Identification of novel mutations in X-linked retinitis pigmentosa families and implications for diagnostic testing

Contains fulltext : 69886.pdf (publisher's version ) (Open Access)PURPOSE: The goal of this study was to identify mutations in X-chromosomal genes associated with retinitis pigmentosa (RP) in patients from Germany, The Netherlands, Denmark, and Switzerland. METHODS: In addition to all coding exons of RP2, exons 1 through 15, 9a, ORF15, 15a and 15b of RPGR were screened for mutations. PCR products were amplified from genomic DNA extracted from blood samples and analyzed by direct sequencing. In one family with apparently dominant inheritance of RP, linkage analysis identified an interval on the X chromosome containing RPGR, and mutation screening revealed a pathogenic variant in this gene. Patients of this family were examined clinically and by X-inactivation studies. RESULTS: This study included 141 RP families with possible X-chromosomal inheritance. In total, we identified 46 families with pathogenic sequence alterations in RPGR and RP2, of which 17 mutations have not been described previously. Two of the novel mutations represent the most 3'-terminal pathogenic sequence variants in RPGR and RP2 reported to date. In exon ORF15 of RPGR, we found eight novel and 14 known mutations. All lead to a disruption of open reading frame. Of the families with suggested X-chromosomal inheritance, 35% showed mutations in ORF15. In addition, we found five novel mutations in other exons of RPGR and four in RP2. Deletions in ORF15 of RPGR were identified in three families in which female carriers showed variable manifestation of the phenotype. Furthermore, an ORF15 mutation was found in an RP patient who additionally carries a 6.4 kbp deletion downstream of the coding region of exon ORF15. We did not identify mutations in 39 sporadic male cases from Switzerland. CONCLUSIONS: RPGR mutations were confirmed to be the most frequent cause of RP in families with an X-chromosomal inheritance pattern. We propose a screening strategy to provide molecular diagnostics in these families

Sex difference and intra-operative tidal volume: Insights from the LAS VEGAS study

BACKGROUND: One key element of lung-protective ventilation is the use of a low tidal volume (VT). A sex difference in use of low tidal volume ventilation (LTVV) has been described in critically ill ICU patients.OBJECTIVES: The aim of this study was to determine whether a sex difference in use of LTVV also exists in operating room patients, and if present what factors drive this difference.DESIGN, PATIENTS AND SETTING: This is a posthoc analysis of LAS VEGAS, a 1-week worldwide observational study in adults requiring intra-operative ventilation during general anaesthesia for surgery in 146 hospitals in 29 countries.MAIN OUTCOME MEASURES: Women and men were compared with respect to use of LTVV, defined as VT of 8 ml kg-1 or less predicted bodyweight (PBW). A VT was deemed 'default' if the set VT was a round number. A mediation analysis assessed which factors may explain the sex difference in use of LTVV during intra-operative ventilation.RESULTS: This analysis includes 9864 patients, of whom 5425 (55%) were women. A default VT was often set, both in women and men; mode VT was 500 ml. Median [IQR] VT was higher in women than in men (8.6 [7.7 to 9.6] vs. 7.6 [6.8 to 8.4] ml kg-1 PBW, P < 0.001). Compared with men, women were twice as likely not to receive LTVV [68.8 vs. 36.0%; relative risk ratio 2.1 (95% CI 1.9 to 2.1), P < 0.001]. In the mediation analysis, patients' height and actual body weight (ABW) explained 81 and 18% of the sex difference in use of LTVV, respectively; it was not explained by the use of a default VT.CONCLUSION: In this worldwide cohort of patients receiving intra-operative ventilation during general anaesthesia for surgery, women received a higher VT than men during intra-operative ventilation. The risk for a female not to receive LTVV during surgery was double that of males. Height and ABW were the two mediators of the sex difference in use of LTVV.TRIAL REGISTRATION: The study was registered at Clinicaltrials.gov, NCT01601223

Absolute Cardiovascular Disease Risk and Shared Decision Making in Primary Care: A Randomized Controlled Trial

PURPOSE We wanted to determine the effect of promoting the effective communication of absolute cardiovascular disease (CVD) risk and shared decision making through disseminating a simple decision aid for use in family practice consultations

Arriba: effects of an educational intervention on prescribing behaviour in prevention of CVD in general practice

Background: Evidence on the effectiveness of educational interventions on prescribing behaviour modification in prevention of cardiovascular disease is still insufficient. We evaluated the effects of a brief educational intervention on prescription of hydroxymethylglutaryl-CoA reductase inhibitors (statins), inhibitors of platelet aggregation (IPA), and antihypertensive agents (AH). Design: Cluster randomised controlled trial with continuous medical education (CME) groups of general practitioners (GPs). Methods: Prescription of statins, IPA, and AH were verified prior to study start (BL), immediately after index consultation (IC), and at follow-up after 6 months (FU). Prescription in patients at high risk (>15% risk of a cardiovascular event in 10 years, based on the Framingham equation) and no prescription in low-risk patients (≤ 15%) were considered appropriate. Results: An intervention effect on prescribing could only be found for IPA. Generally, changes in prescription over time were all directed towards higher prescription rates and persisted to FU, independent of risk status and group allocation. Conclusions: The active implementation of a brief evidence-based educational intervention on global risk in CVD did not lead directly to risk-adjusted changes in prescription. Investigations on an extended time scale would capture whether decision support of this kind would improve prescribing risk-adjusted sustainably

Software-Based Self-Test under Memory, Time and Power Constraints

are undoubtedly one of the most wonderful experiences and the best memories in my life. There are many people, who have contributed to this thesis in one way or another. First and foremost, I would like to thank my first advisor Professor Hans-Joachim Wunderlich for the plenty of freedom given to me and excellent guidelines to progress my work towards the correct direction and present the results in the optimal way. The special thanks should go to my second advisor Professor Sybille Hellebrand from Universität Paderbonn. It is not exaggerated at all that her constructive and invaluable suggestion shapes this thesis in the right form. I am always much impressed by her thoroughness in the work and the amiability. I would like to thank Deutsche Forschungsgemeinschaft (DFG) which supports the topic “Leistungs- und Energiebeschränkung im Selbsttest “ in the program “Grundlagen un

Fundus autofluorescence in children and teenagers with hereditary retinal diseases

INTRODUCTION: In adults, evaluation of fundus autofluorescence (AF) plays an important role in the differential diagnosis of retinal diseases. The aim of this study was to evaluate the feasibility of recording AF in children and teenagers and to define typical AF findings of various hereditary retinal diseases during childhood. METHODS: Fifty patients aged 2 to 16 years with hereditary retinal diseases were analysed using the HRA (Heidelberg Retina Angiograph). To enhance the AF signal, a mean of up to 16 single images was calculated. Twenty healthy children (aged 4-16 years) served as controls. RESULTS: In many children as young as 5 years of age and even in one 2-year-old child good AF images could be obtained. To achieve high quality images, larger image series (about 50 single images) were taken and appropriate single images were chosen manually to calculate the mean. Characteristically, Stargardt disease shows a central oval area of reduced AF, often surrounded by more irregular AF. In patients with Best disease, a central round structure with regular or irregular intense AF is visualised. Some patients with X-linked retinoschisis show central radial structures. In many patients with rod-cone dystrophies, a central oval ring-shaped area of increased AF is present. In early-onset severe retinal dystrophy (EOSRD) with RPE65 mutations AF is completely absent, whereas in other forms of Leber congenital amaurosis, AF is normal. DISCUSSION: Fundus autofluorescence may visualise disease-specific distributions of lipofuscin in the retinal pigment epithelium, often not (yet) visible on ophthalmoscopy. AF images can be used in children to differentiate hereditary retinal diseases and to facilitate follow-up controls. In many cases, four single images are sufficient to analyse the AF pattern

Characterization of a family with X-linked retinitis pigmentosa and variable expressivity in mutation carriers

Pedigree with three generations. Circles represent females and squares represent males. Slashed symbols indicate deceased family members. Filled black symbols denote family members with retinitis pigmentosa (RP), and circles with a dot indicate female mutation carriers who had no history of visual complaints. Horizontal bars designate family members whose genotype was determined by molecular genetic testing. Arrow marks the index patient 25085. The mutation c.2405_2406delAG in exon ORF15 of segregates with the disease in males, and shows variable heterozygote manifestation in females. Fundus pictures of three affected family members show typical pigmentations found in the peripheral retina of patients with RP. Patient age and gender are provided below each fundus photograph. Pattern of X-chromosome inactivation of selected female family members. None showed a unilateral X-inactivation at the AR-locus. The following abbreviations and symbols are used: control nonrandom X-inactivation (C-nr), control random X-inactivation (C-r), HpaII digestion (+), and no HpaII digestion (-).<p><b>Copyright information:</b></p><p>Taken from "Identification of novel mutations in X-linked retinitis pigmentosa families and implications for diagnostic testing"</p><p></p><p>Molecular Vision 2008;14():1081-1093.</p><p>Published online 06 Jun 2008</p><p>PMCID:PMC2426717.</p><p></p

Intraoperative ventilator settings and their association with postoperative pulmonary complications in neurosurgical patients: post-hoc analysis of LAS VEGAS study

Background: Limited information is available regarding intraoperative ventilator settings and the incidence of postoperative pulmonary complications (PPCs) in patients undergoing neurosurgical procedures. The aim of this post-hoc analysis of the 'Multicentre Local ASsessment of VEntilatory management during General Anaesthesia for Surgery' (LAS VEGAS) study was to examine the ventilator settings of patients undergoing neurosurgical procedures, and to explore the association between perioperative variables and the development of PPCs in neurosurgical patients. Methods: Post-hoc analysis of LAS VEGAS study, restricted to patients undergoing neurosurgery. Patients were stratified into groups based on the type of surgery (brain and spine), the occurrence of PPCs and the assess respiratory risk in surgical patients in Catalonia (ARISCAT) score risk for PPCs. Results: Seven hundred eighty-four patients were included in the analysis; 408 patients (52%) underwent spine surgery and 376 patients (48%) brain surgery. Median tidal volume (VT) was 8 ml [Interquartile Range, IQR = 7.3-9] per predicted body weight; median positive end-expiratory pressure (PEEP) was 5 [3 to 5] cmH20. Planned recruitment manoeuvres were used in the 6.9% of patients. No differences in ventilator settings were found among the sub-groups. PPCs occurred in 81 patients (10.3%). Duration of anaesthesia (odds ratio, 1.295 [95% confidence interval 1.067 to 1.572]; p = 0.009) and higher age for the brain group (odds ratio, 0.000 [0.000 to 0.189]; p = 0.031), but not intraoperative ventilator settings were independently associated with development of PPCs. Conclusions: Neurosurgical patients are ventilated with low VT and low PEEP, while recruitment manoeuvres are seldom applied. Intraoperative ventilator settings are not associated with PPCs