Spectrum of mutations in cystinuria patients presenting with prenatal hyperechoic colon.

Cystinuria is a heterogeneous, rare but important cause of inherited kidney stone disease due to mutations in 2 genes: SLC3A1 and SLC7A9. Antenatal hyperechoic colon (HEC) has been reported in some patients as a non-pathological consequence of the intestinal transport defect. We report 83 patients affected by cystinuria: 44 presented prenatally with a HEC (HEC group) and 39 with a classical postnatal form (CC group). SLC3A1 and SLC7A9 were sequenced. All patients were fully genotyped, and the relationship between the genotype and clinical features was analyzed. We identified mutations in SLC3A1 in 80% of the HEC group and in only 49% of the CC group. The SLC3A1 p.Thr216Met mutation was found in 21% of the alleles in the HEC group but was never found in the CC group. Most of the mutations found in the HEC group were considered severe mutations in contrast with the CC group. Twenty-five novel mutations were reported. This study shows a relationship between genotype and the clinical form of cystinuria, suggesting that only the patients with the most severe mutations presented with an HEC. These results emphasized the need for prenatal cystinuria screening using classical third-trimester ultrasound scan and the early management of suspected newborns.

Germline mutations of the CBL gene define a new genetic syndrome with predisposition to juvenile myelomonocytic leukaemia.

BACKGROUND: CBL missense mutations have recently been associated with juvenile myelomonocytic leukaemia (JMML), an aggressive myeloproliferative and myelodysplastic neoplasm of early childhood characterised by excessive macrophage/monocyte proliferation. CBL, an E3 ubiquitin ligase and a multi-adaptor protein, controls proliferative signalling networks by downregulating the growth factor receptor signalling cascades in various cell types. METHODS AND RESULTS: CBL mutations were screened in 65 patients with JMML. A homozygous mutation of CBL was found in leukaemic cells of 4/65 (6%) patients. In all cases, copy neutral loss of heterozygosity of the 11q23 chromosomal region, encompassing the CBL locus, was demonstrated. Three of these four patients displayed additional features suggestive of an underlying developmental condition. A heterozygous germline CBL p.Y371H substitution was found in each of them and was inherited from the father in one patient. The germline mutation represents the first hit, with somatic loss of heterozygosity being the second hit positively selected in JMML cells. The three patients display a variable combination of dysmorphic features, hyperpigmented skin lesions and microcephaly that enable a 'CBL syndrome' to be tentatively delineated. Learning difficulties and postnatal growth retardation may be part of the phenotype. CONCLUSION: A report of germline mutations of CBL in three patients with JMML is presented here, confirming the existence of an unreported inheritable condition associated with a predisposition to JMML.

Outcome of laparoscopic sacrocolpopexy with anterior and posterior mesh.

AIM: The assessment of the postoperative outcome following laparoscopic sacrocolpopexy using anterior and posterior mesh. MATERIAL AND METHODS: In the study were included one hundred and ten women (mean age 62 years with range from 34 to 78) who had laparoscopic sarcoplexy the period 2001-2005. They were contacted and completed postal questionnaires more than one year after surgery and had a follow up in the uro-gynaecology clinic. RESULTS: The median follow up was 21 months. Eighty-three of them (75.4%) answered the postal questionnaire. Good satisfaction was defined as complete disappearance of all genito-urinary symptoms. Moderate satisfaction was defined as a partial disappearance of symptoms, or de novo less annoying symptoms. Dissatisfaction was defined as no change in symptoms, and /or de novo important symptoms. The overall rate of good satisfaction was 74.7% (62/83), moderate satisfaction 15.6% (13/83), and only 9.6% (8/83) were not satisfied. There was no statistical difference among the six different groups (sacrocolpopexy only, plus TVT, plus TVT and hysterectomy, sacrocolpopexy and previous hysterectomy, sacrocolpopexy and TVT with previous hysterectomy), concerning the pre and post operative clinical signs and post operative symptoms. There was a statistically significant difference (p=0.038) regarding dissatisfaction and prolapse relapse between the group that had a previous total hysterectomy combining sacrocolpopexy with TVT and all other groups. The most frequent post operative symptoms were stress incontinence, dysuria and constipation. No severe complications and mesh erosion were observed, despite the two cases of mesh detachment. CONCLUSIONS: Laparoscopic double synthetic mesh sacrocolpopexy seems to be a safe and effective treatment of genitourinary prolapse, with good overall long term outcomes and benefits of the minimal access approach. The presence of the remaining cervix after subtotal hysterectomy, seems to enhance the results of laparoscopic sacrocolpopexy.. Further randomised studies are needed to confirm our results and to compare this method to open and/or vaginal approach.

Long-term outcome in methylmalonic aciduria: a series of 30 French patients.

OBJECTIVE: To better delineate the natural history of patients with methylmalonic aciduria (MMA). STUDY DESIGN: Thirty patients with vitamin-B12-unresponsive MMA (25 aged 1.5 to 22.0 years (y) at the end of the study and 5 who died during a metabolic crisis) were managed following standardized guidelines and studied retrospectively. The median follow-up was 8.3 y (range: 1.4-19.5). Patients were investigated with neuropsychological testing, brain MRIs, inulin clearances, biochemical and genetic studies. RESULTS: Fifteen patients had a neonatal onset. Thirteen patients (43%) had significant neurological impairment. Chronic renal disease (CRD) occurred in 14 patients (47%) with a median age of onset of 6.5 y (range 1.5-18.6). Renal function further deteriorated in 4 patients within a median period of 5.8 y (range 2-7.4). Of 25 patients investigated at the enzymatic level, 17 were classified mut(o), 3 mut- and 5 cblA. Mortality, number of acute decompensations (p=0.031), median MMA urinary excretion (p=0.006) and neurological impairment (p<0.0001) were higher in mut degrees patients compared to mut-/cblA patients. Concerning the CRD, no difference incidence was found although the onset of CRD occurred earlier in mut(o) patients and was more severe. CONCLUSIONS: Our study provides unique data concerning the progression of renal disease in MMA. Patients with mut(o) phenotype have a more severe phenotype and probably an earlier and more severe CRD than patients with mut-/cblA phenotype.

Spontaneous and oxidative stress-induced programmed cell death in lymphocytes from patients with ataxia telangiectasia (AT).

T cell lymphopenia in the peripheral blood lymphocytes (PBL) of patients with AT is mainly caused by a decrease of naive CD45RA+/CD4+ cells followed by a predominance of memory CD45RO+ lymphocytes. To relate these findings to the regulation of programmed cell death, we investigated the activation state and apoptotic level of PBL in 12 patients and healthy controls by flow cytometry. In accordance with previous investigations, the number of naive CD4+/CD45RA+ cells was significantly decreased in patients compared with healthy controls. This disturbed balance of CD45RA and CD45RO was also reflected in higher amounts of activated HLA-DR and CD95 expressing cells, with a concomitant decrease of Bcl-2 protected lymphocytes in the T cell population. With regard to its role in preventing oxidative-induced cell death, we analysed Bcl-2 expression and apoptosis in the presence of oxidative stress. In culture, cells of patients are more susceptible to spontaneous programmed cell death. However, in our stress-inducing system (hypoxanthine/xanthine oxidase system) the number of cells undergoing apoptosis was lower in patients' cell populations compared with controls. In addition, preliminary results suggest that Bcl-2 expression and level of spontaneous apoptosis in patients can be modified by IL-2 and interferon-gamma.

Professional isolation and occupational stress in teachers.

The aim of the study was to investigate the relationship between professional isolation of teachers and their occupational stress. A systematic random sample of 1,110 teachers in Quebec were administered French Canadian versions of the UCLA Loneliness Scale and Teacher Stress Inventory. Analysis gave, as expected, a positive and significant correlation between isolation and occupational stress. This highlights the importance of looking for ways to reduce professional isolation of teachers.

Survival in dogs with nasal adenocarcinoma: 64 cases (1981-1995).

Case records of 64 dogs with nasal adenocarcinoma were reviewed. The effects of age, gender, tumor stage, presence of metastatic lesions, and treatment method on survival time were examined. Surgery groups included rhinotomy (n = 9), transnasal curettage (n = 29), and no surgery (n = 26). Chemotherapy groups included fluorouracil-cyclophosphamide combination therapy (n = 15), mitoxantrone (n = 7), and no chemotherapy (n = 42). Fifty-three dogs received fractionated cobalt 60 radiation therapy. Surgical procedure, chemotherapy group, and stage of primary tumor were not significantly associated with survival time (P > .05). Dogs that received radiation therapy had a significantly longer median survival time (424 days) than dogs that did not (126 days)(P = .0001). The presence of either regional lymph node or pulmonary metastasis was associated with significantly shorter median survival time (109 days) when compared to dogs without metastases (393 days)(P = .0125). When only dogs that had received radiation therapy were considered, neither surgical treatment nor chemotherapy group was associated with significant changes in median survival time. An alternate staging system emphasizing the presence or absence of metastases is proposed.

Accuracy of fluorocrit in determination of blood perflubron concentration.

Previous studies examining the radiosensitizing effects of perfluorochemical emulsions have based dose recommendations on a measurement known as fluorocrit. The fluorocrit is the proportion of blood volume occupied by perfluorochemicals and is measured using standard hematocrit procedures. This measurement is inherently crude and subject to error and variability between different individuals measuring the same sample. Furthermore, the fluorocrit method has not been compared to other quantitative methods to determine its reliability. The purpose of this study was to compare fluorocrit measurements to those obtained by gas chromatographic analysis. A 90% w/v perflubron emulsion was administered to six normal dogs once weekly for four weeks and peripheral blood samples were obtained at specified time points for analysis. A total of 123 blood samples were analyzed by both methods. The relationship between blood fluorocrit and plasma perflubron concentration measured by gas chromatography was examined using regression models. Based on the modest predictive value (r2 = 0.3683) of the derived statistical model, we conclude that fluorocrit measurement is an inaccurate method of estimation of blood perflubron concentration. Caution must, therefore, be exercised when extrapolating data and dose recommendations from reports of studies using flurocrit as the only estimate of blood perflubron concentration.

Hematological and clinical responses to combined mitoxantrone and cyclophosphamide administration to normal cats.

The purpose of this study was to examine the feasibility of a combination chemotherapy protocol ("CYCLONE") in cats, utilizing mitoxantrone and cyclophosphamide. Three normal adult cats were administered mitoxantrone (6.5 mg/m2 intravenously) and cyclophosphamide (100 mg/m2 intravenously) every 21 days for a total of three doses. Individual white blood cell count nadirs (range, 2.0-9.5 x 10(9)/L) and neutrophil count nadirs (range, 0.3 to 5.0 x 10(9)/L) occurred between days 2 and 10 after each dose of chemotherapy. Mean white blood cell count nadirs (range of mean, 5.5 to 8.4 x 10(9)/L) occurred between days 6 and 8, as did the mean neutrophil count nadir (range of mean, 1.7-4.0 x 10(9)/L). Side effects were limited to transient appetite suppression in one cat and loose stools in two cats. Myelosuppression and gastrointestinal side effects were comparable to those observed with single-agent mitoxantrone protocols. Further investigation of this protocol is warranted.