Search

Following publication of this article, the authors noticed an error in Supplementary Table 1. In the original Supplementary Table 1, one of the criteria for control participants was incorrectly given as ‘Report extensive recent symptoms of depression: less than 14 on summed response (where “not at all” = 1 and “nearly every day” = 4) to recent’. This has now been corrected to: ‘Report extensive recent symptoms of depression: less than 5 on summed response (where “not at all” = 1 and “nearly every day” = 4) to recent’.

Aims:To assess the comorbidity rates of alcohol use disorders (AUDs) in bipolar disorder (BD) and to explore possible sources of heterogeneity.Methods:Studies were identified through database searches. Meta-analytic techniques were employed to aggregate data on lifetime comorbidity and to explore possible sources of heterogeneity. Funnel plots were used to detect publication bias.Results:In clinical studies, AUDs affected more than one in three subjects with BD. Significant heterogeneity was found, which was largely explained by the geographical location of study populations and gender ratio of participants. AUDs affected more than one in five women and two in five men.Conclusion:AUDs are highly prevalent in BD. Our study revealed a substantial heterogeneity across studies. Further research including control groups is needed. Patients with BD should be assessed for current and previous AUDs.

Background: Hamstring strains are one of the most common injuries in sport. Previous injury has been found to be one of the greatest risk factors associated with recurrent hamstring strains. Although rehabilitation programmes have been developed and implemented to aid safe and efficient return-to-play, the incidence of hamstring injuries has not decreased. Discussion: As hamstring strains most commonly occur during the eccentric phase of muscle action, rehabilitation should focus on eccentric muscle strengthening. The L-protocol and the Nordic Hamstring Exercise protocol strengthen the hamstring muscles eccentrically. They have been found to be effective in decreasing the incidence of new hamstring strains as well as the rate of recurrence. This commentary therefore aims to suggest changes to the return-to-play criteria following hamstring strains to prevent the seemingly unpreventable.

TNF-α-inhibitors are known to induce skin adverseeffects including psoriasis and alopecia areata. Here, wedescribe a unique pattern of hair loss that has psoriaticand alopecia areata-like features. Diagnosis requiresclinical-pathologic correlation and is supportedby increased catagen/telogen hairs, psoriasiformepidermal hyperplasia, perifollicular lymphocyticinfiltrate, and the presence of eosinophils and plasmacells. Although there are no treatment consensusguidelines, management options include stoppingtherapy, switching to a different TNF-α inhibitor orustekinumab (in severe cases), or continuing TNF-αinhibitor therapy with addition of topical, intralesional,or systemic immunosuppressants.

IntroductionFor women with bipolar disorder, childbirth is a high-risk period with 40–50% experiencing a recurrence and 20% developing a severe episode of postpartum psychosis. Bipolar episodes in the perinatal period affect women and their families.Managing bipolar disorder in pregnancy and postpartum is a challenge. There is lack of literature to inform that and an urgent need for more data.ObjectivesTo develop and validate a risk prediction model for individual prognosis of the risk of recurrence of bipolar disorder for women in the perinatal period.AimsTo provide evidence-based information to help women and the clinicians that look after them make decisions about their care, taking into account the most recent scientific knowledge and their individual characteristics.MethodsThe development of the model will be done in retrospective data from a large clinical cohort from the Bipolar Disorder Research Network (BDRN.org). The validation will be done in a prospectively recruited sample.Participants will be 2181 parous women with a lifetime diagnosis of bipolar disorder from BDRN and 300 prospectively recruited pregnant women with a history of postpartum psychosis or bipolar disorder.Predictors will be chosen based on clinical experience and literature, from data collected via semi-structured interview (in pregnancy and 3 months postpartum, medical and psychiatric notes) e.g. medication, smoking, parity, obstetric complications and sleep.ResultsN/A.ConclusionsWe will present the full prediction model (regression coefficients and model intercept) and report performance measures (with CIs).We will discuss its potential clinical use and implications for future research.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Summary“Schizoaffective” refers to a mix of clinical features associated with prototypical schizophrenia and prototypical bipolar disorder. Such cases are common but definitions have varied substantially. Nosological possibilities considered include (a) a form of schizophrenia, (b) a form of mood disorder, (c) a distinct disorder, (d) some mixture of (a)-(c). In current usage “schizoaffective disorder” tends to be used only when cases cannot be fitted to definitions of schizophrenia or bipolar disorder and such cases have been under-represented in cases collections to date. Methodological and practicalissues continue to cause difficulty for accumulating robust knowledge about schizoaffectivedisorder. Here we consider genetic understanding of schizoaffective disorder, particularly recent findings. These show that bipolar disorder andschizophrenia are not completely separate disease entities and confirm that schizoaffectivedisorder is genetically related to both. Some genetic variants influencerisk broadly across the mood-psychosis spectrum (e.g. Variation at CACNA1C). Some studies have implicated common variation at specific genes and gene families as conferring relatively specific phenotypic risk for a schizoaffective-type clinical pattern (e.g. GABAA receptorgenes). Such findings are of great interest and offer promise ofgreat advances in understanding over the next 20 years. It is important that there is a willingnessof researchers to study schizoaffective cases and to use approaches to phenotypic assessmentand classification that go beyond the traditional approaches enshrined within DSM and ICD.

Gene x environment (G x E) interactions are increasingly thought to have substantial influence on the aetiology and clinical manifestations of complex disorders. In ADHD, although main effects of specific genetic variants and pre- or peri-natal variables have been reported and replicated using pooled analyses, few studies have looked at possible interactions. In a clinical sample of 266 children with ADHD, we tested for interaction between gene variants (in DRD4, DAT1, DRD5, and 5HTT) found to be associated with ADHD in pooled analyses and maternal smoking, alcohol use during pregnancy and birth weight. First, G x E effects on a diagnosis of ADHD were tested using conditional logistic regression analyses. Second, possible modifying effects of G x E on symptoms of associated conduct disorder and oppositional defiant disorder (ODD) were investigated using linear regression analysis. The sample size associated with each of the analyses differed as not each variant had been genotyped for each individual. No effects of G x E on ADHD diagnosis were observed. The results suggest that lower birth weight and maternal smoking during pregnancy may interact with DRD5 and DAT1 (birth weight only) in influencing associated antisocial behavior symptoms (ODD and conduct disorder). These preliminary findings showed no evidence of interaction between previously implicated variants in ADHD and specific environmental risk factors, on diagnosis of the disorder. There may be evidence of G x E on associated antisocial behavior in ADHD, but further investigation is needed.

Lithium is the mainstay prophylactic treatment for bipolar disorder (BD), but treatment response varies considerably across individuals. Patients who respond well to lithium treatment might represent a relatively homogeneous subtype of this genetically and phenotypically diverse disorder. Here, we performed genome-wide association studies (GWAS) to identify (i) specific genetic variations influencing lithium response and (ii) genetic variants associated with risk for lithium-responsive BD. Patients with BD and controls were recruited from Sweden and the United Kingdom. GWAS were performed on 2698 patients with subjectively defined (self-reported) lithium response and 1176 patients with objectively defined (clinically documented) lithium response. We next conducted GWAS comparing lithium responders with healthy controls (1639 subjective responders and 8899 controls; 323 objective responders and 6684 controls). Meta-analyses of Swedish and UK results revealed no significant associations with lithium response within the bipolar subjects. However, when comparing lithium-responsive patients with controls, two imputed markers attained genome-wide significant associations, among which one was validated in confirmatory genotyping (rs116323614, P=2.74 × 10(-8)). It is an intronic single-nucleotide polymorphism (SNP) on chromosome 2q31.2 in the gene SEC14 and spectrin domains 1 (SESTD1), which encodes a protein involved in regulation of phospholipids. Phospholipids have been strongly implicated as lithium treatment targets. Furthermore, we estimated the proportion of variance for lithium-responsive BD explained by common variants ('SNP heritability') as 0.25 and 0.29 using two definitions of lithium response. Our results revealed a genetic variant in SESTD1 associated with risk for lithium-responsive BD, suggesting that the understanding of BD etiology could be furthered by focusing on this subtype of BD.

An association between lower educational attainment (EA) and an increased risk for depression has been confirmed in various western countries. This study examines whether pleiotropic genetic effects contribute to this association. Therefore, data were analyzed from a total of 9662 major depressive disorder (MDD) cases and 14 949 controls (with no lifetime MDD diagnosis) from the Psychiatric Genomics Consortium with additional Dutch and Estonian data. The association of EA and MDD was assessed with logistic regression in 15 138 individuals indicating a significantly negative association in our sample with an odds ratio for MDD 0.78 (0.75-0.82) per standard deviation increase in EA. With data of 884 105 autosomal common single-nucleotide polymorphisms (SNPs), three methods were applied to test for pleiotropy between MDD and EA: (i) genetic profile risk scores (GPRS) derived from training data for EA (independent meta-analysis on similar to 120 000 subjects) and MDD (using a 10-fold leave-one-out procedure in the current sample), (ii) bivariate genomic-relationship-matrix restricted maximum likelihood (GREML) and (iii) SNP effect concordance analysis (SECA). With these methods, we found (i) that the EA-GPRS did not predict MDD status, and MDD-GPRS did not predict EA, (ii) a weak negative genetic correlation with bivariate GREML analyses, but this correlation was not consistently significant, (iii) no evidence for concordance of MDD and EA SNP effects with SECA analysis. To conclude, our study confirms an association of lower EA and MDD risk, but this association was not because of measurable pleiotropic genetic effects, which suggests that environmental factors could be involved, for example, socioeconomic status. Refereed/Peer-reviewed

Background Bipolar disorder (BD) includes a broad range of phenotypic features – most research examining its genetic underpinning focuses on the overall syndrome rather than its subphenotypic components. BD is a highly heritable disorder and while its genetic architecture is not fully elucidated there is increasingly strong support for a very polygenic component with partial polygenic overlap with schizophrenia (SZ). Here we present preliminary results from an analysis examining the association of SZ derived polygenic risk scores (PRS) across different BD subtypes (Bipolar Type 1(BPI), Bipolar Type 2 (BPII) and Schizoaffective disorder (SAD), and subphenotypes defined by the presence of psychosis and its associated level of mood incongruence. Methods We used a UK sample of 3101 BP cases, collected using a consistently administrated interview protocol with OPCRIT confirmed lifetime diagnosis of Research Diagnostic Criteria (RDC - BPI, BPII or SAD). PRS were generated using 1000 genomes (phase3, 2014) imputed genetic data (INFO score>0.8, HWE>1e-6, MAF>0.01) trained on the results from Psychiatric Genetic Consortium (PGC2) SZ GWAS, pruned r2 Results PRS with the SZ association p-value cut-off of 0.5, have shown significant association across the BD subtypes with relative risk ratios RRR = 1.28 (95%CI: 1.18-1.39, p Discussion Preliminary analyses show a genetic - phenotypic association, between polygenic features of schizophrenia and BP characterised by the presence of psychosis, suggesting the phenotypic overlap between SZ and BD may in part be driven by polygenic overlap. This finding is further supported by the association of PRS and level of mood incongruence in the content of psychotic symptoms. These results suggest the PRS effect is not solely mediated though the psychosis subphenotype, at least in the BPI group. Our analyses show promise for the strategy of examining polygenic/phenotypic associations based on fine grained clinical characterisations

Approximately 25% of patients with hemophilia A develop inhibitory antibodies after treatment with factor VIII. Most of the inhibitory activity is directed against epitopes in the A2 and C2 domains. Anti-A2 inhibitory antibodies recognize a 25-residue segment bounded by R484-I508. Several antigenic residues in this segment have been identified, including R484, R489, and P492. The immunogenicity of purified recombinant B domain–deleted (BDD) human factor VIII molecules containing mutations at R484A/R489A or R484A/R489A/P492A was studied in hemophilia A mice. Inhibitory antibody titers in mice receiving the R484A/R489A/P492A mutant, but not the R484A/R489A mutant, were significantly lower than in mice receiving control human BDD factor VIII. The specific coagulant activity and the in vivo clearance and hemostatic efficacy in hemophilia A mice of the R484A/R489A/P492A mutant were indistinguishable from human BDD factor VIII. Thus, the inhibitory antibody response to human factor VIII can be reduced by mutagenesis of a B-cell epitope without apparent loss of function, suggesting that this approach may be useful for developing a safer form of factor VIII in patients with hemophilia A.

Hyate is a commercial plasma-derived porcine factor (F)VIII concentrate that is used in the treatment of patients with inhibitory antibodies to FVIII. OBI-1 is a recombinant B domain-deleted form of porcine FVIII that is in clinical development for the same indication. Hemophilia A mice were presensitized with human FVIII to simulate clinical inhibitory antibody formation and then were randomized to receive OBI-1 or Hyate:C in a comparative immunogenicity trial. OBI-1 or Hyate:C were given in a series of four intravenous injections at weekly intervals at doses of 1, 10, or 100 U kg(-1). Inhibitory antibodies to porcine FVIII were not detected by Bethesda assay in most of the mice given OBI-1 or Hyate:C at doses of 1 or 10 U kg(-1), but were identified in 81% and 94% of mice given 100 U kg(-1) of OBI-1 or Hyate:C, respectively. There was no significant difference between OBI-1 and Hyate:C in inhibitory antibody formation at any dose, although there was a trend toward a lower Bethesda titer in OBI-1-treated mice at 10 U kg(-1) (P = 0.09). Total anti-FVIII antibodies to Hyate:C and OBI-1 were also measured by ELISA using immobilized purified plasma-derived porcine FVIII and OBI-1, respectively, as antigens. At the 10 and 100 U kg(-1) doses, the mean anti-FVIII response was higher in Hyate:C-treated-mice than in OBI-1-treated mice (P = 0.02 and P = 0.004, respectively). The results using this model suggest that OBI-1 may be less immunogenic and safer than Hyate:C in FVIII inhibitor patients.

Fulminant hepatic failure (FHF) in humans produces a bleeding diathesis due in large part to a reduction in the biosynthesis of liver-derived coagulation factors. Remarkably, factor VIII procoagulant activity is elevated in most of these patients despite widespread liver cell death. FHF can be modeled in mice by administration of azoxymethane, the active ingredient found in cycad palm nuts. We compared the expression of factor VIII to other hepatic hemostatic factors in azoxymethane-induced murine FHF. Mice displayed dose-dependent decreases in all coagulation factor activities measured, including factors V, VII, VIII, and IX. At the highest dose of azoxymethane (50 μg/g body weight), factor VIII activity in plasma decreased by 98% within 36 hours after treatment, which was associated with an 80% reduction in hepatic factor VIII messenger RNA (mRNA). In contrast, factor VIII mRNA levels in spleen, kidney, and lung tissue of azoxymethane-treated mice were unchanged. Cellular damage in these mice appeared to be limited to hepatocytes as evident by histologic examination. This finding is supported by 2 observations. First, hepatic mRNA levels of von Willebrand factor, which is synthesized by liver sinusoidal endothelial cells but not hepatocytes, were unchanged. Second, von Willebrand factor was detected antigenically in liver sections of azoxymethane-treated mice by immunofluorescence. These results indicate that the contribution of the liver to factor VIII biosynthesis is not replaced or significantly supplemented by other tissues in this model of FHF.

SummaryHemophilia A is the inherited bleeding disorder that results from mutation of blood coagulation factor VIII (fVIII). Described here is the generation of a regulated expression system producing recombinant murine fVIII. Murine B-domainless fVIII was expressed at a peak level of 4 units/106 cells/24 h in serum-free media. Subsequently, a two-step purification procedure resulted in 5,300-fold enrichment and a 70% yield. Highly purified recombinant murine fVIII had a specific coagulant activity of 660 units per nanomole. It underwent proteolytic processing by thrombin to yield an activated heterotrimer that demonstrated significantly greater stability than activated human fVIII. Recombinant murine fVIII was utilized to generate an anti-fVIII polyclonal antibody. Intravenous injection of recombinant murine fVIII into hemophilia A mice failed to induce a significant anti-fVIII immune response using a schedule that yielded high titer inhibitory antibodies to human fVIII. This may provide an important model for the study of immune tolerance to fVIII.

IntroductionThe perinatal period is a high-risk period for the development of illness episodes in women with bipolar disorder. Relapse rates vary between 9 and 75% depending on the study. The overall risk of a severe episode is approximately 20%. The impact on women, the relationships with their babies and their families can be devastating. In the UK costs to society are £8.1 billion per year-cohort of births. The advice currently given to women is based of general risk rates. Women's needs of information for decision-making in the perinatal period are not being met.ObjectivesTo review the risk prediction approaches used for women with bipolar disorder in the perinatal period.AimsTo understand the existing risk prediction models and approaches used for prognosis of the risk of recurrence of bipolar disorder for women in the perinatal period.MethodsSystematic literature search of public medical electronic databases and grey literature on risk prediction for bipolar episodes in the perinatal period.ResultsWe will present the existing models and approaches used for risk prediction of illness episodes in the perinatal period.ConclusionsAwareness of existing risk prediction models for recurrence of bipolar disorder in the perinatal period will allow better informed risk-benefit analysis of treatment and management options.This person-centred approach will help women and clinicians in their decision-making at this crucial high-risk period.Disclosure of interestThe authors have not supplied their declaration of competing interest.

BackgroundThe relative contribution of demographic, lifestyle and medication factors to the association between affective disorders and cardiometabolic diseases is poorly understood.AimsTo assess the relationship between cardiometabolic disease and features of depresion and bipolar disorder within a large population sample.MethodCross-sectional study of 145 991 UK Biobank participants: multivariate analyses of associations between features of depression or bipolar disorder and five cardiometabolic outcomes, adjusting for confounding factors.ResultsThere were significant associations between mood disorder features and ‘any cardiovascular disease’ (depression odds ratio (OR) = 1.15, 95% CI 1.12–1.19; bipolar OR = 1.28, 95% CI 1.14–1.43) and with hypertension (depression OR = 1.15, 95% CI 1.13–1.18; bipolar OR = 1.26, 95% CI 1.12–1.42). Individuals with features of mood disorder taking psychotropic medication were significantly more likely than controls not on psychotropics to report myocardial infarction (depression OR = 1.47, 95% CI 1.24–1.73; bipolar OR = 2.23, 95% CI 1.53–3.57) and stroke (depression OR = 2.46, 95% CI 2.10–2.80; bipolar OR = 2.31, 95% CI 1.39–3.85).ConclusionsAssociations between features of depression or bipolar disorder and cardiovascular disease outcomes were statistically independent of demographic, lifestyle and medication confounders. Psychotropic medication may also be a risk factor for cardiometabolic disease in individuals without a clear history of mood disorder.

OBJECTIVE: The clinical and pathologic features of hereditary dysphasic disinhibition dementia (HDDD) are described to determine whether it is a variant of known dementias. BACKGROUND: Several dementing disorders have clinical and pathologic similarities with AD, Pick's disease, and the "nonspecific" dementias. A detailed description of clinical and pathologic presentation will aid classification, but ultimately the discovery of causative gene(s) will define these disorders. METHODS: The authors performed a clinical assessment: gross and microscopic pathologic evaluation of brain tissue, genetic linkage studies, and sequence analyses. RESULTS: HDDD is an autosomal-dominant frontotemporal dementia with many similarities to Pick's disease. Salient clinical features are global dementia with disproportionate dysphasia and "frontotemporal" symptoms. A linkage between HDDD and 17q21-22 was shown, with a maximum lod score of 3.68 at zero recombination. CONCLUSIONS: Several dementias have been linked to the same region and have been termed frontotemporal dementia with parkinsonism linked to chromosome 17. These disorders may represent phenotypic variants arising from mutations within a common gene.

Metformin is the most commonly used pharmacological therapy for type 2 diabetes. We report a genome-wide association study for glycemic response to metformin in 1,024 Scottish individuals with type 2 diabetes with replication in two cohorts including 1,783 Scottish individuals and 1,113 individuals from the UK Prospective Diabetes Study. In a combined meta-analysis, we identified a SNP, rs11212617, associated with treatment success (n = 3,920, P = 2.9 P×-9, odds ratio = 1.35, 95% CI 1.22-1.49) at a locus containing ATM, the ataxia telangiectasia mutated gene. In a rat hepatoma cell line, inhibition of ATM with KU-55933 attenuated the phosphorylation and activation of AMP-activated protein kinase in response to metformin. We conclude that ATM, a gene known to be involved in DNA repair and cell cycle control, plays a role in the effect of metformin upstream of AMP-activated protein kinase, and variation in this gene alters glycemic response to metformin.

Strong evidence that rare variants of relatively high penetrance are involved in the etiology of schizophrenia is currently restricted to the data from studies investigating copy number variants and major structural re-arrangements in that disorder. Global tests of the hypothesis of the involvement of fairly high penetrance rare single nucleotide changes or small insertion deletion events await the genesis of data from large-scale sequencing studies, meanwhile, a pragmatic approach to trying to detect such alleles is to target sequencing efforts on genes for which there is compelling evidence from other sources for their involvement in this disorder. We have undertaken a study, which aimed to identify whether rare (frequency ∼0.001%) coding variants in the schizophrenia susceptibility gene ZNF804A are involved in this disorder. We screened the coding regions of the gene in 517 schizophrenic cases and 501 controls, and genotyped rare non-synonymous variants in a case-control sample powered to detect association to rare alleles with an effect size (odds ratio) of 5. No single rare variant was associated with schizophrenia, nor was the burden of rare, or even fairly common, non-synonymous variants. Our results do not support the hypothesis that moderately rare non-synonymous variants at the ZNF804A locus are involved in schizophrenia susceptibility. © 2010 Wiley-Liss, Inc.

We present a method for testing overrepresentation of biological pathways, indexed by gene-ontology terms, in lists of significant SNPs from genome-wide association studies. This method corrects for linkage disequilibrium between SNPs, variable gene size, and multiple testing of nonindependent pathways. The method was applied to the Wellcome Trust Case-Control Consortium Crohn disease (CD) data set. At a general level, the biological basis of CD is relatively well known for a complex genetic trait, and it thus acted as a test of the method. The method, known as ALIGATOR (Association LIst Go AnnoTatOR), successfully detected biological pathways implicated in CD. The method was also applied to a meta-analysis of bipolar disorder, and it implicated the modulation of transcription and cellular activity, including that which occurs via hormonal action, as an important player in pathogenesis.

Traditionally in genetic case-control studies controls have been screened to exclude subjects with a personal history of illness. This control group has the advantage of optimal power to detect loci involved in illness, but requires more work and may incur substantial cost in recruitment. An alternative approach to screening is to use unscreened controls sampled from the general population. Such controls are generally plentiful and inexpensive, but in general there is a risk that some may have the same disease as the cases, which will reduce power to detect associations. We have quantified the extent of this power loss, and produced mathematical formulae for the number of unscreened controls necessary to achieve the same power as a fixed sample of screened controls. The effect of using unscreened controls will also depend on the ratio of the number of screened controls to cases specified in the original study design, and this is also investigated. We have also investigated the cost-benefits of the screened and unscreened approaches, according to variation in the relative costs of sampling screened and unscreened controls, together with genotyping costs. We have, thus, identified the range of situations in which using unscreened controls is a cost-effective alternative to the screened control method and could be considered when designing a study. In many of the typical, real-world situations in complex genetics, the use of unscreened controls is potentially cost-effective and can, in general, be considered for disorders with population prevalence Kp < 0.2. With the steady reduction in genotyping costs and the availability of common sets of “population controls” this design is likely to become increasingly cost effective.

Edited by M Leboyer and F Bellivier. Totowa, NJ: Humana Press, 2003, £82.50 (US$99.50), pp 268. ISBN 1588290379 This book is timely. Psychiatric genetics, which is one of the most challenging areas of medical genetics, currently offers enormous opportunities to improve the understanding of mental illness and the practice of clinical psychiatry. Phenotypic issues are, of course, important in all aspects of complex genetics, and within psychiatric genetics issues of phenotype definition and measurement are crucial. Major molecular genetic investigations using both positional and candidate approaches have been ongoing for several of the major psychiatric disorders over the last 10 or 15 years. Early successes, of …

Mirroring clinical practice, it has been conventional for psychiatric research, including the search for predisposing genes, to proceed under the assumption that schizophrenia and bipolar disorder are separate disease entities with different underlying etiologies. These represent the traditional dichotomous classification of the so-called “functional” psychoses and form the basis of modern psychiatric diagnostic practice. Recent findings emerging in molecular genetic studies of psychoses show increasing evidence that challenges traditional classification categories. Within the context of the Wellcome Trust Case Control Consortium (WTCCC) we have studied 2700 mood-psychosis cases and 3000 controls and several other large-scale studies have been undertaken, including studies of structural genomic variation. The emerging evidence suggests the existence of both relatively specific as well as more general relationships between genotype and psychopathology. For example, in our dataset variation at GABA A receptor genes is associated with susceptibility to a form of illness with mixed features of schizophrenia and bipolar disorder. Genome-wide significant associations at CACNA1C in bipolar disorder and ZNF804A in schizophrenia show evidence for a contribution to susceptibility across the traditional diagnostic boundaries. Evidence from studies of structural genomic variation (copy number variation) suggests the need to reconsider the relationship between schizophrenia and childhood onset neurodevelopmental disorders, such as ADHD and autism. The elucidation of genotype-phenotype relationships is at an early stage, but current findings highlight the need to consider alternative approaches to classification and conceptualisation for psychiatric research, and perhaps, practice.

Editor—Various implications of advances in understanding of the genetic contribution to susceptibility to neuropsychiatric disorders must be debated. Rose’s article on this subject, however, contains important errors of fact, severely misrepresents current research, and is neither reasoned nor balanced.1 He accuses researchers of simplistically assuming that behaviours are genetically determined. In fact, most researchers in the field, ourselves included, are fully aware of the complexity of pathogenesis and accept a model in which both genetic and non-genetic factors influence susceptibility to disease.2–4 Rose makes the unfounded and disingenuous presumption that researchers seek to identify genes “with a view to ... aborting fetuses which show the potential for ... undesirable characteristics or generating drugs which will alleviate the condition, turn gays into straights, or radicals into conservatives.” This emotive statement both misrepresents and trivialises the aim of most research, which is to better define the pathophysiology of major psychiatric disorders such as schizophrenia and bipolar disorder. Rose gives the impression that this desirable end is a fortuitous byproduct of research. In fact, it is the primary motivation. Rose also attacks psychiatrists for creating illnesses where none exist. He offers attention deficit hyperactivity disorder as an example that he claims “was almost unknown in the United Kingdom a decade ago” and berates psychiatrists for prescribing the stimulant methylphenidate as a treatment. Attention deficit hyperactivity disorder may be a new name, but it describes a syndrome that has undergone almost a century of study and is certainly not merely a label for naughty and disruptive children.5 Rose is wrong to claim that it is not a valid diagnosis, and to maintain that people with this condition should not have the opportunity to benefit from potentially effective treatment seems both unsympathetic and arrogant. Most researchers in psychiatric genetics reject the notion of neurogenetic determinism. Their modest goal is to contribute to improved understanding and treatment of the major psychiatric illnesses that cause so much suffering to so many. Rose should stop propounding his familiar but outdated antipsychiatry, antigenetic message and adopt a more constructive and informed position. We need to work together to ensure that the opportunities provided by molecular genetics are used to the benefit of our patients.

A method for analysis of beams composed of fiber composite layers layers is presented. The method is based on the transformed-section concept, and takes into account the effects of Poisson’s ratios and shear coupling. To demonstrate the feasibility of the transformed-section model, numerical solutions are presented for an I-shaped cross-section and are compared to those obtained from lamination theory. For axial loads, the transformed-section models presented herein yields results that are identical to those of lamination theory. For bending moments, the model yields results which, while not exact, are significantly more accurate than those based on the conventional transformed-section model in which the effects of Poisson’s ratio and shear coupling are neglected.

Discrete bilateral electrolytic lesions destroying the lateral half of the cerebral peduncle and the overlying lateral nucleus of the substantia nigra (which disconnect a pathway from the occipital cortex to the brainstem reticular formation) in the rat produced profound losses in retention of a horizontal-vertical discrimination habit. Similarly placed lesions had a significantly smaller amnestic effect on a nonvisual (kinesthetic) discrimination habit. These results, in conjunction with others, suggest that a direct occipitoreticular pathway may be involved in the performance of visual discrimination habits, possibly serving in visuomotor integration, attention to visual cues, and/or formation of visual engrams.

The effect of the new immunosuppressant cyclosporine on survival after total small intestinal allotransplantation (TSIA) was studied in a canine model. Successful TSIA was performed in 34 dogs. Eleven dogs were treated with cyclosporine, 25 mg/kg/day i.m., starting the day before the operation and continuing for four weeks. Thereafter the same dose was given orally. Thirteen dogs were given oral cyclosporine only, 25 mg/kg/day from the day after transplantation. Ten dogs served as controls. The dogs treated with intramuscular and oral cyclosporine survived a mean of 103.8 +/- 39.4 days (mean +/- S.E.M.). The longest survivor died after 432 days. Survival in this group was significantly longer than that of the control dogs, which survived 12.5 +/- 4.6 days. The orally treated dogs survived 30.4 +/- 7.6 days. All control dogs, and seven of the orally treated dogs, but only two of the intramuscularly treated dogs, died of acute rejection. It is concluded that cyclosporine is effective in prolonging survival after TSIA in the dog and reduces the incidence of acute rejection.

• Different species appear to tolerate different amounts of renal ischemia. It is suggested that all kidneys are equally susceptible to ischemic damage, but that the whole animal response varies between species. Mice, rats, rabbits, and pigs were subjected to bilateral nephrectomy. Large animals had relatively smaller kidneys and survived longer than smaller animals. Therefore, the larger the animal, the more time available for recovery of a kidney damaged by ischemia. This adequately explains the apparent species differences in susceptibility to renal ischemia, which are only seen when the kidney is expected to support life immediately. Simple relationships are described, relating metabolic rate, body size, and survival time with no renal function. ( Arch Surg 111:582-584, 1976)

The renal blood supply of 144 rats was occluded for specific periods of time between 120 and 270 minutes. In half the animals the renal capsule was removed. Function was assessed by the ability of the damaged kidney to maintain life after removal of the opposite organ three weeks later. Removal of the renal capsule was found to reduce life-span by two months, which was significant at the 5% level. It is recommended that capsulotomy should be abandoned in human renal transplantation until evidence is obtained of its benefit.