tbuckley/cabot-search huggingface dataset:
TGF-β alters TRPC6 expression and calcium handling via smad2/3 in human airway smooth muscle
Authors: David Wright, Yasin Shaifta, Vladimir Snetkov, Jeremy Ward
Journal: European Respiratory Journal (2013)

Rationale: IL-13 and TGF-β have been shown to affect expression of calcium handling proteins in airway smooth muscle (ASM). We hypothesise they also alter expression of TRPC6 channel proteins.  Methods: Cultured ASM cells were serum starved for 72h before treatment. SMAD2 and SMAD3 siRNAs were transfected using AmaxaTM nucleofector (Lonza). Protein expression was measured via western blots, and intracellular calcium with Fura3-PE/AM.  Results: Treatment of ASM cells for 1 week with TGF-β (10ng/ml) increased TRPC6 protein (285 ± 48% n=17 p  TGF-β significantly reduced SMAD3 protein (p  Conclusions: TGF-β but not IL-13 results in differential increases in TRPC6 splice variant expression, regulated by SMAD2/3. As this was accompanied by reduced calcium mobilisation, we speculate increased expression of non-functional TRPC6 variants may contribute to impaired calcium handling in asthma.
Vivian Byron John Edwards
Authors: R. Edwards
Journal: BMJ (2015)

Vivian Byron John Edwards was one of a dwindling number with memories of prewar Repton. Born in Leicester in 1920, he had a distinguished Repton career, entering the school in 1934, becoming head of priory, a school prefect and representing the school at football hockey and fives which he captained. He excelled at all ball games, but especially at football. as a freescoring centreforward. He gained his “teamer” in 1936 and led the line for a further two seasons. He went on to represent his regimental and hospital football teams. He was also a useful tennis player …
Manipulating cerebral blood flow affects central sleep apnea at high altitude
Authors: Keith Burgess, Samuel Lucas, Kelly Shepherd, Andrew Dawson, Marianne Swart, Kate Thomas, Jui-Lin Fan, Rebekah Lucas, Karen Peebles, Rishi Basnyat, Philip Ainslie
Journal: European Respiratory Journal (2012)

Background

There is an almost universal (>90%) occurrence of central sleep apnea (CSA) in newcomers to high altitude (>5000 m). However, the key factors that determine the severity of CSA upon arrival to high altitude and during acclimatization are not well understood. We hypothesized that cerebral blood flow (CBF) was an important component in the etiology of CSA at high altitude.

Aim

To measure the effects of altering cerebral blood flow (CBF) on central sleep apnoea (CSA) at high altitude.

Methods

12 normal volunteers aged 30 ± 10 years were studied 6-9 days after arrival at 5,050 metres. After control measurements they received ivi Acetazolamide (Acet) 10mgs/kg or oral Indomethacin (Indo) 100mgs with placebo controls in a randomized order on separate nights. Ventilatory Responses (VRs), ABGs, Apnea-Hypopnea Index (AHI) during the first 3 hours of sleep by polysomnography (PSG) and CBF by transcranial Doppler were recorded. AHI was also measured upon arrival and after 12-15 days to control for acclimatization.

Results

CBF rose by 28% with Acet and fell by 23% with Indo. PaCO2 rose from 28 ± 4 to 31 ± 3 mm Hg with Acet (p<0.001), whereas, ABGs were unchanged with Indo. VRs were unchanged with Acet but Indo increased Hypercapnic VR by 43% (p <0.05). AHI was halved by Acet (89 to 47/hr, (p <0.001), but increased 25% with Indo (89 to 112/hr, p <0.05).

Conclusions

Indomethacin reduced CBF and increased Hypercapnic VR and CSA during the first 3 hours of sleep. Whereas Acetazolamide increased CBF but had no effect on VRs yet reduced CSA severity. These results highlight the link between CBF and CSA at high altitude.

Supported by: Peninsula Sleep Laboratory, University of Otago and EVK2CNR.
Practical use of quantiferon test in Norway's largest TB-clinic
Authors: Saeed Vahedi, Cathrine Brunborg, Anne-Marte Bakken Kran
Journal: European Respiratory Journal (2011)

Introduction: Since November2008, Norway's largest TB-clince (Diagnosestasjonen, Oslo University Hospital, Ulleval) has implemented Quantiferon-TB GOLD In-Tube test (QFT) as a supplement to tuberculin skin test (TST)

Aim& objectives: The aim of our study was to evaluate clinical use and consequenses of QFT results for the patient.

Methodes & design: Patients with conclusive QFT result between November 2008 and December 2009, were included in this retrospective cross-sectional study.

Results: 415 patients were included and categorized by reason for referral: Immigrants (31,1%), School children (49.6%), Immunmodulation (7.5%), TB-Contacts (10.6%), Other (1.2%). Only 14 (3,4%) patients had negative TST (Mantoux 35 (OR 3.5) compared to age group<14, reported TB-exposure (OR 4.5), and high-incidence TB region of birth (OR 3.84). QFTresult was the single most important factor for determining clinical outcome: 116 patients (94.3%) of patients with positive QFT tests were selected for either preventive therapy or follow-up, versus 11 (3.8%) of patients with negative tests.

Conclusions: QFT result was the single most influencing factor on the clinicians decisionmaking. Though QFT has reduced numbers of patients given treatment and follow-up, it is important to keep in mind the limited sensitivity of QFT in certain patient groups when interpreting the QFT results.
Autologous bone marrow transplantation for patients with non-Hodgkin's lymphoma and CNS involvement: those transplanted with active CNS disease have a poor outcome--a report by the European Bone Marrow Transplant Lymphoma Registry.
Authors: C D Williams, R Pearce, G Taghipour, E S Green, T Philip, A H Goldstone
Journal: Journal of Clinical Oncology (1994)

CNS involvement of non-Hodgkin's lymphoma (NHL) has always been considered a poor prognostic factor in relation to survival with conventional therapy. However, its effect on the outcome of autologous bone marrow transplantation (ABMT) has not been assessed. We examined this using data from the European Bone Marrow Transplant (EBMT) Lymphoma Registry.One thousand four hundred sixty-four patients with NHL have been reported to the EBMT registry, of whom 62 had CNS involvement. Patients were divided into those who were clear of CNS disease at the time of ABMT and those who were not. Response, complications, and outcome to ABMT were analyzed, as were details of CNS diagnosis, treatment, and prophylaxis.Status at transplant was the only factor that significantly affected outcome of ABMT on univariate analysis (P = .03). The progression-free survival (PFS) rate of the group that had no CNS involvement at ABMT was 42% at 5 years, compared with 27% in a group of stage IV NHL patients without CNS disease (matched for status at transplant and histology). There were four of 45 (8.9%) toxic deaths. The PFS rate of the group that had CNS involvement at ABMT was 9% at a median follow-up time of 71 months, which was significantly different (P = .001) from that of the other group. There were five of 17 (29.4%) toxic deaths (P = .043). Patients who had CNS involvement at diagnosis, as compared with relapse, and those treated with both intrathecal chemotherapy and irradiation had a better outcome.The presence of CNS disease before ABMT but not present at transplant does not adversely affect the outcome of ABMT. In contrast, patients with CNS involvement at the time of ABMT have a poor prognosis, although a small number survive in complete remission (CR).
Distribution of WFDC2/HE4, a putative host defence protein, in the respiratory tract of normal and diseased mice
Authors: Olympia Gianfrancesco, Lynne Bingle, Colin Bingle
Journal: European Respiratory Journal (2013)

WFDC2/HE4 encodes a poorly characterised secretory protein that shares structural similarity to the multifunctional host defence protein, SLPI, through possession of two conserved Whey Acidic Protein/four disulphide-core (WFDC) domains. Like SLPI, WFDC2 is expressed in multiple epithelia within the respiratory tract and although its’ function remains unresolved, recent evidence supports its9 role as an antiproteinase. We have previously shown that it is over-expressed in lung diseases characterised by abnormalities of protease/antiprotease balance, including cystic fibrosis. Nothing is known about the distribution of WFDC2 in the mouse. In this study we have systematically localized the protein in normal adult mice as well in a number of mouse models characterised by epithelial remodelling. Strong WFDC2 staining is seen throughout the airway epithelium from the trachea down to the smallest airways. Staining is also seen in tracheal submucosal glands. No staining is seen in the peripheral lung. Interestingly, staining is absent from the respiratory epithelium of the nasal passages whereas goblet cells stain strongly in these locations. In bleomycin and OVA treated mice there is elevated staining throughout the remodeled epithelium that is not limited to goblet cells and strikingly there is very strong staining within the alveolar (Type II) cells in these regions. Mouse WFDC2 is elevated in a number of chronic disease models and suggests that the gene exhibits a level of promiscuity relating to its molecular regulation. Knowledge of the complex expression pattern of this protein will allow the use of tractable mouse models of disease to dissect its’ function.
Epidemiology of invasive fungal diseases among patients with haematological disorders in the Asia-Pacific: a prospective observational study
Authors: L.Y. Hsu, D.G. Lee, S.P. Yeh, D. Bhurani, B.Q. Khanh, C.Y. Low, L. Norasetthada, T. Chan, Y.L. Kwong, A.K. Vaid, I. Alejandria, M. Mendoza, C.Y. Chen, A. Johnson, T.Y. Tan
Journal: Clinical Microbiology and Infection (2015)
Real World experiences: Pirfenidone is well tolerated and reduces decline in FVC and TLCO at 9 months in IPF
Authors: Nazia Chaudhuri, Annette Duck, Jayne Holme, Rebecca Frank, Colm Leonard
Journal: European Respiratory Journal (2013)

INTRODUCTION: IPF has a 2-5 year mortality from diagnosis. Pirfenidone is the only licenced drug in Europe for IPF. Here we demonstrate our experiences in the UK with Pirfenidone on the named patient programme (NPP).  METHODS: This was a single centre observational study. We retrospectively analysed the data from 40 patients treated with Pirfenidone from September 2011 to January 2012.  RESULTS: Mean age was 65.8 years (range 48-80) with 70% (28/40) males. The average duration of treatment was 42.3 weeks (range 11-74). During this period 9 (22%) patients died due to progression of their IPF. 21/40 (53%) patients experienced gastrointestinal adverse effects. Of these 7 (34%) were self-limiting. 4 (19%) resolved after a dose reduction, in 3 (14%) patients Pirfenidone was restarted after the adverse effect settled and in 7 (33%; 17% total) Pirfenidone was discontinued.  Nine months before and after Pirfenidone commencement we observed a reduction in the decline of FVC and TLCO with a difference in gradients pre and post Pirfenidone of -1.02 vs 0.07 and -2.37 vs 0.07 respectively.  CONCLUSION: Pirfenidone is well tolerated. Adverse effects are predominantly gastrointestinal, self-limiting and occur within 8 weeks of the start of treatment. Although our numbers are small we demonstrate a reduction in the decline of FVC and TLCO at 9 months. Further longitudinal follow-up is required.
Expression of telomerase enzyme as predictive factor of response to first line chemotherapy with gemcitabine/carboplatin in advanced non-small cell lung cancer (IIIB and IV)
Authors: M. Pluma-Jimenez, S. Castillo-Medina, B. Murillo-Ortiz, S. Labastida, I. Alvarado, G. Olivares-Beltran, J. A. Silva, H. Astudillo-De La Vega
Journal: Journal of Clinical Oncology (2006)

17156 Background: Non-small cell lung cancer (NSCLC) is the most frequent neoplasia in the world and the main cause of death for cancer. The palliative chemotherapy is the elected treatment for patients in stage III and IV. The telomerase enzyme is expressed in 82% of neoplasias and its activity is implied in the genomic instability, apoptosis inhibition and cell immortalization. Objective: To determine the predictive value of the expression of the telomerase enzyme with the first line regimen gemcitabine (1 gr/m 2 SC, days 1 and 8) and carboplatino (AUC of 5 in day 1) every 28 days in patients with NSCLC clinical stages IIIB and IV. The response and toxicity rate was also determined. Methods: Patients were recruited in a period between 04/01/2004 and 11/30/2004, ages between 18 and 80, ECOG ≤ 2, measured disease (RECIST), virgin to treatment, permissible hematic biometry for chemotherapy and optimal kidney function. A total of 17 patients with an average age of 61 (range 44 to 77 years old) 9/17 (53%) males and 8/17 (47%) females, 4/17 with clinical stage IV (23%) and 13/17 with clinical stage IIIB (77%) from which: 8/13 (61%) presented pleural effusion. From the total number of patients, 1/17 presented ECOG 0 (6%), 14/17 ECOG 1 (82%) and 2/17 ECOG 2 (12%). The histopathologic diagnosis was adenocarcinoma in 12/17 (70%) and epidermoid carcinoma in 5/17 (30%). A rabbit polyclonal antibody was used to asses the expression of the telomerase enzyme by the immunohistochemical method. Results and Conclusions: It was demonstrated in 11/17 patients that the high expression of telomerase enzyme is directly correlated to the lack of response to treatment (3/11 patients stable disease and 4/11 with progressive disease); and a low or absent expression (4/11 patients) was correlated to a response higher than 30% (p = 0.045). The obtained response rate was lower that the previous ones reported with the regimen gemcitabine (days 1, 8 every 21 days and 1, 8 and 15 every 28 days) presenting a minimum hematologic toxicity. This analysis suggests that the telomerase enzyme could be a response predictive marker in the NSCLC with this therapeutic regimen. No significant financial relationships to disclose.
Clinical Discussion and Review of the Management of Brain Metastases
Authors: Priscilla K. Brastianos, William T. Curry, Kevin S. Oh
Journal: Journal of the National Comprehensive Cancer Network (2013)

Brain metastases are common in patients with cancer and are associated with a poor prognosis. Optimal treatment requires an integrative multidisciplinary approach, and therapeutic options may include stereotactic radiosurgery, whole-brain radiation therapy, surgical resection, chemotherapy, and targeted agents. The goals of therapy are to prolong survival, preserve neurologic function, and palliate symptoms. This article outlines the various therapeutic modalities, factors that guide treatment decisions, and medical management of frequently encountered complications of brain metastases.
LSC 2013 abstract - Early vascular remodelling in pulmonary fibrosis occurs concomitant with proliferation of vascular-associated cells
Authors: Kristina Rydell-Tormanen, Gunilla Westergren-Thorsson
Journal: European Respiratory Journal (2013)

Introduction:  Early manifestations of pulmonary fibrosis may include vascular symptoms e.g. vascular remodelling. Normally this phase goes unnoticed in patients, however to fully understand the pathogenesis, it is essential to understand this early phase. The   aim   was to investigate early vascular remodelling in pulmonary fibrosis, using a model with a specific initiation time.   Methods:  We injected mice subcutaneously with bleomycin (or saline) 3 times/week for 4 weeks. Animals were sacrificed after 1, 2, 3 and 4 weeks. α-SMA area/vessel perimeter (µm 2 /µm) was used to determine vascular remodelling in small parenchymal vessels. Bleomycin induce proliferation and to determine the nature of these cells, the following double-stainings were done; PCNA/α-SMA, PCNA/CD31 and PCNA/NG2.   Results:  Vascular remodelling starts early; at 1, 2 and 3w α-SMA was significantly increased compared to controls. At 4w, difference to controls was detected. A large proportion of the proliferating cells had perivascular localization and was often positive for NG2, whereas few cells were positive for α-SMA and CD31.   Conclusions:  Results suggest vascular remodelling to be an early feature in pulmonary fibrosis. The decreased remodelling at 4w may indicate a shift to a fibrotic phase, supported by our previous findings of increased fibrosis at 4w The remodelling was associated with increased proliferation of vascular-associated cells; smooth muscle and endothelial cells as well as a population likely to be pericytes (NG2-positive cells). Thus it appears that different cell-types contribute to vascular remodelling and the process is dynamic.
Obese asthmatics have reduced exercise capacity and higher ventilation than non-obese asthmatics
Authors: Gaia Mandolesi, Marco Contoli, Brunilda Marku, Eva Bernardi, Luca Pomidori, Annalisa Cogo
Journal: European Respiratory Journal (2012)

Obesity is a modifiable risk factor of asthma (Beuther 2007). Regular exercise is associated to better asthma control but little is known about the exercise capacity and physical activity level (PAL) in obese asthmatics.

Aim Analyze exercise capacity, ventilation (VE) during exercise, physical activity and QoL in obese compared with normal weight asthmatics.

Methods 48 asthmatics (29F), age 57,4±11, regularly visited at Asthma Center of Ferrara University Hospital were submitted to spirometry, 7 days PAL monitoring (Armband®), QoL questionnaire (AQLQ) and walking test (6MWT) with VE analysis (Spiropalm, Cosmed).

Results 

19 subjects were obese (OB), 17 overweight (OW), 12 normal weight (NW). FEV1% was < in subjects with BMI ≥ 25 (72.1±17 vs 81.5±17, ns). PAL (METs) in OB was < OW and NW(1,3±0,2 vs 1,5±0,3; 1,5±0,2, *) independently from the severity of obstruction. No difference in QoL was found.

OB and OW showed a reduced exercise capacity and SpO2% in comparison to NW.

View this table:

table 1





No difference in dyspnea Borg scale (0-10).

VE analysis during 6MWT: OB showed a higher maximal increase (%) in VE than NW, independently from the level of obstruction and mainly due to the increase in tidal volume (TV).

View this table:

table 2





Conclusions In asthmatics, obesity influences negatively the daily physical activity and exercise capacity through mechanisms which appear independent from the severity of bronchial obstruction.
Analysing recurrent hospitalizations in heart failure: a review of statistical methodology, with application to <scp>CHARM</scp>‐Preserved
Authors: Jennifer K. Rogers, Stuart J. Pocock, John J.V. McMurray, Christopher B. Granger, Eric L. Michelson, Jan Östergren, Marc A. Pfeffer, Scott D. Solomon, Karl Swedberg, Salim Yusuf
Journal: European Journal of Heart Failure (2013)
Abstract 1062: Optimized Ventriculo-Arterial Interaction Explains Better Longitudinal Function in Endurance-Trained Athletes by Comparison with Strength-Trained Athletes
Authors: Maria Florescu, Ileana Petcu, Carlo Palombo, Mircea Cinteza, Dragos Vinereanu
Journal: Circulation (2008)

To assess differences in cardiac function induced by endurance- and strength- training. To identify mechanisms of ventriculo-arterial interaction, and their effects on cardiac function. 69 male (21...
Gene Expression Changes in Leukocytes During Cardiopulmonary Bypass Are Dependent on Circuit Coating
Authors: Joerg Seeburger, Jan Hoffmann, Hans Peter Wendel, Gerhard Ziemer, Hermann Aebert
Journal: Circulation (2005)

Background— Cardiopulmonary bypass (CPB) results in a systemic inflammatory response. Leukocytes play a crucial role in inflammatory reactions. Their gene expression profile in the context of CPB is unknown. Methods and Results— In a prospective, randomized, and double-blind clinical trial, 12 male patients underwent elective coronary artery bypass grafting with either heparin-coated (group H) or protein-coated (group P) CPB circuits. Oligonucleotide microarray analyses of 22 283 genes were performed on circulating leukocytes, collected immediately before surgery and 6 hours after CPB. Microarray results were validated with real-time polymerase chain reaction. All patients had uneventful surgery, and no significant differences between groups were observed during the clinical course. Multiple statistical analyses with different methods were performed. Compared with preoperative expression at a threshold value of P &lt;0.01, postoperative expression revealed 814 upregulated and 1187 downregulated genes in group H compared with 99 upregulated and 231 downregulated in group P ( P &lt;0.001). Fifty genes exhibited a &gt;4-fold increase and 27 exhibited a &gt;4-fold decrease in group H, whereas only 7 genes exhibited upregulation and 7 revealed downregulation in group P. Microarray-pathway-profile-finder analyses determined 1405 upregulated and 1454 downregulated pathways in group H compared with 552 upregulated and 818 downregulated pathways in group P ( P &lt;0.01). Pathways related to inflammatory response exhibited highest z scores in group H, reflecting cellular inflammatory activation. Conclusions— Heparin coating resulted in a more profound alteration in leukocyte gene expression when compared with protein coating. Microarray analyses present an innovative approach for the evaluation and understanding of inflammatory reactions associated with CPB.
The familial influence on bilateral testicular germ cell cancer: Medical Research Council study TER2
Authors: S. J. Harland, G. Daugaard, A. Horwich, G. M. Mead, S. D. Fossa, M. Sokal, D. Morgenstern, R. Oliver, P. A. Cook, S. P. Stenning
Journal: Journal of Clinical Oncology (2006)

4590 Background: There is evidence that hereditary predisposition is important in the aetiology of testicular cancer but the mode of inheritance is unknown. Methods: To test the hypothesis that bilateral disease (5% of testis cancer) is a manifestation of hereditary predisposition, a family questionnaire was sent to patients with bilateral disease (cases) and responses compared with institutional controls with unilateral disease (two approached for every case), matched for year of first diagnosis. The primary outcome measure was the risk of testis cancer in the brothers of cases and controls, and a relative risk of between 4.1 and 5.0 was anticipated based on the model of Nicholson and Harland (BJC 1995 71:421–426). Results: Responses from 191 cases and 373 controls have been analysed. No evidence of reduced fertility was found in the parents or grandparents of cases compared to those of controls. Cases (48%) were less likely to have children than controls (64%). The mean (SD) age of onset of testicular cancer was lower in cases (31 (9)) than controls (35 (9)), p &lt; 0.001. The incidence of testis cancer in the relatives of cases and controls are shown in the table . Conclusions: The 4.6-fold greater risk to brothers of cases confirms the role of a familial predisposition in bilateral testicular cancer. Given the incomplete ascertainment for brothers, there is likely to be a greater risk to brothers than fathers. No major effect of an X-linked gene is found. These findings are in keeping with previously described hereditary models for testicular cancer. [Table: see text] No significant financial relationships to disclose.
Calm Study: Secondary Endpoints of a Phase Ii Study of a Novel Oncolytic Immunotherapeutic Agent, Coxsackievirus A21, Delivered Intratumorally in Patients with Advanced Malignant Melanoma
Authors: R.H. Andtbacka, B. Curti, H. Kaufman, G.A. Daniels, J.J. Nemunaitis, L.E. Spitler, S. Hallmeyer, J. Lutzky, S. Schultz, E.D. Whitman, K. Zhou, J.I. Weisberg, D. Shafren
Journal: Annals of Oncology (2014)