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Surgical staging in early-stage uterine cancer is controversial. Preoperative serum CA-125 may be of clinical value in predicting the presence of extra-uterine disease in patients with apparent early-stage endometrial cancer. Between October 6, 2005, and June 17, 2010, 760 patients were enrolled in an international, multicentre, prospective randomized trial (LACE) comparing laparotomy with laparoscopy in the management of endometrial cancer apparently confined to the uterus. Of these, 657 patients with endometrial adenocarcinoma had a preoperative serum CA-125 value recorded. Multiple cross-validation analysis was undertaken to correlate preoperative serum CA-125 with stage of disease (Stage I vs. Stage II+) after surgery. Patients' median preoperative serum CA-125 was 14 U/ml. A cutoff point of 30 U/ml was associated with the smallest misclassification error, and using this cutoff, 98 patients (14.9%) had elevated CA-125 levels. Of those, 36 (36.7%) had evidence of extra-uterine disease. Of the 116 patients (17.7%) with evidence of extra-uterine disease, 31.0% had an elevated CA-125 level. On univariate and multivariable logistic regression analysis, only preoperative CA-125 level, but no other preoperative clinical characteristics were found to be associated with extra-uterine spread of disease. Utilizing a cutoff point of 30 U/ml achieved a sensitivity, specificity, positive predictive value and negative predictive value of 31.0, 88.5, 36.7 and 85.7%, respectively. Elevated CA-125 above 30 U/ml in patients with apparent early-stage disease is a risk factor for the presence of extra-uterine disease and may assist clinicians in the management of patients with clinical Stage I endometrial cancer. Copyright © 2011 UICC.

Purpose: Diagnosis of dysgerminoma in the paediatric age group is uncommon, and most cases arise from dysgenetic gonads of 46, XY pure gonadal dysgenesis (PGD) patients. Bilateral gonadectomy is mandatory in these patients. So, the preoperative diagnosis of PGD is important in order to avoid multiple surgical procedures and delayed patient information in the case of a suspected 'ovarian' tumour. Our aim was to discuss preoperative clues that can lead to suspicion of dysgerminoma in the context of PGD. Material(s) and Method(s): We reviewed the charts of six patients treated for dysgerminoma associated with 46, XY PGD. We focused on particularities of clinical and biological evaluations. Result(s): Median age at diagnosis was 11 years. Pubertal development was absent or incomplete even at late ages. Dysgerminoma was associated with gonadoblastoma foci in all cases. Tumoral marker profile was a normal alfafetoprotein level, a high lactate dehydrogenase level and normal or moderate human chorionic gonadotropin (betaHCG) secretion, except for one patient who had a mixed tumour with notably a choriocarcinoma share (high betaHCG). Follicle-stimulating hormone (FSH) level was very high in all patients tested and, interestingly, also in one prepubertal patient. Conclusion(s): In the case of a suspected ovarian tumour, delayed pubertal development, moderate betaHCG level and elevated FSH level are clinical and biological clues to a diagnosis of dysgerminoma in the context of PGD and should prompt karyotype analysis before surgery. Because FSH is an efficient indirect marker of this condition, we suggest including this analysis in the management of gonadal tumours. © 2011 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.

Background: Elevated levels of soluble adhesion molecules are found in subjects with vascular disease and inconsistently in subjects with conditions predisposing them to atherosclerosis, such as hypercholesterolaemia and diabetes. Oxidized low density lipoprotein (LDL), protein kinase C and lower than normal levels of NO appear to be important for expression of adhesion molecules, raising the possibility that vitamin E is useful for downregulating levels. We have recently shown that administration of 1000 IU vitamin E for 3 months will improve endothelial vasodilator function (EVF) in uncomplicated type-1 diabetes. Objective(s): To determine whether levels of soluble adhesion molecules in young subjects with uncomplicated diabetes are elevated, whether there is a relationship between levels of soluble adhesion molecule and EVF as well as parameters of diabetes and lipid levels and whether an improvement in EVF related to vitamin E therapy is also associated with a decrease in levels of soluble adhesion molecules. Design(s): A randomized, placebo-controlled, study. Result(s): There was no difference between levels of soluble vascular cell adhesion molecule-1 (VCAM-1; 621 +/- 17 versus 635 +/- 37 ng/ml) and P-selectin (59 +/- 2 versus 57 +/- 6 ng/ml) for the diabetic and control groups. For the diabetic cohort, levels of soluble VCAM-1 were inversely related to flow-mediated vasodilatation of the brachial artery (r=-0.41, P < 0.005) and directly related to levels of total cholesterol (r=0.44, P < 0.005) and LDL cholesterol (r=0.42, P < 0.01) and duration of diabetes (r=0.55, P < 0.0005) but there was no relationship with susceptibility of LDL to oxidation or vitamin-E content of LDL. Levels of soluble P-selectin were directly related to duration of diabetes (r=0.43, P < 0.05) and inversely related to size of LDL particles (r=0.32, P < 0.05) but were not related to EVF. Vitamin E produced no change in levels of soluble P-selectin and VCAM-1. Conclusion(s): Levels of so

Introduction: Pulmonary arterial hypertension is a major cause of mortality in systemic sclerosis. N-terminal pro-brain natriuretic peptide (NT-proBNP) has emerged as a candidate biomarker that may enable the early detection of systemic sclerosis-related pulmonary arterial hypertension (SSc-PAH). The objective of our study was to incorporate NT-proBNP into a screening algorithm for SSc-PAH that could potentially replace transthoracic echocardiography (TTE) as a more convenient and less costly "first tier" test. Method(s): NT-proBNP levels were measured in patients from four clinical groups: a group with right heart catheter (RHC)-diagnosed SSc-PAH before commencement of therapy for PAH; a group at high risk of SSc-PAH based on TTE; a group with interstitial lung disease; and systemic sclerosis (SSc) controls with no cardiopulmonary complications. NT-proBNP levels were compared by using ANOVA and correlated with other clinical variables by using simple and multiple linear regression. ROC curve analyses were performed to determine the optimal cut point for NT-proBNP and other clinical variables in prediction of PAH. Result(s): NT-proBNP was highest in the PAH group compared with other groups (P < 0.0001), and higher in the risk group compared with controls (P < 0.0001). NT-proBNP was positively correlated with systolic pulmonary artery pressure (PAP) on TTE (P < 0.0001), and mean PAP (P = 0.013), pulmonary vascular resistance (P = 0.005), and mean right atrial pressure (P = 0.006) on RHC. A composite model wherein patients screened positive if NT-proBNP was >= 209.8 pg/ml, and/or DLCOcorr was < 70.3% with FVC/DLCOcorr >= 1.82, had a sensitivity of 100% and specificity of 77.8% for SSc-PAH. Conclusion(s): We have proposed a screening algorithm for SSc-PAH, incorporating NT-proBNP level and PFTs. This model has high sensitivity and specificity for SSc-PAH and, if positive, should lead to TTE and confirmatory testing for PAH. This screening algorithm must be validated pr

Leukocyte recruitment contributes to acute kidney injury (AKI), but the mechanisms by which leukocytes promote injury are not completely understood. The degranulation of mast cells releases inflammatory molecules, including TNF, but whether these cells participate in the pathogenesis of AKI is unknown. Here, we induced AKI with cisplatin in mast cell-deficient and wild-type mice. Compared with wild-type mice, deficiency of mast cells attenuated renal injury, reduced serum levels of TNF, and reduced recruitment of leukocytes to the inflamed kidney. Mast cell-deficient mice also exhibited significantly lower intrarenal expression of leukocyte chemoattractants. Mast cell-deficient mice reconstituted with mast cells from wild-type mice exhibited similar cisplastin-induced renal damage and serum levels of TNF as wild-type mice. In contrast, mast cell-deficient mice reconstituted with mast cells from TNF-deficient mice continued to demonstrate significant attenuation of cisplatin-induced renal injury. Furthermore, the mast-cell stabilizer sodium chromoglycate also significantly abrogated renal injury in this model of AKI. Taken together, these results suggest that mast cells mediate AKI through the production of TNF. Copyright © 2011 by the American Society of Nephrology.

Objective: To determine that anti-Mullerian hormone (AMH) has been shown to inhibits E2 production in rodents and in luteinized granulosa cells (GC). We determined whether this occurs in human cells most highly expressing AMH (i.e., from small antral follicles) and whether this is an effect on aromatase promoter activity. We also investigated the effects of AMH on other factors determining FSH sensitivity. Design(s): Granulosa cells were exposed to AMH with and without gonadotropins for 48 hours. Setting(s): University laboratory. Patient(s): Not applicable. Intervention(s): None. Main Outcome Measure(s): Aromatase and FSH receptor messenger RNA expression measured using real time quantitative polymerase chain reaction (PCR). Aromatase promoter II activity measured using a luciferase assay. Estradiol, inhibin A and B, and vascular endothelial growth factor production were measured in the conditioned medium. Result(s): The AMH decreased gonadotropin-stimulated aromatase expression and decreased forskolin-stimulated aromatase in KGN cells and this effect was through a dose-dependent inhibition of promoter II. Surprisingly, AMH also reduced FSH receptor mRNA expression. High AMH doses had no effect on inhibin B, whereas a low dose stimulated production. There was no effect on inhibin A or vascular endothelial growth factor. Conclusion(s): The AMH inhibits factors affecting FSH sensitivity. As AMH levels decrease with follicle growth, this inhibition would be removed. The AMH overproduction in anovulatory polycystic ovaries (PCO) may therefore restrict folliculogenesis by an inhibitory effect on FSH sensitivity, thereby contributing to anovulation. © 2011 American Society for Reproductive Medicine.

Background/Methods: Hepatocyte proliferation in viral hepatitis is regulated by a number of growth factors. Activin-A inhibits hepatocyte DNA synthesis while follistatin, a potent activin-A antagonist, promotes liver regeneration. We report the first study of activin-A and follistatin in human viral hepatitis. Sera from 15 normal subjects, 22 hepatitis B and 47 hepatitis C patients were analysed for activin-A and follistatin and correlated with serological and histological markers of liver injury and with specific immunohistochemistry. Result(s): All groups showed immunoreactivity for activin with hepatocyte localisation. Serum activin-A was significantly increased in viral hepatitis patients compared to controls, was greater in hepatitis B compared to hepatitis C, and correlated with serum aminotransferase and hepatitis B viral replication. A concurrent rise in serum follistatin was not observed in either group, but serum follistatin correlated inversely with hepatitis B DNA levels. Although hepatocyte apoptosis in hepatitis C and proliferation in both groups was significantly elevated compared to controls, there was no correlation with serum activin-A or follistatin. Conclusion(s): Activin-A and follistatin are constitutively expressed in human liver and serum concentrations are increased in viral hepatitis. Dysregulation of the activin/follistatin axis may be linked to hepatitis B replication but does not correlate with hepatocyte apoptosis. © 2001 European Association for the Study of the Liver.

Women with absent ovarian function provide an opportunity to investigate the ovarian contribution to secretion of placental proteins (PP), such as PP14, in early pregnancy. We present data on serum PP14 levels in 12 women (median age, 30.5 yr; range, 26-37 yr) with premature ovarian failure (POF) who conceived after ovum donation and embryo transfer with exogenous sex steroid support using transdermal (n = 5) or oral (n = 7) estradiol and vaginal (n = 8) or im (n = 4) progesterone. The women were closely monitored throughout early pregnancy, with measurement of serum levels of estradiol (E2), progesterone (P4), and PP14. Levels of E2 and P4 were entirely normal. Levels of PP14 were significantly subnormal (P = 0.008) in all 12 agonadal women compared with levels of PP14 in a control group of women with normal ovarian function between 6-12 weeks gestation. Basal and peak levels for subjects with absent ovarian function were 40 and 124 mug/L, respectively. For each week between 6-12 weeks of pregnancy, the mean serum levels of PP14 for women with normal ovarian function were between 706-940 mug/L. These observations support the concept that PP14 arises from the ovary in early pregnancy or that factors under the control of the maternal ovary are involved in its production by the endometrium.

Objective: The optimal strategy for elective distant staging of colorectal carcinoma (CRC) has yet to be defined, with current guidelines based on small and limited series. One specific issue requiring review is the value of routine computerized tomographic (CT) chest examination. Also lacking is data on current routine clinical practice. Method(s): A retrospective chart review of consecutive cases of elective surgery for CRC from five hospitals. Result(s): Two hundred and fifty-seven cases were reviewed, 128 colon and 129 rectal primaries. 164 (64%) of patients overall, ranging from 45% to 88% across the individual centres, had a preoperative serum CEA level performed. CT abdomen/pelvis was performed in 222 (86%) of cases, ranging from 69% to 98% per centre. CT chest was performed in 95 (37%) of cases, 47% of rectal vs 29% of colon cancers (P = 0.004). In 17 cases (18%) CT chest examinations revealed abnormalities suspicious for metastatic disease, leading to a change in management in six (35%) of these cases. Of the 17 cases with an abnormal CT chest, in only 5 of the 14 (36%) where carcinoembryonic antigen (CEA) levels were also recorded was this increased, and in only three (21%) was this markedly (> 10 mug/l) elevated. Conclusion(s): Substantial variability exists in the preoperative evaluation of patients with CRC. Many patients do not have a CEA and/or abdominal imaging performed. Where performed, CT chest revealed suspicious findings in a significant number of patients, the vast majority of whom had a normal or near normal CEA. Future studies are required to define optimal preoperative staging. © Journal compilation © 2009 The Association of Coloproctology of Great Britain and Ireland.

Objective: To assess maternal serum activin A as a potential marker of fetal growth restriction. Design(s): A cohort study. Setting(s): A maternal-fetal medicine unit, university teaching hospital. Population: Fifty-seven women with a small fetus (less than 10th centile for gestation) referred for assessment of fetal size by ultrasound biometry. Method(s): At the time of presentation for fetal biometry, maternal blood was collected for activin A measurement. The case records of each woman were independently reviewed after delivery and the pregnancy grouped into one of three groups: constitutionally small fetus, intrauterine growth restricted (IUGR) fetus or IUGR fetus and maternal pre-eclampsia (IUGR-pre-eclampsia). Activin A levels in the three groups were compared. Main Outcome Measure(s): Maternal serum activin A levels. Result(s): Sixteen of the 57 pregnancies were classified as constitutionally small, 17 as IUGR and 24 as IUGR-pre-eclampsia. Expressed as multiples of a normal median (MoMs), the median (95% CI) activin A level in the constitutionally small pregnancies was 1.12 (0.72-1.39) MoMs significantly lower than the level in both the IUGR pregnancies, 3.00 (1.84-4.11) MoMs, and the IUGR-pre-eclampsia pregnancies, 7.96 (5.73-10.62) MoMs (P = 0.002 and 0.0001 for IUGR vs constitutionally small and IUGR-pre-eclampsia vs constitutionally small, respectively). Conclusion(s): Maternal serum activin A may be useful in the assessment of the small for gestational age fetus.

Background: Differentiating between the small healthy fetus and the high risk growth restricted fetus remains a significant obstetric challenge. It has been previously shown that maternal activin A levels are increased in association with fetal growth restriction. Aim(s): To evaluate maternal serum activin A as a marker of fetal growth restriction. Method(s): Prospective cohort study of 62 women referred for fetal assessment because of a clinical suspicion of a small for gestation fetus. Maternal serum levels of activin A were measured with an ELISA. Result(s): Activin A levels, expressed as median (95% CI) MoMs, were similar in the women with a normal-sized fetus and in those with a healthy small for gestational age fetus, 1.14 (95% CI 1.0-1.5) and 1.31 (95% CI 0.8-2.1), respectively (P = 0.97). Compared to the women with a normal-sized fetus or a healthy small fetus, activin A levels were significantly elevated in the women who had an intrauterine fetal growth restriction fetus 2.37 (95% CI 1.6-3.7; P = 0.01 compared to normal and P = 0.04 compared to healthy small). Conclusion(s): These data confirm that circulating activin A is increased in association with fetal growth restriction. However, a single blood sample for activin A will not efficiently discern between healthy and compromised small fetuses. © 2006 The Authors Journal compilation © 2006 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.

Objective - Activated protein C (APC) resistance not related to the factor V Leiden mutation is a risk factor for venous thrombosis. Oral estrogen replacement therapy (ERT) has been reported to induce APC resistance. Little is known about the effect of transdermal estrogen. Methods and Results - We enrolled 196 postmenopausal women who were randomly allocated to receive either 1 mg 17beta-estradiol orally (n=63) or 50 mug 17beta-estradiol transdermally per day (n=68), both associated with 100 mg progesterone daily or placebo (n=65) for 6 months. An activated partial thromboplastin time (APTT)-based test and the effect of APC on thrombin potential (ETP) were used. Oral ERT induced an ETP-based APC resistance compared with both placebo (P=0.006) and transdermal ERT (P<0.001), but there was no significant effect of transdermal ERT compared with placebo (P=0.191). There was no significant effect of ERT on the APTT-based APC sensitivity ratio. Prothrombin fragment 1+2 plasma levels were significantly higher after 6 months of treatment in women allocated to oral ERT compared with those on placebo and transdermal ERT and were positively and significantly correlated with changes in ETP-based APC sensitivity ratio. Conclusions - Our data show that oral, unlike transdermal, estrogen induces APC resistance and activates blood coagulation. These results emphasize the importance of the route of estrogen administration.

Background: Nephrotic syndrome is defined as urine total protein excretion greater than 3.5 g/d or total protein-creatinine ratio greater than 3.5 g/g, low serum albumin level, high serum cholesterol level, and peripheral edema. These threshold levels have not been rigorously evaluated in patients with diabetic kidney disease or by using urine albumin excretion, the preferred measure of proteinuria in patients with diabetes. Study Design: Diagnostic test study. Setting & Participants: Adults with type 2 diabetes, hypertension, and urine total protein level greater than 0.9 g/d enrolled in the Irbesartan in Diabetic Nephropathy Trial. Index Test: Baseline measures of proteinuria (total protein and albumin excretion and protein-creatinine and albumin-creatinine ratios). Linear regression to relate measures. Reference Test: Other signs and symptoms of nephrotic syndrome at baseline (serum albumin < 3.5 g/dL, serum total cholesterol > 260 mg/dL or use of a statin, and edema or use of a loop diuretic); progression of chronic kidney disease during follow-up (doubling of baseline serum creatinine level or requirement for dialysis or kidney transplantation). Logistic regression to relate index and reference tests. Result(s): In 1,608 participants, total urine protein level of 3.5 g/d was equivalent to urine albumin level of 2.2 g/d (95% confidence interval, 1.4 to 3.5). Of 1,467 participants, 641 (44%) had urine total protein level of 3.5 g/d or greater at baseline, 132 (9%) had other signs and symptoms of nephrotic syndrome at baseline, and 385 (26%) had progression of kidney disease during a mean follow-up of 2.6 years. Areas under the receiver operating curves for measures of proteinuria were 0.80 to 0.83 for other signs and symptoms of nephrotic syndrome and 0.72 to 0.74 for kidney disease progression. Threshold levels for nephrotic-range proteinuria and albuminuria were close to the points of maximal accuracy for both outcomes. Limitation(s): Study population limits ge

Background: To compare the hemodynamic and biological effects of high-adsorption continuous veno-venous hemofiltration (CVVH) with standard CVVH in septic shock. Method(s): In a randomized cross-over clinical trial twelve patients with septic shock and multiple organ failure were enrolled at a tertiary intensive care unit. Patients were allocated to either 9 hours of high-adsorption hemofiltration (CVVH with 3 hourly filter change using AN69 hemofilters - 3F-CVVH) or 9 hours of standard hemofiltration (CVVH without filter change - 1F-CVVH). Result(s): Changes in hemodynamic variables, dose of noradrenaline required to maintain a mean arterial pressure greater than 75 mmHg and plasma concentrations of cytokines (IL-6, IL-8, IL-10 and IL-18) were measured. A 9-hour period of 3F-CVVH was associated with greater reduction in noradrenaline dose than a similar period of 1F-CVVH (median reduction: 16 vs. 3.5 mug/min, p=0.036; median percentage reduction: 48.1% vs. 17.5% p=0.028). Unlike 1F-CVVH, 3F-CVVH was associated with a reduction in the plasma concentration of IL-6, IL-10 and IL-18 at 9 hours and a significant decrease 30 minutes after additional filter changes (IL-6: p<0.01, p<0.01; IL-10: p=0.03, p=0.016 and IL-18: p=0.016, p<0.01, respectively). Both, 3F-CVVH and 1F-CVVH were associated with decreased plasma concentrations of IL-8 at 9 hours (p<0.01, p<0.01, respectively). In a confirmatory ex-vivo experiment IL-6 concentrations substantially decreased during 3F-CVVH (at baseline 511pg/mL and at end: 21pg/mL) whereas IL-6 concentrations increased in control blood (at baseline 511pg/mL and at end: 932pg/mL). Conclusion(s): High-adsorption CVVH appears more effective than standard CVVH in decreasing noradrenaline requirements and plasma concentrations of cytokines in septic shock patients. © Wichtig Editore, 2007.

The inhibins are produced and secreted by several ovarian cancers. Monitoring serum levels by immunoassay may be a useful diagnostic aid in the initial assessment of this disease and in monitoring its potential recurrence following surgery. The assays are applicable to women after menopause when the majority of ovarian cancers are detected, and when the normal ovarian production of inhibin is low to negligible. A new inhibin immunoassay (total inhibin ELISA) has been developed with the intention of widespread clinical application. The assay readily detects granulosa cell and mucinous tumours. CA125, a widely used ovarian cancer marker, detects the other main ovarian cancer types (serous, endometrioid, undifferentiated) with high sensitivity. The combination of the two tests detects the majority of ovarian cancers with high specificity (95%) and sensitivity (95%). Studies have been undertaken to assess its application to women in the perimenopausal stage and to younger women during normal reproductive life. These studies are providing a platform for the introduction of the test into clinical practice. © 2004 Elsevier Ireland Ltd. All rights reserved.

The impact of endotoxemia on cerebral endothelium and cerebral blood flow (CBF) regulation was studied in conscious newborn lambs. Bacterial endotoxin [LPS, 2 mug/kg iv] was infused on 3 consecutive days. Cerebrovascular function was assessed by monitoring CBF and cerebral vascular resistance (CVR) over 12 h each day and by the endothelium-dependent vasodilator bradykinin (BK) (n = 10). Inflammatory responses were assessed by plasma tumor necrosis factor-alpha (TNF-alpha, n = 5). Acutely, LPS disrupted the cerebral circulation within 1 h, with peak cerebral vasoconstriction at 3 h (CBF -28 and CVR +118%, P < 0.05) followed by recovery to baseline by 12 h. TNF-alpha and body temperature peaked ~1 h post-LPS. BK-induced vasodilatation (CVR -20%, P < 0.05) declined with each LPS infusion, was abolished after 3 days, and remained absent for at least the subsequent 5 days. Histological evidence of brain injury was found in four of five LPS-treated newborns. We conclude that endotoxin impairs cerebral perfusion in newborn lambs via two mechanisms: 1) acute vasoconstriction (over several hours); and 2) persistent endothelial dysfunction (over several days). Endotoxin-induced circulatory impairments may place the newborn brain at prolonged risk of CBF dysregulation and injury as a legacy of endotoxin exposure. Copyright © 2010 the American Physiological Society.

Background The aim of this study was to assess the psychological features in women with different polycystic ovary syndrome (PCOS) phenotypes [National Institute of Health (NIH) and non-NIH diagnostic criteria] and women without PCOS. Methods An observational, cross-sectional study compared overweight (BMI <25 kg/m2) premenopausal women with PCOS (n 29 NIH and n 25 non-NIH) and controls (n 27). Anxiety and depression were compared between women with NIH or non-NIH PCOS and women without PCOS. Health-related quality of life (HRQoL) domains related to emotions, body hair, weight, infertility and menstrual problems were compared between women with NIH and non-NIH PCOS. Results Overall, women with PCOS had worse anxiety (P 0.007) and depression (P 0.048) compared with women without PCOS. Both women with NIH PCOS and non-NIH PCOS presented more often with moderate anxiety (P 0.005 and P 0.01, respectively) compared with women without PCOS. Women with NIH PCOS had worse HRQoL related to infertility (P 0.012), emotions (P 0.02) and weight (P 0.016). No significant differences were observed between the two PCOS phenotypes for HRQoL domains related to body hair or menstrual problems. Both NIH (beta 0.30, P 0.024) and non-NIH (beta 0.32, P 0.016) PCOS status predicted anxiety, whereas age (beta 0.35, P 0.008) and free androgen index (beta 0.31, P 0.027) predicted depression. Conclusions PCOS is associated with anxiety and depression. Non-NIH phenotypes present with similar psychological profiles to NIH PCOS, indicating increased psychological dysfunction in PCOS, even in milder reproductive phenotypes. However, women with NIH PCOS appear to have worse HRQoL in some areas than women with non-NIH PCOS. Psychological function and HRQoL should be considered in all women with PCOS. © The Author 2012. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.

Objective: Activin A, a member of transforming growth factor-beta superfamily, has been established as a critical cytokine released early in endotoxemia and other inflammatory syndromes. The release of activin A and its binding protein, follistatin during cardiopulmonary bypass (CPB) has not been previously reported. Our study aimed to define the pattern of activin A and follistatin release in a sheep CPB model. Method(s): Control group consisted of left thoractomy alone (n = 6). CPB was performed using either unfractionated heparin (n = 6) or lepirudin (n = 6) as anticoagulant. Unlike heparin, lepirudin does not cause activin A and follistatin release on its own. Serum samples were assayed for activin A, follistatin, tumour necrosis factor-alpha and interleukin-6. Result(s): Compared with the control group, CPB using lepirudin was associated with a biphasic release of activin A. The first peak occurred within the first hour of CPB and a second peak occurred within the early post-operative period, coincident with a large release of follistatin. Close correlation was found between follistatin and IL-6 in the control and lepirudin groups, indicative of a role for follistatin in the acute phase response. In contrast to the control and lepirudin groups, CPB using heparin resulted in a concurrent release of activin A and follistatin. Conclusion(s): CPB is a trigger for the release of biologically-active free activin A into the circulation, at levels considerably greater than that induced by surgery alone. Triggering release of this critical inflammatory cytokine suggests that activin A may contribute to the adverse outcomes associated with systemic inflammation in cardiac surgery. © 2011.

OBJECTIVE: Miscarriage is the commonest complication of human pregnancy. We undertook this study to assess whether inhibin A, pro-alphaC inhibin and/or activin A, products of the corpus luteum and placenta, might be useful in either the prediction or diagnosis of miscarriage. DESIGN: Case-control study. PATIENTS: Ninety-eight asymptomatic women at 6-13 weeks gestation who subsequently had a miscarriage and 198 gestation-matched women with a normal singleton pregnancy. MEASUREMENTS: Maternal serum levels of inhibin A, pro-alphaC inhibin, activin A and human chorionic gonadotrophin (hCG) were measured. RESULT(S): Inhibin A, pro-alphaC and hCG, expressed as multiples of the normal median (MoM; +/-95% confidence intervals) in the miscarriage cases were significantly lower than in the viable controls, 0.56 (0.48-0.69) MoM vs. 1.00 (0.98-1.13) MoM, 0.55 (0.51-0.84) MoM vs. 1.0 (0.86-1.22) MoM and 0.34 (0.23-0.36) MoM vs. 1.00 (0.94-1.08) MoM, respectively (P < 0.0001 for all). Of the three analytes, hCG was the most discriminating between cases and controls. Levels of activin A in the miscarriage cases were not significantly different from controls, 0.96 (0.86-1.07) vs. 1.0 (0.95-1.08). CONCLUSION(S): These data suggest that inhibin A, pro-alphaC inhibin and activin A will not be useful in either the prediction or diagnosis of early pregnancy miscarriage.

BACKGROUND AND OBJECTIVE: Previous studies have shown that serum inhibin as measured by subunit-directed radioimmunoassay (RIA) and inhibin A ELISA was elevated in postmenopausal women with mucinous and granulosa cell cancers, with the RIA showing a more frequent elevation than the inhibin A ELISA. It was thus hypothesised that these cancers may also produce inhibin B or the free alpha subunit. The aim of the study was to identify the forms of inhibin found in a range of ovarian cancers using a range of inhibin assays with varying specificities. DESIGN: Serum samples obtained from women with ovarian cancer were assayed by inhibin B ELISA and Pro-alphaC subunit ELISA and compared with inhibin RIA and inhibin A ELISA. PATIENTS: Blood samples were obtained from 34 postmenopausal women (>55 years) with no history of endocrine disease and from women with ovarian serous cystadenocarcinomas (n=66), mucinous cystadenocarcinomas (n = 20), granulosa cell tumours (n=9- 11), miscellaneous ovarian cancers (n=46) and non ovarian cancers (n = 23). MEASUREMENTS: Inhibin B and inhibin Pro-alphaC subunit levels were determined by ELISA and compared to values obtained by RIA and inhibin A ELISA. Cancers were discriminated from controls based on values obtained 2SD above the geometric mean of the control values. RESULT(S): Granulosa cell tumours were detected by RIA and inhibin B ELISA (100%), Pro-GAMMA ELISA (90%) and inhibin A ELISA (77%). Mucinous tumours were detected by RIA (70%), inhibin B ELISA (60%), Pro-alphaC ELISA (55%) and inhibin A (20%). Serous tumours were detected by RIA (35%) and the other assays (<15%). Miscellaneous tumours were detected by RIA (41%) and other assays <30%. CONCLUSION(S): Ovarian neoplasms may produce a variety of peptides related to the inhibins, including dimeric inhibin A and B. Inhibin B is detected in more ovarian cancers than inhibin A but does not discriminate as well as the alpha subunit directed assays. The higher discrimination index obtaine

Pigment epithelium-derived factor (PEDF) is upregulated in obese rodents and is involved in the development of insulin resistance (IR). We aim to explore the relationships between PEDF, adiposity, insulin sensitivity, and cardiovascular risk factors in obese women with polycystic ovary syndrome (PCOS) and weight-matched controls and to examine the impact of endurance exercise training on PEDF. This prospective cohort intervention study was based at a tertiary medical center. Twenty obese PCOS women and 14 non-PCOS weight-matched women were studied at baseline. PEDF, cardiometabolic markers, detailed body composition, and euglycemic-hyperinsulinemic clamps were performed and measures were repeated in 10 PCOS and 8 non-PCOS women following 12 weeks of intensified aerobic exercise. Mean glucose infusion rate (GIR) was 31.7% lower (P = 0.02) in PCOS compared to controls (175.6 +/- 96.3 and 257.2 +/- 64.3 mg.m 2.min 1) at baseline, yet both PEDF and BMI were similar between groups. PEDF negatively correlated to GIR (r = 0.41, P = 0.03) and high-density lipoprotein (HDL) (r = 0.46, P = 0.01), and positively to cardiovascular risk factors, systolic (r = 0.41, P = 0.02) and diastolic blood pressure (r = 0.47, P = 0.01) and triglycerides (r = 0.49, P = 0.004). The correlation with GIR was not significant after adjusting for fat mass (P = 0.07). Exercise training maintained BMI and increased GIR in both groups; however, plasma PEDF was unchanged. In summary, PEDF is not elevated in PCOS, is not associated with IR when adjusted for fat mass, and is not reduced by endurance exercise training despite improved insulin sensitivity. PEDF was associated with cardiovascular risk factors, suggesting PEDF may be a marker of cardiovascular risk status. © 2012 The Obesity Society.

Context: Management of male infertility and/or androgen deficiency requires accurate hormonal measurements with valid reference intervals. Objective(s): The objective of this study was to develop a valid reference panel of blood samples from healthy eugonadal young men with verified normal reproductive function and to use this panel to evaluate the performance of seven fully automated, commercial multiplex immunoassay platforms used to measure serum total testosterone (T), LH, and FSH. Design(s): This was an observational study of consistency among seven different automated immunoassays for each of total T, LH, and FSH. Each method was implemented in two laboratories, with each repeating the analysis of the full reference panel samples twice. Serum T concentrations were also measured by gas chromatography/mass spectrometry (GC/MS), and serum inhibin B levels were determined by an ELISA. Setting(s): The study was performed at commercial, high-volume, clinical pathology laboratories. Participant(s): From 147 men screened, sera from 124 healthy, reproductively normal men (age, 21-35 yr) with normal sperm output were used as a reference panel. All laboratories selected for elite performance in the national immunoassay quality assurance program agreed to participate. Main Outcome Measure(s): For each of the 868 assays, descriptive statistics were calculated in the natural and log-transformed scales and were analyzed by nested, repeated measures ANOVA after log transformation. Reference intervals, defined as 95% confidence limits, were calculated using arithmetic (natural scale), geometric (log scale) and nonparametric methods. Result(s): Descriptive statistics and reference intervals for serum T, LH, and FSH differed widely and significantly between methods, but variation between laboratories for the same assay was negligible. All T methods showed significant differences in regression slope and intercept in deviance plots as well as in estimated reference ranges compared

Background: High plasma lipoprotein(a) [Lp(a)] level is a strong and important risk factor for cardiovascular disease (CVD). Small-sized apolipoprotein(a) [apo(a)] isoforms (F, B, S1, and S2) are inversely correlated with the high levels of Lp(a) in plasma and significantly associated with CVD. Although the effects of apo(a) phenotypes and various risk factors on Lp(a) status in South Asian population may have been studied in other countries, there are no reports involving these risk factors in Australia. Methods and Results: Factors contributing to variation in Lp(a) were surveyed in 402 (216 males and 186 females) South Asian Melburnians. There was a negative relationship between low alcohol beer per day and Lp(a) in men (P < 0.05). Approximately 21% of the variance of Lp(a) concentration in men and 6% in women were explained by age. Age was positively associated with Lp(a) concentrations in men but negatively in women. The most commonly occurring phenotype was apo(a) S3. In this phenotype, Lp(a) concentrations ranged from non-detectable to 811 mg/l. After adjusting for age, an inverse correlation was observed between Lp(a) concentration and apo(a) phenotypes (P < 0.01). Conclusion(s): Although Lp(a) has been reported to be genetically determined, there are clearly other factors contributing to variations in Lp(a) concentrations in a South Asian population. © 2004 The Canadian Society of Clinical Chemists. All rights reserved.

Background: Evidence for statin therapy In prevention of coronary artery disease is overwhelming. In spite of theoretical benefits, any additional advantage of its early introduction in the management of acute coronary syndrome is, however, uncertain. We therefore investigated differences between plasma levels of the systemic inflammatory markers intercellular adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin, C-reactive protein and interleukin-6 in patients presenting with unstable angina or acute myocardial infarction, and assessed whether the 30-day levels of these markers are influenced by early instigation of the HMG-CoA reductase inhibitor pravastatin. Material(s) and Method(s): 170 (134 male) patients presenting with acute coronary syndrome, but without previous statin therapy, participated. Blood was taken within 24 h of onset of ischaemic pain and again at 30 days. In all, 87 (71 male) participants were treated with pravastatin (20-40 mg daily) and 83 (63 male) with a matched placebo. Result(s): At presentation, interleukin-6 was higher in males than in females (P = 0.008) and lower in those with a pre-existing history of myocardial infarction (P = 0.038). C-reactive protein and interleukin-6 were greater in myocardial infarction, but this difference was lost at 30 days. Thirty-day changes in all parameters were inversely related to level at presentation but not to treatment with pravastatin. Hypertension (P = 0.011) and smoking (P = 0.042) were associated with elevation of C-reactive protein with no difference between unstable angina or acute myocardial infarction. The effect of these individual factors was cumulative. Conclusion(s): Interleukin-6 was greater in acute myocardial infarction than in unstable angina; E-selectin was positively associated with a previous myocardial infarction and inversely related to age. We found no effect of early introduction of pravastatin on systemic inflammatory markers 30 days after acute coronary syndro

PCOS (polycystic ovary syndrome) is associated with reproductive abnormalities, IR (insulin resistance) and elevated risk factors for CVD (cardiovascular disease) and Type 2 diabetes, including endothelial dysfunction. The present study aimed to assess a range of circulating markers of endothelial function in overweight women with and without PCOS. Overweight and obese age- and BMI (body mass index)-matched women with (n=80) and without (n=27) PCOS were assessed in a cross-sectional study. End-point measures were HOMA (homoeostasis model assessment)-IR, androgens, lipids, inflammatory markers [hsCRP (high-sensitivity C-reactive protein)] and endothelial function [FMD (flow-mediated dilation), ADMA (asymmetric dimethylarginine), PAI-1 (plasminogen activator inhibitor-1) and vWF (von Willebrand factor)]. Women with PCOS had elevated HOMA-IR (4.1 +/- 3.4 compared with 1.9 +/- 1.4), free androgen index (9.3 +/- 5.6 compared with 4.6 +/- 3.8), total cholesterol (5.2 +/- 1.0 compared with 4.7 +/- 0.9 mmol/l) and triacylglycerols (triglycerides; 1.4 +/- 0.7 compared with 0.9 +/- 0.3 mmol/l) (P < 0.05 for all), but similar hsCRP compared with women without PCOS. With regard to endothelial function, women with PCOS had elevated ADMA (1.0 +/- 0.4 compared 0.3 +/- 0.1 mumol/l, P < 0.001) and PAI-1 (5.6 +/- 1.8 compared with 4.6 +/- 1.1 units/ml, P = 0.006), a trend towards worsened FMD (11.8 +/- 5.0 compared with 13.5 +/- 4.0%, P = 0.075) and no difference in vWF compared with controls. For all subjects, ADMA (P = 0.002) and PAI-1 (P < 0.001) were increased with higher tertiles of HOMA-IR. Women with PCOS are hyperandrogenic, dyslipidaemic and have IR, and have risk factors for CVD and diabetes including increased circulating markers of endothelial function (ADMA and PAI-1) and a trend towards worse FMD as a global marker of endothelial function. In PCOS, deterioration in endothelial function is related to IR, hyperandrogenism and other factors. © The Authors.

This prospective, single-center cohort study aimed to evaluate the hemostatic response during and after Cardiopulmonary Bypass (CPB) surgery in a large cohort of children up to 6 years of age. Blood samples were drawn at eight time points: post-induction of anesthesia, preunfractionated heparin (UFH), post-UFH, post-initiation of bypass, pre-protamine, post-protamine, post-chest-closure, and 6 h post-chest-closure. As expected, all measures of the UFH effect increased significantly post-UFH bolus and decreased post-protamine administration. However, thrombin generation remained inhibited compared to baseline values despite the post-UFH reversal by protamine. We also demonstrate that residual UFH effect is not responsible for the ongoing inhibition of thrombin observed post-protamine administration. The significant increase in both free and total tissue factor pathway inhibitor levels during the CPB surgery might contribute to the persistent thrombin generation/endogenous thrombin potential inhibition post-protamine administration. This study makes a significant and novel contribution by investigating the physiological mechanisms behind the degree of thrombin inhibition by UFH and the residual levels of thrombin inhibition that continue despite protamine reversal and provides a new foundation for future interventional studies in the setting of paediatric CPB surgery. © Springer Science+Business Media, LLC 2011.

Human saliva mirrors body’s health and well-being and many of the biomolecules present in blood or urine can also be found in salivary secretions. However, biomolecular concentrations in saliva are usually one tenth to one thousandth of the levels in blood (Pfaffe et al., 2011). Sensitive detection technology platforms are therefore required to detect biomolecules in saliva. Another road block to the advancement of salivary diagnostics is the lack of information related to healthy state saliva vs. a diseased saliva, baseline levels and reference ranges and diurnal variations. Saliva has numerous advantages over blood or urine as a diagnostic fluid: (a) the non-invasive nature of sample collection and the simple, safe, painless and cost-effective methods to collect it; (b) unskilled personnel can collect saliva samples at multiple time points; and (c) the total protein concentration is approximately a quarter of that is present in plasma, which makes it easier to investigate low abundance proteins (Pfaffe et al., 2011). Currently, saliva assays are routinely used to determine, diseases such as HIV, drugs and substances of abuse to provide information on exposure and give qualitative information on the type of illicit drug used (Kintz et al., 2009), cortisol levels for diagnosing Cushing’s syndrome (Doi et al., 2008), and use for biomonitoring of exposure to chemicals (Caporossi et al., 2010) to measure hormones (Gröschl, 2009)....

Annals of the Rheumatic Diseases, 71(11), pp.1916-1917; 2012

Clinical Infectious Diseases, 54(8), pp.1145-1147; 2012

Inflammation following ischemic brain injury is correlated with adverse outcome. Preclinical studies indicate that treatment with acetylsalicylic acid + extended-release dipyridamole (ASA + ER-DP) has anti-inflammatory and thereby neuroprotective effects by inhibition of monocyte chemotactic protein-1 (MCP-1) expression. We hypothesized that early treatment with ASA + ER-DP will reduce levels of MCP-1 also in patients with ischemic stroke. The EARLY trial randomized patients with ischemic stroke or TIA to either ASA + ER-DP treatment or ASA monotherapy within 24 h following the event. After 7 days, all patients were treated for up to 90 days with ASA + ER-DP. MCP-1 was determined from blood samples taken from 425 patients on admission and day 8. The change in MCP-1 from admission to day 8 did not differ between patients treated with ASA + ER-DP and ASA monotherapy (p > 0.05). Comparisons within MCP-1 baseline quartiles indicated that patients in the highest quartile (> 217-973 pg/mL) showed improved outcome at 90 days if treated with ASA + ER-DP in comparison to treatment with ASA alone (p = 0.004). Our data does not provide any evidence that treatment with ASA + ER-DP lowers MCP-1 in acute stroke patients. However, MCP-1 may be a useful biomarker for deciding on early stroke therapy, as patients with high MCP-1 at baseline appear to benefit from early treatment with ASA + ER-DP.