A randomized cross-over trial to define neurophysiological correlates of AV-101 N-methyl-d-aspartate receptor blockade in healthy veterans

The kynurenine pathway (KP) is a strategic metabolic system that combines regulation of neuronal excitability via glutamate receptor function and neuroinflammation via other KP metabolites. This pathway has great promise in treatment of depression and suicidality. The KP modulator AV-101 (4-chlorokynurenine, 4-Cl-KYN), an oral prodrug of 7-chlorokynurenic acid (7-Cl-KYNA), an N-methyl-d-aspartate receptor (NMDAR) glycine site antagonist, and of 4-chloro-3-hydroxyanthranilic acid (4-Cl-3-HAA), a suppressor of NMDAR agonist quinolinic acid (QUIN), is a promising potential antidepressant that targets glutamate functioning via the KP. However, a recent placebo-controlled clinical trial of AV-101 in depression found negative results. This raises the question of whether AV-101 can penetrate the brain and engage the NMDAR and KP effectively. To address this problem, ten healthy US military veterans (mean age = 32.6 years ± 6.11; 1 female) completed a phase-1 randomized, double-blind, placebo-controlled, crossover study to examine dose-related effects of AV-101 (720 and 1440 mg) on NMDAR engagement measured by γ-frequency band auditory steady-state response (40 Hz ASSR) and resting EEG. Linear mixed models revealed that 1440 mg AV-101, but not 720 mg, increased 40 Hz ASSR and 40 Hz ASSR γ-inter-trial phase coherence relative to placebo. AV-101 also increased 4-Cl-KYN, 7-Cl-KYNA, 4-Cl-3-HAA, 3-HAA, and KYNA in a dose-dependent manner, without affecting KYN and QUIN. AV-101 was safe and well tolerated. These results corroborate brain target engagement of 1440 mg AV-101 in humans, consistent with blockade of interneuronal NMDAR blockade. Future studies should test higher doses of AV-101 in depression. Suicidal behavior, which has been associated with high QUIN and low KYNA, is also a potential target for AV-101.Subject terms: Biomarkers, Neurophysiology, Neuroscience     

Recurrent Alternate-Sided Homonymous Hemianopia Due to Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-Like Episodes (MELAS): A Case Report

Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) can rarely cause alternate-sided homonymous hemianopia due to stroke-like episodes involving the occipital lobes, as reported in three previously published cases. The authors report an interesting case of a 16-year-old presenting with myoclonic epilepsy due to MELAS with the rare ND3 mitochondrial mutation T10191C, with recurrent alternate-sided homonymous hemianopia. Visual field and corresponding magnetic resonance imaging (MRI) findings are presented. To the authors’ knowledge, this is the first report of recurrent alternate-sided homonymous hemianopia in MELAS with documented visual field and MRI findings with resolution between each episode.     

Transdiaphragmatic extension of hepatic hydatid cyst

Transdiaphragmatic extension of hydatid cyst (HC) or cystic echinococcosis (CE) of the liver is a rare phenomenon. We report a case that presented as a right middle lobe consolidation. The diagnosis of transdiaphragmatic extension of hepatic hydatid cyst was suspected on CT scan of the chest and abdomen, and confirmed operatively. A successful outcome was achieved by a combination of pre- and post-operative albendazole therapy combined with surgery.     

Evaluations of HIV type 1 rev gene diversity and functional domains following perinatal transmission

The human immunodeficiency virus type 1 (HIV-1) rev exons 1 and 2 sequences were analyzed from six mother-infant pairs following perinatal transmission. The rev open reading frame was maintained with a frequency of 93.96% in six mother-infant pairs' sequences. There was a low degree of viral heterogeneity and estimates of genetic diversity in mother-infant pairs' rev sequences. However, the distances of rev sequences between epidemiologically unlinked individuals were greater than in epidemiologically linked mother-infant pairs. Furthermore, phylogenetic parameters revealed that the epidemiologically linked mother-infant pairs were closer evolutionarily to each other as compared with epidemiologically unlinked mother-infant pairs. Both mothers and infants were under positive selection pressure as determined by the ratios of nonsynonymous to synonymous substitutions. The functional domains required for Rev activity, including nuclear export of RNA, RNA binding domain, and nuclear import signals, were conserved in all mother-infant pairs' sequences. The conservation of functional domains of rev and a low degree of heterogeneity following vertical transmission are consistent with an indispensable role of rev in the HIV-1 life cycle.     

A clinical trial of 7 alpha-methyl-19-nortestosterone implants for possible use as a long-acting contraceptive for men

Several preparations of testosterone and its esters are being investigated alone or in combination with other gonadotropin-suppressing agents as possible antifertility agents for men. We studied the effectiveness of 7 alpha-methyl-19-nortestosterone (MENT) as an antispermatogenic agent in men. MENT has been shown to be more potent than testosterone and to be resistant to 5 alpha-reduction. For sustained delivery of MENT, we used a system consisting of ethylene vinyl acetate implants containing MENT acetate (Ac), administered subdermally. Thirty-five normal volunteers were recruited in 3 clinics and were randomly assigned to 1 of 3 doses: 1 (12 men), 2 (11 men), or 4 (12 men) MENT Ac implants. The initial average in vitro release rate of MENT Ac from each implant was approximately 400 micro g/day. Implants were inserted subdermally in the medial aspect of the upper arm under local anesthesia. The duration of treatment was initially designed to be 6 months. However, in 2 clinics the duration of treatment was extended to 9 months for the 2-implant group and to 12 months for the 4-implant group. Dose-related increases in serum MENT levels and decreases in testosterone, LH, and FSH levels were observed. Effects on sperm counts were also dose related. None of the subjects in the 1-implant group exhibited oligozoospermia (sperm count, <3 million/ml). Four subjects in the 2-implant group became oligozoospermic, 2 of whom reached azoospermia. Eight subjects in the 4-implant group reached azoospermia, with 1 exhibiting oligozoospermia, whereas 2 were nonresponders. Side effects generally seen with androgen administration, such as increases in erythrocyte count, hematocrit, and hemoglobin and a decrease in SHBG, were also seen in this study and were reversible. Changes in lipid parameters were moderate and transient. Liver enzymes showed small changes. This study demonstrates that MENT Ac, when administered in a sustained release fashion via subdermal implants, can inhibit spermatogenesis over a prolonged period after a single administration and has the potential to be used as a male contraceptive.     

Maternal pre‐pregnancy body mass index is not associated with infant and young child feeding in low‐income Mexican children 1–24 months old

Pre‐pregnancy overweight and obesity is associated with shorter breastfeeding (BF) duration. Whether pre‐pregnancy overweight and obesity is associated with other aspects of infant and young child feeding (IYCF) has not been investigated. We used data from 370 children born January 1999–September 2001 in a semi‐urban community in Morelos, Mexico, where information on how they were fed was available at 1, 3, 6, 9, 12, 18 and 24 months of age. We modified the World Health Organization's dietary diversity indicator to assess the quality of the complementary foods. An index that included BF, quality of complementary foods and other behaviours was constructed to measure IYCF. We used survival analysis to examine the association of pre‐pregnancy body mass index (pBMI) category and BF duration and mixed models for quality of complementary food and IYCF index. Mean maternal pBMI was 24.4 ± 4.1; 31% were overweight, and 9% were obese. pBMI was not associated with BF duration. Quality of complementary food improved over time (6 months, 1.3 ± 1.3; 24 months, 3.8 ± 1.04). Compared with normal‐weight women, overweight and obese women were more likely to feed from more food groups (0.24 ± 0.11 point, P = 0.03), but this did not improve diet diversity from 6 to 24 months. IYCF index decreased throughout follow‐up (1 month, 7.8 ± 2.4; 24 months, 5.5 ± 1.8), and pBMI was not associated with IYCF (?0.11 ± 0.13 point, P = 0.4). We conclude that heavier women were not engaging in IYCF behaviours that were distinct from those of normal‐weight women from 1 to 24 months post‐partum.