Single nucleotide polymorphisms identification in expressed genes of Schistosoma mansoni

Single nucleotide polymorphism (SNP) markers have been shown to be useful in genetic investigations of medically important parasites and their hosts. In this paper, we describe the prediction and validation of SNPs in ESTs of Schistosoma mansoni. We used 107,417 public sequences of S. mansoni and identified 15,614 high-quality candidate SNPs in 12,184 contigs. The presence of predicted SNPs was observed in well characterized antigens and vaccine candidates such as those coding for myosin; Sm14 and Sm23; cathepsin B and triosephosphate isomerase (TPI). Additionally, SNPs were experimentally validated for the cathepsin B. A comparative model of the S. mansoni cathepsin B was built for predicting the possible consequences of amino acid substitutions on the protein structure. An analysis of the substitutions indicated that the amino acids were mostly located on the surface of the molecule, and we found no evidence for a significant conformational change of the enzyme. However, at least one of the substitutions could result in a structural modification of an epitope.     

Combined activities of secretory phospholipases and eosinophil lysophospholipases induce pulmonary surfactant dysfunction by phospholipid hydrolysis

BACKGROUND: Surfactant dysfunction is implicated in small airway closure in asthma. Increased activity of secretory phospholipase A(2) (sPLA(2)) in the airways is associated with asthma exacerbations. Phosphatidylcholine, the principal component of pulmonary surfactant that maintains small airway patency, is hydrolyzed by sPLA(2). The lysophosphatidylcholine product is the substrate for eosinophil lysophospholipases. OBJECTIVE: To determine whether surfactant phospholipid hydrolysis by the combined activities of sPLA(2)s and eosinophil lysophospholipases induces surfactant dysfunction. METHODS: The effect of these enzymes on surfactant function was determined by capillary surfactometry. Thin layer chromatography was used to correlate enzyme-induced changes in surfactant phospholipid composition and function. Phosphatidylcholine and its hydrolytic products were measured by using mass spectrometry. RESULTS: Eosinophils express a 25-kd lysophospholipase and group IIA sPLA(2). Phospholipase A(2) alone induced only a small decrease in surfactant function, and 25-kd lysophospholipase alone degraded lysophosphatidylcholine but had no effect on surfactant function. The combined actions of sPLA(2) and lysophospholipase produced dose-dependent and time-dependent losses of surfactant function, concomitant with hydrolysis of phosphatidylcholine and lysophosphatidylcholine. Lysates of AML14.3D10 eosinophils induced surfactant dysfunction, indicating these cells express all the necessary lipolytic activities. In contrast, lysates of blood eosinophils required exogenous phospholipase A(2) to induce maximal surfactant dysfunction. CONCLUSION: The combined activities of sPLA(2)s and eosinophil lysophospholipases are necessary to degrade surfactant phospholipids sufficiently to induce functional losses in surfactant activity as reported in asthma. CLINICAL IMPLICATIONS: The phospholipases and lysophospholipases expressed by eosinophils or other airway cells may represent novel therapeutic targets for blocking surfactant degradation, dysfunction, and peripheral airway closure in asthma.     

A randomized,phase 1b study of the pharmacokinetics,pharmacodynamics, safety,and tolerability of bleselumab,a fully human,anti‐CD40 monoclonal antibody,in kidney transplantation

This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of various doses of the anti‐CD40 monoclonal antibody bleselumab (ASKP1240) in de novo kidney transplant recipients receiving concomitant standard immunosuppression over 90 days posttransplant. Transplant recipients were randomized (1:1:1:1:1) to bleselumab 50 mg, 100 mg, 200 mg, or 500 mg, or placebo, in addition to standard maintenance immunosuppression. The primary pharmacokinetic endpoints were AUC_inf, C_max, and AUC_last. The primary pharmacodynamic endpoint was B cell CD40 receptor occupancy over time. Overall, 50 kidney transplant recipients were randomized; 45 received their randomized treatment (bleselumab [n = 37] or placebo [n = 8]). AUC_inf and AUC_last demonstrated a more than dose‐proportional increase in the range of 50‐500 mg, and C_max increased linearly with increasing dose. Maximal receptor occupancy for B cell CD40 was reached at all dose levels and was prolonged as dose increased. No kidney transplant recipients experienced cytokine release syndrome or a thromboembolic event. Treatment‐emergent anti‐bleselumab antibodies were found in one kidney transplant recipient in the bleselumab 50 mg group; these were detected only at Day 7. Overall, bleselumab demonstrated nonlinear pharmacokinetics and dose‐dependent prolonged B cell CD40 receptor occupancy and was well tolerated at all doses (ClinicalTrials.gov: NCT01279538).     

Clinical characteristics and functional outcome of patients with West Nile neuroinvasive disease in Serbia

Neurologic manifestations are prominent characteristic of West Nile virus (WNV) infection. The aim of this article was to describe neurological manifestations in patients with WNV neuroinvasive disease and their functional outcome at discharge in the first human outbreak of WNV infection in Serbia. The study enrolled patients treated in the Clinic for Infectious and Tropical Diseases, Clinical Center Serbia in Belgrade, with serological evidence of acute WNV infection who presented with meningitis, encephalitis and/or acute flaccid paralyses (AFP). Functional outcome at discharge was assessed using modified Rankin Scale (mRS) and Barthel index. Fifty-two patients were analysed. Forty-four (84.6 %) patients had encephalitis, eight (15.4 %) had meningitis, and 13 (25 %) had AFP. Among patients with AFP, 12 resembled poliomyelitis and one had clinical and electrodiagnostic findings consistent with polyradiculoneuritis. Among patients with encephalitis, 17 (32.7 %) had clinical signs of rhombencephalitis, and eight (15.4 %) presented with cerebellitis. Respiratory failure with subsequent mechanical ventilation developed in 13 patients with WNE (29.5 %). Nine (17.3 %) patients died, five (9.6 %) were functionally dependent (mRS 3–5), and 38 (73.1 %) were functionally independent at discharge (mRS 0–2). In univariate analysis, the presence of AFP, respiratory failure and consciousness impairment were found to be predictors of fatal outcome in patients with WNV neuroinvasive disease (p < 0.001, p < 0.001, p = 0.018, respectively). The outbreak of human WNV infection in Serbia caused a notable case fatality ratio, especially in patients with AFP, respiratory failure and consciousness impairment. Rhombencephalitis and cerebellitis could be underestimated presentations of WNV neuroinvasive disease.     

Dietary fiber and risk of coronary heart disease: a pooled analysis of cohort studies

BACKGROUND: Few epidemiologic studies of dietary fiber intake and risk of coronary heart disease have compared fiber types (cereal, fruit, and vegetable) or included sex-specific results. The purpose of this study was to conduct a pooled analysis of dietary fiber and its subtypes and risk of coronary heart disease. METHODS: We analyzed the original data from 10 prospective cohort studies from the United States and Europe to estimate the association between dietary fiber intake and the risk of coronary heart disease. RESULTS: Over 6 to 10 years of follow-up, 5249 incident total coronary cases and 2011 coronary deaths occurred among 91058 men and 245186 women. After adjustment for demographics, body mass index, and lifestyle factors, each 10-g/d increment of energy-adjusted and measurement error-corrected total dietary fiber was associated with a 14% (relative risk [RR], 0.86; 95% confidence interval [CI], 0.78-0.96) decrease in risk of all coronary events and a 27% (RR, 0.73; 95% CI, 0.61-0.87) decrease in risk of coronary death. For cereal, fruit, and vegetable fiber intake (not error corrected), RRs corresponding to 10-g/d increments were 0.90 (95% CI, 0.77-1.07), 0.84 (95% CI, 0.70-0.99), and 1.00 (95% CI, 0.88-1.13), respectively, for all coronary events and 0.75 (95% CI, 0.63-0.91), 0.70 (95% CI, 0.55-0.89), and 1.00 (95% CI, 0.82-1.23), respectively, for deaths. Results were similar for men and women. CONCLUSION: Consumption of dietary fiber from cereals and fruits is inversely associated with risk of coronary heart disease.     

AGEING,MONOAMINES, AND MONOAMINE-OXIDASE LEVELS

Monoamine oxidase (M.A.O.), noradrenaline (N.A.), serotonin (5-H.T.), and 5-hydroxyindoleacetic acid (5-H.I.A.A.) were measured in the hindbrains of 55 patients. Blood-platelet and plasma M.A.O. were also measured in 122 normal, control subjects. There was a marked increase in M.A.O. level with age in human brain, platelet, and plasma. Hindbrain-N.A. decreased significantly with age. N.A. correlated negatively and 5-H.I.A.A. positively with hindbrain M.A.O. levels. The relationships of age to M.A.O. activity and substrate levels reported in this study make it imperative that age effects be considered in studies of amine metabolism in mania, depression, and parkinsonism.     

Dopamine D2 receptor availability is linked to hippocampal–caudate functional connectivity and episodic memory

D1 and D2 dopamine receptors (D1DRs and D2DRs) may contribute differently to various aspects of memory and cognition. The D1DR system has been linked to functions supported by the prefrontal cortex. By contrast, the role of the D2DR system is less clear, although it has been hypothesized that D2DRs make a specific contribution to hippocampus-based cognitive functions. Here we present results from 181 healthy adults between 64 and 68 y of age who underwent comprehensive assessment of episodic memory, working memory, and processing speed, along with MRI and D2DR assessment with [¹¹C]raclopride and PET. Caudate D2DR availability was positively associated with episodic memory but not with working memory or speed. Whole-brain analyses further revealed a relation between hippocampal D2DR availability and episodic memory. Hippocampal and caudate D2DR availability were interrelated, and functional MRI-based resting-state functional connectivity between the ventral caudate and medial temporal cortex increased as a function of caudate D2DR availability. Collectively, these findings indicate that D2DRs make a specific contribution to hippocampus-based cognition by influencing striatal and hippocampal regions, and their interactions.Dopamine (DA) plays a key role in several cognitive processes (1–4). Reductions of D1 and D2 DA receptors (D1DRs and D2DRs) in aging (5–7) have been linked to age-related cognitive deficits (8, 9). The D1DR system has been related to functions supported by the prefrontal cortex (PFC), such as working memory and executive functions (10–12), which may reflect the relatively high density of D1DRs in the PFC (13). However, the role of D2DRs is far less clear. D2DRs are present in the PFC at very low densities (13), and evidence supporting a role for the D2DR system in working memory and executive functions is elusive (10). Pharmacological (14, 15) and PET studies assessing striatal D2DR availability (or binding potential to nondisplacable tissue uptake; BP_ND) with [¹¹C]raclopride (16, 17) have yielded mixed findings in relation to cognition. It has been hypothesized that D2DRs make a specific contribution to hippocampus-based cognitive functions (10, 18, 19). Supporting these claims, positive links between D2DR BP_ND and episodic memory are commonly observed (20–23). PET imaging of hippocampal D2DR BP_ND also provides support for this hypothesis, although some studies indicate that hippocampal D2DRs may be related to both episodic memory and PFC-based executive functions (22, 23), including verbal working memory (24). Medial temporal lobe regions have been implicated in working memory (25, 26), and D2DR-mediated modulation may be exerted via hippocampal–cortical pathways (27). In addition, a [¹¹C]raclopride task-activation PET study demonstrated contributions of striatal D2DRs to a verbal working-memory task (11).Taken together, the specific role of the D2DR system in cognition remains unclear, likely due to the fact that past studies included small and age-heterogeneous samples and lacked comprehensive test batteries that allowed systematic comparison of the role of D2DRs in different cognitive functions. Here we present results from the Cognition, Brain, and Aging (COBRA) study that include assessment of episodic memory, working memory, and processing speed, in combination with [¹¹C]raclopride PET and MRI of 181 healthy adults between 64 and 68 y of age (28). The main analyses concerned caudate D2DR–cognition associations, as this striatal region has been implicated in cognitive functioning (11, 12, 29, 30). Subsequently, whole-brain analyses were conducted to examine extrastriatal (especially hippocampal) D2DRs in relation to cognition. Finally, resting-state functional connectivity patterns were analyzed in relation to D2DR BP_ND, with special focus on interactions between the ventral caudate (31) and medial temporal cortex regions (32, 33).