Biomedical subjects
Publications and source records attributed to A Anderson.
Job satisfaction of the nursing staff at a 1,000-bed neuropsychiatric veterans administration (VA) facility was assessed, with results similar to those of other studies. The greatest source of stress was nurse/supervisor and nurse/physician interpersonal conflict. This article reports on a further study of this factor.
Cytochrome P450 2B1, encoded by CYP2B1, and cytochrome P450 2B2, encoded by CYP2B2, are inducible in rat liver by phenobarbital (PB). We have used cultured adult rat hepatocytes to study molecular mechanisms regulating CYP2B1/CYP2B2 transcription. Northern blot analysis demonstrated that the endogenous CYP2B1/CYP2B2 genes were inducible by PB in such cultures. A PB-responsive element (PBRE) conferring PB inducibility on a reporter gene was identified in the CYP2B2 5'-flanking region. The PBRE was localized to a 163-bp Sau3AI fragment situated between 2155 and 2318 bp upstream from the CYP2B2 transcription start point (tsp). The PBRE also conferred PB responsiveness on an enhancerless heterologous promoter and was active in both orientations both upstream and downstream from the heterologous promoter; hence, it has the properties of a transcriptional enhancer. Gel-retardation assays showed that nuclear extracts of liver cells of untreated and PB-treated rats contained sequence-specific DNA-binding factors that interact with a PBRE-containing DNA fragment. These results may open the way to identifying one or more transcription factors mediating induction of CYP2B2 and CYP2B1 in rat liver.
Sheep infected with maedi visna virus were tested for immune reactivity to recombinant HSP65 and tuberculin PPD from mycobacteria. The results showed that both naturally and experimentally infected animals had elevated IgM but not IgG or IgA antibodies to HSP65 from Mycobacterium leprae or M. bovis. In experimentally infected animals, the elevated IgM antibodies appeared in blood from about 3 to 4 weeks postinfection. Increased T cell proliferative responses to HSP65 and PPD were also found in both naturally and experimentally infected sheep. The T cell responses to HSP65 were substantially inhibited by antibodies to ovine major histocompatibility complex class II molecules, indicating that the responses were class II restricted. Increased expression of a putative HSP65 molecule was observed in synovial membranes from sheep infected with maedi visna virus and goats infected with the related, caprine arthritis encephalitis virus. The results thus show that lentivirus infection induces T and B cell anti-HSP65 immune responses and suggest that synovial inflammation may be due, at least in part, to T and B cell recognition of HSP65-like molecules expressed in joints.
Synovial membranes and cartilage slices from sheep infected with the maedi-visna retrovirus were examined for immunoglobulin deposits by immunohistology. Granular deposits of IgM and IgG were observed in the synovial membranes and upper layers of cartilage from about 40% of virus-infected sheep. These deposits were present in animals with subclinical joint disease, as well as those affected clinically. No significant deposits were found in the synovial membrane or cartilage from normal sheep. Infected animals tended to have reduced cartilage proteoglycan staining. Altered expression of MHC class II, CD1 and adhesion molecules by chondrocytes in cartilage from infected sheep with clinical or subclinical synovitis was observed suggesting that in vivo cell activation is an early event in cartilage degradation in these infections. Exogenously derived antiviral antibodies exhibited molecular mimicry towards chondrocyte antigens, but no in vivo evidence for cross-reactivity was observed. The results showed that IgM and IgG deposits, putatively containing either virus/antivirus immune complexes or autoantibodies were formed in the joints of sheep with clinical or subclinical synovitis. These immune deposits may initiate and perpetuate chronic inflammation with concomitant activation of chondrocytes leading to pannus formation and cartilage destruction.
We used a microdialysis technique to monitor extracellular methotrexate (MTX) levels during the steady state in a rodent model. Microdialysis probes were implanted in the muscle, liver, and kidney of anesthetized male Wistar rats. MTX (18.75-500 mg/kg) was given as a continuous infusion through a venous catheter, and blood samples were obtained through a second venous catheter. Heparinized plasma, ultrafiltered plasma, microdialysis effluent from tissues, and tissue samples (obtained at the end of experiments) were analyzed for MTX content by high-performance liquid chromatography (HPLC). Steady state was demonstrated in the blood and tissues from 2 h until the end of the experiments (6 h). Extracellular drug levels in muscle and liver displayed a linear correlation with doses, whereas kidney levels reached a plateau at an MTX dose of 150 mg/kg per 6 h. Microdialysis-fluid endpoint levels for muscle, liver, and kidney were positively correlated to the endpoint total tissue levels (r2 = 0.80, 0.85, and 0.68, respectively). In the kidneys, the maximal relative tissue MTX accumulation was measured at a total dose of 75 mg/kg per 6 h. At higher doses, the relative drug sequestration declined to less than half of the values observed at this dose. This study demonstrates that the microdialysis technique can provide reproducible data on MTX tissue exposure in an animal model and that it offers a means of serial and reproducible monitoring of extracellular-tissue MTX levels at steady state and over a wide dose range. Pending additional studies, microdialysis may be a helpful technique for elucidating the kinetics of drug delivery to both targeted and toxicity-prone tissues during chemotherapy.
1. The study was undertaken in male patients aged 61-73 years with essential hypertension. 2. The patients had previously had their blood pressure controlled with the drug studied. 3. A randomized crossover study compared the effect of different drug doses on peak (3 h) and trough (24 h) blood pressure compared to placebo. 4. All drug doses used lowered blood pressure at peak response and the responses with different doses of angiotensin converting enzyme inhibitors were similar. The peak response to felodipine had some dose dependency. 5. Trough blood pressure was not different from placebo with enalapril, 5 and 10 mg, perindopril, 2 mg, felodipine, 2.5 mg but was different with enalapril, 20 and 40 mg, perindopril, 4 and 8 mg and felodipine, 5 and 10 mg. 6. Trough peak ratio was dose dependent, with the greatest dependency seen with enalapril which has the shortest half-life. 7. When low doses of enalapril (5 or 10 mg), perindopril (2 mg) or felodipine ER (2.5 mg) are used it is important to check blood pressure prior to the next dose to ensure that control is achieved and maintained.
This study examined whether a neurologic examination at 6 months of age is predictive of neurodevelopmental outcome at 12 months in very-low-birth-weight (VLBW) infants. A neurologic examination and the Bayley Scales of Infant Development were performed at 6 and 12 months with VLBW infants and full-term (FT) controls. VLBW infants were categorized based on early medical complications. High-risk (HR) infants had diagnoses of bronchopulmonary dysplasia, pulmonary immaturity, grade III or IV intraventricular hemorrhage, and/or periventricular leukomalacia. VLBW infants with other diagnoses were placed in the low-risk (LR) group. Total neurologic scores (NS) improved over time for all three groups but improved more for HR infants, who had more abnormal NS at both time points; NS at 6 months predicted neurologic and developmental scores at 12 months for all three groups, but the relation between 6- and 12-month outcomes was strongest for the HR infants. The neurologic examination may be helpful in assessing VLBW infants' need for referral to early childhood intervention programs.
Explore the source record for details and available documents.
Rat-liver microsomes were used to activate aflatoxin B1 for in vitro modification of the pS189 shuttle vector and the related signature vector pSP189, both of which carry the Escherichia coli supF gene as a mutational target. Plasmid degradation was minimized by carrying out the in vitro incubations in the absence of Mg2+ ions. Modified plasmids were transfected into human Ad293 cells, then recovered and electroporated into E. coli MBM7070 for mutant identification. Point mutation frequencies for in vitro modified plasmids were dramatically increased over the spontaneous background level. Mutant plasmids were characterized by DNA-sequence analysis. The vast majority of aflatoxin B1-induced mutations were base substitutions, mostly G:C to T:A transversions. The spectrum of aflatoxin B1-induced mutations in the pS189 supF gene was very similar to that observed previously for the pS189 supF gene with aflatoxin B1 activated by cytochrome P450 1A2 (CYP1A2) synthesized from a cDNA expression vector within transfected Ad293 cells. However, the spectrum for pSP189, which carries the same supF gene as pS189, but with different surrounding sequences, exhibited some notable differences from that of pS189; this suggests that sequence context effects on mutagenic specificity can operate over distances of tens of base pairs.
A recent official report on the Scottish Diet reviews evidence for poor health and poor diets among the Scots, and makes extensive and specific recommendations about dietary change. This paper examines the extent to which reported consumption of fifteen of the food groups discussed in that report vary among four neighbourhoods in Glasgow City. Some foods appear to be typical of a wider Glaswegian (or Scottish) diet and show little variation among neighbourhoods (e.g. semi-skimmed milk, white fish, confectionery, cakes and pastries, savoury snacks). Other foods however show marked differences between neighbourhoods after controlling for sex, age and social class; these include fruit, vegetables, meat (particularly processed meat products), bread, spreading fats, sugar, natural fruit juice and alcohol. This suggests that such intraurban variations in food consumption cannot be explained simply by socio-demographic or socio-economic factors in individuals and that cultural and supply factors also need to be taken into account.
The cytochrome P450 2B subfamily in the rat contains an estimated eight to eleven members at the genomic level. Synthesis in the liver of the prototypic forms P450 2B1 and P450 2B2 is dramatically induced by phenobarbital. The 1.9-kb mRNA for P450 2B3, a third member of the P450 2B subfamily, is constitutively present in rat liver but is not inducible by phenobarbital. We have now cloned and sequenced exonic sequences corresponding to the entire 2B3 mRNA and determined their exon-intron structure, which is identical to that of CYP2B1/CYP2B2 and other CYP2B genes. A putative CYP2B3 transcription start site was identified and CYP2B3 5'- and 3'-flanking sequences were compared to those of CYP2B1 and CYP2B2. CYP2B3, like CYP2B1 and CYP2B2, has a modified TATA box preceding the transcription start site and lacks the canonical polyadenylation signal preceding the poly(A) site. A 2B3 expression vector, pMT2-2B3, directed the synthesis in COS-1 cells of an approximately 50-kD protein detectable on Western blots with a polyclonal antibody and with one of four monoclonal antibodies raised against 2B1 but not with a polyclonal antibody raised against P450 PB6. The 2B3 protein migrated with a slightly higher electrophoretic mobility than 2B1 and comigrated with a protein detected by anti-2B1 antibodies in liver microsomes from untreated rats. The results indicate that a 2B3-like protein is present in rat liver and that it is distinct from P450 PB6 and other known constitutive rat hepatic P450s.
Ten patients who had their blood pressure controlled with enalapril (10 mg, n = 4; 20 mg, n = 6) and 10 control subjects on perindopril (4 mg, n = 6; 8 mg, n = 4) entered a double-blind crossover study. They received placebo or the active drug 1 week apart and had their blood pressure measured at 0, 2, 3, 4, and 24 h. Then they crossed over to the other angiotensin-converting enzyme inhibitors (4 mg perindopril congruent to 10 mg enalapril) and the double-blind study was repeated. Blood pressure control 2 to 4 h after drug administration was similar with both drugs (perindopril = 150 +/- 2/80 +/- 1; enalapril = 150 +/- 2/81 +/- 1). Twenty-four h after administration of perindopril blood pressure was lower than on enalapril (perindopril = 154 +/- 3/85 +/- 2; enalapril = 159 +/- 3/89 +/- 2). Enalapril, 2 to 4 h after administration, caused a greater decrease than placebo, whereas the change with perindopril did not differ from placebo. Twenty-four hours after receiving the active drug the blood pressure of subjects on perindopril did not differ from the peak effect when corrected for placebo and circadian variation, whereas the blood pressure on enalapril was higher. This study indicates that perindopril in the doses used has a longer duration of action than enalapril and is more suited to once daily use.
The kidney and hypertension are critically linked. They appear to be linked particularly by the renin angiotensin system and the control of sodium balance. There are other mechanisms by which the kidney controls hypertension, but there are not as important as the above. In people with intrinsic renal disease hypertension increases the rate of deterioration and such hypertension should be treated energetically to prevent this deterioration. Long-standing chronic mild impairment of renal function leads to hypertension and vascular disease. This hypertension and vascular disease causes further deterioration of renal function, setting up a vicious cycle and an irreversible process unless measures are taken to interrupt the cycle.
OBJECTIVE: To examine socio-demographic correlates of dietary habits at 15 and 18 years. DESIGN: First and second sweeps of a longitudinal survey, based on a two-stage stratified clustered random sample. SETTING: Central Clydeside Conurbation, in the West of Scotland. SUBJECTS: A random sample of 1682 households containing 15-year-olds was approached by Strathclyde Regional Council, 70% of whom agreed to have their names passed on to the MRC. 1009 (86%) of this target sample were interviewed at baseline. 908 (90%) were re-interviewed at age 18. Analyses are restricted to respondents who took part in both data collection sweeps. MEASURES: Questions on meal patterns and food choices were included in the interviews: self-complete questionnaires included a dietary inventory. Social class was measured by reference to the head of household at baseline: information on own labour market position and place of residence was obtained at 18. RESULTS: At 18 there was clear differentiation in food choices and meal patterns according to sex and both parental social class and own current labour market position. Controlling for class, dietary habits at 15 were independently related to future labour market position. Overall changes in eating habits between 15 and 18 were slight, though females were more likely to have increased consumption of foods consistent with current recommendations, while the un/non-employed reduced their consumption of a midday meal. CONCLUSIONS: Dietary habits are established in mid-teens and closely associated with lifestyle, facts which need to be taken into consideration in designing effective nutrition education programmes.
Explore the source record for details and available documents.
We have established a non-human primate model of experimental ocular histoplasmosis. This model has been shown to result in chronic lesions that resemble typical 'histo spots' or choroidal scars but that contain infiltrates of lymphocytes for as long as 10 yr following intracarotid injection of live Histoplasma capsulatum. Using this model, we attempted to reactive these late choroidal lesions via intracarotid challenge with specific antigen (heat-killed H. capsulatum). No clinical changes suggestive of reactivation of these lesions were observed following this antigenic challenge. However, immunopathologic analysis of choroidal lesions at 1, 3 and 7 days after antigenic challenge revealed significant increases in both the numbers of inflammatory cells and the relative percentages of the helper/inducer lymphocyte and macrophage populations. Our results demonstrate that, following antigenic challenge, a cellular change, consistent with a type IV delayed hypersensitivity, can be observed in previously active, but clinically quiescent, histoplasmosis lesions. In light of the many parallels between our primate experimental model and human ocular histoplasmosis, our findings suggest that, in the human, significant immunopathologic activity may occur subclinically in the choroid of affected individuals. It is possible that repeated bouts of subclinical reactivation may induce or enhance chronic choroiditis and, over many years, ultimately produce slow progressive damage to the Bruch's membrane/retinal pigment epithelium complex, resulting in clinically 'active' macular disease and, in selected cases, subretinal neovascularization.
DNA samples from 60 Mapuche Indians, representing 39 maternal lineages, were genetically characterized for (1) nucleotide sequences of the mtDNA control region; (2) presence or absence of a nine base duplication in mtDNA region V; (3) HLA loci DRB1 and DQA1; (4) variation at three nuclear genes with short tandem repeats; and (5) variation at the polymorphic marker D2S44. The genetic profile of the Mapuche population was compared to other Amerinds and to worldwide populations. Two highly polymorphic portions of the mtDNA control region, comprising 650 nucleotides, were amplified by the polymerase chain reaction (PCR) and directly sequenced. The 39 maternal lineages were defined by two or three generation families identified by the Mapuches. These 39 lineages included 19 different mtDNA sequences that could be grouped into four classes. The same classes of sequences appear in other Amerinds from North, Central, and South American populations separated by thousands of miles, suggesting that the origin of the mtDNA patterns predates the migration to the Americas. The mtDNA sequence similarity between Amerind populations suggests that the migration throughout the Americas occurred rapidly relative to the mtDNA mutation rate. HLA DRB1 alleles 1602 and 1402 were frequent among the Mapuches. These alleles also occur at high frequency among other Amerinds in North and South America, but not among Spanish, Chinese or African-American populations. The high frequency of these alleles throughout the Americas, and their specificity to the Americas, supports the hypothesis that Mapuches and other Amerind groups are closely related.(ABSTRACT TRUNCATED AT 250 WORDS)
In all species where it has been tested, the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) has been shown to be a potent carcinogen, and NNK and other nitrosamines may play a role in human tobacco-related carcinogenesis. Purified rat CYP2B1 has been shown to metabolize NNK, and the CYP2B1 gene is expressed constitutively in rat lung. The objectives of this study were to test the capacity of CYP2B1, synthesized from a rat hepatic cDNA in Ad293 cells, to metabolize NNK, and to define the type and the proportions of the final metabolites produced. Ad293 cells were transfected with a CYP2B1 expression vector (pMT2-2B1), or with a control vector and incubated in culture medium containing [3H]NNK, after which alpha-carbon hydroxylation and pyridine N-oxidation metabolites were identified by HPLC analysis and quantitated by scintillation counting. pMT2-2B1-transfected cells were capable of catalyzing alpha-carbon hydroxylation and pyridine N-oxidation of NNK, although the reduction product 4-(methylnitrosamino)-1-(3-pyridyl)-1-butan-1-ol(NNAL) was the major metabolite formed in cells regardless of transfection treatment. The total amount of alpha-carbon hydroxylation metabolites produced by pMT2-2B1-transfected cells was greater than that of pyridine N-oxidation metabolites. However, pMT2-2B1 transfected cells produced approximately ten-fold more pyridine N-oxidation metabolites and only two-fold more alpha-carbon hydroxylation metabolites than control cells. Furthermore, the amount of NNAL-N-oxide was much lower than that of NNK-N-oxide in the medium of pMT2-2B1-transfected cells, even though the amount of available NNAL, resulting from carbonyl reduction of NNK, was very high; this suggests that NNAL is poorly N-oxidized by CYP2B1 compared to NNK. These results show that within living cells NNK was metabolized by CYP2B1 via both the pyridine N-oxidation and alpha-carbon hydroxylation pathways. However, CYP2B1 preferentially catalyzed pyridine N-oxidation, which is considered to be a deactivation reaction.