C329X in KRIT1 is a founder mutation among CCM patients in Sardinia

Cerebral cavernous malformations (CCMs) are CNS vascular anomalies associated with seizures, headaches and hemorrhagic strokes and represent 10–20% of cerebral lesions. CCM is present in 0.1–0.5 of the population. This disorder most often occurs sporadically but may also be familial. Familial cases are inherited as a dominant trait with incomplete penetrance and are estimated to account for KRIT1 10–40% of the patients. The identification of the genes involved in such disorders allows to characterize carriers of the mutations without clear symptoms. The first gene involved in CCM1 is KRIT1. In addition to two other genes have been described: MGC4607 (CCM2) and PDCD10 (CCM3). We selected 13 patients belonging to seven Sardinian families on the basis of clinical symptoms and Magnetic Resonance results. In MGC4607 gene an undescribed exon five deletion likely producing a truncated protein was identified in one family. In two patients with clear phenotype and in three asymptomatic relatives a 4 bp deletion in exon 9 of KRIT1 gene, leading to a premature stop codon, was detected. A unique nonsense mutation (C329X) has been found in seven patients and two asymptomatic subjects belonging to four unrelated families. Haplotype analysis revealed a common origin of this mutation. These data suggest a “founder effect” in Sardinia for the C329X mutation, similar to other mutations described in different populations.     

Ceruloplasmin gene‐deficient mice with experimental autoimmune encephalomyelitis show attenuated early disease evolution

We conducted a microarray study to identify genes that are differentially regulated in the spinal cords of mice with the inflammatory disease experimental autoimmune encephalomyelitis (EAE) relative to healthy mice. In total 181 genes with at least a two‐fold increase in expression were identified, and most of these genes were associated with immune function. Unexpectedly, ceruloplasmin (Cp), a ferroxidase that converts toxic ferrous iron to its nontoxic ferric form and also promotes the efflux of iron from astrocytes in the CNS, was shown to be highly upregulated (13.2‐fold increase) in EAE spinal cord. Expression of Cp protein is known to be increased in several neurological conditions, but the role of Cp regulation in CNS autoimmune disease is not known. To investigate this, we induced EAE in Cp gene knockout, heterozygous, and wild‐type mice. Cp knockout mice were found to have slower disease evolution than wild‐type mice (EAE days 13–17; P = 0.05). Interestingly, Cp knockout mice also exhibited a significant increase in the number of astrocytes with reactive morphology in early EAE compared with wild‐type mice at the same stage of disease. CNS iron levels were not increased with EAE in these mice. Based on these observations, we propose that an increase in Cp expression could contribute to tissue damage in early EAE. In addition, endogenous CP either directly or indirectly inhibits astrocyte reactivity during early disease, which could also worsen early disease evolution. © 2014 Wiley Periodicals, Inc.     

Predictors of compulsory admission in schizophrenia-spectrum patients: excitement, insight, emotion perception

Purpose

We explored socio-demographic and clinical variables associated with compulsory admissions (CA) compared with voluntary admissions in schizophrenia-spectrum patients; moreover, we investigated the ability of excitement, emotion perception, and lack of insight to predict CA.

Methods

119 consecutive schizophrenia-spectrum patients admitted to the Servizio Psichiatrico di Diagnosi e Cura (SPDC = PES = psychiatric emergency service) of the Department of Neuroscience and Mental Health-San Giovanni Battista Hospital of Turin in the period between December 2007 and December 2009 were enrolled in the study. A backward stepwise logistic regression was used to test factors contributing to CA.

Results

CA rate in our sample was 28.5%. Previous CAs, drop-out, severity of illness, positive symptoms, excitement, emotion perception, and insight were significantly different in CA patients compared to voluntary ones. After backward selection of variables, three variables predicted CA in our sample: excitement, impaired emotion perception and lesser insight. Finally, the effect of excitement on CA status seemed partially mediated by emotion perception, the prediction model accounting for 53.8% of the variance of CA status. Conversely, insight seemed not to be a mediator of excitement on CA.

Implications

Understanding CA patterns in special populations represents a first step towards improving clinical decision-making and developing appropriate interventions and service-provision.     

Attentional modulation of neuromagnetic evoked responses in early human visual cortex and parietal lobe following a rank-order rule

Top-down voluntary attention modulates the amplitude of magnetic evoked fields in the human visual cortex. Whether such modulation is flexible enough to adapt to the demands of complex tasks in which abstract rules must be applied to select a target in the presence of distracters remains unclear. We recorded brain neuromagnetic activity using whole-head magnetoencephalography in 14 human subjects during a rule-guided target selection task, and applied event-related Synthetic Aperture Magnetometry to image instantaneous changes in neuromagnetic source activity throughout the brain. During the task subjects selected one of two stimuli (the target) and ignored the other (the distracter) based on a color-rank rule (color 1 > color 2 > color 3). Our results revealed that in early visual color-sensitive areas and the parietal cortex visual stimuli evoke activity that scaled following the rank-order rule. This effect was stronger and occurred later in the parietal lobe (~200 ms after target/distracter onset) relative to early visual areas (~180 ms). Moreover, we found that transient changes in the target's motion direction evoked stronger responses relative to similar changes in the distracter at ~180 ms from change onset in contralateral areas hMT+/V5. These results suggest that during target selection and allocation of attention to a stimulus, top-down signals adjust their intensity following complex selection rules according to the organism's priorities, thereby differentially modulating neuromagnetic activity across visual cortical areas.     

Role of EBV in microRNA dysregulation in Burkitt lymphoma

Since its discovery as the first human tumor virus, Epstein-Barr virus (EBV) has been implicated in the development of a wide range of B-cell lymphoproliferative disorders, the first being Burkitt lymphoma. However, the exact mechanism by which EBV promotes oncogenesis is still matter of discussion. A role in EBV-mediated transformation has been proposed for a novel described class of small non-coding RNAs, the microRNAs (miRNAs). EBV encodes viral miRNAs, through which it may interfere with the physiological regulation exterted by cellular miRNAs. In addition, EBV-coded proteins may also disturb the well-orchestrated mechanisms of regulation of cellular function. In this review, we will focus on the role of EBV in malignant transformation of Burkitt lymphoma, with a particular insight in the interplay between the virus and cellular miRNAs.     

Risk of second cancer in nongastric marginal zone B-cell lymphomas of mucosa-associated lymphoid tissue: a population-based study from northern Italy.

PURPOSE: The aim of this study was to define the risk of second cancer in nongastric marginal zone lymphomas of mucosa-associated lymphoid tissue (MALT). EXPERIMENTAL DESIGN: We considered for the analysis 157 patients with a confirmed histology of marginal zone B-cell lymphoma of MALT, presenting with a clinically prevalent extranodal site of disease, except for stomach. All patients came from two hematologic institutions of Northern Italy. We compared the occurrence of second cancer with respect to the general population by calculating the standardized incidence ratio, with the age- and sex-specific incidence rates of a cancer registry of Northern Italy (Lombardia) as a reference. RESULTS: A history of solid neoplasia was present in 29 (18%) patients for a total number of 30 neoplasms: 25 solid tumors, 2 hematologic diseases (1 Hodgkin's lymphoma and 1 essential thrombocythemia), and 3 nonmelanoma in situ skin cancers. In 4 patients, the site of cancer and lymphoma was the same. In 21 cases the solid tumor preceded the MALToma, in 3 the neoplasm was concomitant, whereas in 6 it was subsequent. For the entire group, the standardized incidence ratio of an additional malignancy was 0.8 [95% confidence interval (95% CI), 0.55-1.17; P = 0.2]. After excluding nonmelanoma skin cancer, the standardized incidence ratio of a second tumor was 0.75 (95% CI, 0.5-1.12; P = 0.2). After excluding all previous malignancies, the standardized incidence ratio of a second cancer was 1.32 (95% CI, 0.69-2.55; P = 0.4). The comparison of risks between males and females was not significant in each group analysis. CONCLUSIONS: Patients with nongastric MALT lymphomas are not at increased risk for other neoplasms compared with the general population of the same geographic area.     

Glycosaminoglycans as a defense mechanism of the urothelium, in children

The quantity variations of glycosaminoglycans (GAGS) in urothelial samples from patients with malformations presenting infectious, obstructive or lithiasis signs have been investigated. They showed a highly significant deficiency in GAGS in patients with recurrent infections of the urinary ways, a more limited deficiency in sufferers from lithiasis and values within the normal range in patients with obstructive malformations.     

Vanadyl as a catalyst of human lipoprotein oxidation

Lipoprotein oxidation, which is relevant to atherogenesis, can be induced by redox-active transition metals, such as copper. Vanadium is a metal usually used as vanadyl to improve metabolic control in diabetic patients; given its redox-active properties, we have investigated possible oxidative effects of the metal on lipoproteins from healthy and diabetic subjects. Beginning from 10 microM, vanadyl, but not vanadate, induced oxidation of the non-HDL fraction, which was inhibited by EDTA, butylated hydroxytoluene and Vitamins E and C, but not by mannitol, SOD and catalase. Differently from copper, vanadyl could oxidize directly lipoprotein lipids, although it showed a lower oxidant activity against critical tryptophan residues of the lipoprotein protein moiety. Moreover, the non-HDL fraction of diabetic patients was more susceptible to vanadyl-dependent oxidation than that of controls. Thus, vanadium, in its reduced form which may be used in humans, can oxidize the non-HDL fraction through oxidative effects exerted especially on lipoprotein lipids; the specific pro-oxidant activity of vanadyl is more evident with lipoproteins of diabetic patients. Given also the tissue accumulating capacity of vanadium conceivably in a reduced form, its prolonged administration to humans, especially to diabetic patients without adequate antioxidant supplementation, needs caution.     

Systemic and intestinal antibody secreting cell responses and protection in gnotobiotic pigs immunized orally with attenuated Wa human rotavirus and Wa 2/6-rotavirus-like-particles associated with immunostimulating complexes

The undesirable side effects and variable efficacy of some oral live rotavirus vaccines in infants have necessitated alternative vaccine approaches. We evaluated a recombinant RFVP2/WaVP6 rotavirus-like-particle (2/6VLP) oral vaccine, using an immunostimulating complex (ISCOM) matrix as adjuvant, in a gnotobiotic (Gn) pig model of human rotavirus (HRV) disease. The 2/6VLPs adhered to the ISCOM-matrix (2/6VLP-ISCOM ) and were antigenic, but they failed to induce protection. However, when combined with attenuated (Att) HRV for oral priming, the 2/6VLP-ISCOM vaccine was effective as a booster and induced partial protection against virulent Wa HRV. The 250 microg 2/6VLP dose was more effective than 100 microg. The highest mean numbers of IgA antibody secreting cells evaluated by ELISPOT in intestinal lymphoid tissues were in pigs receiving AttHRV+2/6VLP-ISCOM or three doses of AttHRV and were associated with the highest protection rates.