Transcriptional dysregulation of autophagy in the muscle of a mouse model of Duchenne muscular dystrophy.

It has been reported that autophagic activity is disturbed in the skeletal muscles of dystrophin-deficient mdx mice and patients with Duchenne muscular dystrophy (DMD). Transcriptional regulations of autophagy by FoxO transcription factors (FoxOs) and transcription factor EB (TFEB) play critical roles in adaptation to cellular stress conditions. Here, we investigated whether autophagic activity is dysregulated at the transcription level in dystrophin-deficient muscles. Expression levels of autophagy-related genes were globally decreased in tibialis anterior and soleus muscles of mdx mice compared with those of wild-type mice. DNA microarray data from the NCBI database also showed that genes related to autophagy were globally downregulated in muscles from patients with DMD. These downregulated genes are known as targets of FoxOs and TFEB. Immunostaining showed that nuclear localization of FoxO1 and FoxO3a was decreased in mdx mice. Western blot analyses demonstrated increases in phosphorylation levels of FoxO1 and FoxO3a in mdx mice. Nuclear localization of TFEB was also reduced in mdx mice, which was associated with elevated phosphorylation levels of TFEB. Collectively, the results suggest that autophagy is disturbed in dystrophin-deficient muscles via transcriptional downregulation due to phosphorylation-mediated suppression of FoxOs and TFEB.

Resveratrol, a SIRT1 activator, attenuates aging-associated alterations in skeletal muscle and heart in mice.

Aging is associated with impairment of multiple organs, including skeletal muscle and heart. In this study, we investigated whether resveratrol, an activator of an NAD+-dependent protein deacetylase Sirtuin-1 (SIRT1), attenuates age-related sarcopenia and cardiomyocyte hypertrophy in mice. Treatment of mice with resveratrol (0.4 g/kg diet) from 28 weeks of age for 32 weeks prevented aging-associated shortening of rotarod riding time. In the tibialis anterior (TA) muscle, histogram analysis showed that the atrophic muscle was increased in 60-week-old (wo) mice compared with 20-wo mice, which was attenuated by resveratrol. In the heart, resveratrol attenuated an aging-associated increase in the cardiomyocyte diameter. Acetylated proteins were increased and autophagic activity was reduced in the TA muscle of 60-wo mice compared with those of 20-wo mice. Resveratrol treatment reduced levels of acetylated proteins and restored autophagic activity in the TA muscle. Aging-related reduction in myocardial autophagy was also suppressed by resveratrol. Skeletal muscle-specific SIRT1 knockout mice showed increases in acetylated proteins and atrophic muscle fibers and reduced autophagic activity in the TA muscle. These results suggest that activation of SIRT1 by treatment with resveratrol suppresses sarcopenia and cardiomyocyte hypertrophy by restoration of autophagy in mice.

Exploration of autonomic regulation reflecting on pathophysiological change of sepsis: a prospective observational study.

Aim: It remains unclear how autonomic regulation modulates pathophysiological changes of sepsis. This study aims to analyze and clarify those in patients with suspected sepsis. Methods: In this single-centered, prospective, observational study, adult patients who had an infection, a quick Sequential Organ Failure Assessment score of 2 or more at the emergency department, and underwent intensive care were screened. Heart rate variability (HRV) and serum adrenaline were measured immediately after arrival. The primary outcome was defined as vasopressor dependence during 48 h after arrival. Results: A total of 63 patients were included. All the patients had SOFA score of 2 or more on admission. Vasopressor dependence, renal replacement therapy, and in-hospital mortality were associated with higher adrenaline (which reflects sympathetic adrenergic system activity). Bacteremia was associated with lower high-frequency components of HRV (parasympathetic nerve activity). The HRV parameter of sympathetic nerve activity had no significant association with the outcomes. In the multivariate logistic regression model adjusted for age and sex, vasopressor dependence remained associated with higher adrenaline (cut-off 0.11 ng/mL, odds ratio 9.71, 95% confidence interval 2.55-37; P = 0.000874), and lower high-frequency components with bacteremia (17.2 ms2, odds ratio 4.86, 95% confidence interval 1.36-17.4; P = 0.0152). There were no significant correlations between parameters of HRV and serum adrenaline. Conclusion: Hypoperfusion, organ dysfunction, and in-hospital mortality were associated with an increased sympathetic adrenergic activity. Bacteremia was associated with decreased parasympathetic nerve activity. The autonomic regulator may involve a multilayered and differentiated modulating process for sepsis.

An Autopsy Case of Fulminant, Suppurative Bacterial Myocarditis Caused by Group B Streptococcus.

A 61-year-old woman was admitted to our hospital with a fever, nausea, diarrhea, and back pain. Her condition rapidly deteriorated, and she was transferred to the intensive-care unit for mechanical circulatory support and antibiotics, but she died 40 hours after admission. Autopsy findings showed necrotic and suppurative myocardial changes due to group B Streptococcus (GBS). To date, only one case of bacterial myocarditis caused by GBS has been reported. We herein report a case of GBS myocarditis, the etiology of which is poorly understood due to the limited number of cases. Bacterial myocarditis should be considered in patients with sepsis and myocardial dysfunction.

Statistical analysis of anti-mamushi venom serum injection time and clinical course.

AIM: Early injection of anti-mamushi venom serum (antiserum) is believed to be effective for the treatment of patients with mamushi bites. However, there is no firm information that indicates the time range constituting "early" injection. We tried to quantify the cut-off time of antiserum injection that brings favorable clinical courses by clarifying the relationship between the injection time and clinical outcome. METHODS: We retrospectively analyzed the relationships between the time after bite, injection time of the antiserum, swelling grades, and laboratory values. RESULTS: The injection time of the antiserum in severe cases was significantly delayed as compared with non-severe cases. The best cut-off time of the antiserum injection that could distinguish non-severe and severe cases was 14 h. In the group that received the antiserum within 14 h, the antiserum injection may have successfully arrested the grade progression in a substantial number of cases. In the other group receiving the antiserum beyond 14 h, the grades in many cases possibly may have peaked by the time of antiserum injection. CONCLUSION: The cut-off time of early injection for favorable clinical course was determined to be 14 h. A statistical basis concerning the appropriate antiserum injection time was made to help prevent a severe clinical course due to delayed injection.

Clinical characteristics of non-convulsive status epilepticus diagnosed by simplified continuous electroencephalogram monitoring at an emergency intensive care unit.

Aim: The present study aimed to elucidate the clinical characteristics of non-convulsive status epilepticus (NCSE) in patients with altered mental status (AMS). Methods: This single-center retrospective study comprised 149 patients who were hospitalized between March 1, 2015 and September 30, 2015 at the emergency intensive care unit (ICU) of the Kagawa University Hospital (Kagawa, Japan). The primary outcome was NCSE incidence. The secondary outcome was the comparison of duration of ICU stay, hospital stay, and a favorable neurological outcome, as assessed using the modified Rankin Scale score, at discharge from our hospital between patients with and without NCSE. Favorable neurological outcome and poor neurological outcome were defined as modified Rankin Scale scores of 0-2 and 3-6, respectively. Results: Simplified continuous electroencephalogram was used to monitor 36 patients (median age, 68 years; 69.4% males) with acute AMS; among them, NCSE was observed in 11 (30.1%) patients. Rates of favorable neurological outcome, duration of ICU stay, and hospital stay were not significantly different between the NCSE and non-NCSE groups (P = 0.45, P = 0.30, and P = 0.26, respectively). Conclusion: Approximately 30% of the patients with AMS admitted to emergency ICUs developed NCSE. The outcomes of AMS patients with and without NCSE did not differ significantly when appropriate medical attention and antiepileptic drugs were initiated. Simplified continuous electroencephalogram monitoring may be recommended in patients with AMS in emergency ICU to obtain early detection of NCSE followed by appropriate intervention.

A lethal case of mamushi (Gloydius blomhoffii) bite: severe bowel symptoms as a lethal sign.

Case: We report a lethal case of a mamushi (Gloydius blomhoffii) bite. An 84-year-old woman was bitten by a mamushi snake on her right elbow. She was initially treated at another hospital, however, because the swelling expanded and her renal function worsened, she was transferred to our hospital. Compartment syndrome, thrombocytopenia, respiratory arrest, and elevated creatinine kinase and lactose dehydrogenase levels were seen; renal failure progressed, and ileus and peritonitis due to colon perforation occurred. Outcome: The patient died 35 days after the bite. An autopsy revealed widespread necrosis of the ileum, colon, and liver. Conclusion: This report supplies useful clinical information on the treatment of severe mamushi bite cases, and severe abdominal symptoms, such as ileus and melena, may be a lethal sign.

Critical Care Management Focused on Optimizing Brain Function After Cardiac Arrest.

The discussion of neurocritical care management in post-cardiac arrest syndrome (PCAS) has generally focused on target values used for targeted temperature management (TTM). There has been less attention paid to target values for systemic and cerebral parameters to minimize secondary brain damage in PCAS. And the neurologic indications for TTM to produce a favorable neurologic outcome remain to be determined. Critical care management of PCAS patients is fundamental and essential for both cardiologists and general intensivists to improve neurologic outcome, because definitive therapy of PCAS includes both special management of the cause of cardiac arrest, such as coronary intervention to ischemic heart disease, and intensive management of the results of cardiac arrest, such as ventilation strategies to avoid brain ischemia. We reviewed the literature and the latest research about the following issues and propose practical care recommendations. Issues are (1) prediction of TTM candidate on admission, (2) cerebral blood flow and metabolism and target value of them, (3) seizure management using continuous electroencephalography, (4) target value of hemodynamic stabilization and its method, (5) management and analysis of respiration, (6) sedation and its monitoring, (7) shivering control and its monitoring, and (8) glucose management. We hope to establish standards of neurocritical care to optimize brain function and produce a favorable neurologic outcome.

Association Between Comorbidities, Nutritional Status, and Anticlotting Drugs and Neurologic Outcomes in Geriatric Patients with Traumatic Brain Injury.

BACKGROUND: Several studies using trauma data banks and registers showed that age, Glasgow Coma Scale (GCS), Injury Severity Score, and intraventricular hemorrhage were independent factors for neurologic outcomes in geriatric patients with traumatic brain injury (TBI). However, these analyses did not comprehensively evaluate factors particularly associated with geriatric patients. We aimed to identify factors particularly associated with geriatric patients that affect neurologic outcomes in TBI. METHODS: Patients aged ≥65 years who were hospitalized consecutively in Kagawa University Hospital with severe TBI between 1 January 2008 and 31 October 2015 were retrospectively reviewed. We evaluated background factors particularly associated with geriatric patients, including comorbidities (Charlson Comorbidity Index [CCI]), nutritional status (serum albumin level), and presence/absence of antiplatelet and anticoagulant drugs, in addition to baseline characteristics. Multivariate analyses were performed to identify independent predictors of unfavorable neurologic outcomes (UO), as defined as a Glasgow Outcome Scale score of 1-3 at discharge from hospital. The association between CCI and UO was evaluated in a subgroup analysis. RESULTS: UO occurred in 65.0% of 140 patients. Multivariate analyses showed that the CCI (odds ratio, 1.91; 95% confidence interval, 1.21-3.29; P = 0.011), age, and GCS were independent predictors of UO. In subgroup analyses of patients with an initial GCS score of 13-15, the rate of UO significantly increased with CCI score (CCI 0, 35.5%; CCI 1 or 2, 39.4%; CCI >2, 83.3%; P < 0.01). CONCLUSIONS: CCI was an independent predictor of UO in geriatric patients with severe TBI.