The Effect of Melatonin on Behavioral, Molecular, and Histopathological Changes in Cuprizone Model of Demyelination

Multiple sclerosis (MS) is an autoimmune, demyelinating disease of the central nervous system. The protective effects of melatonin (MLT) on various neurodegenerative diseases, including MS, have been suggested. In the present study, we examined the effect of MLT on demyelination, apoptosis, inflammation, and behavioral dysfunctions in the cuprizone toxic model of demyelination. C57BL/6J mice were fed a chaw containing 0.2 % cuprizone for 5 weeks and received two doses of MLT (50 and 100 mg/kg) intraperitoneally for the last 7 days of cuprizone diet. Administration of MLT improved motor behavior deficits induced by cuprizone diet. MLT dose-dependently decreased the mean number of apoptotic cells via decreasing caspase-3 and Bax as well as increasing Bcl-2 levels. In addition, MLT significantly enhanced nuclear factor-κB activation and decreased heme oxygenase-1 level. However, MLT had no effect on interleukin-6 and myelin protein production. Our data revealed that MLT improved neurological deficits and enhanced cell survival but was not able to initiate myelin production in the cuprizone model of demyelination. These findings may be important for the design of potential MLT therapy in demyelinating disorders, such as MS. © 2015, Springer Science+Business Media New York

Serum levels of vitamins A and D, and zinc in children with acute diarrhea: A cross-sectional study

Background: Diarrhea is a leading cause of mortality and morbidity during the early life period especially in developing countries. Micronutrients deficiencies have been proposed either as a risk factor or a consequence of diarrhea. Association studies highlight the relation of vitamins and minerals' deficiencies with acute diarrhea. In this regard we aimed to evaluate the status of vitamins A and D, and zinc serum levels in children with acute diarrhea. Methods: In this cross sectional study performed in a referral teaching hospital, we measured and compared baseline vitamin A, 25-hydroxy vitamin D (25(OH)D), and zinc serum levels in 25 children admitted with acute diarrhea and 25 other children who were admitted for undergoing elective surgeries. Results: 25-(OH)D levels were significantly lower in the diarrhea group (p=0.03). We were unable to demonstrate a significant difference in the levels of vitamin A and zinc between the case and control groups (p= 0.14 and p=0.07, respectively). Conclusion: We observed lower serum 25(OH)D levels in children with acute diarrhea. Whether this finding indicates a premorbid risk factor or simply a consequence of diarrhea needs further studies. Regardless of the cause and effect relationship, supplementation with vitamin D in acute diarrhea remains as a plausible consideration

Endoscopic screening for precancerous lesions of the esophagus in a high risk area in northern Iran

Background: Esophageal squamous cell carcinoma (ESCC) is a major health problem in many developing countries, including Iran. ESCC has a very poor prognosis, largely due to late diagnosis. As a first step in developing an early detection and treatment program, we conducted a population-based endoscopic screening for ESCC and its precursor lesion, esophageal squamous dysplasia (ESD), in asymptomatic adults from Golestan Province, northern Iran (a high-risk area for ESCC) to evaluate the feasibility of such a program and to document the prevalence and risk factor correlates of ESD. Methods: This cross-sectional study was conducted among participants of the Golestan Cohort Study (GCS), a population-based cohort of 50,000 adults in eastern Golestan Province. Randomly selected GCS participants were invited by telephone. Those who accepted were referred to a central endoscopy clinic. Eligible subjects who consented were asked to complete a brief questionnaire. Detailed information about selected risk factors was obtained from the GCS main database. Endoscopic examination with was performed with Lugol's iodine staining; biopsies were taken from unstained lesions as well as the normally stained mucosa of the esophagus, and the biopsies were diagnosed by expert pathologists according to previously described criteria. Results: In total, 1906 GCS subjects were invited, of whom only 302 (15.8%) were successfully enrolled. Esophagitis (29.5%) and ESD (6.0%) were the most common pathological diagnoses. Turkmen ethnicity (adjusted OR = 8.61; 95%CI: 2.48-29.83), being older than the median age (OR = 7.7; 95% CI: 1.99-29.87), and using deep frying cooking methods (OR = 4.65; 95%CI: 1.19-18.22) were the strongest predictors for ESD. There were significant relationships between esophagitis and smoking (p-value<0.001), drinking hot tea (P value = 0.02) and lack of education (P value = 0.004). Conclusion: We observed a low rate of participation in endoscopic screening. The overall prevalence of ESD was 6.0%. Developing non-endoscopic primary screening methods and screening individuals with one or more risk factors may improve these rates

Cerebrospinal fluid lead level in patients with idiopathic seizure

Background: Convulsion is one of the common cause of hospital admission in children. Idiopathic seizure is when no anatomic, electrolytic, metabolic or hemorrhagic causes are found. Recently, lead poisoning, which is considered when serum lead levels are higher than the normal levels (previously 10 µg/dl changed to 5 µg/dl). Even lower levels of lead inflict harmful consequences in central nervous system (CNS) development in pediatric group. Due to air pollution and high lead level in air of Tehran, investigation the probable role of lead in producing or predisposing convulsion in children is very important. To determine the cerebrospinal fluid (CSF) lead level in children with idiopathic convulsion in compare with nonconvulsive ones (control). Methods: A case-control study upon 60 children (30 convulsive and 30 nonconvulsive control) admitted in Rasoul Akram and Ali Asghar University Hospitals, Tehran, from 2012 to 2013 had done. One ml of CSF obtained and lead level determined by atomic absorption test. Results: The mean age between cases and controls was not different (mean= 30.18+27.36 vs 25.46±20.56 months, P= 0.1). The CSF lead level (µg/dl) had not meaningful difference between 2 groups (3.43+3.07 vs 2.78+2.77, P= 0.3), and no related to type of convulsion in cases (P= 0.7), the area under the curve (AUC) was 0.588; 1-0.433, P= 0.2). The CSF lead cutoff was 1.65 µg/dl; sensitivity of 70, specificity of 46, PPV and NPV was 56 and 60 respectively. Conclusion: The toxic blood level for lead is 3.5 µg/dl. The CSF lead level; even in little amount (1.65 µg/dl) is an acceptable sensitivity but lower specificity for differentiation the convulsive from nonconvulsive children. Although the role of genetic and other causes should be considered in idiopathic convulsion, probably, the high level of lead in CSF could predispose those children to convulsion. It can effect CNS development in children even in small amounts. Indeed, long-term effects of lead which continue to adulthood should be considered as well. Hence, it is paramount to rectify the ambient air lead pollution in Tehran. © 2015 Tehran University of Medical Sciences. All rights reserved

Interactions between human immunodeficiency virus (HIV)-1 Vpr expression and innate immunity influence neurovirulence

<p>Abstract</p> <p>Background</p> <p>Viral diversity and abundance are defining properties of human immunodeficiency virus (HIV)-1's biology and pathogenicity. Despite the increasing availability of antiretroviral therapy, HIV-associated dementia (HAD) continues to be a devastating consequence of HIV-1 infection of the brain although the underlying disease mechanisms remain uncertain. Herein, molecular diversity within the HIV-1 non-structural gene, Vpr, was examined in RNA sequences derived from brain and blood of HIV/AIDS patients with or without HIV-associated dementia (HAD) together with the ensuing pathobiological effects.</p> <p>Results</p> <p>Cloned brain- and blood-derived full length <it>vpr </it>alleles revealed that amino acid residue 77 within the brain-derived alleles distinguished HAD (77Q) from non-demented (ND) HIV/AIDS patients (77R) (<it>p </it>< 0.05) although <it>vpr </it>transcripts were more frequently detected in HAD brains (<it>p </it>< 0.05). Full length HIV-1 clones encoding the 77R-ND residue induced higher <it>IFN-α</it>, <it>MX1 </it>and <it>BST-2 </it>transcript levels in human glia relative to the 77Q-HAD encoding virus (<it>p </it>< 0.05) but both viruses exhibited similar levels of gene expression and replication. Myeloid cells transfected with 77Q-(p<it>Vpr77Q-HAD</it>), 77R (p<it>Vpr77R-ND</it>) or Vpr null (p<it>Vpr</it>^<it>(-)</it>)-containing vectors showed that the p<it>Vpr77R-ND </it>vector induced higher levels of immune gene expression (<it>p </it>< 0.05) and increased neurotoxicity (<it>p </it>< 0.05). Vpr peptides (amino acids 70-96) containing the 77Q-HAD or 77R-ND motifs induced similar levels of cytosolic calcium activation when exposed to human neurons. Human glia exposed to the 77R-ND peptide activated higher transcript levels of <it>IFN-α</it>, <it>MX1</it>, <it>PRKRA </it>and <it>BST-2 </it>relative to 77Q-HAD peptide (<it>p </it>< 0.05). The Vpr 77R-ND peptide was also more neurotoxic in a concentration-dependent manner when exposed to human neurons (<it>p </it>< 0.05). Stereotaxic implantation of full length Vpr, 77Q-HAD or 77R-ND peptides into the basal ganglia of mice revealed that full length Vpr and the 77R-ND peptide caused greater neurobehavioral deficits and neuronal injury compared with 77Q-HAD peptide-implanted animals (<it>p </it>< 0.05).</p> <p>Conclusions</p> <p>These observations underscored the potent neuropathogenic properties of Vpr but also indicated viral diversity modulates innate neuroimmunity and neurodegeneration.</p

Proteinase-activated receptor 2 modulates neuroinflammation in experimental autoimmune encephalomyelitis and multiple sclerosis

The proteinase-activated receptors (PARs) are widely recognized for their modulatory properties of inflammation and neurodegeneration. We investigated the role of PAR2 in the pathogenesis of multiple sclerosis (MS) in humans and experimental autoimmune encephalomyelitis (EAE) in mice. PAR2 expression was increased on astrocytes and infiltrating macrophages in human MS and murine EAE central nervous system (CNS) white matter (P < 0.05). Macrophages and astrocytes from PAR2 wild-type (WT) and knockout (KO) mice exhibited differential immune gene expression with PAR2 KO macrophages showing significantly higher interleukin 10 production after lipopolysaccharide stimulation (P < 0.001). PAR2 activation in macrophages resulted in the release of soluble oligodendrocyte cytotoxins (P < 0.01). Myelin oligodendrocyte glycoprotein–induced EAE caused more severe inflammatory gene expression in the CNS of PAR2 WT animals (P < 0.05), together with enhanced T cell proliferation and interferon γ production (P < 0.05), compared with KO littermates. Indeed, PAR2 WT animals showed markedly greater microglial activation and T lymphocyte infiltration accompanied by worsened demyelination and axonal injury in the CNS compared with their PAR2 KO littermates. Enhanced neuropathological changes were associated with a more severe progressive relapsing disease phenotype (P < 0.001) in WT animals. These findings reveal previously unreported pathogenic interactions between CNS PAR2 expression and neuroinflammation with ensuing demyelination and axonal injury