Homozygous Truncating Intragenic Duplication in TUSC3 Responsible for Rare Autosomal Recessive Nonsyndromic Intellectual Disability with No Clinical or Biochemical Metabolic Markers.

Intellectual disability (ID), which affects around 2-3% of the general population, is classically divided into syndromic and nonsyndromic forms, with several modes of inheritance. Nonsyndromic autosomal recessive ID (NS-ARID) appears extremely heterogeneous with numerous genes identified to date, including inborn errors of metabolism. The TUSC3 gene encodes a subunit of the endoplasmic reticulum (ER)-bound oligosaccharyltransferase complex, which mediates a key step of N-glycosylation. To date, only five families with NS-ARID and TUSC3 mutations or rearrangements have been reported in the literature. All patients had speech delay, moderate-to-severe ID, and moderate facial dysmorphism. Microcephaly was noted in one third of patients, as was short stature. No patients had congenital malformation except one patient with unilateral cryptorchidism. Glycosylation analyses of patients' fibroblasts showed normal N-glycan synthesis and transfer. We present a review of the 19 patients previously described in the literature and report on a sixth consanguineous family including two affected sibs, with intellectual disability, unspecific dysmorphic features, and no additional malformations identified by high-resolution array-CGH. A homozygous truncating intragenic duplication of the TUSC3 gene leading to an aberrant transcript was detected in two siblings. This observation, which is the first reported case of TUSC3 homozygous duplication, confirms the implication of TUSC3 in NS-ARID and the power of the high-resolution array-CGH in identifying intragenic rearrangements of genes implicated in nonsyndromic ID and rare diseases.

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.

What can we learn from old microdeletion syndromes using array-CGH screening?

Most microdeletion syndromes identified before the implementation of array-comparative genomic hybridization (array-CGH) were presumed to be well-defined clinical entities. However, the introduction of whole-genome screening led not only to the description of new syndromes but also to the recognition of a broader spectrum of features for well-known syndromes. Here, we report on 10 patients presenting with mental retardation associated with atypical features not suggestive of a known microdeletion and a normal standard karyotype. Array-CGH analyses revealed five microdeletions in the DiGeorge region, three microdeletions in the Williams-Beuren region and two microdeletions in the Smith-Magenis region. Reevaluation in these patients confirmed that the diagnosis remained difficult on clinical grounds and emphasized that well-known genomic disorders can have a phenotype that is heterogeneous and more variable than originally thought. The widespread use of array-CGH shows that such patients may be more readily achieved on the basis of genotype rather than phenotype.

Comparative study on two kidney graft rinsing and preservation solutions in terms of the post-transplantation risk of delayed graft function and cost.

OBJECTIVE: To determine whether Belzer solution (Viaspan, Bristol-Myers Squibb, Brussels, Belgium), which is more expensive than Eurocollins solution, was better at preventing delayed graft function (DGF) and whether it was cost-effective as it could potentially reduce post-transplantation complications. METHOD: The risk of occurrence of complications associated with the use of these two rinsing and preserving solutions was estimated from a survey of 106 patients undergoing renal transplantation between 1 January 1993 and 31 March 1998. Both efficacy and adverse outcomes were recorded along with the costs directly associated with the transplantation procedure in the hospital setting: hospitalization, rinsing and preserving solutions, medical and technical interventions and diagnostic tests. RESULTS: For the 45 kidney grafts rinsed and preserved with Eurocollins (strategy S1: n1 = 45) the cost/graft was estimated at 40 euros. With Viaspan (strategy S2: n2 = 61) the corresponding cost/graft was 424 euros. Logistic regression analysis showed that Viaspan was better than Eurocollins solution (ebeta = 0.437; P = 0.05) in preventing DGF. Overall, S2 was less expensive than S1, from the hospital's perspective. The mean difference per patient was 278 euros, which amounts to a saving of 2% of the total cost per renal transplantation. For rinsing and preserving kidney grafts Belzer solution is therefore preferable to Eurocollins solution.

[Prescriptions and consumption of hypnotic and anxiolytic drugs in the South University Hospital of Marseille]. / Prescription et consommation des médicaments hypnotiques et anxiolytiques dans les services de médecine des hôpitaux sud du CHU de Marseille.

An investigation of prescription and consumption of hypnotic and anxiolytic drugs in hospital was carried out and has associated a transverse prescription study and a prospective consumption study. The prescription study was undertaken on one day in several medical departments of Sainte-Marguerite Hospital in Marseille in February 1999. Of the 91 hospitalized patients included, 42 (46 per cent) had been prescribed a hypnotic or anxiolytic. Furthermore, the quantities of drugs taken out of the pharmacy during the month of February were 1.54 time more than those prescribed. This discrepancy was even more obvious in the case of certain benzodiazepines such as bromazepam (ratio from 1 to 4) and lorazepam (ratio from 1 to 8). Self-prescription and patients being supplied without a prescription are the hypotheses advanced to explain this phenomenon.

Phase II trial of paclitaxel and carboplatin in metastatic small-cell lung cancer: a Groupe Français de Pneumo-Cancérologie study.

PURPOSE: To evaluate the efficacy and safety of paclitaxel and carboplatin in the treatment of previously untreated patients with metastatic small-cell lung cancer (SCLC). PATIENTS AND METHODS: Eligible patients were aged 18 to 75 years with an Eastern Cooperative Oncology Group (ECOG) score < or = 2 and life expectancy > or = 12 weeks. Paclitaxel (200 mg/m(2)) was infused over 3 hours, before carboplatin (area under the curve [AUC] 6; Calvert formula) infused over 1 hour, once every 3 weeks for six cycles maximum. Prednisolone, dexchlorpheniramine, and ranitidine were standard premedication. Response to treatment was assessed every two cycles, and nonresponding patients were withdrawn from the trial to receive standard chemotherapy. RESULTS: Of the 50 patients entering the study, 48 and 46 patients were assessable for toxicity and response, respectively. The overall response rate was 65%, with complete responses in three patients. Five patients had stable disease (11%) and 11 patients experienced progressive disease (24%). Median survival was 38 weeks, and median duration of response was 20 weeks. One-year survival was 22.5%. For a total of 232 cycles, grade 3 and 4 toxicity was 33% for neutropenia, 3.5% for thrombocytopenia, and 4% for anemia. Four patients had neutropenic fever (one toxic death). Nonhematologic toxicity was mainly grade 1 and 2 paresthesia (21% of patients); grade 3 myalgia/arthralgia was observed in 6.5% of patients. CONCLUSION: First-line chemotherapy with paclitaxel and carboplatin in metastatic SCLC achieved a response rate and survival similar to standard regimens. With 1-day administration and a tolerable toxicity profile, this combination merits further investigation.

[Hospital information systems ineffectiveness in costing ambulatory chemotherapy in pulmonary oncology]. / Insuffisance de la valorisation PMSI de la chimiothérapie ambulatoire en oncologie pulmonaire.

The real cost of medical consumption was compared with the proportion of medication consumption of (the) GHM n(o) 681 (homogeneous group of patients, chemotherapy for cancer in day care) in the French case mix system (PMSI). For those patients in our thoracic oncology unit (Sainte-Marguerite Hospital, Marseille, France), the real medication cost was calculated from prices paid by the hospital, then compared to the expected expenditures for the medication consumption of the GHM 681, i.e. 678 French francs (24.1% of the 225 ISA points (synthetic activity index)). Over a period of 2 months in 1998, 87 patients (mean age 63 +/- 11) had 194 chemotherapy sessions in day care, with multi-drug therapy in 38 cases. Vinorelbine or gemcitabine represented 81% of the single drug chemotherapy. In 84% of the single drug and 76% of the multi-drug chemotherapy, the real cost of medication consumption was above the allocated budget. The mean cost for single drug chemotherapy was 1722 FF and 2920 FF for multi-drug chemotherapy. The budget allocated by the PMSI shows a deficit in the most cases. To avoid a restriction in the use of some drugs, it appears that the French system of budget evaluation needs to be improved.

[Amphotericin B into parenteral lipid emulsions. Galenic stability of mixtures. Preliminary results]. / L'amphotéricine B dans des émulsions lipidiques parentérales. Stabilité galénique des mélanges. Résultats préliminaires.

The amphotericin B in glucose solution is the reference's treatment of the major systemic mycoses. Because of its bad tolerance, certain authors put forward others vehicules such as fat emulsions. The aim of our work has been to study the physico-chemical stability of two regeneration's methods; P1: direct regeneration. P2: regeneration of 50mg of Fungizone in 5 ml of glucose serum and laced with 45 ml of Ivelip 20% versus PR: 50 mg of Fungizone in 50 ml of glucose serum. Our results seem to show that the P1 is totally incompatible with a parenteral administration, because 23% of the granulometric population has a diameter superior to 5 microns. The solution P2 seems better even if the pH is different from PR and a light depot comes after reconstitution.

[Treatments by local injections of botulinum toxin in neurology. Indications and results]. / Traitements par injections locales de toxine botulique en neurologie. Indications et résultats.

Local injections of botulinum toxin constitute the only truly effective treatment of certain abnormal movements and focal dystonias. The authors describe its indications and report on their personal experience. One hundred and seventeen patients were treated: 48 for blepharospasm, 46 for hemifacial spasm and 23 for spasmodic torticollis. The results were evaluated by means of a score taking into account the effectiveness of treatment, the duration of this effectiveness, the side-effects, if any, observed, and the course of the neurological disorder after several series of injections. The results were good or excellent in 91 percent of patients with hemifacial spasm and 79 percent of patients with blepharospasm. Spasmodic torticollis was much improved in 35 percent of the cases and less, but satisfactorily, improved in 48 percent. In this disease, the muscles which antagonize those responsible for the dystonia must absolutely be re-educated.