First-in-Man Open Clinical Trial of a Combined rdESAT-6 and rCFP-10 Tuberculosis Specific Skin Test Reagent

Tuberculin is still the only available skin test reagent for the diagnosis of mycobacterial infection. The product has a remarkable sensitivity, but poor specificity. Previous studies, including two human phase I clinical trials, have indicated that rdESAT-6 has a potential as an improved skin test reagent. Animal studies have shown that the sensitivity may be increased by inclusion of the genetically related CFP-10 antigen in the preparation without loosing specificity.In this study a Lactococcus fermented, recombinant skin test reagent consisting of a 1ratio1 wt/wt of rdESAT-6 and CFP-10 was manufactured according to GMP standards and tested for the first time in 42 healthy adult volunteers. The two doses of 0.01 microg or 0.1 microg were injected intradermally by the Mantoux technique with 6 or 12 weeks interval. No serious adverse events and only mild adverse reactions were reported. The reagent elicited a positive skin test reaction after the first injection in one participant, who most likely was latently infected with M. tuberculosis as indicated by an appreciable IFN gamma response just below the Quantiferon(R) cut-off level at the screening visit. None of the remaining participants in the four groups had any skin test reactions and sensitisation by the reagent could therefore be excluded.The investigational skin test reagent rdESAT-6 and CFP-10 appeared safe and non-sensitising in this first-in-man clinical trial in human volunteers and can now be tested in larger clinical trials involving individuals with latent M. tuberculosis infection or active TB disease.ClinicalTrials.gov NCT00793702

Prevalence and anatomical location of muscle tenderness in adults with nonspecific neck/shoulder pain

<p>Abstract</p> <p>Background</p> <p>Many adults experience bothersome neck/shoulder pain. While research and treatment strategies often focus on the upper trapezius, other neck/shoulder muscles may be affected as well. The aim of the present study is to evaluate the prevalence and anatomical location of muscle tenderness in adults with nonspecific neck/shoulder pain.</p> <p>Methods</p> <p>Clinical neck/shoulder examination at two large office workplaces in Copenhagen, Denmark. 174 women and 24 men (aged 25-65 years) with nonspecific neck/shoulder pain for a duration of at least 30 days during the previous year and a pain intensity of at least 2 on a modified VAS-scale of 0-10 participated. Exclusion criteria were traumatic injuries or other serious chronic disease. Using a standardized finger pressure of 2 kg, palpable tenderness were performed of eight anatomical neck/shoulder locations in the left and right side on a scale of 'no tenderness', 'some tenderness' and 'severe tenderness'.</p> <p>Results</p> <p>In women, the levator scapulae, neck extensors and infraspinatus showed the highest prevalence of severe tenderness (18-30%). In comparison, the prevalence of severe tenderness in the upper trapezius, occipital border and supraspinatus was 13-19%. Severe tenderness of the medial deltoid was least prevalent (0-1%). In men, the prevalence of severe tenderness in the levator scapulae was 13-21%, and ranged between 0-8% in the remainder of the examined anatomical locations.</p> <p>Conclusions</p> <p>A high prevalence of tenderness exists in several anatomical locations of the neck/shoulder complex among adults with nonspecific neck/shoulder pain. Future research should focus on several neck/shoulder muscles, including the levator scapulae, neck extensors and infraspinatus, and not only the upper trapezius.</p> <p>Trial Registration</p> <p><a href="http://www.controlled-trials.com/ISRCTN60264809">ISRCTN60264809</a></p

Association of Exposure to Phthalates with Endometriosis and Uterine Leiomyomata: Findings from NHANES, 1999-2004

BACKGROUND. Phthalates are ubiquitous chemicals used in consumer products. Some phthalates are reproductive toxicants in experimental animals, but human data are limited. OBJECTIVE. We conducted a cross-sectional study of urinary phthalate metabolite concentrations in relation to self-reported history of endometriosis and uterine leiomyomata among 1,227 women 20-54 years of age from three cycles of the National Health and Nutrition Examination Survey (NHANES), 1999-2004. METHODS. We examined four phthalate metabolites: mono(2-ethylhexyl) phthalate (MEHP), monobutyl phthalate (MBP), monoethyl phthalate (MEP), and monobenzyl phthalate (MBzP). From the last two NHANES cycles, we also examined mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and mono(2-ethyl-5-oxohexyl) phthalate (MEOHP). We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for potential confounders. RESULTS. Eighty-seven (7%) and 151 (12%) women reported diagnoses of endometriosis and leiomyomata, respectively. The ORs comparing the highest versus lowest three quartiles of urinary MBP were 1.36 (95% CI, 0.77-2.41) for endometriosis, 1.56 (95% CI, 0.93-2.61) for leiomyomata, and 1.71 (95% CI, 1.07-2.75) for both conditions combined. The corresponding ORs for MEHP were 0.44 (95% CI, 0.19-1.02) for endometriosis, 0.63 (95% CI, 0.35-1.12) for leiomyomata, and 0.59 (95% CI, 0.37-0.95) for both conditions combined. Findings for MEHHP and MEOHP agreed with findings for MEHP with respect to endometriosis only. We observed null associations for MEP and MBzP. Associations were similar when we excluded women diagnosed > 7 years before their NHANES evaluation. CONCLUSION. The positive associations for MBP and inverse associations for MEHP in relation to endometriosis and leiomyomata warrant investigation in prospective studies

Accurate masses and radii of normal stars: modern results and applications

This paper presents and discusses a critical compilation of accurate, fundamental determinations of stellar masses and radii. We have identified 95 detached binary systems containing 190 stars (94 eclipsing systems, and alpha Centauri) that satisfy our criterion that the mass and radius of both stars be known to 3% or better. To these we add interstellar reddening, effective temperature, metal abundance, rotational velocity and apsidal motion determinations when available, and we compute a number of other physical parameters, notably luminosity and distance. We discuss the use of this information for testing models of stellar evolution. The amount and quality of the data also allow us to analyse the tidal evolution of the systems in considerable depth, testing prescriptions of rotational synchronisation and orbital circularisation in greater detail than possible before. The new data also enable us to derive empirical calibrations of M and R for single (post-) main-sequence stars above 0.6 M(Sun). Simple, polynomial functions of T(eff), log g and [Fe/H] yield M and R with errors of 6% and 3%, respectively. Excellent agreement is found with independent determinations for host stars of transiting extrasolar planets, and good agreement with determinations of M and R from stellar models as constrained by trigonometric parallaxes and spectroscopic values of T(eff) and [Fe/H]. Finally, we list a set of 23 interferometric binaries with masses known to better than 3%, but without fundamental radius determinations (except alpha Aur). We discuss the prospects for improving these and other stellar parameters in the near future.Comment: 56 pages including figures and tables. To appear in The Astronomy and Astrophysics Review. Ascii versions of the tables will appear in the online version of the articl

Elemental distributions and mineral parageneses of the Skaergaard PGE-Au mineralisation: consequences of accumulation, redistribution, and equilibration in an upward-migrating mush zone

This is the author accepted manuscript. The final version is available from Oxford University Press via the DOI in this recordThe Skaergaard PGE-Au mineralisation, aka the Platinova Reef, is a syn-magmatic Platinum Group Element (PGE) and gold (Au) mineralisation that formed after crystallisation of ∼74% of the bulk melt of the intrusion. It is hosted in a more than 600 m deep and bowl-shaped succession of gabbroic macro-rhythmic layers in the upper 100 m of the Middle Zone. The precious metal mineralisation comprises a series of concordant, but compositionally zoned, mineralisation levels identified by distinct PGE, Au and Cu peaks. They formed due to local sulphide saturation in stratiform concentrations of interstitial and evolved mush melts in six MLs over > 2000 years. The PGE-Au mineralisation is compared to a stack of gold-rimmed saucers of PGE-rich gabbro of upward decreasing size. Fundamentally different crystallisation and mineralisation scenarios have been proposed for the mineralisation, including offset reef type models based on sulphide saturation in the melt from which the silicate host crystallised, and the here argued model which restricts the same processes to the melt of the inward migrating mush zone of the magma chamber. The latter is supported by: i) a 3D summary of the parageneses of precious metal minerals and phases (> 4000 grains) from 32 samples across the mineralisation; ii) a 3D compilation of all bulk rock assay data; and iii) a principal component analysis (PCA) of PGE, Au, Cu, and selected major and trace elements. In the main PGE-mineralisation level (Pd5 alias Pd-Zone) the precious metal mineral paragenesis varies across the intrusion with precious metal sulphides and Au-alloys at the W-margin to Precambrian basement, precious metal plumbide and Au- and Ag alloys at the E-margin to flood basalts, and skaergaardite (PdCu) and intermetallic compounds and alloys of PGE-Au and Cu in the central parts of the mineralisation. Precious metal parageneses are distinct for a given sector of the intrusion, i.e., drill core (local control), rather than for a given stratigraphic or temporal interval in the accumulated gabbros. The precious metal “grade times width” number (average g/t x metres) for the mineralisation at an upper and a lower cut off of 100 ppb PGE or Au increases from ∼20 to ∼45 g toward the centre of the mineralisation due to ponding of precious metal bearing melt. A strong increase in (Pd+Pt+Au)/Cu and dominance of (PdCu) alloys in the lower and central parts of the mineralisation demonstrate the partial dissolution of droplets of Cu-rich sulphide melt and fractionation of precious metal ratios. The precious metal parageneses, the distribution of precious metals in the mineralisation, and the PCA support initial accumulation of precious metals in the melt of the mush in the floor, followed by equilibration, sulphide saturation, and reactions with residual and immiscible Fe-rich silicate melt in a series of macro-rhythmic layers in the stratified and upward migrating mush zone in the floor of the magma chamber. Syn-magmatic and upward redistribution of precious metals sets the Skaergaard PGE-Au Mineralisation apart from conventional reef type and offset-reef type precious metal mineralisations, and characterize “Skaergaard type” precious metal deposits.Geological Survey of Denmark and Greenlan

Organizational factors and depression management in community-based primary care settings

Abstract Background Evidence-based quality improvement models for depression have not been fully implemented in routine primary care settings. To date, few studies have examined the organizational factors associated with depression management in real-world primary care practice. To successfully implement quality improvement models for depression, there must be a better understanding of the relevant organizational structure and processes of the primary care setting. The objective of this study is to describe these organizational features of routine primary care practice, and the organization of depression care, using survey questions derived from an evidence-based framework. Methods We used this framework to implement a survey of 27 practices comprised of 49 unique offices within a large primary care practice network in western Pennsylvania. Survey questions addressed practice structure (e.g., human resources, leadership, information technology (IT) infrastructure, and external incentives) and process features (e.g., staff performance, degree of integrated depression care, and IT performance). Results The results of our survey demonstrated substantial variation across the practice network of organizational factors pertinent to implementation of evidence-based depression management. Notably, quality improvement capability and IT infrastructure were widespread, but specific application to depression care differed between practices, as did coordination and communication tasks surrounding depression treatment. Conclusions The primary care practices in the network that we surveyed are at differing stages in their organization and implementation of evidence-based depression management. Practical surveys such as this may serve to better direct implementation of these quality improvement strategies for depression by improving understanding of the organizational barriers and facilitators that exist within both practices and practice networks. In addition, survey information can inform efforts of individual primary care practices in customizing intervention strategies to improve depression management.http://deepblue.lib.umich.edu/bitstream/2027.42/78269/1/1748-5908-4-84.xmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/78269/2/1748-5908-4-84-S1.PDFhttp://deepblue.lib.umich.edu/bitstream/2027.42/78269/3/1748-5908-4-84.pdfPeer Reviewe

Housekeeping genes for quantitative expression studies in the three-spined stickleback Gasterosteus aculeatus

Background During the last years the quantification of immune response under immunological challenges, e.g. parasitation, has been a major focus of research. In this context, the expression of immune response genes in teleost fish has been surveyed for scientific and commercial purposes. Despite the fact that it was shown in teleostei and other taxa that the gene for beta-actin is not the most stably expressed housekeeping gene (HKG), depending on the tissue and experimental treatment, the gene has been us Results To establish a reliable method for the measurement of immune gene expression in Gasterosteus aculeatus, sequences from the now available genome database and an EST library of the same species were used to select oligonucleotide primers for HKG, in order to perform quantitative reverse-transcription (RT) PCR. The expression stability of ten candidate reference genes was evaluated in three different tissues, and in five parasite treatment groups, using the three algorithms BestKeeper, geNorm and N Conclusion As they were the most stably expressed genes in all tissues examined, we suggest using the genes for the L13a ribosomal binding protein and ubiquitin as alternative or additional reference genes in expression analysis in Gasterosteus aculeatus.

ESAT-6/CFP10 Skin Test Predicts Disease in M. tuberculosis-Infected Guinea Pigs

Background: Targeted preventive chemotherapy of individuals with progressive subclinical (incipient) disease before it becomes contagious would break the chain of tuberculosis transmission in high endemic regions. We have studied the ability of a skin test response to ESAT-6 and CFP10 (E6/C10) to predict later development of tuberculosis disease in the guinea pig model. Methods and Findings: Guinea pigs, either vaccinated with BCG or unvaccinated, were infected with a low dose of Mycobacterium tuberculosis by the aerosol route and the development of delayed type hypersensitivity responses to E6/C10 and to purified protein derivative (PPD) were followed until the onset of clinical disease. We demonstrated a negative correlation between the size of the skin test response and the time to the onset of clinical disease; a large E6/C10 skin test response correlated to a shorter survival time post skin testing, while a small E6/C10 skin test reaction correlated with a longer survival time (r = 20.6 and P,0.0001). No correlation was found using PPD. Conclusions: Our data suggest that it may be possible to develop a prognostic skin test based on E6/C10 that will allow the identification of individuals with incipient disease, who have the highest risk of developing active tuberculosis in the near future

Defining antimicrobial prescribing quality indicators: what is a new prescription?

Contains fulltext : 95791.pdf (publisher's version ) (Open Access): Since guidelines on antibiotic drug treatment often focus on appropriate first choice drugs, assessment of guideline adherence should only concentrate on the first drug prescribed, and not on subsequent antibiotics prescribed after failure of the first one. PURPOSE: To determine a valid cut-off point for a definition of "first" or "new" prescription in indicators for the assessment of the quality of antibiotic drug treatment on the basis of pharmaceutical data. METHODS: Three possible definitions for the term "new prescription" were compared, based on three different periods of time, viz. more than 35, 28, or 21 days after starting a previous antibiotic. In an observational study, 1,225 antimicrobial prescriptions from the medical files of five family practices were audited ("clinical classification") and compared with a classification based on the three definitions ("technical classification"). Agreement between these clinical and technical classifications was determined by calculating Cohen's kappa. The technical classification was analyzed as a diagnostic test, using the clinical classification as the gold standard, and sensitivity, specificity, likelihood ratios, and post-test probabilities were calculated. RESULTS: Defining "new prescription" as "more than 35 days after a previous prescription was issued" resulted in a Cohen's kappa of 0.93 (95% CI 0.92-0.98). The diagnostic value of this definition was extremely high, with a sensitivity of 0.976, specificity of 0.987, positive likelihood ratio of 77.7, and negative likelihood ratio of 0.02. CONCLUSION: We recommend using a cut-off value of 35 days since the last antimicrobial prescription as the definition of a "new prescription" when no diagnostic information is available, i.e., when using pharmaceutical data to assess the quality of antibiotic prescribing behavior.01 januari 201