tbuckley/cabot-search huggingface dataset:
Endothelin-Induced Increased Nitric Oxide Mediates Augmented Distal Nephron Acidification as a Result of Dietary Protein
Authors: Donald E. Wesson, Jan Simoni, Sharma Prabhakar
Journal: Journal of the American Society of Nephrology (2006)

Tested was the hypothesis that enhanced nitric oxide (NO) production that is stimulated by increased renal endothelin activity mediates decreased distal nephron HCO(3) secretion that is induced by dietary protein. Munich-Wistar rats that ate minimum electrolyte diets with 50% casein-provided protein (HiPro) compared with controls that ate 20% protein for 3 wk had higher urine excretion of endothelin-1 (80 +/- 15.7 versus 29 +/- 3.9 fmol/kg body wt per d; P < 0.02) and of the NO metabolites NO(2)/NO(3) (21.2 +/- 1.9 versus 14.9 +/- 0.8 mumol/kg body wt per d; P < 0.03). Bosentan, an endothelin A/B receptor antagonist, reduced HiPro rats' urine excretion of net acid (5859 +/- 654 versus 8017 +/- 1103 micromol/d; P < 0.03, paired t test) and NO(2)/NO(3) (18.1 +/- 1.1 versus 22.9 +/- 2.0 micromol/kg body wt per d; P < 0.05, paired t test). N-nitro-l-arginine methyl ester (L-NAME), an NO synthase inhibitor, also decreased urine net acid excretion (6621 +/- 717 versus 8449 +/- 1086 micromol/d; P < 0.05, paired t test) but was not additive to bosentan. L-NAME increased in situ late distal nephron HCO(3) delivery in HiPro rats (18.8 +/- 1.7 versus 9.6 +/- 1.4 pmol/mm per min; P < 0.001) that was mediated by increased distal nephron HCO(3) secretion (-7.2 +/- 0.7 versus -3.5 +/- 0.4 pmol/mm per min; P < 0.001) without changes in distal nephron transtubule HCO(3) permeability or H(+) secretion. Bosentan decreased H(+) secretion and increased HCO(3) secretion in the distal nephron of HiPro rats, but L-NAME had no additive effect on either component. The data support that dietary protein augments distal nephron acidification through decreased HCO(3) secretion that is mediated through endothelin-stimulated NO.
Subacute bronchial toxicity induced by an electronic cigarette: take home message
Authors: Riccardo Polosa, Davide Campagna, Donald Tashkin
Journal: Thorax (2014)

The case-based discussion of an adult smoker with respiratory symptoms and worsened pulmonary function shortly after switching to an electronic cigarette (e-cig)1 can be interpreted differently.

Ironically, some people experience transient (days/weeks) worsening of respiratory symptoms (cough, wheezing, chest tightness) after quitting.2 Cough and breathlessness have been reported when switching to e-cigs, but progressive improvement in respiratory symptoms is usually observed with regular use of these products.3 …
MRI versus conventional measures of disease activity and structural damage in evaluating treatment efficacy in juvenile idiopathic arthritis
Authors: C Malattia, A Consolaro, S Pederzoli, A Madeo, A Pistorio, M Mazzoni, C Mattiuz, GM Magnano, S Viola, A Buoncompagni, E Palmisani, R Hasija, N Ruperto, A Ravelli, A Martini
Journal: Annals of the Rheumatic Diseases (2012)

To compare the American College of Rheumatology paediatric (ACRp) response criteria and conventional radiography with MRI findings in a cohort of patients with juvenile idiopathic arthritis.Forty consecutive patients (30 girls, 10 boys; median age 10.8 years) with arthritis of the wrist starting treatment with disease-modifying antirheumatic drugs or biological agents were recruited. At 1-year follow-up the treatment response was assessed by ACRp criteria and radiographic progression using the adapted Sharp/van der Heijde method. Wrist MRIs were evaluated using both the paediatric-MRI and the OMERACT rheumatoid arthritis MRI scores. Sensitivity to change of clinical and imaging variables was assessed by standardised response mean (SRM) and relative efficiency (RE) was used to compare SRMs.ACRp90 responders showed a significantly higher decrease in MRI synovitis score (median change -4) than non-responders (median change 0), ACRp30-50 responders (median change 0) and ACRp70 responders (median change -1) (p=0.0006, Kruskal-Wallis test). Non-responders showed significantly higher radiographic progression than ACRp90 responders (pB=0.016). The MRI synovitis score showed a greater responsiveness to change (SRM 1.69) compared with the majority of ACR core set of variables. MRI erosion scores were less responsive than conventional radiography in detecting destructive changes (RE <1). MRI follow-up revealed no signs of inflammation in four out of 24 wrists with clinically inactive disease.Only ACRp90 responders showed a significant decrease in synovitis and the halting of structural damage, suggesting that levels of response higher than ACRp30 are more appropriate for assessing drug efficacy. The excellent responsiveness of MRI and its ability to detect subclinical synovitis make it a promising outcome measure.
Gastric Mucosal pH and Blood Flow during Weaning from Mechanical Ventilation in Patients with Chronic Obstructive Pulmonary Disease
Authors: NICOLAS BOCQUILLON, DANIEL MATHIEU, RÉMI NEVIERE, NATHALIE LEFEBVRE, XAVIER MARECHAL, FRANCIS WATTEL
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

To determine if gastric intramucosal pH changes during weaning from mechanical ventilation are related to gastric mucosal blood flow modifications, we studied 16 ventilator-supported patients with chronic obstructive pulmonary disease (COPD) who tolerated a 2-h trial of spontaneous breathing with pressure support ventilation and were successfully extubated and 11 patients with COPD who failed such a trial. Gastric mucosal perfusion was assessed using gastric intramucosal pH (pH(i)) by tonometry and laser-Doppler flowmetry. During the weaning attempt, the failure weaning group developed a rapid, shallow breathing pattern with acute respiratory acidosis. The pH(i) was lower and gastric intramucosal PCO(2) (PCO(2)im) was higher in the failure weaning group than in the successful weaning group (p < 0.05). No change in gastric intramucosal-arterial PCO(2) difference was observed and a linear correlation was found between arterial PCO(2) and PCO(2)im (r(2) = 0.70; p < 0.001). Cardiac index increased in the failure group (p < 0.05) and remained stable in the success group whereas gastric mucosal blood flow decreased in the failure group (H(120) (min): -22 +/- 11% from baseline; p < 0.05) and increased in the success group (H(120) (min): 85 +/- 27% from baseline; p < 0.05). We conclude that gastric intramucosal pH changes during a 2-h weaning trial are mainly due to arterial PCO(2) variations. Nevertheless, gastric mucosal blood flow changes do occur and differ according to the weaning success or failure.
Idiopathic calcified myocardial mass
Authors: D. Patterson, D. Gibson, R. Gomes, L. McDonald, E. Olsen, J. Parker, D. Ross
Journal: Thorax (1974)

<b>Patterson, D., Gibson, D., Gomes, R., McDonald, L., Olsen, E., Parker, J., and Ross, D. (1974).</b><i>Thorax,</i><b>29,</b> 589-594. <b>Idiopathic calcified myocardial mass.</b> Myocardial calcification can be subdivided into three groups—metastatic, dystrophic or an extension inwards from the pericardium. This case in which the calcified myocardial mass was initially delineated by radiography and by echocardiography and subsequently removed does not fit into any subdivision and has been termed idiopathic.
HMGB1 and RAGE in Inflammation and Cancer
Authors: Gary P. Sims, Daniel C. Rowe, Svend T. Rietdijk, Ronald Herbst, Anthony J. Coyle
Journal: Annual Review of Immunology (2010)

The immune system has evolved to respond not only to pathogens, but also to signals released from dying cells. Cell death through necrosis induces inflammation, whereas apoptotic cell death provides an important signal for tolerance induction. High mobility group box 1 (HMGB1) is a DNA-binding nuclear protein, released actively following cytokine stimulation as well as passively during cell death; it is the prototypic damage-associated molecular pattern (DAMP) molecule and has been implicated in several inflammatory disorders. HMGB1 can associate with other molecules, including TLR ligands and cytokines, and activates cells through the differential engagement of multiple surface receptors including TLR2, TLR4, and RAGE. RAGE is a multiligand receptor that binds structurally diverse molecules, including not only HMGB1, but also S100 family members and amyloid-β. RAGE activation has been implicated in sterile inflammation as well as in cancer, diabetes, and Alzheimer's disease. While HMGB1 through interactions with TLRs may also be important, this review focuses on the role of the HMGB1-RAGE axis in inflammation and cancer.
Strategies against multidrug-resistant tuberculosis
Authors: R. Loddenkemper, D. Sagebiel, A. Brendel
Journal: European Respiratory Journal (2002)

The rise of multidrug-resistant tuberculosis (MDR-TB), defined as tuberculosis showing resistance to at least isoniazid and rifampicin, is a serious threat to tuberculosis control in some high prevalence countries and may have some impact on low prevalence regions as well. The World Health Organization estimates that 50 million people worldwide are infected with MDR-TB, and that, in the year 2000, 273,000 (3.1%) MDR-TB cases were among the 8.7 million new tuberculosis cases. In 1998, the highest MDR-TB rates among new cases and the highest combined (new and previously treated cases) MDR-TB rates were found in Estonia (14.1 and 18.1%), Henan province in China (10.8 and 15.1%), Latvia (9.0 and 12.0%), and Ivanovo Oblast (9.0 and 12.3%) and Tomsk Oblast (6.5 and 13.7%) in the Russian Federation. The risk factors for MDR-TB are previous treatment or relapse, originating from "hot spot" areas, a history of imprisonment, homelessness and possibly also human immunodeficiency virus. The treatment of multidrug-resistant tuberculosis is difficult due to side-effects and a treatment duration of up to 3 yrs, which is expensive and often unsuccessful. Therefore, strategies for the treatment and prevention of multidrug-resistant tuberculosis are urgently required. This requires functioning tuberculosis control programmes (directly observed treatment short course), and, in some high prevalence countries, the introduction of second-line drugs on the basis of appropriate susceptibility testing (directly observed treatment short course-Plus). Only the future will show whether this "ticking time bomb" can be defused.
A genome-wide association study identifies susceptibility loci for nonsyndromic sagittal craniosynostosis near BMP2 and within BBS9
Authors: Cristina M Justice, Garima Yagnik, Yoonhee Kim, Inga Peter, Ethylin Wang Jabs, Monica Erazo, Xiaoqian Ye, Edmond Ainehsazan, Lisong Shi, Michael L Cunningham, Virginia Kimonis, Tony Roscioli, Steven A Wall, Andrew O M Wilkie, Joan Stoler, Joan T Richtsmeier, Yann Heuzé, Pedro A Sanchez-Lara, Michael F Buckley, Charlotte M Druschel, James L Mills, Michele Caggana, Paul A Romitti, Denise M Kay, Craig Senders, Peter J Taub, Ophir D Klein, James Boggan, Marike Zwienenberg-Lee, Cyrill Naydenov, Jinoh Kim, Alexander F Wilson, Simeon A Boyadjiev
Journal: Nature Genetics (2012)
Phase I and Pharmacokinetic Study of Prinomastat, a Matrix Metalloprotease Inhibitor
Authors: Kenneth R. Hande, Mary Collier, Linda Paradiso, Jill Stuart-Smith, Mary Dixon, Neil Clendeninn, Geoff Yeun, Donna Alberti, Kim Binger, George Wilding
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Prinomastat is a matrix metalloprotease (MMP) inhibitor with selectivity for MMPs 2, 3, 9, 13, and 14. Inhibition of these MMPs has been postulated to block tumor invasion and metastasis. This Phase I, dose-escalation study was designed to evaluate the acute and chronic toxicities of various doses of prinomastat and to determine prinomastat pharmacokinetics. Experimental Design: Seventy-five patients with advanced cancer were given 1, 2, 5, 10, 25, 50, or 100 mg prinomastat orally twice daily until tumor progression or development of significant toxicities. Prinomastat pharmacokinetics were measured on day 29 of therapy. Results: The primary toxicities identified were joint and muscle-related pain, which were generally reversible with treatment rest and/or dose reduction. No dose-limiting toxicities were noted within the first 4 weeks of treatment, but grade 2–3 arthralgias and myalgias were noted 2–3 months after initiation of therapy in &amp;gt;25% of patients at doses &amp;gt;25 mg twice a day. The frequency and severity of symptoms were dose related. Plasma prinomastat concentrations greater than the Ki for MMPs 2 and 9 were achieved at all of the dose levels. Conclusions: Doses of 5–10 mg bid were recommended for additional trials, because this dose range was well tolerated for a treatment duration of at least 3 months and achieves trough plasma concentrations 10–100-fold greater than the Ki (in vitro inhibition constant) for the targeted MMPs (2 and 9).
Antiviral activity of clevudine [?-FMAU, (1-(2-fluoro-5-methyl-β, ?-arabinofuranosyl) uracil)] against woodchuck hepatitis virus replication and gene expression in chronically infected woodchucks (Marmota monax)
Authors: Simon F. Peek, Paul J. Cote, James R. Jacob, Ilia A. Toshkov, William E. Hornbuckle, Betty H. Baldwin, Frances V. Wells, C. K. Chu, John L. Gerin, Bud C. Tennant, Brent E. Korba
Journal: Hepatology (2001)

l–FMAU [1–(2–fluoro–5–methyl–β,l–arabinofuranosyl) uracil] has been shown to be an effective inhibitor of hepatitis B virus (HBV) and duck hepatitis B virus replication in cell culture and duck hepatitis B virus replication in acutely infected Peking ducks. The woodchuck hepatitis virus (WHV) and its natural host, the Eastern woodchuck ( Marmota monax ), have been established as a predictive model for the evaluation of antiviral therapies against chronic HBV infection. In this report, the antiviral activity of l–FMAU against WHV replication in chronically infected woodchucks is described. Four weeks of once–daily oral administration of l–FMAU significantly reduced viremia, antigenemia, intrahepatic WHV replication, and intrahepatic expression of woodchuck hepatitis virus core antigen (WHcAg) in a dose–dependent manner. At the highest dose administered (10 mg/kg/d), significant reductions of intrahepatic WHV RNA and covalently closed circular (ccc)WHV–DNA levels also were observed. The reduction in viremia was remarkably rapid at the higher doses of l–FMAU, with greater than 1,000–fold reductions in WHV–DNA serum levels observed after as little as 2 to 3 days of therapy. Following the withdrawal of therapy, a dose–related delay in viremia rebound was observed. At the highest doses used, viremia remained significantly suppressed in at least one half of the treated animals for 10 to 12 weeks' posttreatment. No evidence of drug–related toxicity was observed in the treated animals. l–FMAU is an exceptionally potent antihepadnaviral agent in vitro and in vivo , and is a suitable candidate for antiviral therapy of chronic HBV infection.
Tumor Suppressive Effects of Bromodomain-Containing Protein 7 (BRD7) in Epithelial Ovarian Carcinoma
Authors: Young-Ae Park, Jeong-Won Lee, Hye-Sun Kim, Yoo-Young Lee, Tae-Joong Kim, Chel Hun Choi, Jung-Joo Choi, Hye-Kyung Jeon, Young Jae Cho, Ji Yoon Ryu, Byoung-Gie Kim, Duk-Soo Bae
Journal: Clinical Cancer Research (2013)

Bromodomain-containing protein 7 (BRD7), which is a subunit of SWI/SNF complex, has been recently suggested as a novel tumor suppressor in several cancers. In this study, we investigated the tumor suppressive effect of BRD7 in epithelial ovarian cancer.We analyzed the expression of BRD7 in human ovarian tissues with real-time PCR. To investigate the functional role of BRD7, we transfected ovarian cancer cells (A2780 and SKOV3) with BRD7 plasmid and checked the cell viability, apoptosis, and invasion. The activities of BRD7 in the signaling pathways associated with carcinogenesis were also tested. In addition, we used the orthotopic mouse model for ovarian cancer to evaluate tumor growth-inhibiting effect by administration of BRD7 plasmid.The BRD7 expression was downregulated in the ovarian cancer tissues compared with normal (P < 0.05), high-grade serous cancer exhibited significantly decreased expression of BRD7 compared with low-grade (P < 0.01) serous cancer. Transfection of BRD7 plasmid to A2780 (p53-wild) or SKOV3 (p53-null) ovarian cancer cells showed the tumor suppressive effects assessed by cell viability, apoptosis, and invasion assay and especially significantly decreased tumor weight in orthotopic mouse model (A2780). Moreover, we found that tumor suppressive effects of BRD7 are independent to the presence of p53 activity in ovarian cancer cells. BRD7 negatively regulated β-catenin pathway, resulting in decreased its accumulation in the nucleus.These results suggested that BRD7 acts as a tumor suppressor in epithelial ovarian cancers independently of p53 activity, via negative regulation of β-catenin pathway.
Evidence based medicine: what it is and what it isn't
Authors: D. L Sackett, W. M C Rosenberg, J A M. Gray, R B. Haynes, W S. Richardson
Journal: BMJ (1996)

It's about integrating individual clinical expertise and the best external evidence

Evidence based medicine, whose philosophical origins extend back to mid-19th century Paris and earlier, remains a hot topic for clinicians, public health practitioners, purchasers, planners, and the public. There are now frequent workshops in how to practice and teach it (one sponsored by the BMJ will be held in London on 24 April); undergraduate1 and postgraduate2 training programmes are incorporating it3 (or pondering how to do so); British centres for evidence based practice have been established or planned in adult medicine, child health, surgery, pathology, pharmacotherapy, nursing, general practice, and dentistry; the Cochrane Collaboration and Britain's Centre for Review and Dissemination in York are providing systematic reviews of the effects of health care; new evidence based practice journals are being launched; and it has become a common topic in the lay media. But enthusiasm has been mixed with some negative reaction.4 5 6 Criticism has ranged from evidence based medicine being old hat to it being a dangerous innovation, perpetrated by the arrogant to serve cost cutters and suppress clinical freedom. As evidence based medicine continues to evolve and adapt, now is a useful time to refine the discussion of what it is and what it is not.

Evidence based medicine is the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients. The …
Vaccination with recombinant modified vaccinia virus Ankara prevents the onset of intestinal allergy in mice
Authors: C. Bohnen, A. Wangorsch, S. Schülke, H. Nakajima-Adachi, S. Hachimura, M. Burggraf, Y. Süzer, A. Schwantes, G. Sutter, Z. Waibler, G. Reese, M. Toda, S. Scheurer, S. Vieths
Journal: Allergy (2013)

Background Modified vaccinia virus Ankara (MVA)-encoding antigens are considered as safe vaccine candidates for various infectious diseases in humans. Here, we investigated the immune-modulating properties of MVA-encoding ovalbumin (MVA-OVA) on the allergen-specific immune response. Methods The immune-modulating properties of MVA-OVA were investigated using GM-CSF-differentiated BMDCs from C57BL/6 mice. OVA expression upon MVA-OVA infection of BMDCs was monitored. Activation and maturation markers on viable MVA-OVA-infected mDCs were analyzed by flow cytometry. Secretion of INF-γ, IL-2, and IL-10 was determined in a co-culture of BMDCs infected with wtMVA or MVA-OVA and OVA-specific OT-I CD8+ and OT-II CD4+ T cells. BALB/c mice were vaccinated with wtMVA, MVA-OVA, or PBS, sensitized to OVA/alum and challenged with a diet containing chicken egg white. OVA-specific IgE, IgG1, and IgG2a and cytokine secretion from mesenteric lymph node (MLN) cells were analyzed. Body weight, body temperature, food uptake, intestinal inflammation, and health condition of mice were monitored. Results Infection with wtMVA and MVA-OVA induced comparable activation of mDCs. MVA-OVA-infected BMDCs expressed OVA and induced enhanced IFN-γ and IL-2 secretion from OVA-specific CD8+ T cells in comparison with OVA, wtMVA, or OVA plus wtMVA. Prophylactic vaccination with MVA-OVA significantly repressed OVA-specific IgE, whereas OVA-specific IgG2a was induced. MVA-OVA vaccination suppressed TH2 cytokine production in MLN cells and prevented the onset of allergic symptoms and inflammation in a mouse model of OVA-induced intestinal allergy. Conclusion Modified vaccinia virus Ankara-ovalbumin (MVA-OVA) vaccination induces a strong OVA-specific TH1- immune response, likely mediated by the induction of IFN-γ and IgG2a. Finally, MVA-based vaccines need to be evaluated for their therapeutic potential in established allergy models.
Aggravation of polycystic kidney disease in Han
Authors: V E Torres, R J Bengal, R D Litwiller, D M Wilson
Journal: Journal of the American Society of Nephrology (1997)

The administration of ammonium chloride or of sodium or potassium bicarbonate has marked effects on the development of polycystic kidney disease (PKD) in Han:SPRD rats. Because of the possibility that these effects are mediated by changes in redox metabolism, the aim of this study was to determine whether depletion of glutathione, the most abundant and important cellular thiol and scavenger of reactive oxygen species, would affect the development of PKD in this animal model. +/+ and cy/+ Han:SPRD rats were treated with: (1) L-buthionine(S,R)-sulfoximine (BSO), a specific inhibitor of gamma-glutamylcysteine synthetase, the rate-limiting enzyme for the synthesis of glutathione; (2) glutathione monoethyl ester (GME), a compound that is known to increase the intracellular levels of glutathione; or (3) BSO and GME. Treatment with these drugs was started at 3 wk of age, and the animals were killed at 6 or 8 wk of age. Renal levels of oxidized glutathione were significantly higher in cy/+ than in +/+ rats, whereas no significant differences in reduced glutathione were detected. The administration of BSO caused a marked reduction in the levels of glutathione. The administration of GME caused a significant increase in the levels of glutathione at 2 h, but not at 12 h, after the administration. The increase in the renal levels of glutathione 2 h after the administration of GME was less in the rats treated with BSO than in the rats not receiving this drug, indicating that in part the increase in glutathione level was due to de novo synthesis. BSO-induced glutathione depletion was accompanied by a marked aggravation of the renal cystic disease, as reflected by kidney weights, histological scores, and plasma urea concentrations. However, the administration of GME did not lessen the cystic disease and did not reverse the effects of BSO. The transient effect of GME administration and the simultaneous increases in the levels of cysteine and oxidized glutathione, in addition to reduced glutathione, may explain the lack of protection by GME. These data support the notion that changes in redox metabolism may affect the development of PKD.