Spatial and temporal mapping of de novo mutations in schizophrenia to a fetal prefrontal cortical network.

Genes disrupted in schizophrenia may be revealed by de novo mutations in affected persons from otherwise healthy families. Furthermore, during normal brain development, genes are expressed in patterns specific to developmental stage and neuroanatomical structure. We identified de novo mutations in persons with schizophrenia and then mapped the responsible genes onto transcriptome profiles of normal human brain tissues from age 13 weeks gestation to adulthood. In the dorsolateral and ventrolateral prefrontal cortex during fetal development, genes harboring damaging de novo mutations in schizophrenia formed a network significantly enriched for transcriptional coexpression and protein interaction. The 50 genes in the network function in neuronal migration, synaptic transmission, signaling, transcriptional regulation, and transport. These results suggest that disruptions of fetal prefrontal cortical neurogenesis are critical to the pathophysiology of schizophrenia. These results also support the feasibility of integrating genomic and transcriptome analyses to map critical neurodevelopmental processes in time and space in the brain.

The Alabama Coalition for a Healthier Black belt: a proof of concept project.

The Alabama Coalition for a Healthier Black was a demonstration of concept project. This paper is a descriptive and qualitative overview of this 2.5 year project. Limited key project results are reported here. Located in the rural Black Belt region of Alabama this coalition had several key aims: to develop a collaboration between primary care and mental health care through co-location of services; use of video-conferencing capability to provide mental health services more efficiently; enhanced training in rural healthcare; and development of stigma reduction campaigns along with other coalition partner specific initiatives. Co-location and telepsychiatry implementation produced the major challenges and resulting adaptations to original aims. Despite many challenges these new service patterns were put into place and appear to be sustainable.

Evaluation of HLA polymorphisms in relation to schizophrenia risk and infectious exposure.

BACKGROUND: Genome-wide association studies (GWAS) implicate single nucleotide polymorphisms (SNPs) on chromosome 6p21.3-22.1, the human leukocyte antigen (HLA) region, as common risk factors for schizophrenia (SZ). Other studies implicate viral and protozoan exposure. Our study tests chromosome 6p SNPs for effects on SZ risk with and without exposure. METHOD: GWAS-significant SNPs and ancestry-informative marker SNPs were analyzed among African American patients with SZ (n = 604) and controls (n = 404). Exposure to herpes simplex virus, type 1 (HSV-1), cytomegalovirus (CMV), and Toxoplasma gondii (TOX) was assayed using specific antibody assays. RESULTS: Five SNPs were nominally associated with SZ, adjusted for population admixture (P < .05, uncorrected for multiple comparisons). These SNPs were next analyzed in relation to infectious exposure. Multivariate analysis indicated significant association between rs3130297 genotype and HSV-1 exposure; the associated allele was different from the SZ risk allele. CONCLUSIONS: We propose a model for the genesis of SZ incorporating genomic variation in the HLA region and neurotropic viral exposure for testing in additional, independent African American samples.

Project among African-Americans to explore risks for schizophrenia (PAARTNERS): evidence for impairment and heritability of neurocognitive functioning in families of schizophrenia patients.

OBJECTIVE: Neurocognitive impairments in schizophrenia are well replicated and widely regarded as candidate endophenotypes that may facilitate understanding of schizophrenia genetics and pathophysiology. The Project Among African-Americans to Explore Risks for Schizophrenia (PAARTNERS) aims to identify genes underlying liability to schizophrenia. The unprecedented size of its study group (N=1,872), made possible through use of a computerized neurocognitive battery, can help further investigation of the genetics of neurocognition. The current analysis evaluated two characteristics not fully addressed in prior research: 1) heritability of neurocognition in African American families and 2) relationship between neurocognition and psychopathology in families of African American probands with schizophrenia or schizoaffective disorder. METHOD: Across eight data collection sites, patients with schizophrenia or schizoaffective disorder (N=610), their biological relatives (N=928), and community comparison subjects (N=334) completed a standardized diagnostic evaluation and the computerized neurocognitive battery. Performance accuracy and response time (speed) were measured separately for 10 neurocognitive domains. RESULTS: The patients with schizophrenia or schizoaffective disorder exhibited less accuracy and speed in most neurocognitive domains than their relatives both with and without other psychiatric disorders, who in turn were more impaired than comparison subjects in most domains. Estimated trait heritability after inclusion of the mean effect of diagnostic status, age, and sex revealed significant heritabilities for most neurocognitive domains, with the highest for accuracy of abstraction/flexibility, verbal memory, face memory, spatial processing, and emotion processing and for speed of attention. CONCLUSION: Neurocognitive functions in African American families are heritable and associated with schizophrenia. They show potential for gene-mapping studies.

Paxbeta: a novel family of lophotrochozoan Pax genes.

Paxbeta is a novel gene family restricted to the bilaterian superphylum Lophotrochozoa. The Paxbeta paired domain is highly diverged from other bilaterian Pax genes, and we were unable to identify an unambiguous sister-group by phylogenetic sequence analysis. However, conservation of a paired domain intron suggests that the Paxbeta genes arose by duplication and divergence from an ancestral Pax2/5/8 gene. We have identified Paxbeta genes in annelids, molluscs, a nemertean, a brachiopod, and a flatworm, indicating that the founding gene duplication occurred before the separation of those taxa and therefore early in the lophotrochozoan radiation. The leech Helobdella has two genes in this family, Hau-Paxbeta1 and -Paxbeta2, which are expressed during embryonic development. Hau-Paxbeta1 is present in the zygote as a localized maternal transcript, and both show dynamic patterns of apparently zygotic expression during later stages. These later expression patterns differ significantly, but both genes are expressed broadly in the mesoderm and also in the central nervous system during organogenesis.

Hunchback-like protein is expressed in cleavage blastomeres, gastrula epithelium, and ciliary structures in gastropods.

We report the expression of Hunchback (Hb)-like protein during embryonic and larval development in two caenogastropods, Crepidula fornicata and Ilyanassa obsoleta. During the cleavage stages of these species, Hb-like protein is uniformly expressed in micromere and macromere nuclei. At gastrulation, gastropod Hb-like protein is expressed in the surface epithelium that undergoes epiboly. During organogenesis, gastropod Hb-like protein is expressed in the developing ciliated structures associated with feeding and locomotion. We find no detectable gradient or regionalization of Hb-like protein in gastropod embryos or larvae that resembles the graded Hb pattern of expression observed in dipteran insect embryos. Rather we found that the spatiotemporal expression profile of gastropod Hb-like protein is nearly identical to the Hb-like patterns obtained from the polychaete Capitella sp. I and is highly similar to those reported for clitellate annelids. Based upon the comparative data collected from both ecdysozoans and lophotrochozoan lineages, our results support the hypothesis that the role of Hb in anteroposterior patterning is a derived trait specific to arthropods, and that the ancestral function of lophotrochozoan Hb-like protein played a role in the formation of the cleavage-stage blastomeres and the gastrula epithelium and in structures associated with larval feeding and locomotion.

Characterization and outcome of patients with severe symptomatic aortic stenosis referred for percutaneous aortic valve replacement.

OBJECTIVE: Many high-risk patients with severe symptomatic aortic stenosis are not referred for surgical aortic valve replacement. Although this patient population remains ill-defined, many of these patients are now being referred for percutaneous aortic valve replacement. We sought to define the characteristics and outcomes of patients referred for percutaneous aortic valve replacement. METHODS: Between February 2006 and March 2007, 92 patients were screened for percutaneous aortic valve replacement. Clinical and echocardiographic characteristics of patients undergoing surgical aortic valve replacement, percutaneous aortic valve replacement, balloon aortic valvuloplasty, or no intervention were compared. The primary end point was all-cause mortality. RESULTS: Nineteen patients underwent successful surgical aortic valve replacement, 18 patients underwent percutaneous aortic valve replacement, and 36 patients had no intervention. Thirty patients underwent balloon aortic valvuloplasty, and of these, 8 patients were bridged to percutaneous aortic valve replacement and 3 were bridged to surgical aortic valve replacement. Of the remaining 19 patients undergoing balloon aortic valvuloplasty, bridging to percutaneous aortic valve replacement could not be accomplished because of death (n = 9 [47%)], exclusion from the percutaneous aortic valve replacement protocol (n = 6 [32%]), and some patients improved after balloon aortic valvuloplasty and declined percutaneous aortic valve replacement (n = 4 [21%]). The most common reasons for no intervention included death while awaiting definitive treatment (n = 10 [28%]), patient uninterested in percutaneous aortic valve replacement (n = 10 [28%]), and questionable severity of symptoms or aortic stenosis (n = 9 [25%]). Patients not undergoing aortic valve replacement had higher mortality compared with those undergoing aortic valve replacement (44% vs 14%) over a mean duration of 220 days. CONCLUSION: Symptomatic patients with severe aortic stenosis have high mortality if timely aortic valve replacement is not feasible. Twenty percent of the patients referred for percutaneous aortic valve replacement underwent surgical aortic valve replacement with good outcome. Patients undergoing balloon aortic valvuloplasty alone or no intervention had unfavorable outcomes.

Anesthesia in the cardiac catheterization laboratory and electrophysiology laboratory.

Procedures and interventions in the cardiac catheterization laboratory (CCL) and electrophysiology laboratory (EPL) are more complex and involve acutely ill patients. Safely caring for this growing patient population in the CCL and EPL is now a concern for all anesthesiologists and cardiologists. Anesthesiologists are uniquely trained to care for this complex patient population, allowing the cardiologist to focus on completing the interventional procedure successfully.

An 11-year, single-institution analysis of intra-aortic balloon pump use in cardiac surgery.

OBJECTIVES: The primary objective of this study was to analyze perioperative intra-aortic balloon pump (IABP) insertion in patients undergoing cardiac surgery in the authors' institution from 1995 to 2005 and to propose an explanation for changes in use over this period. A secondary objective was to assess patient variables associated with IABP use. DESIGN: This is a retrospective study including patients who underwent cardiac surgery between 1995 and 2005. SETTING: The Cardiothoracic Anesthesia Patient Registry of a single teaching institution was queried to obtain the required information. PARTICIPANTS: Thirty thousand two hundred sixty-nine cardiac surgery patients. INTERVENTIONS: Intra-aortic balloon pump insertion before surgery, after cardiopulmonary bypass, or in the cardiovascular intensive care unit was assessed in patients who underwent isolated coronary artery bypass graft surgery, valve surgery, or both. Select patient variables were analyzed for their association with IABP insertion. Transesophageal echocardiography (TEE) examinations, milrinone use, and mortality rates also were determined. MEASUREMENTS AND MAIN RESULTS: Among 30,269 cardiac surgery patients, 1,310 (4.32%) underwent IABP insertion. Combined preoperative, intraoperative, and postoperative IABP use decreased from 7.8% in 1995 to 3.0% in 2005. Simultaneously, the intraoperative use of milrinone increased from 4.8% to 8.8% and postoperative use increased from 5.2% to 7.8%. The number of intraoperative TEE examinations more than doubled from approximately 1,700 to 3,500. The overall mortality for patients with preoperative, intraoperative, and postoperative IABP insertion was 12.6%, 17.5%, and 47.7%, respectively. CONCLUSIONS: From 1995 to 2005, preoperative, intraoperative, and postoperative IABP use decreased by approximately 60% in cardiac surgery patients. Simultaneously, the use of TEE and milrinone each doubled. Although a cause-effect relationship cannot be established from the present study's observational data, the trends coincide and may be related.

Project among African-Americans to explore risks for schizophrenia (PAARTNERS): recruitment and assessment methods.

The Project among African-Americans to Explore Risks for Schizophrenia (PAARTNERS) is a multi-site, NIMH-funded study that seeks to identify genetic polymorphisms that confer susceptibility to schizophrenia among African-Americans by linkage mapping and targeted association analyses. Because deficits in certain dimensions of cognitive ability are thought to underlie liability to schizophrenia, the project also examines cognitive abilities in individuals affected by schizophrenia and their extended family members. This article describes PAARTNERS study design, ascertainment methods and preliminary sample characteristics. We aim to recruit a sample of 1260 African-American families, all of whom have at least one proband with schizophrenia or schizoaffective disorder. The data collection protocol includes a structured Diagnostic Interview for Genetic Studies, Family Interview for Genetic Studies, focused neurocognitive assessment, medical records review, and the collection of blood or buccal cells for genetic analyses. We have currently completed study procedures for 106 affected sib-pair, 457 case-parent trio and 23 multiplex families. A total of 289 probands have completed the best estimate final diagnosis process and 1153 probands and family members have been administered the computerized neuropsychological battery. This project lays the foundation for future analysis of cognitive and behavioral endophenotypes. This novel integration of diagnostic, neurocognitive and genetic data will also generate valuable information for future phenotypic and genetic studies of schizophrenia.

The divergent roles of the segmentation gene hunchback.

The hunchback (hb) gene is a member of the gap class of segmentation genes first identified in the dipteran insect Drosophila melanogastor. The hb gene encodes a C(2)H(2) zinc finger transcription factor whose primary function is to regulate the expression of its target genes along the anteroposterior (AP) axis based on its distribution in the blastoderm embryo. The loss of zygotic hb in Drosophila results in a "gap" in anterior pattern elements that include the loss of labial and thoracic segments in addition to the fusion of the abdominal segments 7 and 8. The hunchback protein is also expressed in the extraembryonic epithelial tissues and the developing nervous system in the zygote. Although the role of hunchback in AP patterning is likely to be an ancestral trait to the insect clade, higher order comparisons of hunchback orthologs suggest that it is a derived trait specific to the arthropod and/or insect lineage. This view is supported by a combination of comparative gene expression data, phylogenetic analyses, and an examination of the evolution of structural domains in the hb protein isolated from annelids, nematodes, and insects. The 3 independent lines of comparative data strongly support the idea that the anterior organizing function of hb originated in the arthropod and/or insect lineage and that its roles in epithelial and CNS patterning are likely to be broadly conserved within protostomes.

Immediate post-LVAD implant support: two approaches.

Increased use of left ventricular assist devices (LVAD) as bridges to transplant has revealed the need for short-term right heart support for deairing and right ventricular recovery. The two approaches described are implemented as the patient is weaned from regular cardiopulmonary bypass. Dependent on patient needs, the surgeon may select a high-flow or low-flow approach to what is essentially right heart bypass. Both methods use the existing venous drainage from the right side of the heart. The higher flow returns blood through a 0.25-in tube connected to a modified adult vent (AV) to the pulmonary artery (PA). This provides flows as high as 3.5 L/min. The low-flow method uses the cardioplegia line, which goes unused during LVAD insertion. It is attached to the same modified AV cannula, placed into the PA, with flows between 400 and 600 ml/min. Each method has its advantages, disadvantages, and quirks. The results are functionally successful in allowing support of the right heart and deairing of the ventricular device.

A brief neuropsychological testing battery for evaluating patients with schizophrenia.

Current conceptualizations of schizophrenia include neurocognitive impairment, particularly in aspects of attention, memory, and executive functioning. Evaluation of these cognitive abilities typically involves use of comprehensive batteries which may take up to six hours to complete. The current study examined the effectiveness of a briefer battery to detect cognitive impairments usually seen in schizophrenia as established by previous studies using more lengthy and labor intensive protocols. The current study involved 61 outpatients with schizophrenia who were separated into three subgroups: paranoid type (n = 20), undifferentiated type (n = 21), and schizoaffective (n = 20). The majority of the patients were male (61%), African-American (52%), and of low socio-economic status. The mean age was 41.4 years (SD = 8.8), and the mean years of education was 11.7 (SD = 6.8). For the overall sample, results revealed mild to moderate impairments in memory, construction, concept formation, response set maintenance, psychomotor speed, and visual speed of information processing. Post-hoc analyses revealed significant differences between subgroups on Similarities and psychomotor speed, with the undifferentiated group performing more poorly than the paranoid or schizoaffective groups. In conclusion, the current brief battery minimized respondent burden in terms of both time demands and level of task complexity. However, it was also sensitive enough to capture many of the same cognitive weaknesses as those reported when using more labor-intensive neuropsychological test protocols.

Expression of hunchback protein in a subset of ectodermal teloblasts of the oligochaete annelid Tubifex.

The early expression patterns of hunchback protein (T-hb protein) were examined in the oligochaete Tubifex, using an antibody raised to the LZF2 protein in leech. This antibody recognizes a 60-kDa polypeptide in the Tubifex embryo. Before teloblastogenesis, T-hb protein is expressed in every cleavage-stage blastomere. At the completion of teloblastogenesis, the only cells expressing T-hb are a fraction of the micromere-derived epithelial cells. During gastrulation, nuclear T-hb is seen in spreading micromere-derived epithelial cells and also in a subset of ectodermal teloblasts. Comparisons of these results with those from other annelids suggest that hb expression in the early cleavage blastomeres and the micromere-derived epithelium are features highly conserved among annelids. In contrast, hb expression in teloblasts appears to be an innovation evolved in the oligochaetes.