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Biomedical subjects

S L Martin

Publications and source records attributed to S L Martin.

At least 37 records · Page 2Linked to original sources
PubMed2000

Inhibition of Escherichia coli glucosamine synthetase by novel electrophilic analogues of glutamine--comparison with 6-diazo-5-oxo-norleucine.

A series of electrophilic glutamine analogues based on 6-diazo-5-oxo-norleucine has been prepared, using novel synthetic routes, and evaluated as inhibitors of Escherichia coli glucosamine synthetase. The gamma-dimethylsulphonium salt analogue of glutamine was found to be one of the most potent inactivators of this enzyme yet reported, with an apparent second order rate constant (k2/Ki) of 3.5 x 10(5) M(-1) min(-1).

Antimetabolites, Antineoplastic↗
PubMed2000

Deletion analysis defines distinct functional domains for protein-protein and nucleic acid interactions in the ORF1 protein of mouse LINE-1.

LINE-1, or L1, is a non-LTR retrotransposon in mammals. Retrotransposition of L1 requires the action of two element-encoded proteins, ORF1p and ORF2p. ORF2p provides essential enzymatic activities for the reverse transcription and integration of a newly transposed copy of L1, whereas the exact role of ORF1p is less well understood. The 43 kDa ORF1p copurifies as a large complex with L1 RNA in extracts of human and mouse cells. Mouse ORF1p purified from Escherichia coli binds RNA and single-stranded DNA in vitro, exhibits nucleic acid chaperone activity, and is capable of protein-protein interaction. In this study we create a series of deletions in the ORF1 sequence, express the truncated proteins and examine their activities to delineate the region of ORF1p responsible for these different functions. By both yeast two-hybrid analysis and GST pull-down assay, the protein-protein interaction domain is defined as a coiled-coil domain that encompasses about one third of the protein near its N terminus. Based on data obtained with UV-cross-linking, electrophoretic mobility-shift assay and an annealing assay, the C-terminal one third of ORF1p is both necessary and sufficient for nucleic acid binding and to promote annealing of complementary oligonucleotides. Separation of these activities into different domains of ORF1p will facilitate detailed biochemical analyses of the structure and function of this protein and understanding of its role during L1 retrotransposition.

Animals↗
PubMed2000

Asymmetric preference of serine proteases toward phosphonate and phosphinate esters.

We have previously reported the asymmetric synthesis of (alpha-aminoalkyl) diphenylphosphonate and phosphinate derivatives designed as inhibitors of chymotrypsin- and elastase-like proteases. This paper reports the first kinetic evaluation of individual epimers of the (alpha-aminoalkyl) diphenylphosphonates as inactivators of chymotrypsin, cathepsin G and neutrophil elastase (HNE). Results show that the (R)-epimers consistently function as more potent irreversible inactivators of their respective target proteases than the corresponding (S)-epimers. Additionally, phosphinate analogues were found to be consistently superior to their diphenylphosphonate counterparts. For example, Cbz. Phe(P)(OPh)-(CH(2))(2)-CO(2)Et inactivates cathepsin G approximately 45-fold more rapidly (k(i)/K(i) = 1.2 x 10(5) M(-1). min(-1)) than the analogous Cbz.Phe(P)(OPh)(2) (2.6 x 10(3) M(-1). min(-1)). Similarly, Cbz.Val(P)(OPh)-(CH(2))(2)-CO(2)Et was found to inactivate HNE some 3-fold more efficiently than Cbz.Val(P)(OPh)(2) (6.5 x 10(3) and 2.0 x 10(3) M(-1). min(-1), respectively).

Cathepsin G↗
PubMed2000

Effect of sequence variation in meningococcal PorA outer membrane protein on the effectiveness of a hexavalent PorA outer membrane vesicle vaccine.

Though meningococcal serogroup C conjugate vaccines have been introduced into the UK infant immunisation schedule, there is currently no vaccine solution for serogroup B disease. PorA outer membrane protein (OMP) is a potential serogroup B vaccine candidate. A hexavalent PorA outer membrane vesicle (OMV) vaccine has been evaluated in phase I and II trials with promising results. This vaccine contains six different PorA OMPs each representing a different serosubtype. However, considerable sequence variation occurs in the variable regions (VRs) encoding these serosubtypes. By using recombinant P1.5,10 PorA variants we have demonstrated that the killing of this particular serosubtype combination was due mainly to the induction of antibody to the VR2 (P1.10) epitope region, and that after three or four doses of vaccine there was a significant reduction in the killing of variants P1.10a (three doses, p<0.0001; four doses, p = 0.003) and P1.10f (three doses, p<0.0001; four doses, p = 0.002), as compared to responses to the P1.10 strain, when the P1.10 serosubtype was used as the immunogen. Since large numbers of serosubtype variants are known to exist, this finding may have implications for the use of PorA as a meningococcal serogroup B vaccine.

Antibodies, Bacterial↗
PubMed2000

Why Helicobacter pylori has Lewis antigens.

In mimicry with human gastric epithelial cells, the lipopolysaccharide of Helicobacter pylori expresses Lewis blood group antigens. Recent data suggest that molecular mimicry does not promote immune evasion, nor does it lead to induction of autoantibodies, but that H. pylori Lewis X mediates adhesion to gastric epithelial cells and is essential for colonization.

Bacterial Adhesion↗
PubMed2000

Activation of myocardial angiogenesis and upregulation of fibroblast growth factor-2 in transmyocardial-revascularization-treated mice.

OBJECTIVE: To evaluate the growth factor responses associated with myocardial angiogenesis. DESIGN: Mice were treated with transmyocardial revascularization (TMR) and evaluated for angiogenic and growth factor responses. METHODS: TMR was performed via thoractomy with a 27 g needle. At 2, 5, and 7 days post-treatment, hearts were removed from the TMR treated and control groups, then assayed for angiogenesis, fibroblast growth factor (FGF)-2 expression and vascular endothelial cell growth factor (VEGF) expression. RESULTS: TMR caused an angiogenic reaction in the myocardial blood vessels at 7 days post-TMR treatment. Elevated FGF-2 corresponded with increased TMR related angiogenesis. VEGF levels only increased in hearts that were prewounded then TMR treated. CONCLUSIONS: The data show that TMR stimulates myocardial angiogenesis. The angiogenic reaction is mediated by FGF-2 which increased in most experimental treatment groups. The VEGF response was more specific, requiring prewounding then TMR treatment for a VEGF increase.

Animals↗
PubMed2000

Meningococcal serogroup C-specific IgG antibody responses and serum bactericidal titres in children following vaccination with a meningococcal A/C polysaccharide vaccine.

In the UK, a co-ordinated series of phase II studies is being undertaken with meningococcal serogroup C conjugate (MCC) vaccines. The use of meningococcal A/C polysaccharide (MACP) vaccines in control arms in young children has been avoided because of the well recognised short comings of these vaccines. Following a cluster of serogroup C disease centred on a day nursery, intervention by MACP vaccination was performed as an outbreak control measure. Using this cohort, serogroup C-specific IgG ELISA and serum bactericidal assays (SBA) were performed using both de-O-acetylated (Oac(-)) and acetylated (Oac(+)) serogroup C antigen, the measurement of primarily high avidity antibody and using baby rabbit or human complement in the SBA. The effect of subject age (either less than or greater than 2 years of age) was assessed for the different assays and significant differences (P<0.05) were found using both antigen sources in the high avidity ELISA and in the rabbit complement SBA but not in the standard ELISA. When assessing results from different studies it is important that methodologies utilised allow such comparisons since the choice of reagents can have a profound influence. The importance of standardised assays is paramount at a time where immunogenicity trials are replacing efficacy trials for the introduction of MCC vaccines.

Animals↗
PubMed2000

mRNA stability and polysome loss in hibernating Arctic ground squirrels (Spermophilus parryii).

All small mammalian hibernators periodically rewarm from torpor to high, euthermic body temperatures for brief intervals throughout the hibernating season. The functional significance of these arousal episodes is unknown, but one suggestion is that rewarming may be related to replacement of gene products lost during torpor due to degradation of mRNA. To assess the stability of mRNA as a function of the hibernation state, we examined the poly(A) tail lengths of liver mRNA from arctic ground squirrels sacrificed during four hibernation states (early and late during a torpor bout and early and late following arousal from torpor) and from active ground squirrels sacrificed in the summer. Poly(A) tail lengths were not altered during torpor, suggesting either that mRNA is stabilized or that transcription continues during torpor. In mRNA isolated from torpid ground squirrels, we observed a pattern of 12 poly(A) residues at greater densities approximately every 27 nucleotides along the poly(A) tail, which is a pattern consistent with binding of poly(A)-binding protein. The intensity of this pattern was significantly reduced following arousal from torpor and undetectable in mRNA obtained from summer ground squirrels. Analyses of polysome profiles revealed a significant reduction in polyribosomes in torpid animals, indicating that translation is depressed during torpor.

Animals↗
PubMed2000

Factors predicting completion of a home visitation program by high-risk pregnant women: the North Carolina Maternal Outreach Worker Program.

OBJECTIVES: This study sought to identify characteristics of high-risk pregnant women that predicted long-term participation in a home visitation program. METHODS: Data regarding sociodemographic characteristics, perceived needs, psychological functioning, substance use, and informal social support were collected prospectively from 152 short-term and 221 long-term program participants. RESULTS: In comparison with short-term participants, long-term participants were more likely to have been African American, married, nonsmokers, and enrolled in the program during their second trimester of pregnancy, and they were more likely to have had emotional and instrumental support needs. CONCLUSIONS: Women with greater social support needs and healthier behaviors were more receptive to long-term home visitation than other women.

Adolescent↗
PubMed2000

Solid-phase synthesis and biological screening of N-alpha-mercaptoamide template-based matrix metalloprotease inhibitors.

A series of N-alpha-mercaptoacetyl containing dipeptides have been prepared on solid-phase supports as putative matrix metalloprotease (MMP) inhibitors. Inhibitor design was based on a positional scanning approach of the amino acids present within a template molecule, previously shown to be an MMP inhibitor with good pharmacological characteristics. This study is the first step in a unique programme, designed to expand the repertoire of molecular templates which can be chosen as starting points for the development of more focused parallel and/or combinatorial libraries of MMP inhibitors as a means to accelerate the lead discovery process. This paper reports the success of such an approach in the development of agents with activity against a number of pathologically important MMPs. After screening of these positional scanning libraries, we have obtained important SAR information, in particular, pharmacophores with the ability to impart selectivity for particular MMP species.

Fluorometry↗
PubMed2000

Monitoring of somatosensory and motor evoked potentials during open reduction and internal fixation of pelvis and acetabular fractures.

Monitoring of motor and somatosensory evoked potentials provides instantaneous intraoperative assessment of a patient's neurologic status. Monitoring of the sciatic nerve through motor and somatosensory evoked potentials can be used during open reduction and internal fixation of pelvic and acetabular fractures. A review of 12 pelvic and acetabular fractures treated with open reduction and internal fixation was conducted and assessed with a combination of intraoperative motor and somatosensory evoked potential monitoring. Results revealed intraoperative motor evoked potential monitoring was 100% sensitive and 100% specific in predicting postoperative sciatic nerve deficits, whereas somatosensory evoked potentials were not accurate in predicting postoperative sciatic nerve deficits. Combined monitoring of the sciatic nerve with motor and somatosensory evoked potentials is beneficial at predicting postoperative sciatic nerve deficits during open reduction and internal fixation of pelvic and acetabular fractures.

Acetabulum↗
PubMed2000

Deletion of Dad1 in mice induces an apoptosis-associated embryonic death.

Dad1 is a putative anti-apoptosis gene identified in several distantly related organisms. Expression of Dad1 in transfected cells inhibits apoptosis in vitro. To determine whether Dad1 has a similar function in vivo, we used gene targeting to delete Dad1. Heterozygous adult mice (+/-) show no obvious phenotype or abnormalities, but genotype analysis of over 100 offspring from heterozygous matings detected no weanling, homozygous Dad1 null (-/-) mice. Subsequent analysis of embryos from heterozygous matings detected Dad1 null (-/-) embryos at E3.5 but no later, suggesting Dad1 is required for development beyond the late blastocyst stage. Increased levels of apoptosis were observed in cultured embryos lacking a functional copy of the gene, consistent with an anti-apoptotic role for Dad1.

Animals↗
PubMed1999

Sexual behaviors and reproductive health outcomes: associations with wife abuse in India.

CONTEXT: Wife abuse has been associated with a variety of health concerns. Associations between abuse and reproductive health in India are not well known. OBJECTIVE: To examine relationships between men's reports of wife abuse and reproductive health issues in northern India. DESIGN: Structured face-to-face interviews were conducted as part of the male reproductive health supplement of the PERFORM System of Indicators Survey, a systematic multistage survey conducted in 1995-1996. SETTING: The northern state of Uttar Pradesh, one of the least developed states in India. PARTICIPANTS: A total of 6632 married men aged 15 to 65 years who lived with their wives and completed all survey questions for the study variables reported here. MAIN MEASURES: Physically and sexually abusive behaviors toward wives, sexual activities outside marriage, sexually transmitted disease (STD) symptoms, contraception use, unplanned pregnancies, and sociodemographic characteristics. RESULTS: Fifty-four percent of men reported not abusing their wives, while 17% reported physically but not sexually abusing their wives, 22% reported sexual abuse without physical force, and 7% reported sexual abuse with physical force. Abuse was more common among men who had extramarital sex (for sexual abuse using force: odds ratio [OR], 6.22; 95% confidence interval [CI], 3.98-9.72). Similarly, men who had STD symptoms were more likely to abuse their wives (with current symptoms: OR, 2.43; 95% CI, 1.73-3.42). Unplanned pregnancies were significantly more common among wives of abusive men, especially sexually abusive men who used force (OR, 2.62; 95% CI, 1.91-3.60). CONCLUSIONS: Wife abuse appears to be fairly common in northern India. Our findings that abusive men were more likely to engage in extramarital sex and have STD symptoms suggest that these men may be acquiring STDs from their extramarital relationships, thereby placing their wives at risk for STD acquisition, sometimes via sexual abuse. These abusive sexual behaviors also may result in an elevated rate of unplanned pregnancies.

Adolescent↗
PubMed1999

Domestic violence in northern India.

This study examined the prevalence and characteristics of wife abuse as reported by nearly 6,700 married men living in five districts of northern India during 1995-1996. In addition, associations between wife abuse and sociodemographic factors were investigated to enable two theoretical/conceptual perspectives regarding abuse to be evaluated: that abuse is more common among families under stress and among more "private" families. The district-specific percentages of men who reported physically abusing their wives ranged from 18% to 45%, with 18-40% of the men in each district having had nonconsensual sex with their wives and 4-9% having physically forced their wives to have sex. The authors used logistic regression analyses to control for a variety of sociodemographic variables and found positive associations between wife abuse and stress-related factors, including the husband having a low educational level, the couple living in poverty, the husband being young when he first lived with his wife, and the couple having multiple children. Contrariwise, there was no strong empirical support for the idea that wife abuse may be more common in more "private" families.

Battered Women↗
PubMed1999

A recombinant trimeric surfactant protein D carbohydrate recognition domain inhibits respiratory syncytial virus infection in vitro and in vivo.

The pulmonary collectin, lung surfactant protein D (SP-D), plays a role in host defense mediated by the interaction of surface carbohydrates of inhaled pathogens with the lectin domains of SP-D. Respiratory syncytial virus (RSV), the most important viral pathogen of neonates and infants, encodes a highly glycosylated attachment protein, G. Binding studies were performed with G protein from RSV (human, A2 strain) and both native and recombinant human SP-D. The effect of recombinant trimeric SP-D lectin domains (rSP-D) on the interaction between RSV and host cells was determined by two methods: an infectivity study with monolayers of Hep-2C cells and in vivo infections in BALB/c mice. These studies show that full-length and recombinant SP-D bind to RSV G protein in a concentration-dependent manner. Both EDTA and mannan inhibited binding of full-length SP-D. These results indicate that binding occurs via the carbohydrate recognition domain of the SP-D. The recombinant SP-D inhibited RSV infectivity in cell culture in a dose-dependent manner, giving 100% inhibition of replication. Intranasal administration of recombinant SP-D to RSV-infected mice inhibited replication of the virus in the lungs, reducing levels of lung virus by 80%. These results suggest that SP-D plays a major role in clearing RSV from the lungs.

Animals↗
PubMed1999

The effect of implementing a more comprehensive screening for substance use among pregnant women in North Carolina.

OBJECTIVES: Substance use during pregnancy causes significant morbidity and mortality. Screening for substance use provides opportunity for intervention and treatment, but is often overlooked in prenatal care with today's fiscal climate and preconceived ideas about who uses substances. The purpose of this study was to determine the effect of implementing a more comprehensive screening procedure for identifying substance-using pregnant women. METHODS: Two hundred randomly selected prenatal patients screened using the old procedure for substance use during pregnancy were compared to 400 randomly selected patients screened after implementation of a new, more detailed screening procedure. The old screening approach included three check-boxes concerning substance use during pregnancy: one for "Smoking/alcohol," one for "Drug use (any)," and one for "Drug addiction/alcoholism." The new screening procedure included more detailed questions about the frequency of cigarette, alcohol, and illegal drug use during pregnancy. RESULTS: Compared with the old approach, the new screening protocol increased reporting of smoking/alcohol use from 21% to 72% (relative risk = 2.63, 95% confidence interval = 2.231, 3.108); reporting of any drug use from 12% to 18% (relative risk = 1.07, 95% confidence interval = 1.002, 1.150); and reporting of alcoholism/drug abuse from 0% to 6% (relative risk = 1.06, 95% confidence interval = 1.038, 1.090). CONCLUSIONS: Our study suggests that more detailed screening using direct questions concerning the amount and frequency of substance use increases reporting of prenatal substance use as compared to screening approaches using only "yes/no" style check boxes.

Adult↗