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Biomedical subjects

C K Williams

Publications and source records attributed to C K Williams.

At least 19 recordsLinked to original sources
PubMed2002

Risk assessment for release of genetically modified organisms: a virus to reduce the fertility of introduced wild mice, Mus domesticus.

Risk assessment is a key task in developing genetically modified organisms (GMOs) intended for release into the environment. A risk assessment protocol is described, focusing on genetically modified biological control agents intended to reduce fertility in mammalian pests. The protocol is being applied to development of an immunocontraceptive murine cytomegalovirus vaccine intended to reduce the frequency and extent of costly troublesome plagues of introduced house mice, Mus domesticus, in southern Australia. Success of the agent, including regulatory approval for release to target populations, will depend on demonstrated biosafety, on the biophysical consequences of releasing the agent, and on public perceptions of the consequences and ongoing risks. The proposed risk assessment protocol addresses biosafety and the biophysical and social risks. It elicits perceptions of interaction and risk from the project scientists and from representatives of interested or affected sectors of society. The perceptions are documented for examination interactively in subsequent socially inclusive formal risk assessments. Representatives of the relevant social sectors participate with the scientists, iteratively if needed, in a workshop to assess the risks of releasing the particular GMO into the environment, using a formal inductive procedure, GENHAZ, designed specifically for assessment and management of the risks of GMOs. Use of this protocol is intended to precede and complement risk assessment and risk management procedures specified by gene technology legislation and regulations.

Animals↗
PubMed2001

Comparing Bayesian neural network algorithms for classifying segmented outdoor images.

In this paper we investigate the Bayesian training of neural networks for region labelling of segmented outdoor scenes; the data are drawn from the Sowerby Image Database of British Aerospace. Neural networks are trained with two Bayesian methods, (i) the evidence framework of MacKay (1992a,b) and (ii) a Markov Chain Monte Carlo method due to Neal (1996). The performance of the two methods is compared to evaluating the empirical learning curves of neural networks trained with the two methods. We also investigate the use of the Automatic Relevance Determination method for input feature selection.

Algorithms↗
PubMed1999

Functional consensus for mammalian osmotic response elements.

The molecular mechanisms underlying adaptation to hyperosmotic stress through the accumulation of organic osmolytes are largely unknown. Yet, among organisms, this is an almost universal phenomenon. In mammals, the cells of the renal medulla are uniquely exposed to high and variable salt concentrations; in response, renal cells accumulate the osmolyte sorbitol through increased transcription of the aldose reductase (AR) gene. In cloning the rabbit AR gene, we found the first evidence of an osmotic response region in a eukaryotic gene. More recently, we functionally defined a minimal essential osmotic response element (ORE) having the sequence CGGAAAATCAC(C) (bp -1105 to -1094). In the present study, we systematically replaced each base with every other possible nucleotide and tested the resulting sequences individually in reporter gene constructs. Additionally, we categorized hyperosmotic response by electrophoretic mobility shift assays of a 17-bp sequence (-1108 to -1092) containing the native ORE as a probe against which the test constructs would compete for binding. In this manner, binding activity was assessed for the full range of osmotic responses obtained. Thus we have arrived at a functional consensus for the mammalian ORE, NGGAAAWDHMC(N). This finding should accelerate the discovery of genes previously unrecognized as being osmotically regulated.

Aldehyde Reductase↗
PubMed1998

Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer. National Cancer Institute of Canada Clinical Trials Group.

PURPOSE: To determine the relative efficacy of an intensive cyclophosphamide, epirubicin, and fluorouracil (CEF) adjuvant chemotherapy regimen compared with cyclophosphamide, methotrexate, and fluorouracil (CMF) in node-positive breast cancer. PATIENTS AND METHODS: Premenopausal women with node-positive breast cancer were randomly allocated to receive either cyclophosphamide 100 mg/m2 orally days 1 through 14; methotrexate 40 mg/m2 intravenously (i.v.) days 1 and 8; and fluorouracil 600 mg/m2 i.v. days 1 and 8 or cyclophosphomide 75 mg/m2 orally days 1 through 14; epirubicin 60 mg/m2 i.v. days 1 and 8; and fluorouracil 500 mg/m2 i.v. days 1 and 8. Each cycle was administered monthly for 6 months. Patients administered CEF received antibiotic prophylaxis with cotrimoxazole two tablets twice a day for the duration of chemotherapy. RESULTS: The median follow-up was 59 months. One hundred sixty-nine of the 359 CMF patients developed recurrence compared with 132 of the 351 CEF patients. The corresponding 5-year relapse-free survival rates were 53% and 63%, respectively (P = .009). One hundred seven CMF patients died compared with 85 CEF patients. The corresponding 5-year actuarial survival rates were 70% and 77%, respectively (P = .03). The rate of hospitalization for febrile neutropenia was 1.1% in the CMF group compared with 8.5% in the CEF group. There was one case of congestive heart failure in a patient who received CMF compared with none in the CEF group. Acute leukemia occurred in five patients in the CEF group. CONCLUSION: The results of this trial show the superiority of CEF over CMF in terms of both disease-free and overall survival in premenopausal women with axillary node-positive breast cancer.

Adult↗
PubMed1997

Development and use of virus-vectored immunocontraception.

Virus-vectored immunocontraception (VVIC) is perceived to present biological risks, real or baseless, which create social and political constraints to deploying VVIC for managing vertebrate pests. Developing and deploying VVIC must be justified and address biological, social and political risks. Future needs for pest management will influence deployment of VVIC. Projections of human society and pest impact on agriculture and conservation suggest increasing need for cost-beneficial strategies. Best strategies are likely to integrate various methods, possibly including forms of VVIC. Processes identifying future pest impacts and roles for VVIC are shown using the rabbit in Australia. Present research developing VVIC aims to test physiological feasibility, to develop it for specific pests, and address aspects of ecological feasibility. Minimizing biological risks through choosing species-specific antigens and, if possible, viral vectors, is central and overseen by regulatory authorities. International collaborators study related valued species to develop protective strategies. Excellent science can withstand legal or public challenge to safe and cost-beneficial VVIC if aided by information needed by the public exposed to media distortion of scientific debate, complex argument and concepts of probability and risk. Sound science needs support from strategies for public processes to enable cost-beneficial management of vertebrate pests.

Animals↗
PubMed1997

Baylisascaris sp. found in a wild northern bobwhite (Colinus virginianus).

During a telemetry study conducted between 1993 and 1995 in east-central Kansas (USA) on northern bobwhite (Colinus virginianus) populations, a wild adult male quail was found with signs of disorientation and torticollis in August 1994 in Lyon County, Kansas. Based on histological and parasitological examination, it was determined that the bird was infected with larval nematodes of the genus Baylisascaris spp. This is the first known recorded case of Baylisascaris sp. in a wild game bird species.

Animals↗
PubMed1996

ORE, a eukaryotic minimal essential osmotic response element. The aldose reductase gene in hyperosmotic stress.

Organisms, almost universally, adapt to hyperosmotic stress through increased accumulation of organic osmolytes but the molecular mechanisms have only begun to be addressed. Among mammalian tissues, renal medullary cells are uniquely exposed to extreme hyperosmotic stress. Sorbitol, synthesized through aldose reductase, is a predominant osmolyte induced under hyperosmotic conditions in renal cells. Using a rabbit renal cell line, we originally demonstrated that hyperosmotic stress induces transcription of the aldose reductase gene. Recently, we cloned the rabbit aldose reductase gene, characterized its structure, and found the first evidence of an osmotic response region in a eukaryotic gene. Now, we have progressively subdivided this 3221-base pair (bp) region into discrete fragments in reporter gene constructs. Thereby, we have functionally defined the smallest sequence able to confer hyperosmotic response on a downstream gene independent of other putative cis-elements, that is, a minimal essential osmotic response element (ORE). The sequence of the ORE is CGGAAAATCAC(C) (bp -1105/-1094). A 17-bp fragment (-1108/-1092) containing the ORE used as a probe in electrophoretic mobility shift assays suggests hyperosmotic induction of a slowly migrating band. Isolation of trans-acting factor(s) and characterization of their interaction with the ORE should elucidate the basic mechanisms for regulation of gene expression by hyperosmotic stress.

Aldehyde Reductase↗
PubMed1996

Betaine transporter cDNA cloning and effect of osmolytes on its mRNA induction.

Cells generally adapt to long-term hyperosmolality by accumulating compatible organic osmolytes, thereby helping to normalize both volume and intracellular inorganic ion concentration. When organic osmolytes are accumulated, as in renal inner medullary cells, it is the sum of their concentrations that is theoretically important. In effect, when one organic osmolyte rises, the others generally fall to maintain their sum approximately constant. The present study addresses the mechanism controlling betaine accumulation. Hypertonicity induces accumulation of betaine, sorbitol, inositol, and other organic osmolytes in PAP-HT25 cells, a line derived from rabbit renal papilla. Hypertonicity increases the betaine transporter expression in these cells. To obtain a specific probe for betaine transporter mRNA, we cloned from PAP-HT25 cells a cDNA that encodes the full protein. We then examined the effect of betaine, sorbitol, and inositol on betaine transporter mRNA abundance. Increased accumulation of any of these three organic osmolytes reduces betaine transporter mRNA. We previously observed similar results for aldose reductase, the enzyme responsible for osmotically regulated sorbitol accumulation. We conclude that the accumulation of organic osmolytes regulates betaine transporter gene expression. Because the aldose reductase gene is controlled in a similar fashion, we surmise that the two genes share a common signal for induction.

Amino Acid Sequence↗
PubMed1994

Cloning, genomic organization, and osmotic response of the aldose reductase gene.

Diverse organisms accumulate organic osmolytes to adapt to hyperosmotic stress. The molecular basis of eukaryotic gene osmoregulation remains obscure. Aldose reductase [AR; alditol:NAD(P)+ 1-oxidoreductase, EC 1.1.1.21], which catalyzes the conversion of glucose to sorbitol (an organic osmolyte), is induced in renal medullary cells under hyperosmotic conditions. Elevated extracellular NaCl increases AR mRNA transcription in PAP-HT25 cells, a cell line derived from the rabbit renal papilla. We have cloned and characterized the rabbit AR gene to determine how it is regulated by hyperosmolality. The length of the gene, not including 5' or 3' flanking regions, is approximately 14.7 kilobases (kb) organized into 10 exons and 9 introns. The transcription start site is 36 base pairs upstream of the initiator methionine codon. A 5-kb fragment containing approximately 3.5 kb of 5' flanking region was isolated. The 3.5-kb sequence was examined for basal promoter activity and hyperosmotic response in luciferase reporter gene constructs. A 235-base-pair fragment (base pairs -208 to +27) was able to drive the downstream reporter gene in transfected PAP-HT25 cells under isoosmotic conditions (300 mosmol/kg of H2O). When this fragment plus the remaining upstream sequence (from approximately base pair -3429 to base pair +27) was used, cells in hyperosmotic medium (500 mosmol/kg of H2O) showed about 40-fold induction of luciferase expression compared with cells in isoosmotic medium. The upstream fragment (from approximately base pair -3429 to base pair -192) also conferred osmotic response to a heterologous promoter (B19). This finding evidences putative osmotic response element(s) (OREs) within a specific DNA fragment in a eukaryotic genome. Identification and characterization of OREs within this fragment and their associated trans-acting factors should reveal the molecular mechanisms of gene regulation in osmotic stress.

Aldehyde Reductase↗
PubMed1994

Water channel vesicles from toad urinary bladder contain a family of proteins present in other tissues.

Antidiuretic hormone (ADH) stimulation causes the fusion and subsequent retrieval of cytoplasmic vesicles containing water channels (WCV) with the apical membrane of toad bladder granular cells. Previously, we showed that purified WCV contain 12 major protein bands on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. To identify various WCV proteins, we screened a panel of mouse monoclonal antibodies and characterized an immunoglobulin G1 monoclonal antibody, 5E5, that recognizes integral membrane WCV proteins of 38, 33, and 31 kDa. Immunocytochemistry and Western blot analyses show that 5E5 binds to multivesicular body endosomes shown previously to contain ADH water channels. In addition, 5E5 recognizes these proteins in selected cells of the skin, intestine, liver, kidney, spleen, and lung. However, 5E5 does not appear to recognize components of the water channel itself. We conclude that WCV contain several membrane proteins recognized by 5E5 that are present in certain cells of the other organs. Monoclonal 5E5 provides a probe to determine the structure and function of these endosomal proteins as well as their role in the ADH water permeability response.

Animals↗
PubMed1994

Some epidemiological features of the human T-cell lymphotropic virus type I (HTLV-I) and ATL in Nigerians.

With a seroprevalence rate (SPR) of 6%-10% among healthy adult blood donors (ABD), Nigeria and other African locales represent an endemic zone for HTLV-I. We studied SPR in patients with leukaemia, lymphomas, solid tumours, and chronic disorders, as well as in groups of men and women with varying sexual lifestyles. Serum specimens were screened with ELISA and then confirmed with Western blot (WB). Sexual practices were investigated among volunteers of different sexual backgrounds by means of a questionnaire. Female prostitutes (FP) (13.0%) and patients with sexually transmitted diseases (STDP) (16.7%) had the highest SPR while a low rate occurred in religious celibate males (RCM) but not in religious celibate females (RCF) (11.8%). Heterosexual activity as well as geographical location of the place of birth constituted the most important risk factors for HTLV-I. HIV antibodies were demonstrable in none of the study subjects. ATL was associated with 100% SPR (4/4) while SPR in other clinical states were not different from normal. Western blot profile was rarely of strong poly band but more frequently of weak oligo band pattern with absent or weak p19 compared to p24. Only 18% of non Hodgkin's lymphoma in Ibadan, Nigeria was seropositive compared to 50% and > 60% in Japanese and Caribbean endemic zones respectively. The high SPR and aberrant WB profiles indicate reactivity to HTLV-I and to an HTLV-II-like activity, probably a new virus in the region. Excluding the aberrant WB profile, SPR based on HTLV-I-related profile was 3.8%-4.8% in ABD, 13% in FP, 10% in STDP, 1.9% in RCM, 0% in RCF, and 25% in ATL patients. The HTLV-II-related profile showed no such heterosexual association, but occurred in 75% of ATL patients. HTLV-I and probably and an HTLV-II-like virus appear to play a role in STD and lymphoma epidemiology in Nigeria.

Adult↗
PubMed1993

Frequency of adult T-cell leukaemia/lymphoma and HTLV-I in Ibadan, Nigeria.

Sera from a small sample of adult blood donors, healthy school children and patients with lymphoma, leukaemia, non-haematologic cancer, congenital and inflammatory disorders from Ibadan, Nigeria were screened for HTLV-I antibody by an enzyme-linked immunoabsorbent assay and confirmed by investigational Western blot. Seventy-nine of 236 positively screened samples could not be tested for confirmation. Seropositive reactivity was observed in nine of 123 blood donors, and 3 of 46 healthy school children but banding patterns on Western blot were often sparse. Among non-Burkitt's non Hodgkin's lymphoma patients six of 30 were HTLV-I positive including four of four with clinical features of adult T-cell leukaemia (ATL). Other clinical conditions had a frequency of positivity indistinguishable from healthy donors. Western blot patterns ranged from strong with multiple bands, which were uncommon, to those with only p24 and p21 envelope positive which were frequent. Given the relative paucity of clinical ATL and the unusual Western blot patterns the true rate of HTLV-I infection may be lower than estimated. It is possible that a cross-reactive HTLV-I-like virus accounts for this pattern.

Adolescent↗
PubMed1993

Geographical distribution of acute lymphoblastic leukaemia subtypes: second report of the collaborative group study.

Childhood acute lymphoblastic leukemia (ALL) T and B precursor subtypes have been identified by standardised immunophenotyping in different geographic and ethnic settings. Comparison of the relative frequencies and estimated incidence rates of the major subtypes indicates very similar values, with the striking exception of black childhood populations in Africa in which there appears to be a significant and selective deficit in the incidence of the common (B-cell precursor) subset of ALL. There is suggestive evidence for a similar bias in ALL subtypes in South Africans of mixed ethnic origin and in Mapuche Indians from Chile. Several interpretations of these data are possible but the one favoured attributes these differences primarily to socio-economic factors and patterns of infection in infancy.

Adolescent↗
PubMed1990

Continuous in-vitro cultivation of Plasmodium falciparum in Ibadan: solutions to scientific and logistical problems.

The technique of continuous in-vitro cultivation of Plasmodium falciparum has not been widely applied in malaria-endemic areas, due to scientific as well as purely logistical problems. Methods for solving or coping with these problems are described. They have already proved effective for over 4 years. The parasites harvested have been satisfactory, as judged by reproducible logarithmic growth curves and normal morphology in Leishman-stained smears as well as phase-contrast microscopy of wet-preparations. They have also been successfully used as antigen sources in the malarial fluorescent-antibody test and to investigate enhanced platelet aggregation in experimental malaria.

Animals↗
PubMed1988

Haemolytic anaemia associated with Nigerian barbecued meat (red suya).

Five cases of haemolytic anaemia occurring in male Nigerians following the ingestion of spiced barbecued meat (suya) are described. Although suya is a popular food item in various parts of Nigeria, all five patients described in this report had consumed a special brand, called red suya, purchased from vendors at a popular road junction between the cities of Lagos and Ibadan. Ingestion of the culprit suya sample was followed within 24 h by malaise and fever, while passage of dark-coloured urine and jaundice followed 1-3 days thereafter. Glucose-6-phosphate dehydrogenase (G6PD) deficiency was demonstrated by a fluorescent screening test in all cases, while the enzyme phenotype was shown to be GdA- in all four cases studied by starch-gel electrophoresis, thus suggesting that G6PD deficiency was a predisposing factor in the cases reported in this series. The haemolytic disease was self-limiting and full recovery followed in all cases. In view of the markedly circumscribed range from where the patients originated, the culprit agent responsible for the haemolytic disease is believed to be a recently introduced food additive that is probably accessible only to a limited number of suya vendors.

Adult↗
PubMed1987

Iatrogenic and idiopathic acute myelogenous leukemia: a comparison of clinical features and treatment complications.

We have compared the clinical and laboratory features as well as treatment complications observed in 6 patients with iatrogenic acute myelogenous leukemia (I-AML) with those of 26 patients with idiopathic acute myelogenous leukemia (AML). I-AML patients were significantly younger and their disease appeared less virulent on admission than in the AML patients. Following identical chemotherapy, hemorrhagic complications and the need for platelet support were found to be similar for both groups. Major infections, including systemic candidiasis and Gram-negative septicemias, occurred 3 times more frequently among I-AML than AML patients. More marked suppression and delayed regeneration of the bone marrow also occurred in I-AML patients. These observations and other factors, such as post-splenectomy state and inherent immune deficiency among surgically staged lymphoma patients as well as radiation induced immunologic impairment, may have contributed to the increased propensity to develop infection observed in this group of patients. Five of the 6 I-AML and 17 of the 26 AML patients achieved remission. We attribute the satisfactory outcome in our I-AML patients to treatment in a protective environment and availability of facilities for hematologic supportive care.

Adult↗