Low-flow time and outcomes in out-of-hospital cardiac arrest patients treated with extracorporeal cardiopulmonary resuscitation.

INTRODUCTION: In out-of-hospital cardiac arrest (OHCA) patients with extracorporeal cardiopulmonary resuscitation (ECPR), the association between low-flow time, the duration between the initiation of conventional cardiopulmonary resuscitation and the establishment of ECPR, and outcomes has not been clearly determined. METHODS: This was a secondary analysis of the retrospective multicenter registry in Japan. This study registered patients ≥18 years old who were admitted to the emergency department for OHCA and underwent ECPR between January, 2013 and December, 2018. Low-flow time was defined as the time from initiation of conventional cardiopulmonary resuscitation to the establishment of ECPR, and patients were categorized into two groups according to the visualized association of the restricted cubic spline curve. The primary outcome was survival discharge. Cubic spline analyses and multivariable logistic regression analyses were performed to assess the nonlinear associations between low-flow time and outcomes. RESULTS: A total of 1,524 patients were included. The median age was 60 years, and the median low-flow time was 52 (42-53) mins. The overall survival at hospital discharge and favorable neurological outcomes were 27.8% and 14.2%, respectively. The cubic spline analysis showed a decreased trend of survival discharge rates and favorable neurological outcomes with shorter low-flow time between 20 and 60 mins, with little change between the following 60 and 80 mins. The multivariable logistic regression analyses showed that patients with long low-flow time (>40 mins) compared to those with short low-flow time (0-40 mins) had significantly worse survival (adjusted odds ratio 0.42; 95% confidence intervals, 0.31-0.57) and neurological outcomes (0.65; 0.45-0.95, respectively). CONCLUSIONS: The survival discharge and neurological outcomes of patients with low-flow time shorter than 40 min are better than those of patients with longer low-flow time.

Unicompartmental Knee Arthroplasty for Osteoarthritis Eliminates Lateral Thrust: Associations between Lateral Thrust Detected by Inertial Measurement Units and Clinical Outcomes.

The purpose of this study was to investigate the relationship between clinical outcomes and lateral thrust before and after unicompartmental knee arthroplasty (UKA) using inertial measurement sensor units. Eleven knees were evaluated with gait analysis. The varus angular velocity was used to evaluate lateral thrust. The femorotibial angle (FTA) and hip-knee-ankle angle (HKA) were used to evaluate lower-limb alignment, and the Oxford Knee Score (OKS) and Japanese Orthopaedic Association Score (JOA) were used to evaluate clinical outcomes. The mean pre-UKA peak varus velocity was 37.1 ± 9.8°/s, and that for post-UKA was 28.8 ± 9.1°/s (p = 0.00003), such that instabilities clearly improved. Assuming the definition of lateral thrust is when the varus angular velocity is more than 28.1°/s, 81.8% of patients had lateral thrust preoperatively, but this decreased to 55.6% postoperatively, such that the symptoms and objective findings improved. Both OKS and JOA improved after surgery. In addition, HKA was -7.9° preoperatively and -5.8° postoperatively (p = 0.024), and FTA was 181.4° preoperatively and 178.4° postoperatively (p = 0.012). There was a positive correlation between postoperative JOA and FTA, indicating that changes in postoperative alignment affected clinical outcomes. This study quantitatively evaluated the disappearance of lateral thrust by UKA, and it found that the stability can be achieved by UKA for unstable knees with lateral thrust.

Changes in Corticospinal Excitability and Motor Control During Cerebellar Transcranial Direct Current Stimulation in Healthy Individuals.

Cerebellar transcranial direct current stimulation (ctDCS) modulates the primary motor cortex (M1) via cerebellar brain inhibition (CBI), which affects motor control in humans. However, the effects of ctDCS on motor control are inconsistent because of an incomplete understanding of the real-time changes in the M1 excitability that occur during ctDCS, which determines motor output under regulation by the cerebellum. This study investigated changes in corticospinal excitability and motor control during ctDCS in healthy individuals. In total, 37 healthy individuals participated in three separate experiments. ctDCS (2 mA) was applied to the cerebellar hemisphere during the rest condition or a pinch force-tracking task. Motor-evoked potential (MEP) amplitude and the F-wave were assessed before, during, and after ctDCS, and pinch force control was assessed before and during ctDCS. The MEP amplitudes were significantly decreased during anodal ctDCS from 13 min after the onset of stimulation, whereas the F-wave was not changed. No significant changes in MEP amplitudes were observed during cathodal and sham ctDCS conditions. The MEP amplitudes were decreased during anodal ctDCS when combined with the pinch force-tracking task, and pinch force control was impaired during anodal ctDCS relative to sham ctDCS. The MEP amplitudes were not significantly changed before and after all ctDCS conditions. Motor cortical excitability was suppressed during anodal ctDCS, and motor control was unskilled during anodal ctDCS when combined with a motor task in healthy individuals. Our findings provided a basic understanding of the clinical application of ctDCS to neurorehabilitation.

Targeted therapy using polymyxin B hemadsorption in patients with sepsis: a post-hoc analysis of the JSEPTIC-DIC study and the EUPHRATES trial.

BACKGROUND: Polymyxin B hemadsorption (PMX-HA) reduces blood endotoxin levels, but characteristics of patients with sepsis likely to benefit from PMX-HA are not well known. We sought to identify patient subgroups likely to benefit from PMX-HA. METHODS: We retrospectively identified 1911 patients with sepsis from a retrospective observational study in Japan (the JSEPTIC-DIC study) and 286 patients with endotoxemic septic shock from a randomized controlled trial in North America that restricted patients to those with high endotoxin activity (the EUPHRATES trial). We applied the machine learning-based causal forest model to the JSEPTIC-DIC cohort to investigate heterogeneity in treatment effects of PMX-HA on 28-day survival after adjusting for potential confounders and ascertain the best criteria for PMX-HA use. The derived criteria for targeted therapy by PMX-HA were validated using the EUPHRATES trial cohort. RESULTS: The causal forest model revealed heterogeneity in treatment effects of PMX-HA. Since patients having higher treatment effects were more likely to have severe coagulopathy and hyperlactatemia, we identified the potential treatment targets of PMX-HA as patients with PT-INR > 1.4 or lactate > 3 mmol/L. In the EUPHRATES trial cohort, PMX-HA use on the targeted subpopulation (75% of all patients) was significantly associated with higher 28-day survival (PMX-HA vs. control, 68% vs. 52%; treatment effect of PMX-HA, + 16% [95% CI + 2.2% to + 30%], p = 0.02). CONCLUSIONS: Abnormal coagulation and hyperlactatemia in septic patients with high endotoxin activity appear to be helpful to identify patients who may benefit most from PMX-HA. Our findings will inform enrollment criteria for future interventional trials targeting patients with coagulopathy and hyperlactatemia.

Neurological Analysis Based on the Terminal End of the Spinal Cord and the Narrowest Level of Injured Spine in Thoracolumbar Spinal Injuries.

This study aimed to clarify neurological differences among the epiconus, conus medullaris, and cauda equina syndromes. Eighty-seven patients who underwent surgery for acute thoracolumbar spinal injuries were assessed. We defined the epiconus as the region from the terminal end of the spinal cord to the proximal 1.0 to 2.25 vertebral bodies, the conus medullaris as the region proximal to < 1.0 vertebral bodies, and the cauda equina as the distal part of the nerve roots originating from the spinal cord. On the basis of the distance from the terminal end of the spinal cord to the narrowest level of the spinal canal, the narrowest levels were ordered as follows: the epiconus followed by the conus medullaris and cauda equina. The narrowest levels were the epiconus in 22 patients, conus medullaris in 37 patients, and cauda equina in 25 patients. On admission, significantly more patients had a narrowed epiconus of Frankel grades A-C than a narrowed cauda equina. At the final follow-up, there were no significant differences in neurological recovery among those with epiconus, conus medullaris, or cauda equina syndrome. Anatomically classifying the narrowest lesion is useful for clarifying the differences and similarities among these three syndromes.

[Posterior reversible encephalopathy syndrome during nilotinib treatment for chronic myeloid leukemia].

Here we present the case of a 50-year-old woman with chronic myeloid leukemia who received nilotinib as initial treatment. After about 2 years of nilotinib therapy, she developed headache, blurred vision, impaired consciousness, and marked hypertension. Posterior reversible encephalopathy syndrome (PRES) was diagnosed, and was strongly suspected to be a vascular adverse event caused by nilotinib. Nilotinib was withheld and the patient was treated with antihypertensive drugs under ventilator management. Her symptoms resolved quickly. The most likely cause of PRES is systemic arterial hypertension and endothelial dysfunction due to direct injury leading to dysfunction at the level of the blood-brain barrier, along with the resultant vasogenic edema. PRES has been reported with some tyrosine kinase inhibitors, but this is the first case of PRES during nilotinib treatment.

Web-based application for predicting the potential target phenotype for recombinant human thrombomodulin therapy in patients with sepsis: analysis of three multicentre registries.

A recent randomised controlled trial failed to demonstrate a beneficial effect of recombinant human thrombomodulin (rhTM) on sepsis. However, there is still controversy in the effects of rhTM for sepsis due to the heterogeneity of the study population. We previously identified patients with a distinct phenotype that could be a potential target of rhTM therapy (rhTM target phenotype). However, for application in the clinical setting, a simple tool for determining this target is necessary. Thus, using three multicentre sepsis registries, we aimed to develop and validate a machine learning model for predicting presence of the target phenotype that we previously identified for targeted rhTM therapy. The predictors were platelet count, PT-INR, fibrinogen, fibrinogen/fibrin degradation products, and D-dimer. We also implemented the model as a web-based application. Two of the three registries were used for model development (n = 3694), and the remaining registry was used for validation (n = 1184). Approximately 8-9% of patients had the rhTM target phenotype in each cohort. In the validation, the C statistic of the developed model for predicting the rhTM target phenotype was 0.996 (95% CI 0.993-0.998), with a sensitivity of 0.991 and a specificity of 0.967. Among patients who were predicted to have the potential target phenotype (predicted target patients) in the validation cohort (n = 142), rhTM use was associated with a lower in-hospital mortality (adjusted risk difference, - 31.3% [- 53.5 to - 9.1%]). The developed model was able to accurately predict the rhTM target phenotype. The model, which is available as a web-based application, could profoundly benefit clinicians and researchers investigating the heterogeneity in the treatment effects of rhTM and its mechanisms.

Electrical stimulation of the common peroneal nerve and its effects on the relationship between corticomuscular coherence and motor control in healthy adults.

BACKGROUND: Sensory input via neuromuscular electrical stimulation (NMES) may contribute to synchronization between motor cortex and spinal motor neurons and motor performance improvement in healthy adults and stroke patients. However, the optimal NMES parameters used to enhance physiological activity and motor performance remain unclear. In this study, we focused on sensory feedback induced by a beta-band frequency NMES (ß-NMES) based on corticomuscular coherence (CMC) and investigated the effects of ß-NMES on CMC and steady-state of isometric ankle dorsiflexion in healthy volunteers. Twenty-four participants received ß-NMES at the peak beta-band CMC or fixed NMES (f-NMES) at 100 Hz on different days. NMES was applied to the right part of the common peroneal nerve for 20 min. The stimulation intensity was 95% of the motor threshold with a pulse width of 1 ms. The beta-band CMC and the coefficient of variation of force (Force CV) were assessed during isometric ankle dorsiflexion for 2 min. In the complementary experiment, we applied ß-NMES to 14 participants and assessed beta-band CMC and motor evoked potentials (MEPs) with transcranial magnetic stimulation. RESULTS: No significant changes in the means of beta-band CMC, Force CV, and MEPs were observed before and after NMES conditions. Changes in beta-band CMC were correlated to (a) changes in Force CV immediately, at 10 min, and at 20 min after ß-NMES (all cases, p < 0.05) and (b) changes in MEPs immediately after ß-NMES (p = 0.01). No correlations were found after f-NMES. CONCLUSIONS: Our results suggest that the sensory input via NMES was inadequate to change the beta-band CMC, corticospinal excitability, and voluntary motor output. Whereas, the ß-NMES affects the relationship between changes in beta-band CMC, Force CV, and MEPs. These findings may provide the information to develop NMES parameters for neurorehabilitation in patients with motor dysfunction.

Single-Session Cerebellar Transcranial Direct Current Stimulation Affects Postural Control Learning and Cerebellar Brain Inhibition in Healthy Individuals.

Cerebellar transcranial direct current stimulation (ctDCS) modulates cerebellar activity and postural control. However, the effects of ctDCS on postural control learning and the mechanisms associated with these effects remain unclear. To examine the effects of single-session ctDCS on postural control learning and cerebellar brain inhibition (CBI) of the primary motor cortex in healthy individuals. In this triple-blind, sham-controlled study, 36 participants were allocated randomly to one of three groups: (1) anodal ctDCS group, (2) cathodal ctDCS group, and (3) sham ctDCS group. ctDCS (2 mA) was applied to the cerebellar brain for 20 min prior to six blocks of standing postural control training (each block consisted of five trials of a 30-s tracking task). CBI and corticospinal excitability of the tibialis anterior muscle were assessed at baseline, immediately after, 1 day after, and 7 days after training. Skill acquisition following training was significantly reduced in both the anodal and cathodal ctDCS groups compared with the sham ctDCS group. Changes in performance measured 1 day after and 7 days after training did not differ among the groups. In the anodal ctDCS group, CBI significantly increased after training, whereas corticospinal excitability decreased. Anodal ctDCS-induced CBI changes were correlated with the learning formation of postural control (r = 0.55, P = 0.04). Single-session anodal and cathodal ctDCS could suppress the skill acquisition of postural control in healthy individuals. The CBI changes induced by anodal ctDCS may affect the learning process of postural control.

Coagulation phenotypes in sepsis and effects of recombinant human thrombomodulin: an analysis of three multicentre observational studies.

BACKGROUND: A recent randomised trial showed that recombinant thrombomodulin did not benefit patients who had sepsis with coagulopathy and organ dysfunction. Several recent studies suggested presence of clinical phenotypes in patients with sepsis and heterogenous treatment effects across different sepsis phenotypes. We examined the latent phenotypes of sepsis with coagulopathy and the associations between thrombomodulin treatment and the 28-day and in-hospital mortality for each phenotype. METHODS: This was a secondary analysis of multicentre registries containing data on patients (aged ≥ 16 years) who were admitted to intensive care units for severe sepsis or septic shock in Japan. Three multicentre registries were divided into derivation (two registries) and validation (one registry) cohorts. Phenotypes were derived using k-means with coagulation markers, platelet counts, prothrombin time/international normalised ratios, fibrinogen, fibrinogen/fibrin-degradation-products (FDP), D-dimer, and antithrombin activities. Associations between thrombomodulin treatment and survival outcomes (28-day and in-hospital mortality) were assessed in the derived clusters using a generalised estimating equation. RESULTS: Four sepsis phenotypes were derived from 3694 patients in the derivation cohort. Cluster dA (n = 323) had severe coagulopathy with high FDP and D-dimer levels, severe organ dysfunction, and high mortality. Cluster dB had severe disease with moderate coagulopathy. Clusters dC and dD had moderate and mild disease with and without coagulopathy, respectively. Thrombomodulin was associated with a lower 28-day (adjusted risk difference [RD]: - 17.8% [95% CI - 28.7 to - 6.9%]) and in-hospital (adjusted RD: - 17.7% [95% CI - 27.6 to - 7.8%]) mortality only in cluster dA. Sepsis phenotypes were similar in the validation cohort, and thrombomodulin treatment was also associated with lower 28-day (RD: - 24.9% [95% CI - 49.1 to - 0.7%]) and in-hospital mortality (RD: - 30.9% [95% CI - 55.3 to - 6.6%]). CONCLUSIONS: We identified four coagulation marker-based sepsis phenotypes. The treatment effects of thrombomodulin varied across sepsis phenotypes. This finding will facilitate future trials of thrombomodulin, in which a sepsis phenotype with high FDP and D-dimer can be targeted.

Association of Body Weight Change and Fluid Balance With Extubation Failure in Intensive Care Unit Patients: A Single-Center Observational Study.

PURPOSE: To elucidate whether fluid balance and body weight change are associated with failed planned extubation. MATERIALS AND METHODS: Patients who received invasive mechanical ventilation for over 24 hours were enrolled and divided into extubation success and extubation failure groups. Fluid balance and body weight fluctuation within 24 and 48 hours before extubation and from admission to planned extubation were calculated. The primary outcome was extubation failure (ie, all-cause reintubation within 72 hours). The association of extubation failure with fluid balance and body weight change was assessed via logistic regression analysis. RESULTS: Extubation failure occurred in 12(7.4%)/161 patients. The extubation success group had a significantly lower fluid balance within 24 hours before extubation than did the extubation failure group (-276 mL [-1111 to 456] vs 1217 mL [503 to 1875], P = .002). However, fluid balance within 48 hours before extubation, cumulative fluid balance, and body weight change were not significantly different between the 2 groups. The sensitivity and specificity of water balance +1000 mL within 24 hours before extubation for the extubation failure group were 0.54 and 0.84, respectively, based on the receiver operating characteristic curve. Logistic regression analysis showed that fluid balance within 24 hours before extubation was associated with extubation failure (odds ratio: 22.9, 95% confidence interval: 4.1-128.4). CONCLUSIONS: A larger fluid balance within 24 hours before extubation is associated with extubation failure. Thus, fluid balance may be a good indicator of extubation outcome.

A nationwide survey on the incidence and characteristics of traumatic spinal cord injury in Japan in 2018.

STUDY DESIGN: Retrospective epidemiological study. OBJECTIVES: Since the causes and incidences of traumatic spinal cord injury (TSCI) in each country change over time, up-to-date epidemiological studies are required for countermeasures against TSCI. However, no nationwide survey in Japan has been conducted for about 30 years. The purpose of this study was therefore to investigate the recent incidence and characteristics of TSCI in Japan. SETTING: Japan METHODS: Survey sheets were sent to all hospitals (emergency and acute care hospitals) that treated TSCI persons in Japan in 2018 and case notes were retrospectively reviewed. Frankel grade E cases were excluded from analysis. RESULTS: The response rate was 74.4% (2804 of 3771 hospitals). The estimated annual incidence of TSCI excluding Frankel E was 49 per million, with a median age of 70.0 years and individuals in their 70s as the largest age group. Male-to-female ratio was 3:1. Cervical cord injuries occurred in 88.1%. Frankel D was the most frequent grade (46.3%), followed by Frankel C (33.0%). The most frequent cause was fall on level surface (38.6%), followed by traffic accident (20.1%). The proportion of fall on level surface increased with age. TSCI due to sports was the most frequent cause in teenagers (43.2%). CONCLUSIONS: This nationwide survey in Japan showed that estimated incidence of TSCI, rate of cervical cord injury, and incomplete injury by falls appear to be increasing with the aging of the population.

Expert consensus on surgical treatment for adolescent idiopathic scoliosis in Japan.

BACKGROUND: Surgical treatment for adolescent idiopathic scoliosis (AIS) has changed significantly with the advent of new medical devices and surgical procedures. Today, pre- and postoperative management differs widely between institutions. The purpose of this study is to establish consensus regarding the surgical management of AIS in Japan through the use of a questionnaire survey of experienced spine deformity surgeons. METHODS: From February to March 2020, experienced spine deformity surgeons who perform more than 25 cases of AIS surgery annually were asked to respond to a questionnaire request regarding AIS surgical management formulated by the International Affairs Committee of the Japanese Scoliosis Society. For each of the questions, consensus was achieved upon a 70% agreement among respondents. RESULTS: Responses were received from 25 of the 32 (78%) experienced spine deformity surgeons. The average age of the responding surgeons was 52 years with an average practice experience of 28 year. Consensus was achieved on 74 (76%) of the 97 aspects of care presented in the questionnaire and is broken down as follows: 12 of 17 items for preoperative management, all 5 items for perioperative management, 11 of 14 items for surgical technique, 9 of 15 items for implant selection, 6 of 8 items for bone grafting, 7 of 10 items for blood conservation, 5 of 7 items for postoperative management, all 17 items for postoperative evaluation, and 2 of 4 items for aftercare. CONCLUSIONS: Expert consensus was achieved on 74 aspects of the surgical management of AIS in Japan. In implant selection and aftercare, consensus was obtained in less than 70% of the aspects, revealing differences in AIS management between institutions. These findings on AIS surgery in Japan, informed by expert opinion, will conceivably help spine deformity surgeons determine appropriate surgical management of AIS.

[Monitoring and Neurocritical Care of Severe Traumatic Brain Injury].

The main objectives of critical care of severe traumatic brain injury(TBI)are the prevention and treatment of intracranial hypertension and secondary brain insults, preservation of cerebral perfusion pressure, and optimization of cerebral oxygenation. The critical care management of severe TBI will be discussed with a focus on the monitoring and avoidance or minimization of secondary brain insults, with emphasis on understanding the underlying physiology and pathophysiology. The evolution of critical care of severe traumatic brain injury will also be discussed along with the accumulating knowledge and experience.

Increase in circulating ACE-positive endothelial microparticles during acute lung injury.

Circulating endothelial microparticles (EMPs) are considered to be markers of endothelial injury, and lung microvascular endothelial cells express higher levels of angiotensin-converting enzyme (ACE). The aim of this study is to examine whether the number of ACE+ microvascular EMPs could be a prognostic marker for the development of acute respiratory distress syndrome (ARDS) in septic patients.The numbers of EMPs and ACE+ EMPs in the culture supernatant from human microvascular endothelial cells, as well as in the blood of mouse lung injury models and septic patients (n=82), were examined using flow cytometry.ACE+ EMPs in the culture supernatant from pulmonary microvascular endothelial cells increased after exposure to an inflammatory stimulus. In the mouse lung injury models, the circulating ACE+ EMPs and ACE+ EMP/EMP ratio were higher than in the controls (p<0.001). The ACE+ EMP/EMP ratio was correlated with the wet/dry lung ratio (rs=0.775, p<0.001). The circulating ACE+ EMPs and ACE+ EMP/EMP ratio on admission were significantly increased in septic patients who developed ARDS compared with septic patients who did not (p<0.001).Therefore, circulating ACE+ EMPs may be a prognostic marker for the development of ARDS in the septic patients.

Efficacy and Safety of a Weekly Cyclophosphamide-Bortezomib-Dexamethasone Regimen as Induction Therapy Prior to Autologous Stem Cell Transplantation in Japanese Patients with Newly Diagnosed Multiple Myeloma: A Phase 2 Multicenter Trial.

We assessed the efficacy and safety of weekly cyclophosphamide-bortezomib-dexamethasone (CBD) induction prior to autologous stem cell transplantation (ASCT) in newly diagnosed Japanese patients with multiple myeloma (MM). This regimen consisted of four 28-day cycles of once-weekly oral cyclophosphamide (300 mg/m2), subcutaneous bortezomib (1.3 mg/m2), and oral dexamethasone (40 mg). Responding patients underwent stem cell collection followed by ASCT. The primary endpoint was the postinduction rate of achieving a near complete response (nCR) or better. Among the 38 enrolled patients, a complete response (CR), an nCR, a very good partial response (VGPR), and a partial response (PR) were achieved in 10.5, 2.6, 23.7, and 36.8% of cases, respectively. A grade 4 hematological adverse event (AE) was observed in 1 patient. Grade 3-4 infection, including febrile neutropenia, was observed in 4 patients (10.5%). Although 2 patients dropped out due to AE, 94.7% of the patients completed the induction phase. However, because of a poor response to induction chemotherapy (

An epidemiological study of traumatic spinal cord injuries in the fastest aging area in Japan.

STUDY DESIGN: Retrospective epidemiological study. OBJECTIVE: To investigate the epidemiology of traumatic spinal cord injury (TSCI) in the fastest aging area in Japan. SETTING: Hospitals in Akita Prefecture, Japan. Akita Prefecture has the highest ratio of people aged 65 or older in Japan (30.4% in 2012 and 34.6% in 2016). METHODS: Patients with acute TSCI who required hospital treatment between 2012 and 2016 were included. The incidence of TSCI, cause, level, skeletal injury, and Frankel grade were investigated. RESULTS: The mean annual incidence of TSCI excluding Frankel E was 86 per million (range 86-104 per million) during the 5-year study period, with a mean age of 65.9 years (male, 75.1%) and patients in their 60s as the largest age group. Cervical injury was seen in 89.8%, and cervical TSCI without skeletal injury was seen in 65.5%. Frankel D was the most common neurological deficit (53.5%). The most common cause was falls on level surfaces (32.1%), followed by low falls (21.6%) and road traffic accidents (15.6%). CONCLUSIONS: Recent incidence and characteristics of TSCI in the fastest aging society in Japan are presented. The incidence of incomplete cervical TSCI and falls on level surfaces appear to be increasing.

Roles of Nicotine in the Development of Intracranial Aneurysm Rupture.

Background and Purpose- Tobacco cigarette smoking is considered to be a strong risk factor for intracranial aneurysmal rupture. Nicotine is a major biologically active constituent of tobacco products. Nicotine's interactions with vascular cell nicotinic acetylcholine receptors containing α7 subunits (α7*-nAChR) are thought to promote local inflammation and sustained angiogenesis. In this study, using a mouse intracranial aneurysm model, we assessed potential contributions of nicotine exposure and activation of α7*-nAChR to the development of aneurysmal rupture. Methods- Intracranial aneurysms were induced by a combination of deoxycorticosterone-salt induced hypertension and a single-dose elastase injection into cerebrospinal fluid in mice. Results- Exposure to nicotine or an α7*-nAChR-selective agonist significantly increased aneurysm rupture rate. Coexposure to an α7*-nAChR antagonist abolished nicotine's deleterious effect. In addition, nicotine's promotion of aneurysm rupture was absent in smooth muscle cell-specific α7*-nAChR subunit knockout mice but not in mice lacking α7*-nAChR on endothelial cells or macrophages. Nicotine treatment increased the mRNA levels of vascular endothelial growth factor, platelet-derived growth factor-B, and inflammatory cytokines. α7*-nAChR antagonist reversed nicotine-induced upregulation of these growth factors and cytokines. Conclusions- Our findings indicate that nicotine exposure promotes aneurysmal rupture through actions on vascular smooth muscle cell α7*-nAChR.

Attenuated accumulation of regulatory T cells and reduced production of interleukin 10 lead to the exacerbation of tissue injury in a mouse model of acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is a pathological condition that involves diffuse lung injury and severe hypoxemia caused by pulmonary and systemic diseases. We have established a mouse model of severe ARDS, developed by intratracheal injection of α-galactosylceramide (α-GalCer), an activator of natural killer T (NKT) cells, followed by LPS. In the present study, we used this model to investigate the regulatory mechanism in the early inflammatory response during acute lung injury. In α-GalCer/LPS-treated mice, the number of CD4+ CD25+ Foxp3+ regulatory T (Treg) cells and the expression of a Treg cell-tropic chemokine, secondary lymphoid-tissue chemokine (SLC), in the lungs was significantly lower than in mice treated with LPS alone. Giving recombinant (r)SLC increased the number of Treg cells in α-GalCer/LPS-treated mice. Treatment with anti-IFN-γ mAb enhanced the expression of SLC and the accumulation of Treg cells in the lungs of α-GalCer/LPS-treated mice, whereas giving recombinant (r)IFN-γ reduced the number of Treg cells in mice treated with LPS alone. IL-10 production was significantly lower in α-GalCer/LPS-treated mice than in mice treated with LPS alone. Giving rIL-10 prolonged survival and attenuated lung injury as a result of reduced production of inflammatory cytokines (such as IL-1ß, IL-6, TNF-α, and IFN-γ) and chemokines (including MCP-1, RANTES, IP-10, Mig, MIP-2, and KC) in α-GalCer/LPS-treated mice. Treatment with anti-IFN-γ mAb enhanced IL-10 production in α-GalCer/LPS-treated mice. These results suggest that the attenuated accumulation of Treg cells may be involved in the development of severe ARDS through a reduction in the synthesis of IL-10.

Calcifying nested stromal epithelial tumor of the liver in a patient with Klinefelter syndrome: a case report and review of the literature.

BACKGROUND: Calcifying nested stromal epithelial tumor (CNSET) is a primary neoplasm of the liver, characterized by well-demarcated nests consisting of spindle and epithelioid cells with calcification and bone formation. An association of Cushing syndrome with CNSET has drawn attention, but the origin of CNSET has not been clarified. CASE PRESENTATION: We report here the case of a 20-year-old male with Klinefelter syndrome who underwent liver resection for an increasing liver tumor that was pathologically diagnosed with CNSET. He was postoperatively followed up and received several examinations, and recurrences and extrahepatic lymph node metastases were detected on the 64th day after surgery. Chemoembolization and chemotherapy were not effective, leading to tumor progression with development of progressive liver failure, and the patient finally died 164 days after hepatectomy. CONCLUSIONS: This case suggests that an imbalance of hormones affects the genesis and progression of CNSET, and indicates the importance of closely following patients with CNSET by imaging with attention to hepatic recurrence and extrahepatic metastases.