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R Williams

Publications and source records attributed to R Williams.

At least 109 records · Page 6Linked to original sources
PubMed2001

Bioavailability and bioequivalence: an FDA regulatory overview.

Bioavailability and/or bioequivalence studies play a key role in the drug development period for both new drug products and their generic equivalents. For both, these studies are also important in the postapproval period in the presence of certain manufacturing changes. Like many regulatory studies, the assessment of bioavailability and bioequivalence can generally be achieved by considering the following three questions. What is the primary question of the study? What are the tests that can be used to address the question? What degree of confidence is needed for the test outcome? This article reviews the regulatory science of bioavailability and bioequivalence and provides FDA's recommendations for drug sponsors who intend to establish bioavailability and/or demonstrate bioequivalence for their pharmaceutical products during the developmental process or after approval.

Biological Availability↗
PubMed2001

HLA class II alleles in Chinese patients with hepatocellular carcinoma.

BACKGROUND/AIMS: Recent reports of an association between human leucocyte antigens (HLA) and persistence of hepatitis B virus infection, and the familial clustering of hepatocellular carcinoma raise the question of genetic susceptibility. Previous studies have been limited to serological phenotyping of HLA B and DR antigens. The aim of this study was to use molecular genotyping to investigate HLA class II as a risk factor for the development of hepatocellular carcinoma in Hong Kong Chinese. METHODS: We determined HLA DRB1, DQA1, DQB1 and DPB1 alleles in 123 hepatitis B surface antigen positive patients (84 with hepatocellular carcinoma and 39 without) and 124 matched controls. RESULTS: The alleles DRB1*1501 (36% of HCC patients versus 19% of controls, odds ratio=2.44), DQA1*0102 (42% versus 26%, odds ratio=2.07), and DPB1*0501 (80% versus 63%, odds ratio=2.35) were significantly more common in patients with hepatocellular carcinoma, and DQA1*03 (36% versus 56%, odds ratio=0.53), DQB1*0302 (4.% versus 13%, odds ratio=0.25) and DPB1*0201 (14% versus 29%, odds ratio=0.4) were found at significantly lower frequencies. CONCLUSIONS: Although none of these associations was significant after correction for multiple testing, this report suggests that further investigations are warranted.

Adolescent↗
PubMed2001

Ethnic differences in anthropometric and lifestyle measures related to coronary heart disease risk between South Asian, Italian and general-population British women living in the west of Scotland.

AIMS: To compare anthropometric measurements and to define their behavioural associations in migrant and British-born South Asians (who have increased cardiovascular risk) or Italians (who have reduced cardiovascular risk), and in the general population of British women living in the west of Scotland. STUDY DESIGN: Cross-sectional survey of women aged 20-42 y, selected mainly from birth registration data, which included 63 migrant South Asians, 56 British-born South Asians, 39 migrant Italians, 51 British-born Italians, and 50 subjects representative of the general population of women, all resident in the west of Scotland. MEASUREMENTS: Height, weight, body mass index (BMI), and waist and hip circumferences. RESULTS: With age adjustment, migrant South Asians (0.88) had greater waist-to-hip ratio than British-born South Asians (0.84; P<0.05), while there was no difference between migrant (0.81) and British-born (0.79) Italian groups. Both migrant (P<0.001) and British-born South Asian (P<0.05) groups had higher waist-to-hip ratio and were about 3 cm shorter than Italian groups and the general population. Neither weight nor BMI were different between ethnic groups. Waist and hip circumferences were not different between migrant and British-born ethnic minority groups. Migrant South Asians (86.8 cm) had significantly (P<0.05) larger waist circumference than the general population (78.6 cm). British-born Italian women (103.0 cm) had larger hip circumference than the general population of women (96.4 cm), while other groups had similar hip circumferences. Additional adjustments for physical activity, smoking, alcohol consumption and parity reduced the differences in anthropometric measurements: only waist-to-hip ratio of migrant South Asians remained significantly (P<0.01) higher than that of the general population women. CONCLUSIONS: The adverse anthropometric indicators of cardiovascular risk in migrant South Asian women are substantially explained by their lifestyle factors and parity. British-born South Asian women are more similar to the general population women. Anthropometric differences between migrant or British-born Italians and the general population women are small.

Adult↗
PubMed2001

Autoantibodies to human cytosol: a marker of sporadic porphyria cutanea tarda.

The enzymes potentially involved in the pathogenesis of sporadic porphyria cutanea tarda (PCT) reside in liver cytosoles and microsomes. PCT is frequently associated with hepatitis C virus (HCV) infection, which is in turn associated with autoimmune manifestations. To investigate whether autoimmune reactions, possibly triggered by HCV, are involved in the pathogenesis of PCT, we measured by immunoblot autoantibodies to human cytosolic and microsomal liver fractions in 82 patients with PCT (77% with HCV infection), 105 with other liver disorders and 40 healthy subjects. Anti-liver cytosolic antibodies were more frequent in PCT patients (38/82, 46%) than in pathological controls (P < 0.05-P < 0.001) or in healthy subjects (3/40, 8%, P < 0.001). Among PCT patients, anticytosolic antibodies were more frequent in HCV positive (36/63, 57%) than in HCV negative (2/19, 11%, P < 0.05) cases. Reactivity to a 40-kDa cytosolic polypeptide was present in 20 PCT patients (19 HCV positive), being more frequent than in all pathological controls (P < 0.01-P < 0.0001). Histological activity index (P = 0.04) and antibodies to HCV (P = 0.027) - but not HCV RNA - were associated independently with anticytosolic antibodies as assessed by multivariate analysis. In contrast, frequency of antiliver microsomal antibodies was similar in PCT patients (24/82, 29%) and pathological controls (8-26%), being higher in the autoimmune hepatitis control group (23/23, 100%, P < 0.0001). In conclusion, anticytosolic antibodies, particularly to a 40-kDa polypeptide, are frequent in PCT and associated with HCV infection and severity of liver damage.

Adult↗
PubMed2001

Receptor-mediated endocytosis of Neisseria gonorrhoeae into primary human urethral epithelial cells: the role of the asialoglycoprotein receptor.

Urethral epithelial cells are invaded by Neisseria gonorrhoeae during gonococcal infection in men. To understand further the mechanisms of gonococcal entry into host cells, we used the primary human urethral epithelial cells (PHUECs) tissue culture system recently developed by our laboratory. These studies showed that human asialoglycoprotein receptor (ASGP-R) and the terminal lactosamine of lacto-N-neotetraose-expressing gonococcal lipooligosaccharide (LOS) play an important role in invasion of PHUECs. Microscopy studies showed that ASGP-R traffics to the cell surface after gonococcal challenge. Co-localization of ASGP-R with gonococci was observed. As ASGP-R-mediated endocytosis is clathrin dependent, clathrin localization in PHUECs was examined after infection. Infected PHUECs showed increased clathrin recruitment and co-localization of clathrin and gonococci. Preincubating PHUECs in 0.3 M sucrose or monodansylcadaverine (MDC), which both inhibit clathrin-coated pit formation, resulted in decreased invasion. N. gonorrhoeae strain 1291 produces a single LOS glycoform that terminates with Gal(beta1-4)GlcNac(beta1-3)Gal(beta1-4)Glc (lacto-N-neotetraose). Invasion assays showed that strain 1291 invades significantly more than four isogenic mutants expressing truncated LOS. Sialylation of strain 1291 LOS inhibited invasion significantly. Preincubation of PHUECs in asialofetuin (ASF), an ASGP-R ligand, significantly reduced invasion. A dose-response reduction in invasion was observed in PHUECs preincubated with increasing concentrations of NaOH-deacylated 1291 LOS. These studies indicated that an interaction between lacto-N-neotetraose-terminal LOS and ASGP-R allows gonococcal entry into PHUECs.

Amino Sugars↗
PubMed2001

Graft dysfunction mimicking autoimmune hepatitis following liver transplantation in adults.

In children, a type of graft dysfunction associated with autoimmune features has been described. We have identified 7 adult liver-transplant (LT) recipients from a series of over 1,000 consecutive transplant recipients who presented between 0.3 years and 7.2 years following transplantation with characteristic symptoms, autoantibody profiles, and histologic findings of autoimmune disease. The indications for transplantation were Ecstasy overdose, alcohol-related cirrhosis, primary sclerosing cholangitis (PSC) (2), primary biliary cirrhosis (PBC), hepatitis C cirrhosis, and cryptogenic cirrhosis. Two patterns of de novo autoantibody development were noted; anti-liver-kidney-microsome (LKM) antibody development at high titer in association with an aspartate transaminase (AST) > 500 and antinuclear (ANA) and antismooth muscle (AMA) antibody development at titers >1/80 with lower AST levels. All cases had elevated IgG. Liver biopsies showed changes of an autoimmune-type hepatitis with portal and periportal hepatitis in association with a marked infiltrate of plasma cells, lymphocytes, and bridging collapse. Two patients lost their grafts because of the disease. Patients were treated with reintroduction of steroids and azathioprine in cases in which it had been withdrawn. Major histocompatibility class I and II mismatching did not incur risk. Eight of 12 liver allografts were acquired from either DRB*0301- or DRB*0401-positive donors, and 4 recipients were DRB*0301-positive. This series illustrates that both symptoms and histologic findings of graft dysfunction compatible with autoimmune hepatitis (AIH) exist in adult LT recipients. Graft loss may be a consequence. This entity may represent a specific type of rejection that should currently be classified as "graft dysfunction mimicking autoimmune hepatitis."

Adult↗
PubMed2001

TT virus infection in patients with primary hypogammaglobulinaemia: natural history and relationship to liver disease in the immunocompromised host.

BACKGROUND: TT virus (TTV) is a recently discovered human DNA virus with worldwide distribution, but with no clear disease association. The possibility of an enhanced TTV virulence in patients with immunodeficiencies has not yet been investigated but is of particular interest because other viruses have been demonstrated to cause severe and rapid liver disease in such patients. Here we analysed the characteristics of TTV infection in a large cohort of patients with primary hypogammaglobulinaemia (PHG) and whether TTV has a role in the frequently observed cryptogenic liver disease in these patients. METHODS: 83 Norwegian patients with PHG (serum immunoglobulin G < 2 g/L), receiving substitution treatment with immunoglobulins, were followed regularly for median 10.2 years (range 2-30). TTV DNA was sought in serum samples and three immunoglobulin preparations by polymerase chain reaction; TTV DNA quantitation, DNA sequencing and phylogenetic analysis were performed in selected samples. RESULTS: TTV DNA was detected in 27 of 83 (32.5%) patients and was not associated with a particular type of PHG. The prevalence of TTV infection was dependent on intravenous immunoglobulin administration, duration of therapy and patient's age. TTV DNA was found in two of three currently used immunoglobulin preparations. In the longitudinal study, whether TTV was cleared or newly acquired had no impact on liver function tests and no particular TTV strain was found in patients with more severe liver disease. CONCLUSIONS: TTV infection is common in patients with PHG. Treatment with immunoglobulins has a role in the transmission of TTV in these patients. However, we found no evidence of TTV-induced liver disease in this group of immunocompromised patients.

Adult↗
PubMed2001

Application of "VITALS": visual indicators of teaching and learning success in reporting student evaluations of clinical teachers.

CONTEXT: At the College of Medicine and Medical Sciences, Arabian Gulf University, Bahrain, a system has been introduced in which clerkship students evaluate clinical faculty using Visual Indicators of Teaching and Learning Success (VITALS). OBJECTIVE: To describe the use of VITALS in reporting student feedback on teaching and learning effectiveness of clinical faculty in the clerkship. DESIGN: Descriptive study. SUBJECTS: A total of 210 clerkship students evaluated 76 clinical tutors over a period of 3 years. Feedback was also obtained from seven programme managers and one supportive staff member. METHOD: Nine indicators of effective clinical teaching were identified through a literature search. Students individually reported on clinical faculty teaching capabilities using a 5-point, Likert-type scale. Cumulative reports of students' feedback on clinical faculty teaching were prepared using opposing bar graphs, reflecting perceived areas of strength or weakness in each teacher's performance. RESULTS: A total of 1450 evaluation forms were completed by 180 of 210 students (85.7%). VITALS graph representations of students' perceptions of clinical tutors were communicated to each clinical tutor at the end of each clerkship and academic year. Twenty-one students out of 53 who gave written comments were related to VITALS. They reflected a positive view of VITALS as a process or tool of faculty evaluation. Clinical faculty (18), programme managers(7) and supporting staff (1) gave comments indicating acceptance of the system. CONCLUSION: This preliminary study suggests that VITALS could be an effective tool for improving clinical teaching. It is acceptable to students, faculty and managers of educational programmes. The database reflecting their teaching and educational profiles were used to provide clinical faculty with constructive feedback.

Journal Article↗
PubMed2001

Analysis of wine for penicillin.

This study addresses the question of whether the antibiotic Penicillin, which is produced by the common mold Penicillium notatum, could possibly become a contaminate of wine during the fermentation process. The significance of this study is related to the potential health effects this agent might produce in those consumers who have an allergic response to Penicillin. It has been estimated that between 6% and 8% of the American population is subject to this type of allergic response. A method is developed for the detection of penicillin in wines using high-pressure liquid chromatography. We demonstrate that penicillin G hydrolyzes rapidly in wine with first-order kinetics, and the half-life of this antibiotic is 147 min in a typical commercial wine. An analysis of a number of commercial wines shows no evidence of the presence of penicillin, which should negate the question of any allergic response associated with this potential contaminate.

Chromatography, High Pressure Liquid↗
PubMed2001

Multicenter trial of sentinel node biopsy for breast cancer using both technetium sulfur colloid and isosulfan blue dye.

OBJECTIVE: To determine the factors associated with false-negative results on sentinel node biopsy and sentinel node localization (identification rate) in patients with breast cancer enrolled in a multicenter trial using a combination technique of isosulfan blue with technetium sulfur colloid (Tc99). SUMMARY BACKGROUND DATA: Sentinel node biopsy is a diagnostic test used to detect breast cancer metastases. To test the reliability of this method, a complete lymph node dissection must be performed to determine the false-negative rate. Single-institution series have reported excellent results, although one multicenter trial reported a false-negative rate as high as 29% using radioisotope alone. A multicenter trial was initiated to test combined use of Tc99 and isosulfan blue. METHODS: Investigators (both private-practice and academic surgeons) were recruited after attending a course on the technique of sentinel node biopsy. No investigator participated in a learning trial before entering patients. Tc99 and isosulfan blue were injected into the peritumoral region. RESULTS: Five hundred twenty-nine patients underwent 535 sentinel node biopsy procedures for an overall identification rate in finding a sentinel node of 87% and a false-negative rate of 13%. The identification rate increased and the false-negative rate decreased to 90% and 4.3%, respectively, after investigators had performed more than 30 cases. Univariate analysis of tumor showed the poorest success rate with older patients and inexperienced surgeons. Multivariate analysis identified both age and experience as independent predictors of failure. However, with older patients, inexperienced surgeons, and patients with five or more metastatic axillary nodes, the false-negative rate was consistently greater. CONCLUSIONS: This multicenter trial, from both private practice and academic institutions, is an excellent indicator of the general utility of sentinel node biopsy. It establishes the factors that play an important role (patient age, surgical experience, tumor location) and those that are irrelevant (prior surgery, tumor size, Tc99 timing). This widens the applicability of the technique and identifies factors that require further investigation.

Adult↗
PubMed2001

Ability of laboratories to detect emerging antimicrobial resistance: proficiency testing and quality control results from the World Health Organization's external quality assurance system for antimicrobial susceptibility testing.

The accuracy of antimicrobial susceptibility data submitted by microbiology laboratories to national and international surveillance systems has been debated for a number of years. To assess the accuracy of data submitted to the World Health Organization by users of the WHONET software, the Centers for Disease Control and Prevention distributed six bacterial isolates representing key antimicrobial-resistance phenotypes to approximately 130 laboratories, all but one of which were outside of the United States, for antimicrobial susceptibility testing as part of the World Health Organization's External Quality Assurance System for Antimicrobial Susceptibility Testing. Each laboratory also was asked to submit 10 consecutive quality control values for several key organism-drug combinations. Most laboratories were able to detect methicillin (oxacillin) resistance in Staphylococcus aureus, high-level vancomycin resistance in Enterococcus faecium, and resistance to extended-spectrum cephalosporins in Klebsiella pneumoniae. Many laboratories, particularly those using disk diffusion tests, had difficulty in recognizing reduced susceptibility to penicillin in an isolate of Streptococcus pneumoniae. The most difficult phenotype for laboratories to detect was reduced susceptibility to vancomycin in an isolate of Staphylococcus epidermidis. The proficiency testing challenge also included a request for biochemical identification of a gram-negative bacillus, which most laboratories recognized as Enterobacter cloacae. Although only a small subset of laboratories have submitted their quality control data, it is clear that many of these laboratories generate disk diffusion results for oxacillin when testing S. aureus ATCC 25923 and S. pneumoniae ATCC 49619 that are outside of the acceptable quality control range. The narrow quality control range for vancomycin also proved to be a challenge for many of the laboratories submitting data; approximately 27% of results were out of range. Thus, it is important to establish the proficiency of laboratories submitting data to surveillance systems in which the organisms are tested locally, particularly for penicillin resistance in pneumococci and glycopeptide resistance in staphylococci.

Anti-Bacterial Agents↗