Treatment history and baseline viral load, but not viral tropism or CCR-5 genotype, influence prolonged antiviral efficacy of highly active antiretroviral treatment

BACKGROUND: The efficacy of highly active antiretroviral treatment (HAART) in HIV-1 disease may vary between nucleoside-naive and experienced patients as well as between patients with different viral phenotypes and in different stages of disease. OBJECTIVE: To investigate variables of importance for successful long-term viral suppression by analysing virological, clinical and immunological characteristics at initiation of protease inhibitor treatment on suppression of HIV RNA over 1 year. DESIGN: An open, non-randomized, observational clinical study. SETTING: Venh?lsan, Department of Dermatovenereology, S?der Hospital, Stockholm, Sweden. PATIENTS: A total of 147 unselected advanced patients with known HIV-1 infection for a mean of 7 years, of whom 37% had AIDS and who started treatment with a protease inhibitor during 1996. INTERVENTIONS: All patients received HAART with at least two nucleoside analogues in combination with either indinavir (81%) or ritonavir (19%). The majority (77%) had been previously treated with nucleoside analogues for a mean of 39 months. MEASUREMENTS: CD4+ lymphocyte count, plasma HIV-1 RNA, viral phenotype and HIV-1 coreceptor CCR-5 genotype at baseline. Viral load and CD4+ lymphocyte count were determined every 3 months. RESULTS: Patients were analysed on an intention-to-treat basis. The mean CD4+ lymphocyte count at baseline was 170 x 10(6)/l and the median viral load was 68 600 copies/ml. Heterozygosity for the delta32 deletion of the CCR-5 gene (delta32/wt) was found in 27%. MT-2 positive virus (syncytium-inducing) was isolated in 46%. Logistic regression revealed that nucleoside analogue experience and baseline log10 HIV-1 RNA were the only factors independently related to plasma HIV-1 RNA levels below 500 copies/ml after 1 year of treatment, which was found in 69%. CONCLUSION: The virological outcome after 1 year of HAART was strongly correlated to prior treatment history and baseline viral load, whereas CD4+ lymphocyte count, CCR-5 genotype and viral biological phenotype had less influence. The long-term antiviral efficacy of HAART was lowest in individuals with previous nucleoside analogue treatment and a high baseline viral load. In these individuals an even more aggressive treatment should be considered.     

Detection of point mutations by solid-phase methods

Several techniques exist that permit the efficient distinction among characterized DNA sequence variants. In this review we discuss a number of such analytic procedures. These techniques all take advantage of a variety solid supports to prepare and analyze reaction products. The described diagnostic principles are now being applied for the development of miniaturized assay formats, suitable for automated detection of large sets of sequences in clinical samples.     

Soluble tumour necrosis factor receptor release after anti-CD3 monoclonal antibody treatment in mice is independent of tumour necrosis factor-alpha release

The involvement of TNF-alpha in the release of soluble TNF receptors was assessed in mice, treated with anti-CD3 monoclonal antibodies. After treatment with three different anti-CD3 mAb, we simultaneously studied serum levels of TNF-alpha, soluble TNF receptor P55 and P75. All three anti-CD3 mAb triggered the release of both of the soluble TNF receptors, whereas only one of the anti-CD3 mAb triggered TNF-alpha release. These data demonstrate that in our model soluble TNF receptor release is independent of TNF-alpha release.     

Neurobehavioral effects from exposure to dental amalgam Hg(o): new distinctions between recent exposure and Hg body burden

Potential toxicity from exposure to mercury vapor (Hg(o)) from dental amalgam fillings is the subject of current public health debate in many countries. We evaluated potential central nervous system (CNS) toxicity associated with handling Hg-containing amalgam materials among dental personnel with very low levels of Hg(o) exposure (i.e., urinary Hg <4 microg/l), applying a neurobehavioral test battery to evaluate CNS functions in relation to both recent exposure and Hg body burden. New distinctions between subtle preclinical effects on symptoms, mood, motor function, and cognition were found associated with Hg body burden as compared with those associated with recent exposure. The pattern of results, comparable to findings previously reported among subjects with urinary Hg >50 microg/l, presents convincing new evidence of adverse behavioral effects associated with low Hg(o) exposures within the range of that received by the general population.     

Craf-1 protein kinase is essential for mouse development

The complete cDNA of the mouse integral membrane protein 2B gene (Itm2b) was determined by sequence analysis of expressed sequence tag (EST) clone L26775 and a clone isolated from a cDNA library of the osteogenic stromal cell line MN7 (Mathieu et al., 1992. Calcif. Tissue Int. 50, 362-371) and by 5' rapid amplification of cDNA ends (RACE). Alignment of different mouse ESTs confirmed the entire sequence. Northern blot analysis of different neonatal and adult mouse tissues showed that Itm2b is ubiquitously expressed. There are three mRNAs with different lengths in neonatal as well as in adult tissues, originating from alternative polyadenylation by usage of one consensus and two additional variant polyadenylation signals. The cDNA sequence of the human Itm2b homolog (ITM2B) was assembled using data from available human ESTs. Both the mouse and the human gene code for a protein of 266 amino acids (aa) that is homologous to a previously described integral membrane protein, Itm2A, of which the expression is restricted to osteo- and chondrogenic tissues. Itm2A and Itm2B belong to a family of type II integral membrane proteins, which contains a third member, Itm2C (Deleersnijder et al., 1996. J. Biol. Chem. 271, 19475-19482). The human ITM2B and mouse Itm2b genes were previously mapped as unknown ESTs to conserved syntenic regions Homo sapiens 13q12-13 and Mus musculus 14.     

Overtraining and glycogen depletion hypothesis

Low muscle glycogen levels due to consecutive days of extensive exercise have been shown to cause fatigue and thus decrements in performance. Low muscle glycogen levels could also lead to oxidation of the branched chain amino acids and central fatigue. Therefore, the questions become, can low muscle glycogen not only lead to peripheral and central fatigue but also to overtraining, and if so can overtraining be avoided by consuming sufficient quantities of carbohydrates? Research on swimmers has shown that those who were nonresponsive to an increase in their training load had low levels of muscle glycogen and consumed insufficient energy and carbohydrates. However, cyclists who increased their training load for 2 wk but also increased carbohydrate intake to maintain muscle glycogen levels still met the criteria of over-reaching (short-term overtraining) and might have met the criteria for overtraining had the subjects been followed for a longer period of time. Thus, some other mechanism than reduced muscle glycogen levels must be responsible for the development and occurrence of overtraining.     

Neurophysiologic study of beta-thalassemia patients

Neurophysiologic investigations were performed in 34 Chinese patients with beta-thalassemia major maintained on long-term desferrioxamine treatment to look for subclinical toxicity in the auditory, visual, peripheral, or central neural pathways. In the auditory pathway study, four patients (12%) had mild sensorineural hearing impairment. Two patients (6%) had increased P 100 latencies in the visual evoked potential study, and nine patients (26%) had abnormal electroretinogram results. All had normal electrooculograms. Ophthalmoscopic examination was abnormal in three patients (9%), and three (9%) had a visual field defect. In the peripheral or central nervous pathways, seven patients (21%) had sensory neuropathy, of which three cases were probably related to diabetes mellitus. All had normal motor conduction velocities. Four patients (12%) had increased cortical latencies of median or posterior tibial somatosensory evoked potential. Abnormalities in multiple neural pathways were seen in four patients (12%). There was a significant association between subclinical toxicity to the peripheral or central nervous systems and serum ferritin level (P < .03) and the presence of diabetes mellitus (P < .002). There was no significant relationship between the age, dosage, or duration of desferrioxamine used and the increased risk of neurotoxicity to the auditory, visual, peripheral, or central nervous systems. There was also no association between the risk of neurotoxicity and the serum zinc, copper, or fructosamine levels.