tbuckley/cabot-search huggingface dataset:
CD4+ immune escape and subsequent T-cell failure following chimpanzee immunization against hepatitis C virus
Authors: Montserrat Puig, Kathleen Mihalik, John C. Tilton, Ollie Williams, Michael Merchlinsky, Mark Connors, Stephen M. Feinstone, Marian E. Major
Journal: Hepatology (2006)

Hepatitis C is a major cause of chronic liver disease, with 170 million individuals infected worldwide and no available vaccine. We analyzed the effects of an induced T-cell response in 3 chimpanzees, targeting nonstructural proteins in the absence of neutralizing antibodies. In all animals the specific T-cell response modified the outcome of infection, producing a 10- to 1,000-fold reduction in peak virus titers. The challenge of 2 immunized animals that had been previously exposed to hepatitis C virus resulted in subclinical infections. Immune responses in the third animal, naive prior to immunization, limited viral replication immediately, evidenced by a 30-fold reduction in virus titer by week 2, declining to a nonquantifiable level by week 6. After 10 weeks of immunological control, we observed a resurgence of virus, followed by progression to a persistent infection. Comparing virus evolution with T-cell recognition, we demonstrated that: (i) resurgence was concomitant with the emergence of new dominant viral populations bearing single amino acid changes in the NS3 and NS5A regions, (ii) these mutations resulted in a loss of CD4+ T-cell recognition, and (iii) subsequent to viral resurgence and immune escape a large fraction of NS3-specific T cells became impaired in their ability to secrete IFN-gamma and proliferate. In contrast, NS3-specific responses were sustained in the recovered/immunized animals presenting with subclinical infections. In conclusion, viral escape from CD4+ T cells can result in the eventual failure of an induced T-cell response that initially controls infection. Vaccines that can induce strong T-cell responses prior to challenge will not necessarily prevent persistent HCV infection.
Long‐term reduction in local inflammation by a lipid raft molecule in atopic dermatitis
Authors: S. Dölle, D. Hoser, C. Rasche, C. Loddenkemper, M. Maurer, T. Zuberbier, M. Worm
Journal: Allergy (2010)

The complex pathogenesis of atopic dermatitis (AD) is guided by cell surface receptor-mediated signal transduction regulated in lipid rafts. Miltefosine is a raft-modulating molecule targeting cell membranes. With this controlled clinical study, the clinical and immunomodulatory efficacy of miltefosine was investigated in patients with AD in comparison with a topical corticosteroid treatment.Sixteen patients with AD were treated topically with miltefosine and hydrocortisone localized on representative AD target lesions for 3 weeks. To assess the clinical efficacy, the three item severity (TIS) score was evaluated before, during and after treatment as well as after 4-week-follow-up period. To study the anti-inflammatory effect of miltefosine on the cellular T cell pattern, skin biopsies were analysed before and after treatment.The TIS score dropped in both groups significantly after treatment. A carry-over effect was exclusively seen for miltefosine after discontinuing the treatment. These findings were substantiated by thermographic imaging with a significant decrease in the maximum temperature (T(max)) after miltefosine application (P = 0.034, DeltaT(max) = 1.7 degrees C [2.1-3.9]). Immunohistochemically, a reduction in lesional CD4(+)-infiltrating T cells was observed in both treatments. Moreover, increased FoxP3(+) cells were present in the skin after miltefosine treatment (before 5.4% [1.9-9.8], after 6.2% [3.5-9.5]).We demonstrate that miltefosine is locally active in patients with AD and led to a sustained clinical improvement in local skin inflammation. Moreover, the increased frequency of FoxP3(+) cells in the skin of patients with AD suggests its immunomodulatory properties.
Unexplained Hematuria
Authors: George V. Burkholder
Journal: JAMA (1969)

Twenty-five of 237 cases of hematuria were classified as unexplained. The patients with this condition were subjected to a battery of 24 laboratory tests, intravenous pyelography, cystourethroscopy, infusion nephrotomography, arteriography, and renal biopsy. Additional diagnostic information was uncovered for 14 patients. Glomerular disease was the probable source of bleeding in ten. Hematuria was cited as secondary to sickle cell trait disease in three. An unusual renal arteriovenous fistula was the cause of bleeding in one patient. Three patients had hyperuricemia. Excretory urography and cystourethroscopy must always be done but nephrotomography, arteriography, and renal biopsy do not have sufficient diagnostic return to warrant routine use in patients with unexplained hematuria. The clinician must weigh (1) the severity of the bleeding, (2) the likelihood of recovery of significant information, and (3) the possibility of serious complications of the tests when he decides whether to employ them in his evaluation.
Total body calcium in rheumatoid arthritis: effects of disease activity and corticosteroid treatment.
Authors: D M Reid, N S Kennedy, M A Smith, P Tothill, G Nuki
Journal: BMJ (1982)

Rheumatoid arthritis may be associated with generalised as well as periarticular osteoporosis. To assess the extent of bone loss and the influence of corticosteroid treatment total body calcium was measured by in-vivo neutron activation analysis in 63 patients with rheumatoid arthritis treated with non-steroidal anti-inflammatory drugs alone and 31 treated with additional low-dose corticosteroids. The results were compared with those in 40 normal controls matched for age, sex, and menopausal state. There were significant reductions in mean total body calcium in the group treated with non-steroidal anti-inflammatory drugs (5.3% in men; 6.8% in women) and greater reductions in the corticosteroid-treated patients (11.5% in men, 15.5% in women). The reduction was correlated with disease duration and activity in the patients treated with non-steroid anti-inflammatory drugs alone. Measured total body calcium was significantly less than the values predicted when this relation was used in the corticosteroid-treated patients. The data suggest that increased bone loss in patients with rheumatoid arthritis treated with corticosteroids is attributable to drug treatment rather than disease activity. Many patients with rheumatoid arthritis treated with low-dosage corticosteroids and some postmenopausal women with the disease are likely to be at risk from the complications of osteoporosis.
What Is a Geriatrician?
Authors: Valery A. Portnoi
Journal: JAMA (1980)

THE COMMITTEE on Aging and Medical Education of the Institute of Medicine (IOM) at the National Academy of Sciences has released a report that may have an important impact on the future of medical education and residency training programs. One of the most important recommendations of the committee was to incorporate "a broad and relevant body of knowledge" on aging into the formal curricula of medical students and to require every physician (except pediatricians) to have an appropriate exposure to the principles of geriatric medicine.<sup>1</sup> While realizing that there are features specific to geriatric practice, the committee failed to provide a definition of such a practice and recommends against the establishment of a subspecialty of geriatrics. Paul Beeson, chairman of the IOM committee, said that geriatric medicine should be considered as an academic specialty, rather than a practical field, comparable with infectious diseases, which "is weakly represented as a
Smoking and hypoxemia caused by hepatopulmonary syndrome before and after liver transplantation
Authors: Giovanni Rolla, Luisa Brussino, Luca Dutto, Antonio Ottobrelli, Caterina Bucca
Journal: Hepatology (2001)

Severe hypoxemia may occur in patients with liver disease as a result of abnormal intrapulmonary vasodilatations (hepatopulmonary syndrome, HPS). Liver transplantation (LT) is the only effective treatment of HPS, with a quite variable delay of improvement of oxygenation. Smoking, by decreasing respiratory nitric oxide (NO), apparently contributed to improved oxygenation in a 44-year-old man with alcohol-induced cirrhosis, complicated by HPS, who underwent LT. The patient quit smoking just before LT, when his PaO(2) was 29 mm Hg and exhaled NO (eNO) 28 ppb, a value far above the normal limits (9.6 +/- 3.2 ppb). After LT, oxygenation remained poor and eNO remained high for more than 4 months, when the patient started to smoke again (blood HbCO going up to 5%). At that time eNO decreased to 6 ppb and PaO(2) increased to 67 mm Hg. The strict relationship between eNO and oxygenation observed in this case reinforces the hypothesis that NO is the most important vasodilating mediator in HPS. Smoking may have hastened the resolution of HPS after LT by inhibiting respiratory NO and/or through a generalized impairment of endothelium-dependent vasodilation.
RED: ADHD under the “micro-scope” of the rat model
Authors: Katya Rubia
Journal: Behavioral and Brain Sciences (2005)

derived from a rat model, the theory of sagvolden et al. offers an all-explanatory model of attention-deficit/hyperactivity disorder (adhd) anatomy, behaviour, and cognition as being caused predominantly by a hypo-dopaminergic mesolimbic (affecting the mesocortical and nigrostriatal) system, leading to abnormal reward and extinction processes. this model suffers from oversimplification and reductionism, reflecting the limitations of the use of animal models to explain higher mental disorders.
Dutch doctors publish guide to “careful suicide”
Authors: Tony Sheldon
Journal: BMJ (2008)

Five years after a major reorganisation of England's neonatal services, large and unexplained variations between regions in mortality among neonates still exist, concludes a new report from the House of Commons Public Accounts Committee.England's 178 neonatal care units were ordered in 2003 to reorganise into 23 regional networks.But that reorganisation has failed to address discrepancies between regions; and two regions, Essex and the Northern, have still not formally merged into unified organisations after five years.In 2005 the neonatal mortality rate among babies born at more than 22 weeks' gestation varied from 1.8 deaths per 1000 live births in the Surrey and Sussex region to 4.8 in the South West Midlands.The Conservative MP Edward Leigh, who chairs the Public Accounts Committee, said that the 2003 reorganisation "has had limited effect in reducing regional variations in mortality rates of babies born prematurely or suffering an illness [and] needing specialist care."The Department of Health was unable to confirm whether these discrepancies were due to disparities in care or to demographic factors, he said.Primary care trusts, Mr Leigh added, "need to improve their understanding of the Reorganisation of neonatal service in England fails to iron out regional variation in death rates UK NEWS Regulation of alternative medicine faces more delays, p 1395 WoRld NEWS dutch doctors make advice on suicide available to public, p 1394 bmj.com Germany promises protection to hospital doctors over longer working hours
Exposure to Lead in Children — How Low Is Low Enough?
Authors: Walter J. Rogan, James H. Ware
Journal: New England Journal of Medicine (2003)

Encephalopathy in childhood due to lead poisoning was described more than 100 years ago, and cognitive sequelae after recovery were reported in 1943. During the past three decades, epidemiologic studies have demonstrated inverse associations between blood lead concentrations and children's IQs at successively lower lead concentrations. In response, the Centers for Disease Control and Prevention (CDC) repeatedly lowered its definition of an elevated blood lead concentration, which now stands at 10 μg per deciliter (0.483 μmol per liter) (see Figure). Since the removal of lead from gasoline, the median blood lead concentration in U.S. children has fallen from 15 μg . . .
Re: Monique J. Roobol, Fritz H. Schröder, Pim van Leeuwen, et al. Performance of the Prostate Cancer Antigen 3 (PCA3) Gene and Prostate-Specific Antigen in Prescreened Men: Exploring the Value of PCA3 for a First-line Diagnostic Test. Eur Urol 2010;58:475–81
Authors: David Connolly, Rachel Hutton, Patrick F. Keane
Journal: European Urology (2010)
PD09-05: SU2C Phase Ib Study of pan-PI3K Inhibitor BKM120 Plus Aromatase Inhibitor Letrozole in ER+/HER2− Metastatic Breast Cancer (MBC).
Authors: IA Mayer, JM Balko, MG Kuba, ME Sanders, J Yap, Y Li, E Winer, CL Arteaga
Journal: Cancer Research (2011)

Abstract Background: Experimental evidence and clinical data suggest that PIK3CA mutations (present in approximately 35% of ER+ cancers) are associated with de novo or acquired resistance to antiestrogen therapy. Considering that most breast cancers resistant to antiestrogen therapy retain ER and estrogen sensitivity, treatment of ER+ breast cancers with single-agent PI3K-targeted therapy may be insufficient to inhibit tumor growth. Materials and Methods: To evaluate safety/tolerability, we initiated a phase Ib clinical trial of letrozole with the pan-PI3K inhibitor BKM120 (Novartis) in post-menopausal patients with ER+/HER2−MBC. Letrozole (2.5 mg/d) and BKM120 (100 mg/d) were given on a 28-day cycle. When necessary, BKM120 was reduced to 80 and 60 mg/day. Treatment was continued until unacceptable toxicity or progression of disease. Disease was assessed every 2 months. FDG-PET imaging was performed at 2 weeks to identify changes indicative of pharmacodynamic modulation of PI3K/AKT. Results: Twenty patients have been accrued; all but 2 patients had previously progressed on an aromatase inhibitor (AI) in the metastatic setting. Median age was 56 years; 85% of patients had metastatic bone disease, 70%, visceral metastases. Twelve patients are still on treatment, 2 of these are currently on BKM120 80 mg/day. Three patients discontinued treatment within 2 months of initiation due to grade 3 transaminitis, grade 2 irritability, and grade 2 hyperglycemia, despite dose reductions and/or optimal treatment. Most common toxicities are summarized in the table below. Transaminase elevation was the only DLT at 100 mg/d BKM120. Of the 12 evaluable patients that completed at least 8 weeks of treatment, 1 had a partial response, 7 had stable disease, and 4 had disease progression (RECIST). So far 3 patients have been on treatment for &amp;gt;4 months. Over 50% of patients had &amp;gt;25% reduction in their peak SUV at the 2-week FDG-PET scan. Discussion: The letrozole + BKM120 combination is active in patients with ER+/HER2− MBC refractory to previous therapy with an AI. At this time, all patients’ primary diagnostic tumor biopsies and/or metastatic biopsies are being analyzed for the presence of PIK3CA, AKT1, or PTEN mutations and PTEN loss (immunohistochemistry). FDG-PET imaging at 2 weeks appears to be a useful pharmacodynamic biomarker of PI3K pathway inhibition. Correlation of mutational analysis with clinical benefit will be presented at the meeting. Despite an overall safe side effect profile, an alternative administration schedule of BKM120 with letrozole is planned to enhance tolerability of the combination. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD09-05.
Current Opinion in General Surgery
Authors: Dawn Bick
Journal: JAMA (1995)

This new series features reviews by noted invited authors who address a wide variety of subjects. These reviews deal with all major aspects of general surgery. The editor, from Cornell University Medical College in New York, works with an editorial board consisting of internationally recognized senior surgeons from the United States, Europe, and Asia. This annual publication was initiated in 1993. Editor John Daly explains the purpose, scope, and audience of<i>Current Opinion in General Surgery</i>in the preface to the first issue: the journal intends to offer a review of the world's scientific literature by experts in the field and to summarize the state-of-the-art practice of the subdisciplines in general surgery. The material is presented as an up-to-date combination of detailed overviews of clinical and laboratory research, along with focused editorial comments that incorporate controversial issues within each topic. Every issue includes sections entitled "Critical Care and Trauma," "Metabolism
P130 Limits of agreement for peak expiratory flow measured by mini-Wright's meter and a pneumotachograph
Authors: S. J. Oliver, E. Ingram, D. Fynn, D. S. Urquhart
Journal: Thorax (2010)

<h3>Abstract</h3> <h3>Background</h3> Allostatic Load is a construct used to quantify the cumulative burden of exposure to stressors that, over the course of an individual’s life, exert a toll on the body’s physiological functions, increasing risks of various chronic ailments and conditions. Studies attempting to quantify allostatic load have used a variety of clinical biomarkers representing primary and secondary mediators. In this study, we demonstrate the value of including red blood cell distribution width (RDW) among the panel of clinical parameters used to calculate allostatic load. <h3>Methods</h3> We develop a novel formulation of allostatic load using RDW and other standard biomarkers. This index is computed using clinical laboratory data from the NHANES study. The predictive validity of the new index for tertiary outcomes (all-cause mortality and physician-assessed health status) is compared to that of the current formulation using Harrell’s C index, ROC analysis and regression-based goodness-of-fit measures. <h3>Results</h3> Inclusion of RDW as an allostatic load biomarker yields a significantly improved index. It demonstrates a superior ability to predict mortality, health status and biological age than the standard formulation currently in use. <h3>Conclusion</h3> RDW has shown strong correlations with mortality and a broad spectrum of diseases. A review of the existing literature on allostatic load reveals its underutilization in this area, despite being a standard component of blood count panels. This study is the first to demonstrate its usefulness as a potential allostatic load biomarker.
HIGH PREVALENCE OF IRON DEFICIENCY IN PATIENTS ADMITTED FOR ACUTE DECOMPENSATED HEART FAILURE: A FRENCH STUDY (CARDIOFER)
Authors: Alain Cohen-Solal, Thibaud Damy, Olivier Hanon, Mohamed Terbah, Thierry Laperche, Sebastien Kerebel, Faiez Zannad, Jean Philippe Baguet, Christophe Leclercq, Victor Concas, Ladan Duvillié, Bernadette Darné, Alexandre Mebazaa
Journal: Journal of the American College of Cardiology (2014)
Activation events during thymic selection.
Authors: A Bendelac, P Matzinger, R A Seder, W E Paul, R H Schwartz
Journal: The Journal of Experimental Medicine (1992)

During their differentiation in the mouse thymus, CD4+8- cells undergo several of the sequential changes observed upon normal activation of mature, peripheral CD4+ lymphocytes. Expression of CD69, an early activation marker, is first observed on a minority of cells at the T cell receptor (TCR)lo/med double-positive stage, is maximal (50-90%) on heat-stable antigen (HSA)hi TCRhi double-positive, HSAhi TCRmed CD4+8lo, and HSAhi TCRhi CD4+8- cells, and is downmodulated at the mature HSAlo CD4+8- stage. In contrast, CD44, a late activation marker, is selectively expressed at the HSAlo stage. The set of lymphokines that CD4+8- thymocytes can produce upon stimulation also characteristically expands from mainly interleukin 2 (IL-2) at the HSAhi stage, to IL-2 and very large amounts of IL-4, IL-5, IL-10, and interferon gamma (IFN-gamma) at the HSAlo stage. 1 in 30 HSAlo CD4+8- adult thymocytes secrete IL-4 upon stimulation through their TCR. This frequency is 25% of the frequency of IL-2 producers, about 100-fold above that of peripheral (mainly resting) CD4+ T cells. With time after their generation in organ culture, CD4+8- thymocytes lose their capacity to secrete IL-4, IL-5, and IFN-gamma, but not IL-2. Similarly, the frequency of IL-4, but not of IL-2, producers progressively decreases after emigration to the periphery as judged by direct comparison between thymic and splenic CD4+ cells in newborns, or by following the fate of intrathymically labeled CD4+8- cells in adults after their migration to the spleen. This sequence suggests that thymic selection results from an activation process rather than a simple rescue from death at the double-positive stage, and shows that the functional changes induced after intrathymic activation, although transient, are still evident after export to the periphery.
THE PROGNOSIS OF GENERALIZED PUSTULAR PSORIASIS TERENCE
Authors: J. RYAN, HARVEY BAKER
Journal: British Journal of Dermatology (1971)

Summary.— Data concerning 155 patients with all types of generalized pustular psoriasis have been reviewed. Generalized pustular psoriasis of Yon Zumbusch type is a severe disease. Thirty‐four of 106 patients followed up have died. In 26 of these, death was attributable to the disease or its treatment. G.P.P. developing from acral pustulosis (acrodermatitis continua) has the worst prognosis and is likely to prove fatal. G.P.P. evolving from ordinary, pustular palmo‐plantar or atypical fiexural forms of psoriasis has a better prognosis and may remit spontaneously. The use of steroids systemically for ordinary or erythrodermic psoriasis may precipitate G.P.P. and perpetuate the severe phase of psoriasis. Methotrexate is advocated for the treatment of the severe acute phase; but, in some patients, systemic steroid therapy cannot be avoided.
Abstract 1740: Inverse association of depletion of interferon-induced protein with tetratricopeptide repeats 2 with increased distant metastasis in patients with oral squamous cell carcinoma
Authors: Kuo-chu Lai, Chung-Ji Liu, Kuo-Wei Chang, Te-Chang Lee
Journal: Cancer Research (2012)

Abstract Interferon-induced protein with tetratricopeptide repeats 2 (IFIT2), one of most responsive interferon-stimulated genes, is inversely associated with prognosis of patients with oral cancer. In the present study, we further demonstrated that IFIT2 mRNA and protein expression was positively associated with E-cadherin expression in tissue specimens of oral squamous carcinoma cancer (OSCC). Loss of E-cadherin and IFIT2 was observed at the invasive front, suggesting that loss of IFIT2 may induce EMT and lead to metastasis in OSCCs. Accordingly, we found that OSCC patients with lower IFIT2 (IFIT2 &amp;lt; 50%) levels had higher distant metastatic rates and poorer prognoses compared to OSCC patients expressing higher levels of IFIT2 (IFIT2 ≤ 50%). In stable IFIT2-depleted OSCC cells, we observed epithelial-mesenchymal transition (EMT) and found enhanced cell motility and invasiveness when compared to control cells. Furthermore, our results indicated that atypical protein kinase C (aPKC) signaling was activated in IFIT2-depleted cells. Inhibition of aPKC by a specific myristoylated PKC∈ pseudosubstrate or aPKC siRNA abolished IFIT2 depletion-induced EMT, migration, and invasion, indicating that activation of aPKC signaling plays an essential role in the cellular activities induced by IFIT2 depletion. Our study demonstrates that IFIT2 depletion activates the aPKC pathway and hence induces EMT, cell migration, invasion and metastasis. Taken together, IFIT2, a protein responsible for interferon stimulation, may prevent OSCC from metastasizing and may serve as a prognostic marker. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1740. doi:1538-7445.AM2012-1740