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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: To characterise disease course and remission in a longitudinal observational study of newly diagnosed, initially treatment-naïve patients with seropositive rheumatoid arthritis (RA). Methods: Patients with early untreated seropositive RA were recruited from 28 UK centres. Multiple clinical and laboratory measures were collected every 3 months for up to 18 months. Disease activity was measured using the 28-joint Disease Activity Score with C-reactive protein (DAS28-CRP) and Simplified Disease Activity Index (SDAI). Logistic regression models examined clinical predictors of 6-month remission and latent class mixed models characterised disease course. Results: We enrolled 275 patients of whom 267 met full eligibility and provided baseline data. According to SDAI definition, 24.3% attained 6-month remission. Lower baseline Health Assessment Questionnaire (HAQ) and SDAI predicted 6-month remission (p = 0.013 and 0.011). Alcohol intake and baseline prescribing of methotrexate with a second disease-modifying antirheumatic drug (DMARD; vs monotherapy without glucocorticoids) were also predictive. Three distinct SDAI trajectory subpopulations emerged; corresponding to an inadequate responder group (6.5%), and higher and lower baseline activity responder groups (22.4% and 71.1%). Baseline HAQ and Short Form-36 Health Survey – Mental Component Score (SF-36 MCS) distinguished these groups. In addition, a number of baseline clinical predictors correlated with disease activity severity within subpopulations. Beneficial effects of alcohol intake were found across subpopulations. Conclusion: Three distinct disease trajectory subpopulations were identified. Differential effects of functional and mental well-being, alcohol consumption, and baseline RA medication prescribing on disease activity severity were found across subpopulations. Heterogeneity across trajectories cannot be fully explained by baseline clinical predictors. We hypothesise that biological markers collected early in disease course (within 6 months) may help patient management and better targeting of existing and novel therapies. [ABSTRACT FROM AUTHOR]

Abstract 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.

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]

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]

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.

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 V 1/2 s of activation and inactivation were -25 and -86 mV, respectively. The current was highly sensitive to tetrodotoxin (IC 50  = 1.5 nM) and the Na V 1.7 subtype-selective blocker, PF-05089771 (IC 50  = 8.6 nM), consistent with Na V 1.7 as the underlying pore-forming α subunit. Two Na V 1.7-selective antibodies caused membrane-delineated staining of isolated SMC, as did a nonselective pan-Na V antibody. RT-PCR, performed on groups of ∼15 isolated SMCs, revealed transcripts for Na V 1.7 in 7/8 samples. Veratridine (30 µM), a nonselective Na V 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 PGE 2 (prostaglandin E 2 ), 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 Na V 1.7 channels that are capable of modulating contractile activity, at least under experimental conditions.

Objectives: To investigate inequalities in stillbirth rates by ethnicity to facilitate development of initiatives to target those at highest risk., Design: Population-based perinatal mortality surveillance linked to national birth and death registration (Mothers and Babies: Reducing Risk through Audits and Confidential Enquiries across the UK)., Setting: UK., Participants: 4 391 569 singleton births at ≥24 +0 weeks gestation between 2014 and 2019., Main Outcome Measures: Stillbirth rate difference per 1000 total births by ethnicity., Results: Adjusted absolute differences in stillbirth rates were higher for babies of black African (3.83, 95% CI 3.35 to 4.32), black Caribbean (3.60, 95% CI 2.65 to 4.55) and Pakistani (2.99, 95% CI 2.58 to 3.40) ethnicities compared with white ethnicities. Higher proportions of babies of Bangladeshi (42%), black African (39%), other black (39%) and black Caribbean (37%) ethnicities were from most deprived areas, which were associated with an additional risk of 1.50 stillbirths per 1000 births (95% CI 1.32 to 1.67). Exploring primary cause of death, higher stillbirth rates due to congenital anomalies were observed in babies of Pakistani, Bangladeshi and black African ethnicities (range 0.63-1.05 per 1000 births) and more placental causes in black ethnicities (range 1.97 to 2.24 per 1000 births). For the whole population, over 40% of stillbirths were of unknown cause; however, this was particularly high for babies of other Asian (60%), Bangladeshi (58%) and Indian (52%) ethnicities., Conclusions: Stillbirth rates declined in the UK, but substantial excess risk of stillbirth persists among babies of black and Asian ethnicities. The combined disadvantage for black, Pakistani and Bangladeshi ethnicities who are more likely to live in most deprived areas is associated with considerably higher rates. Key causes of death were congenital anomalies and placental causes. Improved strategies for investigation of stillbirth causes are needed to reduce unexplained deaths so that interventions can be targeted to reduce stillbirths., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Continence services in the UK have developed at different rates within differing care models, resulting in scattered and inconsistent services. Consequently, questions remain about the most cost-effective method of delivering these services., Aim: To evaluate the impact of a new service led by a continence nurse practitioner compared with existing primary/secondary care provision for people with urinary incontinence and storage symptoms., Design of Study: Randomised controlled trial with a 3- and 6-month follow-up in men and women (n = 3746) aged 40 years and over living in private households (intervention [n = 2958]; control [n = 788])., Setting: Leicestershire and Rutland, UK., Method: The continence nurse practitioner intervention comprised a continence service provided by specially trained nurses delivering evidence-based interventions using predetermined care pathways. They delivered an 8-week primary intervention package that included advice on diet and fluids; bladder training; pelvic floor awareness and lifestyle advice. The standard care arm comprised access to existing primary care including GP and continence advisory services in the area. Outcome measures were recorded at 3 and 6 months post-randomisation., Results: The percentage of individuals who improved (with at least one symptom alleviated) at 3 months was 59% in the intervention group compared with 48% in the standard care group (difference of 11%, 95% CI = 7 to 16; P<0.001) The percentage of people reporting no symptoms or 'cured' was 25% in the intervention group and 15% in the standard care group (difference of 10%, 95% CI = 6 to 13, P = 0.001). At 6 months the difference was maintained. There was a significant difference in impact scores between the two groups at 3 and 6 months., Conclusions: The continence nurse practitioner-led intervention reduced the symptoms of incontinence, frequency, urgency and nocturia at 3 and 6 months; impact was reduced; and satisfaction with the new service was high.

Mycograb (NeuTec Pharma plc) is a human genetically recombinant antibody against fungal heat shock protein 90 (HSP90). Antibody to HSP90 is closely associated with recovery in patients with invasive candidiasis who are receiving amphotericin B (AMB). Using in vitro assays developed for efficacy assessment of chemotherapeutic antifungal drugs, Mycograb showed activity against a wide range of yeast species (MICs against Candida albicans [fluconazole [FLC]-sensitive and FLC-resistant strains], Candida krusei, Candida tropicalis, Candida glabrata, and Candida parapsilosis, 128 to 256 microg/ml). Mycograb (4 or 8 microg/ml) showed synergy with AMB, the fractional inhibitory index being 0.09 to 0.31. Synergy was not evident with FLC, except for FLC-sensitive C. albicans. Murine kinetics showed that Mycograb at 2 mg/kg produced a maximum concentration of drug in serum of 4.7 microg/ml, a half-life at alpha phase of 3.75 min, a half-life at beta phase of 2.34 h, and an area under the concentration-time curve from 0 to t h of 155 microg. min/ml. Mycograb (2 mg/kg) alone produced significant improvement in murine candidiasis caused by each species: (i). a reduction (Scheffe's test, P < 0.05) in the mean organ colony count for the FLC-resistant strain of C. albicans (kidney, liver, and spleen), C. krusei (liver and spleen), C. glabrata (liver and spleen), C. tropicalis (kidney), and C. parapsilosis (kidney, liver, and spleen) and (ii). a statistically significant increase in the number of negative biopsy specimens (Fisher's exact test, P < 0.05) for C. glabrata (kidney), C. tropicalis (liver and spleen), and C. parapsilosis (liver). AMB (0.6 mg/kg) alone cleared the C. tropicalis infection but failed to clear infections caused by C. albicans, C. krusei, C. glabrata, or C. parapsilosis. Synergy with AMB, defined as an increase (Fisher's exact test, P < 0.05) in the number of negative biopsy specimens compared with those obtained using AMB alone, occurred with the FLC-resistant strain of C. albicans (kidney), C. krusei (spleen), C. glabrata (spleen), and C. parapsilosis (liver and spleen). Only by combining Mycograb with AMB was complete resolution of infection achieved for C. albicans, C. krusei, and C. glabrata.

Background: The uptake of influenza vaccination among older people is suboptimal. Contact with a doctor or nurse is associated with older people deciding to accept influenza vaccination., Aim: To compare different forms of approach in improving uptake of influenza vaccination among patients aged 75 years and over in primary care., Design of Study: Randomised controlled trial., Setting: One large rural general practice serving the town and surrounding area of Melton Mowbray, Leicestershire., Method: All 2,052 patients aged 75 years and over, registered with the practice and not living in nursing/residential homes or sheltered accommodation, were included in the study. One-third of patients were randomised to receive an offer of influenza vaccination as part of an over-75 health check administered by a practice nurse in the patient's home, and two-thirds of patients were randomised to receive a personal letter of invitation to attend an influenza vaccination clinic held at the surgery. The main outcome measure was uptake of influenza vaccination., Results: Six hundred and eighty patients were randomised to the health check arm of the trial and 1,372 were randomised to receive a personal letter. Of those randomised to the health check arm, 468 received the health check from the nurse. Overall, the difference in influenza vaccination uptake was 6.4% (95% confidence interval [CI] = 2.2% to 10.4%) with 67.9% (n = 932) of those who were sent a personal letter actually receiving the vaccine, compared with 74.3% (n = 505) of those offered a combined health check and influenza vaccination (P = 0.003)., Conclusion: Combining home-based over- 75 health checks with influenza vaccination can improve uptake among older patients. However this intervention is likely to be costly and its effect on influenza vaccination rates is modest. The difference in uptake is greater among those who do not routinely comeforwardfor vaccination and a more viable option may be to target these patients.

Background: There is a lack of evidence on the most effective primary care management of older people with minor depression., Aim: To evaluate a follow-up assessment by the community mental health team (CMHT) for older people with depressive symptoms identified by practice nurses at a health check for people over the age of 75 years., Design of Study: A pragmatic randomised controlled trial., Setting: A single large general practice in Leicestershire., Method: Patients receiving a health check administered by a practice nurse and scoring 5 or more on the 15-item Geriatric Depression Scale (GDS15) were randomised to either follow-up by the CMHT or routine general practitioner (GP) care. The GDS15 score was measured at the subsequent health check 18 months later., Results: Forty-seven patients were randomised to CMHT assessment and 46 to routine GP care. Uptake of the intervention was 72% (n = 34). At the follow-up health check a greater proportion of the control group had improved GDS15 scores (P = 0.08). Following assessment, the CMHT recommended their further involvement in the care of 12 patients and this was authorised by patients' GPs in six cases., Conclusions: A follow-up mental health assessment by a member of the local CMHT was not effective in improving outcomes for mildly depressed older people. Other than random error possible reasons for this include the length of follow-up and a failure to meet raised expectations among the intervention group. If complex referral procedures do not improve outcomes for this group, then specialist community services should play a more prominent part in the training of practice staff to care for their depressed older patients.