tbuckley/cabot-search huggingface dataset:
Effect of an ambulatory diagnostic and treatment programme in patients with sleep apnoea
Authors: A. L. Andreu, E. Chiner, J. N. Sancho-Chust, E. Pastor, M. Llombart, E. Gomez-Merino, C. Senent, F. Barbe
Journal: European Respiratory Journal (2011)

The aim of this study to evaluate the efficacy of a home-based programme on clinical response, continuous positive airway pressure (CPAP) compliance and cost in a population of high pre-test probability of suffering obstructive sleep apnoea syndrome (OSAS). Patients were randomised into the following three groups. Group A: home respiratory polygraphy (RP) and home follow-up; group B: hospital polysomnography and hospital follow-up; and group C: home RP and hospital follow-up. Evaluation during 6 months included Epworth Sleepiness Scale (ESS), Functional Outcomes Sleep Questionnaire (FOSQ), and daily activity and symptom questionnaires. Compliance was assessed by memory cards (group A) and using an hourly counter (groups B and C). 66 patients were included (22 per branch), 83% were males, aged mean±sd 52±10 yrs, body mass index 34±7kg·m(-2), apnoea/hypopnoea index 43±20 h(-1), CPAP pressure 8±2 cmH(2)O, with no between-group differences. Clinical response showed an ESS of mean±sd 15±3 to 6±4, a FOSQ of 16±3 to 18±2, symptoms of 43±7 to 25±7, and activity of 37±11 to 25±8. At the end of the study, compliance was: group A 73%, group B 68% and group C 57%. The cost per patient was: group A €590±43, group B €894±11 and group C €644±93 (p<0.001). In conclusion, patients with a high initial probability of having OSAS can be diagnosed and treated in a home setting, with a high level of CPAP compliance and lower cost than using either a hospital-based approach or home RP/hospital follow-up.
Is aromatization of testosterone to estradiol required for inhibition of luteinizing hormone secretion in men?
Authors: R J Santen
Journal: Journal of Clinical Investigation (1975)

A variety of studies in man and animals demonstrate that testosterone (T) is aromatized to estradiol (E) in the hypothalamus and limbic system. These observations suggested the possibility that conversion to E is an absolute requirement for the biologic activity of T on the hypothalamic-pituitary axis. Since this hypothesis implies a common mechanism of action of these two steroids, the demonstration of divergent effects of T and E on luteinizing hormone (LH) secretion would exclude this possibility. To test this hypothesis, the actions of T and E on three separate aspects of LH release (mean LH, pulsatile LH secretion, and responsiveness to LH-releasing hormone [LH-RH]) were contrasted. T and E, infused at two times their respective production rates into normal men, reduced mean LH levels similarly during 6 h of steroid infusion and for 6 h thereafter. However, these steroids exerted different effects on pulsatile secretion. E reduced the amplitude of spontaneous LH pulse from pre- and postinfusion control levels of 75+/-14 and 68+/-5.6% (SEM) to 39+/-5.7%. In contrast, T increased pulse amplited to 96+/-14% and decreased pulse frequency from basal levels of 3.4+/-0.31 to 1.8+/-0.31 pulses/6h. The site of suppressive action was determined by administering 25 microgms of LH-RH to the same men during T and E infusions and during three additional control periods without steroid administration. LH-RH produced similar 170-190% increments in serum LH during the three control periods and during T infusion. In contrast, E markedly blunted (76+/-31%, p less than 0.005) the LH response to LH-RH. Under the conditions of acute steroid infusion at doses (utilized in these experiments) producing similar inhibition of mean LH, E but not T acted directly on the pituitary to diminish LH-RH responsiveness. As further support that androgens can act without conversion to estrogens, the effects of a nonaromatizable androgen, dihydrotestosterone (DHT), on mean LH levels were studied. DHT, infused at the same rate as T, suppressed mean LH to a similar but somewhat greater extent than T. Since T and E produced divergent effects on LH secretion and a nonaromatizable androgen, DHT, suppressed mean LH, aromatization is not a necessary prerequisite for the action of androgens on the hypothalamic-pituitary axis.
Cell Adhesion Molecule L1 Disrupts E-Cadherin-Containing Adherens Junctions and Increases Scattering and Motility of MCF7 Breast Carcinoma Cells
Authors: Michael Shtutman, Elina Levina, Patrice Ohouo, Mirza Baig, Igor B. Roninson
Journal: Cancer Research (2006)

Abstract The first steps of invasion and metastasis include the dissociation of adherens junctions and the induction of migratory phenotype, through a program that resembles epithelial-mesenchymal transition (EMT). The L1 cell adhesion molecule, which is normally found primarily in the brain, was recently shown to be expressed in different types of cancer and to have tumor-promoting activity. We now find that L1 mediates EMT-like events in MCF7 breast carcinoma cells. MCF7 predominantly expresses the nonneuronal isoform of L1, as do 16 of 17 other cell lines derived from different types of cancer. L1 protein expression in MCF7 cells, which form E-cadherin-containing adherens junctions, is inversely related to cell density. Analysis of MCF7 cells with overexpression or knockdown of nonneuronal L1 isoform revealed that L1 expression leads to the disruption of adherens junctions and increases β-catenin transcriptional activity. As a result, L1 expression promotes the scattering of epithelial cells from compact colonies. Expression of the full-length L1 protein, but not of its soluble extracellular moiety, increases the motility of the MCF7 epithelial monolayer in a wound-healing assay, in which L1 expression is preferentially observed and required in cells leading the movement of the monolayer. Based on these results, we propose a model for the role of L1 as a trigger of EMT-like events in transformed epithelial cells. (Cancer Res 2006; 66(23): 11370-80)
Decreased Mitochondrial DNA Content in Posttreatment Salivary Rinses from Head and Neck Cancer Patients
Authors: Wei-Wen Jiang, Eli Rosenbaum, Elizabeth Mambo, Marianna Zahurak, Brett Masayesva, Andre Lopes Carvalho, Shaoyu Zhou, William H. Westra, Anthony J. Alberg, David Sidransky, Wayne Koch, Joseph A. Califano
Journal: Clinical Cancer Research (2006)

Abstract Purpose and Experimental Design: Alterations in mitochondrial DNA (mtDNA) sequence and content have been described in human tissues and tumors in association with smoking exposure. We did quantitative PCR analysis of cytochrome c oxidase (Cox) I and Cox II genes to measure changes in mtDNA content in pretreatment and posttreatment salivary rinses obtained from 76 patients undergoing surgical resection for primary head and neck squamous cell carcinoma. We also examined the relationship between changes in mtDNA content and postoperative radiation therapy, smoking exposure, alcohol intake, and other clinical characteristics. Results: Overall, mtDNA content in posttreatment saliva was significantly decreased. The mean change for Cox I was −0.21 [95% confidence interval (95% CI), −0.44 to 0.01, P = 0.06] and for Cox II was −0.31 (95% CI, −0.55 to −0.08, P = 0.01). Patients in the radiation therapy group exhibited a significant decrease compared with the nonradiated group (P = 0.03 for Cox I; P = 0.05 for Cox II). In addition, significant decreases in Cox I (−0.71; 95% CI, −1.17 to −0.25, P = 0.005) and Cox II (−0.65; 95% CI, −1.17 to −0.13, P = 0.02) were found in never-smoking patients but not in former or current smokers. Conclusion: Our data suggest that salivary mtDNA content is decreased in never smokers and in response to radiation therapy after primary surgical resection.
Tumor regrowth between surgery and initiation of adjuvant therapy in patients with newly diagnosed glioblastoma
Authors: Andrea Pirzkall, Colleen McGue, Suja Saraswathy, Soonmee Cha, Raymond Liu, Scott Vandenberg, Kathleen R. Lamborn, Mitchel S. Berger, Susan M. Chang, Sarah J. Nelson
Journal: Neuro-Oncology (2009)

To assess incidence and degree of regrowth in glioblastoma between surgery and radiation therapy (RT) and to correlate regrowth with presurgical imaging and survival, we examined images of 32 patients with newly diagnosed glioblastoma who underwent MR spectroscopic imaging (MRSI), perfusion-weighted imaging (PWI), and diffusion-weighted imaging (DWI) prior to surgery, after surgery, and prior to RT/temozolomide. Contrast enhancement (CE) in the pre-RT MR image was compared with postsurgical DWI to differentiate tumor growth from postsurgical infarct. MRSI and PWI parameters were analyzed prior to surgery and pre-RT. Postsurgical MRI indicated that 18 patients had gross total and 14 subtotal resections. Twenty-one patients showed reduced diffusion, and 25 patients showed new or increased CE. In eight patients (25%), the new CE was confined to areas of postsurgical reduced diffusion. In the other 17 patients (53%), new CE was found to be indicative of tumor growth or a combination of tumor growth and surgical injury. Higher perfusion and creatine within nonenhancing tumor in the presurgery MR were associated with subsequent tumor growth. High levels of choline and reduced diffusion in pre-RT CE suggested active metabolism and tumor cell proliferation. Median survival was 14.6 months in patients with interim tumor growth and 24 months in patients with no growth. Increased volume or new onset of CE between surgery and RT was attributed to tumor growth in 53% of patients and was associated with shorter survival. This suggests that reducing the time between surgery and adjuvant therapy may be important. The acquisition of metabolic and physiologic imaging data prior to adjuvant therapy may also be valuable in assessing regions of new CE and nonenhancing tumor.
Eplerenone in Patients with Systolic Heart Failure and Mild Symptoms
Authors: Faiez Zannad, John J.V. McMurray, Henry Krum, Dirk J. van Veldhuisen, Karl Swedberg, Harry Shi, John Vincent, Stuart J. Pocock, Bertram Pitt
Journal: New England Journal of Medicine (2010)

Mineralocorticoid antagonists improve survival among patients with chronic, severe systolic heart failure and heart failure after myocardial infarction. We evaluated the effects of eplerenone in patients with chronic systolic heart failure and mild symptoms.
Airways inflammation in chronic bronchitis: the effects of smoking and alpha1-antitrypsin deficiency
Authors: A.T Hill, D.L Bayley, E.J. Campbell, S.L Hill, R.A Stockley
Journal: European Respiratory Journal (2000)

Airways inflammation in chronic bronchitis is thought predominantly to be a direct consequence of neutrophil recruitment and release of elastase in response to factors such as cigarette smoke. The aims of this study were to assess the role of smoking and determine whether the serum elastase inhibitor alpha1-antitrypsin (alpha1AT) influenced the process. Airways inflammation was compared between patients with chronic obstructive bronchitis with (n=39) and without (n=42) severe alpha1AT deficiency. The authors assessed the sputum concentration of the neutrophil chemoattractants interleukin-8 (IL-8) and leukotriene (LT)B4, myeloperoxidase (MPO) as a marker of neutrophil influx, neutrophil elastase activity and its natural inhibitors, alpha1AT and secretory leukoprotease inhibitor (SLPI). Finally serum alpha1AT was measured to determine the degree of protein leakage (sputum sol serum alpha1AT ratio). Compared to current smokers, the exsmokers had a lower concentration of the chemoattractant IL-8 (p<0.05) and a lower MPO concentration, although this failed to reach conventional statistical significance (p=0.06). Patients with alpha1AT deficiency had greater inflammation in the larger airways with increased LTB4 (p<0.005), MPO (p<0.001), neutrophil elastase activity (p<0.01), protein leak (p<0.001), and were found to have a lower anti-proteinase screen with both reduced sputum alpha1AT (p<0.001) and SLPI concentrations (p<0.05). The reduction in sputum interleukin-8 levels in exsmokers may decrease neutrophil influx and thus explain the slower rate of neutrophil mediated progression of lung disease compared to subjects who continue to smoke. Patients with alpha1-antitrypsin deficiency had greater inflammation suggesting that alpha1-antitrypsin plays an important role in protecting the larger airways from the inflammatory effects of elastase activity and may explain their more rapid progression of disease.
Bronchoscopic inter-operator diagnostic yield for lung malignancy: benchmarking for trainees
Authors: A. Kahlon, M.E. Phitidis, A. Ponnuswamy, S. Scott, J.P. Finnerty
Journal: European Respiratory Journal (2012)

Introduction  British Thoracic Society guidelines suggest that in cases of endoscopically visible malignancy, bronchoscopists should aim for a minimum diagnostic yield of 80%. There is no recommendation however for the diagnostic yield that trainees should achieve before becoming independent bronchoscopists. We conducted a preliminary study in our bronchoscopy unit, comparing inter-operator diagnostic yield for cases of definite endoscopically visible malignancy, aiming to introduce a benchmark for trainees.  Method  We retrospectively looked at 775 bronchoscopies performed by three experienced bronchoscopists. Data was collected on the type of abnormality seen, the likelihood of malignancy, sampling modalities used and positivity rate of samples (histology/cytology) i.e. the diagnostic yield.  Results  A total of 114 bronchoscopies were reported as definite tumours, of which 103 were diagnosed as lung malignancies. The diagnostic yield when a definite tumour was seen on bronchoscopy was 90.9% (60/66) for operator 1, 72.8% (8/11) for operator 2, and 94.6% (35/37) for operator 3, with an overall average of 86.1%. The standard deviation for bronchoscopist success ratio was calculated at 9.55, making the lower limit for success (percentage of positive diagnostic yield) 75%.  Conclusion  Locally our experienced bronchoscopists are exceeding the 80% diagnostic yield in cases of a definite tumour. Using the lower limit for success, we suggest that 95% of trainee bronchoscopists should be achieving a minimum diagnostic yield of 75%. More data is needed in order to obtain more robust statistical data which can be developed into realistic benchmarks and assessment tools to measure trainee competency.
A Phase 1 Dose Escalation Study of the Safety and Pharmacokinetics of the Novel Proteasome Inhibitor Carfilzomib (PR-171) in Patients with Hematologic Malignancies
Authors: Owen A. O'Connor, A. Keith Stewart, Marcy Vallone, Christopher J. Molineaux, Lori A. Kunkel, John F. Gerecitano, Robert Z. Orlowski
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Carfilzomib (formerly PR-171) is a novel proteasome inhibitor of the epoxyketone class that is selective and structurally distinct from bortezomib. Proteasome inhibition by carfilzomib is mechanistically irreversible. Consequently, proteasome inhibition is more sustained with carfilzomib than with bortezomib. Experimental Design: In a phase 1 trial evaluating the safety and efficacy of carfilzomib in relapsed or refractory hematologic malignancies, eight dose groups of three to six patients received 5 consecutive days of carfilzomib i.v. push at doses of 1.2, 2.4, 4, 6, 8.4, 11, 15, and 20 mg/m2 within 14-day cycles. Results: Twenty-nine patients enrolled that were relapsed or refractory after at least two prior therapies. Nonhematologic toxicities included fatigue, nausea, and diarrhea in more than one third of patientsmostly grade 1 or 2 in severity. At 20 mg/m2, grade 3 febrile neutropenia and grade 4 thrombocytopenia were reported, establishing 15 mg/m2 as the maximum tolerated dose. No grade 3 or 4 peripheral neuropathies were reported. Antitumor activity was observed at doses 11 mg/m2: one unconfirmed complete response (mantle cell), one partial response (multiple myeloma), and two minimal responses (multiple myeloma and Waldenstrm's macroglobulinemia). Conclusion: This is the first clinical use of carfilzomib that shows tolerability and clinical activity in multiple hematologic malignancies using consecutive-day dosing. (Clin Cancer Res 2009;15(22):708591)
Demonstration of islet-autoreactive CD8 T cells in insulitic lesions from recent onset and long-term type 1 diabetes patients
Authors: Ken T. Coppieters, Francesco Dotta, Natalie Amirian, Peter D. Campbell, Thomas W.H. Kay, Mark A. Atkinson, Bart O. Roep, Matthias G. von Herrath
Journal: The Journal of Experimental Medicine (2012)

A direct association of islet-autoreactive T cells with β cell destruction in human pancreatic islets from type 1 diabetes (T1D) patients has never been demonstrated, and little is known about disease progression after diagnosis. Frozen pancreas samples were obtained from 45 cadaveric T1D donors with disease durations ranging from 1 wk to >50 yr, 14 nondiabetic controls, 5 nondiabetics with islet autoantibodies, 2 cases of gestational diabetes, and 6 T2D patients. Sections were systematically analyzed for the presence of insulin-sufficient β cells, CD8(+) insulitic lesions, and HLA class I hyperexpression. Finally, consecutive sections from HLA-A2-expressing individuals were probed for CD8 T cell reactivity against six defined islet autoantigens associated with T1D by in situ tetramer staining. Both single and multiple CD8 T cell autoreactivities were detected within individual islets in a subset of patients up to 8 yr after clinical diagnosis. Pathological features such as HLA class I hyperexpression and insulitis were specific for T1D and persisted in a small portion of the patients with longstanding disease. Insulitic lesions consistently presented in a multifocal pattern with varying degrees of infiltration and β cell loss across affected organs. Our observations provide the first direct proof for islet autoreactivity within human islets and underscore the heterogeneous and chronic disease course.
A clinicopathological review of interstitial pneumonia with marked IgG4 positive plasma cells infiltration
Authors: Satoshi Ikeda, Tomohisa Baba, Machiko Arita, Tamiko Takemura, Takashi Ogura, Tadashi Ishida
Journal: European Respiratory Journal (2013)

Background;  There are few reports describing IgG 4 -related interstitial pneumonia (IP). Moreover, the clinical features of IgG 4 -related pulmonary disease without extra-thoracic manifestations are not well defined.   Objectives;  The aims of the present study were to clarify the clinical characteristics and pathological findings of IP with marked IgG 4  positive plasmacyte infiltration and to determine whether these cases should be diagnosed as a subtype of IgG 4 -related disease or not.   Methods;  From 2001 to 2012 inclusive, 15 patients (pts) were diagnosed by surgical lung biopsy with IP with marked plasmacyte infiltration. Among them, 7 pts were enrolled into our study, in whom immunostaining confirmed IP with marked IgG 4  positive plasmacyte infiltration (IgG 4 + plasma cells / IgG+ plasma cells > 40%).   Results;  All 7 pts were male and had a history of smoking. Serum IgG 4  level range was from 217 to 1070 mg/dl and antinuclear antibodies were highly positive in 5 pts. Histopathologically, NSIP pattern was found in 6 pts. Eosinophilic infiltration, obliterative phlebitis and storiform fibrosis were not evident. Lymphoid follicle with germinal center was observed in all cases. Five of 7 pts met the criteria for lung dominant connective tissue disease proposed by Fisher. Clinical response to corticosteroid therapy was good in all cases, but lung cancer developed in 3 pts.   Discussions;  The clinical efficacy of corticosteroid-therapy and high frequency of lung carcinoma was noteworthy. These cases may involve an independent disease group separate from typical IgG4-related disease or connective tissue disease associated with interstitial pneumonia.
Extensive variation in the ddl gene of penicillin-resistant Streptococcus pneumoniae results from a hitchhiking effect driven by the penicillin-binding protein 2b gene
Authors: M C Enright, B G Spratt
Journal: Molecular Biology and Evolution (1999)

An internal fragment of the ddl gene, encoding the cytoplasmic enzyme D-alanyl-D-alanine ligase, was sequenced from 566 isolates of Streptococcus pneumoniae and single isolates of Streptococcus mitis and Streptococcus oralis. The 52 alleles found among the S. pneumoniae isolates fell into two groups. Group A alleles were very uniform in sequence and were present in both penicillin-susceptible and penicillin-resistant pneumococci. Group B alleles were much more diverse and were found only in penicillin-resistant isolates. The Streptococcus oralis and Streptococcus mitis alleles were less diverged from group A alleles than some of the group B pneumococcal alleles, suggesting that the latter alleles contain interspecies recombinational replacements. The ddl gene was located 783 bp downstream of the penicillin-binding protein 2b gene (pbp2b). Sequencing of the pbp2b-recR-ddl-murF region of three penicillin-resistant pneumococci that had diverged ddl alleles showed that the whole region from pbp2b to ddl (or beyond) was highly diverged (about 8%) compared with the sequences from three penicillin-susceptible isolates. The high levels of diversity in the group B ddl alleles from penicillin-resistant isolates were ascribed to a hitchhiking effect whereby interspecies recombinational exchanges at pbp2b, selected by penicillin usage, often extend into, or through, the ddl gene. The data allow the average size of the interspecies recombinational replacements to be estimated at about 6 kb.
Markers of treatment failure in hospitalised community acquired pneumonia
Authors: R Menendez, M Cavalcanti, S Reyes, J Mensa, R Martinez, M A Marcos, X Filella, M Niederman, A Torres
Journal: Thorax (2008)

<h3>Background:</h3> Lack of response to treatment in community acquired pneumonia (CAP) worsens outcome. We evaluated the systemic cytokine profile (tumour necrosis factor α, interleukin (IL)1, IL6, IL8 and IL10), C reactive protein (CRP) and procalcitonin (PCT) in patients with CAP who had treatment failure. <h3>Methods:</h3> A prospective study was performed in hospitalised patients with CAP. Cytokines, PCT and CRP measurements were obtained on day 1 and after 72 h of treatment. Treatment failure was the endpoint evaluated, with separation of those with early (⩽72 h) or late failure. <h3>Results:</h3> 453 patients were included: 84 (18%) had treatment failure, of whom 38 (8%) were early failures. Median levels of IL6, PCT and CRP on days 1 and 3 and median levels of IL8 on day 1 were significantly higher in patients with any treatment failure. Logistic regression analysis demonstrated that values above the cut-off points for IL6 (⩾169 pg/ml), IL8 (⩾14 pg/ml) and CRP (⩾21.9 mg/dl) on day 1 had independent predictive value for any treatment failure after adjustment for initial severity; relative risks (OR) found were 1.9, 2.2 and 2.6, respectively. Increased levels for CRP and PCT on day 1 were also independent predictors for early failure. Increased levels for IL6 and CRP were the best predictors of late failure. <h3>Conclusions:</h3> Serum levels of CRP, IL6 and PCT on days 1 and 3 were independently associated with a higher risk of any treatment failure. Low levels of PCT and CRP on day 1 had a high negative predictive value for early failure.
Mechanisms of adipose tissue redistribution with rosiglitazone treatment in various adipose depots
Authors: Jun Goo Kang, Cheol-Young Park, Sung-Hee Ihm, Hyung Joon Yoo, Heesoon Park, Eun Jung Rhee, Jong Chul Won, Won Young Lee, Ki Won Oh, Sung Woo Park, Sun Woo Kim
Journal: Metabolism (2009)