tbuckley/cabot-search huggingface dataset:
Circulatory Dynamics and the Effects of Respiration During Ventricular Asystole in Dogs with Complete Heart Block
Authors: Madison S. Spach, Emile M. Scarpelli
Journal: Circulation Research (1962)

Pressure-flow changes during ventricular asystole (but with atrial activity present) were studied in 11 dogs with complete heart block. The influence of respiration on these parameters was evaluated during spontaneous breathing, intermittent positive pressure respiration, and apnea. During spontaneous breathing, the pulmonary artery pressure initially fell below the right atrial pressure following the onset of ventricular asystole. Both pressures then showed a gradual rise which was accompanied by flow of blood into the pulmonary artery (estimated to be 121 to 139 ml./min.). The mean pressure in the left atrium became greater than that in the pulmonary artery, concomitant with a gradual rise in the end-expiratory intrathoracic pressure. Despite this mean pressure change, flow from the pulmonary artery to the left atrium was demonstrated. Analysis of the instantaneous pressures during the atrial cycle showed that flow could occur during early atrial diastole in both phases of respiration and throughout atrial diastole during inspiration. Following each atrial beat, the left atrium received blood from the pulmonary veins and left ventricle (mitral regurgitation). There was a continued fall in the aortic pressure and, when it was exceeded by the left atrial systolic pressure, blood was propelled into the aorta. These pressure-flow changes were affected by positive pressure respiration and apnea. All pressures were significantly lower during these respiratory conditions and flow from the pulmonary artery to left atrium could not be demonstrated. The marked effects of respiration on the circulatory dynamics in animals during ventricular asystole must be considered in the interpretation of the results of studies, particularly in thoracotomized or apneic dogs, whenever there are conditions of low flow or pressure in the central circulation.
THE MEDIATOR OF CELLULAR IMMUNITY
Authors: F. T. Koster, D. D. McGregor, G. B. Mackaness
Journal: The Journal of Experimental Medicine (1971)

Peritoneal exudates from rats which have survived an infection with L. monocytogenes can protect cyclophosphamide-treated recipients against a Listeria challenge. They are more effective in this respect than cells obtained from the spleen or thoracic duct lymph. Since exudate cells from normal rats and inocula prepared from the resident peritoneal cell populations of infected donors are unable to inhibit the challenge infection, the protective cells must belong to a class of lymphocytes that emerges from the blood in response to inflammation. It is significant therefore that thoracic duct lymphocytes formed during an acute Listeria infection can move into exudates induced by a variety of inflammatory stimuli. The affinity of newly formed lymphocytes for inflamed tissue points to a mechanism whereby the host marshalls its cellular defenses at sites of bacterial invasion. The tendency of short-lived lymphocytes to leave inflamed vessels might also explain their short-circulating life-span.
Authors' response to Meredith and Hull
Authors: Moloy Dey, Lola Lawyi, Roger S Wilson
Journal: Journal of the Royal Society of Medicine (2012)

We thank Meredith and Hull for the interest in our article about orbital Wegener's granulomatosis in a 9-year-old child as the initial presentation.1 As stated in the article it is important for these patients to be managed by specialist centres which deal with paediatric immunological disease.
An uncommon burn
Authors: B. Arun, J. Jacob, J.P. Byrne
Journal: British Journal of Dermatology (2008)

Conflicts of interest: none declared. Sir, We report a rare case of inhaler‐induced burn in a 13‐year‐old boy caused by applying the nozzle of the inhaler to his hand and discharging the inhaler. A 13‐year‐old boy presented with a 4‐day history of blisters around the edge of an erythematous patch on the dorsum of his left hand, which had been present for a year. His sister suffered from asthma. On examination, there was a well‐demarcated erythematous patch on the dorsum of his left hand with crusts from ruptured blisters around the edge of the patch (Fig. 1). On further questioning, he admitted having developed this red patch 1 year previously after he had applied the nozzle of his sister’s salbutamol inhaler onto his hand and discharged it a few times playfully. The repetition of this practice had resulted in the inhaler‐induced burns we see in this picture. Inhaler‐induced burn is very rare, and to our knowledge there are only three cases reported in the literature.1 2–3 All three patients were asthmatic. Chemical burn from the pharmaceutical/preservative/propellant aerosol, cold injury to the skin or mechanical abrasive effect of the aerosol blasts were the suggested mechanisms of injury. Burge et al. suggested that the physical signs of inhaler‐induced burn are similar to those seen after a standardized cryotherapy freeze injury to the skin.4 Children who gain access to inhalers may find them to be interesting toys. They could then sustain chemical burns due to inappropriate discharge onto the skin. We need to be aware of this effect of commonly used inhalers and warn parents, teachers and children in order to avoid these injuries.
Mucosal IL-10 and TGF-β play crucial roles in preventing LPS-driven, IFN-γ–mediated epithelial damage in human colon explants
Authors: Anne Jarry, Céline Bossard, Chantal Bou-Hanna, Damien Masson, Eric Espaze, Marc G. Denis, Christian L. Laboisse
Journal: Journal of Clinical Investigation (2008)

IL-10 is an immunomodulatory cytokine that plays an obligate role in preventing spontaneous enterocolitis in mice. However, little is known about IL-10 function in the human intestinal mucosa. We showed here that IL-10 was constitutively expressed and secreted by the human normal colonic mucosa, including epithelial cells. Depletion of IL-10 in mucosal explants induced both downregulation of the IL-10–inducible, immunosuppressive gene BCL3 and upregulation of IFN-γ, TNF-α, and IL-17. Interestingly, TGF-β blockade also strongly induced IFN-γ production. In addition, the high levels of IFN-γ produced upon IL-10 depletion were responsible for surface epithelium damage and crypt loss, mainly by apoptosis. Polymyxin B, used as a scavenger of endogenous LPS, abolished both IFN-γ production and epithelial barrier disruption. Finally, adding a commensal bacteria strain to mucosa explant cultures depleted of both IL-10 and LPS reproduced the ability of endogenous LPS to induce IFN-γ secretion. These findings demonstrate that IL-10 ablation leads to an endogenous IFN-γ–mediated inflammatory response via LPS from commensal bacteria in the human colonic mucosa. We also found that both IL-10 and TGF-β play crucial roles in maintaining human colonic mucosa homeostasis.
Intervention for Recoarctation in the Single Ventricle Reconstruction Trial
Authors: Kevin D. Hill, John F. Rhodes, Ranjit Aiyagari, G. Hamilton Baker, Lisa Bergersen, Paul J. Chai, Gregory A. Fleming, J. Curt Fudge, Matthew J. Gillespie, Robert G. Gray, Russel Hirsch, Kyong-Jin Lee, Jennifer S. Li, Richard G. Ohye, Matthew E. Oster, Sara K. Pasquali, Andrew N. Pelech, Wolfgang A.K. Radtke, Cheryl M. Takao, Julie A. Vincent, Christoph P. Hornik
Journal: Circulation (2013)

Background— Recoarctation after the Norwood procedure increases risk for mortality. The Single Ventricle Reconstruction (SVR) trial randomized subjects with a single right ventricle undergoing a Norwood procedure to a modified Blalock-Taussig shunt or a right ventricle–pulmonary artery shunt. We sought to determine the incidence of recoarctation, risk factors, and outcomes in the SVR trial. Methods and Results— Recoarctation was defined by intervention, either catheter based or surgical. Univariate analysis and multivariable Cox proportional hazard models were performed with adjustment for center. Of the 549 SVR subjects, 97 (18%) underwent 131 interventions (92 balloon aortoplasty, 39 surgical) for recoarctation at a median age of 4.9 months (range, 1.1–10.5 months). Intervention typically occurred at pre–stage II catheterization (n=71, 54%) or at stage II surgery (n=38, 29%). In multivariable analysis, recoarctation was associated with the shunt type in place at the end of the Norwood procedure (hazard ratio, 2.0 for right ventricle–pulmonary artery shunt versus modified Blalock-Taussig shunt; P =0.02), and Norwood discharge peak echo-Doppler arch gradient (hazard ratio, 1.07 per 1 mm Hg; P &lt;0.01). Subjects with recoarctation demonstrated comorbidities at pre–stage II evaluation, including higher pulmonary arterial pressures (15.4±3.0 versus 14.5±3.5 mm Hg; P =0.05), higher pulmonary vascular resistance (2.6±1.6 versus 2.0±1.0 Wood units·m 2 ; P =0.04), and increased echocardiographic volumes (end-diastolic volume, 126±39 versus 112±33 mL/BSA 1.3 , where BSA is body surface area; P =0.02). There was no difference in 12-month postrandomization transplantation-free survival between those with and without recoarctation ( P =0.14). Conclusions— Recoarctation is common after Norwood and contributes to pre–stage II comorbidities. Although with intervention there is no associated increase in 1-year transplantation/mortality, further evaluation is warranted to evaluate the effects of associated morbidities. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00115934.
Oronasopharyngeal suction versus wiping of the mouth and nose at birth: a randomised equivalency trial
Authors: John Kelleher, Ramachandra Bhat, Ariel A Salas, Dylan Addis, Emily C Mills, Himel Mallick, Arvind Tripathi, Elizabeth P Pruitt, Claire Roane, Tara McNair, John Owen, Namasivayam Ambalavanan, Waldemar A Carlo
Journal: The Lancet (2013)
Cardiovascular Risk Factors and Morbidity in Long-Term Survivors of Testicular Cancer: A 20-Year Follow-Up Study
Authors: Hege S. Haugnes, Torgeir Wethal, Nina Aass, Olav Dahl, Olbjørn Klepp, Carl W. Langberg, Tom Wilsgaard, Roy M. Bremnes, Sophie D. Fosså
Journal: Journal of Clinical Oncology (2010)

Purpose To evaluate the prevalence of cardiovascular risk factors and long-term incidence of cardiovascular disease (CVD) in survivors of testicular cancer (TC). Methods Overall, 990 men treated for unilateral TC (1980 to 1994) were included in this national follow-up study (2007 to 2008). They were categorized into four treatment groups: surgery (n = 206), radiotherapy only (RT; n = 386), chemotherapy only (n = 364), and combined RT/chemotherapy (n = 34). Age-matched male controls from the general population (ie, NORMs) were included (n = 990). Survivors of TC who were diagnosed with CVD before or within 2 years after the TC diagnosis were excluded from analyses of CVD end points. Results Median observation time was 19 years (range, 13 to 28 years). All cytotoxic treatment groups had significantly increased prevalences of antihypertensive medication, and survivors in the RT and RT/chemotherapy groups had higher prevalences of diabetes (RT: odds ratio [OR], 2.3; 95% CI, 1.5 to 3.7; RT/chemotherapy: OR, 3.9; 95% CI, 1.4 to 10.9) compared with NORMs. Overall 74 survivors of TC (8.0%) experienced atherosclerotic disease during follow-up. Increased risks for atherosclerotic disease were observed in age-adjusted Cox regression analyses after any cytotoxic treatment when compared with surgery only (RT: hazard ratio [HR], 2.3; 95% CI, 1.04 to 5.3; chemotherapy: HR, 2.6; 95% CI, 1.1 to 5.9; RT/chemotherapy: HR, 4.8; 95% CI, 1.6 to 14.4). Treatment with cisplatin, bleomycin, and etoposide (BEP) alone had a 5.7-fold higher risk (95% CI, 1.9 to 17.1 fold) for coronary artery disease compared with surgery only and a 3.1-fold higher risk (95% CI, 1.2 to 7.7 fold) for myocardial infarction compared with NORMs. Conclusion Treatment with infradiaphragmatic RT and/or cisplatin-based chemotherapy, particularly the BEP regimen, increases the long-term risk for CVD in survivors of TC.
Extraordinary potentiation of isoproterenol cardiotoxicity by corticoid pretreatment
Authors: G. GUIDERI, M. A. BARLETTA, D. LEHR
Journal: Cardiovascular Research (1974)

In albino rats, chronically pretreated with desoxycorticosterone acetate (DCA) and saline, the cardiotoxicity of the β-adrenergic agonist, isoproterenol, was enormously potentiated (about 20,000 times!). In such animals, a small dose of isoproterenol (6 (μg per 100 g body weight) which otherwise does not produce any irregularities of cardiac rhythm, consistently induced severe arrhythmias, usually leading to ventricular fibrillation and death. Following the same pretreatment, the α- and β-adrenergic agonist, epinephrine, elicited arrhythmias and ventricular fibrillation less consistently and only in the presence of α-adrenergic receptor blockade. Hydrocortisone was less effective than DCA in sensitizing the myocardium to isoproterenol. Substantial enhancement of isoproterenol cardiotoxicity was demonstrated also in the guinea pig pretreated with DCA and saline. The possibility of a potentially lethal drug-drug interaction in patients on prolonged corticoid therapy receiving large dosages of isoproterenol or other β-adrenergic agonists is considered.
Exhaled nitric oxide and bronchial responsiveness in healthy subjects exposed to organic dust
Authors: B-;M. Sundblad, B-;M. Larsson, L. Palmberg, K. Larsson
Journal: European Respiratory Journal (2002)

Inhalation of organic dust from swine houses causes an intense inflammatory reaction in the respiratory tract, and increased bronchial responsiveness to methacholine in healthy subjects. The aims of the present study were to investigate whether exhaled nitric oxide (NO) is a marker of the inflammation caused by exposure to organic dust (swine dust), whether there is a relationship between an increase in exhaled NO and bronchial responsiveness, and also whether wearing a half-mask influences the airway reaction (assessed by exhaled NO) and the increased bronchial responsiveness. Thirty-three healthy nonatopic, nonsmoking subjects were exposed during 3 h of light work in a swine confinement building. Eleven of the subjects were wearing a half-mask and 22 were unprotected. Lung function, bronchial responsiveness and exhaled NO were measured before and after exposure. The provocative concentration causing a 20% fall in forced expiratory volume in one second fell by 2.7 (2.1–4.1) (median (25th–75th percentiles)) doubling concentration steps in subjects without a half-mask and by 1.5 (0.9–2.9) doubling concentration steps in subject wearing a mask. Exhaled NO increased from 7.5 (5.7–13.7) parts per billion (ppb) before to 13.4 (10.5–17.5) ppb after exposure in the unprotected group and was unaltered (8.3 (6.1–14.1) to 8.6 (6.6–14.6) ppb) in the group wearing a half-mask. There was no correlation between NO increase and provocative dose causing a 20% fall in the forced expiratory volume in one second decrease. In conclusion, bronchial responsiveness and exhaled nitric oxide increased after exposure to a swine confinement facility. Half-mask abolished the increase in exhaled nitric oxide levels, but influenced the increase in bronchial responsiveness to a minor extent. These results indicate that these two outcome measures reflect different aspects of airway inflammation induced by exposure to a farming environment.
Endarterectomy for Asymptomatic Carotid Artery Stenosis-Reply
Authors: James F. Toole
Journal: JAMA (1995)

In Reply.  —To respond fully to the important issues raised in the above letters would vastly exceed the space allotted herein. Consequently, many points will be addressed in subsequent publications (B. Young, W. Moore, J. Robertson, et al, unpublished data, 1995; W. Moore, B. Young, W. Baker, unpublished data, 1995).  When the ACAS was initiated in 1985, arteriography had a high complication rate, ultrasound imaging was not well developed, and there was negative sentiment regarding carotid endarterectomy because platelet antiaggregating agents were thought to suffice. Our study reflects these constraints because, once initiated, the ACAS could not be restructured.  Dr Foster misunderstands the statistical methods used for contrasting the results of medical with surgical management. When the Monitoring Committee determined that ACAS stopping boundaries had been crossed at a median (not mean) of 2.7 years, our follow-up exceeded 3 years in 44% of patients and 4 years in 26% of
Campaign to eliminate disfiguring disease is stepped up
Authors: F. Fleck
Journal: BMJ (2002)

A global campaign spearheaded by the World Health Organization to eliminate one of the world's most disfiguring diseases, lymphatic filariasis, has been stepped up to reach 350 million people—a third of the billion people at risk—by 2005.

Members of the Global Alliance for the Elimination of Lymphatic Filariasis, a coalition of 80 countries, 30 aid agencies, donors, research institutes, non-governmental organisations, and two pharmaceutical companies, GlaxoSmithKline and Merck, set the ambitious target at a conference in Delhi this month.

While smallpox is the only disease that has so far …
An Arthritis‐Suppressive and Treg Cell–Inducing CD4+ T Cell Epitope Is Functional in the Context of HLA‐Restricted T Cell Responses
Authors: Charlotte de Wolf, Ruurd van der Zee, Ineke den Braber, Tibor Glant, Bernard Maillère, Emmanuel Favry, Menno van Lummel, Frits Koning, Aad Hoek, Irene Ludwig, Willem van Eden, Femke Broere
Journal: Arthritis & Rheumatology (2015)

We previously showed that mycobacterial Hsp70-derived peptide B29 induced B29-specific Treg cells that suppressed experimental arthritis in mice via cross-recognition of their mammalian Hsp70 homologs. The aim of the current study was to characterize B29 binding and specific CD4+ T cell responses in the context of human major histocompatibility complex (MHC) molecules.Competitive binding assays were performed to examine binding of peptide B29 and its mammalian homologs to HLA molecules. The effect of B29 immunization in HLA-DQ8-transgenic mice with proteoglycan-induced arthritis was assessed, followed by ex vivo restimulation with B29 to examine the T cell response. Human peripheral blood mononuclear cells were used to investigate the presence of B29-specific T cells with immunoregulatory potential.The binding affinity of the B29 peptide was high to moderate for multiple HLA-DR and HLA-DQ molecules, including those highly associated with rheumatoid arthritis. This binding was considered to be functional, because B29 immunization resulted in the suppression of arthritis and T cell responses in HLA-DQ8-transgenic mice. In humans, we demonstrated the presence and expansion of B29-specific CD4+ T cells, which were cross-reactive with the mammalian homologs. Using HLA-DR4+ tetramers specific for B29 or the mammalian homolog mB29b, we showed expansion of cross-reactive T cells, especially the human FoxP3+ CD4+CD25+ T cell population, after in vitro stimulation with B29.These results demonstrated a conserved fine specificity and functionality of B29-induced Treg cell responses in the context of the human MHC. Based on these findings, a path for translation of the experimental findings for B29 into a clinical immunomodulatory therapeutic approach is within reach.
Phase I study of BMS-663513, a fully human anti-CD137 agonist monoclonal antibody, in patients (pts) with advanced cancer (CA)
Authors: M. Sznol, F. S. Hodi, K. Margolin, D. F. McDermott, M. S. Ernstoff, J. M. Kirkwood, C. Wojtaszek, D. Feltquate, T. Logan
Journal: Journal of Clinical Oncology (2008)

3007 Background: CD137 is a member of the TNFR family and functions as a costimulatory molecule. In preclinical studies BMS- 663513, a fully human anti-CD137 agonist monoclonal antibody provided costimulation to CD8+ and CD4+ T-cells, leading to enhanced IFNγ production, cytolytic activity, and increased survival. We conducted a first-in-human phase I dose-escalation study of BMS-663513 in pts with CA. Methods: BMS-663513 was administered IV every 3 weeks. In Part 1, the dose was escalated (0.3, 1, 3, 6, 10, and 15 mg/kg) in cohorts of 3–6 pts. In Part 2, pts with melanoma, RCC, and ovarian CA, 30 per CA, were stratified by tumor type and randomized to receive 1, 3, and 10 mg/kg dose levels. Tumor response (modified WHO) was determined after the 4th dose and then every 2 doses. After 4 doses, treatment continued in pts with antitumor activity and without dose-limiting toxicity (DLT). Tumor biopsies were obtained from pts in Part 1 pretreatment and during cycle 2; PBMC, serum, and plasma were also obtained from all pts at select times for exploratory biomarker analysis. Results: 83 pts (54 melanoma, 15 RCC, 13 ovarian and 1 prostate) have been treated. Part 2 melanoma enrollment is complete. In Part 1, single DLTs were reported in the 0.3 mg/kg (Gr 3 neutropenia), and 15 mg/kg (Gr 4 neutropenia) cohorts. Overall, fatigue (All, 26%, Gr 3–4, 3%), reversible Gr 3–4 transaminitis (11%) and Gr 3–4 neutropenia (5%) were the most common agent-related AEs. 3 PRs (18+ mo, 3+ mo, 1.5+ mo, all melanoma) and 4 SD (10 mo, 6 mo, 6 mo, 4+ mo) occurred at all three doses tested in expansion cohorts. Preliminary biomarker analysis demonstrated increased expression of IFN-inducible genes in peripheral blood, serum neopterin levels, and percentage of circulating activated (HLA-DR+, CD69+) CD8 and CD4 T-cells following a single treatment. Increased expression of CD8a and IFNγ were detected in post- treatment biopsies in a subset of pts. Conclusions: BMS-663513 was tolerable across a wide dose range (0.3–15 mg/kg). As a single agent, BMS-663513 demonstrates clinical activity that justifies its further evaluation both as a single agent and in combination with other treatment modalities. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb
A dose-finding study of gemcitabine and vinorelbine in advanced previously treated malignancies
Authors: J.P. Delord, E. Raymond, M. Chaouche, P. Ruffle, M. Ducreux, S. Faivre, V. Boige, T. Le Chevalier, O. Rixe, E. Baudin, P. Pautier, J.M. Rodier, N. Chouaki, B. Escudier, L. Kayitalire, J.P. Armand
Journal: Annals of Oncology (2000)
Cerebral amyloid-β proteostasis is regulated by the membrane transport protein ABCC1 in mice
Authors: Markus Krohn, Cathleen Lange, Jacqueline Hofrichter, Katja Scheffler, Jan Stenzel, Johannes Steffen, Toni Schumacher, Thomas Brüning, Anne-Sophie Plath, Franziska Alfen, Anke Schmidt, Felix Winter, Katja Rateitschak, Andreas Wree, Jörg Gsponer, Lary C. Walker, Jens Pahnke
Journal: Journal of Clinical Investigation (2011)

In Alzheimer disease (AD), the intracerebral accumulation of amyloid-β (Aβ) peptides is a critical yet poorly understood process. Aβ clearance via the blood-brain barrier is reduced by approximately 30% in AD patients, but the underlying mechanisms remain elusive. ABC transporters have been implicated in the regulation of Aβ levels in the brain. Using a mouse model of AD in which the animals were further genetically modified to lack specific ABC transporters, here we have shown that the transporter ABCC1 has an important role in cerebral Aβ clearance and accumulation. Deficiency of ABCC1 substantially increased cerebral Aβ levels without altering the expression of most enzymes that would favor the production of Aβ from the Aβ precursor protein. In contrast, activation of ABCC1 using thiethylperazine (a drug approved by the FDA to relieve nausea and vomiting) markedly reduced Aβ load in a mouse model of AD expressing ABCC1 but not in such mice lacking ABCC1. Thus, by altering the temporal aggregation profile of Aβ, pharmacological activation of ABC transporters could impede the neurodegenerative cascade that culminates in the dementia of AD.