Clinical course of epilepsy and white matter abnormality linked to a novel DYRK1A variant.

Epilepsy and white matter abnormality have been reported in DYRK1A-related intellectual disability syndrome; however, the clinical course has yet to be elucidated. Here, we report the clinical course of an 18-year-old male with a novel heterozygous DYRK1A variant (NM_001396.4: c.957C>G, p.Tyr319*); based on previous reports, epilepsy with this syndrome tends to be well controlled. Follow-up MRIs of the patient's lesion revealed slightly reduced signal intensity compared to the first image.

Clinical Characteristics of Fragile X Syndrome Patients in Japan.

BACKGROUND: Fragile X syndrome (FXS) is a well-known X-linked disorder clinically characterized by intellectual disability and autistic features. However, diagnosed Japanese FXS cases have been fewer than expected, and clinical features of Japanese FXS patients remain unknown. METHODS: We evaluated the clinical features of Japanese FXS patients using the results of a questionnaire-based survey. RESULTS: We presented the characteristics of seven patients aged 6 to 20 years. Long face and large ears were observed in five of seven patients. Macrocephaly was observed in four of five patients. The meaningful word was first seen at a certain time point between 18 and 72 months (median = 60 months). Developmental quotient or intellectual quotient ranged between 20 and 48 (median = 29). Behavioral disorders were seen in all patients (autistic spectrum disorder in six patients, hyperactivity in five patients). Five patients were diagnosed by polymerase chain reaction analysis, and two patients were diagnosed by the cytogenetic study. All physicians ordered FXS genetic testing for suspicious cases because of clinical manifestations. CONCLUSION: In the present study, a long face, large ears, macrocephaly, autistic spectrum disorder, and hyperactivity were observed in almost cases, and these characteristics might be common features in Japanese FXS patients. Our finding indicated the importance of clinical manifestations to diagnosis FXS. However, the sample size of the present study is small, and these features are also seen to patients with other disorders. We consider that genetic testing for FXS should be performed on a wider range of intellectually disabled cases.

Duchenne muscular dystrophy-like phenotype in an LGMD2I patient with novel FKRP gene variants.

A 32-year-old man initially received a diagnosis of Duchenne muscular dystrophy (DMD). Genetic analysis revealed two novel heterozygous FKRP variants: c.169G>A (p.Glu57Lys) and c.692G>A (p.Trp231*). These results indicated that the patient had limb-girdle muscular dystrophy type 2I (LGMD2I) caused by recessive FKRP variants. Patients with LGMD2I and DMD have many overlapping phenotypes. LGMD2I should be considered in patients who have a DMD phenotype but not a DMD pathogenic variant.

Hepatitis E outbreak at a nursing home for aged people in Hokkaido, Japan, between February and March 2016.

BACKGROUND: Infection with hepatitis E virus (HEV) genotypes 3 and 4 are usually asymptomatic but can occasionally result in life-threatening acute hepatitis. To date, only sporadic cases together with a few outbreaks have been documented. Seroprevalence studies with assays for the detection of HEV IgG antibodies, suggest that HEV is more prevalent than previously thought, even in non-endemic regions. OBJECTIVES: The aim of this study was to characterize an outbreak of hepatitis E (HE) in a nursing home for aged people between February and March 2016. STUDY DESIGN: After the identification of two cases living in the same nursing home, the presence of antibodies against HEV and HEV RNA were examined in serum samples collected from the other residents and staff members to identify any additional cases. An epidemiological investigation was also carried out. RESULTS: Only 4 patients showed mild symptoms such as anorexia, abdominal pain and fatigue. Among the 125 persons tested, 28 residents and one dietitian were confirmed positive for anti-HEV IgA or IgM antibodies, and/or HEV RNA. Eight samples had only IgG antibodies. Finally, 22 cases were notified with HE on the basis of the presence of IgA antibodies. All HEV isolates obtained were 99.8-100% identical and belonged to genotype 3. CONCLUSION: HEV infections seem to be under-reported or underestimated possibly due to cases being generally asymptomatic. Testing for the presence of both anti-HEV antibodies and HEV RNA would be beneficial for both the comprehensive diagnosis of HE infections and the prevention of further infections.

Gene profiles during root canal treatment in experimental rat periapical lesions.

The purpose of this study was to profile gene expression in periapical lesions during root canal treatment (RCT). Periapical lesions were induced experimentally by exposing the pulp in Sprague-Dawley rats. After 3 wk, the animals received root canal filling (RCF) and were sacrificed 1 or 4 wk later. From the periapical tissues, total RNA was extracted and processed for cDNA-microarray analysis. The lesions were histologically and radiographically confirmed to expand 4 wk after pulp exposure (inflammation phase) and to stabilize 4 wk after RCF (healing phase). In approximately 30,000 genes on the microarray, 203 genes were up-regulated to more than 5-fold (e.g., IL-1beta), and 864 genes were down-regulated to less than 20% of baseline level (e.g., caspase 8) in inflammation phase. Compared with inflammation phase, we found that 133 genes were up-regulated (e.g., IL-1alpha) and 50 genes were down-regulated (e.g., defensin alpha5) in healing phase. Corresponding to the gene expression profiles, accumulation of IL-1alpha and IL-1beta was observed in the periapical lesions by immunohistochemistry. These gene profiles might be useful in diagnosing the healing process of periapical lesions.

cAMP-response element binding protein (CREB) regulates cyclosporine-A-mediated down-regulation of cathepsin B and L synthesis.

Cyclosporin A (CsA) is an immunosuppressant with severe side effects including gingival overgrowth. We have previously reported that CsA impairs the activity of the lysosomal enzymes cathepsin B and L in human gingival fibroblasts (HGFs). Here, we have examined the effects of CsA on the DNA-binding activity of the cyclic AMP response element-binding protein (CREB) and cell viability, and the effects of CREB on cathepsin B and L synthesis and activity in HGFs. We have confirmed that CsA down-regulates cathepsin B and L synthesis. Further, CsA has no effect on cell viability and dramatically impairs CREB-DNA binding activity. Importantly, the synthesis of cathepsin B and L is down-regulated, and their activity is also significantly impaired in HGFs transfected with plasmid expressing dominant-negative CREB. These results suggest that CREB is essential for the CsA-mediated down-regulation of cathepsin B and L synthesis in HGFs.

Transcriptional regulation of beta-defensin-2 by lipopolysaccharide in cultured human cervical carcinoma (HeLa) cells.

Human beta-defensin-2 (hBD-2) is an antimicrobial peptide with a broad spectrum of antimicrobial activity against bacteria, yeast and fungi. Here, we analyzed the transcriptional regulation of hBD-2 in cultured human cervical carcinoma (HeLa) cells with or without lipopolysaccharide (LPS). DNA from position -329 to -39 in the hBD-2 promoter region contained the consensus binding sites for transcription factors, one site for nuclear factor for IL-6 expression (NF-IL6) and two sites for nuclear factor-(kappa)B (NF-(kappa)B). Reporter gene assays for promoter activity revealed that the region had the highest level of responsiveness to LPS. Furthermore, mutations in both of the NF-(kappa)B binding sites caused a significant reduction of the responsiveness to LPS, whereas mutation in the NF-IL6 binding site resulted in an elevation of the basal promoter activity. Electrophoretic mobility shift assays demonstrated that LPS induced the binding of HeLa nuclear factors to 60-bp probe containing the two NF-(kappa)B binding sites, suggesting that the sites were essential for the binding. Our results suggest that the two NF-(kappa)B binding sites contribute to LPS-mediated hBD-2 transcription while the NF-IL6 binding site represses LPS-independent hBD-2 transcription in the HeLa cells.

Antibacterial activity of synthetic human B defensin-2 against periodontal bacteria.

The oral epithelium is continuously exposed to a variety of microbial challenges that can cause infectious diseases such as periodontal disease. Human B Defensin-2 (hBD-2) is a cationic antimicrobial peptide with low molecular weight, which is inducible from oral epithelial cells upon either bacterial infection or stimulation with inflammatory cytokines. This peptide has a broad antimicrobial spectrum that includes gram-positive bacteria, gram-negative bacteria, and fungi. Therefore, it is thought that hBD-2 plays an important role as one of natural immunities to bacterial infection. However, its activity is inhibited by body fluids such as serum. The aim of this study was to assess the antibacterial activity of synthetic hBD-2 against oral bacteria in the presence of saliva or serum. The antibacterial activity of synthetic hBD-2 was tested against Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis, Streptococcus mutans, and Escherichia coli. Antibacterial broth assay and diffusion assay were performed in vitro. The antibacterial activity of hBD-2 was approximately equal to that of minocycline at equimolar concentrations. Furthermore, the activity of hBD-2 remained at 60% in the presence of 80% saliva, whereas no activity remained in the presence of 20% serum. Our results suggest the possibility that synthetic hBD-2 could be useful to prevent infection by periodontal bacteria.