Clinical use of a rapid collagen binding assay for von Willebrand factor cleaving protease in patients with thrombotic thrombocytopenic purpura

A simple collagen binding assay (CBA) for measuring activity of the von Willebrand factor cleaving protease in clinical samples is described, and results of fifty masked plasmapheresis samples rom patients with TTP/HUS and other diseases are presented. There was 97.5% concordance between the CBA and a multimer gel assay. The CBA identified low protease activity in 78% of patients who had a clinical syndrome consistent with TTP/HUS and in 2 of 10 sick controls, giving it a positive predictive value of 0.94. The heterogeneity regarding the presence or absence of vWF protease activity in patients with TTP/HUS was confirmed by finding a low negative predictive value of 0.50 with the CBA. The CBA detected inhibitors of the protease in 26 of 29 patients (90%) with TTP/HUS and low protease activity levels. The CBA is a useful clinical assay for examining von Willebrand factor protease activity and detecting inhibitors against the protease.     

Iron status, movement disorders, and acute phase response in elderly psychiatric patients.

The previously reported relation between iron deficiency and movement disorders was studied in a population with a high prevalence of both problems. There was no evidence of a direct statistical relation between iron deficiency and movement disorders. Significant associations were, however, found between movement disorders and features of the acute phase response to physiological stress. Indices of iron status are known to be affected by the acute phase response and it is suggested that the previously reported abnormalities in iron status may be secondary to this.     

Regional and Voxel‐Wise Comparisons of Blood Flow Measurements Between Dynamic Susceptibility Contrast Magnetic Resonance Imaging (DSC‐MRI) and Arterial Spin Labeling (ASL) in Brain Tumors

The objective of the current study was to evaluate the regional and voxel‐wise correlation between dynamic susceptibility contrast (DSC) and arterial spin labeling (ASL) perfusion magnetic resonance imaging (MRI) measurement of cerebral blood flow (CBF) in patients with brain tumors. Thirty patients with histologically verified brain tumors were evaluated in the current study. DSC‐MRI was performed by first using a preload dose of gadolinium contrast, then collecting a dynamic image acquisition during a bolus of contrast, followed by posthoc contrast agent leakage correction. Pseudocontinuous ASL was collected using 30 pairs of tag and control acquisition using a 3‐dimensional gradient‐echo spin‐echo (GRASE) acquisition. All images were registered to a high‐resolution anatomical atlas. Average CBF measurements within regions of contrast‐enhancement and T2 hyperintensity were evaluated between the two modalities. Additionally, voxel‐wise correlation between CBF measurements obtained with DSC and ASL were assessed. Results demonstrated a positive linear correlation between DSC and ASL measurements of CBF when regional average values were compared; however, a statistically significant voxel‐wise correlation was only observed in around 30‐40% of patients. These results suggest DSC and ASL may provide regionally similar, but spatially different measurements of CBF.     

Central actions of CRF on thermogenesis are mediated by pro-opiomelanocortin products

Corticotrophin-releasing factor (CRF) causes central activation of thermogenesis. The aim of this study was to investigate whether this action is mediated by ACTH or other peptides derived from the ACTH precursor pro-opiomelanocortin (POMC) within the CNS. Central (intracerebroventricular) injection of rat CRF caused dose-dependent increases in resting oxygen consumption (VO2) in conscious rats (maximal 26 +/- 5% at 2 nmol CRF). These responses were significantly attenuated by pretreatment (i.c.v.) with either a monoclonal antibody raised to gamma 1MSH or with naloxone which antagonises beta-endorphin (beta-EP) actions. The increases were not affected by pretreatment with monoclonal antibodies to ACTH or the N-terminal of POMC. Central injections of gamma 1-melanocyte-stimulating hormone (MSH) or beta-EP caused dose-dependent increases in VO2 (maximal at 0.5-1.5 pmol) and these were markedly inhibited by pretreatment with the anti-gamma 1-MSH antibody or naloxone respectively. Injection of ACTH or alpha MSH did not significantly affect VO2 at doses up to 2 nmol. These data indicate that the central actions of CRF on thermogenesis may be mediated, at least in part, by release of gamma MSH and/or beta-EP.     

Influence of a calcium dependent protease inhibitor on platelet activation and secretion

Continuous proteolysis resulting in consumption of major cytoskeletal proteins may be essential for platelet activation and aggregation. In this study we evaluated the effect of a known protease inhibitor, Leupeptin, on agonist induced platelet aggregation and secretion. Platelets exposed to 10 ugs/ml of Leupeptin did not aggregate in response to the action of thrombin (0.2u/ml). However, a concentration of Leupeptin as high as 250 ugs/ml did not prevent arachidonate induced aggregation and secretion. Leupeptin (100 ugs/ml) effectively blocked thrombin (0.2 u/ml) induced elevation of cytosolic calcium, but did not affect arachidonate induced elevation of platelet intracellular calcium levels. At a concentration of 100 ug/ml, Leupeptin effectively blocked thrombin (0.5u/ml) induced clot formation of platelet poor plasma, suggesting that it can exert its effect on thrombin by preventing fibrinogen degradation. Effective K_i for the competitive inhibition of thrombin induced hydrolysis of a chromogenic substrate, S2238, by Leupeptin was 2.4 uM. Leupeptin inhibition of platelet function was reversible by washing platelets free of the polypeptide. Results of our study demonstrate that Leupeptin inhibits thrombin induced platelet activation, probably by interfering with its proteolytic activity on the platelet surface membrane. However, inhibition of platelet surface membrane associated proteases did not prevent activation of platelets by other agonists.     

Survey of consumer and non-consumer mental health service providers on assertive community treatment teams in Ontario

Reflecting the increasing trend of consumers as providers in mental health services, the standards for Assertive Community Treatment (ACT) teams in Ontario, Canada require the hiring of at least 0.5 full-time equivalent consumer as a service provider. Through a mail-out survey, we explored how the consumer position has been integrated into these ACT teams. It was found that despite some variation in the roles and degree of integration of the consumers on these teams, consumers were generally well-incorporated team members with equal or better job satisfaction as compared to other employees.     

Altered Integration of Structural Covariance Networks in Young Children With Type 1 Diabetes

Type 1 diabetes mellitus (T1D), one of the most frequent chronic diseases in children, is associated with glucose dysregulation that contributes to an increased risk for neurocognitive deficits. While there is a bulk of evidence regarding neurocognitive deficits in adults with T1D, little is known about how early‐onset T1D affects neural networks in young children. Recent data demonstrated widespread alterations in regional gray matter and white matter associated with T1D in young children. These widespread neuroanatomical changes might impact the organization of large‐scale brain networks. In the present study, we applied graph‐theoretical analysis to test whether the organization of structural covariance networks in the brain for a cohort of young children with T1D (N = 141) is altered compared to healthy controls (HC; N = 69). While the networks in both groups followed a small world organization—an architecture that is simultaneously highly segregated and integrated—the T1D network showed significantly longer path length compared with HC, suggesting reduced global integration of brain networks in young children with T1D. In addition, network robustness analysis revealed that the T1D network model showed more vulnerability to neural insult compared with HC. These results suggest that early‐onset T1D negatively impacts the global organization of structural covariance networks and influences the trajectory of brain development in childhood. This is the first study to examine structural covariance networks in young children with T1D. Improving glycemic control for young children with T1D might help prevent alterations in brain networks in this population. Hum Brain Mapp 37:4034–4046, 2016. © 2016 Wiley Periodicals, Inc .     

Heart-rate response to alpha<Subscript>2</Subscript>-adrenergic receptor antagonism by antipsychotics

Purpose

To explore the relationship between antipsychotic-associated antagonism of alpha₂-adrenergic receptors and resting heart rate in individuals with schizophrenia.

Methods

Thirty-one inpatients treated with antipsychotics were included in this exploratory analysis. Antipsychotic doses were converted to haloperidol equivalents for alpha₂-adrenergic receptor antagonism. Resting heart rate was measured with the patient in the seated upright posture.

Results

After controlling for confounding variables, the relationship between alpha₂-adrenergic receptor antagonism and resting heart rate demonstrated a positive linear effect (P = 0.002) as well as a nonlinear effect that accounted for an additional 14% of the variability in resting heart rate (P = 0.005).

Conclusion

The observed inverted-U relationship between alpha₂-adrenergic receptor antagonism and resting heart rate can possibly be attributed to an altered response of beta₁-adrenergic receptors to increased norepinephrine release. Further investigations are required to confirm this exploratory finding, taking into account additional variables that include other receptors which either directly or indirectly influence heart rate.

ClinicalTrials.gov Identifier

NCT01392885.