No abstract

Selenium, a trace element that is fundamental to human health, is incorporated into some proteins as selenocysteine (Sec), generating a family of selenoproteins. Sec incorporation is mediated by a multiprotein complex that includes Sec insertion sequence-binding protein 2 (SECISBP2; also known as SBP2). Here, we describe subjects with compound heterozygous defects in the SECISBP2 gene. These individuals have reduced synthesis of most of the 25 known human selenoproteins, resulting in a complex phenotype. Azoospermia, with failure of the latter stages of spermatogenesis, was associated with a lack of testis-enriched selenoproteins. An axial muscular dystrophy was also present, with features similar to myopathies caused by mutations in selenoprotein N (SEPN1). Cutaneous deficiencies of antioxidant selenoenzymes, increased cellular ROS, and susceptibility to ultraviolet radiation-induced oxidative damage may mediate the observed photosensitivity. Reduced levels of selenoproteins in peripheral blood cells were associated with impaired T lymphocyte proliferation, abnormal mononuclear cell cytokine secretion, and telomere shortening. Paradoxically, raised ROS in affected subjects was associated with enhanced systemic and cellular insulin sensitivity, similar to findings in mice lacking the antioxidant selenoenzyme glutathione peroxidase 1 (GPx1). Thus, mutation of SECISBP2 is associated with a multisystem disorder with defective biosynthesis of many selenoproteins, highlighting their role in diverse biological processes.

Periventricular leukomalacia (PVL) occurring in premature infants, represents a major precursor for neurological and intellectual impairment, and cerebral palsy in later life. The disorder is characterized by multifocal areas of necrosis found deep in the cortical white matter, which are often symmetrical and occur adjacent to the lateral ventricles. There is no known cure for PVL. Factors predisposing to PVL include birth trauma, asphyxia and respiratory failure, cardiopulmonary defects, premature birth/low birthweight, associated immature cerebrovascular development and lack of appropriate autoregulation of cerebral blood flow in response to hypoxic-ischemic insults. The intrinsic vulnerability of oligodendrocyte precursors is considered as central to the pathogenesis of PVL. These cells are susceptible to a variety of injurious stimuli including free radicals and excitotoxicity induced by hypoxic-ischemic injury (resulting from cerebral hypoperfusion), lack of trophic stimuli, as well as secondary associated events involving microglial and astrocytic activation and the release of pro-inflammatory cytokines TNF-alpha and IL-6. It is yet unclear whether activated astrocytes and microglia act as principal participants in the development of PVL lesions, or whether they are representatives of an incidental pathological response directed towards repair of tissue injury in PVL. Nevertheless, the accumulated evidence points to a pathological contribution of microglia towards damage. The topography of lesions in PVL most likely reflects a combination of the relatively immature cerebrovasculature together with a failure in perfusion and/or hypoxia during the greatest period of vulnerability occurring around mid-to-late gestation. Mechanisms underlying the pathogenesis of PVL have so far been related to prenatal ischemic injury to the brain initiated within the third trimester, which result in global cognitive and developmental delay and motor disturbances. Over the past few years, several epidemiological and experimental studies have implicated intrauterine infection and chorioamnionitis as causative in the pathogenesis of PVL. In particular, recent investigations have shown that inflammatory responses in the fetus and neonate can contribute towards neonatal brain injury and development-related disabilities including cerebral palsy. This review presents current concepts on the pathogenesis of PVL and emphasizes the increasing evidence for an inflammatory pathogenic component to this disorder, either resulting from hypoxic-ischemic injury or from infection. These findings provide the basis for clinical approaches targeted at protecting the premature brain from inflammatory damage, which may prove beneficial for treating PVL, if identified early in pathogenesis.

The relationship between the variance and mean rate of discharges of simple cells in the cat striate cortex has been examined when mean rate was varied by changing either stimulus spatial frequency or contrast. In both cases, the variance was related to the mean discharge rate by an exponent of about 1.15; the relation was thus roughly linear. The discharge variance was on average 1.7 times the mean rate for data obtained from measurements of the neurones' spatial frequency tuning curves, and 1.48 times the mean for data from the response-contrast determination. However, this difference was not statistically significant.

Simple and complex forms of dysembryoplastic neuroepithelial tumors (DNTs) are readily recognizable but forms with diffuse growth pattern, and hybrid tumors, that is, mixed DNT and ganglioglioma (DNT/GG), are more contentious entities. Rare DNTs have shown aggressive behavior. We reviewed cortical growth patterns, immunophenotype (including CD34, nestin and calbindin), genetic profile, and outcome in 101 DNT in adults. Simple (n = 18), complex (n = 31), diffuse (n = 35) DNT, and mixed DNT/GG (n = 17) showed no difference in age of onset, associated seizure type, or outcome (67.5% free from seizure; mean follow-up, 6 years). CD34 was seen in 61%, calbindin in 57%, and nestin in 86% of all DNT types; these markers were less common in simple DNT. Peritumoral cortical changes (Layer I hypercellularity [61%], satellite nodules [51.6%]) were frequent, but dyslamination (cortical dysplasia) was not identified. Molecular genetic abnormalities identified in 17 cases were IDH1 mutation (n = 3), 1p/19q loss (n = 10), isolated loss 9q (n = 2), and PTEN loss (n = 3), which were not associated with tumor type or location, higher cell proliferation, or distinguishing clinical features (mean age of epilepsy onset, 9 years; age at surgery = 31 years; 69% free from seizure); none had progression on magnetic resonance imaging (mean follow-up, 6 years). No single feature was predictive of seizure-free outcome, but there was a trend for better outcome in CD34-positive tumors (p = 0.07). One case has shown transformation to a higher grade. This study supports the existence of a range of subtypes of DNT some with overlapping features with ganglioglioma; molecular genetic abnormalities were not predictive of atypical behavior.

No abstract

We have recently begun to gain a clearer understanding of the phasing and patterns of colonization of the developing human brain by microglia. In this study we investigated the distribution, morphology and phenotype of microglia specifically within the wall of the human telencephalon from 12 to 24 gestational weeks (gw), a period that corresponds to the development of thalamocortical fibres passing through the transient subplate region of the developing cerebral wall. Sections from a total of 45 human fetal brains were immunoreacted to detect CD68 and MHC class II antigens and histochemically reacted with RCA-1 and tomato lectins. These markers were differentially expressed by anatomically discrete populations of microglia in the cerebral wall: two cell populations were noted during the initial phase of colonization (12-14 gw): (i) CD68++ RCA-1+ MHC II- amoeboid cells aligned within the subplate, and (ii) RCA-1++ CD68- MHC II- progenitors in the marginal layer and lower cortical plate that progressively ramified within the subplate, without seemingly passing through an 'amoeboid' state. At this stage microglia were largely absent from the germinal layers and the intermediate zone. From 14 to 15 gw, however, MHC class II positive cells were also detected within germinal layers and in the corpus callosum, and these cells, which coexpressed CD68 antigen (a marker associated with phagocytosis), further populated the lower half of the telencephalon from 18 to 24 gw. These findings are discussed in relation to developmental events that take place during the second trimester within the wall of the telencephalon.

SUMMARY1. The behaviour of neurones in cat striate cortex was examined in response to moving sinusoidal gratings and flashed bright and dark lines. The responses were summarized by three indices: discreteness was a measure of the degree of separation of inhibitory and excitatory regions in the receptive field; spatial summation ratio showed the degree of spatial summation within each region; relative modulation was a measure of the degree of modulation in the response to a moving grating.2. Some neurones had receptive fields with completely discrete excitatory and inhibitory regions; others responded equally to stimulus onset and offset throughout their receptive fields; however, some had overlapping excitatory and inhibitory regions. The degree of overlap varied continuously from complete separation to complete overlap.3. For neurones with discrete receptive fields, the widths of the regions were compared with the width ofthe bars in a grating ofoptimum spatial frequency to assess the degree of spatial summation within the regions. Most neurones with discrete receptive fields showed roughly predictable spatial summation, in that the two width measures agreed; but about 10 % of them had receptive field regions that were too large by a factor of over two.4. The neurones which showed incomplete spatial summation also had considerable overlap of their excitatory and inhibitory regions.5. The waveforms of the responses to moving gratings of optimal spatial frequency were examined. The degree ofmodulation in the response was continuously distributed between low values typical of complex cells and high values typical of simple cells; the distribution was not bimodal. The degree of response modulation was closely correlated with the degree to which the excitatory and inhibitory regions in the receptive field were discrete.6. Both the degree of spatial summation and the degree of response modulation have been previously proposed as means for distinguishing simple and complex cells. In the present study, the continuity of the distributions of both indices ensured that neither index alone could be used to class all neurones unequivocally.7. However, a criterion based on two indices did allow classification. Simple and complex cells showed distinctive behaviour. However, complex cells with distinguishable excitatory and inhibitory regions in their receptive fields were not distinctly different from other complex cells.