Viral dynamics of primary viremia and antiretroviral therapy in simian immunodeficiency virus infection

Mathematical modeling of viral replication dynamics, based on sequential measurements of levels of virion-associated RNA in plasma during antiretroviral treatment, has led to fundamental new insights into human immunodeficiency virus type 1 pathogenesis. We took advantage of the simian immunodeficiency virus (SIV)-infected macaque model to perform detailed measurements and mathematical modeling during primary infection and during treatment of established infection with the antiretroviral drug (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA). The calculated clearance half-life for productively infected cells during resolution of the peak viremia of primary infection was on the order of 1 day, with slightly shorter clearance half-lives calculated during PMPA treatment. Viral reproduction rates upon discontinuation of PMPA treatment after 2 weeks were approximately twofold greater than those obtained just prior to initiation of treatment in the same animals, likely reflecting accumulation of susceptible target cells during treatment. The basic reproductive ratio (R0) for the spread of SIV infection in vivo, which represents the number of productively infected cells derived from each productively infected cell at the beginning of infection, was also estimated. This parameter quantifies the extent to which antiviral therapy or vaccination must limit the initial spread of virus to prevent establishment of chronic disseminated infection. The results thus provide an important guide for efforts to develop vaccines against SIV and, by extension, human immunodeficiency virus.     

Resumption of mitosis during post-thaw culture: a key parameter in selecting the right embryos for transfer

A new oxidative pathway for the degradation of caffeine(1,3,7-Trimethylxanthine, I) by a mixed culture consisting of strains belonging to the genera Klebsiella and Rhodococcus is presented. The mixed culture does not initiate degradation by N-demethylation either complete or partial, but instead carries out oxidation at the C-8 position resulting in the formation of 1,3,7-trimethyluric acid (TMU, II) which further gets degraded to 3,6,8-trimethylallantoin (TMA, III). Both TMU and TMA are hitherto not shown to be formed in the microbial system. Further degradation of TMA (III) by caffeine grown cells yields dimethylurea (VII) as one of the metabolites. Oxygen uptake studies indicated that caffeine(I) grown cells oxidized TMU(II), TMA (III), glyoxalic acid (VI), dimethylurea(VII), and monomethylurea(V), but not monomethyl and dimethyluric acids. The mixed culture does not accept theophylline(1,3-dimethylxanthine), theobromine(3,7-dimethylxanthine), and paraxanthine(1,7-dimethylxanthine) as the carbon source.     

Foetal alcohol syndrome in Saskatchewan: unchanged incidence in a 20-year period

Ethers and thioethers of monosaccharides have been synthesised which show potent toxicity to mouse (LD50 > or = 4 g.kg-1 O.W. and 0.2 to 1.5 g.kg-1 I.P.W.). A study of calcium antagonist activity for the full series of compounds indicated that the activity was similar for both O- and S- ethers and maximum activities were observed for monoacetoneglucose ethers possessing carbon chain close to 8 carbons.     

Regional lipid peroxidation and protein oxidation in rat brain after hyperbaric oxygen exposure

Reactive oxygen species may participate in development of neurological toxicity resulting from hyperbaric oxygen exposure. To explore the possibility that increased reactive O2 metabolite generation may result in oxidative modification of lipids and proteins, rats were exposed to five atmospheres (gauge pressure) of O2 until development of an electroencephalographic seizure. Lipid peroxidation (as thiobarbituric acid-reactive substances) and protein oxidation (as 2,4-dinitrophenyl-hydrazones) were measured in five brain regions. Oxidized and reduced glutathione were also determined because of their role in regulating lipid peroxidation. Lipid peroxidation was confined to the frontal cortex and hippocampus, while protein oxidation (in both cytoplasmic and membranous fractions) and increased oxidized glutathione was evident throughout the brain. These results support a role for formation of reactive O2 metabolites from hyperbaric O2 exposure and suggest that protein oxidation, especially in soluble proteins, may be one of the most sensitive measures.     

Differential divalent cation requirements uncouple the assembly and catalytic reactions of human immunodeficiency virus type 1 integrase

Previous in vitro analyses have shown that the human immunodeficiency virus type 1 (HIV-1) integrase uses either manganese or magnesium to assemble as a stable complex on the donor substrate and to catalyze strand transfer. We now demonstrate that subsequent to assembly, catalysis of both 3' end processing and strand transfer requires a divalent cation cofactor and that the divalent cation requirements for assembly and catalysis can be functionally distinguished based on the ability to utilize calcium and cobalt, respectively. The different divalent cation requirements manifest by these processes are exploited to uncouple assembly and catalysis, thus staging the reaction. Staged 3' end processing and strand transfer assays are then used in conjunction with exonuclease III protection analysis to investigate the effects of integrase inhibitors on each step in the reaction. Analysis of a series of related inhibitors demonstrates that these types of compounds affect assembly and not either catalytic process, therefore reconciling the apparent disparate results obtained for such inhibitors in assays using isolated preintegration complexes. These studies provide evidence for a distinct role of the divalent cation cofactor in assembly and catalysis and have implications for both the identification and characterization of integrase inhibitors.     

Reasons for personnel turnover in a private health facility

In this article 1 describe efforts to build a genetically informative, population-based sample of black twins to study physical frailty and aging in the United States. This project involves the use of governmental registries combined with sampling techniques developed to overcome limitations in the registry data. Two analytical approaches to measures of disability are included to illustrate the types of questions that can be addressed with this sample. These results suggest that physical disability in late life has both genetic and environmental determinants. Only with a genetically informative sample can evidence be collected indicating that frailty may be driven by fixed processes (i.e., disability resulting from activation of senescence genes), fluid processes (i.e., disability resulting from changes in the features of the environment), or a combination of both.     

Polymorphonuclear neutrophil granulocyte chemotactic hyperresponsiveness in a case of canine acromegaly

Growth hormone (GH) has recently been shown to affect polymorphonuclear neutrophil granulocyte (PMN) function and to be secreted by mononuclear cells, indicating that the hormone may be active in an immunophysiologic network, acting as an endo- or paracrine priming agent. The purpose of the present study was to evaluate the chemotactic responsiveness of canine peripheral PMN in a dog with acromegaly, caused by spontaneous, progesterone-induced hypersecretion of GH and, secondary to this, a seven-fold increase in insulin-like growth factor I (IGF-I). The chemotactic responsiveness towards zymosan-activated serum (ZAS) and leukotriene B4 (LTB4) was evaluated at a time when the dog suffered from acromegaly and again 57 days after corrective surgery (ovariohysterectomy). The experiments showed that PMN from the patient exhibited enhanced chemotactic migration that appeared to be associated with the hypersomatotropic condition as judged from the reversibility of the phenomenon. The glucose intolerance and elevated serum alkaline phosphatase that were observed in the acromegalic dog were also shown to be reversible following surgery.     

Effect of process distillation on mutagenicity and cell-transformation activity of solvent-refined,coal-derived liquids

Blended SRC-II process streams, representing a full boiling range distillate material, were fractionally distilled into non-overlapping 50 °F cuts with boiling points between 300 and 850 °F. Another set of 18 distillate cuts were obtained with boiling points ranging between 138 and 1055 °F. Distillate cuts were assayed for mutagenic activity using the histidine reversion assay with Salmonella typhimurium strains TA98, TA100, TA1535 and TA1537, as well as for mammalian-cell transformation activity in the Syrian hamster embryo test, and DNA damage in the prophage induction assay. Samples were also separated into chemical class fractions by alumina column chromatography and analysed by high resolution gas chromatography so that the chemical composition of the cuts could be related to their relative activity in the different assays. In the mammalian cell transformation and microbial mutagenicity assays, significant activity was found almost exclusively in distillate cuts with components boiling > 700 °F, with the highest activity in the transformation assay observed for cuts > 800 °F. All of the distillate cuts showed increased levels of DNA damage as expressed by lambda prophage induction in Escherichia coli 8177. However, the greatest activity was associated with distillate cuts with boiling points in the 800 °F + range. Chemical analysis of the 50 °F distillate cuts showed a variety of polycyclic aromatic hydrocarbons (PAH) and amino-PAH compounds to be present in the distillate cuts boiling > 700 °F and essentially absent from cuts boiling < 700 °F. The sample set of non-overlapping (50 °F) cuts were reblended according to the proportions of each cut found in the original blend material. These reblended composites were then assayed to compare their activity with that predicted from the activities of the component distillate cuts. The reblending experiments indicated the microbial mutagenicity response was essentially additive. Mammalian cell transformation activities were non-additive, indicating a compositional effect on the expression of transforming agents in the complex mixture.