Transcriptome sequencing implicates dorsal striatum-specific gene network, immune response and energy metabolism pathways in bipolar disorder.

Bipolar disorder (BD) is a highly heritable and heterogeneous mental illness whose manifestations often include impulsive and risk-taking behavior. This particular phenotype suggests that abnormal striatal function could be involved in BD etiology, yet most transcriptomic studies of this disorder have concentrated on cortical brain regions. We believe we report the first transcriptome sequencing of the postmortem human dorsal striatum comparing bipolar (18) and control (17) subjects. Fourteen genes were detected as differentially expressed at a 5% false discovery rate, including a few immune response genes such as NLRC5, S100A12, LILRA4 and FCGBP, as well as an assortment of non-protein coding genes. Functional pathway analysis found an enrichment of upregulated genes across many immune/inflammation pathways and an enrichment of downregulated genes among oxidative phosphorylation pathways. Co-expression network analysis revealed 20 modules of highly interconnected genes; two of the modules were significantly enriched for BD susceptibility single-nucleotide polymorphisms deriving from a large genome-wide association study data set. Remarkably, the module with the highest genetic association signal for BD, which contained many genes from signaling pathways, was also enriched in markers characteristic of gene expression in dorsal striatum medium spiny neurons-unlike most other modules, which showed no such regional and neuronal specificity. These findings draw a link between BD etiology at the gene level and a specific brain region, and highlight striatal signaling pathways as potential targets for the development of novel treatments to manage BD.

Novel, primate-specific PDE10A isoform highlights gene expression complexity in human striatum with implications on the molecular pathology of bipolar disorder.

Bipolar disorder is a highly heritable neuropsychiatric disorder affecting nearly 2.5% of the population. Prior genetic studies identified a panel of common and rare single-nucleotide polymorphisms associated with the disease that map to the first intron of the PDE10A gene. RNA sequencing of striatal brain tissue from bipolar and healthy control subjects identified a novel transcript of PDE10A, named PDE10A19, that codes for a PDE10A isoform with a unique N terminus. Genomic sequences that can encode the novel N terminus were conserved in other primates but not rodents. The RNA transcript was expressed at equal or greater levels in the human striatum compared with the two annotated transcripts, PDE10A1 and PDE10A2. The PDE10A19 transcript was detected in polysomal fractions; western blotting experiments confirmed that the RNA transcript is translated into protein. Immunocytochemistry studies using transfected mouse striatal and cortical neurons demonstrated that the PDE10A19 protein distributes to the cytosol, like PDE10A1, and unlike PDE10A2, which is associated with plasma membranes. Immunoprecipitation and immunocytochemical experiments revealed that the PDE10A19 isoform interacts physically with PDE10A2 and, when expressed at elevated levels, interferes with the plasma membrane localization of PDE10A2. These studies illustrate the complexity of PDE10A gene expression in the human brain and highlight the need to unravel the gene's complex and complete coding capabilities along with its transcriptional and translational regulation to guide the development of therapeutic agents that target the protein for the treatment of neuropsychiatric illness.

Decision-making impairment in schizophrenia: relationships with positive symptomatology.

Abnormal decision-making (DM) performance has been reported in several neurobehavioral disorders such as schizophrenia, addiction, and obsessive compulsive disorders. The exploration of DM correlates in terms of symptom formation may add more knowledge about the meanings of DM performance in schizophrenia. We examined the Iowa Gambling Task (IGT) and its relationship with clinical symptoms, evaluated by Positive and Negative Symptom Scale (PANSS), in 40 schizophrenic patients and 20 controls. Schizophrenic patients did worse on IGT performance with a significant difference between the two groups in Net Score. PANSS positive symptoms were negatively correlated with Net Score and advantageous choices and directly with disadvantageous choices. Results suggest that persons with schizophrenia display a pattern of compromised DM related to positive symptoms.

Use of the Griffiths Mental Development Scales in an agro-industrial province in the Philippines.

BACKGROUND: There is a need to assess neurobehavioral performance of children in developing countries using standardized developmental tools. METHODS: The Griffiths Mental Development Scales was evaluated in the Philippines by comparing the performance of 742 Filipino children longitudinally at 6, 12 and 24 months old to those of their British counterparts. RESULTS: The mean general and subquotient scores of Filipino children were all within average for age. Comparison with British children showed that except for performance subscales, Filipino children had significantly higher developmental subquotients at 6 months old. As the Filipino infants grew older, their developmental subquotients in all subscales were significantly lower, except for personal and social skills at 24 months old. The genetic predisposition as evidenced by modest maternal scores on the Wechsler Intelligence Scales and lack of familiarity with test materials are factors that may influence the developmental patterns of Filipino children. CONCLUSION: Although the performance of the Filipino children in the Griffiths test were within average with age, their performance on developmental subquotients at later ages of 12 and 24 months were significantly lower than British children and may have been influenced by differences in ethnicity, cultural traditions and limited environmental resources.

Dimensional, non-taxonic latent structure of psychotic symptoms in a student sample.

INTRODUCTION: We examined the construct of psychosis using the self-report instrument CAPE (Community Assessment of Psychic Experiences) in a sample of 1,323 students. MATERIALS AND METHODS: Taxometric analysis was carried out using Taxometric Programs for the R Computing Environment. The MAXCOV CCFI was 0.34, indicating a dimensional latent structure. All other taxometric analysis yielded very similar results indicative of dimensional structure. CONCLUSION: In this study, using powerful analytic techniques designed expressly for the purpose, i.e. taxometric analysis, the latent construct of psychosis in a sample of young students appeared to be consistent with a dimensional, non-taxonic latent structure.

Validation of the Mayo Dysphagia Questionnaire.

While multiple instruments characterize upper gastrointestinal symptoms, a validated instrument devoted to the measurement of a spectrum of esophageal dysphagia attributes is not available. Therefore, we constructed and validated the Mayo Dysphagia Questionnaire (MDQ). The 27 items of the MDQ underwent content validity, feasibility, concurrent validity, reproducibility, internal consistency, and construct validity testing. To assess content validity, five esophageal subspecialty gastroenterologists reviewed the items to ensure inclusion of pertinent domains. Feasibility testing was done with eight outpatients who refined problematic items. To assess concurrent validity, 70 patient responses on the MDQ were compared to responses gathered in a structured patient-physician interview. A separate group of 70 outpatients completed the MDQ twice to assess the reproducibility of each item. A total of 148 patients participated in the validation process (78 [53%] men; mean age 62). On average, the MDQ took 6 minutes to complete. A single item (odynophagia) tested poorly with a kappa value of <0.4. Otherwise, the majority of concurrent validity kappa values were in the good to excellent range with a mean of 0.63 (95% CI 0.22-0.89). The majority of reproducibility kappa values were also in the good to excellent range with a median kappa value of 0.76 (interquartile range: 0.67-0.81). Cronbach's alpha values were excellent in the range of 0.86-0.88. Spearman rank correlation coefficients to assess construct validity were also excellent in the range of 0.87-0.98. Thus, the MDQ is a concise instrument that demonstrates overall excellent concurrent validity, reproducibility, internal consistency, and construct validity for the features of esophageal dysphagia.

Human antibody responses of patients living in endemic areas for schistosomiasis to the tegumental protein Sm29 identified through genomic studies.

Surface proteins of schistosomes are exposed to host tissues and thus present as potential candidate molecules for the development of new intervention strategies. Herein, we have identified a new tegumental protein of Schistosoma mansoni, termed Sm29. In silico analysis revealed a signal peptide, three glycosylation sites and a transmembrane region on Sm29 amino acid sequence. Sm29 transcription in mammalian developmental stages cDNA libraries of S. mansoni was verified by PCR using specific primers for Sm29 nucleotide sequence and it revealed the presence of transcripts in schistosomula and adult worm stages of the parasite. Sm29 (40-169) fragment was produced in Escherichia coli and purified by affinity chromatography to be used in the immunological assays. Confocal microscopy confirmed bioinformatic studies, revealing that Sm29 is a membrane-bound protein localized on the tegument of S. mansoni adult worm. ELISA was performed using rSm29 protein to investigate the antibody isotype profile to Sm29 in sera of patients living in endemic areas for schistosomiasis. IgG1 and IgG3 subclass antibodies to rSm29 were predominant in sera of individuals naturally resistant to infection and resistant to re-infection whereas low levels of IgM, IgA or IgE were measured. Since, IgG1 and IgG3 are involved in parasite killing and in protective immunity the findings reported here suggest the use of Sm29 as a potential candidate vaccine against schistosomiasis.

Muscle and tendon size relationships in a paralyzed chick embryo model of clubfoot.

Clubfoot is a birth defect that may be related to muscle weakness or imbalance. The purpose of this study was to examine the relationships among muscle and tendon size and embryonic motility in a paralyzed chick embryo model of clubfoot and arthrogryposis. Decamethonium bromide, a neuromuscular blocking agent, was administered to a series of embryos in five dosage groups, producing a cohort of embryos with various degrees of paralysis and atrophy of tendons and muscle. Embryonic movement frequency was monitored, and after death in late gestation, the cross-sectional areas of the calf musculature and the gastrocnemius tendon proximal to the ankle were measured histologically. Significant correlations were found between embryonic motility and both muscle (r2 = 0.52) and tendon (r2 = 0.77) areas. In addition, a significant correlation (r2 = 0.74) was found between muscle and tendon areas, suggesting that a measurement of one may be used to predict the other.

Ultrasonic energy in phacoemulsification: mechanical cutting and cavitation.

Ultrasound energy has two components. The first is mechanical cutting energy, which many believe is the sole energy in phacoemulsification. A second, less studied type of energy is produced by the sonic wave part of ultrasound, which produces cycles. These cycles can create little bubbles or cavities. Under the right circumstances and at a critical point (i.e., maximum cavity enlargement), they implode with tremendous negative energy and heat. This implosion creates a cavity in a process known as cavitation. This article discusses both types of energy and explores the advantages and disadvantages of cavitation.

Divide and conquer phacoemulsification. One-handed variant.

A one-handed variation of Gimbel's "divide and conquer" phacoemulsification technique is described. Instead of bimanual cracking, the lens sections are cut, rotated, cut, and removed in sequence.

Astigmatically neutral sutured small incision.

The desire for rapid visual rehabilitation following phacoemulsification for cataract and intraocular lens implantation has stimulated a quest for an "astigmatically neutral" incision. We have evaluated an underemphasized aspect of wound closure technique for a small incision wound (5.1 mm). The essential element of the technique is reinflation of the anterior chamber after a nylon shoelace suture is placed and tied once but before the knot is finally secured. The resulting changes in corneal curvature are analyzed. Results are presented at two weeks and six weeks postoperatively. We have termed this technique post-suture inflation.

Ambulance ride: fixed or floating stretcher?

The alternatives of a purpose-bult ambulance and a specially designed stretcher suspension system were considered and the features of the latter assessed by subjective and objective tests. The results showed a significant improvement in the quality of the ride offered to the patient.