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BACKGROUND: The prevalence of atrial fibrillation(AF) and diabetes mellitus is rising to epidemic proportions. We aimed to assess the impact of diabetes on the management and outcomes of patients with AF.METHODS: The EORP-AF General Long-Term Registry is a prospective, observational registry from 250 centres across 27 European countries. Outcomes of interest were as follows: i)rhythm control interventions; ii)quality of life; iii)healthcare resource utilisation; and iv)major adverse events.RESULTS: Of 11,028 patients with AF, the median age was 71 (63-77) years and 2537 (23.0%) had diabetes. Median follow-up was 24 months. Diabetes was related to increased use of anticoagulation but less rhythm control interventions. Using multivariable analysis, at 2-year follow-up, patients with diabetes were associated with greater levels of anxiety (p = 0.038) compared to those without diabetes. Overall, diabetes was associated with worse health during follow-up, as indicated by Health Utility Score and Visual Analogue Scale. Healthcare resource utilisation was greater with diabetes in terms of length of hospital stay (8.1 (±8.2) vs. 6.1 (±6.7) days); cardiology and internal medicine/general practitioner visits; and emergency room admissions. Diabetes was an independent risk factor of major adverse cardiovascular event (MACE; HR 1.26 [95% CI, 1.04-1.52]), all-cause mortality (HR 1.28 [95% CI, 1.08-1.52]), and cardiovascular mortality (HR 1.41 [95% CI, 1.09-1.83]).CONCLUSION: In this contemporary AF cohort, diabetes was present in 1 in 4 patients and it served as an independent risk factor for reduced quality of life, greater healthcare resource utilisation and excess MACE, all-cause mortality and cardiovascular mortality. There was increased use of anticoagulation therapy in diabetes but with less rhythm control interventions.

Background The validity of circulating tumour DNA (ctDNA) as an indicator of disease progression compared to medical imaging in patients with metastatic melanoma requires detailed evaluation. Methods Here, we carried out a retrospective ctDNA analysis of 108 plasma samples collected at the time of disease progression. We also analysed a validation cohort of 66 metastatic melanoma patients monitored prospectively after response to systemic therapy. Results ctDNA was detected in 62% of patients at the time of disease progression. For 67 patients that responded to treatment, the mean ctDNA level at progressive disease was significantly higher than at the time of response (P N = 15). Conclusions These results highlight the low efficacy of ctDNA to detect disease progression in melanoma when compared mainly to standard positron emission tomography imaging.

Background: Glucose transport from blood to interstitial fluid impacts performance of interstitially-placed continuous glucose monitoring (CGM) sensors. We examined time series offsets (“lag times”) of the G7 CGM system (Dexcom) . Methods: In a pivotal accuracy study conducted in the US, 316 adults with diabetes wearing 6sensors participated in clinic sessions that included glucose manipulations and frequent venous plasma glucose (YSI) determinations. G7 values were obtained every 5 min and interpolated to provide values at 1-min intervals. Each YSI value was associated with 21 G7 values obtained from min before to min after. The absolute relative difference (ARD) was calculated for each YSI:G7 pair and each sensor’s lag was estimated as the time with the lowest mean ARD. Results: A lag time of 2 minutes provided the lowest mean ARD of 8.6% and the highest %20/20 agreement rate of 94.4%. The Figure shows summary statistics for the distribution of sensor-specific lag times. Lag times of ≤0 min (where interstitial glucose leads blood glucose) were observed for 2 (33.0%) of the sensors. Conclusions: The distribution of G7 time series offsets suggests that CGM values may most accurately reflect previous or upcoming blood glucose values. This finding is likely due to technological innovations in G7’s hardware and algorithm. The minimal lag time observed should provide users with confidence in using CGM to manage their diabetes. Disclosure X.Zhang: Employee; Dexcom, Inc. J.L.Reid: Employee; Dexcom, Inc., GenMark Diagnostics. T.C.Walker: Employee; Dexcom, Inc., Stock/Shareholder; Dexcom, Inc. J.Welsh: Employee; Dexcom, Inc. A.Balo: Employee; Dexcom, Inc. Funding Dexcom, Inc.

Purpose: We evaluated the predictive value of pretreatment ctDNA to inform therapeutic outcomes in patients with metastatic melanoma relative to type and line of treatment. Experimental Design: Plasma circulating tumor DNA (ctDNA) was quantified in 125 samples collected from 110 patients prior to commencing treatment with immune checkpoint inhibitors (ICIs), as first- (n = 32) or second-line (n = 27) regimens, or prior to commencing first-line BRAF/MEK inhibitor therapy (n = 66). An external validation cohort included 128 patients commencing ICI therapies in the first- (N = 77) or second-line (N = 51) settings. Results: In the discovery cohort, low ctDNA (≤20 copies/mL) prior to commencing therapy predicted longer progression-free survival (PFS) in patients treated with first-line ICIs [HR, 0.20; 95% confidence interval (CI) 0.07–0.53; P < 0.0001], but not in the second-line setting. An independent cohort validated that ctDNA is predictive of PFS in the first-line setting (HR, 0.42; 95% CI, 0.22–0.83; P = 0.006), but not in the second-line ICI setting. Moreover, ctDNA prior to commencing ICI treatment was not predictive of PFS for patients pretreated with BRAF/MEK inhibitors in either the discovery or validation cohorts. Reduced PFS and overall survival were observed in patients with high ctDNA receiving anti–PD-1 monotherapy, relative to those treated with combination anti–CTLA-4/anti–PD-1 inhibitors. Conclusions: Pretreatment ctDNA is a reliable indicator of patient outcome in the first-line ICI treatment setting, but not in the second-line ICI setting, especially in patients pretreated with BRAF/MEK inhibitors. Preliminary evidence indicated that treatment-naïve patients with high ctDNA may preferentially benefit from combined ICIs.

BACKGROUND: Cardiac troponins (cTn) have been reported to be predictors for adverse outcomes in atrial fibrillation (AF), patients, but their actual use is still unclear.AIM: To assess the factors associated with cTn testing in routine practice and evaluate the association with outcomes.METHODS: Patients enrolled in the ESC-EHRA EORP-AF General Long-Term Registry were stratified into 3 groups according to cTn levels as (i) cTn not tested, (ii) cTn in range (≤99th percentile), (iii) cTn elevated (>99th percentile). The composite outcome of any thromboembolism /any acute coronary syndrome/cardiovascular (CV) death, defined as Major Adverse Cardiovascular Events (MACE) and all-cause death were the main endpoints.RESULTS: Among 10 445 AF patients (median age 71 years, 40.3% females) cTn were tested in 2834 (27.1%). cTn was elevated in 904/2834 (31.9%) and in-range in 1930/2834 (68.1%) patients. Female sex, in-hospital enrollment, first-detected AF, CV risk factors, history of coronary artery disease, and atypical AF symptoms were independently associated with cTn testing. Elevated cTn were independently associated with a higher risk for MACE (Model 1, hazard ratio [HR] 1.74, 95% confidence interval [CI] 1.40-2.16, Model 2, HR 1.62, 95% CI 1.28-2.05; Model 3 HR 1.76, 95% CI 1.37-2.26) and all-cause death (Model 1, HR 1.45, 95% CI 1.21-1.74; Model 2, HR 1.36, 95% CI 1.12-1.66; Model 3, HR 1.38, 95% CI 1.12-1.71).CONCLUSIONS: Elevated cTn levels were associated with an increased risk of all-cause mortality and adverse CV events. Clinical factors that might enhance the need to rule out CAD were associated with cTn testing.

In this study, we evaluated the predictive value of circulating tumour DNA (ctDNA) to inform therapeutic outcomes in metastatic melanoma patients receiving systemic therapies. We analysed 142 plasma samples from metastatic melanoma patients prior to commencement of systemic therapy: 70 were treated with BRAF/MEK inhibitors and 72 with immunotherapies. Patient-specific droplet digital polymerase chain reaction assays were designed for ctDNA detection. Plasma ctDNA was detected in 56% of patients prior to first-line anti-PD1 and/or anti-CTLA-4 treatment. The detection rate in the immunotherapy cohort was comparably lower than those with BRAF inhibitors (76%, p = 0.0149). Decreasing ctDNA levels within 12 weeks of treatment was strongly concordant with treatment response (Cohen&rsquo, s k = 0.798, p &lt, 0.001) and predictive of longer progression free survival. Notably, a slower kinetic of ctDNA decline was observed in patients treated with immunotherapy compared to those on BRAF/MEK inhibitors. Whole exome sequencing of ctDNA was also conducted in 9 patients commencing anti-PD-1 therapy to derive tumour mutational burden (TMB) and neoepitope load measurements. The results showed a trend of high TMB and neoepitope load in responders compared to non-responders. Overall, our data suggest that changes in ctDNA can serve as an early indicator of outcomes in metastatic melanoma patients treated with systemic therapies and therefore may serve as a tool to guide treatment decisions.

DOCK3 is a member of the DOCK family of guanine nucleotide exchange factors that function to regulate cell migration, fusion, and overall viability. Previously, we identified a miR-486/Dock3 signaling cascade that was dysregulated in dystrophin-deficient muscle which resulted in the overexpression ofDOCK3, however not much else is known about the role of DOCK3 in muscle. In this work, we characterize the functional role of DOCK3 in normal and dystrophic skeletal muscle. By utilizingDock3global knockout (Dock3KO) mice, we found reducingDock3gene via haploinsufficiency in DMD mice improved dystrophic muscle histology, however complete loss ofDock3worsened overall muscle function on a dystrophin-deficient background. Consistent with this,Dock3KO mice have impaired muscle architecture and myogenic differentiation defects. Moreover, transcriptomic analyses ofDock3knockout muscles reveal a decrease in factors known for myogenesis, suggesting a possible mechanism of action. These studies identifyDOCK3as a novel modulator of muscle fusion and muscle health and may yield additional therapeutic targets for treating dystrophic muscle symptoms.

Background: The development of biomarkers predictive of response to immune checkpoint inhibitor (ICI) therapies in advanced melanoma is an area of great interest in oncology. Our study evaluated the potential role of serum vascular endothelial growth factor (VEGF) as a predictive biomarker of clinical benefit and response to treatment with ICIs.Methods: Pre-treatment peripheral blood samples were obtained from advanced melanoma patients undergoing ICI therapy as monotherapy or in combination at two tertiary care hospitals in Western Australia. Serum VEGF levels were correlated with response to therapy and survival outcomes.Results: Serum VEGF samples were collected from a total of 130 patients treated with ICI therapy (pembrolizumab 73, ipilimumab 15, and ipilimumab/nivolumab combination 42). Median serum VEGF level was significantly higher in the non-responders (82.15 pg/mL) vs. responders (60.40 pg/mL) in the ipilimumab monotherapy cohort (P < 0.0352). However, no difference was seen in VEGF levels between non-responders and responders in pembrolizumab and ipilimumab/nivolumab treated patients.Conclusions: The results of our study confirm previous observations that that high pre-treatment serum VEGF levels in advanced melanoma patients may predict poor response to ipilimumab. However, serum VEGF is not predictive of outcome in patients treated with anti-PD-1 agents alone or in combination with ipilimumab.

Background: Accuracy of a seventh-generation “G7” continuous glucose monitoring (CGM) system was evaluated in children and adolescents with type 1 diabetes (T1D). Methods: Sensors were worn on the upper arm and abdomen. The CGM data were available from 127 of 132 participants, ages 7 to 17 years, across 10.5 days of use, various glucose concentration ranges, and various rates of glucose change for comparisons with temporally matched venous blood glucose measurements (YSI). Data were also available from 28 of 32 participants, ages 2 to 6 years, for whom capillary (fingerstick) blood provided comparator glucose values. Accuracy metrics included the mean absolute relative difference (MARD) between CGM and comparator glucose pairs, the proportion of CGM values within 15 mg/dL or 15% of comparator values Results: For participants aged 7 to 17, a total of 15 437 matched pairs were obtained from 122 arm-placed and 118 abdomen-placed sensors. For arm-placed sensors, the overall MARD was 8.1% and overall %15/15, %20/20, and %30/30 agreement rates were 88.8%, 95.3%, and 98.7%, respectively. For abdomen-placed sensors, the overall MARD was 9.0% and overall %15/15, %20/20, and %30/30 agreement rates were 86.0%, 92.9%, and 97.7%, respectively. Good accuracy was maintained across wear days, glucose ranges, and rates of glucose change. Among those aged 2 to 6, a total of 343 matched pairs provided an overall MARD of 9.3% and an overall %20/20 agreement rate of 91.5%. Conclusions: The G7 CGM placed on the arm or abdomen was accurate in children and adolescents with T1D. NCT#: NCT04794478

Androgens, both in excessive and depleted states, have been implicated in female reproductive health disorders. As such, serum testosterone measurements are frequently ordered by physicians in cases of sexual dysfunction and in women presenting with hirsutism. Commercially available androgen assays have significant limitations in the female population. Furthermore, the measurements themselves are not always informative in patient diagnosis, treatment, or prognosis. This article reviews the limitations of serum androgen measurements in women suspected to have elevated or reduced androgen action. Finally, we consider when therapeutic use of androgen replacement may be appropriate for women with sexual interest/arousal disorders.

Background PD‐1 inhibitors are routinely used for the treatment of advanced melanoma. This study sought to determine whether PD‐L1 expression on circulating tumor cells (CTCs) can serve as a predictive biomarker of clinical benefit and response to treatment with the PD‐1 inhibitor pembrolizumab. Methods Blood samples were collected from patients with metastatic melanoma receiving pembrolizumab, prior to treatment and 6–12 weeks after initiation of therapy. Multiparametric flow cytometry was used to identify CTCs and evaluate the expression of PD‐L1. Results CTCs were detected in 25 of 40 patients (63%). Patients with detectable PD‐L1+ CTCs (14/25, 64%) had significantly longer progression‐free survival (PFS) compared with patients with PD‐L1− CTCs (26.6 months vs. 5.5 months; p = .018). The 12‐month PFS rates were 76% versus 22% in the PD‐L1+ versus PD‐L1− CTCs groups (p = .012), respectively. A multivariate linear regression analysis confirmed that PD‐L1+ CTC is an independent predictive biomarker of PFS (hazard ratio, 0.229; 95% confidence interval, 0.052–1.012; p = .026). Conclusion Our results reveal the potential of CTCs as a noninvasive real‐time biopsy to evaluate PD‐L1 expression in patients with melanoma. PD‐L1 expression on CTCs may be predictive of response to pembrolizumab and longer PFS. Implications for Practice The present data suggest that PD‐L1 expression on circulating tumor cells may predict response to pembrolizumab in advanced melanoma. This needs further validation in a larger trial and, if proven, might be a useful liquid biopsy tool that could be used to stratify patients into groups more likely to respond to immunotherapy, hence leading to health cost savings., The objective of this study was to determine whether PD‐L1 expression on circulating tumor cells can serve as a predictive biomarker of clinical benefit and response to treatment with the PD‐1 inhibitor pembrolizumab.

Immunotherapy is an important and established treatment option for patients with advanced melanoma. Initial anti-PD1 trials arbitrarily defined a two-year treatment duration, but a shorter treatment duration may be appropriate. In this study, we retrospectively assessed 70 patients who stopped anti-PD1 therapy in the absence of progressive disease (PD) to determine clinical outcomes. In our cohort, the median time on treatment was 11.8 months. Complete response was attained at time of anti-PD1 discontinuation in 61 (87%). After a median follow up of 34.2 months (range: 2&ndash, 70.8) post discontinuation, 81% remained disease free. Using ddPCR, we determine the utility of circulating tumour DNA (ctDNA) to predict progressive disease after cessation (n = 38). There was a significant association between presence of ctDNA at cessation and disease progression (p = 0.012, Fisher&rsquo, s exact test) and this conferred a negative and positive predictive value of 0.82 (95% CI: 0.645&ndash, 0.930) and 0.80 (95% CI 0.284&ndash, 0.995), respectively. Additionally, dichotomised treatment-free survival in patients with or without ctDNA at cessation was significantly longer in the latter group (p &lt, 0.001, HR: 0.008, 95% CI: 0.001&ndash, 0.079). Overall, our study confirms that durable disease control can be achieved with cessation of therapy in the absence of disease progression and undetectable ctDNA at cessation was associated with longer treatment-free survival.

Background A significant number of melanoma patients experience recurrence to distant sites, despite having had surgical treatment of the primary lesion, with curative intent. Monitoring of patients for early evidence of disease recurrence would significantly improve management of the disease, allowing timely therapeutic intervention. Circulating tumor DNA (ctDNA) is becoming a well-recognized biomarker for monitoring malignancies and has, in a few studies, been shown to signify disease recurrence earlier than conventional methods. Methods We performed a retrospective analysis of plasma ctDNA using droplet digital PCR (ddPCR) in 30 primary melanoma patients with tumors harboring BRAF, NRAS or TERT promoter mutations. Mutant specific ctDNA, measured during clinical disease course, was compared with disease status in patients with confirmed disease recurrence (n = 3) and in those with no evidence of disease recurrence (n = 27). Results Mutant specific ctDNA was detected in all three patients with disease recurrence at the time of clinically confirmed progression. In one case, plasma ctDNA detection preceded clinical identification of recurrence by an interval of 4 months. CtDNA was not detected in patients who were asymptomatic and had no radiological evidence of recurrence. Conclusions This study demonstrates promising results for the use of ctDNA as an informative monitoring tool for melanoma patients having undergone tumor resection of an early stage primary tumor. The clinical utility of ctDNA for monitoring disease recurrence warrants investigation in prospective studies as it may improve patient outcome.

Objective Insulin is one of several molecules that transmit information about energy balance to the brain. It has been hypothesized that insulin resistance fosters non-homeostatic eating. The objective of the current study was to characterize corticolimbic brain responses to appetitive stimuli in subjects with insulin sensitivities ranging from resistant to normal. Design and Methods Sixteen women diagnosed with Polycystic Ovary Syndrome (PCOS) underwent functional magnetic resonance imaging (fMRI) while viewing pictures of high calorie (HC) foods, low calorie (LC) foods, and control (C) pictures. Results A region of interest analysis of the blood oxygen level dependent (BOLD) signal revealed widespread activation within corticolimbic regions in response to food pictures. Activated regions included the dorsolateral prefrontal cortex (DLPFC), medial prefrontal cortex (mPFC) , insula, nucleus accumbens (NAc), pallidum, ventral tegmental area (VTA), putamen, amygdala, caudate, substantia nigra, hippocampus, pulvinar, and midbrain. Activation of the anterior cingulate, dorsolateral prefrontal cortex (DLPFC), and midbrain by HC food pictures (HC — C) and activation of the lateral orbitofrontal cortex (OFC), pallidum, substantia nigra, ventral tegmental area (VTA), pulvinar, and midbrain by LC food pictures (LC — C) was negatively correlated with insulin sensitivity. In contrast, activation of the OFC, DLPFC, insula, hypothalamus, pallidum, substantia nigra, VTA, pulvinar, and midbrain by the HC — LC contrast was positively correlated with insulin sensitivity, whereas activation of the caudate was negatively correlated. Conclusions The association between insulin sensitivity and corticolimbic responses to food pictures may reflect abnormal brain responses to insulin feedback that contribute to the development and or perpetuation of obesity in PCOS.

Background Multimarker quantitative real-time polymerase chain reaction (qRT-PCR) represents an effective method for detecting circulating tumour cells in the peripheral blood of patients with melanoma. Objectives To investigate whether the phenotype of circulating melanoma cells represents a useful indicator of disease stage, recurrence and treatment efficacy. Methods Peripheral blood was collected from 230 patients with melanoma and 152 healthy controls over a period of 3 years and 9 months. Clinical data and blood samples were collected from patients with primary melanoma (early stages, 0‐II, n = 154) and metastatic melanoma (late stages, III‐IV, n = 76). Each specimen was examined by qRT-PCR analysis for the expression of five markers: MLANA, ABCB5, TGFb2, PAX3d and MCAM. Results In total, 212 of the patients with melanoma (92%) expressed markers in their peripheral blood. Two markers, MLANA and ABCB5, had the greatest prognostic value, and were identified as statistically significant among patients who experienced disease recurrence within our study period, being expressed in 45% (MLANA) and 49% (ABCB5) of patients with recurrence (P =0 AE001 and P =0 AE031, respectively). For patients administered nonsurgical treatments, MCAM expression correlated with poor treatment outcome. Conclusions Circulating tumour cells were detectable at all stages of disease and long after surgical treatment, even when patients were considered disease free. Specifically, expression of ABCB5 and MLANA had significant prognostic value in inferring disease recurrence, while MCAM expression was associated with poor patient outcome after treatment, confirming multimarker qRT-PCR as a potential technique for monitoring disease status.

Forearm blood flow (FBF) was measured in 23 patients with homozygous sickle cell (SS) disease and 20 controls with normal hemoglobin genotype (AA) using venous occlusion air plethysmography to examine the pattern of peripheral blood flow in both groups at rest, and in response to thermal stimuli. The mean resting FBF in SS patients was more than twice that in AA controls (P

Background Deep vein thrombosis (DVT) is an important complication of stroke. Guidelines recommend that DVT prophylaxis should be guided by an assessment of the individual patient9s risk. The authors aimed to develop and test models to predict DVT risk. Methods The Clots in Legs Or sTockings after Stroke (CLOTS) Trial 1 randomised 2518 immobile patients with acute stroke to thigh-length graduated compression stockings (GCS) or no GCS and CLOTS Trial 2 randomised 3114 to thigh-length or below-knee GCS. The authors collected potential predictive variables at baseline and detected DVTs with compression duplex ultrasound scans at about 7–10 days and 25–30 days. The authors developed models with logistic regression to predict DVT in 1242 Trial 2 patients who had two scans and tested the models in the 1422 Trial 1 patients with two scans by estimating the area under the receiver operating characteristic curve (AUC). Results 168 (11.8%) patients in Trial 1 and 122 (9.8%) in Trial 2 had proximal DVTs. A model based on the Trial 2 cohort contained four of the 12 baseline variables: dependent before stroke (OR=3.62, 95% CI 2.15 to 6.08), unable to lift arms off bed (OR 1.89, 95% CI 1.23 to 2.90), history of DVT/pulmonary embolism (OR 3.69, 95% CI 1.98 to 6.88) and diabetes (OR 0.55, 95% CI 0.30 to 0.99). The AUC in the development cohort was 0.65 but only 0.57, 95% CI (0.53 to 0.61) in the Trial 1 cohort, indicating poor discrimination. Conclusions Unfortunately, models based on clinical factors alone discriminate poorly between immobile patients with stroke at high and low risk, and would not facilitate individual tailoring of DVT prophylaxis strategies.

The determination of an optimal haematocrit (H0) has important clinical implications if such a level can be attained, and more importantly, maintained. This is defined as a haematocrit level, above or below which oxygen delivery is deleteriously affected. This study is designed to determine an optimal haematocrit in normal (AA), sickle cell trait (AS) and sickle cell disease (SS) subjects. Twenty-seven apparently healthy subjects having normal haemoglobin genotype, 24 with sickle cell trait and 42 with homozygous sickle cell disease were recruited into the study. Whole blood viscosity (WBV) was measured by a Wells Brookfield Cone and Plate Viscometer at a shear rate of 230 sec-1. Haematocrit was determined by an AC.Tron Coulter Counter. The optimal haematocrit was calculated as the inverse of a constant, K, which was derived from the haematocrit and viscosity data. Our findings showed that the H0 varied significantly among the 3 haemoglobin genotypes, in the order AA vs SS and AS vs SS. Additionally, the data indicated an increased H0 in subjects with sickle cell trait, suggesting a possible impairment in oxygen delivery in these individuals.

Sickle cell anemia (SCA or SS homozygous sickle cell disease) is an inherited blood disorder caused by single 12 nucleotide substitution in the ␤-globin gene that renders their hemoglobin (HbS) much less soluble than normal hemoglobin 13 (HbA) when deoxygenated. The polymerization of HbS upon deoxygenation is the basic pathophysiologic event leading to 14 RBC sickling, hemolysis, vasoocclusion and ultimately to chronic organ damage. The metabolic changes imposed by exercise 15 may initiate sickling and vaso-occlusive episodes. Further, in patients with SCA, exercise limitation may be related to anemia 16 or chronic complications such as pulmonary vascular disease, congestive heart failure and chronic parenchymal lung disease. 17 Few studies have investigated the cardiorespiratory responses of patients with SCA during either symptom-limited maximal 18 exercise test on cyclo-ergometer or during a six minute walk test. Therefore, patients are advised to start exercise slowly and 19 progressively, to maintain adequate hydration during and after exercise, to avoid cold exposure or sudden change in temperature, 20 and to avoid sports associated with mechanical trauma. There are, however, lack of evidence to allow practitioners to prescribe 21 an exercise program for patients with SCA, and individuals are usually encouraged to exercise on a symptom-limited basis. 22 Finally, this review will also highlight the basic principles that are often used for exercise practice and could be used for exercise 23 prescription and rehabilitation in patients with sickle cell anemia.

BACKGROUND We examined the relationship of left ventricular (LV) end-systolic meridional wall stress (LVESS), a measure of LV afterload, with race, gender, other cardiovascular risk factors and LV mass in 3,994 young adults in the Coronary Artery Risk Development in Young Adults (CARDIA) Study. METHODS From transthoracic echocardiography, LVESS was derived from LV internal dimension and posterior wall thickness and systolic blood pressure (BP). RESULTS Adjusted LVESS was significantly greater in black men versus women (59.0 vs. 54.8 dynes/cm, P < 0.01) and in white men versus women (59.0 vs. 55.4 dynes/cm(2), P < 0.01), but did not differ in comparing whites versus blacks either in men or women. In multiple regression analyses, age and LV mass were inversely (P < 0.01) and height was positively (P < 0.01) associated with LVESS. The overall variance of LVESS explained by the models in each race-sex subgroup was low (R(2) less than 0.03), suggesting that standard risk factors contribute little to determining LVESS in young adults. Over a 15-year follow-up period, LVESS, after the adjustment for covarieties, was not associated with the incidence of coronary heart disease (CHD) and cardiovascular disease (CVD) events. CONCLUSION LVESS may not be a useful marker of cardiovascular risk in young adults; further study is needed to determine whether other echocardiographic measures may be more useful predictors.

Objective To determine if the increased risk of cardiovascular disease in patients with lower socioeconomic status could be explained by higher prevalence of known risk factors including hypertension or whether there was an independent effect of deprivation. Methods A retrospective cohort study of mortality was carried out on 3360 patients who attended Glasgow Blood Pressure Unit between 1991 and 2000, followed for a mean period of 8.1 years. Cox proportional hazards models were used to adjust for the effects of age, sex, socioeconomic circumstances, systolic and diastolic blood pressures at baseline and on treatment, smoking, diabetes mellitus, history of angina and myocardial infarction, excessive alcohol consumption, BMI and serum cholesterol. Results Of 442 deaths, 244 (55%) were from cardiovascular diseases. After adjustment, residents of the most deprived areas had a hazard ratio for all cause mortality of 1.46 (95% confidence interval 1.04, 2.04). Adjusted hazard ratio for death from cardiovascular disease in the most deprived areas was 1.65 (1.04, 2.60) compared with those from the most affluent areas. Conclusion Socioeconomic deprivation appears to have a significant independent effect on risks of death from cardiovascular disease.

Vascular abnormalities are more prevalent in the lower extremities in diabetic patients and may cause diminished perfusion to surrounding tissues. We sought to identify blood flow abnormalities in the leg of diabetic patients with peripheral occlusive arterial disease (POAD) and to determine whether these were associated with abnormalities in rheological determinants, namely, plasma fibrinogen concentration (PFC), relative plasma viscosity (RPV), hematocrit (Hct), and whole blood viscosity (WBV). Seventeen diabetic patients with POAD were compared with 40 diabetic patients without POAD and 19 nondiabetic control subjects. Blood flow was measured by venous occlusion plethysmography, RPV was measured by capillary viscometry, WBV was measured by a Wells-Brooksfield viscometer [at high (230 s(-1)) and low (23 s(-1)) shear rates], and PFC was measured by the clot-weight method of Ingram [Ingram, G. I. C. (1961). A suggested schedule for the rapid investigation of acute haemostatic failure. Journal of Clinical Pathology, 14, 356-360]. Ankle blood flow (Q(ak)) was significantly lower in diabetic patients with POAD than in diabetic patients without POAD (P.05). PFC was higher and Hct was lower in diabetic patients with POAD than in diabetic patients without POAD (P.05). RPV was 1.97+/-0.15 versus 1.92+/-0.15 in diabetic patients with POAD and diabetic patients without POAD, respectively (P.05). There was no significant difference in WBV at low or high shear rates between the groups studied. There was a correlation between WBV at low shear rate and arterial flow in the calf (Q(c)) (r=.94) and great toe (r=.95) in diabetic patients with POAD, and between Q(c) and WBV at high (r=-.465) and low (r=-.472) shear rates in diabetic patients without POAD (P.05). We conclude that vasodilatation occurring in diabetic patients without POAD is severely restricted or absent in diabetic patients with POAD. Increased plasma fibrinogen and plasma viscosity may contribute to this phenomenon.

Sickle cell disease is characterized by altered blood rheology due to a reduced haematocrit and a resulting lowered viscosity. Oxygen carriage, and consequently oxygen delivery, may be deleteriously affected if the haematocrit reduction is such as to limit oxygen uptake from the lungs and delivery to the tissues. The present study seeks to determine and compare the oxygen delivery index (ODI) in subjects with normal and abnormal haemoglobin genotypes. Thirty four apparently healthy subjects having normal haemoglobin genotype (AA), 27 with sickle cell trait (AS) and 50 with homozygous sickle cell disease (SS) were recruited into the study. Whole blood viscosity was measured at low and high shear rates of 23 s(-1) and 230 s(-1), respectively, using a Wells Brookfield Cone and Plate Viscometer. Haematocrit was determined using an AC.Tron Coulter Counter. The oxygen delivery index was calculated as the ratio of the haematocrit to whole blood viscosity. There was a statistically significant difference in the ODI in the SS group compared with both the AA and AS groups. There was no statistical significance in the ODI between the AA and AS groups. The ODI may be considered as a useful assessment of oxygen delivery in subjects with sickle cell disease.

Studies performed in the past two decades have unequivocally shown that several of the components of the metabolic syndrome are associated with indirect and direct markers of adrenergic overdrive. This is the case for hypertension and obesity, in which resting tachycardia, elevated plasma norepinephrine values, increased sympathetic nerve traffic, as well as augmented levels of total and regional norepinephrine spillover have been reported. This is also the case for insulin resistance, i.e. a metabolic condition frequently complicating the various components of the pathological condition identified as the 'metabolic syndrome'. After briefly describing the epidemiological and the cardiovascular risk profile of the disease, this paper will examine the behaviour of the sympathetic nervous system in the metabolic syndrome as well as the mechanisms potentially responsible for this neurogenic abnormality. This will be followed by an analysis of the role played by neuroadrenergic factors in disease progression as well as in the pathogenesis of its complications. Finally, the therapeutic implications of these findings will be highlighted.

Background Lysis of bloody liquid based cytology (LBC) specimens with glacial acetic acid (GAA) is performed to aid cytological interpretation. However, the influence of GAA treatment on HPV detection is not fully understood and in studies designed to assess this, few cases of high-grade disease have been included. Objectives To assess the sensitivity of HPV molecular tests for the detection of high grade cervical disease in GAA treated samples Study design A total of 207 specimens associated with high grade dyskaryosis and treated with GAA were collated prospectively. Overall 140 specimens had underlying CIN2+, including 88 CIN3. All specimens were tested with the Abbott RealTime High Risk HPV test ( rt HPV) and the Qiagen Hybrid Capture 2High Risk HPV DNA test (HC2). Specimens associated with a CIN2+ that were negative by either assay were genotyped. Results The sensitivity of rt HPV for CIN2+ and CIN3+ was 92.8% (87.2, 96.5) and 94.3% (87.2, 98.1) respectively. Sensitivity of the HC2 for CIN2+ and CIN3+ was 97.2% (92.8, 99.2) and 96.6% (90.3, 99.2) respectively. The sensitivity of both assays in GAA treated specimens was thus consistent with the level required for clinical application. HPV negative, CIN2+ specimens were generally attributable to HPV types outside the explicit analytical range of the assays. Conclusions The data indicate that GAA treatment has little impact on the detection of CIN2+ by HPV testing in LBC specimens.

// Elin S. Gray 1 , Helen Rizos 2,8 , Anna L. Reid 1 , Suzanah C. Boyd 2,8 , Michelle R. Pereira 1 , Johnny Lo 3 , Varsha Tembe 4 , James Freeman 1 , Jenny H.J. Lee 4,5 , Richard A. Scolyer 6,8 , Kelvin Siew 9 , Chris Lomma 9 , Adam Cooper 5 , Muhammad A. Khattak 10,11 , Tarek M. Meniawy 9,11 , Georgina V. Long 7,8 , Matteo S. Carlino 5,8 , Michael Millward 9,11 and Melanie Ziman 1,12 1 School of Medical Sciences, Edith Cowan University, Joondalup, Western Australia, Australia 2 Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia 3 School of Engineering, Edith Cowan University, Joondalup, Western Australia, Australia 4 Centre for Cancer Research, The University of Sydney at Westmead Millennium Institute, Westmead Hospital, Westmead, New South Wales, Australia 5 Department of Medical Oncology, Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, New South Wales, Australia 6 Disciplines of Pathology, The University of Sydney, Sydney, New South Wales, Australia 7 Medicine, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia 8 Melanoma Institute Australia, Sydney, New South Wales, Australia 9 Department of Medical Oncology, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia 10 Department of Medical Oncology, Fiona Stanley Hospital, Murdoch, Western Australia, Australia 11 School of Medicine and Pharmacology, The University of Western Australia, Crawley, Western Australia, Australia 12 School of Pathology and Laboratory Medicine, The University of Western Australia, Crawley, Western Australia, Australia Correspondence to: Elin Gray, email: // Keywords : melanoma, ctDNA, acquired resistance, MAPK inhibition, immunotherapy Received : August 03, 2015 Accepted : August 31, 2015 Published : September 22, 2015 Abstract Repeat tumor biopsies to study genomic changes during therapy are difficult, invasive and data are confounded by tumoral heterogeneity. The analysis of circulating tumor DNA (ctDNA) can provide a non-invasive approach to assess prognosis and the genetic evolution of tumors in response to therapy. Mutation-specific droplet digital PCR was used to measure plasma concentrations of oncogenic BRAF and NRAS variants in 48 patients with advanced metastatic melanoma prior to treatment with targeted therapies (vemurafenib, dabrafenib or dabrafenib/trametinib combination) or immunotherapies (ipilimumab, nivolumab or pembrolizumab). Baseline ctDNA levels were evaluated relative to treatment response and progression-free survival (PFS). Tumor-associated ctDNA was detected in the plasma of 35/48 (73%) patients prior to treatment and lower ctDNA levels at this time point were significantly associated with response to treatment and prolonged PFS, irrespective of therapy type. Levels of ctDNA decreased significantly in patients treated with MAPK inhibitors ( p < 0.001) in accordance with response to therapy, but this was not apparent in patients receiving immunotherapies. We show that circulating NRAS mutations, known to confer resistance to BRAF inhibitors, were detected in 3 of 7 (43%) patients progressing on kinase inhibitor therapy. Significantly, ctDNA rebound and circulating mutant NRAS preceded radiological detection of progressive disease. Our data demonstrate that ctDNA is a useful biomarker of response to kinase inhibitor therapy and can be used to monitor tumor evolution and detect the early appearance of resistance effectors.

It is unclear whether hypertension and antihypertensive medication use are associated with breast cancer. In order to examine these associations, we conducted a case-control study among women aged 50-75 years. Breast cancer cases were ascertained via a population-based cancer registry (n=523) and controls were ascertained via random-digit-dialing (n=131). Participants completed a self-administered questionnaire which queried history of hypertension, antihypertensive medication use and risk factors. Unconditional logistic regression was used to estimate the odds ratio (OR) and 95% confidence intervals (CI), adjusted for age, body mass index (BMI), diabetes, smoking, alcohol use, menopausal status, family history of breast or ovarian cancer, age at first full-term pregnancy and education. History of treated hypertension was associated with significant increased risk of breast cancer (OR, 1.77; 95% CI, 1.04-3.03) and this association appeared only in women with BMI > or =25 kg/m(2) (OR, 2.30; 95% CI, 1.12-4.71). Diuretic use was also associated with elevated breast cancer risk (OR, 1.79; 95% CI, 1.07-3.01). The risk associated with diuretic use increased with duration of use (P for trend

BACKGROUND We recently reported the prevalence of aortic regurgitation (AR) by Doppler echocardiography (echo) in obese subjects to be higher than in some previous reports. OBJECTIVE To describe the prevalence of AR in an obese population not taking anorexigens as a function of demographic characteristics, cardiovascular risk factors, and other potential predictors. METHODS In 539 adult subjects, cardiovascular status was evaluated by medical history, physical examination, and Doppler echocardiograms performed according to a standardized imaging protocol. Echocardiographic readers were blinded as to each subject's medical and medication histories. Associations of AR with demographic and comorbid factors were examined. RESULTS Subjects had a mean (+/- SD) body mass index (BMI) of 35 +/- 7 kg/m2, and were predominantly white (87.6%), females (74%), with a mean age of 47 +/- 12 years. AR by Food and Drug Administration criteria (> or =mild) was present in 4.1% of the subjects. Covariates significantly associated with AR were increasing age (P < 0.001), presence of a history of hypertension (P = 0.001), left ventricular (LV) internal dimensions (P < 0.005), and tricuspid and mitral regurgitation grade (P < 0.001). CONCLUSIONS Clinical and Doppler echo evaluation of a large, predominantly obese, adult population revealed that AR was more prevalent than in some previous reports and was highly correlated with increased age, presence of a history of hypertension, LV internal dimensions, tricuspid and mitral regurgitation.

Loss of axon caliber is a primary component of gamma-diketone neuropathy [LoPachin RM, DeCaprio AP. gamma-Diketone central neuropathy: axon atrophy and the role of cytoskeletal protein adduction. Toxicol Appl Pharmacol 2004;199:20-34]. It is possible that this effect is mediated by changes in the density of cytoskeletal components and corresponding spatial relationships. To examine this possibility, morphometric methods were used to quantify the effects of 2,5-hexanedione (HD) intoxication on neurofilament-microtubule densities and nearest neighbor distances in myelinated rubrospinal axons. Rats were exposed to HD at one of two daily dose-rates (175 or 400 mg/kg per day, gavage) until a moderate level of neurotoxicity was achieved (99 or 21 days of intoxication, respectively) as determined by gait analysis and measurements of hindlimb grip strength. Results indicate that, regardless of dose-rate, HD intoxication did not cause changes in axonal neurofilament (NF) density, but did significantly increase microtubule (MT) density. No consistent alterations in interneurofilament or NF-MT distances were detected by ultrastructural morphometric analyses. These data suggest that the axon atrophy induced by HD was not mediated by major disruptions of stationary cytoskeletal organization. Recent biochemical studies of spinal cord from HD intoxicated rats showed that, although the NF protein content in the stationary cytoskeleton (polymer fraction) was not affected, the mobile subunit pool was depleted substantially [LoPachin RM, He D, Reid ML, Opanashuk LA. 2,5-Hexanedione-induced changes in the monomeric neurofilament protein content of rat spinal cord fractions. Toxicol Appl Pharmacol 2004;198:61-73]. The stability of the polymer fraction during HD intoxication is consistent with the absence of significant ultrastructural modifications noted in the present study. Together, these findings implicate loss of mobile NF proteins as the primary mechanism of axon atrophy.

Angiotensin II receptor blockers (ARBs) may produce a number of molecule-specific effects that appear to be independent of interaction with the angiotensin II type 1 (AT 1)-receptor. These include antagonism of the thromboxane A2 receptor, inhibition of platelet aggregation, induction of peroxisome proliferator-activated receptor gamma (PPARγ) activity, and reduction of serum uric acid levels. However, definitive evidence is lacking that these molecule-specific effects give rise to a therapeutic advantage of one ARB over another. Currently, the possibility of a link between a molecule-specific effect of an ARB and an improvement in clinical outcomes is best illustrated by a reduction in serum uric acid levels with losartan. Data from Losartan Intervention For Endpoint reduction in hypertension (LIFE) study suggest treatment-induced decrease in serum uric acid may contribute to the treatment benefit of a losaran-based versus atenolol-based therapy on the composite endpoint (death, myocardial infarction, or stroke). This finding should prompt further studies to investigate the long-term cardioprotective benefits issue of reducing hyperuricaemia in hypertensive patients.

Objective To examine the effect of telmisartan or hydrochlorothiazide on the control of urinary albumin excretion (UAE) in patients with isolated systolic hypertension (ISH) unselected for albuminuria in a pre-planned substudy of a large, multicentre, double-blind, placebo-controlled, randomized study. Methods The Angiotensin II Receptor Antagonist Micardis in Isolated Systolic hypertension (ARAMIS) study compared the antihypertensive efficacy after 6 weeks of once-daily fixed doses of telmisartan 20, 40 or 80 mg versus hydrochlorothiazide 12.5 mg or placebo in patients (n = 1039, aged 35 - 84 years) with ISH (seated blood pressure 150 - 179/ 2.2 - 901.6 mg/l) was detected at baseline in 614 out of 918 patients who were included in the substudy analysis. In the telmisartan group (n = 354, all doses combined), a median reduction in UAE from a baseline of 14.1% [95% confidence interval (CI) 7.3, 21.8] was observed versus 1.1% (95% CI - 13.5 to 16.0) and 2.7% (95% CI - 0.9 to 19.9) in the hydrochlorothiazide (n = 140) and placebo (n U 120) groups, respectively. The difference between telmisartan and hydrochlorothiazide was significant (P = 0.017). Reductions in UAE with telmisartan were observed in patients with baseline normoalbuminuria, microalbuminuria or macroalbuminuria. Telmisartan and hydrochlorothiazide produced comparable reductions in systolic blood pressure in these patients. Conclusion In patients with ISH unselected for baseline albuminuria, telmisartan 20 - 80 mg after 6 weeks' treatment afforded significantly greater lowering of UAE than hydrochlorothiazide 12.5 mg, irrespective of the baseline UAE, and despite comparable reductions in systolic blood pressure with both drugs.

Recently, it has been shown that female rats receiving very large doses (e.g., 2 mg) of estradiol valerate (EV) take considerably more alcoholic beverage than placebo controls. The question asked, with these procedures, is whether the enhanced appetite for alcoholic beverages was specific to those beverages or was a reflection of a general increase in appetite. Female rats were provided with various sweetened beverages. In one experiment, they were provided a palatable saccharin solution (0.25% solution) and a less palatable one (2% saccharin solution). EV treatment led to more intake of the palatable saccharin solution and reduced intake of the less palatable solution. EV induces changes leading to enhanced appetite for some ingesta (including palatable saccharin solutions and alcoholic beverages), but surely not all ingesta.

Purpose: Patients with gut dysbioses are clinically difficult to distinguish from those with food intolerance. The variety known as fungal‐type is associated with the generation of small amounts of ethanol in the blood. A recent study has shown abnormalities of histidine metabolism. In view of this, gastric function was studied. This also provided data on pancreatic function.Design: Two groups of newly referred patients, with similar symptom profiles, attending two clinicians were studied. Group A (42 patients) had positive ethanol fermentation tests: group B (37 patients) did not. There were 20 healthy control subjects. Levels of higher alcohols, short‐chain fatty acids, gastric acid production and pancreatic exocrine secretions were measured and compared statistically.Materials and Methods: Ethanol, higher alcohols and short‐chain fatty acids were measured by gas–liquid chromatography. Gastric acid production, emptying time and pancreatic function were measured using a swallowed transducer.Results: A si...

To identify telmisartan doses that are more effective than placebo and non-inferior to hydrochlorothiazide (HCTZ) 12.5 mg, and are well tolerated, in lowering systolic blood pressure (SBP) in patients with isolated systolic hypertension (ISH).A 2-4-week single-blind placebo run-in was followed by randomization of 1039 patients (age 36-84 years) with ISH [seated SBP 150-179 mmHg and seated diastolic blood pressure (DBP)90 mmHg] to once-daily double-blind treatment with telmisartan 20, 40 or 80 mg, HCTZ 12.5 mg, or placebo. The change in seated trough SBP after 6 weeks compared with baseline was the primary end point. Secondary end points were the percentage achieving the target fall in SBP and the change from baseline in seated trough DBP. Incidence and severity of adverse events and physical examination and laboratory parameters were monitored for the safety evaluation.Baseline demographics in telmisartan 20 mg (n = 206), 40 mg (n = 210), 80 mg (n = 207), HCTZ 12.5 mg (n = 205) and placebo (n = 211) treatment groups were comparable: (mean +/- SD) age, 63.0 +/- 10.9 years; SBP, 162.9 +/- 8.1 mmHg; and DBP 83.4 +/- 5.0 mmHg. No previous antihypertensive therapy had been received by 66% of the patients. Mean reductions in seated trough SBP (adjusted for baseline and country) were: telmisartan 20 mg, 15.6 mmHg (n = 204); 40 mg, 17.9 mmHg (n = 209); and 80 mg, 16.9 mmHg (n = 205), compared with placebo, 11.4 mmHg (n = 208), and HCTZ 12.5 mg, 15.7 mmHg (n = 204). The target fall in seated trough SBP (or =140 mmHg or reduction byor =20 mmHg) was achieved in 46.6% (telmisartan 20 mg), 51.7% (telmisartan 40 mg), 53.9% (telmisartan 80 mg), 27.4% (placebo) and 42.7% (HCTZ 12.5 mg); the response rate was significantly higher for telmisartan 80 mg than for HCTZ 12.5 mg (P = 0.03). All-causality adverse events occurred in 19.9, 17.6 and 20.3% receiving telmisartan 20, 40 and 80 mg, respectively; 20.9% receiving placebo and 22.0% receiving HCTZ 12.5 mg. No drug-related serious adverse events occurred.All doses of telmisartan (20-80 mg) were significantly superior to placebo in reducing SBP in patients with ISH and clinically comparable to HCTZ 12.5 mg. Tolerability of telmisartan was similar to that of placebo.

Objective: To investigate whether underlying medical conditions contribute to the fatigue and high incidence of infections that can occur during repeated intense training. Method: Forty one competitive athletes (22 male, 19 female) with persistent fatigue and/or recurrent infections associated with performance decrements had a thorough medical examination and a series of clinical investigations to identify potential medical causes. Results: Conditions with the potential to cause fatigue and/or recurrent infections were identified in 68% of the athletes. The most common were partial humoral immune deficiency (28%) and unresolved viral infections (27%). Non-fasting hypoglycaemia was common (28%). Other conditions included allergic disease (15%), new or poorly controlled asthma (13%), upper airway dysfunction (5%), sleep disorders (15%), iron depletion (3%), and one case of a thyroid disorder. A positive antinuclear antibody was detected in 21% of the athletes, without any clinical evidence of autoimmune disorders. Evidence of Epstein-Barr virus reactivation was detected in 22% of the athletes tested. Conclusions: Athletes with recurrent infections, fatigue, and associated poor performance may benefit from a thorough investigation of potentially reversible underlying medical conditions, especially when these conditions cause disruption to training and competition. Unresolved viral infections are not routinely assessed in elite athletes, but it may be worth considering in those experiencing fatigue and performing poorly.

Hypertension, aging and a range of neurodegenerative diseases are associated with increased oxidative damage. The present study examined whether superoxide (O2*-) levels in brain are increased during aging in female rats, and the role of superoxide dismutase (SOD) and oestrogen in regulating O2*- levels. Young adult (3 month) and old (11 month) female spontaneously hypertensive stroke prone rats (SHRSP) and normotensive Wistar-Kyoto rats (WKY) were studied. O2*- levels were measured in brain homogenates by lucigenin chemiluminescence and SOD expression by Western blotting. Ageing significantly increased brain O2*- levels in WKY (cortex +216%, hippocampus +320%, striatum +225%) and to a greater extent in SHRSP (cortex +540%, hippocampus +580%, striatum +533%). Older SHRSP showed a decline in cortical Cu/Zn SOD expression compared to young adult SHRSP. Oestrogen did not attenuate O2*- levels. The results show a significant age-dependent increase in brain O2*- levels which is exaggerated in SHRSP. The excess cortical O2*- levels in the SHRSP may be associated with a down-regulation of Cu/Zn SOD but are not related to a decrease in oestrogen.

Rilmenidine is a centrally acting antihypertensive which differs from the other representatives of this class by its very high specificity for the imidazoline I1 receptors and its good tolerability. Recent studies have shown rilmenidine improves glucose tolerance and reduces micro-albuminuria in patients with diabetes mellitus. The evidence of these potentially favorable characteristics encouraged a secondary retrospective analysis of a subgroup of 2738 diabetic patients included in a previous long-term open study of rilmenidine alone, or in combination with other classes of antihypertensives. The antihypertensive efficacy of rilmenidine demonstrated previously in controlled studies was confirmed during the 12-month follow-up. In addition, favorable effects of drug treatment on fasting blood glucose and plasma triglyceride levels were consistent with an improvement in glucose and lipid metabolism during treatment. The profile of adverse events was similar to that observed in the nondiabetic population, the occurrence of postural hypotension being observed in

Each of 30 female Sprague-Dawley rats were given 2 mg of estradiol valerate (EV), 30 others were given placebos. EV is a preparation that delivers estradiol for more than 12 days, but probably less than 20. Fifteen days later, the females had the opportunity to take sweetened alcoholic beverage 24 h a day across 25 days. Subsequently, they could self-administer other alcoholic beverages, including one of only alcohol and water. After a period of abstinence, rats had another opportunity to take sweetened alcoholic beverage (94 to 96 days after the single injection of EV). With every measurement, rats given EV consumed significantly more ethanol than controls. For example, mean of measurements representing daily intake for the fourth week of availability of palatable alcoholic beverage for placebo-treated=5.29 grams of ethanol per kilogram of bodyweight (g'E/kg); for EV-treated=8.13 g'E/kg; P=.003. The data support the conclusion that pharmacological doses of estradiol can induce marked, enduring changes in appetite for alcoholic beverages.

The goal of this study was to determine the presence and correlates of change (Delta) in left ventricular (LV) mass by echocardiography in young adults.Left ventricular mass is known to be a powerful independent predictor for cardiovascular disease events in adults. However, little is known about Delta in LV mass over time in young adults.Coronary Artery Risk Development in Young Adults (CARDIA) is a multicenter, longitudinal, population-based study of black and white men and women who were ages 23 to 35 at the time of their initial two-dimensionally directed M-mode echocardiography exam (year 5); half the cohort had a repeat echocardiography exam five years later (year 10). Data were analyzed from 1,189 participants who had paired echocardiography studies. To minimize reader variability, blinded measurements on initial and repeat echocardiography were performed nearly contemporaneously by the same reader.In multilinear regression analyses, significant (p0.05) predictors of year 10 two-dimensional guided M-mode LV mass included initial LV mass, initial body mass index (BMI) and change in BMI for all race/gender subgroups. Initial systolic blood pressure (SBP) was a significant predictor of year 10 LV mass in white men and black women; change in SBP was significant in black women with a trend towards significance in white women. Left ventricular mass remained constant in all race/gender subgroups, except black women, where it increased (by 5.9 g [mean]). Black women also had the largest increases in BMI and SBP. In black women, a five-year weight gain of 20 pounds and a 15-mm Hg increase in SBP would be expected to be associated with a 9% to 12% increase in LV mass.Particularly in black women, weight and blood pressure control may be important community health and treatment goals to prevent LV hypertrophy.

Clomiphene citrate is an effective inducer of ovulation, but pregnancy rates per cycle remain comparatively low, possibly because of an antiestrogenic effect on the endometrium. Letrozole, a potent, orally active aromatase inhibitor, suppresses the production of estrone from androstenedione and has markedly increased gonadotropin levels in animal studies. A possible role of letrozole in ovulation induction was explored in a randomized, double-blind, pilot study enrolling 19 ovulatory women ranging in age from 18 to 35 years. After a natural cycle, the women received either 2.5 mg of letrozole or 50 mg of clomiphene citrate daily on days 5 to 9 after menstruation. Ovarian follicle formation was monitored by transvaginal ultrasonography. The major measure of outcome was the number of mature follicles measuring at least 18 mm at the time of the LH surge. In the 16 women completing both study cycles, a comparable increase in the number of mature follicles at the LH surge was noted in both treatment groups. The mean number was 2.2 with clomiphene therapy and 1.7 in women given letrozole. Midcycle endometrial thickness averaged 10.1 mm in the clomiphene group and 10.6 mm in the letrozole group during the treatment cycle, not a significant difference. All letrozole-treated women but fewer than 60% of those given clomiphene citrate had trilaminar pattern endometrium at midcycle in the natural cycle. The numbers did not drop significantly in either group during the treatment cycle. Follicular gonadotropin profiles were comparable in the two groups in both natural and medicated cycles. Estradiol levels in treatment cycles were higher with clomiphene and lower than those in natural cycles when letrozole was administered. Letrozole seems to be equivalent to clomiphene citrate for stimulating follicle growth in normally ovulating women. This agent may make women more sensitive to FSH, enhance endometrial development (compared with clomiphene), and increase implantation rates through more physiological estradiol levels. Letrozole should be a useful alternative to clomiphene citrate for ovarian hyperstimulation in both intrauterine insemination and in vitro fertilization.

A series of experiments investigated the effects of a single injection of estradiol valerate (EV) on female rats' consumption of alcoholic beverages. EV provides sustained release of estradiol. Just after an injection of EV, rats' intake of a palatable alcoholic beverage, which had been taken regularly before, is reduced dramatically. Subsequently, rats' intake of alcoholic beverage returns to baseline levels. With continued opportunity to drink, rats take more ethanol than controls. When EV was given 15 and 31 days before the first opportunity to drink an alcoholic beverage, female rats markedly enhanced their intake of ethanol. Once enhanced intakes emerged, they were observed with different kinds of alcoholic beverages and endured for months.

This research was conducted to determine which neurological test or combination of tests can provide sufficient functional information to compliment biochemical or morphological endpoints in mechanistic studies of toxic axonopathies. Using several neurological indices, we evaluated the effects of two prototypical neurotoxicants that cause distal axonopathy: acrylamide monomer (ACR) and 2,5-hexanedione (HD). For each toxicant, rats were exposed to two daily dosing rates (ACR, 50 mg/kg per day i.p. or 21 mg/kg per day, p.o.; HD, 175 or 400 mg/kg per day, p.o.) and neurological endpoints were determined two to three times per week. Specific tests included observations of spontaneous locomotion in an open field, and measurements of hindlimb landing foot splay, forelimb and hindlimb grip strength and the hindlimb extensor thrust response. For all neurological parameters, the magnitude of defect induced by either neurotoxicant was not related to daily dose-rate, e.g. both the lower and higher ACR dose-rates produced the same degree of neurological dysfunction. Instead, dose-rate determined onset and progression of neurotoxicity, e.g. the higher ACR dose-rate produced moderate neurotoxicity after approximately 8 days of intoxication, whereas the lower dose-rate caused moderate neurotoxicity after 26 days. Regardless of dose-rate, ACR-exposed rats exhibited gait abnormalities (ataxia, splayed hindlimbs), in conjunction with increased landing hindfoot spread and decreased hindlimb grip strength and extensor thrust. HD intoxicated rats exhibited hindlimb muscle weakness as indicated by a gait abnormality (dropped hocks) and decreases in grip strength and the extensor thrust response. However, hindlimb landing foot spread was not affected by HD exposure. For both neurotoxicants, gait changes preceded or coincided with alterations in other neurologic indices. These results suggest that observations of spontaneous behavior in an open field represent a practical approach to assessing temporal development and extent of neurological dysfunction induced by axonopathic toxicants such as ACR and HD.

Radial arteries, used in revascularisation surgery, are prone to spasm. We have examined the ability of nitrovasodilators, calcium channel blockers, and K(ATP) channel openers to cause vasodilation, and to attenuate contractions due to depolarisation and receptor activation in radial and mammary arteries used in coronary artery bypass graft surgery. Two to three millimetre rings of artery obtained from patients at surgery were studied in organ baths in vitro. Constriction to KC1 and phenylephrine was examined before and again after treatment of the rings with drug or vehicle. Calcium channel blockers were the only compounds to inhibit contractions to both KC1 and phenylephrine. Sodium nitroprusside attenuated constriction to phenylephrine but not KC1 in both vessels. K(ATP) channel openers similarly attenuated constriction to phenylephrine in radial arteries but were much less effective in mammary arteries. These studies support the continued use of calcium blockers after revascularisation with radial artery but suggest that other classes of drug may be as effective at minimising spasm due to receptor mediated constriction.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a widespread environmental contaminant that has profound deleterious effects on development and reproduction. TCDD may act at one or more levels to alter the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes. The objective of this study was to investigate whether TCDD modulates neuroendocrine systems by altering gene expression of arginine vasopressin (AVP), corticotrophin-releasing hormone (CRH), or pro-opiomelanocortin (POMC), which are important neuroregulators of the HPA and HPG axes. Four groups of female cynomolgus monkeys (Macaca fascicularis) were administered daily oral doses of gelatin capsule containing TCDD (0, 1, 5, or 25 ng/kg body weight) mixed with glucose 5 days a week for 1 year. At the end of the dosing period, animals were euthanized and brains were harvested. CRH, AVP, and POMC mRNA levels were semiquantified by in situ hybridization histochemistry on 30-microm coronal sections of the brain. Blood collected on the day of euthanasia was assayed for cortisol and progesterone. CRH mRNA levels in the paraventricular nucleus (PVN) were significantly increased by the 2 higher TCDD doses (5 and 25 ng/kg/day) compared to controls (p < 0.05). There was a trend towards increased AVP mRNA levels in both the supraoptic nucleus (SON) and PVN. No effect of TCDD on POMC was observed. Cortisol levels were significantly increased in TCDD-exposed animals. Progesterone concentrations and menstruation data indicated that TCDD did not interfere with ovulation. We conclude that TCDD stimulated the HPA axis by a central effect involving CRH, but had no effect on the HPG axis at the doses tested.

Previous studies using pulsed Doppler echocardiography have demonstrated a pattern of abnormal left ventricular relaxation associated with increasing age. Specifically, aging is associated with decreased peak velocity of early diastolic mitral inflow, increased peak velocity of late diastolic inflow, increased isovolumic relaxation time, and early diastolic deceleration time. Abnormal relaxation can progress to significantly elevated left atrial pressure--characterized by increased early peak velocity and shortened isovolumic relaxation time and deceleration time--as part of the disease processes. Left ventricular diastolic dysfunction is highly prevalent, occurring in one half to two thirds of elderly patients with congestive heart failure, in association with normal systolic function. Left ventricular hypertrophy, which is commonly related to systemic arterial hypertension, and ischemic heart disease are the two major causes of abnormal left ventricular diastolic function in the elderly. Recently, newer echocardiographic techniques have been described that allow more accurate evaluation of left ventricular diastolic function. Treatments for left ventricular diastolic dysfunction should focus on the underlying disease etiology as well as on the derangement in left ventricular diastolic function. Although calcium channel blockers and angiotensin-converting enzyme inhibitors have been used clinically to treat diastolic dysfunction, their effects on prognosis remain unproven.

unopposed estrogen replacement therapy (ERT) in non-hysterectomized women creates an unacceptably high risk of endometrial neoplasia that persists even after discontinuation of hormone replacement therapy (HRT). Normally progestin should be given in addition to ERT unless a contraindication to progestin exists: in this circumstance, endometrial surveillance is essential. Continuous combined progestin-estrogen therapy (PERT) appears to offer the greatest protection from endometrial cancer. Accumulated evidence now suggests that ERT has minimal impact on breast cancer risk, especially when compared to other known or suspected breast cancer risk factors. Women developing breast cancer while on ERT have improved survival compared to non-ERT users. Recent reports suggesting an increased breast cancer risk with PERT are based on limited data sets, and are reminiscent of early alarming reports about ERT, which have been largely refuted as larger data sets have become available. Further studies are required to clarify the true impact of PERT on breast cancer and breast cancer mortality.