tbuckley/cabot-search huggingface dataset:
Vps34 Deficiency Reveals the Importance of Endocytosis for Podocyte Homeostasis
Authors: Wibke Bechtel, Martin Helmstädter, Jan Balica, Björn Hartleben, Betina Kiefer, Fatima Hrnjic, Christoph Schell, Oliver Kretz, Shuya Liu, Felix Geist, Dontscho Kerjaschki, Gerd Walz, Tobias B. Huber
Journal: Journal of the American Society of Nephrology (2013)

The molecular mechanisms that maintain podocytes and consequently, the integrity of the glomerular filtration barrier are incompletely understood. Here, we show that the class III phosphoinositide 3-kinase vacuolar protein sorting 34 (Vps34) plays a central role in modulating endocytic pathways, maintaining podocyte homeostasis. In mice, podocyte-specific conditional knockout of Vps34 led to early proteinuria, glomerular scarring, and death within 3-9 weeks of age. Vps34-deficient podocytes exhibited substantial vacuolization and foot process effacement. Although the formation of autophagosomes and autophagic flux were impaired, comparisons between podocyte-specific Vps34-deficient mice, autophagy-deficient mice, and doubly deficient mice suggested that defective autophagy was not primarily responsible for the severe phenotype caused by the loss of Vps34. In fact, Rab5-positive endosomal compartments, endocytosis, and fluid-phase uptake were severely disrupted in Vps34-deficient podocytes. Vps34 deficiency in nephrocytes, the podocyte-like cells of Drosophila melanogaster, resulted in a block between Rab5- and Rab7-positive endosomal compartments. In summary, these data identify Vps34 as a major regulator of endolysosomal pathways in podocytes and underline the fundamental roles of endocytosis and fluid-phase uptake for the maintenance of the glomerular filtration barrier.
Family history, body mass index, selected dietary factors, menstrual history, and risk of moderate to severe acne in adolescents and young adults
Authors: Anna Di Landro, Simone Cazzaniga, Fabio Parazzini, Vito Ingordo, Francesco Cusano, Laura Atzori, Francesco Tripodi Cutrì, Maria Letizia Musumeci, Cornelia Zinetti, Enrico Pezzarossa, Vincenzo Bettoli, Marzia Caproni, Giovanni Lo Scocco, Angela Bonci, Pierluca Bencini, Luigi Naldi
Journal: Journal of the American Academy of Dermatology (2012)
Pulse transit time as a measure of respiratory effort under noninvasive ventilation
Authors: Olivier Contal, Claudio Carnevale, Jean-Christian Borel, AbdelKébir Sabil, Renaud Tamisier, Patrick Lévy, Jean-Paul Janssens, Jean-Louis Pépin
Journal: European Respiratory Journal (2012)

Among the respiratory events that may occur during nocturnal noninvasive ventilation (NIV), differentiating between central and obstructive events requires appropriate indicators of respiratory effort. The aim of the present study was to assess pulse transit time (PTT) as an indicator of respiratory effort under NIV in comparison with oesophageal pressure (P(oes)). During wakefulness, PTT was compared to P(oes) during spontaneous breathing and under NIV with or without induced leaks in 11 healthy individuals. In addition, the contribution of PTT versus P(oes) to differentiation of central from obstructive respiratory events occurring under NIV during sleep was evaluated in 10 patients with obesity hypoventilation syndrome (OHS). From spontaneous breathing to NIV without leaks, respiratory effort decreased significantly whereas, with increasing level of leaks, there was a significant increase in respiratory effort. Changes in PTT accurately reflected changes in P(oes). In OHS patients during nocturnal NIV, intraclass correlation coefficients between P(oes) and PTT were 0.970 for total number of events and 0.970 for percentage of central events. PTT accurately reflects the unloading of respiratory muscles induced by NIV and the increase in respiratory effort during leaks. PTT during sleep is also useful to differentiate central from obstructive respiratory events occurring under NIV.
Positron Emission Tomography With [<sup>18</sup>F]Fluorodeoxyglucose Improves Staging and Patient Management in Patients With Head and Neck Squamous Cell Carcinoma: A Multicenter Prospective Study
Authors: Max Lonneux, Marc Hamoir, Hervé Reychler, Philippe Maingon, Christian Duvillard, Gilles Calais, Boumédiène Bridji, Laurence Digue, Michel Toubeau, Vincent Grégoire
Journal: Journal of Clinical Oncology (2010)

PURPOSE To address the impact of positron emission tomography with [(18)F]fluorodeoxyglucose (PET-FDG) on the initial staging and management of patients with head and neck squamous cell carcinoma (HNSCC). PATIENTS AND METHODS This multicenter, prospective study included 233 patients with newly diagnosed and untreated HNSCC. TNM stage and therapeutic decision were first determined based on the conventional work-up (including physical examination, computed tomography [CT]/magnetic resonance imaging of the head and neck region, and thoracic CT) and sealed in envelope 1. Whole-body PET-FDG was then performed, and subsequent TNM stage and therapeutic decision were written in envelope 2. Changes in TNM stages and in patient management as a result of PET-FDG imaging were recorded. Clinical outcome and histopathology were used as gold standards to validate the TNM stage. Conventional and PET stages were compared using the McNemar test. Results Conventional and PET stage were discordant in 100 (43%) of 233 patients. PET proved to be accurate in 47 patients and inaccurate in 13 patients. TNM status was left unconfirmed in 40 patients because no therapeutic change was expected from the stage difference. Conventional + PET TNM classification (envelope 2) was significantly more accurate than conventional classification (envelope 1; P < .0001, McNemar test). PET-FDG altered the therapeutic plan in 32 (13.7%) of 233 patients. CONCLUSION Adding whole-body PET-FDG to the pretherapeutic conventional staging of HNSCC improved the TNM classification of the disease and altered the management of 13.7% of patients. These findings support the implementation of PET-FDG in the routine imaging work-up of HNSCC.
Effect of methotrexate on intracellular folate pools in purified myeloid precursor cells from normal human bone marrow.
Authors: J Baram, C J Allegra, R L Fine, B A Chabner
Journal: Journal of Clinical Investigation (1987)

We investigated the effects of the antifolate methotrexate on intracellular folate pools of human myeloid precursor cells (MPCs). Immature MPCs, representing 3.2% of the original marrow population, were selected from normal human bone marrow by immune rosetting. The intracellular folate pools were labeled by incubation with 5 X 10(-8) M [3H]5-formyl-FH4 and were quantitated by high performance liquid chromatography. The predominant folates were 5-methyl-tetrahydrofolate (5-methyl-FH4) (36%), 10-formyl-FH4 (41.4%), 5-formyl-FH4 (12.3%), and FH4 (10.3%). A 12-h exposure to 1 microM methotrexate (MTX) resulted in a 34% reduction in the intracellular concentration of 10-formyl-FH4, a 61% decrease in 5-formyl-FH4, and a 62% decrease in 5-methyl-FH4, as well as the appearance and progressive expansion of the FH2 and 10-formyl-FH2 pools. These changes were maximal after 4 h of incubation with MTX. Paralleling the changes in folates, particularly the increase in FH2, were a 64% reduction in myeloid colony formation and a 77% depression of de novo purine synthesis after 4 h of MTX. We conclude that MTX does not produce quantitative depletion of 10-formyl-FH4 and that its antipurine effect may be mediated by direct inhibition of de novo purine synthesis by FH2 and, at later time points, by MTX polyglutamates.
What is this thing called CFA?
Authors: A U Wells, D M Hansell, A G Nicholson
Journal: Thorax (2006)

The term “cryptogenic fibrosing alveolitis”should now be used as strictly synonymous with “idiopathic pulmonary fibrosis”

Arcane diagnostic labels bother clinicians. The diffuse lung disease lexicon is a notorious example. For decades, “diffuse lung disease speak” consisted of an unholy mix of histopathological and clinical terms, varying between countries, within countries and even between medical teams in the same hospital. Radical change was required and proposals were advanced in a joint American Thoracic Society and European Respiratory Society (ATS/ERS) initiative. Terminology for idiopathic interstitial pneumonia was distilled by a core group of clinicians, radiologists and pathologists, and this was then circulated to a larger group of international reviewers and published in 2002.1 The final consensus classification was not, at first sight, straightforward to apply. Indeed, the amorphous entity of “non-specific interstitial pneumonia” (NSIP) continues to vex clinicians and requires further subclassification. However, teething problems aside, the ATS/ERS initiative has been an outstanding success. Clinicians and researchers worldwide now understand each other better than before. The recent move towards large multicentre treatment studies in idiopathic pulmonary fibrosis (IPF), itself a revolution in slow motion, was made possible, in no small part, by this standardisation of terminology and disease definitions.

As the terminology has changed, the article by Rudd et al 2 in the current issue of Thorax (see p 67) is likely to pose difficulties for some non-UK readers. The authors have studied “cryptogenic fibrosing alveolitis” (CFA) as a clinical presentation, as used historically in the UK. The diagnostic criteria, consisting of compatible radiographic, pulmonary function and clinical findings, in the absence of an overt environmental or autoimmune cause, are highly non-specific: compatible, also, with idiopathic interstitial pneumonias other than IPF and a subgroup of patients with hypersensitivity pneumonitis. By contrast, in the ATS/ERS classification,1,3 CFA is explicitly …
Health Risks and Benefits 3 Years After Stopping Randomized Treatment With Estrogen and Progestin
Authors: Gerardo Heiss
Journal: JAMA (2008)

The Women's Health Initiative (WHI) trial of estrogen plus progestin vs placebo was stopped early, after a mean 5.6 years of follow-up, because the overall health risks of hormone therapy exceeded its benefits.To report health outcomes at 3 years (mean 2.4 years of follow-up) after the intervention was stopped.The intervention phase was a double-blind, placebo-controlled, randomized trial of conjugated equine estrogens (CEE) 0.625 mg daily plus medroxyprogesterone acetate (MPA) 2.5 mg daily, in 16,608 women aged 50 through 79 years, recruited by 40 centers from 1993 to 1998. The postintervention phase commenced July 8, 2002, and included 15 730 women.Semi-annual monitoring and outcomes ascertainment continued per trial protocol. The primary end points were coronary heart disease and invasive breast cancer. A global index summarizing the balance of risks and benefits included the 2 primary end points plus stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, and death due to other causes.The risk of cardiovascular events after the intervention was comparable by initial randomized assignments, 1.97% (annualized rate) in the CEE plus MPA (343 events) and 1.91% in the placebo group (323 events). A greater risk of malignancies occurred in the CEE plus MPA than in the placebo group (1.56% [n = 281] vs 1.26% [n = 218]; hazard ratio [HR], 1.24; 95% confidence interval [CI], 1.04-1.48). More breast cancers were diagnosed in women who had been randomly assigned to receive CEE plus MPA vs placebo (0.42% [n = 79] vs 0.33% [n = 60]; HR, 1.27; 95% CI, 0.91-1.78) with a modest trend toward a lower HR during the follow-up after the intervention. All-cause mortality was somewhat higher in the CEE plus MPA than in the placebo group (1.20% [n = 233] vs 1.06% [n = 196]; HR, 1.15; 95% CI, 0.95-1.39). The global index of risks and benefits was unchanged from randomization through March 31, 2005 (HR, 1.12; 95% CI, 1.03-1.21), indicating that the risks of CEE plus MPA exceed the benefits for chronic disease prevention.The increased cardiovascular risks in the women assigned to CEE plus MPA during the intervention period were not observed after the intervention. A greater risk of fatal and nonfatal malignancies occurred after the intervention in the CEE plus MPA group and the global risk index was 12% higher in women randomly assigned to receive CEE plus MPA compared with placebo.clinicaltrials.gov Identifier: NCT00000611.
Parkin cooperates with GDNF/RET signaling to prevent dopaminergic neuron degeneration
Authors: Durga Praveen Meka, Anne Kathrin Müller-Rischart, Prakash Nidadavolu, Behnam Mohammadi, Elisa Motori, Srinivas Kumar Ponna, Helia Aboutalebi, Mahmoud Bassal, Anil Annamneedi, Barbara Finckh, Margit Miesbauer, Natalie Rotermund, Christian Lohr, Jörg Tatzelt, Konstanze F. Winklhofer, Edgar R. Kramer
Journal: Journal of Clinical Investigation (2015)

Parkin and the glial cell line-derived neurotrophic factor (GDNF) receptor RET have both been independently linked to the dopaminergic neuron degeneration that underlies Parkinson's disease (PD). In the present study, we demonstrate that there is genetic crosstalk between parkin and the receptor tyrosine kinase RET in two different mouse models of PD. Mice lacking both parkin and RET exhibited accelerated dopaminergic cell and axonal loss compared with parkin-deficient animals, which showed none, and RET-deficient mice, in which we found moderate degeneration. Transgenic expression of parkin protected the dopaminergic systems of aged RET-deficient mice. Downregulation of either parkin or RET in neuronal cells impaired mitochondrial function and morphology. Parkin expression restored mitochondrial function in GDNF/RET-deficient cells, while GDNF stimulation rescued mitochondrial defects in parkin-deficient cells. In both cases, improved mitochondrial function was the result of activation of the prosurvival NF-κB pathway, which was mediated by RET through the phosphoinositide-3-kinase (PI3K) pathway. Taken together, these observations indicate that parkin and the RET signaling cascade converge to control mitochondrial integrity and thereby properly maintain substantia nigra pars compacta dopaminergic neurons and their innervation in the striatum. The demonstration of crosstalk between parkin and RET highlights the interplay in the protein network that is altered in PD and suggests potential therapeutic targets and strategies to treat PD.
Improving mortality of coronary surgery over first four years of independent practice: retrospective examination of prospectively collected data from 15 surgeons
Authors: Ben Bridgewater, Antony D Grayson, John Au, Ragheb Hassan, Walid C Dihmis, Chris Munsch, Paul Waterworth
Journal: BMJ (2004)

<h3>Abstract</h3> <b>Objective</b> To study the “learning curve” associated with independent practice in coronary artery surgery. <b>Design</b> Retrospective analysis of prospectively collected data. <b>Setting</b> All NHS centres in north west England that carry out cardiac surgery in adults. <b>Participants</b> 18 913 patients undergoing coronary artery surgery for the first time between April 1997 and March 2003, 5678 of whom were operated on by 15 surgeons in the first four years after their consultant appointment. <b>Main outcome measures</b> Observed and predicted mortality (EuroSCORE) for surgeons in their first, second, third, and fourth years after appointment as a consultant compared with figures for established surgeons. <b>Results</b> Overall mortality decreased over the six years of study (P = 0.01). Of the patients operated on by established surgeons or newly appointed consultants, 265/13 235 (2.0%) and 109/5678 (1.9%), respectively, died (P = 0.71). There was a progressive decrease in observed mortality with time after appointment as a consultant from 2.2% in the first year to 1.2% in the fourth year (P = 0.049). This result remained significant after adjustment for time and case mix (P = 0.019). <b>Conclusions</b> Mortality in patients operated on by newly appointed consultant surgeons is similar to mortality in patients operated on by established surgeons. There are significant decreases in crude and risk adjusted mortality in the four years after appointment. These findings should influence the nature of practice in newly appointed surgeons.
Claudin-1 Protein Expression is a Prognostic Marker of Patient Survival in Renal Cell Carcinomas
Authors: Florian R. Fritzsche, Beibei Oelrich, Manfred Johannsen, Ilka Kristiansen, Holger Moch, Klaus Jung, Glen Kristiansen
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Claudin-1 is a tight junction protein described in normal tissues as well as in malignancies. We aimed to assess the diagnostic or prognostic significance of claudin-1 expression in renal cell carcinoma and to correlate the expression of claudin-1 with clinical, histopathologic, and prognostic parameters in renal cell carcinoma. Experimental Design: A tissue microarray was constructed using formalin-fixed, paraffin-embedded tissue from renal cell carcinomas and corresponding normal renal tissue from 318 patients. The protein expression of claudin-1 was assessed and correlated to clinicopathologic tumor parameters including patient survival. A separate cohort of 44 papillary renal cell carcinoma was used for validation of results. Results: Claudin-1 was expressed in 29.9% of renal cell cancer cases. Whereas the vast majority of clear cell carcinomas were negative for claudin-1, most papillary tumors (76-86%) were positive. Claudin-1 expression was associated with markers of unfavorable tumor biology in clear cell renal cell carcinoma, whereas the opposite was valid for papillary renal cell carcinoma. In clear cell renal cell carcinoma claudin-1 positivity was a prognosticator of shortened disease-specific patient survival in univariate analysis (P = 0.008), which also remained significant in multivariate analyses in the clinically important subgroups of nonmetastasized or asymptomatic patients. Conclusions: Claudin-1 is expressed in the majority of papillary renal cell carcinomas, suggesting a diagnostic value of this marker. Its expression is an independent prognosticator of shortened disease-specific patient survival in clinically relevant subgroups of clear cell renal cell carcinoma. Further functional studies are needed to clarify the different biological roles of claudin-1 expression in these histologic subtypes of renal cell carcinoma.
Human leukocyte antigen (HLA) DR15 is associated with reduced incidence of acute GVHD in HLA-matched allogeneic transplantation but does not impact chronic GVHD incidence
Authors: Minoo Battiwalla, Theresa Hahn, Marija Radovic, Hilary Roy, Afrin Wahab, Eileen Duman, Rajinder Bajwa, Swaminathan Padmanabhan, Joanne Becker, A. John Barrett, Philip L. McCarthy
Journal: Blood (2005)
THE STATE OF THE VESSELS OF THE MESENTERY IN SHOCK PRODUCED BY CONSTRICTING THE LIMBS AND THE BEHAVIOR OF THE VESSELS FOLLOWING HEMORRHAGE
Authors: Irvine H. Page, Richard G. Abell
Journal: The Journal of Experimental Medicine (1943)

1. Direct observations of the arteries, arterioles, capillaries, veins, and lymphatics in the mesentery of anesthetized cats put into shock by incomplete occlusion of the circulation of the limbs showed that: (a) Marked constriction of the arteries and arterioles, produced by muscular contraction, occurred usually within an hour after incomplete occlusion of the limbs, lasted several hours, and finally gave way in most instances to relaxation an hour or more before death. The constriction reduced the blood supply to the mesentery and intestine and the venous return from them. It did not, however, interrupt the blood flow. No pooling or stagnation of blood was seen even as a terminal phenomenon. (b) The veins of the mesentery also became constricted but showed less tendency to dilate as death approached. The lymphatics likewise became somewhat narrowed. Even during the terminal stage the leukocytes moved along without change in shape or sticking to the walls of the capillaries or venules. (c) Hematocrit determinations showed progressive hemoconcentration of moderate degree. (d) Autopsy usually showed the presence of small hemorrhages in many parts of the body, especially the heart, liver, spleen, and lungs. (e) Bilateral nephrectomy, suprarenalectomy, and pancreatectomy did not significantly alter the morphological picture elicited by shock induced by restriction of the circulation to the limbs. 2. Removal of large amounts of blood was always followed within a short time by constriction of arteries, arterioles, veins, and lymphatics of the mesentery. 3. Fall in arterial pressure produced by pithing was not accompanied by change in diameter of the arteries, arterioles, veins, or lymphatics, or by blanching of the mesentery or gut.
A Form of Bursal Enlargement
Authors: A. W. M. Robson
Journal: BMJ (1877)

and, through the non-conductive power of coal, they succeeded.The men had lighted candles up to within two dayi of their deliverance.Sleep was irregular and disturbed.Water was swallowed in large quantities.Tabulated Results of Detailed Obser-vations.At Pit's Mouth.Temp.Pulse.Resp.
Impact of treatment completion, intolerance and adverse events on health system costs in a randomised trial of 4 months rifampin or 9 months isoniazid for latent TB
Authors: A. Aspler, R. Long, A. Trajman, M.-J. Dion, K. Khan, K. Schwartzman, D. Menzies
Journal: Thorax (2010)

<h3>Rationale</h3> Treatment for latent tuberculosis infection with isoniazid for 9 months (9INH) has poor completion and serious adverse events, while treatment for 4 months with daily rifampin (4RIF) has significantly higher completion and fewer adverse events. <h3>Objectives</h3> To compare the health system costs of 4RIF and 9INH. <h3>Methods</h3> In a randomised trial conducted in five Canadian centres, one Brazilian and one Saudi Arabian centre, consenting subjects were randomised to receive 4RIF or 9INH. Health system costs were estimated from healthcare utilisation including scheduled and unscheduled visits, investigations and drugs. All activities for all subjects were evaluated using financial information from 2007 from the Montreal Chest Institute. Costs were expressed in Canadian dollars. <h3>Results</h3> Total health system cost per patient allocated to 4RIF was $854 compared with $970 for 9INH (p&lt;0.0001). The average cost per patient for the 328 of 420 (78%) who completed 4RIF therapy was $1094 compared with $1625 for the 254 of 427 (60%) completing 9INH (p&lt;0.0001). Costs were modestly increased in patients with minor intolerance and substantially increased if the treating physician stopped treatment because of possible adverse events. Total costs related to management of adverse events with 9INH were $48 142 compared with $25 684 for 4RIF (p=0.008). Using these data, incremental cost-effectiveness analyses showed that 4RIF would be cost saving and prevent more cases within 2 years if efficacy exceeded 74%, and cost saving if efficacy exceeded 65%. <h3>Conclusions</h3> The 4RIF regimen was significantly cheaper per patient completing treatment because of better completion and fewer adverse events. <h3>RCT registration number</h3> NCT00170209.