Infarct Size Limitation by Bradykinin Receptor Activation Is Mediated by the Mitochondrial But Not by the Sarcolemmal KATP Channel

Earlier studies have shown that activation of bradykinin B₂ receptor triggers protein kinase C (PKC)-mediated cardioprotective mechanism in ischemic preconditioning (PC). In the present study, we examined whether the effector in this B₂-receptor triggered pathway of PC is the ATP sensitive potassium (K_ATP) channel in the mitochondria (mito-K_ATP channel) or K_ATP channel in the sarcolemma (sarc-K_ATP channel). Isolated rabbit hearts were perfused with modified Krebs-Henseleit buffer in a Langendorff mode, and regional myocardial ischemia was induced by occluding a left coronary artery for 30 min and then reperfusing for 2 hours. Infarct size was determined by triphenyltetrazolium chloride staining and expressed as a percentage of area at risk (% IS/AR). Infusion of bradykinin (500 nmol/L) for 15 min prior to ischemia significantly reduced % IS/AR from 37.4 ± 2.9 (SE) of the untreated controls to 12.0 ± 3.3%. This protective effect of bradykinin was completely abolished by coinfusion of 5-hydroxydecanoate (5-HD, 50 mol/L), a selective mito-K_ATP channel blocker (% IS/AR = 44.2 ± 6.4). In contrast, a high dose of HMR1098 (20 mol/L), which is a newly developed sarc-K_ATP channel selective blocker with IC₅₀ of 0.6 mol/L, failed to modify the infarct size limitation by preischemic infusion of bradykinin (% IS/AR = 11.7 ± 3.4). Neither 5-HD nor HMR1098 alone modified infarct size (% IS/AR = 37.8 ± 3.8 and 35.1 ± 6.2, respectively). These results suggest that opening of the mito-K_ATP channel but not the sarc-K_ATP channel is involved in infarct size limitation by a mechanism triggered by bradykinin B₂ receptor activation.     

Risk appraisal and endoscopic screening for esophageal squamous cell carcinoma in Japanese populations

Epidemiological studies have shown several strong predictors for selecting Japanese persons at high risk for esophageal squamous cell carcinoma (ESCC). (1) Alcohol consumption and tobacco smoking synergistically increase the risk, and a low intake of green and yellow vegetables or fruit and a low body mass index also increase the risk of ESCC. (2) The presence of esophageal distinct iodine-unstained lesions and melanosis are associated with an increased risk of ESCC. (3) The combination of alcohol consumption and inactive heterozygous aldehyde dehydrogenase-2 (ALDH2) and less-active homozygous alcohol dehydrogenase-1B (ADH1B) increases the risk of ESCC in a multiplicative fashion. (4) The results of a simple flushing questionnaire predict the ALDH2 phenotype with a high accuracy. (5) High mean corpuscular volume (MCV), which is induced by heavy drinking, high acetaldehyde exposure, heavy smoking, and poor nutrition, may be useful in identifying high-risk persons. Endoscopic screening with esophageal iodine staining in Japanese high-risk populations yields very high rates of early ESCC. Treatment of early ESCC by endoscopic mucosectomy has become a widespread practice in Japan and has succeeded in improving the outcome of this high-mortality cancer. New evidence concerning ALDH2/ADH1B/alcohol flushing/MCV-related cancer susceptibility has renewed interest in alcohol and acetaldehyde as important subjects for cancer research and has served as a powerful tool for cancer prevention and cancer screening of Japanese subjects. Review articles on this topic also appeared in the previous issue (Volume 4 Number 3). An editorial related to this article is available at .     

A case of hepatocellular carcinoma with tuberculoma within tumor tissue

We made a diagnosis of hepatocellular carcinoma and performed partial resection of the liver in a 72 year-old woman. Granulomas were observed within hepatocellular carcinoma in the surgical specimen. Microscopic findings demonstrated the granulomas particularly within the tumor, and showed that they were composed of epithelioid cells with caseous necrosis. These tuberculomas compressed the tumor cells, and many lymphocytes had infiltrated the tumor around the tuberculomas. The cancer stage of the patient was early and her prognosis is good.     

Fas-associated death domain protein is a Fas-mediated apoptosis modulator in synoviocytes

OBJECTIVE: To understand the intracellular regulatory mechanisms in Fas-mediated apoptosis of synoviocytes, we examined the involvement of caspases [caspase-1/ICE (interleukin-1beta converting enzyme), caspase-3/CPP32, and caspase-8/FLICE] and Fas-associated death domain protein (FADD) forming a death-inducing signalling complex (DISC) in Fas-mediated apoptosis of synoviocytes. METHODS: Synoviocytes were obtained from rheumatoid arthritis (RA) and osteoarthritis (OA) patients. The number of dead cells was counted after treatment with anti-Fas monoclonal antibody in the presence of caspase-1-, -3-, or -8-specific inhibitors. The involvement of caspases and FADD in Fas-mediated apoptosis of RA synoviocytes was examined by immunoblot and immunoprecipitation analyses. RESULTS: RA synoviocytes expressed high levels of caspase-3, caspase-8, and FADD compared with OA synoviocytes. Interestingly, Fas ligation activated caspase-8 and caspase-3 with the cleavage of poly(ADP-ribose) polymerase (PARP), corresponding to apoptosis of RA synoviocytes. Furthermore, specific inhibitors for caspase-3 and caspase-8 but not caspase-1 suppressed Fas-induced apoptosis of RA synoviocytes in a dose- and time-dependent manner. Caspase-8-specific inhibitor suppressed the activation of caspase-3 after Fas ligation on RA synoviocytes. Importantly, FADD was selectively recruited to the Fas death domain during Fas-mediated apoptosis of RA synoviocytes, consistent with sensitivity to the Fas-mediated apoptosis. CONCLUSION: Our findings suggest that Fas-mediated apoptosis in synoviocytes may be regulated at the level of recruitment of FADD to the DISC, subsequently leading to the activation of the FADD/caspase-8/caspase-3 signalling pathway.     

Tuning of Sol–Gel Transition in the Mixed Polymer Micelle Solutions of Copolymer Mixtures Consisting of Enantiomeric Diblock and Triblock Copolymers of Polylactide and Poly(ethylene glycol)

Poly(ethylene glycol) (PEG) is partially furanylated with different feed ratios of furfuryl isocyanate and used as the macro initiator of ring‐opening polymerization of l ‐ and d ‐lactides to synthesize copolymer mixtures of furan‐terminated AB diblock and ABA triblock copolymers (poly(oxyethylene)–poly(l ‐lactide)/poly(l ‐lactide)–poly(oxyethylene)–poly(l ‐lactide) and poly(oxyethylene–poly(d ‐lactide)/poly(d ‐lactide)–poly(oxyethylene)–poly‐(d ‐lactide)) having different diblock/triblock ratios. The mixed micelle solutions of these enantiomeric copolymer mixtures undergo sol‐to‐gel or gel‐to‐sol transition depending on the diblock/triblock ratio of the copolymer mixtures. The rheological properties of the mixed micelle solutions could also be controlled by changing the diblock/triblock ratios or the initial furanylation ratio of PEG.

     

Mild decrease in heart rate during early phase of targeted temperature management following tachycardia on admission is associated with unfavorable neurological outcomes after severe traumatic brain injury: a post hoc analysis of a multicenter randomized controlled trial

Background

The association between isolated admission heart rate (HR) and prognosis has been discussed, but not that between gross HR change and neurological outcome in patients with severe traumatic brain injury (TBI). In the acute phase of severe TBI, HR is influenced by several factors (e.g., pain, sympathetic activation, hypovolemia, fever, body temperature). Therefore, admission HR and gross HR change should be examined in patients with TBI treated with a well-designed protocol, such as was done in the Brain Hypothermia (B-HYPO) Study.

Methods

This was a post hoc analysis of the B-HYPO Study, which was conducted as a prospective, multicenter, randomized controlled trial in patients with severe TBI receiving mild therapeutic hypothermia (MTH; 32.0?°C–34.0?°C) or fever control (35.5?°C–37.0?°C) in Japan. Patients with MTH were examined, and HR change (%HR) in the early MTH phase was calculated as follows: [admission HR – HR at day 1]/admission HR?×?100. Patients were divided into six groups, using admission HR (<?80, 80–99, ≤?100) and median of %HR; i.e., group (Admission HR <?80 and %HR ≥?18.6); group (Admission HR <?80 and %HR <?18.6); group (Admission HR 80–99 and %HR ≥?18.6); group (Admission HR 80–99 and %HR <?18.6); group (Admission HR ≥100 and %HR ≥?18.6); and group (Admission HR ≥100 and %HR <?18.6). The primary outcome was an adjusted predicted probability of unfavorable neurological outcome at 6 months after TBI according to Glasgow Outcome Scale score, which is a measure of functional recovery and defined as severe disability, persistent vegetative state, and death.

Results

Overall, 79 patients with MTH (52.7% of the original trial) were examined; among these, unfavorable neurological outcomes were observed in 53.2%. Among all the groups, group (Admission HR ≥100 and %HR <?18.6) exhibited the highest proportion of unfavorable outcomes, and 82.3% of patients had an adjusted predicted probability of unfavorable outcomes, whereas those in group (Admission HR <?80 and %HR ≥?18.6) developed only 22.8% (p?=?0.04).

Conclusions

Mild HR decrease during the early phase of targeted temperature management following tachycardia at admission can be associated with unfavorable neurological outcomes after severe TBI.

     

Leucine-rich alpha-2 glycoprotein is a potential biomarker to monitor disease activity in inflammatory bowel disease receiving adalimumab: PLANET study

Journal of Gastroenterology - This multicenter prospective study (UMIN000019958) aimed to evaluate the usefulness of serum leucin-rich alpha-2 glycoprotein (LRG) levels in monitoring disease...     

Does Reperfusion per se Kill Myocytes in the Heart?

Journal of Thrombosis and Thrombolysis -     

Interleukin-18 overproduction exacerbates the development of colitis with markedly infiltrated macrophages in interleukin-18 transgenic mice

BACKGROUND AND AIM: The authors have previously shown that production of interleukin (IL)-18 was increased in the inflamed mucosa of patients with Crohn's disease (CD) and blockade of IL-18 ameliorated the murine model of CD. This demonstrated that IL-18 plays a significant role during intestinal inflammation. However, the initial role of IL-18 during intestinal inflammation was unclear; therefore the susceptibility of IL-18 transgenic (Tg) mice to acute dextran sulfate sodium (DSS)-induced colitis was examined. METHODS: Interleukin-18 Tg and wild-type (WT) mice were fed 2.0% of DSS for 8 days. The total clinical scores (bodyweight loss, stool consistency, and rectal bleeding), colon length and histological scores were assessed. The expressions of surface markers and IL-18 on infiltrating lamina propria mononuclear cells were analyzed immunohistochemistrically. Mesenteric lymph node (MLN) cells were isolated and the expressions of CD4+ T-cell activation markers (CD69, CD25 and IL18R) were analyzed by flow cytometry. RESULTS: The IL-18 Tg mice exhibited an increased susceptibility to DSS-induced colitis, as shown by significantly increased clinical, histological scores, and more severe colonic shortening compared with WT mice. Immunohistochemical analysis revealed a significant increase of IL-18 production and CD11b+ macrophages but not CD4+ T cells in the inflamed mucosa in DSS-fed IL-18 Tg compared with DSS-fed WT mice. Furthermore, MLN cells revealed no evidence of increased CD4+ T-cell activation in DSS-fed IL-18 Tg. CONCLUSIONS: These findings suggest that IL-18 overproduction in the mucosa plays an important role in the marked infiltration of macrophages and exacerbates colitis in IL-18 Tg mice.