Search

Background and purpose Motor recovery after stroke can be characterized into two different patterns. A majority of patients recover about 70% of initial impairment, whereas some patients with severe initial deficits show little or no improvement. Here, we investigated whether recovery from visuospatial neglect and aphasia is also separated into two different groups and whether similar proportions of recovery can be expected for the two cognitive functions. Methods We assessed 35 patients with neglect and 14 patients with aphasia at 3 weeks and 3 months after stroke using standardized tests. Recovery patterns were classified with hierarchical clustering and the proportion of recovery was estimated from initial impairment using a linear regression analysis. Results Patients were reliably clustered into two different groups. For patients in the first cluster ( n = 40), recovery followed a linear model where improvement was proportional to initial impairment and achieved 71% of maximal possible recovery for both cognitive deficits. Patients in the second cluster ( n = 9) exhibited poor recovery (<25% of initial impairment). Conclusions Our findings indicate that improvement from neglect or aphasia after stroke shows the same dichotomy and proportionality as observed in motor recovery. This is suggestive of common underlying principles of plasticity, which apply to motor and cognitive functions. [ABSTRACT FROM AUTHOR]

We review several aspects of Huntington's disease (HD), with a special focus on the psychopathological manifestations often identified in patients with this disorder. We discuss the evidence for a higher-than-average prevalence of psychosis, depression, and obsessive-compulsive disorder (OCD) in individuals with HD or at risk for the illness and analyze the possible significance of these findings. Particular emphasis is placed on OCD, in view of the neuroanatomical impairment that this condition shares with HD, the symptomatic similarities between these disorders, and recent findings of an excess of OCD in HD-affected families. We hypothesize that precise characterization of the psychiatric status of some HD patients showing psychopathological manifestations and their families might help to distinguish different clinical subtypes of the disorder. This approach could hold promise in improving the management of HD in the future. [ABSTRACT FROM AUTHOR]

Background: Stem cells or immune cells targeting the central nervous system (CNS) bear significant promises for patients affected by CNS disorders. Brain or spinal cord delivery of therapeutic cells is limited by the blood-brain barrier (BBB) which remains one of the recognized rate-limiting steps. Osmotic BBB disruption (BBBD) has been shown to improve small molecule chemotherapy for brain tumors, but successful delivery of cells in conjunction with BBBD has never been reported.We have used a clinically relevant model (pig) of BBBD to attempt brain delivery of TALL-104, a human leukemic T cell line. TALL-104 cells are potent tumor killers and have demonstrated potential for systemic tumor therapy. The pig model used is analogous to the clinical BBBD procedure. Cells were injected in the carotid artery after labeling with the MRI T1 contrast agent GdHPDO3A. Contrast CT scans were used to quantify BBBD and MRI was used to detect Gd++-loaded cells in the brain. Transcranial Doppler was used to monitor cerebral blood flow. EEG recordings were used to detect seizures. Immunocytochemical detection (Cresyl Violet, anti-human CD8 for TALL-104, Evans Blue for BBB damage, GFAP and NEUN) was performed.Results: At the concentration used TALL-104 cells were tolerated. Incomplete BBBD did not allow cell entry into the brain. MRI scans at 24 and 48 hours post-injection allowed visualization of topographically segregated cells in the hemisphere that underwent successful BBBD. Perivascular location of TALL-104 was confirmed in the BBBD hemisphere by Cresyl violet and CD8 immunocytochemistry. No significant alteration in CBF or EEG activity was recorded during cell injections.Conclusions: Our data show that targeted CNS cell therapy requires blood-brain barrier disruption. MRI-detectable cytotoxic anti-neoplastic cells can be forced to transverse the BBB and accumulate in the perivascular space. The virtual absence of toxicity, the high anti-tumor activity of TALL-104, and the clinical feasibility of human osmotic BBBD suggest that this approach may be adopted to treat brain or spinal cord tumors. In addition, BBBD may favor CNS entry of other cells that normally lack CNS tropism. [ABSTRACT FROM AUTHOR]

Abstract: Malformations of cortical development (MCD) are one of the most common causes of neurological disabilities including autism and epilepsy. To disrupt cortical formation, methylazoxymethanol (MAM) or thalidomide (THAL) has been used to affect neurogenesis or vasculogenesis. Although previous models of MCD have been useful, these models primarily attack a single aspect of cortical development. We hypothesized that simultaneous prenatal exposure to MAM or THAL will lead to the development of a novel and specific type of brain maldevelopment. Rats were prenatally exposed to MAM and THAL. At early postnatal days, brains displayed abnormal ventricular size and hemispheric asymmetry due to altered brain water homeostasis. The postnatal brain was also characterized by gliosis in regions of focal leakage of the blood brain barrier. These morphological abnormalities gradually disappeared at adult stages. Although the adult MAM-THAL rats showed normal cortical morphology, abnormal hippocampal connectivity and mossy fiber sprouting persisted well into adulthood. [Copyright &y& Elsevier]

Abstract: Systemic application of the muscarinic agonist, pilocarpine, is commonly utilized to induce an acute status epilepticus that evolves into a chronic epileptic condition characterized by spontaneous seizures. Recent findings suggest that the status epilepticus induced by pilocarpine may be triggered by changes in the blood–brain barrier (BBB) permeability. We tested the role of the BBB in an acute pilocarpine model by using the in vitro model brain preparation and compared our finding with in vivo data. Arterial perfusion of the in vitro isolated guinea-pig brain with <1 mM pilocarpine did not cause epileptiform activity, but rather reduced synaptic transmission and induced steady fast (20–25 Hz) oscillatory activity in limbic cortices. These effects were reversibly blocked by co-perfusion of the muscarinic antagonist atropine sulfate (5 μM). Brain pilocarpine measurements in vivo and in vitro suggested modest BBB penetration. Pilocarpine induced epileptiform discharges only when perfused with compounds that enhance BBB permeability, such as bradykinin (n=2) or histamine (n=10). This pro-epileptic effect was abolished when the BBB-impermeable muscarinic antagonist atropine methyl bromide (5 μM) was co-perfused with histamine and pilocarpine. In the absence of BBB permeability enhancing drugs, pilocarpine induced epileptiform activity only after arterial perfusion at concentrations >10 mM. Ictal discharges correlated with a high intracerebral pilocarpine concentration measured by high pressure liquid chromatography. We propose that acute epileptiform discharges induced by pilocarpine treatment in the in vitro isolated brain preparation are mediated by a dose-dependent, atropine-sensitive muscarinic effect promoted by an increase in BBB permeability. Pilocarpine accumulation secondary to BBB permeability changes may contribute to in vivo ictogenesis in the pilocarpine epilepsy model. [Copyright &y& Elsevier]

Objective While status epilepticus ( SE) persisting after two antiseizure agents is called refractory ( RSE), super-refractory status epilepticus ( SRSE) defines SE continuing after general anaesthesia. Its prevalence and related clinical profiles have received limited attention, and most studies were restricted to intensive care facilities. We therefore aimed at describing RSE and SRSE frequencies and identifying associated clinical variables. Methods Between 2006 and 2015, consecutive adult SE episodes were prospectively recorded in a registry. Occurrence of RSE and SRSE and their relationship to clinical variables of interest, including outcome, were analysed. Results Of 804 SE episodes, 268 (33.3%) were RSE and 33 (4%) SRSE. Coma induction for SE treatment occurred in 79 (9.8%) episodes. Severe consciousness impairment ( OR 1.67; 95% CI 1.24-2.46; P = 0.001), increasing age ( OR 1.01, 95% CI 1.01-1.02), and lack of remote symptomatic SE aetiology ( OR 0.48; 95% CI 0.32-0.72) were independently associated with RSE, while severe consciousness impairment ( OR 4.26; 95% CI 1.44-12.60) and younger age ( OR 0.96; 95% CI 0.95-0.99) correlated with SRSE; however, most SRSE episodes were not predicted by these variables. Mortality was 15.5% overall, higher in RSE (24.5%) and SRSE (37.9%) than in non-refractory SE (9.8%) ( P < 0.001). Significance Super-refractory status epilepticus appears clearly less prevalent in this cohort than previously reported, probably as it is not restricted to intensive care unit. SRSE emerges in younger patients with marked consciousness impairment, pointing to the underlying severe clinical background, but these variables do not predict most SRSE developments. There is currently a knowledge gap for prediction of SRSE occurrence that needs to be filled. [ABSTRACT FROM AUTHOR]

Introduction: Neuro-vascular rearrangement occurs in brain disorders, including epilepsy. Platelet-derived growth factor receptor beta (PDGFRβ) is used as a marker of perivascular pericytes. Whether PDGFRβ + cell reorganization occurs in regions of neuro-vascular dysplasia associated with seizures is unknown. Methods : We used brain specimens derived from epileptic subjects affected by intractable seizures associated with focal cortical dysplasia (FCD) or temporal lobe epilepsy with hippocampal sclerosis (TLE-HS). Tissues from cryptogenic epilepsy, non-sclerotic hippocampi or peritumoral were used for comparison. An in vivo rat model of neuro-vascular dysplasia was obtained by pre-natal exposure to methyl-axozy methanoic acid (MAM). Status epilepticus (SE) was induced in adult MAM rats by intraperitoneal pilocarpine. MAM tissues were also used to establish organotypic hippocampal cultures (OHC) to further assess pericytes positioning at the dysplastic microvasculature. PDGFRβ and its colocalization with RECA-1 or CD34 were used to segregate perivascular pericytes. PDGFRβ and NG2 or IBA1 colocalization were performed. Rat cortices and hippocampi were used for PDGFRβ western blot analysis. Results: Human FCD displayed the highest perivascular PDGFRβ immunoreactivity, indicating pericytes, and presence of ramified PDGFRβ + cells in the parenchyma and proximal to microvessels. Tissues deriving from human cryptogenic epilepsy displayed a similar pattern of immunoreactivity, although to a lesser extent compared to FCD. In TLE-HS, CD34 vascular proliferation was paralleled by increased perivascular PDGFRβ + pericytes, as compared to non-HS. Parenchymal PDGFRβ immunoreactivity co-localized with NG2 but was distinct from IBA1 + microglia. In MAM rats, we found pericyte-vascular changes in regions characterized by neuronal heterotopias. PDGFRβ immunoreactivity was differentially distributed in the heterotopic and adjacent normal CA1 region. The use of MAM OHC revealed microvascular-pericyte dysplasia at the capillary tree lining the dentate gyrus (DG) molecular layer as compared to control OHC. Severe SE induced PDGFRβ + immunoreactivity mostly in the CA1 region of MAM rats. Conclusion: Our descriptive study points to microvascular-pericyte changes in the epileptic pathology. The possible link between PDGFRβ + cells, neuro-vascular dysplasia and remodeling during seizures is discussed. [ABSTRACT FROM AUTHOR]

P450 metabolic enzymes are expressed in the human and rodent brain. Recent data support their involvement in the pathophysiology of epilepsy. However, the determinants of metabolic enzyme expression in the epileptic brain are unclear. We tested the hypothesis that status epilepticus (SE) or exposure to phenytoin or phenobarbital affects brain expression of the metabolic enzyme CYP2E1. SE was induced in C57BL/6J mice by systemic kainic acid. Brain CYP2E1 expression was evaluated 18–24 h after severe SE by immunohistochemistry. Co-localization with neuronal nuclei (NEUN), glial fibrillary acidic protein (GFAP) and CD31 was determined by confocal microscopy. The effect of phenytoin, carbamazepine and phenobarbital on CYP2E1 expression was evaluated in vivo or by using organotypic hippocampal cultures in vitro . CYP2E1 expression was investigated in brain resections from a cohort of drug-resistant epileptic brain resections and human endothelial cultures (EPI-EC). Immunohistochemistry showed an increase of CYP2E1 expression limited to hippocampal CA2/3 and hilar neurons after severe SE in mice. CYP2E1 expression was also observed at the astrocyte-vascular interface. Analysis of human brain specimens revealed CYP2E1 expression in neurons and vascular endothelial cells (EC). CYP2E1 was expressed in cultured human EC and over-expressed by EPI-EC. When analyzing the effect of drug exposure on CYP2E1 expression we found that, in vivo or in vitro , ethanol increased CYP2E1 levels in the brain and liver. Treatment with phenytoin induced localized CYP2E1 expression in the brain whereas no significant effects were exerted by carbamazepine or phenobarbital. Our data indicate that the effect of acute SE on brain CYP2E1 expression is localized and cell specific. Exposure to selected anti-epileptic drugs could play a role in determining CYP2E1 brain expression. Additional investigation is required to fully reproduce the culprits of P450 enzyme expression as observed in the human epileptic brain. [ABSTRACT FROM AUTHOR]

Objective To present the results of the first 2 years of a human papillomavirus ( HPV) test-based screening programme outside the research context. Design Population-based cohort study. Setting A cervical service screening programme in Italy. Population Women aged 25-64 years invited to screening from April 2009 to April 2011. Methods Eligible women were invited to undergo an HPV test: those with a negative HPV test went on to the next screening episode; those with a positive HPV went on to triage with a Pap smear. Women with positive cytology (i.e. positive for atypical squamous cells of undetermined significance or worse, ASC- US+) were referred to colposcopy, whereas those with negative cytology were referred to repeat HPV testing 1 year later. Main outcome measures Participation rate, positivity at HPV and at triage, referral rate to colposcopy, positive predictive value for cervical intraepithelial neoplasia grade 2+ ( CIN2+) at colposcopy, and detection rate for CIN2+. Results Participation increased compared with the previous Pap programme (60.6 versus 43.9%). The HPV positivity rate was 7.0; 39.6% of Pap smears were scored as positive, and therefore 2.8% of the women screened were referred for immediate colposcopy. The compliance of women who scored positive for HPV and negative for Pap for repeat HPV testing at 12 months was 78.6%, and the HPV positivity rate was 56.6%. The overall referral rate to colposcopy was 4.6%. The overall detection rate for CIN2+ was 4.5 versus 1.5% of the Pap programme (25-34 years, 8.2%; 35+ years, 3.6%). Conclusions Compared with the traditional Pap test, the HPV programme recorded a higher response to invitation and an increased DR for CIN2+. The most critical aspects were the reading of cytology in women that were positive for HPV and the increased workload at colposcopy. [ABSTRACT FROM AUTHOR]

Abstract: Malformations of cortical development (MCD) result from abnormal neuronal positioning during corticogenesis. MCD are believed to be the morphological and perhaps physiological bases of several neurological diseases, spanning from mental retardation to autism and epilepsy. In view of the fact that during development, an appropriate blood supply is necessary to drive organogenesis in other organs, we hypothesized that vasculogenesis plays an important role in brain development and that E15 exposure in rats to the angiogenesis inhibitor thalidomide would cause postnatal MCD. Our results demonstrate that thalidomide inhibits angiogenesis in vitro at concentrations that result in significant morphological alterations in cortical and hippocampal regions of rats prenatally exposed to this vasculotoxin. Abnormal neuronal development was associated with vascular malformations and a leaky blood–brain barrier. Protein extravasation and uptake of fluorescent albumin by neurons, but not glia, was commonly associated with abnormal cortical development. Neuronal hyperexcitability was also a hallmark of these abnormal cortical regions. Our results suggest that prenatal vasculogenesis is required to support normal neuronal migration and maturation. Altering this process leads to failure of normal cerebrovascular development and may have a profound implication for CNS maturation. [Copyright &y& Elsevier]

Ni-based superalloys can withstand a temperature of around 1400 K, while the gas turbine can endure a temperature of around 1800 K thanks to thermal barrier coatings such as Yttria stabilized zirconia (YSZ). The present work attempts to introduce a method for modifying commercial Inconel 625 metal powder to enhance the properties of the additively manufactured component for high temperature applications. Inconel 625 was modified by decorating the particles with submicron Yttria-stabilized zirconia (YSZ) particles in order to develop a metal matrix composite material. The goal of this modification was: 1) to enhance the mechanical properties of the Inconel 625 parts after laser powder bed fusion (LPBF) additive manufacturing; 2) to modify the microstructure of the LPBF parts. The influence of LPBF process parameters on surface integrity, microstructure, porosity, and microhardness of the fabricated samples was analyzed for both Inconel 625 and YSZ decorated Inconel samples. Wide ranges of laser power (50–150 W), and volumetric input energy densities (30–270 J/mm3) were examined to fabricate the parts. A Microhardness increase of 30% was observed in laser-fused composite samples after decorating the initial Inconel 625 powder particles with 1 wt% of YSZ. In addition, the microstructural analysis revealed that the addition of YSZ submicron particles stimulates heterogenous nucleation and results in microstructure refinement during LPBF of Inconel 625. [ABSTRACT FROM AUTHOR]

• In-depth understanding of the mechanical behavior of concrete. • Proposal of a procedure that combines 3D image techniques with FE modelling. • Exact geometric reconstruction of concrete at meso-level via the use of X-ray CT. • Adoption of an upgraded elasto-plastic damage model for the cement paste. • Sound prediction of damage triggering and evolution under generic stress states. The increasing attention to numerical issues related to material modeling is still a strong incentive to develop sound mechanical models that can explain material behavior up to failure. A procedure to handle a robust geometric meso-scale reconstruction of concrete materials is here proposed, based on X-ray Computed Tomography (CT-scan or X-ray CT). This study applies X-ray CT on ordinary concrete made with limestone aggregates. In this case the technique allows to acquire the overall inner geometry and distribution of the aggregates and also voids, thanks to the difference in material density of the components. Solid models have been generated with such technique and discretized in space to be numerically studied via the Finite Element (FE) method. The numerical results are compared with uniaxial compression tests on the same scanned specimens. For the numerical analyses a specific non-associated elasto-plastic constitutive behavior, coupled with damage, is developed for the cement matrix, whereas the coarse aggregates are treated as elastic. The mechanical characteristics of the components are gathered through a specific experimental campaign. The study confirms that a predictive simulation of damage triggering and evolution in concrete under generic 3D stress states requires the characterization of the continuum at a meso-scale level. Comparisons between numerical and experimental results proves the soundness of the proposed constitutive description to evaluate the brittle behaviour of cementitious materials and to satisfactorily simulate damage triggering under generic 3D stress states. [ABSTRACT FROM AUTHOR]