Search PubMed⌕ Search

Biomedical subjects

R Williams

Publications and source records attributed to R Williams.

At least 55 records · Page 3Linked to original sources
PubMed2004

Learning and new discovery with cyclosporine in the Cambridge-King's Programme: a personal view.

Immunosuppressive regimens in the early precyclosporine days of liver transplantation for the Cambridge-King's Programme from 1968 until the early 1980s were inadequate in the control of rejection. The consequent use of high-dose steroids led to many infections, which seriously affected outcome. Nevertheless, occasional patients did well but a consistent increase in survival was not seen until after the introduction of cyclosporine and experience was gained with its proper usage in terms of toxicity. The development of Neoral with its greater oral bioavailability marked a major step forward in the development of the drug. Whether 2-hour postdose monitoring with reduction in rejection frequency and toxicity as described recently better match results with tacrolimus in comparison-controlled trials remains to be determined.

Cyclosporine↗
PubMed2004

A model to study total hepatic ischemia-reperfusion injury.

BACKGROUND: Most experimental animal models for studying hepatic ischemia-reperfusion injury (IRI) involve partial or segmental ischemia of the liver or a portocaval shunt procedure to avoid mesenteric congestion. However, these do not reflect the global ischemia that occurs during liver transplantation. A rabbit model of total hepatic ischemia without a portocaval shunt is described. METHODS: Twenty male New Zealand white rabbits (3.5 +/- 0.3 kg) were allocated to four groups: group 1 (n = 5), sham-operated; group 2 (n = 5), 20-minute total hepatic ischemia; group 3 (n = 5), 25-minute total hepatic ischemia; and group 4 (n = 5), 30-minute total hepatic ischemia. Total hepatic ischemia was induced by occluding the portal inflow vessels (portal vein and artery) with an atraumatic vascular loop and were measurements taken for 2 hours during reperfusion. RESULTS: A total hepatic ischemia of 30 minutes caused severe liver injury resulting in cardiac arrest at 2 hours of reperfusion in all five animals due to metabolic acidosis. Twenty minutes of total ischemia was tolerated and did not produce significant liver injury. Twenty-five minutes of total ischemia was tolerated but at 2 hours of reperfusion, resulted in significant liver injury (68 +/- 41, 283.0 +/- 20.5, and 835.2 +/- 52.7 U/L) compared with the sham-operated group (serum ALT, 25.4 +/- 2.7; serum AST, 47.4 +/- 3.0; serum LDH, 307.6 +/- 44.4 U/L; P < .003). CONCLUSIONS: Rabbits can tolerate 25 minutes of total hepatic ischemia without a portosystemic shunt. This 25-minute ischemia model simulates operative conditions during liver transplantation and will be valuable in studies modulating IRI.

Alanine Transaminase↗
PubMed2004

Epidemiology of diabetic retinopathy and macular oedema: a systematic review.

AIMS: To systematically review the literature on the prevalence and incidence of diabetic retinopathy (DR) and macular oedema (MO). METHODS: A search of the bibliographic databases (Medline, Embase, CINAHL) was conducted up to October 2001. Selected relevant studies were scrutinized and included in the review. RESULTS: A total of 359 studies were included. The studies were reported in nearly 100 different journals and in over 50 countries. The majority of the studies were US-based, with large studies such as the Wisconsin Epidemiologic Study of Diabetic Retinopathy dominating the literature. The studies were quite dated and highly heterogeneous in nature in terms of patient selection with variable inclusion criteria (age range, gender, diabetes duration and type, ethnicity, comorbidity, and DR status, assessment, and classification). CONCLUSIONS: There are inconsistencies between epidemiological studies, and differences in study methods may contribute to conflicting reports of prevalence and incidence of DR and MO in diabetic populations. As new therapies for DR and its associated complications emerge, the need to capture and monitor new epidemiological data becomes increasingly important to be able to assess the impact and effectiveness of these therapies. Robust, longitudinal capture of patient data is, therefore, essential to evaluate the impact of current practice on the epidemiology of diabetic eye complications.

Diabetic Retinopathy↗
PubMed2004

A molecular cell biology of lithium.

Lithium (Li(+)), a mood stabilizer, has profound effects on cultured neurons, offering an opportunity to investigate its cellular biological effects. Here we consider the effect of Li(+) and other psychotropic drugs on growth cone morphology and chemotaxis. Li(+) inhibits GSK-3 (glycogen synthase kinase-3) at a therapeutically relevant concentration. Treated cells show a number of features that arise due to GSK-3 inhibition, such as altered microtubule dynamics, axonal branching and loss of semaphorin 3A-mediated growth cone collapse. Li(+) also causes growth cones to spread; however, a similar effect is seen with two other mood stabilizers, valproic acid and carbamazepine, but without changes in microtubules or axon branching. This common effect of mood stabilizers is mediated by changes in inositol phosphate signalling, not GSK-3 activity. Given the presence of neurogenesis in the adult brain, we speculate that changes in growth cone behaviour could also occur during treatment of mental disorders.

Animals↗
PubMed2004

Tamponade efficiency of perfluorohexyloctane and silicone oil solutions in a model eye chamber.

BACKGROUND/AIM: As no single tamponade agent yet fulfils all the requirements of a long term inferior tamponade, attempts have been made to mix tamponade materials. This study investigated perfluorohexyloctane (F(6)H(8)) and silicone oil solutions designed to take advantage of the high specific gravity and interfacial tension of the F(6)H(8) and the high viscosity of silicone oil. METHODS: Solutions of three different densities were examined (1.01, 1.03 and 1.06 g/cm(3)) inside transparent chambers made of surface modified poly(methylmethacrylate) (PMMA). RESULTS: Compared to F(6)H(8), the solutions had poorer contact with hydrophilic surface of the chambers. The higher the specific gravity of the solution, the better was the contact. The solution with a specific gravity 1.01 g/cm(3) is probably of no use clinically. CONCLUSION: The model eye chamber made of surface modified PMMA is an efficient way of screening and choosing solutions with promising physical properties. Solutions of silicone oil with F(6)H(8) in other proportions or with other semifluorinated alkanes may be of interest.

Chemical Phenomena↗
PubMed2003

Characterization of the human autoimmune response to the major C-terminal epitope of the ribosomal P proteins.

Autoantibodies to the ribosomal phospho (-P) proteins P0, P1, and P2, collectively referred to as Rib-P, are specifically found in 10-40% of patients with systemic lupus erythematosus (SLE). These antibodies are believed to be correlated with lupus nephritis, hepatitis, and central nervous system involvement. The major immunoreactive epitope of these ribosomal antigens has been localized to the carboxy terminus, which is a highly conserved domain of all three proteins and contains two phosphorylated serine residues. The phosphorylated amino acids of the P proteins are known not to be critical epitope determinants. Furthermore, epitope-mapping studies have shown that the major epitope is located within the last 11 C-terminal amino acids. Using peptide arrays we identified more precisely this shared epitope as the six C-terminal amino acids GFGLFD and elucidated the molecular recognition events of anti-Rib-P antibodies at the amino acid level. We identified Phe(111) and Phe(114) of Rib-P2 as the key residues for the interaction, with further contributions of Gly-112 and Asp-115. This amino acid stretch is also present in proteins of several pathogenic micro-organisms such as Trypanosoma cruzi, Brugia malayi, Pseudomonas aeruginosa, Candida albicans, several Leishmania species, and Bartonella henselae. Using newly developed ELISA systems with a C-terminal peptide (C22) and the recombinant proteins (P0, P1, and P2) as antigens we found a high specificity of anti-Rib-P antibodies for SLE and demonstrated positive correlations with anti-U1-C, anti-Sm-B/B' and anti-D and anti-dsDNA antibodies. The sensitivity and specificity in the peptide (C22) based assay varied between 12.8%/100% and 23.4%/96.7% for SLE, depending on the assigned cutoff. In contrast to other studies, we found no significant correlation of anti-Rib-P reactivity with central nervous system manifestations or renal involvement in SLE patients. We conclude that the epitope motif GFGLFD in the C-termini of the ribosomal P proteins is the key determinant of anti-Rib-P antibodies, and that the C22 peptide and the recombinant proteins can be used equally well for the detection of anti-Rib-P antibodies. The role of the major Rib-P epitope in the development of anti-ribosomal P antibodies and in the pathogenesis of SLE remains a subject of further investigation.

Amino Acid Sequence↗
PubMed2003

Negative self-imagery blocks inferences.

Previous research has shown that, unlike non-anxious individuals, people with social phobia fail to generate non-threatening inferences when ambiguous social information is first encountered (i.e. 'on-line'; Hirsch and Mathews Journal of Abnormal Psychology, 109 (2000) 705-712). Patients with social phobia also report negative self-imagery in social situations, while individuals without high social anxiety do not. The negative self-imagery in social phobia may prevent the generation of non-threatening inferences. If so, then training non-anxious individuals to hold in mind a negative self-image should remove the 'on-line' non-threat inferential bias normally evident in this population. In the present study, low anxious volunteers were allocated to negative image training or a control task that did not manipulate self-imagery. Following negative image training, or the control task, volunteers read descriptions of job interviews and at certain points during the text performed lexical decisions. Some decisions were made after ambiguous text that could have been interpreted in both a threatening and a non-threatening manner. In a baseline condition, decisions were made following the text for which there was only one possible inference (either threat or non-threat). The results for the control group replicated earlier findings of a non-threat inferential bias for non-anxious individuals. In contrast, and as predicted, non-anxious volunteers who were trained to hold a negative image in mind lacked any non-threatening inferential bias, and also experienced higher levels of state anxiety.

Adult↗
PubMed2003

Genome-wide scan in a large complex pedigree with predominantly male schizophrenics from the island of Kosrae: evidence for linkage to chromosome 2q.

It is widely accepted that founder populations hold promise for mapping loci for complex traits. However, the outcome of these mapping efforts will most likely depend on the individual demographic characteristics and historical circumstances surrounding the founding of a given genetic isolate. The 'ideal' features of a founder population are currently unknown. The Micronesian islandic population of Kosrae, one of the four islands comprising the Federated States of Micronesia (FSM), was founded by a small number of settlers and went through a secondary genetic 'bottleneck' in the mid-19th century. The potential for reduced etiological (genetic and environmental) heterogeneity, as well as the opportunity to ascertain extended and statistically powerful pedigrees makes the Kosraen population attractive for mapping schizophrenia susceptibility genes. Our exhaustive case ascertainment from this islandic population identified 32 patients who met DSM-IV criteria for schizophrenia or schizoaffective disorder. Three of these were siblings in one nuclear family, and 27 were from a single large and complex schizophrenia kindred that includes a total of 251 individuals. One of the most startling findings in our ascertained sample was the great difference in male and female disease rates. A genome-wide scan provided initial suggestive evidence for linkage to markers on chromosomes 1, 2, 3, 7, 13, 15, 19, and X. Follow-up multipoint analyses gave additional support for a region on 2q37 that includes a schizophrenia locus previously identified in another small genetic isolate, with a well-established recent genealogical history and a small number of founders, located on the eastern border of Finland. In addition to providing further support for a schizophrenia susceptibility locus at 2q37, our results highlight the analytic challenges associated with extremely large and complex pedigrees, as well as the limitations associated with genetic studies of complex traits in small islandic populations.

Adolescent↗
PubMed2003

Remuneration for blood donation and attitudes towards blood donation and receipt in Leeds.

In a survey of attitudes towards remuneration for blood donation in Leeds, the following questions were completed by 489 adults (N), of whom 89 were regular donors, 105 were lapsed donors and 295 had never donated: 'If you needed blood, would you be content if the donor had been paid: yes/no'. 'If I were paid enough I would be less/equally/more likely to donate blood '. The majority (67.7%) of potential recipients would be content if the donor had been paid. The prospect of remuneration made 16.4% of respondents more likely and 14.5% less likely to donate. As the difference is less than 2% of N, offering remuneration may not lead to a significant increase in the number of donations. A statistical comparison (chi2 = 45, d.f. = 2, P << 0.001) showed associations between the responses 'more likely to donate if paid' and 'content to receive blood from a paid donor', and between the responses 'less likely to donate if paid' and 'not content to receive blood from a paid donor'. Age distributions are presented for the donor status categories and the responses to the main questions. Of 129 people who stated a minimum, nonzero payment that would persuade them to donate, 103 (80%) suggested pound sterling 10 or less.

Adolescent↗
PubMed2003

Assessing progression and efficacy of treatment for diabetic retinopathy following the proliferative pathway to blindness: implication for diabetic retinopathy screening in Taiwan.

AIMS: The natural history and treatment efficacy of diabetic retinopathy (DR) play important roles in the evaluation of screening. Therefore, the natural history of DR and rates of transition after treatment (including metabolic control and laser photocoagulation) from no diabetic retinopathy (NDR) to blindness were quantified. METHODS: We studied a cohort of 795 patients with diabetes mellitus (DM) receiving fundus examination in the ophthalmology out-patient department of one medical centre between 1 January 1990 and 31 December 1992 in Taiwan. Follow-up data until 31 December 1998 were collected by chart review. Two multistate Markov models were proposed to assess the efficacy of the treatment regime in reducing progression to blindness. RESULTS: The average times spent in states (i) no diabetic retinopathy (NDR), (ii) background diabetic retinopathy (BDR), (iii) preproliferative diabetic retinopathy (PPDR), and (iv) proliferative retinopathy (PDR) were 10.86 years, 8.33 years, 1.67 years, and 2.17 years, respectively. Early detection of PPDR may lead to a 60% reduction in PDR and an 83% reduction in blindness. Simulated results based on these parameters show that an annual screening programme, a biennial screening regime and a 4-yearly screening regime can lead to 54% (95% confidence interval (CI): 44-62%), 51% (95% CI: 41-59%), and 46% (95% CI: 36-54%) reductions in blindness, respectively. CONCLUSIONS: Assessing the progression of DR following the proliferative pathway in this study suggests that screening for DR is worthwhile and that a 4-year interscreening interval for patients as yet without DR may be justified.

Adult↗
PubMed2003

Opportunistic mycobacterial granuloma in a cat associated with a member of the Mycobacterium terrae complex.

An 18-month-old domestic short-haired neutered male cat presented with a nodular dermal thickening on a digit. Biopsy demonstrated pyogranulomatous inflammation with moderately frequent acid-fast bacilli. A member of theMycobacterium terrae complex was isolated. There was no evidence of systemic involvement. Treatment was initiated with enrofloxacin, rifampicin and clarithromycin. After 2 months there was no longer any clinically apparent dermal thickening. Treatment was continued for a further 3 months using enrofloxacin and rifampicin.

Animals↗
PubMed2003

Genetic susceptibility to vaginal candidiasis.

To enable future studies on host resistance factors and therapy, inbred and outbred mouse strains were tested for susceptibility to vaginal candidiasis. Groups of mice were given 0.5 mg estradiol 3 days before and 4 days after intravaginal challenge with a suspension of Candida albicans. On day 1 after challenge, a swab was used to quantitate infection in all groups and to assure equivalent infection levels. On day 6, this was repeated and the experiment was terminated. BALB/c, the reference strain in repeated experiments, was susceptible, showing persistent infection with levels of cfu at day 6 falling within a range between a twofold decrease and a fourfold increase in relation to day 1 levels. CD-1 outbred mice were markedly resistant, with day 6 cfu levels showing a 74- to 87-fold decrease with respect to day 1 levels, whereas other outbred strains (CF-1, SW, ICR) were susceptible. A BALB/c substrain (ByJ) was also susceptible. With exception of CBA/J, which showed modest resistance, all inbred strains were similarly susceptible, including DBA/2, AKR/J, C3H/HeN, A/J and C57BL/6. The differences between CD-1 and BALB/c mice were also seen with a second C. albicans isolate. Our results show susceptibility to vaginal candidiasis is independent of the major histocompatibility locus H2 haplotype and any effect ascribable to use of particular commercial mouse suppliers. Differences among mouse strains in susceptibility to C. albicans, as seen in previous studies involving nonvaginal challenge routes, are not reflected in this vaginal candidiasis model; in general, such resistance patterns appear specific to the route of challenge administration. The resistance seen in mouse strain CD-1 is of particular interest in that CD-1 is known to be resistant to endocrine disruption by estrogen. Our results suggest this estrogen insensitivity may have broad-ranging effects on processes other than gametogenesis, including vaginal susceptibility to candidiasis.

Animals↗
PubMed2003

Weekly oral paclitaxel as first-line treatment in patients with advanced gastric cancer.

BACKGROUND: Pharmacokinetic study has shown that co-administration of cyclosporin A (CsA), which acts as a P-glycoprotein (P-gp) and CYP-3A blocker, resulted in an 8-fold increase in the systemic exposure of oral paclitaxel. Two doses of oral paclitaxel on 1 day in combination with CsA resulted in higher systemic exposure than single dose administration. PATIENTS AND METHODS: In this phase II study, chemonaïve patients with advanced gastric cancer received oral paclitaxel weekly in two doses of 90 mg/m(2) on the same day; CsA (10 mg/kg) was given 30 min before each dose of oral paclitaxel. RESULTS: In 25 patients, the main toxicities were: nausea CTC grade 2/3, 10 patients (40%); vomiting grade 2/3, 4 patients (20%); diarrhea grade 2/3, 6 patients (24%); neutropenia grade 3/4, 5 patients (20%). In the 24 evaluable patients, eight partial responses were observed, resulting in an overall response rate (ORR) of 33% [95% confidence interval (CI) 18% to 52%]. Eleven patients had stable disease (46%) and 5 patients showed progressive disease (21%). The ORR in the total population was 32% (95% CI 17% to 50%). The median time to progression was 16 weeks (95% CI 9-22). Pharmacokinetic analyses revealed that the mean area under the plasma concentration-time curve (AUC) of orally administered paclitaxel (+/- standard deviation) was 3757.6 +/- 939.4 ng.h/ml in week 1 and 3928.4 +/- 1281 ng.h/ml in week 2. The intrapatient variability in the AUC was 12%. CONCLUSIONS: Oral paclitaxel in combination with CsA is both active and safe in chemonaïve patients with advanced gastric cancer. Toxicities were mainly gastrointestinal.

Adenocarcinoma↗
PubMed2003

Descriptive epidemiology of adult critical care transfers from the emergency department.

AIMS: To describe the nature, frequency, and characteristics of adult critical care transfers originating from the emergency department (ED). METHODS: A one year prospective regional descriptive study using multiple data sources of all critically ill adults transferred from an ED or a minor injuries unit (MIU) within the former Yorkshire Regional Health Authority Area or into a regional critical care facility if originating from an ED or MIU elsewhere. RESULTS: 29 EDs transferred 349 adults into the regional critical care facilities. The median number of transfers per department within the region was 18 (range 1 to 42). Seventeen were transferred from outside the region. A total of 263 (75%) patients were transferred for specialist care and 76 (22%) for non-clinical reasons. Altogether 294 (84%) were admitted to intensive care or a high dependency unit at the receiving hospital. The in-hospital documented mortality rate was 26%. A total of 170 patients (49%) had traumatic pathology of which 101 were principally transferred for management of a head injury. Median time in the ED was 3 hours 5 minutes (range 11 minutes to 17 hours 47 minutes). In 146 (42%) patients the decision to transfer was primarily made by the emergency medicine clinician. A total of 251 (72%) patients were intubated. The documented critical incident rate was 15%. CONCLUSION: Trauma is the most common reason for transfer of the critically ill adult from the ED. A significant number of patients are transferred, however, with medical and surgical conditions and for non-clinical reasons. There continues to be problems with the quality of care that these patients receive. Emergency medicine clinicians must be actively involved in the development of regional critical care systems as a significant proportion of all critically ill adults transferred originate from the ED.

Adult↗
PubMed2003

Intestinal absorption of mixed micellar phylloquinone (vitamin K1) is unreliable in infants with conjugated hyperbilirubinaemia: implications for oral prophylaxis of vitamin K deficiency bleeding.

OBJECTIVE: To compare the pharmacokinetics and efficacy of oral versus intravenous mixed micellar vitamin K prophylaxis in infants with cholestatic liver disease, a known risk factor for vitamin K deficiency bleeding. DESIGN: Prospective randomised controlled study. SETTING: Paediatric Liver Unit. PATIENTS: Forty four infants less than 6 months of age with conjugated hyperbilirubinaemia. MAIN OUTCOME MEASURES: Serum concentrations of vitamin K(1) and undercarboxylated prothrombin (PIVKA-II; a sensitive functional indicator of vitamin K status) before and for up to four days after a single dose of mixed micellar K(1) 1 mg intravenously or 2 mg orally. Comparison of K(1) levels 24 hours after oral K(1) with those from 14 healthy newborns given the same dose. RESULTS: At admission, 18 infants (41%) had elevated levels of serum PIVKA-II and eight (18%) had low K(1) concentrations, indicative of subclinical vitamin K deficiency. Median serum K(1) concentrations were similar in the oral and intravenous groups at baseline (0.92 v 1.15 ng/ml), rising to 139 ng/ml six hours after intravenous K(1) but to only 1.4 ng/ml after oral administration. In the latter group, the low median value (0.95 ng/ml) and wide range (< 0.15-111 ng/ml) of serum K(1) compared unfavourably with the much higher levels (median 77, range 11-263 ng/ml) observed in healthy infants given the same oral dose, and suggested impaired and erratic intestinal absorption in cholestatic infants. The severity of malabsorption was such that only 4/24 (17%) achieved an incremental rise in serum K(1) > 10 ng/ml. CONCLUSIONS: The intestinal absorption of mixed micellar K(1) is unreliable in infants with conjugated hyperbilirubinaemia. Given the strong association between cholestasis and late vitamin K deficiency bleeding, these data provide an explanation for the failure of some oral vitamin K(1) prophylaxis regimens in infants with latent cholestasis.

Administration, Oral↗