Post-immunisation fever and the antibody response to measles-containing vaccines.

Fever is a common adverse event following measles vaccination, more frequent among older children and those receiving Measles-Mumps-Rubella-Varicella vaccine vs. Measles-Mumps-Rubella vaccine, two factors associated with a better antibody response. However, the role of fever in the immunogenicity of measles-containing vaccines (MCV) is unclear. We performed a post-hoc pooled analysis of data of 5 216 11 to 22 month-old children receiving MCV from 2004 to 2012 in Europe and USA to evaluate the association between post-immunisation fever and antibody response, measured by geometric mean concentrations (GMCs). We further evaluated fever as an effect modifier or a mediator in the associations between the type of MCV or the age at first vaccination and vaccine immunogenicity. After the first dose, fever was associated with 60% higher GMCs (95% CI 1.51-1.68). For children vaccinated at ⩾12 months, the fever did not modify and minimally mediated (2% to 3%) the association between age and antibody response. Fever mediated 18% of the association between type of MCV and GMCs. In a model including fever, age and type of vaccine, fever was the strongest predictor of GMCs. These results suggest that fever is associated with a stronger measles antibody response independently of age and type of MCV.

An assessment of gene-by-gene interactions as a tool to unfold missing heritability in dyslexia.

Even if substantial heritability has been reported and candidate genes have been identified extensively, all known marker associations explain only a small proportion of the phenotypic variance of developmental dyslexia (DD) and related quantitative phenotypes. Gene-by-gene interaction (also known as "epistasis"--G × G) triggers a non-additive effect of genes at different loci and should be taken into account in explaining part of the missing heritability of this complex trait. We assessed potential G × G interactions among five DD candidate genes, i.e., DYX1C1, DCDC2, KIAA0319, ROBO1, and GRIN2B, upon DD-related neuropsychological phenotypes in 493 nuclear families with DD, by implementing two complementary regression-based approaches: (1) a general linear model equation whereby the trait is predicted by the main effect of the number of rare alleles of the two genes and by the effect of the interaction between them, and (2) a family-based association test to detect G × G interactions between two unlinked markers by splitting up the association effect into a between- and a within-family genetic orthogonal components. After applying 500,000 permutations and correcting for multiple testing, both methods show that G × G effects between markers within the DYX1C1, KIAA0319/TTRAP, and GRIN2B genes lower the memory letters composite z-score of on average 0.55 standard deviation. We provided initial evidence that the effects of familial transmission of synergistic interactions between genetic risk variants can be exploited in the study of the etiology of DD, explain part of its missing heritability, and assist in designing customized charts of individualized neurocognitive impairments in complex disorders, such as DD.

UGT2B17 gene deletion associated with an increase in bone mineral density similar to the effect of hormone replacement in postmenopausal women.

UNLABELLED: UGT2B17 is one of the most important enzymes for androgen metabolism. In addition, the UGT2B17 gene is one of the most commonly deleted regions of the human genome. The deletion was previously found associated with higher femoral bone density in men and women, and we replicated this association in a sample of postmenopausal who never used hormone therapy. INTRODUCTION: Deletion of the UGT2B17 gene was previously shown to be associated with a higher hip bone mineral density (BMD). Using a PCR assay, we tried to replicate the association among a large group of 2,379 women. We examined the effect of the deletion on femoral neck BMD and lumbar spine BMD according to the menopausal status and hormone replacement therapy (HRT). METHODS: We used a high-throughput PCR assay to identify the gene and the deletion in a population of well-characterized women. Two additional polymorphisms, UGT2B28 deletion and UGT2B15 rs1902023 G > T were also investigated. RESULTS: Only UGT2B17 deletion was associated with LS and FN BMD. Furthermore, the association was seen only among postmenopausal women who had never used hormone replacement as in the first reported association. CONCLUSIONS: We confirmed the association between UGT2B17 deletion and a higher LS and FN BMD. In addition, we show that the association is observed among postmenopausal women who never used HRT consistent with the enzymatic function of UGT2B17. The analysis shows that those having one or two UGT2B17 alleles benefit from HRT, which is not the case for null carriers.

Retinal function and preclinical risk traits in children and adolescents at genetic risk of schizophrenia and bipolar disorder.

BACKGROUND: The millions of children having a parent affected by a major psychiatric disorder may carry, as vulnerability indicators, electroretinographic (ERG) anomalies resembling those seen in adult patients. Our goal was to determine whether ERG anomalies in high-risk youths are related to clinical precursors of a later transition to illness such as the presence of childhood DSM-IV diagnoses, bouts of psychotic like experiences, lower global IQ and social functioning deterioration. METHODS: The 99 youths (53% males) aged 5-27 years had one parent affected by schizophrenia, bipolar disorder or major depressive disorder. They were assessed with a best-estimate DSM-IV diagnoses based on review of medical charts and a structured interview (K-SADS or SCID), global IQ (WISC-V and WAIS-IV), global functioning (GAF scale) and psychotic-like experiences using interviews and a review of medical records. The electroretinogram of rods and cones was recorded. RESULTS: Cone Vmax latency was longer in offspring having psychotic-like experiences, respective adjusted mean [SE] ms of 31.59 [0.27] and of 30.96 [0.14]; P = 0.018). The cone Vmax delayed latency was associated with a lower global IQ (R = -0.18; P = 0.045) and with deteriorated global functioning (GAF; R = -0.25; P = 0.008). In contrast, rods had decreased b-wave amplitude only in offspring with a non-psychotic non-affective DSM diagnoses, respective means [SE] µV of 170.18 [4.90] and of 184.01 [6.12]; P = 0.044). CONCLUSIONS: ERG may mark neurodevelopmental pathways leading to adult illness and have an effect on early pre-clinical traits, giving clues to clinicians for the surveillance of sibling differences in high-risk families.

Impacts et mise en œuvre du service sanitaire des étudiants en santé (SSES) français : étude de cas dans deux académies françaises.

CONTEXTE: Le service sanitaire des étudiants en santé (SSES) est un programme de 2018 de sensibilisation à la promotion de la santé (PS), à destination d'étudiants en santé français. Il comprend un temps de formation et un temps d'action des étudiants sur diverses populations. Il est déployé sur le territoire français sans évaluation préalable. L'étude que nous avons conduite a pour objectifs de i) documenter la perception et le degré d'appropriation des objectifs du SSES par les parties prenantes (étudiants et professionnels encadrants), ii) analyser les interventions réalisées par les étudiants au regard des bonnes pratiques de promotion de la santé (PS). MÉTHODES: Il s'agissait d'une étude de cas qualitative menée dans deux académies de la Région Nouvelle-Aquitaine : Poitiers et Bordeaux. Des entretiens ont été conduits auprès des parties prenantes, ainsi que des observations d'actions menées par les étudiants. RÉSULTATS: Nous avons réalisé 87 entretiens et 18 observations. Les données obtenues montrent que : (i) si les parties prenantes se sont fortement impliquées, les conditions de mise en place étaient difficiles et inégales, (ii) les objectifs se révèlent en décalage avec des enjeux de la prévention dans le système de soins, (iii) les étudiants ont entériné une vision erronée de la PS rationnelle et individualisant les comportements liés à la santé, et (iv) les actions menées contreviennent pour la majorité aux critères de qualité en PS, qu'ils soient pédagogiques, méthodologiques ou éthiques. CONCLUSION: Ces résultats ont été confortés dans l'académie de Normandie. À notre connaissance, aucune autre évaluation de ce type n'est réalisée sur le territoire français. Ceci pose des questions car les impacts observés semblent suffisamment inquiétants pour appeler à une réforme du dispositif, tant sur les objectifs que sur les accompagnements à l'action en PS (ex. sur les déterminants sociaux de la santé).

Differences and similarities in the serotonergic diathesis for suicide attempts and mood disorders: a 22-year longitudinal gene-environment study.

To investigate similarities and differences in the serotonergic diathesis for mood disorders and suicide attempts, we conducted a study in a cohort followed longitudinally for 22 years. A total of 1255 members of this cohort, which is representative of the French-speaking population of Quebec, were investigated. Main outcome measures included (1) mood disorders (bipolar disorder and major depression) and suicide attempts by early adulthood; (2) odds ratios and probabilities associated with 143 single nucleotide polymorphisms in 11 serotonergic genes, acting directly or as moderators in gene-environment interactions with childhood sexual or childhood physical abuse (CPA), and in gene-gene interactions; (3) regression coefficients for putative endophenotypes for mood disorders (childhood anxiousness) and suicide attempts (childhood disruptiveness). Five genes showed significant adjusted effects (HTR2A, TPH1, HTR5A, SLC6A4 and HTR1A). Of these, HTR2A variation influenced both suicide attempts and mood disorders, although through different mechanisms. In suicide attempts, HTR2A variants (rs6561333, rs7997012 and rs1885884) were involved through interactions with histories of sexual and physical abuse whereas in mood disorders through one main effect (rs9316235). In terms of phenotype-specific contributions, TPH1 variation (rs10488683) was relevant only in the diathesis for suicide attempts. Three genes contributed exclusively to mood disorders, one through a main effect (HTR5A (rs1657268)) and two through gene-environment interactions with CPA (HTR1A (rs878567) and SLC6A4 (rs3794808)). Childhood anxiousness did not mediate the effects of HTR2A and HTR5A on mood disorders, nor did childhood disruptiveness mediate the effects of TPH1 on suicide attempts. Of the serotonergic genes implicated in mood disorders and suicidal behaviors, four exhibited phenotype-specific effects, suggesting that despite their high concordance and common genetic determinants, suicide attempts and mood disorders may also have partially independent etiological pathways. To identify where these pathways diverge, we need to understand the differential, phenotype-specific gene-environment interactions such as the ones observed in the present study, using suitably powered samples.

Differential RNA expression between schizophrenic patients and controls of the dystrobrevin binding protein 1 and neuregulin 1 genes in immortalized lymphocytes.

The dystrobrevin binding protein 1 (DTNBP1) and neuregulin 1 (NRG1) genes have been related to schizophrenia (SZ) and bipolar disorder (BP) by several whole-genome linkage and associations studies. Few expression studies in post-mortem brains have also reported a lower or a higher expression of DTNBP1 and NRG1, respectively, in SZ. Since the difficulty to access post-mortem brains, we evaluated RNA expression of DTNBP1 and NRG1 in immortalized lymphocytes of SZ patients and unrelated-family controls. An antipsychotic stimulation was also used to challenge the genetic background of the subjects and enhance differential expression. Immortalized lymphocytes of twelve SZ and twelve controls were grown individually in the presence or not of the antipsychotic olanzapine (Zyprexa; EliLilly). RNA was extracted and pooled in four groups of three SZ and four groups of three controls, and used to probe Agilent 18K microchips. Mean gene expression values were contrasted between SZ and control groups using a T-test. For DTNBP1, RNA expression was lower in SZ than in controls before (-28%; p=0.02) and after (-30%; p=0.01) olanzapine stimulation. Similarly, NRG1 GGF2 isoform showed a lower expression in SZ before (-29%; p=0.04) and after (-33%; p=0.02) olanzapine stimulation. In contrast, NRG1 GGF isoform showed no significant difference between SZ and controls (-7%; p=0.61, +3%; p=0.86, respectively), but was slightly repressed by olanzapine in controls (-8%; p=0.008) but not in SZ (+1%; p=0.91). These results are in agreement with those observed in post-mortem brain when the isoforms involved are considered.

Possible association of the pro-melanin-concentrating hormone gene with a greater body mass index as a side effect of the antipsychotic olanzapine.

Following our report of a linkage at 12q24 with a phenotype of obesity under antipsychotics, we tested the pro-melanin-concentrating hormone (PMCH) candidate gene for a possible association in humans with the body mass index (BMI; kg/m2) in unrelated schizophrenic patients (SZ) receiving antipsychotics (N = 300) and in controls (CTL; N = 150). Subjects were classified in obese (OB) (BMI > or = 30 kg/m2), overweight (25 < or = BMI < 30 kg/m2), and normal weight (BMI < 25 kg/m2) groups. Single nucleotide polymorphisms (SNP) rs7973796 and rs11111201, located 5' at -4.5 kb and 3' at +1.8 kb, respectively, of PMCH were genotyped. Interaction effects of genotypes and antipsychotic treatment on BMI were tested in a covariance analysis with age and gender as covariates. Interaction effects on the prevalence of obesity were tested in a logistic regression analysis. For subjects under 50 years, the effect of the rs7973796 genotype on BMI differed between the SZ patients taking olanzapine and CTL group (interaction P = 0.025). Olanzapine-treated SZ patients carrying the ancestral homozygote genotype showed a higher BMI for rs7973796 (P = 0.016 with the LSMeans t-test) than the variant homozygotes. Accordingly, the ORs for obesity associated with rs7973796 genotypes differed in the SZ patients taking olanzapine compared to the CTL group (interaction P = 0.0094). The G allele was associated with an increase in the odds of obesity in SZ patients taking olanzapine. No association was observed for those over 50 years, or for rs11111201. These results suggest that the common allele of PMCH rs7973796 may be associated with a greater BMI in olanzapine-treated SZ patients.

Optimization of a model of red blood cells for the study of anti-oxidant drugs, in terms of concentration of oxidant and phosphate buffer.

The aggression of erythrocytes by an oxidative stress induces hemolysis. This paper aims to valid a model of erythrocytes in terms of composition of the phosphate buffer solution and of concentration of a well-known oxidant, AAPH. Three compositions of phosphate buffer solution are mixed with three concentrations of oxidant. The influence of these two parameters on hemolysis is independently studied by a variance analysis and a Kruskal-Wallis test when ANOVA is not available. The hemolysis rate increases with time at fixed oxidant concentration, but is not influenced by the composition of the buffer solution. The highest hemolysis rate, 90%, was only measured within 2 h with the highest oxidant concentration. If we retain this concentration of oxidant, the lower concentration of the buffer can by eliminated by a significant less hemolysis and the highest concentration of the buffer can by chosen in regard of the better precision for a similar hemolysis compared to the mean buffer. We hope to study the effect of anti-oxidant agent with such a model of erythrocytes.

Non-invasive measurement of haemodynamics during sleep apnoea.

Sleep apnoeas are accompanied by large variations in heart rate (HR) and blood pressure (BP). This nocturnal variability in BP may be involved in the increased cardiovascular morbidity of these patients. Due to the complex interaction between asphyxia, intrathoracic pressure, cardiac function and autonomic activation, the exact haemodynamic mechanisms are unclear. To evaluate the components of the BP surges at resumption of breathing (RB) a non-invasive beat-to-beat measurement was taken of cardiac output (CO) by the pulse contour analysis of the Finapres signal. Six male normotensive patients, free of medication (37-60 y, BMI 26.5-43.0 kg m-2) were studied during polysomnography (apnoea index: 22-69 h-1). Systolic blood pressure rose from 126.5 +/- 1.3 mmHg at beginning apnoea (P1) to 140.4 +/- 1.3 at RB (P < 0.01, ANOVA). During sleep Stages 2 and 3, stroke volume decreased during RB to 96% of P1 value (NS). Due to an opposite change in HR, CO tended to rise at RB to 106% of P1. Computed total peripheral resistance rose during RB to 105% of P1 value (P < 0.011. Therefore, it is concluded that the surge in BP at RB after apnoea is due to concomitant increases in CO and in TPR. Both rises are presumably a consequence of sympathetic nervous activation by the arterial chemoreceptors.

An assessment of gene-by-environment interactions in developmental dyslexia-related phenotypes.

While the genetic and environmental contributions to developmental dyslexia (DD) have been studied extensively, the effects of identified genetic risk susceptibility and of specified environmental hazardous factors have usually been investigated separately. We assessed potential gene-by-environment (GxE) interactions on DD-related reading, spelling and memory phenotypes. The presence of GxE effects were investigated for the DYX1C1, DCDC2, KIAA0319 and ROBO1 genes, and for seven specified environmental moderators in 165 nuclear families in which at least one member had DD, by implementing a general test for GxE interaction in sib-pair-based association analysis of quantitative traits. Our results support a diathesis-stress model for both reading and memory composites: GxE effects were found between some specified environmental moderators (i.e. maternal smoke during pregnancy, birth weight and socio-economic status) and the DYX1C1-1259C/G marker. We have provided initial evidence that the joint analysis of identified genetic risk susceptibility and measured putative risk factors can be exploited in the study of the etiology of DD and reading-related neuropsychological phenotypes, and may assist in identifying/preventing the occurrence of DD.

Autologous transplantation in CLL patients with B and C Binet stages: final results of the prospective randomized GOELAMS LLC 98 trial.

The relevance of high-dose chemotherapy followed by auto-SCT in CLL remains to be defined. The aim of the prospective, randomized, GOELAMS LLC 98 trial was to compare two strategies in previously untreated CLL patients aged <60 years. Conventional chemotherapy (Arm A) consisted of six monthly courses of CHOP followed by six CHOP courses in every 3 months in those achieving a complete or PR. Arm A was compared with high-dose therapy with auto-SCT (Arm B), used as consolidation after three CHOP courses in case of CR or very good PR. A total of 86 patients were enrolled, of which 39 and 43 patients were evaluable in arm A and arm B, respectively. The primary endpoint was PFS. On an intent-to-treat basis and with a median follow-up time of 77.1 (range 1-135.5) months, the median PFS was 22 months in Arm A and 53 months in Arm B (P<0.0001). Median survival time was 104.7 months in arm A and 107.4 months in arm B. This trial demonstrates that frontline high-dose therapy with auto-SCT prolongs PFS but does not translate into a survival advantage in advanced CLL patients in the pre-rituximab era.

Safety in the preparation of cytotoxic drugs: How to integrate gravimetric control in the quality assurance policy?

PURPOSE: We present the way to integrate gravimetric control (GC) in a centralized preparation of cytotoxic drugs unit. Two different modalities are described. In the first strategy, the balance is located inside the isolator, whereas in the second, it is located outside in order to remove many technical and ergonomic constraints. These two modalities are compared in terms of benefits and limits. METHODS: GC consists in comparing the observed weight variation with the expected weight variation using a precision balance. According to the B-in strategy, this variation is directly attributable to the weight of the cytotoxic solution injected, whereas with the B-out strategy, the weight of various additional components must be taken into account. RESULTS: Five hundred and seventy-seven preparations have been weighed. For "B-in" strategy, the 95% confidence interval is [1.02-1.14%] and every preparation is below the threshold of 5%. For "B-out" strategy, the 95% confidence interval is [2.34-2.63%] and 94% of preparations are below the threshold of 5%. B-in strategy is distinctly more precise than B-out strategy and can be applied to all preparations. However, B-out strategy is a feasible option in practice and enables the detection of an important mistake. All in all, results obtained from B-out strategy can be considered as a quality indicator in the production line. CONCLUSION: Results of GC are helpful in the final step of release, which the pharmacist is responsible for. Many contributions in the quality assurance policy could justify using of GC in every unit.

Impulsive-aggressive behaviours and completed suicide across the life cycle: a predisposition for younger age of suicide.

BACKGROUND: It is unclear whether the association between impulsive-aggressive behaviours and suicide exists across different ages. METHOD: Via psychological autopsy, we examined a total of 645 subjects aged 11-87 years who died by suicide. Proxy-based interviews were conducted using the SCID-I & SCID-II or K-SADS interviews and a series of behavioural and personality-trait assessments. Secondarily, 246 living controls were similarly assessed. RESULTS: Higher levels of impulsivity, lifetime history of aggression, and novelty seeking were associated with younger age of death by suicide, while increasing levels of harm avoidance were associated with increasing age of suicide. This effect was observed after accounting for age-related psychopathology (current and lifetime depressive disorders, lifetime anxiety disorders, current and lifetime substance abuse disorders, psychotic disorders and cluster B personality disorders). Age effects were not due to the characteristics of informants, and such effects were not observed among living controls. When directly controlling for major psychopathology, the interaction between age, levels of impulsivity, aggression and novelty seeking predicted suicide status while controlling for the independent contributions of age and these traits. CONCLUSIONS: Higher levels of impulsive-aggressive traits play a greater role in suicide occurring among younger individuals, with decreasing importance with increasing age.

[Clinical trial of pregnancy terminations in 353 patients where amenorrhea was present for less than 49 days by 600 mg of RU 486 (administered orally) and 500 mg of sulprostone (Nalador) administered intramuscularly]. / Etude clinique de 353 cas d'IVG de moins de 49 jours d'amenorrhee realisee par: 600 mg de RU 486 voie buccale + sulprostone 500 mg IM (Nalador).

PIP: 354 women seeking abortions were treated at a hospital in Paris between February-September 1988 with 600 mg of RU 486 taken orally in 1 dose and an injection of 500 mg sulprostone 48 hours later. The women all had amenorrhea of less than 49 days. 1/3 were 18-25 years old, 1/2 were 25-35, and 16% were over 35. 206 were nulliparas. 110 were married and the rest were separated, widowed, divorced, or single. Sulprostone was injected early in the morning in the hospital and the women were discharged after expulsion of the products of conception, which occurred usually 2 1/2 to 3 1/2 hours later. If expulsion did not occur, the woman returned in 3 days for a sonogram to confirm uterine vacuity. 13 of the 354 women had RU 486 only. 2 refused the sulprostone and underwent aspiration and 11 experienced spontaneous expulsions in the 48 hours following RU 486 administration. 338 of the women had spontaneous expulsions. 2 pregnancies were terminated but not expelled and aspiration was required. 285 of the women expelled in the hospital within 4 hours of sulprostone administration and the other 55 did so at home 6 or more hours later. RU 486 was very well tolerated. Secondary effects were more common with sulprostone but generally subsided within 3 hours. 70 patients required treatment for uterine pain after sulprostone administration. 150 complained of nausea but only 6 required treatment. 5 women required aspiration of curettage for hemorrhage but none required transfusion. In 3 cases the hemorrhages were due to histologically proven retention. 1 patient developed endometritis 3 days after expulsion and another, who had a history of extrauterine pregnancy, developed salpingitis 15 days after expulsion. Both patients were treated with antibiotics. The method appears to be safe and effective. Its major disadvantages are that it prolongs the amount of time required for abortion and it frequently causes pelvic pain. The responsibility of the patient is also increased.^ieng

Pedigree selection and tests of linkage in a Hutterite asthma pedigree.

We explored methods for kinship and linkage analysis in a Hutterite pedigree comprising 1,544 individuals, 72 of whom were diagnosed with asthma. Subpedigrees were selected by (a) identifying nuclear families containing asthmatics, (b) identifying couples with many asthmatic descendants in an ad hoc manner, and (c) finding the most recent common ancestors of all asthmatics. Markov chain Monte Carlo (MCMC) methods were used to estimate allele sharing in the larger subpedigrees and transmission/disequilibrium tests were performed on nuclear families. On chromosome 5q near the cytokine cluster, modest evidence for linkage to asthma was obtained. Using MCMC, we were able to evaluate the evidence for linkage in complex subpedigrees of several hundred individuals, and hence, incorporate some of the co-ancestry of this founder population.