bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tracking anti‐fibrotic pathways of nilotinib and imatinib in experimentally induced liver fibrosis: An insight
Authors: Shiha Gamal E , Abu‐Elsaad Nashwa M , Zalata Khaled R , Ibrahim Tarek M 
Published: August 2014

SummaryThe tyrosine kinase inhibitors imatinib and nilotinib have been suggested to have promising antifibrotic activity in experimental models of liver fibrosis. The aim of the present study was to investigate new pathways underlying this beneficial effect. Hepatic injury was induced in male Wistar rats by intraperitoneal injection of CCl4 for 12 weeks. During the last 8 weeks of treatment, rats were also injected daily intraperitoneally with 20 mg/kg imatinib or 20, 10 or 5 mg/kg nilotinib. At the end of treatment, effects on fibrosis were assessed by measuring serum fibrotic markers and profibrogenic cytokines, as well as by histopathological examination. Possible anti‐inflammatory effects were estimated by measuring levels of inflammatory cytokines in liver tissue. Liver expression of α‐smooth muscle actin, transforming growth factor (TGF)‐β1 antibodies and platelet‐derived growth factor receptor β (PDGFRβ) was evaluated by immunohistochemical staining techniques. Nilotinib (5 and 10 mg/kg) significantly (P < 0.05) decreased all serum fibrotic markers measured, but 20 mg/kg of either nilotinib or imatinib had limited effects. At all doses tested, nilotinib significantly (P < 0.05) decreased the CCl4‐induced increases in tissue inflammatory cytokines. Furthermore, 5 and 10 mg/kg nilotinib significantly decreased TGF‐β1 levels and tissue expression of its antibody, as well expression of PDGFRβ. In conclusion, low doses (5 and 10 but not 20 mg/kg) of nilotinib, rather than imatinib, can control hepatic fibrosis by regulating levels of proinflammatory cytokines, primarily interleukin (IL)‐1 and IL‐6. Nilotinib also controls the signalling pathways of profibrogenic cytokines by lowering TGF‐β1 levels and decreasing expression of PDGFRβ.
Recent progress in gastric arrhythmia: Pathophysiology, clinical significance and future horizons
Authors: O'Grady Gregory , Wang Tim H‐H , Du Peng , Angeli Tim , Lammers Wim JEP , Cheng Leo K 
Published: August 2014

SummaryGastric arrhythmia continues to be of uncertain diagnostic and therapeutic significance. However, recent progress has been substantial, with technical advances, theoretical insights and experimental discoveries offering new translational opportunities. The discoveries that interstitial cells of Cajal (ICC) generate slow waves and that ICC defects are associated with dysmotility have reinvigorated gastric arrhythmia research. Increasing evidence now suggests that ICC depletion and damage, network disruption and channelopathies may lead to aberrant slow wave initiation and conduction. Histological and high‐resolution (HR) electrical mapping studies have now redefined the human ‘gastric conduction system’, providing an improved baseline for arrhythmia research. The application of HR mapping to arrhythmia has also generated important new insights into the spatiotemporal dynamics of arrhythmia onset and maintenance, resulting in the emergence of new provisional classification schemes. Meanwhile, the strong associations between gastric functional disorders and electrogastrography (EGG) abnormalities (e.g. in gastroparesis, unexplained nausea and vomiting and functional dyspepsia) continue to motivate deeper inquiries into the nature and causes of gastrointestinal arrhythmias. In future, technical progress in EGG methods, new HR mapping devices and software, wireless slow wave acquisition systems and improved gastric pacing devices may achieve validated applications in clinical practice. Neurohormonal factors in arrhythmogenesis also continue to be elucidated and a deepening understanding of these mechanisms may open opportunities for drug design for treating arrhythmias. However, for all translational goals, it remains to be seen whether arrhythmia can be corrected in a way that meaningfully improves organ function and symptoms in patients.
B‐Type natriuretic peptide suppression of neutrophil superoxide generation: mechanistic studies in normal subjects
Authors: Liu Saifei , Ngo Doan TM , Stewart Simon , Horowitz John D , Chirkov Yuliy Y 
Published: August 2014

SummaryMany acute cardiovascular disease states are associated with neutrophil infiltration of myocardium and subsequent release of superoxide (O2−) and myeloperoxidase (MPO), which contribute to inflammatory reactions. B‐Type natriuretic peptide (BNP) is known to exert anti‐inflammatory and antifibrotic effects, but it is not known whether these may include interactions with neutrophils. In neutrophils isolated from 20 healthy subjects, we assessed the effect of BNP on the ‘neutrophil burst’ (O2− production and MPO release) stimulated by phorbol myristate acetate (PMA) and N‐formyl‐methionyl‐leucyl‐phenylalanine (fMLP), respectively. Effects of BNP on cGMP accumulation, and the effects of the cell‐permeable cGMP analogue 8‐(4‐chlorophenylthio) guanosine‐cGMP (8‐p‐CPT‐cGMP) and protein kinase G (PKG) inhibition with KT5823 on the neutrophil–BNP interaction were also evaluated. B‐Type natriuretic peptide suppressed O2− release from neutrophils by 23 ± 6% (P < 0.001) and 24 ± 8% (P < 0.05) following PMA and fMLP stimulation, respectively. Although BNP did not significantly increase cGMP formation, 8‐p‐CPT‐cGMP suppressed both PMA‐ and fMLP‐induced neutrophil O2− release by 16% and 28%, respectively (P < 0.05). The PKG inhibitor KT5823 attenuated the effects of BNP on both fMLP‐ and PMA‐associated O2− production. Neither BNP nor 8‐p‐CPT‐cGMP significantly affected MPO release from neutrophils. Suppression of O2− release from neutrophils by BNP may contribute to its anti‐inflammatory and antifibrotic actions.
Transforming growth factor‐β1 mediates psoriasis‐like lesions via a Smad3‐dependent mechanism in mice
Authors: Zhang Yun , Meng Xiao‐Ming , Huang Xiao‐Ru , Wang Xiao‐Jing , Yang Liu , Lan Hui Yao 
Published: August 2014

SummaryTransforming growth factor (TGF)‐β1 signals through downstream Smad‐dependent and ‐independent pathways to exert its biological actions. It has been reported that overexpression of TGF‐β1 results in the development of psoriasis‐like lesions in a mouse model of K5.TGF‐βWT transgenic mice. However, the signalling mechanisms by which TGF‐β1 mediates the development of psoriasis‐like lesions remain unknown. The aim of the present study was to investigate the hypothesis that TGF‐β1 mediates the development of psoriasis‐like lesions via a Smad3‐dependent mechanism. This was tested in a mouse model of K5.TGF‐βWT transgenic mice by blocking TGF‐β signalling with a specific Smad3 inhibitor. Topical treatment with a Smad3 inhibitor markedly blocked TGF‐β/Smad3 signalling and progressive psoriasis‐like lesions in K5.TGF‐βWT transgenic mice, as evidenced by decreased skin severity scores, double skin fold thickness (DSFT) scores, infiltration of CD3+ T cells and F4/80+ macrophages and the degree of fibrosis in the dermis. This was associated with a marked reduction in TGF‐β1, interleukin (IL)‐6, IL‐23 and IL‐17A both locally in skin plaque lesions and systemically in the plasma, resulting in inhibition of both the T helper (Th) 17 cell transcription factor RORγt and accumulation of CD4+IL‐17A+ cells within the skin plaque lesions. In conclusion, TGF‐β1 mediates the development of psoriasis‐like lesions via a Smad3‐dependent, Th17‐mediated mechanism. Targeting TGF‐β/Smad3 signalling with a Smad3 inhibitor may represent a novel and effective therapy for psoriasis.
Multisite phosphorylation of Bcl‐2 via protein kinase Cδ facilitates apoptosis of hypertrophic cardiomyocytes
Authors: Sheng Juan‐Juan , Chen Yan , Chang Hui , Wang Yun‐Ying , Jiao Bo , Yu Zhi‐Bin 
Published: August 2014

SummaryActivated protein kinase Cδ (PKCδ) associated with cardiac hypertrophy moves from the cytoplasm to the mitochondria and subsequently triggers the apoptotic signalling pathway. The underlying mechanisms remain unknown. The aim of the present study was to investigate whether mitochondrial translocation of PKCδ phosphorylates multiple sites of Bcl‐2, resulting in an imbalance between Bcl‐2 and Bak or Bax, thus enhancing the susceptibility of hypertrophic cardiomyocytes to angiotensin II (AngII)‐induced apoptosis. Chronic pressure overload was induced by transverse aortic constriction (TAC) in rats. The apoptotic rate increased in hypertrophied cardiomyocytes. In AngII‐treated hearts (10 nmol/L, 60 min), there was an increase in the number of TERMINAL deoxyribonucleotidyl transferase‐mediated dUTP–digoxigenin nick end‐labelling (TUNEL)‐positive cells; PKCδ inhibition with 500 nmol/L δV1‐1 for 60 min prevented the AngII‐induced increase in apoptosis. In the hypertrophied myocardium, PKCδ expression increased, whereas that of Bcl‐2 decreased compared with the synchronous control. Treatment of hearts with 10 nmol/L AngII for 60 min activated PKCδ and induced translocation of PKCδ to the mitochondria, where activated PKCδ facilitated the phosphorylation of Bcl‐2 at serine‐87 and serine‐70 sites. The multisite phosphorylated Bcl‐2 was released from the mitochondria, and exhibited reduced affinity for Bak and Bax. The imbalance between Bcl‐2 and Bak/Bax induced the release of mitochondrial cytochrome c and then activated the caspase 3 apoptotic pathway during AngII stimulation (10 nmol/L, 60 min) of hypertrophied cardiomyocytes. Inhibition of PKCδ reduced these effects of AngII. The results suggest that PKCδ can counteract the anti‐apoptotic effect of Bcl‐2 and may promote cardiomyocyte apoptosis through multisite phosphorylation of Bcl‐2 in hypertrophied cardiomyocytes.
Do Patient‐Centered Medical Homes Reduce Emergency Department Visits?
Authors: David Guy , Gunnarsson Candace , Saynisch Philip A. , Chawla Ravi , Nigam Somesh 
Published: August 2014

ObjectiveTo assess whether adoption of the patient‐centered medical home (PCMH) reduces emergency department (ED) utilization among patients with and without chronic illness.Data SourcesData from approximately 460,000 Independence Blue Cross patients enrolled in 280 primary care practices, all converting to PCMH status between 2008 and 2012.Research DesignWe estimate the effect of a practice becoming PCMH‐certified on ED visits and costs using a difference‐in‐differences approach which exploits variation in the timing of PCMH certification, employing either practice or patient fixed effects. We analyzed patients with and without chronic illness across six chronic illness categories.Principal FindingsAmong chronically ill patients, transition to PCMH status was associated with 5–8 percent reductions in ED utilization. This finding was robust to a number of specifications, including analyzing avoidable and weekend ED visits alone. The largest reductions in ED visits are concentrated among chronic patients with diabetes and hypertension.ConclusionsAdoption of the PCMH model was associated with lower ED utilization for chronically ill patients, but not for those without chronic illness. The effectiveness of the PCMH model varies by chronic condition. Analysis of weekend and avoidable ED visits suggests that reductions in ED utilization stem from better management of chronic illness rather than expanding access to primary care clinics.
Genomic Resources Notes accepted 1 June 2014 – 31 July 2014
Authors:   Genomic Resources Development Consortium, Havird Justin C. , Santos Scott R. 
Published: August 2014

AbstractThis article documents the public availability of transcriptome sequence data, assembled contigs and annotated contigs and ORFS for five anchialine shrimp species (Crustacea: Atyidae and Alpheidae).
A novel system for bi‐ocular eye‐tracking in vertebrates with laterally placed eyes
Authors: Tyrrell Luke P. , Butler Shannon R. , Yorzinski Jessica L. , Fernández‐Juricic Esteban 
Published: August 2014

Summary

Animals use vision to gather information about their environment and then use that information to make behavioural decisions that affect fitness. They will often move their heads or eyes to inspect areas of interest with their centres of acute vision, such as foveae, to gather high resolution information about potential mates, predation risks, or other aspects of the environment. Few studies to date have been able to accurately determine where laterally eyed animals direct their visual attention and how they use their eyes to gather information.

We present a non‐invasive eye‐tracking system that can simultaneously track the gaze of two eyes. This is particularly useful for studying animals with laterally placed eyes (most vertebrates) where the two eyes are viewing different images. This system can also accommodate comparative studies using animals of varying size, including small animals that are not frequently used in eye‐tracking studies due to constraints of existing eye‐tracking systems. We conducted an eye‐tracking experiment with European starlings (Sturnus vulgaris) to test the eye‐tracking system, calibration methods and highlight relevant aspects of experimental design.

We were able to accurately track the gaze of European starlings with <5 degrees of error. We also found that starlings are more likely to fixate on biologically relevant visual stimuli (e.g. predators and active prey) than simple stimuli (e.g. a dot) in video playbacks.

The method presented here can be used to address ecological and evolutionary questions about where animals direct their attention and how they visually inspect mates, food and predators, as well as address management questions about how animals inspect man‐made objects. This method can also be used to answer fundamental questions about vision, such as how laterally eyed vertebrates coordinate the use of their eyes laterally and binocularly.
Optimal Older Adult Emergency Care: Introducing Multidisciplinary Geriatric Emergency Department Guidelines From the American College of Emergency Physicians, American Geriatrics Society, Emergency Nurses Association, and Society for Academic Emergency Medicine
Authors: Carpenter Christopher R. , Bromley Marilyn , Caterino Jeffrey M. , Chun Audrey , Gerson Lowell W. , Greenspan Jason , Hwang Ula , John David P. , Lyons William L. , Platts‐Mills Timothy F. , Mortensen Betty , Ragsdale Luna , Rosenberg Mark , Wilber Scott 
Published: August 2014

AbstractIn the United States and around the world, effective, efficient, and reliable strategies to provide emergency care to aging adults is challenging crowded emergency departments (EDs) and a strained health care system. In response, geriatric emergency medicine (EM) clinicians, educators, and researchers collaborated with the American College of Emergency Physicians (ACEP), American Geriatrics Society (AGS), Emergency Nurses Association (ENA), and the Society for Academic Emergency Medicine (SAEM) to develop guidelines intended to improve ED geriatric care by enhancing expertise, educational, and quality improvement expectations; equipment; policies; and protocols. These “Geriatric Emergency Department Guidelines” represent the first formal society‐led attempt to characterize the essential attribute of the geriatric ED and received formal approval from the boards of directors for each of the four societies in 2013 and 2014. This article is intended to introduce EM and geriatric health care providers to the guidelines, while providing proposals for educational dissemination, refinement via formal effectiveness evaluations and cost‐effectiveness studies, and institutional credentialing.
Spatial and temporal determinants of golden sun moth Synemon plana distribution
Authors: Kutt A. S. , McKenzie V. J. , Wills T. J. , Retallick R. W. R. , Dalton K. , Kay N. , Melero‐Blanca E. 
Published: August 2014

AbstractIn this study we examined the spatial and temporal variation in a population of the critically endangered golden sun moth Synemon plana over four years in a conservation reserve in south‐eastern Australia. We found golden sun moth spatial distribution and abundance dramatically declined from a peak in extent and abundance from 2008–2009 to 2011–2012 due to a shift from drought to above average rainfall. Autoregressive correlative models indicated that a northerly aspect and landscape position were key predictors of abundance over time, and golden sun moth distribution shifted from wet to dry locations in the landscape. We conclude that: our data provide a counterpoint to conclusions that golden sun moth has been known to persist in very small areas and suggest that distribution can change quite markedly (from large connected populations to small patches) at a local scale, and this will be due to dispersal and survivorship; the variability in the data may have implications for adequate detection of the species over time, especially when populations have contracted and species have a naturally restricted activity and breeding period; and long‐term weather patterns and landscape configuration (aspect, wet or dry position) interact to significantly affect local distribution and abundance over time. This has implications for the species under global change; increased variability in rainfall, temperature, productivity and exotic pasture growth may all alter and interact to either reduce or enhance persistence of golden sun moth populations over time.
Isotretinoin and night blindness
Authors: Teo Ken , Yazdabadi Anousha 
Published: August 2014

AbstractIsotretinoin is an effective and increasingly popular treatment for acne vulgaris. There have been reports of night blindness as a side‐effect of treatment although the evidence does not demonstrate a clear causal relationship between isotretinoin therapy and the risk of night blindness. Nevertheless, considering the lack of evidence in this area, it is important to educate patients about this potential consequence, which may become longstanding and even irreversible, and encourage them to promptly report changes in their night vision.
Extramammary Paget's disease of the perianal region: a 20‐year experience
Authors: Rajendran Saissan , Koh Cherry E. , Solomon Michael J. 
Published: August 2014

AbstractBackgroundTo evaluate the results obtained from cases of perianal Paget's disease (PPD) and to provide a current perspective in the diagnostic evaluation and surgical management of this condition.MethodsA retrospective review of a single quaternary referral centre's experience with PPD from January 1994 to December 2013 was performed. Medical records were reviewed to collect data on demographics, preoperative investigations, complications, pathology and recurrence. A review of existing literature was also performed.ResultsFive patients (four females, one male) with histologically confirmed PPD were identified. The median age of presentation was 72 (range 61 to 78). Three patients were recurrences following previous excisions and first presentations in two patients. Only one patient had an underlying diagnosis of cancer. The median time to diagnosis was 24 months. Four patients underwent wide local excision with skin graft and/or local flap reconstruction and one patient required an abdominoperineal excision for recurrence. Four patients had involved lateral margins despite wide local excision but follow‐up to date has only revealed one local recurrence. A review of available literature suggests that synchronous cancers can occur in up to 33% of patients and that a further 10% may be associated with metachronous cancers. Surveillance recommendations seem anecdotal and do not appear to be supported by available literature.ConclusionPPD is a management challenge. Association with synchronous and metachronous carcinomas may not be as strong as initially thought. Surgery is the mainstay treatment with the need to balance between minimizing disease recurrence and functional sequelae from excessive tissue loss.
Randomised clinical trial: the long‐term safety and tolerability of naloxegol in patients with pain and opioid‐induced constipation
Authors: Webster L. , Chey W. D. , Tack J. , Lappalainen J. , Diva U. , Sostek M. 
Published: August 2014

SummaryBackgroundOpioid‐induced constipation (OIC) is a common adverse effect of opioid therapy.AimTo evaluate the long‐term safety and tolerability of naloxegol, an oral, peripherally acting μ‐opioid receptor antagonist (PAMORA), in patients with noncancer pain and OIC.MethodsA 52‐week, multicenter, open‐label, randomised, parallel‐group phase 3 study was conducted in out‐patients taking 30–1000 morphine‐equivalent units per day for ≥4 weeks. Patients were randomised 2:1 to receive naloxegol 25 mg/day or usual‐care (UC; investigator‐chosen laxative regimen) treatment for OIC.ResultsThe safety set comprised 804 patients (naloxegol, n = 534; UC, n = 270). Mean exposure duration was 268 days with naloxegol and 297 days with UC. Frequency of adverse events (AEs) was 81.8% with naloxegol and 72.2% with UC. Treatment‐emergent AEs occurring more frequently for naloxegol vs. UC were abdominal pain (17.8% vs. 3.3%), diarrhoea (12.9% vs. 5.9%), nausea (9.4% vs. 4.1%), headache (9.0% vs. 4.8%), flatulence (6.9% vs. 1.1%) and upper abdominal pain (5.1% vs. 1.1%). Most naloxegol‐emergent gastrointestinal AEs occurred early, resolving during or after naloxegol discontinuation and were mild or moderate in severity; 11 patients discontinued due to diarrhoea and nine patients owing to abdominal pain. Pain scores and mean daily opioid doses remained stable throughout the study; no attributable opioid withdrawal AEs were observed. Two patients in each group had an adjudicated major adverse cardiovascular event unrelated to study drug; no AEs were reported nor adjudicated as bowel perforations.ConclusionIn patients with noncancer pain and opioid‐induced constipation, naloxegol 25 mg/day up to 52 weeks was generally safe and well tolerated.
Proton pump inhibitor‐responsive oesophageal eosinophilia correlates with downregulation of eotaxin‐3 and Th2 cytokines overexpression
Authors: Molina‐Infante J. , Rivas M. D. , Hernandez‐Alonso M. , Vinagre‐Rodríguez G. , Mateos‐Rodríguez J. M. , Dueñas‐Sadornil C. , Perez‐Gallardo B. , Ferrando‐Lamana L. , Fernandez‐Gonzalez N. , Bañares R. , Zamorano J. 
Published: August 2014

SummaryBackgroundThe molecular basis and effects of proton pump inhibitor (PPI) therapy on PPI‐responsive oesophageal eosinophilia (PPI‐REE) and eosinophilic oesophagitis (EoE) remain unknown.AimTo compare symptom‐histological and cytokine gene expression in PPI‐REE and EoE patients, at baseline and after specific treatment.MethodsIn consecutive adult patients with an EoE phenotype (dysphagia/food impaction, typical endoscopic findings and > 15 eos/HPF), gene expression of eotaxin‐3, IL‐13, and IL‐5 were determined in distal and proximal oesophagus, at baseline and after omeprazole 40 mg b.d. for 8 weeks. PPI‐REE was defined by clinicohistological response. PPI nonresponders (EoE) were offered treatment with topical steroids.ResultsFifty three patients were re‐evaluated on PPI therapy. 23 patients (43%) had PPI‐REE and 30 patients (57%) had EoE. At baseline, eotaxin‐3/IL‐13/IL‐5 gene expression was indistinguishable between EoE and PPI‐REE, excepting increased IL‐5 expression in proximal oesophagus (12.54 vs. 57, P = 0.029). PPI therapy significantly decreased eotaxin‐3/IL‐13 in PPI‐REE, at both oesophageal sites (P ≤ 0.008), and IL‐5 in distal (P = 0.016), but not in proximal oesophagus. Patients with steroid‐responsive EoE also showed a significant decrease in eotaxin‐3/IL‐5 expression at both oesophageal sites. In EoE patients, initial PPI trial significantly decreased distal oesophageal eosinophilia (63.78 to 41.79 eos/HPF, P = 0.025) and led to symptom remission in 16%, but did not influence Th2 markers.ConclusionsBaseline cytokine gene expression in PPI‐REE was nearly indistinguishable from EoE. PPI therapy significantly downregulated oesophageal eotaxin‐3/Th2‐cytokine gene expression in PPI‐REE, similarly to that seen in steroid‐responsive EoE. A subset of EoE patients showed clinicohistological improvement on PPI therapy.