tbuckley/cabot-search huggingface dataset:
Early and Extended Early Bactericidal Activity of Linezolid in Pulmonary Tuberculosis
Authors: Reynaldo Dietze, David Jamil Hadad, Bryan McGee, Lucilia Pereira Dutra Molino, Ethel Leonor Noia Maciel, Charles A. Peloquin, Denise F. Johnson, Sara M. Debanne, Kathleen Eisenach, W. Henry Boom, Moises Palaci, John L. Johnson
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

Rationale: Linezolid, the first oxazolidinone approved for clinical use, has effective in vitro and promising in vivo activity against Mycobacterium tuberculosis.Objectives: To evaluate the early and extended early bactericidal activity of linezolid in patients with pulmonary tuberculosis.Methods: Randomized open label trial. Thirty patients with newly diagnosed smear-positive pulmonary tuberculosis (10 per arm) were assigned to receive isoniazid (300 mg daily) and linezolid (600 mg twice daily or 600 mg once daily) for 7 days. Sputum for quantitative culture was collected for 2 days before and then daily during 7 days of study drug administration. Bactericidal activity was estimated by measuring the decline in bacilli during the first 2 days (early bactericidal activity) and the last 5 days of study drug administration (extended early bactericidal activity).Measurements and Main Results: The mean early bactericidal activity of isoniazid (0.67 log10 cfu/ml/d) was greater than that of linezolid twice and once daily (0.26 and 0.18 log10 cfu/ml/d, respectively). The extended early bactericidal activity of linezolid between Days 2 and 7 was minimal.Conclusions: Linezolid has modest early bactericidal activity against rapidly dividing tubercle bacilli in patients with cavitary pulmonary tuberculosis during the first 2 days of administration, but little extended early bactericidal activity.Clinical trial registered with www.clinicaltrials.gov (NCT00396084).
Epstein-Barr Virus Latent Membrane Protein 2a (Lmp2a) Employs the Slp-65 Signaling Module
Authors: Niklas Engels, Mark Merchant, Rajita Pappu, Andrew C. Chan, Richard Longnecker, Jürgen Wienands
Journal: The Journal of Experimental Medicine (2001)

In latently infected B lymphocytes, the Epstein-Barr virus (EBV) suppresses signal transduction from the antigen receptor through expression of the integral latent membrane protein 2A (LMP2A). At the same time, LMP2A triggers B cell survival by a yet uncharacterized maintenance signal that is normally provided by the antigen receptor. The molecular mechanisms are unknown as LMP2A-regulated signaling cascades have not been described so far. Using a novel mouse model we have identified the intracellular adaptor protein Src homology 2 (SH2) domain–containing leukocyte protein (SLP)-65 as a critical downstream effector of LMP2A in vivo. Biochemical analysis of the underlying signaling pathways revealed that EBV infection causes constitutive tyrosine phosphorylation of one of the two SLP-65 isoforms and complex formation between SLP-65 and the protooncoprotein CrkL (CT10 regulator of kinase like). This leads to antigen receptor-independent phosphorylation of Cbl (Casitas B lineage lymphoma) and C3G. In contrast, phospholipase C-γ2 (PLC-γ2) activation is completely blocked. Our data show that in order to establish a latent EBV infection, LMP2A selectively activates or represses SLP-65–regulated signaling pathways.
Reduced pain during baroreceptor stimulation in patients with symptomatic and silent myocardial ischaemia
Authors: A. Kardos, H. Rau, M. W Greenlee, C. Droste, S. Brody, H. Roskamm
Journal: Cardiovascular Research (1994)

Objective: Baroreceptor activation has been shown to reduce pain, and the accumulation of such pain reduction has been implicated in the operant learning (under certain circumstances) of hypertension. The current study is an examination of differences in the pain dampening effects of baroreceptor activity in patients with symptomatic and asymptomatic myocardial ischaemia. The objective was to determine whether there are differences between patients with symptomatic and silent myocardial ischaemia with respect to their antinociceptive response to baroreceptor stimulation, and, if so, whether these differences could be related to the absence of angina pectoris pain in patients with silent myocardial ischaemia. Methods: Sensory detection and electrical pain thresholds were compared in nine symptomatic and 10 asymptomatic patients with replicable myocardial ischaemia during PRES (phase related external suction) carotid baroreceptor manipulation in which the pressure inside a neck cuff was phase locked in time to the R wave of the ECG and negative pressure was applied during either systole or diastole. Tourniquet pain thresholds were also determined. Results: It was found that (1) external baroreceptor manipulation had no effect on detection thresholds; (2) painful stimuli were judged by both symptomatic and asymptomatic patients as less intense when delivered during maximum baroreceptor activity, (3) symptomatic and asymptomatic patients did not differ in their sensory detection thresholds; and (4) asymptomatic patients had significantly higher ischaemic (tourniquet) pain thresholds than symptomatic patients. Conclusions: The results indicate that baroreceptor activity can modify the intensity of painful stimuli. The degree to which baroreceptor manipulation affects pain does not appear to differ between patients with painful and silent myocardial ischaemia. Thus the baroreceptor dependent pain inhibition effects seems not to be responsible for the higher ischaemic pain threshold found in the silent myocardial ischaemia group. Cardiovascular Research 1994;28:515-518
Cutaneous granulomas associated with primary immunodeficiency disorders
Authors: A. Mitra, B. Pollock, J. Gooi, J.C. Darling, A. Boon, J.A. Newton-Bishop
Journal: British Journal of Dermatology (2005)

Cutaneous granulomas are uncommon in primary immunodeficiency disorders. We report cutaneous granulomas in a child with ataxia telangiectasia (AT) and compare the clinical course with similar lesions in an adult with common variable immunodeficiency (CVI). A 4-year-old female with AT developed cutaneous granulomas as erythematous plaques. The largest lesion appeared on her left cheek and continued to progress despite treatment with topical and intralesional steroids. Disease control was obtained initially with oral antibiotics and low-dose oral steroids. On cessation of oral steroids, significant relapse of the facial granuloma occurred. Pulsed and then oral steroids were required to stop the disease process leaving significant scarring. The second case is of cutaneous granulomas in a 66-year-old man, with CVI, who presented with an erythematous reticulate rash on the legs. We consider it useful to report this patient here as disease control was obtained in a similar way with systemic immunosuppression. In this patient a combination of oral steroids and azathioprine was used. These cutaneous granulomas are thought to be a manifestation of immune dysregulation. No infectious cause has been found so far. We recommend the use of broad-spectrum antibiotics in conjunction with systemic steroids for progressive granulomas, as these patients are immunosuppressed and infection with an unidentified organism cannot be excluded.
Causes of work-exacerbated asthma
Authors: Paul Henneberger, Kjell Torén
Journal: European Respiratory Journal (2012)

RATIONALE. A 2011 Statement of the American Thoracic Society concluded that work-exacerbated asthma (WEA) is common in industrialized nations, with a prevalence of 21.5% in adults with asthma. While there are published lists of workplace agents that can cause occupational asthma, there are no comparable lists for WEA. We reviewed published articles to prepare such a list.  METHODS. We systematically searched the peer-reviewed medical literature to identify articles about WEA published during 1980–2011. We selected articles that reported WEA agents determined case-by-case (from clinical case series, surveillance and worker compensation programs) or in risk-set analyses that used statistical models to determine occupational exposures associated with exacerbation of asthma or WEA.  RESULTS. The literature search identified 13 articles that reported exposures for work-related exacerbation of asthma, including 3 risk-set studies. The studies were conducted in several countries in North America and Europe, and used various criteria for WEA and methods to determine exposures. From studies with WEA identified on a case-by-case basis, the more common types of agents included miscellaneous chemicals, dust, paint, smoke, indoor air quality, and cleaning products. From two risk-set studies conducted in general population settings, exposures with statistically significant (p≤0.05) relative risks of 2.0 or greater included dusts, high exposure to gas and fumes, indoor air quality, physically strenuous work, and probable daily occupational exposure to dust, gases, or fumes.  CONCLUSIONS. Various types of workplace exposures can exacerbate asthma, including irritants, agents with sensitizing traits, and physical factors such as strenuous exercise.
Changes in Medicare Costs with the Growth of Hospice Care in Nursing Homes
Authors: Pedro Gozalo, Michael Plotzke, Vincent Mor, Susan C. Miller, Joan M. Teno
Journal: New England Journal of Medicine (2015)

Nursing home residents' use of hospice has substantially increased. Whether this increase in hospice use reduces end-of-life expenditures is unknown.The expansion of hospice between 2004 and 2009 created a natural experiment, allowing us to conduct a difference-in-differences matched analysis to examine changes in Medicare expenditures in the last year of life that were associated with this expansion. We also assessed intensive care unit (ICU) use in the last 30 days of life and, for patients with advanced dementia, feeding-tube use and hospital transfers within the last 90 days of life. We compared a subset of hospice users from 2009, whose use of hospice was attributed to hospice expansion, with a matched subset of non-hospice users from 2004, who were considered likely to have used hospice had they died in 2009.Of 786,328 nursing home decedents, 27.6% in 2004 and 39.8% in 2009 elected to use hospice. The 2004 and 2009 matched hospice and nonhospice cohorts were similar (mean age, 85 years; 35% male; 25% with cancer). The increase in hospice use was associated with significant decreases in the rates of hospital transfers (2.4 percentage-point reduction), feeding-tube use (1.2 percentage-point reduction), and ICU use (7.1 percentage-point reduction). The mean length of stay in hospice increased from 72.1 days in 2004 to 92.6 days in 2009. Between 2004 and 2009, the expansion of hospice was associated with a mean net increase in Medicare expenditures of $6,761 (95% confidence interval, 6,335 to 7,186), reflecting greater additional spending on hospice care ($10,191) than reduced spending on hospital and other care ($3,430).The growth in hospice care for nursing home residents was associated with less aggressive care near death but at an overall increase in Medicare expenditures. (Funded by the Centers for Medicare and Medicaid Services and the National Institute on Aging.).
Comparison of the Relative Efficacy of Formoterol and Salmeterol in Asthmatic Patients
Authors: MONA PALMQVIST, THOMAS IBSEN, ANDERS MELLÉN, JAN LÖTVALL
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

Studies performed on airway smooth muscle in vitro have indicated that salmeterol is a partial agonist on the β2-receptor in comparison to formoterol. In the present study we evaluated whether these pharmacological differences between salmeterol and formoterol also are applicable to asthmatic patients. The protective effects by increasing cumulative doses of formoterol (12, 60, 120 μ g) and salmeterol (50, 250, 500 μ g) on methacholine-induced bronchoconstriction were evaluated in a double-blind, crossover, placebo-controlled design. Patients were regularly treated with salbutamol 200 μ g twice daily during the study period, to avoid variability in β2-adrenoceptor tolerance. S-potassium, heart rate corrected Q-T interval (Q-Tc), and tremor score were followed as measures of systemic effects. Formoterol dose-dependently protected against methacholine responsiveness (4.6 doubling doses after 120 μ g). Salmeterol, however, showed a flatter dose–response curve, and a significantly weaker maximal protective effect (2.8 doubling doses after 250 μ g). Formoterol caused a significantly higher tremor score and a larger drop in S-potassium than salmeterol at the highest doses. These data show that salmeterol is a partial agonist on the β2-receptor in relation to formoterol in human airways in vivo. Further studies are required to document the clinical consequences of this finding, for example in severe asthmatic patients.
The SeqFEATURE library of 3D functional site models: comparison to existing methods and applications to protein function annotation
Authors: Shirley Wu, Mike P Liang, Russ B Altman
Journal: Genome biology (2008)

Abstract Structural genomics efforts have led to increasing numbers of novel, uncharacterized protein structures with low sequence identity to known proteins, resulting in a growing need for structure-based function recognition tools. Our method, SeqFEATURE, robustly models protein functions described by sequence motifs using a structural representation. We built a library of models that shows good performance compared to other methods. In particular, SeqFEATURE demonstrates significant improvement over other methods when sequence and structural similarity are low.
FHL2 regulates the resolution of tissue damage in chronic inflammatory arthritis
Authors: Viktor Wixler, Christoph Cromme, Eugen Retser, Lars-Henrik Meyer, Neil Smyth, Katja Mühlenberg, Adelheid Korb-Pap, Christina Koers-Wunrau, Yannis Sotsios, Rhonda Bassel-Duby, Dominique Baeten, Paul P Tak, Birgit Niederreiter, Kurt Redlich, Jessica Bertrand, Boris V Skryabin, Stephan Ludwig, Thomas Pap
Journal: Annals of the Rheumatic Diseases (2014)

Objective We analysed the role of the adaptor molecule four-and-a-half Lin11, Isl-1 &amp; Mec-3 (LIM) domain protein 2 (FHL2) in the activation of fibroblast-like synoviocytes in human rheumatoid arthritis (RA) and tumour necrosis factor α (TNFα)-dependent animal models of the disease. Methods Synovial tissues of patients with RA and osteoarthritis (OA) as well as hind paw sections from arthritic human TNFα transgenic (hTNFtg) mice and synovial fibroblasts from these were analysed. The effects of cytokines on the expression of FHL2 and disease-relevant matrixmetalloproteases (MMPs) were determined. Analyses of human tissue specimens from patients treated with anti-TNFα as well as anti-TNFα treatment of hTNFtg mice were performed to substantiate the TNFα effects on FHL2 levels. FHL2 −/− mice and hTNFtg mice (with constitutive or inducible transgene expression) were crossbred to generate TNFα overexpressing FHL2-deficient animals. Signalling pathways were analysed in cells from these mice and in human cells after knock down of FHL2 by western blot. Results FHL2 levels were higher in RA than in OA and in hTNFtg than in wild-type mice. Surprisingly, while transforming growth factor (TGF)β-induced FHL2 expression, TNFα suppressed FHL2. In vivo, anti-TNFα treatment led to higher FHL2 levels both in RA patients and hTNFtg mice. The loss of FHL2 increased joint destruction in hTNFtg mice, which was accompanied by elevated MMP-13. In vitro, TNFα-mediated MMP-13 was significantly higher in FHL2 −/− cells and after knock down of FHL2, which was caused by prolonged p38 MAPK activation. Conclusions These data suggest that FHL2 serves as a protective factor and that, rather than promoting the pathology, the upregulation of FHL2 in RA occurs in frame of a regenerative attempt.
Monitoring and diagnosis of cytomegalovirus infection in renal transplantation.
Authors: B M Murray, D Amsterdam, V Gray, J Myers, J Gerbasi, R Venuto
Journal: Journal of the American Society of Nephrology (1997)

In this study, the utility of the cytomegalovirus antigen (CMV-AG) and the shell vial (SV) tests in the diagnosis and monitoring of posttransplant CMV infection were compared. Previous retrospective studies from the authors' center suggested that the CMV-AG test, which uses monoclonal antibodies to detect viral antigen in circulating peripheral blood leukocytes (PBL) may be both a more sensitive and specific test. A cohort of 32 renal transplant recipients was followed-up prospectively with serial CMV-AG testing, as well as conventional culture and SV for blood and urine and tests for immunoglobulin M (IgM) antibody. It was discovered that the CMV-AG test was not only more sensitive than the SV test in detecting CMV infection, but that the degree of antigenemia as expressed by the number of positive cells per 50,000 PBL correlated with the likelihood and degree of symptomatic infection. All patients with a count > 10 positive cells/50,000 PBL developed clinical symptoms; therefore, this threshold could be useful in deciding clinically whether fever is related to CMV infection. Alternatively, if antigenemia were monitored serially after transplant, the same threshold could be used as a trigger for instituting antiviral therapy, because it was often reached prior to the onset of symptoms and had a high specificity for subsequent symptomatic infection. Such an approach could obviate unnecessary treatment of patients not destined to become symptomatic. Based upon the findings in this study, the CMV-AG test is superior to the SV assay because the actual count helps determine the likelihood that symptoms are a result of the virus and the processing time is shorter, it can be used to monitor the response to therapy and as a guide to the institution of preemptive therapy.
A Golgi-specific protein PAQR3 is closely associated with the progression, metastasis and prognosis of human gastric cancers
Authors: Z.Q. Ling, W. Guo, X.X. Lu, X. Zhu, L.L. Hong, Z. Wang, Z. Wang, Y. Chen
Journal: Annals of Oncology (2014)

The aim of this study is to determine whether PAQR3, a protein specifically localized in the Golgi apparatus, is associated with tumor progression, metastasis and survival of human patients with gastric cancer.
Genome-wide Mapping of DNA Methylation in the Human Malaria Parasite Plasmodium falciparum
Authors: Nadia Ponts, Lijuan Fu, Elena Y. Harris, Jing Zhang, Duk-Won D. Chung, Michael C. Cervantes, Jacques Prudhomme, Vessela Atanasova-Penichon, Enric Zehraoui, Evelien M. Bunnik, Elisandra M. Rodrigues, Stefano Lonardi, Glenn R. Hicks, Yinsheng Wang, Karine G. Le Roch
Journal: Cell Host & Microbe (2013)
The Value of the Sputum Gram's Stain in Community-Acquired Pneumonia
Authors: David F. Boerner
Journal: JAMA (1982)

Expectorated sputum Gram's stain was correlated with clinical presenting data, cultures, serological data, and response to antibiotic therapy in 89 patients admitted with community-acquired pneumonia. The finding of Gram-positive diplococci on Gram's stain correlated with brief antecedent illness,<i>Streptococcus pneumoniae</i>growing from cultures, and a rapid response to single-agent antibiotic therapy. Patients with no predominant pathogen on Gram's stain were clinically indistinguishable from those with Gram-positive diplococci except for a longer antecedent illness, lack of growth of pathogens from cultures, and more prolonged response to antibiotic therapy. Sputum cytological findings and transtracheal cultures were useful in patients with no Gram-positive diplococci on Gram's stain. The sputum Gram's stain is proposed as a sensitive and reliable indicator to guide therapy and predict outcome in adults with community-acquired pneumonia. (<i>JAMA</i>1982;247:642-645)
Activation of focal adhesion kinase enhances the adhesion and invasion of pancreatic cancer cells via extracellular signal-regulated kinase-1/2 signaling pathway activation
Authors: Hirozumi Sawai, Yuji Okada, Hitoshi Funahashi, Yoichi Matsuo, Hiroki Takahashi, Hiromitsu Takeyama, Tadao Manabe
Journal: Molecular Cancer (2005)

Interaction with integrin and focal adhesion kinase (FAK) regulates the cancer cell adhesion and invasion into extracellular matrix (ECM). In addition, phosphorylation of FAK correlates with the increase of cell motility and invasion. Adhesion and spreading of cancer cells on a variety of ECM proteins, including collagen type IV (Coll IV), leads to an increase in tyrosine phosphorylation and activation of FAK. In this study, we investigated the mechanism of activation of FAK and its downstream extracellular signal-regulated kinase (ERK)-1/2 signaling following stimulation by interleukin (IL)-1alpha and adhesion to ECM with subsequent enhancement of pancreatic cancer cell adhesion and invasion.In immunoblotting analysis, all three pancreatic cancer cell lines (AsPC-1, BxPC-3, and Capan-2) expressed the protein of FAK and beta1 integrin. Enhancement of FAK protein association with beta1 integrin when cells were plated on Coll IV was more increased by stimulation with IL-1alpha. Preincubation with anti-beta1 integrin antibody and FAK siRNA transfection inhibited the association of FAK with beta1 integrin of pancreatic cancer cells. FAK phosphorylation was observed by adhesion to Coll IV, furthermore, stronger FAK phosphorylation was observed by stimulation with IL-1alpha of pancreatic cancer cells adhered to Coll IV in time-dependent manner. Genistein, a tyrosine kinase inhibitor, markedly inhibited the FAK phosphorylation. IL-1alpha stimulation and Coll IV adhesion enhanced the activation of Ras, as evidenced by the increased Ras-GTP levels in pancreatic cancer cells. Activation of Ras correlated with the phosphorylation of ERK. While not statistical affecting the apoptosis of pancreatic cancer cells, IL-1alpha-induced adhesion and invasion on Coll IV were inhibited with FAK gene silencing by siRNA, beta1 integrin blocking, and inhibition of FAK phosphorylation. PD98059, a MEK inhibitor, also inhibited IL-1alpha-induced enhancement of adhesion and invasion in pancreatic cancer cells.Our results demonstrated that activation of FAK is involved with the aggressive capability in pancreatic cancer through Ras/ERK signaling pathway. Based on our results, we suggest that the modification of IL-1, FAK, and integrins functions might be a novel therapeutic approach to aggressive spread of pancreatic cancer.
When Should Heart Disease Prevention Begin?
Authors: J. Michael Gaziano
Journal: New England Journal of Medicine (1998)

Early in the next century, cardiovascular disease will probably be the number-one killer worldwide.1 Despite important successes in the past 30 years, unfavorable trends in some coronary risk factors may have contributed to a slowing of the rate of decline in age-adjusted mortality from cardiovascular disease in the United States. Furthermore, given the aging of the population, cardiovascular disease will remain an important public health concern well into the next century even if age-adjusted death rates continue to decline. In this issue of the Journal, Berenson et al.2 contribute important evidence from the Bogalusa Heart Study that even in childhood . . .