Long-term potentiation in the nucleus accumbens requires both NR2A- and NR2B-containing N-methyl-D-aspartate receptors

N-methyl-d-aspartate (NMDA) receptors play crucial roles in several forms of long-term changes in the efficacy of glutamatergic synaptic transmission. The suggestion that the NR2A subunit of the NMDA receptor may be selectively involved in the induction of long-term potentiation (LTP) in the hippocampus and cortex has been challenged. However, the contribution of NR2B in the induction of LTP is not always clearly established. The present study investigates the role of NR2A and NR2B in the induction of LTP in the nucleus accumbens (NAc), a brain region that expresses high levels of NR2B and an NMDA-dependent form of LTP. We recorded extracellular field excitatory postsynaptic potentials/population spikes in slices of mouse NAc. High-frequency stimulation of glutamatergic fibers consistently induced LTP of the field excitatory postsynaptic potential/population spike in the NAc. LTP was abolished in the presence of selective antagonists of either NR2B [R-(R*,S*)-alpha-(4-hydroxyphenyl)-beta-methyl-4-(phenyl-methyl)-1-piperidine propanol and Ifenprodil] or NR2A ([(R)-[(S)-1-(4-bromo-phenyl)-ethylamino]-(2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl)-methyl]-phosphonic acid) subunits. Recordings performed in a low concentration of Mg(2+) ions in the perfusion solution did not reveal a selective involvement of a particular NMDA receptor subunit because either NR2A or NR2B antagonists were able to block LTP. LTP was also abolished in the presence of a low concentration of the non-subunit-selective NMDA receptor antagonist dl-2-amino-5-phosphonopentanoic acid in normal Mg(2+) and low Mg(2+) in the perfusion solution. These results show that the degree of NMDA receptor activation, and not their subunit composition, determines whether LTP is induced in the NAc.     

Hutchinson-Gilford progeria mutant lamin A primarily targets human vascular cells as detected by an anti-Lamin A G608G antibody

Hutchinson-Gilford progeria syndrome (HGPS; Online Mendelian Inheritance in Man accession no. 176670) is a rare disorder that is characterized by segmental premature aging and death between 7 and 20 years of age from severe premature atherosclerosis. Mutations in the LMNA gene are responsible for this syndrome. Approximately 80% of HGPS cases are caused by a G608 (GGC-->GGT) mutation within exon 11 of LMNA, which elicits a deletion of 50 aa near the C terminus of prelamin A. In this article, we present evidence that the mutant lamin A (progerin) accumulates in the nucleus in a cellular age-dependent manner. In human HGPS fibroblast cultures, we observed, concomitantly to nuclear progerin accumulation, severe nuclear envelope deformations and invaginations preventable by farnesyltransferase inhibition. Nuclear alterations affect cell-cycle progression and cell migration and elicit premature senescence. Strikingly, skin biopsy sections from a subject with HGPS showed that the truncated lamin A accumulates primarily in the nuclei of vascular cells. This finding suggests that accumulation of progerin is directly involved in vascular disease in progeria.     

IL-1ß reactivity and the development of severe fatigue after military deployment: a longitudinal study

ABSTRACT: BACKGROUND: It has been suggested that pro-inflammatory cytokine signaling to the brain may contribute to severe fatigue. We propose that not only the level of circulating cytokines, but also increased reactivity of target cells to cytokines contributes to the effect of cytokines on behavior. Based on this concept, we assessed the reactivity of peripheral blood cells to IL-1beta in vitro as a novel approach to investigate whether severe fatigue is associated with increased pro-inflammatory signaling. METHODS: We included 504 soldiers before deployment to a combat-zone. We examined fatigue severity and the response to in vitro stimulation with IL-1beta prior to deployment (T0), and 1 (T1) and 6 months (T2) after deployment. IL-8 production was used as read-out. As a control we determined LPS-induced IL-8 production. The presence of severe fatigue was assessed with the Checklist Individual Strength (CIS-20R). Differences in dose--response and the longitudinal course of IL-1beta and LPS-induced IL-8 production and fatigue severity were investigated using repeated measures ANOVA. RESULTS: At T2, the group who had developed severe fatigue (n = 65) had significantly higher IL-1beta-induced IL-8 production than the non-fatigued group (n = 439). This group difference was not present at T0, but developed over time. Longitudinal analysis revealed that in the non-fatigued group, IL-1beta-induced IL-8 production decreased over time, while IL-1beta-induced IL-8 production in the fatigued group had not decreased. To determine whether the observed group difference was specific for IL-1beta reactivity, we also analyzed longitudinal LPS-induced IL-8 production. We did not observe a group difference in LPS-induced IL-8 production. CONCLUSIONS: Collectively, our findings indicate that severe fatigue is associated with a higher reactivity to IL-1beta. We propose that assessment of the reactivity of the immune system to IL-1beta may represent a promising novel method to investigate the association between behavioral abnormalities and pro-inflammatory cytokine signaling.     

Hepatitis C virus genotypes in the Middle East and North Africa: Distribution,diversity, and patterns

Our objective was to characterize the distribution, diversity and patterns of hepatitis C virus (HCV) genotypes in the Middle East and North Africa (MENA). Source of data was a database of HCV genotype studies in MENA populated using a series of systematic literature searches. Pooled mean proportions were estimated for each genotype and by country using DerSimonian‐Laird random‐effects meta‐analyses. Genotype diversity within countries was assessed using Shannon Diversity Index. Number of chronic infections by genotype and country was calculated using the pooled proportions and country‐specific numbers of chronic infection. Analyses were conducted on 338 genotype studies including 82 257 genotyped individuals. Genotype 1 was dominant (≥50%) in Algeria, Iran, Morocco, Oman, Tunisia, and UAE, and was overall ubiquitous across the region. Genotype 2 was common (10‐50%) in Algeria, Bahrain, Libya, and Morocco. Genotype 3 was dominant in Afghanistan and Pakistan. Genotype 4 was dominant in Egypt, Iraq, Jordan, Palestine, Qatar, Saudi Arabia, and Syria. Genotypes 5, 6, and 7 had limited or no presence across countries. Genotype diversity varied immensely throughout MENA. Weighted by population size, MENA's chronic infections were highest among genotype 3, followed by genotype 4, genotype 1, genotype 2, genotype 5, and genotype 6. Despite ubiquitous presence of genotype 1, the vast majority of chronic infections were of genotypes 3 or 4, because of the sizable epidemics in Pakistan and Egypt. Three sub‐regional patterns were identified: genotype 3 pattern centered in Pakistan, genotype 4 pattern centered in Egypt, and genotype 1 pattern ubiquitous in most MENA countries.     

Efficacy of fish liver oil and propolis as neuroprotective agents in pilocarpine epileptic rats treated with valproate

Objective: To evaluate the action of fish liver oil and propolis in pilocarpine epileptic rats treated with the anticonvulsant drug valproate. Methods: Seven groups of rats were treated daily for six months: control; fish liver oil (0.4 ml/kg b.w); propolis (50 mg/kg b.w); pilocarpine-treated rats (epileptic control); epileptic rats treated with valproate (400 mg/kg b.w); groups 6 and 7, epileptic rats treated with valproate plus fish liver oil or propolis. Results: Pilocarpine administration caused a significant increase in hippocampal dopamine and serotonin levels accompanied with a significant decrease in their levels in serum. Lipid peroxidation level and LDH activity in hippocampus were significantly increased after pilocarpine treatment whereas Na⁺/K⁺-ATPase activity and total antioxidant capacity were significantly decreased compared to the controls. Animals treated with the combined treatments showed a significant improvement in tested parameters towards the normal values of the control. Conclusion: Fish liver oil and propolis when given in combination with valproate, neuroprotected against the neurophysiological disorders induced by pilocarpine epilepsy in rats.     

The clinical and genetic landscape of developmental and epileptic encephalopathies in Egyptian children

Developmental and epileptic encephalopathies (DEEs) are a heterogeneous group of epilepsies characterized by early-onset, refractory seizures associated with developmental regression or impairment, with a heterogeneous genetic landscape including genes implicated in various pathways and mechanisms. We retrospectively studied the clinical and genetic data of patients with genetic DEE who presented at two tertiary centers in Egypt over a 10-year period. Exome sequencing was used for genetic testing. We report 74 patients from 63 unrelated Egyptian families, with a high rate of consanguinity (58%). The most common seizure type was generalized tonic–clonic (58%) and multiple seizure types were common (55%). The most common epilepsy syndrome was early infantile DEE (50%). All patients showed variable degrees of developmental impairment. Microcephaly, hypotonia, ophthalmological involvement and neuroimaging abnormalities were common. Eighteen novel variants were identified and the phenotypes of five DEE genes were expanded with novel phenotype–genotype associations. Obtaining a genetic diagnosis had implications on epilepsy management in 17 patients with variants in 12 genes. In this study, we expand the phenotype and genotype spectrum of DEE in a large single ethnic cohort of patients. Reaching a genetic diagnosis guided precision management of epilepsy in a significant proportion of patients.     

Mental health service use among migrant and Swedish-born children and youth: a register-based cohort study of 472,129 individuals in Stockholm

Social Psychiatry and Psychiatric Epidemiology - Migrant children underutilize mental health services (MHS), but differences according to age, reason for migration, type of problem, and time have...     

Small bowel carcinoid tumor causing intestinal ischemia: A case report with review of the literature

Background: Intestinal carcinoid tumors are well-differentiated neuroendocrine tumors that are capable of secreting bioactive hormones and/or amines; These tumors are uncommon but are the most common primary tumors of the small intestine. Case presentation: We report the case of an 80-year-old woman who presented with a long history (about 14 years ago) of atypical digestive symptoms such as vague abdominal pain, alternating diarrhea, and constipation, treated as functional colopathy without improvement, until the day when she presented with worsening pain that prompted her consultation. CT scan revealed typical manifestations of a carcinoid tumor associated with signs of subacute small bowel ischemia. Despite the surgery being considered a gold standard treatment, it was rejected due to the extent of tumor mesenteric involvement, therefore, the patient received only somatostatin treatment. Conclusion: Small bowel carcinoid tumors are rare, with typical imaging features based on cross-sectional imaging (CE CT/MRI). Intestinal ischemia is a well-known complication that can be a factor in mortality.