tbuckley/cabot-search huggingface dataset:
Diet-Induced Obesity Causes Severe but Reversible Leptin Resistance in Arcuate Melanocortin Neurons
Authors: Pablo J. Enriori, Anne E. Evans, Puspha Sinnayah, Erin E. Jobst, Luciana Tonelli-Lemos, Sonja K. Billes, Maria M. Glavas, Bernadette E. Grayson, Mario Perello, Eduardo A. Nillni, Kevin L. Grove, Michael A. Cowley
Journal: Cell Metabolism (2007)

Despite high leptin levels, most obese humans and rodents lack responsiveness to its appetite-suppressing effects. We demonstrate that leptin modulates NPY/AgRP and α-MSH secretion from the ARH of lean mice. High-fat diet-induced obese (DIO) mice have normal ObRb levels and increased SOCS-3 levels, but leptin fails to modulate peptide secretion and any element of the leptin signaling cascade. Despite this leptin resistance, the melanocortin system downstream of the ARH in DIO mice is over-responsive to melanocortin agonists, probably due to upregulation of MC4R. Lastly, we show that by decreasing the fat content of the mouse's diet, leptin responsiveness of NPY/AgRP and POMC neurons recovered simultaneously, with mice regaining normal leptin sensitivity and glycemic control. These results highlight the physiological importance of leptin sensing in the melanocortin circuits and show that their loss of leptin sensing likely contributes to the pathology of leptin resistance.
Biventricular pacing in patients with hypertrophic cardiomyopathy: beneficial effect on exercise tolerance and symptomatic status
Authors: Christopher A. Rinaldi, Cliff A. Bucknall, Ron D. Simon, Pier Lambiase, Artur Baszko, Julian Bostock, Donna Elliott, Jaswinder S. Gill
Journal: Journal of the American College of Cardiology (2002)
Pro–Prostate-Specific Antigen Measurements in Serum and Tissue Are Associated with Treatment Necessity among Men Enrolled in Expectant Management for Prostate Cancer
Authors: Danil V. Makarov, Sumit Isharwal, Lori J. Sokoll, Patricia Landis, Cameron Marlow, Jonathan I. Epstein, Alan W. Partin, H. Ballentine Carter, Robert W. Veltri
Journal: Clinical Cancer Research (2009)

We assessed the association of quantitative clinical and pathologic information, including serum and tissue pro-prostate-specific antigen (proPSA) measurements, with outcomes among men with prostate cancer in an expectant management (active surveillance) program.We identified 71 men enrolled in expectant management with frozen serum and tissue available from diagnosis: 39 subsequently developed unfavorable biopsies (Gleason score > or =7, > or =3 cores positive for cancer, >50% of any core involved with cancer), whereas 32 maintained favorable biopsies (median follow-up, 3.93 years). Serum total PSA, free PSA (fPSA), and [-2]proPSA were measured by the Beckman Coulter immunoassay. [-5/-7]proPSA was evaluated in cancer and benign-adjacent areas (BAA) by quantitative immunohistochemistry. Cox proportional hazards and Kaplan-Meier analyses were used to identify significant associations with unfavorable biopsy conversion.The ratio [-2]proPSA/% fPSA in serum was significantly higher at diagnosis (0.87 +/- 0.44 versus 0.65 +/- 0.36 pg/mL; P = 0.02) in men developing unfavorable biopsies. [-5/-7]proPSA tissue staining was more intense (4104.09 +/- 3033.50 versus 2418.06 +/- 1606.04; P = 0.03) and comprised a greater fractional area (11.58 +/- 7.08% versus 6.88 +/- 5.20%; P = 0.01) in BAA of these men. Serum [-2]proPSA/% fPSA [hazard ratio, 2.53 (1.18-5.41); P = 0.02], BAA [-5/-7]proPSA % area [hazard ratio, 1.06 (1.01-1.12); P = 0.02] and BAA [-5/-7]proPSA stain intensity [hazard ratio, 1.000213 (1.000071-1.000354); P = 0.003] were significantly associated with unfavorable biopsy in Kaplan-Meier and Cox analyses. Serum [-2]proPSA/% fPSA significantly correlated with BAA [-5/-7]proPSA % area (rho = 0.40; P = 0.002) and BAA [-5/-7]proPSA stain intensity (rho = 0.33; P = 0.016).In a prospective cohort of men enrolled into expectant management for prostate cancer, serum and tissue levels of proPSA at diagnosis are associated with need for subsequent treatment. The increase in serum proPSA/% fPSA might be driven by increased proPSA production from "premalignant" cells in the prostate BAA.
Psychiatric Morbidity Among Homicide Offenders: A Swedish Population Study
Authors: Seena Fazel, Martin Grann
Journal: American Journal of Psychiatry (2004)

OBJECTIVE: The authors examined psychiatric diagnoses of all individuals convicted of homicide and attempted homicide in Sweden from 1988 to 2001 (N=2,005). METHOD: High-quality national crime and hospital registers were linked to investigate standardized psychiatric diagnoses of homicide offenders. RESULTS: The presence or absence of psychiatric diagnoses was ascertained for 1,625 (81%) of the homicide offenders; 1,464 (90%) of these offenders had a psychiatric diagnosis. Twenty percent (N=409) of all 2,005 offenders had a psychotic illness, and 54% (N=589) of a subgroup of 1,091 offenders with information on secondary diagnoses had a personality disorder as a principal or secondary diagnosis. Only 10% of the offenders for whom psychiatric diagnostic information was available had no diagnosis. CONCLUSIONS: Using a comprehensive method for identifying psychiatric illness in homicide offenders, the authors found higher rates of psychiatric morbidity than previous studies. Their findings underline the importance of psychiatric assessment in homicide offenders and suggest that treatment might have a preventive role.
Adefovir dipivoxil therapy for lamivudine-resistant hepatitis B in pre- and post-liver transplantation patients
Authors: Eugene R. Schiff, Ching-Lung Lai, Stefanos Hadziyannis, Peter Neuhaus, Norah Terrault, Massimo Colombo, Hans L. Tillmann, Didier Samuel, Stefan Zeuzem, Leslie Lilly, Maria Rendina, Jean-Pierre Villeneuve, Nicole Lama, Craig James, Michael S. Wulfsohn, Hamid Namini, Christopher Westland, Shelly Xiong, Gavin S. Choy, Sally Van Doren, John Fry, Carol L. Brosgart
Journal: Hepatology (2003)

Three–hundred and twenty–four patients were enrolled in an open–label, multicenter, international study in which pre– and post–liver transplantation (LT) patients with recurrent chronic hepatitis B (CHB) and evidence of lamivudine–resistant HBV were treated with adefovir dipivoxil 10 mg once daily. In the pre– and post–LT cohorts, 128 and 196 patients were treated for a median duration of 18.7 and 56.1 weeks, respectively. In patients who received 48 weeks of treatment, 81% of the pre–LT and 34% of the post–LT cohort achieved undetectable serum hepatitis B virus (HBV) DNA (Roche Amplicor Monitor TM polymerase chain reaction [PCR] assay lower limit of quantification [LLQ] &lt; 400 copies/mL) with a median change in serum HBV DNA from baseline of -4.1 log 10 and -4.3 log 10 copies/mL, respectively. Serum alanine aminotransferase (ALT), albumin, bilirubin, and prothrombin time normalized in 76%, 81%, 50%, and 83% of pre–LT patients and 49%, 76%, 75%, and 20% of post–LT patients. The Child–Pugh–Turcotte (CPT) score improved in over 90% of patients in both cohorts. Genotypic analysis of 122 HBV baseline samples revealed that 98% of these patients had lamivudine–resistant mutant HBV. No adefovir resistance mutations were identified in patients after 48 weeks of therapy. One–year survival was 84% for pre–LT and 93% for post–LT patients (Kaplan–Meier analysis). Treatment–related adverse effects associated with adefovir dipivoxil in this setting were primarily mild to moderate in severity. In conclusion, 48 weeks of adefovir dipivoxil resulted in significant improvements in virologic, biochemical, and clinical parameters in CHB patients pre– and post–LT with lamivudine–resistant HBV.
FACTORS INVOLVED IN THE PRODUCTION OF IMMUNITY WITH PNEUMOCOCCUS VACCINE
Authors: Alvan L. Barach
Journal: The Journal of Experimental Medicine (1931)

1. Pneumococcus vaccine was administered to 29 patients with pneumonia to determine whether a state of immunity could be induced during the course of the disease. Twenty patients received an intravenous injection of pneumococcus vaccine or pneumococcus filtrate. Nine pneumonia patients received an intradermal injection of vaccine. Eight patients with miscellaneous disease received an intravenous or intradermal injection of pneumococcus vaccine. 2. Of 23 tests in which the serum of the patient was studied for the appearance of protective substance after intravenous injection of heterologous pneumococcus vaccine, 20 or 87 per cent showed a positive response within 6 days after the administration of the antigen. The average day of onset was 4.4 days after injection. 3. Of 9 tests of the same character following the intravenous injection of pneumococcus filtrate, 8 or 89 per cent showed a positive response. The average day of onset of protective substance was 5.6 days after injection. 4. The appearance of specific protective substance following heterologous injection of pneumococcus vaccine appeared to be due to the introduction of the vaccine and not to the natural course of the disease, as was shown by negative control experiments. 5. Of 24 tests with intradermal injection of vaccine, 10 or 42 per cent developed slight protective substance of irregular degree 4.5 days after injection. 6. No immediate reactions were observed following the intravenous or intradermal injection of pneumococcus vaccine. One chill occurred after injection of pneumococcus filtrate. Of 20 cases with intravenous injection of pneumococcus vaccine or filtrate, 2 died of their disease, one a case in which homologous vaccine was used and one in which heterologous vaccine was administered. 7. Conclusions concerning the therapeutic value of the introduction of pneumococcus vaccine in pneumonia must await further investigation. These studies demonstrate that specific protective substances generally appear 4 to 5 days after intravenous injection of pneumococcus vaccine during the course of lobar or bronchopneumonia.
Prolonged treatment with recombinant interferon gamma induces erythema nodosum leprosum in lepromatous leprosy patients.
Authors: E P Sampaio, A L Moreira, E N Sarno, A M Malta, G Kaplan
Journal: The Journal of Experimental Medicine (1992)

10 patients with borderline and lepromatous leprosy were selected for a prolonged trial with recombinant interferon gamma (rIFN-gamma). Patients received 30 micrograms intradermally for six injections over a 9-d period, and then either 100 micrograms intradermally every 1 mo for 10 mo or every 2 wk for 5 mo (total, 1.2 mg). Erythema nodosum leprosum (ENL) was induced in 60% of the patients within 6-7 mo, as compared with an incidence of 15% per year with multiple drug therapy alone. The mean whole-body reduction in bacterial index over the first 6 mo was 0.9 log units. Cutaneous induration at the intradermal injection sites of greater than or equal to 15 mm predicted the development of a subsequent reactional state. Monocytes obtained from patients receiving the lymphokine demonstrated an increased respiratory burst and a 2.5-5.1-fold increase in tumor necrosis factor alpha (TNF-alpha) secretion in response to agonists. Patients in ENL had an even higher release of TNF-alpha from monocytes as well as high levels of TNF-alpha in the plasma (mean, 2,000 pg/ml). Thalidomide therapy was required to treat the systemic manifestations of ENL. Control of toxic symptoms with thalidomide was associated with a 50-80% reduction in agonist-stimulated monocyte TNF-alpha secretion. IFN-gamma enhanced the monocyte release of TNF-alpha by 3-7.5-fold (agonist dependent) when added to patient's cells in vitro, and this could be suppressed by the in vitro addition of 10 micrograms/ml of thalidomide.
Cost-effectiveness of tuberculosis control strategies among immigrants and refugees
Authors: K. Dasgupta, D. Menzies
Journal: European Respiratory Journal (2005)

Today, in Western Europe, Canada and the USA, more than half of all new active tuberculosis (TB) cases occur among foreign-born migrants. This article examines the impact of migration from high TB-incidence to low TB-incidence countries, and compares the cost-effectiveness of different TB control strategies. A Medline search was conducted to identify relevant English language publications prior to December 2003. Additional articles were identified from the reference lists from these publications. Despite the high proportion of active cases in low-incidence countries attributable to foreign-born residents, the public health impact is relatively low. Current chest radiograph screening programmes have little impact and are not cost-effective. Screening with sputum culture would improve cost-effectiveness marginally. Treatment of latent infection detected through screening with tuberculin skin testing or chest radiographs may require coercive measures to maximise impact and cost-effectiveness. In contrast, contact tracing, particularly within ethnic communities, appears to be more cost-efficient and less intrusive. In low-incidence countries, screening of migrants at entry has little overall impact and is not a very cost-effective tuberculosis control strategy. More effective alternatives include contact tracing delivered through primary care and increased investment in global tuberculosis control.
The new prescription: industrial injuries benefits for smokers?
Authors: A. SEATON
Journal: Thorax (1998)

Nationalisation of the coal industry by the 1945 Labour Government provided Britain with a unique opportunity for preventing the disablement of coal miners. At that time several thousand miners received disability benefits each year for pneumoconiosis in South Wales alone, and the Medical Research Council had started an important series of investigations into the relationships between dust exposure and disease.1 2 The late Dr John Rogan, Chief Medical Officer of the National Coal Board, with extraordinary far sightedness set up the Pneumoconiosis Field Research which ultimately studied the dust exposure, symptoms, chest radiographs, and lung function of some 50 000 miners over nearly 30 years.3 This research was planned to answer the questions “How much and what kinds of dust cause pneumoconiosis, and what dust concentrations need to be maintained if miners are not to be disabled by the dust that they breathe?” The National Coal Board embarked on a massively costly programme of research into dust control in mines alongside its medical research and, in full consultation with the mining unions, progressively implemented the research results into its practical management of the pneumoconiosis problem. As an example of enlightened management in dealing with work related ill health, this endeavour is unparalleled. The pneumoconiosis statistics tell the story, the disease having largely been eliminated.

Implicit in Dr Rogan’s original question was the understanding that disease other than pneumoconiosis might disable coal miners. This proved to be the case, the research demonstrating impressive evidence of a relationship between dust exposure and airways obstruction and, in accompanying pathological studies, centriacinar emphysema (in the presence of some evidence also of fibrotic nodular pneumoconiosis). This led me to suggest to the Industrial Injuries Advisory Council (IIAC) that in certain circumstances chronic airways obstruction should be regarded as an occupational hazard of coal miners, …
CD28-mediated costimulation of interleukin 2 (IL-2) production plays a critical role in T cell priming for IL-4 and interferon gamma production.
Authors: R A Seder, R N Germain, P S Linsley, W E Paul
Journal: The Journal of Experimental Medicine (1994)

Naive T cells require interleukin 4 (IL-4) to develop into IL-4-producing T cells and IL-4 blocks development of such cells into interferon gamma (IFN-gamma) producers. Prior studies in accessory cell-independent priming systems using antireceptor antibodies as agonists have demonstrated that IL-2 is also necessary for the development of IL-4-producing cells under these culture conditions. Here we have examined the role of IL-2 and the CD28 costimulation pathway in priming for IL-4 and IFN-gamma production using a more physiologic model. This involved antigen presentation by accessory cells to naive CD4+ T cells from transgenic mice whose cells express a T cell receptor (TCR) specific for a cytochrome c peptide in association with I-Ek. With splenic antigen-presenting cells (APCs), inhibition of CD28 costimulation by the fusion protein CTLA4-immunoglobulin (Ig) blocked effective priming. Similarly, transfected fibroblasts expressing both MHC class II and the CD28 ligand B7 could prime for IL-4 production and such priming also was blocked by CTLA4-Ig. However, APCs deficient in CD28 ligands also could prime TCR transgenic T cells to become IL-4 producers if an exogenous source of IL-2, as well as IL-4, was provided, and the inhibition of priming seen with splenic or transfected fibroblast APCs in the presence of CTLA4-Ig could be reversed by addition of IL-2. Likewise, priming for IFN-gamma production could be blocked by CTLA4-Ig and reversed by IL-2. Thus, we conclude that IL-2 plays a critical role in priming naive CD4+ T cells to become IL-4 or IFN-gamma producers. Engagement of the CD28 pathway, although normally important in such priming, is unnecessary in the presence of exogenous IL-2.
Migratory Dendritic Cells Transfer Antigen to a Lymph Node-Resident Dendritic Cell Population for Efficient CTL Priming
Authors: Rhys S. Allan, Jason Waithman, Sammy Bedoui, Claerwen M. Jones, Jose A. Villadangos, Yifan Zhan, Andrew M. Lew, Ken Shortman, William R. Heath, Francis R. Carbone
Journal: Immunity (2006)
Metabolic Consequences of Adenosine Deaminase Deficiency in Mice Are Associated with Defects in Alveogenesis, Pulmonary Inflammation, and Airway Obstruction
Authors: Michael R. Blackburn, Jonathan B. Volmer, Janci L. Thrasher, Hongyan Zhong, Jeff R. Crosby, James J. Lee, Rodney E. Kellems
Journal: The Journal of Experimental Medicine (2000)

Adenosine deaminase (ADA) is a purine catabolic enzyme that manages levels of the biologically active purines adenosine and 2'-deoxyadenosine in tissues and cells. ADA-deficient mice die at 3 wk of age from severe respiratory distress. This phenotype is progressive and is linked to perturbations in pulmonary purine metabolism. The inflammatory changes found in the lungs of ADA-deficient mice included an accumulation of activated alveolar macrophages and eosinophils. These changes were accompanied by a pronounced enlargement of alveolar spaces and increases in mucus production in the bronchial airways. The alveolar enlargement was found to be due in part to abnormal alveogenesis. Lowering adenosine and 2'-deoxyadenosine levels using ADA enzyme therapy decreased the pulmonary eosinophilia and resolved many of the lung histopathologies. In addition, genetically restoring ADA to the forestomach of otherwise ADA-deficient mice prevented adenine metabolic disturbances as well as lung inflammation and damage. These data suggest that disturbances in purinergic signaling mediate the lung inflammation and damage seen in ADA-deficient mice.
Resistance to Trastuzumab in Breast Cancer
Authors: Paula R. Pohlmann, Ingrid A. Mayer, Ray Mernaugh
Journal: Clinical Cancer Research (2009)

Abstract HER2 is a transmembrane oncoprotein encoded by the HER2/neu gene and is overexpressed in approximately 20 to 25% of invasive breast cancers. It can be therapeutically targeted by trastuzumab, a humanized IgG1 kappa light chain monoclonal antibody. Although trastuzumab is currently considered one of the most effective treatments in oncology, a significant number of patients with HER2-overexpressing breast cancer do not benefit from it. Understanding the mechanisms of action and resistance to trastuzumab is therefore crucial for the development of new therapeutic strategies. This review discusses proposed trastuzumab mode of action as well as proposed mechanisms for resistance. Mechanisms for resistance are grouped into four main categories: (1) obstacles preventing trastuzumab binding to HER2; (2) upregulation of HER2 downstream signaling pathways; (3) signaling through alternate pathways; and (4) failure to trigger an immune-mediated mechanism to destroy tumor cells. These potential mechanisms through which trastuzumab resistance may arise have been used as a guide to develop drugs, presently in clinical trials, to overcome resistance. The mechanisms conferring trastuzumab resistance, when completely understood, will provide insight on how best to treat HER2-overexpressing breast cancer. The understanding of each mechanism of resistance is therefore critical for the educated development of strategies to overcome it, as well as for the development of tools that would allow definitive and efficient patient selection for each therapy. (Clin Cancer Res 2009;15(24):7479–91)
Immuno-Modulatory Role of Prolactin in Immune Tissues Driven by the Alternative Promoter
Authors: A. V. McNamara, R. Awais, C. V. Harper, K. Featherstone, S. Semprini, D. G. Spiller, J. J. Mullins, J. R. E. Davis, M. R. H. White
Journal: Endocrine Reviews (2010)

McNamara, A. V. Awais, R. Harper, C. V. Featherstone, K. Semprini, S. Spiller, D. G. Mullins, J. J. Davis, J. R. E. White, M. R. H. 92nd Meeting and Expo of the Endocrine Society (ENDO 2010) Jun 19-22, 2010 San Diego, CA Suppl. 1
The solution to chaos is not chaos
Authors: I. Finlay
Journal: Journal of the Royal Society of Medicine (2007)

The solution to chaos is not chaosIt is difficult to find anyone who has much good to say about Modernising Medical Careers and the Medical Training Application Service process.The process promised: 'Recruitment and selection will be fair, open and legally robust.Selection methods will be specialty specific, but the minimum requirement will be a formal interview.The methodology is being designed by leading educationalists and recruitment specialists.' 1 Earlier documents had also stated: 'Reform is also about securing our workforce for the future as our medical school output rises and is about giving doctors in training a chance of a fulfilling career to their own and to patients' benefit.' 2 And that: 'It is not acceptable that they should at this stage fall out of the training system.' 2 So why has it gone wrong and why have so many junior doctors have lost confidence in the system?The system was introduced hurriedly; juniors saw the rules changing by the week and saw their options become ever more limited as they waded through the online instructions.Perhaps the Department of Health's touching faith in computerized systems added to the problems that were, by and large, predictable.With over 30 000 applicants, the system was flooded.Predictably, it crashed or froze while so many struggled to get their applications in.Most of the applications were not completed in working hours-the junior doctors were far too busy looking after patients-so peak usage occurred on Sunday evenings.Then the online short listing systems failed, so forms were printed off and scored.This removed the quality assurance step of one assessor scoring the same question on every form, and the requisite secondary scoring of about 10% of forms to detect hawks and doves in the scorers did not happen across the board.Some forms reportedly were missed altogether, and for others the paper score was not transferred to the website.Initial undertakings that every form would be scored twice did not materialize.But how secure is online scoring anyway?Could anyone with a password get online and alter a score?At least there are no reports of hackers getting to the website applications.Of course, even perfect short listing
Enhancement of G-CSF–induced stem cell mobilization by antibodies against the β2 integrins LFA-1 and Mac-1
Authors: Gerjo A. Velders, Johannes F. M. Pruijt, Perry Verzaal, Ronald van Os, Yvette van Kooyk, Carl G. Figdor, Evert-Jan F. M. de Kruijf, Roel Willemze, Willem E. Fibbe
Journal: Blood (2002)
Expanded European AIDS case definition
Authors: Rosemary Ancelle-Park, J.P. Klein, A. Stroobant, E. Smith, O. Haikala, M.A. Koch, G. Papaevangelou, J. Walsh, G. Rezza, P.Huberty Krau, R. Coutinho, M.T. Paixão, R. de Andres Medina, M. Bottiger, J. Estermann, N. Gill, J.B. Brunet
Journal: The Lancet (1993)