tbuckley/cabot-search huggingface dataset:
Elimination of IL-10–Inducing T-Helper Epitopes from an IGFBP-2 Vaccine Ensures Potent Antitumor Activity
Authors: Denise L. Cecil, Gregory E. Holt, Kyong Hwa Park, Ekram Gad, Lauren Rastetter, Jennifer Childs, Doreen Higgins, Mary L. Disis
Journal: Cancer Research (2014)

Abstract Immunization against self-tumor antigens can induce T-regulatory cells, which inhibit proliferation of type I CD4+ T-helper (TH1) and CD8+ cytotoxic T cells. Type I T cells are required for potent antitumor immunity. We questioned whether immunosuppressive epitopes could be identified and deleted from a cancer vaccine targeting insulin-like growth factor–binding protein (IGFBP-2) and enhance vaccine efficacy. Screening breast cancer patient lymphocytes with IFN-γ and interleukin (IL)-10 ELISPOT, we found epitopes in the N-terminus of IGFBP-2 that elicited predominantly TH1 whereas the C-terminus stimulated TH2 and mixed TH1/TH2 responses. Epitope-specific TH2 demonstrated a higher functional avidity for antigen than epitopes, which induced IFN-γ (P = 0.014). We immunized TgMMTV-neu mice with DNA constructs encoding IGFBP-2 N-and C-termini. T cell lines expanded from the C-terminus vaccinated animals secreted significantly more type II cytokines than those vaccinated with the N-terminus and could not control tumor growth when infused into tumor-bearing animals. In contrast, N-terminus epitope–specific T cells secreted TH1 cytokines and significantly inhibited tumor growth, as compared with naïve T cells, when adoptively transferred (P = 0.005). To determine whether removal of TH2-inducing epitopes had any effect on the vaccinated antitumor response, we immunized mice with the N-terminus, C-terminus, and a mix of equivalent concentrations of both vaccines. The N-terminus vaccine significantly inhibited tumor growth (P &amp;lt; 0.001) as compared with the C-terminus vaccine, which had no antitumor effect. Mixing the C-terminus with the N-terminus vaccine abrogated the antitumor response of the N-terminus vaccine alone. The clinical efficacy of cancer vaccines targeting self-tumor antigens may be greatly improved by identification and removal of immunosuppressive epitopes. Cancer Res; 74(10); 2710–8. ©2014 AACR.
Allowing relatives to witness resuscitation
Authors: C. A J McLauchlan
Journal: BMJ (1997)

Gulf war illness Why it took so long to decide to investigateEditor-As it is now six years since the Gulf war, it is reasonable to ask why the problem of Gulf war syndrome has not been resolved. 1 As surgeon general in 1991-4 I want to comment on the unravelling timetable during these six years.At no time have we denied that Gulf veterans have been ill-indeed, whenever possible we have actively recommended their appropriate medical management.Secondly, despite press reports, we have always kept an open mind on the presence of a specific Gulf war syndrome.The Gulf conflict in 1990-1 itself was short, casualties mercifully few, and the sickness rates unremarkable; likewise, when troops returned to the UK the daily sickness rate did not increase.Also at that stage little evidence existed of psychiatric illness or post-traumatic stress syndrome.Some 18 to 24 months later, however, we became aware of a campaign by lawyers to recognise a specific Gulf illness.Up to 200 people were on their books, but despite widespread appeals for them to come forward, including two television appeals, only 15 approached the armed forces medical services.Not surprisingly, among these 15 no pattern of illness emerged.They were all managed appropriately.As we were keen to solve the problem, in October 1993 we appointed a single consultant physician, Group Captain Coker, to see all such patients.At first only a trickle of patients came forward-even by June 1994 (three and half years later) he had seen only 30 patients.Over the next two years, however, these numbers increased so that by January 1997, 1100 had been registered, 920 had been seen and fully investigated, and results had been completed and analysed in 519.A preliminary paper in the summer of 1996 concluded: "From our small database it would not appear that there is a unique cluster of symptoms which would suggest a new pattern of illness in veterans." 2 There was, however, a higher than normal incidence of psychiatric and stress related illness.A large battery of tests was uniformly performed on all the patients, with further investigations as necessary.Now it has been agreed that full epidemiological studies are to be undertaken into the incidence of ill health among UK Gulf war veterans and into their reproductive health.In answering the criticism that these expensive studies should have been instigated earlier, I have tried to show how difficult it has been to decide exactly when this decision could have been made.Early on there were very few patients and no evidence of a syndrome.At all stages we have liaised with our counterparts in the United States.They embarked a little earlier on similar studies as they had similar results to their investigations but dealt with greater numbers.An important reason for writing this letter is because our armed forces may well be placed in similar alien environments in future and we owe it to them to provide the best medical support, which of course includes planned protective and scientifically justified measures against likely threats to their health.
Psychoactive Substance Dependence Among Trauma Center Patients
Authors: Carl A. Soderstrom
Journal: JAMA (1992)

<h3>Introduction.</h3> —The practice of assessing only trauma patients with elevated blood alcohol concentrations (BACs) or positive drug screens for psychoactive substance use disorders (PSUDs) was evaluated. <h3>Methods.</h3> —Twenty-four BAC-negative (BAC<sup>-</sup>) (BAC, 0) and 21 BAC-positive (BAC<sup>+</sup>) (BAC, ≥22 mmol/L or 100 mg/dL; mean, 41 mmol/L; range, 24.3 to 79 mmol/L) adult trauma patients were evaluated for alcoholism and other PSUDs using the Structured Clinical Interview (SCI) from the<i>Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition (DSM-III-R)</i>. Approximately half were vehicular crash victims and 78% were men. <h3>Results.</h3> —A total of 64 PSUDs were diagnosed in 31 (68.9%) of the 45 patients; all but one was for dependence (vs abuse). Of the BAC<sup>+</sup>patients, 14 (66.7%) met<i>DSM-III-R</i>criteria for alcohol dependence, 11 (78.6%) of whom also had other PSUDs not related to alcohol. Two other BAC<sup>+</sup>patients had nonalcohol PSUDs. Of the BAC<sup>-</sup>patients, 11 (45.8%) had alcohol dependence, six (54.5%) of whom also had nonalcohol PSUDs. Another four BAC<sup>-</sup>patients had nonalcohol PSUDs. Overall, 76.2% of the BAC<sup>+</sup>patients and 62.5% of the BAC patients had a diagnosis of psychoactive substance dependence. <h3>Conclusion.</h3> —All patients admitted to trauma centers should be assessed for alcoholism and other PSUDs. (<i>JAMA</i>. 1992;267:2756-2759)
Intralymphatic histiocytosis with granuloma formation associated with orthopaedic metal implants
Authors: T. Watanabe, N. Yamada, Y. Yoshida, O. Yamamoto
Journal: British Journal of Dermatology (2007)

A 75‐year‐old man presented with a 1‐year history of asymptomatic reddish‐brown nodules on his left knee, in which orthopaedic metal implants had been inserted for a transformation‐related knee joint disorder. Histopathological examination revealed typical features of mixed cell granuloma with many dilated lymphatics that contained many histiocytes from the upper dermis to subcutaneous fat tissue. Results of qualitative analysis of biopsy specimens by energy‐dispersive X‐ray spectroscopy were positive for molybdenum, which was one of the constituents of the metal implant. We describe the first observation of intralymphatic histiocytosis with granuloma formation in the skin occurring in a patient bearing orthopaedic metal implants for a transformation‐related knee joint disorder.
HIV epidemic in Europe is not under control, WHO says
Authors: N. Hawkes
Journal: BMJ (2011)

HIV infections in Europe are showing a worrying increase, the latest figures from the World Health Organisation’s regional office for Europe show. Despite the development of effective treatments, the HIV epidemic is still not under control, with 118 000 new cases diagnosed in 2010 in the 53 countries that make up WHO’s European region.

The figures, released for World Aids Day, come hard on the heels of data from the Health Protection Agency (HPA) that show there were 6660 newly diagnosed HIV infections in the UK in 2010. WHO says this is the highest number of new diagnoses in the European Union, and the third highest rate of new infections (10.7 per 100 000 population) after Estonia and Latvia.

“After 30 years of the epidemic, and unlike anywhere else in the world, HIV is not …
Leptospirosis in Vietnam
Authors: JACK D. WELSH
Journal: Annals of Internal Medicine (1973)

Comments and Corrections1 November 1973Leptospirosis in VietnamJACK D. WELSH, M.D.JACK D. WELSH, M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-79-5-756_2 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptTo the editor: The article by Berman and associates, "Sporadic Anicteric Leptospirosis in South Vietnam" (Ann Intern Med79:167-173, 1973) was particularly interesting because of previous experience in that country. Rats and swine have been identified as leptospirosis hosts in South Vietnam; 7% of 300 rats tested in Saigon were leptospira-positive (1). Slightly more than half of 157 swine from an abattoir in the Delta yielded agglutination reactions in one or more of four pools of grouped leptospira antigens (2). Twenty-three percent of 343 Vietnamese were leptospira-positive (1), and leptospirosis was a serious problem among French troops between 1950 and...References1. VINH B: A study of leptospirae in Vietnam. Rev Corps Sante; F.A.R.V.N. 20:108-111, 1967 Google Scholar2. FERGUSONWEBB JC: Antibody survey for leptospirosis in swine in Northern IV Corps Tactical Zone, Republic of Vietnam. U.S. Army Medical Research Team (WRAIR) Vietnam and Institute of Pasteur of Vietnam Annual Progress Report. I September 1967-30 June 1968, Washington, D.C., Walter Reed Army Institute of Research, pp. 234-247 Google Scholar3. BESSEIGECHAMBON HL: Réflexions sur les leptospiroses au Viet-Nam. Bull Soc Pathol Exot 52:64-78, 1959 Google Scholar4. WELSHSULZERDOUGLAS JCH: Leptospiral seroreactors in the Mekong Delta of South Vietnam. Southeast Asian J Trop Med Public Health 3:205-207, 1972 MedlineGoogle Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Department of Medicine University of Oklahoma Health Sciences Center Oklahoma City, Oklahoma PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byAssessment of the Validity and Reliability of a Methodology for Measuring the Costs and Quality of Access to Justice 1 November 1973Volume 79, Issue 5Page: 756-756KeywordsAntigensLeptospiraLeptospirosisSwine Issue Published: 1 November 1973 PDF downloadLoading ...
22-Oxacalcitriol suppresses secondary hyperparathyroidism without inducing low bone turnover in dogs with renal failure
Authors: Marie-Claude Monier-Faugere, Zhaopo Geng, Robert M. Friedler, Quanle Qi, Noboru Kubodera, Eduardo Slatopolsky, Hartmut H. Malluche
Journal: Kidney International (1999)
The vestigial enzyme D-dopachrome tautomerase protects the heart against ischemic injury
Authors: Dake Qi, Kwame Atsina, Lintao Qu, Xiaoyue Hu, Xiaohong Wu, Bin Xu, Marta Piecychna, Lin Leng, Günter Fingerle-Rowson, Jiasheng Zhang, Richard Bucala, Lawrence H. Young
Journal: Journal of Clinical Investigation (2014)

The cellular response to stress involves the recruitment and coordination of molecular signaling pathways that prevent cell death. D-dopachrome tautomerase (DDT) is an enzyme that lacks physiologic substrates in mammalian cells, but shares partial sequence and structural homology with macrophage migration inhibitory factor (MIF). Here, we observed that DDT is highly expressed in murine cardiomyocytes and secreted by the heart after ischemic stress. Antibody-dependent neutralization of secreted DDT exacerbated both ischemia-induced cardiac contractile dysfunction and necrosis. We generated cardiomyocyte-specific DDT knockout mice (Myh6-Cre Ddtfl/fl), which demonstrated normal baseline cardiac size and function, but had an impaired physiologic response to ischemia-reperfusion. Hearts from Myh6-Cre Ddtfl/fl mice exhibited more necrosis and LV contractile dysfunction than control hearts after coronary artery ligation and reperfusion. Furthermore, treatment with DDT protected isolated hearts against injury and contractile dysfunction after ischemia-reperfusion. The protective effect of DDT required activation of the metabolic stress enzyme AMP-activated protein kinase (AMPK), which was mediated by a CD74/CaMKK2-dependent mechanism. Together, our data indicate that cardiomyocyte secretion of DDT has important autocrine/paracrine effects during ischemia-reperfusion that protect the heart against injury.
Medical sense and nonsense in biography
Authors: A. Emery
Journal: BMJ (1983)

and FEV,/FVC.In the figure the results, adjusted for age and height, are expressed relative to baseline values of the never smoked group for FEVI, FVC, and FEV1/FVC as 100%.The index FEV1 shows the steepest decline with amount smoked.In contrast, the ratio FEVI/FVC is a misleading indicator as it fails to show deterioration of lung function for moderate, heavy, and very heavy smokers._100 ~C\ *(FVC) ......(FEV/FVC) J 0 909 (FEV1) 90 *e, ~' -<15 15-24 25-34 35+ Smokers (cigarettes smoked /doy)Relation of lung function indices to smoking habits in non-smokers, ex-smokers who have not smoked for eight or more years, and smokers by number of cigarettes smoked a day.Baseline values of non- smokers are taken as 100°,, for the indices FEVI, FVC, and FEVI/FVC.We suggest that at least two indices (FEV1, and FEV1/FVC) should be reported as a matter of routine for all comparisons between groups.Both decline with age but only FEV1 is positively correlated with height.Appropriate adjustments for age and height can be easily made.2We are fairly confident that the subgroup of smokers without airflow obstruction studied by Dr Nemery and others would have been found to have lower FEV1 values than the asymptomatic non-smokers.Also the smokers without airflow obstruction were lighter by about 2 kg, adjusting for height.This difference, although appreciable and in the expected direction, is not significant because of small numbers.We agree entirely with their concluding statement: "From a practical point of view loss of excess weight in middle aged smokers should not always be regarded as favourable, since it could point to deteriorating lung function and chronic obstructive lung disease."To this we would add that it is much better to.be an overweight non-smoker than to be an underweight smoker.3
Impairment of Peripheral Blood Flow Responses in Diabetes Resembles an Enhanced Aging Effect
Authors: Kevin B Stansberry, Michael A Hill, Shane A Shapiro, Patricia M McNitt, Bankim A Bhatt, Aaron I Vinik
Journal: Diabetes Care (1997)

OBJECTIVE To test the hypothesis that skin blood flow responses in the fingertip of diabetic patients are impaired and to examine the role of aging in both healthy control subjects and diabetic patients. RESEARCH DESIGN AND METHODS We measured cutaneous blood flow using laser Doppler techniques in 40 people with diabetes and in 20 age- and sex-matched healthy control subjects. To induce vasoconstriction, subjects were asked to perform three 1-min stressor tasks: mental arithmetic, contralateral hand grip, and immersion of the contralateral hand in ice water. To induce vasodilatation, a local heat stimulus of 45 degrees C was applied for 5 min. RESULTS Basal blood flow did not differ between groups, but vasoconstrictive responses induced by arithmetic or immersion of the contralateral hand in ice-cold water and vasodilatation induced by local heating were severely impaired in diabetic subjects, compared with healthy control subjects (P &amp;lt; 0.01). These responses correlated with autonomic nerve function and deteriorated significantly with advancing age in control subjects, but not in diabetic subjects. Blood flow in younger diabetic subjects resembled that of older control subjects. CONCLUSIONS These data demonstrate that diabetes has effects on precapillaries that may by direct or mediated via autonomic nerves, which result in a deficit that resembles premature aging.
Hypomethylation of long interspersed nuclear element-1 (LINE-1) leads to activation of proto-oncogenes in human colorectal cancer metastasis
Authors: Keun Hur, Paloma Cejas, Jaime Feliu, Juan Moreno-Rubio, Emilio Burgos, C Richard Boland, Ajay Goel
Journal: Gut (2013)

<h3>Objective</h3> Hypomethylation of LINE-1 elements has emerged as a distinguishing feature in human cancers. Limited evidence indicates that some LINE-1 elements encode an additional internal antisense promoter, and increased hypomethylation of this region may lead to inadvertent activation of evolutionarily methylation-silenced downstream genes. However, the significance of this fundamental epigenetic mechanism in colorectal cancer (CRC) has not been investigated previously. <h3>Design</h3> We analysed tissue specimens from 77 CRC patients with matched sets of normal colonic mucosa, primary CRC tissues (PC), and liver metastasis tissues (LM). LINE-1 methylation levels were determined by quantitative bisulfite pyrosequencing. MET, RAB3IP and CHRM3 protein expression was determined by western blotting and IHC. <i>MET</i> proto-oncogene transcription and 5-hydroxymethylcytosine (5-hmc) were evaluated by quantitative real-time-PCR. <h3>Results</h3> Global LINE-1 methylation levels in LM were significantly lower compared with the matched PC (PC=66.2% vs LM=63.8%; p&lt;0.001). More importantly, we observed that specific LINE-1 sequences residing within the intronic regions of multiple proto-oncogenes, <i>MET</i> (p&lt;0.001), <i>RAB3IP</i> (p=0.05) and <i>CHRM3</i> (p=0.01), were significantly hypomethylated in LM tissues compared with corresponding matched PC. Furthermore, reduced methylation of specific LINE-1 elements within the <i>MET</i> gene inversely correlated with induction of <i>MET</i> expression in CRC metastases (R=−0.44; p&lt;0.0001). Finally, increased 5-hmc content was associated with LINE-1 hypomethylation. <h3>Conclusions</h3> Our results provide novel evidence that hypomethylation of specific LINE-1 elements permits inadvertent activation of methylation-silenced <i>MET</i>, <i>RAB3IP</i> and <i>CHRM3</i> proto-oncogenes in CRC metastasis. Moreover, since 5-hmc content inversely correlated with LINE-1 hypomethylation in neoplastic tissues, our results provide important mechanistic insights into the fundamental processes underlying global DNA hypomethylation in human CRC.
A Clinician's Companion: A Study Guide for Effective and Humane Patient Care
Authors: John A. Mihalevich
Journal: JAMA (1987)

Rarely in the medical literature does one find a book that fulfills its title and effectively reaches the reading audience for whom it is intended in such a succint, readable, learnable fashion as does this book. The author's intent is to address topics of "practical medical humanism" oriented to the medical student, house officer, or young practitioner to "stimulate increased concern and questioning by physicians about these issues and to
Efficacy and safety of balloon kyphoplasty compared with non-surgical care for vertebral compression fracture (FREE): a randomised controlled trial
Authors: Douglas Wardlaw, Steven R Cummings, Jan Van Meirhaeghe, Leonard Bastian, John B Tillman, Jonas Ranstam, Richard Eastell, Peter Shabe, Karen Talmadge, Steven Boonen
Journal: The Lancet (2009)
Pancreatic Cancer
Authors: Harold O. Douglass
Journal: JAMA (1974)

Study of 170 patients with carcinoma of the pancreas suggested that initial pancreatoduodenectomy, when the tumor had arisen in the head of the pancreas or periampullary region, resulted in greater relief of symptoms than palliative bypasses. Staged resections offered no greater benefit than biliary bypasses, except to occasional patients with polypoid periampullary carcinomas. After biliary diversion, the frequent need for gastroenterostomy within three months suggested that gastric stasis often antedated the first operation, and it could have been detected by preoperative roentgenograms of the upper gastrointestinal tract. (<i>JAMA</i>229:793-797, 1974)
Abstract 3532A: Development of gene therapy for pancreatic carcinoma: from experimental models to phase I clinical trial.
Authors: Louis Buscail, Barbara Bournet, Fabienne Vernejoul, Hubert Lulka, Gilles Cambois, Naima Hanoun, Fabian Gross, Jean Tiraby, Pierre Cordelier
Journal: Cancer Research (2013)

Abstract Background: the median survival of patients diagnosed with locally advanced or metastatic pancreatic adenocarcinoma (PDA) is 4 to 6 months. Chemotherapies (gemcitabine, FOLFIRINOX) and molecular targeted therapies only offer a marginal survival benefit. Consequently, we developed new strategies based on therapeutic gene transfer to help alleviate the dismal prognosis of PDA. We demonstrated that transferring SSTR2 gene in PDA experimental models strongly inhibited tumor progression. We generated DCK::UMK fusion gene to chemosensitize tumor cells to gemcitabine to provoke tumor shrinkage in immune competent animals. Based on these promising results, we asked whether combining SSTR2 and DCK::UMK genes delivered by a non-viral vector may impede PDA growth in patients. Methods: in this first-in-man clinical trial, 22 patients (12 first line, 10 second line) were included in the CHU of Toulouse from 12/2010 to 9/2012. Four different doses (125, 250, 500 and 1000μg) of the gene therapy product (GTP) were injected twice using endoscopic ultrasound (EUS) (day 1 and day 28). Patients concomitantly received gemcitabine for 2 months. Results: the feasibility of this approach is excellent, as all the patients were successfully injected despite differences in the site and the size of the primary tumor, and pre-existing treatments (biliary stent, surgical bypass). No serious adverse events related to the GTP were recorded. We found that less than 0.001% of GTP was detected in blood, while urine was negative in all cases. We found that CA 19.19 levels decreased in 68% (15/22) of patients following gene therapy. In first line patients, we demonstrated partial tumor shrinkage in 2 cases (16%), stable disease in 9 cases (75%), and tumor progression in 1 case (8%). In these latter patients, progression-free survival and median survival following gene therapy reached 7 and 11.3 months, respectively. Conclusions: all together, we demonstrated for the first time that delivering antitumoral genes using non-viral vectors by EUS is feasible and safe in patients with advanced PDA. As our preliminary results tend to demonstrate therapeutic efficacy, we are currently designing a phase II trial based on this approach. Citation Format: Louis Buscail, Barbara Bournet, Fabienne Vernejoul, Hubert Lulka, Gilles Cambois, Naima Hanoun, Fabian Gross, Jean Tiraby, Pierre Cordelier. Development of gene therapy for pancreatic carcinoma: from experimental models to phase I clinical trial. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3532A. doi:10.1158/1538-7445.AM2013-3532A