Endogenous circulating testosterone and sex hormone-binding globulin levels and measures of myocardial structure and function: the Framingham Heart Study.

BACKGROUND: The relation between endogenous testosterone concentrations and myocardial mass and function remains incompletely understood. OBJECTIVES: To determine the cross-sectional association between endogenous hormone levels with cardiac magnetic resonance measures of myocardial mass, structure, and function in community-dwelling men across a wide age range. METHODS: A total of 720 men from the Framingham Heart Study Offspring Cohort (age range 37-82, mean = 59.6 years) who underwent cardiac magnetic resonance imaging and had hormone levels measured. Total testosterone (measured using liquid chromatography-tandem mass spectrometry), sex hormone-binding globulin (measured using an immunofluorometric assay), and calculated free testosterone levels were assessed in male participants of the Framingham Heart Study Offspring Cohort at examination 7. Cardiac magnetic resonance imaging was performed between examinations 7 and 8 (2002-2006). RESULTS: Age-adjusted linear regression models showed statistically significant association between total testosterone levels and left ventricular mass (p = 0.009), left ventricular mass index (p = 0.006), cardiac output (p = 0.001), and main pulmonary artery diameter (p = 0.008); the association between total testosterone and these cardiac magnetic resonance measures was weak and was not significant after adjustment for established risk factors-age, body mass index, diabetes, and hypertension. Furthermore, calculated free testosterone level was not significantly associated with any measure of myocardial mass or function. Sex hormone-binding globulin level was significantly associated with left ventricular mass (p = 0.002), left ventricular mass index (p = 0.004), cardiac output (p = 0.003), left ventricular ejection fraction (p = 0.039), and main pulmonary artery diameter (p = 0.042) in age-adjusted models; these associations were also rendered non-significant after adjusting for cardiovascular risk factors. CONCLUSIONS: Neither testosterone nor sex hormone-binding globulin levels in men are associated significantly with myocardial mass and function independent of established cardiovascular risk factors.

Decreased protein C function predicts mortality in patients with cirrhosis.

INTRODUCTION: Protein C (PrC), a physiological anticoagulant, regulates inflammation and cell death and has known predictive/therapeutic roles in sepsis. Accumulating evidences suggest plasma hypercoagulability results in progression of fibrosis and formation of microclots causing end-organ dysfunction. We investigated a possible association between natural anticoagulants-PrC, protein S (PrS) and antithrombin III (AT)-and clinical outcomes in cirrhotics. METHODS: Functional PrC, PrS and AT were analysed in 515 cirrhotic patients and compared with 229 noncirrhotics. Among those with cirrhosis, we conducted multivariable predictive model on 3-month survival to assess the prognostic ability of anticoagulants. RESULTS: Protein C (P < .001), PrS (P < .001) and AT (P < .001) levels were lower in cirrhotics compared with noncirrhotics. In addition, patients with Child-Pugh (CP)-C had significantly lower (P < .05) functional PrC, PrS and AT levels than CP-B, CP-A and noncirrhotic patients. Low PrC function correlated with markers of liver dysfunction and inflammation: INR(r = -.72, P < .001), bilirubin (r = -.620, P < .001), albumin (r = .539, P < .001), creatinine (r = -.417, P < .001), ferritin (r = -.68, P = .035), procalcitonin (r = -.79, P = .01), raised ESR (r = .56, P < .001) and liver fibrosis (r = -.840, P < .001). Patients who died (n = 160) had significantly lower median PrC function (23.8%, 16.3-33.0]) compared with those who remained alive (74.9%, [59.7-92.5]); P < .001. In a multivariable predictive model using PrC, and MELD score, we found a significant impact of low PrC levels on survival (P < .001, IRR = 0.97, 95% CI = 0.96-0.98). Receiver operating characteristic (ROC) curve analysis revealed that functional PrC levels <52% were associated with increased mortality (P < .001). CONCLUSION: Low functional protein C level correlated with markers of liver dysfunction, inflammation and sepsis and independently predicted mortality at 3 months in cirrhotics, especially if functional levels were <52%.

Colour versus grey-scale display of images on high-resolution spectral OCT.

AIM: To determine whether colour or grey-scale images from high-resolution spectral optical coherence tomography (OCT) are superior in visualising clinically important details of retinal structures. METHODS: Patients with macular pathologies were imaged using spectral OCT (OTI, Toronto, Canada). Two reviewers independently analysed the retinal structures and pathologies and graded them on a four-point scale on the basis of the visibility. A third reviewer masked to the results then reviewed images where there was a different score for colour versus grey scale. RESULTS: Statistical analysis showed the grey-scale image to be significantly better in visualising the details of epiretinal membrane, photoreceptor and retinal pigment epithelium layer morphology than the colour scale image (p = 0.00088-0.0006). In 16.17% of eyes, the colour image led to the false impression of photoreceptor disruption. CONCLUSION: Grey-scale images are qualitatively superior to the colour-scale images on high-resolution spectral OCT. Colour images can be misleading, as the displayed colours are false colours, and the observer may see a dramatic change in colour and interpret that as a large change in the OCT reflectivity.

Mechanism of psychoactive drug action in the brain: simulation modeling of GABAA receptor interactions at non-equilibrium conditions.

Synaptic transmission requires that the binding of the transmitter to the receptor to occur under rapidly changing transmitter levels, and this binding interaction is unlikely to be at equilibrium. We have sought to numerically solve for binding kinetics using ordinary differential equations and simultaneous difference equations for use in stochastic conditions. The reaction scheme of GABA interacting with the ligand-gated ion-channel demonstrates numerical stiffness. Implicit methods (Backward Euler, ode23s) performed orders of magnitude better than explicit methods (Forward Euler, ode23, RK4, ode45) in terms of step size required for stability, number of steps and cpu time. Interestingly, upon solving the system of 8 ordinary differential equations for the GABA reaction scheme we observed the existence of low dimensional invariant manifolds that may have important consequences for information processing in synapses. We also describe a mathematical approach that models complex receptor interactions in which the timing and amplitude of transmitter release are noisy. Exact solutions for simple bimolecular interactions that include stoichiometric interactions and receptor transitions can be used to model complex reaction schemes. We used the difference method to investigate the information processing capabilities of GABA(A) receptors and to predict how pharmacological agents may modify these properties. Initial simulations using a model for heterosynaptic regulation shows that signal to noise ratios can be decreased in the presence of background presynaptic activity both in the presence and absence of chlorpromazine. These types of simulations provide a platform for investigating the effect of psycho-active drugs on complex responses of transmitter-receptor interactions in noisy cellular environments such as the synapse. Understanding this process of transmitter-receptor interactions may be useful in the development of more specific and highly targeted modes of action.