Persistent Synapse Loss Induced by Repetitive LTD in Developing Rat Hippocampal Neurons

Synaptic pruning is a physiological event that eliminates excessive or inappropriate synapses to form proper synaptic connections during development of neurons. Appropriate synaptic pruning is required for normal neural development. However, the mechanism of synaptic pruning is not fully understood. Strength of synaptic activity under competitive circumstances is thought to act as a selective force for synaptic pruning. Long-term depression (LTD) is a synaptic plasticity showing persistent decreased synaptic efficacy, which is accompanied by morphological changes of dendritic spines including transient retraction. Repetitive induction of LTD has been shown to cause persistent loss of synapses in mature neurons. Here, we show that multiple, but not single, induction of LTD caused a persistent reduction in the number of dendritic synapses in cultured rat developing hippocampal neurons. When LTD was induced in 14 days in vitro cultures by application of (RS)-3,5-dihydroxyphenylglycine (DHPG), a group I metabotropic glutamate receptor (mGluR) agonist, and repeated three times with a one day interval, there was a significant decrease in the number of dendritic synapses. This effect continued up to at least two weeks after the triple LTD induction. The persistent reduction in synapse number occurred in the proximal dendrites, but not the distal dendrites, and was prevented by simultaneous application of the group I/II mGluR antagonist (S)-a-methyl-4-carboxyphenylglycine (MCPG). In conclusion, we found that repetitive LTD induction in developing neurons elicits synaptic pruning and contributes to activity-dependent regulation of synapse number in rat hippocampal neurons

DIP/WISH deficiency enhances synaptic function and performance in the Barnes maze

<p>Abstract</p> <p>Background</p> <p>DIP (diaphanous interacting protein)/WISH (WASP interacting SH3 protein) is a protein involved in cytoskeletal signaling which regulates actin cytoskeleton dynamics and/or microtubules mainly through the activity of Rho-related proteins. Although it is well established that: 1) spine-head volumes change dynamically and reflect the strength of the synapse accompanying long-term functional plasticity of glutamatergic synaptic transmission and 2) actin organization is critically involved in spine formation, the involvement of DIP/WISH in these processes is unknown.</p> <p>Results</p> <p>We found that DIP/WISH-deficient hippocampal CA1 neurons exhibit enhanced long-term potentiation via modulation of both pre- and post-synaptic events. Consistent with these electrophysiological findings, DIP/WISH-deficient mice, particularly at a relatively young age, found the escape hole more rapidly in the Barnes maze test.</p> <p>Conclusions</p> <p>We conclude that DIP/WISH deletion improves performance in the Barnes maze test in mice probably through increased hippocampal long-term potentiation.</p

ホスピス トクシマ ニオケル マッキ ガン カンジャ ノ ボウシュヨウセイ シンケイ ショウコウグン ノ ハッショウ ヒンド ト ソノ リンショウテキ イギ

Neurological complications in advanced cancer occur frequently and therefore an adequate neurological assessment must always be part of patient evaluation in hospice palliative care. Paraneoplastic neurological syndromes are rare, probably affecting less than 1 per cent of patients with cancer, even if the most commonly associated neoplasms, such as small-cell lung cancer and ovarian cancer are considered. Neurological complications were studied in 127 inpatients with advanced cancers. Neurological complications were seen in up to 40 per cent of the patients. The most frequent symptom was derilium, followed in order to lethargy, paraplegia, depression, dementia, hemiplegia, restlessness, aphasia, stupor, facial palsy, recurrent laryngeal nerve palsy, convulsion, and myastenia. Those symptoms were seen in patients in hepatic encephalitis（12）, metastatic brain tumor（9）, metastatic spinal cord injury（8）, depression（4）, paraneoplastic syndrome（4）, hypercalcemia（2）, senile dementia（2）, peripheral neuritis（2）, and cerebral infarction（2）. Of the four patients with paraneoplastic syndrome, one patient had both anti-Hu antibody and anti-VGCC antibody and two patients had anti-neuronal nuclear antibodies. These results indicate that paraneoplastic neurological syndromes are associated more than 1 per cent of patients with advanced cancer

Circadian protection against bacterial skin infection by epidermal CXCL14-mediated innate immunity

体内時計は夜間に自然免疫を発動 --皮膚ケモカインによる自然免疫機構--. 京都大学プレスリリース. 2022-06-16.Biological clocks set for skin immunity. 京都大学プレスリリース. 2022-06-21.The epidermis is the outermost layer of the skin and the body’s primary barrier to external pathogens; however, the early epidermal immune response remains to be mechanistically understood. We show that the chemokine CXCL14, produced by epidermal keratinocytes, exhibits robust circadian fluctuations and initiates innate immunity. Clearance of the skin pathogen Staphylococcus aureus in nocturnal mice was associated with CXCL14 expression, which was high during subjective daytime and low at night. In contrast, in marmosets, a diurnal primate, circadian CXCL14 expression was reversed. Rhythmically expressed CXCL14 binds to S. aureus DNA and induces inflammatory cytokine production by activating Toll-like receptor (TLR)9-dependent innate pathways in dendritic cells and macrophages underneath the epidermis. CXCL14 also promoted phagocytosis by macrophages in a TLR9-independent manner. These data indicate that circadian production of the epidermal chemokine CXCL14 rhythmically suppresses skin bacterial proliferation in mammals by activating the innate immune system

A case of acinar cell carcinoma of the pancreas

Background Acinar cell carcinoma (ACC) is a very rare malignancy and represents only 1% to 2% of pancreatic exocrine carcinomas. At the time of diagnosis, 75% of ACC are resectable. Reliable data concerning effective adjuvant chemotherapy has not been established.Case presentation A 30-mm tumor in the pancreatic tail was incidentally discovered by computed tomography in a 71-yearold man. Several swollen lymph nodes were seen around the main tumor. Endoscopic retrograde cholangiopancreatography (ERCP) revealed disruption of the main pancreatic duct. The patient underwent curative resection (R0) with distal pancreatectomy and node dissection. Histopathological examination revealed ACC with lymph node metastases; adjuvant chemotherapy was performed with gemcitabine after surgery. Twelve months later, the patient showed no sign of recurrence.Conclusion The prognosis of ACC is dismal, although compared to ductal adenocarcinoma, the mean survival appears to be longer. Patients with advanced-stage ACC might benefit from gemcitabine-based adjuvant chemotherapy

先天性血友病患者の移行期の実態

【Introduction】Congenital hemophilia is a category of hemorrhagic disease caused by a genetic defect in the production of coagulation factors. It is treated by administering regular coagulation factor injections on an ongoing basis. Hemophilia is a hereditary illness, often causing social and psychological problems as a result of the disease. To analyze the objective effects of hemophilia, we conducted a retrospective analysis in Tokushima University Hospital. 【Result】All ２３ cases were men between the ages of２０and７２. Hemophilia A was present in１７cases, and hemophilia B was present in six. Nineteen out of ２３ cases were severe, and the others were intermediate. Medical assessments were conducted at pediatrics in seven cases and hematology in １６ cases. Adoption of the self-injection technique was not realized in five cases. Seventeen cases were complicated by hemophilic arthropathy, seven with human immunodeficiency virus（HIV）, and １２ with hepatitis C virus. Eight participants were unemployed, and１７were unmarried. 【Discussion】 Many adult hemophilia patients still visit pediatrics in our hospital. Hemophilia in the period of growth between adolescence and young adulthood is often accompanied by life-altering events such as entering higher education, marriage, and work experience. Therefore, collaboration among professionals of multiple occupations, such as doctors, nurses, pharmacists, medical social workers, and clinical psychologists, is essential. Furthermore, there are many cases of HIV and hepatitis C virus infections complicating hemophilia study due to the stigma surrounding HIV-tainted blood. 【Conclusion】It is imperative that we establish a long-term, sustainable, and multi-disciplinary transitional care and medical support system for patients and their families

HIV感染症およびAIDS患者の臨床的特徴

【Introduction】The survival rate in patients with HIV infection and acquired immunodeficiency syndrome （AIDS） has been improved dramatically due to the advances in anti-HIV drug therapy, while aging-associated complications become a critical issue. The incidence of sudden occurrence of AIDS without prior detection of HIV infection, so called “Ikinari AIDS”, still remains high. 【Objective】We retrospectively analyzed the incidence and clinical characteristics of HIV/AIDS patients in both Tokushima University Hospital and Tokushima Prefectural Central Hospital. 【Results】Eighty four patients （74 males and 10 females） with a median age of 39 years old （range 16 - 85） were enrolled. Thirty-four patients （40.5％） were diagnosed with “Ikinari AIDS” from 2001 to 2020. All 4 patients were diagnosed with “Ikinari AIDS” after 2020. AIDS-defining illnesses were diagnosed as follows ; pneumocystis pneumonia in 21 cases, CMV infection in 8 cases and candidiasis in 6 cases. All patients over 60 years old were suffered from AIDS. Other complications included syphilis in 17 cases, hepatitis B infection in 12 and herpes zoster in 7. 【Discussion/Conclusion】In Tokushima, the incidence rate of “Ikinari AIDS” appeared to be higher than that of national average. COVID - 19 pandemic hampered the public health care services of awareness-raising activity for HIV infection and telephone consultations about HIV, which may become more lease asymptomatic HIV patients without diagnosis. For early diagnosis of HIV/AIDS, it is becoming more important to share information to make early screening of HIV infection among medical staffs, such as medical doctors, dentists, nurses, pharmacists and MSWs

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection