Evaluating Osteoarthritis Management Programs: outcome domain recommendations from the OARSI Joint Effort Initiative.

OBJECTIVE: To develop sets of core and optional recommended domains for describing and evaluating Osteoarthritis Management Programs (OAMPs), with a focus on hip and knee Osteoarthritis (OA). DESIGN: We conducted a 3-round modified Delphi survey involving an international group of researchers, health professionals, health administrators and people with OA. In Round 1, participants ranked the importance of 75 outcome and descriptive domains in five categories: patient impacts, implementation outcomes, and characteristics of the OAMP and its participants and clinicians. Domains ranked as "important" or "essential" by ≥80% of participants were retained, and participants could suggest additional domains. In Round 2, participants rated their level of agreement that each domain was essential for evaluating OAMPs: 0 = strongly disagree to 10 = strongly agree. A domain was retained if ≥80% rated it ≥6. In Round 3, participants rated remaining domains using same scale as in Round 2; a domain was recommended as "core" if ≥80% of participants rated it ≥9 and as "optional" if ≥80% rated it ≥7. RESULTS: A total of 178 individuals from 26 countries participated; 85 completed all survey rounds. Only one domain, "ability to participate in daily activities", met criteria for a core domain; 25 domains met criteria for an optional recommendation: 8 Patient Impacts, 5 Implementation Outcomes, 5 Participant Characteristics, 3 OAMP Characteristics and 4 Clinician Characteristics. CONCLUSION: The ability of patients with OA to participate in daily activities should be evaluated in all OAMPs. Teams evaluating OAMPs should consider including domains from the optional recommended set, with representation from all five categories and based on stakeholder priorities in their local context.

Younger people with rheumatoid arthritis are at increased risk of fracture even before age 50 years: a population-based cohort study.

Less is known about the risk of fracture in people with rheumatoid arthritis aged under 50 than those in older age groups. The study shows that the risk of fracture before age 50 remains significantly higher in those with rheumatoid arthritis than matched controls. This has implications for fracture risk management. INTRODUCTION: To determine the risk of first and subsequent fracture occurring before age 50 in people diagnosed with rheumatoid arthritis (RA) before age 50. METHODS: A retrospective observational cohort study of RA cases with matched controls using data from Clinical Practice Research Datalink (CPRD) of adults ≥ 18 years with diagnosis of RA recorded from 1992 to 2016 in the UK. Patients were followed from index date to the first fracture and subsequent fracture. A total of 36,858 cases were each matched to 3 controls. Incidence rates (IR) and incidence rate ratios (IRR) of first and subsequent fractures were calculated. A multivariate Cox's proportional hazards model was used to calculate the risk of first fracture and of subsequent fracture in the presence of different risk factors. RESULTS: The IR of first and subsequent fractures at any age is significantly higher in cases than controls for patients with onset of RA at any age. This includes first fractures occurring before age 50 for those diagnosed with RA before this age. In women, the rate of first fracture before age 50 are significantly higher than matched controls (IRR 1.29 CI 1.12-1.49), the IRR for subsequent fracture is higher but not significantly so. For men, the IRRs of first and subsequent fractures below age 50 are also higher but not significantly so. Gender, previous fracture, glucocorticoid prescription, osteoporosis diagnosis, alcohol, smoking, and bisphosphonate prescription have a significant effect on the risk of first fracture at any age for RA patients; all these variables except osteoporosis diagnosis and alcohol have a significant effect on the risk of subsequent fracture and first fractures before age 50. CONCLUSIONS: These results indicate an increased risk of first fracture before age 50 in people with RA diagnosed before this age. It is important that patients with RA of all ages are given timely support from the time of diagnosis to protect their bone health.

Development of a core capability framework for qualified health professionals to optimise care for people with osteoarthritis: an OARSI initiative.

OBJECTIVE: Develop a generic trans-disciplinary, skills-based capability framework for health professionals providing care for people with OA. DESIGN: e-Delphi survey. An international inter-professional Delphi Panel (researchers; clinicians; consumer representatives) considered a draft framework (adapted from elsewhere) of 131 specific capabilities mapped to 14 broader capability areas across four domains (A: person-centred approaches; B: assessment, investigation and diagnosis; C: management, interventions and prevention; D: service and professional development). Over three rounds, the Panel rated their agreement (Likert or numerical rating scales) on whether each specific capability in Domains B and C was essential (core) for all health professionals when providing care for all people with OA. Those achieving consensus (≥80% of Panel) rating of ≥ seven out of ten (Round 3) were retained. Generic domains (A and D) were included in the final framework and amended based on Panel comments. RESULTS: 173 people from 31 countries, spanning 18 disciplines and including 26 consumer representatives, participated. The final framework comprised 70 specific capabilities across 13 broad areas i) communication; ii) person-centred care; iii) history-taking; iv) physical assessment; v) investigations and diagnosis; vi) interventions and care planning; vii) prevention and lifestyle interventions; viii) self-management and behaviour change; ix) rehabilitative interventions; x) pharmacotherapy; xi) surgical interventions; xii) referrals and collaborative working; and xiii) evidence-based practice and service development). CONCLUSION: Experts agree that health professionals require an array of skills in person-centred approaches; assessment, investigation and diagnosis; management, interventions and prevention; and service and professional development to provide optimal care for people with OA.

Use of The Global Alliance for Musculoskeletal Health survey module for estimating the population prevalence of musculoskeletal pain: findings from the Solomon Islands.

BACKGROUND: Musculoskeletal (MSK) conditions are common and the biggest global cause of physical disability. The objective of the current study was to estimate the population prevalence of MSK-related pain using a standardized global MSK survey module for the first time. METHODS: A MSK survey module was constructed by the Global Alliance for Musculoskeletal Health Surveillance Taskforce and the Global Burden of Disease MSK Expert Group. The MSK module was included in the 2015 Solomon Islands Demographic and Health Survey. The sampling design was a two-stage stratified, nationally representative sample of households. RESULTS: A total of 9214 participants aged 15-49 years were included in the analysis. The age-standardized four-week prevalence of activity-limiting low back pain, neck pain, and hip and/or knee pain was 16.8, 8.9, and 10.8%, respectively. Prevalence tended to increase with age, and be higher in those with lower levels of education. CONCLUSIONS: Prevalence of activity-limited pain was high in all measured MSK sites. This indicates an important public health issue for the Solomon Islands that needs to be addressed. Efforts should be underpinned by integration with strategies for other non-communicable diseases, aging, disability, and rehabilitation, and with other sectors such as social services, education, industry, and agriculture. Primary prevention strategies and strategies aimed at self-management are likely to have the greatest and most cost-effective impact.

EULAR/EFORT recommendations for management of patients older than 50†years with a fragility fracture and prevention of subsequent fractures.

The European League Against Rheumatism (EULAR) and the European Federation of National Associations of Orthopaedics and Traumatology (EFORT) have recognised the importance of optimal acute care for the patients aged 50 years and over with a recent fragility fracture and the prevention of subsequent fractures in high-risk patients, which can be facilitated by close collaboration between orthopaedic surgeons and rheumatologists or other metabolic bone experts. Therefore, the aim was to establish for the first time collaborative recommendations for these patients. According to the EULAR standard operating procedures for the elaboration and implementation of evidence-based recommendations, 7 rheumatologists, a geriatrician and 10 orthopaedic surgeons met twice under the leadership of 2 convenors, a senior advisor, a clinical epidemiologist and 3 research fellows. After defining the content and procedures of the task force, 10 research questions were formulated, a comprehensive and systematic literature search was performed and the results were presented to the entire committee. 10 recommendations were formulated based on evidence from the literature and after discussion and consensus building in the group. The recommendations included appropriate medical and surgical perioperative care, which requires, especially in the elderly, a multidisciplinary approach including orthogeriatric care. A coordinator should setup a process for the systematic investigations for future fracture risk in all elderly patients with a recent fracture. High-risk patients should have appropriate non-pharmacological and pharmacological treatment to decrease the risk of subsequent fracture.

Hip fracture, mortality risk, and cause of death over two decades.

UNLABELLED: Men and women with hip fracture have higher short-term mortality. This study investigated mortality risk over two decades post-fracture; excess mortality remained high in women up to 10 years and in men up to 20 years. Cardiovascular disease (CVD) and pneumonia were leading causes of death with a long-term doubling of risk. INTRODUCTION: Hip fractures are associated with increased mortality, particularly short term. In this study with a two-decade follow-up, we examined mortality and cause of death compared to the background population. METHODS: We followed 1013 hip fracture patients and 2026 matched community controls for 22 years. Mortality, excess mortality, and cause of death were analyzed and stratified for age and sex. Hazard ratio (HR) was estimated by Cox regression. A competing risk model was fitted to estimate HR for common causes of death (CVD, cancer, pneumonia) in the short and long term (>1 year). RESULTS: For both sexes and at all ages, mortality was higher in hip fracture patients across the observation period with men losing most life years (p < 0.001). Mortality risk was higher for up to 15 years (women (risk ratio (RR) 1.9 [95 % confidence interval (CI) 1.7-2.1]); men (RR 2.8 [2.2-3.5])) and until end of follow-up ((RR 1.8 [1.6-2.0]); (RR 2.7 [2.1-3.3])). Excess mortality by time intervals, censored for the first year, was evident in women (<80 years, up to 10 years; >80 years, for 5 years) and in men <80 years throughout. CVD and pneumonia were predominant causes of death in men and women with an associated higher risk in all age groups. Pneumonia caused excess mortality in men over the entire observation period. CONCLUSION: In a remaining lifetime perspective, all-cause and excess mortality after hip fracture was higher even over two decades of follow-up. CVD and pneumonia reduce life expectancy for the remaining lifetime and highlights the need to further improve post-fracture management.

Vertebral Scheuermann's disease in Europe: prevalence, geographic variation and radiological correlates in men and women aged 50 and over.

UNLABELLED: In 27 centres across Europe, the prevalence of deforming spinal Scheuermann's disease in age-stratified population-based samples of over 10,000 men and women aged 50+ averaged 8% in each sex, but was highly variable between centres. Low DXA BMD was un-associated with Scheuermann's, helping the differential diagnosis from osteoporosis. INTRODUCTION: This study aims to assess the prevalence of Scheuermann's disease of the spine across Europe in men and women over 50 years of age, to quantitate its association with bone mineral density (BMD) and to assess its role as a confounder for the radiographic diagnosis of osteoporotic fracture. METHODS: In 27 centres participating in the population-based European Vertebral Osteoporosis Study (EVOS), standardised lateral radiographs of the lumbar and of the thoracic spine from T4 to L4 were assessed in all those of adequate quality. The presence of Scheuermann's disease, a confounder for prevalent fracture in later life, was defined by the presence of at least one Schmorl's node or irregular endplate together with kyphosis (sagittal Cobb angle >40° between T4 and T12) or a wedged-shaped vertebral body. Alternatively, the (rare) Edgren-Vaino sign was taken as diagnostic. The 6-point-per-vertebral-body (13 vertebrae) method was used to assess osteoporotic vertebral shape and fracture caseness. DXA BMD of the L2-L4 and femoral neck regions was measured in subsets. We also assessed the presence of Scheuermann's by alternative published algorithms when these used the radiographic signs we assessed. RESULTS: Vertebral radiographic images from 4486 men and 5655 women passed all quality checks. Prevalence of Scheuermann's varied considerably between centres, and based on random effect modelling, the overall European prevalence using our method was 8% with no significant difference between sexes. The highest prevalences were seen in Germany, Sweden, the UK and France and low prevalences were seen in Hungary, Poland and Slovakia. Centre-level prevalences in men and women were highly correlated. Scheuermann's was not associated with BMD of the spine or hip. CONCLUSIONS: Since most of the variation in population impact of Scheuermann's was unaccounted for by the radiological and anthropometric data, the search for new genetic and environmental determinants of this disease is encouraged.

Mortality and incident vertebral fractures after 3 years of follow-up among geriatric patients.

UNLABELLED: In a prospective cohort study of 395 geriatric outpatients, mortality after 3 years was associated with prevalent vertebral fractures at baseline. The mortality risk was independently associated with the presence of three or more vertebral fractures at baseline. In the surviving patients, the risk of incident fractures was noteworthy, occurring in 26 % of these patients. INTRODUCTION: The purpose of this study is to determine mortality rate and the incidence of vertebral fractures in a geriatric outpatient group, during a 3-year follow-up period, in a teaching hospital in Amsterdam, The Netherlands. METHODS: This study includes a prospective cohort study of 395 geriatric patients who had their baseline visit at a diagnostic day hospital in 2007 and 2008. They were invited for follow-up 3 years later. Lateral X-rays of the lumbar spine and chest were performed at baseline and after 3 years; vertebral fractures were scored in all patients according to the semi-quantitative method of Genant. RESULTS: After 3 years, mortality was 46 % and associated with prevalent vertebral fractures at baseline (odds ratio (OR), 1.83; 95 % CI, 1.23-2.74). The presence of three or more vertebral fractures at baseline was an independent risk factor for mortality (OR, 3.32; 95 % CI, 1.56-7.07). Other independently associated risk factors were greater age, higher co-morbidity score, and having more prescriptions. Higher cognitive capacity protected against mortality after 3 years. In 72 patients, radiography was repeated. Nineteen patients (26 %) had an incident radiographic vertebral fracture: 16 in those with a prevalent fracture, and 3 in those without a prevalent vertebral fracture at baseline. CONCLUSIONS: In geriatric outpatients, mortality after 3 years was associated with prevalent vertebral fractures at baseline, and the mortality risk was independently associated with 3 or more vertebral fractures at baseline. In survivors, the risk of incident fractures was noteworthy, since these occurred in 26 % of the patients, particularly in those with a prevalent vertebral fracture.

High incidence of vertebral and non-vertebral fractures in the OSTRA cohort study: a 5-year follow-up study in postmenopausal women with rheumatoid arthritis.

UNLABELLED: A 5-year follow-up study was performed in female RA patients with established disease looking at vertebral fractures, scored on spinal X-rays, and non-vertebral fractures. We found a high incidence rate of vertebral and non-vertebral fractures in these patients compared to population-based studies. INTRODUCTION: The aim of this study is to investigate the incidence of vertebral and non-vertebral fractures over a 5-year period in a cohort of postmenopausal patients with established rheumatoid arthritis (RA). METHODS: One hundred and fifty female patients with established RA were included into the OSTRA cohort. The cohort was assessed at baseline and at 5 years for incident vertebral and non-vertebral fractures. Spinal X-rays were taken at baseline and at follow-up and scored using the semi-quantitative method according to Genant. RESULTS: At 5 years, 102 patients (68%) were examined and included in the present analysis. At baseline, the mean age was 61 years, disease duration 17 years, body mass index 25.5 kg/m(2) and 65% of the patients were rheumatoid factor positive. Fifteen percent were treated with bisphosphonates, 25% received calcium supplementation and 20% vitamin-D supplementation at baseline. During the 5-year follow-up, a total of 16 patients out of 102 patients (16%) had a new non-vertebral fracture [annual incidence of 3.2 (95% CI 1.8-5.5) per 100 patients/year]. In 18 patients out of 97 patients (19%), new vertebral fractures were identified on spinal X-ray [annual incidence of 3.7 (95% C.I. 2.2-5.8) per 100 patients/year]. CONCLUSIONS: We found a high incidence of vertebral and non-vertebral fractures in a cohort of women with established RA compared to population-based studies.

Roles of hepatocyte growth factor/scatter factor and the met receptor in the early development of the metanephros.

Several lines of evidence suggest that hepatocyte growth factor/scatter factor (HGF/SF), a soluble protein secreted by embryo fibroblasts and several fibroblast lines, may elicit morphogenesis in adjacent epithelial cells. We investigated the role of HGF/SF and its membrane receptor, the product of the c-met protooncogene, in the early development of the metanephric kidney. At the inception of the mouse metanephros at embryonic day 11, HGF/SF was expressed in the mesenchyme, while met was expressed in both the ureteric bud and the mesenchyme, as assessed by reverse transcription PCR, in situ hybridization, and immunohistochemistry. To further investigate the expression of met in renal mesenchyme, we isolated 13 conditionally immortal clonal cell lines from transgenic mice expressing a temperature-sensitive mutant of the SV-40 large T antigen. Five had the HGF/SF+/met+ phenotype and eight had the HGF/SF-/met+ phenotype. None had the HGF/SF+/met- nor the HGF/SF-/met- phenotypes. Thus the renal mesenchyme contains cells that express HGF/SF and met or met alone. When metanephric rudiments were grown in serum-free organ culture, anti-HGF/SF antibodies (a) inhibited the differentiation of metanephric mesenchymal cells into the epithelial precursors of the nephron; (b) increased cell death within the renal mesenchyme; and (c) perturbed branching morphogenesis of the ureteric bud. These data provide the first demonstration for coexpression of the HGF/SF and met genes in mesenchymal cells during embryonic development and also imply an autocrine and/or paracrine role for HGF/SF and met in the survival of the renal mesenchyme and in the mesenchymal-epithelial transition that occurs during nephrogenesis. They also confirm the postulated paracrine role of HGF/SF in the branching of the ureteric bud.

Chronic musculoskeletal pain and arthritis: impact, attitudes and perceptions.

The aim of this study was to assess the prevalence, management and impact on quality of life of chronic musculoskeletal pain in Ireland by comparing the attitudes and perceptions of sufferers to those of general practice doctors (GPs). A telephone survey was conducted with 498 people with chronic musculoskeletal pain (screened from a total of 3323) and 150 GPs selected randomly from the medical register. The survey was based on a structured questionnaire that asked about the impact of CMP, usual management and perceived benefits and risks of treatment. Chronic musculoskeletal pain, including arthritis, affected one in six of the people screened for the survey. 25% of those surveyed have never consulted a doctor about their condition and many others will have waited up to two years before seeking help. 67% of respondents reported that pain caused significant reduction in their quality of life (measured using the SF-12 scale). The survey also indicated that people with chronic musculoskeletal pain have misconceptions about their condition, treatment options and side effects and patients rarely receive written information from their GP on these subjects. Chronic musculoskeletal pain, including arthritis is common and significantly reduces quality of life in Ireland. People delay seeking medical help, despite being in constant/daily pain. Written information is sparse and misperceptions relating to treatment are common. Improved awareness and valid information may lead to better care for people suffering from CMP in Ireland.

Better arthritis care: What training do community-based health professionals need to improve their care of people with arthritis? A Delphi study.

OBJECTIVE: The aim of the present study was to identify the competencies that non-specialist community-based nurses and allied health professionals (AHPs) need to enable them to assess, care for and manage arthritis appropriately. METHODS: A Delphi survey with an expert panel of 43 rheumatology specialists and expert patients was used to identify the competencies needed by community-based nurses and AHPs to enable them to improve their care of people with arthritis. The process was informed by feedback from focus groups with arthritis patients, community-based nurses and AHPs. RESULTS: The core competencies in arthritis care needed by non-specialist community-based nurses and AHPs were identified. The key goals identified were to increase the understanding of arthritis and its impact on patients' lives, and to increase the ability to help patients to self-manage their condition and access support. Competencies included an understanding of the pathology underlying inflammatory and non-inflammatory arthritis, the ability to distinguish between the two and the ability to recognize early warning signs, with an emphasis on osteoarthritis (OA), rheumatoid arthritis, gout and septic arthritis. Essential competencies included the ability to engage in shared decision making, goal setting and signposting, to provide patients with education and information and to make appropriate referrals. CONCLUSIONS: Health professionals working in the community commonly encounter arthritis as a presenting problem or as a co-morbidity. The quality of care provided to people with inflammatory arthritis and OA in the community is currently variable. The present study identified the core competencies that all community-based nurses and AHPs should have in relation to OA and inflammatory arthritis.

Better arthritis care: Patients' expectations and priorities, the competencies that community-based health professionals need to improve their care of people with arthritis?

OBJECTIVE: The aim of the present study was to identify the competencies that patients think non-specialist community-based nurses and allied health professionals (AHPs) need to enable them to assess, care for and manage arthritis appropriately. METHODS: Four face-to-face focus groups were held with a total of 16 women and nine men with arthritis, to discuss the care they received from community-based health professionals, the skills and knowledge they expected from community-based health professionals and what they prioritized. RESULTS: People with arthritis wanted health providers to have an understanding of the difference between inflammatory arthritis (IA) and osteoarthritis (OA), of how serious OA can be, and of the unpredictability of IA and flares. They emphasized the need for nurses and AHPs to understand the psychosocial impact of arthritis on individuals, family and friends, and the psychological adjustment needed when diagnosed with IA. They wanted community-based health professionals to have some knowledge of the types of drug treatments that people with IA receive and the implications of taking immunosuppressive drugs. They also wanted them to understand the pain associated with arthritis, particularly OA, which participants felt was not taken seriously enough. They wanted nurses and AHPs in the community to be able to give basic advice on pacing and pain management, to make multidisciplinary referrals, to communicate effectively between referral points and to be able to signpost people to sources of help and good, reliable sources of education and information (especially for OA). They also wanted them to understand that patients who have had a diagnosis for a long time are the experts in their own disease. Other areas which were emphasized as being important were good communication skills and taking a holistic approach to caring for people with arthritis. CONCLUSIONS: OA and IA differ significantly, both in their nature and their management. However, patients with arthritis want health professionals working in the community to be able to take a holistic approach to arthritis, with an understanding not just of the physical effects, but also their impact on the lives of patients, their family and their wider social circle, and on their ability to participate. People with OA want their condition to be taken seriously and to be offered appropriate management options, while people with IA want professionals to understand the unpredictability of their condition and to have a basic understanding of the drugs used for its treatment.

The PAX2 tanscription factor is expressed in cystic and hyperproliferative dysplastic epithelia in human kidney malformations.

Human dysplastic kidneys are developmental aberrations which are responsible for many of the very young children with chronic renal failure. They contain poorly differentiated metanephric cells in addition to metaplastic elements. We recently demonstrated that apoptosis was prominent in undifferentiated cells around dysplastic tubules (Winyard, P.J.D., J. Nauta, D.S. Lirenman, P. Hardman, V.R. Sams, R.A. Risdon, and A.S. Woolf. 1996. Kidney Int. 49:135-146), perhaps explaining the tendency of some of these organs to regress. In contrast, apoptosis was rare in dysplastic epithelia which are thought to be ureteric bud malformations. On occasion, these tubules form cysts which distend the abdominal cavity (the multicystic dysplastic kidney) and dysplastic kidneys may rarely become malignant. We now demonstrate that dysplastic tubules maintain a high rate of proliferation postnatally and that PAX2, a potentially oncogenic transcription factor, is expressed in these epithelia. In contrast, both cell proliferation and PAX2 are downregulated during normal maturation of human collecting ducts. We demonstrate that BCL2, a protein which prevents apoptosis in renal mesenchymal to epithelia] conversion, is expressed ectopically in dysplastic kidney epithelia. We propose that dysplastic cyst formation may be understood in terms of aberrant temporal and spatial expression of master genes which are tightly regulated in the normal program of human nephrogenesis.

Building multidisciplinary health workforce capacity to support the implementation of integrated, people-centred Models of Care for musculoskeletal health.

To address the burden of musculoskeletal (MSK) conditions, a competent health workforce is required to support the implementation of MSK models of care. Funding is required to create employment positions with resources for service delivery and training a fit-for-purpose workforce. Training should be aligned to define "entrustable professional activities", and include collaborative skills appropriate to integrated and people-centred care and supported by shared education resources. Greater emphasis on educating MSK healthcare workers as effective trainers of peers, students and patients is required. For quality, efficiency and sustainability of service delivery, education and research capabilities must be integrated across disciplines and within the workforce, with funding models developed based on measured performance indicators from all three domains. Greater awareness of the societal and economic burden of MSK conditions is required to ensure that solutions are prioritised and integrated within healthcare policies from local to regional to international levels. These healthcare policies require consumer engagement and alignment to social, economic, educational and infrastructure policies to optimise effectiveness and efficiency of implementation.

A characterization of the chloride conductance in mesangial cells from the H-2Kb-tsA58 transgenic mouse.

The chloride conductance of conditionally immortalized mesangial cells isolated from the H-2Kb-tsA58 transgenic mouse was studied in cells grown in permissive and non-permissive culture conditions. No differences were found in the magnitude of the chloride conductance in 140 mM tetramethyl ammonium chloride between cells grown in permissive and non-permissive culture conditions (1.08 +/- 0.05 nS and 1.02 +/- 0.05 nS). Selectivity sequences were defined as 1.8I- > 1.2Br- > lCl- and 1.3I- > 1.1Br- > lCl- respectively and both the anion channel inhibitors niflumic acid and ochratoxin A inhibited the chloride conductance in a dose-dependent manner. The chloride conductance was made up from calcium-dependent and calcium-independent components and in the presence of 1 microM free calcium in the pipette this could be increased by the presence of 100 U ml-1 insulin added to the incubation medium. This appeared to increase the sensitivity of the conductance to levels of intracellular calcium as no differences were observed in the presence of either 1 mM or 100 nM pipette calcium. These data indicate that there is a significant chloride conductance in mesangial cells from the H-2Kb-tsA58 transgenic mouse and minimal changes are observed with changes from permissive to non-permissive culture conditions.

Potassium conductances and proliferation in conditionally immortalized renal glomerular mesangial cells from the H-2Kb-tsA58 transgenic mouse.

The effects of the temperature-sensitive, immortalizing Simian Virus 40 T antigen, tsA58, on whole-cell potassium conductances were assessed in renal glomerular mesangial cells from H-2Kb-tsA58 transgenic mice [1]. MTT cell viability assay data indicated that in permissive (33 degrees C, 50 U ml-1 gamma-interferon, IFN+) and non-permissive (37 degrees C, without gamma-interferon, IFN-) culture conditions the oncogene was active and inactive respectively. In IFN+ cells whole-cell currents were inhibited by 10 mM 4-aminopyridine, 1 mM ATP and glibenclamide (glyburide, IC50 = 0.4 microM) and stimulated by cromakalim (EC50 = 40 microM). Furthermore, increases in pipette free calcium activity stimulated the potassium conductance (EC50 = 0.5 microM). Apamin inhibited this conductance (IC50 = 9 nM). None of these effects were observed in IFN- cells. The potassium conductance in IFN- cells was activated by a hyposmotic shock and this was inhibited by Gd3. These data indicate that (1) conductances consistent with ATP-sensitive and small, calcium-activated potassium channels are found in IFN+ cells, (2) an osmotically-sensitive channel is found in IFN- cells and (3) channel expression is dependent upon the activation of tsA58.

Low BMD is less predictive than reported falls for future limb fractures in women across Europe: results from the European Prospective Osteoporosis Study.

We have previously shown that center- and sex-specific fall rates explained one-third of between-center variation in upper limb fractures across Europe. In this current analysis, our aim was to determine how much of the between-center variation in fractures could be attributed to repeated falling, bone mineral density (BMD), and other risk factors in individuals, and to compare the relative contributions of center-specific BMD vs. center-specific fall rates. A clinical history of fracture was assessed prospectively in 2451 men and 2919 women aged 50-80 from 20 centers participating in the European Prospective Osteoporosis Study (EPOS) using standardized questionnaires (mean follow-up = 3 years). Bone mineral density (BMD, femoral neck, trochanter, and/or spine) was measured in 2103 men and 2565 women at these centers. Cox regression was used to model the risk of incident fracture as a function of the person-specific covariates: age, BMD, personal fracture history (PFH), family hip fracture history (FAMHIP), time spent walking/cycling, number of 'all falls' and falls not causing fracture ('fracture-free') during follow-up, alcohol consumption, and body mass index. Center effects were modeled by inclusion of multiplicative gamma-distributed random effects, termed center-shared frailty (CSF), with mean 1 and finite variance theta (theta) acting on the hazard rate. The relative contributions of center-specific fall risk and center-specific BMD on the incidence of limb fractures were evaluated as components of CSF. In women, the risk of any incident nonspine fracture (n = 190) increased with age, PFH, FAMHIP, > or =1 h/day walking/cycling, and number of 'all falls' during follow-up (all P < 0.074). 'Fracture-free' falls (P = 0.726) and femoral neck BMD did not have a significant effect at the individual level, but there was a significant center-shared frailty effect (theta = 0.271, P = 0.001) that was reduced by 4% after adjusting for mean center BMD and reduced by 19% when adjusted for mean center fall rate. Femoral trochanter BMD was a significant determinant of lower limb fractures (n = 53, P = 0.014) and the center-shared frailty effect was significant for upper limb fractures (theta = 0.271, P = 0.011). This upper limb fracture center effect was unchanged after adjusting for mean center BMD but was reduced by 36% after adjusting for center mean fall rates. In men, risk of any nonspine fracture (n = 75) increased with PFH, fall during follow-up (P < 0.026), and with a decrease in trochanteric BMD [RR 1.38 (1.08, 1.79) per 1 SD decrease]. There was no center effect evident (theta = 0.081, P = 0.096). We conclude that BMD alone cannot be validly used to discriminate between the risk of upper limb fractures across populations without taking account of population-specific variations in fall risk and other factors. These variations might reflect shared environmental or possibly genetic factors that contribute quite substantially to the risk of upper limb fractures in women.