Search

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. The consequences of diseases in later life have been judged predominantly through mortality, resulting in an emphasis on the fatal rather than the nonfatal disabling conditions. We use a longitudinal study with follow-up at 2, 6, and 10 years to assess the impact of different diseases on both total life expectancy (TLE) and disability-free life expectancy (DFLE). Methods. The Medical Research Council Cognitive Function and Ageing Study investigators interviewed 13,004 people aged 65 years and older from five U.K. centers starting in 1991. Persons aged 75 years and older were oversampled. Disability (mild, moderate, and severe) was assessed through basic Activities of Daily Living (ADL) and Instrumental ADL (IADL) scales at baseline and at follow-ups at 2, 6, and 10 years. TLE and DFLE were compared for persons with and without each of nine conditions. Results. At age 65, men had a TLE of 15.3 years of which 12.1 (79%) were free of any disability, whereas women of the same age had an average TLE of 19.4 years, 11.0 years (57%) disability-free. Men (women) aged 65 years without stroke had 4.8 (4.6) more years of TLE and 6.5 (5.8) more years DFLE. Without diabetes, men (women) lived 4.4 (5.6) years longer and had 4.1 (5.1) years disability-free. Conclusions. More disability-free years were gained than total life years in persons free of stroke, cognitive impairment, arthritis, and/or visual impairment at baseline. This finding suggests that elimination of these conditions would result in a compression of disability. [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]

Abstract: The effect of socio-economic disadvantage on mortality is well documented and differences exist even at older ages. However, whether this translates into differences in the quality of life lived at older ages is less well studied, and in particular in the proportion of remaining life spent without ill health (healthy life expectancy), a key UK Government target. Although there have been studies exploring socio-economic differences in disability-free life expectancy (DFLE) worldwide, these have tended to focus on a single measure of socio-economic advantage, for example, education, race, social class or income, with the majority based on cross-sectional data from younger populations. In this prospective study we examine differences in DFLE and total life expectancy (TLE) at older ages using a range of measures of socio-economic advantage. We use a longitudinal study of 1480 participants aged 75 years or over in 1988 registered with a UK primary care practice, who were followed up until 2003 with measurements at up to seven time points. Disability was defined as difficulty with any one of five activities of daily living. The largest differences in DFLE for both men and women were found for housing tenure. Women aged 75 years living in owned or mortgaged property could expect to live 1 year extra without disability compared with those living in rented accommodation, while for men the difference was almost 1.5 years. The effect of socio-economic advantage on disability-free and total life expectancies appeared to be larger for men than women. In women, socio-economic advantage had more effect on DFLE than total life expectancy for all indicators considered, thus the socio-economically advantaged experienced a compression of disability. [Copyright &y& Elsevier]

Abstract: Although the association between socioeconomic status and mortality is well documented, there is less work focusing on the association with morbidity in older people. This is partly due to the difficulties of measuring socioeconomic status at older ages. The work that does exist tends to use cross-sectional data and objective measures of socioeconomic status such as education, social class or income. However, these standard measures may be less relevant for older people. In this study, we explore the association between socioeconomic status and disability in older people using a range of individual, household and area level indicators of socioeconomic status, including a subjective measure of adequacy of income. We use cross-sectional data of 1470 participants aged 75 years or over on 31/12/1987 and registered with a UK primary care practice. Of these 719 participants with no disability at baseline were followed up until 2003 with measurements at up to seven time points to determine onset of disability. Disability was defined as difficulty with any one of five activities of daily living. In cross-sectional multivariate analysis, age, housing tenure, living status and a subjective measure of income adequacy were associated with prevalence of disability. In longitudinal analyses, self-perceived adequacy of income showed the strongest association with onset of disability; with those reporting difficulties managing having a median age of onset 80.5 years, 7 years younger than those who felt their income was adequate (median age 87.8 years). The prospective association between self-perceived adequacy of income and onset of disability decreased with age. This subjective measure of income adequacy may signify difficulties in budgeting, but could also capture differences in objective indicators of status not recorded in this study, such as wealth. Further work is needed to explore what causes older people to experience difficulty in managing their money and to understand the mechanisms behind its impact on their physical health. [Copyright &y& Elsevier]

Background: This paper reports the association between self-reported diseases and impairments and 2-year onset of disability in a prospective study of people aged 65 years or older in five urban and rural centers in England and Wales (Medical Research Council Cognitive Function and Ageing Study; MRC-CFAS).Methods: We initially reviewed risk factors for onset of disability in 35 prospective studies of functional decline in older people published in 1998-2001. In the present study, disability was defined as requiring help from another person at least several times a week and was assessed by dependency in activities of daily living. Polytomous and bivariate logistic regression models were fitted for onset of disability and mortality among those nondisabled at baseline (n=7913), adjusting for age, sex, and sociodemography.Results: Among prevalent conditions, arthritis (population-attributable risk 11.4%) and cognitive impairment indicated by a Mini-Mental State Examination score of Conclusions: Cognitive impairment, arthritis, followed by stroke, and problems with vision have major impact on population disability at older ages. Both prevalent and incident conditions must be considered as risk factors to accurately assess potential benefits from prevention. [ABSTRACT FROM AUTHOR]

Abstract: This article reported the identification of heat shock protein 90 (hsp90) homologues by immunoblot in Cryptococcus neoformans. Mycograb®, a genetically recombinant antibody against hsp90, was evaluated against 8 clinical isolates and the National External Quality Assessment Service for Microbiology strain of C. neoformans alone and in combination with amphotericin B, caspofungin, and fluconazole by checkerboard assay. At the end point of an optically clear well, the minimum inhibitory concentration (MIC) 0''s ranged from 256 to 1024 μg/mL for Mycograb®, from 0.5 to 1 μg/mL for amphotericin B, and from 16 to 32 μg/mL for caspofungin. The combination of Mycograb® and amphotericin B produced a fractional inhibitory concentration index from 0.27 to 0.56, indicating a mainly synergistic effect, whereas for caspofungin, it varied from 0.5 to 2. At an end point of ≥50% inhibition, the MIC-2s varied from 16 to 128 μg/mL for Mycograb® and from 0.125 to 16 μg/mL for fluconazole. The fractional inhibitory concentration index classified the combination as indifferent for 5 isolates, additive for 3 more isolates, and synergistic in a single isolate. Time-kill analysis on 2 isolates (F/7844 and F/10156), which had synergistic and additive results with amphotericin B, respectively, on checkerboard was performed with 4–16 μg/mL of Mycograb®, 2–8 μg/mL of fluconazole, and 0.0625–2 μg/mL of amphotericin B. This demonstrated an increasingly static effect with augmenting concentrations of fluconazole and an initial static effect with amphotericin B at lower concentrations, which became fungicidal as the level of drug increased. The addition of either 4 or 8 μg/mL of Mycograb® to 0.5 μg/mL of amphotericin B with C. neoformans F/7844 changed a static effect to a fungicidal effect at 8 h with an increased killing of 1.2 logs at 48 h. With C. neoformans F/10156, the addition of 16 μg/mL of Mycograb® to 0.25 μg/mL of amphotericin B produced a difference in killing from 1 logarithm after 4 h to 1.5 logarithms after 48 h. These data suggest that the combination of amphotericin B and Mycograb® would be worth exploring in the treatment of infection due to C. neoformans. [Copyright &y& Elsevier]

Monotherapy, in the form of amphotericin B or one of its liposomal derivatives, is the usual treatment for invasive fungal infections, due to lack of a safe, effective combination of antifungal drugs. Combination therapy is not necessarily beneficial—there may be mutual antagonism or indifference, increased toxicity or interference with concomitant medication. But the benefits of a well-tolerated, synergistic combination would be great—the enhanced efficacy would improve clinical outcome, reduce the need for prolonged courses of treatment and prevent the emergence of antifungal drug resistance. Antifungal antibodies would be a natural partner in a combinatorial approach to antifungal therapy. Analysis of the antibody response which occurs in patients with invasive candidiasis, being treated with amphotericin B, showed a close correlation between recovery and antibody to the immunodominant heat shock protein 90 (hsp90). The molecular chaperone hsp90 is essential for yeast viability. Mycograb® is a human recombinant antibody to hsp90 which shows intrinsic antifungal activity and synergy with amphotericin B both in vitro and in vivo. It is now the subject of a multinational, double-blind, placebo-controlled trial, in patients with culture-confirmed invasive candidiasis on liposomal amphotericin B. [Copyright &y& Elsevier]

Background Depression is common among older people living in residential and nursing homes. Detection and treatment of late life depression may be sub-optimal in these settings. Aim To report the changes in, and factors associated with, antidepressant use among residents in care homes in 1990 and 1997. Method Censuses of those aged 65 years and over in any type of residential care in the county of Leicestershire, UK, on 27 November 1990 and 30 November 1997. Care staff were asked to complete an assessment form for each resident which included a rating of depression and use of antidepressants. Results The use of antidepressants increased from 11% (484/4415) in 1990 to 18.9% (777/4111) in 1997. Severity of depression as assessed by care staff, gender, younger age, better cognitive functioning, and use of other medications were consistently associated with antidepressant treatment. Antidepressant use was associated with better physical functioning (p = 0.001) in 1990 and frequency of falls in 1997 (p = 0.044). Conclusions Increased use of antidepressants appears to be due to the wider range of antidepressant drugs available since 1990. However there is a need for better methods for care staff to detect depression in residents, and for appropriate action to be taken by those responsible for their medical management. Copyright © 2002 John Wiley & Sons, Ltd. [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]

Assesses DNA fingerprinting for rapid identification of outbreaks of systematic candidiasis. Production of different genotypes; Comparison of DNA fingerprinting with other typing systems; Benefits of DNA fingerprinting.

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.

Objective There is a paucity of data relating to neurodevelopmental outcomes in infants born late and moderately preterm (LMPT; 32+0-36+6 weeks). This paper present the results of a prospective, population-based study of 2-year outcomes following LMPT birth. Design 1130 LMPT and 1255 term-born children were recruited at birth. At 2 years corrected age, parents completed a questionnaire to assess neurosensory (vision, hearing, motor) impairments and the Parent Report of Children's Abilities-Revised to identify cognitive impairment. Relative risks for adverse outcomes were adjusted for sex, socio-economic status and small for gestational age, and weighted to account for over-sampling of term-born multiples. Risk factors for cognitive impairment were explored using multivariable analyses. Results Parents of 638 (57%) LMPT infants and 765 (62%) controls completed questionnaires. Among LMPT infants, 1.6% had neurosensory impairment compared with 0.3% of controls (RR 4.89, 95% CI 1.07 to 22.25). Cognitive impairments were the most common adverse outcome: LMPT 6.3%; controls 2.4% (RR 2.09, 95% CI 1.19 to 3.64). LMPT infants were at twice the risk for neurodevelopmental disability (RR 2.19, 95% CI 1.27 to 3.75). Independent risk factors for cognitive impairment in LMPT infants were male sex, socio-economic disadvantage, non-white ethnicity, preeclampsia and not receiving breast milk at discharge. Conclusions Compared with term-born peers, LMPT infants are at double the risk for neurodevelopmental disability at 2 years of age, with the majority of impairments observed in the cognitive domain. Male sex, socio-economic disadvantage and preeclampsia are independent predictors of low cognitive scores following LMPT birth. [ABSTRACT FROM AUTHOR]

Background: The consequences of diseases in later life have been judged predominantly through mortality, resulting in an emphasis on the fatal rather than the nonfatal disabling conditions. We use a longitudinal study with follow-up at 2, 6, and 10 years to assess the impact of different diseases on both total life expectancy (TLE) and disability-free life expectancy (DFLE).Methods: The Medical Research Council Cognitive Function and Ageing Study investigators interviewed 13,004 people aged 65 years and older from five U.K. centers starting in 1991. Persons aged 75 years and older were oversampled. Disability (mild, moderate, and severe) was assessed through basic Activities of Daily Living (ADL) and Instrumental ADL (IADL) scales at baseline and at follow-ups at 2, 6, and 10 years. TLE and DFLE were compared for persons with and without each of nine conditions.Results: At age 65, men had a TLE of 15.3 years of which 12.1 (79%) were free of any disability, whereas women of the same age had an average TLE of 19.4 years, 11.0 years (57%) disability-free. Men (women) aged 65 years without stroke had 4.8 (4.6) more years of TLE and 6.5 (5.8) more years DFLE. Without diabetes, men (women) lived 4.4 (5.6) years longer and had 4.1 (5.1) years disability-free.Conclusions: More disability-free years were gained than total life years in persons free of stroke, cognitive impairment, arthritis, and/or visual impairment at baseline. This finding suggests that elimination of these conditions would result in a compression of disability. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To investigate the prevalence of isolated urinary and fecal incontinence and double incontinence in community-living stroke survivors and to assess the degree of soiling. DESIGN: Community-based postal survey. SETTING: Leicestershire, United Kingdom. PARTICIPANTS: Sixty-four thousand seven hundred forty-nine community-dwelling residents (aged≥40) were randomly selected from the Leicestershire Health Authority register. Residents living in institutional settings were excluded. MEASUREMENTS: Respondents were asked about previous stroke, urinary and bowel symptoms, and general health and demographic details including age, sex, and ethnicity. Urinary incontinence was defined as leakage several times a month or more often. Major fecal incontinence was defined as soiling of underwear, outer clothing, furnishings, or bedding several times a month or more often. RESULTS: A 65% response rate to the postal survey was obtained, with the return of 39,519 eligible questionnaires; 4% (n=1,483) reported stroke. Five percent of stroke survivors reported major fecal incontinence, with 4.3% reporting fecal and urinary incontinence and 0.8% reporting isolated fecal incontinence. Major fecal incontinence was four and a half times as prevalent in stroke survivors as in the nonstroke population, and stroke survivors were also twice as likely to report soiling of furnishings or bedding. Functional limitations influence the presence of fecal incontinence in the stroke and nonstroke population. CONCLUSION: Fecal incontinence is common in stroke survivors, and the degree of soiling can be considerable. Future research needs to explore the effect fecal incontinence can have on the lives of stroke survivors and on how it can best be managed in those living in the community. [ABSTRACT FROM AUTHOR]

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]

Objectives: To follow up a trial of home-administered influenza vaccination of older people to explore reasons for their immunisation behaviour, including their views on the organisation of services. Methods: Follow-up of original trial using analysis of records of 1865 older people and semi-structured interviews of 25 older people. Results: A once-off home visit does not appear to result in sustained changes in immunisation behaviour. Older people's behaviour appears to be largely explained by their beliefs about immunisation; the organisation of services may exert only small effects. Older people can be characterised as belonging to one of four groups in their orientation towards influenza vaccination: the 'faithful', who are keen to have vaccination; the 'converts', who have been persuaded of the benefits of vaccination and are likely to self-initiate appointments for vaccination; the 'easy-going', who require prompting for vaccination; and the 'sceptics', who perceive influenza vaccination to be ineffective or to be irrelevant for them because of their perceived inherent resistance to influenza. The last group sees vaccination as a form of interference and may be resistant to home visits to administer the vaccine. Conclusions: Targets for immunising older people require more debate because of the delicate balance between achieving herd immunity and preserving autonomy and choice for older people. [ABSTRACT FROM AUTHOR]

Objective: To compare the performance and clinical usefulness of the one-hour and 24-hour pad tests in terms of the relationship with reported symptoms and urodynamic diagnosis.Methods: 341 women aged 40 years and over reporting lower urinary tract symptoms who were recruited to a nurse led continence service, and went on to receive urodynamics, a one-hour and a 24-hour pad test and completed a urinary diary.Results: For both pad tests, there was a significant difference in the amount of urine leaked between the different urodynamic diagnoses (p<0.0001, for the one-hour and p=0.001 for the 24-hour test). Women with sphincter incompetence leaked significantly more than women with detrusor instability, or those with no abnormality. There was a significant difference between the proportion of women dry on a one-hour pad test and those dry on a 24-hour pad test (26.0% versus 38.4%, difference 12.4%; CI 5.5; 19.4). There is a positive relationship between amount of urine leakage and symptom severity expressed in terms of number of incontinent episodes for both pad tests.Conclusion: Both pad tests bore little relationship to the underlying urodynamic diagnosis but there was a positive relationship with symptom severity. The 24-hour pad test appears to be clinically a more useful too than the one-hour test. The two types of pad test are probably assessing incontinence in different ways. We suggest that the minimum data set should include structured questions, diaries and the 24-hour pad test. [Copyright &y& Elsevier]

Objective. To determine how older people's economic resources affect their likelihood of care home entry in the United Kingdom. Methods. In 1988, income, home ownership, and health data were collected for 1.425 people aged 75 +. Participants received up to five subsequent health assessments before the study endpoint (1999), in which care home entry was also recorded. Care home entry was identified thorn death certificates for those who died. Using proportional hazards regression, the effect of home ownership and income on the risk of care home entry was estimated, controlling for predisposing, enabling, and need factors, and health service utilization. Results. Age, living alone, activities of daily living restriction, cognitive impairment, poor/fair self-perceived health, and contact with services increased the risk of care home entry. Home ownership decreased it, Gender was not a significant predictor of care home entry once other factors were controlled for, and no significant effect was found for income. Discussion. UK public authorities can require older home owners to rise the value of their homes to pay for institutional but not community-based care, thus producing a financial incentive to place home owners in institutional settings. However, we find thai home ownership reduces the likelihood of care home entry, suggesting that other factors dominate the decision process. [ABSTRACT FROM AUTHOR]

The occurrence of an outbreak of septicaemias due to vancomycin-resistant Enterococcus faecium (VRE), in Manchester, UK, provided an opportunity to examine the antibody responses in patients infected by the same strain. Immunoblotting sera from 24 cases, six of whom died, showed an immunodominant cluster of antigens at 34, 54 and 97 kDa, with a statistically significant correlate between survival and immunoglobulin G to the 34 and 97 kDa bands (P<0.05). Screening a genomic expression library of VRE with seropositive serum and peritoneal dialysate from a survivor gave a recombinant clone with two contiguous open reading frames, the derived amino acid sequences of which both showed sequence homologue with ABC transporters, with a Walker A and Walker B motif and the signature sequence LSGGQ. The first open reading frame (putative VRE ABC1) showed 57% homologue with YbxA from Bacillus subtilis. A partial sequence (putative VRE ABC2) was also obtained, in the same recombinant clone, of a second ABC transporter with 72% homologue with ybaE from B. subtilis. Affinity selection with the seropositive serum and peritoneal dialysate used to screen the library showed that the eluted antibody bound to the 97, 54, 34 and 30 kDa bands. Direct amino acid sequencing identified this as a possible ABC transporter. Rabbit antiserum against peptides representing Walker A and an area adjacent to the Walker B site cross-reacted with bands at 34, 54, 97, 110 kDa and at 30, 34 and 54 kDa respectively. This therefore appeared to be an immunodominant complex of ABC transporters of which the smallest was the 30 kDa antigen. Epitope mapping of this antigen with seropositive patients’ sera delineated three linear epitopes (KVGIV, FGPKNF and RVAI). The Walker A site represented by peptide 1 (GHNGSGKSTLAKTIN), epitope RVAI represented by peptides 2 (MRRVAIAGVLAMPRE) and 3 (ELSGGQMRRVAIAGV), epitope KVGIV represented by peptide 4 (LKPIRKKVGIVFQFP), and recombinant VRE ABC1 and VRE ABC2 expressed in Escherichia coli pBAD were then used to isolate human genetically recombinant antibodies from a phage antibody display library. An assessment of the protective potential of these antibodies was carried out in a mouse model of the infection. This study suggests that an ABC transporter homologue could be a target for antibody therapy against VRE infections. [Copyright &y& Elsevier]