bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Jak2V617F oncogene associated with myeloproliferative diseases requires a functional FERM domain for transformation and for expression of the Myc and Pim proto-oncogenes
Authors: Wernig Gerlinde , Gonneville Jeffrey R. , Crowley Brian J. , Rodrigues Margret S. , Reddy Mamatha M. , Hudon Heidi E. , Walz Christoph , Reiter Andreas , Podar Klaus , Royer Yohan , Constantinescu Stefan N. , Tomasson Michael H. , Griffin James D. , Gilliland D. Gary , Sattler Martin 
Published: January 2008

Abstract
The V617F activating point mutation in Jak2 is associated with a proportion of myeloproliferative disorders. In normal hematopoietic cells, Jak2 signals only when associated with a growth factor receptor, such as the erythropoietin receptor (EpoR). We sought to identify the molecular requirements for activation of Jak2V617F by introducing a point mutation in the FERM domain (Y114A), required for receptor binding. Whereas BaF3.EpoR cells are readily transformed by Jak2V617F to Epo independence, we found that the addition of the FERM domain mutation blocked transformation and the induction of reactive oxygen species. Further, while cells expressing Jak2V617F had constitutive activation of STAT5, cells expressing Jak2V617F/Y114A did not, suggesting that signaling is defective at a very proximal level. In addition, expression of the Myc and Pim proto-oncogenes by Jak2V617F was found to be FERM domain dependent. An inducible constitutively active STAT5 mutant expressed in BaF3 cells was sufficient to induce Myc and Pim. Finally, the FERM domain in Jak2V617F was also required for abnormal hematopoiesis in transduced primary murine fetal liver cells. Overall, our results suggest that constitutive activation of Jak2 requires an intact FERM domain for a transforming phenotype, and is necessary for activation of the major target of Jak2, STAT5.
Modulation of angiogenesis by ω-3 polyunsaturated fatty acids is mediated by cyclooxygenases
Authors: Szymczak Melissa , Murray Michael , Petrovic Nenad 
Published: January 2008

Abstract
The potential role of dietary fats in cancer is attracting considerable interest within the community. Both epidemiologic and experimental findings suggest that omega-3 polyunsaturated fatty acids (ω-3 PUFAs), which are almost absent from typical Western diets, exert protective effects against cancer progression, although the precise mechanism of this suppression remains unknown. One of the potential targets for ω-3 PUFAs in cancer suppression is angiogenesis, a process of new blood vessel formation within rapidly growing tumors. Here, we demonstrate that ω-6 PUFAs stimulate and ω-3 PUFAs inhibit major proangiogenic processes in human endothelial cells, including the induction of angiopoietin-2 (Ang2) and matrix metalloprotease-9, endothelial invasion, and tube formation, that are usually activated by the major ω-6 PUFA arachidonic acid. The cyclooxygenase (COX)–mediated conversion of PUFAs to prostanoid derivatives participated in modulation of the expression of Ang2. Thus, the ω-6 PUFA–derived prostaglandin E2 augmented, whereas the ω-3 PUFA–derived prostaglandin E3 suppressed the induction of Ang2 by growth factors. Our findings are consistent with the suggestion that PUFAs undergo biotransformation by COX-2 to lipid mediators that modulate tumor angiogenesis, which provides new insight into the beneficial effects of ω-3 PUFAs.
Exposure to hog barn dust alters airway epithelial ciliary beating
Authors: Wyatt T. A. , Sisson J. H. , Von Essen S. G. , Poole J. A. , Romberger D. J. 
Published: January 2008

Swine confinement workers are at increased risk of airway diseases, including mucus membrane irritation syndrome, chronic rhinosinusitis and chronic bronchitis. Dust extracts from swine confinement facilities stimulate the production of pro-inflammatory cytokines in bronchial epithelial cells, including interleukin (IL)-8. As IL-8 is capable of blocking β-agonist-stimulated increases in cilia beating, which impacts on mucociliary clearance, it was hypothesised that hog barn-dust exposure might alter cilia responses to stimulation.To test this hypothesis, ciliated bovine bronchial epithelial cell cultures were exposed to hog barn-dust extract (HDE) and ciliary beat frequency (CBF) was assayed.An elevation in baseline CBF was observed. This effect appeared to be independent of endotoxin but dependent upon nitric oxide. HDE also stimulated nitric oxide production in bronchial epithelial cells; however, stimulation of cilia beating by a β-agonist did not occur in cells pre-exposed to HDE.These data demonstrate that hog barn dust can alter normal stimulation of cilia, suggesting a mechanism for the abrogation of stimulated increases in mucociliary clearance in response to inhaled dust exposure.
Changes in elastic fibres in the small airways and alveoli in COPD
Authors: Black P. N. , Ching P. S. T. , Beaumont B. , Ranasinghe S. , Taylor G. , Merrilees M. J. 
Published: January 2008

Small airways are the major site of airflow obstruction in chronic obstructive pulmonary disease (COPD). This is attributed to loss of elastin in alveoli and fibrosis in small airways. In the present study, it was hypothesised that changes to elastic fibres in alveoli might be paralleled by a similar reduction in elastic fibres in small airways.Tissue blocks from patients who had lobectomy for bronchial carcinoma were studied. Patients were classified as COPD (forced expiratory volume in one second (FEV1) <80% predicted, FEV1/forced vital capacity (FVC) <0.7) or controls (FEV1≥80% pred, FEV1/FVC ≥0.7). Elastic fibres were visualised using Elastic van Gieson staining and the volume fraction (v/f) of elastic fibres was determined as a percentage of tissue volume using point counting. Elastic fibre networks were also visualised by confocal microscopy.The v/f for elastic fibres in alveoli was 18.6% for COPD and 32.8% in controls. In the airways the v/f was 14.6% for COPD and 25.5% in controls. FEV1% predicted was correlated with v/f in both alveoli and small airways.The volume fraction of elastic fibres was reduced to a similar extent in small airways and alveoli in chronic obstructive pulmonary disease and both were correlated with the extent of airflow obstruction. Loss of elastic fibres in small airways may contribute to the development of airflow obstruction in chronic obstructive pulmonary disease.
Standardversuspatient-centred asthma education in the emergency department: a randomised study
Authors: Smith S. , Mitchell C. , Bowler S. 
Published: January 2008

High re-attendance rates are common after asthma emergency department (ED) care. Inadequate patient education has been cited as a potential cause of re-attendance and the optimal format of education is uncertain. The present study aimed to compare the effectiveness of patient-centred education (PCE) and standard asthma patient education on ED re-attendance.A randomised controlled trial was conducted at two inner-city Australian teaching hospitals’ EDs, where patients received either standard patient education (SPE) or PCE. Both groups received a six-topic curriculum. However, PCE patients reordered the topics according to their own priority and thus controlled the order of education.In total, 146 adult patients presenting to EDs with acute asthma were enrolled. After 4 months, ED re-attendance decreased from 22 to 12% in the PCE group and remained unchanged in the SPE group (between group odds ratio 0.4, 95% confidence interval (0.2–1.1)). In 78 patients discharged after ED care, the PCE group had fewer re-attendances after 4 and 12 months (0.3 (0.1–0.9) and 0.3 (0.1–0.8), respectively ). PCE patients with no general practitioner care in the preceding 7 days had fewer re-attendances after 4 and 12 months (0.1 (0.0–0.7) and 0.2 (0.0–0.6), respectively). A trend of better asthma control was evident, with a reduction in activity limitation.In conclusion, patient-centred education offers promise as a brief education process in the emergency department. However, a large multicentre trial of patient-centred education is required.
Cathepsin H and napsin A are active in the alveoli and increased in alveolar proteinosis
Authors: Woischnik M. , Bauer A. , Aboutaam R. , Pamir A. , Stanzel F. , de Blic J. , Griese M. 
Published: January 2008

Pulmonary alveolar proteinosis (PAP) is a group of rare diseases with disturbed homeostasis of alveolar surfactant. While 90% of the primary adult forms are caused by granulocyte-macrophage colony-stimulating factor autoantibodies, the underlying cause of the juvenile form remains unknown. In order to distinguish primary from secondary effects in the pathogenesis of these two forms, the present authors studied the surfactant protein processing proteases napsin A and cathepsin H.In total, 16 controls, 20 patients with juvenile PAP and 13 adults with idiopathic PAP were enrolled. Amounts and activities of the proteases in the bronchoalveolar lavage fluid (BALF) were determined by immunoblotting and specific substrate cleavage.Both proteases were present and active in BALF from controls and increased in juvenile and adult PAP patients. The amount of active cathepsin H in relation to total cathepsin H was increased in PAP patients compared with controls. Cystatin C, the physiological inhibitor of cathepsin H in the alveolar space, was not increased to the same degree as cathepsin H, resulting in an imbalance of inhibitor to protease in the alveolar space.A general defect in napsin A or cathepsin H expression or activity was not the specific cause for abnormal surfactant accumulation in juvenile pulmonary alveolar proteinosis.
Impact of chronic airflow obstruction in a working population
Authors: Roche N. , Dalmay F. , Perez T. , Kuntz C. , Vergnenègre A. , Neukirch F. , Giordanella J-P. , Huchon G. 
Published: January 2008

Data on the individual and collective impact of chronic airflow obstruction at a population level are scarce. In a nationwide survey, dyspnoea, quality of life and missed working days were compared between subjects with and without spirometrically diagnosed chronic airflow obstruction.Subjects aged ≥45 yrs were recruited in French health prevention centres (n = 5,008). Results of pre-bronchodilator spirometry and questionnaires (European Community Respiratory Health Survey-derived questionnaire and European quality of life five-dimension questionnaire) were collected. Adequate datasets were available for 4,764 subjects aged 60±10 yrs (only 2% were aged ≥80 yrs).The prevalence of airflow obstruction (forced expiratory volume in one second/forced vital capacity of <0.70) was 7.5%. The vast majority (93.9%) of cases had not been diagnosed previously. Health status was significantly influenced by dyspnoea. Both were associated with the number of missed working days. Despite mild-to-moderate severity, subjects with chronic airflow obstruction exhibited more dyspnoea, poorer quality of life and higher numbers of missed working days (mean 6.71versus1.45 days·patient−1·yr−1in patients without airflow obstruction, for the population with no known heart or lung disease).In conclusion, even mild-to-moderate airflow obstruction is associated with an impaired health status, which represents an additional argument in favour of early detection in chronic obstructive pulmonary disease.
Right ventricular contractility in systemic sclerosis-associated and idiopathic pulmonary arterial hypertension
Authors: Overbeek M. J. , Lankhaar J-W. , Westerhof N. , Voskuyl A. E. , Boonstra A. , Bronzwaer J. G. F. , Marques K. M. J. , Smit E. F. , Dijkmans B. A. C. , Vonk-Noordegraaf A. 
Published: January 2008

Since systemic sclerosis (SSc) also involves the heart, the aim of the present study was to evaluate possible differences in right ventricular (RV) pump function between SSc-associated pulmonary arterial hypertension (PAH; SScPAH) and idiopathic PAH (IPAH).In 13 limited cutaneous SScPAH and 17 IPAH patients, RV pump function was described using the pump function graph, which relates mean RV pressure (P̄RV) and stroke volume index (SVI). Differences in pump function result in shift or rotation of the pump function graph.P̄RVand SVI were measured using standard catheterisation. The hypothetical isovolumicP̄RV(P̄RV,iso) was estimated using a single-beat method. The pump function graph was approximated by a parabola:P̄RV = P̄RV,iso[1–(SVI/SVImax)2], where SVImaxis the hypothetical maximal SVI at zeroP̄RV, enabling calculation of SVImax.There were no differences in SVI and SVImax. BothP̄RVandP̄RV,isowere significantly lower in SScPAH than in IPAH (P̄RV30.7±8.5versus41.2±9.4 mmHg;P̄RV,iso43.1±12.4versus53.5±10.0 mmHg). Since higher pressures were found at similar SVI, the difference in the pump function graph results from lower contractility in SScPAH than in IPAH.Right ventricular contractility is lower in systemic sclerosis-associated pulmonary arterial hypertension than in idiopathic pulmonary arterial hypertension.
Distinguishing phenotypes of childhood wheeze and cough using latent class analysis
Authors: Spycher B. D. , Silverman M. , Brooke A. M. , Minder C. E. , Kuehni C. E. 
Published: January 2008

Airway disease in childhood comprises a heterogeneous group of disorders. Attempts to distinguish different phenotypes have generally considered few disease dimensions. The present study examines phenotypes of childhood wheeze and chronic cough, by fitting a statistical model to data representing multiple disease dimensions.From a population-based, longitudinal cohort study of 1,650 preschool children, 319 with parent-reported wheeze or chronic cough were included. Phenotypes were identified by latent class analysis using data on symptoms, skin-prick tests, lung function and airway responsiveness from two preschool surveys. These phenotypes were then compared with respect to outcome at school age.The model distinguished three phenotypes of wheeze and two phenotypes of chronic cough. Subsequent wheeze, chronic cough and inhaler use at school age differed clearly between the five phenotypes. The wheeze phenotypes shared features with previously described entities and partly reconciled discrepancies between existing sets of phenotype labels.This novel, multidimensional approach has the potential to identify clinically relevant phenotypes, not only in paediatric disorders but also in adult obstructive airway diseases, where phenotype definition is an equally important issue.
Outcomes in Squamous Cell Carcinoma with Advanced Neck Disease
Authors: Keir James A , Whiteside Olivia JH , Winter Stuart C , Maitra Sushir , Corbridge Rogan C , Cox Graham J 
Published: January 2008

INTRODUCTION Treatment of advanced neck disease (N2c/N3) in head and neck squamous cell carcinoma is contentious. The aim of this study was to review the survival outcome following surgical excision of neck disease and the complications of this surgery. PATIENTS AND METHODS A retrospective review of the case notes of 39 patients treated at the Oxford Radcliffe Infirmary Head and Neck Unit with squamous cell carcinoma and advanced neck metastases confirmed as either pN2c or pN3 on histological examination was performed. Patients were treated with surgery and, in some cases, with adjunctive postoperative radiotherapy at the centre between August 1996 and November 2004. The study sought to establish the demographics, UICC staging/pathology, method of treatment, complications, recurrence and survival. Kaplan-Meier curves were used for statistical analysis of survival. Comparisons were then made between the cohort and historical control groups. RESULTS All patients were UICC stage IV disease. The 2- and 5-year overall survival in patients with resectable disease was 63% and 52%, respectively. DISCUSSION Patients with advanced neck disease have traditionally been thought to have terrible prognosis and, therefore, treatment is controversial. In treating advanced head and neck cancer, there has been a recent trend away from surgery towards chemotherapy and/or radiotherapy. CONCLUSIONS Comparing this study group to historical controls that include chemotherapy and/or radiotherapy, the outcomes appear favourable. The use of a combination of radiotherapy and surgery is advocated; it is suggested that advanced neck disease can have an acceptable prognosis and morbidity and that local disease control may be achieved.
What do Patients Think about being Copied into their GP Letters?
Authors: Pothier David D , Nakivell Paul , Hall Charles EJ 
Published: January 2008

INTRODUCTION Sending patients a copy of the letters that are produced for their referring general practitioners (GPs) from an out-patient consultation is a policy of the UK Department of Health. Little research has been done to establish how patients attending out-patient departments feel about this practice and the effect this may have on the department itself. PATIENTS AND METHOD We asked 500 patients attending our out-patient department to complete a questionnaire. Patients were only included if they had previously been offered a copy letter by our department. RESULTS Of patients, 95% were in favour of the practice and 93.4% understood all or most of the contents of the letter. Dictation in front of the patients made them less likely to request a copy of the letter (P < 0.001). Impact of queries related to the letters was minimal with only three patients making contact with the department during the 3 months that the study was being conducted. CONCLUSIONS Our experience has shown that copying patients into their GP letters is a useful and popular practice for patients and has little impact on the running of the department. Patients also are in favour of having their letter dictated in their presence and this reduces their need to have a copy sent to them.
Bacterial Contamination of Hospital Bed-Control Handsets in a Surgical Setting: A Potential Marker of Contamination of the Healthcare Environment
Authors: Brady RRW , Kalima P , Damani NN , Wilson RG , Dunlop MG 
Published: January 2008

INTRODUCTION Patients undergoing colorectal surgical resections have a high incidence of surgical site infection (SSI). Many patient-specific risk factors have been recognised in association with SSI in such patients, but environmental contamination is increasingly recognised as a contributor to hospital-acquired infection (HAI). This study set out to describe the bacterial contamination of the patient environment, using hospital bed-control handsets, as they are frequently handled by both staff and patients and represent a marker of environmental contamination. PATIENTS AND METHODS On two unannounced sampling events, 1 week apart, 140 bacteriological assessments were made of 70 hospital bed control handsets within a specialist colorectal surgical unit. RESULTS Of the handsets examined, 67 (95.7%) demonstrated at least one bacterial species (52.9% grew 1, 30% grew 2 and 12.9% grew 3 or more bacterial species). Of these, 29 (41.4%) bed-control handsets grew bacteria known to cause nosocomial infection, including 22 (31.4%) handsets which grew Enterococcus spp., 9 (12.9%) which grew MRSA, 2 (2.9%) which grew MSSA, 2 (2.9%) which grew coliforms, and 1 (1.4%) handset which grew anaerobes. At 1-week follow-up, 31 bed-control handsets showed evidence of contamination by the same bacterial species. CONCLUSIONS This study revealed high levels of bacteria known to cause HAI, contaminating hospital bed-control handsets in a surgical setting. Further study is now required to confirm whether hospital environmental contamination is causally involved in SSI.
Three Fatal Cases of Squamous Cell Carcinoma Arising in Chronic Perineal Hidradenitis Suppurativa
Authors: Maclean Gael M , Coleman David J 
Published: January 2008

INTRODUCTION Hidradenitis suppurativa (HS) is a chronic, inflammatory and suppurative disorder of skin bearing apocrine glands. The most severe complication is squamous cell carcinoma (SCC) and we here present three cases, all of which proved fatal, and review the past 40 years of published cases. PATIENTS AND METHODS Three advanced cases of SCC arising in chronic HS have been referred for reconstructive surgery over the past 8 years. Another 28 cases published over the past 40 years were identified using a Medline search (search items in combination: hidradenitis, squamous, carcinoma). RESULTS The male:female ratio was 4:1, most (61%) were perineal or buttock. We found no reports of SCC arising in axillary disease. The symptomatic history of HS prior to SCC diagnosis ranged from 3–50 years with a mean of 25 years. Age at diagnosis of SCC ranged from 27–71 years, and 15 patients (48%) died within 2 years of SCC diagnosis. CONCLUSIONS We advocate that hidradenitis suppurativa arising in extra-axillary sites is a pre-malignant condition, and should not be treated conservatively; curative resection is the mainstay of management.
Nephroureterectomy for Transitional Cell Carcinoma – The Value of Pre-Operative Histology
Authors: Chitale Sudhanshu , Mbakada Rashidi , Irving Stuart , Burgess Neil 
Published: January 2008

INTRODUCTION Nephroureterectomy with excision of a cuff of bladder remains the standard for managing upper tract transitional cell carcinoma (TCC). Increasing use of diagnostic upper tract endoscopy has underlined the importance of obtaining a pre-operative histological diagnosis in order to avoid under-treating high-grade or multifocal disease and over-treating low-grade disease, which could, in selected cases, be managed conservatively. We review nephroureterectomy at our institution over a 10-year period with particular reference to a pre-operative histological diagnosis. PATIENTS AND METHODS Nephroureterectomy was performed in 113 patients from February 1994 to February 2004. Of these cases, 58 were for upper tract TCC and 50 of these 58 had intravenous urography (IVU): 9 had only IVU, 28 had an additional CT scan, 5 had an additional ultrasonography and 8 had additional CT + ultrasonography for pre-operative work-up. Thirty-four of the 58 cases had retrograde pyelography. Nineteen (32.7%) of the 58 cases had a pre-operative ureteroscopy (URS) and biopsy; 14 of these had rigid URS for tumours in the lower (11) and middle (3) thirds of the ureter and 5 had flexible URS for pelvicalyceal tumours by an experienced endourologist. Thirty-one (53%) of the 58 tumours were within the pelvicalyceal system and 27 within the ureter (upper, 5; middle, 3; lower, 19). Forty-eight patients underwent a total nephroureterectomy: 40 had a two incision approach and 8 had an endoscopic resection of the lower ureter. Five of the 58 cases had a sub-total nephroureterectomy and 5 a laparoscopic nephroureterectomy with open excision of lower ureter. RESULTS Nineteen (32.7%) of the 58 patients had a pre-operative histological diagnosis – 17 G2pTa, 1 G1pTa, and 1 G2pT1. Fourteen (74%) biopsies matched the final postoperative histology, but 1 was down-staged, 3 up-staged and 1 up-graded compared to the original histology. Five (12.8%) of 39 patients without pre-operative histology had no TCC in the final surgical specimen: 4 (10.25%) had benign pathology such as capillary haemangioma, urothelial cysts and reactive urothelial changes while one had renal cell carcinoma (RCC). CONCLUSIONS This study underlines the importance of obtaining a pre-operative histological diagnosis in cases with presumed upper tract TCC. Failure to do so can result in unnecessary ablative surgery for benign disease. Such an approach can also help identify multifocality and grade of disease so that treatment of upper tract TCC can be tailored more appropriately with ablative surgery for high-grade or multifocal disease and conservative (endoscopic) therapy for low-grade disease in selected cases. Patients with suspected TCC of the upper tract should be managed at centres where facilities for the comprehensive evaluation of such tumours exist.