Neuropsychological and neuroimaging underpinnings of schizoaffective disorder: a systematic review.

OBJECTIVES: The neurobiological basis and nosological status of schizoaffective disorder remains elusive and controversial. This study provides a systematic review of neurocognitive and neuroimaging findings in the disorder. METHODS: A comprehensive literature search was conducted via PubMed, ScienceDirect, Scopus and Web of Knowledge (from 1949 to 31st March 2015) using the keyword 'schizoaffective disorder' and any of the following terms: 'neuropsychology', 'cognition', 'structural neuroimaging', 'functional neuroimaging', 'multimodal', 'DTI' and 'VBM'. Only studies that explicitly examined a well defined sample, or subsample, of patients with schizoaffective disorder were included. RESULTS: Twenty-two of 43 neuropsychological and 19 of 51 neuroimaging articles fulfilled inclusion criteria. We found a general trend towards schizophrenia and schizoaffective disorder being related to worse cognitive performance than bipolar disorder. Grey matter volume loss in schizoaffective disorder is also more comparable to schizophrenia than to bipolar disorder which seems consistent across further neuroimaging techniques. CONCLUSIONS: Neurocognitive and neuroimaging abnormalities in schizoaffective disorder resemble more schizophrenia than bipolar disorder. This is suggestive for schizoaffective disorder being a subtype of schizophrenia or being part of the continuum spectrum model of psychosis, with schizoaffective disorder being more skewed towards schizophrenia than bipolar disorder.

Brain structural changes in schizoaffective disorder compared to schizophrenia and bipolar disorder.

OBJECTIVE: Brain structural changes in schizoaffective disorder, and how far they resemble those seen in schizophrenia and bipolar disorder, have only been studied to a limited extent. METHOD: Forty-five patients meeting DSM-IV and RDC criteria for schizoaffective disorder, groups of patients with 45 matched schizophrenia and bipolar disorder, and 45 matched healthy controls were examined using voxel-based morphometry (VBM). RESULTS: Analyses comparing each patient group with the healthy control subjects found that the patients with schizoaffective disorder and the patients with schizophrenia showed widespread and overlapping areas of significant volume reduction, but the patients with bipolar disorder did not. A subsequent analysis compared the combined group of patients with the controls followed by extraction of clusters. In regions where the patients differed significantly from the controls, no significant differences in mean volume between patients with schizoaffective disorder and patients with schizophrenia in any of five regions of volume reduction were found, but mean volumes in the patients with bipolar disorder were significantly smaller in three of five. CONCLUSION: The findings provide evidence that, in terms of structural gray matter brain abnormality, schizoaffective disorder resembles schizophrenia more than bipolar disorder.

Medial prefrontal cortex pathology in schizophrenia as revealed by convergent findings from multimodal imaging.

Neuroimaging studies have found evidence of altered brain structure and function in schizophrenia, but have had complex findings regarding the localization of abnormality. We applied multimodal imaging (voxel-based morphometry (VBM), functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) combined with tractography) to 32 chronic schizophrenic patients and matched healthy controls. At a conservative threshold of P=0.01 corrected, structural and functional imaging revealed overlapping regions of abnormality in the medial frontal cortex. DTI found that white matter abnormality predominated in the anterior corpus callosum, and analysis of the anatomical connectivity of representative seed regions again implicated fibres projecting to the medial frontal cortex. There was also evidence of convergent abnormality in the dorsolateral prefrontal cortex, although here the laterality was less consistent across techniques. The medial frontal region identified by these three imaging techniques corresponds to the anterior midline node of the default mode network, a brain system which is believed to support internally directed thought, a state of watchfulness, and/or the maintenance of one's sense of self, and which is of considerable current interest in neuropsychiatric disorders.

[Analysis of small areas of pediatric cancer in the municipality of Murcia (Spain)]. / Análisis en áreas pequeñas del cáncer pediátrico en el municipio de Murcia.

INTRODUCTION: Occasionally, primary care pediatricians notice the presence of small clusters of pediatric cancer (PC), but are often frustrated by the findings after statistical analysis. The study of small areas in spatial epidemiology has led to advances in identifying clusters and the environmental risk factors involved. The purpose of this study was to describe the PC incidence and the spatial distribution at the minimum level of disaggregation possible in Murcia, presenting the first urban municipality map of PC in Spain. MATERIALS AND METHODS: A population-based descriptive study was conducted on the PC cases diagnosed in children younger than 15 years, between 1998 and 2013 in the municipality of Murcia. Cases were classified by sex, age group, and tumor type. Coordinates of home addresses at the time of diagnosis were assigned to each case, and spatial and spatio-temporal analyses were carried out at the level of census tracts, using FleXScan and SatScan. RESULTS: A total of 155 cases of PC were diagnosed during this period. The overall incidence of PC (138/10(6) of children under the age of 15) and the incidence for individual tumor types were within the expected ranges for Europe. A spatio-temporal cluster of Hodgkin lymphoma was identified. CONCLUSIONS: Small area analysis of PC cases may be a useful tool for the identification of PC clusters, which would allow for the generation of hypotheses regarding disease etiology, as well as developing urban models for environmental surveillance of PC.

Protein synthesis inhibition blocks the induction of mossy fiber long-term potentiation in vivo.

Protein synthesis inhibitors block the maintenance of NMDA receptor-dependent long-term potentiation (LTP) both in vivo and in vitro. Protein synthesis inhibitors block mossy fiber(MF) LTP maintenance in vitro, but little is known about the effect of protein synthesis inhibitors on either induction or maintenance in MF-LTP in vivo. Here we study the role of protein synthesis in the induction of long-term potentiation at the mossy fiber-CA3 hippocampal synapse in vivo in anesthetized rats. The protein synthesis inhibitor anisomycin was administered at different doses (0.04, 10, or 40 nmol) into area CA3 15 min before delivering high-frequency stimulation (two times at 100 Hz, 1 sec). Anisomycin blocked MF-LTP induction in a dose-dependent manner; both 40 and 10 nmol blocked MF-LTP induction, but a lower dose of 0.04 nmol was without effect. The inhibitory effect of anisomycin on protein synthesis was determined by measuring the incorporation of [(35)S]methionine into the newly synthesized proteins. Percentages of protein synthesis inhibition were determined by comparing [(35)S] incorporation of anisomycin-treated samples with vehicle controls. Doses of 0.04, 10, or 40 nmol of anisomycin produced 21, 82, or 83% inhibition of [(35)S]methionine incorporation, respectively. The effect of anisomycin was verified using a single dose of the protein synthesis inhibitor cycloheximide (40 nmol). Cycloheximide also blocked MF-LTP induction. These results suggest that protein synthesis plays an important role in the induction of mossy fiber long-term potentiation in vivo.

[Group 2A idiopathic parafoveal telangiectasis]. / Telangiectasias parafoveales idiopáticas tipo 2A.

CASE REPORT: Two cases of group 2A idiopathic parafoveal telangiectasis associated with abnormal glucose metabolism are reported with the typical sings of this disease as well as a foveal vitelliform lesion in one patient, an infrequent association. DISCUSSION: Group 2A idiopathic parafoveal telangiectasis are a disease with well characterized clinical signs, being some very infrequent such as a vitelliform maculopathy. Its pathogenesis seems to be linked to some alterations in the parafoveal capillary network endothelial cells. These alterations are similar to those that appear in the beginning of the diabetic retinopathy.

Use of steady state kinetic methods to elucidate the kinetic and chemical mechanisms of retroviral proteases.

Despite the current plethora of structural data of HIV-1 protease and the availability of potent inhibitors, whose structures are based in part on the presumed mechanism of action of this enzyme, our actual understanding of its chemical mechanism has been until now based largely on the precedents of the mammalian and fungal aspartic proteases and static three-dimensional data. The available steady state kinetic data of the protease, as reviewed here, constitute a first step in a detailed description of the mechanism of the enzyme to complement the structural data.

Water maze training in aged rats: effects on brain metabolic capacity and behavior.

The effects of Morris water maze training on brain metabolism and behavior were compared between aged (20-22 months) and young (2-4 months) Fischer 344 male rats. Each group had yoked controls, which swam the same amount of time as the trained rats but without the platform. This was followed after 9 days by quantitative histochemical mapping of brain cytochrome oxidase, the terminal enzyme for cellular respiration. The aged rats spent a significantly lower percent of time in the correct quadrant and had a longer latency to escape to the hidden platform, relative to the young rats. Metabolic differences between trained aged and young rats were found in regions related to escape under stress: perirhinal cortex, basolateral amygdala and lateral habenula; and vestibular nuclei that guide orientation in three-dimensional space. These differences were not found in the yoked swimming rats. The results suggest that, at the time point investigated, water maze training in aged Fischer 344 rats produces altered oxidative energy metabolism in task-relevant limbic and vestibular regions.

Opioid receptor modulation of mossy fiber synaptogenesis: independence from long-term potentiation.

Long-term potentiation (LTP) at the mossy fiber-CA3 synapse of the rat hippocampus is an NMDA receptor-independent form of synaptic plasticity that is sensitive to opioid receptor antagonists [12]. In the present study, Timm's stain, a zinc detecting histological marker commonly used to infer synaptogenesis in the mossy fiber projection, was used to examine whether synaptogenesis occurs in response to mossy fiber LTP induction in the adult rat in vivo. Seven days following the induction of mossy fiber LTP by non-seizure-inducing high-frequency stimulation of the mossy fibers, a prominent band of Timm's staining appeared bilaterally in the infrapyramidal region of the stratum oriens in area CA3. Staining was more prominent on the side contralateral to the stimulation. Systemic administration of the opioid receptor antagonist naloxone, sufficient to block mossy fiber LTP induction, did not block the development of Timm's staining in the infrapyramidal region ipsilateral to stimulation, but it did block stimulation-induced increases in Timm's staining observed contralaterally. Systemic administration of (+/-) CPP, a competitive NMDA receptor-antagonist, by contrast, did not block the induction of LTP and did not alter the increase in Timm's staining observed either ipsilaterally or contralaterally. The increase in Timm's staining in the infrapyramidal region suggests that mossy fiber synaptogenesis occurs in response to non-seizure inducing stimulation. Synaptogenesis does not appear to be directly related to opioid receptor-dependent mossy fiber LTP induction, because it occurs in the presence of naloxone which blocks LTP. The mossy fiber synaptogenesis occurring contralaterally appears to be regulated by endogenous opioid peptides, because it is blocked by naloxone.

Periodic quasi-orthogonal spline bases and applications to least-squares curve fitting of digital images.

Presents a new covariant basis, dubbed the quasi-orthogonal Q-spline basis, for the space of n-degree periodic uniform splines with k knots. This basis is obtained analogously to the B-spline basis by scaling and periodically translating a single spline function of bounded support. The construction hinges on an important theorem involving the asymptotic behavior (in the dimension) of the inverse of banded Toeplitz matrices. The authors show that the Gram matrix for this basis is nearly diagonal, hence, the name "quasi-orthogonal". The new basis is applied to the problem of approximating closed digital curves in 2D images by least-squares fitting. Since the new spline basis is almost orthogonal, the least-squares solution can be approximated by decimating a convolution between a resolution-dependent kernel and the given data. The approximating curve is expressed as a linear combination of the new spline functions and new "control points". Another convolution maps these control points to the classical B-spline control points. A generalization of the result has relevance to the solution of regularized fitting problems.

Association of formal thought disorder in schizophrenia with structural brain abnormalities in language-related cortical regions.

BACKGROUND: Formal thought disorder (FTD) in schizophrenia has been found to be associated with volume reductions in the left superior temporal cortex. However, there have been negative findings and some studies have also found associations in other cortical regions. METHOD: Fifty-one schizophrenic patients were evaluated for presence of FTD with the Thought, Language and Communication (TLC) scale and underwent whole-brain structural MRI using optimized voxel-based morphometry (VBM). Fifty-nine matched healthy controls were also scanned. RESULTS: Compared to 31 patients without FTD (global TLC rating 0 or 1), 20 patients with FTD (global TLC rating 2-5) showed clusters of volume reduction in the medial frontal and orbitofrontal cortex bilaterally, and in two left-sided areas approximating to Broca's and Wernicke's areas. The pattern of FTD-associated volume reductions was largely different from that found in a comparison between the healthy controls and the patients without FTD. Analysis of correlations within regions-of-interest based on the above clusters indicated that the 'fluent disorganization' component of FTD was correlated with volume reductions in both Broca's and Wernicke's areas, whereas poverty of content of speech was correlated with reductions in the medial frontal/orbitofrontal cortex. CONCLUSIONS: The findings point to a relationship between FTD in schizophrenia and structural brain pathology in brain areas involved in language and executive function.

Characterizing brain anatomical connections using diffusion weighted MRI and graph theory.

A new methodology based on Diffusion Weighted Magnetic Resonance Imaging (DW-MRI) and Graph Theory is presented for characterizing the anatomical connections between brain gray matter areas. In a first step, brain voxels are modeled as nodes of a non-directed graph in which the weight of an arc linking two neighbor nodes is assumed to be proportional to the probability of being connected by nervous fibers. This probability is estimated by means of probabilistic tissue segmentation and intravoxel white matter orientational distribution function, obtained from anatomical MRI and DW-MRI, respectively. A new tractography algorithm for finding white matter routes is also introduced. This algorithm solves the most probable path problem between any two nodes, leading to the assessment of probabilistic brain anatomical connection maps. In a second step, for assessing anatomical connectivity between K gray matter structures, the previous graph is redefined as a K+1 partite graph by partitioning the initial nodes set in K non-overlapped gray matter subsets and one subset clustering the remaining nodes. Three different measures are proposed for quantifying anatomical connections between any pair of gray matter subsets: Anatomical Connection Strength (ACS), Anatomical Connection Density (ACD) and Anatomical Connection Probability (ACP). This methodology was applied to both artificial and actual human data. Results show that nervous fiber pathways between some regions of interest were reconstructed correctly. Additionally, mean connectivity maps of ACS, ACD and ACP between 71 gray matter structures for five healthy subjects are presented.

Postoperative morbidity associated with cesarean delivery among human immunodeficiency virus-seropositive women.

OBJECTIVE: The aim of this study was to compare the complication rates associated with cesarean delivery between human immunodeficiency virus-seropositive women with those among a matched group of human immunodeficiency virus-seronegative subjects. STUDY DESIGN: We conducted a case-control study of 86 human immunodeficiency virus-seropositive women undergoing cesarean delivery between the years 1992 and 2000 at a large, urban teaching institution and a control group of 86 human immunodeficiency virus-seronegative women matched for age, race, year of delivery, and delivery indications. Data were analyzed with the chi2 test and odds ratios. Among human immunodeficiency virus-seropositive women, complications were further stratified according to maternal disease status and use of antiretroviral therapy. RESULTS: Human immunodeficiency virus-seropositive women were significantly more likely than control women to have minor postoperative complications (66.3% vs 41.8%; odds ratio, 2.73; 95% confidence interval, 1.40-6.10), of which febrile morbidity was the most common (62.8% vs 42.7%; P =.003). There was no difference between the groups in the rate of major complications (9.3% vs 3.4%; odds ratio, 2.84; 95% confidence interval, 0.65-14.06). Zidovudine use was associated with a decrease in the maternal morbidity rate (odds ratio, 0.31; 95% confidence interval, 0.07-1.03). CONCLUSION: Postoperative morbidity among human immunodeficiency virus-seropositive women undergoing cesarean delivery was not different from that in a matched control population.

Use of nitrogen-15 kinetic isotope effects to elucidate details of the chemical mechanism of human immunodeficiency virus 1 protease.

We have used 15N kinetic isotope effects of the HIV-1 protease-catalyzed peptidolysis of Ac-Ser-Gln-Asn-Tyr-Pro-Val-Val-NH2 to characterize the chemical mechanism of this enzyme. In addition, the multiple isotope effects have been determined by measuring the 15N kinetic isotope effects in both H2O and D2O. The isotope effects, measured on values of V/K, were determined by the incorporation of a radiolabel (tritium and 14C in peptides bearing the heavy and light isotopes, respectively) at a position remote from the isotopically labeled scissile peptide bond, such that the isotope effect was determined by measurement of the change in the 14C/3H ratio in recovered substrates at various fractions of reaction. At pH = 6.0 (37 degrees C), the nitrogen isotope effects were slightly, but significantly, inverse in both solvents: 15(V/K)H2O = 0.995 +/- 0.002, and 15(V/K)D2O = 0.992 +/- 0.003. The observation of an inverse nitrogen kinetic isotope effect implies that bonding to the nitrogen atom is becoming stiffened in a reaction transition state, and since this inverse isotope effect is enhanced in D2O, this isotope effect likely arises from protonation of the proline nitrogen atom.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibitor binding to the Phe53Trp mutant of HIV-1 protease promotes conformational changes detectable by spectrofluorometry.

HIV-1 protease contains two identical, conformationally mobile loops, known as flaps, which form in part the binding pockets for substrates and inhibitors. We have constructed a site-specific mutant of the protease in which residues Phe-53 and Phe-153 at the end of the flaps have been mutated to Trp residues, in order to incorporate a specific fluorescent probe to monitor conformational changes upon the binding of an inhibitor. The Phe53Trp (F53W) mutant of HIV-1 protease was expressed in Escherichia coli and purified from bacterial lysates. Analysis of the purified mutant protease demonstrated that its kinetic properties were highly similar to those of the wild-type protease. While binding of a potent peptide-analogue inhibitor (Ki = 9 nM) to the wild-type enzyme led to no change in protein fluorescence, a 5-8% increase in fluorescence was observed with the F53W mutant, indicating an enhancement of the Trp fluorescence due to flap movement upon inhibitor binding. Investigation of the kinetics of the F53W protease-inhibitor binding by stopped-flow spectrofluorometry revealed a rapid increase in protein fluorescence upon formation of the enzyme-inhibitor complex. These data were consistent with a one-step mechanistic model of inhibitor binding in which flap movement was concomitant with inhibitor binding, from which respective rate constants of association and dissociation of 2.5 x 10(6) M-1 s-1 and 0.023 s-1 were obtained.