Epidemiology of acute otitis media among young children: A multiple database study in Taiwan

Background/PurposeAcute otitis media (AOM) is a common complication of upper respiratory tract infection (URTI) among children. The purpose of this study was to evaluate the epidemiology of AOM among young children in Taiwan, including the age incidence and seasonality by combining multiple databases.MethodsTwo country-based questionnaire survey studies had been conducted to evaluate the experience of otitis media (OM) among young children: one in 2007 and the other between 2005 and 2010. The number of OM cases (5% of population younger than 7 years) in 2005 and annual visiting rates for URTI from 2005 to 2010 obtained from the National Health Insurance Research Database of Taiwan were collected and comprised the third database. The fourth database comprised ambulatory visits of children with OM to a medical center in central Taiwan between 2005 and 2010.ResultsData from a total of 1099 questionnaires were entered into Database I in 2007, and data from 9705 questionnaires between 2005 and 2010 comprised Database II. There were 86,702 children (younger than 7 years, representing 5% of the whole population for this age group) retrieved from Database III in 2007, and 5,904 cases of OM in children between 2005 and 2010 in a hospital. In Database I, 7.46% children experienced at least one episode of AOM compared with 9.21% in Database II for children aged 5 years and younger. In Database III, 13.2% children younger than 7 years had AOM in 2005. The peak season of AOM among children was from March to May (Databases III and IV).ConclusionAOM was thought to be a very common disease among children; however, this comparative analysis showed that the overall prevalence of AOM among children younger than 5 years was only 20%, much lower than in other countries. AOM was more prevalent during the spring season, and still was similarly common after age 2 years

Effect of length of time from diagnosis to treatment on colorectal cancer survival: A population-based study.

Evidence is limited regarding the effect of diagnosis-to-treatment interval (DTI) on the survival of colorectal cancer (CRC) patients. In addition, previous studies on treatment delay and CRC survival have largely grouped patients from all stages (I-IV) into one cohort. Our study provides analysis on each stage individually. We conducted a retrospective cohort study with 39,000 newly diagnosed CRC patients obtained from the Taiwan Cancer Registry Database from 2004-2010 to examine the effect of DTIs on overall survival. DTIs were divided into 3 groups: ≤ 30 days (36,115 patients, 90.5% of study patients), 31-150 days (2,533, 6.4%), and ≥ 151 days (1,252, 3.15%). Risk of death was increased for DTI 31-150 days (hazard ratio 1.51; 95% confidence interval 1.43-1.59) and DTI ≥ 151 days (1.64; 1.54-1.76) compared to DTI ≤ 30. This risk was consistent across all cancer stages. Additional factors that increased risk of death include male gender, age >75, Charlson Comorbidity Index ≥7, other catastrophic illnesses, lack of multidisciplinary team involvement, and treatment in a low volume center. From these results, we advise that the DTI for all CRC patients, regardless of cancer staging, should be 30 days or less

Heat shock protein 90 is involved in the regulation of HMGA2-driven growth and epithelial-to-mesenchymal transition of colorectal cancer cells

High Mobility Group AT-hook 2 (HMGA2) is a nonhistone chromatin-binding protein which acts as a transcriptional regulating factor involved in gene transcription. In particular, overexpression of HMGA2 has been demonstrated to associate with neoplastic transformation and tumor progression in Colorectal Cancer (CRC). Thus, HMGA2 is a potential therapeutic target in cancer therapy. Heat Shock Protein 90 (Hsp90) is a chaperone protein required for the stability and function for a number of proteins that promote the growth, mobility, and survival of cancer cells. Moreover, it has shown strong positive connections were observed between Hsp90 inhibitors and CRC, which indicated their potential for use in CRC treatment by using combination of data mining and experimental designs. However, little is known about the effect of Hsp90 inhibition on HMGA2 protein expression in CRC. In this study, we tested the hypothesis that Hsp90 may regulate HMGA2 expression and investigated the relationship between Hsp90 and HMGA2 signaling. The use of the second-generation Hsp90 inhibitor, NVP-AUY922, considerably knocked down HMGA2 expression, and the effects of Hsp90 and HMGA2 knockdown were similar. In addition, Hsp90 knockdown abrogates colocalization of Hsp90 and HMGA2 in CRC cells. Moreover, the suppression of HMGA2 protein expression in response to NVP-AUY922 treatment resulted in ubiquitination and subsequent proteasome-dependant degradation of HMGA2. Furthermore, RNAi-mediated silencing of HMGA2 reduced the survival of CRC cells and increased the sensitivity of these cells to chemotherapy. Finally, we found that the NVP-AUY922-dependent mitigation of HMGA2 signaling occurred also through indirect reactivation of the tumor suppressor microRNA (miRNA), let-7a, or the inhibition of ERK-regulated HMGA2 involved in regulating the growth of CRC cells. Collectively, our studies identify the crucial role for the Hsp90-HMGA2 interaction in maintaining CRC cell survival and migration. These findings have significant implications for inhibition HMGA2-dependent tumorigenesis by clinically available Hsp90 inhibitors

Thy-1-induced migration inhibition in vascular endothelial cells through reducing the RhoA activity.

Our previous study indicated that Thy-1, which is expressed on blood vessel endothelium in settings of pathological and a specific of physiological, but not during embryonic, angiogenesis, may be used as a marker for angiogenesis. However, the function of Thy-1 during angiogenesis is still not clear. Here, we demonstrate that knock-down of the endogenous Thy-1 expression by Thy-1 siRNA transfection promoted the migration of human umbilical vein endothelial cells (HUVEC). In contrast, treatment with interleukin-1β (IL-1β) or phorbol-12-myristate-13-acetate (PMA) increased the level of Thy-1 protein and reduced the migration of HUVEC. These effects were abolished by pre-transfection of HUVEC with Thy-1 siRNA to knock-down the expression of Thy-1. Moreover, over-expression of Thy-1 by transfection of HUVEC with Thy-1 pcDNA3.1 decreased the activity of RhoA and Rac-1 and inhibited the adhesion, migration and capillary-like tube formation of these cells. These effects were prevented by co-transfection of the cell with constitutively active RhoA construct (RhoA V14). On the other hand, pre-treatment with a ROCK (a kinase associated with RhoA for transducing RhoA signaling) inhibitor, Y27632, abolished the RhoA V14-induced prevention effect on the Thy-1-induced inhibition of endothelial cell migration and tube formation. Taken together, these results indicate that suppression of the RhoA-mediated pathway might participate in the Thy-1-induced migration inhibition in HUVEC. In the present study, we uncover a completely novel role of Thy-1 in endothelial cell behaviors

Cisd2 is essential to delaying cardiac aging and to maintaining heart functions.

CDGSH iron-sulfur domain-containing protein 2 (Cisd2) is pivotal to mitochondrial integrity and intracellular Ca2+ homeostasis. In the heart of Cisd2 knockout mice, Cisd2 deficiency causes intercalated disc defects and leads to degeneration of the mitochondria and sarcomeres, thereby impairing its electromechanical functioning. Furthermore, Cisd2 deficiency disrupts Ca2+ homeostasis via dysregulation of sarco/endoplasmic reticulum Ca2+-ATPase (Serca2a) activity, resulting in an increased level of basal cytosolic Ca2+ and mitochondrial Ca2+ overload in cardiomyocytes. Most strikingly, in Cisd2 transgenic mice, a persistently high level of Cisd2 is sufficient to delay cardiac aging and attenuate age-related structural defects and functional decline. In addition, it results in a younger cardiac transcriptome pattern during old age. Our findings indicate that Cisd2 plays an essential role in cardiac aging and in the heart's electromechanical functioning. They highlight Cisd2 as a novel drug target when developing therapies to delay cardiac aging and ameliorate age-related cardiac dysfunction

CISD2 Haploinsufficiency Disrupts Calcium Homeostasis, Causes Nonalcoholic Fatty Liver Disease, and Promotes Hepatocellular Carcinoma

CISD2 is located within the chromosome 4q region frequently deleted in hepatocellular carcinoma (HCC). Mice with Cisd2 heterozygous deficiency develop a phenotype similar to the clinical manifestation of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Cisd2 haploinsufficiency causes a low incidence (20%) of spontaneous HCC and promotes HBV-associated and DEN-induced HCC; conversely, 2-fold overexpression of Cisd2 suppresses HCC in these models. Mechanistically, Cisd2 interacts with Serca2b and mediates its Ca2+ pump activity via modulation of Serca2b oxidative modification, which regulates ER Ca2+ uptake and maintains intracellular Ca2+ homeostasis in the hepatocyte. CISD2 haploinsufficiency disrupts calcium homeostasis, causing ER stress and subsequent NAFLD and NASH. Hemizygous deletion and decreased expression of CISD2 are detectable in a substantial fraction of human HCC specimens. These findings substantiate CISD2 as a haploinsufficient tumor suppressor and highlights Cisd2 as a drug target when developing therapies to treat NAFLD/NASH and prevent HCC

Augmented Insulin and Leptin Resistance of High Fat Diet-Fed APPswe/PS1dE9 Transgenic Mice Exacerbate Obesity and Glycemic Dysregulation

Alzheimer’s disease (AD), a progressive neurodegenerative disease is highly associated with metabolic syndromes. We previously demonstrated that glycemic dysregulation and obesity are augmented in high fat diet (HFD)-treated APPswe/PS1dE9 (APP/PS1) transgenic mice. In the current study, the underlying mechanism mediating exacerbated metabolic stresses in HFD APP/PS1 transgenic mice was further examined. APP/PS1 mice developed insulin resistance and, consequently, impaired glucose homeostasis after 10 weeks on HFD. [18F]-2-fluoro-2-deoxy-d-glucose ([18F]-FDG) positron emission tomography showed that interscapular brown adipose tissue is vulnerable to HFD and AD-related pathology. Chronic HFD induced hyperphagia, with limited effects on basal metabolic rates in APP/PS1 transgenic mice. Excessive food intake may be caused by impairment of leptin signaling in the hypothalamus because leptin failed to suppress the food intake of HFD APP/PS1 transgenic mice. Leptin-induced pSTAT3 signaling in the arcuate nucleus was attenuated. Dysregulated energy homeostasis including hyperphagia and exacerbated obesity was elicited prior to the presence of the amyloid pathology in the hypothalamus of HFD APP/PS1 transgenic mice; nevertheless, cortical neuroinflammation and the level of serum Aβ and IL-6 were significantly elevated. Our study demonstrates the pivotal role of AD-related pathology in augmenting HFD-induced insulin and leptin resistance and impairing hypothalamic regulation of energy homeostasis

Effect of Thy-1 on lamellipodia formation, and endothelial cell viability and adhesion.

<p>(a) Over-expression of Thy-1 inhibited the formation of lamellipodia in HUVEC. HUVEC were tranfected with pcDNA3.1 (control) or Thy-1 pcDNA3.1. At 45 h after transfection, phalloidin staining of HUVEC was then performed as described in the Materials and methods. Scale bar, 25 mm. Triangles indicated the lamellipodia. (b) Over-expression of Thy-1 did not affect the viability of HUVEC. The adhesion of Thy-1-transfected HUVEC to collagen was decreased as compared with vector-transfected HUVEC examined by MTT assay (c) or by cell count (d). (e) This effect was also observed in the HMEC-1 transfected with Thy-1 pcDNA3.1. Values represent the means±s.e.mean. (n = 4–6). *<i>p</i><0.05.</p

Role of Thy-1 in HUVEC migration.

<p>(a) Treatment of HUVEC with IL-1β (10 nM) for 24 h significantly increased the level of Thy-1 protein and decreased the migrated cell number. Values represent the means±s.e.mean. (n = 4). *<i>p</i><0.05 different from control group. ^#<i>p</i><0.05 different from the IL-1β-treated group. (b) Treatment of HUVEC with PMA (20 ng/mL) for 24 h caused a 3.83-fold increase of the Thy-1 protein level (upper panel) and a 54% reduction of the migrated cell number (bottom panel). Values represent the means±s.e.mean. (n = 4). *<i>p</i><0.05 different from control group. ^#<i>p</i><0.05 different from the PMA-treated group. (c) Transfection with Thy-1 siRNA increased the HUVEC migration. Values represent the means±s.e.mean. (n = 3). *<i>p</i><0.05. Co, control.</p