Biotinidase catalyzes debiotinylation of histones

Summary Background Posttranslational modifications of histones play important roles in processes such as regulation of gene expression and DNA repair. Recently, evidence has been provided that histones in human cells are modified by covalent attachment of biotin. Aim of the study To determine whether the reverse process (debiotinylation of histones) occurs in biological samples and whether debiotinylation is an enzyme-mediated process; and to characterize the enzyme that mediates debiotinylation of histones. Methods Plasma and lymphocytes from healthy adults and a biotinidase-deficient patient were used as sources of debiotinylating enzymes. Debiotinylation of histones by plasma and lymphocyte proteins was measured using a colorimetric 96-well plate assay. Results Histones were debiotinylated rapidly if incubated with human plasma or lysates of lymphocytes. The following observations are consistent with the hypothesis that debiotinylation is an enzyme-mediated process: (i) Hydrolysis was slower at 4 °C compared to 37 °C; (ii) debiotinylating activity was destroyed when biological samples were heated at 90 °C for 30 min preceding incubation with biotinylated histones; and (iii) rates of debiotinylation were pH dependent. Rates of histone debiotinylation were significantly decreased in biotinidase-deficient samples. Conclusion Debiotinylation of histones in human samples is an enzyme-mediated process that is at least partly catalyzed by biotinidase. Received: 27 September 2001, Accepted: 6 January 2002     

Evaluation and cost assessment of fluoroquinolones in community-acquired respiratory infections

Several new fluoroquinolones have been marketed since the late 1990s. Fluoroquinolones are an effective treatment for most community-acquired respiratory tract infections, including acute sinusitis, acute exacerbations of chronic bronchitis and community-acquired pneumonia. However, other antibiotics, including beta-lactams, macrolides, tetracyclines and trimethoprim-sulfamethoxazole, are also effective against these respiratory infections. From a managed care perspective, it is the subtle differences between the drugs in the eradication of bacterial pathogens, adverse effects, dose regimens, compliance issues, bacterial resistance and cost that determine the best choice for the management of pneumonia, sinusitis or exacerbations of chronic bronchitis. The potential for bacterial resistance is perhaps the only significant barrier to extensive fluoroquinolone use in community-acquired respiratory tract infections. Cost-effectiveness must be balanced with quality care, both from an individual perspective and that of the greater society.     

The impact of acuity on performance of four clinical measures of contrast sensitivity in Alzheimer's disease

Investigations of contrast sensitivity losses in Alzheimer's disease (AD) have yielded mixed findings, with some investigators reporting deficits and others not. Potential reasons for these discrepancies include differences between samples and assessments utilized and the failure of some investigators to account for acuity differences between groups. To investigate these issues, we administered four clinical contrast sensitivity assessments to the same group of AD patients and elderly control participants and examined the impact of acuity on performance for each assessment. Results revealed group differences across the spatial frequency range. Further, group acuity differences significantly affected performance on two of the four measures (the Regan and the Vistech but not on the Pelli-Robson or Freiburg assessments). Information regarding the availability of established age norms, test-retest reliability data, and other factors including the time, cost, and training needed to administer each measure is provided to aid clinicians and researchers in their search for an effective measure of contrast sensitivity.     

La Crosse encephalitis in Eastern Tennessee: clinical,environmental, and entomological characteristics from a blinded cohort study

A blinded cohort study was conducted in 2000 to better understand the emergence of La Crosse virus infection in eastern Tennessee, with special emphasis on the potential mosquito vector(s). Children with suspected central nervous system infection were enrolled at the time of clinical presentation at a large pediatric referral hospital. Clinical, environmental, and entomological data were collected prior to case confirmation. Sixteen of the 40 children included in the final analysis were confirmed to have La Crosse infection by a fourfold increase in antibody titers between collection of acute- and convalescent-phase sera. Factors significantly associated with La Crosse infection included average number of hours per day spent outdoors (5.9 for La Crosse virus cases vs. 4.0 for noncases, p = 0.049); living in a residence with one or more tree holes within 100 m (relative risk = 3.96 vs. no tree holes within 100 m, p = 0.028); and total burden of Aedes albopictus (number of female and male larvae and adults collected at a site), which was more than three times greater around the residences of La Crosse virus cases versus noncases (p = 0.013). Evidence is accumulating that the newly introduced mosquito species Ae. albopictus may be involved in the emergence of La Crosse virus infection in eastern Tennessee.     

The intensity of transmission of hepatitis A and heterogeneities in socio-environmental risk factors in Rio de Janeiro,Brazil

The objective of this work was to assess the intensity of transmission of hepatitis A in Rio de Janeiro, Brazil. We also used the estimation of the parameters of a deterministic model to study the effects of risk factors. Age-specific seroprevalence of antibodies against hepatitis A virus (HAV) was obtained from a survey screening in a city of the metropolitan area of Rio de Janeiro, in 1997. From the seroprevalence data, we estimated the age-dependent force of infection (lambda) and the average age of first infection (A), using a deterministic model. To evaluate the influence of the environmental risk factors, we estimated the same parameters stratifying the sample for the selected socio-environmental risk factors: the number of years of schooling of the female responsible for the house, crowding within the bedroom, number of water taps and fittings, and the presence of sewage in front of the house. For the whole sample, the maximum force of infection estimated was 0.12/year and the average age of infection was 10.1 years. This last parameter decreased as the number of persons per bedroom increased, and also when the number of water taps and the number of years of schooling of the woman responsible for the house decreased. The proposed environmental interventions may lead to a decrease in the intensity of transmission of HAV and an increase in the average age of first infection in the next few years. This may have public health implications, since hepatitis A is more severe in adults. In this context, specific vaccination programmes may be necessary, as in developed countries.     

Telomere dysfunction provokes regional amplification and deletion in cancer genomes

Telomere dysfunction and associated fusion-breakage in the mouse encourages epithelial carcinogenesis and a more humanized genomic profile that includes nonreciprocal translocations (NRTs). Here, array comparative genomic hybridization was used to determine the pathogenic significance of NRTs and to determine whether telomere dysfunction also drives amplifications and deletions of cancer-relevant loci. Compared to tumors arising in mice with intact telomeres, tumors with telomere dysfunction possessed higher levels of genomic instability and showed numerous amplifications and deletions in regions syntenic to human cancer hotspots. These observations suggest that telomere-based crisis provides a mechanism of chromosomal instability, including regional amplifications and deletions, that drives carcinogenesis. This model provides a platform for discovery of genes responsible for the major cancers affecting aged humans.     

Proviral insertion indicates a dominant oncogenic role for Runx1/AML-1 in T-cell lymphoma

The RUNX1/AML1 gene is a frequent target for chromosomal translocations in human leukemia. The biological properties of the resulting fusion products and the finding that haploinsufficiency increases the risk of developing leukemia (W-J. Song et al., Nat. Genet., 23: 166-175, 1999; M. Osata et al., Blood, 93: 1817-1824, 1999) have led to the widely held view that RUNX1 loss-of-function is a key event. However, we now report that the gene is a target for insertional mutagenesis in T-cell lymphomas of mice carrying a MYC oncogene, where promoter insertion results in overexpression without affecting the integrity of the coding sequence. Moreover, Runx1 haploinsufficiency does not accelerate lymphoma development in MYC/Runx2 transgenic or murine leukemia virus-infected mice. These findings reveal that the Runx1 gene can also act as a dominant oncogene and suggest that the involvement of the Runx gene family in human leukemia may be more widespread and complex than previously realized.     

Vascular endothelial growth factor promotes breast carcinoma invasion in an autocrine manner by regulating the chemokine receptor CXCR4

We report that vascular endothelial growth factor (VEGF), a major angiogenic factor, is also arequisite autocrine factor for breast carcinoma invasion in vitro and that the VEGF receptor Neuropilin-1 but not Flt-1 is essential for this function. VEGF regulates expression of the chemokine receptor CXCR4, and this VEGF target is needed for invasion but not for cell survival. CXCR4 mediates migration of breast carcinoma cells toward stromal-derived factor-1, and this migration is dependent on autocrine VEGF. Of interest, a CXCR4-inhibitory peptide that is currently in HIV clinical trials suppressed invasion. Our findings indicate that a VEGF autocrine pathway induces chemokine receptor expression in breast carcinoma cells, thus promoting their directed migration toward specific chemokines.