Differences in expression patterns of cathepsin C/dipeptidyl peptidase I in normal,pathological and aged mouse central nervous system

Cathepsin C (CC) (EC 3.4.14.1, dipeptidyl peptidase I) is a lysosomal cysteine protease that is required for the activation of several granule‐associated serine proteases in vivo. CC has been shown to be constitutively expressed in various tissues, but the enzyme is hardly detectable in central nervous system (CNS) tissues. In the present study, we investigated the regional and cellular distribution of CC in normal, aging and pathological mouse brains. Immunoblotting failed to detect CC protein in whole brain tissues of normal mice, as previously described. However, low proteolytic activity of CC was detected in a brain region‐dependent manner, and granular immunohistochemical signals were found in neuronal perikarya of particular brain regions, including the accessory olfactory bulb, the septum, CA2 of the hippocampus, a part of the cerebral cortex, the medial geniculate, and the inferior colliculus. In aged mice, the number of CC‐positive neurons increased to some extent. The protein level of CC and its proteolytic activity showed significant increases in particular brain regions of mouse models with pathological conditions – the thalamus in cathepsin D‐deficient mice, the hippocampus of ipsilateral brain hemispheres after hypoxic–ischemic brain injury, and peri‐damaged portions of brains after penetrating injury. In such pathological conditions, the majority of the cells that were strongly immunopositive for CC were activated microglia. These lines of evidence suggest that CC is involved in normal neuronal function in certain brain regions, and also participates in inflammatory processes accompanying pathogenesis in the CNS.     

Effect of polyglycolic acid sheets with fibrin glue (MCFP technique) on the healing of wounds after partial resection of the border of the tongue in rabbits: a preliminary study

The aim of this study was to examine the effectiveness of covering wounds to the tongue with a polyglycolic acid (PGA) sheet and fibrin glue. Eighteen mature male Japanese white rabbits had a unilateral glossectomy involving an area 10mm×10mm×2mm. After glossectomy the tongues were covered with PGA sheets 8mm×8mm in size and fibrin glue (mucosal defect covered with fibrin glue and polyglycolic acid sheet=MCFP) 1 week after the operation (n=3), after 2 weeks (n=3), and after 4 weeks (n=3). In control groups, after 1, 2, and 4 weeks (n=3 in each group), the partially resected tongues were closed with absorbable sutures (polyglactin 910). One week (experimental and control groups 1), 2 weeks (experimental and control groups 2) and 4 weeks (experimental and control groups 3) after operation the tongues were harvested and stained for microscopic examination. Histological examination showed that the covered wound surface had not epithelialised and the basal layer had yet to form in experimental group 1, but had formed in experimental group 2. However, in control group 1, epithelialisation of the sutured wound had begun. Immunohistochemical examination showed that, in experimental group 1, the non-uniform epithelial layer of the covered wound surface expressed cytokeratin AE1/AE3, and the epithelial and connective tissue layers stained strongly for FGF-2. Similar results were obtained in experimental group 2, whereas in experimental group 3, FGF-2 was expressed only in the connective tissue layer, and epithelialisation was complete. However, in control group 1, AE1/AE3 was expressed in the epithelial layer, and FGF was expressed in the connective tissue layer beneath the basal layer. In control groups 2 and 3, AE1/AE3 and FGF-2 were expressed in patterns similar to those in experimental groups 2 and 3. We suggest that this method is useful and the operation is simple. However, further testing of the method is needed and it should be widely used clinically before it is recommended.     

Trials of vaccines for pancreatic ductal adenocarcinoma: Is there any hope of an improved prognosis?

Pancreatic tumors are chemoresistant and malignant, and there are very few therapeutic options for pancreatic cancer, as the disease is normally diagnosed at an advanced stage. Although attempts have been made to develop vaccine therapies for pancreatic cancer for a couple of decades, none of the resultant protocols or regimens have succeeded in improving the clinical outcomes of patients. We herein review vaccines tested within the past few years, including peptide, biological and multiple vaccines, and describe the three sets of criteria used to evaluate the therapeutic activity of vaccines in solid tumors.     

The effect of ventilation tube insertion or trans-tympanic silicone plug insertion on a patulous Eustachian tube

Conclusions This study suggests that long-term ventilation tube insertion is the first-choice surgical treatment for a ‘sniff-type’ patulous Eustachian tube (PET). When treating a refractory PET, it is important to determine whether the patient had a habitual sniff. Objectives PET patients were divided into two groups: patients with a habitual sniff (sniff-type PET) and those without a habitual sniff (non-sniff-type PET). This study examined the effects of ventilation tube insertion or silicone plug insertion in each group. Methods Surgical procedures such as ventilation tube insertion or trans-tympanic silicone plug insertion were performed for these patients. Tubotympanoaero-dynamic graphy (TTAG) was also performed to determine the mechanisms underlying these treatments. Results There were 11 cases (17 ears) of sniff-type PET and 20 cases (27 ears) of non-sniff-type PET. An improvement in symptoms was found in 72.7% of the patients who underwent silicone plug insertion (66.7% for sniff-type PET and 74.1% for non-sniff-type PET) and in 90.9% of the patients who underwent ventilation tube insertion for sniff-type PET. In TTAG assessments, many sniff-type PET patients showed significant synchronous changes at high levels of pressure (over 40 daPa) in the external auditory meatus and nasopharynx when performing a slight Valsalva manoeuvre (below 200 daPa).     

Coronary ostium occlusion by coronary cusp displacement in Williams syndrome

Williams syndrome is a contiguous gene deletion syndrome resulting from a heterozygous deletion on chromosome 7q11.23, and is characterized by distinctive facial features and supravalvular aortic stenosis (SVAS). This syndrome rarely presents unpredictable cardiac death, and yet, as illustrated in the present case, it is still not possible to predict it, even on close monitoring. We herein describe the case of a 6‐year‐old Japanese girl with Williams syndrome, who had sudden cardiac collapse due to cardiac infarction after pharyngitis. Cardiac failure followed a critical course that did not respond to catecholamine support or heart rest with extracardiac mechanical support. Although marked coronary stenosis was not present, the left coronary cusp abnormally adhered to the aortic wall, which may synergistically cause coronary ostium occlusion with SVAS. Altered hemodynamic state, even that caused by the common cold, may lead to critical myocardial events in Williams syndrome with SVAS.     

Hypoxia augments MHC class I antigen presentation via facilitation of ERO1‐α‐mediated oxidative folding in murine tumor cells

To establish an effective cancer immunotherapy, it is crucial that cancer cells present a cancer‐specific antigen in a hypoxic area, a hallmark of the tumor microenvironment. Here, we show the impact of hypoxia on MHC class I antigen presentation in vitro and in vivo in murine tumors. Activation of antigen‐specific CTLs by tumor cells that had been pre‐incubated under a condition of hypoxia was enhanced compared with that by tumor cells pre‐incubated under a condition of normoxia. Cell surface expression of MHC class I‐peptide complex on the tumor cells was increased under a condition of hypoxia, thereby leading to higher susceptibility to specific CTLs. We show that the hypoxia‐inducible ER‐resident oxidase ERO1‐α plays an important role in the hypoxia‐induced augmentation of MHC class I‐peptide complex expression. ERO1‐α facilitated oxidative folding of MHC class I heavy chains, thereby resulting in the augmentation of cell surface expression of MHC class I‐peptide complex under hypoxic conditions. These results suggest that since the expression of MHC class I‐peptide complex is augmented in a hypoxic tumor microenvironment, strategies for inhibiting the function of regulatory T cells and myeloid‐derived suppressor cells and/or immunotherapy with immune checkpoint inhibitors are promising for improving cancer immunotherapy.     

Insecticide resistance in potential vector mosquitoes for West Nile virus in Japan

Culex pipiens complex is the significant vector mosquito of West Nile virus. To take stock of the current situation of insecticide susceptibilities and design an ideal mosquito control strategy, we collected Culex pipiens pallens Coquillet, Culex pipiens form molestus Forskal, and Culex quinquefasciatus Say from fields in Japan and conducted bioassays for five larvicides (fenitrothion, temephos, etofenprox, diflubenzuron, and pyriproxyfen) by using a larval dipping method. Among five insecticides tested, obvious reduced susceptibilities were observed for etofenprox, which is the only pyrethroid compound registered as a larvicide in Japan. Twenty-two of 56 colonies exhibited a >10% survival rate at the etofenprox concentration of 5.7 microg/ml, which is a 10 times higher concentration of the working solution. The LC50 of a colony collected from Fukuoka prefecture for etofenprox exceeded 60 microg/ml (resistance ratio >2,307), and this colony also exhibited cross-resistance to other pyrethroids, permethrin (299-fold) and phenothrin (1,200-fold). The insect growth regulators diflubenzuron and pyriproxyfen were found to be sufficiently effective enough to control Culex larvae present, but decreased sensitivities to these insecticides were slightly detected in some colonies of Cx. p. form molestus collected from urban areas. Several etofenprox-resistant colonies of Cx. p. form molestus exhibited simultaneously decreased susceptibilities to other insecticides, including temephos, diflubenzuron, and pyriproxyfen.