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R Williams

Publications and source records attributed to R Williams.

At least 469 records · Page 26Linked to original sources
PubMed1996

Mean difference vs. variability reduction: tradeoffs in aggregate measures for individual bioequivalence. FDA Individual Bioequivalence Working Group.

Aggregate criteria for individual bioequivalence allow a tradeoff between difference in average bioavailability and reduction in within-subject variability. That is, a large difference in the average bioavailability between a test and a reference formulation can be offset by a sufficient reduction in variability of the test formulation. This offset could allow the test formulation to pass many individual bioequivalence criteria. We have identified 4 possible approaches for dealing with this tradeoff issue: say "No problem," since a reduction in variability is desirable; use disaggregate criteria; use general weighted forms of the individual bioequivalence criteria that weight the variance terms; and change the acceptable upper limits to reduce the impact of scaling to the reference formulation's within-subject variability. A dataset with a 14% increase in average bioavailability and a 48% reduction in within-subject standard deviation is used as an example of these issues.

Biological Availability↗
PubMed1995

Protective effects of Osbeckia octandra against galactosamine and tert-butyl hydroperoxide induced hepatocyte damage.

Ayurvedic and other 'traditional' medical practitioners in Sri Lanka use the mature leaves of the plant Osbeckia octandra for its hepatoprotective properties. In this study the effects of an aqueous extract of Osbeckia octandra against injury induced by D-galactosamine and tert-butyl hydroperoxide (TBH) were investigated in freshly isolated rat hepatocytes. The plant extract (500 micrograms/ml) significantly reduced the inhibition of protein synthesis (as assessed by the incorporation of 14C-leucine into protein) in hepatocytes incubated for 1 h with 10 mM galactosamine by a mean of 25.6 +/- 3.6% and decreased the release of cellular lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) enzyme activities into the medium by 55.3% and 32.8%, respectively. With TBH, the plant extract decreased lipid peroxidation (estimated from malondialdehyde formation) by a mean of 29.9 +/- 1.1% together with a 46.8% and 54.7% decrease in the release of LDH and AST, respectively into the incubation medium. Significant protection was also obtained when the Osbeckia extract was added to the incubation medium up to 30 min after pre-exposure of the hepatocytes to either galactosamine or, to a lesser extent, TBH. The results support the use of Osbeckia as a hepatoprotective agent.

Animals↗
PubMed1995

Neurotrophin receptor expression during development of the chick spinal sensory ganglion.

The expression of mRNA for the trk neurotrophin receptors was studied in developing chicken dorsal root ganglion neurones using in situ hybridization histochemistry. trkC mRNA is expressed first, followed by trkB mRNA and finally trkA mRNA. The expression of each receptor begins very early during neurogenesis, and although initially quite widespread throughout the ganglion, the proportion of neurones expressing each receptor reduces as development proceeds. Expression patterns for each receptor become specifically restricted within the ganglion during this time, but during subsequent development the neurones migrate to their final site within the ganglion. From an assessment of the ganglion's ability to respond to neurotrophins in vitro, and from the results of earlier studies, both on the expression of receptors and gene targeting experiments, it is apparent that DRG neurones are dependent on these factors at very early stages of development and not, as previously thought, only after target innervation.

Animals↗
PubMed1995

Hepatology.

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Artificial Organs↗
PubMed1995

IgG donor-specific crossmatches are not associated with graft rejection or poor graft survival after liver transplantation. An assessment by cytotoxicity and flow cytometry.

Early studies in liver transplantation suggested that there was no association between graft outcome or rejection and the presence of alloantibodies before transplantation. More recent reports have suggested lower graft survival rates and a higher incidence of chronic rejection in patients with IgG warm-T crossmatches. In the present study, panel reactive antibody, direct crossmatch testing, and flow cytometry were used to detect preformed antibodies in sera from 158 consecutive adult recipients of first hepatic grafts. The relationship between preformed antidonor antibodies and liver allograft survival and rejection was determined. Twenty-six (17%) patients were panel reactive antibody (PRA)-positive before transplantation, 22 (15%) had positive donor-specific crossmatches, and 14 (9%) were positive by IgG-specific flow cytometry. Cumulative survival distribution and multivariate analysis failed to reveal any significant associations between overall graft survival and antibody status. Graft survival in patients with PRA-positive sera was 81% compared with 77% for those with PRA-negative sera, 68% for those with positive donor-specific crossmatches compared with 80% for those who were donor-specific crossmatch negative, and 79% for those who were antibody positive by flow cytometric analysis compared with 78% for those who were antibody negative. Subgroup analysis also failed to reveal any significant associations. In addition, Cox proportional hazards regression analysis failed to reveal a relationship between acute or chronic graft rejection with the presence or absence of preformed antibodies, irrespective of immunoglobulin class, cell type (T or non-T), specificity, or technique used for antibody detection. In conclusion, there appears to be no association between either donor-specific or "third-party" alloreactive IgG or IgM antibodies and liver transplant survival or rejection. These data do not indicate a need for prospective crossmatching of liver transplant recipients.

Adolescent↗
PubMed1995

Phosphorylation of myosin-I from rat liver by protein kinase C reduces calmodulin binding.

Three isoforms of the cytoskeletal-associated, mechanochemical enzymes known as myosin-I have been purified from rat liver; each coisolates with calmodulin. Incubation of the purified myosin-I's with protein kinase C gamma and 32P-ATP results in phosphorylation of the myosin-I heavy chains. After phosphorylation, the myosin-I isoforms bind less radiolabeled calmodulin in binding assays than observed for control samples. Since the purified isoforms are phosphoproteins as determined by immunoblotting with monoclonal antibodies which recognize phosphoamino acids, these results indicate that phosphorylation might play a role in regulation of myosin-I.

Adenosine Triphosphate↗
PubMed1995

Relationship between early liver graft viability and enzyme activities in effluent preservation solution.

Determination of cellular enzyme activities in washout preservation solution used in hypothermic liver graft storage may allow development of an index that could be clinically valuable in prediction of early post-transplant graft function. In the present study, we collected washed out preservation fluid at the time of graft rinsing from 53 liver recipients. Aspartate aminotransferase and, to a lesser extent, lactate dehydrogenase levels correlated with early postoperative graft viability as assessed by 1-month graft survival and standard biochemical indices of liver function. Those patients with the highest aspartate aminotransferase activity in the washout preservation solution experienced the highest levels of this enzyme postoperatively (area-under-the-curve day 1-3; 1340 vs. 788 IU/L), total bilirubin (area-under-the-curve day 1-5; 901 vs. 538 mumol/L), and rejection frequency (67% vs. 31%) (all P < 0.05), with a significantly lower 1-month graft survival rate compared with patients with low effluent levels (62% vs. 92%, P < 0.05). Two markers of endothelial cell damage, purine nucleoside phosphorylase and a creatine kinase isoenzyme, measured in the fluid did not correlate with early graft viability. It is suggested that assay of aspartate aminotransferase activities in preservation fluid washout samples is a clinically useful indicator of graft viability.

Adult↗
PubMed1995

Azathioprine for long-term maintenance of remission in autoimmune hepatitis.

BACKGROUND: In most patients with autoimmune hepatitis, remission can be maintained with prednisolone, usually in combination with azathioprine, but the majority of patients have a relapse when treatment is stopped and therefore require long-term therapy. Because prolonged corticosteroid therapy may have serious toxic effects, in 1984 we undertook a controlled trial of maintenance therapy with azathioprine alone. None of the 25 patients in that trial had relapses during the follow-up period of one year. We have now followed these 25 patients for 10 years and have treated an additional 47 patients in a similar manner. METHODS: The 72 patients (median age, 47 years; range, 14 to 71) had been in complete remission for at least one year with 5 to 15 mg of prednisolone per day and 1 mg of azathioprine per kilogram per day. The dose of azathioprine was increased to 2 mg per kilogram per day, and the prednisolone was gradually withdrawn. Remission was defined as the absence of symptoms suggestive of a relapse and serum globulin and aspartate aminotransferase concentrations within the normal range, with or without a liver biopsy showing only minimal inflammation. RESULTS: Sixty patients (83 percent) remained in remission while receiving azathioprine alone for a median of 67 months (range, 12 to 128). Of 48 follow-up liver biopsies in 42 patients, 45 showed inactive or minimal disease, and 3 showed moderate disease (2 after one year of therapy and 1 after eight years). After the prednisolone had been withdrawn, 26 patients lost their cushingoid facies, and 32 patients lost weight (median loss, 6.4 kg; range, 1.5 to 22.3). The most common adverse effect was arthralgia (in 38 patients). With the higher dose of azathioprine, four patients had myelosuppression, defined as a decrease in the leukocyte and platelet counts to less than 4000 and 150,000 per cubic millimeter, respectively. Two of these patients (both with pancytopenia) relapsed when the azathioprine was withdrawn; in the other two, remission was maintained with the resumption of prednisolone. Lymphopenia developed in 32 of 56 patients treated with 2 mg of azathioprine per kilogram per day for more than two years. During follow-up, nine patients died: one of liver failure and eight of causes not directly related to their liver disease. CONCLUSIONS: Many patients with autoimmune hepatitis who have been in complete remission for at least one year with prednisolone and azathioprine can remain in remission with a higher dose of azathioprine alone.

Adolescent↗
PubMed1995

Nature of G1/S cell cycle checkpoint defect in ataxia-telangiectasia.

We have previously demonstrated that cells from patients with ataxia-telangiectasia (A-T) fail to show initial delay at several cell cycle checkpoints post-irradiation. In addition a defect in the induction of p53 by ionizing radiation was evident. We demonstrate here that the radiation signal transduction pathway operating through p53, its target gene WAF1, cyclin-dependent kinases and the retinoblastoma (Rb) protein is defective in A-T cells. The defective p53 induction after ionizing radiation, observed previously in A-T cells, was also reflected at the functional level using p53-DNA binding activity, transactivation and transfection with wild type p53. Correction of the defect at the G1/S checkpoint was observed when wild type p53 was constitutively expressed in A-T cells. Exposure of control cells to radiation gave rise to p53 induction and as a consequence increased expression of WAF1 mRNA and protein, but A-T cells were defective in this response. As expected the WAF1 response in irradiated control cells resulted in an inhibition of cyclin-dependent kinase activity including cyclin E-cdk2, which plays an important role in the transition from G1 to S phase. No inhibition of cyclin-dependent kinase activity was observed in A-T cells correlating with the delayed WAF1 response. On the contrary an enhancement of cyclin-dependent kinase activity was seen in A-T cells post-irradiation. An accumulation of the hypophosphorylated form of Rb protein occurred in irradiated control cells compatible with the G1/S phase delay observed in these cells after exposure to radiation. In unirradiated A-T cells the amount of Rb protein was much higher compared to controls and it was mainly in the hyperphosphorylated (functionally inactive) form. In addition, accumulation of the hypophosphorylated form of Rb in A-T cells post-irradiation was defective, consistent with the lack of cell cycle arrest. Thus the failure of the G1/S checkpoint in A-T cells after exposure to ionizing radiation is consistent with a defective radiation signal transduction pathway operating through p53.

Ataxia Telangiectasia↗
PubMed1995

Amlodipine improves hepatic hemodynamic and metabolic function in the isolated perfused rat liver after sequential cold and warm ischemia.

Amlodipine, a long acting calcium antagonist, was used to reduce the adverse effects of ischemic/reperfusion injury studied in isolated perfused rat livers. Amlodipine (10 mumol/L) was added to University of Wisconsin (UW) solution in which the liver was stored for 24 hr at 4 degrees C and incorporated in the saline flush used to displace the UW solution before 20 min of warm ischemia (at 37 degrees C) and reperfusion. Initial median blood flow at 15 min was significantly higher after amlodipine treatment (2.78 vs. 1.41 ml/min/g of liver without amlodipine treatment, P = 0.013) as was the area under the curve of blood flow for the entire 3-hr perfusion (472 vs. 316 ml/g of liver, P = 0.003). Amlodipine treatment induced corresponding increases in oxygen delivery (1302 vs. 896 mumol of O2/g of liver over 3 hr of perfusion, P = 0.003) and oxygen consumption (279 vs. 242 mumol of O2/g of liver over 3 hr, P = 0.06). Initial bile flow at 15 min was increased 4-fold by amlodipine treatment (17.27 vs. 4.59 mg/hr/g of liver for sequential cold and warm ischemia, P = 0.013), and the median area under the curve of bile flow for the entire perfusion increased to 92.2 vs. 53.9 mg/g of liver (P = 0.0006). Amlodipine treatment also reduced glucose release into the perfusate (116 vs. 149 mmol/L/g of liver min over 3 hr, P = 0.03) and prevented hepatocyte injury by reducing alanine aminotransferase release both initially (0.43 vs. 0.96 IU/L/g of liver, P = 0.055) and overall (343 vs. 797 IU/L/g of liver min, P = 0.048). When amlodipine was added only to the UW solution, blood flow increased by 66% initially (P = 0.02) and 32% overall (P = 0.013), but there was no corresponding improvement in hepatic function. Amlodipine may reduce hepatic ischemic/reperfusion injury by cytoprotective effects on parenchymal and non-parenchymal hepatocytes during both preservation and reperfusion leading to an improvement in liver microcirculation and an inhibition of the release of toxic mediators.

Amlodipine↗
PubMed1995

Cooperative manganese (II) activation of 3-phosphoglycerate mutase of Bacillus megaterium: a biological pH-sensing mechanism in bacterial spore formation and germination.

The conversion of 3-P-glycerate mutase of Bacillus megaterium from a catalytically inactive to an active form was markedly more effective with buffered Mn2+ than with just added Mn2+. The previously reported stimulation by threonine disappeared when buffered Mn2+ was used. Activation of mutase showed a sigmoid dependence on Mn2+ concentration when buffered with tetramethylenediamine tetraacetate. The curve obeyed Hill kinetics with a coefficient of 2.1 +/- 0.1. At 0.5 microM free Mn2+, buffered with trimethylenediamine tetraacetate, activation of mutase increased about 73-fold over the pH range 6.6 to 7.4. Plotted against [OH-], the activation showed a strongly sigmoid response with Hill coefficient of 3.5 +/- 0.1. When mutase activated at pH 6.4 and 0.5 microM free Mn2+ in the presence of substrate was transferred to a similar medium at pH 7.4, the rate of product accumulation increased 360-fold within a few minutes. The pH sensitivity conferred upon mutase by low [Mn2+] may account for its large activity decrease during sporulation, and later increase during spore germination, when spore pH, respectively, declines and rises by about 1 unit. These changes result in the accumulation, and later reutilization, of 3-P-glycerate reserves in the spore. Such a pH-sensing function of Mn2+ may have wider biological uses.

Bacillus megaterium↗
PubMed1995

Linkage analysis of late-infantile neuronal ceroid-lipofuscinosis.

The neuronal ceroid-lipofuscinoses (NCL) are a group of neurodegenerative disorders with an autosomal-recessive pattern of inheritance. There are 3 main categories of childhood NCL, namely, infantile, late-infantile, and juvenile NCL. These can be distinguished on the basis of age of onset, clinical course, and histopathology. A number of variant forms of NCL have also been described, and these show symptoms intermediary between the main classical forms. The genes for both the infantile and juvenile forms of NCL have previously been mapped to chromosome areas 1p32 and 16p12, respectively. The gene for late-infantile NCL (LINCL), CLN2, has been excluded from both these loci, but its location is as yet unknown. Recently, CLN5, the gene for the Finnish variant form of LINCL, was mapped to 13q21.1-32. Using the 3 microsatellite markers which were most tightly linked to CLN5, we have excluded CLN2 from this region using a subset of 17 families. Thus, CLN2 represents a fourth distinct genetic locus involved in the pathogenesis of NCL.

Age of Onset↗