Early postinfection antiviral treatment reduces viral load and prevents CD4+ cell decline in HIV type 2-infected macaques

Reports of significant reductions in plasma viral load by anti-HIV drugs have raised the possibility that antiviral therapy, if initiated sufficiently early, may result in sustained control of infection and prolonged clinical benefits. We evaluated the effects of intervention coincident with infection using an antiviral nucleoside, d4T, in Macaca nemestrina infected with a highly pathogenic isolate of HIV-2 (HIV-2[287]). Infection with this virus reproducibly results in high viremia and rapid CD4+ cell depletion, allowing a sensitive measurement of the treatment effect on viral load and clinical outcome. Compared to the control group, d4T-treated macaques showed significantly lower (2-3 log10) plasma- and cell-associated viral load. No CD4+ cell decline was observed in the treatment group while on therapy with d4T whereas CD4+ cells of control macaques declined from a preinfection mean of 32% of PBMCs to below 10%. Notably, when d4T treatment was withdrawn after 16 weeks, five of the six macaques continued to control viral load and have maintained normal CD4+ cell level for more than a year. These results demonstrate that early antiviral intervention, even of a limited duration, may constitute an important strategy against lentiviral-induced disease.     

Prostaglandin production by guinea-pig endometrial cells: effects of caffeine and other modulators of intracellular calcium

The glandular epithelial cells were found to be the main source of PGF2 alpha (the uterine luteolytic hormone) in guinea-pig endometrium. There was a selective increase in PGF2 alpha production by these cells in culture at the time of the cycle (i.e. day 15) at which there is increased PGF2 alpha release from the guinea-pig uterus in vivo. TMB-8 (an intracellular calcium antagonist), W-7, trifluoperazine (both calmodulin antagonists), thapsigargin (an inhibitor of intracellular calcium uptake) and berberine (an inhibitor of calcium release) reduced the output of PGF2 alpha from day 7 glandular epithelial cells indicating that intracellular calcium is necessary for PGF2 alpha production by these cells. In contrast to its stimulatory effect on PGF2 alpha output from the guinea-pig uterus superfused in vitro and guinea-pig endometrium in culture, caffeine inhibited the output of PGF2 alpha from guinea-pig glandular epithelial cells in culture. Its effect was not fully shared by theophylline, nor mimicked by forskolin showing that cyclic AMP is not involved. The inhibitory actions of caffeine and those of the compounds which interfere with the action of intracellular calcium were not additive, suggesting that caffeine modulates the action of intracellular calcium in some way. Caffeine reduced the intracellular free calcium concentration in endometrial cells, but it was not particularly effective in this respect on day 7 glandular epithelial cells. Caffeine may therefore modulate the action of intracellular calcium in some other way.     

Analysis of organometallics dispersed polymer composite irradiated with oxygen ions

Thin films of polymethyl methacrylate (PMMA) were synthesized. Ferric oxalate was dispersed in PMMA films. These films were irradiated with 80 MeV O⁶⁺ ions at a fluence of 1×10¹¹ ions/cm². The radiation induced changes in electrical conductivity, Mössbauer parameter, microhardness and surface roughness were investigated. It is observed that hardness and electrical conductivity of the film increases with the concentration of dispersed ferric oxalate and also with the fluence. It indicates that ion beam irradiation promotes (i) the metal to polymer bonding and (ii) convert the polymeric structure into hydrogen depleted carbon network. Thus irradiation makes the polymer harder and more conductive. Before irradiation, no Mössbauer absorption was observed. The irradiated sample showed Mössbauer absorption, which seems to indicate that there is significant interaction between the metalion and polymer matrix. Atomic force microscopy shows that the average roughness (R _a) of the irradiated film is lower than the unirradiated one.     

Structure and function of gustatory neurons in the nucleus of the solitary tract. III. Classification of terminals using cluster analysis

In sensory systems, insight into synaptic arrangements on cells of known physiological response properties has helped our understanding of the structural basis for these properties. To carry out these types of studies, however, synaptic types in the region of interest must be defined. Unfortunately, defining synaptic types in the brainstem has proved to be a challenging enterprise. Our study was done to classify synapses in the gustatory part of the nucleus solitarius using objective quantitative criteria and a cluster analysis procedure. Cluster analysis allows classification of a population of objects, such as synaptic terminals, into groups that exhibit similar characteristics. Six terminal types were identified using cluster analysis and subsequent analyses of variance and post hoc tests. Unlike classification schemes used for the cerebral cortex, where synaptic apposition density thickness and shape of vesicles is useful (Gray's Type I and II synapses), the concentration of vesicles in a terminal was a more useful measurement with which to classify terminals in the nucleus solitarius. To validate that vesicle density (vesicles/microm2) is a useful defining characteristic to classify terminals in the nucleus solitarius, terminals of a known type were used. GABAergic terminals were identified using postembedding immunohistochemical techniques, and their vesicle density was determined. GABAergic terminals fall into the range of two of the terminal types defined by the cluster analysis and, based on vesicle density, two types of GABAergic terminals were identified. We conclude that vesicle density is a helpful means to identify synapses in this brainstem nucleus.     

Protein sizes and stoichiometry in the chaperone SecB--RBPTI complex estimated by ANS fluorescence

Two unrelated patients of Pakistani origin presented with primary hyperoxaluria type 1 (PH1) at 4 months and 3 years of age, respectively. While the younger patient failed to thrive and suffered from early renal failure, the older one showed a relatively benign history with urolithiasis as the main feature of the disease. In both patients the diagnosis was confirmed by assessment of alanine:glyoxylate aminotransferase catalytic and immunoreactivity in liver biopsy specimens. The underlying genetic defect was found to be a combined deletion and insertion in exon 8 which alters the reading frame of the protein. The nucleotide change introduces a Stu1 restriction site which facilitated typing of additional family members. Both patients and a further affected brother were homozygous for this mutation, while their parents were heterozygous for it. This mutation is the first deletion/insertion identified in PH1. Although rare in our PH1 patient cohort (2.5% of alleles), the finding of 2 homozygous apparently unrelated individuals of the same ethnic origin suggests that it may prove worthwhile to screen other Asian patients for this mutation. These PH1 cases present further evidence that factors other than genotype contribute significantly to the clinical presentation and severity of PH1.     

Candesartan cilexetil reduces chronic renal allograft injury in Fisher-->Lewis rats

OBJECTIVES: To determine the effects of the angiotensin II receptor antagonist, candesartan cilexetil, on glomerular and systemic blood pressures and the development of renal injury in Lewis rat recipients of a single Fisher kidney (F334--> LEW transplantation), an established rat model of chronic renal allograft failure. DESIGN: Recent studies have shown that chronic injury of renal allografts in F334-->LEW rats may be virtually abrogated by supplying the Lewis recipients with two Fisher kidneys or, alternatively, by retaining a native kidney. These findings imply a major contribution from processes associated with nephron loss to the pathogenesis of chronic renal allograft failure, a notion supported by the observation that transplanting two kidneys also normalizes glomerular capillary pressure (PGC) in F344-->LEW rats. Thus, a pharmacological reduction in PGC, by blocking the effects of angiotensin II, should also lessen renal injury in F344-->LEW rats. MATERIALS AND METHODS: Bilaterally nephrectomized F344--> LEW rats were treated with the angiotensin II receptor blocker candesartan cilexetil (TCV-116) at 40 mg/l or with vehicle, administered in drinking water. Proteinuria and systolic blood pressure were assessed monthly, and histological studies were carried out after 24 weeks. The glomerular filtration rate and glomerular pressures were determined after 10 weeks in additional rats by clearance and micropuncture studies. RESULTS: Treatment with candesartan cilexetil lowered systemic blood pressure, normalized PGC at 10 weeks and greatly reduced proteinuria and allograft glomerulosclerosis at 24 weeks. CONCLUSIONS: These data indicate that the development of renal injury in F344-->LEW renal allografts can be prevented by the pharmacological blockade of angiotensin II receptors using candesartan cilexetil. This suggests that angiotensin-dependent processes contribute significantly to chronic injury in this model of late renal allograft failure.     

Free postsynaptic densities in the hippocampus of the female rat

The number of synapses in the adult, female hippocampal CA1 region fluctuates naturally across the estrous cycle in an ovarian steroid-dependent manner. This phasic variation in synapse number occurs without identifiable degenerating synapses. Ultrastructural correlates of the dynamic aspect of this synapse loss and synapse formation thus remain undescribed. During early development, one hallmark of synaptogenesis is the presence of free postsynaptic densities (PSDs). Here we report that the incidence of free PSDs in CA1 fluctuates across the rat estrous cycle. The number of free PSDs is greatest on the afternoon of proestrus and is significantly decreased on the afternoon of estrus, 24 h later. We hypothesize that these free PSDs reflect synapse turnover in the adult CA1 region.