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Biomedical subjects

R Williams

Publications and source records attributed to R Williams.

At least 145 records · Page 8Linked to original sources
PubMed2000

Preoperative mobilization of circulating dendritic cells by Flt3 ligand administration to patients with metastatic colon cancer.

PURPOSE: To evaluate preoperative dendritic cell (DC) mobilization and tumor infiltration after administration of Flt3 ligand (Flt3L) to patients with metastatic colon cancer. PATIENTS AND METHODS: Twelve patients with colon cancer metastatic to the liver or lung received Flt3L (20 microg/kg/d subcutaneously for 14 days for one to three cycles at monthly intervals) before attempted metastasectomy. The number and phenotype of DCs mobilized into peripheral-blood mononuclear cells (PBMCs) were evaluated by flow cytometry. After surgical resection, metastatic tumor tissue was evaluated for DC infiltration. In vivo immune responses to recall antigens were measured. RESULTS: After Flt3L administration, on average, the total number of leukocytes in the peripheral blood increased from 5.9 +/- 1.0 x 10(3)/mm(3) to 11.2 +/- 3.8 x 10(3)/mm(3) (mean +/- SD, P: =. 0001). The percentage of CD11c(+)CD14(-) DCs in PBMCs increased from 2.4% +/- 1.8% to 8.8% +/- 4.7% (P: =.004). Delayed-type hypersensitivity (DTH) responses to recall antigens (CANDIDA:, mumps, and tetanus) showed marginally significant increases in reactivity after Flt3L administration (P: =.06, P: =.03, and P: =.08, respectively). An increase in the number of DCs was observed at the periphery of the tumors of patients who received Flt3L compared with those of patients who had not. CONCLUSION: Flt3L is capable of mobilizing DCs into the peripheral blood of patients with metastatic colon cancer and may be associated with increases in DC infiltration in the peritumoral regions. Flt3L mobilization is associated with a trend toward increased DTH responses to recall antigens in vivo. The use of Flt3L to increase circulating DCs for cancer immunotherapy should be considered.

Adjuvants, Immunologic↗
PubMed2000

An individual bioequivalence criterion: regulatory considerations.

Over the years, concerns have been raised regarding the appropriateness of using the average bioequivalence approach for evaluation of comparability between formulations. In lieu of average bioequivalence, scientists from academia, industry and regulatory agencies have spent considerable effort and time in exploring the concepts of population and individual bioequivalence, and developing the statistical methods to assess the bioavailability metrics using these approaches. Recently, the Food and Drug Administration (FDA) has published a preliminary draft guidance entitled 'In vivo bioequivalence studies based on population and individual bioequivalence approaches'. The concept of prescribability and switchability underscores the difference between the population and individual bioequivalence approaches. The most important consideration for individual bioequivalence, the focus of this paper, rests on the assurance that products deemed bioequivalent can be used interchangeably in the target population (switchability). In addition to the comparison of averages, the individual bioequivalence approach compares within-subject variabilities and assesses subject-by-formulation interaction. The proposed criterion represents substantial departure from the current practice and thus has resulted in extensive public discussion. In contrast to the current average bioequivalence procedure, the proposed individual bioequivalence approach offers flexible equivalence criteria based on the individual therapeutic window and variability of the reference drug product. The proposed criterion rewards manufacture of less variable drug products, allows scaling criteria for highly variable/narrow therapeutic range drugs, and promotes the use of subjects from the general population in bioequivalence studies. The FDA is currently considering various approaches for resolution of issues raised from the public debate on the subject-by-formulation interaction term, statistical methods and resource implications.

Area Under Curve↗
PubMed2000

The beta-subunit of the hepatocyte growth factor/scatter factor (HGF/SF) receptor phosphorylates and associates with CrkII: expression of CrkII enhances HGF/SF-induced mitogenesis.

CrkII, a 40 kDa adaptor possessing a Src homology (SH)2 domain followed by two SH3 domains, although not endowed with catalytic activity, participates in intracellular signalling, presumably by activating the Ras pathway. CrkII was found to be phosphorylated in response to hepatocyte growth factor/scatter factor (HGF/SF) and to associate with the beta-subunit of the HGF receptor (MET). CrkII associated with p(145betaMET) via its SH2 domain. Growth-factor-receptor-bound protein 2 (Grb2) co-immunoprecipitated with CrkII species. By transient transfection of A431 human epidermoid carcinoma cells with wild-type and dominant-negative Grb2 expression constructs lacking either the SH2 or SH3 domains, we have concluded that Grb2 does not contribute to the 'presentation' of CrkII to p(145betaMET). Overexpression of wild-type CrkII in A431 cells enhanced HGF/SF-induced proliferation, while a CrkII dominant-negative mutant lacking the SH2 domain prevented a similar proliferating response to HGF/SF. The effect of CrkII on HGF/SF-induced proliferation was also abolished in cells co-expressing CrkII and Son-of-sevenless lacking the guanine exchange domain, suggesting that CrkII is likely to induce cell proliferation partly via the Ras/mitogen-activated protein kinase route.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Severity of iron overload in patients with sickle cell disease receiving chronic red blood cell transfusion therapy.

Chronic transfusion therapy is being used more frequently to prevent and treat the complications of sickle cell disease. Previous studies have shown that the iron overload that results from such therapy in other patient populations is associated with significant morbidity and mortality. In this study we examined the extent of iron overload as well as the presence of liver injury and the predictive value of ferritin in estimating iron overload in children with sickle cell disease who receive chronic red blood cell transfusions. A poor correlation was observed between serum ferritin and the quantitative iron on liver biopsy (mean 13.68 +/- 6.64 mg/g dry weight; R = 0.350, P =.142). Quantitative iron was highly correlated with the months of transfusion (R = 0.795, P <.001), but serum ferritin at biopsy did not correlate with months of transfusion (R = 0.308, P =.200). Sixteen patients had abnormal biopsies showing mild to moderate changes on evaluation of inflammation or fibrosis. Liver iron was correlated with fibrosis score (R = 0.50, P =.042). No complications were associated with the liver biopsy. Our data suggest that, in patients with sickle cell disease, ferritin is a poor marker for accurately assessing iron overload and should not be used to direct long-term chelation therapy. Despite high levels of liver iron, the associated liver injury was not severe.

Anemia, Sickle Cell↗
PubMed2000

Causes and outcomes of the acute chest syndrome in sickle cell disease. National Acute Chest Syndrome Study Group.

BACKGROUND: The acute chest syndrome is the leading cause of death among patients with sickle cell disease. Since its cause is largely unknown, therapy is supportive. Pilot studies with improved diagnostic techniques suggest that infection and fat embolism are underdiagnosed in patients with the syndrome. METHODS: In a 30-center study, we analyzed 671 episodes of the acute chest syndrome in 538 patients with sickle cell disease to determine the cause, outcome, and response to therapy. We evaluated a treatment protocol that included matched transfusions, bronchodilators, and bronchoscopy. Samples of blood and respiratory tract secretions were sent to central laboratories for antibody testing, culture, DNA testing, and histopathological analyses. RESULTS: Nearly half the patients were initially admitted for another reason, mainly pain. When the acute chest syndrome was diagnosed, patients had hypoxia, decreasing hemoglobin values, and progressive multilobar pneumonia. The mean length of hospitalization was 10.5 days. Thirteen percent of patients required mechanical ventilation, and 3 percent died. Patients who were 20 or more years of age had a more severe course than those who were younger. Neurologic events occurred in 11 percent of patients, among whom 46 percent had respiratory failure. Treatment with phenotypically matched transfusions improved oxygenation, with a 1 percent rate of alloimmunization. One fifth of the patients who were treated with bronchodilators had clinical improvement. Eighty-one percent of patients who required mechanical ventilation recovered. A specific cause of the acute chest syndrome was identified in 38 percent of all episodes and 70 percent of episodes with complete data. Among the specific causes were pulmonary fat embolism and 27 different infectious pathogens. Eighteen patients died, and the most common causes of death were pulmonary emboli and infectious bronchopneumonia. Infection was a contributing factor in 56 percent of the deaths. CONCLUSIONS: Among patients with sickle cell disease, the acute chest syndrome is commonly precipitated by fat embolism and infection, especially community-acquired pneumonia. Among older patients and those with neurologic symptoms, the syndrome often progresses to respiratory failure. Treatment with transfusions and bronchodilators improves oxygenation, and with aggressive treatment, most patients who have respiratory failure recover.

Acute Disease↗
PubMed2000

The role of virus-specific CD8(+) cells in liver damage and viral control during persistent hepatitis B virus infection.

Hepatitis B virus (HBV) is a noncytopathic virus, and the recognition of infected hepatocytes by HBV-specific CD8 cells has been assumed to be the central mechanism causing both liver damage and virus control. To understand the role of cytotoxic T cells in the pathogenesis of HBV infection, we used functional assays that require T cell expansion in vitro and human histocompatibility leukocyte antigen (HLA)-peptide tetramers that allow direct ex vivo quantification of circulating and liver-infiltrating HBV-specific CD8 cells. Two groups of patients with persistent HBV infection were studied: one without liver inflammation and HBV replication, the other with liver inflammation and a high level of HBV replication. Contrary to expectation, a high frequency of intrahepatic HBV-specific CD8 cells was found in the absence of hepatic immunopathology. In contrast, virus-specific T cells were more diluted among liver infiltrates in viremic patients, but their absolute number was similar because of the massive cellular infiltration. Furthermore, inhibition of HBV replication was associated with the presence of a circulating reservoir of CD8(+) cells able to expand after specific virus recognition that was not detectable in highly viremic patients with liver inflammation. These results show that in the presence of an effective HBV-specific CD8 response, inhibition of virus replication can be independent of liver damage. When the HBV-specific CD8 response is unable to control virus replication, it may contribute to liver pathology not only directly but by causing the recruitment of nonvirus-specific T cells.

CD8-Positive T-Lymphocytes↗
PubMed2000

Immunopathogenesis of hepatitis B virus recurrence after liver transplantation.

BACKGROUND AND AIMS: Hepatitis B virus (HBV) recurrence after orthotopic liver transplantation is associated with inflammatory graft changes, despite immunosuppression and donor/recipient HLA mismatch. We investigated whether immune mechanisms are involved in the pathogenesis of hepatitis B after liver transplantation. METHODS: The virus-specific T helper (Th) cell response, activation of Th1/Th2 subpopulations, donor/recipient HLA, and expression of tumor necrosis factor (TNF)-alpha/TNF receptors were determined in 28 patients who underwent transplantation for HBV-related cirrhosis (17 with HBV recurrence and 11 without recurrence) in comparison to 30 nontransplant patients with chronic hepatitis B. RESULTS: Orthotopic liver transplantation recipients with HBV recurrence showed significant hepatitis B core antigen-specific T-cell proliferation, comparable to nontransplant patients, which was not present in transplant recipients without recurrence. In addition, hepatic and serum interleukin (IL)-2, interferon-gamma, and TNF-alpha were enhanced, without changes in IL-4 and IL-10. Phenotypically, hepatic infiltrates in allografts with HBV recurrence were comprised of CD4+ lymphocytes and macrophages with a correlation between interferon-gamma- and TNF-alpha-producing cells and the degree of necroinflammatory activity. There was a marked up-regulation of both TNF-alpha receptors, significantly greater than in nontransplant patients. CONCLUSIONS: These findings suggest that despite immunosuppression, HLA class I-independent immune mechanisms have a significant pathogenic role in liver damage associated with HBV recurrence after liver transplantation.

Adult↗
PubMed2000

Cancer. How was it for you?

A scheme to research the views of cancer patients and their families in the West Midlands has identified good practice and problem areas. Ascertaining the views of users has provided a catalyst for change in the service. Further work to encourage patient participation and feedback is under way.

Feedback↗
PubMed2000

Aldose reductase inhibitors for the prevention and treatment of diabetic peripheral neuropathy.

OBJECTIVES: To assess the efficacy of aldose reductase inhibitors in the prevention, reversal or delay in the progression of diabetic peripheral neuropathy. SEARCH STRATEGY: The Cochrane Diabetes Group's database was searched and the citation lists of identified trials and previous reviews checked. Investigators identified as active in the field were approached for overlooked studies. SELECTION CRITERIA: Randomised controlled trials of aldose reductase inhibitors versus placebo, no treatment or other treatment in diabetic patients with or without clinical neuropathy. DATA COLLECTION AND ANALYSIS: Nerve conduction velocity was the only end point measured in all trials. Treatment effect was evaluated in terms of nerve conduction velocity mean difference in median and peroneal motor and median and sural sensory nerves. MAIN RESULTS: 19 trials, testing 4 different aldose reductase inhibitors for between 4 to 208 weeks duration (median 24 weeks), met the inclusion criteria for the meta-analysis. A small but statistically significant reduction in decline of median and peroneal motor nerve conduction velocities was present in the treated group when compared to the control group (weighted mean 0.66 m/s 95% CI 0.18-1.14 m/s and 0.53 m/s 95% CI 0.02-1.04m/s respectively). No clear benefit of aldose reductase inhibitor treatment was observed in either of the sensory nerves. REVIEWER'S CONCLUSIONS: Although aldose reductase inhibitor treatment has been demonstrated to diminsh the reduction in motor nerve conduction velocity, the clinical relevance of such a change in this outcome measure is uncertain. There was no effect in terms of this outcome measure in the smaller sensory fibres, degeneration of which is primarily responsible for the most common neuropathic syndrome associated with diabetes, that of severe pain and loss of sensation in the extremity leading in some cases to ulceration and eventual amputation.

Aldehyde Reductase↗
PubMed2000

Irish descent, religion and food consumption in the west of Scotland.

Mortality and morbidity of people of Irish descent in Britain is high, including from cardiovascular causes potentially linked with diet. The west of Scotland has long had a pattern of Irish migration, where migrants were poorer than the host population, and their different religious background gave rise to prolonged discrimination. This paper uses data collected in 1987/88 from the west of Scotland Twenty-07 study to test whether dietary differences due to poverty or to other factors have persisted among the descendents of these migrants. Being born of Catholic parents was the index of Irish descent used, these respondents consumed less of a factor represented by fruit, yoghurt and vegetables, and more of one represented by snacks and processed foods than the rest of the sample. The picture for those reporting current Catholic affiliation in adulthood was similar. Differences are largely associated with social class and mediated not by low income but by educational disadvantage. The findings suggest the continuation of a diet affected by limited opportunities for social mobility, and thus by obstacles to sustained educational advancement, among the descendants of Irish migrants even after several generations.

Adolescent↗
PubMed2000

Hepatitis C virus-specific T-cell reactivity during interferon and ribavirin treatment in chronic hepatitis C.

BACKGROUND & AIMS: The role of virus-specific T-helper lymphocyte reactivity in determining the therapeutic response in chronic hepatitis C virus (HCV) infection is not fully understood. METHODS: We studied CD4(+) T lymphocyte proliferation together with interferon (IFN)-gamma and interleukin (IL)-10 production from peripheral blood mononuclear cells in response to 4 HCV antigens (core, NS3, NS4, and NS5) in 25 patients with chronic hepatitis C undergoing antiviral therapy with IFN alone or in combination with ribavirin, prospectively, before, during, and after treatment. RESULTS: HCV-specific T-cell reactivity was uncommon at baseline but increased markedly during antiviral therapy, peaking around treatment weeks 4-8. Resolution of hepatitis C viremia was significantly more likely in patients who developed HCV-specific T-cell proliferation with increased IFN-gamma production. The main difference in T-cell reactivity of patients treated with IFN plus ribavirin was a significantly lower production of IL-10, whereas lymphocyte proliferation was similar to that in patients receiving IFN monotherapy. CONCLUSIONS: Treatment-induced control of hepatitis C viremia is associated with the development of HCV-specific T-cell responses with enhanced IFN-gamma and low IL-10 production. The greater efficacy of combination therapy with IFN-alpha plus ribavirin may be related to its ability to suppress HCV-specific IL-10 production.

Adult↗
PubMed2000

Expenditure on health care incurred by diabetic subjects in a developing country--a study from southern India.

The objective of the study was to estimate the direct costs of diabetes care to patients attending secondary care facilities in Madras, India. A total of 596 subjects were studied, at the Private Hospital for Diabetes Mellitus (PHD) (n = 422), and at the Government General Hospital (GGH) (n = 174). A simple interview schedule enabled a face to face interaction with the patients by the research investigator which elicited a frank and true response. The validity of the data collected was established by independent scrutiny of financial records in a sub sample. Payment bills for expenses of 140 subjects chosen on a random basis from the total sample of 422 PHD patients were compared with the costs reported by the subjects. There were no statistically significant differences both in the inpatient and the outpatient cases between the reported cost and actual cost. Median bill value (total costs)=Rs.1010 (range 195-16700) reported value=880 (110-20355) Z = -0.97, P = 0.33 and, for outpatients, median bill value=Rs.800 (195-4560) reported value=Rs. 740 (110-6320) Z = -1.56, P = 0.12. For inpatients, median bill value = Rs. 4235 (1289-16700) reported value=Rs.5459 (1285-20355), Z = -1.27, P5 years duration of diabetes spent more than those who had <5 years of duration; Rs.5570 (360-75200) and Rs.3220, (460-25600), respectively. All differences between these sub-groups were statistically significant. Within the ambit of economic aspects of the population in a developing country, the direct cost on diabetes health care is very high for many people.

Costs and Cost Analysis↗
PubMed2000

The interleukin-1 and interleukin-10 gene polymorphisms in primary sclerosing cholangitis: no associations with disease susceptibility/resistance.

BACKGROUND/AIMS: Although primary sclerosing cholangitis is believed to be an autoimmune disorder, no tissue-specific auto-antibodies have yet been identified, and the strongest support for an autoimmune aetiology comes from HLA-association studies. Three different HLA haplotypes are associated with susceptibility to the disease and one with protection from it. These HLA haplotypes, however, do not account for all of the disease risk and genes outside the HLA region may also have a role in disease pathogenesis. The aim of this study was to investigate, for the first time, polymorphic genes/sites within the interleukin-1 and interleukin-10 genes in a large well-characterised group of patients. METHODS: Ninety-six patients and 96 control subjects were studied. A single base-exchange polymorphism at position +3953 in the first exon of the IL-1B gene, a penta-allelic repeat sequence in the IL-1 receptor antagonist gene (IL-1RN) and three single base-exchange polymorphisms at positions -592, -819 and -1082 in the IL-10 gene promoter were determined by standard PCR-based techniques. RESULTS: Overall, there was no significant difference in the distribution of any of the IL-1B, IL-1RN or IL-10 alleles or genes sequences comparing patients and controls. In addition, there was no difference when the patients were stratified for the presence and absence of the HLA DRB1*0301 (DR3) allele or concurrent inflammatory bowel disease. CONCLUSION: Neither the IL-1B +3953, IL-1RN microsatellites polymorphisms on chromosome 2q13 nor the IL-10 -592, -819, -1082 promoter gene polymorphisms on chromosome 1q31-32 are associated with susceptibility or resistance to primary sclerosing cholangitis.

Adult↗