Inhibitory effects of albuterol and fenoterol on RANTES and IP-10 expression in bronchial epithelial cells.

Short-acting ß2-adrenoreceptor agonist (SABA) is the major asthma reliever as indicated in the GINA guidelines. Regulated on activation, normal T expressed and secreted (RANTES) is a chemokine that attracts eosinophils, mast cells, and basophils toward site of allergic inflammation. Interferon γ-inducible protein (IP)-10 is a Th1-related chemokine that is also important in asthmatic inflammation and also involved in our immune defense against pathogens. Bronchial epithelial cells are first-line barrier against invasive pathogen and also have immunomodulatory function. However, whether albuterol and fenoterol (two SABAs) have modulatory effects on RANTES and IP-10 expression in bronchial epithelial cells is unknown. The human bronchial epithelial cell lines, BEAS-2B cells, were pre-treated with different concentrations of albuterol, fenoterol or dibutyryl-cAMP (a cyclic AMP analog) before polyinosinic-polycytidylic acid (poly I:C) stimulation. In some condition, BEAS-2B cells were pre-treated with ICI-118551, a selective ß2-adrenoreceptor antagonist, 30 min before albuterol or fenoterol treatment. The levels of RANTES and IP-10 were measured by ELISA. Intracellular signaling was investigated using cAMP assay, mitogen-activated protein kinase (MAPK) inhibitor, nuclear factor (NF)-κB inhibitor, and western blot. Albuterol and fenoterol suppressed poly I:C-induced RANTES and IP-10 expression of BEAS-2B cells. ICI-118551 could partly reverse the suppressive effects of albuterol and fenoterol on RANTES and IP-10 expression. Albuterol and fenoterol increased intracellular cAMP levels. Dibutyryl-cAMP conferred the similar effects of albuterol and fenoterol. Western blot revealed that albuterol suppressed p-ERK, p-JNK and pp38, and also their associated kinase expression. Albuterol had no effect on pp65 expression. Albuterol and fenoterol could suppress poly I:C-induced RANTES and IP-10 expression in human bronchial epithelial cells via at least partly the ß2-adrenoreceptor-cAMP and the MAPK pathways, implicating that albuterol and fenoterol could exert anti-inflammatory effect and benefit asthmatic patients by suppressing RANTES and IP-10 expression. However, these suppressive effects of albuterol and fenoterol may inhibit the defense against viral infection.

Increased mortality of male adults with AIDS related to poor compliance to antiretroviral therapy in Malawi.

OBJECTIVE: To investigate the effect of gender on mortality of HIV-infected adults receiving antiretroviral therapy (ART) and its possible reasons. METHODS: A retrospective study to review the records for outcomes of adult cases receiving ART at Mzuzu Central Hospital, Malawi, between July 2004 and December 2006. RESULTS: Over the study period, 2838 adult AIDS patients received ART. Of these, 2029 (71.5%) were alive and still on ART, 376 (13.2%) were dead and 433 (15.3%) were lost to follow-up. Survival analysis with Kaplan-Meier estimator showed significantly higher survival rates among females than males in WHO stage 1, 2 and 3 (both P < 0.0001) and borderline in stage 4 (P = 0.076). The Cox model revealed a death hazard ratio (males vs. females) of 1.70 (95% confidence interval 1.35-2.15) after controlling for WHO clinical stages, body mass index and age. More men than women were lost to follow-up in all occupations except health workers. CONCLUSIONS: The most important reasons for a higher mortality in male patients starting ART may relate to their seeking medical care at a more advanced stage of immunodeficiency and poorer compliance with therapy. The issue needs to be addressed in scaling up ART programmes in Africa.

Relationship Between being Overweight and Iron Deficiency in Adolescents.

OBJECTIVE: Being overweight has been considered to be a risk factor of iron deficiency (ID). The objective of this study was to examine the relationship between being overweight and body iron status among Taiwanese adolescents. METHODS: A total of 2099 adolescents (1327 female) aged 12-19 years from four middle schools and one college in southern Taiwan participated in this study. Data on sex, age, body weight, height, hemoglobin concentration, plasma ferritin (PF), and serum iron (SI) levels were collected. According to the age- and sex-specific body mass index (BMI) percentiles, the participants were divided into four weight groups: underweight (<5(th) percentile), normal weight (5-84(th) percentile), overweight (85-94(th) percentile), and obese (≥95(th) percentile). A multivariate logistic regression model was used to estimate the odds ratio (OR) and the 95% confidence interval (CI) for each factor. RESULTS: The correlation coefficients of linear regression were positive for BMI-hemoglobin and BMI-PF, but negative for BMI-SI. Compared with the normal-weight group, the obese group had a lower risk of PF level <15 µg/L with an OR (95% CI) of 0.51 (0.30-0.87) but a higher risk of SI <60 µg/dL with an OR (95% CI) of 1.78 (1.34-2.37). The percentages of low PF declined as BMI increased, but the percentages of low SI rose, from underweight to obesity groups. CONCLUSION: The relationship between being overweight and depleted iron store depends on which indicator is used to define the iron deficiency. Being overweight or obese would not be a risk factor of ID in adolescents, if ID were defined by PF rather than SI level.

EVI2B, ATP2A2, S100B, TM4SF3, and OLFM4 as potential prognostic markers for postoperative Taiwanese colorectal cancer patients.

Undetected micrometastasis may play a key role in the early relapse of colorectal cancer (CRC) patients. The aim of this study was to detect circulating tumor cells (CTCs) for predicting early relapse of CRC patients by a weighted enzymatic chip array (WEnCA) and analyze 15 candidate genes associated with CRC carcinogenesis. The genes of 105 postoperative CRC patients were analyzed by membrane array and direct sequencing. We constructed a WEnCA platform including five prognosis-related genes and analyzed the detection rate of WEnCA for CTCs in 30 clinically confirmed CRC relapse patients. Postoperative relapse was significantly correlated with gene overexpression, including EVI2B (p=0.001, OR=4.622), ATP2A2 (p=0.006, OR=4.688), S100B (p=0.001, OR=11.521), TM4SF3 (p=0.001, OR=6.756), and OLFM4 (p=0.008, OR=3.545). Using WEnCA (weighting score of each gene: 5 to EVI2B, 5 to ATP2A2, 12 to S100B, 7 to TM4SF3, and 4 to OLFM4), we could detect CTCs presenting these genotypes in relapsed CRC patients. The sensitivity, specificity, and accuracy were 94.7%, 93.5%, and 97%, respectively. The results of the present study suggest that EVI2B, ATP2A2, S100B, TM4SF3, and OLFM4 could be potential prognostic markers for CRC patients.

CDC25A, VAV1, TP73, BRCA1 and ZAP70 gene overexpression correlates with radiation response in colorectal cancer.

Radiotherapy is increasingly used in adjuvant approaches for colorectal cancer (CRC) to reduce local recurrence and improve survival. However, the principal limitation is the large variability in response among different individuals due to tumor heterogeneity. In the present study, we compared gene expression profiles between radiosensitive and radioresistant colorectal cancer cell lines to identify radiation-related molecules that can be used to evaluate the effects of radiation. The CRC cell line SW620 was irradiated with a high-energy photo beam. Following radiation treatment, RNA was extracted from non-irradiated and irradiated cells, respectively, and gene expression analysis was performed by oligonucleotide microarray and the DAVID bioinformatics method. To further confirm the results, an additional 4 CRC cell lines, COLO205, T84, HCT116, SW480 and SW403 were purchased from ATCC. The radiosensitivities of each were determined by the survival fraction at 2 Gray (SF2) of the surviving cells using the ATPLite assay, and the gene expression profiles after irradiation among the radiosensitive and radioresistant cell lines were analyzed by membrane arrays. The relationships between gene expression and patient clinicopathological features were also analyzed using membrane arrays and RT-PCR. The results from oligonucleotide microarray analysis show that 1601 genes were up-regulated (gene expression ratio of post- to pre-radiation treatment>2). By bioinformatic database analysis, 30 up-regulated genes were identified as involved in DNA damage response pathways, immune response pathways and the complement and coagulation cascades pathway. Fifteen genes showed differential gene expression profiles between radiosensitive (HCT116 and SW620) and radioresistant CRC cell lines (SW403 and SW480). In 110 CRC tissues, we detected five genes CDC25A, VAV1, TP73, BRCA1 and ZAP70 from 15 overexpressed genes that significantly related to prognostic factors (tumor size, advanced stage, invasive depth, lymph node metastasis and differentiation). These findings suggest that CDC25A, VAV1, TP73, BRCA1 and ZAP70 may be novel markers for predicting the effectiveness of radiotherapy in CRC patients.

Suppressive effects of procaterol on expression of IP-10/CXCL 10 and RANTES/CCL 5 by bronchial epithelial cells.

As indicated in the Global Initiative for Asthma guidelines, short-acting ß2-adrenoreceptor agonists (SABAs) are important relievers in asthma exacerbation. Interferon γ-inducible protein (IP)-10/CXCL 10 is a T-helper type 1 (Th1) cell-related chemokine which is important in the recruitment of Th1 cells involved in host immune defense against intracellular pathogens such as viral infection. Regulated on activation, normal T expressed and secreted (RANTES)/CCL 5 is a chemokine which plays a role in attractant of eosinophils, mast cells, and basophils toward the site of allergic inflammation. Bronchial epithelial cells are first-line barriers against pathogen invasion. However, whether SABAs have regulatory effects on the expression of IP-10 and RANTES in bronchial epithelial cells is unknown. BEAS-2B cells, the human bronchial epithelial cell lines, were pretreated with procaterol (one of the SABAs) or dibutyryl-cAMP (a cyclic AMP analog) at different doses for 1 h and then stimulated with poly I:C (10 µg/mL). Supernatants were collected 12 and 24 h after poly I:C stimulation to determine the concentrations of IP-10 and RANTES by ELISA. In some cases, the cells were pretreated with selective ß2-adrenoreceptor antagonist, ICI-118551, 30 min before procaterol treatment. To investigate the intracellular signaling, the cells were pretreated with mitogen-activated protein kinase (MAPK) inhibitors and a NF-κB inhibitor 30 min before procaterol treatment. Western blot was also used to explore the intracellular signaling. Procaterol significantly suppressed poly I:C-induced IP-10 and RANTES in BEAS-2B cells in a dose-dependent manner. ICI-118551, a selective ß2-adrenoreceptor antagonist, could significantly reverse the suppressive effects. Dibutyryl-cAMP could confer the similar effects of procaterol on poly I:C-induced IP-10 and RANTES expression. Data of Western blot revealed that poly I:C-induced p-ERK, p-JNK, and pp38 expression, but not pp65, were suppressed by procaterol. SABAs could suppress poly I:C-induced IP-10 and RANTES expression in bronchial epithelial cells, at least in part, via ß2-adrenoreceptor-cAMP and MAPK-ERK, JNK, and p38 pathways.

Epidemiological features of infantile hypertrophic pyloric stenosis in Taiwanese children: a Nation-Wide Analysis of Cases during 1997-2007.

OBJECTIVE: To describe the epidemiological characteristics of infantile hypertrophic pyloric stenosis (IHPS) in ethnic Chinese children. MATERIALS AND METHODS: We reviewed the National Health Insurance claims database and analyzed data from children less than one year of age who had been diagnosed with IHPS (ICD-9-CM 750.5) and had undergone pyloromyotomy (ICD-9-CM 43.3). We analyzed the incidence, gender, age at diagnosis, length of hospital stay, seasonal variation and cost of IHPS from data collected between January 1997 and December 2007. RESULTS: A total of 1,077 infants met inclusion criteria, including 889 boys and 188 girls. The annual incidence of IHPS ranged from 0.30 to 0.47 per 1,000 live births with a mean incidence of 0.39 per 1,000 live births. Between 2002 and 2007, the incidence showed a declining trend (P = 0.025) with coincidentally increasing trends for both exclusive breastfeeding (P = 0.014) and breastfeeding plus bottle feeding (P = 0.004). The male-to-female rate ratio was dynamic and increased from 3.03 during the first two weeks of life to 8.94 during the 8(th) through 10th weeks of life. The overall male-to-female rate ratio was 4.30. The mean age at diagnosis was 43.1 ± 2.4 days. After analyzing the months of birth and hospital admission, no seasonal variation associated with IHPS was detected. The mean length of hospital stay was 8.28 ± 7.10 days. CONCLUSIONS: The incidence of IHPS in Taiwan, a country with a majority ethnic Chinese population, was lower than observed incidences in Caucasian populations living in Western countries. Breastfeeding campaigns and low maternal smoking rates may contribute to the lower incidence of IHPS in Taiwan. However, additional studies with longer follow-up periods are needed.

Epidemiology of childhood intussusception and determinants of recurrence and operation: analysis of national health insurance data between 1998 and 2007 in Taiwan.

BACKGROUND: To study the epidemiology of childhood intussusception and risk factors of recurrence and operation based on a nationwide data. METHODS: Children with hospitalization due to intussusception (ICD9: 560.0) between 1998 and 2007 were identified from a national health insurance database. The incidence was calculated by age, sex, calendar year and month of admission. Recurrence and operation rates, duration and costs of hospitalization were analyzed. RESULTS: A total of 8217 intussusception-related hospitalizations were identified in 7541 children. The incidence of intussusception peaked between 3 and 36 months of age. Male -to-female incidence rate ratio increased from 1.31 in the first year to 2.52 in the ninth year of life. The overall recurrence and operation rates were 7.9% and 24.9%, respectively. In children less than 1 year old, the recurrence rate was 10.1%, which decreased to 5.3% in children over 3 years old. Multiple logistic regression analysis showed that children receiving operation had a significantly lower risk of recurrence with an odds ratio (95% confidence interval) of 0.31 (0.24-0.41) after controlling for age and sex. There are significantly more cases occurring during the warmer months between May and October compared to the cooler months between November and April. CONCLUSIONS: There was a male predominance of intussusception with a dynamic male-to-female incidence rate ratio. Children under 1 year of age have the highest recurrence and operation rates. Seasonal variation of intussusception was suspected in Taiwan.

Gender difference of alanine aminotransferase elevation may be associated with higher hemoglobin levels among male adolescents.

BACKGROUND: To explore the gender difference of ALT elevation and its association with high hemoglobin levels. METHODS: A cross-sectional study of 3547 adolescents (2005 females, mean age of 16.5?.3 years) who were negative for hepatitis B surface antigen received health checkups in 2006. Body mass index (BMI), levels of hemoglobin, ALT and cholesterol were measured. ALT >42 U/L was defined as elevated ALT. Elevated ALT levels were detected in 112 of the 3547 participants (3.3%), more prevalent in males than in females (5.4% vs. 1.4%, p<0.001). Hemoglobin levels had a significant linear correlation with ALT levels in both genders. Abnormal ALT started to occur if hemoglobin >11 g/dl in females or >13.5 g/dl in males, but the cumulative cases of elevated ALT increased more quickly in males. Proportion of elevated ALT increased as either the BMI or hemoglobin level rise, more apparent in male adolescents. Logistic regression modeling showed odds ratio (95% confidence interval) were 24.7 (15.0-40.6) for BMI ≥27 kg/m(2); 5.5 (2.9-10.4) for BMI 24-27 kg/m(2); 2.7 (1.3-5.5) for Q5 (top 20th percentile) hemoglobin level; and 2.6 (1.6-4.1) for male gender. Further separately fitting the logistic models for two genders, the significance of Q5 hemoglobin level only appeared in the males. CONCLUSIONS: High hemoglobin level is a significant risk factor of ALT elevation after control hepatitis B, obesity and gender. Males have greater risk of abnormal liver function which may be associated with higher hemoglobin levels.

What happens to patients on antiretroviral therapy who transfer out to another facility?

BACKGROUND: Long term retention of patients on antiretroviral therapy (ART) in Africa's rapidly expanding programmes is said to be 60% at 2 years. Many reports from African ART programmes make little mention of patients who are transferred out to another facility, yet Malawi's national figures show a transfer out of 9%. There is no published information about what happens to patients who transfer-out, but this is important because if they transfer-in and stay alive in these other facilities then national retention figures will be better than previously reported. METHODOLOGY/PRINCIPAL FINDINGS: Of all patients started on ART over a three year period in Mzuzu Central Hospital, North Region, Malawi, those who transferred out were identified from the ART register and master cards. Clinic staff attempted to trace these patients to determine whether they had transferred in to a new ART facility and their outcome status. There were 805 patients (19% of the total cohort) who transferred out, of whom 737 (92%) were traced as having transferred in to a new ART facility, with a median time of 1.3 months between transferring-out and transferring-in. Survival probability was superior and deaths were lower in the transfer-out patients compared with those who did not transfer. CONCLUSION/SIGNIFICANCE: In Mzuzu Central Hospital, patients who transfer-out constitute a large proportion of patients not retained on ART at their original clinic of registration. Good documentation of transfer-outs and transfer-ins are needed to keep track of national outcomes. Furthermore, the current practice of regarding transfer-outs as being double counted in national cohorts and subtracting this number from the total national registrations to get the number of new patients started on ART is correct.