Replication and exploratory analysis of 24 candidate risk polymorphisms for neural tube defects.

BACKGROUND: Neural tube defects (NTDs), which are among the most common congenital malformations, are influenced by environmental and genetic factors. Low maternal folate is the strongest known contributing factor, making variants in genes in the folate metabolic pathway attractive candidates for NTD risk. Multiple studies have identified nominally significant allelic associations with NTDs. We tested whether associations detected in a large Irish cohort could be replicated in an independent population. METHODS: Replication tests of 24 nominally significant NTD associations were performed in racially/ethnically matched populations. Family-based tests of fifteen nominally significant single nucleotide polymorphisms (SNPs) were repeated in a cohort of NTD trios (530 cases and their parents) from the United Kingdom, and case-control tests of nine nominally significant SNPs were repeated in a cohort (190 cases, 941 controls) from New York State (NYS). Secondary hypotheses involved evaluating the latter set of nine SNPs for NTD association using alternate case-control models and NTD groupings in white, African American and Hispanic cohorts from NYS. RESULTS: Of the 24 SNPs tested for replication, ADA rs452159 and MTR rs10925260 were significantly associated with isolated NTDs. Of the secondary tests performed, ARID1A rs11247593 was associated with NTDs in whites, and ALDH1A2 rs7169289 was associated with isolated NTDs in African Americans. CONCLUSIONS: We report a number of associations between SNP genotypes and neural tube defects. These associations were nominally significant before correction for multiple hypothesis testing. These corrections are highly conservative for association studies of untested hypotheses, and may be too conservative for replication studies. We therefore believe the true effect of these four nominally significant SNPs on NTD risk will be more definitively determined by further study in other populations, and eventual meta-analysis.

Engineering clustered ligand binding into nonviral vectors: alphavbeta3 targeting as an example.

The development of techniques to efficiently deliver genes using nonviral approaches can broaden the application of gene delivery in medical applications without the safety concerns associated with viral vectors. Here, we designed a clustered integrin-binding platform to enhance the efficiency and targetability of nonviral gene transfer to HeLa cells with low and high densities of alpha(v)beta(3) integrin receptors. Arg-Gly-Asp (RGD) nanoclusters were formed using gold nanoparticles functionalized with RGD peptides and used to modify the surface of DNA/poly(ethylene imine) (PEI) polyplexes. DNA/PEI polyplexes with attached RGD nanoclusters resulted in either 5.4- or 35-fold increase in gene transfer efficiency over unmodified polyplexes for HeLa cells with low- or high-integrin surface density, respectively. The transfection efficiency obtained with the commercially available vector jetPEI-RGD was used for comparison as a vector without clustered binding. JetPEI-RGD exhibited a 1.2-fold enhancement compared to unmodified jetPEI in cells with high densities of alpha(v)beta(3) integrin receptors. The data presented here emphasize the importance of the RGD conformational arrangement on the surface of the polyplex to achieve efficient targeting and gene transfer, and provide an approach to introduce clustering to a wide variety of nanoparticles for gene delivery.

First rank symptoms in first episode psychosis and their relationship to the duration of untreated illness.

Most studies of First Rank Symptoms (FRS) are based on cross-sectional inpatient samples of people with schizophrenia at various stages of illness. We sought to examine the prevalence of FRS in a representative sample of first episode psychosis patients and compare those with and without FRS clinically and in terms of duration of untreated illness. Information was gathered from 158 consecutive cases of first episode psychosis presenting in a defined geographical region through semi-structured interview tools. Of this sample, 40.5% of cases received a diagnosis of schizophrenia. The prevalence of FRS among the entire group was 52.5%. After controlling for multiple testing, no FRS contributed significantly to predicting a diagnosis of schizophrenia. There was no significant relationship between the duration of untreated illness and FRS.

First episode psychosis and the trail to secondary care: help-seeking and health-system delays.

BACKGROUND: People experience delays in receiving effective treatment for many illnesses including psychosis. These delays have adverse consequences in heart disease and cancer, and their causes have been the subject of much research but only in recent years have pathways to care in psychosis received such attention. We sought to establish if, when and where people seek help in the early phase of psychosis in a representative sample. METHODS: One hundred and sixty-five people with first episode psychosis, referred from community-based psychiatric services and a private psychiatric facility to an early intervention service over 18 months, were interviewed with the Structured Clinical Interview for DSM-IV diagnoses. Symptoms were measured using the Schedule for the Assessment of Positive Symptoms, Schedule for the Assessment of Negative Symptoms and the Calgary Scale. Duration of untreated illness (DUI) and duration of untreated psychosis (DUP) were established using the Beiser Scale. Pathways to mental health services were systematically detailed through interviews with patients and their families. RESULTS: The final sample consisted of 142 (88M, 54F) cases after those with psychosis due to a general medical condition and those without pathway and DUP data were excluded. Less than half of participants initiated help seeking themselves. Of those who did seek help (n = 57) 25% did so during the DUI. Those who had a positive family history of mental illness and poorer premorbid adjustment were significantly less likely to seek help for themselves and those who did not seek help were more likely to require hospitalisation. Families were involved in help seeking for 50% of cases and in 1/3 of cases did so without the affected individual participating in the contact. Being younger and having more negative symptoms were associated with having one's family involved in help seeking. Delays to effective treatment from the onset of psychosis were evenly split between "help-seeking delays" and "health-system delays". Having a family member involved in help seeking and better premorbid adjustment were independently associated with shorter help-seeking delays when measured from the onset of psychosis. Being female, having better premorbid adjustment and fewer negative symptoms were associated with shorter help-seeking delays from the onset of illness. Those with a non-affective psychosis had significantly longer system delays. CONCLUSION: Many people with first episode psychosis do not initiate help-seeking for themselves particularly those with a relative affected by mental illness. Those with poor premorbid adjustment are at particular risk of longer delays. Poor premorbid adjustment compounded by long delays to effective treatment reduces the likelihood of a good outcome. Families play a vital role in hastening receipt of effective treatment.

A common variant in MTHFD1L is associated with neural tube defects and mRNA splicing efficiency.

Polymorphisms in folate-related genes have emerged as important risk factors in a range of diseases including neural tube defects (NTDs), cancer, and coronary artery disease (CAD). Having previously identified a polymorphism within the cytoplasmic folate enzyme, MTHFD1, as a maternal risk factor for NTDs, we considered the more recently identified mitochondrial paralogue, MTHFD1L, as a candidate gene for NTD association. We identified a common deletion/insertion polymorphism, rs3832406, c.781-6823ATT(7-9), which influences splicing efficiency and is strongly associated with NTD risk. Three alleles of rs3832406 were detected in the Irish population with varying numbers of ATT repeats: Allele 1 consists of ATT(7), whereas Alleles 2 and 3 consist of ATT(8) and ATT(9), respectively. Allele 2 of this triallelic polymorphism showed a decreased case risk as demonstrated by case-control logistic regression (P=0.002) and by transmission disequilibrium test (TDT) (P=0.001), whereas Allele 1 showed an increased case risk. Allele 3 showed no influence on NTD risk and represents the lowest frequency allele (0.15). Additional single nucleotide polymorphism (SNP) genotyping in the same genomic region provides additional supportive evidence of an association. We demonstrate that two of the three alleles of rs3832406 are functionally different and influence the splicing efficiency of the alternate MTHFD1L mRNA transcripts.

Construction of a high resolution linkage disequilibrium map to evaluate common genetic variation in TP53 and neural tube defect risk in an Irish population.

Genetic and environmental factors contribute to the etiology of neural tube defects (NTDs). While periconceptional folic acid supplementation is known to significantly reduce the risk of NTDs, folate metabolic pathway related factors do not account for all NTDs. Evidence from mouse models indicates that the tumor protein p53 (TP53) is involved in implantation and normal neural tube development. To determine whether genetic variation in TP53 might contribute to NTD risk in humans, we constructed a high resolution linkage disequilibrium (LD) map of the TP53 genomic region based on genotyping 21 markers in an Irish population. We found that nine of these variants can be used to capture the majority of common variation in the TP53 genomic region. In contrast, the 3-marker haplotype commonly reported in the TP53 literature offers limited coverage of the variation in the gene. We used the expanded set of polymorphisms to measure the influence of TP53 on NTDs using both case-control and family based tests of association. We also assayed a functional variant in the p53 regulator MDM2 (rs2279744). Alleles of three noncoding TP53 markers were associated with NTD risk. A case effect was seen with the GG genotype of rs1625895 in intron 6 (OR = 1.37 [1.04-1.79], P = 0.02). A maternal effect was seen with the 135/135 genotype of the intron 1 VNTR (OR = 1.86 [1.16-2.96], P = 0.01) and the TT genotype of rs1614984 (RR = 0.58 [0.37-0.91], P = 0.02). As multiple comparisons were made, these cannot be considered definitive positive findings and additional investigation is required.

Survival and disability in a cohort of neural tube defect births in Dublin, Ireland.

BACKGROUND: Neural tube defects (NTDs) are a major cause of death and disability. Periconceptional folic acid prevents up to 70% of these malformations but public health campaigns to increase use of supplements have had disappointing results: The proposed mandatory fortification of bread products in Ireland has raised concerns about possible side effects. We examined data collected on a cohort of children born with NTDs in an era before fortification/supplementation to illustrate the serious consequences in terms of survival and disability. METHODS: All 623 infants born with NTDs in the Dublin area between 1976 and 1987 were included. Information was collected on mortality and length of survival for those who died, and for those who survived at least 5 years, interview-based data were collected on age, place of residence, prevalence of hydrocephalus, degree of disability, schooling, and IQ. RESULTS: Seventy-four births (12%) were stillborn. Of the livebirths only 41% were alive at 5 years. Factors associated with mortality were type of lesion, level of lesion, presence of other defects, hydrocephalus, year of birth, and gestation. Of the children who survived to 5 years or more, 75% had a disability and 56% were severely disabled. Type of lesion and level of lesion influenced disability risk. Of the survivors, 51% of children had mobility limitations, 59% were incontinent, 42% had hydrocephalus, and 17% had intellectual disability. CONCLUSIONS: These findings illustrate the devastating consequences of NTDs and underline the importance of effective intervention programs with folic acid for prevention.

Is the duration of untreated psychosis temporally stable?

Although there is some evidence that duration of untreated psychosis (DUP) is geographically stable, few have examined whether the phenomenon is temporally stable. We examined DUP in two cohorts within two discrete time periods (1995-1999 and 2003-2005) spanning a decade in the same geographically defined community psychiatric service with no early intervention programme. Patients were diagnosed by Structured Clinical Interview for DSM (SCID) and we determined the DUP using the Beiser Scale. The DUP of the 240 participants did not differ significantly between study periods.

Feasibility of a psychosis information intervention to improve mental health literacy for professional groups in contact with young people.

The aim of this study was to assess the feasibility of a psychosis information intervention for professionals in contact with young people in Ireland. A quasi-experimental pre- and post-intervention design was used. One thousand and thirty-two professionals received an information intervention designed to improve mental health literacy (MHL) and confidence in providing help to people with psychosis. Seven hundred and fifty-five participants completed the Psychosis Information and Confidence Questionnaire pre- and post-intervention. The information intervention significantly improved participants': (1) knowledge of psychosis; (2) ability to recognize signs and symptoms of psychosis; (3) awareness of how to access services; and (4) confidence in providing help to people experiencing psychosis. Findings provide promising support for the intervention's feasibility and acceptability. The intervention enhanced MHL regarding psychosis among professionals in contact with young people. Further research assessing if such improvements translate to the facilitation of appropriate help seeking, the enhanced early detection of psychosis and a reduction of the duration of untreated psychosis is required.

Creating a curriculum on psychosis: a pilot training programme with youth workers.

AIMS: Public education may constitute an effective early intervention strategy to reduce delays in the treatment of psychotic disorders and thereby improve outcome. The purpose of this project was to design, implement and validate a curriculum on early intervention in psychosis for youth workers. METHOD: A training intervention on early intervention in psychosis was designed and delivered through 1-day workshops. Objective and self-perceived competencies were measured before and after the intervention and at 3-month follow up. An additional question was added to assess social distancing from subjects with psychosis. RESULTS: Compared with baseline, the training programme resulted in an improvement in problem identification and symptom recognition skills for vignettes on psychosis (P < 0.05), and in advice on help-seeking behaviour (P < 0.001) and in self-perceived competencies (P < 0.001). Additionally, there was a reduction in social distancing (P < 0.001). These desired outcomes were found to be sustained over a 3-month period. CONCLUSIONS: The training course improved case recognition skills and advice on help-seeking behaviour and resulted in reduction in social distancing in this cohort of youth workers.

Group cognitive behavioural therapy for first episode psychosis: who's referred, who attends and who completes it?

AIM: Most national guidelines recommend psychological therapy for people with first-episode psychosis (FEP) but interventions proven effective in randomized control trials (RCTs) conducted in research settings do not always translate effectively to real-world clinical environments. In a limited health system, it is important to understand the system and patient barriers to participation in effective treatment. We sought to determine what patient characteristics influenced clinicians' decision to refer or not to refer to group cognitive behavioural therapy for FEP and what characteristics were associated with those referred attending/not attending and adhering/not adhering to the programme. METHODS: Between 2006 and 2008, all cases of confirmed FEP from a defined geographical region were examined using the Structured Clinical Interview for DSM-IV-TR Axis I Disorders for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnoses, the Scale for Assessment of Positive Symptoms, Scale for Assessment of Negative Symptoms, Calgary Depression Scale for Schizophrenia and Birchwood Insight Scale. Duration of untreated psychosis was established using the Beiser Scale. RESULTS: Of the 124 (77 males, 47 females) people in the final sample, 88 (72%) were referred for cognitive behavioural therapy (CBT), 52 (59%) attended and 12 (23%) did not complete CBT. Those with higher levels of insight into the need for treatment (U = 740.00, z = -2.63, P = 0.008) and higher levels of positive symptoms (t (120) = -3.064, P = 0.003) were more likely to be referred to CBT. Those with higher educational attainment (χ(2) = 9.48, P = 0.03) and fewer negative symptoms, particularly in relation to global attention (t (85) = 2.32, P = 0.03), were more likely to attend and complete CBT. CONCLUSION: Within an early intervention service for FEP, it appears that individuals with less education, more negative symptoms and less insight experienced significant barriers to successfully completing group CBT. More information for referring clinicians about the benefits of CBT for FEP could help increase referral rates. Assertive outreach for people at risk of disengaging or non-adherence should also be considered.

Are symptoms associated with increased levels of perceived stress in first-episode psychosis?

Several studies report on the presence of external stress and life events prior to the onset and exacerbation of psychotic illness. However, the relationship between the subjective appraisal of stress at first presentation with psychosis is less well understood. This paper reports on the relationship between the individual perception of stress and symptomatology in individuals with first-episode psychosis at presentation to community mental health services. We assessed 123 individuals using standardized measures of symptoms, quality of life, perceived stress, global functioning, and duration of untreated psychosis. At first presentation, people with more depressive symptoms and reduced overall functioning were more likely to report increased levels of perceived stress. In addition, people with less positive symptoms of psychosis were experiencing higher levels of subjective stress. In terms of stress vulnerability models, it is important to consider how functioning and symptoms can influence individual appraisal of stress. Acknowledging this interaction can provide opportunities for nursing interventions directed at enhancing adaptive coping and provide benchmarks for assessing the effectiveness of nursing interventions provided in the acute phase of psychosis. Further research should focus on the interaction between symptoms and individually-appraised stress over time.

Maternal vitamin B12 status and risk of neural tube defects in a population with high neural tube defect prevalence and no folic Acid fortification.

OBJECTIVE: Folic acid fortification has reduced neural tube defect prevalence by 50% to 70%. It is unlikely that fortification levels will be increased to reduce neural tube defect prevalence further. Therefore, it is important to identify other modifiable risk factors. Vitamin B(12) is metabolically related to folate; moreover, previous studies have found low B(12) status in mothers of children affected by neural tube defect. Our objective was to quantify the effect of low B(12) status on neural tube defect risk in a high-prevalence, unfortified population. METHODS: We assessed pregnancy vitamin B(12) status concentrations in blood samples taken at an average of 15 weeks' gestation from 3 independent nested case-control groups of Irish women within population-based cohorts, at a time when vitamin supplementation or food fortification was rare. Group 1 blood samples were from 95 women during a neural tube defect-affected pregnancy and 265 control subjects. Group 2 included blood samples from 107 women who had a previous neural tube defect birth but whose current pregnancy was not affected and 414 control subjects. Group 3 samples were from 76 women during an affected pregnancy and 222 control subjects. RESULTS: Mothers of children affected by neural tube defect had significantly lower B(12) status. In all 3 groups those in the lowest B(12) quartiles, compared with the highest, had between two and threefold higher adjusted odds ratios for being the mother of a child affected by neural tube defect. Pregnancy blood B(12) concentrations of <250 ng/L were associated with the highest risks. CONCLUSIONS: Deficient or inadequate maternal vitamin B(12) status is associated with a significantly increased risk for neural tube defects. We suggest that women have vitamin B(12) levels of >300 ng/L (221 pmol/L) before becoming pregnant. Improving B(12) status beyond this level may afford a further reduction in risk, but this is uncertain.

Suicidality prior to presentation in first-episode psychosis.

INTRODUCTION: Suicide and attempted suicide contribute significantly to the increased mortality and morbidity associated with psychotic illness. The period of highest risk is reportedly in the early years of illness. While the literature concentrates on completed suicide in chronic psychosis, less is understood about attempted suicide in first-episode psychosis (FEP). AIM: We aimed to examine rates and correlates of suicide attempts in individuals with FEP. METHOD: Individuals in this study were all those, both in- and outpatients, diagnosed with FEP over a 2-year period, from a defined catchment area. Assessment included Structured Clinical Interview for DSM-IV, Schedule for Assessment of Positive Symptoms, Schedule for Assessment of Negative Symptoms, Calgary Scale, Beiser Scale and Birchwood Insight Scale. RESULTS: Of 107 patients with FEP, 50 (47%) individuals reported suicidal ideation: 41 (38%) in the month prior to first presentation. Ten individuals (9%) made a suicide attempt. The only factor significantly associated with previous suicide attempt was higher insight scores at first presentation (P = 0.04). CONCLUSION: Individuals with a history of suicide attempt tend to have higher insight into having a mental illness at first presentation.