Voxel-based morphometric multisite collaborative study on schizophrenia

Regional gray matter (GM) abnormalities are well known to exist in patients with chronic schizophrenia. Voxel-based morphometry (VBM) has been previously used on structural magnetic resonance images (MRI) data to characterize these abnormalities. Two multisite schizophrenia studies, the Functional Biomedical Informatics Research Network and the Mind Clinical Imaging Consortium, which include 9 data collection sites, are evaluating the efficacy of pooling structural imaging data across imaging centers. Such a pooling of data could yield the increased statistical power needed to elucidate effects that may not be seen with smaller samples. VBM analyses were performed to evaluate the consistency of patient versus control gray matter concentration (GMC) differences across the study sites, as well as the effects of combining multisite data. Integration of data from both studies yielded a large sample of 503 subjects, including 266 controls and 237 patients diagnosed with schizophrenia, schizoaffective or schizophreniform disorder. The data were analyzed using the combined sample, as well as analyzing each of the 2 multisite studies separately. A consistent pattern of reduced relative GMC in schizophrenia patients compared with controls was found across all study sites. Imaging center-specific effects were evaluated using a region of interest analysis. Overall, the findings support the use of VBM in combined multisite studies. This analysis of schizophrenics and controls from around the United States provides continued supporting evidence for GM deficits in the temporal lobes, anterior cingulate, and frontal regions in patients with schizophrenia spectrum disorders.     

Spectroscopic elucidation of uncoupled transition energies in the major photosynthetic light-harvesting complex,LHCII

Electrostatic couplings between chromophores in photosynthetic pigment–protein complexes, and interactions of pigments with the surrounding protein environment, produce a complicated energy landscape of delocalized excited states. The resultant electronic structure absorbs light and gives rise to energy transfer steps that direct the excitation toward a site of charge separation with near unity quantum efficiency. Knowledge of the transition energies of the uncoupled chromophores is required to describe how the wave functions of the individual pigments combine to form this manifold of delocalized excited states that effectively harvests light energy. In an investigation of the major light-harvesting complex of photosystem II (LHCII), we develop a method based on polarized 2D electronic spectroscopy to experimentally access the energies of the S₀–S₁ transitions in the chromophore site basis. Rotating the linear polarization of the incident laser pulses reveals previously hidden off-diagonal features. We exploit the polarization dependence of energy transfer peaks to find the angles between the excited state transition dipole moments. We show that these angles provide a spectroscopic method to directly inform on the relationship between the delocalized excitons and the individual chlorophylls through the site energies of the uncoupled chromophores.     

Functional reciprocity between Na+ channel Nav1.6 and β1 subunits in the coordinated regulation of excitability and neurite outgrowth

Voltage-gated Na⁺ channel (VGSC) β1 subunits regulate cell–cell adhesion and channel activity in vitro. We previously showed that β1 promotes neurite outgrowth in cerebellar granule neurons (CGNs) via homophilic cell adhesion, fyn kinase, and contactin. Here we demonstrate that β1-mediated neurite outgrowth requires Na⁺ current (I_Na) mediated by Na_v1.6. In addition, β1 is required for high-frequency action potential firing. Transient I_Na is unchanged in Scn1b (β1) null CGNs; however, the resurgent I_Na, thought to underlie high-frequency firing in Na_v1.6-expressing cerebellar neurons, is reduced. The proportion of axon initial segments (AIS) expressing Na_v1.6 is reduced in Scn1b null cerebellar neurons. In place of Na_v1.6 at the AIS, we observed an increase in Na_v1.1, whereas Na_v1.2 was unchanged. This indicates that β1 is required for normal localization of Na_v1.6 at the AIS during the postnatal developmental switch to Na_v1.6-mediated high-frequency firing. In agreement with this, β1 is normally expressed with α subunits at the AIS of P14 CGNs. We propose reciprocity of function between β1 and Na_v1.6 such that β1-mediated neurite outgrowth requires Na_v1.6-mediated I_Na, and Na_v1.6 localization and consequent high-frequency firing require β1. We conclude that VGSC subunits function in macromolecular signaling complexes regulating both neuronal excitability and migration during cerebellar development.     

Bronchoprovocation testing in asthma: effect on exhaled monoxides

Exhaled carbon monoxide and nitric oxide reflect allergic inflammation in asthma and have clinical utility for monitoring disease severity. The effects of allergen challenge and of inflammatory versus non-inflammatory bronchoconstrictive stimuli on the exhalation kinetics of these gases are unclear. The aim of this study is to compare and contrast the effects of methacholine and allergen challenges on the exhaled levels of carbon monoxide and nitric oxide in a cohort of adult subjects with atopic asthma. Eight subjects underwent inhaled allergen testing, nine underwent methacholine testing, and five subjects underwent both tests. Additionally, seven healthy controls underwent a mock challenge. Mixed-expired and end-expiratory carbon monoxide and end-expiratory nitric oxide levels were measured together with spirometry before, during (i.e. after each step of the inhalations), and after the challenges. Decreases in both end-expiratory (-14.4% in 9/11 subjects, p = 0.04) and mixed-expired (-7.5%, 9/11 subjects, p = 0.007) levels of carbon monoxide were noted during the immediate phase of the allergen challenge, with similar reductions after methacholine challenge, but levels were unaffected by repeated forced vital capacity exhalations alone. End-expiratory nitric oxide increased during the immediate phase of allergen challenge in 10/13 subjects (+10.8%, p = 0.05), but decreased after methacholine challenge in 14/14 subjects (-32.2%, p = 0.00009). Bronchospasm negatively modulates exhaled carbon monoxide and nitric oxide, but the inflammatory stimulus of allergen exposure increases exhaled nitric oxide. Measurements of exhaled monoxides may need to be referenced to the FEV(1).     

Resistant hypertension, secondary hypertension, and hypertensive crises: diagnostic evaluation and treatment

Hypertension is a very common modifiable risk factor for cardiovascular morbidity and mortality. Patients with hypertension represent a diverse group. In addition to those with primary hypertension, there are patients whose hypertension is attributable to secondary causes, those with resistant hypertension, and patients who present with a hypertensive crisis. Secondary causes of hypertension account for less than 10% of cases of elevated blood pressure (BP), and screening for these causes is warranted if clinically indicated. Patients with resistant hypertension, whose BP remains uncontrolled in spite of use of 3 or more antihypertensive agents, are at increased cardiovascular risk compared with the general hypertensive population. After potentially correctible causes of uncontrolled BP (pseudoresistance, secondary causes, and intake of interfering substances) are eliminated, patients with true resistant hypertension are managed by encouraging therapeutic lifestyle changes and optimizing the antihypertensive regimen, whereby the clinician ensures that the medications are prescribed at optimal doses using drugs with complementary mechanisms of action, while adding an appropriate diuretic if there are no contraindications. Mineralocorticoid receptor antagonists are formidable add-on agents to the antihypertensive regimen, usually as a fourth drug, and are effective in reducing BP even in patients without biochemical evidence of aldosterone excess. In the setting of a hypertensive crisis, the BP has to be reduced within hours in the case of a hypertensive emergency (elevated BP with evidence of target organ damage) using parenteral agents, and within a few days if there is hypertensive urgency, using oral antihypertensive agents.     

Posttraumatic Stress Disorder,Cardiovascular, and Metabolic Disease: A Review of the Evidence

Background  

Posttraumatic stress disorder (PTSD) is a significant risk factor for cardiovascular and metabolic disease.     

Diffusion tensor imaging in schizophrenia: relationship to symptoms

In this diffusion tensor imaging (DTI) study, the authors investigated white matter integrity in schizophrenia and the relationships between white matter alterations and specific symptoms of the disorder. We compared DTI images of 25 schizophrenia patients and 25 matched healthy controls and performed voxel-wise correlational analyses using the patient's DTI data and their severity scores of positive and negative symptoms. We found diffuse deficits in multiple types of white matter tracts in schizophrenia, and an inverse relationship of DTI fractional anisotropy (FA) values with positive symptom scores in association fibers, supporting a "disconnection" hypothesis of positive symptoms in schizophrenia.     

Addressing the unit of analysis in medical care studies: a systematic review

OBJECTIVE: We assessed the frequency that patients are incorrectly used as the unit of analysis among studies of physicians' patient care behavior in articles published in high impact journals. METHODS: We surveyed 30 high-impact journals across 6 medical fields for articles susceptible to unit of analysis errors published from 1994 to 2005. Three reviewers independently abstracted articles using previously published criteria to determine the presence of analytic errors. RESULTS: One hundred fourteen susceptible articles were found published in 15 journals, 4 journals published the majority (71 of 114 or 62.3%) of studies, 40 were intervention studies, and 74 were noninterventional studies. The unit of analysis error was present in 19 (48%) of the intervention studies and 31 (42%) of the noninterventional studies (overall error rate 44%). The frequency of the error decreased between 1994-1999 (N = 38; 65% error) and 2000-2005 (N = 76; 33% error) (P = 0.001). CONCLUSIONS: Although the frequency of the error in published studies is decreasing, further improvement remains desirable.     

Statistical procedures for analyzing mental health services data

In mental health services research, analyzing service utilization data often poses serious problems, given the presence of substantially skewed data distributions. This article presents a non-technical introduction to statistical methods specifically designed to handle the complexly distributed datasets that represent mental health service use, including Poisson, negative binomial, zero-inflated, and zero-truncated regression models. A flowchart is provided to assist the investigator in selecting the most appropriate method. Finally, a dataset of mental health service use reported by medical patients is described, and a comparison of results across several different statistical methods is presented. Implications of matching data analytic techniques appropriately with the often complexly distributed datasets of mental health services utilization variables are discussed.