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Abstract: Wolfram syndrome 1 (WFS1, OMIM 222300), a rare genetic disorder characterized by optic nerve atrophy, deafness, diabetes insipidus and diabetes mellitus, is caused by mutations of WFS1, encoding WFS1/wolframin. Non-syndromic WFS1 variants are associated with the risk of diabetes mellitus due to altered function of wolframin in pancreatic islet cells, expanding the importance of wolframin. This study extends a previous report for the monkey retina, using immunohistochemistry to localize wolframin on cryostat and paraffin sections of human retina. In addition, the human retinal pigment epithelial (RPE) cell line termed ARPE-19 and retinas from both pigmented and albino mice were studied to assess wolframin localization. In the human retina, wolframin was expressed in retinal ganglion cells, optic axons and the proximal optic nerve. Wolframin expression in the human retinal pigment epithelium (RPE) was confirmed with intense cytoplasmic labeling in ARPE-19 cells. Strong labeling of the RPE was also found in the albino mouse retina. Cryostat sections of the mouse retina showed a more extended pattern of wolframin labeling, including the inner nuclear layer (INL) and photoreceptor inner segments, confirming the recent report of Kawano et al. [Kawano, J., Tanizawa, Y., Shinoda, K., 2008. Wolfram syndrome 1 (Wfs1) gene expression in the normal mouse visual system. J. Comp. Neurol. 510, 1–23]. Absence of these cells in the human specimens despite the use of human-specific antibodies to wolframin may be related to delayed fixation. Loss of wolframin function in RGCs and the unmyelinated portion of retinal axons could explain optic nerve atrophy in Wolfram Syndrome 1. [Copyright &y& Elsevier]

Recent studies (Prabakaran et al. in Mol Psychiat 9:684–697, ; Hanson and Gottesman in BMC Med Genet 6:7, ; Harris et al. in PLoS ONE 3:e3964, ) have suggested that microvascular abnormalities occur in the brains of patients with schizophrenia. To assess the integrity of the microvasculature in subcortical brain regions in schizophrenia, we investigated the microvessel length density, total microvessel length, and microvessel length per neuron using design-based stereologic methods in the caudate nucleus, putamen, nucleus accumbens, mediodorsal nucleus of the thalamus, and lateral nucleus of the amygdala in both hemispheres of 13 postmortem brains from male patients with schizophrenia and 13 age-matched male controls. A general linear model multivariate analysis of variance with diagnosis and hemisphere as fixed factors and illness duration (patients with schizophrenia) or age (controls), postmortem interval and fixation time as covariates showed no statistically significant differences in the brains from the patients with schizophrenia compared to the controls. These data extend our earlier findings in prefrontal cortex area 9 and anterior cingulate cortex area 24 from the same brains (Kreczmanski et al. in Acta Neuropathol 109:510–518, ), that alterations in microvessel length density, total length, and particularly length per neuron cannot be considered characteristic features of schizophrenia. As such, compromised brain metabolism and occurrence of oxidative stress in the brains of patients with schizophrenia are likely caused by other mechanisms such as functional disruption in the coupling of cerebral blood flow to neuronal metabolic needs. [ABSTRACT FROM AUTHOR]

Abstract: It has been postulated that the prefrontal cortices of schizophrenic patients have significant alterations in their neuropil space. However, previous results have been contradictory and inconclusive, reporting both decreases and increases in the prefrontal neuropil. The present study re-examines these findings based on measurements of cell density, and inter-cellular distances within and between cell minicolumns. The results indicate alterations in the neuropil of schizophrenic patients according to both the lamina and cortical area examined. Alterations were present in all cortical areas studied. The findings suggest an alteration in the modulatory systems innervating the cell minicolumn. Furthermore, the lack of variation in core columnarity parameters argues in favor of a defect post-dating the formation of the cell minicolumn. [Copyright &y& Elsevier]

The presence of microvasculature abnormalities in the prefrontal cortex of schizophrenics was proposed in a recent study of molecular signatures of schizophrenia [Prabakaran et al (2004) Mol Psychiat 9:684–697]. To assess this possibility further, we investigated capillary length densities in prefrontal cortex area 9 and anterior cingulate cortex area 24 in postmortem brains from 13 schizophrenics and 13 age- and sex-matched controls. To check that our sample of brains shared cardinal neuropathological features of schizophrenia with previously reported case studies, we also measured cortical gray matter volumes and cortical thickness in areas 9 and 24. The mean cortical gray matter volume was significantly reduced in brains from schizophrenics compared to controls. Mean cortical thickness was significantly reduced in area 24, but not in area 9, in schizophrenics. There were no differences in mean capillary length densities in either area 9 or 24 between the two groups. Thus, alterations in capillary length density in the prefrontal cortex cannot be considered a general feature of schizophrenia. Compromised brain metabolism and occurrence of oxidative stress in the brain of schizophrenics are likely caused by other mechanisms. [ABSTRACT FROM AUTHOR]

Abstract: Wolfram syndrome (WFS1, OMIM 222300) is a rare genetic disorder associated with multiple organ abnormalities, most prominently optic nerve atrophy and diabetes. Mutations in the WFS1 gene coding for wolframin have been identified. The pathogenesis for optic nerve atrophy remains elusive. We here tested the hypothesis that wolframin is expressed in glial cells of the optic nerve and in retinal ganglion cells in the cynomolgus monkey. Paraffin sections through the retina and optic nerve were examined with immunohistochemistry using affinity-purified antibodies to wolframin. Retinal ganglion cells and optic nerve glial cells were found to be strongly labeled. Dual dysfunction of wolframin in optic nerve glial cells and retinal ganglion cells may explain the progressive optic nerve atrophy in Wolfram syndrome. [Copyright &y& Elsevier]

Abstract: It has been postulated that the prefrontal cortices of schizophrenic patients have significant alterations in their interneuronal (neuropil) space. The present study re-examines this finding based on measurements of mean cell spacing within the cell minicolumn. The population studied consisted of 13 male schizophrenic patients (DSM-IV criteria) and 13 age-matched controls. Photomicrographs of Brodmann''s areas 9, 4 (M1), 3b (S1), and 17 (V1) were analyzed with computerized image analysis to measure parameters of minicolumnar morphometry, i.e., columnarity index (CI), minicolumnar width (CW), dispersion of minicolumnar width (VCW), and mean interneuronal distance (MCS). The results indicate alterations in the mean cell spacing of schizophrenic patients according to both the lamina and cortical area examined. The lack of variation in the columnarity index argues in favor of a defect postdating the formation of the cell minicolumn. [Copyright &y& Elsevier]