Underexpression of the 43 kDa inositol polyphosphate 5-phosphatase is associated with spontaneous calcium oscillations and enhanced calcium responses following endothelin-1 stimulation

The 43 kDa inositol polyphosphate 5-phosphatase (5-phosphatase) hydrolyses the signalling molecules inositol 1,4,5-trisphosphate (Ins(1,4,5)P) and inositol 1,3,4,5-tetrakisphosphate (Ins(1,3,4,5)P) and thereby regulates cellular transformation. To investigate the role Ins(1,4,5)P-mediated Ca oscillations play in cellular transformation, we studied Ins(1,4,5)P-mediated Ca responses in cells underexpressing the 43 kDa 5-phosphatase. Chronic reduction in 43 kDa 5-phosphatase enzyme activity resulted in a 2.6-fold increase in the resting Ins(1,4,5)P concentration and a 4.1-fold increase in basal intracellular Ca. The increased Ins(1,4,5)P levels resulted in partial emptying (40%) of the Ins(1,4,5)P-sensitive Ca store, however, store-operated Ca influx remained unchanged. In addition, Ins(1,4,5)P receptors were chronically downregulated in unstimulated cells, as shown by a 53% reduction in [H]Ins(1,4,5)P binding to microsomal receptor sites. Agonist stimulation with endothelin-1 resulted in the rapid rise and fall of Ins(1,4,5)P and Ins(1,3,4,5)P levels, with no significant differences in the rates of hydrolysis of these second messengers in antisenseor vector-transfected cells. These studies indicate, in contrast to its predicted action, the 43 kDa 5-phosphatase does not metabolise Ins(1,4,5)P and Ins(1,3,4,5)P post agonist stimulation. Cells with decreased 43 kDa 5-phosphatase activity exhibited spontaneous Ca oscillations in the absence of any agonist stimulation, and increased sensitivity and amplitude of intracellular Ca responses to both high and low dose endothelin-l stimulation. We conclude the 43 kDa 5-phosphatase exerts a profound influence on Ins(1,4,5)P-induced Ca spiking, both in the unstimulated cell and following agonist stimulation. We propose the enhanced Ca oscillations may mediate cellular transformation in cells underexpressing the 43 kDa 5-phosphatase

Survey of ultrasound practice amongst podiatrists in the UK

Background: Ultrasound in podiatry practice encompasses musculoskeletal ultrasound imaging, vascular hand-held Doppler ultrasound and therapeutic ultrasound. Sonography practice is not regulated by the Health and Care Professions Council (HCPC), with no requirement to hold a formal qualification. The College of Podiatry does not currently define ultrasound training and competencies. This study aimed to determine the current use of ultrasound, training received and mentorship received and/or provided by podiatrists using ultrasound. Methods: A quantitative study utilising a cross-sectional, on-line, single-event survey was undertaken within the UK. Results: Completed surveys were received from 284 podiatrists; 173 (70%) use ultrasound as part of their general practice, 139 (49%) for musculoskeletal problems, 131 (46%) for vascular assessment and 39 (14%) to support their surgical practice. Almost a quarter (n=62) worked for more than one organisation; 202 (71%) were employed by the NHS and/or private sector (n=118, 41%). Nearly all (93%) respondents report using a hand-held vascular Doppler in their daily practice; 216 (82%) to support decisions regarding treatment options, 102 (39%) to provide diagnostic reports for other health professionals, and 34 (13%) to guide nerve blocks. Ultrasound imaging was used by 104 (37%) respondents primarily to aid clinical decision making (n=81) and guide interventions (steroid injections n=67; nerve blocks n=39). Ninety-three percent stated they use ultrasound imaging to treat their own patients, while others scan at the request of other podiatrists (n=28) or health professionals (n=18). Few use ultrasound imaging for research (n=7) or education (n=2). Only 32 (11%) respondents (n=20 private sector) use therapeutic ultrasound to treat patients presenting with musculoskeletal complaints, namely tendon pathologies. Few respondents (18%) had completed formal post-graduate CASE (Consortium for the Accreditation of Sonographic Education) accredited ultrasound courses. Forty (14%) respondents receive ultrasound mentorship; the majority from fellow podiatrists (n=17) or medical colleagues (n=15). Over half (n=127) who do not have ultrasound mentorship indicated they would like a mentor predominantly for ultrasound imaging. Fifty-five (19%) report they currently provide ultrasound mentorship for others. Conclusions: Understanding the scope of ultrasound practice, the training undertaken and the requirements for mentorship will underpin the development of competencies and recommendations defined by the College of Podiatry to support professional development and ensure safe practice.</p

The effectiveness of extra corporeal shock wave therapy for plantar heel pain: a systematic review and meta-analysis

BACKGROUND: There is considerable controversy regarding the effectiveness of extracorporeal shock wave therapy in the management of plantar heel pain. Our aim was to conduct a systematic review of randomised controlled trials to investigate the effectiveness of extracorporeal shock wave therapy and to produce a precise estimate of the likely benefits of this therapy. METHODS: We conducted a systematic review of all randomised controlled trials (RCTs) identified from the Cochrane Controlled trials register, MEDLINE, EMBASE and CINAHL from 1966 until September 2004. We included randomised trials which evaluated extracorporeal shock wave therapy used to treat plantar heel pain. Trials comparing extra corporeal shock wave therapy with placebo or different doses of extra corporeal shock wave therapy were considered for inclusion in the review. We independently applied the inclusion and exclusion criteria to each identified randomised controlled trial, extracted data and assessed the methodological quality of each trial. RESULTS: Six RCTs (n = 897) permitted a pooled estimate of effectiveness based on pain scores collected using 10 cm visual analogue scales for morning pain. The estimated weighted mean difference was 0.42 (95% confidence interval 0.02 to 0.83) representing less than 0.5 cm on a visual analogue scale. There was no evidence of heterogeneity and a fixed effects model was used. CONCLUSION: A meta-analysis of data from six randomised-controlled trials that included a total of 897 patients was statistically significant in favour of extracorporeal shock wave therapy for the treatment of plantar heel pain but the effect size was very small. A sensitivity analysis including only high quality trials did not detect a statistically significant effect

Tendinopathy—from basic science to treatment

Chronic tendon pathology (tendinopathy), although common, is difficult to treat. Tendons possess a highly organized fibrillar matrix, consisting of type I collagen and various 'minor' collagens, proteoglycans and glycoproteins. The tendon matrix is maintained by the resident tenocytes, and there is evidence of a continuous process of matrix remodeling, although the rate of turnover varies at different sites. A change in remodeling activity is associated with the onset of tendinopathy. Major molecular changes include increased expression of type III collagen, fibronectin, tenascin C, aggrecan and biglycan. These changes are consistent with repair, but they might also be an adaptive response to changes in mechanical loading. Repeated minor strain is thought to be the major precipitating factor in tendinopathy, although further work is required to determine whether it is mechanical overstimulation or understimulation that leads to the change in tenocyte activity. Metalloproteinase enzymes have an important role in the tendon matrix, being responsible for the degradation of collagen and proteoglycan in both healthy patients and those with disease. Metalloproteinases that show increased expression in painful tendinopathy include ADAM (a disintegrin and metalloproteinase)-12 and MMP (matrix metalloproteinase)-23. The role of these enzymes in tendon pathology is unknown, and further work is required to identify novel and specific molecular targets for therapy

On consensus biomarker selection

<p>Abstract</p> <p>Background</p> <p>Recent development of mass spectrometry technology enabled the analysis of complex peptide mixtures. A lot of effort is currently devoted to the identification of biomarkers in human body fluids like serum or plasma, based on which new diagnostic tests for different diseases could be constructed. Various biomarker selection procedures have been exploited in recent studies. It has been noted that they often lead to different biomarker lists and as a consequence, the patient classification may also vary.</p> <p>Results</p> <p>Here we propose a new approach to the biomarker selection problem: to apply several competing feature ranking procedures and compute a consensus list of features based on their outcomes. We validate our methods on two proteomic datasets for the diagnosis of ovarian and prostate cancer.</p> <p>Conclusion</p> <p>The proposed methodology can improve the classification results and at the same time provide a unified biomarker list for further biological examinations and interpretation.</p

A method for identifying genetic heterogeneity within phenotypically defined disease subgroups.

Many common diseases show wide phenotypic variation. We present a statistical method for determining whether phenotypically defined subgroups of disease cases represent different genetic architectures, in which disease-associated variants have different effect sizes in two subgroups. Our method models the genome-wide distributions of genetic association statistics with mixture Gaussians. We apply a global test without requiring explicit identification of disease-associated variants, thus maximizing power in comparison to standard variant-by-variant subgroup analysis. Where evidence for genetic subgrouping is found, we present methods for post hoc identification of the contributing genetic variants. We demonstrate the method on a range of simulated and test data sets, for which expected results are already known. We investigate subgroups of individuals with type 1 diabetes (T1D) defined by autoantibody positivity, establishing evidence for differential genetic architecture with positivity for thyroid-peroxidase-specific antibody, driven generally by variants in known T1D-associated genomic regions.We acknowledge the help of the Diabetes and Inflammation Laboratory Data Service for access and quality control procedures on the data sets used in this study. The JDRF/Wellcome Trust Diabetes and Inflammation Laboratory is in receipt of a Wellcome Trust Strategic Award (107212; J.A.T.) and receives funding from the NIHR Cambridge Biomedical Research Centre. J.L. is funded by the NIHR Cambridge Biomedical Research Centre and is on the Wellcome Trust PhD program in Mathematical Genomics and Medicine at the University of Cambridge. C.W. is funded by the MRC (grant MC_UP_1302/5). We thank M. Simmonds, S. Gough, J. Franklyn, and O. Brand for sharing their AITD genetic association data set and all patients with AITD and control subjects for participating in this study. The AITD UK national collection was funded by the Wellcome Trust. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Image-guided versus blind corticosteroid injections in adults with shoulder pain: A systematic review

<p>Abstract</p> <p>Background</p> <p>Corticosteroid injections can be performed blind (landmark-guided) or with image guidance, and this may account for variable clinical outcomes. The objective of this study was to assess the effectiveness and safety of image-guided versus blind corticosteroid injections in improving pain and function among adults with shoulder pain.</p> <p>Methods</p> <p>MEDLINE, the Cochrane Controlled Trials Register and EMBASE were searched to May 2010. Additional studies were identified by searching bibliographies of shortlisted articles. Search items included blind, landmark, anatomical, clinical exam, image-guided, ultrasound, fluoroscopy, steroid injection, frozen shoulder, random allocation, randomized controlled trial (RCT) and clinical trial.</p> <p>Randomized controlled studies comparing image-guided versus blind (landmark-guided) corticosteroid shoulder injections that examined pain, function and/or adverse events were included. Independent extraction was done by two authors using a form with pre-specified data fields, including risk of bias appraisal. Conflicts were resolved by discussion. The decision to pool data was based on assessment of clinical design homogeneity. When warranted, studies were pooled under a random-effects model.</p> <p>Results</p> <p>Two RCTs for pain, function and adverse events (n = 101) met eligibility criteria. No serious threats to validity were found. Both trials compared ultrasound-guided versus landmark-guided injections and were judged similar in clinical design. Low to moderate heterogeneity was observed: shoulder pain I²= 60%, function I²= 22%. A meta-analysis demonstrated greater improvement with ultrasound-guided injections at 6 weeks after injection in both pain (mean difference = 2.23 [95% CI: 1.27, 3.18]), as assessed with a 0 to 10 visual analogue scale, and shoulder function (standardised mean difference = 1.09 [95% CI: 0.61, 1.57]) as assessed with shoulder function scores. Although more adverse events (all mild) were reported with landmark-guided injections, the difference was not statistically significant (risk ratio = 0.20 [95% CI: 0.04, 1.13]).</p> <p>This review was only based on two moderate-sized trials. Blinding of patients was not performed in both trials, causing some risk of bias in outcome assessment since primary endpoints were wholly or partially patient-reported.</p> <p>Conclusion</p> <p>There is a paucity of RCTs on image-guided versus landmark-guided corticosteroid shoulder injections examining pain, function and adverse events. In this review, patients who underwent image-guided (ultrasound) injections had statistically significant greater improvement in shoulder pain and function at 6 weeks after injection. Image-guided (ultrasound) corticosteroid injections potentially offer a significantly greater clinical improvement over blind (landmark-guided) injections in adults with shoulder pain. However, this apparent benefit requires confirmation from further studies (adequately-powered and well-executed RCTs).</p

Family physicians' effort to stay in charge of the medical treatment when patients have home care by district nurses. A grounded theory study

<p>Abstract</p> <p>Background</p> <p>District nurses (DNs) provide home care for old persons with a mixture of chronic diseases, symptoms and reduced functional ability. Family physicians (FPs) have been criticised for their lack of involvement in this care. The aim of this study was to obtain increased knowledge concerning the FP's experience of providing medical treatment for patients with home care provided by DNs by developing a theoretical model that elucidates how FPs handle the problems they encounter regarding the individual patients and their conditions.</p> <p>Methods</p> <p>Semi-structured interviews were conducted with 13 Swedish FPs concerning one of their registered patients with home care by a DN, and the treatment of this patient. Grounded theory methodology (GTM) was used in the analyses.</p> <p>Results</p> <p>The core category was the effort to stay in charge of the medical treatment. This involved three types of problems: gaining sufficient insight, making adequate decisions, and maintaining appropriate medical treatment. For three categories of patients, the FPs had problems staying in charge. Patients with reduced functional ability had problems providing information and maintaining treatment. Patients who were "fixed in their ways" did not provide information and did not comply with recommendations, and for patients with complex conditions, making adequate decisions could be problematic. To overcome the problems, four different strategies were used: relying on information from others, supporting close observation and follow-up by others, being constantly ready to change the goal of the treatment, and relying on others to provide treatment.</p> <p>Conclusion</p> <p>The patients in this study differed from most other patients seen at the healthcare centre as the consultation with the patient could not provide the usual foundation for decisions concerning medical treatment. Information from and collaboration with the DN and other home care providers was essential for the FP's effort to stay in charge of the medical treatment. The complexity of the situation made it problematic for the FP to make adequate decisions about the goal of the medical treatment. The goal of the treatment had to be constantly evaluated based on information from the DN and other care providers, and thus this information was absolutely crucial.</p

Modeling emergency department visit patterns for infectious disease complaints: results and application to disease surveillance

BACKGROUND: Concern over bio-terrorism has led to recognition that traditional public health surveillance for specific conditions is unlikely to provide timely indication of some disease outbreaks, either naturally occurring or induced by a bioweapon. In non-traditional surveillance, the use of health care resources are monitored in "near real" time for the first signs of an outbreak, such as increases in emergency department (ED) visits for respiratory, gastrointestinal or neurological chief complaints (CC). METHODS: We collected ED CCs from 2/1/94 – 5/31/02 as a training set. A first-order model was developed for each of seven CC categories by accounting for long-term, day-of-week, and seasonal effects. We assessed predictive performance on subsequent data from 6/1/02 – 5/31/03, compared CC counts to predictions and confidence limits, and identified anomalies (simulated and real). RESULTS: Each CC category exhibited significant day-of-week differences. For most categories, counts peaked on Monday. There were seasonal cycles in both respiratory and undifferentiated infection complaints and the season-to-season variability in peak date was summarized using a hierarchical model. For example, the average peak date for respiratory complaints was January 22, with a season-to-season standard deviation of 12 days. This season-to-season variation makes it challenging to predict respiratory CCs so we focused our effort and discussion on prediction performance for this difficult category. Total ED visits increased over the study period by 4%, but respiratory complaints decreased by roughly 20%, illustrating that long-term averages in the data set need not reflect future behavior in data subsets. CONCLUSION: We found that ED CCs provided timely indicators for outbreaks. Our approach led to successful identification of a respiratory outbreak one-to-two weeks in advance of reports from the state-wide sentinel flu surveillance and of a reported increase in positive laboratory test results