Hypoglycémie chez des patients porteurs de pompe a insuline [Hypoglycemia in patients treated with an external insulin pump].

Hypoglycemia is a potentially serious complication of insulin therapy. Some insulin-dependent diabetic patients can benefit from continuous subcutaneous insulin infusion therapy (an "insulin pump"), which in most case improves glycemia control and decreases the occurrence of hypoglycemic episodes. However, such events may occur, particularly during initial treatment phases or pregnancy. Severe hypoglycemia is mainly managed by stopping the insulin pump and insuring an adequate carbohydrate intake. Patients with insulin pumps and their entourage should receive specific instruction in the adjustment of pump flow in the presence of dysglycemia-inducing circumstances (illness, physical exertion), as well as in anticipation of high-risk situations, such as motor-vehicle driving.

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.

Ribonucleotide reductase genes of Bacillus prophages: a refuge to introns and intein coding sequences.

The ribonucleotide reductase gene tandem bnrdE/bnrdF in SPbeta-related prophages of different Bacillus spp. isolates presents different configurations of intervening sequences, comprising one to three of six non-homologous splicing elements. Insertion sites of group I introns and intein DNA are clustered in three relatively short segments encoding functionally important domains of the ribonucleotide reductase. Comparison of the bnrdE homologs reveals mutual exclusion of a group I intron and an intein coding sequence flanking the codon that specifies a conserved cysteine. In vivo splicing was demonstrated for all introns. However, for two of them a part of the mRNA precursor molecules remains unspliced. Intergenic bnrdE-bnrdF regions are unexpectedly long, comprising between 238 and 541 nt. The longest encodes a putative polypeptide related to HNH homing endonucleases.

Mutations at a single codon in Mad homology 2 domain of SMAD4 cause Myhre syndrome.

Myhre syndrome (MIM 139210) is a developmental disorder characterized by short stature, short hands and feet, facial dysmorphism, muscular hypertrophy, deafness and cognitive delay. Using exome sequencing of individuals with Myhre syndrome, we identified SMAD4 as a candidate gene that contributes to this syndrome on the basis of its pivotal role in the bone morphogenetic pathway (BMP) and transforming growth factor (TGF)-β signaling. We identified three distinct heterozygous missense SMAD4 mutations affecting the codon for Ile500 in 11 individuals with Myhre syndrome. All three mutations are located in the region of SMAD4 encoding the Mad homology 2 (MH2) domain near the site of monoubiquitination at Lys519, and we found a defect in SMAD4 ubiquitination in fibroblasts from affected individuals. We also observed decreased expression of downstream TGF-β target genes, supporting the idea of impaired TGF-β-mediated transcriptional control in individuals with Myhre syndrome.

Prostaglandin transporter mutations cause pachydermoperiostosis with myelofibrosis.

Pachydermoperiostosis, or primary hypertrophic osteoarthropathy (PHO), is an inherited multisystem disorder, whose features closely mimic the reactive osteoarthropathy that commonly accompanies neoplastic and inflammatory pathologies. We previously described deficiency of the prostaglandin-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (HPGD) as a cause of this condition, implicating elevated circulating prostaglandin E(2) (PGE(2) ) as causative of PHO, and perhaps also as the principal mediator of secondary HO. However, PHO is genetically heterogeneous. Here, we use whole-exome sequencing to identify recessive mutations of the prostaglandin transporter SLCO2A1, in individuals lacking HPGD mutations. We performed exome sequencing of four probands with severe PHO, followed by conventional mutation analysis of SLCO2A1 in nine others. Biallelic SLCO2A1 mutations were identified in 12 of the 13 families. Affected individuals had elevated urinary PGE(2) , but unlike HPGD-deficient patients, also excreted considerable quantities of the PGE(2) metabolite, PGE-M. Clinical differences between the two groups were also identified, notably that SLCO2A1-deficient individuals have a high frequency of severe anemia due to myelofibrosis. These findings reinforce the key role of systemic or local prostaglandin excess as the stimulus to HO. They also suggest that the induction or maintenance of hematopoietic stem cells by prostaglandin may depend upon transporter activity. Hum Mutat 33:1175-1181, 2012. © 2012 Wiley Periodicals, Inc.

The Body Action and Posture Coding System (BAP): Development and Reliability

Several methods are available for coding body movement in nonverbal behavior research, but there is no consensus on a reliable coding system that can be used for the study of emotion expression. Adopting an integrative approach, we developed a new method, the Body Action and Posture (BAP) coding system, for the time-aligned micro description of body movement on an anatomical level (different articulations of body parts), a form level (direction and orientation of movement), and a functional level (communicative and self-regulatory functions). We applied the system to a new corpus of acted emotion portrayals, examined its comprehensiveness and demonstrated intercoder reliability at three levels: a) occurrence, b) temporal precision and c) segmentation. We discuss issues for further validation and propose some research applications.

Vertebrate conserved non coding DNA regions have a high persistence length and a short persistence time.

BACKGROUND: The comparison of complete genomes has revealed surprisingly large numbers of conserved non-protein-coding (CNC) DNA regions. However, the biological function of CNC remains elusive. CNC differ in two aspects from conserved protein-coding regions. They are not conserved across phylum boundaries, and they do not contain readily detectable sub-domains. Here we characterize the persistence length and time of CNC and conserved protein-coding regions in the vertebrate and insect lineages. RESULTS: The persistence length is the length of a genome region over which a certain level of sequence identity is consistently maintained. The persistence time is the evolutionary period during which a conserved region evolves under the same selective constraints.Our main findings are: (i) Insect genomes contain 1.60 times less conserved information than vertebrates; (ii) Vertebrate CNC have a higher persistence length than conserved coding regions or insect CNC; (iii) CNC have shorter persistence times as compared to conserved coding regions in both lineages. CONCLUSION: Higher persistence length of vertebrate CNC indicates that the conserved information in vertebrates and insects is organized in functional elements of different lengths. These findings might be related to the higher morphological complexity of vertebrates and give clues about the structure of active CNC elements.Shorter persistence time might explain the previously puzzling observations of highly conserved CNC within each phylum, and of a lack of conservation between phyla. It suggests that CNC divergence might be a key factor in vertebrate evolution. Further evolutionary studies will help to relate individual CNC to specific developmental processes.

Trends in violent deaths among young people 10-24 years old, in Switzerland, 1969-1997.

PURPOSE: To assess violent death rates and trends between 1969 and 1997 among young people aged 10-24 years old in Switzerland. METHODS: Total causes of death, all external causes of injuries, traffic injuries, suicides and overdoses were retrieved from the databank of the Swiss Federal Statistical Office (SFSO), using the eighth and tenth revisions of the International Classification of Diseases (ICD). Mortality rates per 100,000 individuals were computed by gender and by age (10-14, 15-19, 20-24) using census records as denominators. RESULTS: In 1995-1997, violent deaths represented the primary cause of fatalities among young people. Rates of violent death were much higher among males than among females, with a ratio of 3.5:1 in 1995-1997 and also became increasingly elevated from the age range of 10-14 to 20-24 years (1.9:1-4.4:1). In 1995-1997, violent deaths accounted for 66% (n = 1221) of all fatalities among young people. Among violent deaths, 36% were due to traffic injuries, 13% to other types of injuries, 32% to suicide, 15% to overdoses, 3% to homicides and 1% to undetermined intent. Between 1969 and 1997, rates of traffic injuries decreased in both genders and in the three age groups considered, while rates of suicide remained stable and rates of overdoses stabilised during the nineties after a sharp increase during the eighties. CONCLUSION: Although violent deaths in Switzerland have become significantly less frequent over the last 30 years, they still represent the single greatest cause of fatalities among young people and, as such, constitute a major public health challenge.

BlastR--fast and accurate database searches for non-coding RNAs.

We present and validate BlastR, a method for efficiently and accurately searching non-coding RNAs. Our approach relies on the comparison of di-nucleotides using BlosumR, a new log-odd substitution matrix. In order to use BlosumR for comparison, we recoded RNA sequences into protein-like sequences. We then showed that BlosumR can be used along with the BlastP algorithm in order to search non-coding RNA sequences. Using Rfam as a gold standard, we benchmarked this approach and show BlastR to be more sensitive than BlastN. We also show that BlastR is both faster and more sensitive than BlastP used with a single nucleotide log-odd substitution matrix. BlastR, when used in combination with WU-BlastP, is about 5% more accurate than WU-BlastN and about 50 times slower. The approach shown here is equally effective when combined with the NCBI-Blast package. The software is an open source freeware available from www.tcoffee.org/blastr.html.

Premature epiphyseal closure in an adolescent treated by retinoids for acne: an unusual cause of anterior knee pain.

Retinoids are effective and widely prescribed in the treatment of severe acne. However their use can be associated with numerous side effects. Some rare cases of premature epiphyseal closure were reported. We present the case of a sixteen-year-old soccer player referred for progressive anterior pain in both knees, evoking a patellar problem. Careful pharmacological questioning revealed use of isotretinoin for several months. MRI findings showed an irregularity of the growth plate and an important metaphyso-epiphyseal oedema, more noticeable in the left knee. Retinoid-induced premature epiphyseal closure was diagnosed. The treatment was stopped, with a resolution of pain within two months. After recovery a persisting small sequelar thumbprint-like growth plate lesion was observed on the control MRI. Retinoids induce an invasion of the growth plate by osteoclasts and a decrease in proteoglycans synthesis. It seems that the knee is the most affected joint. This complication being rare, a radiological follow-up of the young patients treated by retinoids is not proposed.

Biased gene conversion and GC-content evolution in the coding sequences of reptiles and vertebrates.

Mammalian and avian genomes are characterized by a substantial spatial heterogeneity of GC-content, which is often interpreted as reflecting the effect of local GC-biased gene conversion (gBGC), a meiotic repair bias that favors G and C over A and T alleles in high-recombining genomic regions. Surprisingly, the first fully sequenced nonavian sauropsid (i.e., reptile), the green anole Anolis carolinensis, revealed a highly homogeneous genomic GC-content landscape, suggesting the possibility that gBGC might not be at work in this lineage. Here, we analyze GC-content evolution at third-codon positions (GC3) in 44 vertebrates species, including eight newly sequenced transcriptomes, with a specific focus on nonavian sauropsids. We report that reptiles, including the green anole, have a genome-wide distribution of GC3 similar to that of mammals and birds, and we infer a strong GC3-heterogeneity to be already present in the tetrapod ancestor. We further show that the dynamic of coding sequence GC-content is largely governed by karyotypic features in vertebrates, notably in the green anole, in agreement with the gBGC hypothesis. The discrepancy between third-codon positions and noncoding DNA regarding GC-content dynamics in the green anole could not be explained by the activity of transposable elements or selection on codon usage. This analysis highlights the unique value of third-codon positions as an insertion/deletion-free marker of nucleotide substitution biases that ultimately affect the evolution of proteins.

Multiple non-ossifying fibromas as a cause of pathological femoral fracture in Jaffe-Campanacci syndrome.

BACKGROUND: Jaffe-Campanacci is a rare syndrome characterised by the association of café-au-lait spots, axillary freckles, multiple non-ossifying fibromas of the long bones and jaw, as well as some features of type 1 neurofibromatosis. There are less than 30 reported cases, and a genetic profile has not yet been determined. Furthermore, it has not been clarified whether it is a subtype of type 1 neurofibromatosis or a separate syndrome. The risk of pathological fracture is over 50%, due to substantial cortical thinning of the weight-bearing bones. CASE PRESENTATION: A 17-year-old female patient, known for type 1 neurofibromatosis, presented with a low-energy distal femoral fracture due to disseminated large non-ossifying fibromas. Investigations revealed all of the distinctive signs of Jaffe-Campanacci syndrome. Both her distal femurs and proximal tibias exhibited multiple non-ossifying fibromas. The fracture was treated by open reduction and internal plate fixation. Some of the bony lesions were biopsied to confirm the diagnosis. The fracture healed eventless, as did the lesions biopsied or involved in the fracture. The other ones healed after curettage and bone grafting performed at the time of plate removal. CONCLUSION: Jaffe-Campanacci is a rare syndrome having unclear interactions with type 1 neurofibromatosis, which still needs to be characterised genetically. It is associated with a high risk of pathological fracture, due to the presence of multiple large non-ossifying fibromas of the long bones, with an expected normal healing time. Curettage and bone grafting promote healing of the lesions and should be considered to prevent pathological fracture. We agree with other authors that all patients with newly-diagnosed type 1 neurofibromatosis should undergo an osseous screening to detect disseminated non-ossifying fibromas, and evaluate the inherent risk of pathological fracture.

The cognitive errors and coping patterns of child molesters as assessed by external observers: a pilot study

Cognitive errors (CE) and coping strategies (CS) are the focus of most cognitive-behavioral treatments for incarcerated child molesters. Several studies have reported differences in CEs and CSs between child molesters and controls. However, the vast majority of these studies assessed cognitive errors and coping using questionnaires, which are known to present a number of important limitations. This pilot study aimed to compare the CEs and CSs of N = 17 incarcerated child abusers and N = 12 controls using observer-rated methods, namely the Cognitive Error Rating Scale (CERS; Drapeau et al., 2005) and the Coping Action Pattern Rating Scale (CAPRS; Perry, Drapeau, & Dunkley, 2005). Results showed that child molesters presented more cognitive errors, in particular positive selective abstraction, and lower coping functioning, such as escape strategies. Treatment and research implications, including the use of observer-rated methods, are discussed.

Mutations in the SPARC-Related Modular Calcium-Binding Protein 1 Gene, SMOC1, Cause Waardenburg Anophthalmia Syndrome.

Waardenburg anophthalmia syndrome, also known as microphthalmia with limb anomalies, ophthalmoacromelic syndrome, and anophthalmia-syndactyly, is a rare autosomal-recessive developmental disorder that has been mapped to 10p11.23. Here we show that this disease is heterogeneous by reporting on a consanguineous family, not linked to the 10p11.23 locus, whose two affected children have a homozygous mutation in SMOC1. Knockdown experiments of the zebrafish smoc1 revealed that smoc1 is important in eye development and that it is expressed in many organs, including brain and somites.