bluuebunny/crossref_metadata_2025_split huggingface dataset:
A collaborative project to improve identification and management of patients with chronic kidney disease in a primary care setting in Greater Manchester
Authors: Humphreys John , Harvey Gill , Coleiro Michelle , Butler Brook , Barclay Anna , Gwozdziewicz Maciek , O'Donoghue Donal , Hegarty Janet 
Published: May 2012

ProblemResearch has demonstrated a knowledge and practice gap in the identification and management of chronic kidney disease (CKD). In 2009, published data showed that general practices in Greater Manchester had a low detection rate for CKD.DesignA 12-month improvement collaborative, supported by an evidence-informed implementation framework and financial incentives.Setting19 general practices from four primary care trusts within Greater Manchester.Key measures for improvementNumber of recorded patients with CKD on practice registers; percentage of patients on registers achieving nationally agreed blood pressure targets.Strategies for changeThe collaborative commenced in September 2009 and involved three joint learning sessions, interspersed with practice level rapid improvement cycles, and supported by an implementation team from the National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care for Greater Manchester.Effects of changeAt baseline, the 19 collaborative practices had 4185 patients on their CKD registers. At final data collection in September 2010, this figure had increased by 1324 to 5509. Blood pressure improved from 34% to 74% of patients on practice registers having a recorded blood pressure within recommended guidelines.Lessons learntEvidence-based improvement can be implemented in practice for chronic disease management. A collaborative approach has been successful in enabling teams to test and apply changes to identify patients and improve care. The model has proved to be more successful for some practices, suggesting a need to develop more context-sensitive approaches to implementation and actively manage the factors that influence the success of the collaborative.
Cultural understanding in the provision of supportive and palliative care: perspectives in relation to an indigenous population
Authors: Johnston Grace , Vukic Adele , Parker Skylan 
Published: May 2012

ObjectivesThe provision of supportive and palliative care for an indigenous people in Nova Scotia, Canada, was examined to further our understanding and thereby improve cultural competency. Most of Nova Scotia's indigenous people are Mi'kmaq. The Mi'kmaq Nation lives in Atlantic Canada as well as New England in the eastern USA.MethodsThemes were identified in the literature and through discussion with seven experts who have Mi'kmaq health and cultural research expertise. This paper has been reviewed and approved by two Mi'kmaq consultants who frequently speak on behalf of the Mi'kmaq people in relation to health and cultural understanding. Recommendations for non-indigenous care providers are presented.ResultsThe themes identified focused on jurisdictional issues and cultural understanding. They are interconnected and grounded in the historic Mi'kmaq context of colonialism. Jurisdictional issues experienced by the Mi'kmaq affect access, continuity and appropriateness of care. Cultural concepts were associated with worldview, spirituality, the role of family and community relationships and communication norms, and thereby with the alignment of values and language in the provision of care. Three Mi'kmaq concepts are noted: apiksiktatulti, nemu'ltus and salite.ConclusionThrough reflection on the situation of Nova Scotia's Mi'kmaq, non-indigenous healthcare providers can assess how they might increase their cultural understanding in the provision of supportive and palliative care. Recommendations relate to the health system, relationships with individual persons and direction for research.
Seasonal variations in healthcare-associated infection in neonates in Canada
Authors: Shah Prakesh S , Yoon Woojin , Kalapesi Zarin , Bassil Kate , Dunn Michael , Lee Shoo K 
Published: May 2012

ObjectiveTo assess the seasonal pattern of healthcare-associated infections (HCAI) among neonates and to describe the trend of HCAI.DesignSecondary analyses of database.SettingThe Canadian Neonatal Network database (2003–2009).ParticipantsNeonates with HCAI defined as blood/cerebrospinal fluid positive with pathogenic organism in a symptomatic infant after 2 days of age.Main outcome measureThe incidence rate for HCAI per 1000 days with a 95% CI, for the 4 warmest months (June–September) was compared with the remaining 8 months, to calculate the incidence rate ratio (IRR).ResultsOf 75 629 total infants, 4305 (5.7%) had HCAI (3367 had 1 and 938 had >1 episodes). Infants who had HCAI were of lower gestation, birth weight and Apgar score; but had higher severity of illness scores and clinical chorioamnionitis. There was a borderline increase in all HCAI (IRR 1.05, 95% CI 1.00 to 1.11) and a significant increase in Gram-negative HCAI (IRR 1.20, 95% CI 1.04 to 1.39) during the summer months. Overall, there was a 20% reduction in HCAI from 4.45/1000 days in January 2003 to 3.54/1000 days in December 2009 (mean difference 0.91/1000 days (95% CI 0.89 to 0.92).ConclusionsGram-negative infections were significantly increased during the summer months of the year compared with the rest of the year among neonates. Overall, there was a significant temporal reduction in HCAI rates over the study period.
Variability of respiratory parameters and extubation readiness in ventilated neonates
Authors: Kaczmarek Jennifer , Kamlin C Omar Farouk , Morley Colin J , Davis Peter G , Sant'Anna Guilherme M 
Published: May 2012

BackgroundA spontaneous breathing trial (SBT) has been used to guide suitability of extubation in VLBW infants. Respiratory variability (RV) has been used to assess extubation readiness in adults but was never investigated in preterms. The combination of a SBT and RV may further improve prediction of successful extubation.Study designUsing data previously collected during the SBT, the following respiratory variables were analysed: inspiratory time (TI), expiratory time (TE), TI/total breath time, tidal volume (VT) and mean inspiratory flow (VT/TI). RV was quantified using time-domain analysis for each respiratory variable and expressed as a variability index (VI). The sensitivity, specificity, positive and negative predictive values (PPV and NPV) of the SBT, each VI and combined SBT+VI were calculated. Extubation failure was defined as need of re-intubation within 72 h.ResultsA total of 44 infants were included. Successfully (n=36) and unsuccessfully (n=8) extubated infants had similar baseline characteristics and number of breaths analysed. VI for VT/TIwas significantly decreased in the failure group. The combination of the SBT and VI of either TIor VTwere the most accurate predictors of successful extubation with a sensitivity of 100% and specificity of 75% and a PPV and NPV for extubation success of 95% and 100%, respectively.ConclusionsA significant decrease in VT/TIvariability occurred in infants requiring re-intubation. The combination of a SBT failure and decreased variability in TIor VTwas highly predictive of failure. This combination is promising but requires prospective evaluation in a larger population.
Transcriptome-level microarray expression profiling implicates IGF-1 and Wnt signalling dysregulation in the pathogenesis of thyroid-associated orbitopathy
Authors: Ezra Daniel G , Krell Jonathan , Rose Geoffrey E , Bailly Maryse , Stebbing Justin , Castellano Leandro 
Published: May 2012

AimsThe pathogenesis of thyroid-associated orbitopathy (TAO) remains unclear. The aim of this study is to elucidate the gene expression profile of orbital fat from patients with active, but untreated, TAO.MethodsA case–control gene expression study was conducted using test samples of orbital fat from TAO patients and control orbital fat specimens; apart from drugs to control thyrotoxicosis, the TAO patients had received no treatment for orbital disease. cDNA expression analysis was performed using the Affymetrix GeneChip Human Genome U133 Plus 2.0 platform and validated using quantitative PCR.ResultsThe highest-ranked differentially expressed genes were dominated by IGF-1 signalling genes. These include IGF-1, IGF-1 receptor binding/signalling genes, such as SOCS3 and IRS2, and downstream signalling and transcriptional regulators, such as SGK (PDK/Akt signalling) and c-JUN. Our microarray data also demonstrate dysregulation of wingless-type MMTV (Wnt) signalling gene expression, including Wnt5a, sFRPs and DKK.ConclusionAltered Wnt signalling confirms previous array findings. Further investigation of the role of Wnt signalling in TAO pathogenesis is warranted. These data also provide the first evidence of dysregulation of IGF-1 pathway genes in TAO tissue, further strengthening the evidence for the role of IGF-1 signalling in the pathogenesis and potential treatment of TAO.
Neuroendocrine cells associated with neuroendocrine carcinoma of the breast: nature and significance
Authors: Kawasaki Tomonori , Mochizuki Kunio , Yamauchi Hideko , Inoue Shingo , Kondo Tetsuo , Oishi Naoki , Nakazawa Tadao , Yamane Tetsu , Koshimizu Yoshihito , Tsunoda Hiroko , Yagata Hiroshi , Inoue Masayuki , Inoue Ayako , Maruyama Takanori , Fujii Hideki , Katoh Ryohei 
Published: May 2012

BackgroundThe developmental mechanisms of breast neuroendocrine carcinoma (B-NEC) have not been sufficiently analysed and are not well understood.AimsTo investigate NE cells in the background tissues surrounding B-NECs.MethodsThree cases (four breasts) having many NE cells in the background tissues of multifocal B-NECs were identified at the University of Yamanashi Hospital and St Luke's International Hospital, Japan. These patients were, respectively, 28-, 31- and 38-year-old women with no familial history of NE tumour. The totally-resected breasts were serially studied by immunohistochemistry for specific NE markers (chromogranin A/synaptophysin) and the morphologies and/or localisation of NE cells were investigated.ResultsImmunohistochemical examination showed extensively-distributed NE cells in the background mammary ducts/lobules of the NECs in all breasts. These NE cells were classifiable into three emerging patterns: isolated/scattered, clustered and circumferential. Their distributions were intermingled and were not clearly related to B-NEC foci. NE cells were morphologically polygonal, oval or columnar with sometimes eosinophilic and/or fine-granular cytoplasm and round-to-ovoid nuclei lacking atypia. Some cells were located between epithelial and myoepithelial cells. Apical snouts were occasionally observed in NE cells forming luminal structures.ConclusionsBenign-appearing NE cells in the parenchyma of a breast with NEC could be regarded as hyperplastic from their emerging patterns and distribution; this NE cell hyperplasia may be associated with the histogenesis of B-NEC as a precancerous condition. These observations might raise questions about the treatment for B-NEC.
Complex adnexal tumours of the skin: a report of three cases and review of literature
Authors: London Vanessa , Saadat Payam , Vadmal Manjunath S 
Published: May 2012

AimsComplex or composite adnexal tumours of the skin (CATS) are unusual neoplasms composed of two or more histopathologically distinct subtypes of appendageal neoplasms coexisting in a single cutaneous lesion. The authors report three examples of CATS, review literature and discuss their probable histogenesis.Methods and resultsOf the three tumours described, one tumour showed a mixture of a proliferating pilar tumour and syringocystadenoma papilliferum, the second lesion was composed of a proliferating pilar tumour and tubulopapillary hidradenoma and the third tumour exhibited a syringocystadenoma papilliferum and tubulopapillary hidradenoma in combination.ConclusionsCATS are rare tumours. The authors reported three unique cases in addition to the 10 other reported cases. These three cases further strengthen the hypothesis of a ‘folliculosebaceous apocrine’ unit as the most likely point of origin of CATS.
MK-626, a dipeptidyl peptidase-4 inhibitor, does not improve the hyperglycemia or hyperinsulinemia of nonobese diabetic MKR mice
Authors: Bhattacharjee Alpana , Allister Emma M. , Wheeler Michael B. 
Published: May 2012

Dipeptidyl peptidase-4 (DPP-4) inhibitors increase circulating levels of incretin hormones, which can enhance insulin secretion and β cell function. The aim of this study was to evaluate the effectiveness of MK-626 (a novel DPP-4 inhibitor) to reduce the hyperglycemia and hyperinsulinemia of nonobese type 2 diabetic MKR mice. Twelve to 14-week-old hyperglycemic MKR mice were gavaged daily with MK-626 (3 mg/kg body weight) or vehicle (0.5% methyl cellulose (MC)) for 2 weeks. MK-626-treated mice displayed no change in body weight or adverse reactions, suggesting good tolerance of the drug. Fed blood glucose was significantly reduced over the 2-week experiment; however, it was also reduced in the MC group, suggesting an effect of gavage alone. Fed plasma insulin and glucagon levels and glucose tolerance of MK-626-treated mice were similar to those of MC mice. Therefore, treatment with MK-626 did not correct the prolonged hyperglycemia and impaired glucose tolerance of MKR mice.
Cardoguard, an Ayurvedic antihypertensive formulation, prevents cardiac remodeling in spontaneously hypertensive rats by inhibition of ERK and PKCε signaling pathways
Authors: Sankar Vandana , Nair Renuka R. , Harikrishnan Vijayakumar S. , Fernandez Adelaide C. , Kumar Cherumanal S. Krishna , Madhavachandran Viswanathamenon 
Published: May 2012

Ayurveda is an Indian system of medicine. Despite clinical efficacy, lack of scientific validation has limited the effective use of Ayurvedic drugs. Cardoguard is an Ayurvedic antihypertensive drug formulated by Nagarjuna Herbal Concentrates Ltd., Kerala, India. Left ventricular hypertrophy (LVH) is a modifiable risk factor, and regression of LVH reduces the propensity for adverse cardiovascular events. This study was taken up with the objective of evaluating the efficacy of Cardoguard in the prevention of cardiac remodeling. Cardoguard was administered orally to 2-month-old spontaneously hypertensive rats for 4 months at a dose of 5 mg·day–1. The dose corresponds to the therapeutic dose calculated on the basis of body surface area. Lower hypertrophy index, decrease in cardiomyocyte area, and reduction of interstitial fibrosis in treated spontaneously hypertensive rats indicate amelioration of cardiac hypertrophy by Cardoguard. Cardiac output increased in response to treatment. Immunostaining for the phosphorylated components of major signaling pathways associated with hypertrophy suggests that prevention of LVH by Cardoguard is possibly mediated through inhibition of extracellular signal-regulated kinases and protein kinase C-ε signaling pathways. Reduced expression of 3-nitrotyrosine in response to the treatment suggests that prevention of cardiac remodeling by Cardoguard is mediated by reduction of oxidative stress.
Protective effect of urantide against ischemia–reperfusion injury via protein kinase C and phosphtidylinositol 3′-kinase – Akt pathway
Authors: Zhang Jun-Yan , Chen Zhi-Wu , Yao Hua 
Published: May 2012

Urantide is the most potent UT receptor antagonist compound found to date. Our previous studies have shown that it has cardioprotective effect against ischemia–reperfusion injury. However, it is unclear which signal transduction pathways are involved in the urantide-induced cardioprotective effect. This study was designed to investigate whether the effect of urantide on myocardial ischemia–reperfusion injury in rats via the protein kinase C (PKC) and phosphatidylinositol 3-kinase (PI3K)–Akt signaling pathway. The results showed that urantide at 10 and 30 µg/kg markedly inhibited the increases in serum creatine kinase fraction and lactate dehydrogenase activities and the level of cardiac troponin I, reduced the ratio of myocardial infarct size to area at risk. Urantide significantly decreased the histological damage to the myocardium and modified the ultrastructural damage in cardiac myocytes. In the presence of chelerythrine (an inhibitor of PKC, 1 mg/kg) or LY294002 (an inhibitor of PI3K–Akt, 0.3 mg/kg), the protective effect of urantide was almost completely abolished. Urantide (30 µg/kg) markedly enhanced the expression of p-Akt protein during myocardial ischemia–reperfusion injury, and this enhancement was significantly attenuated by LY294002. Therefore, our results demonstrate that urantide has a potent protective effect against myocardial ischemia–reperfusion injury in rats that may be involved with the PKC and PI3K–Akt signaling pathways.
Loss of Fibroblast HIF-1α Accelerates Tumorigenesis
Authors: Kim Jung-whan , Evans Colin , Weidemann Alexander , Takeda Norihiko , Lee Yun Sok , Stockmann Christian , Branco-Price Cristina , Brandberg Filip , Leone Gustavo , Ostrowski Michael C. , Johnson Randall S. 
Published: May 2012

Abstract
Solid tumors consist of malignant cells and associated stromal components, including fibroblastic cells that contribute to tumor growth and progression. Although tumor fibrosis and aberrant vascularization contribute to the hypoxia often found in advanced tumors, the contribution of hypoxic signaling within tumor-associated fibroblasts to tumorigenesis remains unknown. In this study, we used a fibroblast-specific promoter to create mice in which key hypoxia regulatory genes, including VHL, HIF-1α, HIF-2α, and VEGF-A, were knocked out specifically in tumor stromal fibroblasts. We found that loss of HIF-1α and its target gene VEGF-A accelerated tumor growth in murine model of mammary cancer. HIF-1α and VEGF-A loss also led to a reduction in vascular density and myeloid cell infiltration, which correlated with improved tumor perfusion. Together, our findings indicate that the fibroblast HIF-1α response is a critical component of tumor vascularization. Cancer Res; 72(13); 3187–95. ©2012 AACR.
Modulation of Activation-Loop Phosphorylation by JAK Inhibitors Is Binding Mode Dependent
Authors: Andraos Rita , Qian Zhiyan , Bonenfant Débora , Rubert Joëlle , Vangrevelinghe Eric , Scheufler Clemens , Marque Fanny , Régnier Catherine H. , De Pover Alain , Ryckelynck Hugues , Bhagwat Neha , Koppikar Priya , Goel Aviva , Wyder Lorenza , Tavares Gisele , Baffert Fabienne , Pissot-Soldermann Carole , Manley Paul W. , Gaul Christoph , Voshol Hans , Levine Ross L. , Sellers William R. , Hofmann Francesco , Radimerski Thomas 
Published: May 2012

Abstract
Janus kinase (JAK) inhibitors are being developed for the treatment of rheumatoid arthritis, psoriasis, myeloproliferative neoplasms, and leukemias. Most of these drugs target the ATP-binding pocket and stabilize the active conformation of the JAK kinases. This type I binding mode can lead to an increase in JAK activation loop phosphorylation, despite blockade of kinase function. Here we report that stabilizing the inactive state via type II inhibition acts in the opposite manner, leading to a loss of activation loop phosphorylation. We used X-ray crystallography to corroborate the binding mode and report for the first time the crystal structure of the JAK2 kinase domain in an inactive conformation. Importantly, JAK inhibitor–induced activation loop phosphorylation requires receptor interaction, as well as intact kinase and pseudokinase domains. Hence, depending on the respective conformation stabilized by a JAK inhibitor, hyperphosphorylation of the activation loop may or may not be elicited.
Significance: This study shows that JAK inhibitors can lead to an increase of activation loop phosphorylation in a manner that is binding mode dependent. Our results highlight the need for detailed understanding of inhibitor mechanism of action, and that it may be possible to devise strategies that avoid target priming using alternative modes of inhibiting JAK kinase activity for the treatment of JAK-dependent diseases. Cancer Discov; 2(6); 512–23. © 2012 AACR.
This article is highlighted in the In This Issue feature, p. 473
Brain-Derived Neurotrophic Factor Protects Against Cardiac Dysfunction After Myocardial Infarction via a Central Nervous System–Mediated Pathway
Authors: Okada Sho , Yokoyama Masataka , Toko Haruhiro , Tateno Kaoru , Moriya Junji , Shimizu Ippei , Nojima Aika , Ito Takashi , Yoshida Yohko , Kobayashi Yoshio , Katagiri Hideki , Minamino Tohru , Komuro Issei 
Published: May 2012

Objective—
The central nervous system is thought to influence the regulation of the cardiovascular system in response to humoral and neural signals from peripheral tissues, but our understanding of the molecular mechanisms involved is still quite limited.

Methods and Results—
Here, we demonstrate a central nervous system–mediated mechanism by which brain-derived neurotrophic factor (BDNF) has a protective effect against cardiac remodeling after myocardial infarction (MI). We generated conditional BDNF knockout mice, in which expression of BDNF was systemically reduced, by using the inducible Cre-loxP system. Two weeks after MI was induced surgically in these mice, systolic function was significantly impaired and cardiac size was markedly increased in conditional BDNF knockout mice compared with controls. Cardiomyocyte death was increased in these mice, along with decreased expression of survival molecules. Deletion of the BDNF receptor (tropomyosin-related kinase B) from the heart also led to the exacerbation of cardiac dysfunction after MI. The plasma levels of BDNF were markedly increased after MI, and this increase was associated with the upregulation of BDNF expression in the brain, but not in the heart. Ablation of afferent nerves from the heart or genetic disruption of neuronal BDNF expression inhibited the increase of plasma BDNF after MI and led to the exacerbation of cardiac dysfunction. Peripheral administration of BDNF significantly restored the cardiac phenotype of neuronal BDNF-deficient mice.

Conclusion—
These results suggest that BDNF expression is upregulated by neural signals from the heart after MI and then protects the myocardium against ischemic injury.