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Biomedical subjects

N J Wilson

Publications and source records attributed to N J Wilson.

At least 37 records · Page 2Linked to original sources
PubMed2000

Short-chain fatty acids reduce expression of specific protein kinase C isoforms in human colonic epithelial cells.

LIM1215 colon cancer cells were used as a model of human colonic epithelium to examine the effects of butyrate on protein kinase C (PKC) activity and isoform expression. On Western blot analysis, LIM1215 cells express the PKC isoforms alpha, beta, epsilon, zeta, and lambda, but not gamma, straight theta, or micro. Treatment with 2 mM butyrate for 48 h reduced cellular PKC activity up to 50% and specifically reduced the expression of PKC alpha and PKC epsilon. Similar results were obtained using Caco-2 colon cancer cells. These effects were neither a consequence of the induction of differentiation itself nor the result of direct or indirect activation of PKC. Although dependent on gene transcription and protein synthesis, the effect was not due to a reduction in the synthesis of PKC protein. Butyrate's effect was independent of its beta-oxidation but was mimicked, at least in part, by trichostatin A, an inhibitor of histone deacetylase.

Butyrates↗
PubMed2000

Cyclosporin for severe childhood atopic dermatitis: short course versus continuous therapy.

Cyclosporin (CyA) has been shown to be highly effective and well tolerated in the short-term treatment of severe childhood atopic dermatitis; however, there is limited experience in its longer-term use. The aim of this study was to compare multiple short courses of CyA with continuous therapy for 1 year, with respect to efficacy, safety, tolerability and quality of life. Children aged 2-16 years, with a diagnosis of severe atopic dermatitis refractory to topical steroid therapy, were randomly assigned to receive short course therapy (multiple courses of 12 weeks) or continuous therapy. The starting dose and maximum dose for all patients was 5 mg/kg per day. Disease activity was monitored using the Six Area Six Sign Atopic Dermatitis score and the 'Rule of Nines' area score. Pruritus, sleep disturbance and irritability were measured using visual analogue scales, and topical therapy was monitored. Safety measurements included monitoring of serum creatinine, blood pressure and adverse events. Forty patients were included in the efficacy analysis, 21 of whom were randomized to the short course group (of whom six were withdrawn) and 19 to the continuous group (of whom five were withdrawn). Significant improvements were seen in all efficacy parameters at every time-point. There were no significant differences between groups, although the improvement was more consistent in the continuous arm. In the short course arm, 7 out of 21 patients could be managed by at least two short courses. The remaining 14 patients includes 12 who could not be controlled by at least two short courses, one patient who failed to return after week 12 and another patient who was withdrawn at week 4 due to an adverse event. Quality of life improved for both the children and their families. Tolerability was considered good or very good in at least 80% of the patients at week 12 and at the end of the study. No clinically significant change was seen in mean serum creatinine and no change was seen in mean blood pressure in either group. CyA is effective in controlling severe atopic dermatitis in children over a 1-year period and is well tolerated. More consistent control is achieved with continuous treatment; however, short course therapy was adequate for some patients, indicating that treatment should be tailored to the individual patient's needs. Short course treatment may produce prolonged remission in some cases and reduce the cumulative exposure to the drug.

Adolescent↗
PubMed2000

A keratin 14 'knockout' mutation in recessive epidermolysis bullosa simplex resulting in less severe disease.

Epidermolysis bullosa simplex (EBS) is a blistering skin disease caused in most cases by mis-sense mutations in genes encoding the basal epidermal keratin (K) 5 and K14. The inheritance is usually autosomal dominant and the mutant keratin proteins appear to exert a dominant negative effect on the keratin intermediate filament cytoskeleton in basal keratinocytes. We report a child with a homozygous K14 mutation resulting in the complete absence of K14 protein in the epidermis; remarkably, he only had mild to moderate disease. Electron microscopy of a skin biopsy showed a marked reduction in numbers of keratin intermediate filaments in the basal keratinocytes. Immunofluorescence microscopy using monoclonal antibody LL001 against K14 showed no staining, suggesting a functional knockout of K14. Sequence analysis of genomic DNA revealed a homozygous mutation in codon 31 of K14 that resulted in a premature stop codon further downstream in exon 1. The child's mother, who is unaffected by the disease, is heterozygous for the mutation. The consanguineous father was unaffected and unavailable for testing. The resulting mRNA is predicted to encode a protein of 116 amino acids, of which the first 30 are identical to the normal K14 sequence, and the remaining 86 residues are mis-sense sequence. Four previously reported cases of autosomal recessive EBS with functional knockout of K14 were severely affected by blistering, in contrast to our patient in whom the predicted protein has only the first 30 amino acids of K14 and is therefore the closest to a true knockout of K14 protein yet identified.

Consanguinity↗
PubMed2000

Racial disparities in participation in biomedical research.

To determine whether minority patients were less likely to participate in biomedical research, perceive positive benefits from such participation, or to recommend research participation to other patients, an observational study was conducted. Sociodemographic and survey data were collected from 5436 users of Department of Veterans Affairs (VA) Ambulatory Care, which included questions about veterans' research participation and related attitudes. Bivariate and multivariate analyses were performed to determine if there were racial differences in the outcomes of interest, controlling for relevant sociodemographic factors. Bivariate and multivariate analyses indicated that there were no racial differences in self-reported research participation, but minority veterans were more likely to perceive a positive effect of research and less likely to recommend research to other veterans. However, subgroup analyses indicated that, of those veterans having negative attitudes about research, minority and less educated veterans were disproportionately represented. In the VA system, racial differences in research participation may dissipate because many sociodemographic factors are controlled. Although we did not observe consistent racial differences in research participation or attitudes, the fact that minority veterans were disproportionately represented among the group with the most negative attitudes about research suggests that further research is necessary to fully understand the racial dynamics of research participation in the VA.

Clinical Trials as Topic↗
PubMed1999

Roles of the mitogen-activated protein kinase family in macrophage responses to colony stimulating factor-1 addition and withdrawal.

Colony stimulating factor-1 (CSF-1) (or macrophage CSF) is involved in the survival, proliferation, differentiation, and activation of cells of the monocyte/macrophage lineage. Because the mitogen-activated protein kinase family members extracellular signal-regulated kinases (ERKs), p38, and c-Jun N-terminal kinase are widely implicated in such cellular functions, we measured their activity in growing and growth-arrested cultures of bone marrow-derived macrophages (BMM), as well as their stimulation by saturating concentrations of CSF-1. ERK activity was approximately 2-fold higher in cycling BMM compared with growth-arrested BMM; in addition, CSF-1-stimulated BMM DNA synthesis was partially inhibited by PD98059, a specific inhibitor of MEK activation, suggesting a role for a mitogen-activated protein-ERK kinase (MEK)/ERK pathway in the control of DNA synthesis but surprisingly not in the control of cyclin D1 mRNA or c-myc mRNA expression. The suppression of BMM apoptosis by CSF-1, i.e. enhanced survival, was not reversed by PD98059, suggesting that a MEK/ERK pathway is not involved in this process. Using a quantitative kinase assay, it was found that CSF-1 gave a slight increase in BMM p38 activity, supporting prior data that CSF-1 is a relatively weak stimulator of inflammatory cytokine production in monocytes/macrophages. Relatively high concentrations of the p38 inhibitor, SKB202190, suppressed CSF-1-stimulated BMM DNA synthesis. No evidence could be obtained for the involvement of p38 activity in BMM apoptosis following CSF-1 withdrawal. We were not able to show that CSF-1 enhanced BMM JNK-1 activity to a significant extent; again, no role could be found for JNK-1 activity in the BMM apoptosis occurring after CSF-1 removal.

Animals↗
PubMed1999

Protein phosphatase 2A is expressed in response to colony-stimulating factor 1 in macrophages and is required for cell cycle progression independently of extracellular signal-regulated protein kinase activity.

Colony-stimulating factor 1 (CSF-1) is required for the development of monocytes/macrophages from progenitor cells and for the survival and activation of mature macrophages. The receptor for CSF-1 is the product of the c-fms proto-oncogene, which, on binding ligand, can stimulate a mitogenic response in the appropriate cells. To investigate which genes are regulated in response to CSF-1-stimulation in murine bone-marrow-derived macrophages (BMM), we employed mRNA differential display reverse transcriptase-mediated PCR to identify cDNA species induced by CSF-1. Both Northern and Western blot analyses confirmed the increased expression of one of the cDNA species identified as coding for the catalytic subunit of protein phosphatase 2A (PP2A), an observation not previously reported during the response to a growth factor. To determine the significance of the increased expression of PP2A in response to CSF-1, the PP2A inhibitor okadaic acid (OA) was added to CSF-1-treated BMM and found to inhibit DNA synthesis in a dose-dependent manner. Further analysis with flow cytometry in the presence of OA led to the novel conclusion that PP2A activity is critical for CSF-1-driven BMM cell cycle progression in both early G1 and S phases. Surprisingly, in the light of previous studies with other cells, the PP2A-dependent proliferation could be dissociated from activation by extracellular signal-regulated protein kinase (ERK) in macrophages because OA did not affect either the basal or CSF-1-induced ERK activity in BMM. Two-dimensional SDS/PAGE analysis of lysates of 32P-labelled BMM, which had been treated with CSF-1 in the presence or absence of OA, identified candidate substrates for PP2A.

Animals↗
PubMed1999

Subclinical aortic perforation with the infant double-button patent ductus arteriosus occluder.

Modification of the double-button (Sideris) patent ductus arteriosus (PDA) occluder has resulted in a single-strut aortic component rather than the conventional cross-strut design. We report the use of this infant PDA occluder for transcatheter closure in three patients with PDA measuring 2 mm, 3.7 mm, and 4 mm. Subclinical aortic perforation with a small aortic aneurysm developed in two patients 1 year after occluder implantation. The third patient had developed a small aortic aneurysm without perforation at 3-month follow-up. All three patients had a residual shunt and underwent successful PDA surgical closure with aortic aneurysmal repair. Single-strut umbrella designs are not recommended for PDA transcatheter closure.

Aorta, Thoracic↗
PubMed1999

Expression of a Y559F mutant CSF-1 receptor in M1 myeloid cells: a role for Src kinases in CSF-1 receptor-mediated differentiation.

We have established two M1 myeloid cell lines, M1/WT cells overexpressing the wild-type CSF-1 receptor and M1/Y559F cells expressing a specific tyrosine mutant. M1/WT cells differentiated in response to CSF-1, with a reduction in their proliferative capacity. CSF-1-mediated differentiation was partially abrogated in the M1/Y559F cells, with a less marked reduction in proliferative capacity. The Src tyrosine kinases c-Src, c-Yes, c-Fyn, and c-Hck were tyrosine phosphorylated in the M1/WT cells in response to CSF-1 and bound to the WT CSF-1R through their SH2 domains. Binding of the Src kinases to the CSF-1 receptor was greatly reduced in the M1/Y559F cells. CSF-1-mediated activation of STAT3 was also abrogated in the M1/Y559F cell line. Treatment of M1/WT cells with the Src family inhibitor PP2 resulted in an inhibition of CSF-1-mediated differentiation, equivalent to that observed in the M1/Y559F cells. These data suggest that the reduced Src binding observed in the M1/Y559F cells may contribute to their reduced ability to differentiate.

Animals↗
PubMed1999

A low mutation rate for chloroplast microsatellites.

We used chloroplast simple sequence repeats (cpSSRs) to examine whether there is any variation present in the chloroplast genome of Pinus torreyana (Parry ex Carrière) that may previously not have been detected using RFLPs. Analysis of 17 cpSSR loci showed no variation, which is consistent with previous cpRFLP work and confirms that the species is descended from an original, highly monomorphic population following a bottleneck. This lack of biological variation in the chloroplast genome of P. torreyana allowed us to estimate the mutation rates at cpSSR loci as between 3. 2 x 10(-5) and 7.9 x 10(-5). This estimate is lower than published mutation rates at nuclear SSR loci but higher than substitution rates elsewhere in the chloroplast genome.

Chloroplasts↗
PubMed1999

Mental illness as a predictor of satisfaction with inpatient care at Veterans Affairs hospitals.

OBJECTIVE: Patient satisfaction ratings are increasingly being used as an indicator of quality of care. However, satisfaction scores do not account for differences in satisfaction among patients that may be attributable to sociodemographic characteristics or type of illness rather than to the quality of service delivery. This study examines the role of psychiatric diagnosis in satisfaction with inpatient care delivered at Department of Veterans Affairs (VA) hospitals. METHODS: Data were taken from a large national VA customer feedback survey of patients discharged from VA hospitals between June 1 and August 31, 1995 (N=38,789). Analyses examined whether patients discharged with a psychiatric diagnosis were less satisfied with care than those discharged with a nonpsychiatric diagnosis. RESULTS: Patients with a psychiatric diagnosis were less satisfied with their care, regardless of whether they were treated in a psychiatric treatment program or a medical unit, and this relationship remained after the analysis adjusted for other determinants of satisfaction. The association between low satisfaction and psychiatric diagnosis was more pronounced among nonblack patients. CONCLUSIONS: The results suggest the need for caution in using patient satisfaction measures to compare mental health programs and other health care programs.

Adult↗
PubMed1998

Gene-pool variation in caledonian and European Scots pine (Pinus sylvestris L.) revealed by chloroplast simple-sequence repeats.

We have used polymorphic chloroplast simple-sequence repeats to analyse levels of genetic variation within and between seven native Scottish and eight mainland European populations of Scots pine (Pinus sylvestris L.). Diversity levels for the Scottish populations based on haplotype frequency were far in excess of those previously obtained using monoterpenes and isozymes and confirmed lower levels of genetic variation within the derelict population at Glen Falloch. The diversity levels were higher than those reported in similar studies in other Pinus species. An analysis of molecular variance (AMOVA) showed that small (3.24-8.81%) but significant (p < or = 0.001) portions of the variation existed between the populations and that there was no significant difference between the Scottish and the mainland European populations. Evidence of population substructure was found in the Rannoch population, which exhibited two subgroups. Finally, one of the loci studied exhibited an allele distribution uncharacteristic of the stepwise mutation model of evolution of simple-sequence repeats, and sequencing of the PCR products revealed that this was due to a duplication rather than slippage in the repeat region. An examination of the distribution of this mutation suggests that it may have occurred fairly recently in the Wester Ross region or that it may be evidence of a refugial population.

Alleles↗
PubMed1998

Oncology management by the "new" Veterans Health Administration.

BACKGROUND: The Veterans Health Administration (VHA) of the Department of Veterans Affairs (VA) manages the largest integrated health care system in the U.S. Cancer is second only to cardiovascular disease as a cause of patient mortality and morbidity. In the fiscal year 1996, malignancies accounted for 49,270 primary diagnoses at the time of discharge from acute hospitals. METHODS: VHA recently developed a national, uniform benefits package that provides oncologic services of prevention and screening, inpatient and outpatient services, rehabilitative care, reconstructive surgery, home health care, respite, and hospice care. VA classifies all hospitals according to American College of Surgeons (ACS) Commission on Cancer criteria and standards. One hundred four of 173 facilities are ACS-approved cancer centers. Eighty-six VA hospitals have cancer registries. RESULTS: VHA has developed a Prevention Index (PI) that consists of nine measures for prevention and early detection of influenza and pneumococcal diseases, tobacco consumption, alcohol abuse, and cancers of the breast, cervix, colon, and prostate. All cancer interventions in the PI showed substantial increases between 1996 and 1997, and all exceeded U.S. Public Health Healthy People 2000 goals. The Veterans Health Administration's performance measure regarding end-of-life planning calls for 95% of eligible patients to receive ongoing care. Current baseline performance is 52% nationally. Measures of patient satisfaction for oncology patients show overall satisfaction at 87%. CONCLUSIONS: The VA healthcare system has substantial expertise in the diagnosis and management of cancer. VHA's unprecedented transformation into a system of integrated networks supports and promotes that expertise. The VHA initiatives described in this article are synergistically working to enhance the consistency and comprehensiveness of high-quality, patient-centered oncologic services.

Delivery of Health Care, Integrated↗
PubMed1998

cAMP enhances CSF-1-induced ERK activity and c-fos mRNA expression via a MEK-dependent and Ras-independent mechanism in macrophages.

Inhibition of MAPK by elevated intracellular cAMP has often been correlated with suppression of growth factor-induced proliferation. However, in murine bone marrow-derived macrophages (BMM) we show that the cAMP analogue, 8-bromo cAMP (8BrcAMP) (1mM), despite being a dramatic G1 phase proliferation inhibitor, increased ERK activity both in the absence and presence of CSF-1; these increases were blocked by PD98059 (100 microM) suggesting MEK dependence. In contrast, CSF-1-stimulated p21Ras activity was blocked by 8BrcAMP thus correlating with the inhibition of proliferation. This is the first report to indicate that elevated intracellular cAMP can activate ERK activity while inhibiting proliferation and the data support the concept in CSF-1-treated macrophages of Ras-independent activation of ERK activity. It was also found that the acute but not the sustained elevation of c-fos mRNA expression due to 8BrcAMP was also MEK dependent indicating that there are separate pathways controlling c-fos mRNA expression in BMM.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1998

Long-term outcome after the mustard repair for simple transposition of the great arteries. 28-year follow-up.

OBJECTIVES: This study examines the late outcome in patients with simple transposition of the great arteries (TGA) after a Mustard operation. BACKGROUND: Continuing medical follow-up for patients after the Mustard procedure, now extending to three decades, is required. The quality of life of adult survivors has not been well documented. METHODS: Survival and quality of life among 113 hospital survivors of the Mustard operation performed for simple TGA between 1964 and 1982 were assessed by medical review and a lifestyle questionnaire. The incidence of right ventricular failure and echocardiographic right ventricular dysfunction (RVD) were determined. A measure of lifestyle, the ability index, was determined. RESULTS: Actuarial survival was 90%, 80%, and 80% at 10, 20, and 28 years, respectively, with 76% of survivors being New York Heart Association class 1. Sudden death, with an incidence of 7% without identifiable risk factors, was the most common cause of late demise. RVD was identified in 18% of patients who had echocardiography, but there was right ventricular failure in only two patients. Seventy-five percent of current survivors lead a normal life, 20% have some symptoms or lifestyle modification, and 5% are unable to work. CONCLUSIONS: The survival of patients to 28 years with the Mustard repair has been good. Late sudden death is the most worrisome feature. There is a 97% freedom from right ventricular failure to date. The quality of life of late survivors is good, most achieving a normal level of education and employment.

Activities of Daily Living↗