tbuckley/cabot-search huggingface dataset:
Kidney Transplantation in the Elderly
Authors: Sarbjit V. Jassal, Murray D. Krahn, Gary Naglie, Jeffrey S. Zaltzman, Janet M. Roscoe, Edward H. Cole, Donald A. Redelmeier
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Transplantation offers superior life expectancy and quality of life compared with dialysis in young patients with end-stage renal failure. However, the initial risks of mortality and morbidity are high. This study used a decision analysis model to evaluate the costs and benefits of kidney transplantation versus continued dialysis for older patients with renal failure. A decision analytic model comparing cadaveric renal transplantation to continued hemodialysis treatment was developed. The base case considered a theoretical cohort of patients aged 65 yr without known comorbidity or contraindications to transplantation who would have to wait 2 yr for a cadaveric transplant. Separate models were constructed for patients with diabetes or cardiovascular disease and for patients receiving an organ after a variety of wait-list times. Probability, utility, and survival data were obtained from published reports and renal registries. For 65-yr-old patients, quality-adjusted life expectancy increased by 1.1 quality-adjusted life years (QALY) at an incremental cost of $67,778 per QALY. Assuming a 2-yr wait-listed time, transplantation remained economically attractive for 70-yr-old patients (incremental cost effectiveness [ICE], $79,359 per QALY) but was less economically attractive for those over 75 yr of age (ICE, $99,553) or for 70-yr-olds with either cardiovascular disease or diabetes (ICE, $126,751 and $161,090 per QALY, respectively). The analytic results were sensitive only to the time spent waiting for the graft. The cost-effectiveness reduced such that the costs associated with one QALY were in excess of $100,000/yr when the probability of a complication was ≥50% per 3-mo cycle and when the utility of transplantation fell below 0.62. If available within a timely period, transplantation may offer substantial clinical benefits to older patients at a reasonable financial cost. Prolonged waiting times dramatically decrease the clinical benefits and economic attractiveness of transplantation, suggesting that living donor transplantation may be of particular benefit in this population. Email: [email protected]
Incidence and Prognostic Value of the Systemic Inflammatory Response Syndrome and Organ Dysfunctions in Ward Patients
Authors: Matthew M. Churpek, Frank J. Zadravecz, Christopher Winslow, Michael D. Howell, Dana P. Edelson
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

Tools that screen inpatients for sepsis use the systemic inflammatory response syndrome (SIRS) criteria and organ dysfunctions, but most studies of these criteria were performed in intensive care unit or emergency room populations.To determine the incidence and prognostic value of SIRS and organ dysfunctions in a multicenter dataset of hospitalized ward patients.Hospitalized ward patients at five hospitals from November 2008 to January 2013 were included. SIRS and organ system dysfunctions were defined using 2001 International Consensus criteria. Patient characteristics and in-hospital mortality were compared among patients meeting two or more SIRS criteria and by the presence or absence of organ system dysfunction.A total of 269,951 patients were included in the study, after excluding 48 patients with missing discharge status. Forty-seven percent (n = 125,841) of the included patients met two or more SIRS criteria at least once during their ward stay. On ward admission, 39,105 (14.5%) patients met two or more SIRS criteria, and patients presenting with SIRS had higher in-hospital mortality than those without SIRS (4.3% vs. 1.2%; P < 0.001). Fourteen percent of patients (n = 36,767) had at least one organ dysfunction at ward admission, and those presenting with organ dysfunction had increased mortality compared with those without organ dysfunction (5.3% vs. 1.1%; P < 0.001).Almost half of patients hospitalized on the wards developed SIRS at least once during their ward stay. Our findings suggest that screening ward patients using SIRS criteria for identifying those with sepsis would be impractical.
Phase I/IIa Study of Cilengitide and Temozolomide With Concomitant Radiotherapy Followed by Cilengitide and Temozolomide Maintenance Therapy in Patients With Newly Diagnosed Glioblastoma
Authors: Roger Stupp, Monika E. Hegi, Bart Neyns, Roland Goldbrunner, Uwe Schlegel, Paul M.J. Clement, Gerhard G. Grabenbauer, Adrian F. Ochsenbein, Matthias Simon, Pierre-Yves Dietrich, Torsten Pietsch, Christine Hicking, Joerg-Christian Tonn, Annie-Claire Diserens, Alessia Pica, Mirjam Hermisson, Stefan Krueger, Martin Picard, Michael Weller
Journal: Journal of Clinical Oncology (2010)

Purpose Invasion and migration are key processes of glioblastoma and are tightly linked to tumor recurrence. Integrin inhibition using cilengitide has shown synergy with chemotherapy and radiotherapy in vitro and promising activity in recurrent glioblastoma. This multicenter, phase I/IIa study investigated the efficacy and safety of cilengitide in combination with standard chemoradiotherapy in newly diagnosed glioblastoma. Patients and Methods Patients (age ≥ 18 to ≤ 70 years) were treated with cilengitide (500 mg) administered twice weekly intravenously in addition to standard radiotherapy with concomitant and adjuvant temozolomide. Treatment was continued until disease progression or for up to 35 weeks. The primary end point was progression-free survival (PFS) at 6 months. Results Fifty-two patients (median age, 57 years; 62% male) were included. Six- and 12-month PFS rates were 69% (95% CI, 54% to 80%) and 33% (95% CI, 21% to 46%). Median PFS was 8 months (95% CI, 6.0 to 10.7 months). Twelve- and 24-month overall survival (OS) rates were 68% (95% CI, 53% to 79%) and 35% (95% CI, 22% to 48%). Median OS was 16.1 months (95% CI, 13.1 to 23.2 months). PFS and OS were longer in patients with tumors with O 6 -methylguanine-DNA methyltransferase (MGMT) promoter methylation (13.4 and 23.2 months) versus those without MGMT promoter methylation (3.4 and 13.1 months). The combination of cilengitide with temozolomide and radiotherapy was well tolerated, with no additional toxicity. No pharmacokinetic interactions between temozolomide and cilengitide were identified. Conclusion Compared with historical controls, the addition of concomitant and adjuvant cilengitide to standard chemoradiotherapy demonstrated promising activity in patients with glioblastoma with MGMT promoter methylation.
IgE antibodies to penicillin are indicative for but not conclusive proof of penicillin allergy
Authors: W. Aberer, M. Zidarn, B. Kranke
Journal: British Journal of Dermatology (2006)

Conflicts of interest: none declared. Sir, Predictive testing for drug hypersensitivity, without an individual history of specific problems, is controversially discussed, as diagnostic procedures might lead to false‐positive as well as false‐negative results due to a lack of high sensitivity and absolute specificity. Thus the specificity of fluorescence enzyme‐linked immunoassay (FEIA) tests for specific IgE for benzylpenicilloyl (BPO) is reported to range between 87% and 100%.1, 2 However, arbitrary definitions of the term ‘specificity’ may give rise to controversial conclusions. We report a healthy young man who, as a student, worked in the aminopenicillin production department of a drug company for 2 years. When he applied for a permanent position in that company he was tested for penicillin antibodies in vitro using the Pharmacia CAP‐FEIA method (Sweden Diagnostics, Uppsala, Sweden): sIgE for penicillin G was 0·64 kU L−1, penicillin V 0·82 kU L−1, ampicillin 1·52 kU L−1 and amoxicillin 0·43 kU L−1, and his total IgE level was 573 kU L−1. On account of this positive test result the job application was turned down. The individual consulted us for a second opinion as he had frequently taken oral antibiotics in the recent past and encountered no difficulties. The laboratory result thus seemed to be clinically irrelevant. We redetermined IgE levels, again using the CAP system: the results remained positive. However, skin prick and intradermal testing with penicillin and amoxicillin at the appropriate test concentrations3 were negative (readings at 20 min, 24 h and 72 h) except for mild erythema at the intradermal test site for amoxicillin (reading at 20 min). Oral provocation with amoxicillin (in combination with clavulanic acid), starting with half the normal dose and progressing rapidly to a predefined daily dose, was well tolerated. No immediate or late reactions occurred. The patient's serum was then sent blinded to an independent laboratory, where the ADVIA Centaur® (Bayer Diagnostics, Tarrytown, NY, U.S.A.) immunoassay system was used. Here the results were negative (< 0·35 kU L−1) for both penicillin V and penicillin G. The patient's negative history, skin tests, provocation test and IgE detection using the ADVIA Centaur® system led us to conclude that he is not allergic to penicillin. Hence the positive IgE test results using the CAP‐FEIA method were deemed to be false‐positive.
De novo mutations in ATP1A3 cause alternating hemiplegia of childhood
Authors: Erin L Heinzen, Kathryn J Swoboda, Yuki Hitomi, Fiorella Gurrieri, Sophie Nicole, Boukje de Vries, F Danilo Tiziano, Bertrand Fontaine, Nicole M Walley, Sinéad Heavin, Eleni Panagiotakaki, Sophie Nicole, Fiorella Gurrieri, Giovanni Neri, Boukje de Vries, Stephany Koelewijn, Jessica Kamphorst, Marije Geilenkirchen, Nadine Pelzer, Laura Laan, Joost Haan, Michel Ferrari, Arn van den Maagdenberg, Claudio Zucca, Maria Teresa Bassi, Filippo Franchini, Rosaria Vavassori, Melania Giannotta, Giuseppe Gobbi, Tiziana Granata, Nardo Nardocci, Elisa De Grandis, Edvige Veneselli, Michela Stagnaro, Fiorella Gurrieri, Giovanni Neri, Federico Vigevano, Eleni Panagiotakaki, Claudia Oechsler, Alexis Arzimanoglou, Sophie Nicole, Melania Giannotta, Giuseppe Gobbi, Miriam Ninan, Brian Neville, Friedrich Ebinger, Carmen Fons, Jaume Campistol, David Kemlink, Sona Nevsimalova, Laura Laan, Cacha Peeters-Scholte, Arn van den Maagdenberg, Paul Casaer, Giorgio Casari, Guenter Sange, Georg Spiel, Filippo Martinelli Boneschi, Claudio Zucca, Maria Teresa Bassi, Tsveta Schyns, Francis Crawley, Dominique Poncelin, Rosaria Vavassori, Stefania Fiori, Emanuela Abiusi, Lorena Di Pietro, Matthew T Sweney, Tara M Newcomb, Louis Viollet, Chad Huff, Lynn B Jorde, Sandra P Reyna, Kelley J Murphy, Kevin V Shianna, Curtis E Gumbs, Latasha Little, Kenneth Silver, Louis J Ptáček, Joost Haan, Michel D Ferrari, Ann M Bye, Geoffrey K Herkes, Charlotte M Whitelaw, David Webb, Bryan J Lynch, Peter Uldall, Mary D King, Ingrid E Scheffer, Giovanni Neri, Alexis Arzimanoglou, Arn M J M van den Maagdenberg, Sanjay M Sisodiya, Mohamad A Mikati, David B Goldstein
Journal: Nature Genetics (2012)
Human Immunodeficiency Virus 1 Envelope Glycoprotein Complex-Induced Apoptosis Involves Mammalian Target of Rapamycin/Fkbp12-Rapamycin–Associated Protein–Mediated P53 Phosphorylation
Authors: Maria Castedo, Karine F. Ferri, Julià Blanco, Thomas Roumier, Nathanael Larochette, Jordi Barretina, Alessandra Amendola, Roberta Nardacci, Didier Métivier, José A. Este, Mauro Piacentini, Guido Kroemer
Journal: The Journal of Experimental Medicine (2001)

Syncytia arising from the fusion of cells expressing a lymphotropic human immunodeficiency virus (HIV)-1–encoded envelope glycoprotein complex (Env) gene with cells expressing the CD4/CXCR4 complex undergo apoptosis through a mitochondrion-controlled pathway initiated by the upregulation of Bax. In syncytial apoptosis, phosphorylation of p53 on serine 15 (p53S15) precedes Bax upregulation, the apoptosis-linked conformational change of Bax, the insertion of Bax in mitochondrial membranes, subsequent release of cytochrome c, caspase activation, and apoptosis. p53S15 phosphorylation also occurs in vivo, in HIV-1+ donors, where it can be detected in preapoptotic and apoptotic syncytia in lymph nodes, as well as in peripheral blood mononuclear cells, correlating with viral load. Syncytium-induced p53S15 phosphorylation is mediated by the upregulation/activation of mammalian target of rapamycin (mTOR), also called FKBP12-rapamycin-associated protein (FRAP), which coimmunoprecipitates with p53. Inhibition of mTOR/FRAP by rapamycin reduces apoptosis in several paradigms of syncytium-dependent death, including in primary CD4+ lymphoblasts infected by HIV-1. Concomitantly, rapamycin inhibits p53S15 phosphorylation, mitochondrial translocation of Bax, loss of the mitochondrial transmembrane potential, mitochondrial release of cytochrome c, and nuclear chromatin condensation. Transfection with dominant negative p53 has a similar antiapoptotic action as rapamycin, upstream of the Bax upregulation/translocation. In summary, we demonstrate that phosphorylation of p53S15 by mTOR/FRAP plays a critical role in syncytial apoptosis driven by HIV-1 Env.
Translocations activating IRF4 identify a subtype of germinal center-derived B-cell lymphoma affecting predominantly children and young adults
Authors: Itziar Salaverria, Claudia Philipp, Ilske Oschlies, Christian W. Kohler, Markus Kreuz, Monika Szczepanowski, Birgit Burkhardt, Heiko Trautmann, Stefan Gesk, Miroslaw Andrusiewicz, Hilmar Berger, Miriam Fey, Lana Harder, Dirk Hasenclever, Michael Hummel, Markus Loeffler, Friederike Mahn, Idoia Martin-Guerrero, Shoji Pellissery, Christiane Pott, Michael Pfreundschuh, Alfred Reiter, Julia Richter, Maciej Rosolowski, Carsten Schwaenen, Harald Stein, Lorenz Trümper, Swen Wessendorf, Rainer Spang, Ralf Küppers, Wolfram Klapper, Reiner Siebert
Journal: Blood (2011)
Late onset bowel dysfunction after pelvic radiotherapy: a national survey of current practice and opinions of gastroenterologists
Authors: C. Henson, S. Davidson, P. Symonds, R. Swindell, J. Andreyev
Journal: Gut (2011)

<h3>Introduction</h3> 17 000 patients receive treatment with radical pelvic radiotherapy annually in the UK. Up to 50% develop significant gastrointestinal (GI) symptoms. The Department of Health estimates that £40 million is wasted on ineffective treatments annually in this patient group. The National Cancer Survivorship Initiative (2007) has identified access to specialist medical care for those with complications after cancer as one of the four key needs of cancer survivors. The authors aimed to determine the current practice of British gastroenterologists with regard to chronic bowel dysfunction after pelvic radiotherapy. <h3>Methods</h3> A questionnaire was developed and sent to all 866 gastroenterologists in the UK up to a maximum of five times by post and by email. <h3>Results</h3> 165 (20%) gastroenterologists responded. 61% see ‘1–4’ patients annually with bowel symptoms after radiotherapy, with only 3% seeing ‘≥20’ per year. Only 43% receive referrals directly from clinical oncologists. The most frequent reasons for referral are stool frequency (70%), rectal bleeding (70%), urgency (66%), loose stool (53%) and faecal incontinence (45%). The most commonly used treatments are antidiarrhoeals (70%), 5ASAs (50%), rectal steroids (46%), bile binders (44%) and dietary modification (42%). Only 18% rate the currently available treatments as effective ‘often’ or ‘most of the time’. 47% of gastroenterologists consider themselves ‘confident with basic cases9, with 11% ‘confident in all cases9. 59% think a gastroenterologist with a specialist interest should manage these patients. Although only 29% think a specific service is required for this patient group, 34% rate the current service as ‘poor’ or ‘fails to meet the needs of patients9. Gastroenterologists state the ideal service would be gastroenterology-lead, multidisciplinary and tertiary with access to all the necessary diagnostic and therapeutic modalities. Low referral rates, poor evidence base and poor funding are cited as reasons for the current patchy services. <h3>Conclusion</h3> The low response rate contrasts strikingly with the high response rate from a parallel survey of clinical oncologists. This suggests that radiation-induced bowel toxicity is not considered a significant clinical issue for gastroenterologists. Although oncologists estimate that up to 24% of their patients develop bowel symptoms, only a small proportion are referred for specialist evaluation. Treatments are considered ineffective, perhaps reflecting lack of experience or expertise. The views expressed suggest that the development of accessible, gastroenterology-lead multidisciplinary services would be the optimal way to meet the needs of this patient group.
IL-23, not IL-12, Directs Autoimmunity to the Goodpasture Antigen
Authors: Joshua D. Ooi, Richard K.S. Phoon, Stephen R. Holdsworth, A. Richard Kitching
Journal: Journal of the American Society of Nephrology (2009)

The autoantigen in Goodpasture disease is the noncollagenous domain of α3 type IV collagen [α3(IV)NC1]. We previously demonstrated that IL-12p40<sup>−/−</sup> mice are protected from experimental autoimmune anti–glomerular basement membrane (anti-GBM) glomerulonephritis, seemingly defining a role for IL-12 in this disease; however, the recent identification of IL-23, a heterodimer composed of IL-12p40 and IL-23p19 subunits, raises the possibility that IL-23, rather than IL-12, may modulate this disease instead. We immunized wild-type, IL-12p35<sup>−/−</sup> (IL-12 deficient, IL-23 intact), IL-12p40<sup>−/−</sup> (deficient in both IL-12 and IL-23), and IL-23p19<sup>−/−</sup> (IL-12 intact, IL-23 deficient) mice with recombinant mouse α3(IV)NC1. Wild-type mice developed autoreactivity to α3(IV)NC1: Humoral responses, cellular responses, renal histologic abnormalities, leukocyte accumulation, autoantibody deposition, and IL-17A mRNA expression (a cytokine produced by the IL-23–maintained Th17 subset). IL-23 but not IL-12 was detected in the immune system. Regardless of the presence of IL-12, mice deficient in IL-23 were protected, but mice with IL-23 were not. Both IL-23–deficient strains exhibited lower autoantibody titers, reduced cellular reactivity, diminished cytokine production (IFN-γ [Th1], IL-17A [Th17], TNF, and monocyte chemoattractant protein 1), and less renal disease and glomerular IgG deposition. The deficient responses in the absence of IL-23 were not due to increased regulatory T cells; IL-12p40<sup>−/−</sup> and IL-23p19<sup>−/−</sup> mice did not show increased proportions of CD4<sup>+</sup>CD25<sup>+</sup>FoxP3<sup>+</sup> cells or IL-10 levels early in the immune response. In conclusion, autoreactivity to the Goodpasture antigen is directed primarily by IL-23, absence of which results in hyporeactivity including but extending beyond a deficient Th17 response.
Reply to J. Zhu et al
Authors: Saroj Niraula, Lisa W. Le, Ian F. Tannock
Journal: Journal of Clinical Oncology (2013)

We thank Zhu and Zheng for their interest and comments on our study. As indicated in our publication, we included heterogeneous stages of prostate cancer among and within studies. However, results of these trials were comparable with regard to time to development of castration-resistant disease, time off treatment in the intermittent strategy, quality of life, and survival. Furthermore, we believe that presence of metastasis versus rising PSA reflects more a difference between overt and occult metastasis (extent of disease), thereby allowing us to fit one recommendation to all. As indicated by Zhu and Zheng, most trials showed increased nonprostate cancer–related deaths with continuous androgen deprivation therapy (CAD) and increased prostate cancer–related deaths with intermittent androgen deprivation therapy (IAD). Although we agree that pre-existing comorbidity can influence toxicity of an intervention, none of the studies were powered to evaluate subgroups, and the randomized nature of the included studies should have distributed any comorbidity between the groups. Also, the baseline level of PSA in the study by Salonen et al, although numerically different between the groups, has a wide standard deviation around the mean, warranting cautious interpretation (116.0 173.4 ng/mL in the IAD group and 186.3 454.4 ng/mL in the CAD group). We do not agree that we should interpret the results of the two large trials by Crook et al and Hussein et al as having a trend to favor one strategy versus the other: the hazard ratio for overall survival with IAD compared with CAD was 1.03 for the first study and 1.10 for the second, with 95% CIs encompassing unity. Nine randomized controlled trials, three of them of good quality and four of fair quality according to standard prespecified criteria, have shown no consistent survival advantage of one strategy versus the other, with IAD being more favorable in terms of some quality of life scores, cost and convenience. We disagree that further resources should be spent to address the same question in further randomized controlled trials.
Mature hepatocytes exhibit unexpected plasticity by direct dedifferentiation into liver progenitor cells in culture
Authors: Yixin Chen, Philip P. Wong, Lucas Sjeklocha, Clifford J. Steer, Behnan M. Sahin
Journal: Hepatology (2011)

Although there have been numerous reports describing the isolation of liver progenitor cells from the adult liver, their exact origin has not been clearly defined; and the role played by mature hepatocytes as direct contributors to the hepatic progenitor cell pool has remained largely unknown. Here, we report strong evidence that mature hepatocytes in culture have the capacity to dedifferentiate into a population of adult liver progenitors without genetic or epigenetic manipulations. By using highly purified mature hepatocytes, which were obtained from untreated, healthy rat liver and labeled with fluorescent dye PKH2, we found that hepatocytes in culture gave rise to a population of PKH2-positive liver progenitor cells. These cells, liver-derived progenitor cells, which share phenotypic similarities with oval cells, were previously reported to be capable of forming mature hepatocytes, both in culture and in animals. Studies done at various time points during the course of dedifferentiation cultures revealed that hepatocytes rapidly transformed into liver progenitors within 1 week through a transient oval cell-like stage. This finding was supported by lineage-tracing studies involving double-transgenic AlbuminCreXRosa26 mice expressing β-galactosidase exclusively in hepatocytes. Cultures set up with hepatocytes obtained from these mice resulted in the generation of β-galactosidase-positive liver progenitor cells, demonstrating that they were a direct dedifferentiation product of mature hepatocytes. Additionally, these progenitors differentiated into hepatocytes in vivo when transplanted into rats that had undergone retrorsine pretreatment and partial hepatectomy.Our studies provide strong evidence for the unexpected plasticity of mature hepatocytes to dedifferentiate into progenitor cells in culture, and this may potentially have a significant effect on the treatment of liver diseases requiring liver or hepatocyte transplantation.