A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression

CONTEXT: Existing therapies for major depression have a lag of onset of action of several weeks, resulting in considerable morbidity. Exploring pharmacological strategies that have rapid onset of antidepressant effects within a few days and that are sustained would have an enormous impact on patient care. Converging lines of evidence suggest the role of the glutamatergic system in the pathophysiology and treatment of mood disorders. OBJECTIVE: To determine whether a rapid antidepressant effect can be achieved with an antagonist at the N-methyl-D-aspartate receptor in subjects with major depression. DESIGN: A randomized, placebo-controlled, double-blind crossover study from November 2004 to September 2005. SETTING: Mood Disorders Research Unit at the National Institute of Mental Health.Patients Eighteen subjects with DSM-IV major depression (treatment resistant). INTERVENTIONS: After a 2-week drug-free period, subjects were given an intravenous infusion of either ketamine hydrochloride (0.5 mg/kg) or placebo on 2 test days, a week apart. Subjects were rated at baseline and at 40, 80, 110, and 230 minutes and 1, 2, 3, and 7 days postinfusion.Main Outcome Measure Changes in scores on the primary efficacy measure, the 21-item Hamilton Depression Rating Scale. RESULTS: Subjects receiving ketamine showed significant improvement in depression compared with subjects receiving placebo within 110 minutes after injection, which remained significant throughout the following week. The effect size for the drug difference was very large (d = 1.46 [95% confidence interval, 0.91-2.01]) after 24 hours and moderate to large (d = 0.68 [95% confidence interval, 0.13-1.23]) after 1 week. Of the 17 subjects treated with ketamine, 71% met response and 29% met remission criteria the day following ketamine infusion. Thirty-five percent of subjects maintained response for at least 1 week. CONCLUSIONS: Robust and rapid antidepressant effects resulted from a single intravenous dose of an N-methyl-D-aspartate antagonist; onset occurred within 2 hours postinfusion and continued to remain significant for 1 week.     

Modeling and sensitivity analysis of acoustic release of Doxorubicin from unstabilized pluronic P105 using an artificial neural network model

This paper models steady state acoustic release of Doxorubicin (Dox) from Pluronic P105 micelles using Artificial Neural Networks (ANN). Previously collected release data were compiled and used to train, validate, and test an ANN model. Sensitivity analysis was then performed on the following operating conditions: ultrasonic frequency, power density, Pluronic P105 concentration, and temperature. The model showed that drug release was most efficient at lower frequencies. The analysis also demonstrated that release increases as the power density increases. Sensitivity plots of ultrasound intensity revealed a drug release threshold of 0.015 W/cm2 and 0.38 W/cm2 at 20 and 70 kHz, respectively. The presence of a power density threshold provides strong evidence that cavitation plays an important role in acoustically activated drug release from polymeric micelles. Based on the developed model, Dox release is not a strong function of temperature, suggesting that thermal effects do not play a major role in the physical mechanism involved. Finally, sensitivity plots of P105 concentration indicated that higher release was observed at lower copolymer concentrations.     

Protective Role of Epigallocatechin Gallate in a Rat Model of Cisplatin-Induced Cerebral Inflammation and Oxidative Damage: Impact of Modulating NF-κB and Nrf2

Neurotoxicity Research - Cisplatin is a widely used chemotherapeutic agent in treating various types of cancers. However, it can induce neurotoxicity and nephrotoxicity, limiting its dose and...     

Overexpression of the cell adhesion protein neuroligin‐1 induces learning deficits and impairs synaptic plasticity by altering the ratio of excitation to inhibition in the hippocampus

Trans‐synaptic cell‐adhesion molecules have been implicated in regulating CNS synaptogenesis. Among these, the Neuroligin (NL) family (NLs 1–4) of postsynaptic adhesion proteins has been shown to promote the development and specification of excitatory versus inhibitory synapses. NLs form a heterophilic complex with the presynaptic transmembrane protein Neurexin (NRX). A differential association of NLs with postsynaptic scaffolding proteins and NRX isoforms has been suggested to regulate the ratio of excitatory to inhibitory synapses (E/I ratio). Using transgenic mice, we have tested this hypothesis by overexpressing NL1 in vivo to determine whether the relative levels of these cell adhesion molecules may influence synapse maturation, long‐term potentiation (LTP), and/or learning. We found that NL1‐overexpressing mice show significant deficits in memory acquisition, but not in memory retrieval. Golgi and electron microscopy analysis revealed changes in synapse morphology indicative of increased maturation of excitatory synapses. In parallel, electrophysiological examination indicated a shift in the synaptic activity toward increased excitation as well as impairment in LTP induction. Our results demonstrate that altered balance in the expression of molecules necessary for synapse specification and development (such as NL1) can lead to defects in memory formation and synaptic plasticity and outline the importance of rigidly controlled synaptic maturation processes. © 2009 Wiley‐Liss, Inc.     

Automated Opportunistic Osteoporosis Screening in Routine Computed Tomography of the Spine: Comparison With Dedicated Quantitative CT

Opportunistic osteoporosis screening in nondedicated routine computed tomography (CT) is of increasing importance. The purpose of this study was to compare lumbar volumetric bone mineral density (vBMD) assessed by a convolutional neural network (CNN)-based framework in routine CT to vBMD from dedicated quantitative CT (QCT), and to evaluate the ability of vBMD and surrogate measurements of Hounsfield units (HU) to distinguish between patients with and without osteoporotic vertebral fractures (VFs). A total of 144 patients (median age: 70.7 years, 93 females) with clinical routine CT (eight different CT scanners, 120 kVp or 140 kVp, with and without intravenous contrast medium) and dedicated QCT acquired within ≤30 days were included. Vertebral measurements included (i) vBMD from the CNN-based approach including automated vertebral body labeling, segmentation, and correction of the contrast media phase for routine CT data (vBMD_OPP), (ii) vBMD from dedicated QCT (vBMD_QCT), and (iii) noncalibrated HU from vertebral bodies of routine CT data as previously proposed for immanent opportunistic osteoporosis screening based on CT attenuation. The intraclass correlation coefficient (ICC) for vBMD_QCT versus vBMD_OPP indicated better agreement (ICC = 0.913) than the ICC for vBMD_QCT versus noncalibrated HU (ICC = 0.704). Bland-Altman analysis showed data points from 137 patients (95.1%) within the limits of agreement (LOA) of −23.2 to 25.0 mg/cm³ for vBMD_QCT versus vBMD_OPP. Osteoporosis (vBMD <80 mg/cm³) was detected in 89 patients (vBMD_QCT) and 88 patients (vBMD_OPP), whereas no patient crossed the diagnostic thresholds from normal vBMD to osteoporosis or vice versa. In a subcohort of 88 patients (thoracolumbar spine covered by imaging for VF reading), 69 patients showed one or more prevalent VFs, and the performance for discrimination between patients with and without VFs was best for vBMD_OPP (area under the curve [AUC] = 0.862; 95% confidence interval [CI], 0.771–0.953). In conclusion, automated opportunistic osteoporosis screening in routine CT of various scanner setups is feasible and may demonstrate high diagnostic accuracy for prevalent VFs. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).     

Somatosensory evoked potentials and magnetic resonance imaging of the central nervous system in early multiple sclerosis

Journal of Neurology - Somatosensory evoked potentials (SSEP) are still broadly used, although not explicitly recommended, for the diagnostic work-up of suspected multiple sclerosis (MS). To relate...     

The effects of gender on health‐related quality of life in pediatric live‐donor kidney transplantation: A single‐center experience in a developing country

El‐Husseini A, Hassan R, Sobh M, Ghoneim M. The effects of gender on health‐related quality of life in pediatric live‐donor kidney transplantation: A single‐center experience in a developing country.
Pediatr Transplantation 2010:14:188–195. © 2009 John Wiley & Sons A/S. Abstract: To evaluate the effects of gender on HRQOL and overall health status in our pediatric kidney transplants. We performed a cross‐sectional study in 77 children who received living renal allo‐transplants in our center between 1981 and 2003. The patients were given a questionnaire at a post‐transplant visit. After completing, the patients returned it in a closed envelope. The questionnaire included demographic questions plus 57 multiple‐choice questions designed to analyze various aspects of post‐transplant life. Overall, the patients show satisfactory HRQOL. Most of the patients lived with their parents (79.2%). The current health status did not cause difficulties at work in 70.1% and did not interfere with the social life in 62.3% of patients. Physical and sexual growth was delayed in 48% and 85.7% of patients, respectively. A total of 67.5% of patients had normal health life or minor symptoms with normal activity. There was no significant effect of gender on HRQOL except for onset of puberty, sexual function, practicing sports, and obesity. Overall, the patients show satisfactory HRQOL. There was mild significant effect of gender on HRQOL. These findings may help health care professionals to develop gender‐specific interventions to optimize HRQOL of kidney transplants.     

Early intervention in bipolar disorder,part II: therapeutics

Recent evidence has shown that early pharmacological and psychosocial treatment dramatically ameliorates poor prognosis and outcome for individuals with psychotic disorders, reducing conversion rates to full‐blown illness and decreasing symptom severity. In a companion paper, we discussed methodological issues pertaining to early intervention in bipolar disorder (BPD), reviewed clinical studies that focus on high‐risk subjects as well as first‐episode patients, and reviewed findings from brain imaging studies in the offspring of individuals with BPD as well as in first‐episode patients. In this paper, we discuss how drugs that modulate cellular and neural plasticity cascades are likely to benefit patients in the very early stages of BPD, because they target some of the core pathophysiological mechanisms of this devastating illness. Cellular and molecular mechanisms of action of agents with neurotrophic and neuroplastic properties are discussed, with a particular emphasis on lithium and valproate. We also discuss their potential use as early intervention strategies for improving symptoms and functioning in patients in the earliest stages of BPD, as well as high‐risk individuals.