Chronic alcohol exposure reduces hippocampal neurogenesis and dendritic growth of newborn neurons

Hippocampal neurogenesis is known as the formation of new neurons from the proliferating neural progenitor cells (NPC) at the dentate gyrus. Cell proliferation, survival, differentiation and maturation are critical stages leading to the generation of healthy neurons. As all of these stages can be influenced by alcohol exposure, we studied the effects of chronic alcohol on each process by immunocytochemistry for stage-specific antigens and prelabelling newborn cells with bromodeoxyuridine (BrdU). Rats were administered alcohol liquid diet or control diet for one, two or four weeks. We found that cell proliferation was inhibited as proliferating cell nuclear antigen (PCNA) expression was reduced by approximately 50% in alcohol-treated animals at all time points. Doublecortin (DCX), a microtubule protein expressed early in differentiating neurons, was progressively decreased over the duration of exposure and significantly reduced after two and four weeks of drinking. Morphological analyses of DCX-positive cells revealed that four weeks of alcohol treatment reduced the size of the dendritic tree including the total length of apical dendrites, number of nodes and endings. Furthermore, BrdU labelling demonstrated a dramatic decrease in cell survival after four weeks of drinking, while cell death was increased by such treatment. Confocal analysis indicated that over 80% of BrdU+ cells colabelled with NeuN suggesting that alcohol reduced neurogenesis. In conclusion, chronic alcohol exposure disrupts neurogenesis by decreasing NPC proliferation, inhibiting cell survival and altering morphological maturation of newborn neurons. These data implicate impaired hippocampal neurogenesis with the cognitive and affective dysfunction associated with chronic alcoholism.     

Amelioration of the cerebrovascular amyloidosis in a transgenic model of Alzheimer’s disease with the neurotrophic compound Cerebrolysin™

Summary. Increased production and reduced clearance of amyloid (A) plays a central role in the pathogenesis of Alzheimers disease (AD). We have recently shown that the neurotrophic peptide mixture Cerebrolysin (Cbl) has the ability of improving synaptic functioning and reducing amyloid deposition in a transgenic (tg) animal model of Alzheimers disease (AD). Since in AD, potentially toxic A aggregates accumulate not only around neurons but also in the blood vessels, then it is important to investigate whether bioactive compounds such as Cbl might have the capacity to ameliorate the age-related cerebral amyloid angiopathy (CAA) in tg models. To this end, tg mice expressing mutant human amyloid precursor protein (APP) under the Thy1 promoter were treated with Cbl or saline alone starting at 7 or 12 months of age for a total of three months. Neuropathological analysis with an antibody against A showed that Cbl decreased amyloid deposition around the blood vessels in a time dependant manner. These effects were accompanied by a reduction in perivascular microgliosis and astrogliosis and increased expression of markers of vascular fitness such as CD31 and ZO-1. No lymphocytic infiltration was observed associated with A in the vessels. Consistent with these findings, ultrastructural analysis showed that while in tg mice treated with saline alone there was an abundant accumulation of amyloid fibers in the vascular wall accompanied by thickening of the basal membrane and endothelial cell damage, in Cbl-treated mice there was considerable reduction in the subcellular alterations of endothelial and smooth muscle cells with preservation of basal membranes and intercellular junctions. Taken together, these results suggest that Cbl treatment might have beneficial effects in patients with cognitive impairment due to cerebrovascular amyloidosis by reducing A accumulation and promoting the preservation of the cerebrovasculature.     

Vision impairment and hearing loss among community-dwelling older Americans: implications for health and functioning

OBJECTIVES: We investigated the health, activity, and social participation of people aged 70 years or older with vision impairment, hearing loss, or both. METHODS: We examined the 1994 Second Supplement on Aging to determine the health and activities of these 3 groups compared with those without sensory loss. We calculated odds ratios and classified variables according to the International Classification of Functioning, Disability and Health framework. RESULTS: Older people with only hearing loss reported disparities in health, activities, and social roles; those with only vision impairment reported greater disparities; and those with both reported the greatest disparities. CONCLUSIONS: A hierarchical pattern emerged as impairments predicted consistent disparities in activities and social participation. This population's patterns of health and activities have public health implications.     

Tyrosine hydroxylase expression is affected by sexual vigor and social environment in male Cnemidophorus inornatus

Although the distribution of catecholamine-synthesizing cells has been described for a variety of taxa, less is known about the functional significance of particular populations in nonmammalian species, especially reptiles. To understand the role of these populations in the display of social behaviors in lizards, we studied the interactive effects of sexual vigor (sexually vigorous vs. sluggish) and social condition (housing in isolation vs. with females) on the number and somal areas of cells expressing tyrosine hydroxylase (TH), a rate-limiting enzyme in catecholamine synthesis, in male whiptail lizards, Cnemidophorus inornatus. We found that, regardless of social condition, sexually vigorous males had more TH-immunoreactive (TH-ir) cells in the dorsal hypothalamus (DH) relative to sluggish males. Sexually vigorous males also had more TH-ir cells in the substantia nigra pars compacta (SNpc), but this difference was significant only among males housed with females. Sexually vigorous males that had been housed with females had smaller TH-ir cells in the preoptic area (POA) than vigorous males housed in isolation. On the other hand, no significant differences were found in the anterior hypothalamus. These results highlight the regional heterogeneity in the plasticity of TH expression and suggest that, just as in other species, the DH, SNpc, and POA might be involved in the expression of social behaviors and in behavioral plasticity following social experiences in lizards.     

Pharmacokinetics of 2-chlorodeoxyadenosine in a child undergoing hemofiltration and hemodialysis for acute renal failure

The clearance of 2-chlorodeoxyadenosine (2-CdA) in patients with renal insufficiency has not been characterized previously. The authors describe the clinical course and the pharmacokinetics of 2-CdA in a child with acute monoblastic leukemia who experienced acute renal failure during treatment with cytarabine and 2-CdA. 2-CdA (9 mg/m per day) was infused over 30 minutes daily for 5 days. Plasma and dialysate concentrations of 2-CdA were measured by high-performance liquid chromatography. The rate of this patient's 2-CdA clearance was lower than the rates reported for children with normal renal function. The average clearance rate, reflecting systemic clearance and clearance by continuous venovenous hemofiltration and hemodialysis, was 12.4 L/hour per m for the first 3 days of 2-CdA therapy. He did not experience untoward hematologic toxicity. Because high 2-CdA plasma concentrations were observed in this patient, clinicians are advised to exercise caution when using this drug in patients with renal dysfunction. More experience in the administration of 2-CdA to patients with renal insufficiency will be necessary to determine the need for dosage adjustment.     

Probing biotransformation relationships among pyridoacridines by focusing on oxygenated analogues

The presence of the MeO-5 in the structure 5-methoxyamphimidine (5) is unusual in the light of a recent analysis of the relationships among sponge- and tunicate-derived pyridoacridines. We explore a possible biochemical pathway, from neoamphimidine (2) to 5-methoxyamphimidine (5). The results of semiempirical and ab initio calculations are presented to help understand the relationships that favor the formation of 5 versus the formation of undiscovered bis-oxygenated pyridoacridines.     

Structures and cytotoxic properties of trichoverroids and their macrolide analogues produced by saltwater culture of Myrothecium verrucaria

Saltwater culture of Myrothecium verrucaria, separated from a Spongia sp. collected in Hawaii, was a source of three new trichothecenes, 3-hydroxyroridin E (1a), 13'-acetyltrichoverrin B (2), and miophytocen C (3) and nine known related compounds (1b, 4, 5, 6, 7a, 7b, 8, 9a, and 9b). The stereostructures of the new compounds were established on the basis of 1D and 2D NMR spectral analyses and a chemical transformation. At the same time, the stereostructures of known compounds, 1b, 4, and 5 reported previously were also elucidated. All the compounds except 3 showed significant cytotoxicity against murine and human tumor cell lines. Moreover, the structure-activity relationships (SARs) were established from the results of the bioassay data.     

Randomised controlled trial of prophylactic etamsylate: follow up at 2 years of age

AIM: To assess the role of etamsylate in reducing the risk of haemorrhagic brain damage and its consequences. DESIGN: Follow up of babies recruited into a randomised controlled trial. METHODS: A total of 334 infants born before 33 weeks gestation in France and Greece were randomly allocated within the first four hours of birth either to receive etamsylate or to act as controls. The principal outcomes in the trial were death or impairment and/or disability at the age of 2 years. RESULTS: Fifty nine children were lost to follow up. A total of 115 (34%) either died or had some impairment or disability, and 88 (26%) either died or had severe impairment or disability at 2 years of age. These outcomes did not differ significantly between the two randomised groups: relative risks and 95% confidence intervals 1.14 (0.78 to 1.4) and 1.17 (0.82 to 1.68) respectively. The findings were similar for all the prespecified subgroup analyses stratified by key prognostic factors at trial entry: country of birth, gestational age < or >or= 29 weeks, inborn or outborn, age < or >or= 1 hour, and with or without cerebral scan abnormality. CONCLUSION: These findings do not support the use of etamsylate. Other strategies need to be evaluated for the prevention of mortality and morbidity in these vulnerable infants.