Fyn phosphorylates AMPK to inhibit AMPK activity and AMP-dependent activation of autophagy

We previously demonstrated that proto-oncogene Fyn decreased energy expenditure and increased metabolic phenotypes. Also Fyn decreased autophagy-mediated muscle mass by directly inhibiting LKB1 and stimulating STAT3 activities, respectively. AMPK, a downstream target of LKB1, was recently identified as a key molecule controlling autophagy. Here we identified that Fyn phosphorylates the α subunit of AMPK on Y436 and inhibits AMPK enzymatic activity without altering the assembly state of the AMPK heterotrimeric complex. As pro-inflammatory mediators are reported modulators of the autophagy processes, treatment with the pro-inflammatory cytokine TNFα resulted in 1) increased Fyn activity 2) stimulated Fyn-dependent AMPKα tyrosine phosphorylation and 3) decreased AICAR-dependent AMPK activation. Importantly, TNFα induced inhibition of autophagy was not observed when AMPKα was mutated on Y436. 4) These data demonstrate that Fyn plays an important role in relaying the effects of TNFα on autophagy and apoptosis via phosphorylation and inhibition of AMPK

Contribution of Thyrotropin-Releasing Hormone to Cerebellar Long-Term Depression and Motor Learning

Thyrotropin-releasing hormone (TRH) regulates various physiological activities through activation of receptors expressed in a broad range of cells in the central nervous system. The cerebellum expresses TRH receptors in granule cells and molecular layer interneurons. However, the function of TRH in the cerebellum remains to be clarified. Here, using TRH knockout (KO) mice we studied the role of TRH in the cerebellum. Immunohistochemistry showed no gross morphological differences between KO mice and wild-type (WT) littermates in the cerebellum. In the rotarod test, the initial performance of KO mice was comparable to that of WT littermates, but the learning speed of KO mice was significantly lower than that of WT littermates, suggesting impaired motor learning. The motor learning deficit in KO mice was rescued by intraperitoneal injection of TRH. Electrophysiology revealed absence of long-term depression (LTD) at parallel fiber-Purkinje cell synapses in KO mice, which was rescued by bath-application of TRH. TRH was shown to increase cyclic guanosine monophosphate (cGMP) content in the cerebellum. Since nitric oxide (NO) stimulates cGMP synthesis in the cerebellum, we examined whether NO-cGMP pathway was involved in TRH-mediated LTD rescue in KO mice. Pharmacological blockade of NO synthase and subsequent cGMP production prevented TRH-induced LTD expression in KO mice, whereas increase in cGMP signal in Purkinje cells by 8-bromoguanosine cyclic 3’,5’-monophosphate, a membrane-permeable cGMP analog, restored LTD without TRH application. These results suggest that TRH is involved in cerebellar LTD presumably by upregulating the basal cGMP level in Purkinje cells, and, consequently, in motor learning

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

Dapagliflozin rescues endoplasmic reticulum stress-mediated cell death

The new type 2 diabetes drug, dapagliflozin, reduces blood glucose levels and body weight by inhibiting sodium glucose transporter 2 (SGLT2) in proximal tubular cells. SGLT2 inhibitors might modulate glucose influx into renal tubular cells, thereby regulating the metabolic conditions that cause endoplasmic reticulum (ER) stress in the cells. In this study, we examined the effect of dapagliflozin on ER stress in the HK-2 proximal tubular cell line and in the kidney of db/db mice to characterise its function in diabetic nephropathy (DN). We found that dapagliflozin regulated ER stress-mediated apoptosis in vitro and in vivo. Only the elf2α-ATF4-CHOP pathway was regulated under these conditions. Notably, the drug rescued C2 ceramide-induced ER stress-mediated apoptosis and ER stress-mediated apoptosis, which might occur in DN, in db/db mice. Our study shows a novel role for dapagliflozin as an inhibitor of ER stress and suggests that dapagliflozin might be useful for the prevention of DN

A comparison of intubation efficacy between Airway Scope and McGrath MAC video laryngoscopes by medical trainees: A randomized crossover manikin study

Background: It is important especially for medical novices to select an appropriate laryngoscope by which tracheal intubation is performed efficiently and easily. Video laryngoscopes are divided into two types based on the presence or absence of a channel for inserting a tracheal tube into the blade. The Airway Scope (AWS) with a channel and the McGrath MAC (MG) without a channel were compared. Methods: This study was designed as an open randomized crossover manikin trial. Participants were 40 medical trainees. The intubation success rate, the intubation time, number of tooth injuries, and percent of glottic opening (POGO) of the initial intubation maneuver were measured. Results: Regarding the primary outcome, the success rate (actual figure [proportion] {95% confidence interval}) was comparable between the AWS and the MG (34 [85%] {73.8-96.2} and 32 [80%] {76.4-92.6}). The intubation time (median [interquartile range, IQR]) was also comparable between the AWS and the MG (33.3 [22.2-50.6] s and 33.7 [20.3-85.4] s). The same was true for the following: the frequency of dental trauma (median [IQR]), was comparable between the AWS and the MG (0 [0-0.15] and 0 [0-0.25]); POGO (median [IQR]), was comparable between the AWS and the MG (80 [60-92.5] % and 80 [60-90] %). All measures were not significantly different. The frequency dental trauma was clearly lower in these video laryngoscopes. Conclusions: The success rate of intubation, intubation time, POGO, and frequency of dental trauma were comparable between the AWS and the MG by medical trainees. No significant differences were found. The AWS and the MG have roughly equivalent intubation performance for medical trainees.departmental bulletin pape

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"日本では古くからいちしくは薬の木と言われ,昔はどの家の庭先にも1～2本植えられ,非京に身近かな果物であったが,現在では各家庭の庭先から姿がみられなくなった ここ愛知県の三河地方は米の転換作物としていちじくの栽培に積極的に取り組み,日本一の生産地となっている いちじくの果実は生食するのが一般的であるが,果実の保存ができないので,安城市では加工品として新たにいちじくワインやジャムを開発し,特産品として精力的に販売を進めている そこで,いちじくワインの食味特性と嗜好特性を知るため,従来あるぶどうワインと比較しつつ,老若男女をパネルとして官能検査を行った その結果,いちじくワインの特性が明らかになり,改良点,普及対象,飲み方について新たな知見が得られたので報告する

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"愛知県安城農協ではいちじく果実の加工品として,前報で述べたワインの他にシャムも製造し,特産品として販売している.西欧では種々の果実をジャムにして食しているが,日本では,いちご,りんご,夏みかんのジャムが主である 近年,食の洋風化に伴いアンズ,ブルーベリーなども加わり,シャムの種類も多くなった.いちじくはペクチン音量が多くジャムに適した果物といえるが,安城で試みられたのが始めてである.そこで日常よく食しているいちごジャムと比較しつつ,いちじくジャムの食味特性と嗜好特性を明らかにするため,老若男女のパネルを用い官能検査を行った その結果,幾つかの知見が得られたので報告する

A Case of Type 2 Amiodarone-Induced Thyrotoxicosis That Underwent Total Thyroidectomy under High-Dose Steroid Administration

Amiodarone is used commonly and effectively in the treatment of arrhythmia; however, it may cause thyrotoxicosis categorized into two types: iodine-induced hyperthyroidism (type 1 amiodarone-induced thyrotoxicosis (AIT)) and destructive thyroiditis (type 2 AIT). We experienced a case of type 2 AIT, in which high-dose steroid was administered intravenously, and we finally decided to perform total thyroidectomy, resulting in a complete cure of the AIT. Even though steroid had been administered to the patient (maximum 80 mg of prednisolone), the operation was performed safely and no acute adrenal crisis as steroid withdrawal syndrome was found after the operation. Few cases of type 2 AIT that underwent total thyroidectomy with high-dose steroid administration have been reported. The current case suggests that total thyroidectomy should be taken into consideration for patients with AIT who cannot be controlled by medical treatment and even in those under high-dose steroid administration

Continuous or Transient High Level of Glucose Exposure Differentially Increases Coronary Artery Endothelial Cell Proliferation and Human Colon Cancer Cell Proliferation

We studied effect of high glucose levels on coronary artery endothelial cell proliferation and human colon cancer cell proliferation. To examine the long-term effect of glucose exposure on cell growth, cells were cultured for 14 days in the absence or presence of 183 mg/dL D-glucose addition in the culture medium. Short effect of elevated glucose levels was examined by addition of 183 mg/dL D-glucose addition in the culture medium for just one hour per day followed by changing the culture to standard medium (5.5 mM D-glucose) during the next 23-hours period. Cell proliferation was estimated by 2,3-Bis (2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carbox-anilide (XTT) assay and phosphor-Erk western blot analysis. We found that coronary artery endothelial cell proliferation was significantly increased in the culture medium with the acute one-hour addition of 183 mg/dL D-glucose compared to the absence or chronic presence of 183 mg/dL D-glucose addition in the culture medium. In contrast, colon cancer cell proliferation was significantly increased in the continuous presence of 183 mg/dL D-glucose addition in the culture medium compared to the acute one-hour addition of glucose. The extent of Erk2 phosphorylation paralleled with the relative changes in cellular proliferation in both cell types. Taken together, these results suggested that continuous or transient high level of glucose exposure differentially effects coronary artery endothelial and human colon cancer cell proliferation