaeda Taro,Nakada Taka-Aki,Abe Ryuzo,Oda Shigeto
PloS one
INTRODUCTION:Red blood cell (RBC) transfusion is associated with poor clinical outcome in critically ill patients. We investigated the predictive value of biomarkers on intensive care units (ICU) admission for RBC transfusion within 28 days. METHODS:Critically ill patients (n = 175) who admitted to our ICU with organ dysfunction and an expected stay of ≥ 48 hours, without hemorrhage, were prospectively studied (derivation cohort, n = 121; validation cohort, n = 54). Serum levels of 12 biomarkers (hemoglobin, creatinine, albumin, interleukin-6 [IL-6], erythropoietin, Fe, total iron binding capacity [TIBC], transferrin, ferritin, transferrin saturation, folate, and vitamin B12) were measured upon ICU admission, days 7, 14, 21 and 28. RESULTS:Among the 12 biomarkers measured upon ICU admission, levels of hemoglobin, albumin, IL-6, TIBC, transferrin and ferritin were statistically different between transfusion and non-transfusion group. Of 6 biomarkers, TIBC upon ICU admission had the highest area under the curve value (0.835 [95% confidence interval] = 0.765-0.906) for predicting RBC transfusion (cut-off value = 234.5 μg/dL; sensitivity = 0.906, specificity = 0.632). This result was confirmed in validation cohort, whose sensitivity and specificity were 0.888 and 0.694, respectively. Measurement of these biomarkers every seven days revealed that albumin, TIBC and transferrin were statistically different between groups throughout hospitalization until 28 days. In validation cohort, patients in the transfusion group had significantly higher serum hepcidin levels than those in the non-transfusion group (P = 0.004). In addition, joint analysis across derivation and validation cohorts revealed that the serum IL-6 levels were higher in the transfusion group (P = 0.0014). CONCLUSION:Decreased TIBC upon ICU admission has high predictive value for RBC transfusion unrelated to hemorrhage within 28 days.
10.1371/journal.pone.0210067
Long-term effect of thymectomy plus prednisone versus prednisone alone in patients with non-thymomatous myasthenia gravis: 2-year extension of the MGTX randomised trial.
The Lancet. Neurology
BACKGROUND:The Thymectomy Trial in Non-Thymomatous Myasthenia Gravis Patients Receiving Prednisone (MGTX) showed that thymectomy combined with prednisone was superior to prednisone alone in improving clinical status as measured by the Quantitative Myasthenia Gravis (QMG) score in patients with generalised non-thymomatous myasthenia gravis at 3 years. We investigated the long-term effects of thymectomy up to 5 years on clinical status, medication requirements, and adverse events. METHODS:We did a rater-blinded 2-year extension study at 36 centres in 15 countries for all patients who completed the randomised controlled MGTX and were willing to participate. MGTX patients were aged 18 to 65 years at enrolment, had generalised non-thymomatous myasthenia gravis of less than 5 years' duration, had acetylcholine receptor antibody titres of 1·00 nmol/L or higher (or concentrations of 0·50-0·99 nmol/L if diagnosis was confirmed by positive edrophonium or abnormal repetitive nerve stimulation, or abnormal single fibre electromyography), had Myasthenia Gravis Foundation of America Clinical Classification Class II-IV disease, and were on optimal anticholinesterase therapy with or without oral corticosteroids. In MGTX, patients were randomly assigned (1:1) to either thymectomy plus prednisone or prednisone alone. All patients in both groups received oral prednisone at doses titrated up to 100 mg on alternate days until they achieved minimal manifestation status. The primary endpoints of the extension phase were the time-weighted means of the QMG score and alternate-day prednisone dose from month 0 to month 60. Analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00294658. It is closed to new participants, with follow-up completed. FINDINGS:Of the 111 patients who completed the 3-year MGTX, 68 (61%) entered the extension study between Sept 1, 2009, and Aug 26, 2015 (33 in the prednisone alone group and 35 in the prednisone plus thymectomy group). 50 (74%) patients completed the 60-month assessment, 24 in the prednisone alone group and 26 in the prednisone plus thymectomy group. At 5 years, patients in the thymectomy plus prednisone group had significantly lower time-weighted mean QMG scores (5·47 [SD 3·87] vs 9·34 [5·08]; p=0·0007) and mean alternate-day prednisone doses (24 mg [SD 21] vs 48 mg [29]; p=0·0002) than did those in the prednisone alone group. 14 (42%) of 33 patients in the prednisone group, and 12 (34%) of 35 in the thymectomy plus prednisone group, had at least one adverse event by month 60. No treatment-related deaths were reported during the extension phase. INTERPRETATION:At 5 years, thymectomy plus prednisone continues to confer benefits in patients with generalised non-thymomatous myasthenia gravis compared with prednisone alone. Although caution is appropriate when generalising our findings because of the small sample size of our study, they nevertheless provide further support for the benefits of thymectomy in patients with generalised non-thymomatous myasthenia gravis. FUNDING:National Institutes of Health, National Institute of Neurological Disorders and Stroke.
10.1016/S1474-4422(18)30392-2
Patient Safety Outcomes under Flexible and Standard Resident Duty-Hour Rules.
Silber Jeffrey H,Bellini Lisa M,Shea Judy A,Desai Sanjay V,Dinges David F,Basner Mathias,Even-Shoshan Orit,Hill Alexander S,Hochman Lauren L,Katz Joel T,Ross Richard N,Shade David M,Small Dylan S,Sternberg Alice L,Tonascia James,Volpp Kevin G,Asch David A,
The New England journal of medicine
BACKGROUND:Concern persists that extended shifts in medical residency programs may adversely affect patient safety. METHODS:We conducted a cluster-randomized noninferiority trial in 63 internal-medicine residency programs during the 2015-2016 academic year. Programs underwent randomization to a group with standard duty hours, as adopted by the Accreditation Council for Graduate Medical Education (ACGME) in July 2011, or to a group with more flexible duty-hour rules that did not specify limits on shift length or mandatory time off between shifts. The primary outcome for each program was the change in unadjusted 30-day mortality from the pretrial year to the trial year, as ascertained from Medicare claims. We hypothesized that the change in 30-day mortality in the flexible programs would not be worse than the change in the standard programs (difference-in-difference analysis) by more than 1 percentage point (noninferiority margin). Secondary outcomes were changes in five other patient safety measures and risk-adjusted outcomes for all measures. RESULTS:The change in 30-day mortality (primary outcome) among the patients in the flexible programs (12.5% in the trial year vs. 12.6% in the pretrial year) was noninferior to that in the standard programs (12.2% in the trial year vs. 12.7% in the pretrial year). The test for noninferiority was significant (P = 0.03), with an estimate of the upper limit of the one-sided 95% confidence interval (0.93%) for a between-group difference in the change in mortality that was less than the prespecified noninferiority margin of 1 percentage point. Differences in changes between the flexible programs and the standard programs in the unadjusted rate of readmission at 7 days, patient safety indicators, and Medicare payments were also below 1 percentage point; the noninferiority criterion was not met for 30-day readmissions or prolonged length of hospital stay. Risk-adjusted measures generally showed similar findings. CONCLUSIONS:Allowing program directors flexibility in adjusting duty-hour schedules for trainees did not adversely affect 30-day mortality or several other measured outcomes of patient safety. (Funded by the National Heart, Lung, and Blood Institute and Accreditation Council for Graduate Medical Education; iCOMPARE ClinicalTrials.gov number, NCT02274818.).
10.1056/NEJMoa1810642
Pregnancy-Adapted YEARS Algorithm for Diagnosis of Suspected Pulmonary Embolism.
van der Pol Liselotte M,Tromeur Cecile,Bistervels Ingrid M,Ni Ainle Fionnuala,van Bemmel Thomas,Bertoletti Laurent,Couturaud Francis,van Dooren Yordi P A,Elias Antoine,Faber Laura M,Hofstee Herman M A,van der Hulle Tom,Kruip Marieke J H A,Maignan Maxime,Mairuhu Albert T A,Middeldorp Saskia,Nijkeuter Mathilde,Roy Pierre-Marie,Sanchez Olivier,Schmidt Jeannot,Ten Wolde Marije,Klok Frederikus A,Huisman Menno V,
The New England journal of medicine
BACKGROUND:Pulmonary embolism is one of the leading causes of maternal death in the Western world. Because of the low specificity and sensitivity of the d-dimer test, all pregnant women with suspected pulmonary embolism undergo computed tomographic (CT) pulmonary angiography or ventilation-perfusion scanning, both of which involve radiation exposure to the mother and fetus. Whether a pregnancy-adapted algorithm could be used to safely avoid diagnostic imaging in pregnant women with suspected pulmonary embolism is unknown. METHODS:In a prospective study involving pregnant women with suspected pulmonary embolism, we assessed three criteria from the YEARS algorithm (clinical signs of deep-vein thrombosis, hemoptysis, and pulmonary embolism as the most likely diagnosis) and measured the d-dimer level. Pulmonary embolism was ruled out if none of the three criteria were met and the d-dimer level was less than 1000 ng per milliliter or if one or more of the three criteria were met and the d-dimer level was less than 500 ng per milliliter. Adaptation of the YEARS algorithm for pregnant women involved compression ultrasonography for women with symptoms of deep-vein thrombosis; if the results were positive (i.e., a clot was present), CT pulmonary angiography was not performed. All patients in whom pulmonary embolism had not been ruled out underwent CT pulmonary angiography. The primary outcome was the incidence of venous thromboembolism at 3 months. The secondary outcome was the proportion of patients in whom CT pulmonary angiography was not indicated to safely rule out pulmonary embolism. RESULTS:A total of 510 women were screened, of whom 12 (2.4%) were excluded. Pulmonary embolism was diagnosed in 20 patients (4.0%) at baseline. During follow-up, popliteal deep-vein thrombosis was diagnosed in 1 patient (0.21%; 95% confidence interval [CI], 0.04 to 1.2); no patient had pulmonary embolism. CT pulmonary angiography was not indicated, and thus was avoided, in 195 patients (39%; 95% CI, 35 to 44). The efficiency of the algorithm was highest during the first trimester of pregnancy and lowest during the third trimester; CT pulmonary angiography was avoided in 65% of patients who began the study in the first trimester and in 32% who began the study in the third trimester. CONCLUSIONS:Pulmonary embolism was safely ruled out by the pregnancy-adapted YEARS diagnostic algorithm across all trimesters of pregnancy. CT pulmonary angiography was avoided in 32 to 65% of patients. (Funded by Leiden University Medical Center and 17 other participating hospitals; Artemis Netherlands Trial Register number, NL5726.).
10.1056/NEJMoa1813865
Cervical screening and risk of adenosquamous and rare histological types of invasive cervical carcinoma: population based nested case-control study.
Lei Jiayao,Andrae Bengt,Ploner Alexander,Lagheden Camilla,Eklund Carina,Nordqvist Kleppe Sara,Wang Jiangrong,Fang Fang,Dillner Joakim,Elfström K Miriam,Sparén Pär
BMJ (Clinical research ed.)
OBJECTIVES:To examine the association of cervical cytology screening with the risk of adenosquamous cell carcinoma (ASC) and rare histological types of invasive cervical carcinoma (RICC), using comprehensive registry data, and to assess tumour human papillomavirus status of ASC and RICC. DESIGN:Nationwide, population based, nested case-control study. SETTING:Sweden. PARTICIPANTS:All cases of invasive cervical carcinoma in Sweden during 2002-11 (4254 confirmed cases after clinical and histopathological review). 338 cases were neither squamous cell carcinoma nor adenocarcinoma, including 164 cases of ASC and 174 cases of RICC (glassy cell carcinoma, clear cell carcinoma, small cell carcinoma, neuroendocrine cell carcinoma, large cell carcinoma, and undifferentiated carcinoma). 30 birth year matched controls from the general Swedish population were matched to each case by applying incidence density sampling. MAIN OUTCOME MEASURES:Conditional logistic regression was used to calculate odds ratios, interpreted as incidence rate ratios, for risk of ASC and RICC in relation to screening status and screening history, adjusted for education. Human papillomavirus distribution of ASC and RICC was based on available archival tumour tissues from most Swedish pathology biobanks. RESULTS:Women with two screening tests in the previous two recommended screening intervals had a lower risk of ASC (incidence rate ratio 0.22, 95% confidence interval 0.14 to 0.34) and RICC (0.34, 0.21 to 0.55), compared with women without any test. High risk human papillomavirus was detected in 148/211 (70%) cases with valid human papillomavirus results from tumour tissues. The risk reduction among women with tumours that were positive (incidence rate ratio 0.28, 0.18 to 0.46) and negative (0.27, 0.13 to 0.59) for high risk human papillomavirus was similar, compared with women who did not attend any test. CONCLUSIONS:Cervical screening is associated with reduced risk of ASC and RICC, and most ASC and RICC are positive for high risk human papillomavirus. This evidence provides a benchmark for evaluating future cervical screening strategies.
10.1136/bmj.l1207
Models to predict outcomes after primary debulking surgery: Independent validation of models to predict suboptimal cytoreduction and gross residual disease.
Kumar Amanika,Sheedy Shannon,Kim Bohyun,Suidan Rudy,Sarasohn Debra M,Nikolovski Ines,Lakhman Yulia,McGree Michaela E,Weaver Amy L,Chi Dennis,Cliby William A
Gynecologic oncology
OBJECTIVE:Treatment planning requires accurate estimation of surgical complexity (SC) and residual disease (RD) at primary debulking surgery (PDS) for advanced ovarian cancer (OC). We sought to independently validate two published computed tomography (CT) prediction models. METHODS:We included stage IIIC/IV OC patients who underwent PDS from 2003 to 2011. Two prediction models which included imaging and clinical variables to predict RD > 1 and any gross RD, respectively, were applied to our cohort. Two radiologists scored CTs. Discrimination was estimated using the c-index and calibration were assessed by comparing the observed and predicted estimates. RESULTS:The validation cohort consisted of 276 patients; median age of the cohort was 64 years old and majority had serous histology. The validation and model development cohorts were similar in terms of baseline characteristics, however the RD rates differed between cohorts (9.4% vs 25.4% had RD >1 cm; 50.7% vs. 66.6% had gross RD). Model 1, the model to predict RD >1 cm, did not validate well. The c-index of 0.653 for the validation cohort was lower than reported in the development cohort (0.758) and the model over-predicted the proportion with RD >1 cm. The second model to predict gross RD had excellent discrimination with a c-index of 0.762. CONCLUSIONS:We are able to validate a CT model to predict presence of gross RD in an independent center; the separate model to predict RD >1 cm did not validate. Application of the model to predict gross RD can help with clinical decision making in advanced ovarian cancer.
10.1016/j.ygyno.2019.04.011
Sensitivity and Specificity of Smartphone-Based Retinal Imaging for Diabetic Retinopathy: A Comparative Study.
Sengupta Sabyasachi,Sindal Manavi D,Baskaran Prabu,Pan Utsab,Venkatesh Rengaraj
Ophthalmology. Retina
PURPOSE:To determine the sensitivity and specificity of a smartphone-based fundus camera, the Remidio Fundus on Phone (FOP; Remidio Innovative Solutions Pvt. Ltd., Bengaluru, India) in detecting diabetic retinopathy (DR) compared with a conventional tabletop fundus camera and clinical examination. DESIGN:Cross-sectional, single-site, instrument validation study. PARTICIPANTS:Consecutive patients with diabetes who had no DR (n = 55 eyes), mild to moderate nonproliferative diabetic retinopathy (NPDR; n = 70 eyes), severe NPDR (n = 46 eyes), proliferative diabetic retinopathy (PDR; n = 62 eyes), and diabetic macular edema (DME; n = 44 eyes). METHODS:All participants underwent a dilated examination to determine the grade of DR. Then all participants had mydriatic 45° fundus photographs obtained from three fields of view with the Remidio FOP and a Topcon tabletop fundus camera (Topcon Medical Systems, Inc., Oakland, NJ). Two masked retina specialists graded images for DR and DME, using National Health Service guidelines as well as for image quality using predefined criteria. MAIN OUTCOME MEASURE:Sensitivity and specificity of the Remidio FOP for the detection of any DR compared to clinical examination. RESULTS:One hundred thirty-five subjects (233 eyes) were recruited for the study. Compared with the reference clinical examination, using images from the Remidio FOP, graders 1 and 2 reported a sensitivity of 93.1% (95% confidence interval [CI] = 88.3-96.4) and 94.3% (95% CI = 89.7-97.2) and a specificity of 89.1% (95% CI = 68.2-92.2) and 94.5% (95% CI = 84.9-98.9), respectively, in identifying any DR (κ = 0.55; 95% CI = 0.50-0.57). With images from the Topcon camera, graders reported similar sensitivities and specificities with marginally better agreement (κ = 0.68; 95% CI = 0.67-0.73). The sensitivity of detecting DR gradually increased from R1 to R3 disease using both cameras. Both graders classified significantly fewer images as "ungradable" (2.6%-4.3% for Topcon vs. 1.7%-2.1% for Remidio FOP) and more images as excellent from the Remidio FOP (59%-74%) than the Topcon device (52%-61%). CONCLUSIONS:The Remidio FOP device was found to have high sensitivity and specificity for the detection of any grade of DR with good agreement between graders. The rate of ungradable images was acceptably low and image quality was marginally better with the Remidio FOP.
10.1016/j.oret.2018.09.016
Changes in mammographic density over time and the risk of breast cancer: An observational cohort study.
Román Marta,Sala Maria,Baré Marisa,Posso Margarita,Vidal Carmen,Louro Javier,Sánchez Mar,Peñalva Lupe,Castells Xavier,
Breast (Edinburgh, Scotland)
BACKGROUND:The effect of changes in mammographic density over time on the risk of breast cancer remains inconclusive. METHODS:We used information from four centres of the Breast Cancer Screening Program in Spain in the period 1996-2015. We analysed individual level data from 117,388 women first screened age 50-54, with at least two screening examinations. Breast density was determined using the BI-RADS classification (A to D in increasing order) at earliest and latest screening examination. Adjusted Poisson regression models were used to estimate the relative risk (RR) and 95% confidence intervals (95%CI) of the association between changes in mammographic density and breast cancer risk over time. RESULTS:During an average 5.8 years of follow-up, 1592 (1.36%) women had a breast cancer diagnosis. An increase in density category increased breast cancer risk, and a decrease in density decreased the risk, compared with women who remained in the same BI-RADS category. Women whose density category increased from B to C or B to D had a RR of 1.55 (95%CI = 1.24-1.94) and 2.32 (95%CI = 1.48-3.63), respectively. The RR for women whose density increased from C to D was 1.51 (95%CI = 1.03-2.22). Changes in BI-RADS density were similarly associated with the risk for invasive cancer than for ductal carcinoma in situ. CONCLUSIONS:Although a modest proportion of women changed BI-RADS density category, mammographic density changes modulated the risk of breast cancer and identified women at a differential risk. Using two longitudinal measures of BI-RADS density could help target women for risk-based screening strategies.
10.1016/j.breast.2019.04.007
Research progress in the relationship between type 2 diabetes mellitus and intestinal flora.
Ma Quantao,Li Yaqi,Li Pengfei,Wang Min,Wang Jingkang,Tang Ziyan,Wang Ting,Luo Linglong,Wang Chunguo,Wang Ting,Zhao Baosheng
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
Type 2 diabetes mellitus (T2DM) is a common clinical chronic disease, while its pathogenesis is still inconclusive. Intestinal flora, the largest micro-ecological system in the human body, is involved in, meanwhile has a major impact on the body's material and energy metabolism. Recent studies have shown that in addition to obesity, genetics, and islet dysfunction, the disturbance of intestinal flora may partly give rise to diabetes. In this paper, we summarized the current research on the correlation between T2DM and intestinal flora, and concluded the pathological mechanisms of intestinal flora involved in T2DM. Moreover, the ideas and methods of prevention and treatment of T2DM based on intestinal flora were proposed, providing theoretical basis and literature reference for the treatment of T2DM and its complications based on the regulation of intestinal flora.
10.1016/j.biopha.2019.109138
Paternal preconception folate intake in relation to gestational age at delivery and birthweight of newborns conceived through assisted reproduction.
Martín-Calvo Nerea,Mínguez-Alarcón Lidia,Gaskins Audrey J,Nassan Feiby L,Williams Paige L,Souter Irene,Hauser Russ,Chavarro Jorge E,
Reproductive biomedicine online
RESEARCH QUESTION:Studies in rodents have shown that paternal folate intake prior to conception is associated with pregnancy and offspring outcomes. The aim of this study was to assess whether those associations might apply to humans as well. DESIGN:Between 2007 and 2017, the study prospectively analysed data from 108 couples participating in a preconception cohort of couples undergoing fertility treatment using their own gametes, whose treatment resulted in 113 pregnancies during the course of the study. Paternal and maternal preconception folate intake was assessed using a validated food frequency questionnaire. Linear mixed models were used to assess whether paternal preconception folate intake was associated with gestational age at delivery and gestational age-specific birthweight, while accounting for correlated data and potential confounders. RESULTS:In a multivariable-adjusted model, a 400 μg/day increase in preconception paternal folate intake was associated with a 2.6-day longer gestation (95% confidence interval 0.8-4.3) after adjusting for potential confounders, including maternal folate intake. Similar associations were found for folate from food and supplements. Maternal folate intake was not associated with gestational age at delivery. Neither paternal nor maternal folate intake was associated with gestational-age-specific birthweight. CONCLUSIONS:Higher paternal preconception folate intake was associated with slightly longer gestation among live births achieved through assisted reproduction. The results suggest that preconception exposures of the father may have an impact on the health of his offspring, and therefore that preconception care should shift from a woman-centric to a couple-based approach.
10.1016/j.rbmo.2019.07.005
Predictors of uterine fibroid volume reduction under ulipristal acetate: a prospective MRI study.
Netter Antoine,Pauly Vanessa,Siles Pascale,Pivano Audrey,Vidal Vincent,Agostini Aubert
Reproductive biomedicine online
RESEARCH QUESTION:Can patient and/or uterine fibroid characteristics predict the volume reduction of fibroids under ulipristal acetate (UPA) treatment? DESIGN:This was a monocentric observational prospective cohort study of women with symptomatic fibroids who were willing to undergo surgery after a 3-month treatment of daily 5 mg doses of UPA. Patients underwent magnetic resonance imaging before and after treatment, and the volumes of the three largest fibroids were assessed. The reduction in volume was assessed qualitatively: fibroids decreasing in volume were considered to be 'responsive' to treatment, and fibroids that were stable or increased in volume were considered to be 'non-responsive'. Comparisons were made of patient (age and body mass index) and fibroid (initial volume, number and location) characteristics between fibroids that were responsive and non-responsive to UPA treatment. RESULTS:Fifty-three women were included in the final analysis and 116 fibroids were measured. The initial number and initial volume of the fibroids were statistically associated with the response to UPA treatment (adjusted odds ratio [OR] 0.645, 95% confidence interval [CI] 0.461-0.903, P = 0.0115 for number of fibroids, and adjusted OR 1.447, 95% CI 1.063-1.970, P = 0.0195 for initial volume, with a log-linear relationship). Submucosal fibroids had a higher response rate to treatment (i.e. a decrease in volume) than intramural fibroids (21/25 [84.0%] versus 15/28 [53.6%]; P = 0.0490; adjusted OR 4.478, 95% CI 1.007-19.918). CONCLUSIONS:The location, initial volume and number of fibroids may allow prediction of the outcome of a single 3-month treatment course of daily 5 mg doses of UPA in terms of reduction in volume before surgery.
10.1016/j.rbmo.2019.07.028
Differences in the Composition of Vaginal Microbiota between Women Exhibiting Spleen-Deficiency Syndrome and Women with Damp-Heat Syndrome, Two of the Most Common Syndromes of Vaginitis in Traditional Chinese Medicine.
Evidence-based complementary and alternative medicine : eCAM
Spleen-deficiency syndrome and damp-heat syndrome are the two most common syndromes of vaginitis in traditional Chinese medicine (TCM). Although it is known that the vaginal microbiota is closely associated with vaginitis, present studies have not fully elucidated the relationship between the composition of the vaginal microbiome and type of TCM syndrome because of the limitations in the present reductionist approaches. Samples of vaginal secretions were collected from patients with bacterial vaginitis and healthy subjects with spleen-deficiency syndrome and damp-heat syndrome, in order to analyze the constitution of the vaginal microflora using 16S rRNA sequencing methods that encompass taxonomic units, alpha diversity rarefaction curves, and principal component analyses. This prospective study indicated that there was a statistically significant difference in the composition of the vaginal microbiome between patients with spleen-deficiency syndrome and patients with damp-heat syndrome. was the dominant microbiota in patients with spleen-deficiency syndrome. This can serve as a biomarker for differentiating spleen-deficiency syndrome and damp-heat syndrome. In addition, as indicated by the findings on the samples, patients with bacterial vaginitis of dominant abundance in might be prone to manifest spleen-deficiency syndrome, while patients with bacterial vaginitis of dominant abundance in might be prone to manifest damp-heat syndrome. These present findings can provide a new approach to acquire a scientific understanding of the syndromes of TCM, which in turn would benefit the development of personalized medicine, in terms of ancient medicine and complex biological systems.
10.1155/2019/5456379
Comparison of retrobulbar and periocular injections of lignocaine by computerised tomography.
Ropo A,Nikki P,Ruusuvaara P,Kivisaari L
The British journal of ophthalmology
Ten patients undergoing cataract surgery were given a local anaesthetic with lignocaine solution which was mixed with iohexol contrast medium. The location of the needle and the substance injected was determined by computerised tomography following retrobulbar or periocular anaesthesia. The retrobulbarly inserted needles were within the muscle cone, directed towards the optic foramen. The periocular needles were outside the muscle cone, tangentially along the orbital floor or pointing slightly upwards. After the retrobulbar injection the contrast medium was seen within the cone immediately after the injection and outside the cone as early as 3 minutes after the injection. With the periocular technique, however, diffusion of the anaesthetic in the opposite direction (that is, into the muscle cone) was rapid. The contrast medium was identified inside the muscle cone 2 minutes after the injection. Compression with an intraocular pressure reduction device after both of these techniques prevented exophthalmos. It is concluded that retrobulbar-like anaesthesia can also be induced by an appropriate periocular technique.
10.1136/bjo.75.7.417
Graves orbitopathy: correlation of CT and clinical findings.
Nugent R A,Belkin R I,Neigel J M,Rootman J,Robertson W D,Spinelli J,Graeb D A
Radiology
The clinical and high-resolution computed tomographic (CT) findings in 71 patients (142 orbits) with Graves orbitopathy and 20 healthy patients (40 orbits) were retrospectively reviewed. The orbits with orbitopathy were subgrouped at clinical examination into those with (n = 18) and those without (n = 124) optic neuropathy. Mean extraocular muscle diameters and the calculated muscle diameter index were significantly increased in all orbits with ophthalmopathy, particularly in those with optic neuropathy. Graves orbitopathy affected the superior muscle group (63.4%) more than the medial (61.3%) or inferior (57%) recti. The most common pattern of muscle involvement involved all five measured extraocular muscles. Solitary muscle involvement most frequently involved the superior muscle group (6.3%). Significant enlargements of the retrobulbar optic nerve sheath and superior ophthalmic vein were noted only in orbits with optic neuropathy. Anterior displacement of the lacrimal gland at CT correlated with clinical palpability and occurred more frequently in patients with optic neuropathy. Severe apical crowding was the most sensitive indication of optic neuropathy at CT.
10.1148/radiology.177.3.2243967
Clinical criteria for the assessment of disease activity in Graves' ophthalmopathy: a novel approach.
Mourits M P,Koornneef L,Wiersinga W M,Prummel M F,Berghout A,van der Gaag R
The British journal of ophthalmology
Patients with serious inflammatory Graves' ophthalmopathy should be treated with anti-inflammatory drugs or radiotherapy to prevent complications like fibrosis, while those with non-inflammatory ophthalmopathy may be treated by surgery immediately. It is often difficult, however, to distinguish inflammatory from non-inflammatory Graves' disease. We therefore present a simple clinical classification here to differentiate between these two conditions. This classification is based on the classical signs of inflammation--pain, redness, swelling, and impaired function. After two consecutive clinical examinations an 'activity score' can be determined, ranging from 0 to 10 points. In a retrospective study testing the efficacy of this classification we found that patients with an activity score of 3 or more at the beginning of therapy responded well to anti-inflammatory drugs, while those with a lower activity score mostly did not. Comparing the pretreatment activity score with the degree of enlargement of the extraocular muscles on the CT scan, we found a significant correlation between these two parameters: the higher the activity score, the more the enlargement of the muscles. We conclude that this classification facilitates the proper selection of patients for treatment.
10.1136/bjo.73.8.639
Age and gender influence the severity of thyroid-associated ophthalmopathy: a study of 101 patients attending a combined thyroid-eye clinic.
Perros P,Crombie A L,Matthews J N,Kendall-Taylor P
Clinical endocrinology
BACKGROUND:The pathogenesis of thyroid-associated ophthalmopathy is thought to be autoimmune, although environmental and genetic factors are also considered to be important. As the morbidity of thyroid-associated ophthalmopathy is considerable and treatment often unsatisfactory, there a need to identify possible predisposing factors. OBJECTIVE:The study was undertaken in order to ascertain the relationship between age, gender and severity of thyroid-associated ophthalmopathy. PATIENTS:One hundred and one consecutive patients with thyroid-associated ophthalmopathy who presented over a period of 5 years to a combined thyroid-eye clinic. METHODS:Patients were assessed by grading their inflammatory signs and degree of diplopia, and by measurement of exophthalmos, palpebral aperture, differential intraocular pressure, and visual acuity. On the basis of the above an ophthalmopathy index was devised to grade the overall severity of eye disease. RESULTS:The mean age was 49.2 years (SD 13.4), the female-to-male ratio was 4.05, and mean ophthalmopathy index 6.49 (SD 3.3). Optic nerve compression was present in 9.9% of patients. There was a positive relationship between age and ophthalmopathy index (P < 0.001); after correcting for age, males had an average ophthalmopathy index 41% greater than that of females. CONCLUSION:There is an association between severity of thyroid-associated ophthalmopathy and (i) advancing age and (ii) female-to-male ratio, which has not been previously described. Patients over the age of 60 (particularly males) with Graves' disease appear to be at risk of developing severe eye disease.
Orbital measurement in black and white populations.
Barretto R L,Mathog R H
The Laryngoscope
OBJECTIVE:Obtain measurements of globe projection, intercanthal distance (ICD), interpupillary distance (IPD), palpebral fissure width (PFW), and palpebral fissure height (PFH) in a population of presumably normal white and black adults to determine if any significant differences exist between these groups. STUDY DESIGN:Prospective direct measurement of cohorts regarding orbital and globe measurements in a tertiary medical center. METHODS:Measurements of globe projection, ICD, IPD, PFW, and PFH were taken in 61 black adults and directly compared with measures taken from 65 white adults in an outpatient setting. Mean values and ranges were calculated and compared between races and sexes using an unpaired t test. RESULTS:A significant difference was found between races for globe projection, with black males demonstrating a mean projection of 18.23+/-2.26 mm as compared with 17+/-2.65 mm for white males (P < .025). Black females demonstrated a mean projection of 17.27+/-1.44 mm as compared with 15.98+/-2.22 mm for white females (P < .01). Similar differences were seen for measures of IPD and PFW, with greater mean values for black as compared with white adults. No racial differences existed for ICD or PFH. CONCLUSIONS:These findings suggest that racial differences exist for certain measures of globe and orbital position, i.e., projection, IPD, and PFW. Racial background should be considered when evaluating orbital anatomy.
Association of thyrotrophin receptor antibodies with the clinical features of Graves' ophthalmopathy.
Gerding M N,van der Meer J W,Broenink M,Bakker O,Wiersinga W M,Prummel M F
Clinical endocrinology
OBJECTIVE:Graves' ophthalmopathy (GO) and Graves' hyperthyroidism are closely associated diseases and thought to be caused by the same autoimmune process. An obvious explanation for this would be the presence of autoantibodies reacting with an autoantigen present in the orbit and the thyroid gland. The TSH-Receptor (TSH-R) antibodies are a likely candidate, because they cause Graves' hyperthyroidism and the TSH-R appears to be present also in orbital tissues. If TSH-R antibodies are responsible for the ophthalmopathy one would expect their titres to correlate with clinical characteristics of the eye disease. The aim of the present study is to see whether TSH-R antibodies are related to the activity and severity of the thyroid-associated ophthalmopathy. DESIGN AND PATIENTS:TSH-R antibody levels were measured as TBII (TRAK assay), and TSI (cAMP response of a TSH-R transfected cell line) in serum of 63 patients with untreated moderately severe GO, accompanying Graves' thyroid disease; all patients had been euthyroid for > 2 months. RESULTS:TBII and TSI titres were strongly related to each other. TBII or TSI titres did not correlate with thyroidal or orbital disease duration, nor with TPO antibody levels. In contrast, we found a striking and highly significant correlation between the Clinical Activity Score (CAS) of the eye disease, and both TBII (r = 0.54; P < 0.0001) and TSI (r = 0.50; P < 0.0001). In addition, a weaker but significant relation was found between proptosis (in mm) and TBII (r = 0.36; P = 0.004) and TSI (r = 0.49; P = 0.0001). No correlation was found with eye muscle motility. CONCLUSION:TSH-R antibody levels correlate directly with clinical features of Graves' ophthalmopathy. The results support the hypothesis of a pathogenetic role of TSH-R antibodies and the TSH-R in the orbit of Graves' ophthalmopathy patients.
Thyroid eye disease.
Scott I U,Siatkowski M R
Seminars in ophthalmology
Thyroid eye disease is the most common cause of unilateral and bilateral proptosis in adults. It occurs most frequently in women aged 30 to 50 years. Clinical features include eyelid retraction, periorbital edema, conjunctival injection and chemosis, proptosis, extraocular muscle restriction, exposure keratopathy, and optic nerve compromise. Thyroid eye disease differs from idiopathic orbital myositis in that the latter is characterized by a more acute onset, more severe pain, and a rapid response to systemic corticosteroid therapy. Echography and computed tomography in thyroid eye disease reveal enlarged extraocular muscle bellies with relative sparing of the tendons. Despite evidence of an immune-mediated cause, the precise pathophysiologic mechanisms of thyroid eye disease remain unknown.
10.3109/08820539909056064
Effect of hospitalisation on liver enzymes in healthy subjects.
Narjes H,Nehmiz G
European journal of clinical pharmacology
OBJECTIVES:The aims of the present evaluation were to determine whether the elevations in liver enzymes observed in phase-I trials are more common in subjects being hospitalised than in ambulatory subjects and to assess the relevance of these elevations. We therefore investigated the effect of hospitalisation on liver enzyme levels in subjects of all phase-I trials of sufficient length performed at the two Human Pharmacology Centres of Boehringer Ingelheim, located in Biberach and Ingelheim, Germany, over a 10-year period. METHODS:The evaluation was based on 29 phase-I trials conducted between 1987 and 1996. These trials consisted of at least 4 days of observation of 220 subjects on placebo treatment in 273 trial participations. The mean changes (transformed into reference ranges) in the liver enzymes alkaline phosphatase, gamma glutamyl transpeptidase, aspartate aminotransferase, alanine aminotransferase and the AST/ALT ratio of hospitalised subjects were compared with those of ambulatory subjects. RESULTS:A small but statistically significant increase in the mean of the parameters GGT, AST and ALT during phase-I trials was observed in hospitalised subjects compared with ambulatory subjects. The increases were: 8% of the reference range width for GGT, 8% for AST and 17% for the ALT, although the differences were small in absolute terms. A relevant increase (defined as an increase to above the reference range or by at least 50% of the reference range) was more common in hospitalised subjects. CONCLUSION:Hospitalisation, although it is believed to protect subjects from confounding environmental factors, can itself be associated with increases in liver enzyme levels. The definition of a relevant increase can be used to identify subjects who need further evaluation. The cause of the increase in liver enzyme levels remains unclear.
Using morphologic parameters of extraocular muscles for diagnosis and follow-up of Graves' ophthalmopathy: diameters, areas, or volumes?
Szucs-Farkas Zsolt,Toth Judit,Balazs Erzsebet,Galuska Laszlo,Burman Kenneth D,Karanyi Zsolt,Leovey Andras,Nagy Endre V
AJR. American journal of roentgenology
OBJECTIVE:The objective of this study was to find the most appropriate, accurate, and convenient muscle parameter that can be used as a substitute for volume in monitoring the effectiveness of therapy of patients with Graves' ophthalmopathy. SUBJECTS AND METHODS:The four rectus muscles in 110 orbits (35 patients and 20 control subjects) were evaluated with MR imaging. The diameter at the largest extent of the muscle belly, as well as the long and the short diameters and the cross-sectional areas in a preselected coronal scan, were measured for each muscle and were compared with the corresponding muscle volume measured on contiguous T1-weighted transverse slices. RESULTS:The measured coronal area correlated well with the volume of the superior (r = 0.694, p < 0.0001) and inferior (r = 0.783, p < 0.0001) recti, and the largest transverse diameter showed strong correlation with the volume of the lateral (r = 0.868, p < 0.0001) and medial (r = 0.869, p < 0.0001) recti. For the latter muscle, the coronal area also exhibited a good correlation with the volume (r = 0.838, p < 0.0001). Coronal cross-sectional areas can be well estimated by measuring both the short and long coronal muscle diameters (r values were between 0.914 and 0.966; p < 0.0001). CONCLUSION:In Graves' ophthalmopathy, the volume of three of the rectus muscles can be well estimated by simple measurements on a single coronal slice, and the largest transverse diameter of the lateral rectus is suitable for the same purpose.
10.2214/ajr.179.4.1791005
Clinical signs of orbital wall fractures as a function of anatomic location.
Jank Siegfried,Schuchter Barbara,Emshoff Rüdiger,Strobl Heinrich,Koehler Julius,Nicasi Alessandro,Norer Burghard,Baldissera Ivo
Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics
OBJECTIVE:The objective of this study was to see whether clinical signs of medial orbital wall fractures distinguished these fractures from fractures of the lateral orbital wall and the orbital floor. STUDY DESIGN:The orbital fractures of 424 patients were analyzed. The patients were divided into 2 groups: (1) patients with orbital fractures with a medial orbital wall component and (2) patients with orbital fractures without a medial orbital wall component. RESULTS:Orbital fractures with involvement of the medial orbital wall showed a significantly higher incidence (P =.001) of diplopia and exophthalmos (P =.039) than fractures without involvement of the medial wall. CONCLUSION:Posttraumatic orbital clinical signs are associated with a higher incidence of medial orbital wall component fracture. Apparent lack of involvement of the medial orbital wall should not be an exclusion criterion for a surgical intervention when clinical orbital signs exist.
10.1016/S1079210403003172
Localization of local anesthetic solution by magnetic resonance imaging.
Niemi-Murola Leila,Krootila Kari,Kivisaari Riku,Kangasmäki Aki,Kivisaari Leena,Maunuksela Eeva-Liisa
Ophthalmology
PURPOSE:The aim of this study was to examine the distribution of local anesthetic solution by magnetic resonance imaging (MRI) after combined peribulbar and retrobulbar, superomedial retrobulbar, and sub-Tenon's injection in relation to clinical akinesia. DESIGN:Randomized clinical trial. PARTICIPANTS:Fifteen patients scheduled for cataract surgery, 5 patients in each group. METHODS:Five patients received combined peribulbar and retrobulbar anesthesia, 5 patients received superomedial retrobulbar injection, and 5 patients had sub-Tenon's injection, all with a combination of bupivacaine 0.75%, lidocaine 2%, and hyaluronidase. The MRI scans were performed before the injection and up to 35 minutes after the injection. RESULTS AND CONCLUSIONS:Reliable anesthesia is achieved using a combined peribulbar and retrobulbar block and a relatively great volume of local anesthetic solution, which spreads throughout the orbit, as evidenced by MRI. After superomedial retrobulbar and sub-Tenon's injection, the local anesthetic solution accumulates behind the globe. Sub-Tenon's injection gives good analgesia and slight akinesia with a very small volume. Superomedial retrobulbar injection and combined peribulbar and retrobulbar block provide a similar degree of exophthalmos, which seems to be the result of the volume injected behind the globe.
10.1016/j.ophtha.2003.05.026
Treatment of thyroid associated ophthalmopathy with periocular injections of triamcinolone.
The British journal of ophthalmology
AIM:To evaluate the efficacy of periocular triamcinolone acetonide for the treatment of thyroid associated ophthalmopathy (TAO), and the presence of ocular or systemic adverse effects. METHODS:A multicentre prospective pilot study was performed on patients diagnosed with Graves' ophthalmopathy less than 6 months before entry to the study. Patients were admitted to the study and were randomised into two groups: treatment and control. The treatment group received four doses of 20 mg of triamcinolone acetate 40 mg/ml in a peribulbar injection to the inferolateral orbital quadrant. Both groups were evaluated by measuring the area of binocular vision without diplopia on a Goldmann perimeter and the size of the extraocular muscles on computed tomography (CT) scans. Ophthalmological and systemic examinations were done to rule out ocular and systemic adverse effects. Follow up was 6 months for both groups. RESULTS:50 patients were eligible for the study. 41 patients completed the study. There was an increase in the area of binocular vision without diplopia in the treatment group (Sigma initial: mean 231.1 (SD 99.9) and final absolute change, mean 107.1 (SD 129.0)) compared to the control group (Sigma initial: mean 350.7 (SD 86.5) and final absolute change, mean -4.5 (SD 67.6)). The sizes of the extraocular muscles were reduced in the treatment group (mean (inferior rectus initial values): 1.3 (0.7), final percentage change: -13.2 (25.7), medial rectus initial values: 1.2 (0.6), final percentage change: -8.2 (20.7), superior rectus-levator palpebrae initial values: 1.2 (0.6), final percentage change: -9.5 (29.1), lateral rectus initial values: 1.0 (0.4), final percentage change: -11.5 (20.6)) compared to the control group (inferior rectus initial values: 0.9 (0.3), final percentage change: -4.0 (21.5), medial rectus initial values: 0.9 (0.3), final percentage change: 0.6 (22.4), superior rectus-levator palpebrae initial values: 0.9 (0.3), final percentage change: 12.5 (37.5), lateral rectus initial values: 0.9 (0.4), final percentage change: -0.5 (31.6)). Both measurements (degree of diplopia and muscle thickness) were statistically significant between groups (initial - final). No systemic or ocular adverse effects were found. CONCLUSIONS:Triamcinolone administered as a periocular injection is effective in reducing diplopia and the sizes of extraocular muscles in TAO ophthalmopathy of recent onset. This form of treatment is not associated with systemic or ocular side effects.
10.1136/bjo.2004.046193
Clinical results of anti-inflammatory therapy in Graves' ophthalmopathy and association with thyroidal autoantibodies.
Eckstein Anja K,Plicht Marco,Lax Hildegard,Hirche Herbert,Quadbeck Beate,Mann Klaus,Steuhl Klaus P,Esser Joachim,Morgenthaler Nils G
Clinical endocrinology
OBJECTIVE:Graves' ophthalmopathy (GO) is clinically associated with autoimmune thyroid disease, and autoantibodies to thyroidal antigens, especially to the TSH-receptor (TRAb), might be involved in the disease process. While there is mounting evidence that TRAb are associated with GO at the onset of the disease, so far no studies have looked at the association between thyroidal autoantibodies and the clinical outcome of GO therapy. The aim of this retrospective study was to evaluate whether TSH binding inhibitory immunoglobulins (TBII) and thyroid stimulating antibodies (TSAb) are still associated with the clinical activity and severity of GO after the completion of anti-inflammatory therapy. In addition, we wanted to elucidate whether thyroid peroxidase (TPO) or thyroglobulin (TG) autoantibodies (TPOAb and TGAb) are in any way related to GO. DESIGN PATIENTS AND MEASUREMENTS: Clinical activity score (CAS) and the severity of GO (modified NOSPECS score) were assessed in 108 patients with GO after steroid therapy and, if indicated, orbital irradiation. Patients were grouped according to their clinical presentation and autoantibody levels (TBII, TSAb, TPOAb and TGAb) were measured. After therapy for hyperthyroidism, all patients were clinically euthyroid but showed clear heterogeneity for GO 4-12 months after the end of anti-inflammatory therapy. Fifty-two patients had inactive GO, 41 had moderately active and 15 still had very active (non-responsive) GO. Concerning severity, 27 patients had mild GO, 64 moderately severe and 17 severe GO. RESULTS:TBII titres were still positive in 14 (93%) of 15 patients in the non-responsive group (CAS > 6) compared to 22 (42%) of 52 patients (P < 0.001) with post-therapeutic inactive GO (CAS </= 2). A similar result was seen between TBII levels and the NOSPECS score. The simultaneous presence of TBII and TSAb was associated with significantly higher activity and severity [odds ratios: 4.9 (activity); 9.0 (severity)] than the presence of TBII without measurable TSAb [odds ratios: 2.1 (activity), 2.0 (severity)] in comparison to absence of both antibodies. Only TBII and TSAb, but not TPOAb or TGAb medians, increased statistically significantly with CAS or NOSPECS scores. Both scores were positively associated with TBII (CAS: r = 0.31 P < 0.001; NOSPECS: r = 0.38, P < 0.0001) and, to a lesser degree, with TSAb (CAS: r = 0.27, P < 0.007, and NOSPECS: r = 0.29, P < 0.003). This association was independent of the treatment of hyperthyroidism, although highest levels of TBII were seen after radioiodine treatment. The NOSPECS score was negatively associated with TGAb (r =-0.27, P < 0.01) but not with TPOAb, while both showed no association with the CAS score. CONCLUSIONS:We conclude that the persistence of TBII and TSAb levels in patients with therapy-resistant disease in comparison to patients with inactive disease supports the role of TRAb in the pathogenesis of GO. Furthermore, the fact that, even after anti-inflammatory therapy, TBII and TSAb levels and prevalence still correlate with the severity and activity of GO suggests not only a trigger but also a possible role in the maintenance of the autoimmune process in the orbits.
10.1111/j.1365-2265.2004.02143.x
Mildly elevated liver transaminase levels in the asymptomatic patient.
Giboney Paul T
American family physician
Mild elevations in liver chemistry tests such as alanine transaminase and aspartate transaminase can reveal serious underlying conditions or have transient and benign etiologies. Potential causes of liver transaminase elevations include viral hepatitis, alcohol use, medication use, steatosis or steatohepatitis, and cirrhosis. The history should be thorough, with special attention given to the use of medications, vitamins, herbs, drugs, and alcohol; family history; and any history of blood-product transfusions. Other common health conditions, such as diabetes, heart disease, and thyroid disease, can cause or augment liver transaminase elevations. The recent American Gastroenterological Association guideline regarding the evaluation and management of abnormal liver chemistry tests proposes a practical, algorithmic approach when the history and physical examination do not reveal the cause. In addition to liver chemistries, an initial serologic evaluation includes a prothrombin time; albumin; complete blood count with platelets; hepatitis A, B, and C serologies; and iron studies. Depending on the etiology, management strategies may include cessation of alcohol use, attention to medications, control of diabetes, and modification of lifestyle factors such as obesity. If elevations persist after an appropriate period of observation, further testing may include ultrasonography and other serum studies. In some cases, biopsy may be indicated.
Quantification of cells expressing the thyrotropin receptor in extraocular muscles in thyroid associated orbitopathy.
Boschi A,Daumerie Ch,Spiritus M,Beguin C,Senou M,Yuksel D,Duplicy M,Costagliola S,Ludgate M,Many M C
The British journal of ophthalmology
BACKGROUND/AIM:Thyroid associated orbitopathy (TAO) and Graves' disease (GD) have an autoimmune pathogenesis, possibly related to the thyrotropin receptor (TSHR). The aim of this study was to determine whether TSHR immunoreactivity is correlated with disease severity or serum TSHR antibody (TRAB) levels. METHODS:Orbital tissues from 30 patients with TAO were compared with those of 20 patients with strabismus and four with non-thyroid orbital inflammation. TSHR was detected by immunohistochemistry and TRAB were measured by radioreceptor assay. RESULTS:No TSHR immunoreactivity was detected in the 24 control orbital tissues, whereas in all TAO biopsies elongated fibroblast-like cells, expressing TSHR, were present. These cells were located between the muscle cells, which were separated by oedema in the acute phase but fibrous tissue in the chronic phase of disease. Semi-thin sections showed numerous mast cells present in the chronic phase and in close contact with adipocytes. The number of TSHR immunostained cells was high in early disease, decreased with disease duration, and was positively correlated with TRAB levels at the onset of TAO. CONCLUSION:TSHR immunoreactivity was demonstrated specifically in TAO orbits which highlights the importance of TRAB early in the pathogenesis.
10.1136/bjo.2004.050807
Liver markers and development of the metabolic syndrome: the insulin resistance atherosclerosis study.
Hanley Anthony J G,Williams Ken,Festa Andreas,Wagenknecht Lynne E,D'Agostino Ralph B,Haffner Steven M
Diabetes
Nonalcoholic fatty liver disease (NAFLD) is emerging as a component of the metabolic syndrome, although it is not known whether markers of NAFLD, including elevated concentrations of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALK), predict the development of metabolic syndrome. Our objective was to investigate the associations of elevated AST, ALT, and other liver markers, including C-reactive protein (CRP), with incident National Cholesterol Education Program-defined metabolic syndrome among 633 subjects in the Insulin Resistance Atherosclerosis Study who were free of metabolic syndrome at baseline. Insulin sensitivity (Si) and acute insulin response (AIR) were directly measured from the frequently sampled intravenous glucose tolerance test among African-American, Hispanic, and non-Hispanic white subjects aged 40-69 years. After 5.2 years, 127 individuals had developed metabolic syndrome. In separate logistic regression models adjusting for age, sex, ethnicity, clinic, and alcohol consumption, subjects in the upper quartiles of ALT, ALK, and CRP were at significantly increased risk of incident metabolic syndrome compared with those in the lowest quartile: ALT, odds ratio 2.50 (95% CI 1.38-4.51); ALK, 2.28 (1.24-4.20); and CRP, 1.33 (1.09-1.63). Subjects in the upper quartile of the AST-to-ALT ratio were at significantly reduced metabolic syndrome risk (0.40 [0.22-0.74]). After further adjustment for waist circumference, Si, AIR, and impaired glucose tolerance, the associations of ALT and the AST-to-ALT ratio with incident metabolic syndrome remained significant (ALT, 2.12 [1.10-4.09]; the AST-to-ALT ratio, 0.48 [0.25-0.95]). These associations were not modified by ethnicity or sex, and they remained significant after exclusion of former and heavy drinkers. In conclusion, NAFLD markers ALT and the AST-to-ALT ratio predict metabolic syndrome independently of potential confounding variables, including directly measured Si and AIR.
10.2337/diabetes.54.11.3140
Buckling and hydraulic mechanisms in orbital blowout fractures: fact or fiction?
Ahmad Fateh,Kirkpatrick Niall A,Lyne Jonathan,Urdang Michael,Waterhouse Norman
The Journal of craniofacial surgery
Since the first description of orbital blowout fractures, there has been much confusion as to their etiology. Two principal mechanisms have been proposed to explain their production, the buckling and the hydraulic mechanisms caused, respectively, by trauma to the orbital rim and the globe of the eye. The aim of this study was to evaluate both mechanisms qualitatively and quantitatively. Our protocol used intact cadavers, quantifiable intraocular pressure, variable and quantifiable force, and quantifiable bone strain distribution with strain gauge analysis. One orbit of each cadaver was used to simulate each of the two mechanisms, allowing direct comparison. Fractures produced by the buckling mechanism were limited to the anterior part of the orbital floor, with strain readings reaching up to 3756 microepsilon. Posteriorly, strain did not exceed 221 microepsilon. In contrast, hydraulic-type fractures were much larger, involving anterior and posterior parts of the floor as well as the medial wall of the orbit. Here, strain exceeded 3756 microepsilon in both parts of the floor. Furthermore, we have demonstrated that the average energy required to fracture the orbital floor by the buckling mechanism is 1.54 J, whereas an average energy of 1.22 J is needed to produce this fracture by the hydraulic mechanism. Our results suggest that efforts to establish one or another mechanism as the primary etiology are misplaced. Both mechanisms produce orbital blowout fractures, with different and specific characteristics. We believe this provides the basis for our reclassification of such fractures.
Thyrotropin receptor autoantibodies are independent risk factors for Graves' ophthalmopathy and help to predict severity and outcome of the disease.
Eckstein Anja K,Plicht Marco,Lax Hildegard,Neuhäuser Markus,Mann Klaus,Lederbogen Sebastian,Heckmann Christian,Esser Joachim,Morgenthaler Nils G
The Journal of clinical endocrinology and metabolism
OBJECTIVE:The objective of this study was to examine whether TSH-receptor antibody [TSH binding inhibitory antibodies (TBII)] levels are associated with the severity of Graves' ophthalmopathy (GO) over the entire course of the disease. METHODS AND PATIENTS:A total of 159 patients with GO were followed for 12-24 months. One year after the first symptoms of GO, all patients were classified into mild or severe GO according to their clinical manifestations. TBII were measured every 3 months after onset of GO. Receiver operating characteristic plot analysis was performed to assess the power to discriminate both patient groups by TBII (specificity >90%). RESULTS:TBII levels and prevalence at each time point during follow-up were significantly higher in patients with a severe course of GO compared with patients with a mild course of GO. Prognostic statements on the course of the disease were possible for about half of the GO patients at all time points (except the first). If at first presentation and at consecutive time points TBII levels were less than 5.7, 2.6, 1.5, 1.5, 1.5, and 1.5 IU/liter, the patients had a 2.3- to 15.6-fold higher chance of a mild course. If 5-8 months after GO onset and at consecutive time points TBII levels were above 8.8, 5.1, 4.8, 2.8, and 2.8 IU/liter, the patients had a 8.7- to 31.1-fold higher risk of a severe course. This relationship of TBII to the severity was independent from age and smoking. CONCLUSION:Follow-up measurements of TBII allow, in half of the patients, assessment of the prognosis of GO and, therefore, could be of additional help for the disease management.
10.1210/jc.2005-2813
Influences of age, gender, smoking, and family history on autoimmune thyroid disease phenotype.
Manji N,Carr-Smith J D,Boelaert K,Allahabadia A,Armitage M,Chatterjee V K,Lazarus J H,Pearce S H S,Vaidya B,Gough S C,Franklyn J A
The Journal of clinical endocrinology and metabolism
CONTEXT:Both genetic and environmental factors contribute to susceptibility to Graves' disease (GD) and Hashimoto's thyroiditis (HT), as well as disease manifestations. OBJECTIVE:The objective of the study was to define how endogenous/environmental factors contribute to variation in phenotype. DESIGN/SETTING:This was a multicenter cohort study. PATIENTS/OUTCOME MEASURES: We prospectively collected clinical/biochemical data as part of the protocol for a United Kingdom DNA collection for GD and HT. We investigated, in 2805 Caucasian subjects, whether age at diagnosis, gender, family history (FH), smoking history, and presence of goiter influenced disease manifestations. RESULTS:For 2405 subjects with GD, the presence of goiter was independently associated with disease severity (serum free T4 at diagnosis) (P < 0.001). Free T4 (P < 0.05) and current smoking (P < 0.001) were both independent predictors of the presence of ophthalmopathy. Approximately half of those with GD (47.4% of females, 40.0% of males) and HT (n = 400) (56.4% of females, 51.7% of males) reported a FH of thyroid dysfunction. In GD, a FH of hyperthyroidism in any relative was more frequent than hypothyroidism (30.1 vs. 24.4% in affected females, P < 0.001). In HT, a FH of hypothyroidism was more common than hyperthyroidism (42.1 vs. 22.8% in affected females, P < 0.001). For GD (P < 0.001) and HT (P < 0.05), a FH was more common in maternal than paternal relatives. The reporting of a parent with thyroid dysfunction (hyper or hypo) was associated with lower median age at diagnosis of both GD (mother with hyperthyroidism, P < 0.001) and HT (father with hypothyroidism, P < 0.05). In GD and HT, there was an inverse relationship between the number of relatives with thyroid dysfunction and age at diagnosis (P < 0.01). CONCLUSIONS:Marked associations among age at diagnosis, disease severity, goiter, ophthalmopathy, smoking, and FH provide evidence for interactions between genetic and environmental/endogenous factors; understanding these may allow preventive measures or better tailoring of therapies.
10.1210/jc.2006-1402
The CD40, CTLA-4, thyroglobulin, TSH receptor, and PTPN22 gene quintet and its contribution to thyroid autoimmunity: back to the future.
Jacobson Eric M,Tomer Yaron
Journal of autoimmunity
Autoimmune thyroid diseases (AITD) are common autoimmune diseases, affecting up to 5% of the general population. Thyroid-directed autoimmunity is manifested in two classical autoimmune conditions, Hashimoto's thyroiditis, resulting in hypothyroidism and Graves' disease resulting in hyperthyroidism. Autoimmune thyroid diseases arise due to an interplay between environmental and genetic factors. In the past decade significant progress has been made in our understanding of the genetic contribution to the etiology of AITD. Indeed, several AITD susceptibility genes have been identified. Some of these susceptibility genes are specific to either Graves' disease or Hashimoto's thyroiditis, while others confer susceptibility to both conditions. Both immunoregulatory genes and thyroid specific genes contribute to the pathogenesis of AITD. The time is now ripe to examine the mechanistic basis for the contribution of genetic factors to the etiology of AITD. In this review, we will focus on the contribution of non-MHC II genes.
10.1016/j.jaut.2007.02.006
Patients with severe Graves' ophthalmopathy have a higher risk of relapsing hyperthyroidism and are unlikely to remain in remission.
Eckstein Anja K,Lax Hildegard,Lösch Christian,Glowacka Diana,Plicht Marco,Mann Klaus,Esser Joachim,Morgenthaler Nils G
Clinical endocrinology
OBJECTIVE:To evaluate the relationship between severity of Graves' ophthalmopathy (GO) and relapse/remission rate of associated thyroid disease. PATIENTS AND METHODS:One hundred and fifty-eight patients with Graves' disease (GD) were seen within the first 6-12 months after the onset of GO and were followed for at least 18 months. During treatment, GO was classified as mild (n = 65) or severe course (n = 93) by severity and activity scores. All patients received standard anti-thyroid drug (ATD) treatment for 1 year, and in cases of relapse another cycle of ATD, thyroidectomy or radioiodine therapy. RESULTS:Following ATD treatment, 27 patients (42%) with a mild course of GO went into thyroid disease remission, while only seven (8%) patients with a severe course of GO achieved remission (P < 0.0001). Eventually, 32 patients (49%) with a mild course needed definitive thyroid therapy and the remaining 9% preferred another cycle of ATD. However, among patients with a severe GO course, 84% needed definitive therapy (P < 0.0001) and 8% opted for another course of ATD treatment. The probability of relapse could also be predicted by TBII levels 12 months after initiation of ATD therapy, as 96.8% of patients with TBII levels above 7.5 IU/l relapsed (odds ratio 24.3). CONCLUSION:Patients with severe GO and high TBII are unlikely to go into remission. This allows early decision-making regarding definitive treatment of the thyroid in GD patients with severe GO or very high TBII levels.
10.1111/j.1365-2265.2007.02933.x
Consensus statement of the European group on Graves' orbitopathy (EUGOGO) on management of Graves' orbitopathy.
Bartalena Luigi,Baldeschi Lelio,Dickinson Alison J,Eckstein Anja,Kendall-Taylor Pat,Marcocci Claudio,Mourits Maarten P,Perros Petros,Boboridis Kostas,Boschi Antonella,Currò Nicola,Daumerie Chantal,Kahaly George J,Krassas Gerasimos,Lane Carol M,Lazarus John H,Marinò Michele,Nardi Marco,Neoh Christopher,Orgiazzi Jacques,Pearce Simon,Pinchera Aldo,Pitz Susanne,Salvi Mario,Sivelli Paolo,Stahl Matthias,von Arx Georg,Wiersinga Wilmar M
Thyroid : official journal of the American Thyroid Association
10.1089/thy.2007.0315
Role of medial orbital wall morphologic properties in orbital blow-out fractures.
Song Won Kyung,Lew Helen,Yoon Jin Sook,Oh Min-Jin,Lee Sang Yeul
Investigative ophthalmology & visual science
PURPOSE:This study compares medial orbital wall supporting structures in patients with isolated inferior and medial wall fractures. METHODS:The morphologic properties in all consecutive patients with periocular trauma who underwent orbital computed tomography (CT) scans from January 2004 to March 2006 were reviewed. On CT scans, the size of the fracture, the number of ethmoid air cell septa, and the length and height of the lamina papyracea were measured. RESULTS:In 118 patients without orbital wall fracture, there were no bilateral differences in the measured structures. We took measurements from the opposite site in patients with fractures in whom it was difficult to visualize the structures at the fractured site. Seventy patients with medial wall fractures and 37 with inferior wall fractures showed no differences in sex, side of impact, etiology of the trauma, association with intraocular injuries, fracture size, anterior and posterior height, anteroposterior length, or the area of the lamina papyracea. In contrast, the number of ethmoid air cell septa was significantly lower (3.09+/-0.86 vs. 3.62+/-0.79, P=0.002) and the lamina papyracea area supported per ethmoid air cell septum was significantly higher (137.55+/-40.11 mm(2) vs. 119.64+/-38.14 mm(2), P=0.028) in patients with medial wall fractures than in those with inferior wall fractures. CONCLUSIONS:Patients with fewer ethmoid air cell septa and a larger lamina papyracea area per septum are more likely to develop medial wall fractures than inferior wall fractures.
10.1167/iovs.08-2204
Repeated peribulbar injections of triamcinolone acetonide: a successful and safe treatment for moderate to severe Graves' ophthalmopathy.
Bordaberry Marcela,Marques Daniela L,Pereira-Lima Julio C,Marcon Italo M,Schmid Helena
Acta ophthalmologica
PURPOSE:In this study, we aimed to evaluate the efficacy of peribulbar triamcinolone injections to treat inflammatory signs of Graves' ophthalmopathy (GO) in patients with moderate to severe GO and associated optic neuropathy (ON). METHODS:Twenty-one patients with active GO [clinical activity score (CAS) > or = 4] and systemic thyroid disease under control were enrolled in this prospective pilot study. Peribulbar triamcinolone acetonide was injected in each orbit (42 eyes), in four doses of 20 mg at 2-week intervals. Ophthalmological examination including CAS evaluation, visual field, computerized tomography (CT) scan and digital photography were performed before and after treatment. RESULTS:Twenty-one patients (11 with moderate disease, 10 with ON) were enrolled in this study and followed for at least 14 months. Initial mean CAS was 6.38 +/- 1.49, which dropped to 1.8 +/- 1.12 after 6 months of treatment (P = 0.01; mean difference of 4.57 +/- 1.56; range 1-8 score points). ON was diagnosed in 10 patients. Of these, 66% improved with peribulbar triamcinolone exclusively. A transitory increase in intraocular pressure in two patients was controlled with topic medication. CONCLUSION:Peribulbar triamcinolone injections reduce the inflammatory signs of moderate GO, as measured by the CAS, and could also be used as an alternative treatment for ON. Randomized clinical trials are needed to compare the results of triamcinolone peribulbar injections to those of other treatment modalities.
10.1111/j.1755-3768.2008.01171.x
Graves ophthalmopathy: the bony orbit in optic neuropathy, its apical angular capacity, and impact on prediction of risk.
Chan L-L,Tan H-E,Fook-Chong S,Teo T-H,Lim L-H,Seah L-L
AJNR. American journal of neuroradiology
BACKGROUND AND PURPOSE:Optic neuropathy (ON), a serious complication of Graves ophthalmopathy, is often subclinical and masked by symptoms of orbitopathy. We examined herein bony and soft-tissue CT features associated with ON, including an angular assessment of orbital apex capacity, and their usefulness in the risk prediction of ON. MATERIALS AND METHODS:The CT scans of 41 patients with Graves ophthalmopathy (17 men, 24 women; mean age, 49.1 years) clinically diagnosed with (19 patients, 32 orbits) or without ON were evaluated by 2 independent raters. Quantitative linear and angular measurements of the orbital structures and bony walls and categoric scores of apical crowding and intracranial fat prolapse were assessed on a clinical workstation. Inter- and intrarater variability of these features was determined. The CT features of the 2 patient groups were compared, and multivariate logistic regression analysis was performed to evaluate the predictive features of ON. RESULTS:Bony orbital angles (P < .005), length of the lateral orbital wall (P < .05), muscular diameters (P < .0005), muscular bulk of the medial rectus muscle relative to the bony orbit (P < .05), and apical crowding (P < .0005) were associated with clinical ON. Stepwise multivariate logistic regression analysis revealed the muscle diameter index and medial and lateral wall angles to be independent predictors. Combining these in a single multivariate equation yielded sensitivity, specificity, and positive and negative predictive values of 73%, 90%, 82%, and 85%, respectively. CONCLUSIONS:Orbital wall angles, especially the medial wall, and muscular enlargement are independent risk predictors.
10.3174/ajnr.A1413
An analysis of 733 surgically treated blowout fractures.
Chi Mi Jung,Ku Myun,Shin Kwang Hun,Baek Sehyun
Ophthalmologica. Journal international d'ophtalmologie. International journal of ophthalmology. Zeitschrift fur Augenheilkunde
PURPOSE:To evaluate current patient demographics and surgical outcomes from a large series of 733 surgically treated orbital fractures from an ophthalmologist's perspective. METHODS:We reviewed the medical records of 733 patients with orbital fracture, who were treated surgically by one of the authors at Gil Hospital, Gachon University, from May 2000 until September 2007. Data regarding patient demographics, signs and symptoms at presentation, cause of injury, nature of fracture, associated ocular and nonocular injury, surgical outcome and complications were collected. RESULTS:Male patients outnumbered female patients, and blowout fracture occurred most frequently between the ages of 20 and 29 years (mean age 30.7 years). Violent assault was the leading cause of the fractures, followed by fall/slip and traffic accidents. Common signs and symptoms were periorbital ecchymosis, ocular motility restriction, diplopia and enophthalmos. In the pediatric group, diplopia and ocular motility restriction were the most common. Subconjunctival hemorrhage, hyphema and commotio retinae were the most commonly associated ocular injuries. As for the location of fractures, medial wall fractures were the most common, followed by fractures of the inferior wall, and both medial and inferior walls, in order. The most common type of fracture was the 'comminuted' one. In the pediatric group, the percentage of trapdoor-type fracture was higher than in the adult group. Forty-four percent of the patients had diplopia preoperatively and 8.7% postoperatively. The average measurement of difference in the enophthalmos (> or = 2 mm) patient population was improved from 2.62 (+/-SD 0.9) to 1.73 (+/-SD 1.3) after surgery. Ocular motility restriction was preoperatively noted in 297 patients (40.5%), and only 18 patients (2.5%) showed restriction after surgery. CONCLUSION:Young male individuals are at the highest risk for orbital fractures. There are marked differences in the clinical symptomatology and findings between pediatric and adult orbital fractures. Diplopia, enophthalmos and ocular motility restriction improved by repair of fracture.
10.1159/000238932
Navigation-guided reduction and orbital floor reconstruction in the treatment of zygomatic-orbital-maxillary complex fractures.
Yu Hongbo,Shen Guofang,Wang Xudong,Zhang Shilei
Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons
PURPOSE:To evaluate the effectiveness of image-guided navigation on open reduction and orbital floor reconstruction as treatment for zygomatic-orbital-maxillary complex fractures. PATIENTS AND METHODS:Six patients with zygomatic-orbital-maxillary complex fractures were enrolled in the present study. With preoperative planning and 3-dimensional simulation, the normal anatomic structures of the deformed area were recreated by superimposing and comparing the unaffected side with the affected side. The position of dislocated bone for reduction was defined, and surgical simulation was performed. All patients underwent open reduction and orbital floor reconstruction under the guidance of the navigation system. RESULTS:A fairly accurate match between the intraoperative anatomy and the computed tomography images was achieved through registration, with a systematic error of 1-mm difference. With guidance of the navigation system, open reduction of zygomatic-orbital-maxillary complex fractures and orbital floor reconstruction were performed in all cases. The reduction was checked by postoperative computed tomography scans, with a good match with preoperative planning noted. The maximal deviation between the reduction and preoperative planning was less than 2 mm. The symptoms associated with the orbital floor defects were eliminated, and the postoperative facial appearance of the patients was clearly improved. CONCLUSION:Navigation-guided open reduction of zygomatic-orbital-maxillary complex fractures with orbital floor reconstruction can be regarded as a valuable treatment option for this potentially complicated procedure.
10.1016/j.joms.2009.07.058
A novel thyroid stimulating immunoglobulin bioassay is a functional indicator of activity and severity of Graves' orbitopathy.
Lytton S D,Ponto K A,Kanitz M,Matheis N,Kohn L D,Kahaly G J
The Journal of clinical endocrinology and metabolism
CONTEXT:Immunoglobulins stimulating the TSH receptor (TSI) influence thyroid function and likely mediate extrathyroidal manifestations of Graves' disease (GD). OBJECTIVES:The aim of this study was to assess the clinical relevance of TSI in GD patients with or without Graves' orbitopathy (GO), to correlate the TSI levels with activity/severity of GO, and to compare the sensitivity/specificity of a novel TSI bioassay with TSH receptor (TSH-R) binding methods (TRAb). DESIGN:TSI were tested in two reporter cell lines designed to measure Igs binding the TSH-R and transmitting signals for cAMP/CREB/cAMP regulatory element complex-dependent activation of luciferase gene expression. Responsiveness to TSI of the novel chimeric (Mc4) TSH-R (amino acid residues 262-335 of human TSH-R replaced by rat LH-R) was compared with the wild-type (wt) TSH-R. RESULTS:All hyperthyroid GD/GO patients were TSI-positive. TSI were detected in 150 of 155 (97%, Mc4) and 148 of 155 (95%, wt) GO patients, in six of 45 (13%, Mc4) and 20 of 45 (44%, wt) mostly treated GD subjects, and in 0 of 40 (Mc4) and one of 40 (wt) controls. Serum TSI titers were 3- and 8-fold higher in GO vs. GD and control, respectively. All patients with diplopia and optic neuropathy and smokers were TSI-positive. TSI strongly correlated with GO activity (r = 0.87 and r = 0.7; both P < 0.001) and severity (r = 0.87 and r = 0.72; both P < 0.001) in the Mc4 and wt bioassays, respectively. Clinical sensitivity (97 vs. 77%; P < 0.001) and specificity (89 vs. 43%; P < 0.001) of the Mc4/TSI were greater than TRAb in GO. All 11 of 200 (5.5%) TSI-positive/TRAb-negative patients had GO, whereas all seven of 200 (3.5%) TSI-negative/TRAb-positive subjects had GD only. CONCLUSION:The novel Mc4/TSI is a functional indicator of GO activity and severity.
10.1210/jc.2009-2470
Orbital steroid injection versus oral steroid therapy in management of thyroid-related ophthalmopathy.
Alkawas Ayman A,Hussein Atef M,Shahien Ezzat A
Clinical & experimental ophthalmology
BACKGROUND:The aim of this study was to evaluate the efficacy, safety and complications of orbital steroid injection versus oral steroid therapy in the management of thyroid-related ophthalmopathy. METHODS:A total of 29 patients suffering from thyroid ophthalmopathy were included in this study. Patients were randomized into two groups: group I included 15 patients treated with oral prednisolone and group II included 14 patients treated with peribulbar triamcinolone orbital injection. Only 12 patients in both groups (16 female and 8 male) completed the study. RESULTS:Both groups showed improvement in symptoms and in clinical evidence of inflammation with improvement of eye movement and proptosis in most cases. Mean exophthalmometry value before treatment was 22.6 ± 1.98 mm that decreased to 18.6 ± 0.996 mm in group I, compared with 23 ± 1.86 mm that decreased to 19.08 ± 1.16 mm in group II. Mean initial clinical activity score was 4.75 ± 1.2 and 5 ± 1.3 for group I and group II before treatment, respectively, which dropped to 0.83 ± 1.2 and 0.83 ± 1.02, 6 months after treatment, respectively. There was no change in the best-corrected visual acuity in both groups. There was an increase in body weight, blood sugar, blood pressure and gastritis in group I in 66.7%, 33.3%, 50% and 75%, respectively, compared with 0%, 0%, 8.3% and 8.3% in group II. No adverse local side effects were observed in group II. CONCLUSION:Orbital steroid injection for thyroid-related ophthalmopathy is effective and safe. It eliminates the adverse reactions associated with oral corticosteroid use.
10.1111/j.1442-9071.2010.02332.x
Risk factors for development or deterioration of Graves' ophthalmopathy.
Stan Marius N,Bahn Rebecca S
Thyroid : official journal of the American Thyroid Association
BACKGROUND:Graves' ophthalmopathy (GO) significantly impairs the quality of life of affected individuals and the most severe cases can be sight threatening. Given the limited therapeutic options, a strong emphasis should be placed on disease prevention to diminish the significant morbidity associated with this disease. SUMMARY:GO is most prevalent in women and most severe in men. Although some genetic differences between GO patients and Graves' disease patients without ophthalmopathy have been identified, none of the polymorphisms identified to date impart a high enough risk of GO to justify genetic testing to guide therapy or preventive strategies. Poorly defined mechanical factors that appear also to play a role in GO susceptibility will likely be better elucidated with advances in imaging techniques. Tobacco smoking has been consistently linked to development or deterioration of GO. Smokers who receive radioactive iodine have the highest incidence of unfavorable GO outcome, which is proportional to the number of cigarettes smoked per day. Several studies have reported an association between radioactive iodine treatment for Graves' disease and worsening or development of GO. Observational studies suggest that the same appears to be true for thyroid dysfunction, including both hyper- and hypothyroidism. While thyrotropin receptor antibody levels appear to be useful in predicting the course of disease and response to therapy, it is not known whether they are predictive of GO development. The puzzling scenarios of euthyroid or clinically unilateral GO, the large number of nonsmoking GO patients, and the occasional development of GO years after thyroid dysfunction has been treated all underline the multifactorial etiology of this disorder in which no single factor determines the clinical outcome. CONCLUSIONS:GO appears to have a complex genetic basis with multiple susceptibility alleles that act in combination with nongenetic factors to contribute to disease expression.
10.1089/thy.2010.1634
Do subtypes of graves' orbitopathy exist?
Regensburg Noortje I,Wiersinga Wilmar M,Berendschot Tos T J M,Potgieser Peter,Mourits Maarten P
Ophthalmology
PURPOSE:To describe the prevalence of fat and muscle volume (MV) increase in Graves' orbitopathy (GO) patients, calculated from computed tomography scans, and the associated ophthalmic and endocrine characteristics. DESIGN:Consecutive, observational case series. PARTICIPANTS:Ninety-five consecutive Caucasian GO patients attending the thyroid eye clinic. METHODS:Volumetry using age-specific reference values in untreated GO patients who had been rendered euthyroid. MAIN OUTCOME MEASURES:Subgroups in GO and main characteristics. RESULTS:Four subgroups could be distinguished: Group 1, no fat volume (FV) or MV increase (n = 24); group 2, only FV increase (n = 5); group 3, only MV increase (n = 58); and group 4, both FV and MV increase (n = 8). Patients with an increase of MV were older and had higher thyroid-stimulating hormone-binding inhibitory immunoglobulin TBII, more proptosis, and more impaired ductions than those without MV increase. Patients with an increase of FV differed from those without FV increase only in having more proptosis. The clinical activity score did not differ between the 4 groups. CONCLUSIONS:Of these GO patients, 25% have orbital fat and MVs within an age-specific reference range. An increase of the FV is seen in only 14% of GO patients and characterized by proptosis. Muscle enlargement occurs in 70% of patients and is associated with older age, higher TBII values, more proptosis, and impaired motility.
10.1016/j.ophtha.2010.04.004
pROC: an open-source package for R and S+ to analyze and compare ROC curves.
BMC bioinformatics
BACKGROUND:Receiver operating characteristic (ROC) curves are useful tools to evaluate classifiers in biomedical and bioinformatics applications. However, conclusions are often reached through inconsistent use or insufficient statistical analysis. To support researchers in their ROC curves analysis we developed pROC, a package for R and S+ that contains a set of tools displaying, analyzing, smoothing and comparing ROC curves in a user-friendly, object-oriented and flexible interface. RESULTS:With data previously imported into the R or S+ environment, the pROC package builds ROC curves and includes functions for computing confidence intervals, statistical tests for comparing total or partial area under the curve or the operating points of different classifiers, and methods for smoothing ROC curves. Intermediary and final results are visualised in user-friendly interfaces. A case study based on published clinical and biomarker data shows how to perform a typical ROC analysis with pROC. CONCLUSIONS:pROC is a package for R and S+ specifically dedicated to ROC analysis. It proposes multiple statistical tests to compare ROC curves, and in particular partial areas under the curve, allowing proper ROC interpretation. pROC is available in two versions: in the R programming language or with a graphical user interface in the S+ statistical software. It is accessible at http://expasy.org/tools/pROC/ under the GNU General Public License. It is also distributed through the CRAN and CSAN public repositories, facilitating its installation.
10.1186/1471-2105-12-77
Orbital blowout fractures and race.
de Silva Don Julian,Rose Geoffrey E
Ophthalmology
PURPOSE:To examine the type of orbital blowout fracture and its variation with race. DESIGN:Retrospective review of computed tomography (CT) scans and demography in an unselected cohort of patients with orbital blowout fractures. PARTICIPANTS:Patients with a high-resolution CT scan of adequate quality for analysis who presented with an orbital blowout fracture to the Orbital Clinic at Moorfields Eye Hospital. Patients with fractures involving the orbital rim or the cranium, or with penetrating injuries of the globe or orbit, were omitted from the study. METHODS:Demographic and ethnic information was collected for each patient, and the orbital scans were reviewed by a single observer. On the basis of coronal and axial imaging, a fracture was classified as affecting up to 4 areas: the floor lateral to the infraorbital canal (area 1, "A1"), the floor medial to the canal ("A2"), the maxillo-ethmoidal strut ("inferomedial" strut, "A3"), and the medial wall blowout fracture ("A4"); with fractures involving the inferomedial strut, it was noted whether there was displacement or rotation of the strut. Ethnic origin was classified as Caucasian, Afro-Caribbean, or Asian (Oriental or Indian). MAIN OUTCOME MEASURES:The proportion of different walls involved in orbital blowout fractures within 3 ethnic groups. RESULTS:A total of 152 patients (125 men, 82%) had imaging adequate for analysis; 103 (68%) were Caucasian, 19 (12%) were Afro-Caribbean, and 30 (20%) were Asian. Caucasians most commonly had floor fractures (A1 or A2 in 56 orbits, 54%) compared with 10 of 103 purely medial fractures (A4, 10%); in contrast, medial fractures were the most common type in Afro-Caribbean patients (7/19 cases, 37%), and purely floor fractures occurred in only 2 cases (10%) (P<0.005). Asian patients had results similar to those for Caucasian patients, with isolated floor fractures being the most common (14/30 cases, 47%). CONCLUSIONS:Most blowout fractures involve the orbital floor in Caucasian and Asians, whereas in Afro-Caribbeans the most common site for fracture is the medial wall. FINANCIAL DISCLOSURE(S):The author(s) have no proprietary or commercial interest in any materials discussed in this article.
10.1016/j.ophtha.2011.05.001
Role of inferior orbital wall morphologic properties in isolated orbital blow-out fracture.
Park Jong-Seo,Lew Helen,Lee Sang-Yeul
Ophthalmic research
PURPOSE:To compare inferior orbital wall morphology between isolated inferior and medial orbital wall fracture patients. METHODS:The morphologic properties of patients with isolated blow-out fractures involving the medial wall or inferior wall treated from August 2004 to August 2009 were reviewed. The cross-sectional area, thickness, gradient, and curvature of the inferior wall were measured via orbital CT in the opposite non-traumatized eye. RESULTS:Patients with isolated inferior wall fractures (n = 77) and isolated medial wall fractures (n = 78) evidenced no differences in sex, age, etiology of trauma, laterality of trauma, and associated concomitant intraocular injuries. The cross-sectional area, thickness, and gradient of the inferior wall did not differ significantly between the 2 groups. However, the coefficient of curvature was significantly greater in patients with inferior wall fracture than in patients with medial wall fracture (0.016 ± 0.006 vs. 0.006 ± 0.002, respectively; p = 0.000). CONCLUSION:Patients with more convex and steep inferior walls are more likely to incur isolated inferior wall fractures than isolated medial wall fractures.
10.1159/000326894
Incidence of hyperthyroidism in Sweden.
Abraham-Nordling Mirna,Byström Kristina,Törring Ove,Lantz Mikael,Berg Gertrud,Calissendorff Jan,Nyström Helena Filipsson,Jansson Svante,Jörneskog Gun,Karlsson F Anders,Nyström Ernst,Ohrling Hans,Orn Thomas,Hallengren Bengt,Wallin Göran
European journal of endocrinology
INTRODUCTION:The incidence of hyperthyroidism has been reported in various countries to be 23-93/100,000 inhabitants per year. This extended study has evaluated the incidence for ~40% of the Swedish population of 9 million inhabitants. Sweden is considered to be iodine sufficient country. METHODS:All patients including children, who were newly diagnosed with overt hyperthyroidism in the years 2003-2005, were prospectively registered in a multicenter study. The inclusion criteria are as follows: clinical symptoms and/or signs of hyperthyroidism with plasma TSH concentration below 0.2 mIE/l and increased plasma levels of free/total triiodothyronine and/or free/total thyroxine. Patients with relapse of hyperthyroidism or thyroiditis were not included. The diagnosis of Graves' disease (GD), toxic multinodular goiter (TMNG) and solitary toxic adenoma (STA), smoking, initial treatment, occurrence of thyroid-associated eye symptoms/signs, and demographic data were registered. RESULTS:A total of 2916 patients were diagnosed with de novo hyperthyroidism showing the total incidence of 27.6/100,000 inhabitants per year. The incidence of GD was 21.0/100,000 and toxic nodular goiter (TNG=STA+TMNG) occurred in 692 patients, corresponding to an annual incidence of 6.5/100,000. The incidence was higher in women compared with men (4.2:1). Seventy-five percent of the patients were diagnosed with GD, in whom thyroid-associated eye symptoms/signs occurred during diagnosis in every fifth patient. Geographical differences were observed. CONCLUSION:The incidence of hyperthyroidism in Sweden is in a lower range compared with international reports. Seventy-five percent of patients with hyperthyroidism had GD and 20% of them had thyroid-associated eye symptoms/signs during diagnosis. The observed geographical differences require further studies.
10.1530/EJE-11-0548
Optimal management of Graves orbitopathy: a multidisciplinary approach.
Soeters M R,van Zeijl C J J,Boelen A,Kloos R,Saeed P,Vriesendorp T M,Mourits M P
The Netherlands journal of medicine
Graves' thyroid disease is a relatively common disorder in endocrinology and general internal medicine practice. Graves' hyperthyroidism is mediated by circulating stimulating autoantibodies. Up to 60% of patients with Graves' hyperthyroidism develop some form of Graves' orbitopathy. Immune reactivity to the thyroid-stimulating hormone receptor is also thought to play a role in the immunopathogenesis of Graves' orbitopathy. Graves' orbitopathy is characterised by a wide open eye appearance, caused by upper eyelid retraction and soft-tissue swelling that causes exophthalmus. Symptoms include photophobia, sandy feeling in the eye, painful eye movements and diplopia. Visual acuity may be reduced. In some cases emergency treatment is necessary to prevent irreversible vision loss. Smoking should be stopped. Mild to moderate Graves' orbitopathy may be an indication for corticosteroid treatment or radiotherapy. Once inflammatory signs and symptoms have waned, surgery can be performed to correct residual diplopia, exophthalmus or lid retraction. The presence of Graves' orbitopathy has consequences for the management of Graves' hyperthyroidism. Adequately controlled Graves' thyroid dysfunction is likely to improve Graves' orbitopathy, while radioactive iodine treatment can worsen the condition. Due to the wide variety in clinical presentation and the possible interference between treatment of thyroid disease and eye disease, the management of more complicated patients with Graves' orbitopathy can best be performed in combined thyroid-eye clinics, in which the patient is seen simultaneously by the ophthalmologist and the endocrinologist.
Thyroid associated orbitopathy.
Maheshwari Rajat,Weis Ezekiel
Indian journal of ophthalmology
Thyroid associated orbitopathy, also known as Graves' orbitopathy, is typically a self-limiting autoimmune process associated with dysthyroid states. The clinical presentation may vary from very mild disease to severe irreversible sight-threatening complications. Despite ongoing basic science and clinical research, the pathogenesis and highly effective therapeutic strategies remain elusive. The present article reviews the pathophysiology, clinical presentation, and management of this common, yet poorly understood disease, which remains a challenge to the ophthalmologist.
10.4103/0301-4738.94048
Evaluating Graves' orbitopathy.
Dolman Peter J
Best practice & research. Clinical endocrinology & metabolism
Graves' Orbitopathy (GO) is an immune-mediated disorder causing inflammation and expansion of orbital fat and muscle. The resulting spectrum of ocular and orbital changes may cause significant visual and cosmetic morbidity and are graded as disease severity. The disease follows a biphasic course with an active or progressive phase followed by a quiescent or stable phase: the temporal status is graded as disease activity. Grading systems for GO include Werner's NO SPECS and European Group on Graves' Orbitopathy (EUGOGO)'s severity scales, the Clinical Activity Score (CAS) and the VISA Classification (for severity and activity). Diagnosis of GO is based on recognition of clinical features and may be supported by thyroid function and immune testing, and orbital imaging. The endocrinologist or internist may play an important role in early recognition and diagnosis of GO, in grading severity and activity, and in arranging appropriate referral to an ophthalmologist based on this evaluation.
10.1016/j.beem.2011.11.007
Epidemiology of Graves' orbitopathy (GO) and relationship with thyroid disease.
Lazarus John H
Best practice & research. Clinical endocrinology & metabolism
The incidence of Graves' orbitopathy (GO) is 16/100,000 in females and 2.9/100,000 in males as studied in Olmsted county. It can be calculated that the approximate prevalence is 0.25%. There is a gender bimodal distribution. Go usually occurs at the time of onset of the hyperthyroidism but may present up to a year before that time or as long as 5 years afterwards. Around 10-15% of patients have never been hyperthyroid and some are hypothyroid at GO presentation. Although the incidence of GO has probably been decreasing during the last 2 decades definite figures for this assertion are not available. Risk factors that may influence the incidence of GO include cigarette smoking and radioiodine treatment of hyperthyroidism. There are also complex genetic factors with multiple susceptibility alleles that contribute to the expression of the disease. The probability is that a reduction of the incidence of GO will be achieved by influencing the environmental factors.
10.1016/j.beem.2011.10.005
Immunopathogenesis of Graves' ophthalmopathy: the role of the TSH receptor.
Iyer Seethalakshmi,Bahn Rebecca
Best practice & research. Clinical endocrinology & metabolism
Graves' ophthalmopathy is an inflammatory autoimmune disorder of the orbit. The close clinical and temporal relationships between Graves' hyperthyroidism and ophthalmopathy have long suggested that both conditions derive from a single systemic process and share the thyrotropin receptor as a common autoantigen. This receptor is expressed not only in thyroid follicular cells, but also in orbital fibroblasts with higher levels measured in orbital cells from ophthalmopathy patients than in cells from normal individuals. Recent studies from several laboratories have shown that thyrotropin receptor activation in orbital fibroblasts enhances hyaluronic acid synthesis and adipogenesis, both cellular functions that appear to be upregulated in the diseased orbit. The phosphoinositide 3-kinase/Akt signaling cascade, along with other effector pathways including adenylyl cyclase/cAMP, appears to mediate these processes. Future therapies for this condition may involve inhibition of thyrotropin receptor signaling in orbital fibroblasts.
10.1016/j.beem.2011.10.003
Quantitative computed tomographic predictors of compressive optic neuropathy in patients with thyroid orbitopathy: a volumetric analysis.
Weis Ezekiel,Heran Manraj K S,Jhamb Ashu,Chan Andy K,Chiu Jack P,Hurley Michael C,Rootman Jack
Ophthalmology
PURPOSE:To evaluate the relationship between orbital bony geometry and the volume of the intraorbital structures in predicting compressive dysthyroid optic neuropathy (DON). DESIGN:Retrospective, consecutive case series. PARTICIPANTS:Images of 198 orbits from 99 patients suffering from thyroid-related orbitopathy were reviewed. METHODS:Clinical examination and computed tomography of the orbits, including volumetric analysis, were performed on all patients. MAIN OUTCOME MEASURES:Clinical and radiologic predictors of DON. RESULTS:Significant volumetric univariate predictors of compressive optic neuropathy included medial rectus volume (P = 0.005), lateral rectus volume (P = 0.011), superior muscle group volume (P = 0.04), and total rectus muscle volume (P = 0.015). Inferior rectus muscle volume, orbital volume, bony orbital apex angle, globe diameter, and bony medial wall contour were not associated with optic neuropathy. Multivariate modeling found medial rectus volume the only independently significant predictor. Univariate modeling of simple rectus diameter measurements found medial rectus axial diameter (P = 0.003) and total recti diameter (P = 0.016) predictive of optic neuropathy. Lateral rectus, superior rectus, and inferior rectus diameters were not predictive. Multivariate modeling found only medial rectus diameter to be a significant independent predictor of optic neuropathy. The area under the receiver operating characteristic curve was not different between the volumetric and rectus diameter curves. CONCLUSIONS:Medial rectus size was found to be the most important quantifiable predictor of compressive optic neuropathy in patients with optic neuropathy. In this study, simple maximum medial rectus diameter, as measured on axial scans, was equally predictive of compressive optic neuropathy as the more involved volumetric calculation. Assessment of orbital geometry, including bowing of the medial wall, orbital apex angle, globe diameter, and orbital volume, were not found to be predictive of DON.
10.1016/j.ophtha.2012.04.021
Public health relevance of Graves' orbitopathy.
Ponto Katharina A,Merkesdal Sonja,Hommel Gerhard,Pitz Susanne,Pfeiffer Norbert,Kahaly George J
The Journal of clinical endocrinology and metabolism
CONTEXT:Disfiguring proptosis and functional impairment in patients with Graves' orbitopathy (GO) may lead to impaired earning capacity and to considerable indirect/direct costs. OBJECTIVE:The aim of the study was to investigate the public health relevance of GO. DESIGN AND SETTING:This cross-sectional study was performed between 2005 and 2009 at a multidisciplinary university orbital center. PATIENTS:A total of 310 unselected patients with GO of various degrees of severity and activity participated in the study. INTERVENTIONS:We conducted an observational study. MAIN OUTCOME MEASURES:We measured work disability and sick leave as well as the resulting indirect/direct costs of GO-specific therapies. RESULTS:Of 215 employed patients, 47 (21.9%) were temporarily work disabled, and 12 (5.6%) were permanently work disabled. Five (2.3%) had lost their jobs, and nine (4.2%) had retired early. The mean duration of sick leave was 22.3 d/yr. Compared with the German average of 11.6 d/yr, 32 (15%) patients had taken longer sick leaves. The duration of sick leave correlated with the disease severity (P = 0.015), and work disability correlated with diplopia (P < 0.001). Multivariable analysis identified diplopia as the principal predictor for work disability (odds ratio, 1.7; P < 0.001). The average costs due to sick leave and work disability ranged between 3,301€ (4,153$) and 6,683€ (8,407$) per patient per year. Direct costs were 388 ± 56€ (488 ± 70$) per patient per year and per year were higher in sight-threatening GO (1,185 ± 2,569€; 1,491 ± 3,232$) than in moderate-to-severe (373 ± 896€; 469 ± 1,127$; P = 0.013) or in mild GO (332 ± 857€; 418 ± 1,078$; P = 0.016). Total indirect costs ranged between 3,318€ (4,174$) (friction cost method) and 6,738€ (8,476$) (human capital approach). Work impairment as well as direct and indirect costs of GO significantly correlated with the scores of the internationally standardized and specific GO quality-of-life questionnaire. CONCLUSIONS:Productivity loss and a prolonged therapy for GO incur great indirect and direct costs.
10.1210/jc.2012-3119
Anatomy of the inferior orbital fissure: implications for endoscopic cranial base surgery.
De Battista Juan Carlos,Zimmer Lee A,Theodosopoulos Philip V,Froelich Sebastien C,Keller Jeffrey T
Journal of neurological surgery. Part B, Skull base
Considering many approaches to the skull base confront the inferior orbital fissure (IOF) or sphenomaxillary fissure, the authors examine this anatomy as an important endoscopic surgical landmark. In morphometric analyses of 50 adult human dry skulls from both sexes, we divided the length of the IOF into three segments (anterolateral, middle, posteromedial). Hemotoxylin- and eosin-stained sections were analyzed. Dissections were performed using transnasal endoscopy in four formalin-fixed cadaveric cranial specimens (eight sides); three endoscopic approaches to the IOF were performed. IOF length ranged from 25 to 35 mm (mean 29 mm). Length/width of the individual anterolateral, middle, and posteromedial segments averaged 6.46/5, 4.95/3.2, and 17.6/ 2.4 mm, respectively. Smooth muscle within the IOF had a consistent relationship with several important anatomical landmarks. The maxillary antrostomy, total ethmoidectomy approach allowed access to the posteromedial segment of the fissure. The endoscopic modified, medial maxillectomy approach allowed access to the middle and posterior-medial segment. The Caldwell-Luc approach allowed complete exposure of the IOF. The IOF serves as an important anatomic landmark during endonasal endoscopic approaches to the skull base and orbit. Each of the three segments provides a characteristic endoscopic corridor, unique to the orbit and different fossas surrounding the fissure.
10.1055/s-0032-1301398
Prevalence and natural history of Graves' orbitopathy in the XXI century.
Piantanida E,Tanda M L,Lai A,Sassi L,Bartalena L
Journal of endocrinological investigation
Graves' orbitopathy (GO) is an autoimmune disorder and the main extrathyroidal expression of Graves' disease. There is a spectrum of ocular involvement in Graves' disease, from complete absence of symptoms and signs to sight-threatening conditions. The prevalence of GO varies in different published series of Graves' patients, due to confounding factors (new diagnosis vs long-lasting disease, way of defining and assessing ocular involvement, treatment of hyperthyroidism with potentially GO-modifying treatments, such as radioiodine). Recent studies, however, suggest that most Graves' patients have mild or no GO at presentation, while moderate-to-severe GO is rare, and sight-threatening GO (mostly due to dysthyroid optic neuropathy) is exceptional in non-tertiary referral centers. The natural course of GO is incompletely defined, particularly in patients with moderate- to-severe GO, because these patients require prompt and disease-modifying therapies for orbital disease. In patients with mild GO at presentation, progression to severe forms is rare, while partial or complete remission is frequent. Progression of pre-existing GO or de novo occurrence of GO is more likely in smokers. There seems to be a trend towards a decline in progression of GO, possibly due to a better control of risk factors (cigarette smoking, thyroid dysfunction, etc.) and a closer interaction between endocrinologists and ophthalmologists allowing an improved integrated management of thyroid and orbital disease.
10.3275/8937
The thyroid and the kidney: a complex interplay in health and disease.
Dousdampanis Periklis,Trigka Konstantina,Vagenakis Georgios A,Fourtounas Costas
The International journal of artificial organs
Thyroid hormones may directly affect the kidney and altered kidney function may also contribute to thyroid disorders. The renal manifestations of thyroid disorders are based on hemodynamic alterations or/and to direct effects of thyroid hormones. The renin-angiotensin system plays a crucial role in the cross-talk between the thyroid and the kidney. Hypothyroidism may be accompanied by an increase of serum creatinine and reduction of glomerular filtration rate (GFR), whereas hyperthyroidism may increase GFR. Treatment of thyroid disorders may lead to normalization of GFR. Primary and subclinical hypothyroidism and low triiodothyronine (T3) syndrome are common features in patients with chronic kidney disease (CKD). In addition low levels of thyroid hormones may predict a higher risk of cardiovascular and overall mortality in patients with end-stage renal disease. The causal nature of this correlation remains uncertain. In this review, special emphasis is given to the thyroid pathophysiology, its impact on kidney function and CKD and the interpretation of laboratorial findings of thyroid dysfunction in CKD.
10.5301/ijao.5000300
MicroRNA profiling implies new markers of chemoresistance of triple-negative breast cancer.
Ouyang Mao,Li Yongxin,Ye Sheng,Ma Jieyi,Lu Liming,Lv Weiming,Chang Guangqi,Li Xiaoxi,Li Qing,Wang Shenming,Wang Wenjian
PloS one
OBJECTIVE:Triple-negative breast cancer (TNBC) patients with truly chemosensitive disease still represent a minority among all TNBC patients. The aim of the present study is to identify microRNAs (miRNAs) that correlate with TNBC chemoresistance. METHODS:In this study, we conducted miRNAs profile comparison between triple-negative breast cancer (TNBCs) and normal breast tissues by microRNA array. Quantitative real-time PCR (qRT-PCR) was utilized to confirm the specific deregulated miRNAs change trend. We used starBase 2.1 and GOrilla to predict the potential targets of the specific miRNAs. Cells viability and apoptosis assays were employed to determine the effect of alteration of the specific miRNAs in TNBC cells on the chemosensitivity. RESULTS:We identified 11 specific deregulated miRNAs, including 5 up-regulated miRNAs (miR-155-5p, miR-21-3p, miR-181a-5p, miR-181b-5p, and miR-183-5p) and 6 down-regulated miRNAs (miR-10b-5p, miR-451a, miR-125b-5p, miR-31-5p, miR-195-5p and miR-130a-3p). Thereafter, this result was confirmed by qRT-PCR. We predicted the potential targets of the candidate miRNAs and found that they are involved in cancer-associated pathways. For the first time, we found that miR-130a-3p and miR-451a were down-regulated in TNBC. 9 of the 11 specific deregulated miRNAs were found to be associated with chemoresistance. In vitro assays, we found that up-regulation of either miR-130a-3p or miR-451a in MDA-MB-231 cells significantly changed the cells sensitivity to doxorubicin. The results suggest that TNBC chemotherapy might be affected by a cluster of miRNAs. CONCLUSION:The abnormal expression miRNAs in TNBC are mainly chemoresistance related. This might be part of reason that TNBC likely to evade from chemotherapy resulting in early relapse and high risk of death. To alter their expression status might be a potential therapeutic strategy to improve the outcome of chemotherapy for TNBC patients.
10.1371/journal.pone.0096228
Intimate partner violence: an underappreciated etiology of orbital floor fractures.
Clark Thomas J,Renner Lynette M,Sobel Rachel K,Carter Keith D,Nerad Jeffrey A,Allen Richard C,Shriver Erin M
Ophthalmic plastic and reconstructive surgery
PURPOSE:To evaluate the prevalence of intimate partner violence (IPV) in a large population of female orbital floor fracture patients and provide recommendations on effectively identifying and referring IPV survivors. METHODS:Retrospective review of facial fracture patients examined at the University of Iowa Hospitals and Clinics between January 1995 and April 2013. International Classification of Diseases, Ninth Revision, codes and medical record review were used to determine the prevalence of IPV victimization and clinical outcomes. RESULTS:A total of 1,354 women and 4,296 men sustained facial fractures. Of these, 405 women and 1,246 men sustained orbital floor fractures. Leading mechanisms of orbital floor fractures in women were motor vehicle collisions (29.9%) and falls (24.7%). Twenty percent had no etiology documented. Intimate partner violence-associated assault was the third leading documented cause of orbital floor fractures in women (7.6%) followed by non-IPV-associated assault (7.2%). Among women with orbital floor fractures due to assault, leading patterns of injury included the following: isolated orbital floor fractures (38.7%, 12/31 in IPV patients; 55.2%, 16/29 in non-IPV patients), zygomaticomaxillary complex fractures (35.5%, 11/31 in IPV patients; 17.2%, 5/29 in non-IPV patients), and orbital floor plus medial wall fractures (16.1%, 5/31 in IPV patients; 24.1%, 7/29 in non-IPV patients). Involvement of ancillary services was documented in 20.0% (7 law enforcement and 5 social service agencies, 12/60) of assault-related orbital floor fracture cases. Ascertainment of patient safety was documented in 1.7% (1/60) of these cases. CONCLUSIONS:Ophthalmologists treating orbital floor fracture patients should maintain a high index of suspicion for IPV and screen accordingly. Following IPV disclosure, patient safety should be assessed and referral provided.
10.1097/IOP.0000000000000165
The relationship between thyroid function and estimated glomerular filtration rate in patients with chronic kidney disease.
Rhee Connie M,Kalantar-Zadeh Kamyar,Streja Elani,Carrero Juan-Jesus,Ma Jennie Z,Lu Jun L,Kovesdy Csaba P
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association
BACKGROUND:Recent studies have shown an increasing risk of hypothyroidism with incrementally lower estimated glomerular filtration rate (eGFR) in cohorts comprised of patients with normal to mildly impaired kidney function. We sought to confirm these findings in a nationally representative cohort of Veterans Affairs patients with moderate-to-severe chronic kidney disease (CKD). METHODS:This study examined the association between kidney function and hypothyroidism among 461 607 veterans with Stage 3 to 5 CKD who underwent repeated measurements of serum creatinine and thyrotropin (TSH) at identical time points between October 2004 and September 2006. Kidney function was defined by eGFR using the Chronic Kidney Disease Epidemiology Collaboration formula. In primary analyses, the association between eGFR and hypothyroidism (defined as serum TSH > 5 mIU/L and/or receipt of thyroid hormone supplementation) was estimated using multivariable random effects logistic regression. In secondary analyses, the association between eGFR and serum TSH level was estimated using multivariable random effects linear regression. RESULTS:At baseline, 68.9, 25.5, 5.3 and 0.3% of patients had Stage 3A, 3B, 4 and 5 CKD, respectively. For every 10 mL/min/1.73 m(2) lower eGFR, there was an 18% higher risk of hypothyroidism: adjusted odds ratio 1.18 [95% confidence interval (CI) 1.17-1.20, P < 0.001]. In secondary analyses, we observed that a 10 mL/min/1.73 m(2) lower eGFR was associated with a 0.11 mIU/L higher serum TSH (95% CI 0.10-0.11 mIU/L higher serum TSH, P < 0.001). CONCLUSIONS:In a nationally representative cohort of patients with moderate-to-severe CKD, there is an inverse association between eGFR and risk of hypothyroidism.
10.1093/ndt/gfu303
Orbital blowout fracture location in Japanese and Chinese patients.
Sun Michelle T,Wu Wencan,Watanabe Akihide,Kakizaki Hirohiko,Chen Ben,Ueda Kosuke,Katori Nobutada,Takahashi Yasuhiro,Selva Dinesh
Japanese journal of ophthalmology
PURPOSE:To characterize the location of orbital blowout fractures in Asian individuals. METHODS:This was a retrospective review of 470 consecutive Asian patients with orbital blowout fractures who presented to four tertiary care hospitals in Japan and China. Computed tomography (CT) characterized the location and severity of fractures involving the medial wall, the orbital floor, and/or the maxilloethmoidal strut. RESULTS:A total of 475 orbital blowout fractures were identified. More than one fracture location was involved in 19% of all cases. The medial orbital wall was the most commonly involved location, presenting in 29 cases (61%), of which 204 (43%) were isolated medial blowout fractures. The orbital floor was the second most common location involved, present in 226 cases (48%) with 150 isolated orbital floor fractures (32%), while the maxilloethmoidal strut was involved in 45 cases (9%) with 30 of those being isolated strut fractures (6%). The majority of fractures (62%) were classified as moderately severe, whilst 14% were mild, and 24% were severe. Associated nasal fractures were present in 16% of the cases. CONCLUSIONS:Orbital blowout fractures in Japanese and Chinese individuals occur most commonly in the medial wall. This is in contrast to previous reports on white individuals, who tend to sustain fractures involving the orbital floor rather than the medial wall.
10.1007/s10384-014-0357-x
MiRNA-21 promotes fibrosis in orbital fibroblasts from thyroid-associated ophthalmopathy.
Tong Bo-ding,Xiao Man-Yi,Zeng Jie-Xi,Xiong Wei
Molecular vision
PURPOSE:This study aimed to determine the role of miR-21 in orbital fibroblasts obtained from donors with thyroid-associated ophthalmopathy (TAO) and to elucidate the regulation of fibrosis by miR-21 in the pathological process of TAO. METHODS:The expression of miR-21 was investigated in orbital tissues from 26 donors with TAO and 10 donors without TAO. Human orbital fibroblasts were cultivated from TAO donors, and the role of miR-21 in orbital fibroblast proliferation, apoptosis, and differentiation was analyzed. Moreover, the effect of transforming growth factor-beta1 (TGF-β1) on miR-21 expression was also analyzed. In addition, the regulation of miR-21 in TGF-β1-induced collagen production was determined. RESULTS:The expression of miR-21 in orbital fibroblasts from TAO was higher than in donors without TAO. Additional experiments demonstrated that miR-21 enhanced proliferation, decreased apoptosis, and promoted differentiation in TAO orbital fibroblasts. Moreover, this study also showed that TGF-β1 induced miR-21 expression in a time- and dose-dependent manner and miR-21 promoted collagen I mRNA expression and total collagen production induced by TGF-β1. Additionally, miR-21 activated the TGF-β1/Smad signaling pathway by enhancing Smad3 phosphorylation. CONCLUSIONS:The present study shows that miR-21 regulates cell proliferation, apoptosis, and differentiation in orbital fibroblasts from TAO, and acts as a mediator in TGF-β1-induced collagen production. These data predict a close association between miR-21 and orbital muscle fibrosis, and provide a novel therapeutic target for TAO.
Surgical anatomy and variations of the infraorbital nerve.
Ference Elisabeth H,Smith Stephanie S,Conley David,Chandra Rakesh K
The Laryngoscope
OBJECTIVES/HYPOTHESIS:To assess relevant variations in the anatomical course of the infraorbital nerve (ION). This understanding may reduce the risk of surgical injury. METHODS:A total of 100 consecutive computed-tomography sinus studies obtained in a tertiary referral center were reviewed, and measurements were made of the 200 IONs. Anatomic variants were classified into three types based on the degree to which (if any) the nerve's course descended from the maxillary roof into the sinus lumen. RESULTS:A total of 60.5% of IONs were entirely contained within the sinus roof. In 27.0%, the nerve canal descended below the roof but remained juxtaposed to it. In 12.5%, the ION descended into the sinus lumen. The proportion of IONs descending into the sinus significantly increased to 27.7% when an infraorbital ethmoid cell was present (chi-square P < 0.001) and to 50% when the nerve was contained within a lamella of such a cell (chi-square P < 0.001). Descended nerves terminated in a foramen located an average of 11.9 ± 2.5 mm below the infraorbital rim, significantly further below the orbit than nondescended nerves (t test P < 0.001). Descended nerves were located a mean distance of 8.6 ± 2.9 mm below the sinus roof and traversed the sinus lumen diagonally for a mean length of 15.4 ± 3.1 mm. CONCLUSIONS:Descent of the ION into the maxillary sinus is a common anatomic variant that is more prevalent in the setting of an ipsilateral infraorbital ethmoid cell. Descended nerves are associated with the foramen significantly further below the inferior orbital rim than those of nondescended nerves. These observations may help surgeons avoid iatrogenic ION injury. LEVEL OF EVIDENCE:N/A.
10.1002/lary.25089
Protrusion of the Infraorbital Nerve into the Maxillary Sinus on CT: Prevalence, Proposed Grading Method, and Suggested Clinical Implications.
Lantos J E,Pearlman A N,Gupta A,Chazen J L,Zimmerman R D,Shatzkes D R,Phillips C D
AJNR. American journal of neuroradiology
BACKGROUND AND PURPOSE:The infraorbital nerve arises from the maxillary branch of the trigeminal nerve and normally traverses the orbital floor in the infraorbital canal. Sometimes, however, the infraorbital canal protrudes into the maxillary sinus separate from the orbital floor. We systematically studied the prevalence of this variant. MATERIALS AND METHODS:We performed a retrospective review of 500 consecutive sinus CTs performed at our outpatient centers. The infraorbital nerve protruded into the maxillary sinus if the entire wall of the infraorbital canal was separate from the walls of the sinus. We recorded the length of the bony septum that attached the infraorbital canal to the wall of the maxillary sinus and noted whether the protrusion was bilateral. We also measured the distance from the inferior orbital rim where the infraorbital canal begins to protrude into the sinus. RESULTS:There was a prevalence of 10.8% for infraorbital canal protrusion into the maxillary sinus and 5.6% for bilateral protrusion. The median length of the bony septum attaching the infraorbital canal to a maxillary sinus wall, which was invariably present, was 4 mm. The median distance at which the infraorbital nerve began to protrude into the sinus was 11 mm posterior to the inferior orbital rim. CONCLUSIONS:Although this condition has been reported in only 3 patients previously, infraorbital canal protrusion into the maxillary sinus was present in >10% of our cohort. Identification of this variant on CT could help a surgeon avoid patient injury.
10.3174/ajnr.A4588
An overview of thyroid eye disease.
McAlinden Colm
Eye and vision (London, England)
Thyroid eye disease (also known as Graves' ophthalmopathy) is a complex orbital inflammatory disease, which can be sight threatening, debilitating and disfiguring. This overview discusses the epidemiology, risk factors, pathogenesis, presentation, ophthalmic clinical features, investigations and treatment of thyroid eye disease.
10.1186/s40662-014-0009-8
[Aspartate aminotransferase--key enzyme in the human systemic metabolism].
Otto-Ślusarczyk Dagmara,Graboń Wojciech,Mielczarek-Puta Magdalena
Postepy higieny i medycyny doswiadczalnej (Online)
Aspartate aminotransferase is an organ-nonspecific enzyme located in many tissues of the human body where it catalyzes reversible reaction of transamination. There are two aspartate aminotransferase isoforms--cytoplasmic (AST1) and mitochondrial (AST2), that usually occur together and interact with each other metabolically. Both isoforms are homodimers containing highly conservative regions responsible for catalytic properties of enzyme. The common feature of all aspartate aminotransfeses is Lys - 259 residue covalent binding with prosthetic group - pyridoxal phosphate. The differences in the primary structure of AST isoforms determine their physico-chemical, kinetic and immunological properties. Because of the low concentration of L-aspartate (L-Asp) in the blood, AST is the only enzyme, which supply of this amino acid as a substrate for many metabolic processes, such as urea cycle or purine and pyrimidine nucleotides in the liver, synthesis of L-arginine in the kidney and purine nucleotide cycle in the brain and the skeletal muscle. AST is also involved in D-aspartate production that regulates the metabolic activity at the auto-, para- and endocrine level. Aspartate aminotransferase is a part of the malate-aspartate shuttle in the myocardium, is involved in gluconeogenesis in the liver and kidney, glyceroneogenesis in the adipose tissue, and synthesis of neurotransmitters and neuro-glial pathway in the brain. Recently, the significant role of AST in glutaminolysis - normal metabolic pathway in tumor cells, was demonstrated. The article is devoted the role of AST, known primarily as a diagnostic liver enzyme, in metabolism of various human tissues and organs.
10.5604/17322693.1197373
An anatomical study of the orbital floor in relation to the infraorbital groove: implications of predisposition to orbital floor fracture site.
Takahashi Yasuhiro,Nakano Takashi,Miyazaki Hidetaka,Kakizaki Hirohiko
Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie
PURPOSE:To examine the anatomy of the orbital floor in relation to the infraorbital groove. METHODS:Twenty-two Japanese cadavers aged 86.9 ± 6.0 years at death were used. We examined whether the bony overhang on the infraorbital nerve extending laterally was connected to the segment medial to the infraorbital groove. The bone thicknesses at 1, 2, and 3 mm anterior to the junction between the infraorbital groove and the inferior orbital fissure were measured along the groove. We examined the angle between the infraorbital groove and the orbital floor, both at the medial and lateral margins, at the thinnest point in the above three measurement points. We used the measurement values examined in the left orbits to prevent doubling the number of the orbits. RESULTS:The bony overhang was not connected to the medial segment in 19 (86.4 %) orbits. The thickness at the thinnest point was thinner in the medial portion (1.02 ± 1.20 mm) than in the lateral portion (2.60 ± 1.82 mm; p = 0.001). The angle between the medial margin and the orbital floor was obtuse (156.5° ± 12.3°), compared with that of the lateral margin (104.0° ± 17.0°; p < 0.001). CONCLUSIONS:The results of this study imply that the medial portion has an anatomical weakness and few supportive structures. Although these findings were obtained only from Japanese cadavers, there may be associated with frequent occurrences of an orbital floor fracture just medial to the infraorbital groove.
10.1007/s00417-016-3455-2
A randomized double-blind controlled trial of the use of dydrogesterone in women with threatened miscarriage in the first trimester: study protocol for a randomized controlled trial.
Chan Diana Man Ka,Cheung Ka Wang,Yung Sofie Shuk Fei,Lee Vivian Chi Yan,Li Raymond Hang Wun,Ng Ernest Hung Yu
Trials
BACKGROUND:Miscarriage is a common complication of pregnancy occurring in 15-20 % of all clinically recognized pregnancies. Currently, there is still no good scientific evidence to support the routine use of progestogens for the treatment of threatened miscarriage because the existing studies were not large enough to show a significant difference and some of them were not randomized or double-blind. METHODS:This is a double-blind, randomized controlled trial. A total of 400 patients presenting with first-trimester threatened miscarriage will be enrolled. They will be randomized to take dydrogesterone 40 mg per os, followed by 10 mg per os three times a day or placebo until twelve completed weeks of gestation or 1 week after the bleeding has stopped, whichever is longer. The primary outcome is the percentage of miscarriage before 20 weeks of gestation. DISCUSSION:We postulate that the dydrogesterone therapy will significantly reduce the risk of miscarriage in women with threatened miscarriage. TRIAL REGISTRATION:This study is registered at ClinicalTrials.gov, NCT02128685 . Registered on 29 April 2014.
10.1186/s13063-016-1509-8
Predicting late enophthalmos: Differences between medial and inferior orbital wall fractures.
Choi Jaehoon,Park Sang Woo,Kim Junhyung,Park Jeongseob,Kim Jun Sik
Journal of plastic, reconstructive & aesthetic surgery : JPRAS
INTRODUCTION:The purpose of this study was to compare the strength of the relationships between predictors and late-onset enophthalmos in medial and inferior orbital wall fractures and to determine the most significant predictive factor of enophthalmos in medial or inferior orbital wall fracture. METHODS:Sixty-three adult patients with unilateral medial or inferior orbital wall fracture who had been left untreated for more than two months were enrolled in this study. Patients who had accompanying multiple orbital wall fractures and those with orbital-zygomatic fractures were excluded. Orbital defect area and herniated muscle and fat volumes were evaluated using computed tomography. The degree of enophthalmos was measured using a Hertel exophthalmometer. RESULTS:Herniated muscle and fat volumes were positively correlated with defect area in the medial orbital wall fracture but showed no positive correlation with inferior orbital wall fracture. In the medial orbital wall fracture group, enophthalmos was positively correlated with defect area and herniated muscle and fat volumes. Defect area was more highly related to enophthalmos than other analyzed metrics. The defect area predictive of enophthalmos was 1.98 cm. However, enophthalmos was positively correlated only with herniated fat volume in inferior orbital wall fracture. The herniated fat volume predictive of enophthalmos was 343.50 mm. CONCLUSION:Orbital defect area in medial orbital wall fracture and herniated fat volume in inferior orbital wall fracture were the most significant predictors of late-onset enophthalmos.
10.1016/j.bjps.2016.08.004
[Lucy's cancer(s): A prehistorical origin?]
Chene G,Lamblin G,Le Bail-Carval K,Beaufils E,Chabert P,Gaucherand P,Mellier G,Coppens Y
Gynecologie, obstetrique & fertilite
OBJECTIVES:The recent discovery of the earliest hominin cancer, a 1.7-million-year-old osteosarcoma from South Africa has raised the question of the origin of cancer and its determinants. We aimed to determine whether malignant and benign tumors exist in the past societies. METHODS:A review of literature using Medline database and Google about benign and malignant tumors in prehistory and antiquity. Only cases with morphological and paraclinical analysis were included. The following keywords were used: cancer; paleopathology; malignant neoplasia; benign tumor; leiomyoma; myoma; breast cancer; mummies; soft tissue tumor; Antiquity. RESULTS:Thirty-five articles were found in wich there were 34 malignant tumors, 10 benign tumors and 11 gynecological benign tumors. CONCLUSIONS:The fact that there were some malignant tumors, even few tumors and probably underdiagnosed, in the past may be evidence that cancer is not only a disease of the modern world. Cancer may be indeed a moving target: we have likely predisposing genes to cancer inherited from our ancestors. The malignant disease could therefore appear because of our modern lifestyle (carcinogens and risk factors related to the modern industrial society).
10.1016/j.gyobfe.2016.10.001
Biomechanic Factors Associated With Orbital Floor Fractures.
Patel Sagar,Andrecovich Christopher,Silverman Michael,Zhang Liying,Shkoukani Mahdii
JAMA facial plastic surgery
IMPORTANCE:Orbital floor fractures are commonly seen in clinical practice, yet the etiology underlying the mechanism of fracture is not well understood. Current research focuses on the buckling theory and hydraulic theory, which implicate trauma to the orbital rim and the globe, respectively. OBJECTIVE:To elucidate and define the biomechanical factors involved in an orbital floor fracture. DESIGN, SETTING, AND PARTICIPANTS:A total of 10 orbits from 5 heads (3 male and 2 female) were used for this study. These came from fresh, unfixed human postmortem cadavers that were each selected so that the cause of death did not interfere with the integrity of orbital walls. Using a drop tower with an accelerometer, we measured impact force on the globe and rim of cadaver heads affixed with strain gauges. RESULTS:The mean impacts for rim and globe trauma were 3.9 J (95% CI, 3.4-4.3 J) and 3.9 J (95% CI, 3.5-4.3 J), respectively. Despite similar impact forces to the globe and rim, strain-gauge data displayed greater mean strain for globe impact (6563 μS) compared with rim impact (3530 μS); however, these data were not statistically significant (95% CI, 3598-8953 μS; P = .94). CONCLUSIONS AND RELEVANCE:Our results suggest that trauma directly to the globe predisposes a patient to a more posterior fracture while trauma to the rim demonstrates an anterior predilection. Both the hydraulic and buckling mechanisms of fracture exist and demonstrate similar fracture thresholds. LEVEL OF EVIDENCE:NA.
10.1001/jamafacial.2016.2153
Thyroid-associated Ophthalmopathy.
Şahlı Esra,Gündüz Kaan
Turkish journal of ophthalmology
Thyroid-associated ophthalmopathy is the most frequent extrathyroidal involvement of Graves' disease but it sometimes occurs in euthyroid or hypothyroid patients. Thyroid-associated ophthalmopathy is an autoimmune disorder, but its pathogenesis is not completely understood. Autoimmunity against putative antigens shared by the thyroid and the orbit plays a role in the pathogenesis of disease. There is an increased volume of extraocular muscles, orbital connective and adipose tissues. Clinical findings of thyroid-associated ophthalmopathy are soft tissue involvement, eyelid retraction, proptosis, compressive optic neuropathy, and restrictive myopathy. To assess the activity of the ophthalmopathy and response to treatment, clinical activity score, which includes manifestations reflecting inflammatory changes, can be used. Supportive approaches can control symptoms and signs in mild cases. In severe active disease, systemic steroid and/or orbital radiotherapy are the main treatments. In inactive disease with proptosis, orbital decompression can be preferred. Miscellaneous treatments such as immunosuppressive drugs, somatostatin analogs, plasmapheresis, intravenous immunoglobulins and anticytokine therapies have been used in patients who are resistant to conventional treatments. Rehabilitative surgeries are often needed after treatment.
10.4274/tjo.80688
United States Multicenter Clinical Trial of Corneal Collagen Crosslinking for Keratoconus Treatment.
Hersh Peter S,Stulting R Doyle,Muller David,Durrie Daniel S,Rajpal Rajesh K,
Ophthalmology
PURPOSE:To evaluate the safety and efficacy of corneal collagen crosslinking (CXL) for the treatment of progressive keratoconus. DESIGN:Prospective, randomized, multicenter, controlled clinical trial. PARTICIPANTS:Patients with progressive keratoconus (n = 205). METHODS:The treatment group underwent standard CXL and the sham control group received riboflavin alone without removal of the epithelium. MAIN OUTCOME MEASURES:The primary efficacy criterion was the change over 1 year of topography-derived maximum keratometry value, comparing treatment with control group. Secondary outcomes evaluated were corrected distance visual acuity (CDVA), uncorrected distance visual acuity (UDVA), manifest refraction spherical equivalent, endothelial cell count, and adverse events. RESULTS:In the CXL treatment group, the maximum keratometry value decreased by 1.6 diopters (D) from baseline to 1 year, whereas keratoconus continued to progress in the control group. In the treatment group, the maximum keratometry value decreased by 2.0 D or more in 28 eyes (31.5%) and increased by 2.0 D or more in 5 eyes (5.6%). The CDVA improved by an average of 5.7 logarithm of the minimum angle of resolution (logMAR) units. Twenty-three eyes (27.7%) gained and 5 eyes lost (6.0%) 10 logMAR or more. The UDVA improved 4.4 logMAR. Corneal haze was the most frequently reported CXL-related adverse finding. There were no significant changes in endothelial cell count 1 year after treatment. CONCLUSIONS:Corneal collagen crosslinking was effective in improving the maximum keratometry value, CDVA, and UCVA in eyes with progressive keratoconus 1 year after treatment, with an excellent safety profile. Corneal collagen crosslinking affords the keratoconic patient an important new option to decrease progression of this ectatic corneal process.
10.1016/j.ophtha.2017.03.052
New methods in the diagnosis of cancer and gene therapy of cancer based on nanoparticles.
Zaimy M A,Saffarzadeh N,Mohammadi A,Pourghadamyari H,Izadi P,Sarli A,Moghaddam L K,Paschepari S R,Azizi H,Torkamandi S,Tavakkoly-Bazzaz J
Cancer gene therapy
Cancer is one of the leading cause of death in the world with the prevalence of >10 million mortalities annually. Current cancer treatments include surgical intervention, radiation, and taking chemotherapeutic drugs, which often kill the healthy cells and result in toxicity in patients. Therefore, researchers are looking for ways to be able to eliminate just cancerous cells. Intra-tumor heterogeneity of cancerous cells is the main obstacle on the way of an effective cancer treatment. However, better comprehension of molecular basis of tumor and the advent of new diagnostic technologies can help to improve the treatment of various cancers. Therefore, study of epigenetic changes, gene expression of cancerous cells and employing methods that enable us to correct or minimize these changes is critically important. In this paper, we will review the recent advanced strategies being used in the field of cancer research.
10.1038/cgt.2017.16
Neutrophil-to-lymphocyte ratio in thyroid ophthalmopathy.
Celik T
Bratislavske lekarske listy
PURPOSE:To evaluate the neutrophil-to-lymphocyte ratio (NLR) levels to predict the severity of inflammation in thyroid ophthalmopathy (TO). METHODS:Fifty-six patients with TO and 40 healthy subjects were included in this study. TO patients were divided into two groups according to clinical activity score (CAS). Group 1 included 24 active TO patients and Group 2 included 32 inactive TO patients. The thyroid status, white blood cell (WBC), neutrophil, and lymphocyte counts were performed. NLR was calculated by dividing the neutrophil count by the lymphocyte count. RESULTS:The mean age was 53.6 ± 5.4 in active TO group, 54.2 ± 5.6 in inactive TO group, and 52.7 ± 5.2 in the control group. The WBC, neutrophil, lymphocyte and NLR levels were higher in patients with TO than in the control group (p < 0.05). A significant difference in NLR was found between the inactive and active TO groups (p < 0.05). CONCLUSION:NLR values were found to be higher in patients with TO than in controls. NLRvalues were also found higher in active TO patients than in inactive TO patients (Tab. 3, Ref. 26).
10.4149/BLL_2017_095
Effects of infraorbital nerve's anatomical course on the fracture pattern of the orbital floor.
Kim Junhyung,Park Sang Woo,Choi Jaehoon,Jeong Woonhyeok,Kim Ryeolwoo
Journal of plastic, reconstructive & aesthetic surgery : JPRAS
In this study, details of the infraorbital nerve's (ION's) anatomical course variants were compared using computed tomography (CT), and relationships between the variants and fracture patterns in the orbital floor were investigated. Fifty-two normal individuals and 50 patients with unilateral isolated orbital floor fractures were enrolled in this study. Four measurements in normal individuals and five measurements in fracture patients were obtained in parasagittal sections. The anatomical variations of the ION were categorized into three types according to the classification by Ferences et al. Among the normal individuals, 42 orbits were classified as type 1 ION, 48 orbits as type 2, and 14 orbits as type 3. The distance from the inferior orbital rim to the upper border of the inferior orbital foramen and the length of descension portion of the ION in type 1 ION were significantly shorter than in type 2 and type 3 IONs. In patients with orbital floor fractures, the distance from the inferior orbital rim to the upper border of the inferior orbital foramen was positively correlated with herniation level of bone and soft tissue. The ION had three anatomical variants according to the degree of descension in the anterior portion of the orbit. When fracture of the orbital floor occurs in patients with type 1 ION, inferior displacement of the fractured orbital bone and orbital soft tissue may be less severe than in patients with other ION types.
10.1016/j.bjps.2017.10.006
Angiopoietin-like protein 8 in early pregnancy improves the prediction of gestational diabetes.
Huang Yun,Chen Xin,Chen Xiaohong,Feng Yu,Guo Heming,Li Sicheng,Dai Ting,Jiang Rong,Zhang Xiaoyan,Fang Chen,Hu Ji
Diabetologia
AIMS/HYPOTHESIS:Screening high-risk individuals for gestational diabetes mellitus (GDM) in early pregnancy conventionally relies on established maternal risk factors; however, the sensitivity and specificity of these factors are not satisfactory. The present study aimed to determine whether the concentration of angiopoietin-like protein 8 (ANGPTL8), either alone or combined with other risk factors in early pregnancy, could be used to predict subsequent GDM. METHODS:From August 2015 to January 2016, 474 women receiving prenatal care at around 12-16 weeks of gestation were recruited into the study. ANGPTL8 levels were measured at the first prenatal visit. All the participants received a 75 g OGTT during weeks 24-28 of gestation. RESULTS:ANGPTL8 levels in early pregnancy were considerably higher in women who developed GDM than those who maintained normal glucose tolerance (2822 ± 938 vs 2120 ± 1118 pg/ml, respectively; p < 0.0001). Multivariable logistic regression revealed that ANGPTL8 levels were significantly associated with risk of GDM independent of conventional risk factors. In addition, women in the highest quartile of ANGPTL8 concentration had an 8.75-fold higher risk of developing GDM compared with women in the lowest quartile (OR8.75, 95%CI 2.43, 31.58). More importantly, incorporating ANGPTL8 into the conventional prediction model significantly increased the AUC for prediction of GDM (0.772vs 0.725; p = 0.019). CONCLUSIONS:Our study suggests that ANGPTL8 levels in early pregnancy are significantly and independently associated with risk of GDM at 24-28 weeks of gestation. Combining ANGPTL8 levels with conventional risk factors could thus improve the prediction of GDM.
10.1007/s00125-017-4505-y
A nomogram to predict the survival of stage IIIA-N2 non-small cell lung cancer after surgery.
Mao Qixing,Xia Wenjie,Dong Gaochao,Chen Shuqi,Wang Anpeng,Jin Guangfu,Jiang Feng,Xu Lin
The Journal of thoracic and cardiovascular surgery
OBJECTIVE:Postoperative survival of patients with stage IIIA-N2 non-small cell lung cancer (NSCLC) is highly heterogeneous. Here, we aimed to identify variables associated with postoperative survival and develop a tool for survival prediction. METHODS:A retrospective review was performed in the Surveillance, Epidemiology, and End Results database from January 2004 to December 2009. Significant variables were selected by use of the backward stepwise method. The nomogram was constructed with multivariable Cox regression. The model's performance was evaluated by concordance index and calibration curve. The model was validated via an independent cohort from the Jiangsu Cancer Hospital Lung Cancer Center. RESULTS:A total of 1809 patients with stage IIIA-N2 NSCLC who underwent surgery were included in the training cohort. Age, sex, grade, histology, tumor size, visceral pleural invasion, positive lymph nodes, lymph nodes examined, and surgery type (lobectomy vs pneumonectomy) were identified as significant prognostic variables using backward stepwise method. A nomogram was developed from the training cohort and validated using an independent Chinese cohort. The concordance index of the model was 0.673 (95% confidence interval, 0.654-0.692) in training cohort and 0.664 in validation cohort (95% confidence interval, 0.614-0.714). The calibration plot showed optimal consistency between nomogram predicted survival and observed survival. Survival analyses demonstrated significant differences between different subgroups stratified by prognostic scores. CONCLUSIONS:This nomogram provided the individual survival prediction for patients with stage IIIA-N2 NSCLC after surgery, which might benefit survival counseling for patients and clinicians, clinical trial design and follow-up, as well as postoperative strategy-making.
10.1016/j.jtcvs.2017.11.098
Relationship between serum cholesterol and Graves' orbitopathy (GO): a confirmatory study.
Lanzolla G,Sabini E,Profilo M A,Mazzi B,Sframeli A,Rocchi R,Menconi F,Leo M,Nardi M,Vitti P,Marcocci C,Marinò M
Journal of endocrinological investigation
BACKGROUND:It has been suggested that high cholesterol represents a risk factor for Graves' orbitopathy (GO). In a recent cross-sectional study, a correlation between cholesterol and the presence of GO was found in patients with a Graves' disease (GD) of recent onset. To confirm this observation, we conducted a retrospective investigation in consecutive patients with GD. The primary outcome was the relationship between the presence of GO and low-density lipoprotein (LDL)-cholesterol. METHODS:The design entailed the inclusion of consecutive patients with a GD of recent onset, with or without GO, who came to our observation to receive radioiodine over a period of 6 months, and a stratification aimed at having two homogeneous group of patients in terms of thyroid function. A total of 86 patients fulfilled the inclusion and evaded the exclusion criteria. All patients underwent an ophthalmological assessment and serum lipids were measured. RESULTS:Serum levels of LDL-cholesterol were significantly higher in patients with GO (135.3 ± 41.3 mg/dL) compared with those without GO (106.6 ± 23.9 mg/dL, P = 0.0007). In a similar manner, serum levels of total cholesterol were higher in patients with GO (211.6 ± 44.0 mg/dL) than in those without GO (176.0 ± 27.2 mg/dL, P = 0.0001). There was no relationship between GO severity and activity and cholesterol. There was no relationship between GO and high-density lipoprotein-cholesterol or triglycerides. CONCLUSIONS:Our study confirms a relationship between the presence of GO and cholesterol in patients with GD of recent onset. Whether lowering of cholesterol ameliorates, GO remains to be established.
10.1007/s40618-018-0915-z
Tumor microenvironment: recent advances in various cancer treatments.
Wang J-J,Lei K-F,Han F
European review for medical and pharmacological sciences
This is a review regarding different types of cancer treatments. We aimed at analyzing the tumor microenvironment and the recent trends for the therapeutic applications and effectiveness for several kinds of cancers. Traditionally the cancer treatment was based on the neoplastic cells. Methods such as surgery, radiation, chemotherapy, and immunotherapy, which were targeted on the highly proliferating mutated tumor cells, have been investigated. The tumor microenvironment describes the non-cancerous cells in the tumor and has enabled to investigate the behavior and response of the cancer cells to a treatment process; it consists in a tissue that may have a predictive significance for tumor behavior and response to therapy. These include fibroblasts, immune cells and cells that comprise the blood vessels. It also includes the proteins produced by all of the cells present in the tumor that support the growth of the cancer cells. By monitoring changes in the tumor microenvironment using its molecular and cellular profiles as the tumor progresses will be vital for identifying cell or protein targets for the cancer prevention and its therapeutic purposes.
10.26355/eurrev_201806_15270
Recent Updates on the Relationship between Cancer and Autoimmune Pancreatitis.
Okamoto Ayana,Watanabe Tomohiro,Kamata Ken,Minaga Kosuke,Kudo Masatoshi
Internal medicine (Tokyo, Japan)
Autoimmune pancreatitis (AIP) is now considered a pancreatic manifestation of a newly proposed disease condition, IgG4-related disease (IgG4-RD). IgG4-RD is characterized by enhanced IgG4 antibody responses and multiple organ involvements. Recent epidemiological studies have addressed the incidence of cancer in patients with AIP and/or IgG4-RD. Surprisingly, a significant number of AIP patients were detected with cancer at or within one year of the diagnosis of AIP. Furthermore, around 50% of all cancers detected in AIP patients comprised mainly 3 types (gastric, lung, and prostate cancer). Thus, AIP appears to be associated with cancer of other organs rather than the pancreas itself, which suggests that AIP is not a pre-cancerous condition of the pancreas. Moreover, the simultaneous occurrence of cancer and AIP in many patients has led to the establishment of an attractive concept that AIP might sometimes arise from co-existing cancers as a paraneoplastic syndrome.
10.2169/internalmedicine.2210-18
Association of Type 1 Diabetes With Standardized Test Scores of Danish Schoolchildren.
Skipper Niels,Gaulke Amanda,Sildorf Stine Møller,Eriksen Tine M,Nielsen Nick Fabrin,Svensson Jannet
JAMA
Importance:Type 1 diabetes has been associated with cardiovascular disease and late complications such as retinopathy and nephropathy. However, it is unclear whether there is an association between type 1 diabetes and school performance in children. Objective:To compare standardized reading and mathematics test scores of schoolchildren with type 1 diabetes vs those without diabetes. Design, Setting, and Participants:Population-based retrospective cohort study from January 1, 2011, to December 31, 2015 (end date of follow-up), including Danish public schoolchildren attending grades 2, 3, 4, 6, and 8. Test scores were obtained in math (n = 524 764) and reading (n = 1 037 006). Linear regression models compared outcomes with and without adjustment for socioeconomic characteristics. Exposures:Type 1 diabetes. Main Outcomes and Measures:Primary outcomes were pooled test scores in math and reading (range, 1-100). Results:Among 631 620 included public schoolchildren, the mean (SD) age was 10.31 (SD, 2.42) years, and 51% were male; 2031 had a confirmed diagnosis of type 1 diabetes. Overall, the mean combined score in math and reading was 56.11 (SD, 24.93). There were no significant differences in test scores found between children with type 1 diabetes (mean, 56.56) and children without diabetes (mean, 56.11; difference, 0.45 [95% CI, -0.31 to 1.22]). The estimated difference in test scores between children with and without type 1 diabetes from a linear regression model with adjustment for grade, test topic, and year was 0.24 (95% CI, -0.90 to 1.39) and 0.45 (95% CI, -0.58 to 1.49) with additional adjustment for socioeconomic status. Conclusions and Relevance:Among Danish public schoolchildren, there was no significant difference in standardized reading and mathematics test scores of children with type 1 diabetes compared with test scores of children without diabetes.
10.1001/jama.2018.21819
Computed Tomography-Based Prediction of Exophthalmos Reduction After Deep Lateral Orbital Wall Decompression for Graves' Orbitopathy.
Kitaguchi Yoshiyuki,Takahashi Yasuhiro,Kakizaki Hirohiko
Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie
PURPOSE:To examine the predictability of exophthalmos reduction using preoperative computed tomography (CT) in deep lateral orbital wall decompression for Graves' orbitopathy. METHODS:This was a retrospective, observational, case-control study conducted at a single institution. Forty-three patients (43 orbits) who were treated with deep lateral decompression with (27 patients) and without (16 patients) fat removal. Multivariate linear regression analyses were used to identify factors influencing exophthalmos reduction 3 months postoperatively. Variables investigated included age; smoking history; history of corticosteroid therapy and/or radiotherapy; preoperative diplopia; width, depth, and height of the greater wing of the sphenoid bone (trigone); and volume of fat removed. The influence of these parameters on the area of the orbital opening was also analyzed. RESULTS:Trigone width and amount of fat removed were positively correlated with exophthalmos reduction (both, P < .050); none of the other variables exhibited significant correlations. The predictive equation for postoperative reduction in Hertel exophthalmometric values was 0.57 + 0.15 × trigone width (mm) + 1.1 × fat removed (cm). Depth and height were positively correlated (both, P < .050) and width was negatively correlated (P = .0045) with orbital opening area. CONCLUSIONS:Trigone width and amount of fat removed were positive predictors of exophthalmos reduction after deep lateral decompression. Trigone width was inversely associated with orbital width, and results showed that larger exophthalmos reductions could be achieved in narrower orbits. This CT-based prediction method will assist preoperative decision-making regarding additional fat removal and/or removal of another orbital wall.
10.1007/s00417-019-04500-1
Intraorbital Steroid Injection for Active Thyroid Ophthalmopathy.
Journal of ophthalmic & vision research
PURPOSE:To evaluate the effect of orbital steroid injections in patients with active thyroid ophthalmopathy resistant to or dependent on systemic steroids, or with complications related to systemic steroid use. METHODS:This prospective non-comparative case series includes 31 eyes of 17 patients with active thyroid ophthalmopathy and clinical activity score (CAS) of 3 or more, without compressive optic neuropathy or overt exposure keratopathy. All subjects had a history of previous systemic steroid use (with steroid resistance or dependence) or had developed complications related to steroids. A combination of steroids including triamcinolone acetonide 20 mg and dexamethasone 4 mg was injected in the upper and lower retroseptal orbital spaces three or four times at one-month intervals. The patients were examined periodically after each injection and at least three months after the last injection. RESULTS:Mean pre-injection CAS was 5.2 1.3 which was improved to 1.6 1 after the fourth injection ( 0.001). Upper and lower lid retraction improved in 100% and 68.2% of the affected eyes, respectively. Strabismus completely resolved in one of five affected patients and the most significant improvement was observed in supraduction. Mean improvement in exophthalmos was 1.2 1.1 mm. Visual acuity did not significantly change after the injections. Eyelid ecchymosis and/or subconjunctival hemorrhage was observed in 7.1% and intraocular pressure rise occurred in 8.8% of eyes. CONCLUSION:Orbital steroid injections can be used for the treatment of active thyroid ophthalmopathy when the patient is resistant to or dependent on systemic steroids or has developed complications of systemic steroids.
10.18502/jovr.v15i1.5948
Correlation between serum anti-TSH receptor autoantibodies (TRAbs) and the clinical feature of Graves' orbitopathy.
Nicolì F,Lanzolla G,Mantuano M,Ionni I,Mazzi B,Leo M,Sframeli A,Posarelli C,Maglionico M N,Figus M,Nardi M,Marcocci C,Marinò M
Journal of endocrinological investigation
BACKGROUND:Graves' orbitopathy (GO) is the most common extrathyroidal manifestation of Graves' disease (GD). Several studies support the involvement of TSH receptor autoantibodies (TRAbs) in the pathogenesis of GO, and a correlation between GO features and TRAbs has been reported, but not confirmed by all studies. Thus, we conducted a cross-sectional investigation to determine whether there is a correlation between TRAbs and the clinical features of GO in an initial phase of the eye disease. METHODS:Ninety consecutive patients with untreated GO (67 women and 23 men, age 48.9 ± 12.6 years) were included. Patients who had received treatments other than anti-thyroid drugs for hyperthyroidism or lubricants for GO were excluded. All patients underwent an endocrinological and ophthalmological evaluation, the latter including exophthalmometry, measurement of eyelid width, clinical activity score (CAS), visual acuity, assessment of diplopia, and NOSPECS score. TRAb levels were measured by a third-generation competitive immunoassay. RESULTS:There was a statistically significant, direct correlation between serum TRAb levels and CAS by linear regression analysis (R = 0.278, P = 0.007). The correlation was confirmed by a multiple regression analysis (R = 0.285; P = 0.006) including age and FT3 levels, which also correlated with CAS. There were no relationships between TRAbs and exophthalmometry, eyelid aperture, degree of diplopia, visual acuity, and NOSPECS score. CONCLUSIONS:The levels of TRAb in subjects with a recent-onset, untreated GO are directly correlated with the clinical activity of the disease, confirming a possible role of these antibodies in the pathogenesis of GO.
10.1007/s40618-020-01353-y
Prevalence and severity of orbital blowout fractures.
Khojastepour L,Moannaei M,Eftekharian H R,Khaghaninejad M S,Mahjoori-Ghasrodashti M,Tavanafar S
The British journal of oral & maxillofacial surgery
We aimed to study the prevalence of orbital blowout fractures and evaluate the causes and the location of orbital cavity fractures. In this cross-sectional study, the medical records of all patients admitted with facial trauma were assessed, sociodemographic information as well as the aetiology of trauma extracted, and the computed tomographic images of the patients were reassessed. Location of orbital blowout fractures and the severity of orbital fractures were evaluated. A total of 203 cases had blowout fractures (175 male and 28 female patients with a mean (SD) age of 36 (16) years. Road traffic accidents (n=139, 69%) were the most common cause of orbital blowout fractures. Falls (n=29, 14%) and assault (n=20, 10%) were the other causes of trauma to the orbital structure, which resulted in blowout fractures. The medial wall was the most commonly involved location (n=81, 40%) followed by orbital floor (n=64, 32%), the combination of medial wall and floor (n=36, 18%), medial wall and maxilloethmoidal strut combination (n=13, 6%), and all the three locations altogether (n=9, 4%). Most of the blow-out fractures had mild severity (n=107, 53%). There was a significant relation between the severity and location of the blowout fractures (p<0.001).
10.1016/j.bjoms.2020.07.001
Peribulbar injection of glucocorticoids for thyroid-associated ophthalmopathy and factors affecting therapeutic effectiveness: A retrospective cohort study of 386 cases.
Wang Yujiao,Du Baixue,Yang Mei,Zhu Yanyan,He Weimin
Experimental and therapeutic medicine
Thyroid-associated ophthalmopathy (TAO) is common in Graves' disease. However, to date, no standard treatment has been established for TAO. The present study aimed to assess peribulbar injection of corticosteroids for TAO treatment as well as factors affecting therapeutic effectiveness. A retrospective cohort study was performed at West China Hospital, Sichuan University (Chengdu, China). Patients with TAO were administered peribulbar injection of triamcinolone acetonide and dexamethasone monthly. Ocular signs after each injection were assessed until the end of treatment. All patients were followed up for at least six months. Best corrected visual acuity, proptosis values, eye motility assessed by the Hess chart, as well as eyelid width and downward movement were determined. In addition, clinical data were retrospectively reviewed to explore factors affecting therapeutic effectiveness by logistic regression analysis. In the present study, 386 patients with TAO (515 eyes) were evaluated; 71.37% of cases of eyelid swelling were relieved and upper eyelid retraction was improved in 47.58% of affected patients. Eye movement disorders, diplopia and strabismus were all alleviated to varying degrees, with few adverse reactions. Logistic regression analysis demonstrated that therapeutic effectiveness was relatively lower in males [odds ratio (OR)=0.32, P=0.001] and patients with thyroid dysfunction (OR=0.41, P=0.002), and that non-smokers had a higher odds of substantial improvement (OR=4.62, P=0.008). The duration of TAO was not significantly associated with the clinical outcome. Patients with reduced disease severity and elevated clinical activity score exhibited higher effectiveness (all P<0.05). In conclusion, peribulbar injection of corticosteroids is effective in treating mild to moderate TAO, with the therapeutic response affected by gender, smoking and disease severity.
10.3892/etm.2020.8896
Neutrophil-to-Lymphocyte, Monocyte-to-Lymphocyte and Platelet-to-Lymphocyte Ratios in Relation to Clinical Parameters and Smoking Status in Patients with Graves' Orbitopathy-Novel Insight into Old Tests.
Journal of clinical medicine
Graves' orbitopathy (GO) is an autoimmune disease with a chronic inflammatory background. Smoking behavior is the main environmental factor responsible for the transition of this major extra thyroidal manifestation of Graves' disease (GD) from the subclinical to the overt form. Complete blood count-derived parameters are suggested to be novel inflammatory indices. The aim of this retrospective study was to investigate the association between neutrophil-to-lymphocyte (NLR), monocyte-to-lymphocyte (MLR), and platelet-to-lymphocyte ratios (PLR) with selected clinical parameters and smoking status in 406 GD patients with ( = 168) and without GO ( = 238). The control group consisted of 100 healthy individuals. The activity of GO was graded according to Clinical Activity Score. Significantly higher white blood cells (WBC), neutrophil, and NLR ( < 0.05) values were observed in GD patients with GO compared with those without GO. PLR values were significantly higher in GO patients than in the controls. WBC (6.81 ± 1.56 vs. 5.70 ± 1.23) and neutrophils (3.89 ± 1.06 vs. 3.15 ± 0.95) count was higher in active GO patients than in those with inactive GO. Positive correlation ( < 0.05) between CAS score and WBC, neutrophil and monocyte count, and NLR was found. Smoking was associated with higher WBC ( = 0.040), neutrophil ( = 0.049), PLR ( = 0.032) values. Multivariate analysis revealed that WBC, NLR may be risk factors for GO development. WBC, neutrophil, NLR and PLR values seem to be useful tools in the assessment of inflammation in GD.
10.3390/jcm9103111
Epidemiology, Natural History, Risk Factors, and Prevention of Graves' Orbitopathy.
Bartalena Luigi,Piantanida Eliana,Gallo Daniela,Lai Adriana,Tanda Maria Laura
Frontiers in endocrinology
GO is the most frequent extrathyroidal manifestation of Graves' disease, although it may rarely occur in euthyroid/hypothyroid patients with chronic autoimmune thyroiditis. It is a relatively infrequent disorder, and men tend to have more severe ocular involvement at an older age. The prevalence of GO is lower than in the past among patients with recent onset Graves' hyperthyroidism, and moderate-to-severe forms requiring aggressive treatments are no more than 5-6% of all cases of GO. After an initial inflammatory (active) phase and a phase of stabilization (plateau phase), GO tends to improve and eventually inactivates (inactive or burnt-out phase). Minimal-to-mild GO often remits spontaneously, but complete almost never occurs when GO is more than mild. Several risk factors contribute to its development on a yet undefined genetic background. Cigarette smoking is the most important of them. Early diagnosis, control and removal of modifiable risk factors, early treatment of mild forms of GO may effectively limit the risk of progression to more severe forms, which have a profound and dramatic impact on the quality of life of affected individuals, and remain a therapeutic challenge, often requiring long-lasting and multiple medical and surgical therapies.
10.3389/fendo.2020.615993
Prognostic factors of restrictive myopathy in thyroid eye disease.
Choi Jae Hwan,Noh Hoon,Kim Yoon-Duck,Woo Kyung In
Scientific reports
To investigate the prognostic factors of extraocular muscle restriction in patients with thyroid eye disease (TED), 65 patients with TED and restrictive myopathy were evaluated. Demographics, clinical activity score (CAS), smoking status, thyroid disease status, thyroid hormone status, thyroid autoantibody status, orbital computed tomography (CT) scan at initial presentation, and treatment regimens were assessed. The movements of the most severely affected extraocular muscles were categorized into five grades. The patients were divided into the improved and the not-improved group based on the improvement in the limitation of the extraocular muscle excursion (LOM) throughout the follow-up, and the groups were compared using clinical factors. The mean LOM significantly improved from 2.3 ± 1.1 to 1.7 ± 1.2 after 1 year of follow-up. The excursion of the most restricted muscle improved in 32 patients but not in 33 patients during the follow-up. The initial concentration of the thyroid-stimulating antibody (TSAb) was significantly lower in the improved (229.3 ± 114.1) than in the not-improved group (345.0 ± 178.6) (P = 0.02) Age, sex, smoking status, CAS, thyroid status, and muscle thickness on the CT scan did not significantly differ in the groups. This study showed that the initial concentration of TSAb is a factor affecting the recovery of restrictive myopathy.
10.1038/s41598-021-93275-9
Imaging of the medial rectus muscle predicts the development of optic neuropathy in thyroid eye disease.
Scientific reports
Goal of the study was to evaluate bony orbit remodeling and extraocular muscle (EOM) volume in thyroid eye disease (TED) and their role as predicting factors for development of dysthyroid optic neuropathy (DON). Orbital computed tomography of 92 patients with TED with (76 orbits) or without DON (98 orbits) were retrospectively evaluated. Orbits (n = 40) of subjects without TED served as controls. Measurements of the bony orbit as well as EOM volume were incorporated into a generalized linear mixed model to predict DON. The angle of the medial orbital wall was significantly smaller (p < 0.001) in patients with TED (- 2.3 ± 3.6°) compared to patients with TED + DON (1.0 ± 4.1°). Both groups differed significantly from controls (- 4.2 ± 2.7°). Bowing of the medial orbital wall correlated positively with muscle volume (r = 0.564; p < 0.001). Total EOM volume was significantly larger in TED + DON (7.6 ± 2.5cm) compared to TED only (5.6 ± 3.0cm; p < 0.001) or controls (2.6 ± 0.5cm). Multivariate analysis revealed the medial rectus muscle volume (TED: 1.06 ± 0.48cm vs. TED + DON: 2.16 ± 0.84cm) as the strongest predictor, achieving a specifity of 86.7% and a sensitivity of 73.7% in diagnosing DON in univariate analysis. Though characterized by a wide range of variability, increased medial rectus muscle volume is the strongest predictor for DON in our patient cohort with TED when analyzing a single muscle.
10.1038/s41598-022-10043-z
The Incidence and Risk Factors of Medial and Inferior Orbital Wall Fractures in Korea: A Nationwide Cohort Study.
Journal of clinical medicine
PURPOSE:We aimed to investigate orbital wall fracture incidence and risk factors in the general Korean population. METHOD:The Korea National Health Insurance Service-National Sample Cohort dataset was analyzed to find subjects with an orbital wall fracture between 2011 and 2015 (based on the diagnosis code) and to identify incident cases involving a preceding disease-free period of 8 years. The incidence of orbital wall fracture in the general population was estimated, and the type of orbital wall fracture was categorized. Sociodemographic risk factors were also examined using Cox regression analysis. RESULTS:Among 1,080,309 cohort subjects, 2415 individuals with newly diagnosed orbital wall fractures were identified. The overall incidence of orbital wall fractures was estimated as 46.19 (95% CI: 44.37-48.06) per 100,000 person-years. The incidence was high at 10-29 and 80+ years old and showed a male predominance with an average male-to-female ratio of 3.33. The most common type was isolated inferior orbital wall fracture (59.4%), followed by isolated medial orbital wall fracture (23.7%), combination fracture (15.0%), and naso-orbito-ethmoid fracture (1.5%). Of the fracture patients, 648 subjects (26.8%) underwent orbital wall fracture repair surgeries. Male sex, rural residence, and low income were associated with an increased risk of orbital wall fractures. CONCLUSIONS:The incidence of orbital wall fractures in Korea varied according to age groups and was positively associated with male sex, rural residency, and low economic income. The most common fracture type was an isolated inferior orbital wall fracture.
10.3390/jcm11092306
Risk prediction of dysthyroid optic neuropathy based on CT imaging features combined the bony orbit with the soft tissue structures.
Frontiers in medicine
Purpose:To analyze computed tomographic (CT) imaging features of patients with dysthyroid optic neuropathy (DON) retrospectively and deduce a more appropriate predictive model. Methods:The CT scans and medical records of 60 patients with clinically proven Graves' ophthalmopathy (GO) with (26 women and 10 men) and without DON (16 women and 8 men) were retrospectively reviewed, and 20 age- and sex-matched control participants (12 women and 8 men) were enrolled consecutively. The bony orbit [orbital rim angle (ORA), medial and lateral orbital wall angles (MWA and LWA), orbital apex angle (OAA), and length of the lateral orbital wall (LWL)], and the soft tissue structures [maximum extraocular muscle diameters (Max EOMD), muscle diameter index (MDI), medial and lateral rectus bulk from inter-zygomatic line (MRIZL and LRIZL), proptosis, intraorbital optic nerve stretching length (IONSL), superior ophthalmic vein diameter (SOVD), apical crowding, and presence of intracranial fat prolapse] were assessed on a clinical workstation. The CT features among groups were compared, and a multivariate logistic regression analysis was performed to evaluate the predictive features of DON. Results:All bony orbital angle indicators, except ORA ( = 0.461), were statistically different among the three groups (all < 0.05). The values of MWA, LWA, OAA, and LWL were larger in the orbits with the DON group than in the orbits without the DON group (all < 0.05). The MDI, MRIZL, proptosis, IONSL, and SOVD were statistically significantly different among the three groups (all < 0.05), in which the orbits with the DON group were significantly higher than the orbits without the DON group and control group. The apical crowding was more severe in the orbits with the DON group than in the orbits without the DON group ( = 0.000). There were no significant differences in the LRIZL and the presence of intracranial fat prolapse (all > 0.05). The multivariate regression analysis showed that the MWA, MDI, and SOVD were the independent factors predictive of DON. The sensitivity and specificity for the presence of DON by combining these three indicators were 89 and 83%, respectively. Conclusion:Bone and soft tissue CT features are useful in the risk prediction of DON, especially the MWA, MDI, and SOVD were the independent factors predictive of DON.
10.3389/fmed.2022.936819
Acupuncture for Chronic Severe Functional Constipation: A Randomized Trial.
Liu Zhishun,Yan Shiyan,Wu Jiani,He Liyun,Li Ning,Dong Guirong,Fang Jianqiao,Fu Wenbin,Fu Lixin,Sun Jianhua,Wang Linpeng,Wang Shun,Yang Jun,Zhang Hongxing,Zhang Jianbin,Zhao Jiping,Zhou Wei,Zhou Zhongyu,Ai Yanke,Zhou Kehua,Liu Jia,Xu Huanfang,Cai Yuying,Liu Baoyan
Annals of internal medicine
BACKGROUND:Acupuncture has been used for chronic constipation, but evidence for its effectiveness remains scarce. OBJECTIVE:To determine the efficacy of electroacupuncture (EA) for chronic severe functional constipation (CSFC). DESIGN:Randomized, parallel, sham-controlled trial. (ClinicalTrials.gov: NCT01726504). SETTING:15 hospitals in China. PARTICIPANTS:Patients with CSFC and no serious underlying pathologic cause for constipation. INTERVENTION:28 sessions of EA at traditional acupoints or sham EA (SA) at nonacupoints over 8 weeks. MEASUREMENTS:The primary outcome was the change from baseline in mean weekly complete spontaneous bowel movements (CSBMs) during weeks 1 to 8. Participants were followed until week 20. RESULTS:1075 patients (536 and 539 in the EA and SA groups, respectively) were enrolled. The increase from baseline in mean weekly CSBMs during weeks 1 to 8 was 1.76 (95% CI, 1.61 to 1.89) in the EA group and 0.87 (CI, 0.73 to 0.97) in the SA group (between-group difference, 0.90 [CI, 0.74 to 1.10]; P < 0.001). The change from baseline in mean weekly CSBMs during weeks 9 to 20 was 1.96 (CI, 1.78 to 2.11) in the EA group and 0.89 (CI, 0.69 to 0.95) in the SA group (between-group difference, 1.09 [CI, 0.94 to 1.31]; P < 0.001). The proportion of patients having 3 or more mean weekly CSBMs in the EA group was 31.3% and 37.7% over the treatment and follow-up periods, respectively, compared with 12.1% and 14.1% in the SA group (P < 0.001). Acupuncture-related adverse events during treatment were infrequent in both groups, and all were mild or transient. LIMITATIONS:Longer-term follow-up was not assessed. Acupuncturists could not be blinded. CONCLUSION:Eight weeks of EA increases CSBMs and is safe for the treatment of CSFC. Additional study is warranted to evaluate a longer-term treatment and follow-up. PRIMARY FUNDING SOURCE:Ministry of Science and Technology of the People's Republic of China through the Twelfth Five-Year National Science and Technology Pillar Program.
10.7326/M15-3118