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M Humphries

Publications and source records attributed to M Humphries.

At least 19 recordsLinked to original sources
PubMed2006

Aberrant retinal tight junction and adherens junction protein expression in an animal model of autosomal dominant Retinitis pigmentosa: the Rho(-/-) mouse.

Retinitis pigmentosa (RP) comprises a heterogeneous group of inherited diseases that are characterised by primary degeneration of rod photoreceptors and secondary degeneration of cone photoreceptors in the retina. Additional pathological changes include vascular changes and invasion of the inner retina by retinal pigment epithelial (RPE) cells. RP represents a major cause of progressive retinal disease worldwide. Using a mouse model of autosomal dominant Retinitis pigmentosa (adRP) with retinopathy induced by targeted disruption of the rhodopsin gene Rho(-/-), we have analysed the levels of expression of a range of tight and adherens junction associated proteins, in order to further elucidate the pathogenic mechanisms occurring at an early stage of this condition. Using western blot analysis and indirect immunostaining of retinal cryosections from 6-week-old mice from a C-129 background we have determined changes, if any, in the levels of expression and localisation of a series of tight and adherens junction associated proteins, including Zonula Occludens-1 (ZO-1), occludin, N-Cadherin, p120-Catenin, alpha-Catenin, gamma-Catenin, beta-Catenin, and E-Cadherin. We have found an up-regulation of the tight junction and adherens junction associated protein Zonula Occludens-1 (ZO-1) in the neural retina of 6-week-old Rho(-/-) knockout mice compared with 6-week-old Wild-Type (WT) mice. Following immunohistochemistry, however, it appears, that ZO-1, beta-Catenin and p120-Catenin expression at the Outer Limiting Membrane (OLM) of the Rho(-/-) retina is compromised, in part, compared to WT animals of the same age. We hypothesise that these retinal changes following photoreceptor cell death may contribute to the pathogenesis of adRP. Our findings of changes in the levels of expression of ZO-1 and associated adherens junction proteins beta-Catenin and p120-Catenin at the OLM in 6-week-old Rho(-/-) mice provide evidence for tight junction and adherens junction associated protein modifications in an animal model of autosomal dominant RP (adRP).

Adherens Junctions↗
PubMed2005

Efficacy and safety of salmeterol/fluticasone propionate delivered via a hydrofluoroalkane metered dose inhaler in Chinese patients with moderate asthma poorly controlled with inhaled corticosteroids.

A randomised, open-label, multicentre study compared the efficacy and tolerability of salmeterol 25 microg/fluticasone propionate 125 microg (two puffs, twice daily) delivered via a hydrofluoroalkane metered-dose inhaler (HFA-MDI) and salmeterol 50microg/fluticasone propionate 250 microg (one puff, twice daily) delivered via a Diskus inhaler in Chinese patients with moderate asthma uncontrolled with inhaled corticosteroids (ICSs). Morning peak expiratory flow (PEF) was the primary efficacy endpoint. Secondary endpoints included evening PEF, forced expiratory volume in 1 s, day and night symptom scores, rescue medication and patient self-evaluation of efficacy. Safety was assessed according to adverse events recorded. Both treatments were equipotent and significantly improved morning PEF (HFA-MDI 40 l/min; Diskus 42 l/min; p < 0.05) and all secondary endpoints (p < 0.05) from baseline, over 1-4 weeks. Similarly, both treatments were well tolerated. Salmeterol/fluticasone propionate delivered via an HFA-MDI or Diskus inhaler provides a choice of efficacious delivery systems in Chinese patients whose asthma is poorly controlled on ICSs alone.

Administration, Inhalation↗
PubMed2004

Testing computational hypotheses of brain systems function: a case study with the basal ganglia.

We develop a methodology for testing computational hypotheses about neural functionality articulated in models at the systems level of description. In this approach, the first step is to attempt the construction of a model of the underlying brain system which is consistent with the known anatomy and physiology, but which is also able to exhibit functional properties consistent with a putative computational hypothesis. If this is successful, the second step consists of including additional known pathways into the model and testing the new models to see whether they show an improvement in functional performance (using appropriate performance metrics). A positive outcome is taken as evidence in support of the hypothesis. A final step is to construct 'control' models by including pathways that are not consistent with biological data. In this case a performance detriment is taken as support for the hypothesis. The methodology is applied to the basal ganglia, and builds on a previously published model of this system (Gurney et al 2001 Biol. Cybern. 84 401-23) which was based on the hypothesis that the basal ganglia perform action selection. The realistically constrained models show a selection benefit, while control models show a decrement in selection ability. These results, taken together, provide further validation of our selection hypothesis of basal ganglia function.

Animals↗
PubMed2003

The prophylactic use of a proton pump inhibitor before food and alcohol.

BACKGROUND: Patients report that the prophylactic consumption of a proton pump inhibitor minimizes gastrointestinal symptoms expected to be provoked by late-night food and alcohol consumption. The efficacy of this practice has not been studied formally. AIM: To perform a randomized, double-blind, placebo-controlled trial of a single dose of lansoprazole (30 mg) taken prior to a large meal and alcohol consumption. METHODS: Study subjects were recruited randomly from local primary care and hospital physicians. Each participant (n = 56; 37 male, 19 female; mean age, 38 years) completed questionnaires before and after the meal. Approximately 90 min prior to the provocative meal, participants were witnessed taking either placebo or 30 mg lansoprazole. Bar tokens were dispensed to permit the accurate quantification of alcohol consumption (mean, 15 units). RESULTS: Forty per cent of subjects reported significant reflux symptoms. For the entire group, there was no significant difference between lansoprazole and placebo. Post-prandial reflux was more frequent in those consuming > 15 units of alcohol (13/26, 50%) compared with those consuming < 15 units (7/30, 24%; P < 0.05). In the group who consumed > 15 units of alcohol, lansoprazole was associated with a lower rate of heartburn (5/15, 33%) compared with placebo (8/11, 73%; P < 0.05). CONCLUSION: A single dose of a proton pump inhibitor prior to indulgence was only associated with reduced heartburn in those consuming > 15 units of alcohol.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2001

Activation of beta(1) integrins mediates proliferation and inhibits apoptosis of intestinal CD4-positive lymphocytes.

A characteristic of lamina propria lymphocytes (LPL) is their low proliferative response to stimuli of the CD3 pathway. beta(1) integrins were expressed on LPL; however, their function is unknown. Therefore, we determined whether beta(1) integrins contribute to T cell responses by providing costimulatory signals. Integrins on CD4(+) LPL of controls and patients with inflammatory bowel disease were characterized by flow cytometry. Cells were stimulated by anti-CD3 or anti-CD2 antibodies either alone or in combination with a stimulatory beta(1) integrin antibody (12G10). Proliferation and apoptosis were measured by [(3)H]thymidine pulsing or flow cytometry. Cytokine mRNA and apoptosis-related transcripts were quantified by reverse transcriptase-PCR. We demonstrated that beta(1) integrin costimulation restored CD3-induced proliferation of CD4(+) LPL and reduced activation-induced apoptosis. Activation of beta(1) integrins by addition of 12G10 antibody to CD3-stimulated cells restored their capacity to express proinflammatory cytokine transcripts. Further, expression of the activated form of beta(1) integrins was significantly elevated on LPL from inflamed mucosa. These studies demonstrate that beta(1) integrin costimulation modulates the response of LPL after TCR stimulation. An increased expression of activated beta(1) integrins on LPL in intestinal inflammation may abolish their unresponsiveness to antigens and perpetuate the inflammatory process.

Adult↗
PubMed2000

Timolol lowers intraocular pressure but does not inhibit the development of experimental myopia in chick.

Reports of intraocular pressure (IOP) being higher in myopes than emmetropes and of myopes being over-represented in glaucoma statistics, are consistent with a role of IOP in the excessive eye growth typically associated with myopia. We tested the hypothesis, based on these observations, that ocular hypotensive drugs would slow myopia progression using the chick as an animal model and timolol as an example of such a drug. To induce myopia, chicks (n = 56) were fitted with either monocular translucent diffusers or -15 D spectacle lenses from day 8. The drug treatment protocol comprised topical applications of 0.4% benoxinate, a local anaesthetic (to improve drug absorption), followed either by 0.5% timolol or distilled water (control), either daily (1000 hr) or twice daily (1000, 1600 hr). Refractive errors and ocular dimensions were measured on days 12 and 17. We also verified the ocular hypotensive effect of timolol in both normal (n = 8) and myopic (n = 12 diffusers; n = 12-15 D lenses) chicks. Here, we took baseline IOP measurements, instilled timolol and then monitored IOP over a further 5-9 hr. We found no difference in the amount of myopia produced in the timolol and control groups at either measurement time point (e.g. day 17, once per day application, diffusers: -26.9 +/- 3.3 D vs -22.7 +/- 9.1 D; lenses: -14.9 +/- 3.8 D vs -14.9 +/- 3.6 D). This was in spite of the fact that timolol did lower IOP in both normal and myopic chicks (27 and 18% reduction, respectively) While timolol does have an ocular hypotensive effect in the chick, it does not inhibit the development of myopia in this animal model.

Analysis of Variance↗
PubMed2000

Visceral adipose tissue and markers of the insulin resistance syndrome in obese black and white teenagers.

OBJECTIVE: To determine the relationships between visceral and general adiposity, cardiovascular fitness, and markers of the insulin resistance syndrome in obese black and white teenagers. RESEARCH METHODS AND PROCEDURES: Cross-sectional survey of 81 obese 13- to 16-year-old youths. Visceral adipose tissue was measured with magnetic resonance imaging, and percentage body fat was measured with dual-energy X-ray absorptiometry. Cardiovascular fitness was assessed with a submaximal treadmill test. Fasting blood samples were analyzed for lipids/lipoproteins and insulin. Resting blood pressure was obtained using an automated cuff. RESULTS: Visceral adipose tissue was significantly correlated with unfavorable levels of: triacylglycerol (r = 0.27, p < 0.05), total cholesterol (r = 0.27, p < 0.05), high-density lipoprotein cholesterol (r = -0.26, p < 0.05), the ratio of total cholesterol/high-density lipoprotein cholesterol (r = 0.42, p < 0.01), low-density lipoprotein cholesterol (r = 0.27, p < 0.05), apolipoprotein B (r = 0.38, p < 0.01), and systolic blood pressure (r = 0.30, p < 0.01). Multiple regression analyses revealed that visceral adipose tissue was more powerful than percentage body fat for explaining variance in lipoproteins (e.g., for the ratio of total cholesterol/high-density lipoprotein cholesterol, r2 = 0.13, p < 0.01, and for systolic blood pressure, r2 = 0.07, p < 0.05). Ethnicity was the most powerful of the demographic predictors for blood lipids (r2 = 0.15 for triacylglycerol with lower levels in blacks; r2 = 0.10 for high-density lipoprotein cholesterol with higher levels in blacks; r2 = 0.06 for the ratio of total cholesterol/high-density lipoprotein cholesterol with lower levels in blacks). Cardiovascular fitness was not retained as a significant predictor of markers of the insulin resistance syndrome. DISCUSSION: Some of the deleterious relationships between visceral adiposity and markers for the insulin resistance syndrome seen in adults were already present in these obese young people.

Adipose Tissue↗
PubMed1999

Beagle 2: a proposed exobiology lander for ESA's 2003 Mars Express mission.

The aim of the proposed Beagle 2 small lander for ESA's 2003 Mars Express mission is to search for organic material on and below the surface of Mars and to study the inorganic chemistry and mineralogy of the landing site. The lander will have a total mass of 60kg including entry, descent, and landing system. Experiments will be deployed on the surface using a robotic arm. It will use a mechanical mole and grinder to obtain samples from below the surface, under rocks, and inside rocks. Sample analysis by a mass spectrometer will include isotopic analysis. An optical microscope, an X-ray spectrometer and a Mossbauer spectrometer will conduct in-situ rock studies.

Equipment Design↗
PubMed1999

Effects of exercise training and its cessation on components of the insulin resistance syndrome in obese children.

OBJECTIVE: To determine the effect of exercise training (ET) on components of the insulin resistance syndrome (IRS) in obese children. DESIGN: Randomized, modified cross-over study, with subjects assigned to one of two conditions: (1) 4 months of ET followed by 4 months of no-ET; or (2) 4 months of no-ET followed by 4 months of ET. Measurements were made at three time points: 0, 4 and 8 months. SUBJECTS: 79 obese, but otherwise healthy children (age: 7-11 y, percent fat (%fat) 27-61%). MEASUREMENTS: Plasma lipid and lipoprotein concentrations, plasma insulin and glucose concentrations; %fat; submaximal heart rate (HR) as an index of fitness. EXERCISE TRAINING: ET was offered 5 d/week 40 min/d. For the 73 children who completed 4 months of ET, the mean attendance was 80% (that is, 4 d/week) and the average HR during ET was 157 bpm. RESULTS: Significant (P < 0.05) group x time interactions were found for plasma triglyceride (TG) and insulin concentrations and %fat. The average change for both groups, from just before ET to just after the 4 month ET was -0.24 mmol.l-1 for TG, -25.4 pmol.l-1 for insulin and -1.6 units for %fat. When Group 1 ceased ET, over the following 4 month period the average change for insulin was +26.6 pmol.l-1 and for %fat +1.3 units. CONCLUSION: Some components (plasma TG, insulin, %fat) of the IRS are improved as a result of 4 months of ET in obese children. However, the benefits of ET are lost when obese children become less active.

Analysis of Variance↗
PubMed1999

Retinitis pigmentosa and progressive sensorineural hearing loss caused by a C12258A mutation in the mitochondrial MTTS2 gene.

Family ZMK is a large Irish kindred that segregates progressive sensorineural hearing loss and retinitis pigmentosa. The symptoms in the family are almost identical to those observed in Usher syndrome type III. Unlike that in Usher syndrome type III, the inheritance pattern in this family is compatible with dominant, X-linked dominant, or maternal inheritance. Prior linkage studies had resulted in exclusion of most candidate loci and >90% of the genome. A tentative location for a causative nuclear gene had been established on 9q; however, it is notable that no markers were found at zero recombination with respect to the disease gene. The marked variability in symptoms, together with the observation of subclinical muscle abnormalities in a single muscle biopsy, stimulated sequencing of the entire mtDNA in affected and unaffected individuals. This revealed a number of previously reported polymorphisms and/or silent substitutions. However, a C-->A transversion at position 12258 in the gene encoding the second mitochondrial serine tRNA, MTTS2, was heteroplasmic and was found in family members only. This sequence change was not present in 270 normal individuals from the same ethnic background. The consensus C at this position is highly conserved and is present in species as divergent from Homo sapiens as vulture and platypus. The mutation probably disrupts the amino acid-acceptor stem of the tRNA molecule, affecting aminoacylation of the tRNA and thereby reducing the efficiency and accuracy of mitochondrial translation. In summary, the data presented provide substantial evidence that the C12258A mtDNA mutation is causative of the disease phenotype in family ZMK.

Animals↗
PubMed1990

Human nidogen gene: identification of multiple RFLP and exclusion as candidate gene in a family with epidermolysis bullosa (EBS2) with evidence for linkage to chromosome 1.

Epidermolysis bullosa (EB) is a group of heritable blistering diseases affecting the dermal-epidermal basement membrane zone. We have recently provided evidence for genetic linkage of the molecular defect in a large family with dominant simplex, generalized (Koebner) type of EB (EBS2) to the long arm of chromosome 1. Because human nidogen gene has been mapped to chromosomal locus 1q43 in the human genome, we examined the possibility that nidogen, an integral component of all basement membranes, would be the candidate gene in this family of EBS2. Restriction fragment-length polymorphism, which was shown with several restriction endonucleases to be present within the nidogen gene, was utilized for linkage analyses. The results using an informative PvuII polymorphism as a marker of allelic inheritance supported exclusion of the EBS2 locus from approximately 10 cM in either side of the nidogen locus, when Lod score of -2.0 was taken as the limit of exclusion. This study demonstrates the feasibility of examining other families with EB for possible linkage to the nidogen locus.

Chromosomes, Human, Pair 1↗
PubMed1990

Evaluation of drug-induced prostatic involution in dogs by transabdominal B-mode ultrasonography.

The relative antiandrogen-induced prostate involution activity of the newly synthesized hydroxyflutamide pro-drug was compared with that of flutamide in 25 Beagles. Secondary antiandrogen activity of both drugs on the testes and mammary tissue was investigated. Daily oral administration of both compounds at 2 dosages (ie, 2.5 and 5.0 mg/kg of body weight) during a 7-week period was monitored by transabdominal ultrasonography of the prostate twice a week. Cross-sectional area estimates of the prostate gland calculated from oblique dorsoventral, and transverse sonographic measurements were diminished significantly in some of the treated dogs as early as day 14 of drug administration. All treated dogs had significant differences in reduction by day 47. Involution was related directly to dose (P less than 0.05), but no difference was observed between test compounds. Differences in secondary antiandrogen activity were not remarkable. Flutamide was not found to have any activity advantage in vivo over hydroxyflutamide. It was concluded that ultrasonography can be a highly effective means of monitoring prostate size, and of monitoring drug-induced involution over time.

Animals↗
PubMed1984

A new approach to tuberculosis notification.

A tuberculosis notification system was initiated which used several sources--the doctor, the diagnostic services of bacteriology, histopathology and radiology, and the pharmacy. The results of six months' notifications have shown that the pharmacy was by far the most complete source (74% of all new cases); doctors notified only 21% of all new cases. The combination of both doctors and the pharmacy was the most complete pair, notifying 85% of all new cases. It is suggested that consideration should be given to the use of pharmacies as a source of notification both in other settings and for other diseases.

Bacteriology↗
PubMed1984

A single-blind comparison of oral and intravaginal treatments in acute and recurrent vaginal candidosis in general practice.

Sixty-three patients with acute or recurrent vaginal candidosis were allocated to treatment with either oral ketoconazole (200 mg twice daily for 5 days) or clotrimazole 100 mg vaginal tablets (one per night for 6 days). Analysis of the results of doctor and patient assessment showed that both treatments were highly effective in reducing the signs and symptoms of infection. Mycological cure rates were similar for both ketoconazole (82%) and clotrimazole (86%). The corresponding mycological relapse rates were 0% and 18%. A significantly higher number of patients expressed a preference for oral treatment (p less than 0.05).

Administration, Oral↗