Epstein-Barr virus reactivation-related meningoencephalitis with transverse myelitis in pregnancy.

Key Clinical Message: Consider the differential of Epstein-Barr virus (EBV) reactivation in pregnant women who develop progressive meningoencephalitis and transverse myelitis. EBV nucleic acid amplification should be considered in immunosuppressed patients. Abstract: A 32-year-old G10P6M3K22 pregnant female presented to a regional hospital with progressive severe neurological and behavioral deficits. Magnetic resonance revealed cervical transverse myelitis. Lumbar puncture confirmed Epstein-Barr virus (EBV) DNA on a background of IgG-positive EBV serology. A diagnosis of EBV reactivation-related meningoencephalitis with transverse myelitis in pregnancy was concluded.

A Clinical and Molecular Genetic Study of 50 Families with Autosomal Recessive Parkinsonism Revealed Known and Novel Gene Mutations.

In this study, the role of known Parkinson's disease (PD) genes was examined in families with autosomal recessive (AR) parkinsonism to assist with the differential diagnosis of PD. Some families without mutations in known genes were also subject to whole genome sequencing with the objective to identify novel parkinsonism-related genes. Families were selected from 4000 clinical files of patients with PD or parkinsonism. AR inheritance pattern, consanguinity, and a minimum of two affected individuals per family were used as inclusion criteria. For disease gene/mutation identification, multiplex ligation-dependent probe amplification, quantitative PCR, linkage, and Sanger and whole genome sequencing assays were carried out. A total of 116 patients (50 families) were examined. Fifty-four patients (46.55%; 22 families) were found to carry pathogenic mutations in known genes while a novel gene, not previously associated with parkinsonism, was found mutated in a single family (2 patients). Pathogenic mutations, including missense, nonsense, frameshift, and exon rearrangements, were found in Parkin, PINK1, DJ-1, SYNJ1, and VAC14 genes. In conclusion, variable phenotypic expressivity was seen across all families.

Support for "Disease-Only" Genotypes and Excess of Homozygosity at the CYTH4 Primate-Specific GTTT-Repeat in Schizophrenia.

OBJECTIVE: The role of short tandem repeats (STRs) in the control of gene expression among species is being increasingly understood following the identification of several instances in which certain STRs occur identically, or expand differentially, in primates versus nonprimates. These STRs may regulate genes that participate in characteristics that are associated with the divergence of primates from sibling orders (e.g., brain higher order functions). The CYTH4 gene contains the longest tetranucleotide STR in its core promoter, at 7-repeats, and links to the evolution of human and nonhuman primates. Allele and genotype distribution of this STR were studied in patients affected by schizophrenia (SCZ) and controls. METHODS: High-resolution data were obtained on the allele and genotype distribution of the CYTH4 STR and a novel C > T single-nucleotide polymorphism (SNP) at its immediate upstream sequence in 255 patients with SCZ and 249 controls. Each sample was sequenced twice using the fluorescent dye termination method. RESULTS: Novel alleles were detected at the long extreme of the GTTT-repeat, at 10- and 11-repeats, in the SCZ cases and controls. Excess of homozygosity was observed for the entire range of alleles across the GTTT-repeat and the C > T SNP in the SCZ patients in comparison with the controls (Yates corrected p < 0.011). Three genotypes consisting of the 11-repeat allele (i.e., 11/11, 10/11, and 7/11) were detected only in the SCZ patients (i.e., disease-only genotypes), and contributed to 2.3% of the SCZ genotypes (Mid p exact <0.007). The frequency of the 11-repeat allele was estimated at 0.02 and 0.006 in the SCZ patients and controls, respectively (Mid p exact <0.006). CONCLUSION: This indicates that STR genotypes that are absent in the control group may be risk factors for SCZ. Future studies are warranted to test the significance of our findings.

Association of ß-Secretase Functional Polymorphism with Risk of Schizophrenia.

AIM: The NRG1-ERBB4 neurotransmitter signaling pathway plays a key role in the pathogenesis of schizophrenia (SZ). The intronic single-nucleotide polymorphism rs707284 in ERBB4 links to PI3K-AKT suppression in SZ. Another protein indirectly affecting NRG1-ERBB4 signaling is ß-secretase, which is encoded by the BACE1 gene, and activates NRG1 by proteolytic cleavage. In this study, we aimed to investigate the association of ERBB4 rs707284 and BACE1 rs490460 with the risk of SZ in an Iranian population. SUBJECTS AND METHODS: A total of 973 subjects, including 480 SZ patients and 493 healthy controls, matched by ethnicity, age, and gender, were recruited in a case-control study. Genomic DNA was extracted from peripheral blood of all subjects and genotyping of rs707284 and rs490460 was performed using polymerase chain reaction (PCR)-restriction fragment length polymorphism and tetra-primer amplification refractory mutation system (tetra-ARMS) PCR genotyping assays, respectively. RESULTS: A significant association was observed between the rs490460 T allele and SZ (p = 0.0002, odds ratio 0.69, 95% confidence interval 0.57-0.84). There was no association between the risk of SZ and rs707284. CONCLUSION: Our data indicate that rs490460 is associated with the risk of SZ. In silico analysis indicates that rs490460 may be a potential splicing site, which affects protein structure. Replication studies are needed to confirm our data.

SIPA1L2, MIR4697, GCH1 and VPS13C loci and risk of Parkinson's diseases in Iranian population: A case-control study.

Parkinson's disease (PD) is the second most common neurodegenerative disorder. Prevalence of PD increases steadily with age. A recent meta-analysis of genome-wide association studies has identified six new loci to be linked with PD. Here we investigated the association of four of these new loci, SIPA1L2, MIR4697, GCH1 and VPS13C with PD in an Iranian population. Through a case-control study a total of 1800 subjects comprising 600 PD patients and 1200 unrelated healthy controls were recruited. Rs10797576, rs329648, rs11158026 and rs2414739 related to SIPA1L2, MIR4697, GCH1 and VPS13C loci respectively, were genotyped in all subjects. The difference of genotype and allele frequencies between case and control groups were investigated using chi-square test and logistic regression models with R software. Genotype and allele frequencies were significantly different in PD patients and control group for rs329648, rs11158026 and rs2414739 (p-value=0.018, 0.025, and 0.009 respectively for allele frequency differences). There was no difference in genotype nor allele frequencies between the two groups for rs10797576. We replicated the association of three new loci which are proposed for PD. More studies in other populations and also functional analysis are required to clear the role of these variants in PD.

Genetic Analysis of the ZNF512B, SLC41A1, and ALDH2 Polymorphisms in Parkinson's Disease in the Iranian Population.

AIMS: Parkinson's disease (PD) is one of the most common neurodegenerative disorders; its etiology includes both genetic and environmental factors and their interactions. The ZNF512B, SLC41A1, and ALDH2 genes have recently been identified as contributing to PD. In this study we investigated the association of alleles of these genes with PD in the Iranian population. METHODS: In a case-control study, rs2275294, rs11240569, and rs4767944, three single nucleotide polymorphisms in ZNF512B, SLC41A1, and ALDH2 genes, respectively, were genotyped in 490 PD patients and 490 controls. The genotype and allele frequencies were compared between the two groups using chi-square and logistic regression tests. RESULTS: A significant association between the rs11240569 polymorphism and a reduced risk of PD was found (p = 0.014, OR = 0.76, 95% CI: 0.60-0.94 for allele frequencies). We did not find any associations between PD and the rs2275294 and rs4767944 polymorphisms. CONCLUSION: The association of rs11240569 polymorphism in SLC41A1 gene with reduced risk of PD was replicated in our population.

Evaluation of the Persian version of modified fatigue impact scale in Iranian patients with multiple sclerosis.

BACKGROUND: Fatigue, a major cause of disability in individuals with multiple sclerosis (MS), is associated with reduced quality of life. The aim of this study was to evaluate the reliability and reproducibility of the Persian version of Modified Fatigue Impact Scale (MFIS) in Iranian patients with MS. METHODS: This study included 15 subjects with clinically definite MS, 15 hospitalized patients with MS, and 15 hospitalized patients with other chronic illnesses (as controls). They filled in the Persian version of the MFIS twice with a three-day interval. MFIS items were analyzed and the correlation coefficient was calculated. RESULTS: THERE WAS A GOOD CORRELATION BETWEEN THE SCORES OF THE TWO MEASUREMENTS (CORRELATION COEFFICIENT: 0.984, P < 0.001) especially in physical and cognitive subgroups. The reproducibility of psychosocial subscale was lower than physical and cognitive subscales. CONCLUSION: According to our findings, the Persian version of the MFIS has a good reliability and reproducibility for assessment of fatigue in patients with MS.

Hyperhomocysteinemia, folateo and B12 vitamin in Iranian patients with acute ischemic stroke.

BACKGROUND: The objective of this study was to evaluate the association of some factors such as serum levels of homocysteine, folate and B12 vitamin with stroke in acute ischemic stroke patients. METHODS: In this case control study, serum levels of homocysteine, folate and B12 vitamin in 93 patients with acute ischemic stroke admitted to Imam Khomeini Hospital between September 2008 and January 2010, and 93 healthy controls were measured. Cerebrovascular risk factors including age, sex, hypertension, hyperlipidemia, smoking, diabetes mellitus, alcohol consumption, coronary artery disease and obesity were recorded. The results were compared between the case and control groups. RESULTS: The mean ± standard deviation (SD) of fasting total homocysteine (tHcy) level in acute ischemic stroke patients was 20.58 ± 19.6 µmol/l, which was significantly higher than that of control group being 14.11 ± 9.5 µmol/l (P = 0.002). 39 (41.9%) stroke cases and 25 (26.8%) controls had hyperhomocysteinemia. There were no significant relationships between tHcy, folate and B12 vitamin levels with the above mentioned cerebrovascular risk factors except for smoking (p> 0.05). No significant difference in B12 vitamin and folate levels between patients and healthy controls were detected (P> 0.05). CONCLUSION: Hyperhomocysteinemia is common in Iranian patients with acute ischemic stroke and might play a role as an independent risk factor in stroke.

Expression of cell adhesion molecule CD44 in gastric adenocarcinoma and its prognostic importance.

AIM: To evaluate the relation of cluster of differentiation 44 (CD44) expression with clinicopathological features of gastric adenocarcinoma, and also its effect on prognosis with an emphasis on the differences between intestinal and diffuse types. METHODS: From 2000 to 2006, 100 patients with gastric adenocarcinoma, who had undergone total or subtotal gastrectomy without any prior treatment, were studied. Haematoxylin and eosin (HE) staining was used for histological evaluation, including the type (Lauren's classification) and grading of the tumor. The expression of CD44 in the gastric adenocarcinoma mucosa and the adjacent mucosa were determined by immunohistochemistry. The survival analysis was obtained using the Kaplan-Meier test. RESULTS: Of 100 patients, 74 (74%) patients were male. The tumors were categorized as intestinal type (78%) or diffuse type (22%). Sixty-five percent of patients were CD44-positive. CD44 expression was not detected in normal gastric mucosa. Rather, CD44 was more commonly expressed in the intestinal subtype (P=0.002). A significant relation was seen between the grade of tumor and the expression of CD44 (P=0.014). The survival analysis showed a poor prognosis of patients with CD44-positive tumors (P=0.008); and this was more prominent in the intestinal (P=0.001) rather than diffuse type. CONCLUSION: Cell adhesion molecule CD44 is highly expressed in gastric adenocarcinoma. CD44 expression is correlated with a poor prognosis in patients with the intestinal type of gastric adenocarcinoma. CD44 can, therefore, be utilized as a prognostic marker for this group of patients.

p16 promoter hypermethylation: a useful serum marker for early detection of gastric cancer.

AIM: To determine p16 promoter hypermethylation in gastric tumoral tissue and serum samples, its impact on p16-protein expression, and correlation with clinical and histological features. METHODS: Samples were obtained from 52 histologically confirmed cases of gastric adenocarcinoma. Gastric tissue and serum of 50 age- and sex-matched individuals with normal gastroscopy and biopsy were obtained as control samples. Methylation-specific polymerase chain reaction (MSP) was used to evaluate methylation status of p16 promoter. p16-protein expression was analyzed by immunohistochemical staining on paraffin-embedded sections. RESULTS: Methylation was detected in 44.2% (23/52) of tumoral tissues. 60.9% of them were also methylated in serum, i.e., 26.9% of all patients (14/52). Methylation was not detected in tissue and sera of control samples. p16-protein expression was decreased in 61.5% of cases (32/52), and was significantly associated with promoter hypermethylation (P < 0.001). Methylation was significantly more frequent in higher pathological grades (P < 0.05). Methylation was not associated with other clinicopathological features and environmental factors including H pylori infection and smoking. CONCLUSION: p16 promoter hypermethylation is an important event in gastric carcinogenesis. It is the principle mechanism of p16 gene silencing. It is related to malignant tumor behavior. Detection of DNA methylation in serum may be a biomarker for early detection of gastric cancer.