tbuckley/cabot-search huggingface dataset:
Markers Indicating Deterioration of Pulmonary <i>Mycobacterium avium-intracellulare</i> Infection
Authors: YOSHITAKA YAMAZAKI, KEISHI KUBO, AKEMI TAKAMIZAWA, HIROSHI YAMAMOTO, TAKAYUKI HONDA, SHUSUKE SONE
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

To predict the natural history of pulmonary Mycobacterium avium-intracellulare (MAI) infection with nodular bronchiectasis, we retrospectively evaluated clinical manifestations, laboratory data, and bronchoalveolar lavage fluid (BALF) findings in 57 patients. The patients received follow-up chest computed tomographic scans and testing for sputum bacteriology between intervals of at least 12 mo. They were divided into two groups after observation for 28 ± 13 mo: deteriorated (n = 34) and not-deteriorated (n = 23). There were no patients with spontaneous improvement. At the start of observation, the mean age was greater in the deteriorated group (69 ± 9 yr) than in the not-deteriorated group (57 ± 9 yr). The mean body-mass index was lower in the deteriorated group (19.2 ± 3.1 kg/m2) than in the not-deteriorated group (21.5 ± 1.5 kg/m2). C-reactive protein, erythrocyte sedimentation rate, and carbohydrate antigen 19-9 were significantly elevated in the deteriorated group. The BALF findings of the deteriorated group showed that the neutrophil cell counts were significantly increased. Thirty-four of 57 patients with pulmonary MAI infection with nodular bronchiectasis had progressive clinical and/or radiographic disease. The older and thinner patients tended to become worse. Neutrophil-related inflammation associated with a decrease in CD4 + lymphocyte might reflect the progression of pulmonary MAI infection with nodular bronchiectasis. Yamazaki Y, Kubo K, Takamizawa A, Yamamoto H, Honda T, Sone S. Markers indicating deterioration of pulmonary Mycobacterium avium-intracellulare infection.
β-Blockers are associated with a reduction in COPD exacerbations
Authors: Surya P Bhatt, James M Wells, Gregory L Kinney, George R Washko, Matthew Budoff, Young-il Kim, William C Bailey, Hrudaya Nath, John E Hokanson, Edwin K Silverman, James Crapo, Mark T Dransfield
Journal: Thorax (2015)

Background While some retrospective studies have suggested that β-blocker use in patients with COPD is associated with a reduction in the frequency of acute exacerbations and lower mortality, there is concern that their use in patients with severe COPD on home oxygen may be harmful. Methods Subjects with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 2–4 COPD participating in a prospective follow-up of the COPDGene cohort, a multicentre observational cohort of current and former smokers were recruited. Total and severe exacerbation rates were compared between groups categorised by β-blocker use on longitudinal follow-up using negative binomial regression analyses, after adjustment for demographics, airflow obstruction, %emphysema on CT, respiratory medications, presence of coronary artery disease, congestive heart failure and coronary artery calcification, and after adjustment for propensity to prescribe β-blockers. Results 3464 subjects were included. During a median of 2.1 years of follow-up, β-blocker use was associated with a significantly lower rate of total (incidence risk ratio (IRR) 0.73, 95% CI 0.60 to 0.90; p=0.003) and severe exacerbations (IRR 0.67, 95% CI 0.48 to 0.93; p=0.016). In those with GOLD stage 3 and 4 and on home oxygen, use of β-blockers was again associated with a reduction in the rate of total (IRR 0.33, 95% CI 0.19 to 0.58; p&lt;0.001) and severe exacerbations (IRR 0.35, 95% CI 0.16 to 0.76; p=0.008). Exacerbation reduction was greatest in GOLD stage B. There was no difference in all-cause mortality with β-blocker use. Conclusions β-Blockers are associated with a significant reduction in COPD exacerbations regardless of severity of airflow obstruction. The findings of this study should be tested in a randomised, placebo-controlled trial. Trial registration number (ClinicalTrials.gov NCT00608764 ).
The Apicomplexan Whole-Genome Phylogeny: An Analysis of Incongruence among Gene Trees
Authors: C.-H. Kuo, J. P. Wares, J. C. Kissinger
Journal: Molecular Biology and Evolution (2008)

The protistan phylum Apicomplexa contains many important pathogens and is the subject of intense genome sequencing efforts. Based upon the genome sequences from seven apicomplexan species and a ciliate outgroup, we identified 268 single-copy genes suitable for phylogenetic inference. Both concatenation and consensus approaches inferred the same species tree topology. This topology is consistent with most prior conceptions of apicomplexan evolution based upon ultrastructural and developmental characters, that is, the piroplasm genera Theileria and Babesia form the sister group to the Plasmodium species, the coccidian genera Eimeria and Toxoplasma are monophyletic and are the sister group to the Plasmodium species and piroplasm genera, and Cryptosporidium forms the sister group to the above mentioned with the ciliate Tetrahymena as the outgroup. The level of incongruence among gene trees appears to be high at first glance; only 19% of the genes support the species tree, and a total of 48 different gene-tree topologies are observed. Detailed investigations suggest that the low signal-to-noise ratio in many genes may be the main source of incongruence. The probability of being consistent with the species tree increases as a function of the minimum bootstrap support observed at tree nodes for a given gene tree. Moreover, gene sequences that generate high bootstrap support are robust to the changes in alignment parameters or phylogenetic method used. However, caution should be taken in that some genes can infer a "wrong" tree with strong support because of paralogy, model violations, or other causes. The importance of examining multiple, unlinked genes that possess a strong phylogenetic signal cannot be overstated.
Hypermethylation of the DNA Repair Gene O6-Methylguanine DNA Methyltransferase and Survival of Patients With Diffuse Large B-Cell Lymphoma
Authors: Manel Esteller, Gianluca Gaidano, Steven N. Goodman, Vittorina Zagonel, Daniela Capello, Barbara Botto, Davide Rossi, Annunziata Gloghini, Umberto Vitolo, Antonino Carbone, Stephen B. Baylin, James G. Herman
Journal: JNCI Journal of the National Cancer Institute (2002)

Background: The gene encoding the DNA repair enzyme O6-methylguanine DNA methyltransferase (MGMT) is transcriptionally silenced by promoter hypermethylation in several human cancers, including diffuse large B-cell lymphoma (B-DLCL). MGMT promoter hypermethylation is a favorable prognostic marker in patients with brain tumors treated with alkylating agents. Methods: In a retrospective cohort study, we used methylation-specific polymerase chain reaction to analyze the MGMT promoter methylation status in tumor DNA of B-DLCL patients receiving cyclophosphamide as part of multidrug regimens. Molecular data were compared with patient response with the use of Student's t test. Disease-free survival and overall survival were estimated by the Kaplan–Meier method and compared with the use of the log-rank test. Multivariable survival analyses were performed with the Cox proportional hazards model. All statistical tests were two-sided. Results: Thirty (36%) of 84 B-DLCL patients showed MGMT promoter hypermethylation in their lymphomas. The presence of MGMT methylation was associated with a statistically significant increase in overall survival (hazard ratio for time to death for nonmethylation versus methylation = 2.8; 95% confidence interval (CI) = 1.2 to 7.5; P = .01) and progression-free survival (hazard ratio for time to progression for nonmethylation versus methylation = 2.6; 95% CI = 1.3 to 5.8; P = .02). MGMT promoter hypermethylation was both independent of and stronger than established prognostic factors, such as age, disease stage, serum lactic dehydrogenase level, and performance status. Conclusion: MGMT promoter hypermethylation appears to be a useful marker for predicting survival in patients with B-DLCL treated with multidrug regimens including cyclophosphamide.
Treatment of active rheumatoid arthritis with leflunomide: two year follow up of a double blind, placebo controlled trial versus sulfasalazine
Authors: D L Scott
Journal: Annals of the Rheumatic Diseases (2001)

Recent studies have demonstrated the short term efficacy of leflunomide. This study evaluates the efficacy and safety of leflunomide and sulfasalazine in rheumatoid arthritis over a two year follow up period.358 patients with rheumatoid arthritis in a double blind trial were randomly allocated to receive either leflunomide 20 mg/day, placebo, or sulfasalazine 2 g/day. Those completing six months of treatment (n=230) were given the option to continue in 12 (n=168) and 24 (n=146) month double blinded extensions; the placebo group switched to sulfasalazine. This report compares efficacy and safety of leflunomide with sulfasalazine in the 6, 12, and 24 month patient cohorts.The efficacy seen at six months was maintained at 12 and 24 months. Twenty four month cohorts on leflunomide showed significant improvement compared with sulfasalazine in doctor (-1.46 v -1.11, p=0.03) and patient (-1.61 v -1.04, p<0.001) global assessments, ACR20% response (82% v 60%, p<0.01), and functional ability (Deltamean HAQ -0.65 v -0.36, p=0.0149; DeltaHAQ disability index -0.89 v -0.60, p=0.059). Improvement in other variables was comparable for the two drugs, including slowing of disease progression. Improved HAQ scores in 6, 12, and 24 month leflunomide cohorts were seen in both non-responders (24%, 29%, 35%, respectively v sulfasalazine 8%, 10%, 27%) and ACR20% responders (leflunomide 63%, 62%, 66% v sulfasalazine 50%, 64%, 44%). Leflunomide is well tolerated at doses of 20 mg. No unexpected adverse events or late toxicity were noted during the two year period. Diarrhoea, nausea, and alopecia were less frequent with continued treatment.These long term data confirm that leflunomide is an efficacious and safe disease modifying antirheumatic drug.
Nutritional Implications of Genetic Taste Variation: The Role of PROP Sensitivity and Other Taste Phenotypes
Authors: Beverly J. Tepper
Journal: Annual Review of Nutrition (2008)

Genetic sensitivity to the bitter taste of phenylthiocarbamide and 6-n-propylthiouracil (PROP) is a well-studied human trait. It has been hypothesized that this phenotype is a marker for individual differences in taste perception that influence food preferences and dietary behavior with subsequent links to body weight and chronic disease risk. Steady progress has been made over the past several decades in defining the involvement of this phenotype and its underlying gene, TAS2R38, in this complex behavioral pathway. However, more work needs to be done to fully determine its overall nutritional and health significance. The primary goal of this review is to assess our current understanding of the role of the PROP bitter taste phenotype in food selection and body weight in both children and adults. A brief history of the field is included and controversies surrounding the use of different PROP screening methods are addressed. The contribution of other receptors (both bitter and nonbitter) to human taste variation is also discussed.
DYT16, a novel young-onset dystonia-parkinsonism disorder: identification of a segregating mutation in the stress-response protein PRKRA
Authors: Sarah Camargos, Sonja Scholz, Javier Simón-Sánchez, Coro Paisán-Ruiz, Patrick Lewis, Dena Hernandez, Jinhui Ding, J Raphael Gibbs, Mark R Cookson, Jose Bras, Rita Guerreiro, Catarina Resende Oliveira, Andrew Lees, John Hardy, Francisco Cardoso, Andrew B Singleton
Journal: The Lancet Neurology (2008)
Mortality in heart failure patients with nocturnal Cheyne-Stokes respiration receiving adaptive servoventilation (ASV) therapy
Authors: Olaf Oldenburg, Thomas Bitter, Birgit Wellmann, Natalie Prib, Britta Körber, Zisis Dimitriadis, Birgit Krause, Thomas Fischbach, Dieter Horstkotte
Journal: European Respiratory Journal (2012)

Sleep-disordered breathing (SDB) with Cheyne-Stokes respiration (CSR) is of major prognostic impact in heart failure (HF) patients. Adaptive Servoventilation (ASV) therapy was recently introduced to especially treat CSR in these patients. First results on mortality (time of death, left-ventricular assist device (LVAD) device implantation and heart transplantation (HTX)) of a prospective registry are presented.  A total of 186 HF patients (NYHA ≥ II, EF ≤ 45%), treated according to present HF guidelines, with nocturnal CSA (apnoea-hypopnoea-Index, AHI ≥ 15/h) received additional ASV treatment (AutoSet CS, ResMed) and were included into a prospective registry. Mean age at inclusion (168 male, 91%) was 67 ± 11 years, BMI 28.8 ± 4.2 kg/qm, NYHA functional class 2.6 ±0.6, NT-proBNP levels 2722 ± 3420 pg/ml, left ventricular ejection fraction 31 ± 8% and peak VO 2  during cardiopulmonary exercise testing 14.4 ± 4.7 ml/kg/min. AHI before ASV initiation was 38.8 ± 14.8/h, apnoea-index 22.2 ± 15.2/h. After 20.7 ± 16.1 months a total of 35 patients (18.8%) reached a final endpoint: 28 (15.1%) died, 6 (3.2%) received HTX and one (0.5%) LVAD implantation. Within the follow-up period, ASV therapy was discontinued by 26 patients (14.0%) and 15 patients (8.1%) met indication for cardiac resynchronization therapy (CRT).  Mortality in HF patients with nocturnal CSA and ASV treatment remains high. If there is any reduction in mortality and/or hospitalization is currently be investigated by 2 randomized controlled trials, first results are not expected before 2014. With 14% discontinuation, ASV therapy seems to be well tolerated and accepted.
Identification of a Novel Subgroup of Melanomas with KIT/Cyclin-Dependent Kinase-4 Overexpression
Authors: Keiran S.M. Smalley, Rooha Contractor, Thiennga K. Nguyen, Min Xiao, Robin Edwards, Viswanathan Muthusamy, Alastair J. King, Keith T. Flaherty, Marcus Bosenberg, Meenhard Herlyn, Katherine L. Nathanson
Journal: Cancer Research (2008)

Abstract Although many melanomas harbor either activating mutations in BRAF or NRAS, there remains a substantial, yet little known, group of tumors without either mutation. Here, we used a genomic strategy to define a novel group of melanoma cell lines with co-overexpression of cyclin-dependent kinase 4 (CDK4) and KIT. Although this subgroup lacked any known KIT mutations, they had high phospho-KIT receptor expression, indicating receptor activity. Quantitative PCR confirmed the existence of a similar KIT/CDK4 subgroup in human melanoma samples. Pharmacologic studies showed the KIT/CDK4-overexpressing subgroup to be resistant to BRAF inhibitors but sensitive to imatinib in both in vitro and in vivo melanoma models. Mechanistically, imatinib treatment led to increased apoptosis and G1 phase cell cycle arrest associated with the inhibition of phospho-ERK and increased expression of p27KIP. Other melanoma cell lines, which retained some KIT expression but lacked phospho-KIT, were not sensitive to imatinib, suggesting that KIT expression alone is not predictive of response. We suggest that co-overexpression of KIT/CDK4 is a potential mechanism of oncogenic transformation in some BRAF/NRAS wild-type melanomas. This group of melanomas may be a subpopulation for which imatinib or other KIT inhibitors may constitute optimal therapy. [Cancer Res 2008;68(14):5743–52]
Authorship
Authors: Linda J. Wilcox
Journal: JAMA (1998)

Disputes associated with achieving recognition for work done may affect both morale and subsequent resource allocation to medical researchers.To assess authorship disputes brought to the Ombuds Office.The Ombuds Office, Harvard Medical School, Dental School, School of Public Health, and affiliated hospitals.Change in number of queries related to authorship between 1991 to 1992 and 1996 to 1997.Disputes increased from 8 (2.3%) of 355 issues brought to the office in 1991 to 1992 to 59 (10.7%) of 551 issues in 1996 to 1997. They also increased from involving 0.06% of the total population of faculty, staff, and students affiliated with the schools in 1991 to 1992 to 0.33% of the total population in 1996 to 1997. Such problems appear to occur more often for women (53% of complaints in 1994-1995 through 1996-1997) and for non-US citizens (21 % of complaints in 1991-1992 through 1996-1997).Authorship disputes are increasingly frequent. Institutions should increase enforcement of published authorship standards and place more emphasis on managerial skills for laboratory and research department heads.
Mechanisms of TNF-α– and RANKL-mediated osteoclastogenesis and bone resorption in psoriatic arthritis
Authors: Christopher T. Ritchlin, Sally A. Haas-Smith, Ping Li, David G. Hicks, Edward M. Schwarz
Journal: Journal of Clinical Investigation (2003)

Psoriatic arthritis (PsA) is an inflammatory joint disease characterized by extensive bone resorption. The mechanisms underlying this matrix loss have not been elucidated. We report here that blood samples from PsA patients, particularly those with bone erosions visible on plain radiographs, exhibit a marked increase in osteoclast precursors (OCPs) compared with those from healthy controls. Moreover, PsA PBMCs readily formed osteoclasts in vitro without exogenous receptor activator of NF-κB ligand (RANKL) or MCSF. Both osteoprotegerin (OPG) and anti-TNF antibodies inhibited osteoclast formation. Additionally, cultured PsA PBMCs spontaneously secreted higher levels of TNF-α than did healthy controls. In vivo, OCP frequency declined substantially in PsA patients following treatment with anti-TNF agents. Immunohistochemical analysis of subchondral bone and synovium revealed RANK-positive perivascular mononuclear cells and osteoclasts in PsA specimens. RANKL expression was dramatically upregulated in the synovial lining layer, while OPG immunostaining was restricted to the endothelium. These results suggest a model for understanding the pathogenesis of aggressive bone erosions in PsA. OCPs arise from TNF-α–activated PBMCs that migrate to the inflamed synovium and subchondral bone, where they are exposed to unopposed RANKL and TNF-α. This leads to osteoclastogenesis at the erosion front and in subchondral bone, resulting in a bidirectional assault on psoriatic bone.
The Transcription Factor GATA-6 Regulates Pathological Cardiac Hypertrophy
Authors: Jop H. van Berlo, John W. Elrod, Maarten M.G. van den Hoogenhof, Allen J. York, Bruce J. Aronow, Stephen A. Duncan, Jeffery D. Molkentin
Journal: Circulation Research (2010)

The transcriptional code that programs maladaptive cardiac hypertrophy involves the zinc finger-containing DNA binding factor GATA-4. The highly related transcription factor GATA-6 is also expressed in the adult heart, although its role in controlling the hypertrophic program is unknown.To determine the role of GATA-6 in cardiac hypertrophy and homeostasis.Here, we performed a cardiomyocyte-specific conditional gene targeting approach for Gata6, as well as a transgenic approach to overexpress GATA-6 in the mouse heart. Deletion of Gata6-loxP with Nkx2.5-cre produced late embryonic lethality with heart defects, whereas deletion with β-myosin heavy chain-cre (βMHC-cre) produced viable adults with >95% loss of GATA-6 protein in the heart. These latter mice were subjected to pressure overload-induced hypertrophy for 2 and 6 weeks, which showed a significant reduction in cardiac hypertrophy similar to that observed Gata4 heart-specific deleted mice. Gata6-deleted mice subjected to pressure overload also developed heart failure, whereas control mice maintained proper cardiac function. Gata6-deleted mice also developed less cardiac hypertrophy following 2 weeks of angiotensin II/phenylephrine infusion. Controlled GATA-6 overexpression in the heart induced hypertrophy with aging and predisposed to greater hypertrophy with pressure overload stimulation. Combinatorial deletion of Gata4 and Gata6 from the adult heart resulted in dilated cardiomyopathy and lethality by 16 weeks of age. Mechanistically, deletion of Gata6 from the heart resulted in fundamental changes in the levels of key regulatory genes and myocyte differentiation-specific genes.These results indicate that GATA-6 is both necessary and sufficient for regulating the cardiac hypertrophic response and differentiated gene expression, both alone and in coordination with GATA-4.
Predictive Markers for Late Cervical Metastasis in Stage I and II Invasive Squamous Cell Carcinoma of the Oral Tongue
Authors: Sang-Chul Lim, Shichuan Zhang, Genichiro Ishii, Yasushi Endoh, Keiji Kodama, Shinichi Miyamoto, Ryuichi Hayashi, Satoshi Ebihara, Jae-Shik Cho, Atsushi Ochiai
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Patients with oral tongue carcinoma treated by intraoral excision only should be followed up carefully for cervical lymph node metastasis and salvaged immediately if found, because some patients have a more aggressive clinical course. The purpose of this study was to find useful markers for predicting late cervical metastasis in patients with stage I and II invasive squamous cell carcinoma of the oral tongue. Experimental Design: We investigated clinicopathologic factors and immunohistochemical biomarkers predicting late cervical metastasis in surgical specimens from 56 patients with T1–2N0M0 invasive squamous cell carcinoma of the oral tongue who did not undergo elective neck dissection. Histopathologic factors including tumor thickness, mode of invasion, Broders grade, total score of three different malignancy grading systems, eight other clinicopathologic parameters, and immunohistochemical expression of p53, cyclin D1, Ki-67, epidermal growth factor receptor, microvessel density, cyclooxygenase-2, MUC1, laminin-5 γ2, E-cadherin, and β-catenin were examined. All of the clinicopathologic factors and immunohistochemical expression of biomarkers were compared in terms of survival. Results: In the univariate analysis, tumor thickness (P = 0.009), Broders grade (P = 0.017), nest shape (P = 0.005), mode of invasion (P &amp;lt; 0.001), Anneroth score (P = 0.029), Bryne score (P &amp;lt; 0.001), and E-cadherin expression (P = 0.003) were correlated with late cervical metastasis. Multivariate analysis on late cervical metastasis revealed that tumor thickness &amp;gt;4 mm, mode of invasion grade 3 or 4, and E-cadherin expression were independent factors. Late cervical metastasis was the only prognostic factor for overall survival (P = 0.002). Conclusions: Our results indicate that patients with stage I and II invasive squamous cell carcinoma of the oral tongue with tumor thickness &amp;gt;4 mm, mode of invasion grade 3 or 4, and low expression of E-cadherin should be considered a high-risk group for late cervical metastasis when a wait-and-see policy for the neck is adopted.
Pores of Kohn
Authors: J. L. Cordingley
Journal: Thorax (1972)

The history of the investigations into interalveolar communications (pores of Kohn) shows that the question whether they exist and, if so, their nature has for approximately a century been contentious. The present electron microscopic study of the lungs of mice demonstrates that alveolar pores are normal structures, with edges composed of intact alveolar wall. A number of planes are demonstrated from which a fully compatible reconstruction is made. It is concluded that pores are round or oval structures frequently having at least one type II alveolar cell forming part of their boundary. It is further postulated that pores may be divided by a capillary column stretching across the space, resulting in two openings. A type II alveolar cell forming part of the pore wall may straddle the capillary column. Alveolar macrophages may be found lying free in the pore or lying astride a capillary column. When lying in a corner position type II cells may occupy the full wall thickness and face into three alveoli.