Vaginal microbiome in early pregnancy and subsequent risk of spontaneous preterm birth: a case-control study.

OBJECTIVES: To explore differences in the vaginal microbiome between preterm and term deliveries. DESIGN: Nested case-control study in 3D cohort (design, develop, discover). SETTING: Quebec, Canada. SAMPLE: Ninety-four women with spontaneous preterm birth as cases [17 early (<34 weeks) and 77 late (34-36 weeks) preterm birth] and 356 women as controls with term delivery (≥37 weeks). METHODS: To assess the vaginal microbiome by sequencing the V4 region of the 16S ribosomal RNA (rRNA) gene in swabs self-collected during early pregnancy. MAIN OUTCOME MEASURES: Comparison of relative abundance of bacterial operational taxonomic units and oligotypes and identifying vaginal community state types (CSTs) in early or late spontaneous preterm and term deliveries. RESULTS: Lactobacillus gasseri/ Lactobacillus johnsonii (coefficient -5.36, 95% CI -8.07 to -2.65), Lactobacillus crispatus (99%)/ Lactobacillus acidophilus (99%) (-4.58, 95% CI -6.20 to -2.96), Lactobacillus iners (99%)/ Ralstonia solanacearum (99%) (-3.98, 95% CI -6.48 to -1.47) and Bifidobacterium longum/ Bifidobacterium breve (-8.84, 95% CI -12.96 to -4.73) were associated with decreased risk of early but not late preterm birth. Six vaginal CSTs were identified: four dominated by Lactobacillus; one with presence of bacterial vaginosis-associated bacteria (Gardnerella vaginalis, Atopobium vaginae and Veillonellaceae bacterium) (CST IV); and one with nondominance of Lactobacillus (CST VI). CST IV was associated with increased risk of early (4.22, 95% CI 1.24-24.85) but not late (1.63, 95% CI 0.68-5.04) preterm birth, compared with CST VI. CONCLUSIONS: Lactobacillus gasseri/L. johnsonii, L. crispatus/L. acidophilus, L. iners/R. solanacearum and B. longum/B. breve may be associated with decreased risk of early preterm birth. A bacterial vaginosis-related vaginal CST versus a CST nondominated by Lactobacillus may be associated with increased risk of early preterm birth. TWEETABLE ABSTRACT: Largest study of its kind finds certain species of vaginal Lactobacillus + Bifidobacterium may relate to lower risk of preterm birth.

A SNAP25 promoter variant is associated with early-onset bipolar disorder and a high expression level in brain.

Bipolar disorder (BD) is one of the most common and persistent psychiatric disorders. Early-onset BD has been shown to be the most severe and familial form. We recently carried out a whole-genome linkage analysis on sibpairs affected by early-onset BD and showed that the 20p12 region was more frequently shared in our families than expected by chance. The synaptosomal-associated protein SNAP25 is a presynaptic plasma membrane protein essential for the triggering of vesicular fusion and neurotransmitter release, and for which abnormal protein levels have been reported in postmortem studies of bipolar patients. We hypothesised that variations in the gene encoding SNAP25, located on chromosome 20p12, might influence the susceptibility to early-onset BD. We screened SNAP25 for mutations and performed a case-control association study in 197 patients with early-onset BD, 202 patients with late-onset BD and 136 unaffected subjects. In addition, we analysed the expression level of the two SNAP25 isoforms in 60 brains. We showed that one variant, located in the promoter region, was associated with early-onset BD but not with the late-onset subgroup. In addition, individuals homozygous for this variant showed a significant higher SNAP25b expression level in prefrontal cortex. These results show that variations in SNAP25, associated with an increased gene expression level in prefrontal cortex, might predispose to early-onset BD. Further analyses of this gene, as well as analysis of genes encoding for the SNAP25 protein partners, are required to understand the impact of such molecular mechanisms in BD.

[Enterovirus-related pericarditis and mediastinitis after heart surgery: a case report]. / Péricardite et médiastinite à entérovirus après chirurgie cardiaque: description d'un cas.

We report a case of enterovirus related pericarditis associated to mediastinitis in a hospitalised 53-year-old male after heart surgery. Mediastinitis caused by enterovirus has not previously been described.

[A mixed acid-base disorder revealing a cystic dystrophy of aberrant pancreatic tissue]. / Un trouble métabolique complexe révélateur d'une dystrophie kystique sur pancréas aberrant.

We report about a patient presenting with a mixed acid-base disorder. His blood gas analysis showed a metabolic acidosis caused by renal failure and lactic acidosis combined with a hypochloraemic alkalosis. The underlying pathology was a cystic dystrophy of aberrant pancreatic tissue leading to excessive vomiting, extracellular dehydration with a renal failure and hypochloraemia.

Association between circadian genes, bipolar disorders and chronotypes.

Abnormalities in circadian rhythms play an important role in the pathogenesis of bipolar disorders (BD). Previous genetic studies have reported discrepant results regarding associations between circadian genes and susceptibility to BD. Furthermore, plausible behavioral consequences of at-risk variants remain unclear since there is a paucity of correlates with phenotypic biomarkers such as chronotypes. Here, we combined association studies with a genotype/phenotype correlation in order to determine which circadian genes variants may be associated with the circadian phenotypes observed in patients with BD. First, we compared the allele frequencies of 353 single nucleotide polymorphisms spanning 21 circadian genes in two independent samples of patients with BD and controls. The meta-analysis combining both samples showed a significant association between rs774045 in TIMELESS (OR = 1.49 95%CI[1.18-1.88]; p = 0.0008) and rs782931 in RORA (OR = 1.31 95%CI[1.12-1.54]; p = 0.0006) and BD. Then we used a "reverse phenotyping approach" to look for association between these two polymorphisms and circadian phenotypes in a subsample of patients and controls. We found that rs774045 was associated with eveningness (p = 0.04) and languid circadian type (p = 0.01), whereas rs782931 was associated with rigid circadian type (p = 0.01). Altogether, these findings suggest that these variants in the TIMELESS and RORA genes may confer susceptibility to BD and impact on circadian phenotypes in carriers who thus had lower ability to properly adapt to external cues.

Molecular characteristics of Human Endogenous Retrovirus type-W in schizophrenia and bipolar disorder.

Epidemiological and genome-wide association studies of severe psychiatric disorders such as schizophrenia (SZ) and bipolar disorder (BD), suggest complex interactions between multiple genetic elements and environmental factors. The involvement of genetic elements such as Human Endogenous Retroviruses type 'W' family (HERV-W) has consistently been associated with SZ. HERV-W envelope gene (env) is activated by environmental factors and encodes a protein displaying inflammation and neurotoxicity. The present study addressed the molecular characteristics of HERV-W env in SZ and BD. Hundred and thirty-six patients, 91 with BD, 45 with SZ and 73 healthy controls (HC) were included. HERV-W env transcription was found to be elevated in BD (P<10-4) and in SZ (P=0.012) as compared with HC, but with higher values in BD than in SZ group (P<0.01). The corresponding DNA copy number was paradoxically lower in the genome of patients with BD (P=0.0016) or SZ (P<0.0003) than in HC. Differences in nucleotide sequence of HERV-W env were found between patients with SZ and BD as compared with HC, as well as between SZ and BD. The molecular characteristics of HERV-W env also differ from what was observed in Multiple Sclerosis (MS) and may represent distinct features of the genome of patients with BD and SZ. The seroprevalence for Toxoplasma gondii yielded low but significant association with HERV-W transcriptional level in a subgroup of BD and SZ, suggesting a potential role in particular patients. A global hypothesis of mechanisms inducing such major psychoses is discussed, placing HERV-W at the crossroads between environmental, genetic and immunological factors. Thus, particular infections would act as activators of HERV-W elements in earliest life, resulting in the production of an HERV-W envelope protein, which then stimulates pro-inflammatory and neurotoxic cascades. This hypothesis needs to be further explored as it may yield major changes in our understanding and treatment of severe psychotic disorders.

Mutations in the protamine 1 gene associated with male infertility.

In elongating spermatids, human sperm chromatin undergoes a complex compaction in which the transition proteins are extensively replaced by the protamine proteins. Several human studies demonstrate that expression of the protamine proteins is altered in some men with male infertility. For this study, we screened the PRM1 (protamine 1) gene for mutations in a large cohort of 281 men seeking infertility treatment. We identified the c.102G>T transversion that results in an p.Arg34Ser amino acid change in two men. One of these patients presented with oligozoospermia associated with increased sperm DNA fragmentation. The second individual was normospermic but together with his partner sought treatment for idiopathic couple infertility. We also identified a novel missense mutation (c.119G>A, p.Cys40Tyr) in a man with oligoasthenozoospermia. These mutations were not observed in control populations. Interestingly, we also detected variants both 5' and 3' to the PRM1 open-reading frame specifically in infertile individuals. Four individuals with unexplained severe oligozoospermia were heterozygote for a c.-107G>C change that is located at -15 bp from the transcription initiation site of the gene. This mutation may influence PRM1 expression. In addition, a c.*51G>C variant was detected in the 3'UTR of PRM1 specifically in a man with severe oligoasthenozoospermia.

Haplotypes, mutations and male fertility: the story of the testis-specific ubiquitin protease USP26.

Recently, mutations in the X-linked ubiquitin protease 26 (USP26) gene have been proposed to be associated with male infertility. In particular a 371insACA, 494T>C and 1423C>T haplotype, which results in a T123-124ins, L165S and H475Y amino acid change respectively, has been reported to be associated with Sertoli cell-only syndrome (SCOS) and an absence of sperm in the ejaculate. Here, we demonstrate that two of these changes actually correspond to the ancestral sequence of the gene and that the USP26 haplotype is present in significant frequencies in sub-Saharan African and South and East Asian populations, including in individuals with known fertility. This indicates that the allele is not associated with infertility. The pattern of frequency distribution of the derived haplotype (371delACA, 494T), which is present at high frequencies in most non-African populations could be interpreted as either a result of migration followed by simple genetic drift or alternatively as positive selection acting on the derived alleles. The latter hypothesis seems likely, because there is evidence of strong positive selection acting on the USP26 gene.

Oestrogen withdrawal associated psychoses.

OBJECTIVE: Oestrogen withdrawal has been hypothesized as playing a causal role in puerperal psychoses. However, oestrogen withdrawal exists in conditions others than puerperium. We searched the published case reports where a decrease in oestrogen levels not occurring during puerperium was associated with a psychotic disorder, in order to evaluate the relevance of this hypothesis. These cases were defined as oestrogen withdrawal associated psychoses. METHOD: A systematic research of the literature was conducted for the period 1960-2000. RESULTS: We identified 26 observations reporting an association between a psychotic disorder and a phase of oestrogen withdrawal. Psychotic episodes were short and reversible with recurrences reported when oestrogen withdrawal recurred. Puerperal psychosis was frequently reported in the history of patients. CONCLUSION: The oestrogen withdrawal hypothesis can be extended to certain psychotic episodes not occurring during in puerperium. This provides an additional argument for the clinical relevance of oestrogen withdrawal in puerperal and related psychoses.