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Biomedical subjects

P Walsh

Publications and source records attributed to P Walsh.

At least 55 records · Page 3Linked to original sources
PubMed1999

Characterization of an autoantigen associated with chronic ulcerative stomatitis: the CUSP autoantigen is a member of the p53 family.

A unique clinical syndrome has been described in which patients have chronic oral ulceration and autoantibodies to nuclei of stratified squamous epithelium. We have characterized the autoantibodies from patients sera and found that the major autoantigen is a 70 kDa epithelial nuclear protein. Sequencing of the cDNA for this protein, chronic ulcerative stomatitis protein, revealed it to be homologous to the p53 tumor suppressor and to the p73 putative tumor suppressor, and to be a splicing variant of the KET gene. The p53-like genes, p73 and the several KET splicing variants, are recently described genes of uncertain biologic and pathologic significance. This study provides the first clear association of a p53-like protein with a disease process.

Autoantigens↗
PubMed1999

Overexpression of mutant ras in human melanoma increases invasiveness, proliferation and anchorage-independent growth in vitro and induces tumour formation and cachexia in vivo.

Malignant melanoma is the deadliest form of skin cancer. Previous studies have shown that the incidence of ras mutation increases with progression of melanoma, but that such mutations may not be present in the earliest radial growth phase melanomas. Recently it has been proposed that introduction of ras mutations into cells deficient in tumour suppressor genes such as p16 (INK4a) is sufficient to induce characteristics of cellular transformation such as anchorage-independent growth and tumour formation in vivo. To test this hypothesis in human melanoma, mutant N-ras, mutant H-ras or wild-type H-ras genes were transfected by electroporation into WM35 cells, a p16-deficient human melanoma cell line of low invasive potential. Increased expression of mutant ras p21 enhanced anchorage-dependent cell growth on tissue culture plastic. In addition, overexpression of mutant N-ras and H-ras, but not of wild-type H-ras, increased the experimental invasive potential, inducing anchorage-independent growth in soft agar, increasing cell motility measured by time-lapse video microscopy, and increasing invasiveness through reconstituted basement membranes. Finally, overexpression of mutant H-ras in melanoma cells was shown to increase tumorigenicity and to induce cachexia when H-ras transfected cell lines were injected subcutaneously in severe combined immunodeficiency (SCID) mice. Thus the addition of activating ras mutations to a melanoma cell line already deficient in p16 leads to enhanced proliferation, survival and migration in vitro and to enhanced subcutaneous tumour formation in vivo. This phenotype is typical of the behaviour of vertical growth phase (VGP) melanoma, and we propose that activation of the ras signalling pathway in the presence of deletions in p16 or related tumour suppressors can induce the VGP melanoma phenotype.

Animals↗
PubMed1998

The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. Finasteride Long-Term Efficacy and Safety Study Group.

BACKGROUND: Finasteride is known to improve urinary symptoms in men with benign prostatic hyperplasia, but the extent to which the benefit is sustained and whether finasteride reduces the incidence of related events, including the need for surgery and the development of acute urinary retention, is not known. METHODS: In this double-blind, randomized, placebo-controlled trial, we studied 3040 men with moderate-to-severe urinary symptoms and enlarged prostate glands who were treated daily with 5 mg of finasteride or placebo for four years. Symptom scores (on a scale of 1 to 34), urinary flow rates, and the occurrence of outcome events were assessed every four months in 3016 men. Prostate volume was measured in a subgroup of the men. Complete data on outcomes were available for 2760 men. RESULTS: During the four-year study period, 152 of the 1503 men in the placebo group (10 percent) and 69 of the 1513 men in the finasteride group (5 percent) underwent surgery for benign prostatic hyperplasia (reduction in risk with finasteride, 55 percent; 95 percent confidence interval, 41 to 65 percent). Acute urinary retention developed in 99 men (7 percent) in the placebo group and 42 men (3 percent) in the finasteride group (reduction in risk with finasteride, 57 percent; 95 percent confidence interval, 40 to 69 percent). Among the men who completed the study, the mean decreases in the symptom score were 3.3 in the finasteride group and 1.3 in the placebo group (P<0.001). Treatment with finasteride also significantly improved urinary flow rates and reduced prostate volume (P<0.001). CONCLUSIONS: Among men with symptoms of urinary obstruction and prostatic enlargement, treatment with finasteride for four years reduces symptoms and prostate volume, increases the urinary flow rate, and reduces the risk of surgery and acute urinary retention.

5-alpha Reductase Inhibitors↗
PubMed1998

Belgian doctors' attitudes on the management of patients in persistent vegetative state (PVS): ethical and regulatory aspects.

BACKGROUND: The best care and management of patients in persistent vegetative state (PVS) has been the subject of sustained moral and legal debate for a number of years. However, the views of specialist doctors in Belgium involved in the care for patients in PVS are largely unknown. METHODS: A postal questionnaire was sent to 403 members of Belgian Societies of Neurosurgeons, Neurologists and Rehabilitation Doctors. Their views were sought on various aspects of the management and care of PVS, focusing on the issue of the appropriateness of non-treatment and the withdrawal of artificial feeding. FINDINGS: Of the 208 doctors who completed the questionnaires (52%), 172 (83%) indicated that they had been involved in the management of a patient in PVS. 88% of the responding doctors thought it was sometimes appropriate not to treat acute infections or other life-threatening conditions in a PVS patient. Fifty-six percent considered it sometimes appropriate to withdraw artificial feeding. About three-quarter of physicians who considered both treatment-limiting decisions appropriate thought that such decisions could be considered within the first year of the patient being in PVS. Forty percent accorded a decisive influence to an advance directive and only a small number of doctors considered the influence of the patient's family in the decision to withdraw artificial feeding as decisive. Over 80% of the clinicians disagreed with the view that each decision about withdrawing artificial nutrition and hydration (ANH) should come before the courts. INTERPRETATION: Doctors in Belgium seem to be more reluctant to withdraw artificial feeding than not to treat acute infections or other life-threatening conditions in PVS. The reason for this difference appeared to be connected with the moral as well as with the clinical content of the decision. The broad variety of answers on the interval when the vegetative state is to be regarded as permanent and when treatment-limiting decisions are appropriate, could be due to the lack of official guidelines in Belgium. There seems however to be no consensus about a future policy in Belgium for making decisions about the withdrawal of ANH.

Attitude of Health Personnel↗
PubMed1998

Numerical evaluation of the production of radionuclides in a nuclear reactor (Part I).

Numerical evaluation of nuclear transmutations is essential for optimization of radionuclide production. Accordingly, we have developed a generalized computer program called LAURA for predicting the production rates of radionuclides in a nuclear reactor. The program is generalized in the sense that it can be used for calculation of the production rate of any member of a network undergoing spontaneous decay and/or induced neutron transformation in a nuclear reactor. In this paper (Part I), we describe the mathematical basis for the development of LAURA. Expressions based on the Rubinson (1949) approach have been used for the evaluation of the depletion functions. This method is also valid when some of the depletion constants have identical values; thus, the approximate solution of Raykin and Shlyakhter (1989) can be used to account for the effects of feedback due to alpha decay.

Algorithms↗
PubMed1998

Numerical evaluation of the production of radionuclides in a nuclear reactor (Part II).

A computer program called LAURA has been developed to predict the production rates of any member of a nuclei network undergoing spontaneous decay and/or induced neutron transformation in a nuclear reactor. The theoretical bases for the development of LAURA were discussed in Part I. In particular, in Part I, we described how an expression based on the Rubinson (1949) approach is used to evaluate the depletion function. In this paper (Part II), we describe the full simulation of radionuclide production including the decomposition of a reaction network into independent linear chains, provisions for periodic reactor shutdown and restart, and implementation of an approximate solution given by Raykin and Shlyakhter (1989) to account for the effect of feedback due to alpha decay. Also included are some examples which demonstrate possible uses for LAURA.

Computer Simulation↗
PubMed1998

Evidence for a prostate cancer susceptibility locus on the X chromosome.

Over 200,000 new prostate cancer cases are diagnosed in the United States each year, accounting for more than 35% of all cancer cases affecting men, and resulting in 40,000 deaths annually. Attempts to characterize genes predisposing to prostate cancer have been hampered by a high phenocopy rate, the late age of onset of the disease and, in the absence of distinguishing clinical features, the inability to stratify patients into subgroups relative to suspected genetic locus heterogeneity. We previously performed a genome-wide search for hereditary prostate cancer (HPC) genes, finding evidence of a prostate cancer susceptibility locus on chromosome 1 (termed HPC1; ref. 2). Here we present evidence for the location of a second prostate cancer susceptibility gene, which by heterogeneity estimates accounts for approximately 16% of HPC cases. This HPC locus resides on the X chromosome (Xq27-28), a finding consistent with results of previous population-based studies suggesting an X-linked mode of HPC inheritance. Linkage to Xq27-28 was observed in a combined study population of 360 prostate cancer families collected at four independent sites in North America, Finland and Sweden. A maximum two-point lod score of 4.60 was observed at DXS1113, theta=0.26, in the combined data set. Parametric multipoint and non-parametric analyses provided results consistent with the two-point analysis. Significant evidence for genetic locus heterogeneity was observed, with similar estimates of the proportion of linked families in each separate family collection. Genetic mapping of the locus represents an important initial step in the identification of an X-linked gene implicated in the aetiology of HPC.

Adult↗
PubMed1997

Heredity and prostate cancer: a study of World War II veteran twins.

BACKGROUND: Increased risk of prostate cancer among men with a family history of the disease has been observed in several epidemiological studies, and family studies have identified hereditary prostate cancer characterized by early onset and autosomal dominant inheritance. METHODS: In this study, we examine prostate cancer heritability among twins in the NAS-NRC Twin Registry, with cases ascertained from a number of sources: recent telephone interviews, Medicare and Department of Veterans Affairs hospitalizations, previous mail questionnaires, and death certificates. A total of 1,009 prostate cancer cases were identified among the cohort of 31,848 veteran twins born in the years 1917-1927. RESULTS: Probandwise concordance for prostate cancer was substantially higher among monozygous twin pairs, 27.1%, than among dizygous twin pairs, 7.1% (P < 0.001). CONCLUSIONS: These data suggest that genetic influences account for approximately 57%, and environmental influences for 43%, of the variability in twin liability for prostate cancer.

Aged↗
PubMed1997

Pulsatile urea excretion in the toadfish (Opsanus beta) is due to a pulsatile excretion mechanism, not a pulsatile production mechanism

When subjected to a crowding/confinement protocol in the laboratory, toadfish become facultatively ureotelic, excreting approximately 90 % of their nitrogenous waste as urea-nitrogen (urea-N). The great majority of this excretion occurs via large, irregular pulses from the head region which occur on average once per day, with a duration of 3 h or less. Pulses measured chemically by the appearance of urea-N in the external water were identical to those measured by assaying [14C]urea appearance in the water from the blood plasma. Individual toadfish maintained plasma urea concentrations over widely differing ranges (6600&shy;39 890 &micro;mol-N l-1). However, independent of absolute levels, both [14C]urea and total urea were distributed at ratios close to unity between the blood plasma and the water compartments of liver and white muscle. At times of pulsatile excretion, plasma urea concentration fell sharply. These decreases, distributed throughout the tissues of the whole body, closely matched the sizes of the measured excretion pulses. Between pulses, plasma urea concentration increased steadily at a much slower rate; the rate of rise, when distributed throughout the tissues of the whole body, corresponded to the time-averaged excretion rate over the whole day. Infusion of a typical pulse amount of urea immediately after the end of a natural pulse event raised plasma urea concentration slightly above the pre-pulse level, but did not induce another pulse event. Plasma cortisol levels declined by approximately 60 % over the 4 h period prior to a natural pulse event and then rose quickly again once the pulse had occurred. These results indicate that urea pulses are due to activation of an excretion mechanism that rapidly clears urea from the blood plasma, thereby lowering stores throughout the whole body. Metabolic production of urea is continuous and is not responsible for pulsatile excretion. The pulse event is not triggered by a specific plasma urea threshold, but may involve the hypothalamo&shy;interrenal axis.

Journal Article↗
PubMed1997

The use of biothesiometry to detect neuropathy in children and adolescents with IDDM.

OBJECTIVE: To develop clinically useful reference ranges for vibration perception thresholds (VPTs), using biothesiometry in children and adolescents and to assess the reliability of the technique to identify subclinical neuropathy in subjects with IDDM at this age and to examine a large population-based sample of pediatric patients. RESEARCH DESIGN AND METHODS: VPTs were measured using a handheld biothesiometer at the medial malleolus and hallux in 232 nondiabetic children and adolescents aged 7-18 years (12.9 +/- 4.2 years) and a population-based sample of 307 young IDDM patients (13.3 +/- 4.6 years of age). The mean of three readings at each site was correlated with height, pubertal status, and age for all subjects and, in addition for the IDDM sample, with the duration of IDDM, ambient blood glucose, and mean HbA1c from diagnosis. Those IDDM subjects found to have elevated VPTs (> 97th percentile), and a control group of patients with IDDM underwent nerve conduction studies to determine the sensitivity and specificity of biothesiometry to detect abnormal neural function in children. Interoperator reliability was assessed in a separate trial in which two operators measured VPTs independently in the same 11 children. RESULTS: In the nondiabetic control subjects, height demonstrated the best correlation with VPT measures, and a reference range was thus established with percentile charts, using mean VPT and height. VPTs were higher in the diabetic sample, compared with the nondiabetic sample (P < 0.05). Of the children, 28 (9.1%) had VPT values > 97th percentile developed from studies of the nondiabetic subjects; of these, 11 were younger than 11 years and 8 were prepubertal. Nerve conduction studies confirmed reduced conduction velocity and prolonged distal latencies in those with abnormal VPTs, compared with normal control subjects and IDDM patients with normal VPTs. Sensitivity of biothesiometry to reflect abnormal nerve function was estimated as 82% and specificity as 75% at this age. Interoperator variation was small (7.25% of total variance). CONCLUSIONS: Biothesiometry is a useful noninvasive tool for the detection of subclinical neuropathy in children and adolescents. The use of height-related reference ranges may make screening for neuropathy more feasible in younger patients and allow large-scale longitudiral analysis of its development.

Adolescent↗
PubMed1997

Lesion size is a factor for determining the rate of port-wine stain clearing following pulsed dye laser treatment in adults.

Seventy-four adult patients with facial, truncal, and extremity port-wine stains (PWS) were treated with the flashlamp-pumped pulsed dye laser (PDL) with laser output ranging from 6.0 to 7.5 J/cm2. Response to treatment was analyzed by comparing the area of involvement following each treatment with the area of involvement measured in the first treatment session. All the PWS responded with 25 to 90 percent lightening, and 85.1 percent of patients achieved 25 percent clearing. However, only 36.5 percent achieved 50 percent clearing, and none of the patients achieved 100 percent clearing. None of four patients with PWS greater than 100 cm2 achieved 50 percent clearing following a mean of 17.2 +/- 5.7 treatments. These data emphasize the importance of objectively documenting clinical response to PDL treatment of PWS. Adult patients need to be made aware that complete clearing may not be obtainable by PDL treatment alone. This is especially important for adult patients with PWS larger than 100 cm2.

Adult↗
PubMed1996

Bioethics for clinicians: 1. Consent.

Patients are entitled to make decisions about their medical care and to be given relevant information on which to base such decisions. The physicians obligation to obtain the patient's consent to treatment is grounded in the ethical principles of patient autonomy and respect for persons and is affirmed by Canadian law and professional policy. A large body of research supports the view that the process of obtaining consent can improve patient satisfaction and compliance and, ultimately, health outcomes. An exception to the requirement to obtain consent is the emergency treatment of incapable persons, provided there is no reason to believe that the treatment would be contrary to the person's wishes if he or she were capable.

Aged↗
PubMed1996

Survey of British clinicians' views on management of patients in persistent vegetative state.

BACKGROUND: The best care and management of patients in persistent vegetative state (PVS) has been the subject of sustained moral and legal debate for a number of years. However, the views of clinicians in the UK involved in caring for patients in PVS are largely unknown. METHODS: A postal questionnaire was sent to 1882 consultant members of the British Association of Orthopaedic Surgeons, the Association of British Neurologists, the Society of British Neurosurgeons, and the British Society of Rehabilitation Medicine. Their views were sought on various aspects of the management and care of PVS, in particular the appropriateness of a decision not to treat and a decision to withdraw artificial nutrition and hydration (ANH). FINDINGS: 1027 doctors responded (55%) of whom 558 (54%) had experience of managing patients in PVS. Over 90% of responding doctors considered that it could be appropriate not to treat acute infections and other life-threatening conditions. 65% of doctors considered that withdrawal of ANH could be appropriate. About two-thirds of doctors who thought treatment-limiting decisions could be appropriate thought that such decisions could be considered with the first 12 months of the patient being in PVS. Despite recent case law, less than half the doctors responding to the survey thought that an advance directive made by the patient should have a decisive influence in determining treatment-limiting decisions. Most doctors would like decisions about withdrawing ANH to be made in conjunction with family members and in accordance with agreed guidelines but without the need to go to court. INTERPRETATION: There is a broad consensus among doctors that treatment-limiting decisions are sometimes appropriate for patients in PVS, irrespective of whether they have experience of the condition or of the specialty to which they belong. However, two thirds of doctors said that such decisions can be considered at a time earlier than that recommended by the British Medical Association. It is not clear why some doctors thought a decision not to treat could be appropriate while a decision to withdraw ANH would not be.

Advance Directives↗
PubMed1996

Candida albicans induces selective expansion of human T lymphocytes expressing the T-cell receptor variable region V beta 5.1.

Candida albicans is a common pathogen which can present major problems as an opportunistic skin pathogen in patients with immunodeficiency. The exact nature of the T cell responses to C. albicans is poorly understood. The purpose of this study was to determine whether C. albicans could stimulate the selective expansion of T lymphocytes expressing particular V beta gene segments. Human T lymphocytes stimulated in vitro with an extract of C. albicans were analyzed for T cell receptor V beta gene expression by using a quantitative PCR technique. We found that stimulation of peripheral blood mononuclear cells (PBMC) produced a selective increase in the expression of V beta 5.1 and 5.2 gene transcripts. Using cytofluorographic analysis with available anti-V beta monoclonal antibodies, we verified that there was a significant selective expansion (P = 0.035) of V beta 5.1 positive T lymphocytes in PBMC from six subjects stimulated in vitro with C. albicans. PCR analysis of V beta 5.1 expansion in 10 subjects showed increases in V beta 5.1 gene transcripts in 7/10 subjects. More importantly, analysis of the T cell infiltrate 48 h after intradermal injections with C. albicans also showed significant expression of V beta 5.1 in the infiltrates, along with the infiltration of V beta 8.1 + T cells. The selective expansion of V beta 5.1 bearing T lymphocytes in PBMC stimulated with C. albicans and in skin test reactions to C. albicans suggests that a restricted population of T cells react to C. albicans. Furthermore, our present data raise the provocative possibility that one or more antigens in C. albicans can act as a superantigen, producing selective expansion of a population of T lymphocytes bearing a particular V beta specificity.

Antibodies, Monoclonal↗
PubMed1995

Comparative study of DNA adducts levels in white sucker fish (Catostomus commersoni) from the basin of the St. Lawrence River (Canada).

The levels of DNA adducts in the hepatic tissue of the white sucker fish species Catostomus commersoni were determined by 32P-postlabelling. The fish were caught at four sites: two sites near the city of Windsor (Québec, Canada) on the St. François River, a downstream tributary of the St. Lawrence River, and two sites in the St. Lawrence River itself, near the city of Montréal (Québec, Canada). The latter sites are known to be contaminated by many pollutants including polycyclic aromatic hydrocarbons. Total adduct levels in all fish ranged from 25.1-178.0 adducts per 10(9) nucleotides. White sucker from the selected sites of the St. Lawrence River had a significantly higher mean level of DNA adducts than those of the St. François River (129.4 vs 56.8, respectively). These results suggest that the effluents of many heavy industries (e.g. from a Soderberg aluminium plant) flowing in the St. Lawrence River are more likely to produce genotoxic damage to fish than those released in one of its tributary, and mainly associated to the activities of a small town and a nearby pulp and paper mill.

Animals↗