Truncating variants of the DLG4 gene are responsible for intellectual disability with marfanoid features.

Marfanoid habitus (MH) combined with intellectual disability (ID) is a genetically and clinically heterogeneous group of overlapping disorders. We performed exome sequencing in 33 trios and 31 single probands to identify novel genes specific to MH-ID. After the search for variants in known disease-causing genes and non-disease-causing genes with classical approaches, we searched for variants in non-disease-causing genes whose pLI was above 0.9 (ExAC Consortium data), in which truncating variants were found in at least 3 unrelated patients. Only DLG4 gene met these criteria. Data from the literature and various databases also indicated its implication in ID. DLG4 encodes post-synaptic density protein 95 (PSD-95), a protein expressed in various tissues, including the brain. In neurons, PSD-95 is located at the post-synaptic density, and is associated with glutamatergic receptor signaling (NMDA and AMPA). PSD-95 probably participates in dendritogenesis. Two patients were heterozygous for de novo frameshift variants and one patient carried a a consensus splice site variant. Gene expression studies supported their pathogenicity through haploinsufficiency and loss-of-function. Patients exhibited mild-to-moderate ID, similar marfanoid features, including a long face, high-arched palate, long and thin fingers, pectus excavatum, scoliosis and ophthalmological manifestations (nystagmus or strabismus). Our study emphasizes the role of DLG4 as a novel post-synaptic-associated gene involved in syndromic ID associated with MH.

Systematic molecular and cytogenetic screening of 100 patients with marfanoid syndromes and intellectual disability.

The association of marfanoid habitus (MH) and intellectual disability (ID) has been reported in the literature, with overlapping presentations and genetic heterogeneity. A hundred patients (71 males and 29 females) with a MH and ID were recruited. Custom-designed 244K array-CGH (Agilent®; Agilent Technologies Inc., Santa Clara, CA) and MED12, ZDHHC9, UPF3B, FBN1, TGFBR1 and TGFBR2 sequencing analyses were performed. Eighty patients could be classified as isolated MH and ID: 12 chromosomal imbalances, 1 FBN1 mutation and 1 possibly pathogenic MED12 mutation were found (17%). Twenty patients could be classified as ID with other extra-skeletal features of the Marfan syndrome (MFS) spectrum: 4 pathogenic FBN1 mutations and 4 chromosomal imbalances were found (2 patients with both FBN1 mutation and chromosomal rearrangement) (29%). These results suggest either that there are more loci with genes yet to be discovered or that MH can also be a relatively non-specific feature of patients with ID. The search for aortic complications is mandatory even if MH is associated with ID since FBN1 mutations or rearrangements were found in some patients. The excess of males is in favour of the involvement of other X-linked genes. Although it was impossible to make a diagnosis in 80% of patients, these results will improve genetic counselling in families.

[Managing the open abdomen with vacuum-assisted closure therapy: retrospective evaluation of 22 patients]. / Prise en charge des abdomens ouverts par la thérapie vacuum-assisted closure (VAC): évaluation rétrospective de 22 malades.

BACKGROUND: The authors reviewed their experience in the management of "open abdomen" using the vacuum-assisted closure device (VAC), in order to assess its morbidity particularly in terms of fistula, and the outcome of abdominal wall integrity. METHODS: Between January 2003 and October 2006, 22 patients required management with an "open abdomen" technique (18 patients were managed with the VAC abdominal dressing device with application of a specific sheet and 4 other patients simply required a dressing with the polyurethane sponge). The mean age was 55 years, and M/F sex ratio was 2.67. Indications were abdominal compartment syndrome in 7 patients, initial "abdominal closure" after trauma in one patient, severe abdominal sepsis in 7 patients, and abdominal wound dehiscence where closure was impossible in 7 patients. RESULTS: There were no enteric fistulae. Two infections were seen--a chronic suppuration which resolved with antibiotic therapy and a deep abscess which was drained with radiologic guidance. Of the 18 cases of "open abdomen" managed with the VAC, 15 were alive. Six (40%) underwent a delayed primary closure at a mean interval of 9 days; the others underwent secondary healing by granulation, and 10 eventually underwent split thickness skin grafting at a mean interval of 50 days. With VAC closure of the "open abdomen", the development of ventral hernia is an anticipated outcome; in four cases, patients underwent abdominal wall reconstruction at an interval of one year. CONCLUSION: Laparostomy or "open abdomen" using the VAC dressing system should be considered an established and well-defined technique which provides temporary abdominal coverage with limited morbidity.

Development of a (silent) speech recognition system for patients following laryngectomy.

Surgical voice restoration post-laryngectomy has a number of limitations and drawbacks. The present gold standard involves the use of a tracheo-oesophageal fistula (TOF) valve to divert air from the lungs into the throat, which vibrates, and from this, speech can be formed. Not all patients can use these valves and those who do are susceptible to complications associated with valve failure. Thus there is still a place for other voice restoration options. With advances in electronic miniaturization and portable computing power a computing-intensive solution has been investigated. Magnets were placed on the lips, teeth and tongue of a volunteer causing a change in the surrounding magnetic field when the individual mouthed words. These changes were detected by 6 dual axis magnetic sensors, which were incorporated into a pair of special glasses. The resulting signals were compared to training data recorded previously by means of a dynamic time warping algorithm using dynamic programming. When compared to a small vocabulary database, the patterns were found to be recognised with an accuracy of 97% for words and 94% for phonemes. On this basis we plan to develop a speech system for patients who have lost laryngeal function.

[Dual chamber rate responsive pacing and chronotropic insufficiency. Comparison of double and respiratory sensors]. / Stimulation double chambre à fréquence asservie et incompétence chronotrope. Comparaison d'un capteur d'activité, de ventilation et d'un double capteur.

Late responsive DDD pacemakers are the most technically advanced devices presently available. These pacemakers are particularly useful in patients with chronotropic insufficiency when the sinus node is incapable of accelerating during exercise. The latest pacemakers have two sensors to reproduce optimal physiological sinus acceleration. The aim of this study was to analyse the performances of a new rate responsive pacemaker with a double activity and respiratory sensor, the interaction of which is automatically controlled by a sophisticated algorithm, in 12 patients (8 men and 4 women) with a mean age of 75 +/- 7 years. Analysis was based on the performance of the sensors used singly or in association: during three exercise stress tests with measurement of the VO2 max; during everyday activities using the data archived by the pacemaker and the answers to a simplified questionnaire on quality of life. The results showed that during exercise stress testing with measurement of VO2 max, the best performances were obtained with the double sensor or the respiratory sensor compared with the activity sensor alone, suggesting that these two sensors are more effective in intense exercise. This tendency was also observed in the analysis of the memory bank of the pacemaker which showed that the total duration of the faster heart rates was greater with the two sensors. On the other hand, the quality of life was not significantly different, whichever sensor was studied. Longer scale trials are necessary to appreciate the real value of these new double sensor pacing devices and to identify the best indications for their usage.

[Main virulence factors in Escherichia coli isolates from swine over two weeks old with edema disease and/or E. coli diarrhea]. / Hauptvirulenzfaktoren bei Escherichia coli-Isolaten von über zwei Wochen alten Schweinen mit Odemkrankheit und/oder Colidiarrhöe.

The OK antigens and the fimbriae F4 of E. coli with haemolysis isolated from 113 cases of oedema disease and/or diarrhoea were identified serologically. The genes for F18 and for enterotoxins LT, STIa and STII as well as Shigatoxin Stx2e were determined by PCR. Fimbrial variants F18ab and F18ac were distinguished by means of indirect immunofluorescence on smears prepared from the intestinal mucosa and from cultures grown under appropriate conditions. Adhesive fimbriae were detected with every case or isolate, respectively, by means of at least one out of the techniques mentioned above. The serogroup O149:K91 with fimbriae F4ac (K88ac) and genes for the enterotoxins LT and STII was most prevalent. Serogroup O139:K12 with fimbriae F18ab and the gene for Stx2e was second, whereas serogroups O141ab and O141ac with fimbriae F18ac and genes for Stx2e, STII and often LT were much less prevalent. The serogroup O147:K89 with fimbriae F18ac, and genes for STIa and STII was detected for the first time in Switzerland.

Role of fimbriae F18 for actively acquired immunity against porcine enterotoxigenic Escherichia coli.

Enterotoxigenic (ETEC) and enterotoxaemic (ETEEC) Escherichia (E.) coli that express F18 (F107) fimbriate colonize the small intestine and cause diarrhoea and/or oedema disease in weaned pigs. So far, two antigenic variants of F18 can be distinguished with a common antigenic factor designated 'a' and two specific factors called 'b' and 'c'. In this study the existence of crosswise anti-colonization immunity between E. coli strains that express F18ab or F18ac fimbrial variants, respectively, was demonstrated. Weaned pigs of susceptible genotype with respect to susceptibility to adhesion of E. coli with fimbriae F18 were inoculated with E. coli strains 3064STM (0157:K-:H-:F18ab; resistant to streptomycin) and 8199RIF (0141ab:K-:H4:F18ac; resistant to rifampicin). The faecal shedding was compared subsequent to immunization and homologous or heterologous challenge. An enzyme-linked immunosorbent assay (ELISA) was applied to measure IgA, IgM and IgG antibodies against the F18ab and F18ac antigens in saliva, faeces, serum and intestinal wash samples. About 8 log CFU/g of the inoculated strains were found in faeces of all pigs following immunization as well as in non-immunized controls after challenge. Bacterial counts of the inoculated strains after challenge were between 2 and 5 log lower, without any difference between homologous and heterologous challenge. Intestinal colonization with fimbriated E. coli resulted in production of significantly increased levels of anti-fimbrial antibodies, especially IgA, in serum and intestinal wash samples. There were higher levels of homologous than of heterologous anti-fimbrial antibodies. Production of antibodies against F18a or against another common fimbrial antigen is probably responsible for crosswise anti-colonization immunity between E. coli strains with F18ab and F18ac fimbrial variants. Serum F18-specific IgA may be a useful indicator of a mucosal immune response directed against F18 fimbriae.

Dose-dependent kinetics for theophylline: observations among ambulatory asthmatic children.

In order to assess the clinical impact of dose-dependent kinetics for theophylline, the relationship between serum concentration and daily dosage among patients under the care of the University of Iowa Pediatric Allergy and Pulmonary Service was examined. Dosage was titrated clinically, with the final adjustment based on a serum theophylline measurement. Of 200 charts initially reviewed, 42 patients were found in whom at least two peak serum concentrations had been measured at different doses of the same theophylline preparation. In 30 (15% of initial 200) of these 42 patients, the percent change in serum concentration exceeded the percent change in dose by at least 50%. Subsequently, 300 additional charts were reviewed to identify a total of 26 patients with three steady-state serum concentrations at three different doses. Only five of these patients demonstrated a linear relationship between dose and serum concentration; the other 21 demonstrated disproportionate changes compatible with parallel first-order and dose-dependent kinetics. Thus, clinically important dose-dependent kinetics for theophylline occur in at least 15% of children, and theophylline dosage therefore must be adjusted in small increments in order to avoid disproportionately large changes in serum concentration with consequent risks of toxicity during continuous therapy.