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Biomedical subjects

S A Williams

Publications and source records attributed to S A Williams.

At least 73 records · Page 4Linked to original sources
PubMed1997

The relationship between deprivation, ethnicity and dental health in 5-year-old children in Leeds, UK.

OBJECTIVE: To investigate the relationship between material deprivation, ethnicity, dental health and related behaviour in the five-year-old population of Leeds. DESIGN: Analytical survey using a stratified cluster sample of primary schools and a questionnaire to parents. Children were assigned to one of five bands according to the ranking of the Townsend deprivation index for the census enumeration district in which they lived. Standard clinical criteria were used. SETTING: Clinical examinations were carried out in school by four trained and calibrated examiners. PARTICIPANTS: Two thousand six hundred and seventy seven children were examined and 1881 parental questionnaires were returned (70 per cent response). OUTCOME MEASURES: Caries experience expressed as mean dmft. RESULTS: Caries experience increased significantly with deprivation. Deprivation gradients were found in reported dental visiting, parental dental attendance and use of the Community Dental Service. Differences in caries experience between ethnic groups were independent of deprivation score with Asian children from the most deprived districts having a higher mean dmft than their white Caucasian and Afro-Caribbean counterparts (4.80, 3.21, 2.00; P < 0.001). Muslim Asians had significantly higher (P < 0.001) caries experience (dmft = 4.63) than non-Muslim Asians (dmft = 2.08) and the difference was maintained when the effect of deprivation was controlled (P < 0.05). CONCLUSIONS: The Townsend index is a useful indicator of dental health and related behaviour among populations but does not explain variations between ethnic groups.

Asia↗
PubMed1997

Effects of phosphodiester and phosphorothioate antisense oligodeoxynucleotides on cell lines which overexpress c-myc: implications for the treatment of Burkitt's lymphoma.

The product of the c-myc proto-oncogene is a highly conserved nuclear phosphoprotein whose expression is closely linked to cellular proliferation and differentiation. We have been interested in developing an antisense oligodeoxynucleotide (ODN) strategy to inhibit the proliferation of c-myc-dependent malignancies for use in future specific therapies and bone marrow purging regimens. Our experimental approach was to incubate either antisense or sense ODNs, spanning the 5' cap region of the c-myc gene, with c-myc overexpressing cell lines (HL-60) Raji, MJBL, CA-46) for up to seven days. Proliferation assay to test the inhibitory effect of an unmodified antisense ODN 15-mer (GCACAGCTCGGGGGT) showed that concentrations as low as 50 micrograms/ml significantly decreased proliferation of HL-60 cells by approximately 40% (P < 0.0001; n = 6) compared to controls. Clonogenic assays showed that the same antisense ODN inhibited colony formation by MJBL (40%0 and Raji (52%) cells. Subsequent experiments to study the effect of a more nuclease-stable, phosphorothioate-modified antisense ODN 18-mer (GCAGCACAGCTCGGGGGT) revealed 66% inhibition of HL-60 cell proliferation at 96 and 120 hours at 50 micrograms/ml, whereas sense ODN control had no effect. However, tenfold less of the modified antisense ODN (1 micrograms/ml) was required to inhibit proliferation of HL-60 cells by 50% compared to the unmodified antisense ODN. A decrease in the HL-60 native c-myc protein level was also observed with 100 micrograms/ml of modified antisense ODN, but not with the sense ODN control, by immunoblot analysis. Additionally, concentrations up to 10 micrograms/ml of either modified antisense or sense ODN did not decrease CFU-GM formation (145 +/- 35%, P = 0.27) in human bone marrow, suggesting that these levels of ODN would have a negligible effect on normal hematopoietic cells. These pilot data suggest that modified antisense ODN directed at the cap region of the c-myc gene could specifically inhibit c-myc expression at a single, lower dose than unmodified ODN and may play a future role in inhibiting the growth of c-myc-dependent malignant cells.

Blotting, Southern↗
PubMed1996

Chitinase genes expressed by infective larvae of the filarial nematodes, Acanthocheilonema viteae and Onchocerca volvulus.

State-specific products of 220 and 75 kDa were identified by metabolic labelling of infective larvae of the filarial nematode Acanthocheilonema viteae in ticks. Synthesis was temperature sensitive, occurring at 27 degrees C but not at 37 degrees C. These products were secreted 3-6 days after leaving the vector during post-infective development, but subsequent expression was not detected. The smaller protein with a pI of 6.2, was purified by two-dimensional electrophoresis and the N-terminal amino acid sequence was derived. This provisionally identified the protein as a chitinase, which was confirmed biochemically by glycol-chitin substrate gel electrophoresis. The polymerase chain reaction was used to amplify a product from a cDNA library of A. viteae infective larvae. The nucleotide sequence codes for a putative signal peptide of 20 amino acids and a mature protein of 504 residues (Mr 56 kDa), exhibiting 69% identity (81% similarity allowing for conservative substitutions) with the MF1 chitinase described from microfilariae of Brugia malayi. N-linked glycosylation may account for some, or all, of the discrepancy in Mr between the predicted polypeptide and the native parasite product (75 kDa). Primers based on the A. viteae sequence were used to amplify a related sequence from a cDNA library of Onchocerca volvulus infective larvae. The O. volvulus cDNA codes for a 20-amino acid signal peptide followed by 477 residues with an Mr of 54 kDa, and shares 67% identity with the A. viteae chitinase (80% similarity allowing for conservative substitutions) and 69% identity with the B. malayi MF1 molecule. It is proposed that chitinases expressed by infective stages of these filarial nematodes may play a role in ecdysis during post-infective development.

Amino Acid Sequence↗
PubMed1996

Genes expressed in Brugia malayi infective third stage larvae.

We have used a tag sequencing approach to survey genes expressed in the third stage infective larvae of the human filarial nematode parasite Brugia malayi. RNA was isolated from late vector-stage L3 larvae after days 9 or 10 of infection in mosquitos, and converted to cDNA by reverse transcriptase. Double-stranded cDNA was produced by either conventional methods (non-SL cDNA library) or by PCR using the nematode spliced leader (SLI) and oligo(dT) primers (SL cDNA library). Two clone libraries (one from SL and one from non-SL cDNAs) were constructed in lambda ZapII. A set of these full-length clones was selected and 596 inserts were sequenced from the 5' end. We have identified 364 B. malayi genes (the majority of which are new) that encode housekeeping proteins, structural proteins, proteins of immediate immunological or drug-discovery interest as well as a large class of novel sequences which may prove to have significant involvement in host invasion. Extensive, genome-wide approaches to the analysis of larval gene expression are now possible for B. malayi. We present several examples of this approach.

Amino Acid Sequence↗
PubMed1996

Passage of a delta-opioid receptor selective enkephalin, [D-penicillamine2,5] enkephalin, across the blood-brain and the blood-cerebrospinal fluid barriers.

[D-Penicillamine2,5] enkephalin (DPDPE) is an enzymatically stable, delta-opioid receptor-selective peptide, which produces analgesia when given intracerebroventricularly. However, because only modest analgesic effects were seen after subcutaneous administration of DPDPE, it has been inferred that it does not cross the blood-brain barrier well. In this present study, a vascular brain perfusion technique in anesthetized rats was used to measure directly whether [3H]DPDPE could cross the blood-brain and/or the blood-CSF barriers. The results indicated that the brain uptake of [3H]DPDPE was significantly greater than that of [14C]sucrose, a vascular marker (p < 0.01), and than that of [3H]DPDPE into the CSF (p < 0.01). Furthermore, HPLC analysis confirmed the integrity of the 3H to DPDPE and demonstrated that intact [3H]DPDPE entered the brain. Although 1 mM leucine-enkephalin failed to inhibit uptake of [3H]DPDPE, unlabeled DPDPE (100 microM) caused a significant inhibition of the brain uptake (p < 0.01) but not the CSF uptake of [3H]DPDPE. These data provide evidence that intact [3H]DPDPE enters the CNS of anesthetized rats by saturable and nonsaturable mechanisms. In addition, the saturable mechanism is likely to be found at the blood-brain barrier, with the blood-CSF barrier playing only a minor role in the brain uptake of this peptide.

Animals↗
PubMed1996

Evaluation of a polymerase chain reaction-based assay for diagnosis of Wuchereria bancrofti infection.

To assess the utility of a polymerase chain reaction (PCR)-based method for diagnosis of Wuchereria bancrofti infection, blood, plasma, and paraffin-embedded tissue samples were tested using a PCR-based assay that detects a W. bancrofti-specific repetitive DNA sequence. The assay was positive in 100 microL of blood from 40 of 42 microfilaria-positive subjects, the 2 subjects with negative assays having microfilarial counts of 1. Samples from 127 uninfected subjects were PCR-negative. The assay was also positive in 7 of 10 daytime samples in regions where infection is nocturnally periodic; PCR amplification from paraffin-embedded sections established the diagnosis of W. bancrofti infection in another 2 cases. A microtiter ELISA plate-based method was developed for rapid evaluation of large numbers of samples. These results suggest that this PCR-based assay will be useful in diagnosis of W. bancrofti infection in a variety of clinical settings.

Adult↗
PubMed1996

Innovative strategies for promoting clinical scholarship: a holistic approach.

The article discusses a holistic approach to clinical scholarship by examining dimensions of scholarship and patterns of knowing. Innovative clinical teaching strategies in relation to these dimensions of scholarship and patterns of knowing are identified. Experiential learning, content mapping, and portable patient problem packs are explored. Knowledge building and creativity in the process of educating students are imperative. Nurse educators are challenged to develop new paradigms for nursing education that create a dynamic learning environment and result in enhanced clinical scholarship.

Clinical Competence↗
PubMed1996

Brain-derived neurotrophic factor and peripheral nerve regeneration: a functional evaluation.

The potential benefit of brain-derived neurotrophic factor (BDNF) on motor-nerve regeneration after transection injury in 24 adult rats was evaluated after entubulation repair. Gait analysis for ankle angle and tension transduction device (TTD) strain-gauge measurements yielded functional evaluation of regeneration. The BDNF (15 mg/mL) or phosphate buffered saline (control) was injected into the silicone elastomer (Silastic) channel. Gait analysis performed 0, 2, 4, 6, 10, and 12 weeks after injury demonstrated a significant difference between uninjured and injured legs of 23 and 43 degrees, respectively (P<.001, analysis of variance). The TTD evaluation 13 weeks after injury demonstrated a significant decrease in force development of injured compared to uninjured legs, 148 and 58 g, respectively (P<.001). No functional benefits were demonstrated between BDNF-treated versus control-treated animals in either model for a single exposure to BDNF.

Animals↗
PubMed1996

The dental management of children with sickle cell disease and beta-thalassaemia: a review.

This paper reviews two groups of haemoglobinopathies: sickle cell disorders and beta-thalassaemias. The medical aspects and dental management of children with these conditions are discussed. These conditions are rare in the white indigenous population of the UK but affect a sizeable proportion of the minority ethnic community. Dentists need to be aware of the medical implications for patients who have these disorders and should co-ordinate their dental care accordingly.

Anemia, Sickle Cell↗
PubMed1996

The biological activity of the corticotropin-releasing hormone receptor-adenylate cyclase complex in human myometrium is reduced at the end of pregnancy.

We recently suggested that placentally derived CRH might influence human parturition via specific receptor mechanisms. We identified a human myometrial CRH receptor that changes to a high affinity state in the later stages of pregnancy and becomes coupled to the adenylate cyclase system. The purpose of this study was to investigate the functional capacity of this receptor in myometrial tissue obtained from women being delivered electively by cesarian section at term (38-40 weeks gestation) and preterm (30-35 weeks gestation) before the onset of labor. Myometrial membrane suspensions were prepared by differential centrifugation, and the production of cAMP after stimulation with various test substances was measured by RIA. In preterm myometrium, both human CRH and cholera toxin stimulated cAMP production. This effect was significantly reduced in term myometrium. The adenylate cyclase was functionally active in term myometrium, as demonstrated by the use of forskolin. Furthermore, pertussis toxin pretreatment of term myometrial membranes did not increase the response to CRH. These results suggest that in human pregnant myometrium at term, there is a modification in the coupling mechanisms between CRH receptors and the catalytic component of adenylate cyclase, resulting in a reduction of CRH-stimulated cAMP production.

Adenylate Cyclase Toxin↗
PubMed1996

A polymerase chain reaction assay for detection of the parasite Wuchereria bancrofti in human blood samples.

To identify Wuchereria bancrofti DNA sequences that could be used as the basis for a simple and rapid parasite detection assay, a genomic library of W. bancrofti was constructed and screened for highly repeated DNA. The repeat found with the highest copy number was 195 basepairs (bps) long, 77% AT, and 300 copies per haploid genome. This sequence was designated the Ssp I repeat because it has a unique recognition site for that restriction endonuclease in all or most of the repeat copies. The Ssp I repeat DNA family is dispersed, genus-specific, and exists in all of the different geographic isolates of W. bancrofti tested. Based on DNA sequence analysis of this repeat, we have developed an assay to detect very small quantities of W. bancrofti DNA using the polymerase chain reaction (PCR). With this PCR assay, the Ssp I repeat was detected in as little as 1 pg of w. bancrofti genomic DNA (about 1% of the DNA in one microfilaria) added to 100 microliters of human blood. The PCR assay also amplified Ssp I repeat DNA from geographic isolates of W. bancrofti from around the world but not from other species of filariae or from human or mosquito DNA. Microfilaria-positive human blood samples collected in Mauke, Cook Islands were shown to be Ssp I PCR-positive, while microfilaria-negative samples were PCR-negative. The specificity and sensitivity of the Ssp I PCR assay indicates that this approach has significant potential for improved screening of large human populations for active W. bancrofti infection.

Animals↗
PubMed1996

Absence of a sertraline-mediated effect on the pharmacokinetics and pharmacodynamics of carbamazepine.

UNLABELLED: A double-blind, randomized, placebo-controlled study was conducted in 14 healthy male volunteers to assess the effects of sertraline on the pharmacokinetics and pharmacodynamics of carbamazepine. METHOD: Subjects received carbamazepine 200 mg once daily for 2 days and every 12 hours thereafter. On Days 16 to 32, subjects also received either sertraline or placebo daily. The dose of sertraline was increased from 50 to 200 mg daily over 7 days; the 200-mg dose was given for 10 days. Samples for pharmacokinetic analyses were obtained on Days 15 and 32; trough plasma concentrations of carbamazepine and its principal metabolite, carbamazepine-10, 11-epoxide (CBZ-E), were determined daily beginning on Day 13. Cognitive function testing was performed on Day 1 before carbamazepine dosing (baseline), Day 15 (carbamazepine alone), and Day 32 (carbamazepine plus sertraline or placebo). RESULTS: There were no significant differences between the sertraline and placebo groups in any of the pharmacokinetic parameters for carbamazepine or CBZ-E. Carbamazepine alone impaired cognitive function. The addition of sertraline did not potentiate these effects. Side effects were reported by 2 subjects in each group, but none were severe. CONCLUSION: These findings indicate that sertraline does not affect the pharmacokinetics of carbamazepine or its principal metabolite and does not potentiate the cognitive effects of carbamazepine.

1-Naphthylamine↗
PubMed1996

Absence of effect of sertraline on the pharmacokinetics and pharmacodynamics of phenytoin.

UNLABELLED: A double-blind, randomized, placebo-controlled study assessed the effects of sertraline on the pharmacokinetics and pharmacodynamics of phenytoin in 30 healthy male volunteers. METHOD: All subjects received phenytoin throughout the study. The dose of phenytoin was 100 mg three times daily; steady-state trough plasma phenytoin concentrations were determined on Day 6. Concurrent treatment with sertraline (16 subjects) or placebo (13 subjects) was initiated on Day 8 and continued throughout the study in those subjects whose trough plasma phenytoin concentrations were between 5 and 20 micrograms/mL. The dose of sertraline was increased from 50 to 200 mg/day over 7 days; the 200-mg dose was then administered for 10 days. The plasma phenytoin concentration-time profile was determined on Day 7 before the start of sertraline or placebo dosing and at the end of dosing on Day 24. Psychometric testing was done before and after dosing on Days 0, 7, and 24. RESULTS: There were no significant differences between the sertraline group and the placebo group in the pharmacokinetic parameters of phenytoin. In addition, there was no indication that administration of phenytoin alone or concomitant administration of phenytoin and sertraline impaired cognitive function. Treatment-related side effects, primarily headache and nausea, were reported in 8 of 16 sertraline subjects and in 5 of 13 placebo subjects. Two subjects in the sertraline group withdrew because of side effects (rash), and 3 subjects in the placebo group withdrew because of side effects (rash and headache). CONCLUSION: High dosages of setraline did not affect the pharmacokinetics or the pharmacodynamics of phenytoin in ths study performed in healthy volunteers.

1-Naphthylamine↗
PubMed1996

Absence of effect of sertraline on time-based sensitization of cognitive impairment with haloperidol.

UNLABELLED: This double-blind, randomized, placebo-controlled study evaluated the effects of haloperidol alone and haloperidol plus sertraline on cognitive and psychomotor function in 24 healthy male subjects. METHOD: All subjects received placebo on Day 1 and haloperidol 2 mg on Days 2 and 25. From Days 9 to 25, subjects were randomly assigned to either sertraline (12 subjects) or placebo (12 subjects); the sertraline dose was titrated from 50 to 200 mg/day from Days 9 to 16, and remained at 200 mg/day for the final 10 days of the drug administration period. Cognitive function testing was performed before dosing and over a 24-hour period after dosing on Days 1, 2, and 25. RESULTS: Impairment of cognitive function was observed 6 to 8 hours after administration of haloperidol on Day 2 but was not evident 23 hours after dosing. When single-dose haloperidol was given again 25 days later, greater impairment with earlier onset was noted in several tests in both treatment groups, suggesting enhancement of this effect. There was no indication that sertraline exacerbated the impairment produced by haloperidol since an equivalent effect also occurred in the placebo group. Three subjects (2 on sertraline and 1 on placebo) withdrew from the study because of side effects. Ten subjects in each group reported side effects related to treatment. The side effect profiles of sertraline and of placebo were similar. CONCLUSION: Haloperidol produced a clear profile of cognitive impairment that was not worsened by concomitant sertraline administration.

1-Naphthylamine↗
PubMed1996

Oral health and health related behaviours among three-year-old children born to first and second generation Pakistani mothers in Bradford, UK.

Many young Muslim children whose families originated from the Indian sub-continent have poorer levels of oral health than their indigenous White peers, but it is unclear whether and to what extent subsequent generations may be similarly disadvantaged. This study aimed to compare dental health and associated behavioural attributes among United Kingdom-born three-year-old children of first and second generation Pakistani Muslim mothers resident in areas of social deprivation in Bradford, West Yorkshire. Multi-lingual interviews completed a home-based, semi-structured questionnaire, and a dental examination was conducted at a subsequent visit on 226 children, 117 with Pakistan-born mothers and 109 born in the UK. When the two generation groups were compared, no differences were observed in infant feeding practices, oral hygiene routines or dental attendance patterns, in mothers' attendance at ante-natal classes, or their knowledge of caries prevention. However, a higher proportion of UK-born mothers were able to speak English and reported that they had attended a dentist themselves, had received advice there, and were better informed of categories exempt from dental charges. A 24-hour retrospective qualitative dietary recall indicated that children of UK-born mothers consumed, on average, more frequent intakes of foods classified in the 'bread and cereal' group and of sweet drinks at meal times. While there were no significant differences in the proportion who were cavity free, children of UK-born mothers had higher mean caries experience (dmft=2.30) compared with those of Pakistan-born mothers (dmft=1.38). It was concluded that the total burden of dental caries experience among a subsequent generation of Pakistani children was higher than that of the previous generation. Poor dental health is likely to remain a challenge in this community for the foreseeable future.

Adult↗
PubMed1996

Blood-to-central nervous system entry and stability of biphalin, a unique double-enkephalin analog, and its halogenated derivatives.

Biphalin (Tyr-D-Ala-Gly-Phe-NH)2 is a unique opioid peptide analog that contains two active enkephalin pharmacophores and is more potent than morphine and etorphine in eliciting analgesia after intrathecal administration. After systemic administration, only a small amount was detected in the brain, but analgesia was observed. Because halogenation of enkephalin analogs has been shown to increase the brain uptake after systemic administration, our research group synthesized both p-[Cl-Phe4,4']biphalin and p-[F-Phe4,4']biphalin. The aim of the present study was to characterize and compare the blood-to-central nervous system (CNS) pharmacokinetics and biological stability of biphalin and related halogenated analogs. The initial screening used an in vitro blood-brain barrier model and identified p-[Cl-Phe4,4')biphalin as the enkephalin analog with the best potential for greater CNS entry. The CNS uptake and stability of biphalin and p-[Cl-Phe4,4']biphalin was examined further using an in situ brain perfusion technique coupled to high-performance liquid chromatography analysis. Both biphalin and its chlorohalogenated analog, were found to significantly enter the CNS through both the blood-brain and blood-cerebrospinal fluid barriers. Chlorohalogenation of biphalin was shown to both improve CNS entry, most likely through an enhancement in lipophilicity, and increase biological stability. This study suggests that incorporation of chlorohalogens at the p-Phe4,4' position is a promising structural modification in the development of biphalin as a successful opioid drug for the clinic.

Analgesics↗