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Biomedical subjects

J P Davis

Publications and source records attributed to J P Davis.

At least 19 recordsLinked to original sources
PubMed1997

APEASPFIRFamide, a novel FMRFamide-related decapeptide from Caenorhabditis elegans: structure and myoactivity.

To date, 9 FMRFamide-related peptides (FaRPs) have been identified in Caenorhabditis elegans. Eight of these peptides are encoded on the flp-1 gene. However, AF2 (KHEYLRFamide) which was not co-encoded was the most abundant FaRP identified in ethanolic extracts. Further radioimmunometrical screening of acidified ethanol extracts of C. elegans has revealed the presence of other novel FaRPs, which are not encoded on the flp-1 gene. One of these peptides has been isolated by sequential rpHPLC and subjected to Edman degradation analysis and gas-phase sequencing and the unequivocal primary structure of the decapeptide Ala-Pro-Glu-Ala-Ser-Pro-Phe-Ile-Arg-Phe-NH2 was determined following a single gas-phase sequencing run. The molecular mass of the peptide was found to be 1133.7 Da, determined using a time-of-flight mass spectrometer. Synthetic replicates of this peptide were found to induce a profound relaxation of both dorsal and ventral somatic muscle-strip preparations of Ascaris suum with a threshold for activity of 10 nM. The inhibitory response was not dependent on the presence of nerve cords, indicating a post-synaptic site-of-action. The relaxation was Ca(+2)- and Cl(-)-independent but was abolished in high-K+ medium and could be distinguished from those of other inhibitory nematode FaRPs, including PF1 (SDPNFLRFamide) and PF4 (KPNFIRFamide).

Amino Acid Sequence↗
PubMed1997

Endoglin gene polymorphism as a risk factor for sporadic intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) is a common and serious type of stroke. Recent studies have shown that inherited factors that affect the development of the vessel wall can increase the risk of ICH. We studied endoglin as a candidate gene in patients with sporadic ICH, since mutations in this gene can cause telangiectasia formation. One hundred three patients with sporadic ICH and 202 controls were studied. The polymerase chain reaction and single-strand conformational polymorphism analysis were used to screen for mutations in exon 7 of the endoglin gene. No coding mutations in exon 7 were identified in the ICH patients or controls. A 6-base intronic insertion was found 26 bases beyond the 3' end of exon 7. The homozygous form of the insertion was present in 9 of 103 (8.7%) ICH patients compared with 4 of 202 (2.0%) controls, p = 0.012 (odds ratio 4.8 [95% confidence interval, 1.28, 21.60]). Analysis of the endoglin transcript around the insertion did not reveal any changes in the RNA sequence. There were no obvious clinical features that distinguished the ICH patients with the homozygous insertion from the other patients. The pathophysiologic mechanism underlying this association remains to be determined.

Adult↗
PubMed1997

Impact of a massive waterborne cryptosporidiosis outbreak on child care facilities in metropolitan Milwaukee, Wisconsin.

OBJECTIVE: We describe the impact of the 1993 waterborne cryptosporidiosis outbreak on metropolitan Milwaukee child care homes and centers. METHODS: Information on outbreak-related illness and changes in policies and practices was collected from directors of 117 facilities. Stool specimens from 129 diapered children from 11 centers were screened for Cryptosporidium. RESULTS: Most (74%) facility directors reported children or staff with diarrhea during the outbreak; however, only 4 (3.4%) facilities closed because of illness among staff or children. During the outbreak child care homes were less likely to exclude children with diarrhea than were child care centers. Among diapered children attending centers the Cryptosporidium prevalence was 30%; 29% of infected children had no history of diarrhea associated with the Milwaukee outbreak. CONCLUSIONS: Facilities continued to operate during the outbreak despite considerable illness among children and staff. The news media were effective means for providing public health information to child care facilities. Although secondary transmission undoubtedly took place in child care facilities, the presence of children with asymptomatic Cryptosporidium infections did not result in an increased risk of diarrhea in infant and toddler rooms.

Adult↗
PubMed1997

Sodium-independent inward chloride pumping in rat cardiac ventricular cells.

The intracellular Cl concentration ([Cl]i) in rat cardiac ventricular muscle, measured with double-barreled microelectrodes in vitro, was 21.3 +/- 1.5 (SD) mM [number of observations (n) = 46]. With the Na-K-Cl cotransport inhibitor bumetanide (10 microM), it fell to 13.4 +/- 1.4 mM (n = 27), and with 1 mM acetazolamide, it fell further, to 7.2 +/- 1.5 mM (n = 5), close to equilibrium with the membrane potential. In the absence of Na, [Cl]i was 15.9 +/- 1.4 mM (n = 8), and with 1 mM acetazolamide, it fell to 6.5 +/- 0.6 mM (n = 4), again close to equilibrium. The bumetanide- and Na-insensitive components of inward Cl pumping were inhibited by chlorothiazide and ethacrynic acid but were unaffected by the Na-Cl cotransport inhibitor metolazone. There was inhibition of Na-K-Cl cotransport by chlorothiazide = acetazolamide > metolazone. The anion exchange inhibitor 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid and HCO3 had no effect on [Cl]i in any condition. Thus Cl accumulation in the rat ventricle is fully accounted for by two systems, namely, Na-K-Cl cotransport and an Na-independent, possibly primary active, process.

Acetazolamide↗
PubMed1997

Depression in adults with intellectual disability. Part 1: A review.

OBJECTIVE: To examine the available literature regarding prevalence, clinical features and treatment of depression in adults with intellectual disability (ID). METHOD: A review of standard texts of ID and available literature examining psychiatric problems of individuals with ID. RESULTS: Few methodologically sound studies of prevalence have been reported. The clinical features of depression in adults with ID appear to vary with level of disability; in those with higher levels of disability in particular, irritability and anger, self-injurious and aggressive behaviour, psychomotor change and loss of activities of daily living skills may be observed rather than "classic' depressive symptoms. No systematic treatment studies have been reported; case reports support the efficacy of cognitive and behavioural strategies, antidepressants and electroconvulsive therapy. CONCLUSIONS: Well designed studies to assess the prevalence and evaluate the treatment of depression in individuals with ID are urgently needed. Design of these studies will need to address the questions of reliability and validity of diagnosis in individuals with ID and examine the appropriateness of available diagnostic criteria.

Adult↗
PubMed1997

Depression in adults with intellectual disability. Part 2: A pilot study.

OBJECTIVES: To identify adults with intellectual disability (ID) with a depressive disorder referred to a tertiary consultation clinic for psychiatric assessment; to investigate common presenting features of depression in adults with ID; to assess the utility of visual analogue scale (VAS) measures of emotion/behaviour, the CORE measure of psychomotor disturbance, and substitutive diagnostic criteria in the assessment of depressive disorders in this patient group. METHOD: Over a 6-month period 47 patients were seen for psychiatric evaluation. Patients in whom a diagnosis of depression was made were further assessed using: VAS measures of depression, irritability, verbal aggression, physical aggression, temper outbursts, regressed behaviour; CORE measure of psychomotor disturbance; and substitutive diagnostic criteria designed by the authors. RESULTS: Ten patients were found to have a depressive disorder. Substitutive criteria resulted in a greater rate of diagnosis than standard DSM-IV criteria. The VAS measure of irritability was highly scored for all 10 depressed patients. All 10 depressed patients were assigned to the melancholic subgroup according to CORE score. CONCLUSIONS: Standard assessment measures and diagnostic criteria may require modification to enhance their utility in this patient group. Melancholic features require further investigation.

Adult↗
PubMed1996

Evidence against a contribution by Na(+)-Cl- cotransport to chloride accumulation in rat arterial smooth muscle.

1. Chloride accumulation into rat saphenous arterial smooth muscle has been examined using chloride-sensitive microelectrodes, to assess the contribution of Na(+)-Cl-cotransport. 2. Bumetanide (10 microM) produced a fall in intracellular chloride ([Cl-]i), and a hyperpolarization of membrane potential (Em). However, [Cl-]i remained above the equilibrium level predicted from the membrane potential, indicating a residual accumulation. 3. Replacement of extracellular sodium with N-methyl-D-glucamine or choline caused a fall in [Cl-]i similar to that observed with bumetanide, but the hyperpolarization of Em was larger. In Na(+)-free media, bumetanide had no effect. [Cl-]i remained significantly above equilibrium. 4. In the presence of bumetanide, chlorothiazide produced a further dose-dependent fall in [Cl-]i, and hyperpolarization of Em. However, although [Cl-]i fell more than with bumetanide alone, it remained significantly above equilibrium. Metolazone was without effect at 100 microM. 5. In the presence of bumetanide, ethacrynic acid and N-ethyl maleimide caused a dose-dependent hyperpolarization of Em and a fall in [Cl-]i to equilibrium. 6. The third inward chloride pump in rat saphenous arterial smooth muscle appears not to be a form of Na(+)-Cl- cotransport. The potency series of thiazide diuretic action (acetazolamide > chlorothiazide > metolazone) differed significantly from that published for Na(+)-Cl- cotransport, and there is no sodium dependence.

Animals↗
PubMed1996

The immunosuppressive metabolite of leflunomide is a potent inhibitor of human dihydroorotate dehydrogenase.

The active metabolite of leflunomide. A771726, is a novel immunosuppressive compound that has been shown to be a powerful antiproliferative agent for mononuclear and T-cells. The molecular mechanism of action for this compound has not been clearly established. In vitro cellular and enzymatic assays, however, demonstrate that leflunomide is an inhibitor of several protein tyrosine kinases, with IC50 values between 30 and 100 microM. The in vivo properties of A771726 are reminiscent of another immunosuppressive agent, brequinar sodium, which has been shown to be a nonomolar inhibitor (Ki = 10-30 nM) of the enzyme dihydroorotate dehydrogenase (DHODase). On the basis, we have investigated the effects of leflunomide and A771726 on the activity of purified recombinant human DHODase. We find that A771726 is a potent inhibitor of DHODase (Ki = 179 +/- 19 nM), while the parent compound, leflunomide, had no inhibitory effect at concentrations as high as 1 microM. Studies of the dependence of inhibition on the concentrations of the substrates ubiquinone and dihydroorotate demonstrate that A771726 is a competitive inhibitor of the ubiquinone binding site and is noncompetitive with respect to dihydroorotate. The potency of A771726 as a DHODase inhibitor is thus 100-100-fold greater than that reported for its inhibition of protein tyrosine kinases. These data suggest that an alternative explanation for the immunosuppressive efficacy of A771726 may be the potent inhibition of DHODase by this compound.

Aniline Compounds↗
PubMed1996

Increased risk of reported pertussis and hospitalization associated with pertussis in low birth weight children.

OBJECTIVES: To determine whether low birth weight (LBW) children are at greater risk of reported pertussis and complications of pertussis in the first 2 years of life than are normal birth weight (NBW) children. STUDY DESIGN: We performed a secondary analysis of three data sets containing statewide information among Wisconsin residents for children born between January 1, 1981, and December 31, 1990. We identified all reported cases of pertussis among children younger than 2 years of age and linked this information with birth certificate data and hospitalization data to determine the relative risk of reported pertussis in LBW compared with NBW children. We also compared the frequency of reported complications of pertussis in LBW and NBW children. RESULTS: We analyzed reports of 549 pertussis cases; 49 cases occurred in LBW children. The LBW children were significantly more likely to have reported pertussis than were NBW children (relative risk 1.86; 95% confidence interval 1.33, 2.38). The rates of pneumonia and seizures did not differ among LBW and NBW children; however, LBW children with reported pertussis were significantly more likely to be hospitalized than were NBW children (relative risk 1.40; 95% confidence interval 1.11, 1.69). CONCLUSION: In addition to timely vaccination of all infants, efforts are needed to determine additional ways to reduce the risk of pertussis among LBW infants and children.

Age of Onset↗
PubMed1996

Cryptosporidiosis in Wisconsin: a case-control study of post-outbreak transmission.

During March-April 1993, an estimated 403000 residents of the 5-county greater Milwaukee, Wisconsin area developed cryptosporidiosis after drinking contaminated municipal water. Although the number of cases dropped precipitously after the implicated water plant closed on 9 April, cases continued to occur. To investigate risk factors for post-outbreak cryptosporidiosis, 33 Milwaukee-area residents who had laboratory-confirmed Cryptosporidium infection with onset of diarrhoea between 1 May and 27 June 1993 were interviewed by telephone. Of these, 28 (85%) had onset of diarrhoea during May, 12 (36%) had watery diarrhoea during the outbreak, and 5(15%) were HIV-infected. In a neighbourhood-matched case-control study, immunosuppression (matched odds ratio (MOR) not calculable, 95% confidence interval (CI) 3.0, infinity) and having a child less than 5 years old in the household (MOR = 17.0, CI 2.0, 395.0) were independently associated with infection. When persons who had diarrhoea during the outbreak were excluded, immunosuppression remained significantly associated with illness (MOR not calculable, CI 1.6, infinity). Cryptosporidium transmission continued after this massive waterborne outbreak but decreased rapidly within 2 months.

AIDS-Related Opportunistic Infections↗
PubMed1996

Comparative effects of selective cyclooxygenase 1 and cyclooxygenase 2 inhibitors on myeloperoxidase and 3 alpha-hydroxysteroid dehydrogenase.

The clinical efficacy of non-steroidal anti-inflammatory drugs (NSAIDs) is believed to result from the ability of these compounds to inhibit the inducible isoform of the enzyme cyclooxygenase, COX2. The gastrointestinal and renal side effects of these drugs, in contrast, are thought to relate to their ability to inhibit the constitutive isozyme, COX1. There is structural and pharmacological evidence that suggests that NSAIDs may also inhibit two unrelated enzymes, myeloperoxidase (MP) and 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD), potentially with untoward consequences for the patient. Our laboratories have been investigating a new structural class of potential COX inhibitors, the tri-cyclic aromatics. In this study we have examined the inhibitory potency of selected compounds for the enzymes human COX1, human COX2, human MP, and rat liver 3 alpha-HSD. The compounds selected span a range of COX isoform selectivities, from specific for COX2 to selective for COX1 only, and include three representative tri-cyclic aromatics. We found that compounds within the tri-cyclic aromatic class do not act as potent inhibitors of either myeloperoxidase or 3 alpha-HSD. These results demonstrate the unique inhibitor selectivity that can be achieved with the tri-cyclic aromatics. Examples of COX1 selective, and COX2 selective inhibitors within this structural class are presented.

3-Hydroxysteroid Dehydrogenases↗
PubMed1996

Reduction of risk of watery diarrhea with point-of-use water filters during a massive outbreak of waterborne Cryptosporidium infection in Milwaukee, Wisconsin, 1993.

The occurrence of a massive waterborne outbreak of Cryptosporidium infection in Milwaukee, Wisconsin provided an opportunity to evaluate the effectiveness of point-of-use home water filters in preventing diarrheal illness associated with Cryptosporidium infection. Of 155 filter owners who responded to a televised request to contact the City of Milwaukee Health Department, 99 (64%) completed a self-administered questionnaire regarding their sources of drinking water, the characteristics of their home water filters, and diarrheal illness during the outbreak. Diarrhea among respondents was independently associated with residence in southern or central Milwaukee (the area served by the implicated South water treatment plant), having a home water filter with a pore diameter of greater than 1 micron, and drinking unfiltered tap water in a public building in southern Milwaukee. Among residents of southern and central Milwaukee, two (18%) of 11 persons who drank only submicron-filtered water at home and who did not drink unfiltered South plant water at work had watery diarrhea, compared with 50% (n = 2), 63% (n = 35), and 80% (n = 15) who reported drinking South plant water that was unfiltered or passed through a filter with a pore diameter > 1 micron at work only, home only, or both home and work, respectively (P = 0.02). The data indicate that use of submicron point-of-use water filters may reduce risk of waterborne cryptosporidiosis.

Adult↗
PubMed1996

Measles vaccination during the respiratory virus season and risk of vaccine failure.

OBJECTIVE: To determine whether measles vaccine failure is more common in persons who were vaccinated during the respiratory virus season, when they were more likely to have had concurrent minor illnesses. DESIGN: Population-based case series and case-control study. SETTING: Wisconsin and Ohio. SUBJECTS: The case series included all 545 of the states' residents who had confirmed measles reported during 1985 through 1990 and a history of receiving a single dose of measles vaccine during 1975 through 1988 at 15 to 59 months of age. In a case-control study restricted to 1984 through 1988 vaccinees, season of vaccination was compared in 170 case children and 6070 control students. MAIN OUTCOME MEASURE: Risk of clinical vaccine failure after measles vaccination during the respiratory virus season (September through May) or the peak season (November through March) compared with summertime (June through August), after adjustment for age at vaccination and place of residence. RESULTS: In the case series of persons with vaccine failure, the proportion who had been vaccinated during the respiratory virus season (74.7%) was no greater than expected (September through May = 74.8% of the year). In the case-control study, vaccination during the respiratory virus season (odds ratio, 0.92; 95% confidence interval, 0.66 to 1.30) or the peak season (odds ratio, 0.93) did not increase the risk of vaccine failure. CONCLUSION: Despite the high and strongly seasonal prevalence of viral respiratory illness in young children, routine childhood measles vaccination during the respiratory virus season does not increase their risk of vaccine failure. Findings provide epidemiologic support for recently strengthened recommendations that measles vaccination not be deferred in children with minor respiratory illnesses.

Antibody Formation↗
PubMed1995

Isolation of AF2 (KHEYLRFamide) from Caenorhabditis elegans: evidence for the presence of more than one FMRFamide-related peptide-encoding gene.

Numerous FMRFamide-related peptides (FaRPs) have been isolated and sequenced from extracts of free-living and parasitic nematodes. The most abundant FaRP identified in ethanolic/methanolic extracts of the parasitic forms, Ascaris suum and Haemonchus contortus and from the free-living nematode, Panagrellus redivivus, was KHEYLRFamide (AF2). Analysis of the nucleotide sequences of cloned FaRP-precursor genes from C. elegans and, more recently, Caenorhabditis vulgaris identified a series of related FaRPs which did not include AF2. An acid-ethanol extract of Caenorhabditis elegans was screened radioimmunometrically for the presence of FaRPs using a C-terminally directed FaRP antiserum. Approximately 300 pmols of the most abundant immunoreactive peptide was purified to homogeneity and 30 pmols was subjected to Edman degradation analysis and gas-phase sequencing. The unequivocal primary structure of the heptapeptide, Lys-His-Glu-Tyr-Leu-Arg-Phe-NH2 (AF2) was determined following a single gas-phase sequencing run. The molecular mass of the peptide was determined using a time-of-flight mass spectrometer and was found to be 920 (MH+)+, which was consistent with the theoretical mass of C-terminally amidated AF2. These results indicate that C. elegans possesses more than one FaRP gene.

Amino Acid Sequence↗
PubMed1995

Alignment editing and identification of consensus secondary structures for nucleic acid sequences: interactive use of dot matrix representations.

We present a computer-aided approach for identifying and aligning consensus secondary structure within a set of functionally related oligonucleotide sequences aligned by sequence. The method relies on visualization of secondary structure using a generalization of the dot matrix representation appropriate for consensus sequence data sets. An interactive computer program implementing such a visualization of consensus structure has been developed. The program allows for alignment editing, data and display filtering and various modes of base pair representation, including co-variation. The utility of this approach is demonstrated with four sample data sets derived from in vitro selection experiments and one data set comprising tRNA sequences.

Algorithms↗
PubMed1995

Recombinant human dihydroorotate dehydrogenase: expression, purification, and characterization of a catalytically functional truncated enzyme.

An N-terminally truncated cDNA for human dihydroorotate dehydrogenase (DHODase) was placed under the control of the inducible T7 lac promoter in a pyrimidine auxotrophic strain of Escherichia coli lacking the endogenous enzyme. Induction of gene expression rescued growth in media lacking exogenous pyrimidines. The recombinant enzyme was purified to homogeneity from detergent extracts of bacterial membranes by two chromatographic steps. The purity of the resulting enzyme was judged to be > 95% based on SDS-PAGE with Coomassie staining. The enzyme displays an apparent molecular weight of ca. 40 kDa on SDS-PAGE and ca. 120 kDa on native size-exclusion chromatography, suggesting that the native enzyme is multimeric. Recombinant DHODase displayed a specific activity and Km for dihydroorotate that were similar to those for the enzymes from bovine and human liver tissue. The pH dependence of the activity of the recombinant enzyme was likewise similar to that of the enzyme from human liver and may indicate the involvement of a critical histidine residue in catalytic turnover; only eight histidine residues remain in the truncated version of DHODase used here. The catalytic activity of the recombinant enzyme is inhibited in a dose-dependent fashion by the histidine-selective modifying agent diethylpyrocarbonate. These results further suggest a potential role for histidine in enzyme turnover. Brequinar sodium, an experimental drug which has been shown to be a nanomolar noncompetitive inhibitor of mammalian DHODases, inhibited the activity of the purified recombinant enzyme with a Ki value similar to that for enzyme derived from human liver tissue. The recombinant DHODase thus displays enzymatic behavior similar to the 50-kDa full-length human liver enzyme, illustrating that the catalytically essential structural features of the enzyme, as well as the site of Brequinar binding, are contained within the 40-kDa truncated version of the enzyme that was expressed here.

Amino Acid Sequence↗
PubMed1995

The pharmacology of FMRFamide-related neuropeptides in nematodes: new opportunities for rational anthelmintic discovery?

The chemotherapeutic control of helminth parasites is compromised by the limited number of classes of anthelmintic drugs. Discovery of novel anthelmintics is impeded by the lack of novel screening technologies that overcome the difficulties inherent in screens based on whole organism toxicity. The development and implementation of mechanism-based screens for new anthelmintics offers great promise for the revitalization of antiparasitic drug discovery. However, mechanism-based screens must be based on a thorough understanding of the proteins or processes that offer the best chance for selective chemotherapeutic intervention. Basic research on the characterization of nematode FMRFamide-related peptides (FaRPs) has revealed that these peptides are ubiquitously distributed in helminths. Chemical identification of a number of nematode FaRPs has been achieved, and these peptides have potent and profound effects on the nematode neuromuscular system. Physiological processes mediated by nematode FaRPs (and other helminth neuropeptides) offer potential targets for the discovery of novel anthelmintics.

Amino Acid Sequence↗