In the era of humanitarian crisis, young women continue to die in childbirth in Mali.

Maternal mortality occurs mostly in contexts of poverty and health system collapse. Mali has a very high maternal mortality rate and this extremely high mortality rate is due in part to longstanding constraints in maternal health services. The central region has been particularly affected by the humanitarian crisis in recent years, and maternal health has been aggravated by the conflict. Sominé Dolo Hospital is located in Mopti, central region. In the last decade, a high number of pregnant or delivering women have died in this hospital.We conducted a retrospective and exhaustive study of maternal deaths occurring in Mopti hospital. Between 2007 and 2019, 420 women died, with an average of 32 deaths per year. The years 2014-2015 and the last 2 years have been particularly deadly, with 40 and 50 deaths in 2018 and 2019, respectively. The main causes were hypertensive disorders/eclampsia and haemorrhage. 80% of these women's deaths were preventable. Two major explanations result in these maternal deaths in Sominé Dolo's hospital: first, a lack of accessible and safe blood, and second, the absence of a reference and evacuation referral system, all of which are aggravated by security issues in and around Mopti.Access to quality hospital care is in dire need in the Mopti region. There is an urgent need for a safe blood collection system and free of charge for pregnant women. We also strongly recommend that the referral/evacuation system be reinvigorated, and that universal health coverage be strengthened.

Gene expression and association analyses of LIM (PDLIM5) in bipolar disorder and schizophrenia.

We previously reported that expression level of LIM (ENH, PDLIM5) was significantly and commonly increased in the brains of patients with bipolar disorder, schizophrenia, and major depression. Expression of LIM was decreased in the lymphoblastoid cells derived from patients with bipolar disorders and schizophrenia. LIM protein reportedly plays an important role in linking protein kinase C with calcium channel. These findings suggested the role of LIM in the pathophysiology of bipolar disorder and schizophrenia. To further investigate the role of LIM in these mental disorders, we performed a replication study of gene expression analysis and performed genetic association studies. Upregulation of LIM was confirmed in the independent sample set obtained from Stanley Array Collection. No effect of sample pH or medication was observed. Genetic association study revealed the association of single nucleotide polymorphism (SNP)1 (rs10008257) with bipolar disorder. In an independent sample set, SNP2 (rs2433320) close to SNP1 was associated with bipolar disorder. In total samples, haplotype of these two SNPs was associated with bipolar disorder. No association was observed in case-control analysis and family-based association analysis in schizophrenia. These results suggest that SNPs in the upstream region of LIM may confer the genetic risk for bipolar disorder.

Association study of C825T polymorphism of the G-protein b3 subunit gene with schizophrenia and mood disorders.

Alterations of G proteins have been implicated in major psychiatric illnesses. A C825T polymorphism of a gene encoding the beta3 subunit of heterotrimeric G proteins (GNB3) was reported to be associated with several pathological conditions, such as hypertension and depressive disorder. We examined whether this polymorphism is associated with functional psychoses in a Japanese sample of 370 schizophrenics, 164 bipolars, 68 depressive patients, and 198 controls. We obtained no evidence for an association of the polymorphism with any diagnostic group.

Glial cell line-derived neurotrophic factor (GDNF) gene and schizophrenia: polymorphism screening and association analysis.

The glial cell line-derived neurotrophic factor (GDNF) is an important neurotrophic and potential differentiation factor for dopaminergic systems. Both the dopamine theory and the neurodevelopmental hypothesis of schizophrenia suggest that alterations of GDNF functions could be involved in the pathogenesis of schizophrenia. Using polymerase chain reaction and single strand conformational polymorphism analysis, we searched for polymorphisms in the GDNF gene in 50 patients with schizophrenia. No evidence was obtained, however, for the presence of polymorphisms in the DNA sequence encoding GDNF mature peptide in our patients. We then examined a trinucleotide repeat (AGG)(n) polymorphism in the 3'-UTR of the GDNF gene for allelic association in a Japanese sample of 99 schizophrenic patients and 98 control subjects. There was no significant difference in the overall distribution of the allele between the two groups. When each allele was examined separately, the allele (AGG)(10) was more common in schizophrenic patients than in control subjects, but this finding was not significant when multiple testing was taken into account in the analysis. Overall, we obtained no solid evidence for the involvement of the GDNF gene in the pathogenesis of schizophrenia, although further studies in larger numbers of subjects will be required to conclude whether the trinucleotide repeat polymorphism is associated with the development of schizophrenia.

Exon/intron boundaries, novel polymorphisms, and association analysis with schizophrenia of the human synaptic vesicle monoamine transporter (SVMT) gene.

The synaptic vesicular monoamine transporter (SVMT), alternatively vesicular monoamine transporter 2 (VMAT2), pumps cytosolic monoamines including dopamine, norepinephrine, serotonin, and histamine into synaptic vesicles. Altered functions of SVMT have been implicated in the pathogensis of several neuropsychiatric diseases. We determined exon/intron boundaries of the human SVMT gene and performed mutational analysis for the exonic and neighboring intronic regions of the gene. Detected polymorphisms were subject to association analysis with schizophrenia in a family-based design. The human SVMT gene consists, of 16 exons and 15 introns, which is consistent with the murine SVMT gene. When mutational analysis was performed by the single strand conformational polymorphism (SSCP) analysis, we found two and four single nucleotide polymorphisms (SNPs) in exons and neighboring introns, respectively. Neither exonic SNP results in an amino acid change. In family-based association analyses in a sample of 50 Japanese schizophrenics and their parents, no significant association was found for the intronic polymorphisms. Our data suggest that there is no common polymorphism in the SVMT gene affecting the primary structure of the human SVMT protein. Furthermore, we obtained no evidence for the major effect of the novel polymorphisms on susceptibility to schizophrenia.

Obstetric complications and schizophrenia: prenatal underdevelopment and subsequent neurodevelopmental impairment.

BACKGROUND: Many studies have shown an association between obstetric complications and schizophrenia. AIMS: To investigate the possible relationship between prenatal underdevelopment, neurodevelopmental abnormality and subsequent schizophrenia. METHOD: The literature was reviewed. In particular, by pooling data from recently published reports, we examined whether low birthweight (< 2500 g) is a risk factor for schizophrenia. RESULTS: Low birthweight was significantly more common for subjects with schizophrenia than for control subjects: P < 0.00001, odds ratio 2.6 (95% CI 2.0 to 3.3). Individuals born prematurely are at greater risk of perinatal brain damage and subsequent neurodevelopmental abnormalities, which may constitute vulnerability to the development of schizophrenia. Patients with schizophrenia who had low birthweights also tended to have poor premorbid psychosocial adjustment. CONCLUSIONS: Low birthweight is a modest, but definite, risk factor for schizophrenia. Brain damage associated with prenatal underdevelopment has a role in the pathogenesis of poor premorbid functioning and subsequent neurodevelopmental impairment in some cases of schizophrenia.

A novel polymorphism of the brain-derived neurotrophic factor (BDNF) gene associated with late-onset Alzheimer's disease.

Several lines of evidence have suggested altered functions of the brain-derived neurotrophic factor (BDNF) in the pathogenesis of neurodegenerative diseases including Alzheimer's disease (AD). In the search for polymorphisms in the 5'-flanking and 5'-noncoding regions of the BDNF gene, we found a novel nucleotide substitution (C270T) in the noncoding region. We performed an association study between this polymorphism and AD in a Japanese sample of 170 patients with sporadic AD (51 early-onset and 119 late-onset) and 498 controls. The frequency of individuals who carried the mutated type (T270) was significantly more common in patients with late-onset AD than in controls (P = 0.00004, odds ratio: 3.8, 95% CI 1.9-7.4). However, there was no significant difference in the genotype distribution between the patients with early-onset AD and the controls, although this might be due to the small sample size of the early-onset group. Our results suggest that the C270T polymorphism of the BDNF gene or other unknown polymorphisms, which are in linkage disequilibrium, give susceptibility to late-onset AD. We obtained no evidence for the possible interactions between the BDNF and apolipoprotein E (APOE) genes, suggesting that the possible effect of the BDNF gene on the development of late-onset AD might be independent of the APOE genotype.

Mitochondrial DNA polymorphisms in bipolar disorder.

BACKGROUND: Previous studies suggested mitochondrial abnormality in bipolar disorder: (1) possible contribution of parent-of-origin effect in transmission of bipolar disorder; (2) abnormal brain phosphorus metabolism detected by phosphorus-31 magnetic resonance spectroscopy; (3) comorbidity of affective disorders in patients with mitochondrial encephalopathy; (4) increased levels of the 4977bp deletion of mitochondrial DNA (mtDNA) in the postmortem brains. We investigated mtDNA polymorphisms in association with bipolar disorder. METHODS: Twelve PCR fragments including all tRNA genes were examined by the single-strand conformation polymorphism method in 43 bipolar patients. All observed polymorphisms were sequenced. Association of these polymorphisms with bipolar disorder was examined by restriction fragment length polymorphism method in 135 bipolar patients and 187 controls. RESULTS: In total, we found 28 polymorphisms including 14 polymorphisms that have not been reported previously. The A10398G polymorphism was significantly associated with bipolar disorder (10398A genotype: 33.1% in bipolar, 22.2% in the control, P<0.05). Although this difference was not significant after Bonferroni correction, the CA haplotype of the 5178 and 10398 polymorphisms was still significantly associated with bipolar disorder (CA haplotype: 33.6% in bipolar, 16.8% in control, P<0.001). Three rare mutations substituting evolutionary conserved bases; A5539G in tRNA(Trp) gene, A5747G in the origin of L-strand replication, and A8537G in ATPase subunit-6 and -8 genes, were found in patients with family history in which maternal transmission was suspected. DISCUSSION: The 5178C/10398A haplotype in mtDNA may be a risk factor of bipolar disorder (odds ratio, 2.4). Pathophysiological significance of rare mtDNA mutations needs to be verified in the future. This finding may imply the pathophysiological significance of mtDNA in bipolar disorder.

No evidence for an association between the Glu298Asp polymorphism of the NOS3 gene and Alzheimer's disease.

Recently a significant association of a missense mutation (Glu298Asp) of the endothelial nitric oxide synthase (NOS3) gene with late-onset Alzheimer's disease (LOAD) was reported. We tried to replicate this finding in a Japanese sample of 121 patients with LOAD, 51 with early-onset AD (EOAD), and 165 medical controls. However, the genotype and allelic distributions for the Glu298Asp polymorphism were similar for these three groups, suggesting that the Glu298Asp polymorphism of the NOS3 gene has no relevance to the development of AD in Japanese.

Association of bipolar disorder with the 5178 polymorphism in mitochondrial DNA.

Parent-of-origin effect in transmission of bipolar disorder and abnormal phosphorus-31 magnetic resonance spectroscopy ((31)P-MRS) findings in the brain in patients with bipolar disorder implicate pathophysiological role of mitochondrial DNA in bipolar disorder. The authors examined possible association of bipolar disorder with the 5178 polymorphism in mitochondrial DNA. Genotype frequencies of the 5178 polymorphism were examined by polymerase chain reaction-restriction fragment length polymorphism method in 145 patients with bipolar disorder and 184 controls. The rate of 5178C genotype was significantly higher in patients with bipolar disorder (81/125 (64.8%), P < 0.05) compared with controls (98/184 (53.2%)) when paternally transmitted cases were excluded. This effect was more prominent in patients with bipolar II disorder (5178C: 28/37, 75.6%, P < 0.02 to controls). Bipolar II patients with 5178A genotype without family history had significantly later age at onset (56.0 +/- 14.7 years, P < 0.05) than other bipolar patients. Brain intracellular pH measured by (31)P-MRS was significantly higher in bipolar patients with 5178A (7.04 +/- 0.03, n = 7, P < 0.05) than those with 5178C (7.00 +/- 0.03, n = 7). There was no difference of subcortical hyperintensity scores by magnetic resonance imaging between patients with 5178A and those with 5178C. These results suggest that the 5178 polymorphism in mitochondrial DNA may regulate vulnerability to bipolar disorder via alteration of brain energy metabolism. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:182-186, 2000.

Intra-uterine physical growth in schizophrenia: evidence confirming excess of premature birth.

BACKGROUND: Many studies have suggested a possible aetiological role for obstetric complications in the development of schizophrenia. We focused on prenatal physical growth in schizophrenia, a contentious issue in the literature. METHODS: We compared gestational age at birth, birth weight (BW) and birth head circumference (BHC) between 312 schizophrenics and 517 controls, and between 187 schizophrenics and their matched healthy siblings. Information on obstetric histories was obtained from the Maternal and Child Health Handbooks (i.e. contemporaneous records). RESULTS: Gestational age at birth was significantly earlier in the schizophrenics than in the controls (P = 0.017). Pre-term birth (gestational age of 36 weeks or less) was more common in schizophrenics than in controls (8.0% v. 3.4%, P = 0.005, odds ratio 2.5). Low BW (2500 g or less) was more frequent in schizophrenics than in controls (9.6% v. 4.6%, P = 0.005, odds ratio 2.2). The schizophrenics had significantly lighter BW (P = 0.0003) and tended to have smaller BHC (P = 0.081) compared with controls. However, multiple regression analysis showed that there was no significant difference in BW or BHC between the schizophrenics and controls when gestational age and maternal weight were controlled. There was no significant difference in BW or BHC between schizophrenics and their siblings, although the schizophrenics tended to be born at earlier gestational age than their siblings. CONCLUSIONS: Our results suggest that prematurity at birth is associated with a risk of developing schizophrenia in adulthood. When gestational age and maternal body weight were allowed for, there was no evidence that schizophrenics tend to have lower mean BW or smaller BHC.

Alzheimer's disease and 5-HTTLPR polymorphism of the serotonin transporter gene: no evidence for an association.

Recently two independent research groups consistently reported a significant association between the serotonin transporter (5-HTT) gene and late-onset sporadic Alzheimer's disease (AD). They found that the "short" allele of the 5-HTT gene-linked polymorphic region (5-HTTLPR), which is associated with reduced transcriptional activity of the gene, increases the risk of developing late-onset AD. The present study tried to replicate this finding in a Japanese sample. We genotyped 41 patients with early-onset AD (<65 years), 82 with late-onset AD, and 336 controls. There was no significant difference in genotype or allele distribution between either patient group and controls in our sample, suggesting that the 5-HTTLPR does not play a major role in the pathogenesis of AD in Japanese.

Human leukocyte antigen and season of birth in Japanese patients with schizophrenia.

OBJECTIVE: Five Japanese studies, to the authors' knowledge, without exception, have consistently shown an increased frequency of human leukocyte antigen (HLA)-DR1 in patients with schizophrenia. This suggests an association between HLA-DR1 and schizophrenia in the Japanese population. The mechanism of the association is unknown; however, prenatal infections may be involved. The present study explored factors, including winter birth, that might correlate with this mechanism. Age at onset and gender were also studied. METHOD: Factors were compared between Japanese patients with schizophrenia with and in those without HLA-DR1 (N=60 and N=307, respectively). RESULTS: A significantly higher incidence of births in February and March was observed in patients with (31.7%) than those without (15. 6%) HLA-DR1. No association was found between the presence of HLA-DR1 and other variables. CONCLUSIONS: Although this result is preliminary, it may suggest an interaction between HLA and winter birth in the development of schizophrenia in the Japanese population.

Cytogenetic findings in 250 schizophrenics: evidence confirming an excess of the X chromosome aneuploidies and pericentric inversion of chromosome 9.

Chromosomal abnormalities may be of help in identifying disease genes. To search for susceptibility loci for schizophrenia, we have performed chromosomal examinations by using the GTG banding technique for 250 schizophrenics. We found five cases with an aneuploidy of the X chromosome and ten cases with pericentric inversion of chromosome 9 [inv (9)]. These results confirmed an excess of the X chromosome aneuploidies in schizophrenia, indicating a possible involvement of the X chromosome in the pathogenesis of the illness. The observed incidence (4.0%) of inv (9) in our schizophrenic sample was significantly higher (p=0.013) than that reported in the general population in Japan (1.7%). Although inv (9) has been considered to be a normal variant, our observation implies a possible association between inv (9) and schizophrenia, suggesting that a susceptibility locus for the disease may be located at a breakpoint of the inversion on chromosome 9.

Paroxysmal kinesigenic choreoathetosis locus maps to chromosome 16p11.2-q12.1.

Paroxysmal kinesigenic choreoathetosis (PKC), the most frequently described type of paroxysmal dyskinesia, is characterized by recurrent, brief attacks of involuntary movements induced by sudden voluntary movements. Some patients with PKC have a history of infantile afebrile convulsions with a favorable outcome. To localize the PKC locus, we performed genomewide linkage analysis on eight Japanese families with autosomal dominant PKC. Two-point linkage analysis provided a maximum LOD score of 10.27 (recombination fraction [theta] =.00; penetrance [p] =.7) at marker D16S3081, and a maximum multipoint LOD score for a subset of markers was calculated to be 11.51 (p = 0.8) at D16S3080. Haplotype analysis defined the disease locus within a region of approximately 12.4 cM between D16S3093 and D16S416. P1-derived artificial chromosome clones containing loci D16S3093 and D16S416 were mapped, by use of FISH, to 16p11.2 and 16q12.1, respectively. Thus, in the eight families studied, the chromosomal localization of the PKC critical region (PKCR) is 16p11.2-q12.1. The PKCR overlaps with a region responsible for "infantile convulsions and paroxysmal choreoathetosis" (MIM 602066), a recently recognized clinical entity with benign infantile convulsions and nonkinesigenic paroxysmal dyskinesias.

Autosome search for schizophrenia susceptibility genes in multiply affected families.

We have analysed 298 polymorphic markers in 13 families multiply affected with schizophrenia and related disorders using a combination of radiolabelled and fluorescent-based methodologies. The markers were distributed throughout the autosomes at an average spacing of 12.8 cM. The data were analysed with two-point linkage analysis (MLINK) and heterogeneity testing (HOMOG). Several genetic models were used ranging from near dominant to fully recessive. Multi-point analysis was performed for 27 regions demonstrating either contiguously positive lod scores in two or more consecutive markers, and in regions with two-point lod score(s) of 1.0 or above in a single marker. A proportion of the multi-point regions have been implicated in previous studies, thereby decreasing risk of false-positive results. However neither our two-point, nor multi-point scores reached the threshold value for significance of 3. 6. Nevertheless three regions were suggestive of linkage.