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Background A controlled human infection model for assessing tuberculosis (TB) immunity can accelerate new vaccine development. Methods In this phase 1 dose escalation trial, 92 healthy adults received a single intradermal injection of 2 × 106 to 16 × 106 colony-forming units of Bacillus Calmette-Guérin (BCG). The primary endpoints were safety and BCG shedding as measured by quantitative polymerase chain reaction, colony-forming unit plating, and MGIT BACTEC culture. Results Doses up to 8 × 106 were safe, and there was evidence for increased BCG shedding with dose escalation. The MGIT time-to-positivity assay was the most consistent and precise measure of shedding. Power analyses indicated that 10% differences in MGIT time to positivity (area under the curve) could be detected in small cohorts (n = 30). Potential biomarkers of mycobacterial immunity were identified that correlated with shedding. Transcriptomic analysis uncovered dose- and time-dependent effects of BCG challenge and identified a putative transcriptional TB protective signature. Furthermore, we identified immunologic and transcriptomal differences that could represent an immune component underlying the observed higher rate of TB disease incidence in males. Conclusions The safety, reactogenicity, and immunogenicity profiles indicate that this BCG human challenge model is feasible for assessing in vivo TB immunity and could facilitate the vaccine development process. Clinical Trials Registration NCT01868464 (ClinicalTrials.gov). [ABSTRACT FROM AUTHOR]

Abstract Various symptoms of mental illness occur commonly during pregnancy. It is estimated that serious mental disorders, including major depression, bipolar disorder, schizophrenia, panic and other anxiety disorders, occur with [...]

Progesterone (PG) has been shown to provide substantial neuroprotection after traumatic brain injury (TBI) in multiple animal models. As a first step in assessing applicability to humans, the authors examined [...]

Background Venlafaxine is a dual serotonin (5-HT) and norepinephrine reuptake inhibitor. The specific dose at which it begins to efficiently engage the norepinephrine transporter (NET) remained to be determined. Paroxetine is generally considered as a selective 5-HT reuptake inhibitor but exhibits some affinity for NET. Atomoxetine is a NET inhibitor but also has some affinity for the 5-HT reuptake transporter (SERT). Methods This study examined the effects of forced titration of venlafaxine from 75 to 300 mg/d, paroxetine from 20 to 50 mg/d, or atomoxetine from 25 to 80 mg/d in 32 patients with major depressive disorder. Inhibition of SERT was estimated using the depletion of whole-blood 5-HT. Inhibition of NET was assessed using the attenuation of the systolic blood pressure produced by i.v. injections of tyramine. Results All 3 medications significantly reduced 5-HT levels at the initiating regimens: venlafaxine and paroxetine by approximately 60% and atomoxetine by 16%. The 3 subsequent regimens of venlafaxine and paroxetine reduced 5-HT levels by over 90%, but the highest dose of atomoxetine only reached a 40% inhibition. Atomoxetine dose dependently inhibited the tyramine pressor response from the lowest dose, venlafaxine from 225 mg/d, and paroxetine left it unaltered throughout. Conclusion These results confirm that venlafaxine and paroxetine are potent SERT inhibitors over their usual therapeutic range but that venlafaxine starts inhibiting NET only at 225 mg/d, whereas paroxetine remains selective for SERT up to 50 mg/d. Atomoxetine dose dependently inhibits NET from a low dose but does not inhibit SERT to a clinically relevant degree. [ABSTRACT FROM AUTHOR]

A study on cortisol responses among alcoholic Asians with varied ALDH2 genotypes revealed that the subjects had higher cortisol levels after consuming alcohols than subjects with other patterns of genotypes. Asians who possess ALDH2*2 alleles and flush after consuming alcohol experience serious reactions to alcohol when compared to the non-flushing Asians with ALDH2*1/2*1 genotype. Subjects who are homozygous for ALDH2*2 possess exceptionally high cortisol levels within 90, 120 and 150 minutes after consuming alcohol.

Abstract Background Limited controlled data exist to guide treatment choices for clinicians caring for patients with major depressive disorder (MDD). Although many putative predictors of treatment response have been reported, most were identified through retrospective analyses of existing datasets and very few have been replicated in a manner that can impact clinical practice. One major confound in previous studies examining predictors of treatment response is the patient’s treatment history, which may affect both the predictor of interest and treatment outcomes. Moreover, prior treatment history provides an important source of selection bias, thereby limiting generalizability. Consequently, we initiated a randomized clinical trial designed to identify factors that moderate response to three treatments for MDD among patients never treated previously for the condition. Methods/design Treatment-naïve adults aged 18 to 65 years with moderate-to-severe, non-psychotic MDD are randomized equally to one of three 12-week treatment arms: (1) cognitive behavior therapy (CBT, 16 sessions); (2) duloxetine (30–60 mg/d); or (3) escitalopram (10–20 mg/d). Prior to randomization, patients undergo multiple assessments, including resting state functional magnetic resonance imaging (fMRI), immune markers, DNA and gene expression products, and dexamethasone-corticotropin-releasing hormone (Dex/CRH) testing. Prior to or shortly after randomization, patients also complete a comprehensive personality assessment. Repeat assessment of the biological measures (fMRI, immune markers, and gene expression products) occurs at an early time-point in treatment, and upon completion of 12-week treatment, when a second Dex/CRH test is also conducted. Patients remitting by the end of this acute treatment phase are then eligible to enter a 21-month follow-up phase, with quarterly visits to monitor for recurrence. Non-remitters are offered augmentation treatment for a second 12-week course of treatment, during which they receive a combination of CBT and antidepressant medication. Predictors of the primary outcome, remission, will be identified for overall and treatment-specific effects, and a statistical model incorporating multiple predictors will be developed to predict outcomes. Discussion The PReDICT study’s evaluation of biological, psychological, and clinical factors that may differentially impact treatment outcomes represents a sizeable step toward developing personalized treatments for MDD. Identified predictors should help guide the selection of initial treatments, and identify those patients most vulnerable to recurrence, who thus warrant maintenance or combination treatments to achieve and maintain wellness. Trial registration Clinicaltrials.gov Identifier: NCT00360399. Registered 02 AUG 2006. First patient randomized 09 FEB 2007.

Context.--Laboratory medicine is an integral component of patient care. Approximately 60% to 70% of medical decisions are based on laboratory results. Physicians in specialties that order the tests are teaching medical students laboratory medicine and test use with minimal input from laboratory scientists who implement and maintain the quality control for those tests. Objective.--To develop, implement, and evaluate a 1.5-day medical student clinical laboratory experience for fourth-year medical students in their last month of training. Design.--The experience was devised and directed by laboratory scientists and included a panel discussion, laboratory tours, case studies that focused on the goals and objectives recently published by the Academy of Clinical Laboratory Physicians and Scientists, and medical-student presentations highlighting salient points of the experience. The same knowledge quiz was administered at the beginning and end of the experience and 84 students took both quizzes. Results.--A score of 7 or more was obtained by 16 students (19%) on the initial quiz, whereas 34 (40%) obtained the same score on the final quiz; the improvement was found to be statistically significant (P = .002; t = 3.215), particularly in 3 out of the 10 questions administered. Conclusions.--Although the assessment can only measure a small amount of knowledge recently acquired, the improvement observed by fourth-year medical students devoting a short period to learning laboratory medicine principles was encouraging. This medical student clinical laboratory experience format allowed teaching of a select group of laboratory medicine principles in 1.5 days to an entire medical school class. (Arch Pathol Lab Med. 2012;136:1423-1429; doi: 10.5858/arpa.2011-0537-EP), Laboratory results provide objective data about patient health across the continuum of patient care. (1) In addition, laboratory results enable health care providers to assess early disease risk, opt for [...]