Immunoelectron microscopic and biochemical studies of caspase-cleaved tau in a mouse model of tauopathy

Neurofibrillary tangles (NFTs) have been implicated in mediating neuronal death and disease progression in human tauopathies; however, mounting in vivo data suggest that NFTs may not be the primary initiators of neurotoxicity. Caspase activity has been implicated in processes associated with the development of tauopathy, but the position that caspase activation holds in neurodegenerative cascades remains uncertain. Using multiphoton real-time imaging microscopy, de Calignon et al recently demonstrated that caspase activation precedes and leads to tangle formation within 24 hours in the rTg4510 mouse model of tauopathy. Here, we used immunoelectron microscopy to determine whether caspase-cleaved tau was present in NFTs of rTg4510 mice. Using a caspase-cleaved tau-specific antibody (TauC3), we found very little immunogold labeling in NFTs in the brains of rTg4510 mice. By immunohistochemistry, the number of TauC3-positive neurons was far less than the numbers of neurons stained with the MC1 antibody, which recognizes abnormal conformations of tau. Biochemically, caspase-cleaved tau was barely detectable in fractions of rTg4510 mouse brain extracts. Our data suggest that caspase activation might be one of multiple routes through which NFT formation occurs, rather than an obligatory initiation step in pathologic tau production in rTg4510 mice.     

Balloon occlusion retrograde transvenous obliteration for inferior mesenteric vein-systemic shunt

Two cases of portosystemic encephalopathy caused by an inferior mesenteric vein (IMV)-internal iliac vein shunt and an IMV-renal vein shunt are presented. IMV and systemic varicosity consisted of a first functional segment, a stagnant segment, and a second functional segment. Both patients underwent balloon occlusion retrograde transvenous obliteration (BRTO), using a microcatheter, to occlude the stagnant segment selectively. Although transient portal vein thrombosis was observed in case 1 and aggravation of esophageal varices was observed in case 2, these complications were tolerable. Following BRTO, the portosystemic encephalopathy in both cases resolved, and serum ammonia levels, although elevated, remained within the normal range.     

Idiopathic myointimal hyperplasia of mesenteric veins: Rare case of ischemic colitis mimicking inflammatory bowel disease

Idiopathic myointimal hyperplasia of mesenteric veins (IMHMV) is a rare and poorly understood ischemic colitis that occurs in the rectosigmoid colon of predominantly young, previously healthy, male patients. A 76‐year‐old Japanese man presented to our hospital with a 1‐year history of worsening diarrhea, lower abdominal pain, and weight loss (−6 kg). Laboratory evaluation revealed white blood cell count of 13 200/μL, C‐reactive protein level of 2.0 mg/dL (normal range, 0.0–0.3), and negative results for stool culture (including Clostridium difficile). Colonoscopy showed circumferential and edematous narrowing of the sigmoid colon with deep longitude ulceration. Biopsy was done and examination of the specimen demonstrated no specific ischemia. The patient was treated with bowel rest, antibiotics, and i.v. fluids; however, his symptoms worsened. Finally, sigmoidectomy was carried out. Histological examination demonstrated significant myointimal hyperplasia of mesenteric veins leading to thickening and stenosis of the venous lumen. Therefore, the final diagnosis was IMHMV. Three months following sigmoidectomy, he was asymptomatic.     

Epidemiological trends of imported infectious diseases in Japan: Analysis of imported 2-year infectious disease registry data

IntroductionThe epidemiology of infectious diseases in Japan remains undefined despite the increasing tourism. GeoSentinel, an epidemiological surveillance system for reporting imported infectious diseases, has only two participating facilities in Japan. Although the number of infectious diseases is reported by the National Institute of Infectious Diseases, there is no detailed clinical information about these cases. Therefore, we established J-RIDA (Japan Registry for Infectious Diseases from Abroad) to clarify the status of imported infectious diseases in Japan and provide detailed information.MethodsJ-RIDA was started as a registry of imported infectious diseases. Case registration began in October 2017. Between October 2017 and September 2019, 15 medical institutions participated in this clinical study. The registry collected information about the patient's age, sex, nationality, chief complaint, consultation date, date of onset, whether visit was made to a travel clinic before travel, blood test results (if samples were collected), travel history, and final diagnosis.ResultsOf the 3046 cases included in this study, 46.7% to Southeast Asia, 13.0% to Africa, 13.7% to East Asia, 11.5% to South Asia, 7.5% to Europe, 3.8% to Central and South America, 4.6% to North America, 3.9% to Oceania, and 2.8% to Central and west Asia. More than 85% of chief complaints were fever and general symptoms, gastrointestinal symptoms, respiratory symptoms, or dermatologic problems. The most common diseases were travelers’ diarrhea, animal bite, upper respiratory infection, influenza, and dengue fever.ConclusionsWe summarized two-year cases registered in Japan's imported infectious disease registry. These results will significantly contribute to the epidemiology in Japan.     

The three-dimensional motions of glenohumeral joint under semi-loaded condition during arm abduction using vertically open MRI

BACKGROUND: Magnetic resonance imaging is an accurate non-invasive tool for visualizing muscles, tendons, and bones. It also provides 3D coordinate values. The purpose of the present study was to visualize and quantify the 3D positions of the glenohumeral joint during isometric abduction of the arm using vertically open magnetic resonance imaging. METHODS: We examined 14 shoulders of seven healthy volunteers. Magnetic resonance images were obtained in a seated position and in seven static positions of the arm from 0 degrees to maximum abduction using vertically open magnetic resonance imaging. 3D surface models were created and 3D movements of each bone in the glenohumeral joint were calculated using a computer algorithm. We analyzed the translation and contact pattern of the glenohumeral joint. FINDINGS: In supero-inferior direction, the humeral head translated slight inferiorly from +1.9 (SD 1.0) mm at 0 degrees to +0.8 (SD 1.8) mm at the maximum abduction. In antero-posterior direction, the humeral head translated anteriorly from 0 degrees to 90 degrees (mean +2.4, SD 2.6 mm) and posteriorly from 90 degrees to 150 degrees of abduction (mean -1.4, SD 2.7 mm). Furthermore, the humeral head had a unique contact patterns with the glenoid; the contact part of the humeral head with the glenoid changed from the central part to the posterior in the midrange of abduction. INTERPRETATION: The humeral head showed a small translation in the antero-posterior direction between 90 degrees and 150 degrees of abduction. In addition, the posterior part of the humeral head contacted the glenoid in this range of abduction. These findings of motion patterns in asymptomatic subjects will be necessary when comparing the kinematics with pathologic condition such as the glenohumeral instability and rotator cuff tear.     

Prostaglandin E(2) receptor EP(4)-selective agonist (ONO-4819) increases bone formation by modulating mesenchymal cell differentiation

Prostaglandin E₂ (PGE₂) positively regulates bone resorption and formation mainly mediated through the EP₄ receptor, a subtype of PGE₂ receptors. ONO-4819, an EP₄ receptor-selective agonist, has been shown to increase bone volume, density, and strength; however, the mechanism of these effects has yet to be fully elucidated. To explore this matter, ONO-4819 (10 μg/kg) was injected into intact rats twice a day for 5 weeks, and their bones were then analyzed by morphological techniques. The effects of ONO-4819 on the differentiation of bone cells were also examined in vitro. Bone morphometric analysis showed that osteoblast number, bone volume, mineral apposition rate, and bone formation rate were significantly increased by ONO-4819, whereas osteoclast number was not affected. Immunohistochemical examination demonstrated that ONO-4819 increased the number of Runx2- and Osterix-positive osteoblasts in rats. In vitro studies using the multipotent mesenchymal cell line C3H10T1/2 showed that ONO-4819 induced alkaline phosphatase (ALPase) activity and up-regulated the mRNA expression of ALPase and Osterix. In contrast, ONO-4819 reduced the mRNA expression of peroxisome proliferator-activated receptor γ (PPARγ) and inhibited adipocyte differentiation of C3H10T1/2 cells, which findings are consistent with the observation that the age-dependent increase in adipocyte number in the bone marrow was significantly suppressed in the ONO-4819-treated animals. ONO-4819 also dose-dependently increased osteoclast-like cell formation in vitro, but the required concentrations were much higher than those to induce osteoblast differentiation. These results collectively suggest that ONO-4819 increased bone formation by stimulating osteoblast differentiation and function, possibly through modulating mesenchymal cell differentiation in the bone.