Cotrimoxazole prophylaxis reduces morbidity and mortality in HIV-1-infected children, but mechanisms for these benefits are unclear.
CHAP was a randomized trial comparing cotrimoxazole prophylaxis ...with placebo in HIV-infected children in Zambia where background bacterial resistance to cotrimoxazole is high. We compared causes of mortality and hospital admissions, and antibiotic use between randomized groups.
Of 534 children (median age, 4.4 years; 32% 1-2 years), 186 died and 166 had one or more hospital admissions not ending in death. Cotrimoxazole prophylaxis was associated with lower mortality, both outside hospital (P = 0.01) and following hospital admission (P = 0.005). The largest excess of hospital deaths in the placebo group was from respiratory infections 22/56 (39%) placebo versus 10/35 (29%) cotrimoxazole. By 2 years, the cumulative probability of dying in hospital from a serious bacterial infection (predominantly pneumonia) was 7% on cotrimoxazole and 12% on placebo (P = 0.08). There was a trend towards lower admission rates for serious bacterial infections in the cotrimoxazole group (19.1 per 100 child-years at risk versus 28.5 in the placebo group, P = 0.09). Despite less total follow-up due to higher mortality, more antibiotics (particularly penicillin) were prescribed in the placebo group in year one 6083 compared to 4972 days in the cotrimoxazole group (P = 0.05).
Cotrimoxazole prophylaxis appears to mainly reduce death and hospital admissions from respiratory infections, supported further by lower rates of antibiotic prescribing. As such infections occur at high CD4 cell counts and are common in Africa, the role of continuing cotrimoxazole prophylaxis after starting antiretroviral therapy requires investigation.
The genome of the flowering plant Arabidopsis thaliana has five
chromosomes. Here we report the sequence of the largest,
chromosome 1, in two contigs of around 14.2 and 14.6 megabases. The contigs
...extend from the telomeres to the centromeric borders, regions rich in transposons,
retrotransposons and repetitive elements such as the 180-base-pair repeat.
The chromosome represents 25% of the genome and contains about 6,850 open
reading frames, 236 transfer RNAs (tRNAs) and 12 small nuclear RNAs. There
are two clusters of tRNA genes at different places on the chromosome. One
consists of 27 tRNAPro genes and the other contains 27 tandem
repeats of tRNATyr-tRNATyr-tRNASergenes.
Chromosome 1 contains about 300 gene families with clustered duplications.
There are also many repeat elements, representing 8% of the sequence.
Herpesvirus replication involves the expression of over 80 viral genes in a well ordered sequence, leading to the production of new virions. Viral genes expressed during the earliest phases of ...replication often regulate both viral and cellular genes. Therefore, they have the potential to bring about dramatic functional changes within the cell. Replication and transcription activator (RTA) is a potent immediate early transcription activator of the g-herpesvirus family. This family includes Epstein-Barr virus and Kaposi sarcoma-associated herpesvirus, human pathogens associated with malignancy. Here we combine gene array technology with transcription factor profiling to identify the earliest DNA promoter and cellular transcription factor targets of RTA in the cellular genome. We find that expression of RTA leads to both activation and inhibition of distinct groups of cellular genes. The identity of the target genes suggests that RTA rapidly changes the cellular environment to counteract cell death pathways, support growth factor signaling, and also promote immune evasion of the infected cell. Transcription factor profiling of the target gene promoters highlighted distinct pathways involved in gene activation at specific time points. Most notable throughout was the high level of cAMP-response element-binding protein (CREB)-response elements in RTA target genes. We find that RTA can function as either an activator or an inhibitor of CREB-response genes, depending on the promoter context. The association with CREB also highlights a novel connection and coordination between viral and cellular 'immediate early' responses.
Degeneration of neurons in Alzheimer's disease is mediated by beta-amyloid peptide by diverse mechanisms, which include a putative apoptotic component stimulated by unidentified signaling events. ...This report describes a novel beta-amyloid peptide-binding protein (denoted BBP) containing a G protein-coupling module. BBP is one member of a family of three proteins containing this conserved structure. The BBP subtype bound human beta-amyloid peptide in vitro with high affinity and specificity. Expression of BBP in cell culture induced caspase-dependent vulnerability to beta-amyloid peptide toxicity. Expression of a signaling-deficient dominant negative BBP mutant suppressed sensitivity of human Ntera-2 neurons to beta-amyloid peptide mediated toxicity. These findings suggest that BBP is a target of neurotoxic beta-amyloid peptide and provide new insight into the molecular pathophysiology of Alzheimer's disease.
Degeneration of neurons in Alzheimer's disease is mediated by β-amyloid peptide by diverse mechanisms, which include a putative
apoptotic component stimulated by unidentified signaling events. This ...report describes a novel β-amyloid peptide-binding protein
(denoted BBP) containing a G protein-coupling module. BBP is one member of a family of three proteins containing this conserved
structure. The BBP subtype bound human β-amyloid peptide in vitro with high affinity and specificity. Expression of BBP in cell culture induced caspase-dependent vulnerability to β-amyloid
peptide toxicity. Expression of a signaling-deficient dominant negative BBP mutant suppressed sensitivity of human Ntera-2
neurons to β-amyloid peptide mediated toxicity. These findings suggest that BBP is a target of neurotoxic β-amyloid peptide
and provide new insight into the molecular pathophysiology of Alzheimer's disease.
Degeneration of neurons in Alzheimer's disease is mediated by μ-amyloid peptide by diverse mechanisms, which include a putative apoptotic component stimulated by unidentified signaling events. This ...report describes a novel μ-amyloid peptide-binding protein (denoted BBP) containing a G protein-coupling module. BBP is one member of a family of three proteins containing this conserved structure. The BBP subtype bound human μ-amyloid peptidein vitro with high affinity and specificity. Expression of BBP in cell culture induced caspase-dependent vulnerability to μ-amyloid peptide toxicity. Expression of a signaling-deficient dominant negative BBP mutant suppressed sensitivity of human Ntera-2 neurons to μ-amyloid peptide mediated toxicity. These findings suggest that BBP is a target of neurotoxic μ-amyloid peptide and provide new insight into the molecular pathophysiology of Alzheimer's disease.
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