Prime-boost vaccination with heterologous live vectors encoding SIV gag and multimeric HIV-1 gp160 protein: efficacy against repeated mucosal R5 clade C SHIV challenges

We sought to induce primate immunodeficiency virus-specific cellular and neutralizing antibody (nAb) responses in rhesus macaques (RM) through a bimodal vaccine approach. RM were immunized intragastrically (i.g.) with the live-attenuated Listeria monocytogenes (Lm) vector Lmdd-BdopSIVgag encoding SIVmac239 gag. SIV Gag-specific cellular responses were boosted by intranasal and intratracheal administration of replication-competent adenovirus (Ad5hr-SIVgag) encoding the same gag. To broaden antiviral immunity, the RM were immunized with multimeric HIV clade C (HIV-C) gp160 and HIV Tat. SIV Gag-specific cellular immune responses and HIV-1 nAb developed in some RM. The animals were challenged intrarectally with five low doses of R5 SHIV-1157ipEL-p, encoding a heterologous HIV-C Env (22.1% divergent to the Env immunogen). All five controls became viremic. One out of ten vaccinees was completely protected and another had low peak viremia. Sera from the completely and partially protected RM neutralized the challenge virus >90%; these RM also had strong SIV Gag-specific proliferation of CD8⁺ T cells. Peak and area under the curve of plasma viremia (during acute phase) among vaccinees was lower than for controls, but did not attain significance. The completely protected RM showed persistently low numbers of the α4β7-expressing CD4⁺ T cells; the latter have been implicated as preferential virus targets in vivo. Thus, vaccine-induced immune responses and relatively lower numbers of potential target cells were associated with protection.     

A pro-convulsive carbamazepine metabolite: quinolinic acid in drug resistant epileptic human brain

Drugs and their metabolites often produce undesirable effects. These may be due to a number of mechanisms, including biotransformation by P450 enzymes which are not exclusively expressed by hepatocytes but also by endothelial cells in brain from epileptics. The possibility thus exists that the potency of systemically administered central nervous system therapeutics can be modulated by a metabolic blood-brain barrier (BBB). Surgical brain specimens and blood samples (ex vivo) were obtained from drug-resistant epileptic subjects receiving the antiepileptic drug carbamazepine prior to temporal lobectomies. An in vitro blood-brain barrier model was then established using primary cell culture derived from the same brain specimens. The pattern of carbamazepine (CBZ) metabolism was evaluated in vitro and ex vivo using high performance liquid chromatography-mass spectroscopy. Accelerated mass spectroscopy was used to identify (14)C metabolites deriving from the parent (14)C-carbamazepine. Under our experimental conditions carbamazepine levels could not be detected in drug resistant epileptic brain ex situ; low levels of carbamazepine were detected in the brain side of the in vitro BBB established with endothelial cells derived from the same patients. Four carbamazepine-derived fractions were detected in brain samples in vitro and ex vivo. HPLC-accelerated mass spectroscopy confirmed that these signals derived from (14)C-carbamazepine administered as parental drug. Carbamazepine 10, 11 epoxide (CBZ-EPO) and 10, 11-dihydro-10, 11-dihydrooxy-carbamazepine (DiOH-CBZ) were also detected in the fractions analyzed. (14)C-enriched fractions were subsequently analyzed by mass spectrometry to reveal micromolar concentrations of quinolinic acid (QA). Remarkably, the disappearance of carbamazepine-epoxide (at a rate of 5% per hour) was comparable to the rate of quinolinic acid production (3% per hour). This suggested that quinolinic acid may be a result of carbamazepine metabolism. Quinolinic acid was not detected in the brain of patients who received antiepileptic drugs other than carbamazepine prior to surgery or in brain endothelial cultures obtained from a control patient. Our data suggest that a drug resistant BBB not only impedes drug access to the brain but may also allow the formation of neurotoxic metabolites.     

The role of avoidance in the phenomenology of obsessive-compulsive disorder

BackgroundPathologic levels of ritualistic avoidance (also known as active avoidance) are common in the clinical presentation of obsessive-compulsive disorder (OCD). Despite its clinical relevance, there has been little examination of active avoidance as a ritualistic compulsion in adults with OCD.ObjectiveThe objective of this study is to determine if adults with OCD who engage in ritualistic avoidance have greater obsessive-compulsive, anxiety, and depressive symptom severity and different comorbidity patterns than adults who do not engage in ritualistic avoidance.MethodAdults with OCD (n = 133) completed an evaluation that included clinician ratings of obsessive-compulsive severity; overall illness severity; and self-reported ratings of anxiety, depression, and obsessive-compulsive severity.ResultsRitualized avoidance was endorsed by greater than 25% of the sample. Avoidant subjects and, more specifically, contaminant avoidant and reading-writing avoidant subjects presented with elevated levels of obsessive-compulsive symptom severity and greater overall clinical severity than comparison patients who did not engage in each respective avoidance ritual.ConclusionsPatients who engage in ritualized avoidance exhibited greater obsessive-compulsive symptom severity than patients who did not. These findings suggest that ritualized avoidance functions as a compulsion for adults with OCD and that avoidance should receive careful consideration in assessment and treatment.     

Small dense LDL particles - a predictor of coronary artery disease evaluated by invasive and CT-based techniques: a case-control study

Background  

Coronary angiography is the current standard method to evaluate coronary atherosclerosis in patients with suspected angina pectoris, but non-invasive CT scanning of the coronaries are increasingly used for the same purpose.     

Several Conventional Risk Markers Suggesting Presence of Albuminuria Are Weak Among Rural Africans With Hypertension

The objective of this cross‐sectional study was to investigate risk markers indicating the presence of albuminuria in patients with hypertension in rural sub‐Saharan Africa (SSA). Urine albumin‐creatinine ratio, glycated hemoglobin (HbA_1c), blood pressure, anthropometry, and other patient characteristics including medications were assessed. We identified 160 patients with hypertension, of whom 68 (42.5%) were co‐diagnosed with diabetes mellitus (DM). Among the included participants, 57 (35.6%) had albuminuria (microalbuminuria [n=43] and macroalbuminuria [n=14]). A backward multivariate logistic regression model identified age (per 10‐year increment) (odds ratio [OR], 1.42; 95% confidence interval [CI], 1.03–1.95), HbA_1c >53 compared with <48 mmol/mol (OR, 3.81; 95% CI, 1.74–8.35), and treatment with dihydropyridine calcium channel blockers (OR, 2.59; 95% CI, 1.09–6.16) as the variables significantly associated with albuminuria. Only dysregulated DM and age were the conventional risk markers that seemed to suggest albuminuria among patients with hypertension in rural SSA.     

Glycine‐modified growth hormone secretagogues identified in seized doping material

A number of unknown pharmaceutical preparations seized by Danish customs authorities were submitted for liquid chromatography–high resolution mass spectrometry (LC–HRMS) analysis. Comparison with reference standards unequivocally identified the content of the powders as analogs of the growth hormone secretagogues GHRP‐2 (Pralmorelin), GHRP‐6, Ipamorelin, and modified growth hormone releasing factor (modified GRF 1–29), which can be used as performance‐enhancing substances in sports. In all cases, the detected modification involved the addition of an extra glycine amino acid at the N‐terminus, and analytical methods targeting growth hormone secretagogues should hence be updated accordingly.