A0001 in Friedreich ataxia: Biochemical characterization and effects in a clinical trial

This study tested the ability of A0001 (α-tocopheryl quinone; EPI-A0001), a potent antioxidant, to improve in vitro measures, glucose metabolism, and neurological function in Friedreich ataxia. We used an in vitro study of protection from cell toxicity followed by a double-blind, randomized, placebo-controlled trial of 2 doses of A0001 in 31 adults with Friedreich ataxia. The primary clinical trial outcome was the Disposition Index, a measure of diabetic tendency, from a frequently sampled intravenous glucose tolerance test, evaluated 4 weeks into therapy. Secondary neurologic measures included the Friedreich Ataxia Rating Scale. A0001 potently inhibited cell death in Friedreich ataxia models in vitro. For the clinical trial, mean guanine-adenine-adenine repeat length was 699, and mean age was 31 years. Four weeks after treatment initiation, differences in changes in the Disposition Index between subjects treated with A0001 and placebo were not statistically significant. In contrast, a dose-dependent improvement in the Friedreich Ataxia Rating Scale score was observed. Patients on placebo improved 2.0 rating scale points, whereas patients on low-dose A0001 improved by 4.9 points (P = .04) and patients on a high dose improved by 6.1 points (P < .01). Although A0001 did not alter the Disposition Index, it caused a dose-dependent improvement in neurologic function, as measured by the Friedreich Ataxia Rating Scale. Longer studies will assess the reproducibility and persistence of neurologic benefit.     

Solubilization and in Vitro Spermicidal Assessment of Nonoxynol-9 and Selected Fractions Using Rabbit Spermatozoa

Selected oligomers representing the high, medium, and low molecular weight fractions of the spermicidal agent Nonoxynol-9 (N-9) were separated by HPLC. Nonoxynol-9 and the isolated fractions were formulated with polyvinylpyrrolidone (PVP) in order to increase their water solubility, particularly that of the insoluble low molecular weight fraction. The in vitro spermicidal activity of three molecular weight fractions were compared to that of N-9, using rabbit spermatozoa, at equimolar concentrations. Nonoxynol-9/PVP was far more effective in immobilizing the sperm than either N-9 alone or the separate fractions. The relative spermicidal activity of the oligomers was of the order middle molecular weight > high molecular weight > low molecular weight.     

Cerebral blood flow and morphological changes after hypoxic-ischaemic injury in preterm lambs

Aim: To evaluate the effect of cerebral hypoxia-ischaemia induced by partial occlusion of the umbilical cord on the relationship of the regional cerebral blood flow and the cerebral cell death in near-term fetal lambs. Methods: Fifteen near-term lambs were assigned to two hypoxic-ischaemic groups with or without life support (3 h), and a healthy one. Hypoxia-ischaemia was induced by partial occlusion of the umbilical cord (60 min). Routine light and electron microscopy, and the TUNEL method for apoptosis were performed. Regional cerebral blood flow was measured by coloured microspheres. Cardiovascular, gas exchange and pH parameters were also evaluated. Results: Both hypoxic-ischaemic groups produced a transient acidosis and a decrease of base excess in comparison to the healthy group. Cortical and cerebellar zones, where the regional cerebral blood flow values were similar to baseline, showed an increased number of oligodendrocyte-like apoptotic cells. In contrast, in the inner zones, where regional cerebral blood flow was increased, the number of apoptotic cells did not increase. Necrotic neurons were observed in the basal nuclei, mesencephalon, pons and deep cerebellar nuclei.

Conclusion: Our results suggest that regional cerebral blood flow and the presence of apoptotic cells, 3 h after hypoxic-ischemic injury, are correlated.     

Combined paclitaxel and cetuximab achieved a major response on the skin metastases of a patient with epidermal growth factor receptor-positive, estrogen receptor-negative, progesterone receptor-negative and human epidermal growth factor receptor-2-negative (triple-negative) breast cancer

The epidermal growth factor receptor, a transmembrane receptor tyrosine kinase of the erbB family, is expressed in 15-30% of all breast cancers. Anti-epidermal growth factor receptor agent cetuximab is an IgG1 chimeric monoclonal antibody with a potent antitumor activity. Cetuximab competes with ligand binding to the epidermal growth factor receptor ectodomain, resulting in an efficient blockade of tumor-promoting downstream signaling pathways. Large clinical studies recently demonstrated cetuximab synergy with radiotherapy and chemotherapy agent irinotecan. Studies in human breast cancer xenografts showed cetuximab synergy with paclitaxel, a potent mitosis spindle-cell stabilizer. In this report, combined paclitaxel and cetuximab achieved a major reduction of the skin metastases of a heavily pretreated patient with epidermal growth factor receptor-positive, estrogen receptor-negative, progesterone receptor-negative and human epidermal growth factor receptor-2-negative (triple-negative) invasive ductal breast carcinoma. Treatment was well-tolerated overall and response was not correlated with the appearance of major cetuximab-induced acneiform rash.     

High‐throughput sequencing of a 4.1 Mb linkage interval reveals FLVCR2 deletions and mutations in lethal cerebral vasculopathy

Rare lethal disease gene identification remains a challenging issue, but it is amenable to new techniques in high‐throughput sequencing (HTS). Cerebral proliferative glomeruloid vasculopathy (PGV), or Fowler syndrome, is a severe autosomal recessive disorder of brain angiogenesis, resulting in abnormally thickened and aberrant perforating vessels leading to hydranencephaly. In three multiplex consanguineous families, genome‐wide SNP analysis identified a locus of 14 Mb on chromosome 14. In addition, 280 consecutive SNPs were identical in two Turkish families unknown to be related, suggesting a founder mutation reducing the interval to 4.1 Mb. To identify the causative gene, we then specifically enriched for this region with sequence capture and performed HTS in a proband of seven families. Due to technical constraints related to the disease, the average coverage was only 7×. Nonetheless, iterative bioinformatic analyses of the sequence data identified mutations and a large deletion in the FLVCR2 gene, encoding a 12 transmembrane domain‐containing putative transporter. A striking absence of alpha‐smooth muscle actin immunostaining in abnormal vessels in fetal PGV brains, suggests a deficit in pericytes, cells essential for capillary stabilization and remodeling during brain angiogenesis. This is the first lethal disease‐causing gene to be identified by comprehensive HTS of an entire linkage interval. Hum Mutat 31:1–8, 2010. © 2010 Wiley‐Liss, Inc.     

Multiple visceral abscesses due to tuberculosis

Tuberculosis is a global epidemic, especially in India. In immuno-competent host, abdominal tuberculosis most commonly presents as ileo-caecal tuberculosis and ascitis. Presented is a rare case of immuno-competent host with abdominal tuberculosis in the form of multiple visceral abscess.     

Endothelin contributes to basal vascular tone and endothelial dysfunction in human obesity and type 2 diabetes

Endothelium-dependent vasodilation is impaired in clinical states of insulin resistance such as obesity and type 2 diabetes. Individuals who have hyperinsulinemic insulin resistance have relatively elevated circulating levels of endothelin (ET)-1, suggesting that ET-1 may be important in the endothelial dysfunction and alterations of vascular tone in these conditions. In 8 lean subjects, 12 nondiabetic obese subjects, and 8 subjects with type 2 diabetes, we measured basal and methacholine-stimulated rates of leg blood flow (LBF) and total serum nitrates (NOx) before and after the intrafemoral arterial administration of BQ123, a specific blocker of ET(A) receptors. BQ123 produced significant vasodilation in the obese and type 2 diabetic subjects (leg vascular resistance = mean arterial pressure/LBF fell by 34 and 36%; P < 0.005) but not in the lean subjects (13%; P = NS, P = 0.018 comparing all groups). ET(A) blockade did not change basal NOx flux (NOx*LBF). This suggests increased basal ET-1 constrictor tone among obese and type 2 diabetic subjects. BQ123 corrected the baseline defect in endothelium-dependent vasodilation seen in obese and type 2 diabetic subjects, suggesting an important contribution of ET-1 to endothelial dysfunction in these subjects. In contrast to basal conditions, stimulated NOx flux was augmented by BQ123 in obese and type 2 diabetic subjects but not in L subjects (P = 0.04), suggesting a combined effect of ET(A) blockade to reduce constrictor tone and augment dilator tone. Endothelin seems to contribute to endothelial dysfunction and the regulation of vascular tone in human obesity and type 2 diabetes.     

Magnetic sulfonated polysaccharides as efficient catalysts for synthesis of isoxazole-5-one derivatives possessing a substituted pyrrole ring,as anti-cancer agents

Four polysaccharides (chitosan, cellulose, starch, and pectin) were magnetized with magnetic iron oxide (Fe₃O₄) and then sulfonated (except pectin) with chlorosulfonic acid. The obtained solid acids were used as a catalyst in three-component reactions between N-substituted-2-formylpyrrole, hydroxylamine-hydrochloride, and β-keto esters for the synthesis of 4-(2-pyrrolyl) methylene-isoxazole-5-ones. The optimal catalyst system was selected and studied by IR, SEM, TEM and XRD methods. The diverse isoxazoline derivatives (obtained via a mild and simple approach) were also fully characterized by spectroscopic methods and screened for anti-cancer activities against HT-29 and MCF-7 colon and breast cancer and HEK 293 normal cells. The results revealed interesting anti-cancer activities.

Four magnetic polysaccharides containing acidic groups were used as catalysts for the synthesis of 4-(2-pyrrolyl) methylene-isoxazole-5-ones. The products showed anti-cancer activities.