Usefulness of Fibrinogen/Fibrin Degradation Products Value in Differential Diagnosis Between Acute Ischemic Stroke and Acute Aortic Dissection.

A post-marketing surveillance study reported fatalities following tissue plasminogen activator administration in acute aortic dissection (AAD) with the symptoms of acute ischemic stroke (AIS) patients. Therefore, it is important to discriminate AAD from AIS. The present study aimed to investigate whether fibrinogen/fibrin degradation products (FDP) value can be useful in differential diagnosis between AAD and AIS. The study group comprised 20 AAD patients (10 men and 10 women; age 63.9 ± 13.6 years) and 159 AIS patients (91 men and 68 women; age 74.2 ± 10.6 years) who were transported to our hospital from 2007 to 2012. The AAD cases were further divided into patent-type AAD and thrombosed-type AAD. FDP values were significantly higher in the AAD group than in the AIS group (18.15 [5.2 - 249.9] µg/ml vs. 2.3 [1.5 - 4.45] µg/ml ; P < 0.001). In AAD groups, FDP values were significantly higher in the patent-type AAD group (n = 9) than in the thrombosed type AAD group (n = 11) (293.2 µg/ml [63.1 - 419.6 µg/ml ] vs. 5.6 µg/ml [3.8 - 7.9 µg/ml ]. FDP values were significantly higher in patients with AAD than in those with AIS, especially those with patent-type AAD compared with AIS patients. High FDP values may be a useful marker for differential diagnosis between patent-type AAD and AIS.

A Case of Infectious Enterocolitis with Hyperammonemia.

Case reports of hyperammonemia due to urease-producing bacteria are found occasionally, but most of them are associated with urinary tract infections. We experienced a case of infectious enterocolitis with hyperammonemia in which the causative bacteria was speculated to be urease-producing bacteria. A Japanese woman in her 70s had been diagnosed with microscopic polyangiitis in a nearby hospital and was transferred to our hospital. Although the microscopic polyangiitis was relatively under control after treatment with steroids and rituximab, frequent diarrhea with hyperammonemia (324 µg/dl) appeared and she became comatose. Her blood ammonia decreased to 47 µg/dl and her consciousness recovered to a normal state after antibiotic treatment for infectious enterocolitis and ammonia detoxification therapy. Liver dysfunction, portosystemic shunt, excessive protein intake and constipation were not observed, and she took no medications that would cause hyperammonemia. Although culture results could not identify urease-producing bacteria, considering the clinical course, acute hyperammonemia was suspected to be due to urease-producing bacteria infection. It is necessary to consider the influence of urease-producing bacteria as a cause of acute hyperammonemia not only in urinary tract infections but also in infective enterocolitis.

Low-dose immunoglobulin G is not associated with mortality in patients with sepsis and septic shock.

BACKGROUND: The administration of low-dose intravenous immunoglobulin G (IVIgG) (5 g/day for 3 days; approximate total 0.3 g/kg) is widely used as an adjunctive treatment for patients with sepsis in Japan, but its efficacy in the reduction of mortality has not been evaluated. We investigated whether the administration of low-dose IVIgG is associated with clinically important outcomes including intensive care unit (ICU) and in-hospital mortality. METHODS: This is a post-hoc subgroup analysis of data from a retrospective cohort study, the Japan Septic Disseminated Intravascular Coagulation (JSEPTIC DIC) study. The JSEPTIC DIC study was conducted in 42 ICUs in 40 institutions throughout Japan, and it investigated associations between sepsis-related coagulopathy, anticoagulation therapies, and clinical outcomes of 3195 adult patients with sepsis and septic shock admitted to ICUs from January 2011 through December 2013. To investigate associations between low-dose IVIgG administration and mortalities, propensity score-based matching analysis was used. RESULTS: IVIgG was administered to 960 patients (30.8%). Patients who received IVIgG were more severely ill than those who did not (Acute Physiology and Chronic Health Evaluation (APACHE) II score 24.2 ± 8.8 vs 22.6 ± 8.7, p < 0.001). They had higher ICU mortality (22.8% vs 17.4%, p < 0.001), but similar in-hospital mortality (34.4% vs 31.0%, p = 0.066). In propensity score-matched analysis, 653 pairs were created. Both ICU mortality and in-hospital mortality were similar between the two groups (21.0% vs 18.1%, p = 0.185, and 32.9% vs 28.6%, p = 0.093, respectively) using generalized estimating equations fitted with logistic regression models adjusted for other therapeutic interventions. The administration of IVIgG was not associated with ICU or in-hospital mortality (odds ratio (OR) 0.883; 95% confidence interval (CI) 0.655-1.192, p = 0.417, and OR 0.957, 95% CI, 0.724-1.265, p = 0.758, respectively). CONCLUSIONS: In this analysis of a large cohort of patients with sepsis and septic shock, the administration of low-dose IVIgG as an adjunctive therapy was not associated with a decrease in ICU or in-hospital mortality. TRIAL REGISTRATION: University Hospital Medical Information Network Individual Clinical Trials Registry, UMIN-CTR000012543 . Registered on 10 December 2013.

Antithrombin Supplementation and Mortality in Sepsis-Induced Disseminated Intravascular Coagulation: A Multicenter Retrospective Observational Study.

Supplemental doses of antithrombin (AT) are widely used to treat sepsis-induced disseminated intravascular coagulation (DIC) in Japan. However, evidence on the benefits of AT supplementation for DIC is insufficient. This multicenter retrospective observational study aimed to clarify the effect of AT supplementation on sepsis-induced DIC using propensity score analyses. Data from 3,195 consecutive adult patients admitted to 42 intensive care units for severe sepsis treatment were retrospectively analyzed; 1,784 patients were diagnosed with DIC (n = 715, AT group; n = 1,069, control group). Inverse probability of treatment-weighted propensity score analysis indicated a statistically significant association between AT supplementation and lower in-hospital all-cause mortality (n = 1,784, odds ratio [95% confidence intervals]: 0.748 [0.572-0.978], P = 0.034). However, quintile-stratified propensity score analysis (n = 1,784, odds ratio: 0.823 [0.646-1.050], P = 0.117) and propensity score matching analysis (461 matching pairs, odds ratio: 0.855 [0.649-1.125], P = 0.263) did not show this association. In the early days after intensive care unit admission, the survival rate was statistically higher in the propensity score-matched AT group than in the propensity score-matched control group (P = 0.007). In DIC patients without concomitant heparin administration, similar results were observed. In conclusion, AT supplementation may be associated with reduced in-hospital all-cause mortality in patients with sepsis-induced DIC. However, the statistical robustness of this connection was not strong. In addition, although the number of transfusions needed in patients with AT supplementation increased, severe bleeding complications did not.

Characteristics, treatments, and outcomes of severe sepsis of 3195 ICU-treated adult patients throughout Japan during 2011-2013.

Severe sepsis is a major concern in the intensive care unit (ICU), although there is very little epidemiological information regarding severe sepsis in Japan. This study evaluated 3195 patients with severe sepsis in 42 ICUs throughout Japan. The patients with severe sepsis had a mean age of 70 ± 15 years and a mean Acute Physiology and Chronic Health Evaluation II score of 23 ± 9. The estimated survival rates at 28 and 90 days after ICU admission were 73.6 and 56.3 %, respectively.

[A Case of Life-Threatening Angioedema Occurred During Prolonged Angiotensin-Converting Enzyme Inhibitor Treatment].

Although angiotensin-converting enzyme (ACE) inhibitors are widely used as the first choice drug for treating hypertension, we have only a superficial understanding of their relationship to angioedema. We report a case of life-threatening angioedema. The case was a 60-year-old man who had been taking an ACE inhibitor for hypertension for 11 years. He visited his home doctor for dyspnea, and tongue and neck swelling. He was transported to our hospital because of the possibility of airway obstruction. On admission, his tongue and neck swelling became more severe. We performed an intubation using an endoscope and started airway management. We also stopped his ACE inhibitor. The severe tongue and neck swelling improved gradually and he was extubated on day 3. On the fifth day he was discharged. We diagnosed angioedema caused by an ACE inhibitor. Although the risk of airway obstruction with ACE inhibitors is acknowledged, we have only a superficial understanding of how prolonged ACE inhibitor treatment induces angioedema. So we should consider angioedema in cases of taking ACE inhibitors, especially in cases of prolonged treatment.

[Examination of relationship between lactate clearance and neurologic outcome in cardiac arrest induced by ventricular fibrillation].

A significant relationship between lactate clearance and mortality rates in cardiac arrest cases has been reported. However, the relationship between lactate clearance and neurologic outcomes in cardiac arrest cases is not clear. We examined lactate clearance in cardiac arrest cases induced by ventricular fibrillation. We investigated 13 patients with cardiac arrest induced by ventricular fibrillation from April, 2006 to March, 2012 in which therapeutic hypothermia was performed. Patients were classified into two groups: those with a favorable neurologic outcome (n=7) and those with a poor outcome (n=6). We compared lactate clearance levels between the two groups. There was no significant difference in lactate concentrations at admission and 8 or 24 hours lactate clearance between the two groups 8 or 24 hours after admission. This result suggests we may not predict the neurologic outcome of cardiac arrest cases induced by ventricular fibrillation using lactate clearance.

[A case of accidental hypothermia caused by cervical spinal cord injury].

Accidental hypothermia is the state in which body temperature falls due for exposure to a chilly environment. In accidental hypothermia, the mortality rate is higher the lower the body temperature. We report a case of a consciousness disorder and severe hypothermia, with a body temperature below 28 degrees C, in which it later became clear that a cervical spinal cord injury had been caused by a small external force. A 70-year-old woman was transported to our hospital in an ambulance for consciousness disturbance and severe hypothermia. At the time of arrival, her rectal temperature was 26.2 degrees C. We promptly performed rewarming. Her consciousness level became clear, but paralysis and diminished sensation were observed below the C5 domain. We suspected cervical spinal cord injury and performed cervical magnetic resonance imaging. She was diagnosed as having C5 cervical spinal cord injury. When there is a consciousness disorder due to accidental hypothermia, it might not be possible to evaluate the neurological value of the cervical spinal cord injury correctly. The presence of cervical spinal cord injury should be considered when patients have a decreased consciousness level due to hypothermia.

Continuous mild heat stress induces differentiation of mammalian myoblasts, shifting fiber type from fast to slow.

Local hyperthermia has been widely used as physical therapy for a number of diseases such as inflammatory osteoarticular disorders, tendinitis, and muscle injury. Local hyperthermia is clinically applied to improve blood and lymphatic flow to decrease swelling of tissues (e.g., skeletal muscle). As for muscle repair following injury, the mechanisms underlying the beneficial effects of hyperthermia-induced muscle repair are unknown. In this study, we investigated the direct effects of continuous heat stress on the differentiation of cultured mammalian myoblasts. Compared with control cultures grown at 37 degrees C, incubation at 39 degrees C (continuous mild heat stress; CMHS) enhanced myotube diameter, whereas myotubes were poorly formed at 41 degrees C by primary human skeletal muscle culture cells, human skeletal muscle myoblasts (HSMMs), and C2C12 mouse myoblasts. In HSMMs and C2C12 cells exposed to CMHS, mRNA and protein levels of myosin heavy chain (MyHC) type I were increased compared with the control cultures. The mRNA level of MyHC IIx was unaltered in HSMMs and decreased in C2C12 cells, compared with cells that were not exposed to heat stress. These results indicated a fast-to-slow fiber-type shift in myoblasts. We also examined upstream signals that might be responsible for the fast-to-slow shift of fiber types. CMHS enhanced the mRNA and protein levels of peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha in HSMMS and C2C12 cells but not the activities of MAPKs (ERK1/2 and p38 MAPK) in HSMMs and C2C12 cells. These data suggest that CMHS induces a fast-to-slow fiber-type shift of mammalian myoblasts through PGC-1alpha.

Age-related increase of insoluble, phosphorylated small heat shock proteins in human skeletal muscle.

Among mammalian heat shock proteins (Hsps), small Hsps (sHsps) are constitutively expressed in skeletal muscles. We investigated age-related changes of phosphorylation and cellular distribution of representative sHsps (Hsp27 and alphaB-crystallin) in human vastus lateralis muscle under resting conditions. We also examined upstream kinases which may be responsible for phosphorylation of sHsps, namely p38 mitogen-activated protein kinase (MAPK), MAPK-activated protein kinase-2, and extracellular signal-regulated kinase-1/2. The study groups consisted of nine young (15-38 years old) and nine aged (51-79 years old) patients who underwent orthopedic surgery. sHsps protein levels were higher in the insoluble fraction of aged muscles. The phosphorylated states of sHsps were enhanced in both the soluble and insoluble fraction of aged patients. The phosphorylated form of each upstream kinase was elevated in aged patients. Ubiquitinated proteins accumulated in the insoluble fractions of aged muscles. Aging mechanisms may affect the activation process of MAPKs, and the phosphorylation and accumulation of sHsps.

Molecular aspects of adrenal regulation for circadian glucocorticoid synthesis by chronic voluntary exercise.

Chronic voluntary running of mice is known to increase the circadian peak of plasma corticosterone without change in the level of adrenocorticotropic hormone (ACTH). In order to investigate how chronic exercise modulates the circadian HPA axis, we used two weeks of voluntary wheel running of mice and confirmed the significant increase of the circadian peak of plasma corticosterone without alteration in ACTH level. To elucidate the mechanisms of exercise modulation on corticosterone synthesis, we first examined the levels of transcripts involved in corticosterone synthesis of the adrenal gland. Among them, only steroidogenic acute regulatory protein (StAR), the rate-limiting factor that transfers substrate cholesterol into inner mitochondrial membrane, showed significantly higher expression in the exercise group. Since the splanchnic nerve input to the adrenal gland has been reported as a factor involved in the direct modulation of corticosterone synthesis, we next examined the expression levels of enzymes for the catecholamine synthesis as indices of sympatho-adrenomedullary activity. We found that the only rate-limiting enzyme, tyrosine hydroxylase (TH), was significantly higher in the adrenals of exercise group. In addition to the increment of StAR and TH mRNA in response to the chronic exercise, surprisingly, we found only these factors showed the circadian variation in its expression levels that was correlated to the circadian rhythm of corticosterone. Chronic exercise seems to alter the circadian corticosterone synthesis, at least partially via altering the levels of circadian-regulated transcripts, StAR and TH of the adrenal gland.

Antiamyloidogenic and neuroprotective functions of cathepsin B: implications for Alzheimer's disease.

Alzheimer's disease (AD) may result from the accumulation of amyloid-beta (Abeta) peptides in the brain. The cysteine protease cathepsin B (CatB) is associated with amyloid plaques in AD brains and has been suspected to increase Abeta production. Here, we demonstrate that CatB actually reduces levels of Abeta peptides, especially the aggregation-prone species Abeta1-42, through proteolytic cleavage. Genetic inactivation of CatB in mice with neuronal expression of familial AD-mutant human amyloid precursor protein (hAPP) increased the relative abundance of Abeta1-42, worsening plaque deposition and other AD-related pathologies. Lentivirus-mediated expression of CatB in aged hAPP mice reduced preexisting amyloid deposits, even thioflavin S-positive plaques. Under cell-free conditions, CatB effectively cleaved Abeta1-42, generating C-terminally truncated Abeta peptides that are less amyloidogenic. Thus, CatB likely fulfills antiamyloidogenic and neuroprotective functions. Insufficient CatB activity might promote AD; increasing CatB activity could counteract the neuropathology of this disease.

Suppression of cofilin phosphorylation in insulin-stimulated ruffling membrane formation in KB cells.

Various cellular events such as cell motility and division are directed by the actin cytoskeleton under the control of its regulatory system. Cofilin is a low molecular weight actin-modulating protein that severs and depolymerizes F-actin and is shown to enhance actin filament dynamics. The activity of cofilin is negatively regulated by phosphorylation at Ser-3. In human epidermoid carcinoma KB cells, insulin treatment induces characteristic ruffling membranes, and it was reported that LIMK1, a cofilin kinase, was activated in these cells treated with insulin. Since cofilin is a key protein responsible for establishing the rapid turnover of actin filaments, it appears to be contradictory that cofilin is phosphorylated (inactivated) by a stimulus that is known to induce the highly dynamic actin structure, ruffling membranes. Therefore, we examined the phosphorylation state of endogenous cofilin in KB cells treated with insulin. The dephosphorylated form of cofilin increased with insulin treatment, as analyzed by nonequilibrium pH gradient gel electrophoresis (NEpHGE)-immunoblotting. Cell labeling with (32)P orthophosphate indicated that cofilin was being continuously phosphorylated and dephosphorylated, and that the apparent insulin-induced dephosphorylation was due to suppression of continuous phosphorylation and not to enhanced dephosphorylation. Further, we examined the localization of the phosphorylated form of cofilin using phospho-specific antibody raised against phosphorylated cofilin. Surprisingly, phosphorylated cofilin was concentrated in the ruffling membranes induced by insulin. These results suggest that the examination of the kinetics and spatial regulation of phosphorylation is critical for the elucidation of the role of cofilin and upstream kinases in actin reorganization.