Biomedical subjects
D Black
Publications and source records attributed to D Black.
In pursuit of a dubious principle.
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Black looks ... at prevention and cure.
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Change in the NHS.
This paper tries to set the current changes in the British National Health Service in historical perspective. The NHS was born in 1948 amid controversy, both political and professional; but in the 50s and 60s a consensus was reached which won it the support of patients and doctors. But in the 70s and 80s it has undergone the stress of successive reorganizations, in the attempt to meet the economic strains imposed by an ageing population and expensive medical advances. The present changes aim to bring about an "internal market," regulated by contract between "purchases" and "providers." Reasons are given for the view that this artificial arrangement will impair the coherence of the NHS, will add administrative expense and complexity, and will impair the important role of general practitioners as "gate-keepers."
Allele loss on chromosome 17q in sporadic ovarian cancer.
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Evidence that thymocyte-activating molecule is mouse CD26 (dipeptidyl peptidase IV).
We previously described a developmentally regulated, Mr 115,000 (reduced) and 110,000/128,000 (nonreduced) mouse T cell-activating molecule (THAM) also expressed on a variety of epithelial cell surfaces, and associated with neutral exoaminopeptidase activity. In the present study, we show that THAM is the mouse counterpart of the human T cell-activating ectoenzyme CD26 (dipeptidyl peptidase IV, DPP IV) and that highly purified THAM lacks neutral exoaminopeptidase activity. This conclusion is based on the following: 1) the N-terminal segments of the THAM Mr 110,000 and 128,000 components shared the same amino acid sequence with the rat DPP IV. These N-termini comprised a short intracytoplasmic tail of six residues followed by a downstream hydrophobic transmembrane segment. 2) THAM-specific mAb H194-112-Affi-Gel immunoadsorbent was capable of removing DPP IV enzymatic activity from mouse thymoma cell detergent extracts. 3) H194-112 reactivity pattern on developing thymocytes was found to parallel that previously reported for membrane-bound DPP IV enzymatic activity. The extent of THAM N-glycosylation, as measured by N-glycanase treatment of H194-112 immunoprecipitates, was found to be similar to that of human and rat DPP IV (i.e., approximately 20 kDa). Cross-linking experiments indicated that THAM was expressed at the cell surface as a dimer of approximately 220 kDa. Its two subunits were found to be structurally related but not identical as shown by their different Mr under nonreducing conditions and by their slightly distinct peptide profiles after proteolytic cleavage. We conclude from these data that DPP IV, in addition to its extracellular matrix receptor and ectoenzymatic functions, is a T cell-activating structure in both human and mouse species.
Psychotropic drugs for problem children.
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Purification and characterization of a brain-specific protein kinase C substrate, neurogranin (p17). Identification of a consensus amino acid sequence between neurogranin and neuromodulin (GAP43) that corresponds to the protein kinase C phosphorylation site and the calmodulin-binding domain.
Neurogranin, formerly designated p17 (Baudier, J., Bronner, C., Kligman, D., and Cole, R. D.) (1989) J. Biol. Chem. 264, 1824-1828), a brain-specific in vitro substrate for protein kinase C (PKC), has been purified to homogeneity from bovine forebrain. The purified protein has a molecular mass of 7837.1 +/- 0.5 Da, determined by electrospray mass spectrometry. In the absence of reducing agent, dimers and higher oligomers accumulated. On sodium dodecyl sulfate-polyacrylamide gels the protein monomer migrated abnormally with an apparent molecular mass of 15,000-19,000 Da, depending on the percentage of polyacrylamide. The native protein is blocked at its amino terminus. The majority of the primary amino acid sequence was determined following proteolytic and chemical fragmentation. A comparison of the amino acid sequence of neurogranin with that of the brain-specific PKC substrate neuromodulin, revealed a strikingly conserved amino acid sequence AA(X)KIQA-SFRGH(X)(X)RKK(X)K. The two proteins are not related over the rest of their sequences. Neurogranin was shown to be phosphorylated in hippocampal slices incubated with 32Pi and phorbol esters stimulated neurogranin phosphorylation, suggesting that neurogranin is likely to be an in vivo substrate for PKC. In vitro phosphorylation of neurogranin by PKC produced a shift of the isoelectric point of the protein (pI 5.6) to a more acidic value (pI 5.4). Tryptic digestion of the phosphorylated protein yielded a single phosphopeptide having the sequence IQASFR, where the serine residue is the phosphorylated amino acid. This phosphopeptide is part of the conserved sequence shared with neuromodulin and also corresponds to the PKC phosphorylation site on neuromodulin (Apel, E. D., Byford, M. F., Au, D., Walsh, K. A., and Storm, D. R. (1990) Biochemistry 29, 2330-2335). Evidence was obtained suggesting that neurogranin binds to calmodulin in the absence of Ca2+, a feature that also characterizes neuromodulin. We propose that the amino acid sequence shared by neurogranin and neuromodulin reflects a functional relationship between these two proteins and that the consensus sequence represents a conserved PKC phosphorylation site and a calmodulin binding domain that characterizes a class of brain-specific PKC substrates.
Applications of PRPP metabolism in human erythrocytes.
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The simian herpesvirus SA8 homologue of the herpes simplex virus gB gene: mapping, sequencing, and comparison to the HSV gB.
The genomic location and DNA sequence of the simian herpesvirus SA8 gene encoding a homologue of the HSV1 gB glycoprotein was determined. Using a cloned gB gene of herpes simplex virus type 1 (HSV1) as probe in Southern blot hybridizations, the SA8 gB gene was localized to a 10-kbp KpnI fragment mapping in the unique long part of the genome. A 2.8 kbp, 68.4% GC segment of this fragment was sequenced. It contained a 2649 nucleotide ORF possibly encoding a 98.4 kDa polypeptide. The predicted amino acid sequence of the SA8 gB polypeptide is 78.4% and 78.9% identical to the sequence of the HSV1 and HSV2 gBs, respectively, and was 88.4% similar or identical to both HSV gB sequences. Structural characteristics predicted for the SA8 gB polypeptide were very similar to those of HSV1 gB. These included a hydrophobic signal sequence of 29 amino acids, conservation of all 10 cysteine residues and 5 of 6 potential N-linked glycosylation sites present in the HSV1 gB, a triple hydrophobic transmembrane domain, and a highly charged cytoplasmic tail region. Both hierarchical cluster analysis and phylogenetic analysis of sequences for gB polypeptides of 12 different herpesviruses demonstrated that the gB glycoprotein of SA8 is most closely related to the HSV gB glycoproteins. Comparison of these closely related gB sequences identified four regions in which non-conservative amino acid substitutions were clustered. Localized regions of the gB polypeptide were identified which are likely to be associated with the conserved structure/function of the polypeptide.
Treatment of cytarabine acral erythema with corticosteroids.
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Human immunodeficiency virus and malaria in a representative sample of childbearing women in Kigali, Rwanda.
In 1986-1987 a consecutive sample of 3702 women presenting to prenatal and pediatric clinics at the only hospital in Kigali, Rwanda, was screened for human immunodeficiency virus (HIV) and malaria infection. The prevalence of HIV antibodies was 29%, and that of malaria parasites was 9%. HIV antibodies were more prevalent in women from the urban center than in those from the outskirts (31% vs. 20%, P less than .001), and malaria parasites showed the opposite prevalence pattern (8% vs. 15%, P less than .001); after stratifying by location, there was no association between HIV and the presence or degree of malaria parasitemia. HIV prevalence was 45% in women who had received a blood transfusion between 1980-1985 (before screening of donated blood began), and 28% among the great majority (94%) who had never been transfused. HIV prevalence was 44% in single mothers. 34% in women in common law unions, and 20% in those in legal marriages. These high rates of infection in the general population of Kigali highlight the need to develop effective programs for preventing further spread of sexually transmitted HIV.
The urinary excretion of the collagen degradation markers pyridinoline and deoxypyridinoline in an experimental rat model of alcoholic bone disease.
(1) The effect of chronic (6 weeks) ethanol feeding on whole-body skeletal tissue in the rat was studied by analysis of the urinary pyridinium crosslinks of collagen, pyridinoline (PYD; found predominantly in the collagens of cartilage and bone and to a lesser extent in other tissues) and deoxypyridinoline (DPD; found only in type I collagen of bone and dentine). (2) The urinary concentrations of total, free and conjugated PYD were unaltered by ethanol feeding. In contrast, there were significant reductions in total and conjugated DPD concentrations. The reduction in the concentration of free DPD did not achieve statistical significance. The urinary PYD/DPD molar ratios, of total and conjugated forms, were increased. (3) Alcohol feeding caused the total 24 hr urinary PYD excretion to fall slightly, by 15%. There were no statistically significant effects on excretion of free and conjugated forms of PYD, nor on the free/total, free/conjugated and conjugated/total molar ratios. In contrast, the 24 hr urinary excretion of total, free and conjugated DPD was significantly reduced by 25-55%. Furthermore, the free/total and free/conjugated molar ratios were significantly increased by 40% and 80%, respectively, and the conjugated/total molar ratio was significantly reduced by 16%. (4) Data from the analysis of plasma electrolytes, enzymes and metabolites did not support the contention that the effects on collagen degradation were a result of secondary organ dysfunction due to alcohol consumption. (5) The results suggest that chronic ethanol feeding for 6 weeks is having a primary effect on skeletal tissue. A reduction in the absolute rate of bone resorption is implicated and ethanol may inhibit the normal formation of the mature crosslinks.
Knowledge, attitudes, and perceived risk of AIDS among urban Rwandan women: relationship to HIV infection and behavior change.
We examined factors associated with perceived risk of AIDS, behavior change, and HIV infection in a representative sample of 1458 child-bearing urban women in Rwanda, central Africa. Although 68% of women reported only one lifetime partner, and the majority (87%) lived with a husband or steady partner, the prevalence of HIV antibodies was still high (32%). Before receiving their HIV test results, the women completed a questionnaire about AIDS knowledge, attitudes, and practices. Knowledge about HIV transmission was high, with 96-98% of women correctly identifying the three primary routes of infection. However, only 16% of women reported taking any action to avoid AIDS in the previous year, and most (11%) had done so merely by asking their male partners to change their behavior. Only 7% of women had ever tried condoms, and many (68%) thought they could be dangerous to use. Women who perceived themselves at risk of AIDS (57%) were more likely to report changing behavior; they were also more likely to be infected with HIV. Other factors associated with behavior change included having known someone with AIDS, having discussed AIDS with a male partner, and believing that condoms are not dangerous. Future interventions should enhance perception of risk, encourage male sexual partners to reduce risky behavior, and increase familiarity with condoms.
Evaluation of urinary hydroxypyridinium crosslink measurements as resorption markers in metabolic bone diseases.
Analyses of the urinary concentration relative to creatinine of the collagen crosslinks, pyridinoline (Pyd) and deoxy-pyridinoline (Dpd) were made in 47 patients with metabolic bone diseases to assess the validity of these assays as indicators of bone resorption. The mean values for patients with Paget's disease of bone, primary hyperparathyroidism and osteomalacia were significantly higher (P less than 0.001) than those for age-matched healthy individuals. During treatment of Paget's disease with bisphosphonates, there was a steady decline in the urinary concentration of the crosslinks to the normal range; this change occurred earlier than for serum alkaline phosphatase. There were significant correlations (P less than 0.01) between the concentrations of both crosslinks and the corresponding values for hydroxyproline. At lower crosslink concentrations, however, these relationships were less marked due to large variations in hydroxyproline values. The results show that measurements of urinary Pyd and Dpd provide clinically applicable indices of bone resorption that are more specific than other markers.