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Isolated smooth muscle cells (SMCs) from mouse bronchus were studied using the whole cell patch-clamp technique at ~21°C. Stepping from -100 mV to -20 mV evoked inward currents of mean amplitude -275 pA. These inactivated (tau = 1.1 ms) and were abolished when external Na+ was substituted with N-Methyl-D-glucamine. In current-voltage protocols, current peaked at -10 mV and reversed between + 20 and + 30 mV. The V1/2s of activation and inactivation were -25 and -86 mV, respectively. The current was highly sensitive to tetrodotoxin (IC50 = 1.5 nM) and the NaV1.7 subtype-selective blocker, PF-05089771 (IC50 = 8.6 nM), consistent with NaV1.7 as the underlying pore-forming α subunit. Two NaV1.7-selective antibodies caused membrane- delineated staining of isolated SMC, as did a nonselective pan-NaV antibody. RT-PCR, performed on groups of ~15 isolated SMCs, revealed transcripts for NaV1.7 in 7/8 samples. Veratridine (30 µM), a nonselective NaV channel activator, reduced peak current evoked by depolarization but induced a sustained current of 40 pA. Both effects were reversed by tetrodotoxin (100 nM). In tension experiments, veratridine (10 µM) induced contractions that were entirely blocked by atropine (1 µM). However, in the presence of atropine, veratridine was able to modulate the pattern of activity induced by a combination of U-46619 (a thromboxane A2 mimetic) and PGE2 (prostaglandin E2), by eliminating bursts in favor of sustained phasic contractions. These effects were readily reversed to control-like activity by tetrodotoxin (100 nM). In conclusion, mouse bronchial SMCs functionally express NaV1.7 channels that are capable of modulating contractile activity, at least under experimental conditions. [ABSTRACT FROM AUTHOR]

Background: the numbers with dementia are projected to double between 2001 and 2040, in line with continued increases in life expectancy. Projections have failed to account for the impact of changing risk factors on future numbers with dementia or disability. Objective: to estimate the size of the disabled population over the next 20 years and explore the impact of treatments that delay onset of cognitive impairment and associated disability. Methods: a dynamic macro-simulation projection model was used to calculate the numbers of older people with disability to 2026. Transition rates to disability and death conditional on a range of conditions, calculated from the MRC Cognitive Function and Ageing Study, were applied to the 1992 England and Wales population. Scenarios for trends in dementia incidence, risk factors and treatment: were devised from a systematic review and applied. Findings: population ageing alone resulted in 39% more older people between 2006 and 2026 and 82% more with disability. A combination of reduced incidence of cognitive impairment and disabling consequences alongside improved survival provided the largest reductions in the disabled population (15,000) and the numbers cognitively impaired (302,000) compared with ageing of the population alone. Interpretation: population ageing alone will increase the disabled older population by over 80% and the numbers cognitively impaired by almost 50% over the next 20 years with serious implications for the provision of care. Research priorities should focus on earlier detection of dementia and its risk factors, thereby allowing earlier and more targeted treatment to alleviate its associated disability. [ABSTRACT FROM AUTHOR]

Background: This study aims to establish the extent of educational differences in the disability transitions of incidence, recovery and mortality in people aged 65 years and over, whether these can be explained by differentials in disease burden and their relative contribution to educational differences in prevalence and disability-free life expectancy (DFLE).Methods: A stratified random sample of 13 004 participants in five areas in England and Wales were interviewed in 1991-94 and followed up at 2, 6 (one centre only) and 10 years. Two levels of disability were analysed: mobility difficulty and activities of daily living (ADL) disability. We fitted logistic regression models to model educational differences in disability prevalence, incidence, recovery and mortality transitions. DFLE was calculated to assess the combined effect of the dynamic transitions.Results: Those with < or =9 years education had higher ADL and mobility disability prevalence and higher incidence and lower recovery of mobility disability. Differences in disability incidence remained after adjustment for comorbidity. Women with the lowest education had shorter life expectancies (1.7 years less at the age of 65 years) than the most educated and had even shorter DFLE (1.9 years free of ADL disability and 2.8 years free of mobility difficulty at the age of 65 years).Conclusions: Differentials in education continue to contribute to prevalence of disability at ages beyond 65 years in both men and women and independently of diseases. These appear to be driven predominantly by differentials in disability incidence that also compound to produce greater differentials in DFLE between education groups than in total years lived. [ABSTRACT FROM AUTHOR]

Background: Projections of health and social care need are highly sensitive to assumptions about cohort trends in health and disability. We use a repeated population-based cross-sectional study from the Cambridgeshire centre of the UK Medical Research Council Cognitive Function and Ageing Study to investigate trends in the health of the young-old UK population Methods: Non-overlapping cohorts of men and women aged 65-69 years in 1991/2 (n = 689) and 1996/7 (n = 687) were compared on: self-reported diseases and conditions; self-rated health; mobility limitation; disability by logistic regression and four-year survival by Cox Proportional Hazards Regression models, with adjustments for differences in socio-economic and lifestyle factors. Results: Survival was similar between cohorts (HR: 0.91, 95% CI: 0.62 to 1.32). There was a significant increase in the number of conditions reported between cohorts, with more participants reporting 3 or more conditions in the new cohort (14.2% vs. 10.1%). When individual conditions were considered, there was a 10% increase in the reporting of arthritis and a significant increase in the reporting of chronic airways obstruction (OR: 1.36, 95% CI: 1.04 to 1.78). Conclusion: This study provides evidence of rising levels of ill-health, as measured by the prevalence of self-reported chronic conditions, in the newer cohorts of the young-old. Though changes in diagnosis or reporting of disease cannot, as yet, be excluded, to better understand whether our findings reflect real increases in ill-health, investment should be made into improved population-based databases, linking self-report and objective measures of health and function, and including those in long-term care. [ABSTRACT FROM AUTHOR]

Analyzes cases of septicemia caused by an epidemic strain of methicillin-resistant Staphylococcus aureus. Prevalence of the S. aureus strain; Resistance to vancomycin; Accumulation of cell wall material; Key role of rifampin in the prevention of deaths caused by the methicillin-resistant S. aureus strain.

Macrophage activating factor (MAF) is produced by antigen-stimulated lymphocytes and activates macrophages for antimicrobial function. The capacity of individual microbial antigens to evoke and regulate this response has been explored using an affinity purified antigen (TB68) of Mycobacterium tuberculosis in combination with T-cell cloning. Four helper/inducer clones are described which responded strongly to this antigen. Three were specific, proliferating only to TB68 antigen and antigenic preparations containing this antigen. However, one of these clones (68.1) did not proliferate to BCG and PPD which contained the TB68 antigen. In addition, another clone, 68.13, also proliferated to other antigenic preparations which did not contain the TB68 antigen. Taken together, these data indicate the presence of several epitopes in the affinity-purified TB68 antigen. All the clones produced MAF, which enhanced H2O2 production in U937 cell lines and conventional macrophages matured from monocytes. Thus, T-cell clones proliferating to a mycobacterial antigen constitutively secrete lymphokinea that activate macrophages to antimicrobial immunity. [ABSTRACT FROM AUTHOR]

Presents a study of the pathogenicity determinants of Candida albicans. Epidemiology, diagnosis and treatment of candidiasis; Pathogenesis of candidiasis; Adhesion and adhesins; Proteinase; Phenotypic and genetic switching; Heat-shock protein 90; Immunotherapy.

A letter to the editor is presented in response to comments made on the author's article by Herbrecht and colleages regarding the double-blind trial comparing combination therapy with Mycograb plus lipid-associated amphotericin B with amphotericin B monotherapy.

Abstract: MAGIC (Multi Agency Geographic Information for the Countryside) is a geoportal created by a partnership of UK government departments and agencies in order to provide access to rural and countryside information for partner organisations, other public and private sector organisations and the wider public. The approach taken by the MAGIC partnership is described against a background of limited apparent success of multi-agency collaborative GIS initiatives of this sort. The resource created by the MAGIC project is described along with other essential elements such as the interagency agreements and data standards needed to support the geoportal. This paper evaluates the success of the geoportal in terms of available quantitative information, such as site usage, and qualitative, but equally important aspects, such as the co-operative partnership created amongst the organisations behind MAGIC. Future priorities for the geoportal are discussed; which include priorities to increase the breadth and depth of data holdings and the need to develop interoperability with other geoportals and web-based sources of information. [Copyright &y& Elsevier]

Provides information on a study that determined factors associated with non-response at each stage of a two-stage survey of late-life depression. Methodology of the study; Results and discussion on the study.

Background. Mycograb (NeuTec Pharma) is a human recombinant monoclonal antibody against heat shock protein 90 that, in laboratory studies, was revealed to have synergy with amphotericin B against a broad spectrum of Candida species. Methods. A double-blind, randomized study was conducted to determine whether lipid-associated amphotericin B plus Mycograb was superior to amphotericin B plus placebo in patients with culture-confirmed invasive candidiasis. Patients received a lipid-associated formulation of amphotericin B plus a 5-day course of Mycograb or placebo, having been stratified on the basis of Candida species (Candida albicans vs. non-albicans species of Candida). Inclusion criteria included clinical evidence of active infection at trial entry plus growth of Candida species on culture of a specimen from a clinically significant site within 3 days after initiation of study treatment. The primary efficacy variable was overall response to treatment (clinical and mycological resolution) by day 10. Results. Of the 139 patients enrolled from Europe and the United States, 117 were included in the modified intention-to-treat population. A complete overall response by day 10 was obtained for 29 (48%) of 61 patients in the amphotericin B group, compared with 47 (84%) of 56 patients in the Mycograb combination therapy group (odds ratio [OR], 5.8; 95% confidence interval [CI], 2.41–13.79; P<.001). The following efficacy criteria were also met: clinical response (52% vs. 86%; OR, 5.4; 95% CI, 2.21–13.39; P<.001), mycological response (54% vs. 89%; OR, 7.1; 95% CI, 2.64–18.94; P<.001), Candida-attributable mortality (18% vs. 4%; OR, 0.2; 95% CI, 0.04–0.80; P = .025), and rate of culture-confirmed clearance of the infection (hazard ratio, 2.3; 95% CI, 1.4–3.8; P = .001). Mycograb was well tolerated. Conclusions. Mycograb plus lipid-associated amphotericin B produced significant clinical and culture-confirmed improvement in outcome for patients with invasive candidiasis. [ABSTRACT FROM AUTHOR]

Heat-shock proteins (hsps) have been identified as molecular chaperones conserved between microbes and man and grouped by their molecular mass and high degree of amino acid homology. This article reviews the major hsps of Saccharomyces cerevisiae, their interactions with trehalose, the effect of fermentation and the role of the heat-shock factor. Information derived from this model, as well as from Neurospora crassa and Achlya ambisexualis, helps in understanding the importance of hsps in the pathogenic fungi, Candida albicans, Cryptococcus neoformans, Aspergillus spp., Histoplasma capsulatum, Paracoccidioides brasiliensis, Trichophyton rubrum, Phycomyces blakesleeanus, Fusarium oxysporum, Coccidioides immitis and Pneumocystis jiroveci. This has been matched with proteomic and genomic information examining hsp expression in response to noxious stimuli. Fungal hsp90 has been identified as a target for immunotherapy by a genetically recombinant antibody. The concept of combining this antibody fragment with an antifungal drug for treating life-threatening fungal infection and the potential interactions with human and microbial hsp90 and nitric oxide is discussed. [ABSTRACT FROM AUTHOR]

Objective: to identify predictive morbidities for urinary storage syndromes including indicators for neurological, musculoskeletal, cardiovascular, immune, lower bowel and psychological systems. This is the first study to test prior hypotheses, based on a literature review. Design: this was a prospective cohort study involving 12,570 female respondents aged 40 or more registered with general practitioners and living at home in Leicestershire. Postal questionnaires were used at baseline and 1-year follow-up (response rates 65 and 79%, respectively). Measures: pure stress urinary incontinence (SUI) and overactive bladder syndrome (OAB) were defined using standardised symptom indicators. Specific morbidities included reported medical diagnoses, standardised symptoms and general health indicators. Associations were identified using logistic regression, adjusting for age and physical impairment, with separate models for general and specific morbidities. Results: multivariate morbidities consistently associated (i.e. both longitudinally and cross-sectionally) were SUI--cystitis and obesity; and OAB--bowel urgency, osteoporosis, imbalance, ankle swelling, cystitis, poor health and old age. Other independent predictors were SUI--multiple sclerosis and joint pain; and OAB--deep vein thrombosis and diabetes. Consistent univariate indicators supported neurological, musculoskeletal, cardiovascular, immunological and psychological connections with both types of storage disorder plus an association with lower bowel problems for OAB. Conclusions: abnormal urinary storage symptoms were predicted by obesity and poor general health, involving a range of systems of the body. OAB showed more extensive links than SUI with specific morbidities, including more medically diagnosed as opposed to symptom-based conditions. These findings were independent of problems with physical impairment. [ABSTRACT FROM AUTHOR]

Objective: To investigate associations between diet and non-dietary lifestyle factors and the onset of overactive bladder (OAB) in men.Subjects: Random sample of community-dwelling men aged 40 years plus.Design and Methods: Baseline data on urinary symptoms and diet were collected from 5454 men using a postal questionnaire and a food-frequency questionnaire. Follow-up data on urinary symptoms were collected from 4887 men in a postal survey one year later. Logistic regression analysis was used to investigate diet and lifestyle factors associated with onset of OAB in the men without OAB at baseline.Results: There was a highly significant negative association between beer intake at baseline and subsequent OAB onset (P=0.001), with reduced risk at all levels of intake compared with those who seldom/never drank beer. Adjustment for total alcohol intake (g ethanol day(-1)) reduced the significance of the association (P=0.02). None of the food groups studied was associated with OAB onset, with the possible exception of potatoes (P=0.05), which showed an increased risk of onset at the highest level of consumption. Physical activity, smoking and obesity were not significantly associated.Conclusions: While most diet and lifestyle factors were not associated with OAB onset, the evidence from this prospective longitudinal study suggests that beer may have a protective role in the development of OAB. This could be due to a non-alcoholic ingredient as well as the alcohol content. [ABSTRACT FROM AUTHOR]