Bax-inhibiting peptide protects glutamate-induced cerebellar granule cell death by blocking Bax translocation

Glutamate-induced excitotoxicity has been implicated in the pathogenesis of various neurological damages and disorders. In the brain damage of immature animals such as neonatal hypoxic-ischemic brain injury, the excitotoxicity appears to be more intimately involved through apoptosis. Bax, a member of the Bcl-2 family proteins, plays a key role in the promotion of apoptosis by translocation from the cytosol to the mitochondria and the release of apoptogenic factors such as cytochrome c. Recently, Bax-inhibiting peptide (BIP), a novel membrane-permeable peptide which can bind Bax in the cytosol and inhibit its translocation to the mitochondria, was developed. To investigate the possibility of a new neuroprotection strategy targeting Bax translocation in glutamate-induced neuronal cell death, cerebellar granule neurons (CGNs) were exposed to glutamate with or without BIP. Pretreatment of CGNs with BIP elicited a dose-dependent reduction of glutamate-induced neuronal cell death as measured by MTT assay. BIP significantly suppressed both the number of TUNEL-positive cells and the increase in caspases 3 and 9 activities induced by glutamate. In addition, immunoblotting after subcellular fractionation revealed that BIP prevented the glutamate-induced Bax translocation to the mitochondria and the release of cytochrome c from the mitochondria. These results suggest that agents capable of inhibiting Bax activity such as BIP might lead to new drugs for glutamate-related diseases in the future.     

Mobility Patterns in Different Age Groups in Japan during the COVID-19 Pandemic: a Small Area Time Series Analysis through March 2021

In the COVID-19 era, movement restrictions are crucial to slow virus transmission and have been implemented in most parts of the world, including Japan. To find new insights on human mobility and movement restrictions encouraged (but not forced) by the emergency declaration in Japan, we analyzed mobility data at 35 major stations and downtown areas in Japan—each defined as an area overlaid by several 125-meter grids—from September 1, 2019 to March 19, 2021. Data on the total number of unique individuals per hour passing through each area were obtained from Yahoo Japan Corporation (i.e., more than 13,500 data points for each area). We examined the temporal trend in the ratio of the rolling seven-day daily average of the total population to a baseline on January 16, 2020, by ten-year age groups in five time frames. We demonstrated that the degree and trend of mobility decline after the declaration of a state of emergency varies across age groups and even at the subregional level. We demonstrated that monitoring dynamic geographic and temporal mobility information stratified by detailed population characteristics can help guide not only exit strategies from an ongoing emergency declaration, but also initial response strategies before the next possible resurgence. Combining such detailed data with data on vaccination coverage and COVID-19 incidence (including the status of the health care delivery system) can help governments and local authorities develop community-specific mobility restriction policies. This could include strengthening incentives to stay home and raising awareness of cognitive errors that weaken people''s resolve to refrain from nonessential movement.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11524-021-00566-7.     

Stimulation of human mesenchymal stem cells and osteoblasts activities in vitro on silicon-releasable scaffolds

Cellular activities of human osteoblasts (HOBs) and mesenchymal stem cells (MSCs) on a silicon-releasable scaffold, siloxane-doped poly(lactic acid) and vaterite composite coated with hydroxycarbonate apatite (SPV-H), were estimated using a medium with or without organic factors, such as dexamethasone (Dex) and beta-glycerophosphate (beta-GP), for inducing mineralization or differentiation. As a control, a composite film containing no silicon (denoted by PV-H) was prepared using poly(lactic acid) and vaterite. HOBs cultured on SPV-H formed some agglomerates, bone nodules, after a 21-day culture in a medium without the organic factors, whereas no agglomerate was observed on PV-H. Laser Raman spectra implied that calcium phosphate precipitated in HOBs on the SPV-H. The silicon species in SPV-H stimulated HOBs to mineralization. The culture tests using MSCs show that the level of alkaline phosphatase (ALP) activity in the cells cultured on SPV-H increased during the 21-day culture in a medium without Dex and beta-GP. The level was unchanged in MSCs cultured on PV-H. In the case of supplementing Dex and beta-GP to the medium, the level of ALP activity in MSCs cultured on SPV-H was higher than that on PV-H at all time points during the 21-day culture. The silicon species in SPV-H were regarded to induce and enhance the osteogenic differentiation of MSCs.     

Establishment of Experimental Eosinophilic Vasculitis by IgE-Mediated Cutaneous Reverse Passive Arthus Reaction

Prominent eosinophil infiltration is a characteristic of some forms of vasculitis, such as Churg-Strauss syndrome, also known as allergic granulomatous vasculitis. In the current study, we established a mouse model of cutaneous eosinophilic vasculitis by the cutaneous reverse passive Arthus reaction using IgE injection instead of IgG. Wild-type C57BL/6 mice were injected with IgE anti-trinitrophenyl antibodies, followed immediately by intravenous administration of trinitrophenyl bovine serum albumin. IgE-mediated immune complex challenge induced substantial hemorrhage with marked infiltration of eosinophils in which neutrophils, mast cells, and macrophages were also mixed. This finding contrasted remarkably with the neutrophil-dominant infiltration pattern in IgG-mediated immune complex challenge. In the lesion, the expression level of monocyte chemotactic protein-3 was increased, and anti-monocyte chemotactic protein-3 treatment resulted in a significant but incomplete blockade of eosinophil recruitment. Furthermore, mice lacking E-selectin, P-selectin, L-selectin, or intercellular adhesion molecule-1, as well as wild-type mice that received anti-vascular cell adhesion molecule-1-blocking antibodies were assessed for the IgE-mediated Arthus reaction. After 24 hours, the loss of P-selectin resulted in a significant reduction in eosinophil accumulation compared with both wild-type mice and other mouse mutants. Collectively, the Fc class of immunoglobulins, which forms these immune complexes, critically determines the disease manifestation of vasculitis. The IgE-mediated cutaneous reverse passive Arthus reaction may serve as an experimental model for cutaneous eosinophilic infiltration in vasculitis as well as in other diseases.Eosinophilia is associated with a variety of infectious, allergic, and inflammatory diseases, including helminth infection, asthma, allergic rhinitis, atopic skin diseases, and inflammatory bowel disease, as well as idiopathic hypereosinophilic syndrome.^1,2 Eosinophils also play a major role in some forms of vasculitis.^3,4 The most prominent example is Churg-Strauss syndrome (CSS; also known as allergic granulomatous vasculitis), which occurs in patients with a history of asthma and is characterized by a necrotizing vasculitis of small arteries and veins, with extravascular granulomas and a marked eosinophilia in the lesion and in the peripheral blood.^3,5,6,7 Activated eosinophils induce tissue destruction and inflammation, while the mechanism that generates eosinophilic vasculitis remains unclear. Several lines of evidence have suggested a role of IgE in CSS. Serum IgE levels are elevated and often correlate with disease activity in CSS. IgE deposition in affected blood vessels is also observed occasionally.⁸ Therefore, the pathogenesis of CSS may involve IgE through immune complex (IC) deposition containing IgE.IC-mediated tissue injury has been implicated in the pathogenesis of vasculitis syndrome. The classical experimental model for such IC-mediated tissue injury is the Arthus reaction, which induces edema and hemorrhage in the skin.^9,10 Currently, most the frequently used is the reverse passive Arthus reaction, in which IgG antibody (Ab) is injected at the site where the investigator wishes the inflammatory response to develop, followed immediately by an intravenous application of the antigen.^{9,10,11,12,13} IgG-induced IC-mediated vascular tissue damage requires the accumulation of neutrophils and mast cells.^{11,12,14,15,16,17,18} This process is tightly regulated by chemotactic factors and adhesive interactions between leukocytes and the vascular endothelium, including selectins, integrins, and Ig superfamily members, including intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1).^19,20,21 Nonetheless, it remains unknown which molecules are responsible for the development of eosinophilic vasculitis.In this study, an experimental mouse model of cutaneous eosinophilic vasculitis was established using the IgE-mediated cutaneous reverse passive Arthus reaction. This model developed a marked accumulation of eosinophils surrounding the blood vessels, resulting in substantial hemorrhage. Thus, this model demonstrates that the Fc class of Ig that forms IC can critically determine the disease manifestation.     

Mutant γPKC found in spinocerebellar ataxia type 14 induces aggregate-independent maldevelopment of dendrites in primary cultured Purkinje cells

Missense mutations in protein kinase Cγ (γPKC) gene have been found in spinocerebellar ataxia type 14 (SCA14), an autosomal dominant neurodegenerative disease. We previously demonstrated that mutant γPKC found in SCA14 is susceptible to aggregation and induces apoptosis in cultured cell lines. In the present study, we investigated whether mutant γPKC formed aggregates and how mutant γPKC affects the morphology and survival of cerebellar Purkinje cells (PCs), which are degenerated in SCA14 patients. Adenovirus-transfected primary cultured PCs expressing mutant γPKC-GFP also had aggregates and underwent apoptosis. Long-term time-lapse observation revealed that PCs have a potential to eliminate aggregates of mutant γPKC-GFP. Mutant γPKC-GFP disturbed the development of PC dendrites and reduced synapse formation, regardless of the presence or absence of its aggregates. In PCs without aggregates, mutant γPKC-GFP formed soluble oligomers, resulting in reduced mobility and attenuated translocation of mutant γPKC-GFP upon stimulation. These molecular properties of mutant γPKC might affect the dendritic morphology in PCs, and be involved in the pathogenesis of SCA14.     

Selective vulnerability of adult cochlear nucleus neurons to de-afferentation by mechanical compression

It is well established that the cochlear nucleus (CN) of developing species is susceptible to loss of synaptic connections from the auditory periphery. Less information is known about how de-afferentation affects the adult auditory system. We investigated the effects of de-afferentation to the adult CN by mechanical compression. This experimental model is quantifiable and highly reproducible. Five weeks after mechanical compression to the axons of the auditory neurons, the total number of neurons in the CN was evaluated using un-biased stereological methods. A region-specific degeneration of neurons in the dorsal cochlear nucleus (DCN) and posteroventral cochlear nucleus (PVCN) by 50% was found. Degeneration of neurons in the anteroventral cochlear nucleus (AVCN) was not found. An imbalance between excitatory and inhibitory synaptic transmission after de-afferentation may have played a crucial role in the development of neuronal cell demise in the CN. The occurrence of a region-specific loss of adult CN neurons illustrates the importance of evaluating all regions of the CN to investigate the effects of de-afferentation. Thus, this experimental model may be promising to obtain not only the basic knowledge on auditory nerve/CN degeneration but also the information relevant to the application of cochlear or auditory brainstem implants.     

The change in home palliative care

A promotion of home palliative care at our clinic has been built with many factors including a home medical care desired by patient's family, governance of the law, progress of medical measures and an improvement of medical cooperation.     

Effective treatment by both anti-androgen therapy and chemotherapy for a patient with advanced salivary duct carcinoma

Salivary ductcarcinoma (SDC)is a high-grade malignant tumor arising predominantly in the parotid gland. Androgen receptor(AR)expression was mainly restricted to SDC in salivary cancer. We report successful treatment of a patient with advanced SDC using an endocrine chemotherapy. A 76-year-old man was hospitalized with lumbalgia and swelling of left submandibular region. Radiological examination indicated a tumor in left submandibular gland and metastatic tumors in lumbar vertebra, accompanied by swollen lymph nodes of the neck, mediastinum. Needle biopsies of both vertebral tumor and cervical lymph node revealed SDC. Positive nuclear staining was observed against AR in tumor cells of our patient by immunohistochemical analysis. He obtained a partial response after 1 course of treatment with both anti-androgen therapy and palliative chemotherapy using paclitaxel. In contrast to previous reports of poor response to chemotherapy alone and short-term survival of patients with SDC, our patient has demonstrated that chemotherapy combined with anti-androgen therapy may be an effective modality as a therapeutic regimen for SDC.     

A case successfully treated with abdominoperineal resection after preoperative chemoradiation therapy for anal cancer

A 46-year-old female was diagnosed with anal squamous cell carcinoma. Chemoradiation therapy was administered for a first-line therapy. Two courses of enforced 5-FU/MMC combination therapy were administered along with radiotherapy (60 Gy). This chemoradiation therapy had complete response. However, three months after, anal cancer had a local recurrence. Since there was no distant metastasis, abdoninoperineal resection was performed. No complications were observed after the operation. We conclude that abdominoperineal resection may be effective in the treatment of anal cancer in cases which the local recurrence was observed after chemoradiation therapy.