Clinical and genetic findings in a large cohort of patients with congenital myopathies due to mutations in the skeletal muscle ryanodine receptor (RYR1) gene

RYR1 mutations are the most common cause of structural congenital myopathies and may exhibit both dominant and recessive inheritance. Histopathological findings are variable and include central cores, multi-minicores, type 1 predominance/ uniformity, fibre type disproportion, increased internal nucleation and fatty and connective tissue. Until recently, diagnostic RYR1 sequencing was limited to mutational hotspots due to the large size of the gene. Since the introduction of full RYR1 sequencing in 2007 we have detected pathogenic mutations in 77 families: 39 had dominant inheritance and 38 recessive inheritance. In some cases with presumably recessive inheritance, only one heterozygous mutation inherited from an asymptomatic parent was identified. Of 28 dominant mutations, 6 were novel; 37 of the 59 recessive mutations were also novel. Dominant mutations were more frequently in recognized hotspot regions, while recessive mutations were distributed throughout the coding sequence. Dominant mutations were predominantly missense, whereas recessive mutations included many nonsense and splice mutations expected to result in reduced RyR1 protein. There was wide clinical variability in patients with both dominant and recessive inheritance. As a group, those with dominant mutations were generally more mildly affected than those with recessive inheritance, who had earlier onset and were weaker with more functional limitations. Extraocular muscle involvement was almost exclusively observed in the recessive group. Bulbar involvement was also more prominent in this group, resulting in a larger number requiring gastrostomy insertion. In conclusion, genomic sequencing of the entire RYR1 leads to the detection of many novel mutations, but may miss large genetic rearrangements in some cases. Assigning pathogenicity to novel mutations is often difficult and interpretation of genetic results in the context of clinical, histological and, increasingly, muscle MRI findings is essential.

The Rise of The Swiss Tax Haven in the Interwar Period: An International Comparison

The history of tax havens during the decades before World War II is still little known. To date, the studies that have focused on the 1920s and 1930s have presented either a very general perspective on the development of tax havens or a narrow national point of view. Based on unpublished historical archives of five countries (Switzerland, Great Britain, Belgium, France, Germany), this paper offers therefore a new comparative appraisal of international tax competition during this period in order to answer the following question: What was the specificity of the Swiss case - already considered a quintessential tax haven at the time - in comparison to other banking centres? The findings of this research study are twofold. First, the 1920s and 1930s appear as something of a golden age of opportunity for avoiding taxation through the relocation of assets. Most of the financial centres granted consistent tax benefits for imported capital, while the limited degree of international cooperation and the usual guarantee of banking secrecy in European countries prevented the taxation of exported assets. Second, within this general environment, the fiscal strategies of a tax haven like Switzerland differed from those of a great financial power like Great Britain. Whereas the Swiss administration readily placed itself at the service of the banking community, British policy was more balanced between the contradictory interests of the Board of Inland Revenue, the Treasury, and the English business circles.

Revue critique d'instruments pour evaluer la douleur chez les personnes cérébrolésées non communicantes aux soins intensifs [Critical review of instruments to assess pain in the non communicative brain injured persons in intensive care].

The purpose of this review is to critically appraise the pain assessment tools for non communicative persons in intensive care available in the literature and to determine their relevance for those with brain injury. Nursing and medical electronic databases were searched to identify pain tools, with a description of psychometric proprieties, in English and French. Seven of the ten tools were considered relevant and systematically evaluated according to the criteria and the indicators in the following five areas: conceptualisation, target population, feasibility and clinical utility, reliability and validity. Results indicate a number of well designed pain tools, but additional work is necessary to establish their accuracy and adequacy for the brain injured non communicative person in intensive care. Recommendations are made to choose the best tool for clinical practice and for research.

Satellizing Galileo? Non-state Authority and Interoperability Standards in the European Global Navigation Satellite System

This paper explores the extent and limits of non-state authority in international affairs. While a number of studies have emphasised the role of state support and the ability of strategically situated actors to capture regulatory processes, they often fail to unpack the conditions under which this takes place. In order to probe the assumption that structural market power, backed by political support, equates regulatory capture, the article examines the interplay of political and economic considerations in the negotiations to establish worldwide interoperability standards needed for the development of Galileo as a genuinely European global navigation satellite system under civil control. It argues that industries supported and identified as strategic by public actors are more likely to capture standardisation processes than those with the largest market share expected to be created by the standards. This suggests that the influence of industries in space, air and maritime traffic control closely related to the militaro-industrial complex remains disproportionate in comparison to the prospective market of location-based services expected to vastly transform business practices, labour relations and many aspects of our daily life.

Comparison of fundus autofluorescence images acquired by the confocal scanning laser ophthalmoscope (488 nm excitation) and the modified Topcon fundus camera (580 nm excitation).

To compare autofluorescence (AF) images obtained with the confocal scanning laser ophthalmoscope (using the Heidelberg retina angiograph; HRA) and the modified Topcon fundus camera, in a routine clinical setting. A prospective comparative study conducted at the Jules-Gonin Eye Hospital. Fifty-six patients from the medical retina clinic. All patients had complete ophthalmic slit-lamp and fundus examinations, colour and red-free fundus photography, AF imaging with both instruments, and fluorescein angiography. Cataract and fixation were graded clinically. AF patterns were analyzed for healthy and pathological features. Differences of image noise were analyzed by cataract grading and fixation. A total of 105 eyes were included. AF patterns discovered by the retina angiograph and the fundus camera images, respectively, were a dark optic disc in 72 % versus 15 %, a dark fovea in 92 % versus 4 %, sub- and intraretinal fluid visible as hyperautofluorescence on HRA images only, lipid exudates visible as hypoautofluorescence on HRA images only. The same autofluorescent pattern was found on both images for geographic atrophy, retinal pigment changes, drusen and haemorrhage. Image noise was significantly associated with the degree of cataract and/or poor fixation, favouring the fundus camera. Images acquired by the fundus camera before and after fluorescein angiography were identical. Fundus AF images differ according to the technical differences of the instruments used. Knowledge of these differences is important not only for correctly interpreting images, but also for selecting the most appropriate instrument for the clinical situation.

Staff eye lens and extremity exposure in interventional cardiology: Results of the ORAMED project

Within the ORAMED project a coordinated measurement program for occupationally exposed medical staff was performed in different hospitals in Europe. The main objectives of ORAMED were to obtain a set of standardized data on doses for staff in interventional cardiology and radiology and to optimize staff protection. Doses were measured with thermoluminescent dosemeters on the ring finger and wrist of both hands, on legs and at the level of the eyes of the main operator performing interventional procedures. In this paper an overview of the doses per procedure measured during 646 interventional cardiology procedures is given for cardiac angiographies and angioplasties (CA/PTCA), radiofrequency ablations (RFA) and pacemaker and defibrillator implantations (PM/ICD). 31% of the monitored procedures were associated with no collective protective equipment, whereas 44% involved a ceiling screen and a table curtain. Although associated with the smallest air kerma - area product (KAP), PM/ICD procedures led to the highest doses. As expected, KAP and doses values exhibited a very large variability. The left side of the operator, most frequently the closest to the X-ray scattering region, was more exposed than his right side. An analysis of the effect of parameters influencing the doses, namely collective protective equipment, X-ray tube configuration and catheter access route, was performed on the doses normalized to KAP. Ceiling screen and table curtain were observed to reduce normalized doses by atmost a factor 4, much smaller than theoretical attenuation factors typical for such protections, i.e. from 10 to 100. This observation was understood as their inappropriate use by the operators and their non-optimized design. Configurations with tube above the patient led to higher normalized doses to the operator than tube below, but the effect of using a biplane X-ray suite was more complex to analyze. For CA/PTCA procedures, the upper part of the operator's body received higher normalized doses for radial than for femoral catheter access, by atmost a factor 5. This could be seen for cases with no collective protection. The eyes were observed to receive the maximum fraction of the annual dose limit almost as frequently as legs and hands, and clearly the most frequently, if the former 150 mSv and new 20 mSv recommended limits for the lens of the eye are considered, respectively.

Bonding and Bridging Social Capital in Step- and First-Time Families and the Issue of Family Boundaries

Divorce and remarriage usually imply a redefinition of family boundaries, with consequences for the production and availability of social capital. This research shows that bonding and bridging social capitals are differentially made available by families. It first hypothesizes that bridging social capital is more likely to be developed in stepfamilies, and bonding social capital in first-time families. Second, the boundaries of family configurations are expected to vary within stepfamilies and within first-time families creating a diversity of family configurations within both structures. Third, in both cases, social capital is expected to depend on the ways in which their family boundaries are set up by individuals by including or excluding ex-partners, new partner's children, siblings, and other family ties. The study is based on a sample of 300 female respondents who have at least one child of their own between 5 and 13 years, 150 from a stepfamily structure and 150 from a first-time family structure. Social capital is empirically operationalized as perceived emotional support in family networks. The results show that individuals in first-time families more often develop bonding social capital and individuals in stepfamilies bridging social capital. In both cases, however, individuals in family configurations based on close blood and conjugal ties more frequently develop bonding social capital, whereas individuals in family configurations based on in-law, stepfamily or friendship ties are more likely to develop bridging social capital.

The use of methylamphetamine chemical profiling in an intelligence-led perspective and the observation of inhomogeneity within seizures

This study focuses on methylamphetamine (MA) seizures made by the Australian Federal Police (AFP) to investigate the use of chemical profiling in an intelligence perspective. Correlation coefficients were used to obtain a similarity degree between a population of linked samples and a population of unlinked samples. Although it was demonstrated that a general framework can be followed for the use of any forensic case data in an intelligence-led perspective, threshold values have to be re-evaluated for each type of illicit drug investigated. Unlike the results obtained in a previous study on 3,4-methylenedioxymethylamphetamine (MDMA) seizures, chemical profiles of MA samples coming from the same seizure showed relative inhomogeneity, limiting their ability to link seizures. Different hypotheses were investigated to obtain a better understanding of this inhomogeneity although no trend was observed. These findings raise an interesting discussion in regards to the homogeneity and representativeness of illicit drug seizures (for intelligence purposes). Further, it also provides some grounds to discuss the initial hypotheses and assumptions that most forensic science studies are based on.

The Identity Style Inventory (ISI-3) and the Utrecht-Management of Identity Commitments Scale (U-MICS): Factor structure, reliability, and convergent validity in French-speaking college students

The purpose of this study was to evaluate the factor structure and the reliability of the French versions of the Identity Style Inventory (ISI-3) and the Utrecht-Management of Identity Commitments Scale (U-MICS) in a sample of college students (N = 457, 18 to 25 years old). Confirmatory factor analyses confirmed the hypothesized three-factor solution of the ISI-3 identity styles (i.e. informational, normative, and diffuse-avoidant styles), the one-factor solution of the ISI-3 identity commitment, and the three-factor structure of the U-MICS (i.e. commitment, in-depth exploration, and reconsideration of commitment). Additionally, theoretically consistent and meaningful associations among the ISI-3, U-MICS, and Ego Identity Process Questionnaire (EIPQ) confirmed convergent validity. Overall, the results of the present study indicate that the French versions of the ISI-3 and UMICS are useful instruments for assessing identity styles and processes, and provide additional support to the cross-cultural validity of these tools.

CD30 in PTCLS: correlation between RNA and protein levels in a large european series from the LYSA

Introduction: CD22 is expressed on most B-non-Hodgkin lymphomas (NHL); inotuzumab ozogamicin (INO) is an anti-CD22 antibody conjugated to calicheamicin. This study evaluated the safety and tolerability of INO plus R-CVP in patients (pts) with relapsed/refractory CD22+ B-NHL. Efficacy data were also collected. Methods: Part 1 of this open-label study identified a maximum tolerated dose (MTD) of INO 0.8mg/m,2 on day 2 plus R-CVP (rituximab 375mg/m,2 cyclophosphamide 750mg/m,2 and vincristine 1.4mg/m,2 on day 1; prednisone 40mg/m,2 on days 1-5) every 21 days. Subsequently, pts were enrolled in the MTD confirmation cohort (part 2, n = 10), which required a dose-limiting toxicity rate of <33% in cycle 1 and <4 pts discontinuing prior to cycle 3 due to an adverse event (AE) in the MTD expansion cohort (part 3, n = 22), which explored preliminary activity. Results: Parts 2 and 3 enrolled 32 pts: 16 pts with diffuse large B-cell lymphoma, 15 with follicular lymphoma and one with mantle cell lymphoma. Median age was 64.5 years (range 44-81 years); 34% of pts had 1 prior regimen, 34% had 2, 28% had ≥3 and 3% had none (median 2; range 0-6).Median treatment duration was five cycles (range 1-6). Part 2 confirmed the MTD as standard dose R-CVP plus INO 0.8mg/m,2; 2/10 pts had a dose-limiting toxicity (grade 3 increased ALT/AST, grade 4 neutropenia requiring G-CSF). One pt discontinued because of an AE prior to cycle 3. Common treatment-related AEs were thrombocytopenia (78%), neutropenia (66%), fatigue (50%), leukopenia (50%), nausea (41%) and lymphopenia (38%); common grade 3/4 AEs were neutropenia (63%), thrombocytopenia (53%), leukopenia (38%) and lymphopenia (31%). There was one case of treatment-related fatal pneumonia with grade 4 neutropenia. Ten pts discontinued treatment due to AEs; thrombocytopenia/delayed platelet recovery was the leading cause (grade 1/2, n = 6; grade 3/4, n = 3). Objective response rate (ORR) was 77% (n = 24/31 evaluable pts), including 26% (n=8/31) with complete response (CR); three pts had stable disease. Of the pts with follicular lymphoma, ORR was 100% (n = 15/15), including seven pts with CR. Of the pts with diffuse large B-cell lymphoma, ORR was 60% (n = 9/16), including one pt with CR. Conclusions: Results suggest that INOplus R-CVP has acceptable toxicity and promising activity in relapsed/refractory CD22+ B-NHL. The most common grade 3/4 AEs were hematologic. Follow-up for progression-free and overall survival is ongoing.

Issues in blood pressure control and the potential role of single-pill combination therapies.

Hypertension (HTN) is a major risk factor for cardiovascular mortality, yet only a small proportion of hypertensive individuals receive appropriate therapy and achieve target blood pressure (BP) values. Factors influencing the success of antihypertensive therapy include physicians' acceptance of guideline BP targets, the efficacy and tolerability of the drug regimen, and patient compliance and persistence with therapy. It is now well recognised that most hypertensive patients require at least two antihypertensive agents to achieve their target BP. However, complicated treatment regimens are a major contributory factor to poor patient compliance. The use of combination therapy for HTN offers a number of advantages over the use of monotherapy, including improved efficacy, as drug combinations with a synergistic mechanism of action can be used. This additive effect means that lower doses of the individual components can be used, which may translate into a decreased likelihood of adverse events. The use of single-pill combination therapy, in which two or more agents are combined in a single dosage form, offers all the benefits of free combination therapy (improved efficacy and tolerability over monotherapy) together with the added benefit of improved patient compliance because of the simplified treatment regimen. The use of single-pill combination therapy may also be associated with cost savings compared with the use of free combinations for reasons of cheaper drug costs, fewer physician visits and fewer hospitalisations for uncontrolled HTN and cardiovascular events. Thus, the use of single-pill combination therapy for HTN should help improve BP goal attainment through improved patient compliance, leading to reduced costs for cardiovascular-related care.