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Background Niraparib is the only poly (adenosine diphosphate-ribose)-polymerase (PARP) inhibitor available as oral monotherapy for maintenance, regardless of BRCA mutational status. Methods This phase I, open-label, non-randomized, dose-escalation study was conducted in Japan using a 3 + 3 design. Adults (≥20 years) with metastatic or locally advanced solid tumours were enrolled. Niraparib 200 mg (cohort 1) or 300 mg (cohort 2) was administered once daily in 21-day cycles (no drug holiday between cycles) until progressive disease (PD) or unacceptable toxicity. The primary objective was to evaluate the safety and tolerability of niraparib in Japanese patients with advanced solid tumours. The number of patients with dose-limiting toxicities in cycle 1 and number with treatment-emergent adverse events were primary endpoints. Secondary endpoints were pharmacokinetics and tumour response. Results There were three patients in cohort 1 and six patients in cohort 2. Only one patient, in cohort 2, developed a dose-limiting toxicity (grade 4 platelet count decreased). All patients in both cohorts developed treatment-emergent adverse events. The most common treatment-related treatment-emergent adverse events were decreased appetite (n = 2) in cohort 1, and platelet count decreased as well as aspartate aminotransferase increased (both n = 5) in cohort 2. Mean Cmax and AUC0–24 of niraparib increased dose-proportionally after multiple doses (accumulation ratio of between 1.64 and 3.65); median tmax was 3–4 h. Two patients, both in cohort 2, had a partial response to treatment. Conclusions Niraparib (200 or 300 mg/day) was tolerable and had a favourable pharmacokinetic profile in Japanese patients with advanced solid tumours., This study investigated the safety of niraparib in Japanese patients with metastatic or locally advanced solid tumours. One patient receiving 300 mg/day developed a dose-limiting toxicity (platelet count decreased)

BackgroundDuring endotracheal intubation training, only providing verbal guidance to students may result in inadequate recognition of the inner larynx and cause delays in mastering endotracheal intubation. Therefore, we introduced a deliberate practice approach to the education of residents in endotracheal intubation. For this purpose, a video laryngoscope was used to give the residents detailed feedback of the anesthesiology faculty. We hypothesized that if the anesthesiology faculty could provide sufficient and precise feedback of the larynx through the video monitor, the residents’ intubation skills would be retained for a more extended period.MethodsThis cluster randomized controlled study enrolled first-year residents who completed a two-month rotation at our department. Each rotation group (2–4 residents) was assigned to the Macintosh laryngoscope (ML) group or the McGRATH MAC video laryngoscope (MML) group. Endotracheal intubation skills were evaluated on a simulated mannequin immediately after the rotation, three months later, and six months later. The primary endpoint was the time required for intubation. The secondary endpoint was the percentage of glottic opening (POGO) score.ResultsForty-six residents participated in this study and were assigned to the ML group (n = 23) or the MML group (n = 23). The time required for intubation was significantly shorter in the MML group than in the ML group. The POGO score did not show any significant differences between the two groups; however, the POGO score of the MML group had a relatively narrower confidence interval than the ML group.ConclusionsWhen comparing endotracheal intubation training using the Macintosh laryngoscope and video laryngoscope, the McGRATH MAC video laryngoscope shortened the intubation procedure and facilitated long-term skill retention.Trial registrationClinical registry and trial number, URL: https://www.umin.ac.jp, UMIN000036643 date of registration: 2019/05/03, This study was retrospectively registered.

Objective To evaluate the efficacy and safety of niraparib in Japanese women with heavily pretreated ovarian cancer. Methods This Phase 2 open-label, single-arm study enrolled Japanese women with homologous recombination deficiency-positive relapsed, high-grade serous ovarian, fallopian tube, or primary peritoneal cancer who had completed 3-4 lines of therapy. The starting dose of niraparib was 300 mg administered once daily in continuous 28-day cycles until objective progressive disease, unacceptable toxicity, consent withdrawal or discontinuation. The primary endpoint, objective response rate (ORR), was assessed by the investigator using RECIST version 1.1. Safety evaluations included the incidence of treatment-emergent adverse events (TEAEs), including serious TEAEs. Results Twenty women were enrolled and the confirmed ORR in the full analysis set (FAS) was 35.0% (7/20), consisting of 1 complete response and 6 partial responses. Disease control rate in the FAS was 90.0%. The most frequently reported TEAEs (>50%) were anemia, nausea, and platelet count decreased. One patient (5.0%) had TEAEs leading to discontinuation of niraparib whereas reductions or interruptions were reported in 14 (70.0%) and 15 (75.0%) patients, respectively. The median dose intensity (202.9 mg daily) corresponded to a relative dose intensity of 67.6%. Conclusion Efficacy and safety of niraparib in heavily pretreated Japanese women was comparable to that seen in an equivalent population of non-Japanese women. No new safety signals were identified. Trial registration ClinicalTrials.gov Identifier: NCT03759600.

We investigated the non-inferiority of continuous rectus sheath block to continuous epidural anesthesia for postoperative analgesia of gynecological cancer patients. One hundred ASA-PS 1–2 patients via a median incision up to 5 cm above the navel were randomized into a continuous epidural anesthesia (CEA) group and a continuous rectus sheath block (CRSB) group. Following surgery, they have controlled with intravenous patient-controlled analgesia (IV-PCA) as basal postoperative analgesia. For patients in the CEA group were administered 0.25% levobupivacaine at 5 mg/h. Patients in the CRSB group, catheters were inserted on both sides of the posterior rectus sheath after surgery. They received 0.25% levobupivacaine on both sides at 7.5 mg/h. To determine whether CRSB is non-inferior to CEA in postoperative treatment, pain at rest and movement was assessed using the Numerical Rating Scale (NRS). The non-inferiority margin of NRS difference between CRSB and CEA was set at 1.3 difference in means. The primary outcome was non-inferiority comparisons of NRS at rest/at movement after surgery, while the secondary outcome included the frequency of requesting IV-PCA and rescue drugs. NRS at rest in the CRSB group was not inferior to that in the CEA group. On the other hand, the NRS at movement at 4, 6, 8, 12 h following surgery in the CRSB group was inferior to CEA. There was no difference in the frequency of requesting IV-PCA and rescue drugs. CRSB showed the non-inferiority to CEA for postoperative analgesia at rest, while CRSB was not non-inferior to CEA at movement in gynecological cancer patients. CRSB would be a substitute when CEA is contraindicated as a component of postoperative multimodal analgesia.

The nucleotide sequence of a sardine preprocalcitonin precursor has been determined from their ultimobranchial glands in the present study. From our analysis of this sequence, we found that sardine procalcitonin was composed of procalcitonin amino-terminal cleavage peptide (N-proCT) (53 amino acids), CT (32 amino acids), and procalcitonin carboxyl-terminal cleavage peptide (C-proCT) (18 amino acids). As compared with C-proCT, N-proCT has been highly conserved among teleosts, reptiles, and birds, which suggests that N-proCT has some bioactivities. Therefore, both sardine N-proCT and sardine CT were synthesized, and their bioactivities for osteoblasts and osteoclasts were examined using our assay system with goldfish scales that consisted of osteoblasts and osteoclasts. As a result, sardine N-proCT (10− 7 M) activated osteoblastic marker enzyme activity, while sardine CT did not change. On the other hand, sardine CT (10− 9 to 10− 7 M) suppressed osteoclastic marker enzyme activity, although sardine N-proCT did not influence enzyme activity. Furthermore, the mRNA expressions of osteoblastic markers such as type 1 collagen and osteocalcin were also promoted by sardine N-proCT (10− 7 M) treatment; however, sardine CT did not influence their expressions. The osteoblastic effects of N-proCT lack agreement. In the present study, we can evaluate exactly the action for osteoblasts because our scale assay system is very sensitive and it is a co-culture system for osteoblasts and osteoclasts with calcified bone matrix. Both CT and N-proCT seem to influence osteoblasts and osteoclasts and promote bone formation by different actions in teleosts. © 2017 Elsevier Inc., Embargo Period 12 months

Based on the outcomes of the TOURMALINE-MM1 trial-a global, randomized, double-blind, placebo-controlled phase III clinical study-the use of an oral proteasome inhibitor has been approved in combination with lenalidomide and dexamethasone (Rd) for the treatment of relapsed/refractory multiple myeloma (MM). In this study, we enrolled 41 Japanese patients, who constituted the safety population. The overall incidence of adverse events (AEs) was similar in IRd and placebo-Rd groups. AEs including thrombocytopenia, skin disorders (rash), vomiting, nausea, and diarrhea occurred more frequently in the IRd group than in the placebo-Rd group. There were no cumulative toxicities, and most toxicities were usually manageable with close monitoring, supportive care, and dose modifications. Compared with the overall safety population, the safety profile of Japanese patients was consistent. Moreover, in Japanese patients, there were no on-study deaths and the incidence of serious AEs was less frequent.

We report the first clinical investigation conducted in Japan to confirm the safety, tolerability, and pharmacokinetics of ixazomib alone and combined with lenalidomide–dexamethasone (Rd) in Japanese patients with relapsed/refractory multiple myeloma. Adult patients with measurable disease and ≥2 prior lines of therapy received oral ixazomib 4.0 mg on days 1, 8, 15 alone or combined with lenalidomide 25 mg on days 1–21 and dexamethasone 40 mg on days 1, 8, 15, 22 in 28-day cycles. Fourteen patients who had received a median of seven prior therapies were enrolled (seven per cohort). One of six evaluable patients in each cohort experienced dose-limiting toxicities [diarrhea, nausea, hypokalemia, hypertension, thrombocytopenia, hyponatremia (ixazomib cohort); thrombocytopenia, and neutropenia (ixazomib + Rd cohort)]. The most common drug-related adverse events were neutropenia, thrombocytopenia, leukopenia, and lymphopenia. Drug-related grade ≥3 adverse events occurring in ≥3 patients per cohort were (ixazomib/ixazomib + Rd cohort, n): neutropenia (4/2), thrombocytopenia (3/2), and lymphopenia (5/2). Ixazomib was rapidly absorbed with a median Tmax of approximately 1–2-h post-dose, and had a geometric mean terminal half-life of 5–6 days. Of 13 response-evaluable patients, one achieved a partial response (duration ∼38 weeks; ixazomib cohort) and seven had stable disease.

Introduction A new disseminated intravascular coagulation (DIC) scoring system was recently announced by Japanese Association for Acute Medicine (JAAM). We have conducted a prospective external validation study to assess the accuracy of this scoring system. Materials and methods All patients admitted to the ICU in a tertiary academic hospital in 2007 were prospectively observed. All patients younger than 15years of age, those who stayed in the ICU for less than 24hours, had cardiac surgery, hematological diseases, recent chemotherapy or radiotherapy or liver cirrhosis were excluded. The remaining patients were then screened using the JAAM DIC scoring system. Results DIC was diagnosed by the JAAM DIC scoring system in 45 of the 242 patients screened (18.6%). The DIC patients were older, had a higher Acute Physiology and Chronic Health Evaluation (APACHE) II score and stayed in the ICU longer in comparison to the non-DIC patients. However, hospital mortality was similar between the two groups (p=0.98). There was no difference in the JAAM DIC score between the surviving and non-surviving DIC patients (p=0.40). A multivariate logistic regression analysis revealed the DIC diagnosed by JAAM to have a non-significant low odds ratio for hospital mortality (OR 0.29, 95%CI 0.08-1.08, p=0.066). Conclusion We have reported an external validation study of the JAAM DIC scoring system, which was conducted outside of the centers where data for developing the score were collected. DIC diagnosed by this scoring system was not related to hospital mortality.

Arachidonylethanolamide (AEA) and 2-arachidonylglycerol (2-AG) are endocannabinoids involved in septic shock, and 8-epi prostaglandin F2alpha (F2-isoprostane) is a biomarker of oxidative stress in biological systems. Because the antibiotic polymyxin B absorbs endocannabinoids as well as endotoxins, direct hemoperfusion therapy with polymyxin B-immobilized fibers (PMX-DHP) decreases serum levels of endocannabinoids. To investigate the features of sepsis and determine the proper use of PMX-DHP, we measured the changes in levels of endocannabinoids and F2-isoprostane in patients with septic shock. Twenty-six patients with septic shock, including those with septic shock induced by peritonitis, underwent laparotomy for drainage. Endocannabinoids absorption with PMX-DHP was examined in two groups of patients: patients whose mean arterial blood pressure (mABP) had increased more than 20 mm Hg (responder group; N = 13); and patients iwhose mABP did not increase or had increased no more than 20 mm Hg (non-responder group; N = 13). Levels of AEA did not change after PMX-DHP in either the non-responder or responder groups, whereas levels of 2-AG decreased significantly after PMX-DHP in the responder group, but not in the non-responder group. F2-isoprostane gradually increased after PMX-DHP treatment; on the other hand, levels of F2-isoprostane remained constant in the responder group. Patients with septic shock are under considerable oxidative stress, and 2-AG plays an important role in the cardiovascular status of these patients. The removal of 2-AG by PMX-DHP benefits patients with septic shock by stabilizing cardiovascular status and decreasing long-term oxidative stress.

Background Neutrophil 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. Methods A 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). Results Patients 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). Conclusions Although 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 material The online version of this article (doi:10.1186/s40560-014-0067-y) contains supplementary material, which is available to authorized users.

Antithrombin III (ATIII) of low doses (1500-3000 units per day for 3-5 days) has been used for treatment of disseminated intravascular coagulation (DIC) for decades in Japan. In this study, we have examined the impact of ATIII practice change on outcome in critically ill patients with sepsis and DIC. From April 2005 to September 2008, all septic patients admitted to our ICU were divided into two groups: before withdrawing ATIII (period 1) and after withdrawing ATIII (period 2). Patients treated with ATIII in the period 1 and those not treated with ATIII in the period 2 were then matched according to the similar Acute Physiology and Chronic Health Evaluation II scores (± 3) and the same diagnosis grouping. Sensitivity analysis was also conducted for patients with DIC. Forty-one out of 98 patients (41.8%) in the period 1 and only one out of 80 patients (1.3%) in the period 2 were treated with ATIII. Thirty pairs of the patients were matched. There was no difference between the two groups regarding the platelet counts and Sepsis-related Organ Failure Assessment scores at day 1 and day 4. A subgroup analysis was conducted with 12 patients diagnosed with DIC out of the 30 pairs. There was no difference between the two DIC groups for platelet counts, Sepsis-related organ failure assessment scores and DIC score at day 1 and also day 4. Although not significant, hospital mortality tended lower in the period 2. This study found that withdrawing ATIII administration from management of septic patients with or without DIC did not influence outcome.

Extravascular lung water (EVLW), as measured by the thermodilution method, reflects the extent of pulmonary edema. Currently, there are no clinically effective treatments for preventing increases in pulmonary vascular permeability, a hallmark of lung pathophysiology, in patients with acute lung injury/acute respiratory distress syndrome (ALI/ARDS). In this study, we examined the contributions of hemodynamic and osmolarity factors, for which appropriate interventions are expected in critical care, to EVLW in patients with ALI/ARDS. We performed a subgroup analysis of a multicenter observational study of patients with acute pulmonary edema. Overall, 207 patients with ALI/ARDS were enrolled in the study. Multivariate regression analysis was used to evaluate the associations of hemodynamic and serum osmolarity parameters with the EVLW index (EVLWI; calculated as EVLW/Ideal body weight). We analyzed factors measured on the day of enrollment (day 0), and on days 1 and 2 after enrollment. Multivariate regression analysis showed that global end-diastolic volume index (GEDVI) was significantly associated with EVLWI measured on days 0, 1, and 2 (P = 0.002, P

Acute respiratory distress syndrome (ARDS) is characterized by the increased pulmonary permeability secondary to diffuse alveolar inflammation and injuries of several origins. Especially, the distinction between a direct (pulmonary injury) and an indirect (extrapulmonary injury) lung injury etiology is gaining more attention as a means of better comprehending the pathophysiology of ARDS. However, there are few reports regarding the quantitative methods distinguishing the degree of pulmonary permeability between ARDS patients due to pulmonary injury and extrapulmonary injury. A prospective, observational, multi-institutional study was performed in 23 intensive care units of academic tertiary referral hospitals throughout Japan. During a 2-year period, all consecutive ARDS-diagnosed adult patients requiring mechanical ventilation were collected in which three experts retrospectively determined the pathophysiological mechanisms leading to ARDS. Patients were classified into two groups: patients with ARDS triggered by extrapulmonary injury (ARDSexp) and those caused by pulmonary injury (ARDSp). The degree of pulmonary permeability using the transpulmonary thermodilution technique was obtained during the first three intensive care unit (ICU) days. In total, 173 patients were assessed including 56 ARDSexp patients and 117 ARDSp patients. Although the Sequential Organ Failure Assessment (SOFA) score was significantly higher in the ARDSexp group than in the ARDSp group, measurements of the pulmonary vascular permeability index (PVPI) were significantly elevated in the ARDSp group on all days: at day 0 (2.9 ± 1.3 of ARDSexp vs. 3.3 ± 1.3 of ARDSp, p = .008), at day 1 (2.8 ± 1.5 of ARDSexp vs. 3.2 ± 1.2 of ARDSp, p = .01), at day 2 (2.4 ± 1.0 of ARDSexp vs. 2.9 ± 1.3 of ARDSp, p = .01). There were no significant differences in mortality at 28 days, mechanical ventilation days, and hospital length of stay between the two groups. The results of this study suggest the existence of several differences in the increased degree of pulmonary permeability between patients with ARDSexp and ARDSp. This report is a sub-group analysis of the study registered with UMIN-CTR ( IDUMIN000003627 ).

In the present study, the complete amino acid sequence of N-terminal procalcitonins (N-proCTs) of stingray (an elasmobranch) and spotlined sardine (a teleost), as well as the partial amino acid sequence of N-proCTs of goldfish (a teleost; three types of N-proCTs) and bullfrog (an amphibian) have been determined. These N-proCTs have some common features to 9 N-proCTs sequenced to date. These features were summarized as follows: 1) The first amino acid residue is Ala or Val. 2) There is no Cys residue in the sequence of N-proCTs. 3) Seven residues (Pro 3 , Leu 19 , Leu 28 , Val 32 , Gln 37 , Gln 45 and Ser 56 ) are conserved in the sequence of N-terminal procalcitonin (N-proCT), at least judging from the present data. 4) Insertion/deletion points are present in the sequence of N-proCTs at the 2nd position, from the 10th to 14th and from 46th to 52nd. We examined whether the N-proCTs can be categorized into several groups by similarity of amino acid residues conserved in the molecules. As a result, the N-proCTs were roughly categorized into 2 groups: a mammalian group, including 2 subgroups and a non-mammalian group, including 3 subgroups. This classification of N-proCTs coincides with that of calcitonin. Sardine N-proCT has no accelerating effects on mitosis and cell differentiation of human osteosarcoma cells, as does the homologous human N-proCT. Further studies are needed to elucidate the biological activity of N-proCTs.

To the Editor: The pulmonary artery catheter (PAC) and PiCCO monitor (Pulsion Medical Systems, Munich, Germany) use the thermodilution technique to measure cardiac output [1]. Because the indicator injection site (central vein) and temperature measurement site (femoral artery) are more distant in PiCCO than in PAC (right atrium and pulmonary artery), PiCCO can potentially detect a wider variety of left-to-right shunts (LRS) than PAC. A 68-year-old man was admitted to the ICU for presumed diagnoses of septic shock and acute kidney injury resulting from an infected right common iliac artery (CIA) aneurysm. He was treated with continuous veno-venous hemodialysis (CVVHD) and vasopressin infusion with massive fluid resuscitation and noradrenaline infusion for septic shock. Ten days after ICU admission, he still required a small amount of noradrenaline and CVVHD. To evaluate his cardiac function and manage his shock state more meticulously, a 5-Fr. catheter (Pulsioncath; Pulsion Medical Systems, Munich, Germany) was inserted in his left femoral artery and was connected to the PiCCO Plus monitor. Despite the absence of hypoxemia and lung infiltrates in the chest X-ray, hemodynamic variables showed low cardiac index (CI, 1.37 l/min/m) and very low intrathoracic blood volume index (ITBVI, 336 ml), with massively increased extravascular lung water index (EVLWI, 43.7 ml/kg) for an average value of two measurements. The thermodilution curve showed a significantly prolonged flattening of the descending portion of the curve, suggesting an LRS. A dynamic computed tomography (CT) scan of the abdomen was subsequently conducted, which revealed an arteriovenous fistula between the right CIA aneurysm and the inferior vena cava. To repair the fistula, endovascular stenting was planned. However, on the day of surgery, the patient suddenly developed cardiac arrest and could not be resuscitated. Although an autopsy was not performed, the cause of cardiac arrest was thought to be rupture of the aneurysm. The dilution curve of LRS is characterized by an early recirculation of the cold indicator, which results in premature flattening of the descending portion of the curve. Previously, only two cases of LRS detected by PiCCO have been reported [2]. One patient had a ventricular septal defect and the other had an aorto-vena caval fistula. One patient had an ITBVI of 857 ml/m, EVLWI of 31.7 ml/kg, and CI of 2.66 l/min/m. Our case showed even more abnormal values of ITBVI and EVLWI than the previous cases. Retrospectively, our patient had probably developed the LRS before ICU admission, when his condition deteriorated. The persistent LRS could have contributed to the sustained shock state and acute kidney injury and might have deteriorated gradually during his stay in the ICU. We think that this is the reason why we found exceptionally low ITBVI and high EVLWI values compared with previous cases. Electronic supplementary material The online version of this article (doi:10.1007/s00540-014-1788-8) contains supplementary material, which is available to authorized users.

Arachidonylethanolamide (AEA) and 2-arachidonylglycerol (2-AG) are endocannabinoids involved in septic shock, and 8-epi prostaglandin F2alpha (F2-isoprostane) is a biomarker of oxidative stress in biological systems. Because the antibiotic polymyxin B absorbs endocannabinoids as well as endotoxins, direct hemoperfusion therapy with polymyxin B-immobilized fibers (PMX-DHP) decreases serum levels of endocannabinoids. To investigate the features of sepsis and determine the proper use of PMX-DHP, we measured the changes in levels of endocannabinoids and F2-isoprostane in patients with septic shock. Twenty-six patients with septic shock, including those with septic shock induced by peritonitis, underwent laparotomy for drainage. Endocannabinoids absorption with PMX-DHP was examined in two groups of patients: patients whose mean arterial blood pressure (mABP) had increased more than 20 mm Hg (responder group; N = 13); and patients iwhose mABP did not increase or had increased no more than 20 mm Hg (non-responder group; N = 13). Levels of AEA did not change after PMX-DHP in either the non-responder or responder groups, whereas levels of 2-AG decreased significantly after PMX-DHP in the responder group, but not in the non-responder group. F2-isoprostane gradually increased after PMX-DHP treatment; on the other hand, levels of F2-isoprostane remained constant in the responder group. Patients with septic shock are under considerable oxidative stress, and 2-AG plays an important role in the cardiovascular status of these patients. The removal of 2-AG by PMX-DHP benefits patients with septic shock by stabilizing cardiovascular status and decreasing long-term oxidative stress.

We recently developed an in vitro assay to study bone metabolism using fish scales that contain osteoblasts, osteoclasts, and calcified bone matrix, all of which are similar to those found in mammalian membrane bone. Using the fish scale assay, we previously reported that the functions of calcemic hormones such as calcitonin and parathyroid hormone in osteoblasts and osteoclasts were similar to those in mammals. Therefore, our fish scale in vitro assay system is suitable for the screening of potential bone-forming compounds. In an attempt to develop molecules that increase bone mass, novel tryptophan derivatives were synthesized and screened for effects on osteoblasts and osteoclasts using the fish scale model. As a result, novel tryptophan derivatives with the ability to possibly increase bone formation were identified, but they had no effect on osteoclast activity. Among the identified derivatives, (S)-(+)-N-acetyl-2,4,6-tribromo-5-methoxytryptophan methyl ester (BTryp) had the strongest activity on osteoblasts. The effect of this chemical on bone formation was confirmed in an ovariectomized (OVX) rat model of post-menopausal osteoporosis. Our data indicated that both trabecular bone mineral density and stress-strain index of the femoral metaphysis of BTryp-treated OVX rats were significantly higher than those of OVX rats. This study identified a bromotryptophan derivative that may have potential use in the treatment of bone diseases, such as osteoporosis.

Background: The features of early-phase acute respiratory distress syndrome (ARDS) are leakage of fluid into the extravascular space and impairment of its reabsorption, resulting in extravascular lung water (EVLW) accumulation. The current study aimed to identify how the initial EVLW values and their change were associated with mortality. Methods: This was a post hoc analysis of the PiCCO Pulmonary Edema Study, a multicenter prospective cohort study that included 23 institutions. Single-indicator transpulmonary thermodilution-derived EVLW index (EVLWi) and conventional prognostic factors were prospectively collected over 48 h after enrollment. Associations between 28-day mortality and each variable including initial (on day 0), mean, maximum, and Δ (subtracting day 2 from day 0) EVLWi were evaluated. Results: We evaluated 192 ARDS patients (median age, 69 years (quartile, 24 years); Sequential Organ Failure Assessment (SOFA) score on admission, 10 (5); all-cause 28-day mortality, 31%). Although no significant differences were found in initial, mean, or maximum EVLWi, Δ-EVLWi was significantly higher (i.e., more reduction in EVLWi) in survivors than in non-survivors (3.0 vs. ?0.3 mL/kg, p = 0.006). Age, maximum, and Δ-SOFA scores and Δ-EVLW were the independent predictors for survival according to the Cox proportional hazard model. Patients with Δ-EVLWi > 2.8 had a significantly higher incidence of survival than those with Δ-EVLWi ? 2.8 (log-rank test, χ2 = 7.08, p = 0.008). Conclusions: Decrease in EVLWi during the first 48 h of ARDS may be associated with 28-day survival. Serial EVLWi measurements may be useful for understanding the pathophysiologic conditions in ARDS patients. A large multination confirmative trial is required., Annals of Intensive Care, 4, 27; 2014

Introduction Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is characterized by features other than increased pulmonary vascular permeability. Pulmonary vascular permeability combined with increased extravascular lung water content has been considered a quantitative diagnostic criterion of ALI/ARDS. This prospective, multi-institutional, observational study aimed to clarify the clinical pathophysiological features of ALI/ARDS and establish its quantitative diagnostic criteria. Methods The extravascular lung water index (EVLWI) and the pulmonary vascular permeability index (PVPI) were measured using the transpulmonary thermodilution method in 266 patients with PaO2/FiO2 ratio ≤ 300 mmHg and bilateral infiltration on chest radiography, in 23 ICUs of academic tertiary referral hospitals. Pulmonary edema was defined as EVLWI ≥ 10 ml/kg. Three experts retrospectively determined the pathophysiological features of respiratory insufficiency by considering the patients' history, clinical presentation, chest computed tomography and radiography, echocardiography, EVLWI and brain natriuretic peptide level, and the time course of all preceding findings under systemic and respiratory therapy. Results Patients were divided into the following three categories on the basis of the pathophysiological diagnostic differentiation of respiratory insufficiency: ALI/ARDS, cardiogenic edema, and pleural effusion with atelectasis, which were noted in 207 patients, 26 patients, and 33 patients, respectively. EVLWI was greater in ALI/ARDS and cardiogenic edema patients than in patients with pleural effusion with atelectasis (18.5 ± 6.8, 14.4 ± 4.0, and 8.3 ± 2.1, respectively; P < 0.01). PVPI was higher in ALI/ARDS patients than in cardiogenic edema or pleural effusion with atelectasis patients (3.2 ± 1.4, 2.0 ± 0.8, and 1.6 ± 0.5; P < 0.01). In ALI/ARDS patients, EVLWI increased with increasing pulmonary vascular permeability (r = 0.729, P < 0.01) and was weakly correlated with intrathoracic blood volume (r = 0.236, P < 0.01). EVLWI was weakly correlated with the PaO2/FiO2 ratio in the ALI/ARDS and cardiogenic edema patients. A PVPI value of 2.6 to 2.85 provided a definitive diagnosis of ALI/ARDS (specificity, 0.90 to 0.95), and a value < 1.7 ruled out an ALI/ARDS diagnosis (specificity, 0.95). Conclusion PVPI may be a useful quantitative diagnostic tool for ARDS in patients with hypoxemic respiratory failure and radiographic infiltrates. Trial registration UMIN-CTR ID UMIN000003627

Endotoxin scattering photometry (ESP) is one of a newly developed clinically applicable method for endotoxin assay. Although ESP is an analogous assay of turbidimetric method, it enables one to detect very small amounts of endotoxin within 1 hour. This is because ESP can directly detect clotting enzyme product, coagulin, which is the first appearance of Limulus amebocyte lysate (LAL) cascade and the precursor of gel clots.

The aim was to verify the hypothesis that extracorporeal therapy with a polymyxin B (PMX) fibre column may prevent septic shock-induced organ dysfunction and that early treatment of septic shock with PMX hemoperfusion may improve patient outcome.

Several studies have shown the effectiveness of non-renal indication of continuous renal replacement therapy (CRRT) or endotoxin-adosorbing fibers (direct hemoperfusion therapy with polymyxin-B immobilized fibers (PMX-DHP)) for patients with septic shock in improving unstable cardiovascular status. This nonrenal indication of CRRT might be the additional benefits that resulted in adsorbing various bioactive lipid mediators with dialyser membranes. PMX-DHP is also known to adosorb various bioactive mediators except endotoxin. In this investigation, the additional benefits of CRRT and PMX-DHP were assessed in patients with septic shock.

Direct hemoperfusion therapy with polymyxin-B immobilized fibers (PMX-DHP) has been widely applied as the therapeutic method for the patients with septic shock in Japan since 1994. Optimal usage of PMX-DHP for the patients with septic shock remains a matter of debate, mainly because of a lack of adequately designed clinical trials.

Endotoxin scattering photometry (ESP) is a newly developed endotoxin assay. The mechanism of ESP is the same as for the turbidimetric method, which is a conventional endotoxin assay in Japan; however, ESP enables one to detect a very small amount of endotoxin within 1 hour. This is because ESP can detect the clotting enzyme product coagulin, which is the first appearance of limulus amebocyte lysate cascade evoked by endotoxin [1].

Perioperative managements for endovascular neurosurgery require some considerations such as minimizing hemodynamic changes and especially avoiding blood pressure elevation accompanying extubation, immobilizing the trunk and lower limbs until bleeding from the site of femoral artery sheath removal has stopped, and monitoring patients in the ICU for at least 12 hours to notice neurological deterioration promptly. The aim of this study was to assess the usefulness of dexmedetomidine as a postoperative sedative drug for endovascular neurosurgery.

Arachidonylethanolamide (AEA) and 2-arachidonyl-glycerol (2-AG) are endocannabinoids involved in septic shock, and 8-epi prostaglandin F2α (F2-isoprostane) is a biomarker of oxidative stress. Because the antibiotic polymyxin-B binds to endotoxins and endocannabinoids, direct hemoperfusion therapy with polymyxin-B-immobilized fibers (PMX-DHP) decreases serum levels of endocannabinoids. To investigate the features of sepsis and to determine the proper usage of PMX-DHP, we compared perioperative changes in levels of endocannabinoids and F2-isoprostane in patients with septic shock