bluuebunny/crossref_metadata_2025 huggingface dataset:
Promoting Health in Low-Income Communities
Authors: Bucher Julia A. , Thompson Cheryl W.
Published: March 2012

As one of the most common chronic illnesses in children in the United States, asthma also is a leading cause for emergency room visits and hospitalizations among youth. Multicomponent interventions are effective in improving asthma symptoms when home visits and education also are part of professional assistance to reduce environmental triggers. This article will report the results of one such educational program, Asthma Safe Kids (ASK), delivered through an academic urban nurse managed center. It will compare barriers to ASK program delivery to strengths of a more successful program. In addition, 3 gaps in existing literature about home-based asthma intervention will be presented: (a) current reports do not describe details about planning and implementing programs or identify components that weakened outreach or implementation; (b) lists of partnerships do not include urban academic nurse managed centers, a resource for in-home asthma program startup and sustainability in more than 100 neighborhoods and clinics; and (c) conceptual frameworks for program planning and delivery are not identified. Applying an interactional approach to community programming—different from community-based participatory research—is suggested to improve participant recruitment and family outreach and, ultimately, to reduce asthma-related exacerbations among children and adolescents.
Evaluation and Characterization of Environmental Risks and Asthma Management Knowledge and Awareness Through Surveys of Coaches, Athlete Parents/Guardians, and Athletes
Authors: Therkorn Jennifer H. , Shendell Derek G.
Published: March 2012

Objective. Athletes may face unique barriers to asthma management and are exposed to many different environmental factors while playing sports. The authors’ goal was to study participation in sports and perceptions of environmental exposures (health risks) and barriers to asthma management for adolescent and young adult athletes. The need for asthma education among coaches was also investigated. Methods. This study targeted 3 populations: (a) coaches of middle school through college level athletes, (b) parents/guardians of middle school through college level athletes, and (c) college athletes. Online surveys were conducted anonymously. Questions addressed sport-specific asthma management barriers, perceived environmental exposures (health risks), athlete training intensities, and asthma knowledge and awareness among surveyed coaches. Results. There were 120 participants (26 coaches, 37 college athletes, 57 athlete parents/guardians). Most reported perceived environmental health concerns and potential barriers to asthma management for athletes, with 94% and 84% of participants reporting at least one, respectively. There were observed differences in the numbers of environmental health concerns and potential barriers to asthma management reported per person across surveyed populations depending on sport, training intensity, and athlete asthma status. The percentage of correct responses by coaches to 5 asthma knowledge questions ranged from 12% to 88%. Conclusions. Research should further investigate how to prioritize and develop interventions to address potential barriers to asthma management for adolescent athletes in both school and community parks and recreation facility settings. Additionally, solutions are needed to mitigate outdoor and indoor environmental health concerns of athletes. Coaches may benefit from increased asthma awareness and educational interventions aimed at improving asthma knowledge specific to athletics.
Impact of the Choosing the Best Program in Communities Committed to Abstinence Education
Authors: Lieberman Lisa , Su Haiyan
Published: March 2012

States vary in standards for sex education, some requiring an emphasis on abstinence. Schools seek to identify curricula that reflect local community values and meet state standards. Choosing the Best (CTB), a classroom-based abstinence education curriculum, has been implemented in 75 Georgia school districts since 1995. CTB Inc., sought to determine if this popular program had an impact on abstinence attitudes, intentions, and behavior. Six Georgia public schools (1,143 ninth graders) participated in the study in 2009-2010. Four randomly assigned schools received the CTB curriculum, taught by trained CTB staff. Two control schools received their usual textbook-based abstinence lessons. Surveys were conducted at the beginning and end of 9th grade, and the beginning of 10th grade. Data demonstrated significant impact of CTB at the end of 9th grade on commitment to abstinence, proabstinence beliefs and attitudes, intentions to maintain abstinence, and lower onset of sexual intercourse, and at the beginning of 10th grade on proabstinence attitudes. In two communities that sought an abstinence education approach, CTB had a short-term impact on abstinence attitudes, commitment, and behaviors, and a longer term impact on abstinence attitudes only.
Adult patients with acute lymphoblastic leukemia and molecular failure display a poor prognosis and are candidates for stem cell transplantation and targeted therapies
Authors: Gökbuget Nicola , Kneba Michael , Raff Thorsten , Trautmann Heiko , Bartram Claus-Rainer , Arnold Renate , Fietkau Rainer , Freund Mathias , Ganser Arnold , Ludwig Wolf-Dieter , Maschmeyer Georg , Rieder Harald , Schwartz Stefan , Serve Hubert , Thiel Eckhard , Brüggemann Monika , Hoelzer Dieter
Published: March 2012

Quantification of minimal residual disease (MRD) by real-time PCR directed to TCR and Ig gene rearrangements allows a refined evaluation of response in acute lymphoblastic leukemia (ALL). The German Multicenter Study Group for Adult ALL prospectively evaluated molecular response after induction/consolidation chemotherapy according to standardized methods and terminology in patients with Philadelphia chromosome-negative ALL. The cytologic complete response (CR) rate was 89% after induction phases 1 and 2. At this time point the molecular CR rate was 70% in 580 patients with cytologic CR and evaluable MRD. Patients with molecular CR after consolidation had a significantly higher probability of continuous complete remission (CCR; 74% vs 35%; P < .0001) and of overall survival (80% vs 42%; P = .0001) compared with patients with molecular failure. Patients with molecular failure without stem cell transplantation (SCT) in first CR relapsed after a median time of 7.6 months; CCR and survival at 5 years only reached 12% and 33%, respectively. Quantitative MRD assessment identified patients with molecular failure as a new high-risk group. These patients display resistance to conventional drugs and are candidates for treatment with targeted, experimental drugs and allogeneic SCT. Molecular response was shown to be highly predictive for outcome and therefore constitutes a relevant study end point. The studies are registered at www.clinicaltrials.gov as NCT00199056 and NCT00198991.
5-azacytidine and decitabine exert proapoptotic effects on neoplastic mast cells: role of FAS-demethylation and FAS re-expression, and synergism with FAS-ligand
Authors: Ghanim Viviane , Herrmann Harald , Heller Gerwin , Peter Barbara , Hadzijusufovic Emir , Blatt Katharina , Schuch Karina , Cerny-Reiterer Sabine , Mirkina Irina , Karlic Heidrun , Pickl Winfried F. , Zöchbauer-Müller Sabine , Valent Peter
Published: March 2012

Aggressive systemic mastocytosis (ASM) and mast cell leukemia (MCL) are advanced hematopoietic neoplasms with poor prognosis. In these patients, neoplastic mast cells (MCs) are resistant against various drugs. We examined the effects of 2 demethylating agents, 5-azacytidine and decitabine on growth and survival of neoplastic MCs and the MC line HMC-1. Two HMC-1 subclones were used, HMC-1.1 lacking KIT D816V and HMC-1.2 exhibiting KIT D816V. Both agents induced apoptosis in HMC-1.1 and HMC-1.2 cells. Decitabine, but not 5-azacytidine, also produced a G2/M cell-cycle arrest in HMC-1 cells. Drug-induced apoptosis was accompanied by cleavage of caspase-8 and caspase-3 as well as FAS-demethylation and FAS–re-expression in neoplastic MCs. Furthermore, both demethylating agents were found to synergize with the FAS-ligand in inducing apoptosis in neoplastic MCs. Correspondingly, siRNA against FAS was found to block drug-induced expression of FAS and drug-induced apoptosis in HMC-1 cells. Neither 5-azacytidine nor decitabine induced substantial apoptosis or growth arrest in normal MCs or normal bone marrow cells. Together, 5-azacytidine and decitabine exert growth-inhibitory and proapoptotic effects in neoplastic MCs. These effects are mediated through “FAS–re-expression” and are augmented by the FAS-ligand. Whether epigenetic drugs produce antineoplastic effects in vivo in patients with ASM and MCL remains to be determined.
A targeted complement-dependent strategy to improve the outcome of mAb therapy, and characterization in a murine model of metastatic cancer
Authors: Elvington Michelle , Huang Yuxiang , Morgan B. Paul , Qiao Fei , van Rooijen Nico , Atkinson Carl , Tomlinson Stephen
Published: March 2012

Complement inhibitors expressed on tumor cells provide an evasion mechanism against mAb therapy and may modulate the development of an acquired antitumor immune response. Here we investigate a strategy to amplify mAb-targeted complement activation on a tumor cell, independent of a requirement to target and block complement inhibitor expression or function, which is difficult to achieve in vivo. We constructed a murine fusion protein, CR2Fc, and demonstrated that the protein targets to C3 activation products deposited on a tumor cell by a specific mAb, and amplifies mAb-dependent complement activation and tumor cell lysis in vitro. In syngeneic models of metastatic lymphoma (EL4) and melanoma (B16), CR2Fc significantly enhanced the outcome of mAb therapy. Subsequent studies using the EL4 model with various genetically modified mice and macrophage-depleted mice revealed that CR2Fc enhanced the therapeutic effect of mAb therapy via both macrophage-dependent FcγR-mediated antibody-dependent cellular cytotoxicity, and by direct complement-mediated lysis. Complement activation products can also modulate adaptive immunity, but we found no evidence that either mAb or CR2Fc treatment had any effect on an antitumor humoral or cellular immune response. CR2Fc represents a potential adjuvant treatment to increase the effectiveness of mAb therapy of cancer.
Donor versus no-donor comparison of newly diagnosed myeloma patients included in the HOVON-50 multiple myeloma study
Authors: Lokhorst Henk M. , van der Holt Bronno , Cornelissen Jan J. , Kersten Marie-José , van Oers Marinus , Raymakers Reinier , Minnema Monique C. , Zweegman Sonja , Janssen Jeroen J. , Zijlmans Mark , Bos Gerard , Schaap Nicolaas , Wittebol Shulamiet , de Weerdt Okke , Ammerlaan Rianne , Sonneveld Pieter
Published: March 2012

To prospectively evaluate allogeneic stem cell transplantation (allo-SCT) for myeloma as part of first-line therapy, a donor versus no-donor analysis was performed of patients treated in the HOVON-50 study, a study that was originally designed to examine thalidomide combined with intensive therapy. Two hundred sixty patients having received an autologous-SCT fulfilled the criteria to be included, 138 patients without an HLA-identical sibling donor and 122 patients with a donor. After a median follow-up of 77 months, complete remission, progression-free survival (PFS), and overall survival were not significantly different between the 2 groups. PFS at 6 years was 28% for patients with a donor versus 22% for patients without a donor (P = .19) and overall survival at 6 years from high-dose melphalan was 55%, irrespective of having a donor (P = .68). Cumulative incidence of nonrelapse mortality at 6 years after autologous-SCT was 16% in the donor group versus 3% in the no-donor group (P < .001). However, PFS was significantly prolonged in the 99 patients who actually proceeded to allo-SCT compared with the 115 patients who continued maintenance or received a second high-dose melphalan, but the difference did not translate into a prolonged survival benefit. These results do not support a general application of allo-SCT in all myeloma patients as part of first-line therapy.
Multilineage dysplasia does not influence prognosis in CEBPA-mutated AML, supporting the WHO proposal to classify these patients as a unique entity
Authors: Bacher Ulrike , Schnittger Susanne , Macijewski Katja , Grossmann Vera , Kohlmann Alexander , Alpermann Tamara , Kowarsch Andreas , Nadarajah Niroshan , Kern Wolfgang , Haferlach Claudia , Haferlach Torsten
Published: March 2012

In 2008, the World Health Organization introduced CEBPA (encoding the CCAAT/enhancer binding protein)–mutated acute myeloid leukemia (AML) as a provisional entity. However, the classification of CEBPA-mutated AML with multilineage dysplasia (MLD; ≥ 50% dysplastic cells in 2-3 lineages) remains to be clarified. In the present study, we investigated 108 CEBPA-mutated AML patients for the impact of MLD, karyotype, and additional mutations. MLD+ patients differed from MLD− patients only by lower mean WBC counts, not by biologic characteristics, cytogenetic risk profiles, or additional mutations. Survival was better for female patients, patients < 60 years of age, for intermediate versus adverse karyotypes, and, in the case of FLT3-ITD negativity, biallelic versus monoallelic/homozygous CEBPA mutations. In contrast, 2-year overall survival and event-free survival did not differ significantly between MLD+ and MLD− patients. By univariable Cox regression analysis, sex, age, WBC count, and cytogenetic risk category were related to overall survival, but MLD was not. Therefore, because dysplasia is not relevant for this subtype, CEBPA-mutated AML patients should be characterized only according to mutation status, cytogenetic risk group, or additional mutations.
Dynamic HoxB4-regulatory network during embryonic stem cell differentiation to hematopoietic cells
Authors: Fan Rong , Bonde Sabrina , Gao Peng , Sotomayor Brendan , Chen Changya , Mouw Tyler , Zavazava Nicholas , Tan Kai
Published: March 2012

Efficient in vitro generation of hematopoietic stem cells (HSCs) from embryonic stem cells (ESCs) holds great promise for cell-based therapies to treat hematologic diseases. To date, HoxB4 remains the most effective transcription factor (TF) the overexpression of which in ESCs confers long-term repopulating ability to ESC-derived HSCs. Despite its importance, the components and dynamics of the HoxB4 transcriptional regulatory network is poorly understood, hindering efforts to develop more efficient protocols for in vitro derivation of HSCs. In the present study, we performed global gene-expression profiling and ChIP coupled with deep sequencing at 4 stages of the HoxB4-mediated ESC differentiation toward HSCs. Joint analyses of ChIP/deep sequencing and gene-expression profiling unveiled several global features of the HoxB4 regulatory network. First, it is highly dynamic and gradually expands during the differentiation process. Second, HoxB4 functions as a master regulator of hematopoiesis by regulating multiple hematopoietic TFs and chromatin-modification enzymes. Third, HoxB4 acts in different combinations with 4 other hematopoietic TFs (Fli1, Meis1, Runx1, and Scl) to regulate distinct sets of pathways. Finally, the results of our study suggest that down-regulation of mitochondria and lysosomal genes by HoxB4 plays a role in the impaired lymphoid lineage development from ESC-derived HSCs.
A neutrophil elastase inhibitor prevents bleomycin-induced pulmonary fibrosis in mice
Authors: Takemasa Akihiro , Ishii Yoshiki , Fukuda Takeshi
Published: March 2012

Neutrophil elastase plays pivotal roles in the pathogenesis of pulmonary fibrosis. The neutrophil elastase inhibitor, sivelestat, could alleviate pulmonary fibrosis; however, the antifibrotic mechanisms have not yet been clarified. We examined the antifibrotic mechanisms, mainly focusing on a key fibrotic cytokine, transforming growth factor (TGF)-β1, in this study.

To elucidate the antifibrotic mechanisms of sivelestat, we examined a murine model of bleomycin-induced early-stage pulmonary fibrosis. After intratracheal instillation of bleomycin, sivelestat was administered intraperitoneally once a day for 7 or 14 days. Bronchoalveolar lavage fluid and lung samples were examined on day 7 or day 14 after bleomycin instillation.

In the bleomycin-induced early-stage pulmonary fibrosis model, the neutrophil elastase level was increased in the lungs. Sivelestat significantly inhibited the increase in lung collagen content, fibrotic changes, the numbers of total cells (including macrophages, neutrophils and lymphocytes), the levels of the active form of TGF-β1 and phospho-Smad2 in bleomycin-induced early-stage pulmonary fibrosis. The total TGF-β1 levels and relative changes of TGF-β1 mRNA expression, however, were not decreased significantly by sivelestat.

These results suggest that sivelestat alleviated bleomycin-induced pulmonary fibrosisviainhibition of both TGF-β activation and inflammatory cell recruitment in the lung.
Codon Deviation Coefficient: a novel measure for estimating codon usage bias and its statistical significance
Authors: Zhang Zhang , Li Jun , Cui Peng , Ding Feng , Li Ang , Townsend Jeffrey P , Yu Jun
Published: March 2012

Background

Genetic mutation, selective pressure for translational efficiency and accuracy, level of gene expression, and protein function through natural selection are all believed to lead to codon usage bias (CUB). Therefore, informative measurement of CUB is of fundamental importance to making inferences regarding gene function and genome evolution. However, extant measures of CUB have not fully accounted for the quantitative effect of background nucleotide composition and have not statistically evaluated the significance of CUB in sequence analysis.

Results

Here we propose a novel measure--Codon Deviation Coefficient (CDC)--that provides an informative measurement of CUB and its statistical significance without requiring any prior knowledge. Unlike previous measures, CDC estimates CUB by accounting for background nucleotide compositions tailored to codon positions and adopts the bootstrapping to assess the statistical significance of CUB for any given sequence. We evaluate CDC by examining its effectiveness on simulated sequences and empirical data and show that CDC outperforms extant measures by achieving a more informative estimation of CUB and its statistical significance.

Conclusions

As validated by both simulated and empirical data, CDC provides a highly informative quantification of CUB and its statistical significance, useful for determining comparative magnitudes and patterns of biased codon usage for genes or genomes with diverse sequence compositions.
Molecular diversity, population structure, and linkage disequilibrium in a worldwide collection of tobacco (Nicotiana tabacum L.) germplasm
Authors: Fricano Agostino , Bakaher Nicolas , Corvo Marcello Del , Piffanelli Pietro , Donini Paolo , Stella Alessandra , Ivanov Nikolai V , Pozzi Carlo
Published: March 2012

Background

The goals of our study were to assess the phylogeny and the population structure of tobacco accessions representing a wide range of genetic diversity; identify a subset of accessions as a core collection capturing most of the existing genetic diversity; and estimate, in the tobacco core collection, the extent of linkage disequilibrium (LD) in seven genomic regions using simple sequence repeat (SSR) markers. To this end, a collection of accessions were genotyped with SSR markers. Molecular diversity was evaluated and LD was analyzed across seven regions of the genome.

Results

A genotyping database for 312 tobacco accessions was profiled with 49 SSR markers. Principal Coordinate Analysis (PCoA) and Bayesian cluster analysis revealed structuring of the tobacco population with regard to commercial classes and six main clades were identified, which correspond to "Oriental", Flue-Cured", "Burley", "Dark", "Primitive", and "Other" classes. Pairwise kinship was calculated between accessions, and an overall low level of co-ancestry was observed. A set of 89 genotypes was identified that captured the whole genetic diversity detected at the 49 loci. LD was evaluated on these genotypes, using 422 SSR markers mapping on seven linkage groups. LD was estimated as squared correlation of allele frequencies (r

2
). The pattern of intrachromosomal LD revealed that in tobacco LD extended up to distances as great as 75 cM with r

2
> 0.05 or up to 1 cM with r

2
> 0.2. The pattern of LD was clearly dependent on the population structure.

Conclusions

A global population of tobacco is highly structured. Clustering highlights the accessions with the same market class. LD in tobacco extends up to 75 cM and is strongly dependent on the population structure.
Individual patient data meta-analysis of survival data using Poisson regression models
Authors: Crowther Michael J , Riley Richard D , Staessen Jan A , Wang Jiguang , Gueyffier Francois , Lambert Paul C
Published: March 2012

Background

An Individual Patient Data (IPD) meta-analysis is often considered the gold-standard for synthesising survival data from clinical trials. An IPD meta-analysis can be achieved by either a two-stage or a one-stage approach, depending on whether the trials are analysed separately or simultaneously. A range of one-stage hierarchical Cox models have been previously proposed, but these are known to be computationally intensive and are not currently available in all standard statistical software. We describe an alternative approach using Poisson based Generalised Linear Models (GLMs).

Methods

We illustrate, through application and simulation, the Poisson approach both classically and in a Bayesian framework, in two-stage and one-stage approaches. We outline the benefits of our one-stage approach through extension to modelling treatment-covariate interactions and non-proportional hazards. Ten trials of hypertension treatment, with all-cause death the outcome of interest, are used to apply and assess the approach.

Results

We show that the Poisson approach obtains almost identical estimates to the Cox model, is additionally computationally efficient and directly estimates the baseline hazard. Some downward bias is observed in classical estimates of the heterogeneity in the treatment effect, with improved performance from the Bayesian approach.

Conclusion

Our approach provides a highly flexible and computationally efficient framework, available in all standard statistical software, to the investigation of not only heterogeneity, but the presence of non-proportional hazards and treatment effect modifiers.
Dynamics of pneumococcal nasopharyngeal carriage in healthy children attending a day care center in northern Spain. influence of detection techniques on the results
Authors: Ercibengoa María , Arostegi Nerea , Marimón José M , Alonso Marta , Pérez-Trallero Emilio
Published: March 2012

Background

Pneumococcal nasopharyngeal carriage precedes invasive infection and is the source for dissemination of the disease. Differences in sampling methodology, isolation or identification techniques, as well as the period (pre -or post-vaccination) when the study was performed, can influence the reported rates of colonization and the distribution of serotypes carried.

Objectives

To evaluate the prevalence and dynamics of pneumococcal nasopharyngeal colonization in healthy children aged 6-34 months attending a day care center with a high level of hygiene and no overcrowding. The study was performed 3-4 years after the 7-valent pneumococcal vaccine was introduced, using multiple methodologies to detect and characterize the isolates.

Methods

Over 12 months, 25 children were sampled three times, 53 children twice and 27 children once. Three Streptococcus pneumoniae typing techniques were used: Quellung, Pneumotest-Latex-kit and multiplex-polymerase chain reaction (PCR). The similarity of isolates of the same serotype was established by pulsed field gel electrophoresis (PFGE) and occasionally the multilocus sequence type (ST) was also determined.

Results

Overall pneumococcal carriage and multiple colonization rates were 89.5% (94/105) and 39%, respectively. Among 218 pneumococci detected, 21 different serotypes and 13 non-typeable isolates were found. The most prevalent serotypes were 19A, 16F and 15B. Serotypes 15B, 19A and 21 were mainly found as single carriage; in contrast serotypes 6B, 11A and 20, as well as infrequent serotypes, were isolated mainly as part of multiple carriage. Most 19A isolates were ST193 but most serotypes showed high genetic heterogeneity. Changes in the pneumococci colonizing each child were frequent and the same serotype detected on two occasions frequently showed a different genotype. By multiplex-PCR, 100% of pneumococci could be detected and 94% could be serotyped versus 80.3% by the Quellung reaction and Pneumotest-Latex in combination (p < 0.001).

Conclusions

Rates of S. pneumoniae carriage and multiple colonization were very high. Prevalent serotypes differed from those found in similar studies in the pre-vaccination period. In the same child, clearance of a pneumococcal strain and acquisition of a new one was frequent in a short period of time. The most effective technique for detecting pneumococcal nasopharyngeal carriers was multiplex-PCR.
Clinical relevance of ErbB-2/HER2 nuclear expression in breast cancer
Authors: Schillaci Roxana , Guzmán Pablo , Cayrol Florencia , Beguelin Wendy , Díaz Flaqué María C , Proietti Cecilia J , Pineda Viviana , Palazzi Jorge , Frahm Isabel , Charreau Eduardo H , Maronna Esteban , Roa Juan C , Elizalde Patricia V
Published: March 2012

Background

The biological relevance of nuclear ErbB-2/HER2 (NuclErbB-2) presence in breast tumors remains unexplored. In this study we assessed the clinical significance of ErbB-2 nuclear localization in primary invasive breast cancer. The reporting recommendations for tumor marker prognostic studies (REMARK) guidelines were used as reference.

Methods

Tissue microarrays from a cohort of 273 primary invasive breast carcinomas from women living in Chile, a Latin American country, were examined for membrane (MembErbB-2) and NuclErbB-2 expression by an immunofluorescence (IF) protocol we developed. ErbB-2 expression was also evaluated by immunohistochemistry (IHC) with a series of antibodies. Correlation between NuclErbB-2 and MembErbB-2, and between NuclErbB-2 and clinicopathological characteristics of tumors was studied. The prognostic value of NuclErbB-2 in overall survival (OS) was evaluated using Kaplan-Meier method, and Cox model was used to explore NuclErbB-2 as independent prognostic factor for OS.

Results

The IF protocol we developed showed significantly higher sensitivity for detection of NuclErbB-2 than IHC procedures, while its specificity and sensitivity to detect MembErbB-2 were comparable to those of IHC procedures. We found 33.6% NuclErbB-2 positivity, 14.2% MembErbB-2 overexpression by IF, and 13.0% MembErbB-2 prevalence by IHC in our cohort. We identified NuclErbB-2 positivity as a significant independent predictor of worse OS in patients with MembErbB-2 overexpression. NuclErbB-2 was also a biomarker of lower OS in tumors that overexpress MembErbB-2 and lack steroid hormone receptors.

Conclusions

We revealed a novel role for NuclErbB-2 as an independent prognostic factor of poor clinical outcome in MembErbB-2-positive breast tumors. Our work indicates that patients presenting NuclErbB-2 may need new therapeutic strategies involving specific blockage of ErbB-2 nuclear migration.
Diarrhea incidence in low- and middle-income countries in 1990 and 2010: a systematic review
Authors: Fischer Walker Christa L , Perin Jamie , Aryee Martin J , Boschi-Pinto Cynthia , Black Robert E
Published: March 2012

Background

Diarrhea is recognized as a leading cause of morbidity and mortality among children under 5 years of age in low- and middle-income countries yet updated estimates of diarrhea incidence by age for these countries are greatly needed. We conducted a systematic literature review to identify cohort studies that sought to quantify diarrhea incidence among any age group of children 0-59 mo of age.

Methods

We used the Expectation-Maximization algorithm as a part of a two-stage regression model to handle diverse age data and overall incidence rate variation by study to generate country specific incidence rates for low- and middle-income countries for 1990 and 2010. We then calculated regional incidence rates and uncertainty ranges using the bootstrap method, and estimated the total number of episodes for children 0-59 mo of age in 1990 and 2010.

Results

We estimate that incidence has declined from 3.4 episodes/child year in 1990 to 2.9 episodes/child year in 2010. As was the case previously, incidence rates are highest among infants 6-11 mo of age; 4.5 episodes/child year in 2010. Among these 139 countries there were nearly 1.9 billion episodes of childhood diarrhea in 1990 and nearly 1.7 billion episodes in 2010.

Conclusions

Although our results indicate that diarrhea incidence rates may be declining slightly, the total burden on the health of each child due to multiple episodes per year is tremendous and additional funds are needed to improve both prevention and treatment practices in low- and middle-income countries.
Pattern and levels of spending allocated to HIV prevention programs in low- and middle-income countries
Authors: Amico Peter , Gobet Benjamin , Avila-Figueroa Carlos , Aran Christian , De Lay Paul
Published: March 2012

Background

AIDS continues to spread at an estimated 2.6 new million infections per year, making the prevention of HIV transmission a critical public health issue. The dramatic growth in global resources for AIDS has produced a steady scale-up in treatment and care that has not been equally matched by preventive services. This paper is a detailed analysis of how countries are choosing to spend these more limited prevention funds.

Methods

We analyzed prevention spending in 69 low- and middle-income countries with a variety of epidemic types, using data from national domestic spending reports. Spending information was from public and international sources and was analyzed based on the National AIDS Spending Assessment (NASA) methods and classifications.

Results

Overall, prevention received 21% of HIV resources compared to 53% of funding allocated to treatment and care. Prevention relies primarily on international donors, who accounted for 65% of all prevention resources and 93% of funding in low-income countries. For the subset of 53 countries that provided detailed spending information, we found that 60% of prevention resources were spent in five areas: communication for social and behavioral change (16%), voluntary counselling and testing (14%), prevention of mother-to-child transmission (13%), blood safety (10%) and condom programs (7%). Only 7% of funding was spent on most-at-risk populations and less than 1% on male circumcision. Spending patterns did not consistently reflect current evidence and the HIV specific transmission context of each country.

Conclusions

Despite recognition of its importance, countries are not allocating resources in ways that are likely to achieve the greatest impact on prevention across all epidemic types. Within prevention spending itself, a greater share of resources need to be matched with interventions that approximate the specific needs and drivers of each country's epidemic.
Relative risk of renal disease among people living with HIV: a systematic review and meta-analysis
Authors: Islam Fakhrul M , Wu Jianyun , Jansson James , Wilson David P
Published: March 2012

Background

Antiretroviral therapy (ART) has substantially decreased mortality and HIV-related morbidity. However, other morbidities appear to be more common among PLHIV than in the general population. This study aimed to estimate the relative risk of renal disease among people living with HIV (PLHIV) compared to the HIV-uninfected population.

Methods

We conducted a systematic review and meta-analysis of relative risks of renal disease among populations of PLHIV reported in studies from the peer-reviewed literature. We searched Medline for relevant journal articles published before September 2010, yielding papers published during or after 2002. We also searched conference proceedings of the International AIDS Society (IAS) and Conference on Retroviruses and Opportunistic Infections (CROI) prior to and including 2010. Eligible studies were observational studies reporting renal disease defined as acute or chronic reduced renal function with glomerular filtration rate less than or equal to 60 ml/min/1.73 m2 among HIV-positive adults. Pooled relative risks were calculated for various groupings, including class of ART drugs administered.

Results

The overall relative risk of renal disease was 3.87 (95% CI: 2.85-6.85) among HIV-infected people compared to HIV-uninfected people. The relative risk of renal disease among people with late-stage HIV infection (AIDS) was 3.32 (1.86-5.93) compared to other PLHIV. The relative risk of renal disease among PLHIV who were receiving antiretroviral therapy (ART) was 0.54 (0.29-0.99) compared to treatment-naïve PLHIV; the relative risk of renal disease among PLHIV who were treated with tenofovir was 1.56 (0.83-2.93) compared to PLHIV who were treated with non-tenofovir therapy. The risk of renal disease was also found to significantly increase with age.

Conclusion

PLHIV are at increased risk of renal disease, with greater risk at later stages of infection and at older ages. ART prolongs survival and decreases the risk of renal disease. However, less reduction in renal disease risk occurs for Tenofovir-containing ART than for other regimens.
Care management for Type 2 diabetes in the United States: a systematic review and meta-analysis
Authors: Egginton Jason S , Ridgeway Jennifer L , Shah Nilay D , Balasubramaniam Saranya , Emmanuel Joann R , Prokop Larry J , Montori Victor M , Murad Mohammad Hassan
Published: March 2012

Background

This systematic review and meta-analysis aims at assessing the composition and performance of care management models evaluated in the last decade and their impact on patient important outcomes.

Methods

A comprehensive literature search of electronic bibliographic databases was performed to identify care management trials in type 2 diabetes. Random effects meta-analysis was used when feasible to pool outcome measures.

Results

Fifty-two studies were eligible. Most commonly reported were surrogate outcomes (such as HbA1c and LDL), followed by process measures (clinic visit or testing frequency). Less frequently reported were quality of life, patient satisfaction, self-care, and healthcare utilization. Most care management modalities were carved out from primary care. Meta-analysis demonstrated a statistically significant but trivial reduction of HbA1c (weighted difference in means -0.21%, 95% confidence interval -0.40 to -0.03, p < .03) and LDL-cholesterol (weighted difference in means -3.38 mg/dL, 95% confidence interval -6.27 to -0.49, p < .02).

Conclusions

Most care management programs for patients with type 2 diabetes are 'carved-out', accomplish limited effects on metabolic outcomes, and have unknown effects on patient important outcomes. Comparative effectiveness research of different models of care management is needed to inform the design of medical homes for patients with chronic conditions.
Multiple effects of electroporation on the adhesive behaviour of breast cancer cells and fibroblasts
Authors: Pehlivanova Viktoria N , Tsoneva Iana H , Tzoneva Rumiana D
Published: March 2012

Background

Recently electroporation using biphasic pulses was successfully applied in clinical developments for treating tumours in humans and animals. We evaluated the effects of electrical treatment on cell adhesion behaviour of breast cancer cells and fibroblasts. By applying bipolar electrical pulses we studied short- and long-lived effects on cell adhesion and survival, actin cytoskeleton and cell adhesion contacts in adherent cancer cells and fibroblasts.

Methods

Two cancer cell lines (MDA-MB-231 and MCF-7) and one fibroblast cell line 3T3 were used. Cells were exposed to high field intensity (200 - 1000 V/cm). Cell adhesion and survival after electrical exposure were studied by crystal violet assay and MTS assay. Cytoskeleton rearrangement and cell adhesion contacts were visualized by actin staining and fluorescent microscope.

Results

The degree of electropermeabilization of the adherent cells elevated steadily with the increasing of the field intensity. Adhesion behaviour of fibroblasts and MCF-7 was not significantly affected by electrotreatment. Interestingly, treating the loosely adhesive cancer cell line MDA-MB-231 with 200 V/cm and 500 V/cm resulted in increased cell adhesion. Cell replication of both studied cancer cell lines was disturbed after electropermeabilization. Electroporation influenced the actin cytoskeleton in cancer cells and fibroblasts in different ways. Since it disturbed temporarily the actin cytoskeleton in 3T3 cells, in cancer cells treated with lower and middle field intensity actin cytoskeleton was well presented in stress fibers, filopodia and lamellipodia. The electrotreatment for cancer cells provoked preferentially cell-cell adhesion contacts for MCF-7 and cell-ECM contacts for MDA-MB- 231.

Conclusions

Cell adhesion and survival as well as the type of cell adhesion (cell-ECM or cell-cell adhesion) induced by the electroporation process is cell specific. The application of suitable electric pulses can provoke changes in the cytoskeleton organization and cell adhesiveness, which could contribute to the restriction of tumour invasion and thus leads to the amplification of anti-tumour effect of electroporation-based tumour therapy.
Klotho-beta overexpression as a novel target for suppressing proliferation and fibroblast growth factor receptor-4 signaling in hepatocellular carcinoma
Authors: Poh Weijie , Wong Winnie , Ong Huimin , Aung Myat Oo , Lim Seng Gee , Chua Boon Tin , Ho Han Kiat
Published: March 2012

Background

We had previously demonstrated overexpression of fibroblast growth factor receptor-4 (FGFR4) in hepatocellular carcinoma (HCC). However, additional molecular mechanisms resulting in amplified FGFR4 signaling in HCC remain under-studied. Here, we studied the mechanistic role of its co-receptor klotho-beta (KLB) in driving elevated FGFR4 activity in HCC progression.

Results

Quantitative real-time PCR analysis identified frequent elevation of KLB gene expression in HCC tumors relative to matched non-tumor tissue, with a more than two-fold increase correlating with development of multiple tumors in patients. KLB-silencing in Huh7 cells decreased cell proliferation and suppressed FGFR4 downstream signaling. While transient repression of KLB-FGFR4 signaling decreased protein expression of alpha-fetoprotein (AFP), a HCC diagnostic marker, prolonged inhibition enriched for resistant HCC cells exhibiting increased liver stemness.

Conclusions

Elevated KLB expression in HCC tissues provides further credence to the oncogenic role of increased FGFR4 signaling in HCC progression and represents a novel biomarker to identify additional patients amenable to anti-FGFR4 therapy. The restricted tissue expression profile of KLB, together with the anti-proliferative effect observed with KLB-silencing, also qualifies it as a specific and potent therapeutic target for HCC patients. The enrichment of a liver stem cell-like population in response to extended KLB-FGFR4 repression necessitates further investigation to target the development of drug resistance.
Malignant paraganglioma of the mesentery: a case report and review of literature
Authors: Chetrit Michael , Dubé Pierre , Royal Virginie , Leblanc Guy , Sideris Lucas
Published: March 2012

Paragangliomas represent only 10% of chromaffin tissue tumors and those arising from the mesentery seem to be a rare occurrence. We report a case of a 55 year old man in whom an abdominal mass was discovered fortuitously by ultrasonography during a routine health exam. He presented occasional heart palpitations and diaphoresis as well as a well-demarcated mass upon abdominal physical examination. CT scan revealed a solid polylobulated mass in the right lower quadrant. Exploration laparotomy revealed a voluminous multi-nodular tumoral mass, which contained hemorrhagic spots. Histopathological studies confirmed the presence of a paraganglioma. The excision of the mass as well as the surrounding intestine and mesentery also revealed two lymphatic metastases, the first among 14 documented cases to be described concerning mesenteric paragangliomas. One year follow up and CT scan revealed neither recurrence nor the presence of distant metastases.
Circulating miR-378 and miR-451 in serum are potential biomarkers for renal cell carcinoma
Authors: Redova Martina , Poprach Alexandr , Nekvindova Jana , Iliev Robert , Radova Lenka , Lakomy Radek , Svoboda Marek , Vyzula Rostislav , Slaby Ondrej
Published: March 2012

Background

There is no standard serum biomarker used for diagnosis or early detection of recurrence for renal cell carcinoma (RCC) patients. MicroRNAs (miRNAs) are abundant and highly stable in blood serum, and have been recently described as powerful circulating biomarkers in a wide range of solid cancers. Our aim was to identify miRNA signature that can distinguish the blood serum of RCC patients and matched healthy controls and validate identified miRNAs as potential biomarkers for RCC.

Methods

In the screening phase of the study, blood serum of 15 RCC patients and 12 matched healthy controls were analyzed by use of the TaqMan Low-Density Arrays enabling parallel identification of expression levels of 667 miRNAs through qRT-PCR-based approach. In the validation phase, identified miRNAs were further evaluated on the independent group of 90 RCC patients and 35 matched healthy controls by use of individual qRT-PCR assays and statistically evaluated.

Results

We identified 30 miRNAs differentially expressed between serum of RCC patients and healthy controls: 19 miRNAs were up-regulated and 11 miRNAs were down-regulated in RCC patients. MiR-378, miR-451 and miR-150 were further evaluated in the independent group of patients, and two of them were successfully validated: levels of miR-378 were increased (p = 0.0003, AUC = 0.71), miR-451 levels were decreased (p < 0.0001, AUC = 0.77) in serum of RCC patients. Combination of miR-378 and miR-451 enable identification of RCC serum with the sensitivity of 81%, specificity 83% and AUC = 0.86.

Conclusions

Circulating miRNAs in serum are promising biomarkers in RCC.
Hardware oriented, quasi-optimal detectors for iterative and non-iterative MIMO receivers
Authors: Tomasoni Alessandro , Siti Massimiliano , Ferrari Marco , Bellini Sandro
Published: March 2012

In this article we study hardware-oriented versions of the recently appeared Layered ORthogonal lattice Detector (LORD) and Turbo LORD (T-LORD). LORD and T-LORD are attractive Multiple-Input Multiple-Output (MIMO) detection algorithms, that aim to approach the optimal Maximum-Likelihood (ML) and Maximum-A-Posteriori (MAP) performance, respectively, yet allowing a complexity quadratic in the number of transmitting antennas rather than exponential. LORD and T-LORD are also well suited to a hardware (e.g., ASIC or FPGA) implementation because of their regularity, parallelism, deterministic latency, and complexity. Nevertheless, their complexity is still high in case of high cardinality constellations, such as the 64-QAM foreseen by the 802.11n standard. We show that, when only global latency constraints exist, e.g., a fixed time to detect the whole OFDM symbol, the LORD and T-LORD complexity can be remarkably reduced, still approaching the ML and MAP performance, respectively. Notwithstanding the suboptimal low-complexity and hardware-oriented implementation, LORD and T-LORD approach the EXtrinsic Information Transfer of the ML and MAP detectors, respectively. To focus on a specific setting, we consider the indoor MIMO wireless LAN 802.11n standard, taking into account errors in channel estimation and a frequency selective, spatially correlated channel model.
Advances in establishment and analysis of three-dimensional tumor spheroid-based functional assays for target validation and drug evaluation
Authors: Vinci Maria , Gowan Sharon , Boxall Frances , Patterson Lisa , Zimmermann Miriam , Court William , Lomas Cara , Mendiola Marta , Hardisson David , Eccles Suzanne A
Published: March 2012

Background

There is overwhelming evidence that in vitro three-dimensional tumor cell cultures more accurately reflect the complex in vivo microenvironment than simple two-dimensional cell monolayers, not least with respect to gene expression profiles, signaling pathway activity and drug sensitivity. However, most currently available three-dimensional techniques are time consuming and/or lack reproducibility; thus standardized and rapid protocols are urgently needed.

Results

To address this requirement, we have developed a versatile toolkit of reproducible three-dimensional tumor spheroid models for dynamic, automated, quantitative imaging and analysis that are compatible with routine high-throughput preclinical studies. Not only do these microplate methods measure three-dimensional tumor growth, but they have also been significantly enhanced to facilitate a range of functional assays exemplifying additional key hallmarks of cancer, namely cell motility and matrix invasion. Moreover, mutual tissue invasion and angiogenesis is accommodated by coculturing tumor spheroids with murine embryoid bodies within which angiogenic differentiation occurs. Highly malignant human tumor cells were selected to exemplify therapeutic effects of three specific molecularly-targeted agents: PI-103 (phosphatidylinositol-3-kinase (PI3K)-mammalian target of rapamycin (mTOR) inhibitor), 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) (heat shock protein 90 (HSP90) inhibitor) and CCT130234 (in-house phospholipase C (PLC)γ inhibitor). Fully automated analysis using a Celigo cytometer was validated for tumor spheroid growth and invasion against standard image analysis techniques, with excellent reproducibility and significantly increased throughput. In addition, we discovered key differential sensitivities to targeted agents between two-dimensional and three-dimensional cultures, and also demonstrated enhanced potency of some agents against cell migration/invasion compared with proliferation, suggesting their preferential utility in metastatic disease.

Conclusions

We have established and validated a suite of highly reproducible tumor microplate three-dimensional functional assays to enhance the biological relevance of early preclinical cancer studies. We believe these assays will increase the translational predictive value of in vitro drug evaluation studies and reduce the need for in vivo studies by more effective triaging of compounds.