Cognitive functioning during highly active antiretroviral therapy interruption in human immunodeficiency virus type 1 infection

Although no longer considered therapeutically beneficial, antiretroviral treatment interruptions (TIs) still occur frequently among patients with human immunodeficiency virus (HIV) infection for a variety of reasons. TIs typically result in viral rebound and worsening immunosuppression, which in turn are risk factors for neurocognitive decline and dementia. We sought to determine the extent of neurocognitive risk with TIs and subsequent reintroduction of highly active antiretroviral therapy (HAART) by using a comprehensive, sensitive neuropsychological assessment and by concurrently determining changes in plasma and cerebrospinal fluid (CSF) viral load and CD4 counts. Prospective, serial, clinical evaluations including neuropsychological (NP) testing and measurement of plasma HIV RNA and CD4 count and mood state were performed on HIV-1—infected individuals (N=11) at three time points: (1) prior to a TI, while on HAART; (2) after TIs averaging 6 months; and (3) after reinitiating HAART therapy. During TI, plasma HIV RNA increased and CD4 counts declined significantly, but NP performance did not change. Following reinitiation of HAART, viral loads fell below pre-TI levels, and CD4 counts rose. Improved viral suppression and immune restoration with reinitiation of HAART resulted in significant improvement in neurocognitive performance. No changes on comprehensive questionnaires of mood state were observed in relation to TI. NP performance and mood state remained stable during TIs despite worsened viral loads and CD4 counts. Because “practice effects” are generally greatest between the first and second NP testing sessions, improvement at the third, post-TI time point was unlikely to be accounted for by practice. TIs of up to 6 months appear to be neurocognitively and psychiatrically safe for most patients.     

Population pharmacokinetics of abacavir in plasma and cerebrospinal fluid

The distribution of abacavir into the cerebrospinal fluid (CSF) was assessed by use of a population pharmacokinetic analysis. Plasma and CSF abacavir concentrations in 54 subjects were determined. The abacavir CSF/plasma ratio averaged 36% and increased throughout the dose interval. Abacavir penetrates into the CSF in adequate concentrations to inhibit local human immunodeficiency virus replication.     

Treatment of acute toxoplasmosis with intravenous clindamycin

The interim results are presented of an ongoing large-scale, prospective, randomized study to determine the potential role of clindamycin in the treatment of toxoplasmic encephalitis. Patients were seropositive forToxoplasma gondii antibodies and had clinical signs compatible with toxoplasmic encephalitis. Data was available on 33 patients, 15 of whom received pyrimethamine p.o. / clindamycin i.v. and then p.o., and 18 of whom received pyrimethamine p.o./sulfadiazine p.o. The interim evaluation did not reveal a remarkable difference between the two regimens in the clinical or radiologic response. Adverse reactions to both regimens were common and frequently multiple, there being more adverse gastrointestinal reactions in patients on pyrimethamine/clindamycin and more adverse hematological reactions in those on pyrimethamine/sulfadiazine.Supported by the University of California's University-wide AIDS Research Program.     

The genome of Schistosoma mansoni: isolation of DNA, its size, bases and repetitive sequences

DNA has been prepared from adults and cercariae of Schistosoma mansoni utilizing a technique that involves centrifugation through cesium chloride. The DNA isolated from S. mansoni adults and that isolated from cercariae were found to be indistinguishable in all analyses. No modified bases were detected by chromatography or comparative endonuclease restriction. Cot analysis demonstrated that the haploid genome of S. mansoni is 0.26 pg (2.7 X 10(8) base pairs) and that the genome contains both moderately and highly repeated components. Some of the repetitive fraction of DNA consists of tandemly repeated ribosomal genes of which there are 500-1000 copies per genome (1.8-3.6% of the total DNA). Four other non-ribosomal repetitive sequences (comprising at least a further 2.0% of the total DNA) have been isolated from a DNA clone bank and their arrangement within the S. mansoni genome investigated by restriction and Southern blot analysis. These cloned segments of DNA appear in many different locations within the genome and thus are reminiscent of the interspersed DNA sequences described in higher eukaryotic organisms.     

Structure of the circumsporozoite gene of Plasmodium malariae

The sequence of the gene encoding the circumsporozoite protein of Plasmodium malariae was determined. The central immunodominant region of the protein consists of 45 copies of the sequence Asn-Ala-Ala-Gly and 6 copies of the sequence Asn-Asp-Ala-Gly. The CSP of the monkey parasite Plasmodium brasilianum contains the same repetitive sequences. Further comparison of the two genes in regions outside the immunodominant domains reveals only three nucleotide differences and each results in an amino acid change. One is centered in a putative T-cell determinant bearing region, the second is in the putative liver binding site, and the third is part of a degenerate repeat at the start of the immunodominant region.     

Differentiation of schistosomes by species, strain, and sex by using cloned DNA markers.

We have detected species, strain, and sex-specific genetic markers for the genus Schistosoma by Southern blot analysis of its DNA using cloned DNA segments of the Schistosoma mansoni ribosomal gene as probes. Restriction analysis of DNA from eight different strains of S. mansoni, from Africa and the Caribbean, revealed that the predominant or major DNA fragment containing the ribosomal gene unit was the same in each but that low copy number or minor fragments containing the gene varied. It was shown that the detection of these minor fragments could serve as the basis for both strain differentiation and the analysis of individual differences within a strain. Analysis of the parents and progeny of a genetic cross revealed sex-linked markers and suggested that these markers are inherited in a Mendelian fashion. DNAs from the species Schistosoma haematobium and Schistosoma japonicum were also analyzed. Differences in the length of the major repeating unit of the ribosomal gene served to distinguish each species. Furthermore, an array of minor bands was detected in each species, suggesting that strains of S. haematobium and S. japonicum could be differentiated in the same manner as S. mansoni strains.     

Nephrolithiasis and risk of hypertension in women

Cross-sectional and prospective studies of men suggest a positive association between nephrolithiasis and hypertension. However, this association remains controversial in women. We conducted a prospective study of the relation between nephrolithiasis and the risk for hypertension in the Nurses' Health Study, a cohort of 89,376 women aged 34 to 59 years in 1980. Information on the history of nephrolithiasis, physician-diagnosed hypertension, and other relevant exposures was obtained by biennial mailed questionnaire. A history of nephrolithiasis before 1980 was reported by 2,558 women (2.9%), and a history of hypertension was reported by 11,883 women (13.3%). Among women without hypertension before 1980, 12,540 women reported a new diagnosis of hypertension between 1980 and 1992, during 711,039 person-years of follow-up. Compared with those without a history of nephrolithiasis, the age-adjusted relative risk (RR) for incident hypertension in women with such a history was 1.36 (95% confidence interval [CI], 1.20 to 1.43). After further adjustment for body mass index (BMI) and the intake of calcium, sodium, potassium, magnesium, caffeine, and alcohol, the RR was only slightly attenuated (RR=1.24; 95% CI, 1.13 to 1.37). In contrast, the occurrence of incident nephrolithiasis during follow-up was similar in women with hypertension at baseline compared with women without (adjusted odds ratio [OR]=1.01; 95% CI, 0.85 to 1.20). These data are consistent with the results obtained in men and support the hypothesis that a history of nephrolithiasis is associated with an increased risk for subsequent hypertension. Dietary factors, such as the intake of calcium, sodium, and potassium, do not explain this association. Unidentified pathogenic mechanisms common to nephrolithiasis and hypertension may be responsible for the development of both disorders.