Eight years experience from a skeletal dysplasia referral center in a tertiary hospital in Southern India: A model for the diagnosis and treatment of rare diseases in a developing country.

We report on a series of 514 consecutive diagnoses of skeletal dysplasia made over an 8-year period at a tertiary hospital in Kerala, India. The most common diagnostic groups were dysostosis multiplex group (n = 73) followed by FGFR3 (n = 49) and osteogenesis imperfecta and decreased bone density group (n = 41). Molecular confirmation was obtained in 109 cases. Clinical and radiographic evaluation was obtained in close diagnostic collaboration with expert groups abroad through Internet communication for difficult cases. This has allowed for targeted biochemical and molecular studies leading to the correct identification of rare or novel conditions, which has not only helped affected families by allowing for improved genetic counseling and prenatal diagnosis but also resulted in several scientific contributions. We conclude that (1) the spectrum of genetic bone disease in Kerala, India, is similar to that of other parts of the world, but recessive entities may be more frequent because of widespread consanguinity; (2) prenatal detection of skeletal dysplasias remains relatively rare because of limited access to expert prenatal ultrasound facilities; (3) because of the low accessibility to molecular tests, precise clinical-radiographic phenotyping remains the mainstay of diagnosis and counseling and of gatekeeping to efficient laboratory testing; (4) good phenotyping allows, a significant contribution to the recognition and characterization of novel entities. We suggest that the tight collaboration between a local reference center with dedicated personnel and expert diagnostic networks may be a proficient model to bring current diagnostics to developing countries. © 2014 Wiley Periodicals, Inc.

Soins aux mineurs non accompagnés (MNA): l'expérience lausannoise [Caring for unaccompanied minors: an experience from Lausanne].

La prise en charge médicale du mineur non accompagné est complexe et nécessite la mise en place d'un réseau biopsychosocial. A Lausanne, l'Unité multidisciplinaire de santé des adolescents (UMSA) joue un rôle préventif et curatif pour cette population extrêmement vulnérable. Une prise en charge psychologique rapide est souvent nécessaire en raison des événements de vie dramatiques auxquels la plupart de ces adolescents ont été confrontés. L'absence de projet d'avenir pour la majorité de ces adolescents reste une entrave majeure à leur développement et à leur santé mentale et physique. Medical treatment of an unaccompanied minor is made more complicated firstly by its connections with the politics of immigration and secondly by the difficulty in gaining recognition of the priority of the minor's interests. Enabling healthcare teams to travel and meet these particularly vulnerable youths makes medical care more accessible to them and facilitates an optimal bio-psycho-social treatment. For most of these adolescents it is their lack of plans for the future which remains the major obstacle to their development and mental and physical health.

Prévalence de la dénutrition chez 143 adultes en bilan prétransplantation hépatique. Experience lausannoise de 1997 a 2005 [Prevalence of undernutrition in 143 patients before liver transplantation. The Lausanne experience between 1997 and 2005]

The prevalence of undernutrition was prospectively studied in 143 patients before liver transplantation between 1997 and 2005. Nutritional assessment is a particularly tricky problem in cirrhosis and mid-arm muscle circumference is considered as the best reliable anthropometric tool. In this prospective study, prevalence rate is very high (61%) and undernutrition is more frequent in alcoholic cirrhotic patients. In conclusion, these patients should benefit from an early dietician intervention before liver transplantation.

Inbreeding avoidance through kin recognition: choosy females boost male dispersal.

Inbreeding avoidance is predicted to induce sex biases in dispersal. But which sex should disperse? In polygynous species, females pay higher costs to inbreeding and thus might be expected to disperse more, but empirical evidence consistently reveals male biases. Here, we show that theoretical expectations change drastically if females are allowed to avoid inbreeding via kin recognition. At high inbreeding loads, females should prefer immigrants over residents, thereby boosting male dispersal. At lower inbreeding loads, by contrast, inclusive fitness benefits should induce females to prefer relatives, thereby promoting male philopatry. This result points to disruptive effects of sexual selection. The inbreeding load that females are ready to accept is surprisingly high. In absence of search costs, females should prefer related partners as long as delta<r/(1+r) where r is relatedness and delta is the fecundity loss relative to an outbred mating. This amounts to fitness losses up to one-fifth for a half-sib mating and one-third for a full-sib mating, which lie in the upper range of inbreeding depression values currently reported in natural populations. The observation of active inbreeding avoidance in a polygynous species thus suggests that inbreeding depression exceeds this threshold in the species under scrutiny or that inbred matings at least partly forfeit other mating opportunities for males. Our model also shows that female choosiness should decline rapidly with search costs, stemming from, for example, reproductive delays. Species under strong time constraints on reproduction should thus be tolerant of inbreeding.

Women's decision making and experience of subsequent pregnancy following stillbirth.

INTRODUCTION: This study sought to increase understanding of women's thoughts and feelings about decision making and the experience of subsequent pregnancy following stillbirth (intrauterine death after 24 weeks' gestation). METHODS: Eleven women were interviewed, 8 of whom were pregnant at the time of the interview. Modified grounded theory was used to guide the research methodology and to analyze the data. RESULTS: A model was developed to illustrate women's experiences of decision making in relation to subsequent pregnancy and of subsequent pregnancy itself. DISCUSSION: The results of the current study have significant implications for women who have experienced stillbirth and the health professionals who work with them. Based on the model, women may find it helpful to discuss their beliefs in relation to healing and health professionals to provide support with this in mind. Women and their partners may also benefit from explanations and support about the potentially conflicting emotions they may experience during this time.

Comparison of two osteoporotic fracture management pathways: experience at 1 year

Introduction: Osteoporosis presenting as low-impact fractures to traumatology units is often undiagnosed and under-treated. Results from the Osteocare study in Lausanne (a nurse based intervention, passive pathway) showed that only 19% of patients received management for osteoporosis, and in the literature [1], the rate is between 10-25%. We have evaluated a different management concept, based on the systematic assessment of patients with osteoporotic fractures during and after hospitalization (active pathway). Methods: Inpatients admitted to the Department of Musculoskeletal Medicine for a fragility fracture were identified by a nurse according to a predefined questionnaire and were then clinically evaluated by a doctor. Based on the results, a management plan was proposed to the patients. Patients could choose between follow up either by their GP or by the Centre of Bone Disease of the CHUV. For patients who chose follow-up in our Centre, we assessed their adherence to medical follow-up 1 year inclusion. The results of patients who had been evaluated in our cohort between the 1 November 2008 and the 1 December 2009 were analysed. Results: 573 inpatients received specific management of their osteoporotic fracture over 18 months. The mean age was 77 y (31-99), 81% were women (203 hip fractures, 40 pelvis fractures, 101 arm fractures, 57 vertebral fractures, 63 ankle fractures, and 25 others sites). During the study period, 303 patients received a proposition of a specific treatment. 39 (13%) chose a follow up with the GP, 19 (6%) dead and 245 (81%) preferred a follow up in our Centre. After 1 year, 166 (67%) patients are under follow up in our outpatient clinic. Conclusion: With an active clinical pathway that starts during the hospitalization, consisting on a nursing evaluation followed by a medical consultation by an expert in osteoporosis, the adherence increased from 19% to 67% in terms of follow up. These results lead us to propose a consultation with a doctor experienced in osteoporosis after all osteoporotic fractures.

Outcome and Experience from the Swiss Mammography Screening Pilot Programmes

BACKGROUND:The Swiss breast cancer screening pilot programme was conducted in 3 districts of theFrench-speaking canton of Vaud (ca. 300,000 resident women) between October 1993 and January 1999.Women aged 50 to 69 were invited by mail every 2 years for a free of charge screening mammography (doubleview, multiple reading). This first ever-organised cancer screening programme in Switzerland showed thefeasibility and acceptability of this kind of public health intervention in the liberal Swiss healthcare system, whichwas the main objective of the pilot programme. This mammographic screening programme was extended to thewhole canton in 1999, and contributed to the implementation of similar programmes in 2 neighbouring cantons. OBJECTIVE:To appraise the use, the quality and the effectiveness of the Swiss screening pilot programme. METHODS:About 15,000 women (aged 50-69) were enrolled. Logistic regression analyses were performedseparately to identify determinants of initial and subsequent attendance. Standard indicators of quality,effectiveness and impact of the programme were assessed and compared with European recommendations. Tothis intent, linkage with data from the Vaud Cancer Registry was performed. RESULTS:About half the target population was screened at least once during the pilot trial. Participation washigher among Swiss than foreigners, among widowed or married women than among single, divorced or separatedones. Attendance also increased with age and decreasing distance between residence and the dedicatedscreening centre. Apart from Swiss citizenship, socio-demographic factors were not associated with reattendance.Intensity of prior recruitment, outcome of previous screening test (positive vs. negative) and indicators of women'shealth behaviour (time of last mammography prior to initial screen, smoking status) were the main determinants ofreattendance. Programme performance and quality indicators were, overall, in line with European Guidelines. Theywere overall more favourable among 60-69 than 50-59 year-olds and improved over time. CONCLUSION:The objectives of the pilot programme were met. Even if participation should increase in order toreach European standards, performance indicators overall met quality requirements. Ways to improve screeninguse, quality and effectiveness were devised and taken into account for the generalisation of the programme.

Evaluation of prenatal diagnosis of cleft lip with or without cleft palate and cleft palate by ultrasound: experience from 20 European registries. EUROSCAN study group.

Ultrasound scans in the mid-trimester of pregnancy are now a routine part of antenatal care in most European countries. Using data from registries of congenital anomalies a study was undertaken in Europe. The objective of the study was to evaluate prenatal detection of cleft lip with or without cleft palate (CL(P)) and cleft palate (CP). All CL(P) and CPs suspected prenatally and identified at birth in the period 1996-98 were registered from 20 Congenital Malformation Registers from the following European countries: Austria, Croatia, Denmark, France, Germany, Italy, Lithuania, Spain, Switzerland, The Netherlands, UK, Ukraine. These registries followed the same methodology. A total of 709,027 births were covered; 7758 cases with congenital malformations were registered. Included in the study were 751 cases reported with facial clefts: 553 CL(P) and 198 CP. The prenatal diagnosis by transabdominal ultrasound of CL(P) was made in 65/366 cases with an isolated malformation, in 32/62 cases with chromosomal anomaly, in 30/89 cases with multiple malformations and in 21/36 syndromic cases. The prenatal diagnosis of CP was made in 13/198 cases. One hundred pregnancies were terminated (13%); in 97 of these the cleft was associated with other malformations.

Brittle cornea syndrome: recognition, molecular diagnosis and management.

Brittle cornea syndrome (BCS) is an autosomal recessive disorder characterised by extreme corneal thinning and fragility. Corneal rupture can therefore occur either spontaneously or following minimal trauma in affected patients. Two genes, ZNF469 and PRDM5, have now been identified, in which causative pathogenic mutations collectively account for the condition in nearly all patients with BCS ascertained to date. Therefore, effective molecular diagnosis is now available for affected patients, and those at risk of being heterozygous carriers for BCS. We have previously identified mutations in ZNF469 in 14 families (in addition to 6 reported by others in the literature), and in PRDM5 in 8 families (with 1 further family now published by others). Clinical features include extreme corneal thinning with rupture, high myopia, blue sclerae, deafness of mixed aetiology with hypercompliant tympanic membranes, and variable skeletal manifestations. Corneal rupture may be the presenting feature of BCS, and it is possible that this may be incorrectly attributed to non-accidental injury. Mainstays of management include the prevention of ocular rupture by provision of protective polycarbonate spectacles, careful monitoring of visual and auditory function, and assessment for skeletal complications such as developmental dysplasia of the hip. Effective management depends upon appropriate identification of affected individuals, which may be challenging given the phenotypic overlap of BCS with other connective tissue disorders.

Recognition of RNA virus by RIG-I results in activation of CARD9 and inflammasome signaling for interleukin 1 beta production.

Interleukin 1 beta (IL-1 beta) is a potent proinflammatory factor during viral infection. Its production is tightly controlled by transcription of Il1b dependent on the transcription factor NF-kappaB and subsequent processing of pro-IL-1 beta by an inflammasome. However, the sensors and mechanisms that facilitate RNA virus-induced production of IL-1 beta are not well defined. Here we report a dual role for the RNA helicase RIG-I in RNA virus-induced proinflammatory responses. Whereas RIG-I-mediated activation of NF-kappaB required the signaling adaptor MAVS and a complex of the adaptors CARD9 and Bcl-10, RIG-I also bound to the adaptor ASC to trigger caspase-1-dependent inflammasome activation by a mechanism independent of MAVS, CARD9 and the Nod-like receptor protein NLRP3. Our results identify the CARD9-Bcl-10 module as an essential component of the RIG-I-dependent proinflammatory response and establish RIG-I as a sensor able to activate the inflammasome in response to certain RNA viruses.

Theoretical study on receptor-G protein recognition: new insights into the mechanisms of the alpha1b-adrenergic recptor activation

This work compares the structural/dynamics features of the wild-type alb-adrenergic receptor (AR) with those of the D142A active mutant and the agonist-bound state. The two active receptor forms were compared in their isolated states as well as in their ability to form homodimers and to recognize the G alpha q beta 1 gamma 2 heterotrimer. The analysis of the isolated structures revealed that, although the mutation- and agonist-induced active states of the alpha 1b-AR are different, they, however, share several structural peculiarities including (a) the release of some constraining interactions found in the wild-type receptor and (b) the opening of a cytosolic crevice formed by the second and third intracellular loops and the cytosolic extensions of helices 5 and 6. Accordingly, also their tendency to form homodimers shows commonalties and differences. In fact, in both the active receptor forms, helix 6 plays a crucial role in mediating homodimerization. However, the homodimeric models result from different interhelical assemblies. On the same line of evidence, in both of the active receptor forms, the cytosolic opened crevice recognizes similar domains on the G protein. However, the docking solutions are differently populated and the receptor-G protein preorientation models suggest that the final complexes should be characterized by different interaction patterns.