Type I hyperprolinemia: genotype/phenotype correlations.

Type I hyperprolinemia (HPI) is an autosomal recessive disorder associated with cognitive and psychiatric troubles, caused by alterations of the Proline Dehydrogenase gene (PRODH) at 22q11. HPI results from PRODH deletion and/or missense mutations reducing proline oxidase (POX) activity. The goals of this study were first to measure in controls the frequency of PRODH variations described in HPI patients, second to assess the functional effect of PRODH mutations on POX activity, and finally to establish genotype/enzymatic activity correlations in a new series of HPI patients. Eight of 14 variants occurred at polymorphic frequency in 114 controls. POX activity was determined for six novel mutations and two haplotypes. The c.1331G>A, p.G444D allele has a drastic effect, whereas the c.23C>T, p.P8L allele and the c.[56C>A; 172G>A], p.[Q19P; A58T] haplotype result in a moderate decrease in activity. Among the 19 HPI patients, 10 had a predicted residual activity <50%. Eight out of nine subjects with a predicted residual activity > or = 50% bore at least one c.824C>A, p.T275N allele, which has no detrimental effect on activity but whose frequency in controls is only 3%. Our results suggest that PRODH mutations lead to a decreased POX activity or affect other biological parameters causing hyperprolinemia.

IRF4 regulates IL-17A promoter activity and controls RORγt-dependent Th17 colitis in vivo.

Background: The transcription factor IRF4 is involved in several T-cell-dependent chronic inflammatory diseases. To elucidate the mechanisms for pathological cytokine production in colitis, we addressed the role of the IRF transcription factors in human inflammatory bowel disease (IBD) and experimental colitis.Methods: IRF levels and cytokine production in IBD patients were studied as well as the effects of IRF4 deficiency in experimental colitis.Results: In contrast to IRF1, IRF5, and IRF8, IRF4 expression in IBD was augmented in the presence of active inflammation. Furthermore, IRF4 levels significantly correlated with IL-6 and IL-17 mRNA expression and to a lesser extent with IL-22 mRNA expression in IBD. To further explore the role of IRF4 under in vivo conditions, we studied IRF4-deficient and wildtype mice in experimental colitis. In contrast to DSS colitis, IRF4 deficiency was protective in T-cell-dependent transfer colitis associated with reduced ROR alpha/gamma t levels and impaired IL-6, IL-17a, and IL-22 production, suggesting that IRF4 acts as a master regulator of mucosal Th17 cell differentiation. Subsequent mechanistic studies using database analysis, chromatin immunoprecipitation, and electrophoretic mobility shift assays identified a novel IRF4 binding site in the IL-17 gene promoter. Overexpression of IRF4 using retroviral infection induced IL-17 production and IL-17 together with IL-6 induced ROR gamma t expression.Conclusions: IRF4 can directly bind to the IL-17 promotor and induces mucosal ROR gamma t levels and IL-17 gene expression thereby controlling Th17-dependent colitis. Targeting of this molecular mechanism may lead to novel therapeutic approaches in human IBD.

Oligodendroglia metabolically support axons and contribute to neurodegeneration.

Oligodendroglia support axon survival and function through mechanisms independent of myelination, and their dysfunction leads to axon degeneration in several diseases. The cause of this degeneration has not been determined, but lack of energy metabolites such as glucose or lactate has been proposed. Lactate is transported exclusively by monocarboxylate transporters, and changes to these transporters alter lactate production and use. Here we show that the most abundant lactate transporter in the central nervous system, monocarboxylate transporter 1 (MCT1, also known as SLC16A1), is highly enriched within oligodendroglia and that disruption of this transporter produces axon damage and neuron loss in animal and cell culture models. In addition, this same transporter is reduced in patients with, and in mouse models of, amyotrophic lateral sclerosis, suggesting a role for oligodendroglial MCT1 in pathogenesis. The role of oligodendroglia in axon function and neuron survival has been elusive; this study defines a new fundamental mechanism by which oligodendroglia support neurons and axons.

Acquired antibody responses against Plasmodium vivax infection vary with host genotype for duffy antigen receptor for chemokines (DARC).

BACKGROUND: Polymorphism of the Duffy Antigen Receptor for Chemokines (DARC) is associated with susceptibility to and the severity of Plasmodium vivax malaria in humans. P. vivax uses DARC to invade erythrocytes. Individuals lacking DARC are 'resistant' to P. vivax erythrocytic infection. However, susceptibility to P. vivax in DARC+ individuals is reported to vary between specific DARC genotypes. We hypothesized that the natural acquisition of antibodies to P. vivax blood stages may vary with the host genotype and the level of DARC expression. Furthermore, high parasitemia has been reported to effect the acquisition of immunity against pre-erythrocytic parasites. We investigated the correlation between host DARC genotypes and the frequency and magnitude of antibodies against P. vivax erythrocytic stage antigens. METHODOLOGY/FINDINGS: We assessed the frequencies and magnitudes of antibody responses against P. vivax and P. falciparum sporozoite and erythrocytic antigens in Colombian donors from malaria-endemic regions. The frequency and level of naturally-acquired antibodies against the P. vivax erythrocytic antigens merozoite surface protein 1 (PvMSP1) and Duffy binding protein (PvDBP) varied with the host DARC genotypes. Donors with one negative allele (FY*B/FY*Bnull and FY*A/FY*Bnull) were more likely to have anti-PvMSP1 and anti-PvDBP antibodies than those with two positive alleles (FY*B/FY*B and FY*A/FY*B). The lower IgG3 and IgG1 components of the total IgG response may account for the decreased responses to P. vivax erythrocytic antigens with FY*A/FY*B and FY*B/FY*B genotypes. No such association was detected with P. falciparum erythrocytic antigens, which does not use DARC for erythrocyte invasion. CONCLUSION/SIGNIFICANCE: Individuals with higher DARC expression, which is associated with higher susceptibility to P. vivax infection, exhibited low frequencies and magnitudes of P. vivax blood-stage specific antibody responses. This may indicate that one of the primary mechanisms by which P. vivax evades host immunity is through DARC indirectly down-regulating humoral responses against erythrocytic invasion and development.

The concept of instability: a French perspective on the concept of ADHD.

Historical references to the emergence of the current concept of ADHD typically cite descriptions from medical textbooks by Weikard (1775) and Crichton (An inquiry into the nature and origin of mental derangement: Comprehending a concise system of the physiology and pathology of the human mind and a history of the passion and their affects. Cardell Jr and Davies, Londres, 1798) on attention disorders, poems of Hoffman on hyperactive and impulsive behaviors (Der Struwwelpeter. Frankfurt am Main, Literarische Anstalt, 1843), as well as the work of Still (Lancet 1:1008-1012, 1077-1082, 1163-1168, 1902a, Lancet 159(4102):1008-1013, 1902b, Lancet 159(4103):1077-1082, 1902c, Lancet 159(4104):1163-1168, 1902d) on impulsive behaviors and defective moral regulation of behavior. The notion of "instability" developed by French physicians between 1887 and 1910 is rarely mentioned and often ignored. Writings from this period show that in France, the emergence of the concept of ADHD according to modern terminology comes from the notion of "mental instability" introduced in the 1890s under the leadership of Désiré-Magloire Bourneville at the Hospital Bicêtre in Paris, based on his observations of children and adolescents who had been labeled "abnormal" and placed in medical and educational institutions. In the early twentieth century, elaborating on the observations of Bourneville, Jean Phillipe and Georges Paul-Boncour showed the presence of a subgroup of "unstable" children who suffered from a disease entity in its own right within the population of "abnormal" schoolchildren (the terminology of the time). This new pathological entity included symptoms of hyperactivity, impulsivity and inattention, corresponding to today's classic triad of ADHD symptoms. While noting the lack of behavioral inhibition, clinical descriptions of Bourneville, Philip and Paul-Boncour also considered the notion of "moral disorder" which at that time played an important role in psychopathology. This resulted in some degree of confusion between impulsive symptoms and major behavioral disturbances often associated with ADHD.

The major genetic determinants of HIV-1 control affect HLA class I peptide presentation.

Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified >300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alleles. These results implicate the nature of the HLA-viral peptide interaction as the major factor modulating durable control of HIV infection.

Ex vivo analysis of human antigen-specific CD8+ T-cell responses: quality assessment of fluorescent HLA-A2 multimer and interferon-gamma ELISPOT assays for patient immune monitoring.

The authors developed a standardized approach for immune monitoring of antigen-specific CD8+ T cells within peripheral blood lymphocytes (PBLs) that combines direct ex vivo analysis of Melan-A/MART-1 and influenza-specific CD8+ T cells with HLA-A2/peptide multimers and interferon-gamma ELISPOT assays. Here the authors assessed the quality of results obtained with 180 PBLs from healthy donors and melanoma patients. Reproducibility of the multimer assay was good (average of 15% variation). In the absence of in vivo antigen-specific T-cell responses, physiologic fluctuations of multimer-positive T cells was low, with variation coefficients of 20% for Melan-A and 28% for influenza-specific T cells. In contrast, patients with vaccination-induced T-cell responses had significantly increased T-cell frequencies clearly exceeding physiologic fluctuations. Comparable results were obtained with ELISPOT assays. In conclusion, this approach is well suited to assess T-cell responses as biologic endpoints in clinical vaccine studies.

Évaluation d'un score simplifié de bas débit cardiaque chez l'enfant.

1.1 Objectifs Le syndrome de bas débit cardiaque est une appréciation clinique (Hoffman et al.) dont les signes sont peu sensibles, peu spécifiques, souvent tardifs et dont la mesure chez l'enfant est rendue impossible en clinique pour des raisons techniques et de fiabilités des systèmes de mesures. Aucun score n'est applicable à l'heure actuelle chez l'enfant. C'est pourquoi, ces 10 dernières années, de nombreuses équipes se sont penchée activement sur ce problème afin de définir des marqueurs performants prédisant la survenue du LCOS après chirurgie cardiaque chez l'enfant. Cette étude s'est attachée à réunir ses marqueurs cardiaques, de les combiner et de les inclure dans un score de bas débit cardiaque. 1.2 Méthode Enfants et nouveau-nés ayant subit une chirurgie cardiaque au CHUV, après malformation cardiaque congénitale, entre janvier 2010 et octobre 2011 (N=48). Age : 8 jours à 13 ans (médiane : 16.3 mois). Deux scores développés. Soumission à l'aveugle de la liste des patients à un comité d'expert pour identifier les patients en LCOS à 48h post-chirurgie, puis comparaison avec le résultat du score. Les paramètres du premier score (SCORE 1), sont agendées de manière ordinales, alors que dans le deuxième score (SCORE 2) elles le sont de manière dichotomiques. Valeurs cut-off supérieures et inférieures des scores choisies selon une recherche extensive dans la littérature. Les valeurs cut-off intermédiaires (SCORE 1) ont été choisies au hasard. 1.3 Résultats La régression logistique multivariée pour la prédiction d'un LCOS à 48h, démontre que seul le score d'amine durant les 24 premières heures et un prédicteur indépendant de LCOS (OR 16.6 [2.6- 105.5] p<0.0001). Ce paramètre est bien corrélé avec le résultat des experts avec un coefficient de corrélation r=0.57 (p<0.0001). Les spécificités des deux scores (AUC=0.78 (p<0.0001) respectivement AUC=0.81 (p<0.0001)) sont de 71% respectivement 93.5%, les sensibilités de 70.6% respectivement 41.2 %, VPP de 57.1% respectivement 77.8%, VPN de 81.5 % respectivement 74.4%. Les tests du khi2 valent 7.7 (p=0.006) respectivement 8.69 (p=003), rejettent l'hypothèse nulle d'indépendance entre le résultat des experts et celui prédit par le score. 1.4 Conclusions Les scores développés dans le cadre de cette étude ne montrent pas une corrélation significative avec l'apparition d'un bas débit cardiaque. Même si le choix des paramètres permettant de quantifier l'apparition d'un bas débit cardiaque à 48h fût réalisé selon une recherche extensive dans la littérature, le design rétrospectif de l'étude, n'a pas permit de vérifier efficacement la relation entre l'apparition d'un bas débit cardiaque et le score de bas débit cardiaque.

Circulating carotenoids and risk of breast cancer: pooled analysis of eight prospective studies.

Background Carotenoids, micronutrients in fruits and vegetables, may reduce breast cancer risk. Most, but not all, past studies of circulating carotenoids and breast cancer have found an inverse association with at least one carotenoid, although the specific carotenoid has varied across studies. Methods We conducted a pooled analysis of eight cohort studies comprising more than 80% of the world's published prospective data on plasma or serum carotenoids and breast cancer, including 3055 case subjects and 3956 matched control subjects. To account for laboratory differences and examine population differences across studies, we recalibrated participant carotenoid levels to a common standard by reassaying 20 plasma or serum samples from each cohort together at the same laboratory. Using conditional logistic regression, adjusting for several breast cancer risk factors, we calculated relative risks (RRs) and 95% confidence intervals (CIs) using quintiles defined among the control subjects from all studies. All P values are two-sided. Results Statistically significant inverse associations with breast cancer were observed for α-carotene (top vs bottom quintile RR = 0.87, 95% CI = 0.71 to 1.05, Ptrend = .04), β-carotene (RR = 0.83, 95% CI = 0.70 to 0.98, Ptrend = .02), lutein+zeaxanthin (RR = 0.84, 95% CI = 0.70 to 1.01, Ptrend = .05), lycopene (RR = 0.78, 95% CI = 0.62 to 0.99, Ptrend = .02), and total carotenoids (RR = 0.81, 95% CI = 0.68 to 0.96, Ptrend = .01). β-Cryptoxanthin was not statistically significantly associated with risk. Tests for heterogeneity across studies were not statistically significant. For several carotenoids, associations appeared stronger for estrogen receptor negative (ER(-)) than for ER(+) tumors (eg, β-carotene: ER(-): top vs bottom quintile RR = 0.52, 95% CI = 0.36 to 0.77, Ptrend = .001; ER(+): RR = 0.83, 95% CI = 0.66 to 1.04, Ptrend = .06; Pheterogeneity = .01). Conclusions This comprehensive prospective analysis suggests women with higher circulating levels of α-carotene, β-carotene, lutein+zeaxanthin, lycopene, and total carotenoids may be at reduced risk of breast cancer.

Hundreds of variants clustered in genomic loci and biological pathways affect human height.

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Association of genetic variation with systolic and diastolic blood pressure among African Americans: the Candidate Gene Association Resource study.

The prevalence of hypertension in African Americans (AAs) is higher than in other US groups; yet, few have performed genome-wide association studies (GWASs) in AA. Among people of European descent, GWASs have identified genetic variants at 13 loci that are associated with blood pressure. It is unknown if these variants confer susceptibility in people of African ancestry. Here, we examined genome-wide and candidate gene associations with systolic blood pressure (SBP) and diastolic blood pressure (DBP) using the Candidate Gene Association Resource (CARe) consortium consisting of 8591 AAs. Genotypes included genome-wide single-nucleotide polymorphism (SNP) data utilizing the Affymetrix 6.0 array with imputation to 2.5 million HapMap SNPs and candidate gene SNP data utilizing a 50K cardiovascular gene-centric array (ITMAT-Broad-CARe [IBC] array). For Affymetrix data, the strongest signal for DBP was rs10474346 (P= 3.6 × 10(-8)) located near GPR98 and ARRDC3. For SBP, the strongest signal was rs2258119 in C21orf91 (P= 4.7 × 10(-8)). The top IBC association for SBP was rs2012318 (P= 6.4 × 10(-6)) near SLC25A42 and for DBP was rs2523586 (P= 1.3 × 10(-6)) near HLA-B. None of the top variants replicated in additional AA (n = 11 882) or European-American (n = 69 899) cohorts. We replicated previously reported European-American blood pressure SNPs in our AA samples (SH2B3, P= 0.009; TBX3-TBX5, P= 0.03; and CSK-ULK3, P= 0.0004). These genetic loci represent the best evidence of genetic influences on SBP and DBP in AAs to date. More broadly, this work supports that notion that blood pressure among AAs is a trait with genetic underpinnings but also with significant complexity.

An integrated encyclopedia of DNA elements in the human genome.

The human genome encodes the blueprint of life, but the function of the vast majority of its nearly three billion bases is unknown. The Encyclopedia of DNA Elements (ENCODE) project has systematically mapped regions of transcription, transcription factor association, chromatin structure and histone modification. These data enabled us to assign biochemical functions for 80% of the genome, in particular outside of the well-studied protein-coding regions. Many discovered candidate regulatory elements are physically associated with one another and with expressed genes, providing new insights into the mechanisms of gene regulation. The newly identified elements also show a statistical correspondence to sequence variants linked to human disease, and can thereby guide interpretation of this variation. Overall, the project provides new insights into the organization and regulation of our genes and genome, and is an expansive resource of functional annotations for biomedical research.