Suppression of eosinophilic airway inflammation by treatment with alpha-galactosylceramide

To clarify the essential role of NKT cells in allergy, we investigated the contribution of NKT cells to the pathogenesis of eosinophilic airway inflammation using alpha-galactosylceramide (alpha-GalCer), a selective ligand for NKT cells. Although continuous administration of alpha-GalCer during ovalbumin (OVA) sensitization increased OVA-specific IgE levels and worsened eosinophil inflammation, a single administration of alpha-GalCer at the time of OVA challenge completely prevented eosinophilic infiltration in wild-type mice. This inhibitory effect of alpha-GalCer was associated with a decrease in airway hyperresponsiveness, an increase in IFN-gamma, and decreases in IL-4, IL-5 and IL-13 levels in the bronchoalveolar lavage fluids. Analysis of lung lymphocytes revealed that production of IFN-gamma increased in NK cells, but not in T or NKT cells, following alpha-GalCer administration. Induction of vascular cell adhesion molecule-1 in the lungs of wild-type mice was also significantly attenuated by treatment with alpha-GalCer. These effects of alpha-GalCer were abrogated in J alpha281-/- mice, which lack NKT cells, and in wild-type mice treated with anti-IFN-gamma Ab. Hence, our data indicate that alpha-GalCer suppresses allergen-induced eosinophilic airway inflammation, possibly by inducing a Th1 bias that results in inhibition of eosinophil adhesion to the lung vessels.     

Role of c-kit receptor tyrosine kinase in the development, survival and neoplastic transformation of mast cells

The c-kit gene is allelic with the dominant spotting ( W ) locus on mouse chromosome 5 and encodes a receptor tyrosine kinase. The llgand for c-klt receptor is stem cell factor (SCF), which is the principal growth factor for mast cells. The loss-of-function mutations of c-kit receptor affect the development of mast cells, thereby resulting in a depletion of mast cells. The abundant expression of c-ktt receptor is indispensable for the survival of mast cells. In addition, the galn-of-function mutations of c-kit receptor were found in several tumor mast cell lines. When these galn-of-function mutations were introduced to cells of murine interleukin (IL)-3-dependent cell lines, the expression of c-kit receptor with constitutive tyrosine kinase activity not only abrogated the IL-3 requirement of the cells, but also caused them to become tumorlgenic in nude athymic mice. The gain-of-function mutations of c-kit receptor appear to result in the malignant transformation of mast cells. Taken together, the signals from the c-ktt receptor are essential for the development, survival, and malignant transformation of mast cells.     

Molecular analysis in Japanese patients with Charcot-Marie-Tooth disease: DGGE analysis for PMP22, MPZ,and Cx32/GJB1 mutations

Charcot-Marie-Tooth disease (CMT) is a heterogeneous disorder and is traditionally classified into two major types, CMT type 1 (CMT1) and CMT type 2 (CMT2). Most CMT1 patients are associated with the duplication of 17p11.2-p12 (CMT1A duplication) and small numbers of patients have mutations of the peripheral myelin protein 22 (PMP22), myelin protein zero (MPZ), connexin 32 (Cx32/GJB1), and early growth response 2 (EGR2) genes. Some mutations of MPZ and Cx32 were also associated with the clinical CMT2 phenotype. We constructed denaturing gradient gel electrophoresis (DGGE) analysis as a screening method for PMP22, MPZ, and Cx32 mutations and studied 161 CMT patients without CMT1A duplication. We detected 27 mutations of three genes including 15 novel mutations; six of PMP22, three of MPZ, and six of Cx32. We finally identified 21 causative mutations in 22 unrelated patients and five polymorphic mutations. Eighteen of 22 patients carrying PMP22, MPZ, or Cx32 mutations presented with CMT1 and four of them with MPZ or Cx32 mutations presented with the CMT2 phenotype. DGGE analysis was sensitive for screening for those gene mutations, but causative gene mutation was not identified in many of the Japanese patients with CMT, especially with CMT1. Other candidate genes should be studied to elucidate the genetic basis of Japanese CMT patients.     

Analysis of photopolymerization behavior of UDMA/TEGDMA resin mixture and its composite by differential scanning calorimetry

The aim of this study was to investigate the extent of polymerization (Ep) in terms of polymerization rate of UDMA/TEGDMA resin mixtures and its composite resin, by using a differential scanning calorimeter (DSC) technique employing a photopolymerization apparatus. The resin mixtures used in this study consisted of urethane dimethacrylate (UDMA) as a base monomer and triethyleneglycol dimethacrylate (TEGDMA) as a low viscosity monomer. The concentration of TEGDMA in the mixed monomer was varied to 0, 20, 40, 60, 80, and 100 mol %. Additionally, using a base monomer consisting of 60 mol % UDMA and 40 mol % TEGDMA, four kinds of composites with silica filler of 0, 20, 40, 60, and 70 wt %, were prepared in this study. The general reaction profile and Ep values were obtained from the DSC curves. Increasing the concentration of TEGDMA resulted in a decrease in the viscosity of the UDMA/TEGDMA mixture, a delay in the time to maximum polymerization rate, and an increase in the Ep values of the resin mixtures. Furthermore, Ep values decreased with increasing filler content between 0 and 60 wt % but did not decrease further between 60 and 70 wt %.     

Angiopoietins and angiopoietin-like proteins in angiogenesis.

Vascular network formation requires several endothelial cell growth factors. These factors have a potent angiogenic effect, and their precise coordination is essential for vascular development. Among them, angiopoietins function through the Tie2 receptor, whose signaling is critical to regulate vascular stabilization and remodeling. It has been reported that the angiopoietin/Tie2 signal is involved in survival and migration of endothelial cells and regulates vascular remodeling and maintenance of vascular integrity. More recent studies demonstrate that angiopoietin/Tie2 signaling is also required for lymphangiogenesis. The authors and several other groups have identified six angiopoietin-like proteins (Angptls) containing a coiled-coil domain and a fibrinogen-like domain, both of which are characteristic of angiopoietins. Interestingly, Angptls also function in angiogenesis through regulating survival and migration of endothelial cells, although Angptls do not bind the angiopoietin receptor Tie2. Currently, Angptls are orphan ligands, but they have been reported to have pleiotropic effects not only on vascular cells but also on metabolism and tumor biology. Here, the authors review current findings relating to the roles of angiopoietins and Angptls in vascular biology and discuss molecular mechanisms relevant to these factors and angiogenesis.     

Conformation and gas permeability of poly(α-amino acid) membranes

The permeability of some poly(?-amino acid) (PAA) membranes like such of poly(N,δ-carbobenzoxy-L -lysine) (PCBL), poly(N,δ-carbobenzoxy-L -ornithine) (PCBO) as well as of copolymers of L -lysine and carbobenzoxy-L -lysine to oxygen and carbon dioxide were determined at different water content especially with regard to their use for artificial lungs. The conformations of these polymer membranes were studied by means of IR-spectra and X-ray diffraction. The results on the diffusion coefficient obtained for PCBL and PCBO were analysed in terms of Eyring's theory. They suggest that the microvoids in the interstices between the α-helices, assumed on the basis of X-ray analyses, play an important role, especially below the glass transition temperature T_g of the side-chains. This seems also to contribute partly to the diffusion of gas through the membrane even above T_g and results in an abnormally high “apparent activation energy” of diffusion in the wet state below T_g. It was found that the permeability of the membrane of partially decarbobenzoxylated PCBL for oxygen in a certain temperature range is higher than that for carbon dioxide. This has never been observed for any other synthetic polymer, because usually carbon dioxide has a higher solubility in these materials than oxygen. In the case of the partially decarbobenzoxylated PCBL membranes, however, the diffusion coefficient of carbon dioxide, and therefore the permeation of this gas, decreases much more than that of oxygen with increasing decarbobenzoxylation accompanied by the formation of β-structure and concomitantly the formation of intermolecular hydrogen bonds. Obviously, this phenomenon may be responsible for the permselectivity of these membranes for oxygen compared with carbon dioxide.     

Brighton epistaxis balloon: application for cranio-facial injury

Head injury patients often complicate facial and/or multiple injuries other than cranio-cerebral insults and perplex the emergency staffs. The authors used Brighton epistaxis balloon for such patients with massive nasal bleeding and reported the utility of the balloon not only in such state of emergency but also for a few days to control the hemorrhage mostly caused by craniobasal fractures or rupture of the adjacent vessels. One hundred and twenty-nine patients were transported and hospitalized in Department of Emergency Medicine, University of Tokyo Hospital, Tokyo, Japan during the period from October, 1981 to January, 1983. Nasal bleeding was noted in 29 cases of them and the balloon was used in 10 cases, who were from 19 to 76 years of age, all males and suffered from basal fractures or craniofacial injuries. Six cases of them were also accompanied with fractures in the extremities or pelvis, hemopneumothorax and/or intra-abdominal bleeding and could not but put on "Military anti-shock trousers" for the management of hypovolemic shock, hence the nasal bleeding should be managed immediately in the emergency room. In these situations the balloon was inserted into both nasal cavities in all the patients, to control successfully the nasal hemorrhages one of which contaminated cerebrospinal fluid and three of which were sure to be pulsatile due to arterial injury. The Brighton epistaxis balloon is to be removed within twelve or twenty-four hours, but in the authors' cases the mean duration for the hemostasis was 58.9 hours for 6 survivors and 49.6 hours for all 10 cases.(ABSTRACT TRUNCATED AT 250 WORDS)     

Impact of chronic kidney disease on oncological outcomes in patients with high-risk non-muscle-invasive bladder cancer who underwent adjuvant bacillus Calmette-Guérin therapy

ObjectivesTo investigate the impact of chronic kidney disease (CKD) on oncological outcomes in patients with high-risk non-muscle invasive bladder cancer (NMIBC) who underwent adjuvant induction bacillus Calmette-Guérin (BCG) therapy after transurethral resection of bladder tumor (TURBT).Materials and MethodsWe conducted a multi-institutional retrospective study assessing 209 patients with high-risk NMIBC who underwent TURBT and subsequent adjuvant induction BCG therapy from December 1998 to April 2019. Patients were divided into 2 groups: those with preoperative estimated glomerular filtration rate (eGFR) ≥ 60 ml/min/1.73 m² (non-CKD group), and those with eGFR < 60 ml/min/1.73 m² (CKD group). Primary endpoints were intravesical recurrence-free survival (RFS) and muscle-invasive bladder cancer (MIBC)-free survival. Background-adjusted multivariate analyses with the inverse probability of treatment weighting (IPTW) method using the propensity score were performed to evaluate the impact of CKD on intravesical RFS, MIBC-free survival, metastasis-free survival, cancer-specific survival, and overall survival. Moreover, multivariable analyses were performed to assess the impact of CKD on intravesical recurrence and MIBC progression, adjusting for the competing risk of death using the Fine-Gray competing risk regression model.ResultsMedian age and follow-up period after TURBT were 72 years and 45 months, respectively. Of 209 patients, 71 (34%) were diagnosed with CKD before TURBT. Background-adjusted multivariate analyses with the IPTW method indicated that CKD was significantly associated with shorter intravesical RFS, MIBC-free survival, metastasis-free survival, cancer-specific survival, and overall survival. In the Fine-Gray competing risk regression model, CKD showed significantly higher probabilities of intravesical recurrence and MIBC progression, with an adjusted subdistribution hazard ratio of 1.886 (95% confidence interval 1.069–3.330, P = 0.028) and 3.740 (95% confidence interval 1.060–13.20, P = 0.040), respectively.ConclusionsCKD presents a risk factor of poor oncological outcomes in patients with high-risk NMIBC who underwent adjuvant induction BCG therapy after TURBT.     

The effect of frailty on the quality of life and lower urinary symptoms following robot-assisted radical prostatectomy: A longitudinal analysis (FRARP-QL Study)

ObjectivesWe aimed to evaluate the effect of frailty on health-related quality-of-life (HRQOL) and lower urinary symptoms (LUTS) following robot-assisted radical prostatectomy (RARP) in patients with prostate cancer (CaP).Materials and MethodsWe longitudinally evaluated geriatric 8 (G8), HRQOL, and LUTS for 12 months in 118 patients with RARP from January 2017 to April 2020. Patients were divided into frail (G8 ≤14) and nonfrail (G8 >14) groups. We compared the effect of frailty on HRQOL and LUTS between the frail and nonfrail groups before and 12 months after RARP.ResultsThe median age of patients was 68 years. The number of patients in the frail and nonfrail groups were 41 and 77, respectively. No significant difference in patients’ background was observed between the groups, except for the presence of cardiovascular disease (22% vs. 7.8%, P = 0.041). There was no significant difference in HRQOLs and LUTS between the groups at baseline. Similarly, HRQOLs, LUTS, and pad-free continence rates were not significantly different between the groups at 12 months after RARP. In the nonfrail group, LUTS at 12 months following RARP significantly improved compared to those at the baseline, but it did not significantly improve in the frail group. Multivariable logistic regression analysis demonstrated that frailty was not significantly associated with LUTS worsening.ConclusionsFrailty was not significantly associated with the worsening of HRQOL, LUTS, and pad-free continence rates in patients treated with RARP.