A polymorphism in the regulatory region of PRNP is associated with increased risk of sporadic Creutzfeldt-Jakob disease

Background: Creutzfeldt-Jakob disease (CJD) is a rare transmissible neurodegenerative disorder. An important determinant for CJD risk and phenotype is the M129V polymorphism of the human prion protein gene (PRNP), but there are also other coding and non-coding polymorphisms inside this gene.Methods: We tested whether three non-coding polymorphism located inside the PRNP regulatory region (C-101G, G310C and T385C) were associated with risk of CJD and with age at onset in a United Kingdom population-based sample of 131 sporadic CJD (sCJD) patients and 194 controls.Results: We found no disease association for either PRNP C-101G or PRNP T385C. Although the crude analysis did not show a significant association between PRNP G310C and sCJD (OR: 1.5; 95%CI = 0.7 to 2.9), after adjusting by PRNP M129V genotype, it resulted that being a C allele carrier at PRNP G310C was significantly (p = 0.03) associated with a 2.4 fold increased risk of developing sCJD (95%CI = 1.1 to 5.4). Additionally, haplotypes carrying PRNP 310C coupled with PRNP 129M were significantly overrepresented in patients (p = 0.02) compared to controls. Cases of sCJD carrying a PRNP 310C allele presented at a younger age (on average 8.9 years younger than those without this allele), which was of statistical significance (p = 0.05). As expected, methionine and valine homozygosity at PRNP M129V increased significantly the risk of sCJD, alone and adjusted by PRNP G310C (OR MM/MV = 7.3; 95%CI 3.9 to 13.5 and OR VV/MV = 4.0; 95%CI 1.7 to 9.3).Conclusions: Our findings support the hypothesis that genetic variations in the PRNP promoter may have a role in the pathogenesis of sCJD

Rapid tests and urine sampling techniques for the diagnosis of urinary tract infection (UTI) in children under five years: a systematic review

Background: Urinary tract infection (UTI) is one of the most common sources of infection in children under five. Prompt diagnosis and treatment is important to reduce the risk of renal scarring. Rapid, cost-effective, methods of UTI diagnosis are required as an alternative to culture. Methods: We conducted a systematic review to determine the diagnostic accuracy of rapid tests for detecting UTI in children under five years of age. Results: The evidence supports the use of dipstick positive for both leukocyte esterase and nitrite (pooled LR+ = 28.2, 95% CI: 17.3, 46.0) or microscopy positive for both pyuria and bacteriuria (pooled LR+ = 37.0, 95% CI: 11.0, 125.9) to rule in UTI. Similarly dipstick negative for both LE and nitrite (Pooled LR- = 0.20, 95% CI: 0.16, 0.26) or microscopy negative for both pyuria and bacteriuria (Pooled LR- = 0.11, 95% CI: 0.05, 0.23) can be used to rule out UTI. A test for glucose showed promise in potty-trained children. However, all studies were over 30 years old. Further evaluation of this test may be useful. Conclusion: Dipstick negative for both LE and nitrite or microscopic analysis negative for both pyuria and bacteriuria of a clean voided urine, bag, or nappy/pad specimen may reasonably be used to rule out UTI. These patients can then reasonably be excluded from further investigation, without the need for confirmatory culture. Similarly, combinations of positive tests could be used to rule in UTI, and trigger further investigation

Identification of Limited English Proficient Patients in Clinical Care

BackgroundStandardized means to identify patients likely to benefit from language assistance are needed.ObjectiveTo evaluate the accuracy of the U.S. Census English proficiency question (Census-LEP) in predicting patients' ability to communicate effectively in English.DesignWe investigated the sensitivity and specificity of the Census-LEP alone or in combination with a question on preferred language for medical care for predicting patient-reported ability to discuss symptoms and understand physician recommendations in English.ParticipantsThree hundred and two patients > 18 who spoke Spanish and/or English recruited from a cardiology clinic and an inpatient general medical-surgical ward in 2004-2005.ResultsOne hundred ninety-eight (66%) participants reported speaking English less than "very well" and 166 (55%) less than "well"; 157 (52%) preferred receiving their medical care in Spanish. Overall, 135 (45%) were able to discuss symptoms and 143 (48%) to understand physician recommendations in English. The Census-LEP with a high-threshold (less than "very well") had the highest sensitivity for predicting effective communication (100% Discuss; 98.7% Understand), but the lowest specificity (72.6% Discuss; 67.1% Understand). The composite measure of Census-LEP and preferred language for medical care provided a significant increase in specificity (91.9% Discuss; 83.9% Understand), with only a marginal decrease in sensitivity (99.4% Discuss; 96.7% Understand).ConclusionsUsing the Census-LEP item with a high-threshold of less than "very well" as a screening question, followed by a language preference for medical care question, is recommended for inclusive and accurate identification of patients likely to benefit from language assistance

An assessment of the usefulness of a rapid immuno-chromatographic test, "Determine™ malaria pf" in evaluation of intervention measures in forest villages of central India

BACKGROUND: Plasmodium falciparum malaria, is a major health problem in forested tribal belt of central India. Rapid and accurate methods are needed for the diagnosis of P. falciparum. We performed a blinded evaluation of the recently introduced Determine™ malaria pf test (Abbott, Laboratories, Japan) compared with microscopy and splenomegaly in children in epidemic prone areas of district Mandla to assess the impact of intervention measures. METHODS: Children aged 2–10 yrs with and without fever were examined for spleen enlargement by medical specialist by establishing a mobile field clinic. From these children thick blood smears were prepared from finger prick and read by a technician. Simultaneously, rapid tests were performed by a field lab attendant. The figures for specificity, sensitivity and predictive values were calculated using microscopy as gold standard. RESULTS: In all 349 children were examined. The sensitivity and specificity for Determine rapid diagnostic test were 91 and 80% respectively. The positive predictive values (PPV), negative predictive values (NPV) and accuracy of the test were respectively 79, 91 and 85%. On the contrary, the sensitivity and specificity of spleen in detecting malaria infection were 57 and 74 % respectively with PPV of 73%, NPV 59 % and an accuracy of 65%. CONCLUSIONS: Determine™ malaria rapid diagnostic test is easier and quicker to perform and has other advantages over microscopy in not requiring prior training of personnel or quality control. Thus, highlighting the usefulness of a rapid antigen test in assessing prevailing malaria situation in remote areas

First nationwide survey on cardiovascular risk factors in Grand-Duchy of Luxembourg (ORISCAV-LUX)

BACKGROUND: The ORISCAV-LUX study is the first baseline survey of an on-going cardiovascular health monitoring programme in Grand-Duchy of Luxembourg. The main objectives of the present manuscript were 1) to describe the study design and conduct, and 2) to present the salient outcomes of the study, in particular the prevalence of the potentially modifiable and treatable cardiovascular disease risk factors in the adult population residing in Luxembourg. METHOD: ORISCAV-LUX is a cross-sectional study based on a random sample of 4496 subjects, stratified by gender, age categories and district, drawn from the national insurance registry of 18-69 years aged Luxembourg residents, assuming a response rate of 30% and a proportion of 5% of institutionalized subjects in each stratum. The cardiovascular health status was assessed by means of a self-administered questionnaire, clinical and anthropometric measures, as well as by blood, urine and hair examinations. The potentially modifiable and treatable risk factors studied included smoking, hypertension, dyslipidemia, diabetes mellitus, and obesity. Both univariate and multivariate statistical analyses used weighted methods to account for the stratified sampling scheme. RESULTS: A total of 1432 subjects took part in the survey, yielding a participation rate of 32.2%. This figure is higher than the minimal sample size of 1285 subjects as estimated by power calculation. The most predominant cardiovascular risk factors were dyslipidemia (69.9%), hypertension (34.5%), smoking (22.3%), and obesity (20.9%), while diabetes amounted 4.4%. All prevalence rates increased with age (except smoking) with marked gender differences (except diabetes). There was a significant difference in the prevalence of hypertension and of lipid disorders by geographic region of birth. The proportion of subjects cumulating two or more cardiovascular risk factors increased remarkably with age and was more predominant in men than in women (P<0.0001). Only 14.7% of men and 23.1% of women were free of any cardiovascular risk factor. High prevalence of non-treated CVRF, notably for hypertension and dyslipidemia, were observed in the study population. CONCLUSION: The population-based ORISCAV-LUX survey revealed a high prevalence of potentially modifiable and treatable cardiovascular risk factors among apparently healthy subjects; significant gender and age-specific differences were seen not only for single but also for combined risk factors. From a public health perspective, these preliminary findings stress the urgent need for early routine health examinations, preventive interventions and lifestyle behavioural changes, even in young asymptomatic adults, to decrease cardiovascular morbidity and mortality in Luxembourg

How does study quality affect the results of a diagnostic meta-analysis?

Background: The use of systematic literature review to inform evidence based practice in diagnostics is rapidly expanding. Although the primary diagnostic literature is extensive, studies are often of low methodological quality or poorly reported. There has been no rigorously evaluated, evidence based tool to assess the methodological quality of diagnostic studies. The primary objective of this study was to determine the extent to which variations in the quality of primary studies impact the results of a diagnostic meta-analysis and whether this differs with diagnostic test type. A secondary objective was to contribute to the evaluation of QUADAS, an evidence-based tool for the assessment of quality in diagnostic accuracy studies. Methods: This study was conducted as part of large systematic review of tests used in the diagnosis and further investigation of urinary tract infection (UTI) in children. All studies included in this review were assessed using QUADAS, an evidence-based tool for the assessment of quality in systematic reviews of diagnostic accuracy studies. The impact of individual components of QUADAS on a summary measure of diagnostic accuracy was investigated using regression analysis. The review divided the diagnosis and further investigation of UTI into the following three clinical stages: diagnosis of UTI, localisation of infection, and further investigation of the UTI. Each stage used different types of diagnostic test, which were considered to involve different quality concerns. Results: Many of the studies included in our review were poorly reported. The proportion of QUADAS items fulfilled was similar for studies in different sections of the review. However, as might be expected, the individual items fulfilled differed between the three clinical stages. Regression analysis found that different items showed a strong association with test performance for the different tests evaluated. These differences were observed both within and between the three clinical stages assessed by the review. The results of regression analyses were also affected by whether or not a weighting (by sample size) was applied. Our analysis was severely limited by the completeness of reporting and the differences between the index tests evaluated and the reference standards used to confirm diagnoses in the primary studies. Few tests were evaluated by sufficient studies to allow meaningful use of meta-analytic pooling and investigation of heterogeneity. This meant that further analysis to investigate heterogeneity could only be undertaken using a subset of studies, and that the findings are open to various interpretations. Conclusion: Further work is needed to investigate the influence of methodological quality on the results of diagnostic meta-analyses. Large data sets of well-reported primary studies are needed to address this question. Without significant improvements in the completeness of reporting of primary studies, progress in this area will be limited

Dramatic pain relief and resolution of bone inflammation following pamidronate in 9 pediatric patients with persistent chronic recurrent multifocal osteomyelitis (CRMO)

<p>Abstract</p> <p>Background</p> <p>Chronic recurrent multifocal osteomyelitis (CRMO) is an inflammatory, non-infectious osteopathy that affects predominantly patients ≤ 18 years of age. There is no uniformly effective treatment. Our objective is to describe clinical, magnetic resonance imaging (MRI), and bone resorption response to intravenous pamidronate in pediatric CRMO.</p> <p>Methods</p> <p>We report our prospectively documented experience with all CRMO patients treated with pamidronate between 2003 and 2008 at a tertiary pediatric centre. Pamidronate was administered as intravenous cycles. The dose of pamidronate varied among subjects but was given as monthly to every 3 monthly cycles depending on the distance the patient lived from the infusion center. Maximum cumulative dose was ≤ 11.5 mg/kg/year. Pamidronate treatment was continued until resolution of MRI documented bone inflammation. Visual analog scale for pain (VAS) and bone resorption marker urine N-telopeptide/urine creatinine (uNTX/uCr) were measured at baseline, preceding each subsequent pamidronate treatment, at final follow-up, and/or at time of MRI confirmed CRMO flare. MRI of the affected site(s) was obtained at baseline, preceding every 2^ndtreatment, and with suspected CRMO recurrence.</p> <p>Results</p> <p>Nine patients (5 F: 4 M) were treated, with a median (range) age at treatment of 12.9 (4.5–16.3) years, and median (range) duration of symptoms of 18 (6–36) months. VAS decreased from 10/10 to 0–3/10 by the end of first 3–day treatment for all patients. The mean (range) time to complete MRI resolution of bone inflammation was 6.0 (2–12) months. The mean (confidence interval (CI)) baseline uNTX/uCr was 738.83 (CI 464.25, 1013.42)nmol/mmol/creatinine and the mean (CI) decrease from baseline to pamidronate discontinuation was 522.17 (CI 299.77, 744.56)nmol/mmol/creatinine. Median (range) of follow-up was 31.4 (24–54) months. Four patients had MRI confirmed CRMO recurrence, which responded to one pamidronate re-treatment. The mean (range) uNTX/uCr change as a monthly rate from the time of pamidronate discontinuation to flare was 9.41 (1.38–19.85)nmol/mmol/creatinine compared to -29.88 (-96.83–2.01)nmol/mmol/creatinine for patients who did not flare by the time of final follow-up.</p> <p>Conclusion</p> <p>Pamidronate resulted in resolution of pain and MRI documented inflammation in all patients. No patient flared while his/her uNTX/uCr remained suppressed. We propose that pamidronate is an effective second-line therapy in persistent CRMO.</p

Risk of Severe Knee and Hip Osteoarthritis in Relation to Level of Physical Exercise: A Prospective Cohort Study of Long-Distance Skiers in Sweden

Background: To complete long-distance ski races, regular physical exercise is required. This includes not only cross-country skiing but also endurance exercise during the snow-free seasons. The aim of this study was to determine whether the level of physical exercise is associated with future risk of severe osteoarthritis independent of previous diseases and injuries. Methodology/Principal Findings: We used a cohort that consisted of 48 574 men and 5 409 women who participated in the 90 km ski race Vasaloppet at least once between 1989 and 1998. Number of performed races and finishing time were used as estimates of exercise level. By matching to the National Patient Register we identified participants with severe osteoarthritis, defined as arthroplasty of knee or hip due to osteoarthritis. With an average follow-up of 10 years, we identified 528 men and 42 women with incident osteoarthritis. The crude rate was 1.1/1000 person-years for men and 0.8/1000 person-years for women. Compared with racing once, participation in &gt;= 5 races was associated with a 70% higher rate of osteoarthritis (multivariable-adjusted hazard ratio (HR) 1.72, 95% confidence interval (CI) 1.33 to 2.22). The association was dose-dependent with an adjusted HR of 1.09, 95% CI 1.05 to 1.13 for each completed race. A faster finishing time, in comparison with a slow finishing time, was also associated with an increased rate (adjusted HR 1.51, 95% CI 1.14 to 2.01). Contrasting those with 5 or more ski races and a fast finish time to those who only participated once with a slow finish time, the adjusted HR of osteoarthritis was 2.73, 95% CI 1.78 to 4.18. Conclusions/Significance: Participants with multiple and fast races have an increased risk of subsequent arthroplasty of knee and hip due to osteoarthritis, suggesting that intensive exercise may increase the risk

Prion Seeding Activities of Mouse Scrapie Strains with Divergent PrPSc Protease Sensitivities and Amyloid Plaque Content Using RT-QuIC and eQuIC

Different transmissible spongiform encephalopathy (TSE)-associated forms of prion protein (e.g. PrPSc) can vary markedly in ultrastructure and biochemical characteristics, but each is propagated in the host. PrPSc propagation involves conversion from its normal isoform, PrPC, by a seeded or templated polymerization mechanism. Such a mechanism is also the basis of the RT-QuIC and eQuIC prion assays which use recombinant PrP (rPrPSen) as a substrate. These ultrasensitive detection assays have been developed for TSE prions of several host species and sample tissues, but not for murine models which are central to TSE pathogenesis research. Here we have adapted RT-QuIC and eQuIC to various murine prions and evaluated how seeding activity depends on glycophosphatidylinositol (GPI) anchoring and the abundance of amyloid plaques and protease-resistant PrPSc (PrPRes). Scrapie brain dilutions up to 10-8 and 10-13 were detected by RT-QuIC and eQuIC, respectively. Comparisons of scrapie-affected wild-type mice and transgenic mice expressing GPI anchorless PrP showed that, although similar concentrations of seeding activity accumulated in brain, the heavily amyloid-laden anchorless mouse tissue seeded more rapid reactions. Next we compared seeding activities in the brains of mice with similar infectivity titers, but widely divergent PrPRes levels. For this purpose we compared the 263K and 139A scrapie strains in transgenic mice expressing P101L PrPC. Although the brains of 263K-affected mice had no immunoblot-detectable PrPRes, RT-QuIC indicated that seeding activity was comparable to that associated with a high-PrPRes strain, 139A. Thus, in this comparison, RT-QuIC seeding activity correlated more closely with infectivity than with PrPRes levels. We also found that eQuIC, which incorporates a PrPSc immunoprecipitation step, detected seeding activity in plasma from wild-type and anchorless PrP transgenic mice inoculated with 22L, 79A and/or RML scrapie strains. Overall, we conclude that these new mouse-adapted prion seeding assays detect diverse types of PrPSc

Obesity: An overview on its current perspectives and treatment options

Obesity is a multi-factorial disorder, which is often associated with many other significant diseases such as diabetes, hypertension and other cardiovascular diseases, osteoarthritis and certain cancers. The management of obesity will therefore require a comprehensive range of strategies focussing on those with existing weight problems and also on those at high risk of developing obesity. Hence, prevention of obesity during childhood should be considered a priority, as there is a risk of persistence to adulthood. This article highlights various preventive aspects and treatment procedures of obesity with special emphasis on the latest research manifolds