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Biomedical subjects

B Williams

Publications and source records attributed to B Williams.

At least 253 records · Page 14Linked to original sources
PubMed1995

Assessment of hepatitis C viremia using molecular amplification technologies: correlations and clinical implications.

OBJECTIVE: To compare two recently developed molecular techniques for quantitating the levels of hepatitis C virus (HCV) RNA in the serum of patients with a wide spectrum of chronic hepatitis C. DESIGN: Serum samples from 299 patients with HCV viremia, 101 control patients without HCV infection, and 19 consecutive patients receiving systemic interferon therapy were evaluated by a commercially available branched-chain DNA (bDNA) assay and a quantitative competitive polymerase chain reaction (PCR). SETTING: University-based hepatology clinics and reference virology laboratory. PATIENTS: Patients with HCV viremia as defined by results of qualitative RNA PCR, including 53 HCV-infected blood donors, 34 patients receiving renal dialysis, and 212 patients attending a hepatology clinic. RESULTS: Results of in vitro and in vivo experiments indicated that the sensitivity and dynamic range of the PCR assays were greater than those of the bDNA assay. Detection of HCV viremia by the bDNA assay was highly dependent on viral RNA titers, with a sensitivity of 5% at HCV RNA titers of 5.0 logs per mL or less and 94% at titers of 5.5 logs per mL or greater. The best correlation between assays was observed in specimens with HCV RNA titers between 6.0 and 7.5 logs per mL (r = 0.73). In patients with high-titer HCV viremia, including liver transplant recipients and patients with cirrhosis, quantitative PCR results were an average of 12-fold higher than bDNA assay results. Results of repetitive testing of discordant specimens showed that these discrepancies were caused by a high kit-to-kit coefficient of variation (112%) in the bDNA assay. Of 19 patients receiving interferon therapy, 9 (47%) became bDNA negative, but only 5 became quantitative PCR negative. The bDNA-negative, quantitative PCR-positive patients all had relapse when therapy was discontinued. CONCLUSIONS: The bDNA assay has a narrower linear range for quantitation of HCV viremia than quantitative PCR. Because persons with low HCV titers may respond well to therapy, seropositive persons with negative bDNA results should be retested with PCR-based assays. Similarly, the bDNA assay may underestimate the true degree of HCV viremia in persons with end-stage infection (> 10(7) RNA equivalents/mL of sera). Despite these limitations, the combination of bDNA- and PCR-based assays appears to be optimal for selecting and following patients during interferon therapy.

Case-Control Studies↗
PubMed1995

Granulocyte-macrophage colony-stimulating factor is not responsible for the correction of hematopoietic deficiencies in the maturing op/op mouse.

Osteopetrotic (op/op) mice are characterized by an autosomal recessive inactivating mutation resulting in the absence of biologically active colony-stimulating factor-1 (CSF-1). Consequently, young op/op mice have a severe deficiency of macrophages and osteoclasts resulting in excessive bone formation, occlusion of the marrow cavity, and reduced marrow hematopoietic activity. Recently, we showed that the osteopetrosis and hematopoietic deficiencies evident in young op/op mice are not permanent but are progressively corrected with age. There are increases in osteoclast activity; bone resorption; femoral marrow space; and marrow hematopoietic activity, cellularity, and macrophage content. In the present study we show that CSF-1-/- granulocyte-macrophage colony-stimulating factor (GM-CSF)(-/-)-deficient mice also undergo the same pattern of hematopoietic correction as the op/op mouse. Also, like the op/op mouse, the peritoneal cellularity and macrophage content of CSF-1/GM-CSF-deficient mice remains severely reduced. Our data show that the "knockout" of GM-CSF does not change the op/op phenotype, and that GM-CSF is not essential for the correction of the hematopoietic deficiencies in the op/op mouse. Importantly, the data also show that neither GM-CSF nor CSF-1 is an absolute requirement for the commitment of primitive hematopoietic stem cells to the macrophage lineage or for the differentiation of at least some classes of macrophages. This finding suggests that an alternate regulatory factor can be involved in macrophage and osteoclast commitment, differentiation, and function in vivo.

Age Factors↗
PubMed1995

Coordinated induction of the ubiquitin conjugation pathway accompanies the developmentally programmed death of insect skeletal muscle.

The developmentally programmed cell death of abdominal intersegmental muscles in the tobacco hawk-moth Manduca sexta is coincident with a 10-fold induction of the polyubiquitin gene as a hormonally regulated event (Schwartz, L. M., Myer, A., Kosz, L., Engelstein, M., and Maier, C. (1990) Neuron 5, 411-419). Solid phase immunochemical assays measuring intersegmental muscle pools of free and conjugated ubiquitin reveal that the induction of polyubiquitin mRNA is accompanied by a proportional increase in total ubiquitin polypeptide. Ubiquitin conjugate pools increase 10-fold at eclosion, during which loss of muscle protein mass is maximum. A smaller but measurable increase in ubiquitin conjugates is observed earlier in pupal development coincident with a modest enhanced degradation of myofibrillar proteins. Accumulation of ubiquitin conjugates is accompanied by induction in the pathway for polypeptide ligation, including the activating enzyme (E1), several carrier protein (E2) isoforms, and ubiquitin:protein isopeptide ligase (E3). Both accumulation of ubiquitin polypeptide and the enzymes of the conjugation pathway are subject to regulation by declining titers of the insect molting hormone 20-hydroxyecdysone, which signals onset of programmed cell death in the intersegmental muscles. Thus, programmed cell death within the intersegmental muscles is accomplished in part by stimulation of the ubiquitin-mediated degradative pathway through a coordinated induction of ubiquitin and the enzymes responsible for its conjugation to yield proteolytic intermediates. This suggests enzymes required for ubiquitin conjugation may represent additional genes recruited for developmentally programmed death.

Animals↗
PubMed1995

Serum and platelet-derived growth factor-induced expression of vascular permeability factor mRNA by human vascular smooth muscle cells in vitro.

1. Endothelial dysfunction and vascular smooth muscle cell (VSMC) proliferation are key events in the pathogenesis of atherosclerosis. Vascular permeability factor (VPF), an endothelial-cell-specific multifunctional cytokine, was recently described, and has the potential to contribute to the development of endothelial dysfunction. The present study determines whether cultured human VSMCs express mRNA for VPF and whether VPF mRNA expression is influenced by human VSMC proliferation. 2. A 204 bp cDNA fragment, specific for all known variants of VPF mRNA, was cloned and used to demonstrate that human VSMCs express abundant quantities of VPF mRNA, whereas human endothelial cells do not. VPF mRNA levels were markedly diminished in non-proliferating human VSMCs. In contrast, when human VSMCs were stimulated to proliferate by exposure to serum, there was a rapid 6.6-fold increase (P < 0.01 versus time 0 h) in VPF mRNA expression, which was maximal at 3 h and persisted beyond 24 h. The magnitude of the VPF mRNA response in human VSMCs was dependent on the serum concentration. 3. Platelet-derived growth factor also increased VPF mRNA expression by human VSMCs, thus confirming that recognized growth factors for VSMCs also potently influence the VPF gene. 4. In conclusion, VPF mRNA is expressed by human VSMCs, the magnitude of VPF expression being temporally related to the proliferation of human VSMCs and the potency of the growth-promoting stimulus. We propose that VPF produced by proliferating human VSMCs could act as a paracrine hormone to powerfully influence the permeability and growth of the overlying vascular endothelium.(ABSTRACT TRUNCATED AT 250 WORDS)

Arteriosclerosis↗
PubMed1995

Cerebrospinal fluid drainage for syringomyelia.

Twenty-eight years of experience with syringomyelia of various causes in the syringomyelia clinic at the Midland Centre for Neurosurgery and Neurology has provided a database of 723 patients, mostly adults, with either hindbrain herniation, syringomyelia or both. Treatment of syringomyelia by drainage has never been the optimum primary treatment on the basis that the cavity is usually secondary to some other disturbance of the cerebrospinal fluid pathways. Over this period 73 patients had either syrinx drainage (56 syringopleural, 14 syringo-subarachnoid shunts) or other procedure such as myelotomy and cord transection. Ten years after operation only 53.5% and 50% of these two groups respectively continued to remain clinically stable. A complication rate of 15.7% included fatal haemorrhage, infection and displacement of drains. At second operation or necropsy at least 5% of shunts were found to be blocked. All the shunts were inserted without a valve and the lowering of the intrasyrinx pressure has therefore been energetic when the lower end of the drainage tube has been taken to the pleural or peritoneal cavities. This produced collapse of the cord cavities around the tip of the drainage tube and increased the likelihood of blockage. If the mechanisms which were responsible for the syringomyelia were still operative then recurrence was likely to occur alongside the drainage tube leaving the tube immured in the wall of the syrinx cavity. When hydrocephalus was present, in addition treatment of the hydrocephalus by a valved shunt to the peritoneum or to the right atrium was often effective in improving the syringomyelia. This treatment has also been used in patients without hydrocephalus. The mechanisms of improvement were unclear but this treatment stratagem has nevertheless been employed in 45 cases. In 30 out of these 45 cases the drainage of cerebrospinal fluid from outside the syrinx cavities seemed to be worthwhile; 10 patients suffered some form of complication, most of which were reversible; 8 patients were worse following surgery. It is concluded that both drainage of the syringomyelia cavity and also extra-syrinx drainage may have a place in the management of difficult syringomyelia problems although the primary treatment should be to establish the patency of CSF pathways in both hindbrain-related and non-hindbrain-related cases.

Adult↗
PubMed1995

Haematopoietic radioprotection by Cremophor EL: a polyethoxylated castor oil.

The polyethoxylated castor oil, Cremophor EL (Cremophor) is approved for human use as a vehicle for oral and intravenous administration of water-insoluble compounds. Cremophor has also previously been shown to reverse the multidrug resistance phenotype at clinically acceptable doses. This study demonstrates that doses of Cremophor in the range of 25-50 microliters/kg intravenously (i.v.) administered 1 day prior to near-lethal irradiation protected the regenerative capacity of the marrow, resulting in haematopoietic radioprotection and long-term survival of near-lethally-irradiated mice. In normal mice, Cremophor administration (1) markedly reduced the level of serum haematopoietic inhibitory activity 4-8 h following injection; (2) resulted in a transient decrease in femoral bone marrow cellularity and upregulated B220 (B cells), and 7/4 (neutrophils and activated macrophages), but not Thy-1 (T-cells) surface antigen expression in bone marrow cells within 24 h of injection; and (3) transiently elevated the incidence of both primitive and committed haematopoietic progenitor cells detected in clonal agar culture within 48 h of injection. Bone marrow progenitor cell content, and peripheral blood white cell, platelet and reticulocyte counts were unaffected. This suggests that the haematopoietic radioprotection and recovery observed in irradiated mice pretreated with Cremophor may be the result of accessory cell activation and/or modulation of accessory factors regulating haematopoietic progenitor cells. Our data suggest a potential clinical use of Cremophor as an adjunct to, or as a substitute for, cytokines to minimize myelosuppression following cytotoxic therapy.

Animals↗
PubMed1995

Angiotensin converting enzyme inhibitors and calcium antagonists alone or combined: does the progression of diabetic renal disease differ?

BACKGROUND: Over the past two decades numerous studies have evaluated the effects of angiotensin converting enzyme (ACE) inhibitors and calcium antagonists on proteinuria and the progression of diabetic renal disease. Taken together, these studies suggest that certain types of calcium antagonists and ACE inhibitors have distinctive advantages over conventional antihypertensive agents with regard to improving overall and renal survival. Among the unique actions of these two classes of drugs are their effects on matrix proteins apart from their effects in reducing arterial pressure. CONCLUSIONS FROM LITERATURE SURVEY: There is no definitive answer to the question of whether the effects of ACE inhibitors and calcium antagonists are additive when the drugs are used together. However, preliminary data from both animal and clinical studies suggest that combinations of non-dihydropyridine calcium antagonists and ACE inhibitors produce an additional fall in proteinuria and have more favorable side effect profiles than results observed with either drug alone. Therefore, combination therapy with these agents may be valuable, especially in diabetic patients with renal insufficiency in whom arterial pressure is difficult to control.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1995

Inappropriate use of nonpsychotropic medications in nursing homes.

OBJECTIVES: To determine the prevalence and patient-specific predictors of the use of 10 presumptively inappropriate medications used to treat medical conditions among nursing home residents, and to use this information to examine alternative screening strategies using computerized assessment data to identify residents who are at high risk of receiving inappropriate medications. DESIGN: Retrospective, cross-sectional study. PATIENTS: All persons residing in all 252 nursing homes in two states during the last 6 months of 1991 (N = 21,884). MEASUREMENTS: Data were from Minimum Data Set Plus (MDS+) assessments, gathered as part of the Health Care Financing Administration (HCFA) Multistate Nursing Home Casemix and Quality Demonstration Project. The MDS+ is an expanded version of the federally mandated Minimum Data Set (MDS) that includes additional information on medications and their doses and schedules (frequency, standing vs prn). The reliability of the MDS has been demonstrated previously. Medications were defined as inappropriate using explicit criteria from published literature. Outcome measures were the standing use of each or any of 10 presumptively inappropriate medications used to treat medical (rather than psychiatric or behavioral) conditions. Potential predictors of inappropriate medication use included patient demographic characteristics, payer, a proxy measure for length of stay and admission source, functional status, number of standing medications, and state. MAIN RESULTS: A total of 12% of residents were prescribed one or more of 10 presumptively inappropriate medications on a standing basis, a figure that differed substantially between states (14.0% vs 7.4% (P < .001)). The most prevalent inappropriate medications were dipyridamole (5.4% of residents), amitriptyline (3.3%), and methyldopa (1.8%). Among patients receiving 0 to 3, 4 to 6, and 7+ medications, 5%, 12%, and 19%, respectively, were receiving at least one inappropriate medication. In multivariate logistic regression analyses, the strongest predictors of inappropriate medication use were state and the total number of standing medications prescribed. Including other statistically significant predictors of inappropriate medication use (age > 65 years, never having been married, severe functional limitations, being a long-stay patient, and medical diagnosis) did not substantially improve the overall predictive ability of the model. CONCLUSIONS: A substantial proportion of nursing home residents receives presumptively inappropriate medications to treat medical conditions. Selecting persons prescribed large numbers of medications for further review may be the most efficient method for nursing home or pharmacy personnel to identify residents at high risk of receiving inappropriate medications. Extensive additional information on residents' characteristics, although widely available through the Minimum Data Set, does not significantly improve the ability to identify residents receiving inappropriate medications for medical conditions. State-specific policies or provider practices also influence the likelihood of presumptively inappropriate medication use among nursing home residents and deserve further investigation.

Aged↗