Neurodegenerative processes accelerated by protein malnutrition and decelerated by essential amino acids in a tauopathy mouse model.

Protein malnutrition is epidemiologically suggested as a potential risk factor for senile dementia, although molecular mechanisms linking dietary proteins and amino acids to neurodegeneration remain unknown. Here, we show that a low-protein diet resulted in down-regulated expression of synaptic components and a modest acceleration of brain atrophy in mice modeling neurodegenerative tauopathies. Notably, these abnormal phenotypes were robustly rescued by the administration of seven selected essential amino acids. The up-regulation of inflammation-associated gene expression and progressive brain atrophy in the tauopathy model were profoundly suppressed by treatment with these essential amino acids without modifications of tau depositions. Moreover, the levels of kynurenine, an initiator of a pathway inducing neuroinflammatory gliosis and neurotoxicity in the brain, were lowered by treatment through inhibition of kynurenine uptake in the brain. Our findings highlight the importance of specific amino acids as systemic mediators of brain homeostasis against neurodegenerative processes.

Protein Deficiency-Induced Behavioral Abnormalities and Neurotransmitter Loss in Aged Mice Are Ameliorated by Essential Amino Acids.

Nutritional epidemiology shows that insufficient protein intake is related to senile dementia. The levels of protein intake in aged people are positively associated with memory function, and elderly people with high protein intake have a low risk of mild cognitive impairment. Although the beneficial roles of protein nutrition in maintaining brain function in aged people are well demonstrated, little is known about the mechanism by which dietary intake of protein affects memory and brain conditions. We fed aged mice a low protein diet (LPD) for 2 months, which caused behavioral abnormalities, and examined the nutritional effect of essential amino acid administration under LPD conditions. The passive avoidance test revealed that LPD mice demonstrated learning and memory impairment. Similarly, the LPD mice showed agitation and hyperactive behavior in the elevated plus maze test. Moreover, LPD mice exhibited decreased concentrations of gamma-aminobutyric acid (GABA), glutamate, glycine, dopamine, norepinephrine, serotonin and aspartate in the brain. Interestingly, oral administration of seven essential amino acids (EAAs; valine, leucine, isoleucine, lysine, phenylalanine, histidine, and tryptophan) to LPD mice, which can be a source of neurotransmitters, reversed those behavioral changes. The oral administration of EAAs restored the brain concentration of glutamate, which is involved in learning and memory ability and may be associated with the observed behavioral changes. Although the details of the link between decreased amino acid and neurotransmitter concentrations and behavioral abnormalities must be examined in future studies, these findings suggest the importance of dietary protein and essential amino acids for maintaining brain function.

AJS1669, a novel small-molecule muscle glycogen synthase activator, improves glucose metabolism and reduces body fat mass in mice.

Impaired glycogen synthesis and turnover are common in insulin resistance and type 2 diabetes. As glycogen synthase (GS) is a key enzyme involved in the synthetic process, it presents a promising therapeutic target for the treatment of type 2 diabetes. In the present study, we identified a novel, potent and orally available GS activator AJS1669 {sodium 2-[[5-[[4-(4,5-difluoro-2-methylsulfanyl-phenyl)phenoxy] methyl]furan-2-carbonyl]-(2-furylmethyl)amino] acetate}. In vitro, we performed a glycogen synthase 1 (GYS1) activation assay for screening GS activators and identified that the activity of AJS1669 was further potentiated in the presence of glucose-6-phosphate (G6P). In vivo, we used ob/ob mice to evaluate the novel anti-diabetic effects of AJS1669 by measuring basal blood glucose levels, glucose tolerance and body fat mass index. Repeated administration of AJS1669 over 4 weeks reduced blood glucose and hemoglobin A1c (HbA1c) levels in ob/ob mice. AJS1669 also improved glucose tolerance in a dose-dependent manner, and decreased body fat mass. The mRNA levels of genes involved in mitochondrial fatty acid oxidation and mitochondrial biogenesis were elevated in skeletal muscle tissue following AJS1669 treatment. Hepatic tissue of treated mice also exhibited elevated expression of genes associated with fatty acid oxidation. In contrast to ob/ob mice, in C57Bl/6 mice AJS1669 administration did not alter body weight or reduce glucose levels. These results demonstrate that pharmacological agents that activate GYS1, the main GS subtype found in skeletal muscle, have potential for use as novel treatments for diabetes that improve glucose metabolism in skeletal muscle.

The sleep-promoting and hypothermic effects of glycine are mediated by NMDA receptors in the suprachiasmatic nucleus.

The use of glycine as a therapeutic option for improving sleep quality is a novel and safe approach. However, despite clinical evidence of its efficacy, the details of its mechanism remain poorly understood. In this study, we investigated the site of action and sleep-promoting mechanisms of glycine in rats. In acute sleep disturbance, oral administration of glycine-induced non-rapid eye movement (REM) sleep and shortened NREM sleep latency with a simultaneous decrease in core temperature. Oral and intracerebroventricular injection of glycine elevated cutaneous blood flow (CBF) at the plantar surface in a dose-dependent manner, resulting in heat loss. Pretreatment with N-methyl-D-aspartate (NMDA) receptor antagonists AP5 and CGP78608 but not the glycine receptor antagonist strychnine inhibited the CBF increase caused by glycine injection into the brain. Induction of c-Fos expression was observed in the hypothalamic nuclei, including the medial preoptic area (MPO) and the suprachiasmatic nucleus (SCN) shell after glycine administration. Bilateral microinjection of glycine into the SCN elevated CBF in a dose-dependent manner, whereas no effect was observed when glycine was injected into the MPO and dorsal subparaventricular zone. In addition, microinjection of D-serine into the SCN also increased CBF, whereas these effects were blocked in the presence of L-701324. SCN ablation completely abolished the sleep-promoting and hypothermic effects of glycine. These data suggest that exogenous glycine promotes sleep via peripheral vasodilatation through the activation of NMDA receptors in the SCN shell.

Acute and chronic treatment of L-isoleucine ameliorates glucose metabolism in glucose-intolerant and diabetic mice.

The administration of L-isoleucine (isoleucine) has been shown to induce hypoglycemia in normal rats. However, it remains to be elucidated whether isoleucine can improve the blood glucose level in glucose-intolerant or diabetic animals. In the present study, oral isoleucine significantly reduced the blood glucose level after an oral glucose challenge in normal mice, as well as in glucose-intolerant mice fed a high-fat diet (HFD) and db/db mice, a model of severe type 2 diabetes. Isoleucine treatment significantly augmented the blood insulin level after an oral glucose load in HFD mice, but not in normal or db/db mice, suggesting that its hypoglycemic activity was attributable to both insulinotropic and non-insulinotropic mechanisms. Chronic supplementation of isoleucine in mice on a high-fat/high-sucrose diet significantly reduced insulin release after an oral glucose challenge without any change in glucose tolerance curve, suggesting that isoleucine might have an insulin-sensitizing effect along with its acute hypoglycemic effect. These results indicate that both acute and chronic treatment with isoleucine is beneficial for glucose metabolism in glucose-intolerant and diabetic animals.

Beneficial effects of biatrial pacing on cardiac function in patients with bradycardia -- tachycardia syndrome.

BACKGROUND: Biatrial (BiA) pacing prevents atrial fibrillation. By an unknown mechanism. The purpose of this study was to use Doppler echocardiography to evaluate the hemodynamic effects during BiA pacing. METHODS AND RESULTS: The subjects were 7 patients with bradycardia - tachycardia syndrome with an implanted pacemaker. Atrial pacing sites were the right atrial appendage (RAA) and coronary sinus. P wave duration during BiA pacing (123 +/-16 ms) was significantly shorter than during either RAA pacing (167+/-19 ms, p<0.05) or sinus rhythm (148+/-12 ms, p<0.05). Doppler echocardiography revealed a greater cardiac output during BiA pacing than during RAA pacing (4.1+/-1.1 vs 3.5+/-0.7 L/min, p=0.042). The Doppler waveform of transmitral flow indicated that the left ventricular contraction interrupted the atrial filling wave during RAA pacing. The interval between the end of the atrial filling wave of transmitral flow and the mitral valvular closing sound was significantly increased by BiA pacing compared with RAA pacing (56+/-65 vs 40+/-57 ms, p=0.047). CONCLUSION: Cardiac hemodynamics were improved by BiA pacing and reduction of left atrial load may be one of the mechanisms.

[Neurally mediated syncope with significant cardiac arrest and asymptomatic multiple cerebral infarctions: a case report].

A 32-year-old man had suffered episodes of loss of consciousness since childhood. He was admitted to another hospital because of three syncopal episodes in one day. He was referred to our hospital because of asymptomatic multiple lacunae indicating cerebral infarction on magnetic resonance imaging. He lost consciousness with convulsion followed by a 70-second interval of cardiac arrest during blood sampling. He reported the onset of his usual prodromal symptoms after 1 min in the 80 degrees head-up tilt position. He lost consciousness 2 min after returning to the supine position. Electrocardiography demonstrated a 10-second interval of cardiac arrest. Magnetic resonance angiography, carotid arterial echography, brain perfusion scintigraphy, and laboratory chemistry and hematology examinations identified no significant findings. Cerebral infarction had occurred in watershed areas, so hemodynamic change during cardiac arrest may be the main cause of the infarctions. He suffered no further syncopal or presyncopal episodes after implantation of a DDD pacing system.

[Successful defibrillation by disconnection of superior vena cava electrode for high defibrillation threshold: a case report].

A 72-year-old man with dilated cardiomyopathy and sustained ventricular tachycardia was treated with amiodarone. He visited another hospital because of loss of consciousness. Electrocardiography showed 2: 1 atrioventricular block. Ambulatory electrocardiography showed total heart beats were 59,700 per day. He was referred to our hospital to evaluate his heart. Several types of ventricular tachycardia and ventricular fibrillation were induced by program stimulation during the electrophysiological study. Therefore, an implantable cardioverter-defibrillator was introduced. During defibrillation threshold tests, ventricular fibrillation could not be terminated by the maximal output of 31J. Despite changing the polarity and lead position, stable defibrillation could not be obtained. Finally, successful defibrillation could only be achieved by disconnection of the superior vena cava electrode.

Assessment of regional wall motion by strain Doppler during biventricular pacing in patients with conventional indications for a pacemaker.

Biventricular pacing therapy is effective in patients with severe congestive heart failure. Strain Doppler imaging (SDI) is a new tool for measuring regional myocardial deformation. We evaluated regional wall motion by strain Doppler imaging in 13 patients who had conventional indications for a pacemaker (74 +/- 6 years old) and in six with NYHA Class III or IV heart failure with a biventricular pacemaker (HF-RV: during right ventricular pacing, HF-BV: during biventricular pacing). The other seven patients had normal LV function (N-RV). Wall motion was assessed by strain of the myocardium, and the interval between the Q wave of the surface ECG and the peak strain (QPSI) was measured in three septal and three lateral segments. Interventricular contraction delay was determined as the interval between the onset of the left and right ventricular outflow waves. Intraventricular contraction delay was determined as the time difference between minimum and maximum QPSI. Strain of HF-RV was significantly greater than that of N-RV (-9.6%+/- 2.5% vs -14.4%+/- 2.3%, P < 0.0001). Intraventricular contraction delay of HF-RV was significantly greater than that of N-RV (273 +/- 12 vs 151 +/- 69 ms, P = 0.0004). Strain of HF-RV was not significantly greater than that of HF-BV (-9.6% +/- 2.5% vs -10.6% +/- 2.9%). Interventricular contraction delay of HF-RV was greater than that of HF-BV (37.2 +/- 44.7 vs 16.2 +/- 47.4 ms, P < 0.0001). Intraventricular contraction delay of HF-RV was significantly greater than that of HF-BV (322 +/- 101 vs 209 +/- 88 ms, P = 0.0006). In conclusion, biventricular pacing improves both interventricular contraction delay and intraventricular contraction delay in patients with conventional indications for a pacemaker with severe congestive heart failure, and SDI is useful to predict the efficacy of biventricular pacing.

Clinical usefulness of ECG-gated 18F-FDG PET combined with 99mTC-MIBI gated SPECT for evaluating myocardial viability and function.

OBJECTIVES: This study sought to evaluate an imaging approach using gated 99mTc-MIBI (MIBI) SPECT and gated 18F-FDG (FDG) PET for assessment of myocardial viability and cardiac function. METHODS: Forty-eight patients (38 men, mean age 68.1 +/- 9.6 years) underwent ECG-gated FDG PET and MIBI SPECT within a week. The baseline diagnoses were coronary artery disease (31), mitral regurgitation (1), paroxysmal arrhythmia (10), and dilated cardiomyopathy (6). The gated FDG PET data were analyzed using pFAST software, and the gated MIBI SPECT data were analyzed using QGS software. Fifteen patients were diagnosed with myocardial infarction, and follow-up study was performed to assess the functional outcome four months later. An improvement in LVEF of >5% was defined as significant. The LV myocardium was divided into 17 segments, and regional defect scores were visually assessed using a 4-point scale for each segment (0 = normal, 1 = mildly reduced, 2 = moderately reduced, 3 = absent). A segment with a greater defect score on MIBI SPECT than on FDG PET was defined as a mismatch. The patients were divided into two groups: those with at least two mismatched segments (MM-group), and those with none or one (M-group). RESULTS: LVEF, EDV and ESV measured by gated FDG PET were highly correlated with those obtained by gated MIBI SPECT (r = 0.848, 0.855 and 0.911, p < 0.0001, respectively). The mean values of LVEF did not differ significantly, but EDV and ESV obtained by gated FDG PET were significantly grater than those obtained by gated MIBI SPECT (p < 0.0001). In 15 patients diagnosed with myocardial infarction, a significant association (p < 0.05) was found between the relative uptake of FDG PET and MIBI SPECT and the functional outcome 4 months later. Global LV function improved in 6 of the 8 patients showing mismatch but in only 1 of the 7 patients with matched defects, resulting in a sensitivity of 86% and specificity of 75%. The overall accuracy to predict global functional outcome was high (80%). CONCLUSION: This imaging approach allows accurate evaluation of myocardial viability. Furthermore, the high correlations of gated FDG PET and gated MIBI SPECT measurements hold promise for the assessment of left ventricular function using gated FDG PET.

[Assessment of regional wall motion using strain Doppler imaging during right ventricular bifocal pacing in a patient with severe congestive heart failure: a case report].

A 79-year-old man presented with dilated cardiomyopathy and chronic atrial fibrillation. A DDD pacemaker was implanted due to sick sinus syndrome. His left ventricular ejection fraction was 23%. He was repeatedly admitted with congestive heart failure. Although cardiac resynchronization therapy was attempted, insertion of a pacing lead into the coronary sinus failed. Right ventricular bifocal pacing was done. The QRS width was shortened to 155 msec during bifocal pacing and 157 msec during right ventricular outflow pacing from 221 msec during right ventricular apical pacing. Heart failure was improved from New York Heart Association class III to II. Regional wall motion was assessed by strain of the myocardium. Bifocal pacing increased stroke volume due to improvement of longitudinal dyssynchrony of the septal and lateral walls. Bifocal pacing is effective for patients with severe congestive heart failure in whom biventricular pacing therapy has failed. Strain Doppler imaging is useful for the assessment of regional wall motion during cardiac pacing.