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Biomedical subjects

A Forbes

Publications and source records attributed to A Forbes.

At least 127 records · Page 7Linked to original sources
PubMed1998

Nanos and Pumilio have critical roles in the development and function of Drosophila germline stem cells.

The zinc-finger protein Nanos and the RNA-binding protein Pumilio act together to repress the translation of maternal hunchback RNA in the posterior of the Drosophila embryo, thereby allowing abdomen formation. nanos RNA is localized to the posterior pole during oogenesis and the posteriorly synthesized Nanos protein is sequestered into the germ cells as they form in the embryo. This maternally provided Nanos protein is present in germ cells throughout embryogenesis. Here we show that maternally deposited Nanos protein is essential for germ cell migration. Lack of zygotic activity of nanos and pumilio has a dramatic effect on germline development of homozygous females. Given the coordinate function of nanos and pumilio in embryonic patterning, we analyzed the role of these genes in oogenesis. We find that both genes act in the germline. Although the nanos and pumilio ovarian phenotypes have similarities and both genes ultimately affect germline stem cell development, the focus of these phenotypes appears to be different. While pumilio mutant ovaries fail to maintain stem cells and all germline cells differentiate into egg chambers, the focus of nanos function seems to lie in the differentiation of the stem cell progeny, the cystoblast. Consistent with the model that nanos and pumilio have different phenotypic foci during oogenesis, we detect high levels of Pumilio protein in the germline stem cells and high levels of Nanos in the dividing cystoblasts. We therefore suggest that, in contrast to embryonic patterning, Nanos and Pumilio may interact with different partners in the germline.

Animals↗
PubMed1998

Alterations in non-insulin-mediated glucose uptake in the elderly patient with diabetes.

It is increasingly recognized that alterations in non-insulin-mediated glucose uptake (NIMGU) play an important pathogenic role in disorders of carbohydrate metabolism. This study was conducted to determine whether NIMGU is impaired in elderly patients with type 2 diabetes. Healthy elderly control subjects (n = 19, age 76 +/- 1 years, BMI 26.8 +/- 1.1 kg/m2) and elderly patients with type 2 diabetes (n = 19, age 76 +/- 2 years, BMI 27.5 +/- 0.9 kg/m2) underwent a 240-min glucose clamp study. Octreotide was infused to suppress endogenous insulin release, and tritiated glucose methodology was used to measure glucose uptake and disposal rates. For the first 180 min, glucose was kept at fasting levels. From 180 to 240 min, glucose was increased to 11 mmol/l. At fasting glucose levels, glucose uptake was similar in both groups. However, glucose clearance was reduced in patients with diabetes (control 1.68 +/- 0.05 ml x kg(-1) x min(-1); diabetes 1.34 +/- 0.07 ml x kg(-1) x min(-1), P < 0.0001). During hyperglycemia, glucose uptake was reduced in patients with diabetes (control 3.16 +/- 0.09 mg x kg(-1) x min(-1); diabetes 2.57 +/- 0.11 mg x kg(-1) x min(-1), P < 0.0001). Peripheral glucose effectiveness (SG) was less in patients with diabetes (control 1.28 +/- 0.04 ml x kg(-1) x min(-1); diabetes 0.94 +/- 0.08 ml x kg(-1) x min(-1), P < 0.0001). Hepatic glucose output and hepatic SG were not different between groups. We conclude that the effect of glucose on glucose uptake is impaired in elderly patients with type 2 diabetes, a finding that may have therapeutic implications for this patient population.

Adipose Tissue↗
PubMed1998

Alterations in classical cadherins associated with progression in ulcerative and Crohn's colitis.

Human colitis is a condition associated with a spectrum of altered morphologic changes and cellular adhesion. The role of cadherins, which are powerful morphoregulatory cell adhesion molecules, in colitis is provocative and as yet unknown. Herein, we present results that suggest a strong correlation between the deregulation of two cadherin molecules, E- and P-cadherins, and the progression of human colitis. We examined the expression and structural integrity of E- and P-cadherins in inflamed, dysplastic, or neoplastic human ulcerative colitis (UC) (n=58), human Crohn's colitis (n = 30), and normal tissue (n = 20) to assess cadherin function in normal and abnormal epithelium. E-cadherin is strongly expressed in normal colorectal epithelium, whereas in left-sided UC it is either down-regulated or has a single-base pair mutation in exon 4 resulting in an amino acid alteration (6 of 58 UC cases). By contrast, P-cadherin is dramatically up-regulated in both Crohn's disease and ulcerative colitis and especially in dysplastic ulcerative tissue. In vitro transfected SW-480 colorectal cells containing E-cadherin mutations identical to those in vivo were associated with increased spontaneous disaggregation compared with cells transfected with wild-type E-cadherin. Based on this evidence, we hypothesize that a small subset of colorectal cells expressing mutant E-cadherin are associated with widespread ulceration, whereas those expressing P-cadherin are associated with a rapidly dividing immature phenotype that includes dysplasia. The differential expression of mutated and wild-type cadherins examined herein are associated with a broad spectrum of abnormal epithelial phenotypes, lymphocyte integrin binding, and resistance to denudation, as is seen in the colitis adenocarcinoma sequence.

Adult↗
PubMed1997

Mesalazine preparations.

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Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1997

Association of adult glioma with medical conditions, family and reproductive history.

A population-based case-control study of 416 histologically diagnosed, incident gliomas in adults was carried out in Melbourne, Australia, to determine whether past medical, family or reproductive histories are risk factors for developing glioma. A total of 422 controls were selected from the Australian electoral roll and matched to cases for age, sex and post code of residence. An increased risk of developing glioma was observed among first-born individuals OR (95% CI) 2.0 (1.4-2.9). It is possible that this effect is due to residual confounding by socio-economic status or that it is a chance finding. Alternatively, it may be that this is due to some other effect linked to the first pregnancy, such as maternal age, birth weight or circumstances of delivery. There was no apparent association between the development of glioma and other neuropsychiatric or general medical conditions or with family history or reproductive history. Allergies (asthma and eczema) were not associated with a decreased risk of glioma, as has previously been suggested.

Adult↗
PubMed1997

Randomised controlled trial of CDP571 antibody to tumour necrosis factor-alpha in Crohn's disease.

BACKGROUND: Tumour necrosis factor-alpha (TNF alpha) is thought to have a central role in the pathogenesis of Crohn's disease. We tested the hypothesis that CDP571, a genetically engineered human antibody to TNF alpha, is effective in modifying disease activity in patients with moderately active Crohn's disease. METHODS: In this double-blind, placebo-controlled study, 31 patients were randomly assigned to CDP571 (n = 21) or placebo (n = 10). The primary endpoint was change in Crohn's disease activity index 2 weeks after a single infusion of CDP571 (5 mg/kg), or human albumin as placebo. One patient who attended no follow-up assessments was excluded from the analyses (CDP571 group). FINDINGS: The median Crohn's disease activity index fell from 263 (IQR 186.5-323.5) at baseline to 167 (137.5-294.0) at 2 weeks in the CDP571-treated patients (p = 0.0003); the change in the placebo group (253 [240-334] to 247 [183-256]) was not significant. In the treated group, there were also significant differences between baseline and 2 weeks in Harvey-Bradshaw score (p = 0.0005), key symptom score (p = 0.049), alpha 1-glycoprotein concentration (p = 0.012), and erythrocyte sedimentation rate (p = 0.01); concentrations of C-reactive protein fell, but not significantly (p = 0.067). Six patients achieved remission (Crohn's disease activity index < or = 150) and three others had activity indices of 156 or lower. There were no significant changes in the placebo group. INTERPRETATION: A single 5 mg/kg infusion of CDP571 reduced disease activity in Crohn's disease at 2 weeks. These data suggest that antibody neutralisation of TNF alpha is a potentially effective strategy in the management of Crohn's disease. The use of CDP571 in Crohn's disease requires further study.

Adolescent↗
PubMed1997

Linkage analysis of bronchial hyperreactivity and atopy with chromosome 11q13.

There are two key clinical features of asthma: allergy and bronchial hyperreactivity (BHR). Some pedigree studies of atopy have indicated linkage with the high affinity IgE receptor (Fc epsilon RI-beta) gene on chromosome 11q13, but others failed to confirm this linkage. We examined the genetic linkage of three polymorphic microsatellite markers to atopy and BHR in 120 affected sibling pairs recruited from the general community. We found no linkage to atopy at any of the three 11q13 loci studied. Our findings also do not favour linkage between BHR and loci approximately 8-9 cM either side of the Fc epsilon RI-beta gene.

Adult↗
PubMed1997

Determinants of plasma concentrations of nicotine and cotinine during cigarette smoking and transdermal nicotine treatment.

OBJECTIVE: Interindividual variability in plasma concentrations of nicotine and its proximate metabolite, cotinine, is considerable during smoking and transdermal nicotine treatment, even among individuals taking in nominally similar doses of nicotine. This report explores the determinants of this variability and the utility of baseline (smoking) plasma concentrations to predict concentrations during transdermal nicotine treatment. METHODS: Data were analysed from a smoking cessation study (n = 466), and from a pharmacokinetic study (n = 12). Multiple regression models examined the relationships of plasma concentrations to individual characteristics such as smoking pattern, absorbed dose of nicotine, and pharmacokinetic parameters. RESULTS: Plasma concentrations of nicotine and cotinine were highly variable in both studies. Indirect estimates of plasma clearance (baseline plasma concentration divided by cigarettes per day) together with other factors could account for 18 to 33% of the variability during transdermal nicotine treatment in the smoking cessation study. In contrast, 75 to 99% was accounted for by direct measurements of plasma clearances and systemic dose of nicotine in the pharmacokinetic study. CONCLUSION: Plasma concentrations of nicotine and cotinine during transdermal nicotine treatment are poorly predicted by clinical history or baseline plasma concentrations. This is a result of inadequate characterisation of highly variable individual pharmacokinetic parameters and absorbed dose of nicotine. Considering the interindividual variability of plasma nicotine and cotinine concentrations together with the lack of clinical end-points for transdermal nicotine dosing, it seems logical to investigate the utility of a therapeutic drug monitoring approach for transdermal nicotine treatment-particularly for high dose regimens (> 22 mg per 24 hours).

Administration, Cutaneous↗
PubMed1997

Attendance at an asthma educational intervention: characteristics of participants and non-participants.

As part of an evaluation of the patient education component of the Australian Asthma Management plan, a randomized, controlled trial of asthma education was conducted in 1994/95 at the outpatient asthma and allergy clinic of The Alfred Hospital, a tertiary referral hospital in Melbourne, Australia. The objective of the study was to investigate which demographic and clinical characteristics were associated with attendance at asthma educational session. A total of 125 asthmatics aged over 16 years agreed to participate in the programme, and full compliance with the programme was 43.2%. Allocation to immediate, rather than delayed, education and age were the only significant predictors of attendance. Subjects randomized to the intervention were approximately three times more likely to attend than control subjects (OR = 3.3, 95% CI 1.5-7.3). Asthmatics over 60 years old were approximately six times more likely to attend (OR = 6.6, 95% CI 2.2-19.8) than the age group 16-30 years. The increasing trend in attendance across age categories was highly significant (P < 0.001). There was no relationship between attendance and gender, medication, atopy, smoking status or the physical accessibility of the hospital. Despite offering incentives and conducting the education sessions at subjects' preferred times, their compliance in attending sessions was poor. Over half of the asthmatics, who had expressed interest, failed to attend for their educational sessions. An alternative strategy is required to improve participation by young and employed asthmatics at hospital-based asthma education programmes.

Adolescent↗
PubMed1997

Retrospective assessment of occupational exposure to chemicals in community-based studies: validity and repeatability of industrial hygiene panel ratings.

BACKGROUND: Occupational hygiene panels are increasingly being used to rate retrospective occupational exposures to chemicals in community-based studies. This study aimed to assess the validity, reliability and feasibility of using such an expert panel in a brain tumour case-control study. METHODS: A panel of five experts was recruited to rate exposure to 21 chemicals for 298 job descriptions to investigate the level of agreement. Validity was assessed by comparing the ratings of the experts for 49 of the jobs with objective quantitative exposure data which existed for these jobs. Repeatability was assessed by comparing the results for 50 resubmissions. RESULTS: Specificity was high for reporting that exposure occurred (all above 90%), but sensitivity was variable with values between 48% and 79%. Weaker validity was found for rating exposure level and exposure frequency. The raters showed the greatest inter-rater agreement for exposure to three of the 21 chemicals considered (kappa = 0.64 for cutting fluids, kappa = 0.57 for welding fumes and kappa = 0.42 for lubricating oils). Intra-rater reliability, based on the 50 resubmitted jobs, was fair to good (kappa = 0.46, 0.73). CONCLUSIONS: The potential effect of exposure misclassification from using expert panels was quantified and found to be a significant source of bias. The optimum situation occurred where three of the five raters concurred, where an odds ratio of 2.2 was observed for a true odds ratio of 4.0. Future studies which plan to use expert panels should screen the experts for their suitability by validating their performance against jobs with known exposure data.

Bias↗
PubMed1997

Tumour recurrence is associated with Jass grouping but not with differences in E-cadherin expression in moderately differentiated Dukes' B colorectal cancers.

AIMS: To assess whether immunohistochemical expression of the putative invasion suppressor, E-cadherin, is associated with tumour recurrence in colorectal cancer, independent of Dukes' stage and degree of differentiation, and thus to determine whether measurement of E-cadherin is clinically useful. METHODS: 90 moderately differentiated Dukes' B colorectal carcinomas from patients who had been followed up for at least six years were examined. All were from curative resections performed at St Mark's Hospital and the tumours were shown, on histology, to be clear of all resection margins. Tumours were reviewed and additionally classified in accordance with the Jass grouping system. Immunohistochemical analysis of E-cadherin expression was performed for each tumour using the monoclonal antibody HECD 1. RESULTS: The Jass group ranged between I and III and there was a significant association between Jass group and tumour recurrence (p < 0.05). Positive E-cadherin expression was seen in 40/69 (58%) of non-recurrent and 13/21 (62%) recurrent cases respectively. There was no significant difference in E-cadherin expression between the two groups of tumours. CONCLUSIONS: Even when controlled for Dukes' stage and differentiation, the Jass grouping system yields useful prognostic information; E-cadherin, however, does not predict outcome in the important group of moderately differentiated Dukes' B colon cancers, and may be of little independent prognostic value in other colon cancers.

Cadherins↗
PubMed1997

Prevalence of reduced bone mineral density in systemic lupus erythematosus and the role of steroids.

OBJECTIVE: To determine the prevalence of reduced bone mineral density (BMD) in a large female cohort of systemic lupus erythematosus (SLE) and to determine the role of steroids and disease related variables. METHODS: All females with SLE managed by rheumatologists affiliated with a single center were invited to undergo BMD measurement of the lumbar spine and left femoral neck by dual energy X-ray absorptiometry (DEXA), standardized examination, and medical record review. RESULTS: Ninety-seven females with a mean (SD) age of 44.2 (14.9) years were studied. Low bone mass [defined as BMD > 1 standard deviation (SD) below young adult mean] was present in 44.3 and 42.1% at the lumbar spine and femoral neck, respectively. Osteoporosis (defined as BMD > 2.5 SD below young adult mean) was present in 13.4 and 6.3% at the lumbar spine and femoral neck, respectively. Steroid usage showed a strong inverse relationship with BMD in the lumbar spine, but a less strong relationship in the femoral neck. CONCLUSION: The findings of high prevalence of reduced BMD and association with steroid therapy have important implications for the routine management of SLE.

Absorptiometry, Photon↗
PubMed1997

Low dose interferon gamma for refractory Crohn's disease.

AIM: Direct cytokine modulation may benefit patients with inflammatory bowel disease. PATIENTS: Subcutaneous interferon gamma (1.5 microgram/kg) was given three times a week in an open pilot study to four patients with active Crohn's disease unresponsive to standard immunosuppressive drug treatment. RESULTS: In one patient, the C-reactive protein and Crohn's disease activity index returned to normal and the patient became asymptomatic. The other three patients did not complete the 12-week treatment course, one because of drug failure, one because of drug side effects, and one because of incidental disease. However, the Crohn's disease activity index fell substantially and the C-reactive protein returned to normal in three out of four patients. CONCLUSIONS: Interferon gamma may have a role in the treatment of resistant patients, but only if the dose can be optimised and drug side effects overcome.

Adult↗
PubMed1997

Germ plasm assembly and germ cell migration in Drosophila.

Many aspects of germ cell behavior, migration, and gonad formation are shared between vertebrate and invertebrate species. For example, a specialized germ plasm has been observed in many species including Caenorhabditis elegans and Xenopus. Furthermore, the fact that Vasa marks germ cells in many species suggests that even certain molecular aspects of germ cells may be common between different organisms. In most organisms, germ cells initially form at a location away from their target mesodermal tissues and have to migrate to reach the mesoderm. Further genetic studies will reveal the extent to which molecular aspects of germ cell migration and gonad formation are conserved.

Animals↗