Ulcerative proctitis is a frequent location of paediatric-onset UC and not a minor disease: a population-based study.

OBJECTIVE: Natural history of paediatric-onset ulcerative proctitis (UP) is poorly described. Our aim was to describe the phenotype and disease course of incident UP in a population-based study of paediatric-onset UC. PATIENTS AND METHODS: All patients with UC diagnosed <17 years from 1988 to 2004, and followed during >2 years have been extracted from a population-based registry. UC location was defined according to the Paris classification. Cumulative risks for use of immunosuppressants (IS), anti-tumour necrosis factor alpha (TNF-α) therapy, colonic extension and colectomy were described using Kaplan-Meier method. Risk factors for colonic extension were assessed using Cox proportional hazards models. RESULTS: 158 patients with paediatric-onset UC (91 females) with a median age at diagnosis of 14.5 years (Q1: 11.4-Q3: 16.1) have been identified and followed during a median of 11.4 years (8.2-15.8). Among them, 25% had UP (E1) at diagnosis and 49% of them presented a colonic extension at maximal follow-up. In these children, the cumulative risk for colonic extension was 10% at 1 year, 45% at 5 years and 52% at 10 years. No parameter at diagnosis was associated with colonic extension in the UP (E1 group). IS use was significantly lower in patients with UP than in those with E2, E3 or E4 location (p=0.049). For the UP cohort, the cumulative risk for colectomy was 3% at 1 year, 10% at 5 years, 13% at 10 years and 13% at 15 years. Risks for colonic extension, treatment with anti-TNF-α and colectomy did not differ between the E1 group and the E2-E3-E4 group. CONCLUSIONS: UP is frequent in paediatric-onset UC and should not be considered as a minor disease. Compared with more extensive UC locations, risks for colonic extension, anti-TNF-α therapy and colectomy were similar in UP, whereas the risk for use of IM was lower.

Stochastic coreceptor shut-off is restricted to the CD4 lineage maturation pathway.

Kinetics of mature T cell generation in the thymus of normal or major histocompatibility complex (MHC) class I- or II-deficient mice were studied by the bromodeoxyuridine pulse labeling method. As previously described, the early activation and final maturation phases were found to be synchronous for the two T cell lineages, but CD4+8- cells were generated faster than CD4-8+ cells in MHC class I- and II-deficient mice, respectively. CD8 downregulation started on day 2 after cell proliferation even in the absence of MHC class II expression. CD8 downregulation thus appears to be stochastic at its beginning. By contrast, CD4 shut-off was found totally instructive, as the generation of CD4lo8+ cells with a high TCR density was not observed in class I-deficient mice. The analysis of the V beta 14 TCR frequencies in CD4/8 subsets in normal and MHC-deficient mice confirmed that CD4 and CD8 generation pathways are not symmetrical. These findings show that commitment towards the CD4+8- or CD4-8+ phenotype is controlled at the CD8lo step for the former and at the CD4+8+ double-positive stage for the latter.

Two Caucasian families with the hepatocyte nuclear factor-1alpha mutation Tyr218Cys.

We report on the first two Caucasian families with the MODY3 HNF-1alpha mutation Tyr218Cys. Clinical and laboratory examinations are shown in detail. Patients with HNF-1alpha related MODY may develop the full spectrum of diabetic complications. Therefore, early detection of family members with MODY3 is warranted.

Incidence and Phenotype at Diagnosis of Very-early-onset Compared with Later-onset Paediatric Inflammatory Bowel Disease: A Population-based Study [1988-2011].

BACKGROUND AND AIMS: Very-early-onset inflammatory bowel disease [VEO-IBD] is a form of IBD that is distinct from that of children with an older onset. We compared changes over time in the incidence and phenotype at diagnosis between two groups according to age at IBD diagnosis: VEO-IBD diagnosed before the age of 6 years, and early-onset IBD [EO-IBD] diagnosed between 6 and 16 years of age. METHODS: Data were obtained from a cohort enrolled in a prospective French population-based registry from 1988 to 2011. RESULTS: Among the 1412 paediatric cases [< 17 years], 42 [3%] were VEO-IBD. In the VEO-IBD group, the incidence remained stable over the study period. In contrast, the incidence of EO-IBD increased from 4.4/105 in 1988-1990 to 9.5/105 in 2009-2011 [+116%; p < 10-4]. Crohn's disease [CD] was the most common IBD, regardless of age, but ulcerative colitis [UC] and unclassified IBD were more common in VEO-IBD cases [40% vs 26%; p = 0.04]. VEO-IBD diagnosis was most often performed in hospital [69% vs 43%; p < 10-3]. Rectal bleeding and mucous stools were more common in patients with VEO-IBD, whereas weight loss and abdominal pain were more frequent in those with EO-IBD. Regarding CD, isolated colonic disease was more common in the VEO-IBD group [39% vs 14%; p = 0.003]. CONCLUSIONS: In this large population-based cohort, the incidence of VEO-IBD was low and stable from 1988 to 2011, with a specific clinical presentation. These results suggest a probable genetic origin for VEO-IBD, whereas the increase in EO-IBD might be linked to environmental factors.

Thy-1 modulation and cell proliferation at early steps of intrathymic bone marrow cell differentiation.

Intrathymic (IT) transfer of bone marrow (BM) precursor cells in sublethally irradiated hosts has been widely used to study T cell differentiation and maturation. In this report we have used double congenic mice Ly 5.1 Thy 1.1 (host) and Ly 5.2 Thy 1.2 (donor) and detected cycling Ly 5.2+ BM cells by in vivo bromodeoxyuridine incorporation, before induction of the Thy 1.2 antigen. Until Day 9 post-transfer, some donor type cells express a high level of Thy 1.2 together with macrophage and granulocyte markers. A few days later, a Thy 1.2low population transiently B220+ was detected. Thereafter, donor type cells expressed an intermediate Thy 1.2 brightness; this population then persisted and surpassed the other subsets. Our findings permitted to establish a relationship between cell cycle and Thy 1 fluorescence intensity according to the sequence: Thy 1low resting, Thy 1low cycling, Thy 1high cycling, Thy 1high resting. Moreover, we have shown that cells from the myeloïd and B lineages can, in vivo, transiently express the Thy 1 antigen, develop and differentiate within the thymus microenvironment.

Usability Flaws in Medication Alerting Systems: Impact on Usage and Work System.

OBJECTIVES: Previous research has shown that medication alerting systems face usability issues. There has been no previous attempt to systematically explore the consequences of usability flaws in such systems on users (i.e. usage problems) and work systems (i.e. negative outcomes). This paper aims at exploring and synthesizing the consequences of usability flaws in terms of usage problems and negative outcomes on the work system. METHODS: A secondary analysis of 26 papers included in a prior systematic review of the usability flaws in medication alerting was performed. Usage problems and negative outcomes were extracted and sorted. Links between usability flaws, usage problems, and negative outcomes were also analyzed. RESULTS: Poor usability generates a large variety of consequences. It impacts the user from a cognitive, behavioral, emotional, and attitudinal perspective. Ultimately, usability flaws have negative consequences on the workflow, the effectiveness of the technology, the medication management process, and, more importantly, patient safety. Only few complete pathways leading from usability flaws to negative outcomes were identified. CONCLUSION: Usability flaws in medication alerting systems impede users, and ultimately their work system, and negatively impact patient safety. Therefore, the usability dimension may act as a hidden explanatory variable that could explain, at least partly, the (absence of) intended outcomes of new technology.

Mutation screening of the urocortin gene: identification of new single nucleotide polymorphisms and association studies with obesity in French Caucasians.

A linkage between obesity-related phenotypes and the 2p21-23 locus has been reported previously. The urocortin (UCN) gene resides at this interval, and its protein decreases appetite behavior, suggesting that UCN may be a candidate gene for susceptibility to obesity. We localized the UCN gene by radiation hybrid mapping, and the surrounding markers were genotyped in a collection of French families. Evidence for linkage was shown between the marker D2S165 and leptin levels (LOD score, 1.34; P = 0.006) and between D2S2247 and the z-score of body mass index (LOD score, 1.829; P = 0.0019). The gene was screened for SNPs in 96 obese patients. Four new variants were established. Two single nucleotide polymorphisms were located in the promoter (-535 A-->G, -286 G-->A), one in intron 1 (+31 C-->G), and one in the 3'-untranslated region (+34 C-->T). Association studies in cohorts of 722 unrelated obese and 381 control subjects and transmission disequilibrium tests, performed for the two frequent promoter polymorphisms, in 120 families (894 individuals) showed that no association was present between these variants and obesity, obesity-related phenotypes, and diabetes. Thus, our analyses of the genetic variations of the UCN gene suggest that, at least in French Caucasians, they do not represent a major cause of obesity.

Dissection of an inverted X(p21.3q27.1) chromosome associated with mental retardation.

In a 6 year old boy referred for mental retardation, fragile X syndrome was ruled out by cytogenetic and molecular analyses. Cytogenetic investigations revealed an inverted X chromosome (p21.3q27.1). A similar chromosomal rearrangement was detected in his mildly mentally retarded mother. Fluorescence in situ hybridization (FISH), using a panel of ordered YAC clones, allowed the identification of YACs spanning both the Xp21.3 and Xq27.1 breakpoints, where many non-specific mental retardation loci have been reported so far. Further investigations by FISH showed that the IL1RAPL1 gene at Xp21.3 was disrupted by the X chromosome inversion and therefore its inactivation may be related to the mental retardation observed in our patients.

Delayed spontaneous alternation in intact and cerebellectomized control and lurcher mutant mice: differential role of cerebellar cortex and deep cerebellar nuclei.

Lurcher mutant (+/Lc) mice exhibit a massive loss of neurons in the cerebellar cortex and in the inferior olivary nucleus while deep cerebellar nuclei are essentially intact. To discriminate the respective participation of the cerebellar cortex and deep structures in learning and memory, the authors subjected 3- to 6-month-old +/Lc mice to a delayed spontaneous alternation task to test their working and long-term spatial memories. Results show that wild type (+/+) mice alternated above chance even after a 1-hr delay between the forced and choice trials, whereas in +/Lc mice, long-term memory was impaired. Cerebellectomized +/+ mice behave as +/Lc mice (working memory was preserved but long-term memory was not), whereas in the cerebellectomized +/Lc mice, both working and long-term memories were altered. These results are discussed in terms of relationships between the cerebellum and the hippocampus.

Cytogenetics in multiple myeloma: a multicenter study of 24 patients with t(11;14)(q13;q32) or its variant.

Twenty-two patients with multiple myeloma (MM) with a classical t(11;14)(q13;q32) and two complex variants also involving 11q13 and 14q32 regions are reported. We show that t(11;14) (q13;q32) is predominantly noticed in stages II and III and never in stage I patients. Translocation (11;14)(q13;q32) is predominantly observed in hypodiploid or pseudodiploid clones associated with total or partial monosomy of chromosome 13 and additional structural changes in chromosome 1. These translocations may be discovered not only in standard cultures (24-48 hours) without stimulation, but also in cytokine-stimulated cultures (granulocyte macrophage colony-stimulating factor and interleukin 6). The t(11;14)(q13;q32) as a primary or secondary event in MM is discussed, because, in one patient, it was only discovered at relapse.

Differential roles of cerebellar cortex and deep cerebellar nuclei in the learning of the equilibrium behavior: studies in intact and cerebellectomized lurcher mutant mice.

Three- to 6-month-old lurcher mutant mice (+/lc), which exhibit a massive loss of neurons in the cerebellar cortex and in the inferior olivary nucleus but whose deep cerebellar nuclei are essentially intact, were trained daily, for 9 days, to maintain their equilibrium upon a rota rod rotating at 20 or 30 revolutions per minute (rpm). Their scores were measured and their behavior upon the rotating rod quantified in comparison to those of matched control (+/+) mice. Lurcher mice were able to learn to maintain their equilibrium efficiently when rotated at 20 rpm but were not when rotated at 30 rpm. After cerebellectomy, the equilibrium capabilities of the animals were much altered, especially in +/lc. These results show that the deep cerebellar nuclei are sufficient for motor learning, provided the task is not too difficult (20 rpm), but that the cerebellar cortex is required when the task is more difficult (30 rpm). Therefore, it can be concluded that the adaptive motor capabilities of lurcher mice are less developed than those of control animals.

Genetic study of the CD36 gene in a French diabetic population.

OBJECTIVES: CD36 is a multifunctional membrane receptor widely expressed in different tissues which binds and internalizes oxidized low-density lipoprotein. In rodents, CD36 gene variations modulate glucose homeostasis and contribute to metabolic syndrome associated with type 2 diabetes but the effects in human are unknown. METHODS: We screened the entire coding sequence of the CD36 gene in 272 individuals and we genotyped both rare and frequent variants in 454 T2D subjects and 221 controls. RESULTS: We detected five mutations, P191P and N247S were only found each in one family and did not segregate with diabetes, the three others (A/C-178 in the promoter, A/G-10 in intron 3 and (GGGTTGAGA) insertion in intron 13) being equally frequent in diabetic subjects and in controls. However, adiponectin levels, a marker for insulin sensitivity, were significantly associated with the -178 A/C promoter variant allele (p=0.003, p corrected for multiple testing=0.036), possibly reflecting association with insulin-resistance in the French population. CONCLUSION: Thus, the -178 A/C SNP promoter mutation in the CD36 gene represents a putative genetic marker for insulin-resistance in the French population, although it does not appear to contribute to the genetic risk for T2D.

[Ki67 in young patients with breast cancer]. / Ki67 chez les patientes jeunes présentant un cancer du sein.

UNLABELLED: The aim of the study was to compare KI67 in young breast cancer patients (pts) (35 years or less), and in older ones. Forty-three young pts treated between January 1, 2006 and December 31, 2008 as well as pts more than 35 years treated in the same institution in 2006 were considered. Biomarker studies were carried out on a surgical specimen or on a biopsy before neoadjuvant chemotherapy if any. Young pts had a higher median value of KI67 (30% [3-95] versus 10% [0-90] P<0.0001) a higher rate of SBR3 (44 versus 28% P<04), of mitotic index 3 (35 versus 13% P<0.001). ER was less frequently positive (56 versus 87%, P<0.001) as well as PR (38 versus 68% P<0.001). HER2 was more frequently amplified in young pts (24 versus 10% P<0.007). Young pts more frequently had a triple negative breast cancer (TNBC) (31 versus 8% P<0.001). In TNBC pts, KI67 was higher in younger pts (70% [10-95] versus 38% [2-80] P=0.06). Among young pts, TNBC had a higher KI67 than non TNBC (70% [10-95 versus 20% [3-60] P<0.001). CONCLUSION: KI67 is significantly higher in young pts than in older ones. TNBC is significantly more frequent; among young pts, and KI67 is significantly higher in TNBC.

Haplotypes in the promoter region of the ADIPOQ gene are associated with increased diabetes risk in a German Caucasian population.

Adiponectin, which is encoded by the ADIPOQ gene, has been shown to modulate insulin sensitivity and glucose homeostasis. Plasma adiponectin levels are decreased in type 2 diabetes and obesity. Genetic variations within the ADIPOQ gene are associated with decreased adiponectin hormone levels. To analyze specific single-nucleotide polymorphisms (SNPs) and their association with T2D, 365 German subjects with T2D and 323 control subjects were screened. Three common SNPs - +45T>G in exon 2, and 2 promoter variants SNPs -11391G>A and -11377C>G - were analyzed. We found that the variant allele of SNP -11391G>A was significantly more frequent in the diabetic patient group than in the control group (p=0.003). Carrying the haplotype of SNP -11391A and SNP -11377C was associated with a 1.50-fold (p=0.03) increase in diabetes risk. The combination of the A-C haplotype and the G-C haplotype was associated with significantly elevated diabetes risk (OR=2.82 (95% CI: 1.35-5.91), p=0.006) after correction for BMI and age. Our observations suggest that diploid combinations of haplotype in the adiponectin gene promoter region contribute to the genetic risk of T2D in individuals from a German Caucasian population.

Hypoadiponectinaemia and high risk of type 2 diabetes are associated with adiponectin-encoding (ACDC) gene promoter variants in morbid obesity: evidence for a role of ACDC in diabesity.

AIMS/HYPOTHESIS: Morbid obesity (BMI>40 kg/m(2)) affecting 0.5-5% of the adult population worldwide is a major risk factor for type 2 diabetes. We aimed to elucidate the genetic bases of diabetes associated with obesity (diabesity), and to analyse the impact of corpulence on the effects of diabetes susceptibility genes. METHODS: We genotyped known single nucleotide polymorphisms (SNPs) in the adiponectin-encoding adipocyte C1q and collagen-domain-containing (ACDC) gene (-11,391G>A, -11,377C>G, +45T>G and +276G>T), the peroxisome proliferator-activated receptor gamma (PPARG) Pro12Ala SNP and ACDC exon 3 variants in 703 French morbidly obese subjects (BMI 47.6+/-7.4 kg/m(2)), 808 non-obese subjects (BMI<30 kg/m(2)) and 493 obese subjects (30< or =BMI<40 kg/m(2)). RESULTS: Two 5'-ACDC SNPs -11,391G>A, -11,377C>G were associated with adiponectin levels (p=0.0003, p=0.008) and defined a "low-level" haplotype associated with decreased adiponectin levels (p=0.0002) and insulin sensitivity (p=0.01) and with a risk of type 2 diabetes that was twice as high (p=0.002). In contrast, the prevalence of the PPARG Pro12Ala was identical in diabetic and normoglycaemic morbidly obese subjects. The PPARG Pro12 allele only displayed a trend of association with type 2 diabetes in the non-obese group. ACDC exon 3 variants were associated with type 2 diabetes in the non-obese group only (odds ratio 7.85, p<0.0001). In contrast, the 5'-ACDC "low-level" haplotype was associated with type 2 diabetes in obese and morbidly obese subjects (odds ratio 1.73 and 1.92) but not in non-obese individuals. CONCLUSIONS/INTERPRETATION: These data clarify the contribution of the 5'-ACDC SNPs to the risk of diabesity. Their interaction with corpulence suggests for the first time a different genetic profile of type 2 diabetes in morbidly obese patients compared with in less obese individuals.