Elucidation of Substituent-Responsive Reactivities via Hierarchical and Asymmetric Assemblies in Crystalline p-Quinodimethane Derivatives.

We propose a mechanism for substituent-responsive reactivities of p-quinodimethane derivatives with four ester groups through their hierarchical and asymmetric assembly modes. Four asymmetric 7,8,8-tris(methoxycarbonyl)-p-quinodimethanes with a 7-positioned ethoxycarbonyl (2 a(H)), 2'-fluoroethoxycarbonyl (2 b(F)), 2'-chloroethoxycarbonyl (2 c(Cl)), or 2'-bromoethoxycarbonyl (2 d(Br)) were synthesized and crystallized. 2 a(H), 2 b(F) and 2 d(Br) afforded only one shape crystal, while 2 c(Cl) did two polymorphic 2 c(Cl)-α and 2 c(Cl)-ß. UV-irradiation induced topochemical polymerization for 2 a(H), no reactions for 2 b(F) and 2 c(Cl)-α, and [6+6] photocycloaddition dimerization for 2 c(Cl)-ß and 2 d(Br). Such substituent-responsive reactivities and crystal structures were compared with those of the known symmetric 7,7,8,8-tetrakis(alkoxycarbonyl)-p-quinodimethanes such as 7,7,8,8-tetrakis(methoxycarbonyl)- (1 a(Me)-α and 1 a(Me)-ß), 7,7,8,8-tetrakis(ethoxycarbonyl)- (1 b(Et)), and 7,7,8,8-tetrakis(bromoethoxycarbonyl)- (1 c(BrEt)). The comparative study clarified that the reactivities and crystal structures are classified into four types that link to each other. This linkage is understandable when we analyze the crystal structures through the following hierarchical and asymmetric assemblies; conformers, dimers, one dimensional (1D)-columns, two dimensional (2D)-sheets, and three dimensional (3D)-stacked sheets (3D-crystals). This supramolecular viewpoint is supported by intermolecular interaction energies among neighbored molecules with the density functional theory (DFT) calculation. Such research enables us to elucidate the substituent-responsive reactivities of the crystals, and reminds us of the selection of the right path in a so-called "maze game".

Prediction of successful guidewire crossing of below-the-knee chronic total occlusions using a Japanese scoring system.

OBJECTIVE: To develop a scoring system that can adequately predict a successful guidewire crossing (S-GC) of below-the-knee (BTK) chronic total occlusions (CTOs) in angiographic evaluation. METHODS: A retrospective, multicenter, nonrandomized study examined 448 consecutive BTK CTOs in 299 patients treated with endovascular therapy in seven Japanese medical centers from April 2012 to April 2020. The cohort was classified into two groups: an S-GC group and a failed guidewire crossing group. RESULTS: The final logistic regression model created by a backward stepwise multivariate logistic regression model included five variables: "No outflow of the target vessel," "CTO length ≥200 mm," "Reference vessel diameter <2.0 mm," "Calcification at the proximal entry point," and "Blunt type at entry point." Optimisms were adjusted using 1000 bootstrap samples with replacement and candidate's risk score models developed according to optimism-adjusted correlation coefficients of risk factors. Choosing the best model as the Japanese-BTK (J-BTK) CTO score by comparing the optimism-adjusted area under receiver-operating characteristic curves it was decided to assign one point to "Blunt type at the proximal entry point," one point to "Calcification at the proximal entry point," one point to "Reference vessel diameter <2.0 mm," one point to "CTO length ≥200 mm," and two points to "No outflow of the target vessel." This rule was then used to categorize BTK CTOs into four grades with varying probabilities of S-GC: grade A (J-BTK CTO score of 0 and 1), grade B (score of 2 and 3), grade C (score of 4 and 5), and grade D (score of 6). Rates of S-GC in each grade (grades A, B, C, and D) were 97.3%, 76.8%, 19.3%, and 0%, respectively. Lesions categorized as grade C or D have a lower chance of S-GC. Internal validation was performed using the Hosmer-Lemeshow test (P = .99). CONCLUSIONS: The J-BTK CTO score predicts the probability of an S-GC of BTK CTOs and stratifies the difficulty of endovascular therapy for BTK CTOs in angiographic evaluation.

Self-Assembly of 4-(Diethylboryl)pyridine: Crystal Structures of the Cyclic Pentamer and Hexamer and Their Solvent-Dependent Selective Crystallization.

Two distinct oligomeric structures were obtained by the self-assembly of 4-(diethylboryl)pyridine (1). In the (1)H NMR spectrum of 1 in CDCl3, at least two sets of signals were observed for the pyridyl α- and ß-hydrogen atoms. ESI-MS, VPO, and TLC analysis revealed that 1 assembles mainly into a mixture of cyclic pentamers and hexamers in solution via intermolecular boron-nitrogen coordination bonds. Crystallization of 1 in THF by vapor diffusion of EtOH or in CHCl3 afforded the cyclic hexamer incorporating one THF molecule (16·THF) or 1.5 mol equiv of chloroform molecule (16·CHCl3), respectively. Similarly, a solution of 1 in a mixture of benzene and hexane furnished the cyclic pentamer bearing two benzene molecules (15·C6H6). It seems that the solvent differences affected the crystallization of the two distinct cyclic oligomers of 1, either of which was cocrystallized predominantly with the solvent molecule. Thermogravimetric analysis of the crystals and NMR studies of the solution revealed that the noncovalent interactions between the host and guest are not strong enough to hold the guest molecule in the cavity.

Impact of use of angiotensin II receptor blocker on all-cause mortality in hemodialysis patients: prospective cohort study using a propensity-score analysis.

BACKGROUND: It is controversial whether treatment with an angiotensin II receptor blocker (ARB) or a calcium channel blocker (CCB) improves prognosis of hemodialysis (HD) patients. METHODS: This study was designed as a multicenter prospective cohort study. HD patients (n = 1071) were enrolled from 22 institutes in January 2009 and followed up for 3 years. Patients with missing data, kidney transplantation or retraction of consent during the follow-up period (n = 204) were excluded, and 867 patients contributed to analysis of mortality. Propensity score (PS) for use of ARB and that for CCB was calculated using a multiple logistic regression model. RESULTS: ARB and CCB were prescribed in 45.6 and 54.7 % of patients at enrollment. During the 3-year follow-up period, all-cause mortality and cardiovascular mortality rates were 18.8 and 5.1 %, respectively. Kaplan-Meier curves showed that all-cause and cardiovascular mortality rates were lower in the ARB group than in the non-ARB group, though the mortality rates were similar in the CCB group and non-CCB group. In PS-stratified Cox regression analysis, ARB treatment was associated with 34 and 45 % reduction of all-cause death and cardiovascular death, respectively. In PS matching analysis, ARB treatment was associated with a significant reduction (46 % reduction) in the risk of all-cause death. A significant impact of CCB treatment on all-cause or cardiovascular mortality was not detected in PS analysis. CONCLUSIONS: The use of an ARB, but not a CCB, is associated with reduced all-cause and cardiovascular mortalities in patients on HD.

Excessive degradation of adenine nucleotides by up-regulated AMP deaminase underlies afterload-induced diastolic dysfunction in the type 2 diabetic heart.

Type 2 diabetes mellitus (T2DM) is often complicated with diastolic heart failure, which decompensates under increased afterload. Focusing on cardiac metabolomes, we examined mechanisms by which T2DM augments ventricular diastolic stiffness in response to pressure overloading. Pressure-volume relationships (PVRs) and myocardial metabolomes were determined at baseline and during elevation of aortic pressure by phenylephrine infusion in a model of T2DM, OLETF, and its non-diabetic control, LETO. Pressure overloading augmented diastolic stiffness without change in systolic reserve in OLETF as indicated by a left-upward shift of end-diastolic PVR. In contrast, PVRs under cardioplegic arrest in buffer-perfused isolated hearts were similar in OLETF and LETO, indicating that extracellular matrix or titin remodeling does not contribute to the afterload-induced increase in stiffness of the beating ventricle of OLETF. Metabolome analyses revealed impaired glycolysis and facilitation of the pentose phosphate pathway in OLETF. Pressure overloading significantly reduced ATP and total adenine nucleotides by 34% and 40%, respectively, in OLETF but not in LETO, while NADH-to-NAD(+) ratios were similar in the two groups. The decline in ATP by pressure overloading in OLETF was associated with increased inosine 5-monophosphate and decreased adenosine levels, being consistent with the 2.5-times higher activity of cardiac AMP deaminase in OLETF. Tissue ATP level was negatively correlated with tau of LV pressure and LVEDP. These results suggest that ATP depletion due to excessive degradation of adenine nucleotides by up-regulated AMP deaminase underlies ventricular stiffening during acute pressure overloading in T2DM hearts.

Nonvisualized type III endoleak masquerading as endotension: a case report.

Here, we describe a case of nonvisualized type III endoleak masquerading as endotension that was diagnosed by opening the aneurysm sac during surgery and successfully treated surgically. A 79-year-old man underwent endovascular aneurysm repair (EVAR) 4 years previously for an aneurysm that had enlarged gradually without endoleak. An open surgical operation was performed. The sac pressure was 132 mm Hg-similar to the preoperative systolic blood pressure-and nonpulsatile. After the aneurysm sac was opened without clamping the aorta, a type III endoleak from the suture point of the prosthetic endograft was detected. The prosthetic graft was successfully replaced with a Y-graft. The current findings suggest that nonvisualized type III endoleaks may be a potential cause of endotension.

Type 2 diabetes induces subendocardium-predominant reduction in transient outward K+ current with downregulation of Kv4.2 and KChIP2.

In the present study, we examined if and how cardiac ion channels are modified by type 2 diabetes mellitus (T2DM). Subendocardial (Endo) myocytes and subepicardial (Epi) myocytes were isolated from left ventricles of Otsuka-Long-Evans-Tokushima Fatty rats (OLETF) rats, a rat model of T2DM, and Otsuka-Long-Evans-Tokushima (LETO) rats (nondiabetic control rats). Endo and Epi myocytes were used for whole cell patch-clamp recordings and for protein and mRNA analyses. Action potential durations in Endo and Epi myocytes were longer in OLETF rats than in LETO rats, and the difference was larger in Endo myocytes. Steady-state transient outward K+ current (Ito) density was reduced in Endo but not Epi myocytes of OLETF rats compared with LETO rats, although the contribution of the fast component of Ito recovery from inactivation was smaller in both Endo and Epi myocytes of OLETF rats than in LETO rats. Kv4.2 protein was reduced only in Endo myocytes in OLETF rats, although voltage-gated K+ channel-interacting protein 2 (KChIP2) protein levels in both Endo and Epi myocytes were lower in OLETF rats than in LETO rats. Corresponding regional differences in mRNA levels of KChIP2 and Kv4.2 were observed between OLETF and LETO rats. mRNA levels of Iroquois homeobox 5 in Endo myocytes were 53% higher in OLETF rats than in LETO rats. Densities of inward rectifier K+ current and L-type Ca2+ current and mRNA levels of Kv4.3 and Kv1.4 were similar in OLETF and LETO rats. In conclusion, T2DM induces Endo-predominant prolongation of the action potential duration via a reduction of the fast component of Ito recovery from inactivation and reduced steady-state Ito, in which downregulation of Kv4.2 and KChIP2 may be involved. Increased Iroquois homeobox 5 expression may underlie Kv4.2 downregulation in T2DM.

Influence of the COVID-19 pandemic on the achievement of guideline targets for HbA1c, blood pressure, and LDL cholesterol in people with diabetes in Japan.

Objective: In this study, we investigated whether the COVID-19 pandemic affected achievement of guideline targets for HbA1c, blood pressure (BP), and low-density lipoprotein (LDL) cholesterol in people with diabetes mellitus (DM). Materials and methods: Data for 556 people with DM who were treated regularly for 4 years before and during the COVID-19 pandemic in Japan were analyzed in this retrospective study. Achieved targets were defined as HbA1c < 7.0%, BP < 130/80 mmHg, and LDL cholesterol < 100 or < 120 mg/dL depending on the presence or absence of coronary artery disease. Results: In 2019, before the start of the COVID-19 pandemic, achievement rates of guideline targets for HbA1c, BP and LDL cholesterol were 53.4%, 45.9% and 75.7%, respectively. In 2020, the achievement rates for HbA1c and BP targets were significantly decreased to 40.8% and 31.3%, respectively. The achievement rates for the HbA1c target gradually recovered to 49.3% in 2021 and to 51.1% in 2022. However, recovery in achieving the BP target was slow, remaining at 40.5% even in 2022. On the other hand, the achievement rate for the LDL cholesterol target was not affected and remained relatively high during the COVID-19 pandemic. Conclusions: The rates of achieving therapeutic targets for HbA1c and BP have not been high enough in people with DM, and the rates were further reduced by lifestyle changes due to the COVID-19 pandemic. Although there has been a trend toward improvement with the lifting of behavioral restrictions, more intensified treatment is necessary to achieve good control. Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-024-00715-8.

Hemolytic Anemia Occurring 14 Years after Ascending Aortic Replacement for Acute Type A Aortic Dissection Due to Aortic Pseudoaneurysm Derived from Anastomotic Leakage: A Case Report.

A 64-year-old male patient who presented with symptoms indicative of hemolytic anemia was referred to our hospital. After obtaining the patient's history, it was found that hemolysis occurred 14 years after he underwent ascending aortic replacement for acute type A aortic dissection. Enhanced computed tomography revealed an aortic pseudoaneurysm at the proximal anastomosis, which was thought to be the cause of hemolysis. Furthermore, aortic valve regurgitation and dilatation of the sinus of Valsalva were also found on a transthoracic echocardiogram. Therefore, the Bentall procedure was performed. During the surgery, aortic pseudoaneurysm formation and vascular graft stenosis were observed. The postoperative course was uneventful, and hemolysis diminished soon after the surgery.

Clinical outcome of intraoperative hemodialysis using a hemoconcentrator during cardiopulmonary bypass for dialysis-dependent patients.

OBJECTIVES: The basic materials and structure of a hemoconcentrator incorporated into cardiopulmonary bypass (CPB) circuits are similar to those of hemodialyzers. Gravity drainage hemodiafiltration (GHDF) is an easy-to-use intraoperative renal replacement therapy (RRT) that utilizes a hemoconcentrator. This study aimed to verify whether GHDF can correct electrolyte imbalance and remove uremic toxins in dialysis-dependent patients and to evaluate the clinical outcomes of GHDF by comparing it with a conventional method of dilutional ultrafiltration (DUF). METHODS: This study retrospectively compared perioperative clinical values of 41 dialysis-dependent patients (21 patients with GHDF and 20 patients with DUF) who underwent open-heart surgery. Changes in serum parameters before and after passing through the hemoconcentrator were also compared. RESULTS: Compared to DUF, GHDF significantly lowered potassium, blood urea nitrogen, and creatinine levels at the outflow of the hemoconcentrator. Less catecholamine was needed to wean CPB in GHDF than in DUF. The P/F ratio (arterial blood oxygen pressure/inhaled oxygen concentration) at the end of surgery was significantly higher in GHDF than in DUF (450.8 ± 149.7 vs. 279.3 ± 153.5; p < 0.001). Postoperative intubation time was shorter in GHDF than in DUF (8.3 ± 5.9 vs. 18.7 ± 16.1 h; p = 0.006). The major morbidity and mortality rates were comparable in both groups. CONCLUSIONS: GHDF removed both potassium and uremic toxins more efficiently than DUF in dialysis-dependent patients. Less catecholamine was needed to wean CPB using GHDF. It improved the immediate postoperative respiratory function and enabled earlier extubation. GHDF is a novel and effective option for intraoperative RRT in dialysis-dependent patients undergoing open-heart surgery.

Cytoprotective regulation of the mitochondrial permeability transition pore is impaired in type 2 diabetic Goto-Kakizaki rat hearts.

Our recent studies indicated that up-regulation of calcineurin activity and unfolded protein responses (UPRs) disrupt cytoprotective Akt- and ERK-signaling in OLETF, a model of obese type 2 diabetes (T2DM). To determine whether the mechanisms can be generalized, we used Goto-Kakizaki rats (GK), a model of non-obese T2DM, in this study. Infarct sizes after 20-min ischemia/2-h reperfusion were similar in GK and non-diabetic controls, Wistar rats (Wistar). However, erythropoietin (EPO) limited infarct size in Wistar (64.0±5.3% vs. 45.7±4.4%, p<0.05) but not in GK (56.2±2.2% vs. 52.6±2.3%). Levels of calcineurin activity and EPO-induced phosphorylation of Akt and ERK were similar in GK and Wistar, though cytosolic HSP70 level was 50% lower and mitochondrial HSP60 level was 60% higher in GK. EPO preserved mitochondrial calcium retention capacity (CRC), an index of the threshold for opening of the mitochondrial permeability transition pore (mPTP), after ischemia/reperfusion in Wistar but not in GK. Interaction of cyclophilin D (CypD) with mitochondrial inorganic phosphate carrier (PiC), which sensitizes the mPTP, was enhanced in GK. There was a negative exponential relationship between CypD-PiC interaction and CRC upon reperfusion, indicating that increase in CRC by reduction of CypD-PiC interaction is smaller when CypD-PiC interaction level is at a higher range. A chemical chaperone, 4-phenylbutyric acid, attenuated the changes in HSPs and CypD-PiC interaction and restored responses of CRC and infarct size to EPO in GK. These results suggest that cytoprotective regulation of the mPTP is impaired in GK by enhanced CypD-PiC interaction in which UPRs are involved.

Role of connexin-43 in protective PI3K-Akt-GSK-3ß signaling in cardiomyocytes.

Sarcolemmal connexin-43 (Cx43) and mitochondrial Cx43 play distinct roles: formation of gap junctions and production of reactive oxygen species (ROS) for redox signaling. In this study, we examined the hypothesis that Cx43 contributes to activation of a major cytoprotective signal pathway, phosphoinositide 3-kinase (PI3K)-Akt-glycogen synthase kinase-3ß (GSK-3ß) signaling, in cardiomyocytes. A δ-opioid receptor agonist {[d-Ala(2),d-Leu(5)]enkephalin acetate (DADLE)}, endothelin-1 (ET-1), and insulin-like growth factor-1 (IGF-1) induced phosphorylation of Akt and GSK-3ß in H9c2 cardiomyocytes. Reduction of Cx43 protein to 20% of the normal level by Cx43 small interfering RNA abolished phosphorylation of Akt and GSK-3ß induced by DADLE or ET-1 but not that induced by IGF-1. DADLE and IGF-1 protected H9c2 cells from necrosis after treatment with H(2)O(2) or antimycin A. The protection by DADLE or ET-1, but not that by IGF-1, was lost by reduction of Cx43 protein expression. In contrast to Akt and GSK-3ß, PKC-ε, ERK and p38 mitogen-activated protein kinase were phosphorylated by ET-1 in Cx43-knocked-down cells. Like diazoxide, an activator of the mitochondrial ATP-sensitive K(+) channel, DADLE and ET-1 induced significant ROS production in mitochondria, although such an effect was not observed for IGF-1. Cx43 knockdown did not attenuate the mitochondrial ROS production by DADLE or ET-1. Cx43 was coimmunoprecipitated with the ß-subunit of G protein (Gß), and knockdown of Gß mimicked the effect of Cx43 knockdown on ET-1-induced phosphorylation of Akt and GSK-3ß. These results suggest that Cx43 contributes to activation of class I(B) PI3K in PI3K-Akt-GSK-3ß signaling possibly as a cofactor of Gß in cardiomyocytes.

Effects of diabetes on myocardial infarct size and cardioprotection by preconditioning and postconditioning.

In spite of the current optimal therapy, the mortality of patients with ischemic heart disease (IHD) remains high, particularly in cases with diabetes mellitus (DM) as a co-morbidity. Myocardial infarct size is a major determinant of prognosis in IHD patients, and development of a novel strategy to limit infarction is of great clinical importance. Ischemic preconditioning (PC), postconditioning (PostC) and their mimetic agents have been shown to reduce infarct size in experiments using healthy animals. However, a variety of pharmacological agents have failed to demonstrate infarct size limitation in clinical trials. One of the possible reasons for the discrepancy between the results of animal experiments and clinical trials is that co-morbidities, including DM, modified myocardial responses to ischemia/reperfusion and to cardioprotective agents. Here we summarize observations of the effects of DM on myocardial infarct size and ischemic PC and PostC and discuss perspectives for protection of DM hearts.

Angiotensin II type 1 receptor-mediated upregulation of calcineurin activity underlies impairment of cardioprotective signaling in diabetic hearts.

RATIONALE: The diabetic heart is resistant to ischemic preconditioning because of diabetes-associated impairment of phosphatidylinositol 3-kinase (PI3K)-Akt signaling. The mechanism by which PI3K-Akt signaling is impaired by diabetes remains unclear. OBJECTIVE: Here, we examined the hypothesis that phosphorylation of Jak2 upstream of PI3K is impaired in diabetic hearts by an angiotensin II type 1 (AT1) receptor-mediated mechanism. METHODS AND RESULTS: Infarct size (as percentage of risk area) after 20-minute ischemia/2-hour reperfusion was larger in a rat model of type 2 diabetes (Otsuka-Long-Evans-Tokushima fatty [OLETF] rat) than in its control (Long-Evans-Tokushima-Otsuka [LETO] rat) (60.4+/-1.6% versus 48.4+/-1.3%). Activation of Jak2-mediated signaling by erythropoietin or DADLE ([D-Ala2, D-Leu5]-enkephalin acetate), a delta-opioid receptor agonist, limited infarct size in LETO rats (27.7+/-3.4% and 24.8+/-5.0%) but not in OLETF rats (53.9+/-5.3% and 55.0+/-2.2%). Blockade of the AT1 receptor by valsartan or losartan for 2 weeks restored the myocardial response of OLETF rats to erythropoietin-induced infarct size limitation (39.4+/-4.9% and 31.2+/-7.5). In OLETF rats, erythropoietin failed to phosphorylate both Jak2 and Akt, and calcineurin activity was significantly higher than in LETO rats. Two-week treatment with valsartan normalized calcineurin activity in OLETF rats and restored the response of Jak2 to erythropoietin. This effect of AT1 receptor blockade was mimicked by inhibition of calcineurin by FK506. CONCLUSIONS: These results suggest that the diabetic heart is refractory to protection by Jak2-activating ligands because of AT1 receptor-mediated upregulation of calcineurin activity.

Effects of Sacubitril/Valsartan on Glycemic Control in Japanese Patients With Heart Failure and/or Hypertension.

Background: Post hoc analysis of the PARADIGM-HF trial showed that sacubitril/valsartan (S/V) was more effective than enalapril in lowering HbA1c in patients with heart failure and diabetes. Methods and Results: In the present study, the effect of S/V on glycemic control was retrospectively analyzed in 150 patients (median age 74 years) who were prescribed S/V for the treatment of heart failure and/or hypertension. After a median period of 13 weeks treatment, mean (±SD) HbA1c levels decreased significantly from 6.56±0.68% to 6.49±0.63%. The decrease in HbA1c was evident in patients with (n=111), but not in those without, diabetes. There were no significant changes in renal function after S/V treatment, but systolic blood pressure was significantly reduced from 141±21 to 134±19 mmHg. Ninety patients had N-terminal pro B-type natriuretic peptide (NT-proBNP) tested, and S/V significantly decreased median NT-proBNP concentrations from 1,026 to 618 pg/mL; however, there was no correlation between the degree of decrease in HbA1c and that in NT-proBNP. Multiple regression analysis revealed that being diabetic, rather than having heart failure, was a significant independent variable for a reduction in HbA1c. Conclusions: Treatment with S/V improved glycemic control in patients with heart failure and/or hypertension, especially in those with concomitant diabetes. This favorable effect on glucose metabolism may be mediated by neprilysin inhibition and is desirable in the treatment of heart failure and hypertension in diabetic patients.

Impact of the COVID-19 Pandemic on Glycemic Control and Blood Pressure Control in Patients with Diabetes in Japan.

Objective In this study, we investigated whether and how the COVID-19 pandemic affected glycemic control and blood pressure (BP) control in patients with diabetes mellitus (DM). Methods DM patients whose HbA1c level was measured regularly before and after the declaration of a state of emergency were included in this study. Some patients were given questionnaires about changes in their lifestyle to determine the factors affecting glycemic control and BP control. Results The median HbA1c level of the 804 patients increased significantly from 6.8% before the state of emergency to 7.1% and 7.0% during and after the state of emergency, respectively. This was in contrast to the decrease one year earlier due to seasonal variations. In the 176 patients who responded to the questionnaire, the HbA1c level also increased significantly during and after the state of emergency. The worsening of glycemic control was more pronounced in the group that had achieved HbA1c of <7% before the state of emergency than in those with higher values. Unlike the rise in HbA1c, the BP did not rise during the state of emergency but did rise significantly afterwards. There was no marked decrease in HbA1c or BP after the state of emergency, even in patients who responded that they were much more careful with their diet, ate less, or exercised more. Conclusions The COVID-19 pandemic worsened glycemic control and BP control, even in patients who perceived no marked change in their diet or exercise, suggesting that more active lifestyle guidance is necessary for good treatment of DM patients.

Characteristics of patients with emergency attendance for severe hypoglycemia and hyperglycemia in a general hospital in Japan.

ABSTRACT: Despite advances in treatments for diabetes mellitus (DM), severe acute glycemic crises still occur. In this study, the characteristics of patients who were transported to an emergency department due to acute glycemic crises were investigated.We enrolled patients who were transported to our hospital by ambulance due to hypoglycemia or hyperglycemia during the period from January 2015 to December 2019. Initial glucose levels below 70 mg/dL and above 250 mg/dL were defined as hypoglycemia and hyperglycemia, respectively.In the 5-year period, 16,910 patients were transported to our hospital by ambulance. Of those patients, 87 patients (0.51%) were diagnosed with hypoglycemia, 26 patients (0.15%) were diagnosed with hyperglycemia and 1 patient was diagnosed with lactic acidosis. Compared to patients with hypoglycemia, blood urea nitrogen, serum potassium and hemoglobin levels were higher in patients with hyperglycemia. Systolic blood pressure was lower and pulse rate was higher in patients with hyperglycemia, possibly reflecting dehydration in hyperglycemia. Patients with hyperglycemia were younger (63 vs 70 years old, median), more likely to be hospitalized (92.3% vs 23.0%) with poorer prognosis (23.1% vs 4.6%) than those with hypoglycemia. In 64 DM patients with hypoglycemia, 34 patients were treated with insulin and 24 patients were treated with sulfonylurea or glinide, and their medication was often inappropriate. Excessive alcohol intake and malnutrition were the main causes of hypoglycemia in 23 non-DM patients. The main reasons for hyperglycemia were interrupted treatment, forgetting insulin injection and infection.To avoid acute glycemic crises, optimization of anti-DM therapy and education of patients are needed.

Roles of phospho-GSK-3ß in myocardial protection afforded by activation of the mitochondrial K ATP channel.

The aim of this study was to determine the roles of glycogen synthase kinase-3ß (GSK-3ß) in cardioprotection by activation of the mitochondrial ATP-sensitive K(+) channel (mK(ATP) channel). In isolated rat hearts, an mK(ATP) activator, diazoxide, and a GSK-3ß inhibitor, SB216763, similarly limited infarct size and the combination of these agents did not afford further protection. The protection by pre-ischemic treatment with diazoxide was abolished by inhibition of protein kinase C-ε (PKC-ε) or phosphatidylinositol-3-kinase (PI3K) upon reperfusion. Infusion of a GSK-3ß inhibitor (LiCl), but not diazoxide, during reperfusion limited infarct size. Inhibition of PKC-ε or PI3K did not affect the protection by LiCl. Diazoxide infusion alone did not induce GSK-3ß phosphorylation. However, diazoxide infusion before ischemia increased mitochondrial phospho-GSK-3ß level and reduced cyclophilin-D (CypD) binding to adenine nucleotide translocase (ANT) at 10 min after reperfusion. This diazoxide-induced GSK-3ß phosphorylation was inhibited by blockade of the mK(ATP) channel before ischemia and by blockade of PKC-ε, PI3K or the adenosine A2b receptor at the time of reperfusion. Inhibition of GSK-3ß by LiCl during reperfusion increased phospho-GSK-3ß but had no significant effect on CypD-ANT binding. These results suggest that GSK-3ß phosphorylation at the time of reperfusion by a PKC-ε, PI3K- and A2b receptor-dependent mechanism contributes to prevention of myocardial necrosis by pre-ischemic activation of the mK(ATP) channel. Inhibition of CypD-ANT interaction may contribute to mK(ATP)-induced myocardial protection, though it is not the sole mechanism of phospho-GSK-3ß-mediated cytoprotection.

Mobile Thrombus in the Ascending Aorta.

A 65-year-old male who presented with dizziness, dysarthria, and disability of his left hand was admitted to our hospital. Magnetic resonance imaging of the head revealed cerebral infarction and enhanced computed tomography revealed a suspicious thrombus in the ascending aorta. He did not have a coagulation disorder. We performed ascending aortic replacement and removed the thrombus with the aortic wall in order to avoid any recurrences. Here we report the successful treatment of the case from clinical and pathological points of view with some findings.