Apical hypertrophic cardiomyopathy and hepatitis C virus infection.

The familial form of hypertrophic cardiomyopathy (HCM) is attributed to mutations in the genes for contractile proteins, but the etiology of non-familial form remains unknown. This study was designed to examine the clinical features, histopathologic changes, and hepatitis C virus (HCV) genomes in patients with HCM associated with HCV infection. Anti-HCV antibody was present in the sera of 9 of 65 patients (13.8%) with HCM versus 2.41% in a control population of voluntary blood donors in Japan, a statistically significant difference (p<0.0001). Among these 9 patients, 6 had ace-of-spades-shaped deformities of the left ventricle with apical hypertrophy. Myocardial fibrosis was found in all patients, and mild cellular infiltration was observed in 5 patients. Type 1b HCV RNA was present in the sera of 5 of the 9 patients. The copy number of HCV was 5.5x10(3)-8.6x10(5) genomes/ml serum, and multiple clones of HCV were detected in the sera of each patient by an analysis of the hypervariable regions using fluorescent single-strand conformation polymorphism. Positive strands of HCV were found in the hearts of 5 patients, and negative strands in the hearts of 2 patients. A high prevalence of HCV infection was found in patients with HCM, particularly of the apical variety, suggesting that HCV is an important causal agent in the pathogenesis of the disease.     

Suppressive effects of Perilla frutescens on spontaneous IgA nephropathy in ddY mice.

Perilla frutescens (perilla) is a common herb used in Japan for garnishing raw seafood to protect the alimentary tract from inflammatory diseases. The present study was performed to investigate whether or not perilla prevents the development of lesions of IgA nephropathy in ddY mice which spontaneously develop this disease. After orally administering perilla extract to ddY mice from 8 to 42 weeks of age, the changes in urine, serum, and kidneys were evaluated. Perilla extract significantly suppressed proteinuria and glomerular IgA deposition (p < 0.01 and p < 0.05, respectively). The decreased serum IgA concentration in perilla-treated mice showed a significant correlation with glomerular IgA deposition. Such findings suggest that perilla reduced glomerular IgA deposition via suppression of IgA production in the serum. On the other hand, the nitric oxide concentration in the serum of perilla-treated mice was significantly higher than that observed in the controls. The addition of the sera of perilla-treated mice to quiescent cultured murine mesangial cells resulted in a cell proliferation which was less than in controls, suggesting that perilla might either directly prevent mesangial cell proliferation or prevent proliferation by regulating circulating cytokines. Such results indicate that perilla should prevent IgA nephropathy, thus representing a promising herbal medicine for glomerulonephritis.     

Ultrastructural localization of dominantly increased fibronectin in the markedly thickened glomerular basement membrane in a selectively mated murine high IgA strain (HIGA mice).

To clarify which matrix component(s) contributes to glomerular sclerosis with mesangial IgA deposits in a murine high serum IgA strain (HIGA) derived from ddY mice, morphological and immunopathological analyses of glomeruli were performed in comparison with original ddY and BALB/c mice as controls. Significantly increased thickness of the glomerular basement membrane (GBM), especially the lamina densa, was observed in HIGA mice. Immunofluorescent staining showed marked increases in levels of fibronectin and laminin in both the mesangium and capillary wall in aged HIGA mice. Analysis of the distribution of immunogold-labeled antibody in GBM revealed a significant increase (p < 0.0001) and specific orientation of fibronectin in the endothelial side, which suggested that mesangial fibronectin produced at high levels due to IgA deposition extended to the endothelial side of GBM and contributed to the thickening of GBM with further development to glomerulosclerosis in the HIGA mice.     

Glial fibrillary acidic protein mutations in adult‐onset Alexander disease: clinical features observed in 12 Japanese patients

Yoshida T, Sasayama H, Mizuta I, Okamoto Y, Yoshida M, Riku Y, Hayashi Y, Yonezu T, Takata Y, Ohnari K, Okuda S, Aiba I, Nakagawa M. Glial fibrillary acidic protein mutations in adult‐onset Alexander disease: clinical features observed in 12 Japanese patients.
Acta Neurol Scand: 2011: 124: 104–108.
© 2010 John Wiley & Sons A/S. Objective – To clarify the clinical manifestations of adult‐onset Alexander disease (AOAD) in Japanese patients with glial fibrillary acidic protein (GFAP) gene mutations. Methods and materials – Twelve patients of AOAD with GFAP mutations detected in our centre were examined for neurological and magnetic resonance imaging (MRI) findings. Results – Major symptoms were pyramidal and bulbar signs. In addition, three patients presented abnormal behaviour and/or memory disturbance. Two of the three patients also had Parkinsonism and had been diagnosed with fronto‐temporal dementia or progressive supranuclear palsy until GFAP mutations were detected. Abnormalities of the medulla oblongata and cervical spinal cord were observed on MRI in all patients. Conclusions – Patients presenting with pyramidal and/or bulbar signs with abnormalities of the medulla oblongata and cervical spinal cord on MRI should be considered for GFAP analysis as this is the typical presentation of AOAD. Abnormal behaviour and cognitive disorders including deterioration of memory were rare symptoms but could be an obstacle to diagnosing Alexander disease.     

Neuroanatomical correlates of attention‐deficit–hyperactivity disorder accounting for comorbid oppositional defiant disorder and conduct disorder

Aim: An increasing number of neuroimaging studies have been conducted to uncover the pathophysiology of attention‐deficit–hyperactivity disorder (ADHD). The findings are inconsistent, however, at least partially due to methodological differences. In the present study voxel‐based morphometry (VBM) was used to evaluate brain morphology in ADHD subjects after taking into account the confounding effect of oppositional defiant disorder (ODD) and conduct disorder (CD) comorbidity. Methods: Eighteen children with ADHD and 17 age‐ and gender‐matched typically developing subjects underwent high‐spatial resolution magnetic resonance imaging. The regional gray matter volume differences between the children with ADHD and controls were examined with and without accounting for comorbid ODD and CD in a voxel‐by‐voxel manner throughout the entire brain. Results: The VBM indicated significantly smaller regional gray matter volume in regions including the bilateral temporal polar and occipital cortices and the left amygdala in subjects with ADHD compared with controls. Significantly smaller regional gray matter volumes were demonstrated in more extensive regions including the bilateral temporal polar cortices, bilateral amygdala, right occipital cortex, right superior temporal sulcus, and left middle frontal gyrus after controlling for the confounding effect of comorbid ODD and CD. Conclusion: Morphological abnormalities in ADHD were seen not only in the regions associated with executive functioning but also in the regions associated with social cognition. When the effect of comorbid CD and ODD was taken into account, there were more extensive regions with significantly smaller volume in ADHD compared to controls.     

An Immune-Modulating Diet in Combination with Chemotherapy Prevents Cancer Cachexia by Attenuating Systemic Inflammation in Colon 26 Tumor-Bearing Mice

Cancer cachexia is characterized by muscle wasting caused partly by systemic inflammation. We previously demonstrated an immune-modulating diet (IMD), an enteral diet enriched with immunonutrition and whey-hydrolyzed peptides, to have antiinflammatory effects in some experimental models. Here, we investigated whether the IMD in combination with chemotherapy could prevent cancer cachexia in colon 26 tumor-bearing mice. Forty tumor-bearing mice were randomized into 5 groups: tumor-bearing control (TB), low dose 5-fluorouracil (5-FU) and standard diet (LF/ST), low dose 5-FU and IMD (LF/IMD), high dose 5-FU and standard diet (HF/ST) and high dose 5-FU and IMD (HF/IMD). The ST and IMD mice received a standard diet or the IMD ad libitum for 21 days. Muscle mass in the IMD mice was significantly higher than that in the ST mice. The LF/IMD in addition to the HF/ST and HF/IMD mice preserved their body and carcass weights. Plasma prostaglandin E₂ levels were significantly lower in the IMD mice than in the ST mice. A combined effect was also observed in plasma interleukin-6, glucose, and vascular endothelial growth factor levels. Tumor weight was not affected by different diets. In conclusion, the IMD in combination with chemotherapy prevented cancer cachexia without suppressing chemotherapeutic efficacy.     

MicroRNA-183 upregulates HIF-1α by targeting isocitrate dehydrogenase 2 (IDH2) in glioma cells

MicroRNAs (miRs) are small, non-coding RNAs that regulate gene expression and contribute to cell proliferation, differentiation and metabolism. Our previous study revealed the extensive modulation of a set of miRs in malignant glioma. In that study, miR microarray analysis demonstrated the upregulation of microRNA-183 (miR-183) in glioblastomas. Therefore, we examined the expression levels of miR-183 in various types of gliomas and the association of miR-183 with isocitrate dehydrogenase 2 (IDH2), which has complementary sequences to miR-183 in its 3′-untranslated region (3′UTR). In present study, we used real-time PCR analysis to demonstrate that miR-183 is upregulated in the majority of high-grade gliomas and glioma cell lines compared with peripheral, non-tumorous brain tissue. The mRNA and protein expression levels of IDH2 are downregulated via the overexpression of miR-183 mimic RNA in glioma cells. Additionally, IDH2 mRNA expression is upregulated in glioma cells expressing anti-miR-183. We verified that miR-183 directly affects IDH2 mRNA levels in glioma cells using luciferase assays. In malignant glioma specimens, the expression levels of IDH2 were lower in tumors than in the peripheral, non-tumorous brain tissues. HIF-1α levels were upregulated in glioma cells following transfection with miR-183 mimic RNA or IDH2 siRNA. Moreover, vascular endothelial growth factor and glucose transporter 1, which are downstream molecules of HIF-1α, were upregulated in cells transfected with miR-183 mimic RNA. These results suggest that miR-183 upregulation in malignant gliomas induces HIF-1α expression by targeting IDH2 and may play a role in glioma biology.     

Glutamatergic changes in the cerebral white matter associated with schizophrenic exacerbation

Ota M, Ishikawa M, Sato N, Hori H, Sasayama D, Hattori K, Teraishi T, Nakata Y, Kunugi H. Glutamatergic changes in the cerebral white matter associated with schizophrenic exacerbation. Objective: Glutamatergic dysfunction in the brain has been implicated in the pathophysiology of schizophrenia. This study was aimed to examine several brain chemical mediators, including Glx (glutamate + glutamine), using ¹H magnetic resonance spectroscopy (MRS) in medicated patients with schizophrenia, with and without psychotic exacerbation. Method: ¹H MRS was acquired in 24 patients with schizophrenia, with psychotic exacerbation; 22 patients without exacerbation; and 27 age‐ and sex‐matched healthy volunteers. The levels of metabolites were measured in the left frontal and inferior parietal white matter and compared across the three groups. Results: The Glx level was significantly elevated in the left inferior parietal white matter in the patients with psychotic exacerbation in comparison with that in the healthy volunteers and the patients without exacerbation (P < 0.05). We also detected that there was a significant correlation between Positive and Negative Syndrome Scale‐positive scale and Glx level in the left parietal white matter (r = 0.51, P < 0.001). Conclusion: Higher than normal Glx levels indicate glutamatergic overactivity in the left inferior parietal white matter with schizophrenic exacerbation, a finding that is in accordance with the glutamatergic hypothesis in schizophrenia. The Glx level measured by ¹H MRS could be a biomarker for exacerbation in schizophrenia.     

Association between the functional polymorphism (C3435T) of the gene encoding P-glycoprotein (ABCB1) and major depressive disorder in the Japanese population

Human P-glycoprotein (P-gp), which is encoded by ABCB1 (ATP-binding cassette, sub-family B member 1), is expressed in the blood brain barrier and protects the brain from many kinds of drugs and toxins including glucocorticoids by acting as an efflux pump. We examined whether functional polymorphisms of ABCB1 give susceptibility to major depressive disorder (MDD). The five functional single nucleotide polymorphisms (SNPs), A-41G (rs2188524), T-129C (rs3213619), C1236T (Gly412Gly: rs1128503), G2677A/T (Ala893Ser/Thr: rs2032582), and C3435T (Ile1145Ile: rs1045642) were genotyped in 631 MDD patients and 1100 controls in the Japanese population. A tri-allelic SNP, G2677A/T, was genotyped by pyrosequencing and the remaining SNPs were genotyped by the TaqMan 5′-exonuclease allelic discrimination assay. The minor T3435 allele was significantly increased in MDD patients than in the controls (χ² = 4.5, df = 1, p = 0.034, odds ratio [OR] 1.16, 95% confidential interval [CI] 1.01–1.34). Homozygotes for the T3435 allele was significantly more common in patients than in the controls (χ² = 7.5, df = 1, p = 0.0062, OR 1.43, 95%CI 1.11–1.85). With respect to the other 4 SNPs, there was no significant difference in genotype or allele distribution. In the haplotype-based analysis, the proportion of individuals with the TT1236-TT3435 haploid genotype was significantly increased in patients than in controls (χ² = 8.5, df = 1, p = 0.0037, OR 1.50, 95%CI 1.14–1.98). Our results suggest that the T3435 allele or carrying two copies of this allele confers susceptibility to MDD in the Japanese population.     

Genome-wide meta-analyses of smoking behaviors in African Americans

The identification and exploration of genetic loci that influence smoking behaviors have been conducted primarily in populations of the European ancestry. Here we report results of the first genome-wide association study meta-analysis of smoking behavior in African Americans in the Study of Tobacco in Minority Populations Genetics Consortium (n=32 389). We identified one non-coding single-nucleotide polymorphism (SNP; rs2036527[A]) on chromosome 15q25.1 associated with smoking quantity (cigarettes per day), which exceeded genome-wide significance (β=0.040, s.e.=0.007, P=1.84 × 10⁻⁸). This variant is present in the 5′-distal enhancer region of the CHRNA5 gene and defines the primary index signal reported in studies of the European ancestry. No other SNP reached genome-wide significance for smoking initiation (SI, ever vs never smoking), age of SI, or smoking cessation (SC, former vs current smoking). Informative associations that approached genome-wide significance included three modestly correlated variants, at 15q25.1 within PSMA4, CHRNA5 and CHRNA3 for smoking quantity, which are associated with a second signal previously reported in studies in European ancestry populations, and a signal represented by three SNPs in the SPOCK2 gene on chr10q22.1. The association at 15q25.1 confirms this region as an important susceptibility locus for smoking quantity in men and women of African ancestry. Larger studies will be needed to validate the suggestive loci that did not reach genome-wide significance and further elucidate the contribution of genetic variation to disparities in cigarette consumption, SC and smoking-attributable disease between African Americans and European Americans.