Mayumi Nakahara

Recombinant Thrombomodulin Protects Mice against Histone-Induced Lethal Thromboembolism

Introduction Recent studies have shown that histones, the chief protein component of chromatin, are released into the extracellular space during sepsis, trauma, and ischemia-reperfusion injury, and act as major mediators of the death of an organism. This study was designed to elucidate the cellular and molecular basis of histone-induced lethality and to assess the protective effects of recombinant thrombomodulin (rTM). rTM has been approved for the treatment of disseminated intravascular coagulation (DIC) in Japan, and is currently undergoing a phase III clinical trial in the United States. Methods Histone H3 levels in plasma of healthy volunteers and patients with sepsis and DIC were measured using enzyme-linked immunosorbent assay. Male C57BL/6 mice were injected intravenously with purified histones, and pathological examinations were performed. The protective effects of rTM against histone toxicity were analyzed both in vitro and in mice. Results Histone H3 was not detectable in plasma of healthy volunteers, but significant levels were observed in patients with sepsis and DIC. These levels were higher in non-survivors than in survivors. Extracellular histones triggered platelet aggregation, leading to thrombotic occlusion of pulmonary capillaries and subsequent right-sided heart failure in mice. These mice displayed symptoms of DIC, including thrombocytopenia, prolonged prothrombin time, decreased fibrinogen, fibrin deposition in capillaries, and bleeding. Platelet depletion protected mice from histone-induced death in the first 30 minutes, suggesting that vessel occlusion by platelet-rich thrombi might be responsible for death during the early phase. Furthermore, rTM bound to extracellular histones, suppressed histone-induced platelet aggregation, thrombotic occlusion of pulmonary capillaries, and dilatation of the right ventricle, and rescued mice from lethal thromboembolism. Conclusions Extracellular histones cause massive thromboembolism associated with consumptive coagulopathy, which is diagnostically indistinguishable from DIC. rTM binds to histones and neutralizes the prothrombotic action of histones. This may contribute to the effectiveness of rTM against DIC.

Sepsis-induced myocardial dysfunction: pathophysiology and management

Sepsis is aggravated by an inappropriate immune response to invading microorganisms, which occasionally leads to multiple organ failure. Several lines of evidence suggest that the ventricular myocardium is depressed during sepsis with features of diastolic dysfunction. Potential candidates responsible for septic cardiomyopathy include pathogen-associated molecular patterns (PAMPs), cytokines, and nitric oxide. Extracellular histones and high-mobility group box 1 that function as endogenous damage-associated molecular patterns (DAMPs) also contribute to the myocardial dysfunction associated with sepsis. If untreated, persistent shock causes cellular injury and the liberation of further DAMPs. Like PAMPs, DAMPs have the potential to activate inflammation, creating a vicious circle. Early infection control with adequate antibiotic care is important during septic shock to decrease PAMPs arising from invasive microorganisms. Early aggressive fluid resuscitation as well as the administration of vasopressors and inotropes is also important to reduce DAMPs generated by damaged cells although excessive volume loading, and prolonged administration of catecholamines might be harmful. This review delineates some features of septic myocardial dysfunction, assesses its most common underlying mechanisms, and briefly outlines current therapeutic strategies and potential future approaches.

Cerebral monitoring using near-infrared time-resolved spectroscopy and postoperative cognitive dysfunction.

Abstract Recently, near-infrared time-resolved spectroscopy (TRS), which is an effective means of quantitatively monitoring tissue oxygenation, has been developed. We examined whether postoperative cognitive dysfunction (POCD) can be predicted by cerebral monitoring using TRS during cardiac surgery.

Non-invasive Monitoring of Hepatic Oxygenation Using Time-Resolved Spectroscopy

UNLABELLED The aim of the present study was to investigate whether changes in hepatic oxygenation can be detected by time-resolved spectroscopy (TRS) placed on the skin surface above the liver. METHODS With approval of the local Hospital Ethics Committee and informed consent, six healthy volunteers aged 28.8 (25-36) years, and five patients with chronic renal failure aged 70.6 (58-81) years were studied. In six healthy volunteers, following echography, TRS (TRS-10, Hamamatsu Photonics K.K., Hamamatsu, Japan) probes consisting of a near-infrared light (at 760, 800, 835 nm) emitter and a receiver optode, were placed 4 cm apart on the abdominal skin surface above the liver or at least 10 cm distant from the liver. In five patients with chronic renal failure, following echography, TRS probes were placed 4 cm apart on the skin surface above the liver during hemodialysis (HD). RESULTS In six healthy volunteers, the values of abdominal total hemoglobin concentration (tHb) were significantly higher in the liver area than in the other area (80.6±26.81 vs 44.6±23.1 μM, p=0.0017), while the value of abdominal SO2 in the liver area was nearly the same as that in the other area (71.5±3.6 vs 73.6±4.6%, p=0.19). The values of mean optical pathlength and scattering coefficient (μs) at 800 nm in the liver area were significantly different from those in the other area (21.3±4.9 vs 29.2±5 cm, p=0.0004, and 7.97±1.14 vs 9.02±0.51 cm(-1), p=0.015). One of five patients with chronic renal failure complained of severe abdominal pain during HD, and abdominal SO2 decreased from 53 to 22%; however, pain relief occurred following cessation of HD, and SO2 recovered to the baseline level. CONCLUSIONS Our data suggest that the optical properties of the liver may be measured by the TRS placed on the skin surface, and the hepatic oxygenation may act as a non-invasive monitoring for early detection of intestinal ischemia.

0633. Time-resolved spectroscopy using non-invasive monitoring may detect hapatic ischemia

The aim of the present study was to investigate whether the changes in hepatic oxygenation can be detected by time-resolved spectroscopy (TRS) placed on the skin surface above the liver.