Tomoya Hirose

Treatment effects of recombinant human soluble thrombomodulin in patients with severe sepsis: a historical control study

IntroductionCross-talk between the coagulation system and inflammatory reactions during sepsis causes organ damage followed by multiple organ dysfunction syndrome or even death. Therefore, anticoagulant therapies have been expected to be beneficial in the treatment of severe sepsis. Recombinant human soluble thrombomodulin (rhTM) binds to thrombin to inactivate coagulation, and the thrombin-rhTM complex activates protein C to produce activated protein C. The purpose of this study was to examine the efficacy of rhTM for treating patients with sepsis-induced disseminated intravascular coagulation (DIC).MethodsThis study comprised 65 patients with sepsis-induced DIC who required ventilatory management. All patients fulfilled the criteria of severe sepsis and the International Society on Thrombosis and Haemostasis criteria for overt DIC. The initial 45 patients were treated without rhTM (control group), and the following 20 consecutive patients were treated with rhTM (0.06 mg/kg/day) for six days (rhTM group). The primary outcome measure was 28-day mortality. Stepwise multivariate Cox regression analysis was used to assess which independent variables were associated with mortality. Comparisons of Sequential Organ Failure Assessment (SOFA) score on sequential days between the two groups were analyzed by repeated measures analysis of variance.ResultsCox regression analysis showed 28-day mortality to be significantly lower in the rhTM group than in the control group (adjusted hazard ratio, 0.303; 95% confidence interval, 0.106 to 0.871; P = 0.027). SOFA score in the rhTM group decreased significantly in comparison with that in the control group (P = 0.028). In the post hoc test, SOFA score decreased rapidly in the rhTM group compared with that in the control group on day 1 (P < 0.05).ConclusionsWe found that rhTM administration may improve organ dysfunction in patients with sepsis-induced DIC. Further clinical investigations are necessary to evaluate the effect of rhTM on the pathophysiology of sepsis-induced DIC.

Nature of Electron Transport by Pyridine-Based Tripodal Anchors: Potential for Robust and Conductive Single-Molecule Junctions with Gold Electrodes

We have designed and synthesized a pyridine-based tripodal anchor unit to construct a single-molecule junction with a gold electrode. The advantage of tripodal anchoring to a gold surface was unambiguously demonstrated by cyclic voltammetry measurements. X-ray photoelectron spectroscopy measurements indicated that the π orbital of pyridine contributes to the physical adsorption of the tripodal anchor unit to the gold surface. The conductance of a single-molecule junction that consists of the tripodal anchor and diphenyl acetylene was measured by modified scanning tunneling microscope techniques and successfully determined to be 5 ± 1 × 10(-4)G(0). Finally, by analyzing the transport mechanism based on ab initio calculations, the participation of the π orbital of the anchor moieties was predicted. The tripodal structure is expected to form a robust junction, and pyridine is predicted to achieve π-channel electric transport.

Presence of Neutrophil Extracellular Traps and Citrullinated Histone H3 in the Bloodstream of Critically Ill Patients

Neutrophil extracellular traps (NETs), a newly identified immune mechanism, are induced by inflammatory stimuli. Modification by citrullination of histone H3 is thought to be involved in the in vitro formation of NETs. The purposes of this study were to evaluate whether NETs and citrullinated histone H3 (Cit-H3) are present in the bloodstream of critically ill patients and to identify correlations with clinical and biological parameters. Blood samples were collected from intubated patients at the time of ICU admission from April to June 2011. To identify NETs, DNA and histone H3 were visualized simultaneously by immunofluorescence in blood smears. Cit-H3 was detected using a specific antibody. We assessed relationships of the presence of NETs and Cit-H3 with the existence of bacteria in tracheal aspirate, SIRS, diagnosis, WBC count, and concentrations of IL-8, TNF-α, cf-DNA, lactate, and HMGB1. Forty-nine patients were included. The median of age was 66.0 (IQR: 52.5–76.0) years. The diagnoses included trauma (7, 14.3%), infection (14, 28.6%), resuscitation from cardiopulmonary arrest (8, 16.3%), acute poisoning (4, 8.1%), heart disease (4, 8.1%), brain stroke (8, 16.3%), heat stroke (2, 4.1%), and others (2, 4.1%). We identified NETs in 5 patients and Cit-H3 in 11 patients. NETs and/or Cit-H3 were observed more frequently in “the presence of bacteria in tracheal aspirate” group (11/22, 50.0%) than in “the absence of bacteria in tracheal aspirate” group (4/27, 14.8%) (p<.01). Multiple logistic regression analysis showed that only the presence of bacteria in tracheal aspirate was significantly associated with the presence of NETs and/or Cit-H3. The presence of bacteria in tracheal aspirate may be one important factor associated with NET formation. NETs may play a pivotal role in the biological defense against the dissemination of pathogens from the respiratory tract to the bloodstream in potentially infected patients.

Altered balance of the aminogram in patients with sepsis – The relation to mortality

BACKGROUND & AIMS Protein metabolism is important in healing wounds, supporting immune function, and maintaining lean body mass. Determination of adequate requirements of amino acids has not been thoroughly clarified in critically ill patients. The purpose of this study was to evaluate 23 plasma amino acids in patients with sepsis and determine prognostic factors. METHODS This study was a retrospective study. Plasma aminograms were measured in patients with sepsis. We evaluated minimum and maximum values of each amino acid and evaluated prognostic factors by multivariate logistic regression analysis and classification and regression tree (CART) analysis. RESULTS The study comprised 77 patients. The median intensive care unit (ICU) stay was 30 days (interquartile range 19.5-55.5 days). Whole mortality rate was 39.0%. Maximum values of glutamine, glutamate, glycine, alanine, methionine, phenylalanine, and histidine and minimum values of glutamate, taurine, serine, isoleucine, leucine, tyrosine, ornithine, tryptophan, and arginine were significantly different between survivors and non-survivors (P < 0.05). Statistical analysis using CART analysis revealed the minimum value of glutamate and maximum value of methionine to be significant prognostic factors for mortality (P < 0.05). CONCLUSION Plasma aminograms were significantly altered in patients with sepsis. Altered balance of aminograms was significantly associated with mortality in patients with sepsis requiring a long ICU stay.

Synthesis of tripodal anchor units bearing selenium functional groups and their adsorption behaviour on gold

The synthesis of new selenium-functionalized tripodal anchor units composed by a tetraphenylmethane core with three selenocyanate or selenol arms has been successfully accomplished and CV, XPS and UPS measurements of their monolayers on a gold surface were investigated.

Identification of neutrophil extracellular traps in the blood of patients with systemic inflammatory response syndrome.

Objective Neutrophils are able to form ‘neutrophil extracellular traps’ (NETs), which they use to trap and kill pathogens such as bacteria and fungi at the foci of infection. This observational study investigated the presence of NETs in the blood from critically ill patients and healthy volunteers. Methods Fluorescent triple-colour immunocytochemical analysis of blood smears collected from patients with systemic inflammatory response syndrome (SIRS; associated with various clinical conditions) who had been hospitalized in the intensive care unit, and healthy volunteers, was undertaken to identify NETs in the blood. Blood smears were stained for DNA, histone H1 and neutrophil elastase. Results NETs were identified in 10 of 21 (47.6%) blood samples from the study group compared with none of the blood samples from eight healthy volunteers. Conclusion These data suggest that fluorescent triple-colour immunocytochemical staining of NETs in the blood could be used to simplify the early identification of critically ill patients with SIRS. Larger studies are required to clarify the pathophysiological role of NETs in this specific patient population.

Refractory hypoglycemia and subsequent cardiogenic shock in starvation and refeeding: report of three cases.

OBJECTIVE Although starvation is associated with high in-hospital mortality, its related cardiac complications are not sufficiently understood. The aim of this study was to determine the clinical course and pathogenesis of cardiac complications in malnourished patients. METHODS We reviewed three cases of hypoglycemia and hypotriglyceridemia with cardiac complications in starvation. RESULTS This report concerns three patients, respectively suffering from anorexia nervosa, esophageal carcinoma, and Parkinsons disease. Their ages ranged from 18 to 70 y, body mass index was 11.5 ± 1.5 kg/m2 (mean ± SD), and the main symptom was coma. The average blood glucose level was 15.7 ± 7.8 mg/dL without any history of insulin use or diabetes mellitus. In all cases, hypoglycemia was refractory and repetitive so that continuous glucose administration was required to maintain euglycemia. Serum triglyceride and non-esterified fatty acid levels were also very low (7 ± 4 mg/dL and 10 ± 9.1 μEq/L, respectively). Levels of serum potassium, phosphate, and magnesium were almost normal at admission. The main cardiac complications included Takotsubo cardiomyopathy and cardiac arrest. All patients survived as a result of intensive treatment. CONCLUSIONS Repetitive severe hypoglycemia without known background causes should be viewed as an important sign. Once this occurs, the administration of a much higher caloric input than usual accompanied by intensive monitoring will be required to maintain appropriate glucose levels. The early identification of such patients seems to be essential to reduce the high risk for cardiac complications during starvation and refeeding.

Neutrophil extracellular traps in bronchial aspirates: a quantitative analysis

Neutrophil extracellular traps (NETs) are structures composed of DNA and granular proteins, which rapidly trap and kill pathogens. The formation of NETs has been detected during infection in animal experiments, but their role in humans is unclear. The purposes of this study were to quantitatively evaluate the production of NETs during acute respiratory infection and to study the relationship between the NET length and various inflammatory mediators. We examined bronchial aspirates collected from nine intubated patients in an intensive care unit. Samples were collected at the onset of acute respiratory infection (day 0) and on days 1, 3–5, and 6–8. The NET length was visualised by immunohistochemistry and quantified using computer tracing software. The NET length was measured and compared at each time point. The length differed significantly between time points (p<0.001). NETs were significantly longer on day 1 than on day 0 (p<0.001). Neutrophils released NETs abundantly in response to respiratory infection and regression analysis showed that NET length correlated with six clinical parameters (white blood cells, platelets, lactate, CXC ligand-2, interleukin-8, and procalcitonin) as the explanatory variables. NETs in bronchial aspirates may reflect disease progression of respiratory infections. Quantification of NETs in bronchial aspirates may provide a new indicator of inflammation. NET length increases with respiratory inflammation which correlates with progression of infections http://ow.ly/sPbEX

Case of invasive nontypable Haemophilus influenzae respiratory tract infection with a large quantity of neutrophil extracellular traps in sputum.

Haemophilus influenzae type b was once the most common cause of invasive H. influenzae infection, but the incidence of this disease has decreased markedly with introduction of conjugate vaccines to prevent the disease. In contrast, the incidence of invasive infection caused by nontypable H. influenzae has increased in the US and in European countries. Neutrophil extracellular traps (NETs) are fibrous structures released extracellularly from activated neutrophils during inflammation, including in pneumonia, and rapidly trap and kill pathogens as a first line of immunological defense. However, their function and pathological role have not been fully investigated. Here, we report a case of fatal nontypable H. influenzae infection with severe pneumonia and bacteremia in an adult found to have a vast amount of NETs in his sputum. The patient had a two-day history of common cold-like symptoms and was taken to the emergency room as a cardiopulmonary arrest. He recovered temporarily, but died soon afterwards, although appropriate antibiotic therapy and general management had been instituted. Massive lobular pneumonia and sepsis due to nontypable H. influenzae was found, in spite of H. influenzae type b vaccine being available. His sputum showed numerous bacteria phagocytosed by neutrophils, and immunohistological staining indicated a number of NETs containing DNA, histone H3, and neutrophil elastase. This case highlights an association between formation of NETs and severe respiratory and septic infection. An increase in severe nontypable H. influenzae disease can be expected as a result of “pathogen shift” due to increased use of the H. influenzae type b vaccine in Japan.

Fewer REBOA complications with smaller devices and partial occlusion: evidence from a multicentre registry in Japan

Background Resuscitative endovascular balloon occlusion of the aorta (REBOA) performed by emergency physicians has been gaining acceptance as a less invasive technique than resuscitative thoracotomy. Objective To evaluate access-related complications and duration of occlusions during REBOA. Methods Patients with haemorrhagic shock requiring REBOA, from 18 hospitals in Japan, included in the DIRECT-IABO Registry were studied. REBOA-related characteristics were compared between non-survivors and survivors at 24 hours. 24-Hour survivors were categorised into groups with small (≤8 Fr), large (≥9 Fr) or unusual sheaths (oversized or multiple) to assess the relationship between the sheath size and complications. Haemodynamic response, occlusion duration and outcomes were compared between groups with partial and complete REBOA. Results Between August 2011 and December 2015, 142 adults undergoing REBOA were analysed. REBOA procedures were predominantly (94%) performed by emergency medicine (EM) physicians. The median duration of the small sheath (n=53) was 19 hours compared with 7.5 hours for the larger sheaths (P=0.025). Smaller sheaths were more likely to be removed using external manual compression (96% vs 45%, P<0.001). One case of a common femoral artery thrombus (large group) and two cases of amputation (unusual group) were identified. Partial REBOA was carried out in more cases (n=78) and resulted in a better haemodynamic response than complete REBOA (improvement in haemodynamics, 92% vs 70%, P=0.004; achievement of stability, 78% vs 51%, P=0.007) and allowed longer occlusion duration (median 58 vs 33 min, P=0.041). No statistically significant difference in 24-hour or 30-day survival was found between partial and complete REBOA. Conclusion In Japan, EM physicians undertake the majority of REBOA procedures. Smaller sheaths appear to have fewer complications despite relatively prolonged placement and require external compression on removal. Although REBOA is a rarely performed procedure, partial REBOA, which may extend the occlusion duration without a reduction in survival, is used more commonly in Japan.