tbuckley/cabot-search huggingface dataset:
The emerging role of the contractile and vascular reserves in pulmonary arterial hypertension
Authors: Edmund M.T. Lau, David S. Celermajer, Robert Naeije
Journal: European Respiratory Journal (2015)

We agree with our colleagues J.C. Grignola and E. Domingo on the importance of measurements of both right ventricular (RV) and pulmonary vascular reserve in patients with pulmonary arterial hypertension, and that further studies are needed to define the most relevant variables and optimal methodology [1]. They have a point that isometric-phase measures of RV systolic function, such as isovolumic myocardial acceleration, may be preferable, as they are less load-dependent than more commonly assessed indices, such as the S ′ wave, tricuspid annular plane systolic excursion, fractional area change or ejection fraction. Isometric-phase measurements best correlate with the gold-standard end-systolic elastance in intact experimental animals [2]. The maximum velocity of isovolumic contraction has been shown to be a stronger predictor of outcome than a number of other echocardiographic measurements of RV function in patients with severe pulmonary hypertension [3]. However, what matters in the end is how RV contractility increases in a fashion adapted to afterload [4]. This may be disclosed by simpler surrogate measurements of contractile reserve such as changes in RV peak systolic pressure during exercise [5]. Clinical utility and optimal indices of RV contractile reserve in PAH remains an open question <http://ow.ly/L7XbS>
Risk Reduction Strategies for Ductal Carcinoma In Situ
Authors: Adam L. Cohen, John H. Ward
Journal: Journal of the National Comprehensive Cancer Network (2010)

Ductal carcinoma in situ (DCIS) is a premalignant condition that, if left untreated, may progress to invasive breast cancer. After lumpectomy, DCIS can recur, and about half of recurrences are invasive. In 4 randomized trials, radiation has been shown to decrease the local recurrence rate by about half, though it does not change survival. Based on the results of 3 randomized trials, tamoxifen probably decreases cancer recurrence by about 30%, particularly in young women. Low fat diets, weight loss, and physical activity decrease invasive breast cancer recurrence and may be recommended to certain women with DCIS. Prognostic factors include age, extent of DCIS, margin status, grade, and presence of necrosis, although how these affect adjuvant therapy is unclear. Research evaluating other drugs to reduce recurrence risk and on different ways of delivering radiation continues.
Efficacy and safety of abediterol, a long-acting β2-adrenergic agonist (LABA); three phase II trials in asthma
Authors: Jutta Beier, Dave Singh, Rainard Fuhr, Sandrine Ruiz, Beatriz Seoane, Eric Massana, Eulalia Jimenez, Helena Pujol, Carol Astbury, Gonzalo De Miquel
Journal: European Respiratory Journal (2014)

Background   Abediterol (LAS100977) is a novel LABA in development as a fixed dose combination with an inhaled corticosteroid for the treatment of asthma and COPD. We report efficacy and safety data from three Phase II trials of abediterol in patients with persistent, stable asthma.   Methods   Abediterol was assessed in three randomized, double-blind, placebo-controlled, crossover trials. Single doses were administered in the morning via Cyclohaler ®  (Study 1 and 2) or Genuair ®  (Study 3). Studies 1 and 3 had active comparators (salmeterol and salbutamol, respectively). Change from baseline in FEV 1  was assessed and treatment emergent adverse events (TEAEs) were recorded.   Results   In total, 25, 28 and 62 patients were randomized to treatment in Studies 1, 2 and 3, respectively (all male in Studies 1 and 2). Over a range of doses (0.313, 0.625, 1.25, 2.5, 5, 10 and 25 µg), abediterol produced rapid (≤ 15 minutes post-dose), sustained, clinically significant bronchodilation versus placebo. Trough FEV 1  was significantly higher with all doses of abediterol versus placebo (table). TEAEs were consistent with the drug class and most were mild to moderate in intensity.   Conclusion   Abediterol was generally safe and well tolerated, producing rapid, sustained, clinically significant improvements in bronchodilation versus placebo in patients with asthma.
Bone metastases: pathophysiology and management policy.
Authors: O S Nielsen, A J Munro, I F Tannock
Journal: Journal of Clinical Oncology (1991)

The pathophysiology and options for management of bone metastases as well as criteria for determining response to therapy are reviewed. Bone metastases are frequently one of the first signs of disseminated disease in cancer patients. In the majority of patients, the primary tumor is in the breast, prostate, or lungs. Although almost all patients will die of their disease, a proportion of the patients will survive for several years. Treatment is primarily palliative: the intention is to relieve pain, prevent fractures, maintain activity and mobility, and, if possible, to prolong survival. Therapeutic options include local treatment with radiotherapy and/or surgery, and systemic treatment using chemotherapy, endocrine therapy, radioisotopes, agents such as diphosphonates, which inhibit resorption of bone, as well as analgesic and antiinflammatory drugs. The mechanisms by which pain is relieved by several of these therapies remain unclear but actions beyond a simple tumoricidal effect appear to be important. There have been few randomized trials comparing the therapeutic options, and the criteria for assessing response to therapy have, in general, been poorly defined. There is a need for rigorous clinical investigations that assess the efficacy of the various therapeutic possibilities by using well-defined and validated criteria of response.
Inspiratory and expiratory airways resistance in relation to exercise-induced bronchoconstriction (EIB) and airways inflammation
Authors: Henrik Johansson, Pasquale Pompilio, Margareta Emtner, Raffaele Dellaca, Andrei Malinovschi
Journal: European Respiratory Journal (2014)

Airways resistance measured by forced oscillation technique (FOT) is suggested to be a more sensitive marker of airway obstruction than spirometry. The significance of increased airways resistance after bronchial challenge in absence of significant FEV 1 -fall has not been studied. Furthermore, the choice of using inspiratory or expiratory resistance is debated.  Exhaled NO (FeNO) at baseline and FEV 1  and within-breath inspiratory and expiratory resistance at 5 Hz (R 5insp  and R 5exp ) were measured before and 10 minutes after a standardized exercise test in 116 children, aged 13-16 years, a subsample from a population-based study where subjects with current asthma were excluded. EIB was defined as a FEV 1 -fall≥10%.  Higher baseline R 5insp  levels, but similar FEV 1  levels (p=0.14) and R 5exp  (p=0.73), were found in subjects with EIB (n=34) vs without (n=82): 3.39 ± 0.12 vs 3.14 ± 0.06, p=0.04. Among subjects without EIB (n=82), large (>=25%) increase of R 5insp  (n=14) related to higher FeNO: 17.1 ppb (11.0, 26.6) vs 12.1 (10.7, 13.8), p=0.04. This was not found for large increase (≥25%) of R 5exp  (p=0.32). On the opposite, in subjects with EIB, large increase of R 5exp  (n=13) was associated with higher FeNO at baseline: 28.4 (17.2, 47.0) vs 12.4 (10.1, 15.4) (p 5insp  (p=0.24).  In conclusion, inspiratory resistance appears to be a more sensitive marker of airways obstruction than FEV 1  and exercise-induced changes in this parameter relate to subclinical airways inflammation in subjects without EIB. Exercise-induced changes in expiratory resistance were associated with airways inflammation in subjects with EIB.
Role of bronchial artery embolisation in chronic recurrent haemoptysis
Authors: Debajyoti Bhattacharyya, Kamal Pathak, M.S. Barthwal, Cds Katoch
Journal: European Respiratory Journal (2012)

Introduction: Bronchial artery embolisation (BAE) involves selective bronchial artery angiography, followed by embolisation of identified abnormal vessels. It is useful in massive haemoptysis. But there are only a few literatures on its use in chronic recurrent haemoptysis.  Aims and objectives: To assess the efficacy and safety of BAE in the management of chronic recurrent haemoptysis.  Methods: This is a retrospective study of all patients with chronic recurrent haemoptysis who underwent BAE between January 2007 and January 2012 in a tertiary care hospital. The decision to offer BAE and its timing was jointly made after assessment by respiratory physician and interventional radiologist.  Results: 63 patients, (39 males and 24 females), underwent BAE for chronic recurrent haemoptysis during the period of study. Mean age of patients was 32.5 years (range: 18-81 years). Maximum number of patients recruited in this study had active pulmonary tuberculosis (29 cases – 46.0%). Amongst them, five patients had MDR, and one case had XDR-TB. 18 (28.5%) patients had bronchiectasis. Malignancy was the cause of haemoptysis in 7 (11.1%) cases. Mycetoma was present in 5 (7.9%) cases. One patient (1.5%) had lung abscess. BAE was successful in 58 (92.1%) cases. Bleeding stopped in 3 more patients following repeat procedure within a period of 48 hours. There was no major complication. Three patients had a short period of self limiting febrile illness. Three other patients developed local haematoma which improved following compression of the local part.  Conclusions: BAE is an effective means of controlling chronic recurrent haemoptysis. It is also a safe procedure.
Basic spirometric parameters of coke plant workers over the years
Authors: Emilia Kolarzyk, Wojciech Szot, Joanna Zajac
Journal: European Respiratory Journal (2012)

The aim of this study was to examine respiratory system efficiency in workers employed as coke plant battery staff in Steel Mill in Krakow over the years.  Methods: The spirometric examinations were performed at 3 different times:  1st in 1974 - 65 workers (age: 32,7+4,8 years, period of occupational exposure-8,8+4,6 years); 2nd in 1990 - the same 65 workers (they worked all the time in the same workshop; 48,8+5,1 years; 24,6+4,7 years respectively); 3rd in 2012 - 49 workers (age: 46,27±8,9, period of occupational exposure - 22.4±7.91)  In 1974 -1990 the levels of industrial pollution at workplace were similar. The concentration of SO2 was 15,4±6,6 mg/m3 and exceeded TLV, NOx -2,6±1,5 mg/m3, total dust-7,5-29,1 mg/m3 and free silicon dioxide-1,5-11,5%, geometric dimension of dust granule-3,9-4,5 um. In 2012 due to changes in both ownership of coke plants and increase in workers security, measured values were: SO2 - 8,9±4,4 mg/m3, NOx -2,1±1,1 mg/m3, total dust-0.3-3.0 mg/m3 and free silicon dioxide –2.0-3.6%  Results:  The medians of basic parameters measured at 1st, 2nd and 3rd examination were as follows:  VC - 5,22 l (118,2%N); 4,46 l (91,1%N) and 4,89 l (97,8%N).  FEV1 - 4,19 l (107,2%N); 3,37 l (90,6%N) and 3,81 l (99,94%N).  FEV1/VC: 79%; 76%; and 79,04% respectively.  Conclusions:  After 16 years of occupational exposure to gaseous and dust pollutants (1st & 2nd) significant decline of basic respiratory parameters was noted but they were still in the normal range.  After transformations in Poland the coke plant was modernized and environmental conditions significantly improved therefore it was agree with expectation that the new generation of workers also had the high efficiency of respiratory system.
Placebo-Controlled Study of the D<sub>4</sub>/5-HT<sub>2A</sub> Antagonist Fananserin in the Treatment of Schizophrenia
Authors: Philippe Truffinet, Carol A. Tamminga, Louis F. Fabre, Herbert Y. Meltzer, Marie-Emmanuelle Riviï¿½re, Catherine Papillon-Downey
Journal: American Journal of Psychiatry (1999)

The authors' objective was to assess the potential efficacy of fananserin (RP62203), a potent antagonist at the D4 and serotonin2A (5-HT2A) receptors, on symptoms of schizophrenia.A double-blind, placebo-controlled study was conducted in 97 patients. Doses of fananserin reached 250 mg b.i.d. over 28 days, starting with an 8-day escalation. Most of the patients were men with paranoid schizophrenia; they were approximately 38 years old. The primary outcome measure was the total Positive and Negative Syndrome Scale score. The patients' mean score on the Positive and Negative Syndrome Scale at entry was 91.8 (SD=16.5). A low dropout rate was observed in both groups of patients (19 [30%] of those given fananserin and nine [27%] of those given placebo).The total Positive and Negative Syndrome Scale score of the patients given fananserin decreased at endpoint by a mean of 4.2 points (SD=15.4); the score of the patients given placebo decreased by 6.7 points (SD=19.6). No differences between treatments were found on secondary measures such as the Clinical Global Impression, Positive and Negative Syndrome Scale subscores or individual items, and Brief Psychiatric Rating Scale total score. The patients' extrapyramidal symptoms did not worsen during the trial, but the patients given fananserin had an increase in akathisia. The safety profile was good in both groups of patients.The results of this study do not support the prediction that a selective D4 antagonist associated with strong 5-HT2A antagonism will exhibit an antipsychotic effect.
Techniques in Evacuation Proctography in the Diagnosis of Intractable Constipation and Related Disorders
Authors: A M Roe, D C C Bartolo, N J McC Mortensen
Journal: Journal of the Royal Society of Medicine (1986)

A technique of evacuation proctography using a simple barium and air mixture is described. The study can be easily combined with a barium enema examination. A series of 35 patients with intractable constipation have been studied and compared with 7 controls. Most of the abnormalities seen using more elaborate methods of defaecography were identified. Variants of rectal intussusception were found in 16 patients. Other diagnoses included rectocele, mucosal and full rectal prolapse, accentuation of puborectalis impression and solitary rectal ulcer. The technique should prove useful in the management of patients with disorders of defaecation.
Pathogenicity of Lupus Anti–Ribosomal P Antibodies: Role of Cross‐Reacting Neuronal Surface P Antigen in Glutamatergic Transmission and Plasticity in a Mouse Model
Authors: Fabián Segovia‐Miranda, Felipe Serrano, Agnieszka Dyrda, Estibaliz Ampuero, Claudio Retamal, Marcela Bravo‐Zehnder, Jorge Parodi, Pedro Zamorano, David Valenzuela, Loreto Massardo, Brigitte van Zundert, Nibaldo C. Inestrosa, Alfonso González
Journal: Arthritis & Rheumatology (2015)

Objective To assess whether autoantibodies against ribosomal P (anti‐P), which are possibly pathogenic in neuropsychiatric systemic lupus erythematosus (NPSLE), alter glutamatergic synaptic transmission and to what extent the cross‐reacting neuronal surface P antigen (NSPA) is involved. Methods We analyzed glutamatergic transmission and long‐term potentiation (LTP) mediated by AMPA receptor (AMPAR) and N ‐methyl‐ d ‐aspartate receptor (NMDAR) by field excitatory postsynaptic potential (EPSP) at the CA3–CA1 synapse. AMPAR activation by patch‐clamp recordings in primary ventral spinal cord neurons was analyzed. In primary hippocampal neurons, NSPA distribution was assessed by double immunofluorescence, and intracellular calcium changes were evaluated using Fura‐2 AM. NSPA‐LacZ reporter–knockin mice expressing a truncated NSPA were used to assess NSPA expression pattern and function in the brain using β‐galactosidase staining and comparative electrophysiology, calcium responses, and water maze memory tests. Results NSPA was expressed in the brain in hippocampal CA1, dentate gyrus and ventral, but not dorsal, CA3 regions, encompassing postsynaptic regions and partial colocalization with NMDAR. Notably, NSPA‐LacZ reporter–knockin mice showed impaired memory, and decreased NMDAR activity and LTP, with neurons insensitive to anti‐P autoantibodies. Anti‐P autoantibodies enhanced CA1 postsynaptic transmission, increasing AMPAR and NMDAR activity and leading to LTP abrogation after prolonged (20‐minute) incubation. Conclusion Our findings indicate that the neuronal cell surface target of anti‐P, NSPA, is involved in glutamatergic synaptic transmission and plasticity related to memory in the hippocampus, and mediates the deleterious effects of anti‐P on these processes. Cognitive impairment, as well as other diffuse NPSLE manifestations, may develop when anti‐P autoantibodies have access to brain regions coexpressing NSPA, AMPAR, and NMDAR.
Cancer Mortality Among Patients With Hansen's Disease
Authors: Louise A. Brinton, Robert Hoover, Robert R. Jacobson, Joseph F. Fraumeni
Journal: JNCI Journal of the National Cancer Institute (1984)

For the evaluation of cancer risks associated with immunodeficiencies experienced by patients with Hansen's disease (leprosy) and for the assessment of possible adverse effects of dapsone therapy, a follow-up study was conducted of 1,678 patients admitted to the National Hansen's Disease Center in Carville, La., between 1939 and 1977. Overall, no substantial cancer mortality was observed (standardized mortality ratio=1.3), nor was there any excess among patients exhibiting defects in cellular immunity by virtue of lepromatous forms of the disease. Notable was the absence of any significant excess of lymphoma (5 observed vs. 2.3 expected), despite the predominance of this tumor in certain other immunodeficiency states. Several cancer sites (oral, bladder, and kidney) occurred excessively, but reasons for the elevations were obscure. Although dapsone has been implicated as a carcinogen in laboratory animals, the use of sulfones, including dapsone, did not appear to affect significantly the risk of any cancers in this population.
A codon-based model of nucleotide substitution for protein-coding DNA sequences.
Authors: N Goldman, Z Yang
Journal: Molecular Biology and Evolution (1994)

A codon-based model for the evolution of protein-coding DNA sequences is presented for use in phylogenetic estimation. A Markov process is used to describe substitutions between codons. Transition/transversion rate bias and codon usage bias are allowed in the model, and selective restraints at the protein level are accommodated using physicochemical distances between the amino acids coded for by the codons. Analyses of two data sets suggest that the new codon-based model can provide a better fit to data than can nucleotide-based models and can produce more reliable estimates of certain biologically important measures such as the transition/transversion rate ratio and the synonymous/nonsynonymous substitution rate ratio.
Non-Invasive Cardiac Investigations in Patients Awaiting Renal Transplantation
Authors: E J Langford, A J De Belder, H Cairns, B M Hendry, R J Wainwright
Journal: Journal of the Royal Society of Medicine (1997)

Patients with chronic renal failure undergoing renal transplantation have a high prevalence of cardiovascular disease. Invasive investigation may identify those at risk of cardiac death during or after renal transplantation, but which patients should undergo cardiac catheterization is currently not clear. In 95 patients awaiting renal transplantation we assessed the ability of echocardiography and exercise electrocardiography to identify patients at risk of cardiac death. Echocardiography identified impaired left ventricular (LV) systolic function in 20%, severe in 8%. Of the patients with severe LV dysfunction, 25% died before transplantation. Of those undergoing exercise electrocardiography, 44% did not achieve 85% of maximum predicted heart rate. No coronary artery disease requiring intervention was identified by exercise testing. These findings indicate that echocardiography, but not exercise electrocardiography, should be part of the assessment for renal transplantation.
Liver-Directed Therapies in Patients With Advanced Neuroendocrine Tumors
Authors: Natalie B. Jones, Manisha H. Shah, Mark Bloomston
Journal: Journal of the National Comprehensive Cancer Network (2012)

Neuroendocrine tumors (NETs) are increasing in incidence. Incidental NETs that may have little clinical significance, such as gastric and rectal primaries, are often identified because of increased screening efforts and advanced imaging modalities. Although NETs are biologically indolent cancers, many patients present with incurable metastatic disease to the liver at initial diagnosis. Some literature suggests a delay averaging almost 5 years in making the correct diagnosis based on clinical symptoms. Although surgical resection offers the only potentially curative therapy, liver-directed therapies, such as embolization and ablation, offer effective alternatives to control symptoms and potentially impact overall survival. This article reviews the latest liver-directed approaches to the management of advanced NETs.
Endoplasmic reticulum stress in circulating cystic fibrosis neutrophils
Authors: Killian Hurley, William Leitch, Nessa Banville, Stephen Cox, Kerstin Pohl, Emer Reeves, Noel McElvaney
Journal: European Respiratory Journal (2012)

Introduction:  Cystic fibrosis (CF) is caused by a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. A number of studies have been performed to investigate whether neutrophil dysfunction in CF is primarily as a result of the genetic defect or due to chronic bacterial infection and inflammation.  Aim:  The aim of this study was to provide support for intrinsic alterations in CF, specifically to determine whether accumulation of CFTR within the endoplasmic reticulum (ER) of circulating neutrophils from patients with CF leads to ER stress responses including the release of ER calcium (Ca 2+ ) stores. This study focused on the ER-resident chaperone, GRP78 and ATF6, a transcription factor that coordinates the unfolded protein response (UPR).  Methods:  Neutrophils were purified from whole blood and the cytosols were analysed using Western blotting for ER stress markers ATF6 and GRP78. Intracellular Ca 2+  was determined using a fluorometric assay.  Results:  Western blots revealed that markers of ER stress, GRP78 and cleaved ATF6, were increased in neutrophil cytosols of patients with CF homozygous for the ΔF508 mutation, when compared to healthy controls (n=8 for both groups). In addition, densitometric analysis of immuno-bands confirmed significant up-regulation of both GRP78 and active ATF6 in CF neutrophils compared to control cells (p 2+  was increased in the CF neutrophils compared to healthy controls.  Conclusions:  Our data demonstrates for the first time activation of the UPR  in vivo  in neutrophils isolated from individuals with CF, which may in part explain the exaggerated inflammatory response of these cells.