ABSTRACT
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.
Subject(s)
Inflammatory Bowel Diseases/epidemiology , Adolescent , Age of Onset , Child , Child, Preschool , Colitis, Ulcerative/diagnosis , Colitis, Ulcerative/epidemiology , Colitis, Ulcerative/pathology , Crohn Disease/diagnosis , Crohn Disease/epidemiology , Crohn Disease/pathology , Female , France/epidemiology , Humans , Incidence , Inflammatory Bowel Diseases/diagnosis , Inflammatory Bowel Diseases/pathology , Male , Phenotype , Prospective Studies , RegistriesABSTRACT
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 <17â years from 1988 to 2004, and followed during >2â 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 14.5â years (Q1: 11.4-Q3: 16.1) have been identified and followed during a median of 11.4â 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 1â year, 45% at 5â years and 52% at 10â 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 1â year, 10% at 5â years, 13% at 10â years and 13% at 15â 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.
Subject(s)
Colitis, Ulcerative/diagnosis , Proctitis/diagnosis , Adolescent , Child , Colectomy , Colitis, Ulcerative/physiopathology , Colitis, Ulcerative/therapy , Disease Progression , Female , Follow-Up Studies , Humans , Immunosuppressive Agents/therapeutic use , Kaplan-Meier Estimate , Male , Phenotype , Proctitis/physiopathology , Proctitis/therapy , Prognosis , Proportional Hazards Models , Registries , Retrospective Studies , Risk FactorsABSTRACT
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.
Subject(s)
Medical Order Entry Systems , User-Computer Interface , Decision Support Systems, Clinical , Drug Therapy, Computer-Assisted , Ergonomics , Humans , Medication Errors/prevention & control , Patient SafetyABSTRACT
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.
Subject(s)
Biomarkers, Tumor/analysis , Breast Neoplasms/chemistry , Ki-67 Antigen/analysis , Adult , Age Factors , Breast Neoplasms/pathology , Breast Neoplasms/surgery , Chemotherapy, Adjuvant , Female , Humans , Neoadjuvant Therapy , Prognosis , Receptor, ErbB-3/analysis , Receptors, Estrogen/analysis , Receptors, Progesterone/analysis , Survival Rate , Triple Negative Breast Neoplasms/chemistry , Triple Negative Breast Neoplasms/pathology , Triple Negative Breast Neoplasms/surgeryABSTRACT
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.
Subject(s)
Diabetes Complications/genetics , Diabetes Mellitus, Type 2/genetics , Hepatocyte Nuclear Factor 1-alpha/genetics , Mutation, Missense , Adolescent , Adult , Diabetes Complications/metabolism , Diabetes Mellitus, Type 2/metabolism , Family , Female , Hepatocyte Nuclear Factor 1-alpha/metabolism , Humans , Male , Middle Aged , Pedigree , White PeopleABSTRACT
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.
Subject(s)
Adiponectin/genetics , Diabetes Mellitus, Type 2/genetics , Haplotypes/genetics , Promoter Regions, Genetic/genetics , Case-Control Studies , Female , Gene Frequency , Germany , Humans , Male , Middle Aged , Multivariate Analysis , Polymorphism, Single Nucleotide/genetics , Risk Factors , White PeopleABSTRACT
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.
Subject(s)
Diabetes Mellitus/genetics , Genetic Variation , Intercellular Signaling Peptides and Proteins/genetics , Obesity, Morbid/genetics , Promoter Regions, Genetic , Adiponectin , Diabetes Complications/genetics , Diabetes Mellitus/blood , Family , Female , France , Genotype , Humans , Intercellular Signaling Peptides and Proteins/blood , Intercellular Signaling Peptides and Proteins/deficiency , Male , Obesity, Morbid/blood , PPAR gamma/genetics , Polymorphism, Single Nucleotide , White PeopleABSTRACT
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.
Subject(s)
CD36 Antigens/genetics , Diabetes Mellitus/genetics , Genetic Variation , Mutation , Adiponectin , Base Sequence , Diabetes Mellitus/immunology , Exons/genetics , France , Genotype , Humans , Insulin Resistance/genetics , Intercellular Signaling Peptides and Proteins/blood , Introns/genetics , Polymorphism, Single Nucleotide/genetics , Promoter Regions, Genetic , Reference ValuesABSTRACT
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.
Subject(s)
Chromosome Inversion , Chromosomes, Human, X , Mental Retardation, X-Linked/genetics , Sex Chromosome Aberrations , Child , Chromosome Mapping , Female , Genetic Predisposition to Disease , Humans , In Situ Hybridization, Fluorescence , Karyotyping , Male , PedigreeABSTRACT
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.
Subject(s)
Corticotropin-Releasing Hormone/genetics , Genetic Testing , Mutation , Obesity/genetics , Polymorphism, Genetic/genetics , White People/genetics , Adult , Aged , Base Sequence/genetics , Chromosomes, Human, Pair 2/genetics , Female , France , Gene Frequency , Humans , Male , Middle Aged , Quantitative Trait, Heritable , UrocortinsABSTRACT
Precursor CD4-CD8- (DN) thymocytes rearrange their TCR-beta genes, and only those which succeed in beta-selection subsequently expand and differentiate into immature CD4+CD8+ (DP) thymocytes. The cell subsets corresponding to the successive steps of this transition can be defined in terms of CD44 and CD25 expression. We partially synchronized the differentiation process by eliminating cycling cells with the anti-mitotic agent demecolcine. Using in vivo pulse labeling with bromodeoxyuridine, we determined the order of entry into DNA synthesis of the different DN and transitory (CD4-/lo CD8+) cell subsets. Two independent proliferation phases were identified. The first cells to enter the cell cycle were CD44-CD25lo, and CD4/CD8/TCR-/BrdU four-color staining showed that they all expressed a low density of the TCR-beta chain, an element of the pre-TCR (the TCR-alpha locus is still in germ-line configuration at this stage). Cycling of CD44+CD25+ cells was detected later, and no starting point was observed at the CD44-CD25hi stage. CD8 expression was immediately detectable in cycling cells, but they took 24 h to reach the DP stage. The study of TCR-Calpha-deficient mice showed that beta gene rearrangement occurred once proliferation had ceased at the DP stage, and that it had no influence on the DN-DP transition. These data show that precursor thymocytes undergo two independent waves of expansion, and that the second wave is restricted to cells capable of pre-TCR expression.
Subject(s)
Hematopoiesis , T-Lymphocytes/physiology , Animals , CD4 Antigens/analysis , CD8 Antigens/analysis , Cell Differentiation , Cell Division , Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor , Genes, T-Cell Receptor delta , Hematopoietic Stem Cells/physiology , Hyaluronan Receptors/analysis , Immunophenotyping , Kinetics , Mice , Mice, Inbred C57BL , Receptors, Antigen, T-Cell, alpha-beta/analysis , Receptors, Interleukin-2/analysis , RegenerationABSTRACT
AIMS/HYPOTHESIS: Mutations in the hepatocyte nuclear factor (HNF)-1alpha and glucokinase (GCK) genes are the major causes of monogenic forms of Type II (non-insulin-dependent) diabetes mellitus (Maturity-Onset Diabetes of the Young subtypes, MODY). We evaluated the effectiveness of fluorescent single-strand conformation polymorphism (F-SSCP), denaturing high-performance liquid chromatography (DHPLC) and sequencing based mutation detection in the molecular diagnosis of MODY. Our goal is to identify a rapid, efficient and cost effective mutation detection method for the molecular diagnosis of MODY and other human genetic disorders. METHODS: We evaluated the accuracy of DHPLC in screening for MODY 2 and 3 mutations. In addition, we compared the sensitivity, specificity, cost, handling time and analysis time of fluorescent single-strand conformation polymorphism, denaturing high-performance liquid chromatography and direct sequencing screening methods. RESULTS: Denaturing high-performance liquid chromatography is a recently developed method for mutation detection. It is cost effective, powerful and reliable and quite suitable for 22 out of the 24 fragments required for MODY 2 and 3 testing. However, exons 1 and 7 of the HNF-1alpha gene are very polymorphic and so direct sequencing is faster as well as more efficient and reliable. CONCLUSION/INTERPRETATION: Our results suggest that combining denaturing high-performance liquid chromatography and direct sequencing is a good approach for the routine detection of HNF-1alpha and GCK mutations in MODY families. Denaturing high-performance liquid chromatography appears to be a powerful tool in genetic testing and the method could be applied to the molecular diagnosis of other human genetic diseases.
Subject(s)
DNA-Binding Proteins , Diabetes Mellitus, Type 2/diagnosis , Diabetes Mellitus, Type 2/genetics , Glucokinase/genetics , Mutation , Nuclear Proteins , Transcription Factors/genetics , Base Sequence/genetics , Chromatography, High Pressure Liquid/economics , Chromatography, High Pressure Liquid/methods , Chromatography, High Pressure Liquid/standards , Cost-Benefit Analysis , Diabetes Mellitus, Type 2/classification , Hepatocyte Nuclear Factor 1 , Hepatocyte Nuclear Factor 1-alpha , Hepatocyte Nuclear Factor 1-beta , Humans , Polymorphism, Single-Stranded Conformational , Sensitivity and Specificity , Time FactorsABSTRACT
We report on a small de novo interstitial deletion of the short arm of chromosome 20, 46,XY,del(20)(p12.3p13), in a young boy with hypotonia, moderate development delay, mild facial dysmorphism and severe growth failure. This patient did not show major features of Alagille-Watson Syndrome (AWS) which are common in more proximal 20p deletions. Standard and high resolution chromosome banding analysis revealed an apparent terminal deletion. Nevertheless, using chromosomal fluorescent in situ hybridization (FISH) and molecular analysis with polymorphic markers, we demonstrated that the abnormal chromosome resulted from a de novo interstitial deletion of paternal origin spanning from D20S842 to D20S900 and covering approximately 6 Mb. These findings indicate that a karyotype can lead to insufficient characterization of an apparently terminal deletion, and that one or a few genes in 20p13-->p12.3 bands are important for normal growth.
Subject(s)
Chromosome Deletion , Chromosomes, Human, Pair 20/genetics , Growth Disorders/genetics , Alleles , Chromosome Banding , Contig Mapping , Female , Growth Disorders/physiopathology , Haplotypes/genetics , Humans , In Situ Hybridization, Fluorescence , Infant , Karyotyping , Male , Microsatellite Repeats/genetics , Pedigree , White People/geneticsABSTRACT
AIMS/HYPOTHESIS: The UCP2-UCP3 gene region has been previously associated with obesity and diabetes. In a large representative cohort of Northern France (MONICA project), we studied the effect of a recently reported C/T polymorphism located in the 5' sequences of the UCP3 gene on anthropometric measurements and lipid profile. We also examined the association of this polymorphism with obesity and Type II (non-insulin-dependent) diabetes mellitus. METHODS: The -55 C/T polymorphism of the UCP3 gene has been genotyped in 1155 subjects from the MONICA project. Association studies were done with diabetes, obesity and related phenotypes. Results were ascertained in a second cohort of well-characterized Type II diabetic and control subjects. RESULTS: The variant T allele was associated with a decreased risk of developing Type II diabetes. Frequencies of the T allele were 13.3% compared with 22%, p = 0.04, in the diabetic and control groups, respectively. This observation was confirmed in the second cohort of French Type II diabetic (n = 171) and control (n = 124) subjects: 17.8% compared with 25%, p = 0.03. Moreover, subjects bearing the TT genotype had higher plasma total cholesterol and LDL-cholesterol concentrations (p = 0.0006 and p = 0.001, respectively) than subjects bearing wild or heterozygous genotypes. CONCLUSION/INTERPRETATION: The UCP3 -55 C/T polymorphism was associated with a higher atherogenic profile and modified the risk for the development of Type II diabetes.
Subject(s)
Carrier Proteins/genetics , Diabetes Mellitus, Type 2/blood , Lipids/blood , Polymorphism, Genetic , Adult , Alleles , Blood Glucose/analysis , Body Constitution , Body Mass Index , Cholesterol, LDL/blood , Cohort Studies , Female , France , Genetic Predisposition to Disease , Genotype , Humans , Insulin/blood , Ion Channels , Male , Middle Aged , Mitochondrial Proteins , Obesity/blood , Obesity/genetics , Risk Factors , Uncoupling Protein 3ABSTRACT
B lymphocyte generation in bone marrow (BM) compensates for cell loses. The Fas / Fas ligand (FasL) pathway has been implicated in apoptosis of various cell types. Abnormalities of the Fas receptor or of FasL expression are associated with excessive T cell proliferation and autoimmunity. To examine the role of the Fas / FasL system in B cell differentiation, we created double-chimeric mice by transferring both C57BL / 6 (B6)-Fas(+) and lpr-FasL(+) BM cells into RAG-2(- / -) hosts. Equal numbers of stem cells were co-injected into sublethally irradiated recipients, and their progeny were studied by using antibodies directed against the B6-Ly5. 1(+)5.2(+) and lpr-Ly5.1(-)5.2(+) populations. A longitudinal study lasting for up to 6 months revealed that cells of the lpr phenotype dominated the B6 phenotype in the BM, as a result of their active proliferation. Analysis of the B cell compartment showed more lpr than B6 cells among immature HSA(hi)B220(lo) populations. In contrast, the lpr and B6 phenotypes were equally represented among mature B cells. BM transfer to second hosts indicated that B6-derived B cell progenitors were absent from the first host. These data suggest that activation of the Fas / FasL pathway disturbs the early steps of B cell development and might therefore contribute to the onset of autoimmune disorders.
Subject(s)
B-Lymphocytes/immunology , Bone Marrow Cells/immunology , Membrane Glycoproteins/immunology , fas Receptor/immunology , Animals , Apoptosis/immunology , B-Lymphocytes/cytology , Bone Marrow Cells/cytology , Cell Differentiation/immunology , Fas Ligand Protein , Mice , Mice, Inbred C57BL , Signal Transduction/immunologyABSTRACT
Normal mature thymocytes proliferate before emigrating to the periphery, and continuous bromodeoxyuridine labeling showed that more than 30 % of fully mature thymic emigrants have replicated DNA in the 24 h before exit. The percentage of DNA-synthetizing single-positive (SP) thymocytes is transiently augmented during the postnatal period, with peaks on days 2 and 4 for CD4 and CD8 cells, respectively. Similar kinetics were observed in mouse chimeras made by transfer of normal bone marrow cells into RAG-2-deficient mice. These data show that proliferation of mature thymocytes is developmentally regulated. The proliferation peaks (on days 16 and 18 post transfer) observed in simple bone marrow chimeras were abolished when lymph node T cells were mixed with the bone marrow cell inoculum, suggesting that the peripheral pool controls the late thymic expansion. The phenotype of cycling SP thymocytes is atypical: they do not regulate activation and adhesion surface molecules like peripheral activated T cells.
Subject(s)
T-Lymphocytes/cytology , T-Lymphocytes/physiology , Animals , Animals, Newborn , Bone Marrow Transplantation , CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/physiology , CD8-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/physiology , Cell Differentiation , Cell Division , Cell Movement , Chimera/immunology , DNA-Binding Proteins/deficiency , DNA-Binding Proteins/genetics , Immunophenotyping , Kinetics , Lymphocyte Activation , Lymphocyte Depletion , Mice , Mice, Inbred C57BL , Mice, Knockout , T-Lymphocytes/immunologySubject(s)
DNA Mutational Analysis/methods , DNA-Binding Proteins , Fluorescent Dyes , Genetic Testing/methods , Glucokinase/genetics , Mutation/genetics , Nuclear Proteins , Transcription Factors/genetics , DNA Mutational Analysis/economics , Diabetes Mellitus, Type 2/diagnosis , Diabetes Mellitus, Type 2/genetics , Genetic Testing/economics , Hepatocyte Nuclear Factor 1 , Hepatocyte Nuclear Factor 1-alpha , Hepatocyte Nuclear Factor 1-beta , Heterozygote , Humans , Polymerase Chain Reaction/methods , Rhodamines/chemistry , Rhodamines/metabolism , Sensitivity and SpecificityABSTRACT
AIMS/HYPOTHESIS: The region 2p21-23, containing the proopiomelanocortin gene (POMC), was reported to be linked to leptin concentrations in Mexican-American, French and African-American cohorts. A polyhormone peptide, POMC is expressed in brain, gut, placenta and pancreas. The POMC mutations are responsible for rare cases of early-onset obesity. Thus we examined the contribution of the POMC locus to obesity in French families. METHODS: Single and multipoint linkage studies were done between obesity, obesity associated-phenotypes (leptin values and z-score of the body mass index) and three newly mapped markers surrounding POMC in 264 affected sib-pairs from French obese families. Mutation screening of the exons and intron/exon junctions of the POMC gene was realised by direct sequencing. Association studies were done in 379 unrelated obese patients and 370 non-obese non-diabetic subjects. RESULTS: Linkage analysis confirmed the trend towards linkage between polymorphic markers around POMC and variations of leptin concentrations and z-score (maximum lod score at D2S2337 = 2.03). Mutation screening of the POMC gene in the French Caucasian cohort identified two previously reported polymorphisms. None of these variants was associated with obesity, diabetes or serum leptin and lipid concentrations. CONCLUSION/INTERPRETATION: Our results indicate that mutations in the POMC gene do not contribute to the variance of obesity associated phenotypes, at least in French Caucasians. Given the replicated evidence of linkage between leptin values and the chromosome 2p21-23 region in different populations, it is likely that functional variant(s) in the POMC regulating sequences or in an unknown gene in this region explains this linkage.