Effect of Diesel Exhaust Particles on House Dust Mite–Induced Airway Eosinophilic Inflammation and Remodeling in Mice

Recent research has focused on the effects of ambient particulate pollution and much evidence has indicated that particulate pollution is associated with the onset of asthma and allergy; however, the effect of diesel exhaust particles (DEP) on the development of allergen-induced airway remodeling has not been fully investigated in vivo. In the present study, we examined the effects of DEP on Dermatophagoides farinae allergens (Der f)–induced asthma-like phenotypes in mice. Mice were administered i.t. 8 times with Der f. DEP were injected i.t. with Der f 4 times throughout the experiment or twice at the sensitization period. In both cases, DEP aggravated Der f–induced increases in airway responsiveness to acetylcholine, the number of eosinophils and neutrophils in the bronchoalveolar lavage fluid (BALF), serum Der f–specific IgG1 levels, Th2 cytokines and transforming growth factor-β 1 levels in BALF, and amount of hydroxyproline in the right lungs. Furthermore, goblet cell hyperplasia and subepithelial fibrosis were also markedly aggravated. These findings indicate that DEP can potentiate airway remodeling induced by repeated allergen challenge as well as Th2-drived airway hyperresponsiveness, eosinophilic inflammation, and IgG1 production and that DEP can exhibit adjuvant activity for airway remodeling, probably due to the enhancement of allergen sensitization and/or of Th2 polarizing pathways.     

NATURAL ORIFICE TRANSLUMENAL ENDOSCOPIC SURGERY FOR PREOPERATIVE STAGING IN A PANCREATIC CANCER PATIENT

Background: Many experimental studies have shown the technical feasibility of natural orifice translumenal endoscopic surgery (NOTES). We report the first clinical application of natural orifice transgastric endoscopic peritoneoscopy in Japan for preoperative staging in a patient with pancreatic cancer. Methods: A submucosal tunnel was created for safe peritoneal access and secure closure of the gastric‐incision site. Results: Transgastric peritoneoscopy provided an excellent view and allowed approach to various areas of the abdominal cavity. After confirmation of operative curability, the patient underwent an open standard operation without complication. Conclusions: Natural orifice transgastric endoscopic peritoneoscopy for cancer staging using the submucosal tunnel technique appears to be feasible and safe.     

Mediastinal Cystic Parathyroid Adenoma Diagnosed by Somatostatin Receptor Scintigraphy

A 71-year-old man complained of nausea and loss of appetite for eight months prior to admission. He was transported to a hospital with disorientation and diagnosed with primary hyperparathyroidism by laboratory examinations. However, ultrasonography, computed tomography, and technetium-99m labeled methoxyisobutyl isonitrile (^99mTc-MIBI) with single-photon emission computed tomography did not yield definite results. In contrast, somatostatin receptor scintigraphy successfully identified the lesion responsible for the over-secretion of parathyroid hormone within the middle mediastinum. The tumor was successfully resected by surgery, and a histopathological analysis confirmed the parathyroid adenoma nature of the tumor.     

Significance of Concurrent Chemoradiotherapy as Primary Treatment in Patients with Metastatic Cervical Cancer

(1) This study investigated the prognostic impact of tumor size in patients with metastatic cervical cancer. (2) Methods: Seventy-three cervical cancer patients in our institute were stratified into two groups based on distant metastasis: para-aortic lymph node metastasis alone (IIIC2) or spread to distant visceral organs with or without para-aortic lymph node metastasis (IVB) to identify primary tumor size and concurrent chemoradiotherapy. (3) Results: The overall survival (OS) for patients with a tumor >6.9 cm in size was significantly poorer than that for patients with a tumor ≤6.9 cm in the IVB group (p = 0.0028); the corresponding five-year OS rates in patients with a tumor ≤6.9 and >6.9 cm were 53.3% and 13.4%, respectively. In the multivariate analysis, tumor size and primary treatment were significantly associated with survival in metastatic cervical cancer. (4) Conclusions: Tumor size ≤6.9 cm and concurrent chemoradiotherapy as the primary treatment were favorable prognostic factors for patients with metastatic cervical cancer.     

The orally available spleen tyrosine kinase inhibitor 2-[7-(3,4-dimethoxyphenyl)-imidazo[1,2-c]pyrimidin-5-ylamino]nicotinamide dihydrochloride (BAY 61-3606) blocks antigen-induced airway inflammation in rodents

Spleen tyrosine kinase (Syk) tyrosine kinase plays essential roles in receptors for Fc portion of immunoglobulins and B cell receptor complex signaling in various inflammatory cells; therefore, inhibitors of Syk kinase may show potential as antiasthmatic/allergic therapeutics. We identified 2-[7-(3,4-dimethoxyphenyl)-imidazo[1,2-c]pyrimidin-5-ylamino]-nicotinamide dihydrochloride (BAY 61-3606), a potent (Ki = 7.5 nM) and selective inhibitor of Syk kinase. BAY 61-3606 inhibited not only degranulation (IC50 values between 5 and 46 nM) but also lipid mediator and cytokine synthesis in mast cells. BAY 61-3606 was highly efficacious in basophils obtained from healthy human subjects (IC50 = 10 nM) and seems to be at least as potent in basophils obtained from atopic (high serum IgE) subjects (IC50 = 8.1 nM). B cell receptor activation and receptors for Fc portion of IgG signaling in eosinophils and monocytes were also potently suppressed by BAY 61-3606. Oral administration of BAY 61-3606 to rats significantly suppressed antigen-induced passive cutaneous anaphylactic reaction, bronchoconstriction, and bronchial edema at 3 mg/kg. Furthermore, BAY 61-3606 attenuated antigen-induced airway inflammation in rats. Based on these anti-inflammatory effects of BAY 61-3606 both in vitro and in vivo, it was demonstrated that Syk may play a very critical role in the pathogenesis of allergic reactions.     

Temporal Trends in Outcomes after Out-of-Hospital Cardiac Arrests Witnessed by Emergency Medical Services in Japan: A Population-Based Study

Objective: Survival after out-of-hospital cardiac arrests (OHCA) witnessed by emergency medical service (EMS) personnel has been insufficiently understood. The aim of this study was to evaluate temporal trends in survival after EMS-witnessed OHCAs in Japan. Methods: A nationwide, population-based, observational cohort study of consecutive adult OHCA patients with emergency responder resuscitation attempts from January 2005 to December 2012 in Japan. We assessed the trends in annual incidence, characteristics, and outcomes of OHCA patients witnessed by EMS personnel. Multiple logistic regression analysis was used to assess factors that were potentially associated with neurologically favorable outcome defined as cerebral performance category scale 1or 2. Results: During the study period, a total of 66,760 EMS-witnessed OHCAs were documented. The annual incidence rates per 100,000 persons of EMS-witnessed OHCA patients increased from 4.6 (n = 7219) in 2005 to 4.9 (n = 9256) in 2012 (p for trend = 0.035). The proportion of one-month survival with neurologically favorable outcome improved from 5.9% in 2005 to 8.6% in 2012 (p for trend < 0.001), and the proportion increased from 22.1% in 2005 to 30.2% in 2012 in cases with shockable rhythm (p for trend < 0.001). In a multivariate analysis, adults, male gender, shockable rhythm, presumed cardiac origin, and year were associated with a better neurological outcome. Conclusions: In this population, the proportion of one-month survival with neurologically favorable outcome among OHCA patients witnessed by EMS personnel significantly improved during the study period.     

Essential role of IRAK-4 protein and its kinase activity in Toll-like receptor-mediated immune responses but not in TCR signaling

Interleukin-1 receptor-associated kinase 4 (IRAK-4) was reported to be essential for the Toll-like receptor (TLR)- and T cell receptor (TCR)-mediated signaling leading to the activation of nuclear factor kappaB (NF-kappaB). However, the importance of kinase activity of IRAK family members is unclear. In this study, we investigated the functional role of IRAK-4 activity in vivo by generating mice carrying a knockin mutation (KK213AA) that abrogates its kinase activity. IRAK-4(KN/KN) mice were highly resistant to TLR-induced shock response. The cytokine production in response to TLR ligands was severely impaired in IRAK-4(KN/KN) as well as IRAK-4(-/-) macrophages. The IRAK-4 activity was essential for the activation of signaling pathways leading to mitogen-activated protein kinases. TLR-induced IRAK-4/IRAK-1-dependent and -independent pathways were involved in early induction of NF-kappaB-regulated genes in response to TLR ligands such as tumor necrosis factor alpha and IkappaBzeta. In contrast to a previous paper (Suzuki, N., S. Suzuki, D.G. Millar, M. Unno, H. Hara, T. Calzascia, S. Yamasaki, T. Yokosuka, N.J. Chen, A.R. Elford, et al. 2006. Science. 311:1927-1932), the TCR signaling was not impaired in IRAK-4(-/-) and IRAK-4(KN/KN) mice. Thus, the kinase activity of IRAK-4 is essential for the regulation of TLR-mediated innate immune responses.     

Development of a Tissue‐Engineered Artificial Ligament: Reconstruction of Injured Rabbit Medial Collateral Ligament With Elastin‐Collagen and Ligament Cell Composite Artificial Ligament

Ligament reconstruction using a tissue‐engineered artificial ligament (TEAL) requires regeneration of the ligament‐bone junction such that fixation devices such as screws and end buttons do not have to be used. The objective of this study was to develop a TEAL consisting of elastin‐coated polydioxanone (PDS) sutures covered with elastin and collagen fibers preseeded with ligament cells. In a pilot study, a ring‐type PDS suture with a 2.5 mm (width) bone insertion was constructed with/without elastin coating (Ela‐coat and Non‐coat) and implanted into two bone tunnels, diameter 2.4 mm, in the rabbit tibia (6 cases each) to access the effect of elastin on the bond strength. PDS specimens taken together with the tibia at 6 weeks after implantation indicated growth of bone‐like hard tissues around bone tunnels accompanied with narrowing of the tunnels in the Ela‐coat group and not in the Non‐coat group. The drawout load of the Ela‐coat group was significantly higher (28.0 ± 15.1 N, n = 4) than that of the Non‐coat group (7.6 ± 4.6 N, n = 5). These data can improve the mechanical bulk property of TEAL through extracellular matrix formation. To achieve this TEAL model, 4.5 × 10⁶ ligament cells were seeded on elastin and collagen fibers (2.5 cm × 2.5 cm × 80 µm) prior to coil formation around the elastin‐coated PDS core sutures having ball‐shape ends with a diameter of 2.5 mm. Cell‐seeded and cell‐free TEALs were implanted across the femur and the tibia through bone tunnels with a diameter of 2.4 mm (6 cases each). There was no incidence of TEAL being pulled in 6 weeks. Regardless of the remarkable degradation of PDS observed in the cell‐seeded group, both the elastic modulus and breaking load of the cell‐seeded group (n = 3) were comparable to those of the sham‐operation group (n = 8) (elastic modulus: 15.4 ± 1.3 MPa and 18.5 ± 5.7 MPa; breaking load: 73.0 ± 23.4 N and 104.8 ± 21.8 N, respectively) and higher than those of the cell‐free group (n = 5) (elastic modulus: 5.7 ± 3.6 MPa; breaking load: 48.1 ± 11.3 N) accompanied with narrowed bone tunnels and cartilage matrix formation. These data suggest that elastin increased the bond strength of TEAL and bone. Furthermore, our newly developed TEAL from elastin, collagen, and ligament cells maintained the strength of the TEAL even if PDS was degraded.     

Superficial Surgical Site Infection in Hepatobiliary-Pancreatic Surgery: Subcuticular Suture Versus Skin Staples

Purpose

Postoperative superficial surgical site infection is a major complication in hepatobiliary-pancreatic surgery. We aimed to compare the efficacy of subcuticular sutures versus staples for skin closure in preventing superficial surgical site infection in hepatobiliary-pancreatic surgery.

Methods

Consecutive patients who underwent hepatobiliary-pancreatic surgery at our hospital from October 2006 to March 2011 and from April 2012 to March 2015 were reviewed retrospectively. Superficial surgical site infection incidence was evaluated in patients who received subcuticular sutures and those who received staples for skin closure. Propensity score matching analysis was used to adjust bias from confounding factors.

Results

A total of 691 patients were included. Patients with skin staple closures (n?=?346) were compared with patients with subcuticular suture closures (n?=?345). After a propensity score matching analysis, a significant difference in superficial surgical site infection incidence was found between the skin stapler group (11.3%) and subcuticular sutures group (2.6%). The same comparison was performed by a subgroup analysis and supported this finding in patients after hepatectomy without biliary reconstruction, pancreatoduodenectomy, or open laparotomy surgeries and in patients with body mass index <?25.

Conclusions

Subcuticular suturing after hepatobiliary-pancreatic surgery was more efficacious in reducing postoperative superficial surgical site infection incidence than staples for skin closure.