Immunization (EPI) in Ethiopia: acceptance, coverage, and sustainability

Ethiopia has been engaged in expanding immunization services against the six childhood diseases since 1980. According to plans set at the beginning of the program, the country should have achieved universal child immunization by now. However, the child immunization coverage has never reached the level that is desired to curtail disease transmission and to reduce the morbidity burden associated with the target diseases. This study used the potential of social science research methods in understanding social, cultural, political and economic factors that influence the efficiency and effectiveness of immunization programs in the Ethiopian context. A better understanding of these factors is believed to improve the quality and sustainability of immunization programs. This research focused on relevant issues at micro- and macro-levels. The study basically utilized qualitative research methods involving multiple data collection tools and information sources. Factors related to acceptors, immunization service providers and organization of health services that influence the successful implementation and sustainability of the immunization program in the Ethiopian context are identified and discussed. Strengthening efforts to improve technical capacity of service providers, increasing social mobilization activities, instituting quality assurance schemes and improving management of resources (human, finance and material) are among the major recommendations.     

Tumor cell and endothelial cell therapy of oral cancer by dual tyrosine kinase receptor blockade

Expression of the epidermal growth factor (EGF) and activation of its receptor (EGFR), a tyrosine kinase, are associated with progressive growth of head and neck cancer. Expression of the vascular endothelial growth factor (VEGF) is associated with angiogenesis and progressive growth of tumor. The tyrosine kinase inhibitor NVP-AEE788 (AEE788) blocks the EGF and VEGF signaling pathways. We examined the effects of AEE788 administered alone, or with paclitaxel (Taxol), on the progression of human head and neck cancer implanted orthotopically into nude mice. Cells of two different human oral cancer lines, JMAR and MDA1986, were injected into the tongues of nude mice. Mice with established tumors were randomized to receive three times per week oral AEE788, once weekly injected paclitaxel, AEE788 plus paclitaxel, or placebo. Oral tumors were resected at necropsy. Kinase activity, cell proliferation, apoptosis, and mean vessel density were determined by immunohistochemical immunofluorescent staining. AEE788 inhibited cell growth, induced apoptosis, and reduced the phosphorylation of EGFR, VEGFR-2, AKT, and mitogen-activated protein kinase in both cell lines. Mice treated with AEE788 and AEE788 plus paclitaxel had decreased microvessel density, decreased proliferative index, and increased apoptosis. Hence, AEE788 inhibited tumor vascularization and growth and prolonged survival. Inhibition of EGFR and VEGFR phosphorylation by AEE788 effectively inhibits cellular proliferation of squamous cell carcinoma of the head and neck, induces apoptosis of tumor endothelial cells and tumor cells, and is well tolerated in mice. These data recommend the consideration of patients with head and neck cancer for inclusion in clinical trials of AEE788.     

A novel C/T polymorphism in the core promoter of human de novo cytosine DNA methyltransferase 3B6 is associated with prognosis in head and neck cancer

New biomarkers for head and neck squamous cell carcinoma (HNSCC) patients are being sought to help predict disease outcome, guide treatment, and develop new treatments. In the present study, the association between a novel functional C/T polymorphism in the core promoter of cytosine DNA methyltransferase (DNMT) 3B6 and overall survival of HNSCC patients was investigated. Genomic DNA was extracted from tumor tissue and leukocytes from each HNSCC patient. We used the PCR-restriction fragment length polymorphism (PCR-RFLP) assay to determine the DNMT3B genotype. Kaplan-Meier product-limit method and univariate/multivariate Cox proportional hazard models were used to correlate DNMT3B genotype with overall survival of HNSCC patients who underwent surgical resection. There was a marked association between DNMT3B C/T polymorphism and overall survival of HNSCC patients (P=0.004). The homozygotes (CC-genotype and TT-genotype) survived significantly longer than the heterozygotes (CT-type). The multivariate Cox proportional hazard modeling showed that HNSCC patients with CT-genotype had a hazard ratio of 4.829 over patients with CC-genotype or TT-genotype. A DNMT3B C/T polymorphism has been correlated with survival differences in HNSCC patients. If validated in larger studies, this polymorphism might be used to identify deleterious patterns of gene silencing by methylation in HNSCC.     

Antivascular therapy of human follicular thyroid cancer experimental bone metastasis by blockade of epidermal growth factor receptor and vascular growth factor receptor phosphorylation

Patients suffering from bone metastases of follicular thyroid carcinoma (FTC) have a poor prognosis because of the lack of effective treatment strategies. The overexpression of epidermal growth factor receptor (EGFR) associated with increased vascularity has been implicated in the pathogenesis of FTC and subsequent bone metastases. We hypothesized that inhibiting the phosphorylation of the EGFR and vascular endothelial growth factor receptor (VEGFR) by AEE788, a dual tyrosine kinase inhibitor of EGFR and VEGFR, in combination with paclitaxel would inhibit experimental FTC bone lesions and preserve bone structure. We tested this hypothesis using the human WRO FTC cell line. In culture, AEE788 inhibited the EGF-mediated phosphorylation of EGFR, VEGFR2, mitogen-activated protein kinase, and Akt in culture. AEE788, alone and in combination with paclitaxel, inhibited cell growth and induced apoptosis. When WRO cells were injected into the tibia of nude mice, tumor and endothelial cells within the lesions expressed phosphorylated EGFR, VEGFR, Akt, and mitogen-activated protein kinase that were inhibited by the oral administration of AEE788. Therapy consisting of orally given AEE788 and i.p. injected paclitaxel induced a high level of apoptosis in tumor-associated endothelial cells and tumor cells with the inhibition of tumor growth in the bone and the preservation of bone structure. Collectively, these data show that blocking the phosphorylation of EGFR and VEGFR with AEE788 combined with paclitaxel can significantly inhibit experimental human FTC in the bone of nude mice.     

Chronic lung disease after hematopoietic stem cell transplantation

Tens of thousands of patients undergo hematopoietic stem cell transplantation (HSCT) each year, mainly for hematologic disorders. In addition to the underlying diseases, the chemotherapy and radiation therapy that HSCT recipients receive can result in damage to multiple organ systems. Pulmonary complications develop in 30% to 60% of HSCT recipients. With the widespread use of prophylaxis for certain infections, the spectrum of pulmonary complications after HSCT has shifted from more infectious to noninfectious complications. This article reviews some of the noninfectious, chronic pulmonary complications.     

Internal medicine resident education in the medical intensive care unit: the impact on education and patient care of a scheduling change for didactic sessions

OBJECTIVE: Modifications in residency educational programs are needed to comply with the work-hour limitations introduced by the Accreditation Council for Graduate Medical Education. The objective of this study was to determine the impact of rescheduling critical care didactic sessions on medicine residents' education during their medical intensive care unit (MICU) rotation and on outcomes. DESIGN: A pilot program of nonrandomized design. SETTING: A graduate school of medicine. PATIENTS: All patients admitted during the study periods who authorized their medical records to be reviewed. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We instituted a pilot program that replaced the daily traditional 1-hour post-rounds didactic session with an 8:00 am 30-min session, conducted before work rounds, on weekdays from July 2003 through December 2003. The residents' end-of-rotation examination scores were used to assess the impact on education. The pilot period residents' examination results were compared with the examination results from July 2002 through December 2002. To evaluate the effect on patient care, the Acute Physiology Score, Acute Physiology and Chronic Health Evaluation III score, and predicted and observed lengths of MICU and hospital stay of all patients during these two study periods were abstracted and compared. Forty-eight residents were included in each period of the study. The residents' performance on the examination at the end of MICU rotation improved when the didactic session was moved to 8:00 am (67.9 +/- 13.8 vs. 73.9 +/- 12.1; p = .0270). The statistically significant improvement was limited to the first-year residents. There were 751 and 903 patients, respectively, admitted to the MICU during the 2002 and 2003 study periods. There were no significant differences in Acute Physiology Score and Acute Physiology and Chronic Health Evaluation III score between patients admitted during the two study periods. The observed hospital mortality rate was lower during the second period. There were no statistically significant differences in the adjusted length of MICU and hospital stay between the two periods. CONCLUSION: Early morning didactic sessions improve the educational experience of internal medicine residents rotating in the MICU without compromising patient care.     

Murine lung tumor measurement using respiratory-gated micro-computed tomography

OBJECTIVE: The authors explored micro-computed tomography (micro-CT) to quantify lung tumor number and volume in a specific genetic mouse model for lung cancer. MATERIALS AND METHODS: The authors used K-ras mice, which develop lung adenomas and adenocarcinomas through somatic activation of the K-ras oncogene. Tumor number measured using micro-CT and were compared at necropsy (n = 38 mice). Tumor volume measurement precision (n = 39 mice) and accuracy (multiple tumors from a single mouse) were evaluated. Serial lung tumor volume was assessed in a pilot group (n = 8) of mice in vivo. RESULTS: Tumor number assessed at necropsy and using micro-CT were significantly correlated. Lung tumor volume measurements were both reproducible (2% operator variability) and accurate (6% average error). Strikingly, we observed both tumor growth and shrinkage within individual mice. CONCLUSION: Serial measurements provided evidence of tumor heterogeneity, an unexpected finding given the uniformity of the initiating genetic event. Micro-CT may become a powerful tool for murine lung cancer research in vivo.     

Outcome of diffuse alveolar hemorrhage in hematopoietic stem cell transplant recipients

Previous studies have reported mortality rates of about 80% in hematopoietic stem cell transplant recipients with diffuse alveolar hemorrhage. This retrospective study describes the clinical course of 48 such patients: mean age 47.7 years, 52% autologous transplant and 67% peripheral stem cell source. The hemorrhage occurred within one month of transplant in 28 patients. Symptoms included dyspnea in 92%, fever in 67%, cough in 56%, and hemoptysis in 15%. Intensive care unit admission was required in 85% and mechanical ventilation in 77%. Most of the patients were treated with intravenous methylprednisolone 1 g daily for 3 days and then tapered off after a median of 22 days. The hospital mortality was 48%. The cause of death was respiratory failure in 15 of the 23 deaths. Mortality was 28% in autologous compared with 70% in allogeneic transplant recipients (p = 0.0040). The mortality rate of patients whose hemorrhage occurred within the first 30 days of transplant was 32% compared with 70% of those with late hemorrhage (p = 0.0096). This study shows that survival rate of hematopoietic stem cell transplant recipients with diffuse alveolar hemorrhage is better than previously reported, and that early onset and autologous transplant are favorable prognostic indicators.     

Magnitude and determinants of bottle feeding in rural communities

This cross-sectional study assessed the extent of bottle use in child feeding and the factors associated with its use in rural communities. Data were collected from 1536 children aged 0-23 months and their mothers in Addis Ababa, Ethiopia, through house-to-house visits. The overall prevalence of bottle feeding was 11.3%. Only 11 (6.3%) of the 174 children who were bottle fed were on exclusive bottle feeding. After adjusting for parental and child characteristics, factors such as the residence, maternal education and occupation showed a significant association with bottle feeding practice (P 0.05). In general, the extent of bottle feeding in the studied communities was high, with a higher rate among town women. Improvement in maternal and child health services including education on child feeding are recommended.     

Delta-24 increases the expression and activity of topoisomerase I and enhances the antiglioma effect of irinotecan.

PURPOSE: In this study, we sought to determine whether Delta-24 could sensitize glioma cells to the topoisomerase I inhibitor irinotecan (CPT-11) and to identify the mechanisms underlying this enhanced anticancer effect. EXPERIMENTAL DESIGN: We used human glioblastoma cell lines for the in vitro studies. The expression of topoisomerase I was determined in Western blot analyses, and topoisomerase I activity was determined by measuring the relaxation of a supercoiled DNA. The cell cycle distribution of cells was determined by flow cytometry analysis of the cellular DNA content. Cell viability was quantified by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Tissue culture infection dose assays were used to quantitate adenovirus replication. For the in vivo studies, athymic mice received intracranial/intratumoral injections of Delta-24 in combination with CPT-11, after which animal survival was monitored. RESULTS: Delta-24 infection caused human glioma cells to accumulate in the S phase and induced the expression and activity of topoisomerase I as shown by Western blot and in vitro enzymatic activity assays. Further, we showed that the sequential administration of Delta-24 and CPT-11 to human glioma cell cultures potentiated the CPT-11-mediated anticancer effect in vitro without modifying the replicative phenotype of the oncolytic adenovirus. In vivo experiments showed that the single intratumoral administration of Delta-24 to intracranially implanted human glioma xenografts followed by the systemic administration of CPT-11 resulted in significantly prolonged animal survival. CONCLUSIONS: The combination of Delta-24 treatment with CPT-11 showed an enhanced anticancer effect, which suggests that the interaction between adenoviral and human proteins can be exploited in rational anticancer therapies comprising replication-competent adenoviruses and conventional chemotherapeutic agents.