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Biomedical subjects

N Moss

Publications and source records attributed to N Moss.

At least 19 recordsLinked to original sources
PubMed2000

Assessment of impact on health of residents living near the Nant-y-Gwyddon landfill site: retrospective analysis.

OBJECTIVES: To compare indices of health in a population living near a landfill site with a population matched for socioeconomic status and to review environmental monitoring data. DESIGN: Ecological study with small area statistics and environmental reports. SETTING: Electoral wards in valleys of South Wales. SUBJECTS: Populations in the five wards near the landfill site who had formally complained of odours (exposed population), and comparison populations in 22 wards in the same unitary authority within the same fifth of Townsend score. OUTCOME MEASURES: Mortality, rates of hospital admission, measures of reproductive health (proportion of all births and stillbirths of infants weighing <2500 g; rates of admissions for spontaneous abortion; rates of all reported congenital malformations). Environmental data on site emissions. RESULTS: There were no consistent differences in mortality, rates of hospital admissions, or proportion of low birthweight infants between the two populations. There was an increased maternal risk of having a baby with a congenital abnormality in residents near the site, both before its opening (relative risk 1.9; 95% confidence interval 1.3 to 2.85; P<0.001) and after (1.9; 1.23 to 2.95; P=0.003). Environmental monitoring showed that hydrogen sulphide from the site was probably responsible for odours. CONCLUSIONS: The area surrounding the landfill site has an increased rate of reported congenital malformations, which predated the opening of the landfill, although the cluster of cases of gastroschisis post-dated its opening. Several chemicals emitted from the site, including hydrogen sulphide and benzene, were found in air samples in the nearby community. Further studies of the reproductive risk in such communities are needed to examine the safety of waste disposal sites.

Congenital Abnormalities↗
PubMed2000

Socioeconomic disparities in health in the US: an agenda for action.

Inequality of income and wealth in the US has been growing rapidly since 1972. Evidence of socioeconomic effects on health is documented for many endpoints, and there is evidence that socioeconomic disparities in health are increasing. In Europe, equity in health and health care is a target of the World Health Organization, and has led to a variety of activities to reduce socioeconomic disparities in morbidity and mortality. In the US, activities in the public and private sectors have increased in recent years but attention, especially among the public-at-large in addition to elites, needs to be shifted to socioeconomic disparities. The paper suggests action strategies drawn from the European experience and other US efforts to place public health priorities on the policy agenda. A first step is to create a climate of unacceptability for socioeconomic disparities in health. Recommended activities include improvement and utilization of existing data; dissemination to broad audiences; building on existing initiatives; creating multi-sectoral alliances; formation of state and community task forces; attention to human capital as well as social justice issues; creative use of media; attraction of new funders; and implementation of quantitative targets.

Europe↗
PubMed1999

Ligands for the tyrosine kinase p56lck SH2 domain: discovery of potent dipeptide derivatives with monocharged, nonhydrolyzable phosphate replacements.

p56lck is a member of the src family of tyrosine kinases. Through modular binding units called SH2 domains, p56lck promotes phosphotyrosine-dependent protein-protein interactions and plays a critical role in signal transduction events that lead to T-cell activation. Starting from the phosphorylated dipeptide (2), a high-affinity ligand for the p56lck SH2 domain, we have designed novel dipeptides that contain monocharged, nonhydrolyzable phosphate group replacements and bind to the protein with KD's in the low micromolar range. Replacement of the phosphate group in phosphotyrosine-containing sequences by a (R/S)-hydroxyacetic (compound 8) or an oxamic acid (compound 10) moiety leads to hydrolytically stable, monocharged ligands, with 83- and 233-fold decreases in potency, respectively. This loss in binding affinity can be partially compensated for by incorporating large lipophilic groups at the inhibitor N-terminus. These groups provide up to 13-fold increases in potency depending on the nature of the phosphate replacement. The discovery of potent (2-3 microM), hydrolytically stable dipeptide derivatives, bearing only two charges at physiological pH, represents a significant step toward the discovery of compounds with cellular activity and the development of novel therapeutics for conditions associated with undesired T-cell proliferation.

Crystallography, X-Ray↗
PubMed1999

Phosphotyrosine-containing dipeptides as high-affinity ligands for the p56lck SH2 domain.

Src homology-2 (SH2) domains are noncatalytic motifs containing approximately 100 amino acid residues that are involved in intracellular signal transduction. The phosphotyrosine-containing tetrapeptide Ac-pYEEI binds to the SH2 domain of p56lck (Lck) with an affinity of 0.1 microM. Starting from Ac-pYEEI, we have designed potent antagonists of the Lck SH2 domain which are reduced in peptidic character and in which the three carboxyl groups have been eliminated. The two C-terminal amino acids (EI) have been replaced by benzylamine derivatives and the pY + 1 glutamic acid has been substituted with leucine. The best C-terminal fragment identified, (S)-1-(4-isopropylphenyl)ethylamine, binds to the Lck SH2 domain better than the C-terminal dipeptide EI. Molecular modeling suggests that the substituents at the 4-position of the phenyl ring occupy the pY + 3 lipophilic pocket in the SH2 domain originally occupied by the isoleucine side chain. This new series of phosphotyrosine-containing dipeptides binds to the Lck SH2 domain with potencies comparable to that of tetrapeptide 1.

Binding, Competitive↗
PubMed1999

Glycine improves survival after hemorrhagic shock in the rat.

This study investigated the effect of glycine on hemorrhagic shock in the rat. Rats were bled to maintain mean arterial pressure at 30-35 mm Hg for 1 h and subsequently resuscitated with 60% shed blood and lactated Ringer's solution. Only 20% of rats receiving saline just prior to resuscitation survived 72 h after shock. Survival was increased by glycine (11.2-90.0 mg/kg, i.v.) in a dose-dependent manner (half-maximal effect = 25 mg/kg) and reached maximal values of 78% at 45 mg/kg. Eighteen hours after resuscitation, creatinine phosphokinase increased 23-fold, transaminases increased 33-fold, and creatinine was elevated 2.4-fold, indicating injury to the heart, liver, and kidney, respectively. Pulmonary edema, leukocyte infiltration, and hemorrhage were also observed. In the kidney, proximal tubular necrosis, leukocyte infiltration, and severe hemorrhage in the outer medullary area occurred in rats receiving saline. Glycine reduced these pathological alterations significantly. It has been reported that oxidative stress and tumor necrosis factor(TNF)-alpha-production are involved in the pathophysiology of multiple-organ injury after shock. In this study, free radical production was increased 4-fold during shock, an effect blocked largely by glycine. Increases in intracellular calcium and production of TNF-alpha by isolated Kupffer cells stimulated by endotoxin were elevated significantly by hemorrhagic shock, alterations which were totally prevented by glycine. Taken together, it is concluded that glycine reduces organ injury and mortality caused by hemorrhagic shock by preventing free radical production and TNF-alpha formation.

Animals↗
PubMed1999

Dietary glycine and renal denervation prevents cyclosporin A-induced hydroxyl radical production in rat kidney.

Cyclosporin A (CsA) nephrotoxicity is associated with renal hypoxia and increases in free radicals in the urine. This study was designed to elucidate the mechanism of radical production caused by CsA. Pretreatment of rats with CsA (25 mg/kg, i.g.) for 5 days decreased glomerular filtration rates by 65%, an effect largely prevented by both dietary glycine (5%) or renal denervation. CsA dissolved in olive oil produced a 6-line alpha-(4-pyridyl 1-oxide)-N-tert-butylnitrone (4-POBN)/free radical signal in the urine, which partitioned predominantly into the aqueous phase after chloroform extraction (i.e., it is water soluble). Dimethyl sulfoxide (DMSO) is attacked by the hydroxyl radical to produce a methyl radical; administration of CsA with [(12)C]DMSO produced two radical species in urine, one with hyperfine coupling constants similar to the 4-POBN/methyl radical adduct found in aqueous solution. CsA given with [(13)C]DMSO produced a 12-line spectrum, confirming the formation of hydroxyl radicals. The methyl radical produced by the hydroxyl radical represented 62% of radicals detected in urine but only 15% in bile. Therefore, hydroxyl radicals are produced largely in the kidney. Free radicals in urine were increased about 5-fold by CsA, an effect completely blocked by the inhibitory neurotransmitter, glycine, or by renal denervation. CsA infusion for 30 min increased efferent renal nerve activity 2-fold, and dietary glycine (5%) totally blocked this phenomenon. Taken together, these data are consistent with the hypothesis that CsA increases hydroxyl radical formation by increasing renal nerve activity resulting in vasoconstriction and hypoxia-reoxygenation. Glycine blunts the effect of CsA on the renal nerve, which explains, in part, prevention of nephrotoxicity.

Animals↗
PubMed1998

Antiviral activity of a selective ribonucleotide reductase inhibitor against acyclovir-resistant herpes simplex virus type 1 in vivo.

The present study reports the activity of BILD 1633 SE against acyclovir (ACV)-resistant herpes simplex virus (HSV) infections in athymic nude (nu/nu) mice. BILD 1633 SE is a novel peptidomimetic inhibitor of HSV ribonucleotide reductase (RR). In vitro, it is more potent than ACV against several strains of wild-type as well as ACV-resistant HSV mutants. Its in vivo activity was tested against cutaneous viral infections in athymic nude mice infected with the ACV-resistant isolates HSV type 1 (HSV-1) dlsptk and PAAr5, which contain mutations in the viral thymidine kinase gene and the polymerase gene, respectively. Following cutaneous infection of athymic nude mice, both HSV-1 dlsptk and PAAr5 induced significant, reproducible, and persistent cutaneous lesions that lasted for more than 2 weeks. A 10-day treatment regimen with ACV given topically four times a day as a 5% cream or orally at up to 5 mg/ml in drinking water was partially effective against HSV-1 PAAr5 infection with a reduction of the area under the concentration-time curve (AUC) of 34 to 48%. The effects of ACV against HSV-1 dlsptk infection were not significant when it was administered topically and were only marginal when it was given in drinking water. Treatment under identical conditions with 5% topical BILD 1633 SE significantly reduced the cutaneous lesions caused by both HSV-1 dlsptk and PAAr5 infections. The effect of BILD 1633 SE against HSV-1 PAAr5 infections was more prominent and was inoculum and dose dependent, with AUC reductions of 96 and 67% against infections with 10(6) and 10(7) PFU per inoculation site, respectively. BILD 1633 SE also significantly decreased the lesions caused by HSV-1 dlsptk infection (28 to 51% AUC reduction). Combination therapy with topical BILD 1633 SE (5%) and ACV in drinking water (5 mg/ml) produced an antiviral effect against HSV-1 dlsptk and PAAr5 infections that was more than the sum of the effects of both drugs. This is the first report that a selective HSV RR subunit association inhibitor can be effective against ACV-resistant HSV infections in vivo.

Acyclovir↗
PubMed1998

The effect of WIC and Medicaid on infant mortality in the United States.

OBJECTIVES: This study examine the impact of participation in the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) and Medicaid on risk of infant death in the United States. METHODS: The 1988 National Maternal and Infant Health Survey was used to consider the risk of endogenous and exogenous death among infants of women participating in WIC and Medicaid during pregnancy and the infant's first year. RESULTS: Participation in the WIC program during pregnancy and infancy was associated with a reduced risk of endogenous and exogenous infant deaths (odds ratios [ORs] = 0.68 and 0.62, respectively). The risk of endogenous death among infants whose mothers participated in Medicaid during pregnancy was equal to that of the privately insured (OR = 1.04). Uninsured infants faced higher risks of endogenous death (OR = 1.42). CONCLUSIONS: These results show that it is important to consider the net effect of WIC and Medicaid participation and to differentiate both the timing of program receipt and cause of death. Evidence suggests that WIC and Medicaid programs have beneficial effects for poor women and their infants.

Adult↗
PubMed1997

Effect of California's proposition 187 on the use of primary care clinics.

California's ballot proposition 187, passed by the voters in November 1994, threatened to discontinue undocumented immigrants' eligibility for most health services while mandating that health care professionals report suspected undocumented patients to authorities. Although the proposition has not been put into practice, reports suggest that its passage was associated with a decline in the use of health services by some groups. To assess the effects of the passage of Proposition 187 on the use of primary care services, we surveyed a representative sample of California clinics serving low-income groups (n = 129). Using a mailed questionnaire and phone interviews with clinic directors, we obtained qualitative and quantitative data regarding the effects of the passage of the proposition on clinic use. Among primary care clinics statewide and clinics serving predominantly Latino patients, we detected no significant decline in total monthly visits following the election. Nevertheless, half of clinic directors (51%) thought that the number of clinic visits declined after the passage of Proposition 187, and many directors thought that the deterrent effects of the election persisted for weeks to months after the election. Whereas the number of visits probably declined at some clinics, only a small minority of patients at most primary care clinics could have been deterred from seeking care after the passage of Proposition 187.

California↗
PubMed1996

Peptidomimetic inhibitors of herpes simplex virus ribonucleotide reductase with improved in vivo antiviral activity.

We have been investigating the potential of a new class of antiviral compounds. These peptidomimetic derivatives prevent association of the two subunits of herpes simplex virus (HSV) ribonucleotide reductase (RR), an enzyme necessary for efficient replication of viral DNA. The compounds disclosed in this paper build on our previously published work. Structure-activity studies reveal beneficial modifications that result in improved antiviral potency in cell culture in a murine ocular model of HSV-induced keratitis. These modifications include a stereochemically defined (2,6-dimethylcyclohexyl)amino N-terminus, two ketomethylene amide bond isosteres, and a (1-ethylneopentyl)amino C-terminus. These three modifications led to the preparation of BILD 1351, our most potent antiherpetic agent containing a ureido N-terminus. Incorporation of the C-terminal modification into our inhibitor series based on a (phenylpropionyl)valine N-terminus provided BILD 1357, a significantly more potent antiviral compound than our previously published best compound, BILD 1263.

Animals↗
PubMed1996

Ureido-based peptidomimetic inhibitor of herpes simplex virus ribonucleotide reductase: an investigation of inhibitor bioactive conformation.

We have been investigating peptidomimetic inhibitors of herpes simplex virus (HSV) ribonucleotide reductase (RR). These inhibitors bind to the HSV RR large subunit and consequently prevent subunit association and subsequent enzymatic activity. This report introduces a new series of compounds that contain an extra nitrogen (a ureido function) at the inhibitor N-terminus. This nitrogen improves inhibitor binding potency 50-fold over our first published inhibitor series. Evidence supports that this improvement in potency results from a new hydrogen-bonding contact between the inhibitor and the RR large subunit. This report also provides evidence for the bioactive conformation around two important amino acid residues contained in our inhibitors. A tert-butyl group, which contributes 100-fold to inhibitor potency but does not directly bind to the large subunit, favors an extended beta-strand conformation that is prevalent in solution and in the bound state. More significantly, the bioactive conformation around a pyrrolidine-modified asparagine residue, which contributes over 30 000-fold to inhibitor potency, is elucidated through a series of conformationally restricted analogues.

Enzyme Inhibitors↗
PubMed1996

Accounting for the public's health: an introduction to selected papers from a U.S. conference on "measuring social inequalities in health".

Accounting for, and being accountable to, the public's health requires carefully documenting and analyzing social inequalities in health. Controversies abound over which measures of socioeconomic position to use, at which points in time, and at what level-e.g., individual, household, and neighborhood. Important debates also concern how to analyze these data and relate them to inequalities involving race/ethnicity and gender. Addressing these complex issues is particularly timely in the light of persistent- and even widening- social inequalities in health. To improve tools for evaluating socioeconomic gradients in health, in 1994 the U.S. Public Health Service and National Institutes of Health sponsored a conference on Measuring Social Inequalities in Health. This introduction to the Section on Social Inequalities in Health introduces five articles presented by participants at the conference. Topics include: a historical review of efforts to measure socioeconomic inequalities in health in the U.S. between 1990 and 1950; income dynamics and health; measuring inequalities in health among nonemployed persons; analyzing links between racial/ethnic and socioeconomic disparities in health; and using neighborhood-based socioeconomic data in public health research. Together, these five articles point to a new emphasis on refining methodologies to assess relationships between social position and health and their expression in population patterns of social inequalities in health.

Ethnicity↗
PubMed1995

Peptidomimetic inhibitors of herpes simplex virus ribonucleotide reductase: a new class of antiviral agents.

We have been investigating a new class of antiviral compounds effective against herpes simplex virus (HSV) in vitro and in vivo. Antiviral activity results from inhibition of HSV ribonucleotide reductase (RR). The inhibitors are designed as mimics of the RR small subunit C-terminus, a region essential for RR subunit association and consequently enzymatic activity. Inhibition results from specific binding of the inhibitor to the HSV RR large subunit thereby preventing subunit association. This report details the structure--activity studies that lead to the indentification of BILD 1263, a potent inhibitor of HSV RR subunit association (IC50, 0.2 nM) that also inhibits the replication of HSV types 1 and 2 in cell culture (EC50, 3 and 4 microM) and reduces the severity of HSV-1-induced keratitis in a murine ocular model. The discovery of inhibitors with in vitro antiviral results from a combination of improving inhibitor potency in a RR binding assay and modifying inhibitor physicochemical properties. The importance and possible role of the new structural modifications introduced into this inhibitor series is discussed.

Animals↗