tbuckley/cabot-search huggingface dataset:
P150 Once-daily tiotropium Respimat® reduces risk of severe asthma exacerbation and asthma worsening in symptomatic asthma, independent of allergic and inflammatory status
Authors: R Dahl, T Casale, M Vandewalker, H Schmidt, M Engel, P Moroni-Zentgraf, HAM Kerstjens
Journal: Thorax (2015)

<h3>Background</h3> Four trials explored whether tiotropium Respimat® add-on to at least ICS is effective in the T<sub>H</sub>2 phenotype, determined by high serum immunoglobulin E (IgE) and blood eosinophil values, in reducing risk of severe asthma exacerbation and asthma worsening in adult patients with moderate or severe symptomatic asthma. <h3>Methods</h3> Four Phase III, double-blind, placebo-controlled, parallel-group trials. PrimoTinA-asthma® (two 48-week trials; NCT00776984/NCT00772538; n = 912): tiotropium Respimat® 5 µg or placebo Respimat® add-on to ICS + LABA (≥800 µg budesonide or equivalent); MezzoTinA-asthma® (two 24-week trials; NCT01172808/NCT01172821; n = 2100): tiotropium Respimat® 5 µg, tiotropium Respimat® 2.5 µg or placebo add-on to ICS (400–800 µg budesonide or equivalent). Patients had symptomatic asthma requiring treatment with at least ICS for ≥4 weeks before screening; COPD was excluded. Subgroups of allergic and inflammatory status (IgE and eosinophils) were used to analyse risk of severe exacerbation and asthma worsening, <i>post hoc</i>. Cox regression modelling analyses, adjusted for treatment, IgE or eosinophils and treatment by IgE or eosinophil interaction, were applied to calculate hazard ratios and 95% confidence intervals across IgE (2–2000 μg/L) and eosinophil (0.05–7.00 × 10<sup>9</sup>/L) values. <h3>Results</h3> Severe exacerbation: in PrimoTinA-asthma®, tiotropium Respimat® 5 µg reduced risk in terms of hazard ratio versus placebo Respimat® up to an IgE level of ~1000 µg/L, and consistently across all eosinophil values. In MezzoTinA-asthma®, tiotropium Respimat® 5 µg and 2.5 µg reduced risk versus placebo consistently across all IgE and eosinophil levels. Asthma worsening: in PrimoTinA-asthma®, tiotropium Respimat® 5 µg reduced risk in terms of hazard ratio versus placebo Respimat®, independent of IgE and eosinophils. In MezzoTinA-asthma®, tiotropium Respimat® 5 µg reduced risk versus placebo across all IgE and eosinophil values. Tiotropium Respimat® 2.5 µg reduced risk versus placebo across all IgE values and at eosinophil values &lt;3.00×10<sup>9</sup>/L. <h3>Conclusion</h3> Tiotropium Respimat® add-on to ICS ± LABA reduces risk of severe exacerbation and asthma worsening in patients across severities of symptomatic asthma and a broad range of IgE and eosinophil values, suggesting efficacy independent of underlying allergic/eosinophilic inflammation. Once-daily tiotropium Respimat® may have potential as add-on to at least ICS maintenance therapy in patients with symptomatic asthma, independent of T<sub>H</sub>2 phenotype.
High feasibility and antileukemic efficacy of fludarabine, cytarabine, and idarubicin (FLAI) induction followed by risk‐oriented consolidation: A critical review of a 10‐year, single‐center experience in younger, non M3 AML patients
Authors: Fabio Guolo, Paola Minetto, Marino Clavio, Maurizio Miglino, Carmen Di Grazia, Filippo Ballerini, Giordana Pastori, Daniela Guardo, Nicoletta Colombo, Annalisa Kunkl, Giuseppina Fugazza, Barbara Rebesco, Mario Sessarego, Roberto Massimo Lemoli, Andrea Bacigalupo, Marco Gobbi
Journal: American Journal of Hematology (2016)

About 105 consecutive acute myeloid leukemia (AML) patients treated with the same induction-consolidation program between 2004 and 2013 were retrospectively analyzed. Median age was 47 years. The first induction course included fludarabine (Flu) and high-dose cytarabine (Ara-C) plus idarubicin (Ida), with or without gemtuzumab-ozogamicin (GO) 3 mg/m(2) (FLAI-5). Patients achieving complete remission (CR) received a second course without fludarabine but with higher dose of idarubicin. Patients not achieving CR received an intensified second course. Patients not scheduled for early allogeneic bone marrow transplantation (HSCT) where planned to receive at least two courses of consolidation therapy with Ara-C. Our double induction strategy significantly differs from described fludarabine-containing regimens, as patients achieving CR receive a second course without fludarabine, to avoid excess toxicity, and Ara-C consolidation is administrated at the reduced cumulative dose of 8 g/m(2) per cycle. Toxicity is a major concern in fludarabine containing induction, including the recent Medical Research Council AML15 fludarabine, cytarabine, idaraubicin and G-CSF (FLAG-Ida) arm, and, despite higher anti-leukemic efficacy, only a minority of patients is able to complete the full planned program. In this article, we show that our therapeutic program is generally well tolerated, as most patients were able to receive subsequent therapy at full dose and in a timely manner, with a 30-day mortality of 4.8%. The omission of fludarabine in the second course did not reduce efficacy, as a CR rate of 83% was achieved and 3-year disease-free survival and overall survival (OS) were 49.6% and 50.9%, respectively. Our experience shows that FLAI-5/Ara-C + Ida double induction followed by risk-oriented consolidation therapy can result in good overall outcome with acceptable toxicity. Am. J. Hematol. 91:755-762, 2016. © 2016 Wiley Periodicals, Inc.
Increased Glomerular Filtration Rate after Converting-Enzyme Inhibition in Essential Hypertension
Authors: Norman K. Hollenberg, Stephen L. Swartz, Diane R. Passan, Gordon H. Williams
Journal: New England Journal of Medicine (1979)

To test the influence of an inhibitor of angiotensin-converting enzyme, teprotide (SQ 20881), we administered it to seven patients with essential hypertension and normal renal function and nine with an unequivocal reduction in creatinine clearance, caused by bilateral renal-artery stenosis in two and by essential hypertension in seven. Despite the fall in blood pressure (112.7±4.5 to 100.3±3.9 mm Hg, mean ± S.E.M., P<0.01), there were prompt increases in both creatinine clearance (95.9±10.5 to 109.9±9.5 ml per minute per 1.73 m2 of body-surface area, P<0.01) and sodium excretion (17.0±5.9 to 31.7±7.2 μmol per minute, P<0.01) in patients with essential hypertension. The increase in glomerular filtration rate was most striking, averaging 33 per cent (66.0±10.3 to 88.0±9.2 ml per minute per 1.73 m2, P<0.001) in patients in whom an initial reduction was evident and hypertension was more severe. These observations suggest that a functional element, perhaps involving angiotensin-mediated renal vasoconstriction, frequently has a role in the reduction in glomerular filtration rate that occurs in essential hypertension. This class of agent may improve renal excretory function as it controls hypertension. (N Engl J Med 301:9–12, 1979)
Cardiac Response to Enzyme-Replacement Therapy in Gaucher's Disease
Authors: Marco Spada, Enrico Chiappa, Alberto Ponzone
Journal: New England Journal of Medicine (1998)

To the Editor: Gaucher's disease is the most common lysosomal-storage disorder. It is caused by a deficiency of glucocerebrosidase, which results in an accumulation of glucosylceramide in abdominal...
Nationwide Genomic Screening for Ret Fusion in Advanced Egfr Mutation-Negative Non-Squamous Lung Cancer and Development of Molecular Targeted Therapy in Japan: Lc-Scrum-Japan
Authors: K. Yoh, S. Matsumoto, K. Tsuchihara, T. Kohno, G. Ishii, K. Tsuta, M. Nishio, N. Yamamoto, H. Murakami, M. Satouchi, N. Nogami, T. Seto, S. Umemura, S. Niho, H. Ohmatsu, Y. Ohe, T. Yamanaka, K. Goto
Journal: Annals of Oncology (2014)
Reversible Uremia with Hypercalcemia Due to Vitamin-D Intoxication
Authors: F. Dennette Adams
Journal: New England Journal of Medicine (1951)

CHRONIC renal disease with uremia is usually an irreversible process. A case of reversible uremia is therefore reported as a reminder that the diagnosis is simple if the cause is present and is thought of but is often overlooked because its possibility is not considered. If it is recognized early, cure can be expected.Case ReportA 40-year-old advertising executive was first seen on February 28, 1950, because of progressive weakness, fatigability, dryness of skin and mouth, excessive thirst and polyuria. His past history was irrelevant except for the following: At the age of 14, during a routine insurance examination, . . .
Paediatricians call on royal college to drop financial ties to infant formula firms
Authors: Anne Gulland
Journal: BMJ (2016)

The Royal College of Paediatrics and Child Health is being warned that it risks damaging its reputation if it does not reject income from manufacturers of infant formula milk.

A group of paediatricians has submitted a motion to the college’s annual general meeting on 27 April highlighting the income it receives from manufacturers that have stands at conferences and clinical meetings and the core funding it receives from one manufacturer. The college said that it received income from more than one manufacturer but could not disclose the amounts because of commercial sensitivity.

The paediatricians say that although the college has “progressively distanced” itself from such sponsorship, they warn that receiving any form of funding from manufacturers “will distort public and professional perceptions of the college stance on breast feeding as well as their advice on …
Use of a C1 Esterase Inhibitor Concentrate in Elderly Patients with Hereditary Angioedema: Findings from the International Berinert® (C1-INH) Registry
Authors: Anette Bygum, Inmaculada Martinez-Saguer, Murat Bas, Jeffrey M. Rosch, Jonathan M. Edelman, Mikhail Rojavin, Debora Williams-Herman
Journal: Journal of Allergy and Clinical Immunology (2016)
Cyclophosphamide-Induced Cyclical Neutropenia
Authors: Alec Morley, Frederick Stohlman
Journal: New England Journal of Medicine (1970)

An animal model of a human periodic disease, cyclical neutropenia, was produced in five of nine dogs by administration of a constant daily dose of cyclophosphamide so as to cause mild bone-marrow depression. That this would occur was predicted by a computer model in which granulopoiesis was regarded as being controlled by two feedback loops, one regulating rate of production and the other rate of release of neutrophils. Cyclical neutropenia does not appear to be a specific entity, and its periodicity, and by extension possibly that of other periodic diseases, may be due to the action of feedback control. A hypothetical possibility is that if unrecognized oscillation of blood cell numbers should develop in patients receiving marrow-depressant drugs, estimate of marrow function at any one point of time might give a wrong impression of overall drug effect.
Abstract P2-05-23: TWIST1 silences FOXA1 transcription to promote breast cancer progression
Authors: Y Xu, Z Feng, Y Xu, Q Mo, L Qin, T Sun, H Wu, Y Li, L Liao, J Xu
Journal: Cancer Research (2016)

Abstract TWIST1 promotes epithelial-mesenchymal transition (EMT), invasion and metastasis of breast cancer cells, but the underlying mechanism is still not well understood. We generated mammary gland tumor specific Twist1 knock out mouse model and found that TWIST1 does not affect PyMT-induced mammary tumor initiation and growth but promotes tumor lung metastasis. We identified FOXA1 as a novel direct target of TWIST1 in both mouse and human breast cancer. We further found that TWIST1 inhibits FOXA1 expression through direct binding to its proximal promoter region and recruiting Mi2/nucleosome remodeling and deacetylase (Mi2/NuRD) transcriptional repressor complex. Moreover, TWIST1 also diminished transcriptional activator AP1 binding to FOXA1 promoter. TWIST1 mediated FOXA1 down-regulation is essential for promoting breast cancer migration, invasion and metastasis. FOXA1 significantly inhibits TWIST1 dependent cell migration and invasion capability of MCF7 cells through inhibiting integrin α5, β1 and MMP9 expression. Importantly, TWIST1high FOXA1low correlates with the poorest prognosis in breast cancer patients. Citation Format: Xu Y, Feng Z, Xu Y, Mo Q, Qin L, Sun T, Wu H, Li Y, Liao L, Xu J. TWIST1 silences FOXA1 transcription to promote breast cancer progression. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-05-23.
Laboratory Aids to Diagnosis in Thyroid Disease
Authors: Carl E. Cassidy, W. P. Vanderlaan
Journal: New England Journal of Medicine (1958)

SINCE the determination of the serum protein-bound iodine and the twenty-four-hour thyroidal accumulation of radioactive iodine are tests of thyroid function now commonly employed, it seems worth while to review the factors that modify these tests. In patients whose thyroid status is unclear clinically, the use of one of these tests can sometimes be misleading; however, the estimation of total iodine in conjunction with the protein-bound iodine,1 the thyroid suppression test2 or the administration of thyrotropin3 often adds helpful information.There are several factors that elevate or depress radioactive-iodine uptake and protein-bound iodine quite apart from altered thyroid function.Radioactive-Iodine . . .
Hospital Cost Containment in the 1980s
Authors: William B. Schwartz, Daniel N. Mendelson
Journal: New England Journal of Medicine (1991)

A key strategy used to contain hospital costs during the 1980s was to reduce the total number of admissions and average lengths of stay. We assessed the magnitude of the savings achieved, the effect of the reductions on the rate of increase in costs, and the prospects for future savings through reductions in the number of days patients spend in the hospital (inpatient days).
Immediate Hormonal Therapy Compared with Observation after Radical Prostatectomy and Pelvic Lymphadenectomy in Men with Node-Positive Prostate Cancer
Authors: Edward M. Messing, Judith Manola, Michael Sarosdy, George Wilding, E. David Crawford, Donald Trump
Journal: New England Journal of Medicine (1999)

Because the optimal timing of the institution of antiandrogen therapy for prostate cancer is controversial, we compared immediate and delayed treatment in patients who had minimal residual disease after radical prostatectomy.
Nature of sedation and post-ERCP pancreatitis: is it a question of sedation “not being in my department”?
Authors: Andrew Thomson
Journal: Endoscopy (2016)

In the recent Endoscopy article by Yaghoobi et al. [1], which compared pancreatic sphincterotomy with a sham procedure, there is a good deal of discussion about the lack of association between pancreatic sphincterotomy and an increased risk of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP). The authors also looked at potential confounders, including procedure duration and type of sedation. For patients who underwent procedures with monitored anesthesia care (MAC), longer procedure duration was associated with an increased risk of PEP, whereas for patients under moderate sedation and general anesthesia, no such relationship was apparent – indeed the reverse trend was seen. This disparity was described by the authors as “not clinically plausible.” It is assumed that moderate sedation involved the administration of an intravenous benzodiazepine and possibly a narcotic by nursing staff either in a semi-autonomous fashion consistent with a protocol or under the contemporaneous direction of the endoscopist. MAC presumably refers to patients being given propofol (with or without other intravenous agents) by an anesthesiologist, and general anesthesia, it is assumed, refers to patients being even more heavily sedated by an anesthesiologist to enable endotracheal untubation.
Immunochemoconjugate of anti-DNMT1/HDAC2 bispecific F(ab)2-bsAb linked with cleavable disulfide to vinorelbine induces apoptosis in chemoresistant infiltrating ductal carcinoma (IDC) characterised by HDAC2 overexpression and 5'CpG island hypermethylation of the FHIT, RAR-β2, BRCA-1, APC, p16(CDKN2A), RASSF1A, CDH1(E-cadherin), 14–3-3-σ (stratifin), HIC1 and MDG1 tumor suppressor genes
Authors: E. Michailakis, J. N. Giannios
Journal: Journal of Clinical Oncology (2004)

2088 One of the reasons for chemoresistance to IDC is deacetylation and DNA methylation which causes silencing of tumor suppressor genes(TSGs).DNMT1 interacts with HDAC2 to repress transcription of TSGs. IDC cells obtained by surgical excision from a patient were analysed by IHC,PCR-based LOH, ChIP, MSP,RT-PCR and NB.There was loss of FHIT expression,LOH at FHIT and 5' CpG island methylation of the FHIT .There was transcriptional silencing of the following TSGs: BRCA1,RAR-β2,APC,p16 (CDKN2A), RASSF1A,CDH1(E-cadherin),14–3-3-σ (stratifin),HIC1 and MDG1.There was overexpression of DNMT1 and HDAC2 suggesting a link between histone deacetylation,cytosine methylation,local chromatin condensation and subsequent transcriptional repression.This chemoresistant IDC was defined as CIMP+.We treated IDC cells with anti-DNMT1/HDAC2 bispecific F(ab)2-bsAb linked with cleavable disulfide to VRL . Post-treatment, there was inhibition of HDAC2 and DNMT1 blocking the 5'CpG island methylation of the tumour suppressor genes resulting to transcriptional activation by upregulation of their mRNA. There was histone hyperacetylation which opens chromatin structure in which the DNA is more loosely wrapped around the histones making it more receptive to interaction with transcription factors.Overexpression of the TSGs combined with the MT depolymerizing action of VRL inhibited metabolic activity and DNA synthesis of tumor cells according to MTT and BrdU.Immunological analysis exhibited ADCC.There was induction of PCD in IDC cells according to TUNEL and TEM.A large number of tumor cells formed apoptotic bodies which were phagocytosed by adjacent tumor cells leading to a bystander killing effect.Concluding,this therapeutic approach with immunovinorelbine (IVRL) may revolutionize IDC treatment adding significantly to the current clinical armamentarium. No significant financial relationships to disclose.
Case 37-2003
Authors: Peter B. Kelsey, Steven Chen, Gregory Y. Lauwers
Journal: New England Journal of Medicine (2003)

Presentation of CaseA 79-year-old man was admitted to the hospital because of occlusion at a vascular access site in the right forearm for hemodialysis and worsening intermittent claudication.There was a history of hypertension and coronary artery disease, and the patient had had an acute anterior myocardial infarction six years before this admission, for which he had received tissue plasminogen activator (alteplase); atheroemboli complicated the procedure, and intermittent claudication in both legs and end-stage renal disease developed. After four years of peritoneal dialysis (two years before the current admission), hemodialysis was initiated. Coronary-artery bypass grafting was performed three months . . .
The Dietary Effects of Methyl Donors on Asthma and Allergic Sensitization Is Influenced By the MTHFR C677T Polymorphism
Authors: Yean Jung Choi, Hye Lim Shin, Song-I. Yang, So-Yeon Lee, Sung-Ok Kwon, Eun Lee, Hyun-Ju Cho, Young-Ho Kim, Young Ho Jung, Ji-Won Kwon, Hyung Young Kim, Ju-Hee Seo, Byoung-Ju Kim, Hyo Bin Kim, Ho-Jang Kwon, Se-Young Oh, Soo-Jong Hong
Journal: Journal of Allergy and Clinical Immunology (2016)
Host Influence on Upper Respiratory Flora
Authors: Marjorie Bodwell Dunlap, Henry Stimson Harvey
Journal: New England Journal of Medicine (1956)

THE study of the spread of bacterial pathogens in a free-living human population presents obvious difficulties. We have considered that a practical method was, first, to determine some common endemic pathogens in a given population and, secondly, to observe the incidence and concentration of these organisms in the members of a group of families over a given period.If an organism, once introduced into the family group, were found to be present in approximately equal quantities and with equal frequency in all members, we should assume that no host factors influenced colonization. If, however, the organism, once introduced, were found . . .
The type three secreted effector SipC regulates the trafficking of PERP during<i>Salmonella</i>infection
Authors: Kelly N. Hallstrom, Beth A. McCormick
Journal: Gut Microbes (2016)

Salmonella enterica Typhimurium employs type III secreted effectors to induce cellular invasion and pathogenesis. We previously reported the secreted effector SipA is in part responsible for inducing the apical accumulation of the host membrane protein PERP, a host factor we have shown is key to the inflammatory response induced by Salmonella. We now report that the S. Typhimurium type III secreted effector SipC significantly contributes to PERP redistribution to the apical membrane surface. To our knowledge, this is the first report demonstrating a role for SipC in directing the trafficking of a host membrane protein to the cell surface. In sum, facilitation of PERP trafficking appears to be a result of type III secreted effector-mediated recruitment of vesicles to the apical surface. Our study therefore reveals a new role for SipC, and builds upon previous reports suggesting recruitment of vesicles to the cell surface is important for Salmonella invasion.
Diethylcarbamazine Prophylaxis for Human Loiasis
Authors: Thomas B. Nutman, Kirk D. Miller, Maurita Mulligan, G. Nicholas Reinhardt, Bart J. Currie, Cathy Steel, Eric A. Ottesen
Journal: New England Journal of Medicine (1988)

To determine whether infection with Loa loa could be prevented in temporary residents of endemic areas, we conducted a randomized, double-blind, placebo-controlled trial of diethylcarbamazine as a chemoprophylactic agent. Diethylcarbamazine (300 mg) or placebo was taken orally once a week by Peace Corps volunteers serving in Gabon, Cameroon, and the Central African Republic. The participants were assessed clinically and with serologic and parasitologic testing before and yearly during their two years of service. One hundred one persons satisfactorily completed the study. In Gabon (where exposure to the parasite was heaviest), 6 of 20 volunteers (30 percent) in the placebo group had clinical disease, as compared with none of 16 (0 percent) in the diethylcarbamazine-treated group (P<0.02). Of those taking placebo, 10 of 20 (50 percent) became seropositive for antifilarial IgG antibody, as compared with 2 of 16 (12 percent) in the drug-treated group (P<0.02). Exposure to the parasite appeared to be much lower among the 65 Peace Corps volunteers in Cameroon and the Central African Republic. No volunteer in either group in these countries had overt loiasis; 2 of 40 (5 percent) in the placebo groups in Cameroon and the Central African Republic seroconverted, as compared with none of 25 (0 percent) of those receiving diethylcarbamazine. Occasional nausea was the only symptom significantly associated with the prophylactic drug regimen. We conclude that diethylcarbamazine given orally once weekly can be an effective, acceptable chemoprophylactic agent to prevent loiasis in temporary residents of regions of Africa where Loa loa is endemic. (N Engl J Med 1988; 319:752–6.)