Risk factors associated with respiratory disorders in late preterm infants

Objective: Late preterm infants are still high risk for respiratory problems. The aim of this study was to identify risk factors associated with respiratory problems in Japanese late preterm infants.

Methods: In this retrospective multicenter study, we included singleton late preterm deliveries at 34+^0/7–36+^6/7 weeks of gestation. We excluded cases with congenital anomalies. We defined neonatal respiratory disorders (NRD) as the combination of the need for mechanical ventilation or the use of nasal continuous positive airway pressure. We examined the perinatal risk factors associated with NRD.

Results: We included 683 late preterm infants. We found that 13.7%, 6.8% and 2.6% of the infants with NRD were born at 34, 35 and 36 weeks of gestation, respectively. In a multivariate logistic regression analysis adjusting for confounders, the gestational age (GA) at birth (adjusted odds ratio 0.40 per week [95% confidence interval, 0.25–0.61]), cesarean birth (4.18 [2.11–8.84]), and a low Apgar score (33.3 [9.93–121.3]) were independent risk factors associated with NRD.

Conclusions: An earlier GA, cesarean delivery, and a low Apgar score are independent risk factors associated with NRD in singleton late preterm infants. Patients with late preterm deliveries exhibiting these risk factors should be managed in the intensive delivery setting.     

Cell type-specific involvement of RIG-I in antiviral response

Toll-like receptors (TLRs) play an important role in antiviral response by recognizing viral components. Recently, a RNA helicase, RIG-I, was also suggested to recognize viral double-stranded RNA. However, how these molecules contribute to viral recognition in vivo is poorly understood. We show by gene targeting that RIG-I is essential for induction of type I interferons (IFNs) after infection with RNA viruses in fibroblasts and conventional dendritic cells (DCs). RIG-I induces type I IFNs by activating IRF3 via IkappaB kinase-related kinases. In contrast, plasmacytoid DCs, which produce large amounts of IFN-alpha, use the TLR system rather than RIG-I for viral detection. Taken together, RIG-I and the TLR system exert antiviral responses in a cell type-specific manner.     

Comparative genomic analysis using microarray demonstrates a strong correlation between the presence of the 80-kilobase pathogenicity island and pathogenicity in Kanagawa phenomenon-positive Vibrio parahaemolyticus strains

Vibrio parahaemolyticus is a gram-negative marine bacterium. A limited population of the organisms causes acute gastroenteritis in humans. Almost all of the clinical V. parahaemolyticus isolates exhibit beta-type hemolysis on Wagatsuma agar, known as the Kanagawa phenomenon (KP). KP is induced by the thermostable direct hemolysin produced by the organism and has been considered a crucial marker to distinguish pathogenic strains from nonpathogenic ones. Since 1996, so-called “pandemic clones,” the majority of which belong to serotype O3:K6, have caused worldwide outbreaks of gastroenteritis. In this study, we used a DNA microarray constructed based on the genome sequence of a pandemic V. parahaemolyticus strain, RIMD2210633, to examine the genomic composition of 22 strains of V. parahaemolyticus, including both pathogenic (pandemic and nonpandemic) and nonpathogenic strains. More than 86% of the RIMD2210633 genes were conserved in all of the strains tested. Many variably present genes formed gene clusters on the genome of RIMD2210633 and were probably acquired through lateral gene transfer. At least 65 genes over 11 loci were specifically present in the pandemic strains compared with any of the nonpandemic strains, suggesting that the difference between pandemic and nonpandemic strains is not due to a simple genetic event. Only the genes in the 80-kb pathogenicity island (Vp-PAI) on chromosome II, including two tdh genes and a set of genes for the type III secretion system, were detected only in the KP-positive pathogenic strains. These results strongly suggest that acquisition of this Vp-PAI was crucial for the emergence of V. parahaemolyticus strains that are pathogenic for humans.     

Novel vaccine development strategies for inducing mucosal immunity

To develop protective immune responses against mucosal pathogens, the delivery route and adjuvants for vaccination are important. The host, however, strives to maintain mucosal homeostasis by responding to mucosal antigens with tolerance, instead of immune activation. Thus, induction of mucosal immunity through vaccination is a rather difficult task, and potent mucosal adjuvants, vectors or other special delivery systems are often used, especially in the elderly. By taking advantage of the common mucosal immune system, the targeting of mucosal dendritic cells and microfold epithelial cells may facilitate the induction of effective mucosal immunity. Thus, novel routes of immunization and antigen delivery systems also show great potential for the development of effective and safe mucosal vaccines against various pathogens. The purpose of this review is to introduce several recent approaches to induce mucosal immunity to vaccines, with an emphasis on mucosal tissue targeting, new immunization routes and delivery systems. Defining the mechanisms of mucosal vaccines is as important as their efficacy and safety, and in this article, examples of recent approaches, which will likely accelerate progress in mucosal vaccine development, are discussed.     

Familial 9q22.3 microduplication spanning PTCH1 causes short stature syndrome with mild intellectual disability and dysmorphic features

Partial trisomy 9q involving the duplication of band 9q22 is manifested by a constellation of symptoms including short stature, intellectual disability, microcephaly, pyloric stenosis, facial dysmorphism, and various defects of the heart, distal extremities, eyes, thyroid, and esophagus. In three family members with growth retardation, mild intellectual disability, and mild facial dysmorphism, array-based comparative genomic hybridization analyses showed a familial microduplication at 9q22.3. On the basis of the described functions of the duplicated genes, PTCH1 represents a candidate gene that may be responsible for the phenotypic findings, although the 14 other genes in this duplicated segment may also contribute to the phenotype. The current report provides evidence to support a specific phenotype associated with a 9q22.3 microduplication and confirm localization of a subset of the trisomy 9q phenotype to this chromosomal region.     

Aberrant expression of p27<Superscript>Kip1</Superscript>-interacting cell-cycle regulatory proteins in ovarian clear cell carcinomas and their precursors with special consideration of two distinct multistage clear cell carcinogenetic pathways

We have previously reported that alterations of p27^Kip1-interacting cell-cycle proteins frequently occur during the development of endometriosis-associated ovarian clear cell adenocarcinoma (CCA; Yamamoto et al., Histopathology in press, 20). However, CCA also occurs in association with clear cell adenofibroma (CCAF). In this study, the expressions of p27^Kip1-interacting proteins, i.e., p27^Kip1, Skp2, Cks1, cyclin A, cyclin E, and the Ki-67 labeling index (LI), were analyzed in 25 CCAFs (11 benign and 14 borderline) and 15 CCAF-associated CCAs, and compared with the expression status of each protein in the 23 previously studied endometriosis-associated CCAs. Although aberrant expression of all p27^Kip1-interacting proteins was more frequent in the CCAF-associated CCAs than in the benign CCAFs, statistical significance was found only for Cks1 overexpression. The frequencies of p27^Kip1 downregulation and overexpression of Skp2 and cyclin A were significantly lower in CCAF-associated than in endometriosis-associated CCAs (P < 0.05, respectively). The frequencies of p27^Kip1 downregulation and Skp2 overexpression in borderline CCAFs were significantly lower than those in atypical endometriosis components in endometriosis-associated CCAs (P < 0.05, respectively). Mean Ki-67 LI increased significantly through benign (4.9%) to borderline (11.1%) CCAF and to CCAF-associated CCA (30.6%), but the latter two values were significantly lower than those in atypical endometriosis (21.4%) and endometriosis-associated CCA (46.9%; P < 0.05, respectively). These data suggest that accumulated alterations of p27^Kip1-interacting proteins may accelerate the development of CCAs regardless of their carcinogenetic pathways, but that tumor cells in the CCAF-associated pathway appear to show slower cell-cycle progression than those in the endometriosis-associated pathway, possibly accounting for the distinct clinicopathological features of the two CCA subtypes.     

Tumor endothelial cells express high pentraxin 3 levels

It has been described that tumor progression has many similarities to inflammation and wound healing in terms of the signaling processes involved. Among biological responses, angiogenesis, which is necessary for tumor progression and metastasis, is a common hallmark; therefore, tumor blood vessels have been considered as important therapeutic targets in anticancer therapy. We focused on pentraxin 3 (PTX3), which is a marker of cancer‐related inflammation, but we found no reports on its expression and function in tumor blood vessels. Here we showed that PTX3 is expressed in mouse and human tumor blood vessels based on immunohistochemical analysis. We found that PTX3 is upregulated in primary mouse and human tumor endothelial cells compared to normal endothelial cells. We also showed that PTX3 plays an important role in the proliferation of the tumor endothelial cells. These results suggest that PTX3 is an important target for antiangiogenic therapy.     

Targeting Notch Signaling and Autophagy Increases Cytotoxicity in Glioblastoma Neurospheres

Glioblastomas are highly aggressive tumors that contain treatment resistant stem‐like cells. Therapies targeting developmental pathways such as Notch eliminate many neoplastic glioma cells, including those with stem cell features, but their efficacy can be limited by various mechanisms. One potential avenue for chemotherapeutic resistance is the induction of autophagy, but little is known how it might modulate the response to Notch inhibitors. We used the γ‐secretase inhibitor MRK003 to block Notch pathway activity in glioblastoma neurospheres and assessed its effects on autophagy. A dramatic, several fold increase of LC3B‐II/LC3B‐I autophagy marker was noted on western blots, along with the emergence of punctate LC3B immunostaining in cultured cells. By combining the late stage autophagy inhibitor chloroquine (CQ) with MRK003, a significant induction in apoptosis and reduction in growth was noted as compared to Notch inhibition alone. A similar beneficial effect on inhibition of cloogenicity in soft agar was seen using the combination treatment. These results demonstrated that pharmacological Notch blockade can induce protective autophagy in glioma neurospheres, resulting in chemoresistance, which can be abrogated by combination treatment with autophagy inhibitors.     

Topical ocular dexamethasone decreases intraocular pressure and body weight in rats

Background

Recently, topical dexamethasone-induced ocular hypertension and a consequent loss of retinal ganglion cells (RGCs) have been described in mice. This has been proposed as a model of steroid-induced glaucoma. In this study, we set up and evaluated a similar model in rats.

Results

Ten-week old Sprague Dawley (SD) rats (N?=?12) were used to evaluate the effect of topical 0.1 % dexamethasone (50 μl) administered 3 times daily for 4 weeks. Sodium chloride (0.9 %) was used in another group of rats (N?=?12) that served as the controls. After 1 week, we observed a progressive decrease in body weight in the dexamethasone-treated rats compared both to the pre-treatment baseline and the vehicle-treated rats. In contrast to earlier work that showed elevated Intraocular pressure (IOP) following dexamethasone instillation in mice, IOP in the rats unexpectedly fell to 11.3?±?1.3 mmHg in the treated eyes, compared to 14.8?±?2.4 mmHg in the untreated eyes, after 3 weeks of topical dexamethasone (P?=?0.032). Blood tests performed after 4 weeks of treatment showed a 3.3-fold increase in both plasma cholesterol (P?<?0.001) and alanine transaminase (P?=?0.019) in the dexamethasone-treated rats compared to the control rats. Meanwhile, topical steroid did not induce changes in either plasma blood glucose or glycated hemoglobin (HbA1c). We also did not detect changes in the expression of RGC markers (with real-time PCR) following the treatment.

Conclusions

In contrast to mice, which previously showed increased IOP following the topical administration of dexamethasone, the rats displayed a paradoxical reduction in IOP following a similar treatment. This was accompanied by a loss of body weight without affecting the level of blood glucose.