The effect of atorvastatin on pancreatic beta cell requirement in women with polycystic ovary syndrome

Background There is an increased risk of developing T2DM in women with polycystic ovary syndrome (PCOS) and there is evidence that statins improve metabolic parameters in these patients. However, there is some data to show that statins increase the risk of incipient diabetes. Material and Methods We have previously shown that 12-weeks of atorvastatin improves insulin resistance when measured using HOMA-IR. This post hoc-analysis was designed to look at the effect of atorvastatin on pancreatic β cell function using HOMA-β in the same study. In this randomised, double blind placebo controlled study, 40 medication naïve patients with PCOS were randomized to either atorvastatin 20 mg daily or placebo for 3 months. A 3-month extension study for both groups of patients was undertaken with metformin 1500 mg daily after completing initial 3 months of atorvastatin or placebo. Results There was a significant reduction in HOMA-β (240±3.2vs.177±2.3; pvalue<0.01) after 12 weeks of atorvastatin treatment which was maintained by metformin in the subsequent 12 weeks. There were no changes in HOMA-β after the placebo or after subsequent metformin treatment. There was no linear correlation between reduction in HOMA-β with improvement of free androgen index (FAI) (r2=0.02;p=0.72), testosterone (r2=0.13;p=0.49), SHBG (r2=0.22;p=0.48), hsCRP (r2=0.19;p=0.64), triglycerides (r2=0.09;p=0.12), total cholesterol (r2=0.11;p=0.32) or LDL-C (r2=0.19;p=0.38). Conclusion Treatment with atorvastatin for 12 weeks in women with PCOS significantly reduced HOMA-β. This could be potentially due to fall in βcell requirement with improvement of insulin resistance rather than a reduction of βcell function

Endocannabinoid receptor blockade increases vascular endothelial growth factor and inflammatory markers in obese women with polycystic ovary syndrome

© 2016 John Wiley & Sons Ltd Context: Animal studies suggest that cannabinoid receptor-1 (CB-1) blockade reduces inflammation and neovascularization by decreasing vascular endothelial growth factor (VEGF) levels associated with a reduction in inflammatory markers, thereby potentially reducing cardiovascular risk. Objective: To determine the impact of CB1 antagonism by rimonabant on VEGF and inflammatory markers in obese PCOS women. Design: Randomized, open-labelled parallel study. Setting: Endocrinology outpatient clinic in a referral centre. Subjects: Twenty patients with PCOS (PCOS) and biochemical hyperandrogenaemia with a body mass index of ≥30 kg/m 2 were recruited. Patients were randomized to 1·5 g daily of metformin or 20 mg daily of rimonabant. Main outcome measures: Post hoc review to detect VEGF and pro-inflammatory cytokines TNF-α, IL-1β, IL-1ra, IL-2, IL6, IL-8, IL-10 and MCP-1 before and after 12 weeks of treatment. Results: After 12 weeks of rimonabant treatment, there was a significant increase in VEGF (99·2 ± 17·6 vs 116·2 ± 15·8 pg/ml, P < 0·01) and IL-8 (7·4 ± 11·0 vs 18·1 ± 13·2 pg/ml, P < 0·05) but not after metformin (VEGF P = 0·7; IL-8 P = 0·9). There was no significant difference in the pro-inflammatory cytokines TNF-α, IL-1β, IL-1ra, IL-2, IL6, IL-8, IL-10 and MCP-1 following either treatment. Conclusion: This study suggests that rimonabant CB-I blockade paradoxically raised VEGF and the cytokine IL-8 in obese women with PCOS that may have offset the potential benefit associated with weight loss

Endocannabinoid receptor blockade increases hepatocyte growth factor and reduces insulin levels in obese women with polycystic ovary syndrome

There is evidence from animal and in-vitro studies that activation of the endocannabinoid system (EC) through cannabinoid receptor 1 (CB-1) is associated with liver injury, inflammation and hepatocellular carcinoma.1 Data suggests endogenous cannabinoids (EC) are related to fatty liver metabolism with a role in non-alcoholic fatty liver disease (NAFLD) through modulating lipid metabolism that may be ameliorated by CB1 receptor antagonism with rimonabant.2 This is of particular importance as NAFLD is the most common cause of chronic liver disease with liver dysfunction leading liver cirrhosis. The diagnosis of NAFLD can only be confirmed by a liver biopsy, as liver enzymes such as alanine aminotransferase (ALT) used, as a serum marker may not be elevated

Assessment of Exercise Capacity and Oxygen Consumption Using a 6 min Stepper Test in Older Adults

It is often necessary to assess physical function in older adults to monitor disease progression, rehabilitation or decline in function with age. However, increasing frailty and poor balance that accompany aging are common barriers to exercise testing protocols. We investigated whether a 6-min stepper test (6MST) was acceptable to older adults and provided a measure of exercise capacity and a predicted value for peak aerobic capacity (VO2max). 635 older adults from a tri-ethnic UK population-based cohort were screened to undertake a self-paced 6MST. Expired gas analysis, heart rate and blood pressure monitoring were carried out. A sub-set of 20 participants performed a second 6MST for assessment of reproducibility and a further sub-set of 10 performed the 6-min walk test as verification against a well-recognized and accepted self-paced exercise test. 518 (82%) participants met inclusion criteria and undertook the 6MST (299 men, mean age 71.2 ± 6.4). Step rate showed a strong positive correlation with measured VO2 (r = 0.75, p < 0.001) and VO2 was lower in women (male-female difference in VO2 = 2.61 (95% confidence interval -3.6, -1.7) ml/min/kg; p < 0.001). 20 participants repeated a 6MST, step rate was higher in the second test but the predicted VO2max showed good agreement (mean difference = 0.1 [3.72, 3.95] ml/min/kg). In 10 participants who completed a 6MST and a 6-min walk test there was a strong positive correlation between walking rate and step rate (r = 0.77; p < 0.009) and weaker positive correlations between the tests for measured VO2 and peak heart rate. In conclusion, the 6MST is a convenient, acceptable method of assessing exercise capacity in older adults that allows VO2max to be predicted reproducibly. The test shows good correlation between performance and measured physiological markers of performance and can detect the expected gender differences in measured VO2. Furthermore, the 6MST results correlate with a previously verified and established self-paced exercise test

Androsterone glucuronide to dehydroepiandrosterone sulphate ratio is discriminatory for obese Caucasian women with polycystic ovary syndrome

BACKGROUND: Androsterone glucuronide (ADTG) concentrations have been suggested as a marker of the effects of androgens at the target tissue level. As the mechanism for hyperandrogenemia in obese and nonobese polycystic ovary syndrome (PCOS) may differ, this study compared the different androgen parameters in non-obese compared to obese women with PCOS, and in normal subjects. METHODS: Eleven non-obese and 14 obese women with PCOS were recruited and compared to 11 control women without PCOS. Total testosterone, dehydroepiandrosterone sulphate (DHEAS), ADTG, and androstenedione were analysed using gold standard tandem mass spectrometry, and the free androgen index (FAI) was calculated. RESULTS: Total testosterone, ADTG and androstendione levels did not differ between non-obese (body mass index (BMI) ≤25 kg/m2) and obese PCOS (BMI >25 kg/m2) but all were significantly higher than for controls (p &lt; 0.01). The ADTG to DHEAS ratio was significantly elevated 39 ± 6 (p &lt; 0.01) in obese PCOS in comparison to non-obese PCOS and controls (28 ± 5 and 29 ± 4, respectively). The free androgen index (FAI) and insulin resistance (HOMA-IR) were significantly higher in obese PCOS compared to non-obese PCOS and controls (p &lt; 0.01). DHEAS was significantly higher in the non-obese versus obese PCOS (p &lt; 0.01). All androgen parameters were significantly lower and sex hormone binding globulin (SHBG) significantly higher in normal subjects compared to those with obese and non-obese PCOS. CONCLUSIONS: The ADTG:DHEAS ratio was significantly elevated in obese PCOS compared to non-obese PCOS and controls suggesting that this may be a novel biomarker discriminatory for obese PCOS subjects, perhaps being driven by higher hepatic 5α reductase activity increasing ADTG formation in these women

Penetrating ulcer of the thoracic aorta: What is it? How do we recognize it? How do we manage it?

AbstractBackground: Although classic type A and B aortic dissections have been well described, less is known about the natural history of penetrating atherosclerotic ulcers of the thoracic aorta. This study differentiates penetrating ulcer from aortic dissection, determines the clinical features and natural history of these ulcers, and establishes appropriate correlates regarding optimal treatment. Methods: A retrospective review of patient records and imaging studies was conducted with 198 patients with initial diagnoses of aortic dissection (86 type A, 112 type B) at our institution from 1985 to 1997. Results: Of the 198 patients, 15 (7.6%) were found to have a penetrating aortic ulcer on re-review of computed tomographic scans, magnetic resonance images, angiograms, echocardiograms, intraoperative findings, or pathology reports. Two ulcers (13.3%) were located in the ascending aorta; the other 13 (86.7%) were in the descending aorta. In comparison with those with type A or B aortic dissection, patients with penetrating ulcer were older (mean age 76.6 years, p = 0.018); had larger aortic diameters (mean diameter 6.5 cm); had ulcers primarily in the descending aorta (13 of 15 patients, 86.7%); and more often had ulcers associated with a prior diagnosed or managed AAA (6 of 15 patients, 40.0%; p = 0.0001). Risk for aortic rupture was higher among patients with penetrating ulcers (40.0%) than patients with type A (7.0%) or type B (3.6%) aortic dissection (p = 0.0001). Conclusions: Accurate recognition and differentiation of penetrating ulcers from classic aortic dissection at initial presentation is critical for optimal treatment of these patients. For penetrating ulcer, the prognosis may be more serious than with classic type A or B aortic dissection. Surgical management is advocated for penetrating ulcers in the ascending aorta and for penetrating ulcers in the descending aorta that exhibit early clinical or radiologic signs of deterioration. (J Vasc Surg 1998;27:1006-16.

Lexicality and frequency in specific language impairment: accuracy and error data from two nonword repetition tests

Purpose: Deficits in phonological working memory and deficits in phonological processing have both been considered potential explanatory factors in Specific Language Impairment (SLI). Manipulations of the lexicality and phonotactic frequency of nonwords enable contrasting predictions to be derived from these hypotheses. Method: 18 typically developing (TD) children and 18 children with SLI completed an assessment battery that included tests of language ability, non-verbal intelligence, and two nonword repetition tests that varied in lexicality and frequency. Results: Repetition accuracy showed that children with SLI were unimpaired for short and simple high lexicality nonwords, whereas clear impairments were shown for all low lexicality nonwords. For low lexicality nonwords, greater repetition accuracy was seen for nonwords constructed from high over low frequency phoneme sequences. Children with SLI made the same proportion of errors that substituted a nonsense syllable for a lexical item as TD children, and this was stable across nonword length. Conclusions: The data show support for a phonological processing deficit in children with SLI, where long-term lexical and sub-lexical phonological knowledge mediate the interpretation of nonwords. However, the data also suggest that while phonological processing may provide a key explanation of SLI, a full account is likely to be multi-faceted

The effect of exenatide on cardiovascular risk markers in women with polycystic ovary syndrome

Background: Polycystic ovary syndrome (PCOS) is associated with an adverse cardiovascular risk profile including a prothrombotic state. Exenatide has been shown to be effective at improving insulin sensitivity and weight loss in PCOS; therefore this study was undertaken to assess its effects on weight, endothelial function, inflammatory markers, and fibrin structure/function in overweight/obese women with PCOS.Methods: Thirty overweight/obese anovulatory women with all 3 Rotterdam criteria received exenatide 5 mcg bd for 4 weeks then 10 mcg bd for 12 weeks. The primary outcome was change in weight; secondary outcomes were changes in endothelial function [Reactive Hyperemia-Peripheral Arterial Tonometry (RH-PAT)], serum endothelial markers (ICAM-1, VCAM-1, E-selectin, and P-selectin), change in inflammation (hsCRP), and alteration in clot structure and function [maximum absorbance (MA), and time from full clot formation to 50% lysis (LT)].Results: Twenty patients completed the study. Exenatide reduced weight 111.8 ± 4.8 to 108.6 ± 4.6 kg p = 0.003. Serum endothelial markers changed with a reduction in ICAM-1 (247.2 ± 12.9 to 231.3 ± 11.5 ng/ml p = 0.02), p-selectin (101.1 ± 8.2 to 87.4 ± 6.6 ng/ml p = 0.01), and e-selectin (38.5 ± 3.3 to 33.6 ± 2.6 ng/ml p = 0.03), without an overt change in endothelial function. Inflammation improved (CRP; 8.5 ± 1.4 to 5.6 ± 0.8 mmol/L p = 0.001), there was a reduction in clot function (LT; 2,987 ± 494 to 1,926 ± 321 s p = 0.02) but not clot structure.Conclusion: Exenatide caused a 3% reduction in weight, improved serum markers of endothelial function, inflammation, and clot function reflecting an improvement in cardiovascular risk indices in these women with PCOS. This suggests exenatide could be an effective treatment for obese women with PCOS

The Social Construction of Conspiracy Beliefs: A Q-Methodology Study of How Ordinary People DefineThem and Judge Their Plausibility

Little is known about ordinary people’s understandings of conspiracy beliefs and how these understandings relate to the perspectives of researchers and scholars. Working within a social constructionist epistemological framework, we conducted a Q-methodology study aiming to identify a range of lay perspectives on two key topics: the defining features of conspiracy beliefs; and aspects considered important in judging their plausibility. Fifty-six people (32 men and 24 women), recruited via regional UK Facebook groups, sorted their agreement with a set of statements on each of the two topics. A principal component analysis, followed by varimax rotation, was performed on each data set. Five accounts about the defining features of conspiracy beliefs were identified: that they are false, illogical and harmful; that they are forms of political critique; that there are varied types; that they are entertaining but ineffectual; and that they are held by a self-reinforcing minority. Four accounts about their evaluation were identified: conventional realist criteria; the importance of personal judgement; skeptical realism; and the assessment of critical thinking. The findings are discussed in the context of the literature and limitations of the study are considered. Implications for research and educational and policy interventions are outlined