Prise en compte du risque tératogène dans la prescription chez les femmes en âge de procréer (Evaluation auprès des médecins généralistes)

TOURS-BU Médecine (372612103) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Identification of protease-sensitive but not misfolding PNLIP variants in familial and hereditary pancreatitis

Mutations in the PNLIP gene have recently been implicated in chronic pancreatitis. Several PNLIP missense variants have been reported to cause protein misfolding and endoplasmic reticulum stress although genetic evidence supporting their association with chronic pancreatitis is currently lacking. Protease-sensitive PNLIP missense variants have also been associated with early-onset chronic pancreatitis although the underlying pathological mechanism remains enigmatic. Herein, we provide new evidence to support the association of protease-sensitive PNLIP variants (but not misfolding PNLIP variants) with pancreatitis. Specifically, we identified protease-sensitive PNLIP variants in 5 of 373 probands (1.3%) with a positive family history of pancreatitis. The protease-sensitive variants, p.F300L and p.I265R, were found to segregate with the disease in three families, including one exhibiting a classical autosomal dominant inheritance pattern. Consistent with previous findings, protease-sensitive variant-positive patients were often characterized by early-onset disease and invariably experienced recurrent acute pancreatitis, although none has so far developed chronic pancreatitis

Evidence for the high importance of co-morbid factors in HFE C282Y/H63D patients cared by phlebotomies: results from an observational prospective study.

Despite type I haemochromatosis (HC) is mainly associated with the HFE C282Y/C282Y genotype, a second genotype -C282Y/H63D- has mostly been described in other patients. Its association with HC, apart from any associated co-morbid factors, remains unclear and complex to interpret for physicians. This study assesses the weight of this genotype and the role of co-morbid factors in the occurrence of iron overload. This prospective study included the C282Y/C282Y (n = 172) and C282Y/H63D (n = 58) patients enrolled in a phlebotomy program between 2004 and 2007 in a blood centre of western Brittany (Brest, France), where HC is frequent. We compared prevalence of these two genotypes, as well as patients' profile regarding degree of iron overload and prevalence of co-morbid factors. First, we confirmed the obvious deficit of C282Y/H63D compound heterozygotes among patients cared by phlebotomies. This genotype was 3.0 times less frequent than the C282Y/C282Y genotype among those patients (18.9% vs. 56.0%) whereas it was 4.9 times more frequent in the general population (4.3% vs. 0.9%; p<0.0001). Despite a similar level of hyperferritinaemia, the C282Y/H63D patients who came to medical attention had a milder plasma iron overload, reflected by a lower transferrin saturation median (52.0% vs. 84.0%; p<0.0001). They also exhibited more frequently co-morbid factors, as heavy drinking (26.0% vs. 13.9%; p = 0.0454), overweight (66.7% vs. 39.4%; p = 0.0005) or both (21.3% vs. 2.6%; p<0.0001). Ultimately, they required a lower amount of iron removed to reach depletion (2.1 vs. 3.4 g; p<0.0001), clearly reflecting their lower tissue iron. This study confirms that H63D is a discrete genetic susceptibility factor whose expression is most visible in association with other co-factors. It highlights the importance of searching for co-morbidities in these diagnostic situations and of providing lifestyle and dietary advice

Additional file 1: of Mutational status of synchronous and metachronous tumor samples in patients with metastatic non-small-cell lung cancer

SNaPshot Multiplex analysis of KRAS codons 12 and 13 (HUGO Gene Nomenclature Committee #6407). (ODP 128 kb

Frequency of co-morbid factors in C282Y/H63D and C282Y/C282Y patients who were enrolled in a phlebotomy program at the blood centre of Brest (western Brittany, France) between 2004 and 2007.

<p>Frequency of co-morbid factors in C282Y/H63D and C282Y/C282Y patients who were enrolled in a phlebotomy program at the blood centre of Brest (western Brittany, France) between 2004 and 2007.</p

Comparison of serum markers in C282Y/H63D and C282Y/C282Y patients who were enrolled in a phelebotomy program at the blood centre of Brest (western Brittany, France) between 2004 and 2007.

<p>*Q1: first quartile; Q3: third quartile.</p

Parameter estimates of the linear regression model testing the effect of genotype on the level of serum markers, after adjustment on covariables.

<p>Parameter estimates of the linear regression model testing the effect of genotype on the level of serum markers, after adjustment on covariables.</p

Frequency of <i>HFE</i> genotypes observed in the study population (<i>i.e.</i> among patients enrolled in a phlebotomy programme) and in the general population.

<p>*wt: wild type.</p