Environmental enrichment ameliorated high-fat diet-induced Aβ deposition and memory deficit in APP transgenic mice

The pathogenesis of Alzheimer's disease (AD) is tightly associated with metabolic dysfunctions. In particular, a potential link between type 2 diabetes (T2DM) and AD has been suggested epidemiologically, clinically, and experimentally, and some studies have suggested that exercise or dietary intervention reduces risk of cognitive decline. However, there is little solid molecular evidence for the effective intervention of metabolic dysfunctions for prevention of AD. In the present study, we established the AD model mice with diabetic conditions through high-fat diet (HFD) to examine the effect of environmental enrichment (EE) on HFD-induced AD pathophysiology. Here, we demonstrated that HFD markedly deteriorated memory impairment and increased β-amyloid (Aβ) oligomers as well as Aβ deposition in amyloid precursor protein (APP) transgenic mice, which was reversed by exposure to an enriched environment for 10 weeks, despite the continuation of HFD. These studies provide solid evidence that EE is a useful intervention to ameliorate behavioral changes and AD pathology in HFD-induced aggravation of AD symptoms in APP transgenic mice.     

Computer-Aided Diagnosis for Detection of Lacunar Infarcts on MR Images: ROC Analysis of Radiologists’ Performance

The purpose of this study was to retrospectively evaluate radiologist performance in detection of lacunar infarcts on T1- and T2-weighted images, without and with the use of a computer-aided diagnosis (CAD) scheme. Thirty T1-weighted and 30 T2-weighted MR images obtained from 30 patients were used for assessing observer performance. These images were acquired using the fast spin-echo sequence with a 1.5-T MR imaging scanner. The group included 15 patients (age range, 48-83 years; mean age, 67.2 years; 10 men and five women) with a lacunar infarct and 15 patients (age range, 39-76 years; mean age, 64.0 years; eight men and seven women) without lacunar infarcts. Nine radiologists participated in the study. The radiologists initially interpreted the T1- and T2-weighted images without and then with the use of CAD, which indicated their confidence levels regarding the presence (or absence) of lacunar infarcts and the most likely position of a lesion on each MR scan. The observers' performance without and with the computer output was evaluated by performing receiver operating characteristic analysis. For the nine radiologists, the mean area under the best-fit binormal receiver operating characteristic curve plotted for unit square values of radiologists who interpreted the images without and with the scheme were 0.891 and 0.937, respectively. The performance of the radiologists improved significantly when they used the computer output (p=0.032). The CAD scheme has potential to improve the accuracy of radiologists' performance in detection of lacunar infarcts.     

Rank signaling links the development of invariant γδ T cell progenitors and Aire(+) medullary epithelium

The thymic medulla provides a specialized microenvironment for the negative selection of T cells, with the presence of autoimmune regulator (Aire)-expressing medullary thymic epithelial cells (mTECs) during the embryonic-neonatal period being both necessary and sufficient to establish long-lasting tolerance. Here we showed that emergence of the first cohorts of Aire(+) mTECs at this key developmental stage, prior to αβ T cell repertoire selection, was jointly directed by Rankl(+) lymphoid tissue inducer cells and invariant Vγ5(+) dendritic epidermal T cell (DETC) progenitors that are the first thymocytes to express the products of gene rearrangement. In turn, generation of Aire(+) mTECs then fostered Skint-1-dependent, but Aire-independent, DETC progenitor maturation and the emergence of an invariant DETC repertoire. Hence, our data attributed a functional importance to the temporal development of Vγ5(+) γδ T cells during thymus medulla formation for αβ T cell tolerance induction and demonstrated a Rank-mediated reciprocal link between DETC and Aire(+) mTEC maturation.     

Cyclic compression-induced p38 activation and subsequent MMP13 expression requires Rho/ROCK activity in bovine cartilage explants

Objective

Excessive mechanical stress on the cartilage causes the degradation of the matrix, leading to the osteoarthritis (OA). Matrix metalloproteinases 13 (MMP13) is a major catalytic enzyme in OA and p38 plays an important role in its induction. However, precise pathway inducing p38 activation has not been elucidated. We hypothesized here that the small GTPase Rho and its effector ROCK might function in upper part of the mechanical stress-induced matrix degeneration pathway.

Methods

Bovine metacarpal phalangeal articular cartilage explants were loaded with 1?MPa dynamic compression for 6?h with or without a ROCK specific inhibitor Y27632 or/and a p38 specific inhibitor SB202190. Then p38 phosphorylation and MMP13 expression were assessed by western blot or/and quantitative RT-PCR. Rho-activity was measured by pull-down assay using glutathione S-transferase fusion protein of Rho binding domain.

Results

Cyclic compression caused Rho activation, p38 phosphorylation and MMP13 expression. Both Y27632 and SB202190 were found to block the mechanical stress-enhanced p38 phosphorylation and subsequent MMP13 expression.

Conclusions

The present results show that p38 phosphorylation and MMP13 expression are regulated by Rho/ROCK activation, and support the potential novel pathway that Rho/ROCK is in the upper part of the mechanical stress-induced matrix degeneration cascade in cartilage comprised of p38 and MMP13.     

stx genotype and molecular epidemiological analyses of Shiga toxin-producing Escherichia coli O157:H7/H? in human and cattle isolates

The relationship between human diseases caused by infection with Shiga toxin (Stx)-producing Escherichia coli (STEC) O157 strains and O157 strains isolated from cattle was investigated in an area where stockbreeding is prolific. For this purpose, the stx genotypes, the molecular epidemiological characteristics of 268 STEC O157 strains including 211 human-origin strains and 57 cattle-origin strains, and clinical manifestations of 210 STEC-infected people were analyzed. Of 211 human-origin strains, 92 strains (44%) were of the stx1/stx2 genotype, and 74 strains (35%) were of the stx2c genotype. Most of the people infected with stx2c genotype strains presented no symptoms or mild symptoms such as slight diarrhea, except for 3 patients with bloody diarrhea. Of the 57 cattle-origin strains, 27 strains (47%) were of the stx2c genotype and 17 strains (30%) were of the stx1/stx2 genotype. Pulsed-field gel electrophoresis (PFGE) and insertion sequence (IS) analysis demonstrated that 11 isolates (41%) of the 27 cattle isolates of the stx2c genotype had high homology (>95% identity) with human isolates. These results suggest that some genetic patterns of the stx2c genotype strains might be preserved in cattle or their surrounding environment for several years, and during these periods, they might have opportunities to infect people through various routes. Because of the mild virulence of the stx2c genotype strains, they seemed to be transmitted asymptomatically from cattle to humans and then spread from person to person. It may be a public health concern. Further, they occasionally cause severe symptoms in humans; therefore, caution is warranted for infections by stx2c genotype O157 strains, in addition to stx2-possessing genotype O157 strains.     

Evolution and virulence of Panton-Valentine leukocidin-positive ST30 methicillin-resistant Staphylococcus aureus in the past 30 years in Japan

Methicillin-resistant Staphylococcus aureus (MRSA) includes hospital-acquired MRSA (HAMRSA) and community-acquired MRSA (CA-MRSA). Panton-Valentine leukocidin (PVL)-positive multilocus sequence type 30 (ST30) MRSA is one of worldwide CA-MRSA, which has also persisted in Japan since the 1980s. However, unexpectedly, it was not the same ST30 clone throughout. Before 2000, it was HA-MRSA with spa43 and ψSa3sea (phage Sa3 carrying the sea gene) and only one PVL-positive MRSA in Japan; in the 1980s, ST30 MRSA accounted for 23.5% of HA-MRSA, showed multidrug resistance, had high MICs for oxacillin and imipenem, and caused decubitus and pneumonia in hospitalized patients. A dynamic clonal change (spa43/ψSa3sea→ spa19) occurred around 2000-2002. A rare spa43/ψSa3sea/SCCmecI-IE25923 genotype also emerged. After 2002, the prevalent spa19 clone was CA-MRSA; it accounted for only 0.3% (or less) of MRSA in hospitals but 7.6% of CA-MRSA. Since 2007, PVL-positive CA-MRSA with other ST types (such as ST8, ST22, and ST59) also emerged in Japan, albeit at a low frequency. ST30/spa19 CA-MRSA occasionally caused severe invasive infections and a novel ST1335/spa19 genotype emerged. These ST30/spa19 CA-MRSA and variants were identified by pulsed field gel electrophoresis. Further analysis revealed that PVL-positive ST30/spa19 CA-MRSA is a highlyvirulent, successful clone, having a potential of clonal expansion.     

Variations in the core promoter/pre-core region in HBV genotype C in Japanese and Northern Vietnamese patients

Hepatitis B virus (HBV) subgenotypes Cs (C1) and Ce (C2) are common in East Asia. To investigate the genomic difference of HBV genotype C between two separated regions, 50 subgenotype Cs-infected Vietnamese and 70 subgenotype Ce-infected Japanese patients were enrolled for analysis. The patients were categorized to either a hepatocellular carcinoma group (HCC) or a non-HCC group including liver cirrhosis, chronic hepatitis, and asymptomatic carriers. HBV serology, HBV-DNA level, and variations in core promoter/pre-core region were examined. Phylogenetic analysis based on the full genome sequences and nucleotide sequences partly in the S gene and in the P gene revealed that all Japanese strains (70/70) were subgenotype Ce, and nearly all of the Vietnamese strains (50/51) were subgenotype Cs, excluding one subgenotype C5. C1858 and G1775 were common in the Vietnamese (64% and 40%) but not in the Japanese (0%). The prevalence of C/A1753 in Vietnamese was higher than that in the Japanese (32% vs. 17.1%), however the frequency of A1896 in the Japanese was significantly higher (32.9% vs. 12%, P < 0.05). Most of the Vietnamese patients with HCC had a high level of HBV-DNA, the Japanese HCC had a relatively low level. In the Vietnamese, C/A1753 and C1858 were associated closely with T1762A1764, higher HBV-DNA levels and higher HCC incidence. The multivariate analysis revealed that male, T1653 and C/A1753 were independent risk factors for HCC. The subgenotypes and unique mutations of HBV genotype C in the Vietnamese and Japanese differed, and C/A1753 and C1858 variants might play a role in the pathogenesis of liver disease in Vietnamese patients.     

Clinical features of oral allergy syndrome to plant foods allergens in Kanto regions]

BACKGROUND: Recently, it is recognized that the patients of oral allergy syndrome (OAS) to fruits are increasing. However, there are little knowledges of the background, character, and seriousness about these patients in Kanto regions. OBJECTIVE: We aimed to investigate the clinical features of OAS patients to plant origin foods in Kanto regions. METHODS: The patient, who visited Sagamihara National Hospital from 2000 to 2005 and developed some allergic symptoms to plant origin foods, were studied by a questionary survey. RESULTS: As for the 42 subjects, average age are 36 years old, male:female=8:34, merger of other allergic disease is 35 allergic rhinitis of 42 subjects (83%), 34 of asthma (81%), 14 of atopic dermatitis (33%). The causes of OAS symptoms are 32 rose-family fruits, 34 non-rose family fruits, 14 vegetables, 11 nuts, 2 grains subjects. As for the symptom, only in the oral and pharynx symptoms are found in 12, the systemic symptoms is 29, anaphylaxis is 11 subjects. Allergic rhinitis preceded on the 90% subjects with pollinosis, very high rate. On the other hand, the 20% of all subjects have no symptoms of allergic rhinitis. CONCLUSION: A nasal catarrh symptoms went ahead in most of the OAS subjects in Kanto regions. In addition, considering from some patients have no black alder pollinosis and/or are allergic to many non-rose-family fruits at high frequency, there might be a broad cross-reactivity between many pollens other than alder and plant origin foods.