Reperfusion after brain ischemia causes thrombus formation and microcirculatory disturbances, which are dependent on the platelet glycoprotein Ib-von Willebrand factor (VWF) axis. Because ADAMTS13 cleaves VWF and limits platelet-dependent thrombus growth, ADAMTS13 may ameliorate ischemic brain damage in acute stroke. We investigated the effects of ADAMTS13 on ischemia-reperfusion injury using a 30-minute middle cerebral artery occlusion model in Adamts13 ؊/؊ and wild-type mice. After reperfusion for 0.5 hours, the regional cerebral blood flow in the ischemic cortex was decreased markedly in Adamts13 ؊/؊ mice compared with wild-type mice (P < .05), which also resulted in a larger infarct volume after 24 hours for Adamts13 ؊/؊ compared with wild-type mice (P < .01). Thus, Adamts13 gene deletion aggravated ischemic brain damage, suggesting that ADAMTS13 may protect the brain from ischemia by regulating VWF-platelet interactions after reperfusion. These results indicate that ADAMTS13 may be a useful therapeutic agent for stroke. (Blood. 2010; 115:1650-1653) Introductionvon Willebrand factor (VWF) is a large multimeric protein that plays a key role in thrombus formation by tethering platelets at sites of vascular injury. 1 Smaller VWF multimers are less active, and the potent thrombogenic activity of ultra-large VWF (ULVWF) secreted from endothelium is regulated in vivo through cleavage by ADAMTS13. 2,3 The importance of this mechanism for normal hemostasis is supported by evidence that patients with deficiency of ADAMTS13 function, diagnosed with thrombotic thrombocytopenic purpura, have ULVWF in circulating blood and VWFdependent microvascular thrombosis. 2 Recently, we demonstrated that ADAMTS13 cleaves VWF on the surface of platelet thrombi in a shear force-dependent manner, which limits thrombus growth in vitro. 4 These data suggest that ADAMTS13 is a key molecule that maintains a physiologic balance between hemostasis and thrombosis through regulation of VWF function in vivo.ADAMTS13 function is crucial for preventing thrombosis in the cerebral microvasculature, as indicated by the occurrence of neurologic deficits in thrombotic thrombocytopenic purpura, but the role of ADMTS13 in the pathogenesis of reperfusion injury after arterial thrombosis has not been established. To address this issue, we investigated the role of ADAMTS13 in a transient middle cerebral arterial occlusion (MCAO) model of ischemia-reperfusion injury in the mouse brain 5 using Adamts Ϫ/Ϫ mice. 6 Because brain ischemia-reperfusion injury is dependent on the platelet glycoprotein Ib-VWF axis 7 and platelet thrombosis adversely affects the postischemic cerebral microcirculation 8-11 leading to secondary brain damage, 10 ADAMTS13 may reduce platelet thrombus growth and thereby ameliorate ischemic brain injury by improving the postischemic no-reflow phenomenon. 12 Here we demonstrate that Adamts13 gene deletion aggravates postischemic cerebral blood reflow, resulting in larger infarct volume. This result suggests that ADAMTS13 may indeed supp...

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BackgroundNeutrophil elastase plays an important role in the development and progression of acute respiratory distress syndrome (ARDS). Although the selective elastase inhibitor, sivelestat, is widely used in Japan for treating ARDS patients, its effectiveness remains controversial. The aim of the current study was to investigate the effects of sivelestat in ARDS patients with evidence of increased extravascular lung water by re-analyzing a large multicenter study database.MethodsA post hoc analysis of the PiCCO Pulmonary Edema Study was conducted. This multicenter prospective cohort study included 23 institutions in Japan. Adult mechanically ventilated ARDS patients with an extravascular lung water index of >10 mL/kg were included and propensity score analyses were performed. The endpoints were 28-day mortality and ventilator-free days (VFDs).ResultsPatients were categorized into sivelestat (n = 87) and control (n = 77) groups, from which 329 inverse probability-weighted group patients (162 vs. 167) were generated. The overall 28-day mortality was 31.1% (51/164). There was no significant difference in 28-day mortality between the study groups (sivelestat vs. control; unmatched: 29.9% vs. 32.5%; difference, −2.6%, 95% confidence interval (CI), −16.8 to 14.2; inverse probability-weighted: 24.7% vs. 29.5%, difference, −4.8%, 95% CI, −14.4 to 9.6). Although administration of sivelestat did not alter the number of ventilator-free days (VFDs) in the unmatched (9.6 vs. 9.7 days; difference, 0.1, 95% CI, −3.0 to 3.1), the inverse probability-weighted analysis identified significantly more VFDs in the sivelestat group than in the control group (10.7 vs. 8.4 days, difference, −2.3, 95% CI, −4.4 to −0.2).ConclusionsAlthough sivelestat did not significantly affect 28-day mortality, this treatment may have the potential to increase VFDs in ARDS patients with increased extravascular lung water. Prospective randomized controlled studies are required to confirm the results of the current study.Electronic supplementary materialThe online version of this article (doi:10.1186/s40560-014-0067-y) contains supplementary material, which is available to authorized users.

Our objective was to investigate the plasma levels of brain and atrial natriuretic peptides (BNP and ANP, respectively) in patients with septic shock/severe sepsis and to study the association of BNP and ANP levels with hemodynamic parameters, severity of the disease, and prognosis of those patients. This is a prospective case series study of 22 patients with septic shock, 11 patients with severe sepsis, and 20 healthy volunteers at the Department of Emergency and Critical Care Medicine, Nara Medical University Hospital, Japan. Blood collection was performed on admission and on days 1, 2, and 4. Plasma BNP and ANP levels were measured by radioimmunoassay. Right atrial pressure, mean pulmonary arterial pressure, pulmonary arterial wedge pressure, and left ventricular stroke work index were determined using a thermodilution catheter. Acute Physiological and Chronic Health Evaluation II scores were calculated. Plasma levels of BNP and ANP were markedly elevated in patients with septic shock/severe sepsis compared with controls (BNP, 7 +/- 0.3 pg mL; ANP, 13 +/- 1 pg mL). In patients with septic shock, both BNP and ANP peaked on day 2 (BNP, 987 +/- 160 pg mL; ANP, 103 +/- 17 pg mL). Plasma levels of BNP on day 2 in patients with septic shock significantly correlated with right atrial pressure (r = 0.744, P < 0.01), mean pulmonary arterial pressure (r = 0.670, P < 0.01), pulmonary arterial wedge pressure (r = 0.709, P < 0.01), left ventricular stroke work index (r = -0.552, P < 0.05), Acute Physiological and Chronic Health Evaluation II score (r = 0.581, P < 0.01), and poor prognosis (P < 0.05). The optimal cutoff point for predicting mortality in patients with septic shock was a BNP level of 650 pg mL on day 2, in which sensitivity and specificity were 92% and 80%, respectively. Increased plasma levels of BNP may reflect not only the severity of myocardial depression but also the disease severity and could be of prognostic value in patients with septic shock.

BackgroundCurrent guidelines for cardiopulmonary resuscitation (CPR) emphasise that emergency medical service (EMS) dispatchers should identify sudden cardiac arrest (CA) with abnormal breathing and assist lay rescuers performing CPR. However, lay rescuers description of abnormal breathing may be inconsistent, and it is unclear how EMS dispatchers provide instruction for CPR based on the breathing status of the CA victims described by laypersons.Methods and resultsTo investigate the incidence of abnormal breathing and the association between the EMS dispatcher-assisted CPR instruction and layperson CPR, we retrospectively analysed 283 witnessed CA cases whose information regarding breathing status of CA victims was available from population-based prospective cohort data. In 169 cases (59.7%), laypersons described that the CA victims were breathing in various ways, and that the victims were ‘not breathing’ in 114 cases (40.3%). Victims described as breathing in various ways were provided EMS dispatch-instruction for CPR less frequently than victims described as ‘not breathing’ (27.8% (47/169) vs 84.2% (96/114); p<0.001). Multivariate logistic regression showed that EMS dispatch-instruction for CPR was associated significantly with layperson CPR (adjusted OR, 11.0; 95% CI, 5.72 to 21.2).ConclusionsThis population-based study indicates that 60% of CA victims showed agonal respiration, which was described as breathing in various ways at the time of EMS call. Although EMS dispatch-instruction was associated significantly with an increase in layperson CPR, abnormal breathing was associated with a much lower rate of CPR instruction and, in turn, was related to a much lower rate of bystander CPR.