Psychiatric disorders, myoclonus dystonia, and the epsilon-sarcoglycan gene: a systematic review.

BACKGROUND: Mutations in the maternally imprinted epsilon-sarcoglycan gene occur in 30%-50% of myoclonus-dystonia cases. Psychiatric symptoms, particularly obsessive-compulsive disorder, have been described in some patients. METHODS: We systematically reviewed 22 reports of psychiatric symptoms in myoclonus-dystonia, dividing individuals according to clinical and mutation status. RESULTS: Clinically manifesting mutation carriers demonstrated an excess of psychiatric disorders compared with nonmutation carriers (P < .001). No differences were seen between non-motor-manifesting carriers and nonmutation carriers with the exception of alcohol excess/dependence, higher in non-motor-manifesting carriers. CONCLUSIONS: The results confirm the association of epsilon-sarcoglycan gene mutations with psychiatric disease and suggest a possible separation of the motor and psychiatric effects.

Methylenetetrahydrofolate reductase gene variant (MTHFR C677T) and migraine: a case control study and meta-analysis.

BACKGROUND: Migraine is a common disorder that often coexists with depression. While a functional polymorphism in methyleneterahydrofolate reductase gene (MTHFR C677T) has been implicated in depression; the evidence to support an association of MTHFR with migraine has been inconclusive. We aim to investigate the effect of this variant on propensity for migraine and to perform a systematic review and meta-analysis of studies of MTHFR and migraine to date. METHODS: Individuals with migraine (n = 447) were selected from the Depression Case Control (DeCC) study to investigate the association between migraine and MTHFR C677T single nucleotide polymorphism (SNP) rs1801133 using an additive model compared to non-migraineurs adjusting for depression status. A meta-analysis was performed and included 15 studies of MTHFR and migraine. RESULTS: MTHFR C677T polymorphism was associated with migraine with aura (MA) (OR 1.31, 95% CI 1.01-1.70, p = 0.039) that remained significant after adjusting for age, sex and depression status. A meta-analysis of 15 case-control studies showed that T allele homozygosity is significantly associated with MA (OR = 1.42; 95% CI, 1.10-1.82) and total migraine (OR = 1.37; 95% CI, 1.07-1.76), but not migraine without aura (OR = 1.16; 95% CI, 0.36-3.76). In studies of non-Caucasian population, the TT genotype was associated with total migraine (OR= 3.46; 95% CI, 1.22-9.82), whereas in studies of Caucasians this variant was associated with MA only (OR = 1.28; 95% CI, 1.002-1.63). CONCLUSIONS: MTHFR C677T is associated with MA in individuals selected for depression study. A meta-analysis of 15 studies supports this association and demonstrated effects across ethnic groups.

Migraine in recurrent depression: case-control study.

BACKGROUND: An association between depression and headache is well established, but the specificity to migraine is unclear. AIMS: To investigate the specificity of the association of depression and migraine. METHOD: People with recurrent depression (n=1259) were compared with psychiatrically healthy controls (n=851) to investigate headache defined according to International Headache Society criteria in each group. RESULTS: All headache types were more prevalent in the case group than in the controls. However, the strongest association was between depression and migraine with aura (OR=5.6). Among participants with recurrent headaches, migraine with aura (but not other forms of headache) was highly significantly associated with depression. CONCLUSIONS: The data suggest that not only is there a general relationship between headache and depression but also that among people with recurrent headache there is a specific association between depression and migraine with aura. The association is likely to be explained by overlapping aetiological risk factors.

P2RX7: A bipolar and unipolar disorder candidate susceptibility gene?

The chromosomal region 12q24 has been previously implicated by linkage studies of both bipolar disorder and unipolar mood disorder and we have reported two pedigrees segregating both bipolar disorder and Darier's disease that show linkage across this region. The gene P2RX7 is located in this chromosomal region and has been recently reported as a susceptibility gene for bipolar disorder and unipolar depression. The non-synonymous SNP rs2230912 (resulting in amino-acid polymorphism Q460R) showed the strongest association and has been postulated to be pathogenically relevant. We have investigated this gene in a large UK case-control sample (bipolar I disorder N = 687, unipolar recurrent major depression N = 1,036, controls N = 1,204). Neither rs2230912 nor any of 8 other SNPs genotyped across P2RX7 was found to be associated with mood disorder in general, nor specifically with bipolar or unipolar disorder. Further, sequencing of our two chromosome 12-linked bipolar-Darier families showed no evidence of rare variants at P2RX7 that could explain the linkage. Our data do not provide support for rs2230912 or the other polymorphisms studied within the P2RX7 locus, being involved in susceptibility to mood disorders.

Pollination ecology of the ghost orchid (Dendrophylax lindenii): A first description with new hypotheses for Darwin's orchids.

The structural variation of orchids enables myriad fascinating symbiotic relationships with organisms across kingdoms. Orchids are frequently known for having elaborate arms races with their pollinators that result in intricate morphologies in both parties, and flowers with long corollas hypothesized to be pollinated only by individual species of long tongued hawkmoths are of particular concern for conservation. Florida's endangered ghost orchid, Dendrophylax lindenii, has long been confidently assumed to be pollinated by one species (Cocytius antaeus), despite the presence of a resident community of multiple suitable long-tongued candidates. Here we present the first description of ghost orchid pollination, and describe novel remote camera trapping methods. Pollination of D. lindenii by Pachylia ficus disproves long-standing hypotheses concerning the pollination ecology of long-spurred orchids, and new multiple pollinator hypotheses are proposed. We discuss the broader implications for the conservation of an endangered species, orchids globally, and the importance of Everglades restoration.

Sex differences in symptom patterns of recurrent major depression in siblings.

The objectives of this study were to examine sex differences in depressive symptom patterns in 475 sib pairs with well-defined recurrent major depression and to test the hypotheses that (a) symptom patterns show higher intraclass correlations within same sex sib pairs versus mixed sex sib pairs; and (b) symptoms more associated with women, e.g. atypical depressive and anxiety symptoms, account for differences between male and female siblings within the same family. A total of 878 individuals, with a past history of at least two depressive episodes, were interviewed using the Schedules for Clinical Assessment in Neuropsychiatry interview and diagnosed according to DSM-IV using a computerized scoring program (CATEGO5). Intraclass correlations were compared between mixed and same sex sibs, and a conditional regression analysis in mixed sex sib pairs was performed to test whether specific symptoms account for differences between male and female siblings within the same family. Women showed a significantly earlier onset of depression compared with men (23.0 years, SD=10.6 versus 25.5, SD=12.5 years, P=0.0004), and a significantly greater frequency of several aspects of depressed mood was found in women compared with men, including atypical depressive features of fatiguability, appetite gain, weight gain and hypersomnia. Discordant sib-pair data analyses revealed five symptoms that accounted for the sex differences between siblings (P=.000035): phobia (exp(B)=2.04, P=0.017), hypersomnia (exp(B)=1.37, P=0.055), appetite loss (exp(B)=1.38, P=0.004) and appetite gain (exp(B)=2.19, P<0.001). Sex significantly modifies clinical features of depression and an earlier onset of depression and atypical depressive symptoms occur more frequently in women.

Bipolar affective puerperal psychosis: genome-wide significant evidence for linkage to chromosome 16.

OBJECTIVE: Vulnerability to the triggering of bipolar episodes by childbirth aggregates in families and may define a genetically relevant subtype of bipolar disorder. The authors conducted a search by systematic whole genome linkage scan for loci influencing vulnerability to bipolar affective puerperal psychosis. METHOD: The authors selected families with bipolar disorder from their previous bipolar disorder genome scan, in which there was at least one family member with a manic or psychotic episode with an onset within 6 weeks of delivery. Individuals were coded as affected if they had been diagnosed with bipolar I disorder; bipolar II disorder; or schizoaffective disorder, bipolar type, according to DSM-IV. A total of 36 pedigrees contributed 54 affected sibling pairs to the cohort. A genome scan with 494 microsatellite markers was analyzed using GENEHUNTER and MAPMAKER/SIBS. RESULTS: A genome-wide significant linkage signal was observed on chromosome 16p13, and a genome-wide suggestive linkage was observed on chromosome 8q24. No significant or suggestive linkage was observed in these regions in our original bipolar scan. CONCLUSIONS: This study identifies chromosomal regions that are likely to harbor genes that predispose individuals to bipolar affective puerperal psychosis. The identification of susceptibility genes would enhance understanding of pathogenesis and offer the possibility of improvements in treatment and risk prediction.

Parasitic helminths of free-ranging mink (Neovison vison mink) from southern Florida.

Five free-ranging mink, Neovison vison mink, from in or near the Fakahatchee Strand Preserve State Park, Collier County, Florida (26 degrees 00'N, 81 degrees 25'W), were examined for parasitic helminths. Nine species of helminths were identified (2 trematodes, 5 nematodes, and 2 acanthocephalans). The most prevalent parasites were Molineus patens (4 of 5 mink), mean intensity 173 (range, 12-342); Strongyloides sp. (4 of 5), mean intensity 48 (range, 1-170); Macracanthorhynchus ingens (immature) (4 of 5), mean intensity 2.5 (range, 1-4); and Alaria mustelae (3 of 5), mean intensity 59.3 (range, 11-127). Polymorphus brevis and Dirofilaria lutrae are reported from the mink for the first time.

The Depression Network (DeNT) Study: methodology and sociodemographic characteristics of the first 470 affected sibling pairs from a large multi-site linkage genetic study.

BACKGROUND: The Depression Network Study (DeNt) is a multicentre study designed to identify genes and/or loci linked to and/or associated with susceptibility to unipolar depression in Caucasian families. This study presents the method and socio-demographic details of the first 470 affected sibling pairs recruited from 8 different sites in Europe and the United States of America. METHODS: Probands fulfilling either the Diagnostic and Statistical Manual 4th edition (DSM-IV) or the International Classification of Diseases 10th edition (ICD-10) criteria for recurrent unipolar depression of moderate or severe degree and who had at least one similarly affected sibling were eligible for the study. Detailed clinical and psychological assessments were undertaken on all subjects including an interview using the Schedules for Clinical Assessment in Neuropsychiatry. Blood samples were collected from all participants to extract DNA for linkage analysis. RESULTS: The different sites used different recruitment strategies depending on local health care organisation but despite this there was remarkable similarity across sites for the subjects recruited. Although the Bonn site had significantly older subjects both for age of onset and age at interview, for the sample as a whole, subjects were interviewed in their mid-40s and had experienced the onset of their recurrent depression in their 20s. Preliminary genome screening was able to include 929 out of the 944 subjects (98.4%) typed at 932 autosomal and 544 X chromosome markers. CONCLUSIONS: This paper describes the methodology and the characteristics of the subjects from the 414 families included in the first wave of genotyping from the multi-site DeNT study. Ultimately the study aims to collect affected sibling pairs from approximately 1200 families.

Anonymity and confidentiality: rural teenagers' concerns when accessing sexual health services.

CONTEXT: While confidentiality is recognised as a key aspect of successful health services aimed at young people, most research has looked at the concerns of those in urban centres. This paper reports on qualitative and quantitative data collected from general practitioners (GPs) and young people in a rural health district. OBJECTIVE: To assess the concerns of rural teenagers regarding anonymity and confidentiality when accessing sexual health services. DESIGN: The views of teenagers about using health services for issues of sexual health were sought through an in-school survey of 311 Year 9 and 119 Year 11 students. In addition, 18 single-sex focus groups discussions were conducted in North and East Devon. All GPs in the district were asked to complete a questionnaire. RESULTS: These reveal that the particular concerns of young people from small communities are more to do with the difficulties of remaining anonymous, which are related to visibility and lack of privacy in small communities. These problems were more pervasive among rural young people than those concerns more usually reported about confidential consultations.

Interaction between specific forms of childhood maltreatment and the serotonin transporter gene (5-HTT) in recurrent depressive disorder.

BACKGROUND: There is inconsistent evidence of interaction between stressful events and a serotonin transporter promoter polymorphism (5-HTTLPR) in depression. Recent studies have indicated that the moderating effect of 5-HTTLPR may be strongest when adverse experiences have occurred in childhood and the depressive symptoms persist over time. However, it is unknown whether this gene-environment interaction is present for recurrent depressive disorder and different forms of maltreatment. Therefore, patients with recurrent clinically diagnosed depression and controls screened for the absence of depression were utilised to examine the moderating effect of 5-HTTLPR on associations between specific forms of childhood adversity and recurrent depression. METHOD: A sample of 227 recurrent unipolar depression cases and 228 never psychiatrically ill controls completed the Childhood Trauma Questionnaire to assess exposure to sexual, physical and emotional abuse, physical and emotional neglect in childhood. DNA extracted from blood or cheek swabs was genotyped for the short (s) and long (l) alleles of 5-HTTLPR. RESULTS: All forms of childhood maltreatment were reported as more severe by cases than controls. There was no direct association between 5-HTTLPR and depression. Significant interactions with additive and recessive 5-HTTLPR genetic models were found for overall severity of maltreatment, sexual abuse and to a lesser degree for physical neglect, but not other maltreatment types. LIMITATIONS: The cross-sectional design limits causal inference. Retrospective report of childhood adversity may have reduced the accuracy of the findings. CONCLUSIONS: This study provides support for the role of interplay between 5-HTTLPR and a specific early environmental risk in recurrent depressive disorder.

Genome-wide association study of co-occurring anxiety in major depression.

OBJECTIVES: Co-morbidity between depression and anxiety disorders is common. In this study we define a quantitative measure of anxiety by summating four anxiety items from the SCAN interview in a large collection of major depression (MDD) cases to identify genes contributing to this complex phenotype. METHODS: A total of 1522 MDD cases dichotomised according to those with at least one anxiety item scored (n = 1080) and those without anxiety (n = 442) were analysed, and also compared to 1588 healthy controls at a genome-wide level, to identify genes that may contribute to anxiety in MDD. RESULTS: For the quantitative trait, suggestive evidence of association was detected for two SNPs, and for the dichotomous anxiety present/absent ratings for three SNPs at genome-wide level. In the genome-wide analysis of MDD cases with co-morbid anxiety and healthy controls, two SNPs attained P values of < 5 × 10⁻6. Analysing candidate genes, P values ≤ 0.0005 were found with three SNPs for the quantitative trait and three SNPs for the dichotomous trait. CONCLUSIONS: This study provides an initial genome-wide assessment of possible genetic contribution to anxiety in MDD. Although suggestive evidence of association was found for several SNPs, our findings suggest that there are no common variants strongly associated with anxious depression.

A comprehensive family-based replication study of schizophrenia genes.

IMPORTANCE: Schizophrenia (SCZ) is a devastating psychiatric condition. Identifying the specific genetic variants and pathways that increase susceptibility to SCZ is critical to improve disease understanding and address the urgent need for new drug targets. OBJECTIVE: To identify SCZ susceptibility genes. DESIGN: We integrated results from a meta-analysis of 18 genome-wide association studies (GWAS) involving 1,085,772 single-nucleotide polymorphisms (SNPs) and 6 databases that showed significant informativeness for SCZ. The 9380 most promising SNPs were then specifically genotyped in an independent family-based replication study that, after quality control, consisted of 8107 SNPs. SETTING: Linkage meta-analysis, brain transcriptome meta-analysis, candidate gene database, OMIM, relevant mouse studies, and expression quantitative trait locus databases. PATIENTS: We included 11,185 cases and 10,768 control subjects from 6 databases and, after quality control 6298 individuals (including 3286 cases) from 1811 nuclear families. MAIN OUTCOMES AND MEASURES: Case-control status for SCZ. RESULTS: Replication results showed a highly significant enrichment of SNPs with small P values. Of the SNPs with replication values of P.01, the proportion of SNPs that had the same direction of effects as in the GWAS meta-analysis was 89% in the combined ancestry group (sign test, P < 2.20 x 10(-16) and 93% in subjects of European ancestry only (P < 2.20 < 10(-16)). Our results supported the major histocompatibility complex region showing a3.7-fold overall enrichment of replication values of P < .01 in subjects from European ancestry. We replicated SNPs in TCF4 (P = 2.53 x 10(-10)) and NOTCH4 (P = 3.16 x 10(-7)) that are among the most robust SCZ findings. More novel findings included POM121L2 (P = 3.51 x 10(-7)), AS3MT (P = 9.01 x 10(-7)), CNNM2 (P = 6.07 = 10(-7)), and NT5C2(P = 4.09 x 10(-7)). To explore the many small effects, we performed pathway analyses. The most significant pathways involved neuronal function (axonal guidance, neuronal systems, and L1 cell adhesion molecule interaction)and the immune system (antigen processing, cell adhesion molecules relevant to T cells, and translocation to immunological synapse). CONCLUSIONS AND RELEVANCE: We replicated novel SCZ disease genes and pathogenic pathways. Better understanding the molecular and biological mechanisms involved with schizophrenia may improve disease management and may identify new drug targets.

Spirituality is personal and cannot be forced on others.

In 'Why spirituality is essential for nurses' (features June 6), Stephen Wright and Julia Neuberger appear to assume that we all understand and adhere to a form of supernatural belief, and that everyone understands what spirituality means.

Medicalising normal human conditions is unscientific.

Writing in response to a learning zone article (May 2) on the assessment and treatment of patients experiencing anxiety, David Lee (letters May 16) asks if we are medicalising a range of normal human conditions.

Responsible leadership on the ward would avert more scandals.

Your editorial (July 18) on the timely action needed to prevent poor care in hospitals raises an important issue for the nursing profession.

An ombudsman would encourage nurses to report concerns.

The events at Winterbourne View residential home and failures on the part of the NHS to take up concerns about Sir Jimmy Savile (news October 31) are evidence that whistleblowing policies are not working.

Stressful life events and the serotonin transporter gene (5-HTT) in recurrent clinical depression.

BACKGROUND: An interaction between recent stressful life events (SLEs) and a serotonin transporter promoter polymorphism (5-HTTLPR) in depression has been inconsistently reported. Some of this variability may be due to a previous focus on sub-clinical depression, inclusion of individuals at the lower or upper ends of the age-span, or assumptions concerning the degree of dominance of the low expressing allele. Therefore, a large sample of patients with recurrent clinically diagnosed depression and controls screened for absence of depression was utilised to examine the moderating effect of each 5-HTTLPR genetic model on the association between SLEs and severe depressive episodes. METHOD: A sample of 1236 recurrent unipolar depression cases and 598 age-matched, never psychiatrically ill controls completed the List of Threatening Experiences Questionnaire to assess the number of SLEs experienced in the 6 months prior to the most severe depressive episode (cases) or interview (controls). DNA extracted from blood or cheek swabs was genotyped for the short (s) and long (l) alleles of 5-HTTLPR. RESULTS: A greater number of SLEs were reported by cases than controls and this held across all genotypic groups. There was no main effect of 5-HTTLPR on depression and no evidence of interaction between total SLEs and any of the 5-HTTLPR genetic models. The results were the same for men and women. LIMITATIONS: Utilisation of retrospective self-reported SLEs may have reduced the accuracy of the findings and the cross-sectional design prevents causal inference. CONCLUSIONS: This study failed to find evidence of gene-environment interplay in recurrent clinical depression.

At-risk variant in TCF7L2 for type II diabetes increases risk of schizophrenia.

BACKGROUND: Schizophrenia is associated with increased risk of type II diabetes and metabolic disorders. However, it is unclear whether this comorbidity reflects shared genetic risk factors, at-risk lifestyle, or side effects of antipsychotic medication. METHODS: Eleven known risk variants of type II diabetes were genotyped in patients with schizophrenia in a sample of 410 Danish patients, each matched with two healthy control subjects on sex, birth year, and month. Replication was carried out in a large multinational European sample of 4089 patients with schizophrenia and 17,597 controls (SGENE+) using Mantel-Haenszel test. RESULTS: One type II diabetes at-risk allele located in TCF7L2, rs7903146 [T], was associated with schizophrenia in the discovery sample (p = .0052) and in the replication with an odds ratio of 1.07 (95% confidence interval 1.01-1.14, p = .033). CONCLUSION: The association reported here with a well-known diabetes variant suggests that the observed comorbidity is partially caused by genetic risk variants. This study also demonstrates how genetic studies can successfully examine an epidemiologically derived hypothesis of comorbidity.