bluuebunny/crossref_metadata_2025 huggingface dataset:
Physicians’ attitudes towards office-based delivery of methadone maintenance therapy: results from a cross-sectional survey of Nova Scotia primary-care physicians
Authors: Dooley Jessica , Asbridge Mark , Fraser John , Kirkland Susan
Published: June 2012

Background

Approximately 90,000 Canadians use opioids each year, many of whom experience health and social problems that affect the individual user, families, communities and the health care system. For those who wish to reduce or stop their opioid use, methadone maintenance therapy (MMT) is effective and supporting evidence is well-documented. However, access and availability to MMT is often inconsistent, with greater inequity outside of urban settings. Involving community based primary-care physicians in the delivery of MMT could serve to expand capacity and accessibility of MMT programs. Little is known, however, about the extent to which MMT, particularly office-based delivery, is acceptable to physicians. The aim of this study is to survey physicians about their attitudes towards MMT, particularly office-based delivery, and the perceived barriers and facilitators to MMT delivery.

Methods

In May 2008, facilitated by the College of Physicians and Surgeons of Nova Scotia, a cross-sectional, e-mail survey of 950 primary-care physicians practicing in Nova Scotia, Canada was administered via the OPINIO on-line survey software, to assess the acceptability of office-based MMT. Logistic regressions, adjusted for physician sociodemographic characteristics, were used to examine the association between physicians’ willingness to participate in office-based MMT, and a series of measures capturing physician attitudes and knowledge about treatment approaches, opioid use, and methadone, as well as perceived barriers to MMT.

Results

Overall, 19.8% of primary-care physicians responded to the survey, with 56% who indicated that they would be willing to be involved in MMT under current or similar circumstances; however, willingness was associated with numerous attitudinal and systemic factors. The barriers to involvement in MMT that were frequently cited included a lack of training or experience in MMT, lack of support services, and potential challenges of working with an MMT patient population.

Conclusions

Study findings provide valuable information to help facilitate greater involvement of primary-care physicians in MMT, while highlighting concerns around administration, support, and training. Even limited uptake by primary-care physicians would greatly enhance MMT access in Nova Scotia, particularly for methadone clients located in rural communities. These findings are applicable broadly, to any jurisdictions where office-based MMT is not currently available.
An acidic oligopeptide displayed on AAV2 improves axial muscle tropism after systemic delivery
Authors: Lee Ni-Chung , Falk Darin J , Byrne Barry J , Conlon Thomas J , Clement Nathalie , Porvasnik Stacy , Jorgensen Marda L , Potter Mark , Erger Kirsten E , Watson Rachael , Ghivizzani Steven C , Chiu Hung-Chuan , Chien Yin-Hsiu , Hwu Wuh-Liang
Published: June 2012

Background

The appropriate tropism of adeno-associated virus (AAV) vectors that are systemically injected is crucial for successful gene therapy when local injection is not practical. Acidic oligopeptides have been shown to enhance drug delivery to bones.

Methods

In this study six-L aspartic acids (D6) were inserted into the AAV2 capsid protein sequence between amino acid residues 587 and 588. 129SVE mice were injected with double-stranded wild-type- (WT-) or D6-AAV2 mCherry expression vectors (3.24 x 1010 vg per animal) via the superficial temporal vein within 24 hours of birth.

Results

Fluorescence microscopy and quantitative polymerase chain reaction confirmed higher levels of mCherry expression in the paraspinal and gluteus muscles in the D6-AAV2 injected mice. The results revealed that although D6-AAV2 was less efficient in the transduction of immortalized cells stronger mCherry signals were detected over the spine and pelvis by live imaging in the D6-AAV2-injected mice than were detected in the WT-AAV2-injected mice. In addition, D6-AAV2 lost the liver tropism observed for WT-AAV2.

Conclusions

An acidic oligopeptide displayed on AAV2 improves axial muscle tropism and decreases liver tropism after systemic delivery. This modification should be useful in creating AAV vectors that are suitable for gene therapy for diseases involving the proximal muscles.
Genomic characterization of explant tumorgraft models derived from fresh patient tumor tissue
Authors: Monsma David J , Monks Noel R , Cherba David M , Dylewski Dawna , Eugster Emily , Jahn Hailey , Srikanth Sujata , Scott Stephanie B , Richardson Patrick J , Everts Robin E , Ishkin Aleksandr , Nikolsky Yuri , Resau James H , Sigler Robert , Nickoloff Brian J , Webb Craig P
Published: June 2012

Background

There is resurgence within drug and biomarker development communities for the use of primary tumorgraft models as improved predictors of patient tumor response to novel therapeutic strategies. Despite perceived advantages over cell line derived xenograft models, there is limited data comparing the genotype and phenotype of tumorgrafts to the donor patient tumor, limiting the determination of molecular relevance of the tumorgraft model. This report directly compares the genomic characteristics of patient tumors and the derived tumorgraft models, including gene expression, and oncogenic mutation status.

Methods

Fresh tumor tissues from 182 cancer patients were implanted subcutaneously into immune-compromised mice for the development of primary patient tumorgraft models. Histological assessment was performed on both patient tumors and the resulting tumorgraft models. Somatic mutations in key oncogenes and gene expression levels of resulting tumorgrafts were compared to the matched patient tumors using the OncoCarta (Sequenom, San Diego, CA) and human gene microarray (Affymetrix, Santa Clara, CA) platforms respectively. The genomic stability of the established tumorgrafts was assessed across serialin vivogenerations in a representative subset of models. The genomes of patient tumors that formed tumorgrafts were compared to those that did not to identify the possible molecular basis to successful engraftment or rejection.

Results

Fresh tumor tissues from 182 cancer patients were implanted into immune-compromised mice with forty-nine tumorgraft models that have been successfully established, exhibiting strong histological and genomic fidelity to the originating patient tumors. Comparison of the transcriptomes and oncogenic mutations between the tumorgrafts and the matched patient tumors were found to be stable across four tumorgraft generations. Not only did the various tumors retain the differentiation pattern, but supporting stromal elements were preserved. Those genes down-regulated specifically in tumorgrafts were enriched in biological pathways involved in host immune response, consistent with the immune deficiency status of the host. Patient tumors that successfully formed tumorgrafts were enriched for cell signaling, cell cycle, and cytoskeleton pathways and exhibited evidence of reduced immunogenicity.

Conclusions

The preservation of the patient’s tumor genomic profile and tumor microenvironment supports the view that primary patient tumorgrafts provide a relevant model to support the translation of new therapeutic strategies and personalized medicine approaches in oncology.
Overexpression of ribosome binding protein 1 (RRBP1) in breast cancer
Authors: Telikicherla Deepthi , Marimuthu Arivusudar , Kashyap Manoj Kumar , Ramachandra Y L , Mohan Sujatha , Roa Juan Carlos , Maharudraiah Jagadeesha , Pandey Akhilesh
Published: June 2012

The molecular events that lead to malignant transformation and subsequent metastasis of breast carcinoma include alterations in the cells at genome, transcriptome and proteome levels. In this study, we used publicly available gene expression databases to identify those candidate genes which are upregulated at the mRNA level in breast cancers but have not been systematically validated at the protein level. Based on an extensive literature search, we identified ribosome binding protein 1 (RRBP1) as a candidate that is upregulated at the mRNA level in five different studies but its protein expression had not been investigated. Immunohistochemical labeling of breast cancer tissue microarrays was carried out to determine the expression of RRBP1 in a large panel of breast cancers. We found that RRBP1 was overexpressed in 84% (177/219) of breast carcinoma cases tested. The subcellular localization of RRBP1 was mainly observed to be in the cytoplasm with intense staining in the perinuclear region. Our findings suggest that RRBP1 is an interesting molecule that can be further studied for its potential to serve as a breast cancer biomarker. This study also demonstrates how the integration of biological data from available resources in conjunction with systematic evaluation approaches can be successfully applied to clinical proteomics.
Stability and superstability of generalized quadratic ternary derivations on non-Archimedean ternary Banach algebras: a fixed point approach
Authors: Park Choonkil , Gordji Madjid Eshaghi , Cho Yeol Je
Published: June 2012

Using fixed point method, we prove the Hyers-Ulam stability and the superstability of generalized quadratic ternary derivations on non-Archimedean ternary Banach algebras. Indeed, we investigate the Hyers-Ulam stability and the superstability of the system of functional equations

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Mathematics Subject Classification 2010: Primary 39B52; 47H10; 39B72; 46L57; 17B40; 13N15; 17A40; 20N10.
HIV-1 Tat C-mediated regulation of tumor necrosis factor receptor-associated factor-3 by microRNA 32 in human microglia
Authors: Mishra Ritu , Chhatbar Chintan , Singh Sunit Kumar
Published: June 2012

Background

HIV-1 Tat protein is known to be associated with neuroinflammation, a condition that develops in almost half of patients infected with HIV-1. HIV-1 Tat can alter glial neuroprotective functions, leading to neurotoxicity within the CNS. HIV-1 Tat is known to be secreted from productively infected cells and can affect neighboring uninfected cells by modulating cellular gene expression in a bystander fashion.

Methods

We were interested to study whether exogenous exposure to HIV-1 Tat-C protein perturbs the microRNA (miRNA) expression profile of human microglial cells, leading to altered protein expression. We used protein expression and purification, miRNA overexpression, miRNA knockdown, transfection, site-directed mutagenesis, real-time PCR, luciferase assay and western blotting techniques to perform our study.

Results

HIV-1 Tat-C treatment of human microglial cells resulted in a dose-dependent increase in miR-32 expression. We found that tumor necrosis factor-receptor–associated factor 3 TRAF3) is a direct target for miR-32, and overexpression of miR-32 in CHME3 cells decreased TRAF3 both at the mRNA and the protein level. Recovery of TRAF3 protein expression after transfection of anti-miR-32 and the results of the luciferase reporter assay provided direct evidence of TRAF3 regulation by miR-32. We found that the regulation of interferon regulatory factor 3 (IRF3) and IRF7 is controlled by cellular levels of TRAF3 protein in microglial cells, as after overexpression of miR-32 and application of anti-miR-32, expression levels of IRF3 and IRF7 were inversely regulated by expression levels of TRAF3. Thus, our results suggest a novel miRNA mediated mechanism for regulation of TRAF3 in human microglial cells exposed to HIV-1 Tat C protein. These results may help to elucidate the detrimental neuroinflammatory consequences of HIV-1 Tat C protein in bystander fashion.

Conclusion

HIV-1 Tat protein can modulate TRAF3 expression through miRNA mediated pathway and can change the downstream expression of IRF3 and IRF7. This study demonstrates a novel mechanism of HIV-1 Tat C protein-mediated perturbation of miRNA, resulting in dysregulation of cellular TRAF3.
Recovery of information from multiple imputation: a simulation study
Authors: Lee Katherine J , Carlin John B
Published: June 2012

Background

Multiple imputation is becoming increasingly popular for handling missing data. However, it is often implemented without adequate consideration of whether it offers any advantage over complete case analysis for the research question of interest, or whether potential gains may be offset by bias from a poorly fitting imputation model, particularly as the amount of missing data increases.

Methods

Simulated datasets (n = 1000) drawn from a synthetic population were used to explore information recovery from multiple imputation in estimating the coefficient of a binary exposure variable when various proportions of data (10-90%) were set missing at random in a highly-skewed continuous covariate or in the binary exposure. Imputation was performed using multivariate normal imputation (MVNI), with a simple or zero-skewness log transformation to manage non-normality. Bias, precision, mean-squared error and coverage for a set of regression parameter estimates were compared between multiple imputation and complete case analyses.

Results

For missingness in the continuous covariate, multiple imputation produced less bias and greater precision for the effect of the binary exposure variable, compared with complete case analysis, with larger gains in precision with more missing data. However, even with only moderate missingness, large bias and substantial under-coverage were apparent in estimating the continuous covariate’s effect when skewness was not adequately addressed. For missingness in the binary covariate, all estimates had negligible bias but gains in precision from multiple imputation were minimal, particularly for the coefficient of the binary exposure.

Conclusions

Although multiple imputation can be useful if covariates required for confounding adjustment are missing, benefits are likely to be minimal when data are missing in the exposure variable of interest. Furthermore, when there are large amounts of missingness, multiple imputation can become unreliable and introduce bias not present in a complete case analysis if the imputation model is not appropriate. Epidemiologists dealing with missing data should keep in mind the potential limitations as well as the potential benefits of multiple imputation. Further work is needed to provide clearer guidelines on effective application of this method.
Prediction and identification of mouse cytotoxic T lymphocyte epitopes in Ebola virus glycoproteins
Authors: Wu Shipo , Yu Ting , Song Xiaohong , Yi Shaoqiong , Hou Lihua , Chen Wei
Published: June 2012

Background

Ebola viruses (EBOVs) cause severe hemorrhagic fever with a high mortality rate. At present, there are no licensed vaccines or efficient therapies to combat EBOV infection. Previous studies have shown that both humoral and cellular immune responses are crucial for controlling Ebola infection. CD8+ T cells play an important role in mediating vaccine-induced protective immunity. The objective of this study was to identify H-2d-specific T cell epitopes in EBOV glycoproteins (GPs).

Results

Computer-assisted algorithms were used to predict H-2d-specific T cell epitopes in two species of EBOV (Sudan and Zaire) GP. The predicted peptides were synthesized and identified in BALB/c mice immunized with replication-deficient adenovirus vectors expressing the EBOV GP. Enzyme-linked immunospot assays and intracellular cytokine staining showed that the peptides RPHTPQFLF (Sudan EBOV), GPCAGDFAF and LYDRLASTV (Zaire EBOV) could stimulate splenoctyes in immunized mice to produce large amounts of interferon-gamma.

Conclusion

Three peptides within the GPs of two EBOV strains were identified as T cell epitopes. The identification of these epitopes should facilitate the evaluation of vaccines based on the Ebola virus glycoprotein in a BALB/c mouse model.
Rescue of virulent class I Newcastle disease virus variant 9a5b-D5C1
Authors: Yu Yang , Qiu Xusheng , Xu Dan , Zhan Yuan , Meng Chunchun , Wei Nana , Chen Hongjun , Tan Lei , Yu Shengqing , Liu Xiufan , Qin Aijian , Ding Chan
Published: June 2012

Background

The virulent class I Newcastle disease virus (NDV) variant 9a5b was generated from a nonvirulent NDV isolate Goose/Alaska/415/91 via nine consecutive passages in the chicken air sac, followed by five passages in the chick brain. The evolutionary mechanism of virulence in the class I NDV isolate is not fully understood. To elucidate this evolutionary mechanism, a reverse genetics manipulation specific for class I NDV is indispensable.

Results

A full-length cDNA clone of 9a5b and the helper plasmids pCI-NP, pCI-P, and pCI-L were constructed from segments of cDNA. After these plasmids were co-transfected into BSR T7/5 cells, infectious viral particles were obtained. The rescued viruses were genetically and biologically identical to the parental strain and showed similar pathogenicity in chickens.

Conclusion

A stable recovery method for class I NDV was established. Reverse genetics of the class I NDV variant 9a5b allowed for the generation of genetically altered and virulent NDV, and can be used as a foundation for research on the evolution of virulence in class I NDV isolates.
Effects of Peripheral Inflammation on the Blood-Spinal Cord Barrier
Authors: Xanthos Dimitris N , Püngel Isabella , Wunderbaldinger Gabriele , Sandkühler Jürgen
Published: June 2012

Background:

Changes in the blood-central nervous system barriers occur under pathological conditions including inflammation and contribute to central manifestations of various diseases. After short-lasting peripheral and neurogenic inflammation, the evidence is mixed whether there are consistent blood-spinal cord changes. In the current study, we examine changes in the blood-spinal cord barrier after intraplantar capsaicin and λ-carrageenan using several methods: changes in occludin protein, immunoglobulin G accumulation, and fluorescent dye penetration. We also examine potential sex differences in male and female adult rats.

Results:

After peripheral carrageenan inflammation, but not capsaicin inflammation, immunohistochemistry shows occludin protein in lumbar spinal cord to be significantly altered at 72 hours post-injection. In addition, there is also significant immunoglobulin G detected in lumbar and thoracic spinal cord at this timepoint in both male and female rats. However, acute administration of sodium fluorescein or Evans Blue dyes is not detected in the parenchyma at this timepoint.

Conclusions:

Our results show that carrageenan inflammation induces changes in tight junction protein and immunoglobulin G accumulation, but these may not be indicative of a blood-spinal cord barrier breakdown. These changes appear transiently after peak nociception and may be indicative of reversible pathology that resolves together with inflammation.
Developed-developing country partnerships: Benefits to developed countries?
Authors: Syed Shamsuzzoha B , Dadwal Viva , Rutter Paul , Storr Julie , Hightower Joyce D , Gooden Rachel , Carlet Jean , Nejad Sepideh Bagheri , Kelley Edward T , Donaldson Liam , Pittet Didier
Published: June 2012

Developing countries can generate effective solutions for today’s global health challenges. This paper reviews relevant literature to construct the case for international cooperation, and in particular, developed-developing country partnerships. Standard database and web-based searches were conducted for publications in English between 1990 and 2010. Studies containing full or partial data relating to international cooperation between developed and developing countries were retained for further analysis. Of 227 articles retained through initial screening, 65 were included in the final analysis. The results were two-fold: some articles pointed to intangible benefits accrued by developed country partners, but the majority of information pointed to developing country innovations that can potentially inform health systems in developed countries. This information spanned all six WHO health system components. Ten key health areas where developed countries have the most to learn from the developing world were identified and include, rural health service delivery; skills substitution; decentralisation of management; creative problem-solving; education in communicable disease control; innovation in mobile phone use; low technology simulation training; local product manufacture; health financing; and social entrepreneurship. While there are no guarantees that innovations from developing country experiences can effectively transfer to developed countries, combined developed-developing country learning processes can potentially generate effective solutions for global health systems. However, the global pool of knowledge in this area is virgin and further work needs to be undertaken to advance understanding of health innovation diffusion. Even more urgently, a standardized method for reporting partnership benefits is needed—this is perhaps the single most immediate need in planning for, and realizing, the full potential of international cooperation between developed and developing countries.
Prediction of pathological and oncological outcomes based on extended prostate biopsy results in patients with prostate cancer receiving radical prostatectomy: a single institution study
Authors: Ishizaki Fumio , Hara Noboru , Koike Hiroshi , Kawaguchi Makoto , Tadokoro Akira , Takizawa Itsuhiro , Nishiyama Tsutomu , Takahashi Kota , Hohenfellner Rudolf
Published: June 2012

Background

The prediction of pathological outcomes prior to surgery remains a challenging problem for the appropriate surgical indication of prostate cancer. This study was performed to identify preoperative values predictive of pathological and oncological outcomes based on standardized extended prostate biopsies with core histological results diagrammed/mapped in patients receiving radical prostatectomy for prostate cancer clinically diagnosed as localized or locally advanced disease.

Methods

In 124 patients with clinically localized or locally advanced prostate cancer (cT1c–cT3a) without prior treatment, pathological outcomes on the surgical specimen including seminal vesicle involvement (SVI), positive surgical margin (PSM), and perineural invasion (PNI) were studied in comparison with clinical parameters based on the results of 14-core prostate biopsies comprising sextant, laterally-directed sextant, and bilateral transition zone (TZ) sampling.

Results

Concerning the association of pathological outcomes with oncological outcomes, patients with PSM and PNI on surgical specimens had poorer biochemical-progression-free survival than those without PSM (logrank p = 0.002) and PNI (p = 0.003); it was also poorer concerning SVI, although the difference was not significant (p = 0.120). Concerning the impact of clinical parameters on these pathological outcomes, positive TZ and multiple positive biopsy cores in the prostatic middle were independent values predictive of SVI with multivariate analyses (p = 0.020 and p = 0.025, respectively); both positive TZ and multiple positive prostatic middle biopsies were associated with larger tumor volume (p < 0.001 in both). The percentage of positive biopsy cores (%positive cores) and biopsy Gleason score were independent values predictive of PSM (p = 0.001) and PNI (p = 0.001), respectively. Multiple positive cores in the prostatic base were associated with proximal/bladder-side PSM (p < 0.001), and also linked to poorer biochemical-progression-free survival (p = 0.004). Clinical T stage had no association with these pathological outcomes.

Conclusions

%positive cores and Gleason score in extended biopsies were independent values predictive of PSM and PNI in prostate cancer clinically diagnosed as localized or locally advanced disease, respectively, which were associated with poorer oncological outcomes. When diagramming biopsy-core results, extended biopsy may provide additional information for predicting oncological and pathological outcomes including SVI in patients clinically diagnosed as having localized or locally advanced disease.

Virtual slides

The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/8790262771042628
A serological and bacteriological survey of brucellosis in wild boar (Sus scrofa) in Belgium
Authors: Grégoire Fabien , Mousset Bénédicte , Hanrez David , Michaux Charles , Walravens Karl , Linden Annick
Published: June 2012

Background

Brucellosis is frequently reported among wild boar populations in Europe. The aim of the study was to assess the epidemiological situation in Belgium, regarding the steady increase of wild boar populations over the last decades. Several serological tests were used and compared with culture and IS711 polymerase chain reaction (PCR), to determine the most suitable combination of diagnostic tools for conducting a successful prevalence study in wildlife.

Results

An indirect enzyme-linked immunosorbent assay (iELISA) was used on 1168 sera from hunter-killed wild boar sampled between 2003 and 2007 in 4 natural regions of southern Belgium. Results gave an apparent prevalence of 54.88% (95% CI 52.03-57.73). Prevalence was significantly affected by age and by the year of study, but not by sex nor by the region of sampling. The relative sensitivities of the complement fixation test (CFT), the Rose Bengal test (RBT), and the slow agglutination test (SAT) versus the iELISA differed widely between tests, reaching 62.67%, 46.68%, and 34.77%, respectively. The relative specificities of the CFT, RBT and SAT versus the iELISA were respectively 99.01%, 92.49%, and 99.1%. From seropositive animals (iELISA), 9% were positive by culture and 24% by PCR when testing spleen and/or tonsils. Sensitivity of the PCR was higher on tonsils than on spleen. All bacterial isolates were identified as Brucella suis biovar 2.

Conclusions

Brucellosis is widespread among wild boar in southern Belgium, with seroprevalences having increased over ten years, and constitutes a growing risk of spillback to outdoor-farmed pig herds. The iELISA showed a better sensitivity than the CFT, RBT and SAT. Serological tests must be associated with direct diagnosis and PCR proved more sensitive than culture under wildlife sampling conditions. Spleen and tonsils are lymphoid tissues usually sampled in multi-disease monitoring programs. They remain top-grade organs for direct diagnosis of brucellosis, with a preference for tonsils.
A seroepidemiologic study of Reston ebolavirus in swine in the Philippines
Authors: Sayama Yusuke , Demetria Catalino , Saito Mariko , Azul Rachel R , Taniguchi Satoshi , Fukushi Shuetsu , Yoshikawa Tomoki , Iizuka Itoe , Mizutani Tetsuya , Kurane Ichiro , Malbas Fidelino F , Lupisan Socorro , Catbagan Davinio P , Animas Samuel B , Morales Rieldrin G , Lopez Emelinda L , Dazo Karen Rose C , Cruz Magdalena S , Olveda Remigio , Saijo Masayuki , Oshitani Hitoshi , Morikawa Shigeru
Published: June 2012

Background

Ebola viruses cause viral hemorrhagic fever in humans and non-human primates and are endemic in Africa. Reston ebolavirus (REBOV) has caused several epizootics in cynomolgus monkeys (Macaca fascicularis) but is not associated with any human disease. In late 2008, REBOV infections were identified in swine for the first time in the Philippines.

Methods

A total of 215 swine sera collected at two REBOV-affected farms in 2008, in Pangasinan and Bulacan, were tested for the presence of REBOV-specific antibodies using multiple serodiagnosis systems. A total of 98 swine sera collected in a non-epizootic region, Tarlac, were also tested to clarify the prevalence of REBOV infection in the general swine population in the Philippines.

Results

Some 70 % of swine sera at the affected farms were positive for REBOV antibodies in the multiple serodiagnosis systems. On the other hand, none of the swine sera collected in Tarlac showed positive reactions in any of the diagnosis systems.

Conclusions

The high prevalence of REBOV infection in swine in the affected farms in 2008 suggests that swine is susceptible for REBOV infection. The multiple serological assays used in the study are thought to be useful for future surveillance of REOBV infection in swine in the Philippines.
A simple theoretical framework for understanding heterogeneous differentiation of CD4+ T cells
Authors: Hong Tian , Xing Jianhua , Li Liwu , Tyson John J
Published: June 2012

Background

CD4+ T cells have several subsets of functional phenotypes, which play critical yet diverse roles in the immune system. Pathogen-driven differentiation of these subsets of cells is often heterogeneous in terms of the induced phenotypic diversity. In vitro recapitulation of heterogeneous differentiation under homogeneous experimental conditions indicates some highly regulated mechanisms by which multiple phenotypes of CD4+ T cells can be generated from a single population of naïve CD4+ T cells. Therefore, conceptual understanding of induced heterogeneous differentiation will shed light on the mechanisms controlling the response of populations of CD4+ T cells under physiological conditions.

Results

We present a simple theoretical framework to show how heterogeneous differentiation in a two-master-regulator paradigm can be governed by a signaling network motif common to all subsets of CD4+ T cells. With this motif, a population of naïve CD4+ T cells can integrate the signals from their environment to generate a functionally diverse population with robust commitment of individual cells. Notably, two positive feedback loops in this network motif govern three bistable switches, which in turn, give rise to three types of heterogeneous differentiated states, depending upon particular combinations of input signals. We provide three prototype models illustrating how to use this framework to explain experimental observations and make specific testable predictions.

Conclusions

The process in which several types of T helper cells are generated simultaneously to mount complex immune responses upon pathogenic challenges can be highly regulated, and a simple signaling network motif can be responsible for generating all possible types of heterogeneous populations with respect to a pair of master regulators controlling CD4+ T cell differentiation. The framework provides a mathematical basis for understanding the decision-making mechanisms of CD4+ T cells, and it can be helpful for interpreting experimental results. Mathematical models based on the framework make specific testable predictions that may improve our understanding of this differentiation system.
Incidental renal cell carcinoma presenting in a renal transplant recipient with autosomal dominant polycystic kidney disease: a case report
Authors: Misumi Toshihiro , Ide Kentaro , Onoe Takashi , Banshodani Masataka , Tazawa Hirofumi , Teraoka Yoshifumi , Hotta Ryuichi , Yamashita Masahiro , Tashiro Hirotaka , Ohdan Hideki
Published: June 2012

Introduction

We report an instructive case of incidental renal cell carcinoma in a patient with autosomal dominant polycystic kidney disease who underwent simultaneous bilateral native nephrectomy and living donor renal transplantation.

Case presentation

A 57-year-old Asian man with end-stage kidney disease due to autosomal dominant polycystic kidney disease received a living kidney graft from his brother. Because of recurrent infection, chronic pain and enlarged kidneys, he underwent a bilateral nephrectomy with concomitant renal transplantation. The total weight of the removed kidneys was 6kg; the maximal diameter of the larger kidney was 28cm. His left kidney had a 1cm diameter tumor. Pathology indicated papillary renal cell carcinoma. At the time of this report, the transplant kidney function was normal with no evidence of local recurrence or distant metastasis.

Conclusion

This case shows and reinforces the importance of considering the possibility of an occult malignancy in the native kidneys of patients with autosomal dominant polycystic kidney disease. Simultaneous bilateral native nephrectomy should be considered in these renal transplant recipients not only for preventing the development of adverse symptoms but also for detecting an occult malignancy.
Bickerstaff’s brainstem encephalitis, Miller Fisher syndrome and Guillain-Barré syndrome overlap in an asthma patient with negative anti-ganglioside antibodies
Authors: Han Chongyu , Wang Yuan , Jia Jianping , Ji Xunming , Fredrickson Vance , Ding Yuchuan , Sun Wei , Xu Jia , Sun Yong-Xin
Published: June 2012

Background

Bickerstaff’s brainstem encephalitis (BBE), together with Miller Fisher syndrome (MFS) and Guillain-Barré syndrome (GBS) were considered to form a continuous clinical spectrum. An anti-GQ1b antibody syndrome has been proposed to underlie the common pathophysiology for the three disorders; however, other studies have found a positive anti-GM1 instead of anti-GQ1b antibody.

Case presentation

Here we report a 20-year-old male patient with overlapping BBE, MFS and GBS. The patient had a positive family history of bronchial asthma and had suffered from the condition for over 15 years. He developed BBE symptoms nine days after an asthma exacerbation. During the course of illness, he had significantly elevated IgE levels in both serum and cerebrospinal fluid. Serologic analysis of antibodies against ganglioside complexes (anti-GDIa, anti-GDIb, anti-GM1, anti-GM2, anti-GM3, anti-GQIb and anti-GTIb antibodies) showed negative results.

Conclusions

Since asthma has recently been related to autoimmune disease, our case supports an autoimmune mechanism underlying the clinical spectrum composed of BBE, MFS and GBS. However, contrary to a proposed anti-GQ1b antibody syndrome, we would suggest that pathogenesis of this clinical spectrum is not limited to anti-ganglioside antibodies.
Tissue doppler echocardiography detects preclinical markers of cardiac lesion in MDS patients
Authors: de Castro Cláudio César Monteiro , Gondim Gomes Carlos Bellini , Martins Manoel Ricardo Alves , de Sousa Juliana Cordeiro , Magalhaes Silvia MM , Pinheiro Ronald F
Published: June 2012

Myelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell disorder of elderly people. Cardiac dysfunction is a marker of grim prognosis in MDS. We evaluated cardiac dysfunction of MDS patients with or without transfusion dependency by tissue doppler echocardiography. We found the average values of ventricular end-systolic and end-diastolic volumes in transfusion dependency MDS group higher than others. These results were strongly correlated to hemoglobin levels. Tissue Doppler Echocardiography should be routinely performed in MDS patients to detect preclinical cardiac alterations and prevent more heart insults in this group of chronic anemic aged patients.
RANKL synthesized by articular chondrocytes contributes to juxta-articular bone loss in chronic arthritis
Authors: Martínez-Calatrava Maria J , Prieto-Potín Ivan , Roman-Blas Jorge A , Tardio Lidia , Largo Raquel , Herrero-Beaumont Gabriel
Published: June 2012

Introduction

The receptor activator nuclear factor-kappaB ligand (RANKL) diffuses from articular cartilage to subchondral bone. However, the role of chondrocyte-synthesized RANKL in rheumatoid arthritis-associated juxta-articular bone loss has not yet been explored. This study aimed to determine whether RANKL produced by chondrocytes induces osteoclastogenesis and juxta-articular bone loss associated with chronic arthritis.

Methods

Chronic antigen-induced arthritis (AIA) was induced in New Zealand (NZ) rabbits. Osteoarthritis (OA) and control groups were simultaneously studied. Dual X-ray absorptiometry of subchondral knee bone was performed before sacrifice. Histological analysis and protein expression of RANKL and osteoprotegerin (OPG) were evaluated in joint tissues. Co-cultures of human OA articular chondrocytes with peripheral blood mononuclear cells (PBMCs) from healthy donors were stimulated with macrophage-colony stimulating factor (M-CSF) and prostaglandin E2 (PGE2), then further stained with tartrate-resistant acid phosphatase.

Results

Subchondral bone loss was confirmed in AIA rabbits when compared with controls. The expression of RANKL, OPG and RANKL/OPG ratio in cartilage were increased in AIA compared to control animals, although this pattern was not seen in synovium. Furthermore, RANKL expression and RANKL/OPG ratio were inversely related to subchondral bone mineral density. RANKL expression was observed throughout all cartilage zones of rabbits and was specially increased in the calcified cartilage of AIA animals. Co-cultures demonstrated that PGE2-stimulated human chondrocytes, which produce RANKL, also induce osteoclasts differentiation from PBMCs.

Conclusions

Chondrocyte-synthesized RANKL may contribute to the development of juxta-articular osteoporosis associated with chronic arthritis, by enhancing osteoclastogenesis. These results point out a new mechanism of bone loss in patients with rheumatoid arthritis.
Association between hospital volume and network membership and an analgesia, sedation and delirium order set quality score: a cohort study
Authors: Dale Christopher R , Hayden Shailaja J , Treggiari Miriam M , Curtis J Randall , Seymour Christopher W , Yanez N David , Fan Vincent S
Published: June 2012

Introduction

Protocols for the delivery of analgesia, sedation and delirium care of the critically ill, mechanically ventilated patient have been shown to improve outcomes but are not uniformly used. The extent to which elements of analgesia, sedation and delirium guidelines are incorporated into order sets at hospitals across a geographic area is not known. We hypothesized that both greater hospital volume and membership in a hospital network are associated with greater adherence of order sets to sedation guidelines.

Methods

Sedation order sets from all nonfederal hospitals without pediatric designation in Washington State that provided ongoing care to mechanically ventilated patients were collected and their content systematically abstracted. Hospital data were collected from Washington State sources and interviews with ICU leadership in each hospital. An expert-validated score of order set quality was created based on the 2002 four-society guidelines. Clustered multivariable linear regression was used to assess the relationship between hospital characteristics and the order set quality score.

Results

Fifty-one Washington State hospitals met the inclusion criteria and all provided order sets. Based on expert consensus, 21 elements were included in the analgesia, sedation and delirium order set quality score. Each element was equally weighted and contributed one point to the score. Hospital order set quality scores ranged from 0 to 19 (median = 8, interquartile range 6 to 14). In multivariable analysis, a greater number of acute care days (P = 0.01) and membership in a larger hospital network (P = 0.01) were independently associated with a greater quality score.

Conclusions

Hospital volume and membership in a larger hospital network were independently associated with a higher quality score for ICU analgesia, sedation and delirium order sets. Further research is needed to determine whether greater order-set quality is associated with improved outcomes in the critically ill. The development of critical care networks might be one strategy to improve order set quality scores.
Ten-year survival of cemented total knee replacement in patients aged less than 55 years
Authors: Keenan A. C. M. , Wood A. M. , Arthur C. A. , Jenkins P. J. , Brenkel I. J. , Walmsley P. J.
Published: June 2012

We report the ten-year survival of a cemented total knee replacement (TKR) in patients aged < 55 years at the time of surgery, and compare the functional outcome with that of patients aged > 55 years. The data were collected prospectively and analysed using Kaplan-Meier survival statistics, with revision for any reason, or death, as the endpoint. A total of 203 patients aged < 55 years were identified. Four had moved out of the area and were excluded, leaving a total of 221 TKRs in 199 patients for analysis (101 men and 98 women, mean age 50.6 years (28 to 55)); 171 patients had osteoarthritis and 28 had inflammatory arthritis. Four patients required revision and four died. The ten-year survival using revision as the endpoint was 98.2% (95% confidence interval 94.6 to 99.4). Based on the Oxford knee scores at five and ten years, the rate of dissatisfaction was 18% and 21%, respectively. This was no worse in the patients aged < 55 years than in patients aged > 55 years.

These results demonstrate that the cemented PFC Sigma knee has an excellent survival rate in patients aged < 55 ten years post-operatively, with clinical outcomes similar to those of an older group. We conclude that TKR should not be withheld from patients on the basis of age.
In vivomodels of bone repair
Authors: Mills L. A. , Simpson A. H. R. W.
Published: June 2012

This review is aimed at clinicians appraising preclinical trauma studies and researchers investigating compromised bone healing or novel treatments for fractures. It categorises the clinical scenarios of poor healing of fractures and attempts to match them with the appropriate animal models in the literature.

We performed an extensive literature search of animal models of long bone fracture repair/nonunion and grouped the resulting studies according to the clinical scenario they were attempting to reflect; we then scrutinised them for their reliability and accuracy in reproducing that clinical scenario.

Models for normal fracture repair (primary and secondary), delayed union, nonunion (atrophic and hypertrophic), segmental defects and fractures at risk of impaired healing were identified. Their accuracy in reflecting the clinical scenario ranged greatly and the reliability of reproducing the scenario ranged from 100% to 40%.

It is vital to know the limitations and success of each model when considering its application.
Patient expectations of arthroplasty of the hip and knee
Authors: Scott C. E. H. , Bugler K. E. , Clement N. D. , MacDonald D. , Howie C. R. , Biant L. C.
Published: June 2012

Patient expectations and their fulfilment are an important factor in determining patient-reported outcome and satisfaction of hip (THR) and knee replacement (TKR). The aim of this prospective cohort study was to examine the expectations of patients undergoing THR and TKR, and to identify differences in expectations, predictors of high expectations and the relationship between the fulfilment of expectations and patient-reported outcome measures. During the study period, patients who underwent 346 THRs and 323 TKRs completed an expectation questionnaire, Oxford score and Short-Form 12 (SF-12) score pre-operatively. At one year post-operatively, the Oxford score, SF-12, patient satisfaction and expectation fulfilment were assessed. Univariable and multivariable analysis were performed. Improvements in mobility and daytime pain were the most important expectations in both groups. Expectation level did not differ between THR and TKR. Poor Oxford score, younger age and male gender significantly predicted high pre-operative expectations (p < 0.001). The level of pre-operative expectation was not significantly associated with the fulfilment of expectations or outcome. THR better met the expectations identified as important by patients. TKR failed to meet expectations of kneeling, squatting and stair climbing. High fulfilment of expectation in both THR and TKR was significantly predicted by young age, greater improvements in Oxford score and high pre-operative mental health scores. The fulfilment of expectations was highly correlated with satisfaction.
High-energy open tibial fractures in children
Authors: Monsell F. P. , Howells N. R. , Lawniczak D. , Jeffcote B. , Mitchell S. R.
Published: June 2012

Between 2005 and 2010 ten consecutive children with high-energy open diaphyseal tibial fractures were treated by early reduction and application of a programmable circular external fixator. They were all male with a mean age of 11.5 years (5.2 to 15.4), and they were followed for a mean of 34.5 months (6 to 77). Full weight-bearing was allowed immediately post-operatively. The mean time from application to removal of the frame was 16 weeks (12 to 21). The mean deformity following removal of the frame was 0.15° (0° to 1.5°) of coronal angulation, 0.2° (0° to 2°) sagittal angulation, 1.1 mm (0 to 10) coronal translation, and 0.5 mm (0 to 2) sagittal translation. All patients achieved consolidated bony union and satisfactory wound healing. There were no cases of delayed or nonunion, compartment syndrome or neurovascular injury. Four patients had a mild superficial pin site infection; all settled with a single course of oral antibiotics. No patient had a deep infection or re-fracture following removal of the frame. The time to union was comparable with, or better than, other published methods of stabilisation for these injuries. The stable fixator configuration not only facilitates management of the accompanying soft-tissue injury but enables anatomical post-injury alignment, which is important in view of the limited remodelling potential of the tibia in children aged > ten years. Where appropriate expertise exists, we recommend this technique for the management of high-energy open tibial fractures in children.
The blood-saving effect of tranexamic acid in minimally invasive total knee replacement
Authors: Lin P-C. , Hsu C-H. , Huang C-C. , Chen W-S. , Wang J-W.
Published: June 2012

Tranexamic acid (TEA), an inhibitor of fibrinolysis, reduces blood loss after routine total knee replacement (TKR). However, controversy persists regarding the dosage and timing of administration of this drug during surgery. We performed a prospective randomised controlled study to examine the optimum blood-saving effect of TEA in minimally invasive TKR.

We randomly assigned 151 patients who underwent unilateral minimally invasive TKR to three groups: 1) a placebo group (50 patients); 2) a one-dose TEA group (52 patients), who received one injection of TEA (10 mg/kg) intra-operatively on deflation of the tourniquet; and 3) a two-dose TEA group (49 patients), who received two injections of TEA (10 mg/kg) given pre-operatively and intra-operatively. Total blood loss was calculated from the maximum loss of haemoglobin. All patients were followed clinically for the presence of venous thromboembolism (VTE).

The mean total blood loss was significantly higher in the placebo group than in the other two groups (1222 ml (845 to 2043) versus 1035 ml (397 to 1934) and 986 ml (542 to 1811), respectively (both p < 0.0001)). The mean blood loss was not significantly different between the one- and two-TEA groups (p = 0.148). The mean transfusion rate was higher in the placebo group than in the other two groups (22% versus 3.8% (p = 0.006) and 6.1% (p = 0.041), respectively) and there was no statistically significant difference in the mean transfusion rate between the one- and two-TEA groups (p = 0.672). Only one patient, in the two-dose group, had a radiologically confirmed deep venous thrombosis.

Our prospective randomised controlled study showed that one intra-operative injection of TEA is effective for blood conservation after minimally invasive TKR.