Hypothiocyanous Acid Suppresses PolyI:C-Induced Antiviral Responses by Modulating IRF3 Phosphorylation in Human Airway Epithelial Cells.

Pattern recognition receptors recognize RNA viruses and trigger type I and III interferon (IFN) production and apoptosis to limit viral replication and spread. Some innate immune cells produce oxidants in response to viral infection to protect against invasion. Recent studies have demonstrated the virucidal activity of hypothiocyanous acid (HOSCN), an oxidant generated by the peroxidase-catalyzed reaction of thiocyanate with hydrogen peroxide. However, the effects of HOSCN on host antiviral responses are still unknown. In this study, we aimed to clarify the role of HOSCN in host antiviral responses against RNA viruses in airway epithelial cells using polyinosinic-polycytidylic acid (polyI:C), a mimic of viral RNA. Our results show that HOSCN repressed antiviral responses in NCI-H292 human airway epithelial cells. HOSCN decreased polyI:C-induced apoptosis and the expression levels of IFNB1, IFNL1, IFNL2 and IFNL3 mRNAs. In addition, the induction of other interferon regulatory factor 3 (IRF3)-dependent genes was also suppressed by HOSCN. Further analyses focused on IRF3 revealed that HOSCN inhibited the phosphorylation of IRF3 at Ser386 and Ser396 as well as its dimerization and nuclear translocation by inhibiting the phosphorylation of TANK-binding kinase 1 (TBK1). Furthermore, HOSCN led to the phosphorylation of IRF3 at residues other than Ser386 and Ser396, implying that HOSCN may cause a conformational change in IRF3 to impair its function. Collectively, these results suggest that HOSCN plays a novel signaling role in the antiviral response, acting as a negative regulator of apoptotic and TBK1-IRF3 signaling pathways and limiting IRF3-dependent gene expression.

Pathogen screening and prognostic factors in children with severe ARDS of pulmonary origin.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is one of the most lethal diseases encountered in the pediatric intensive care unit (PICU). The etiological pathogens and prognostic factors of severe ARDS of pulmonary origin in children with respiratory virus infections were prospectively investigated. METHODS: Enrolled children fulfilled the following criteria: (1) PICU admission; (2) age of 1 month to 16 years; (3) diagnosis of infectious pneumonia and respiratory virus infection; and (4) development of severe ARDS within 72 h after PICU admission. Pathogens were detected in the blood and tracheal lavage fluid using molecular techniques and a conventional culture system. The serum levels of inflammatory mediators on the day of PICU admission were examined. RESULTS: Fifty-seven patients (32 boys; median age, 9 months) were enrolled. Multiple virus infections, co-infection with bacteria/fungus, and bacteremia/fungemia were observed in 60%, 49%, and 32% of children, respectively. Adenovirus-B, measles virus, and cytomegalovirus were detected predominantly in tracheal lavage fluid. There were no statistically significant differences between non-survivors and survivors regarding the types of pathogen, incidence of multiple virus infection, gender, age, clinical features, and treatment. The serum levels of interferon (IFN)-γ and the IFN-γ/interleukin (IL)-10 ratio were higher in non-survivors. CONCLUSIONS: IFN-γ upregulation as detected on the day of PICU admission was found to be one of the possible prognostic factors affecting a fatal outcome. These results suggest that modulation of inflammatory responses is critical for the clinical management of children with ARDS.

Adenovirus Type 7 Pneumonia in Children Who Died from Measles-Associated Pneumonia, Hanoi, Vietnam, 2014.

During a 2014 measles outbreak in Vietnam, postmortem pathologic examination of hospitalized children who died showed that adenovirus type 7 pneumonia was a contributory cause of death in children with measles-associated immune suppression. Adenovirus type 7 pneumonia should be recognized as a major cause of secondary infection after measles.

Measurement of blood pressure in a thalidomide-impaired patient who required ovarian cystectomy: A case report.

INTRODUCTION: Thalidomide was available for use over-the-counter between 1958 and 1962, and more than 300 thalidomide-impaired people have been confirmed in Japan. Currently, thalidomide-impaired people are nearing the age of 50 years and sometimes require medical treatment or surgery. However, a sphygmomanometer cannot be used to measure the blood pressure in some thalidomide-impaired people because of upper-limb shortening or hypoplastic defects. We encountered a patient with thalidomide-related upper limb defects who required abdominal ovarian cystectomy. PRESENTATION OF CASE: The patient was a 49-year-old woman (146.5cm, 35.9kg) with thalidomide-related upper-limb defects, but no dysplasia of the lower limbs, who underwent abdominal ovarian cystectomy. During the surgery, the patient's arterial blood pressure was monitored in her lower limbs by both non-invasive and invasive methods, and almost the same variations of the blood pressure between the invasive and non-invasive measurements were observed. DISCUSSION: Usually, blood pressure measurements are performed in a non-invasive manner in the upper limbs, however, such measurement could not be performed in the present case. There are few reports of measurement of the blood pressure or surgery under anaesthesia in thalidomide-impaired patients, and we report here that it was useful to measure the blood pressure in the lower limbs in the current patient. Invasive arterial pressure measurements showed almost the same changes as the non-invasive pressure measurements, although the systolic blood pressure was 10-20mmHg lower than the noninvasively measured systolic blood pressure. CONCLUSION: Non-invasive blood pressure measurements in the lower limbs might be useful in thalidomide-impaired patients requiring blood pressure monitoring, but further studies are required to validate this method.

Effect of invariant natural killer T cells with IL-5 and activated IL-6 receptor in ventilator-associated lung injury in mice.

Mechanical ventilation (MV) is well known to potentially cause ventilator-associated lung injury (VALI). It has also been reported recently that activation of invariant natural killer T (iNKT) cells is involved in the onset/progression of airway inflammation. We analyzed the roles of inflammatory cells, including iNKT cells, and cytokines/chemokines in a mouse model of VALI. C57BL/6 and Vα14(+)NKT cell-deficient (Jα18KO) female mice were subjected to MV for 5 hours. The MV induced lung injury in the mice, with severe histological abnormalities, elevation in the percentages of neutrophils in the bronchoalveolar lavage fluid (BALF), and increase in the number of iNKT cells in the lung. Jα18KO mice subjected to MV for 5 hours also showed lung injury, with decrease of the PaO2/FiO2 ratio (P/F ratio) and elevation of the levels of total protein, IL-5, IL-6, IL-12p40, and keratinocyte-derived cytokine (KC) in the BALF. Intranasal administration of anti-IL-5 monoclonal antibody (mAb) or anti-IL-6 receptor (IL-6R) mAb into the Jα18KO mice prior to the start of MV resulted in significant improvement in the blood oxygenation. In addition, the anti-IL-5 mAb administration was associated with a decrease in the levels of IL-5, IL-9, and IL-6R in the BALF, and anti-IL-6R mAb administration suppressed the mRNA expressions of IL-5, IL-6, IL-6R, and KC. These results suggest that iNKT cells may play a role in attenuating the inflammatory caused by ventilation through IL-5 and IL-6R.

Vascular complications and coagulation-related changes in the perioperative period in Japanese patients undergoing non-cardiac surgery.

AIM: To properly assess the guidance for perioperative management, we undertook a clinical epidemiology study with the primary aim of evaluating the incidence of perioperative vascular complications and their associated factors in a cohort of Japanese patients who underwent non-cardiac surgery in a tertiary medical care center. METHODS: This observational study comprised two parts. In the first part, thrombotic and bleeding events and their risk factors in the perioperative period were evaluated in a total of 2,654 consecutive patients. In the second part, perioperative changes in coagulation-related factors, including the thrombin-antithrombin complex(TAT) and platelet aggregation activity, were serially characterized in 82 individuals randomly chosen from the consecutive patients. RESULTS: The incidence of perioperative vascular complications was as follows: 1.0% for major bleeding, 0.21% for stroke and 0.21% for venous thromboembolism. No episodes of symptomatic myocardial infarction were identified in the studied population. Perioperative changes in coagulation-related factors were found to be complex and correlated in the mixed direction of pro- and anticoagulation. The TAT values showed prolonged(across postoperative days 1-5) and prominent(>116% increase) perioperative activation of coagulation, whereas global coagulation parameters, such as the prothrombin time, showed a tendency of anticoagulation in the immediate postoperative period. CONCLUSIONS: Our data confirm the relatively low incidence of perioperative vascular complications in the general Japanese non-cardiac surgical population. Given the delicate balance between thrombotic and bleeding events, it is important to comprehensively understand the associations between the patient's baseline risk factors and vascular complications for effective clinical management.

[A case of large tracheoesophageal fistula after repair of the right discending aortic arch].

A 77-year-old woman with right aortic arch was diagnosed as aortic dissection (De Bakey IIIb) and hospitalized for conservative treatment. But, her respiratory condition deteriorated due to tracheal stenosis with aortic dissection. Surgical graft replacement of the descending aorta was performed to release tracheal stenosis. Six days after surgery, tracheoesophageal fistula (TEF) was noticed. The size of the fistula was 3 cm in diameter, located 3cm to the oral side from the carina and 23 cm from the incisors. Nineteen days after surgery, an esophageal stent was placed leading to temporary improvement of the respiratory status, but it aggravated again. Unfortunately, she died due to ventricular fibrillation 26 days after surgery. The case is extremely rare with dissection of the right aortic arch. Such a case is considered to be a high risk of TEF, and it is necessary to perform early preventive measures.

Pathological study of archival lung tissues from five fatal cases of avian H5N1 influenza in Vietnam.

Highly pathogenic avian H5N1 influenza virus (H5N1) infection in humans causes acute respiratory distress syndrome, leading to multiple organ failure. Five fatal cases of H5N1 infection in Vietnam were analyzed pathologically to reveal virus distribution, and local proinflammatory cytokine and chemokine expression profiles in formalin-fixed, paraffin-embedded lung tissues. Our main histopathological findings showed diffuse alveolar damage in the lungs. The infiltration of myeloperoxidase-positive and/or CD68 (clone KP-1)-positive neutrophils and monocytes/macrophages was remarkable in the alveolar septa and alveolar spaces. Immunohistochemistry revealed that H5N1 mainly infected alveolar epithelial cells and monocytes/macrophages in lungs. H5N1 replication was confirmed by detecting H5N1 mRNA in epithelial cells using in situ hybridization. Quantitation of H5N1 RNA using quantitative reverse transcription PCR assays revealed that the level of H5N1 RNA was increased in cases during early phases of the disease. We quantified the expression of tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, IL-8, regulated on activation normal T-cell expressed and secreted (commonly known as RANTES), and interferon-gamma-inducible protein of 10 kDa (IP-10) in formalin-fixed, paraffin-embedded lung sections. Their expression levels correlated with H5N1 RNA copy numbers detected in the same lung region. Double immunofluorescence staining revealed that TNF-α, IL-6, IL-8 and IP-10 were expressed in epithelial cells and/or monocytes/macrophages. In particular, IL-6 was also expressed in endothelial cells. The dissemination of H5N1 beyond respiratory organs was not confirmed in two cases examined in this study.

Key role of regulated upon activation normal T-cell expressed and secreted, nonstructural protein1 and myeloperoxidase in cytokine storm induced by influenza virus PR-8 (A/H1N1) infection in A549 bronchial epithelial cells.

Influenza virus infection causes severe respiratory disease such as that due to avian influenza (H5N1). Influenza A viruses proliferate in human epithelial cells, which produce inflammatory cytokines/chemokines as a "cytokine storm" attenuated with the viral nonstructural protein 1 (NS1). Cytokine/chemokine production in A549 epithelial cells infected with influenza A/H1N1 virus (PR-8) or nonstructural protein 1 (NS1) plasmid was examined in vitro. Because tumor necrosis factor-α (TNF-α) and regulated upon activation normal T-cell expressed and secreted (RANTES) are predominantly produced from cells infected with PR-8 virus, the effects of mRNA knockdown of these cytokines were investigated. Small interfering (si)TNF-α down-regulated RANTES expression and secretion of RANTES, interleukin (IL)-8, and monocyte chemotactic protein-1 (MCP-1). In addition, siRANTES suppressed interferon (IFN)-γ expression and secretion of RANTES, IL-8, and MCP-1, suggesting that TNF-α stimulates production of RANTES, IL-8, MCP-1, and IFN-γ, and RANTES also increased IL-8, MCP-1, and IFN-γ. Furthermore, administration of TNF-α promoted increased secretion of RANTES, IL-8, and MCP-1. Administration of RANTES enhanced IL-6, IL-8, and MCP-1 production without PR-8 infection. These results strongly suggest that, as an initial step, TNF-α regulates RANTES production, followed by increase of IL-6, IL-8, and MCP-1 and IFNs concentrations. At a later stage, cells transfected with viral NS1 plasmid showed production of a large amount of IL-8 and MCP-1 in the presence of the H(2)O(2)-myeloperoxidse (MPO) system, suggesting that NS1 of PR-8 may induce a "cytokine storm" from epithelial cells in the presence of an H(2)O(2)-MPO system.

Multidisciplinary nutritional support for autologous hematopoietic stem cell transplantation: a cost-benefit analysis.

OBJECTIVE: The objective of the present study was to evaluate the economic and clinical efficacy of a multidisciplinary nutritional support team (NST) for autologous stem cell transplantation. METHODS: We performed a retrospective cost-benefit analysis of autologous stem cell transplantation (ASCT) in patients with and without NST intervention at a single institute. Patients (n = 120) had undergone 169 ASCTs, 67 before the commencement of NST intervention in September 2005 and 102 after September 2005. The conditioning regimens, prophylactic antibiotics, and supportive care were unchanged from 2001 through 2008. The duration of hospitalization, cost, and laboratory data were analyzed. RESULTS: With NST intervention, the duration of total parenteral nutrition, absence of oral food intake, hospitalization, and therapeutic antibiotic usage were significantly shortened by 11.4, 9.7, 8.1, and 4.5 d, respectively. With NST intervention, the incidence of hepatic adverse events and hyperglycemia was low, and the total cost of hospitalization was significantly decreased by 403 600 yen (US $4484.40). Two cases of therapy-related death were recorded before September 2005. No therapy-related mortality was observed after commencement of NST intervention; however, the difference was not significant. CONCLUSION: Multidisciplinary NST intervention has a positive effect on cost decrease, and it may decrease the incidence of adverse events associated with ASCT and total parenteral nutrition.

[Trends of HIV patients operated at International Medical Center of Japan].

BACKGROUND: HIV-infected patients are on the increase in Japan, and anti-HIV therapy improved their prognosis. It is expected that the number of operations in HIV patients will increase. METHODS: We surveyed the prevalence of HIV 30,188 patients operated at International Medical Center of Japan, a major, HIV/AIDS hospital, from 2001 to 2007. RESULTS: The number of HIV-positive cases was 389 in 7 years, and the prevalence of HIV seropositivity was 1.3% in total, 1.0% in scheduled, and 2.0% in emergent cases. The prevalence of male (2.0%) was higher than female (0.7%) patients and the prevalence was highest (9.2%) in male patients in their 30's. They were parallel with the HIV occurrence trend of Japan. The prevalence was the highest (2.4%) in the division of general surgery, as well as in obstetric and gynecology. The number of major surgery in HIV patients has been increasing. CONCLUSIONS: We assume that the perioperative management in each hospital has become more important. The annual trend of the number of the operations performed in HIV-positive patients at our hospital did not show annual changes.

[Current status of HIV/AIDS anesthetic experiences in Japan--questionnaire for anesthesia teaching hospitals].

BACKGROUND: As the number of HIV-infected patients in Japan increases every year, the opportunity for a HIV-positive patient to undergo an operation is also increasing. METHODS: Authors sent questionnaire to 952 anesthesia teaching hospitals, in order to investigate the experience and management of the HIV-positive anesthetic cases. RESULTS: The reply was obtained from 480 teaching hospitals. One hundred and nine hospitals (22.7%) experienced HIV-positive operation, 367 hospitals (76.5%) had no experience. With regard to the number of experienced HIV-positive cases, only one case was the most numerous answer and most of the hospitals had fewer than ten cases. General anesthesia was selected in 74% of cases, regional anesthesia (spinal or/and epidural anesthesia) were selected in 26% of cases. Preoperative HIV examination for almost all scheduled cases were carried out in 24% of the hospitals, but 23% of the hospitals did not carry out the examination at all. Eighteen percent of the hospitals had a severe rule for the management of a HIV-positive case, and 58% of the hospitals had a rule almost the same as for HBV-HCV positive cases. CONCLUSIONS: Almost one fourth of anesthesia teaching hospitals experienced HIV-positive cases. Anesthesiologists should know how to manage HIV-positive surgical patients and be prepared for the cases.

[Combined use of intrathecal morphine and diclofenac suppository for postoperative analgesia after caesarean section].

BACKGROUND: Intrathecal morphine for postoperative analgesia after caesarean section has been used in Europe and North America, but its use is not common in Japan. METHODS: We randomized 40 parturients to two groups, given either intrathecal saline (control group) or intrathecal morphine 0.05 mg (morphine group) for caesarean section. To both groups, we gave a diclofenac suppository 50 mg every 8 hours after surgery. RESULTS: The area under curve for the visual analogue scale for pain during 24 hours after operation was significantly lower (P < 0.01) in the morphine group than the control group. In addition, the parturients who required pentazocine as a rescue analgesia was significantly fewer in the morphine group (5 parturients) than the control group (11 parturients). There was no significant difference between the two groups in the Apgar score of infants, pH in umbilical cord arterial and venous blood and the incidence of postoperative nausea and vomiting. The incidence of pruritus was significantly higher in the morphine group (11 parturients) than the control group (no parturient). CONCLUSIONS: Intrathecal morphine 0.05 mg and diclofenac suppository 50 mg given every 8 hours produced effective postoperative analgesia with minimum side effects after caesarean section.