bluuebunny/crossref_metadata_2025 huggingface dataset:
Notch promotes vascular maturation by inducing integrin-mediated smooth muscle cell adhesion to the endothelial basement membrane
Authors: Scheppke Lea , Murphy Eric A. , Zarpellon Alessandro , Hofmann Jennifer J. , Merkulova Alona , Shields David J. , Weis Sara M. , Byzova Tatiana V. , Ruggeri Zaverio M. , Iruela-Arispe M. Luisa , Cheresh David A.
Published: December 2011

Vascular development and angiogenesis initially depend on endothelial tip cell invasion, which is followed by a series of maturation steps, including lumen formation and recruitment of perivascular cells. Notch ligands expressed on the endothelium and their cognate receptors expressed on perivascular cells are involved in blood vessel maturation, though little is known regarding the Notchdependent effectors that facilitate perivascular coverage of nascent vessels. Here, we report that vascular smooth muscle cell (VSMC) recognition of the Notch ligand Jagged1 on endothelial cells leads to expression of integrin αvβ3 on VSMCs. Once expressed, integrin αvβ3 facilitates VSMC adhesion to VWF in the endothelial basement membrane of developing retinal arteries, leading to vessel maturation. Genetic or pharmacologic disruption of Jagged1, Notch, αvβ3, or VWF suppresses VSMC coverage of nascent vessels and arterial maturation during vascular development. Therefore, we define a Notch-mediated interaction between the developing endothelium and VSMCs leading to adhesion of VSMCs to the endothelial basement membrane and arterial maturation.
Durable donor engraftment after radioimmunotherapy using α-emitter astatine-211–labeled anti-CD45 antibody for conditioning in allogeneic hematopoietic cell transplantation
Authors: Chen Yun , Kornblit Brian , Hamlin Donald K. , Sale George E. , Santos Erlinda B. , Wilbur D. Scott , Storer Barry E. , Storb Rainer , Sandmaier Brenda M.
Published: December 2011

To reduce toxicity associated with external γ-beam radiation, we investigated radioimmunotherapy with an anti-CD45 mAb labeled with the α-emitter, astatine-211 (211At), as a conditioning regimen in dog leukocyte antigen-identical hematopoietic cell transplantation (HCT). Dose-finding studies in 6 dogs treated with 100 to 618 μCi/kg 211At-labeled anti-CD45 mAb (0.5 mg/kg) without HCT rescue demonstrated dose-dependent myelosuppression with subsequent autologous recovery, and transient liver toxicity in dogs treated with 211At doses less than or equal to 405 μCi/kg. Higher doses of 211At induced clinical liver failure. Subsequently, 8 dogs were conditioned with 155 to 625 μCi/kg 211At-labeled anti-CD45 mAb (0.5 mg/kg) before HCT with dog leukocyte antigen-identical bone marrow followed by a short course of cyclosporine and mycophenolate mofetil immunosuppression. Neutropenia (1-146 cells/μL), lymphopenia (0-270 cells/μL), and thrombocytopenia (1500-6560 platelets/μL) with prompt recovery was observed. Seven dogs had long-term donor mononuclear cell chimerism (19%-58%), whereas 1 dog treated with the lowest 211At dose (155 μCi/kg) had low donor mononuclear cell chimerism (5%). At the end of follow-up (18-53 weeks), only transient liver toxicity and no renal toxicity had been observed. In conclusion, conditioning with 211At-labeled anti-CD45 mAb is safe and efficacious and provides a platform for future clinical trials of nonmyeloablative transplantation with radioimmunotherapy-based conditioning.
Lack of sufficiently strong informative features limits the potential of gene expression analysis as predictive tool for many clinical classification problems
Authors: Hess Kenneth R , Wei Caimiao , Qi Yuan , Iwamoto Takayuki , Symmans W Fraser , Pusztai Lajos
Published: December 2011

Background

Our goal was to examine how various aspects of a gene signature influence the success of developing multi-gene prediction models. We inserted gene signatures into three real data sets by altering the expression level of existing probe sets. We varied the number of probe sets perturbed (signature size), the fold increase of mean probe set expression in perturbed compared to unperturbed data (signature strength) and the number of samples perturbed. Prediction models were trained to identify which cases had been perturbed. Performance was estimated using Monte-Carlo cross validation.

Results

Signature strength had the greatest influence on predictor performance. It was possible to develop almost perfect predictors with as few as 10 features if the fold difference in mean expression values were > 2 even when the spiked samples represented 10% of all samples. We also assessed the gene signature set size and strength for 9 real clinical prediction problems in six different breast cancer data sets.

Conclusions

We found sufficiently large and strong predictive signatures only for distinguishing ER-positive from ER-negative cancers, there were no strong signatures for more subtle prediction problems. Current statistical methods efficiently identify highly informative features in gene expression data if such features exist and accurate models can be built with as few as 10 highly informative features. Features can be considered highly informative if at least 2-fold expression difference exists between comparison groups but such features do not appear to be common for many clinically relevant prediction problems in human data sets.
Progenitor expansion in apc mutants is mediated by Jak/Stat signaling
Authors: Lin Junji , Wang Xu , Dorsky Richard I
Published: December 2011

Background

Mutations inAPC, a negative regulator of the Wnt/ß-catenin pathway, can cause cancer as well as profound developmental defects. In both cases, affected cells adopt a proliferative progenitor state and fail to differentiate. While the upregulation of some target genes of Wnt/ß-catenin signaling has been shown to mediate these phenotypes in individual tissues, it is unclear whether a common mechanism underlies the defects inAPCmutants.

Results

Here we show thatstat3, a known oncogene and a target of ß-catenin in multiple tissues, is upregulated inapcmutant zebrafish embryos. We further demonstrate that Jak/Stat signaling is necessary for the increased level of proliferation and neural progenitor gene expression observed inapcmutants.

Conclusions

Together, our data suggest that the regulation of Jak/Stat signaling may represent a conserved mechanism explaining the expansion of undifferentiated cells downstream ofAPCmutations.
Identification of dysfunctional modules and disease genes in congenital heart disease by a network-based approach
Authors: He Danning , Liu Zhi-Ping , Chen Luonan
Published: December 2011

Background

The incidence of congenital heart disease (CHD) is continuously increasing among infants born alive nowadays, making it one of the leading causes of infant morbidity worldwide. Various studies suggest that both genetic and environmental factors lead to CHD, and therefore identifying its candidate genes and disease-markers has been one of the central topics in CHD research. By using the high-throughput genomic data of CHD which are available recently, network-based methods provide powerful alternatives of systematic analysis of complex diseases and identification of dysfunctional modules and candidate disease genes.

Results

In this paper, by modeling the information flow from source disease genes to targets of differentially expressed genes via a context-specific protein-protein interaction network, we extracted dysfunctional modules which were then validated by various types of measurements and independent datasets. Network topology analysis of these modules revealed major and auxiliary pathways and cellular processes in CHD, demonstrating the biological usefulness of the identified modules. We also prioritized a list of candidate CHD genes from these modules using a guilt-by-association approach, which are well supported by various kinds of literature and experimental evidence.

Conclusions

We provided a network-based analysis to detect dysfunctional modules and disease genes of CHD by modeling the information transmission from source disease genes to targets of differentially expressed genes. Our method resulted in 12 modules from the constructed CHD subnetwork. We further identified and prioritized candidate disease genes of CHD from these dysfunctional modules. In conclusion, module analysis not only revealed several important findings with regard to the underlying molecular mechanisms of CHD, but also suggested the distinct network properties of causal disease genes which lead to identification of candidate CHD genes.
Mycobacterium tuberculosis infection induces non-apoptotic cell death of human dendritic cells
Authors: Ryan Ruth CM , O'Sullivan Mary P , Keane Joseph
Published: December 2011

Background

Dendritic cells (DCs) connect innate and adaptive immunity, and are necessary for an efficient CD4+and CD8+T cell response after infection withMycobacterium tuberculosis(Mtb). We previously described the macrophage cell death response to Mtb infection. To investigate the effect of Mtb infection on human DC viability, we infected these phagocytes with different strains of Mtb and assessed viability, as well as DNA fragmentation and caspase activity. In parallel studies, we assessed the impact of infection on DC maturation, cytokine production and bacillary survival.

Results

Infection of DCs with live Mtb (H37Ra or H37Rv) led to cell death. This cell death proceeded in a caspase-independent manner, and without nuclear fragmentation. In fact, substrate assays demonstrated that Mtb H37Ra-induced cell death progressed without the activation of the executioner caspases, 3/7. Although the death pathway was triggered after infection, the DCs successfully underwent maturation and produced a host-protective cytokine profile. Finally, dying infected DCs were permissive for Mtb H37Ra growth.

Conclusions

Human DCs undergo cell death after infection with live Mtb, in a manner that does not involve executioner caspases, and results in no mycobactericidal effect. Nonetheless, the DC maturation and cytokine profile observed suggests that the infected cells can still contribute to TB immunity.
Heritability and genome-wide association analysis of renal sinus fat accumulation in the Framingham Heart Study
Authors: Foster Meredith C , Yang Qiong , Hwang Shih-Jen , Hoffmann Udo , Fox Caroline S
Published: December 2011

Background

Ectopic fat accumulation in the renal sinus is associated with chronic kidney disease and hypertension. The genetic contributions to renal sinus fat accumulation in humans have not been well characterized.

Methods

The present analysis consists of participants from the Framingham Offspring and Third Generation who underwent computed tomography; renal sinus fat and visceral adipose tissue (VAT) were quantified. Renal sinus fat was natural log transformed and sex- and cohort-specific residuals were created, adjusted for (1) age, (2) age and body mass index (BMI), and (3) age and VAT. Residuals were pooled and used to calculate heritability using variance-components analysis in SOLAR. A genome-wide association study (GWAS) for renal sinus fat was performed using an additive model with approximately 2.5 million imputed single nucleotide polymorphisms (SNPs). Finally, we identified the associations of renal sinus fat in our GWAS results with validated SNPs for renal function (n = 16), BMI (n = 32), and waist-to-hip ratio (WHR, n = 14), and applied a multi-SNP genetic risk score method to determine if the SNPs for each renal and obesity trait were in aggregate associated with renal sinus fat.

Results

The heritability of renal sinus fat was 39% (p < 0.0001); results were not materially different after adjustment for BMI (39%) or VAT (40%). No SNPs reached genome-wide significance in our GWAS. In our candidate gene analysis, we observed nominal, direction consistent associations with renal sinus fat for one SNP associated with renal function (p = 0.01), two associated with BMI (p < 0.03), and two associated with WHR (p < 0.03); however, none remained significant after accounting for multiple testing. Finally, we observed that in aggregate, the 32 SNPs associated with BMI were nominally associated with renal sinus fat (multi-SNP genetic risk score p = 0.03).

Conclusions

Renal sinus fat is a heritable trait, even after accounting for generalized and abdominal adiposity. This provides support for further research into the genetic determinants of renal sinus fat. While our study was underpowered to detect genome-wide significant loci, our candidate gene BMI risk score results suggest that variability in renal sinus fat may be associated with SNPs previously known to be associated with generalized adiposity.
Health problems and disability in long-term sickness absence: ICF coding of medical certificates
Authors: Morgell Roland , Backlund Lars G , Arrelöv Britt , Strender Lars-Erik , Nilsson Gunnar H
Published: December 2011

Background

The purpose of this study was to test the feasibility of International Classification of Functioning, Disability and Health (ICF) and to explore the distribution, including gender differences, of health problems and disabilities as reflected in long-term sickness absence certificates.

Methods

A total of 433 patients with long sick-listing periods, 267 women and 166 men, were included in the study. All certificates exceeding 28 days of sick-listing sent to the local office of the Swedish Social Insurance Administration of a municipality in the Stockholm area were collected during four weeks in 2004-2005. ICD-10 medical diagnosis codes in the certificates were retrieved and free text information on disabilities in body function, body structure or activity and participation were coded according to ICF short version.

Results

In 89.8% of the certificates there were descriptions of disabilities that readily could be classified according to ICF. In a reliability test 123/131 (94%) items of randomly chosen free text information were identically classified by two of the authors. On average 2.4 disability categories (range 0-9) were found per patient; the most frequent were 'Sensation of pain' (35.1% of the patients), 'Emotional functions' (34.1%), 'Energy and drive functions' (22.4%), and 'Sleep functions' (16.9%). The dominating ICD-10 diagnostic groups were 'Mental and behavioural disorders' (34.4%) and 'Diseases of the musculoskeletal system and connective tissue' (32.8%). 'Reaction to severe stress and adjustment disorders' (14.7%), and 'Depressive episode' (11.5%) were the most frequent diagnostic codes. Disabilities in mental functions and activity/participation were more commonly described among women, while disabilities related to the musculoskeletal system were more frequent among men.

Conclusions

Both ICD-10 diagnoses and ICF categories were dominated by mental and musculoskeletal health problems, but there seems to be gender differences, and ICF classification as a complement to ICD-10 could provide a better understanding of the consequences of diseases and how individual patients can cope with their health problems. ICF is feasible for secondary classifying of free text descriptions of disabilities stated in sick-leave certificates and seems to be useful as a complement to ICD-10 for sick-listing management and research.
Influence of preoperative nucleus pulposus status and radiculopathy on outcomes in mono-segmental lumbar total disc replacement: results from a nationwide registry
Authors: Zweig Thomas , Hemmeler Christoph , Aghayev Emin , Melloh Markus , Etter Christian , Röder Christoph
Published: December 2011

Background

Currently, herniated nucleus pulposus (HNP) with radiculopathy and other preconditions are regarded as relative or absolute contraindications for lumbar total disc replacement (TDR). In Switzerland it is left to the surgeon's discretion when to operate. The present study is based on the dataset of SWISSspine, a governmentally mandated health technology assessment registry. We hypothesized that preoperative nucleus pulposus status and presence or absence of radiculopathy has an influence on clinical outcomes in patients treated with mono-segmental lumbar TDR.

Methods

Between March 2005 and April 2009, 416 patients underwent mono-segmental lumbar TDR, which was documented in a prospective observational multicenter mode. The data collection consisted of perioperative and follow-up data (physician based) and clinical outcomes (NASS, EQ-5D).

Patients were divided into four groups according to their preoperative status: 1) group degenerative disc disease ("DDD"): 160 patients without HNP and no radiculopathy, classic precondition for TDR; 2) group "HNP-No radiculopathy": 68 patients with HNP but without radiculopathy; 3) group "Stenosis": 73 patients without HNP but with radiculopathy, and 4) group "HNP-Radiculopathy": 132 patients with HNP and radiculopathy. The groups were compared regarding preoperative patient characteristics and pre- and postoperative VAS and EQ-5D scores using general linear modeling.

Results

Demographics in all four groups were comparable. Regarding the improvement of quality of life (EQ-5D) there were no differences across the four groups. For the two main groups DDD and HNP-Radiculopathy no differences were found in the adjusted postoperative back- and leg pain alleviation levels, in the stenosis group back- and leg pain relief were lower.

Conclusions

Despite higher preoperative leg pain levels, outcomes in lumbar TDR patients with HNP and radiculopathy were similar to outcomes in patients with the classic indication; this because patients with higher preoperative leg pain levels benefit from a relatively greater leg pain alleviation. The group with absence of HNP but presence of radiculopathy showed considerably less benefits from the operation, which is probably related to ongoing degenerative processes of the posterior segmental structures. This observational multicenter study suggests that the diagnoses HNP and radiculopathy, combined or alone, may not have to be considered as absolute or relative contraindications for mono-segmental lumbar TDR anymore, whereas patients without HNP but with radiculopathy seem to be suboptimal candidates for the procedure.
RibM from Streptomyces davawensis is a riboflavin/roseoflavin transporter and may be useful for the optimization of riboflavin production strains
Authors: Hemberger Sabrina , Pedrolli Danielle B , Stolz Jürgen , Vogl Christian , Lehmann Martin , Mack Matthias
Published: December 2011

Background

The bacterium Bacillus subtilis, which is not a natural riboflavin overproducer, has been converted into an excellent production strain by classical mutagenesis and metabolic engineering. To our knowledge, the enhancement of riboflavin excretion from the cytoplasm of overproducing cells has not yet been considered as a target for (further) strain improvement. Here we evaluate the flavin transporter RibM from Streptomyces davawensis with respect to improvement of a riboflavin production strain.

Results

The gene ribM from S. davawensis, coding for a putative facilitator of riboflavin uptake, was codon optimized (ribM

opt
) for expression in B. subtilis. The gene ribM

opt
was functionally introduced into B. subtilis using the isopropyl-β-thiogalactopyranoside (IPTG)-inducible expression plasmid pHT01: Northern-blot analysis of total RNA from IPTG treated recombinant B. subtilis cells revealed a ribM

opt
specific transcript. Western blot analysis showed that the his6-tagged heterologous gene product RibM was present in the cytoplasmic membrane. Expression of ribM in Escherichia coli increased [14C]riboflavin uptake, which was not affected by the protonophore carbonyl cyanide m-chlorophenylhydrazone (CCCP). Expression of ribM

opt
supported growth of a B. subtilis ΔribB::Ermr ΔribU::Kanr double mutant deficient in riboflavin synthesis (ΔribB) and also deficient with respect to riboflavin uptake (ΔribU). Expression of ribM

opt
increased roseoflavin (a toxic riboflavin analog produced by S. davawensis) sensitivity of a B. subtilis ΔribU::Kanr strain. Riboflavin synthesis by a model riboflavin B. subtilis production strain overproducing RibM was increased significantly depending on the amount of the inducer IPTG.

Conclusions

The energy independent flavin facilitator RibM could in principle catalyze riboflavin export and thus may be useful to increase the riboflavin yield in a riboflavin production process using a recombinant RibM overproducing B. subtilis strain (or any other microorganism).
Antibacterial activities of selected Cameroonian spices and their synergistic effects with antibiotics against multidrug-resistant phenotypes
Authors: Fankam Aimé G , Kuete Victor , Voukeng Igor K , Kuiate Jules R , Pages Jean-Marie
Published: December 2011

Background

The emergence of multi-drug resistant (MDR) phenotypes is a major public health problem today in the treatment of bacterial infections. The present study was designed to evaluate the antibacterial activities of the methanol extracts of eleven Cameroonian spices on a panel of twenty nine Gram negative bacteria including MDR strains.

Methods

The phytochemical analysis of the extracts was carried out by standard tests meanwhile the liquid micro-broth dilution was used for all antimicrobial assays.

Results

Phytochemical analysis showed the presence of alkaloids, phenols and tannins in all plants extracts. The results of the antibacterial assays indicated that all tested extracts exert antibacterial activities, with the minimum inhibitory concentration (MIC) values varying from 32 to 1024 μg/ml. The extracts from Dichrostachys glomerata, Beilschmiedia cinnamomea, Aframomum citratum, Piper capense, Echinops giganteus, Fagara xanthoxyloïdes and Olax subscorpioïdea were the most active. In the presence of efflux pump inhibitor, PAßN, the activity of the extract from D. glomerata significantly increased on 69.2% of the tested MDR bacteria. At MIC/5, synergistic effects were noted with the extract of D. glomerata on 75% of the tested bacteria for chloramphenicol (CHL), tetracycline (TET) and norfloxacin (NOR). With B. cinnamomea synergy were observed on 62.5% of the studied MDR bacteria with CHL, cefepime (FEP), NOR and ciprofloxacin (CIP) and 75% with erythromycin (ERY).

Conclusion

The overall results provide information for the possible use of the studied extracts of the spices in the control of bacterial infections involving MDR phenotypes.
Quality of human-computer interaction - results of a national usability survey of hospital-IT in Germany
Authors: Bundschuh Bettina B , Majeed Raphael W , Bürkle Thomas , Kuhn Klaus , Sax Ulrich , Seggewies Christof , Vosseler Cornelia , Röhrig Rainer
Published: December 2011

Background

Due to the increasing functionality of medical information systems, it is hard to imagine day to day work in hospitals without IT support. Therefore, the design of dialogues between humans and information systems is one of the most important issues to be addressed in health care. This survey presents an analysis of the current quality level of human-computer interaction of healthcare-IT in German hospitals, focused on the users' point of view.

Methods

To evaluate the usability of clinical-IT according to the design principles of EN ISO 9241-10 the IsoMetrics Inventory, an assessment tool, was used. The focus of this paper has been put on suitability for task, training effort and conformity with user expectations, differentiated by information systems. Effectiveness has been evaluated with the focus on interoperability and functionality of different IT systems.

Results

4521 persons from 371 hospitals visited the start page of the study, while 1003 persons from 158 hospitals completed the questionnaire. The results show relevant variations between different information systems.

Conclusions

Specialised information systems with defined functionality received better assessments than clinical information systems in general. This could be attributed to the improved customisation of these specialised systems for specific working environments. The results can be used as reference data for evaluation and benchmarking of human computer engineering in clinical health IT context for future studies.
Assessing the contribution of prescribing in primary care by nurses and professionals allied to medicine: a systematic review of literature
Authors: Bhanbhro Sadiq , Drennan Vari M , Grant Robert , Harris Ruth
Published: December 2011

Background

Safe and timely access to effective and appropriate medication through primary care settings is a major concern for all countries addressing both acute and chronic disease burdens. Legislation for nurses and other professionals allied to medicine to prescribe exists in a minority of countries, with more considering introducing legislation. Although there is variation in the range of medicines permitted to be prescribed, questions remain as to the contribution prescribing by nurses and professionals allied to medicine makes to the care of patients in primary care and what is the evidence on which clinicians, commissioners of services and policy makers can consider this innovation.

Methods

A integrative review of literature on non-medical prescribing in primary care was undertaken guided by dimensions of health care quality: effectiveness, acceptability, efficiency and access.

Results

19 papers of 17 empirical studies were identified which provided evidence of patient outcome of non medical prescribing in primary care settings. The majority were undertaken in the UK with only one each from the USA, Canada, Botswana and Zimbabwe. Only two studies investigated clinical outcomes of non-medical prescribing. Seven papers reported on qualitative designs and four of these had fewer than ten participants. Most studies reported that non medical prescribing was widely accepted and viewed positively by patients and professionals.

Conclusions

Primary health care is the setting where timely access to safe and appropriate medicines is most critical for the well-being of any population. The gradual growth over time of legislative authority and in the numbers of non-medical prescribers, particularly nurses, in some countries suggests that the acceptability of non-medical prescribing is based on the perceived value to the health care system as a whole. Our review suggests that there are substantial gaps in the knowledge base to help evidence based policy making in this arena. We suggest that future studies of non-medical prescribing in primary care focus on the broad range of patient and health service outcomes and include economic dimensions.
Combining indoor residual spraying with chlorfenapyr and long-lasting insecticidal bed nets for improved control of pyrethroid-resistant Anopheles gambiae: an experimental hut trial in Benin
Authors: Ngufor Corine , N'Guessan Raphael , Boko Pelagie , Odjo Abibatou , Vigninou Estelle , Asidi Alex , Akogbeto Martin , Rowland Mark
Published: December 2011

Background

Neither indoor residual spraying (IRS) nor long-lasting insecticidal nets (LLINs) are able to fully interrupt transmission in holoendemic Africa as single interventions. The combining of IRS and LLINs presents an opportunity for improved control and management of pyrethroid resistance through the simultaneous presentation of unrelated insecticides.

Method

Chlorfenapyr IRS and a pyrethroid-impregnated polyester LLIN (WHO approved) were tested separately and together in experimental huts in southern Benin against pyrethroid resistant Anopheles gambiae and Culex quinquefasciatus. The bed nets were deliberately holed with either six or 80 holes to examine the effect of increasing wear and tear on protectiveness. Anopheles gambiae were genotyped for the kdr gene to assess the combination's potential to prevent the selection of pyrethroid resistance.

Results

The frequency of kdr was 84%. The overall mortality rates of An. gambiae were 37% and 49% with the six-hole and 80-hole LLINs, respectively, and reached 57% with chlorfenapyr IRS. Overall mortality rates were significantly higher with the combination treatments (82-83%) than with the LLIN or IRS individual treatments. Blood feeding (mosquito biting) rates were lowest with the 6-hole LLIN (12%), intermediate with the 80-hole LLIN (32%) and highest with untreated nets (56% with the 6-hole and 54% with the 80-hole nets). Blood feeding (biting) rates and repellency of mosquitoes with the combination of LLIN and chlorfenapyr IRS showed significant improvement compared to the IRS treatment but did not differ from the LLIN treatments indicating that the LLINs were the primary agents of personal protection. The combination killed significantly higher proportions of Cx. quinquefasciatus (51%, 41%) than the LLIN (15%, 13%) or IRS (32%) treatments.

Conclusion

The chlorfenapyr IRS component was largely responsible for controlling pyrethroid-resistant mosquitoes and the LLIN component was largely responsible for blood feeding inhibition and personal protection. Together, the combination shows potential to provide additional levels of transmission control and personal protection against pyrethroid-resistant mosquitoes, thereby justifying the additional resources required. Chlorfenapyr has potential to manage pyrethroid resistance in the context of an expanding LLIN/IRS strategy.
Broad inhibition of plasmodium falciparum cytoadherence by (+)-epigallocatechin gallate
Authors: Patil Pradeep R , Gemma Sandra , Campiani Giuseppe , Craig Alister G
Published: December 2011

Background

The surface antigen Pf EMP-1 is a key virulence factor of the human malaria parasite implicated in the cytoadherence of Plasmodium falciparum infected erythrocytes to a range of receptors on host endothelium. Among these host receptors, binding to ICAM-1 is related to cerebral malaria. The majority of the mortality in children with cerebral malaria is seen within 24 h of hospital admission despite the use of effective anti-parasite drugs, therefore, the development of adjunctive therapies is urgently needed.

The polyphenolic compound (+)-epigallocatechin gallate ((+)-EGCG) has been previously evaluated for anti-adhesive properties using a small number of laboratory parasite isolates. Here, this property is further explored using a new panel of ICAM-1-binding patient isolates of P. falciparum to ascertain if (+)-EGCG might be effective as a broad spectrum inhibitor of ICAM-1-based cytoadherence.

Methods

Plasmodium falciparum lines, including A4 and ItG as positive controls and nine new ICAM-1 binding patient isolates, were allowed to bind with ICAM-1-Fc protein under static assay conditions in the presence and absence of 50 μM (+)-EGCG. Adhesion levels of all the parasite strains were quantified by microscopy as the mean number of infected erythrocyte (IE) bound per mm2 of surface area and statistical comparisons were made to demonstrate the effect of (+)-EGCG on the binding of various parasite variants to human ICAM-1.

Results

This study revealed that binding of patient isolates to ICAM-1 was reduced significantly with inhibition levels of 37% in patient isolate BC-12 up to a maximum of 80% in patient isolate 8146 at 50 μM (+)-EGCG.

Conclusion

Evaluation of the anti-adhesive property of (+)-EGCG against a new panel of ICAM-1-binding patient isolates of P. falciparum showed that this inhibitor, identified as potential mimic of the L43 loop of human ICAM-1, was effective at blocking cytoadherence.
Influence of mercury exposure on blood pressure, resting heart rate and heart rate variability in French Polynesians: a cross-sectional study
Authors: Valera Beatriz , Dewailly Éric , Poirier Paul , Counil Emilie , Suhas Edouard
Published: December 2011

Background

Populations which diet is rich in seafood are highly exposed to contaminants such as mercury, which could affect cardiovascular risk factors

Objective

To assess the associations between mercury and blood pressure (BP), resting heart rate (HR) and HR variability (HRV) among French Polynesians

Methods

Data were collected among 180 adults (≥ 18 years) and 101 teenagers (12-17 years). HRV was measured using a two-hour ambulatory electrocardiogram (Holter) and BP was measured using a standardized protocol. The association between mercury and HRV and BP parameters was studied using analysis of variance (ANOVA) and analysis of covariance (ANCOVA)

Results

Among teenagers, the high frequency (HF) decreased between the 2nd and 3rd tertile (380 vs. 204 ms2, p = 0.03) and a similar pattern was observed for the square root of the mean squared differences of successive R-R intervals (rMSSD) (43 vs. 30 ms, p = 0.005) after adjusting for confounders. In addition, the ratio low/high frequency (LF/HF) increased between the 2nd and 3rd tertile (2.3 vs. 3.0, p = 0.04). Among adults, the standard deviation of R-R intervals (SDNN) tended to decrease between the 1st and 2nd tertile (84 vs. 75 ms, p = 0.069) after adjusting for confounders. Furthermore, diastolic BP tended to increase between the 2nd and 3rd tertile (86 vs. 91 mm Hg, p = 0.09). No significant difference was observed in resting HR or pulse pressure (PP)

Conclusions

Mercury was associated with decreased HRV among French Polynesian teenagers while no significant association was observed with resting HR, BP, or PP among teenagers or adults
SOX2-RNAi attenuates S-phase entry and induces RhoA-dependent switch to protease-independent amoeboid migration in human glioma cells
Authors: Oppel Felix , Müller Nadja , Schackert Gabriele , Hendruschk Sandy , Martin Daniel , Geiger Kathrin D , Temme Achim
Published: December 2011

Background

SOX2, a high mobility group (HMG)-box containing transcription factor, is a key regulator during development of the nervous system and a persistent marker of neural stem cells. Recent studies suggested a role of SOX2 in tumor progression. In our previous work we detected SOX2 in glioma cells and glioblastoma specimens. Herein, we aim to explore the role of SOX2 for glioma malignancy in particular its role in cell proliferation and migration.

Methods

Retroviral shRNA-vectors were utilized to stably knockdown SOX2 in U343-MG and U373-MG cells. The resulting phenotype was investigated by Western blot, migration/invasion assays, RhoA G-LISA, time lapse video imaging, and orthotopic xenograft experiments.

Results

SOX2 depletion results in pleiotropic effects including attenuated cell proliferation caused by decreased levels of cyclinD1. Also an increased TCF/LEF-signaling and concomitant decrease in Oct4 and Nestin expression was noted. Furthermore, down-regulation of focal adhesion kinase (FAK) signaling and of downstream proteins such as HEF1/NEDD9, matrix metalloproteinases pro-MMP-1 and -2 impaired invasive proteolysis-dependent migration. Yet, cells with knockdown of SOX2 switched to a RhoA-dependent amoeboid-like migration mode which could be blocked by the ROCK inhibitor Y27632 downstream of RhoA-signaling. Orthotopic xenograft experiments revealed a higher tumorigenicity of U343-MG glioma cells transduced with shRNA targeting SOX2 which was characterized by increased dissemination of glioma cells.

Conclusion

Our findings suggest that SOX2 plays a role in the maintenance of a less differentiated glioma cell phenotype. In addition, the results indicate a critical role of SOX2 in adhesion and migration of malignant gliomas.
National and subnational mortality effects of metabolic risk factors and smoking in Iran: a comparative risk assessment
Authors: Farzadfar Farshad , Danaei Goodarz , Namdaritabar Hengameh , Rajaratnam Julie Knoll , Marcus Jacob R , Khosravi Ardeshir , Alikhani Siamak , Murray Christopher JL , Ezzati Majid
Published: December 2011

Background

Mortality from cardiovascular and other chronic diseases has increased in Iran. Our aim was to estimate the effects of smoking and high systolic blood pressure (SBP), fasting plasma glucose (FPG), total cholesterol (TC), and high body mass index (BMI) on mortality and life expectancy, nationally and subnationally, using representative data and comparable methods.

Methods

We used data from the Non-Communicable Disease Surveillance Survey to estimate means and standard deviations for the metabolic risk factors, nationally and by region. Lung cancer mortality was used to measure cumulative exposure to smoking. We used data from the death registration system to estimate age-, sex-, and disease-specific numbers of deaths in 2005, adjusted for incompleteness using demographic methods. We used systematic reviews and meta-analyses of epidemiologic studies to obtain the effect of risk factors on disease-specific mortality. We estimated deaths and life expectancy loss attributable to risk factors using the comparative risk assessment framework.

Results

In 2005, high SBP was responsible for 41,000 (95% uncertainty interval: 38,000, 44,000) deaths in men and 39,000 (36,000, 42,000) deaths in women in Iran. High FPG, BMI, and TC were responsible for about one-third to one-half of deaths attributable to SBP in men and/or women. Smoking was responsible for 9,000 deaths among men and 2,000 among women. If SBP were reduced to optimal levels, life expectancy at birth would increase by 3.2 years (2.6, 3.9) and 4.1 years (3.2, 4.9) in men and women, respectively; the life expectancy gains ranged from 1.1 to 1.8 years for TC, BMI, and FPG. SBP was also responsible for the largest number of deaths in every region, with age-standardized attributable mortality ranging from 257 to 333 deaths per 100,000 adults in different regions.

Discussion

Management of blood pressure through diet, lifestyle, and pharmacological interventions should be a priority in Iran. Interventions for other metabolic risk factors and smoking can also improve population health.
MicroRNA modulation in complex regional pain syndrome
Authors: Orlova Irina A , Alexander Guillermo M , Qureshi Rehman A , Sacan Ahmet , Graziano Alessandro , Barrett James E , Schwartzman Robert J , Ajit Seena K
Published: December 2011

Background

Aberrant expression of small noncoding RNAs called microRNAs (miRNAs) is a common feature of several human diseases. The objective of the study was to identify miRNA modulation in patients with complex regional pain syndrome (CRPS) a chronic pain condition resulting from dysfunction in the central and/or peripheral nervous systems. Due to a multitude of inciting pathologies, symptoms and treatment conditions, the CRPS patient population is very heterogeneous. Our goal was to identify differentially expressed miRNAs in blood and explore their utility in patient stratification.

Methods

We profiled miRNAs in whole blood from 41 patients with CRPS and 20 controls using TaqMan low density array cards. Since neurogenic inflammation is known to play a significant role in CRPS we measured inflammatory markers including chemokines, cytokines, and their soluble receptors in blood from the same individuals. Correlation analyses were performed for miRNAs, inflammatory markers and other parameters including disease symptoms, medication, and comorbid conditions.

Results

Three different groups emerged from miRNA profiling. One group was comprised of 60% of CRPS patients and contained no control subjects. miRNA profiles from the remaining patients were interspersed among control samples in the other two groups. We identified differential expression of 18 miRNAs in CRPS patients. Analysis of inflammatory markers showed that vascular endothelial growth factor (VEGF), interleukin1 receptor antagonist (IL1Ra) and monocyte chemotactic protein-1 (MCP1) were significantly elevated in CRPS patients. VEGF and IL1Ra showed significant correlation with the patients reported pain levels. Analysis of the patients who were clustered according to their miRNA profile revealed correlations that were not significant in the total patient population. Correlation analysis of miRNAs detected in blood with additional parameters identified miRNAs associated with comorbidities such as headache, thyroid disorder and use of narcotics and antiepileptic drugs.

Conclusions

miRNA profiles can be useful in patient stratification and have utility as potential biomarkers for pain. Differentially expressed miRNAs can provide molecular insights into gene regulation and could lead to new therapeutic intervention strategies for CRPS.
Astrocyte elevated gene-1 (AEG-1) is a marker for aggressive salivary gland carcinoma
Authors: Liao Wen-Ting , Guo Ling , Zhong Yi , Wu Yan-Heng , Li Jun , Song Li-Bing
Published: December 2011

Background

Astrocyte elevated gene-1 (AEG-1) is associated with tumorigenesis and progression in diverse human cancers. The present study was aimed to investigate the clinical and prognostic significance of AEG-1 in salivary gland carcinomas (SGC).

Methods

Real-time PCR and western blot analyses were employed to examine AEG-1 expression in two normal salivary gland tissues, eight SGC tissues of various clinical stages, and five pairs of primary SGC and adjacent salivary gland tissues from the same patient. Immunohistochemistry (IHC) was performed to examine AEG-1 protein expression in paraffin-embedded tissues from 141 SGC patients. Statistical analyses was applies to evaluate the diagnostic value and associations of AEG-1 expression with clinical parameters.

Results

AEG-1 expression was evidently up-regulated in SGC tissues compared with that in the normal salivary gland tissues and in matched adjacent salivary gland tissues. AEG-1 protein level was positively correlated with clinical stage (P < 0.001), T classification (P = 0.008), N classification (P = 0.008) and M classifications (P = 0.006). Patients with higher AEG-1 expression had shorter overall survival time, whereas those with lower tumor AEG-1 expression had longer survival time.

Conclusions

Our results suggest that AEG-1 expression is associated with SGC progression and may represent a novel and valuable predictor for prognostic evaluation of SGC patients.
Tight performance bounds for two-way opportunistic amplify-and-forward wireless relaying networks with TDBC protocols
Authors: Jia Xiangdong , Yang Longxiang , Fu Haiyang
Published: December 2011

Based on amplify-and-forward network coding (AFNC) protocol, the outage probability and ergodic capacity of two-way network coding opportunistic relaying (TWOR-AFNC) systems are investigated as well as the corresponding closed-form solutions. For the TWOR-AFNC systems, it is investigated under two scenarios, namely, the TWOR-AFNC systems without direct link (TWOR-AFNC-Nodir) and the TWOR-AFNC systems with direct link (TWOR-AFNC-Dir). First, we investigate TWOR-AFNC-Nodir systems by employing the approximate analysis in high SNR, and obtain closed-form solutions to the cumulative distribution function (CDF) and the probability density function (PDF) of the instantaneous end-to-end signal-to-noise ratio (SNR) with very simple expressions. The derived simple expressions are given by defining an equivalent variable ω

eq-k
(θ), 2 ≤ θ ≤ 3. When θ = 2, the derived results are the tight lower bounds to CDF and PDF. The sequent simulation demonstrates that the derived tight lower bounds are also very effective over the entire SNR region though which the results are derived in high SNR approximation. Then, with the derived tight closed-form lower bound solutions (θ = 2) in TWOR-AFNC-Nodir systems, we investigate TWOR-AFNC-Dir systems as well as the overall comparison of the outage probability and the ergodic capacity between the two system models. The comparison analysis performed over path loss model basis shows that, in urban environment, due to utilizing the direct link the TWOR-AFNC-Dir outperform considerably the TWOR-AF-Nodir systems. However, when the value of path loss exponent is relatively large, the achievable gain is very small and the direct link can be omitted. In this case, the TWOR-AFNC-Dir model can be displaced by TWOR-AFNC-Nodir model having lower implementation complexity.
Non-pharmacological, multicomponent group therapy in patients with degenerative dementia: a 12-month randomized, controlled trial
Authors: Graessel Elmar , Stemmer Renate , Eichenseer Birgit , Pickel Sabine , Donath Carolin , Kornhuber Johannes , Luttenberger Katharina
Published: December 2011

Background

Currently available pharmacological and non-pharmacological treatments have shown only modest effects in slowing the progression of dementia. Our objective was to assess the impact of a long-term non-pharmacological group intervention on cognitive function in dementia patients and on their ability to carry out activities of daily living compared to a control group receiving the usual care.

Methods

A randomized, controlled, single-blind longitudinal trial was conducted with 98 patients (follow-up: n = 61) with primary degenerative dementia in five nursing homes in Bavaria, Germany. The highly standardized intervention consisted of motor stimulation, practice in activities of daily living, and cognitive stimulation (acronym MAKS). It was conducted in groups of ten patients led by two therapists for 2 hours, 6 days a week for 12 months. Control patients received treatment as usual. Cognitive function was assessed using the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog), and the ability to carry out activities of daily living using the Erlangen Test of Activities of Daily Living (E-ADL test) at baseline and after 12 months.

Results

Of the 553 individuals screened, 119 (21.5%) were eligible and 98 (17.7%) were ultimately included in the study. At 12 months, the results of the per protocol analysis (n = 61) showed that cognitive function and the ability to carry out activities of daily living had remained stable in the intervention group but had decreased in the control patients (ADAS-Cog: adjusted mean difference: -7.7, 95% CI -14.0 to -1.4, P = 0.018, Cohen's d = 0.45; E-ADL test: adjusted mean difference: 3.6, 95% CI 0.7 to 6.4, P = 0.015, Cohen's d = 0.50). The effect sizes for the intervention were greater in the subgroup of patients (n = 50) with mild to moderate disease (ADAS-Cog: Cohen's d = 0.67; E-ADL test: Cohen's d = 0.69).

Conclusions

A highly standardized, non-pharmacological, multicomponent group intervention conducted in a nursing-home setting was able to postpone a decline in cognitive function in dementia patients and in their ability to carry out activities of daily living for at least 12 months.

Trial Registration

http://www.isrctn.com Identifier: ISRCTN87391496