Are Genetic Risk Factors for Psychosis Also Associated with Dimension-Specific Psychotic Experiences in Adolescence?

Psychosis has been hypothesised to be a continuously distributed quantitative phenotype and disorders such as schizophrenia and bipolar disorder represent its extreme manifestations. Evidence suggests that common genetic variants play an important role in liability to both schizophrenia and bipolar disorder. Here we tested the hypothesis that these common variants would also influence psychotic experiences measured dimensionally in adolescents in the general population. Our aim was to test whether schizophrenia and bipolar disorder polygenic risk scores (PRS), as well as specific single nucleotide polymorphisms (SNPs) previously identified as risk variants for schizophrenia, were associated with adolescent dimension-specific psychotic experiences. Self-reported Paranoia, Hallucinations, Cognitive Disorganisation, Grandiosity, Anhedonia, and Parent-rated Negative Symptoms, as measured by the Specific Psychotic Experiences Questionnaire (SPEQ), were assessed in a community sample of 2,152 16-year-olds. Polygenic risk scores were calculated using estimates of the log of odds ratios from the Psychiatric Genomics Consortium GWAS stage-1 mega-analysis of schizophrenia and bipolar disorder. The polygenic risk analyses yielded no significant associations between schizophrenia and bipolar disorder PRS and the SPEQ measures. The analyses on the 28 individual SNPs previously associated with schizophrenia found that two SNPs in TCF4 returned a significant association with the SPEQ Paranoia dimension, rs17512836 (p-value = 2.57×10⁻⁴) and rs9960767 (p-value = 6.23×10⁻⁴). Replication in an independent sample of 16-year-olds (N = 3,427) assessed using the Psychotic-Like Symptoms Questionnaire (PLIKS-Q), a composite measure of multiple positive psychotic experiences, failed to yield significant results. Future research with PRS derived from larger samples, as well as larger adolescent validation samples, would improve the predictive power to test these hypotheses further. The challenges of relating adult clinical diagnostic constructs such as schizophrenia to adolescent psychotic experiences at a genetic level are discussed.     

Duration of Untreated Psychosis Is Associated with Temporal and Occipitotemporal Gray Matter Volume Decrease in Treatment Na?ve Schizophrenia

Background

Long duration of untreated psychosis (DUP) is associated with poor treatment outcome. Whether or not DUP is related to brain gray matter volume abnormalities in antipsychotic medication treatment naïve schizophrenia remains unclear at this time.

Methods

Patients with treatment-naïve schizophrenia and healthy controls went through brain scan using high resolution Magnetic Resonance Imaging. DUP was evaluated using the Nottingham Onset Schedule (NOS), and dichotomized as short DUP (≤ 26 weeks) or long DUP (>26 weeks). Voxel-based methods were used for volumetric measure in the brain.

Results

Fifty-seven patients (27 short DUP and 30 long DUP) and 30 healthy controls were included in the analysis. There were significant gray matter volumetric differences among the 3 groups in bilateral parahippocampus gyri, right superior temporal gyrus, left fusiform gyrus, left middle temporal gyrus, and right superior frontal gyrus (p''s<0.01). Compared with healthy controls, the long DUP group had significantly smaller volume in all these regions (p''s <0.05). Compared with the short-DUP group, the long-DUP group had significantly smaller volume in right superior temporal gyrus, left fusiform gyrus, and left middle temporal gyrus (p''s<0.01).

Conclusion

Our findings suggest that DUP is associated with temporal and occipitotemporal gray matter volume decrease in treatment naïve schizophrenia. The brain structural changes in untreated psychosis might contribute to poor treatment response and long-term prognosis in this patient population.     

On the Discovery and Development of Pimavanserin: A Novel Drug Candidate for Parkinson’s Psychosis

Parkinson’s disease psychosis (PDP) is a condition that may develop in up to 60 % of Parkinson’s patients, and is a major reason for nursing home placement for those affected. There are no FDA approved drugs for PDP but low doses of atypical anti-psychotic drugs (APDs) are commonly prescribed off-label. Only low-dose clozapine has shown efficacy in randomized controlled trials, but all APDs have black box warnings related to the increased mortality and morbidity when used in elderly demented patients. Using molecular pharmacological profiling of a large collection of marketed drugs, we discovered that potent inverse agonist activity against 5-HT_2A serotonin receptors was a common feature of atypical APDs, especially the atypical APDs used to treat PDP. Since low-dose clozapine therapy selectively blocks this receptor, it was hypothesized that a highly selective 5-HT_2A receptor inverse agonist might provide good symptom control in patients suffering from PDP, with a greatly improved safety and tolerability profile. A high throughput screening and subsequent chemical lead optimization campaign to develop potent, selective 5-HT_2A receptor inverse agonists was launched, eventually resulting in the discovery of pimavanserin. Pimavanserin displays nanomolar potency as a 5-HT_2A receptor inverse agonist, selectivity for 5-HT_2A over 5-HT_2C receptors, and no meaningful activity at any other G-protein coupled receptor. It demonstrated robust activity in preclinical models of schizophrenia and PDP, and did not worsen motoric symptoms, in contrast to the APDs tested. In a Phase III clinical trial, pimavanserin showed highly significant benefits in the primary endpoint, the scale for assessment of positive symptoms-PD, a scale adapted for use in PDP. In addition, improvements in all other efficacy endpoints, including physician’s clinical global impression, caregiver burden, night-time sleep quality and daytime wakefulness, were seen. Pimavanserin demonstrated good safety and tolerability and did not worsen motoric symptoms as assessed by the unified Parkinson’s disease rating scale parts II and III. An open-label extension study has further demonstrated that pimavanserin is safe and well-tolerated with long-term use. Pimavanserin may therefore offer a viable treatment option for patients suffering from PDP.     

Regional Brain Atrophy and Functional Disconnection in Broca’s Area in Individuals at Ultra-High Risk for Psychosis and Schizophrenia

Background

Abnormalities in cognitive abilities such as verbal fluency and in cognitive-related brain regions, particularly Broca’s area, have been reported in patients with schizophrenia. Additionally, previous studies have demonstrated that structural and functional abnormalities in Broca’s area were associated with clinical symptoms and cognitive deficits in patients with schizophrenia, suggesting that deficits in this area may reflect the core pathology of schizophrenia. Thus, it is important to understand how the structural volume and functional connectivity in this area changes at rest according to the course of the illness.

Methods/Principal Findings

We used magnetic resonance imaging (MRI) to measure the structural volume of Broca’s area as a region of interest in 16 schizophrenia, 16 ultra-high risk (UHR), and 23 healthy matched controls. We also assessed verbal fluency and analyzed differences across groups in the functional connectivity patterns using resting-state functional MRI. The UHR group showed significantly reduced structural volume in Broca’s area and significantly reduced functional connectivity between Broca’s area and the lateral and medial frontal cortex as well as decreased cognitive performance. Altered functional connectivity in patients was correlated with their positive symptoms.

Conclusions/Significance

Our results suggest the existence of functional disconnections in Broca’s area, even during resting-states, among those with schizophrenia as well as those at UHR for this disorder. These alterations may contribute to their clinical symptoms, suggesting that this is one of the key regions involved in the pathophysiology of schizophrenia.     

Should patients with renal failure associated with myeloma be dialysed?

In a study of renal function in multiple myeloma seven patients presented with renal failure and three developed it 16-106 months after diagnosis. All were dialysed. Infection with dehydration was a precipitating factor in all seven cases of acute or acute on chronic renal failure. Of these, two patients recovered normal renal function and one other was left with permanent renal impairment but no longer required dialysis. Results from the seven patients with acute renal failure and for the three with more chronic features support the practice of dialysis for all patients who present with renal failure. Dialysis is not indicated for those patients with progressive myelomatous disease. The study showed no evidence that chemotherapy permitted recovery from established renal failure. The prognosis in this elderly group is heavily dependent on the presence of cardiovascular or other degenerative disease.     

Reactions of carbohydrate α-nitroepoxides with dimethylamine and with methylmagnesium iodide

Methyl 2,3-anhydro-4,6-O-benzylidene-3-C-nitro-β-d-allopyranoside (1), as well as its β-d-manno (2) and α- d-manno (3) isomers, reacted with dimethylamine to give the same, crystalline 3-(dimethylamino) adduct (4) of 1,5-anhydro-4,6-O-benzylidene-2-deoxy-2-(dimethylamino)-d-erythro-hex-1-en-3-ulose (5). The enulose 5 was obtained from 4 by the action of silica gel. Similarly, the β-d-gulo (6) and α-d-talo (7) stereoisomers of 1–3 afforded a 3-(dimethylamino) adduct (8) of the d-threo isomer (9) of 5. Reaction of dimethylamine with 5,6-anhydro-1,2-O-isopropylidene-6-C-nitro-α-d-glucofuranose (10) yielded a mixture of two diastereoisomeric (possibly anometic at C-6) 5-deoxy-5-(dimethylamino)-1,2-O-isopropylideric-α-d-hexodialdo-1,4:6,3-difuranoses (11). The β-glycoside 1 and the α-glycoside 3 reacted with methylmagnesium iodide to produce methyl 4,6-O-benzylidene-3-deoxy-3-C-methyl-3-(N-hydroxy-N-methylamino)-β- and -α-d-hexopyranosides (12) and (13), respectively; both products had the 1,2-trans configuration, but their configurations at the quaternary center C-3 have not been determined.     

Interaction of Loach DNA Polymerase δ with DNA Duplexes with Single-Strand Gaps

The interaction of DNA polymerase purified from eggs of the teleost fish Misgurnus fossilis (loach) with DNA duplexes with single-strand gaps of 1-13 nucleotides was studied. In the absence of template-restricting DNA, the enzyme elongated primers on single-stranded DNA templates in a distributive manner. However, in the presence of the proximal 5"-terminus restricting the template, the enzyme activity significantly increased. In this case, the enzyme was capable of processive synthesis by filling gaps of 5-9 nucleotides in DNA duplexes. These data indicate that DNA polymerase can interact with both the 3"- and 5"-termini located upstream and downstream from the gap. Analysis of the complexes formed by DNA polymerase and different DNA substrates by electrophoretic mobility shift assay confirmed the assumption that this enzyme can interact with the proximal 5"-terminus restricting the gap. DNA polymerase displayed much higher affinity in duplexes with gaps of approximately 10 nucleotides compared to the standard template–primer complexes. Maximal affinity was observed in experiments with DNA substrates containing unpaired 3"-tails in primers. The results of this study suggest that DNA polymerase exerts high activity in the cell nuclei during repair of DNA intermediates with single strand gaps and unpaired 3"-termini.     

Is Treatment with Trimetazidine Beneficial in Patients with Chronic Heart Failure?

Background

Whether additional benefit can be achieved with the use of trimetazidine (TMZ) in patients with chronic heart failure (CHF) remains controversial. We therefore performed a meta-analysis of randomized controlled trials (RCTs) to evaluate the effects of TMZ treatment in CHF patients.

Methods

We searched PubMed, EMBASE, and Cochrane databases through October 2013 and included 19 RCTs involving 994 CHF patients who underwent TMZ or placebo treatment. Risk ratio (RR) and weighted mean differences (WMD) were calculated using fixed or random effects models.

Results

TMZ therapy was associated with considerable improvement in left ventricular ejection fraction (WMD: 7.29%, 95% CI: 6.49 to 8.09, p<0.01) and New York Heart Association classification (WMD: −0.55, 95% CI: −0.81 to −0.28, p<0.01). Moreover, treatment with TMZ also resulted in significant decrease in left ventricular end-systolic volume (WMD: −17.09 ml, 95% CI: −20.15 to −14.04, p<0.01), left ventricular end-diastolic volume (WMD: −11.24 ml, 95% CI: −14.06 to −8.42, p<0.01), hospitalization for cardiac causes (RR: 0.43, 95% CI: 0.21 to 0.91, p = 0.03), B-type natriuretic peptide (BNP; WMD: −157.08 pg/ml, 95% CI: −176.55 to −137.62, p<0.01) and C-reactive protein (CRP; WMD: −1.86 mg/l, 95% CI: −2.81 to −0.90, p<0.01). However, there were no significant differences in exercise duration and all-cause mortality between patients treated with TMZ and placebo.

Conclusions

TMZ treatment in CHF patients may improve clinical symptoms and cardiac function, reduce hospitalization for cardiac causes, and decrease serum levels of BNP and CRP.     

X-linked mental retardation with Marfanoid habitus: a changing phenotype with age?

In this report, we present two further examples of X-linked mental retardation with Marfanoid habitus. Follow-up data on these two patients reveal that the clinical diagnosis of this syndrome is extremely difficult, if not impossible before puberty, as the Marfanoid habitus only becomes strikingly evident during adolescence.     

Should young ever be better off with one parent than with two?

We analyze models of parental care, providing the first systematiccomparison of the care given to young by one parent versus bytwo parents. In the Houston-Davies model of care, young alwaysdo better with two parents rather than with one parent. Whenone parent decides about its level of care before the other,then the young may do better with one parent when the costsof care for the parents are asymmetric. When the level of parentaleffort is reached by negotiation, there are cases in which youngdo better with one parent, even when costs are symmetric. Theanalysis suggests empirical ways to differentiate between differentresponse rules.     

Glycoconjugate with terminal α galactose

Summary Glycoconjugates associated with the basal cell layer of various types of epithelia in the mouse and rat were examined histochemically with a battery of lectinhorseradish peroxidase (HRP) conjugates of differing sugar binding specificities. Basal cells in paraffin sections of composite tissue blocks stained with an isolectin from Griffonia simplicifolia (GSA I-B₄) specific for terminal -galactose residues but failed to react with the other lectins. Basal cells in epithelium lining striated and excretory ducts of salivary and lacrimal glands, tongue, esophagus, trachea, renal calyx, ureter, urinary bladder, urethra, epididymis and vas deferens stained selectively and intensely for content of a glycoconjugate with terminal -galactose. This galactoconjugate appeared associated with the plasmalemma of basal cells. Basal cells with a galactocalyx formed an intermittent to continuous layer generally increasing in prevalence distally in glandular duct systems. A minor population of pyramido-columnar cells with cytosolic GSA I-B₄ reactivity occurred in striated ducts and appeared less numerous in intralobular excretory ducts and more prevalent in extraglandular ducts. In trachea and renal pelvis, the GSA I-B₄ positive cell profiles ranged from low cuboidal to tall pyramidal in contour, but the latter appeared not to reach the lumen. In contrast, no GSA I-B₄ positive basal cells were seen in any segment of the pancreatic or bile ducts or in the epithelium of the gastrointestinal tract. These findings suggest that the basal cells found in similar sites in different epithelia and possessing in common a unique -galactoconjugate may function in a manner common to all and not simply in providing progenitor cells for epithelial renewal. The location and distribution of GSA I-B₄ reactive basal cells in diverse epithelia suggests that through their -galactocalyx they serve in maintaining the established composition of luminal fluid perhaps by impeding the transepithelial movement of fluid and ions.In honour of Prof. P. van DuijnThis research was supported by National Institutes of Health Grants HL-29775 and AM-10956