tbuckley/cabot-search huggingface dataset:
Severe acute respiratory syndrome and its impact on professionalism: qualitative study of physicians' behaviour during an emerging healthcare crisis
Authors: Sharon E Straus, Kumanan Wilson, Gloria Rambaldini, Darlyne Rath, Yulia Lin, Wayne L Gold, Moira K Kapral
Journal: BMJ (2004)

<h3>Abstract</h3> <b>Objective</b> To explore issues of medical professionalism in the context of severe acute respiratory syndrome (SARS), a new emerging health threat. <b>Design</b> Qualitative interviews analysed with grounded theory methodology. <b>Setting</b> University hospitals in Toronto, Canada, during the SARS outbreak in 2003. <b>Participants</b> 14 staff physicians from divisions of infectious diseases, general internal medicine, and critical care medicine. <b>Results</b> Of 14 attending physicians, four became ill during the outbreak. Participants described their experiences during the outbreak and highlighted several themes about values inherent to medical professionalism that arose during this crisis including the balance between care of patients and accepted personal risk, confidentiality, appropriate interactions between physicians and patients, ethical research conduct, and role modelling of professionalism for junior doctors. <b>Conclusion</b> Despite concerns raised by professional societies about the erosion of professionalism, participants in this study amply demonstrated the necessary qualities during the recent healthcare crisis. However, there were several examples of strained professional behaviour witnessed by the participants and these examples highlight aspects of medical professionalism that medical educators and professional organisations should address in the future, including the balance between personal safety and duty of care.
Catheter Stimulation of Cardiac Parasympathetic Nerves in Humans
Authors: Patrick Schauerte, Karl Mischke, Jurgita Plisiene, Matthias Waldmann, Markus Zarse, Christoph Stellbrink, Thomas Schimpf, Christian Knackstedt, Anil Sinha, Peter Hanrath
Journal: Circulation (2001)

Background Cardiac parasympathetic nerves run alongside the superior vena cava (SVC) and accumulate particularly epicardially adjacent to the orifice of the coronary sinus (CS). In animals, these nerves can be electrically stimulated inside the SVC or CS, which results in negative chronotropic/dromotropic effects and negative inotropic effects in the atria but not the ventricles. Parasympathetic nerve stimulation (PS) with 20 Hz in the CS, however, also excites the atria, thereby inducing atrial fibrillation. The present study overcomes this limitation by applying high-frequency nerve stimuli within the atrial refractory period. Using this technique, we investigated for the first time whether neurophysiological effects similar to those in animals can be obtained in humans. Methods and Results In 25 patients, parasympathetic nerves were stimulated via a multipolar electrode catheter placed in the SVC (stimulation with 20 Hz; n=14) or CS (pulsed 200-Hz stimuli; n=11). A significant sinus rate decrease and prolongation of the antegrade Wenckebach period was achieved during PS in the SVC. During PS in the CS, a graded-response prolongation of the antegrade Wenckebach interval was observed with increasing PS voltage until third-degree AV block occurred in 8 of 11 patients. The negative chronotropic/dromotropic effects started and terminated immediately after the onset and termination of PS, respectively. Atropine abolished these effects (n=11). Conclusions Human parasympathetic efferent nerve stimulation induces reversible negative chronotropic and dromotropic effects. PS may serve as an adjunctive tool for the diagnosis/treatment of supraventricular tachycardias and may be beneficial for ventricular rate slowing during tachycardic atrial fibrillation in patients with congestive heart failure.
HLA-Cw6 and HLA-DRB1*07 together are associated with less severe joint disease in psoriatic arthritis
Authors: P. Y P C Ho, A. Barton, J. Worthington, W. Thomson, A. J Silman, I. N Bruce
Journal: Annals of the Rheumatic Diseases (2007)

Human leucocyte antigen (HLA) genes predict disease severity in psoriasis (HLA-Cw6) and rheumatoid arthritis (shared epitope (SE)), but the situation is unclear for psoriatic arthritis (PsA).To determine the association of the HLA-Cw6 and HLA-DRB1 gene with disease severity in a large UK cohort with PsA.Genotyping of the HLA-Cw and HLA-DRB1 loci was undertaken in DNA samples from patients with PsA (n = 480). Stratification and regression analysis were used within the PsA cases to determine whether HLA-Cw6, HLA-DRB1 or the presence of the SE alleles predicted disease severity as measured by the Health Assessment Questionnaire score, the total number of damaged or involved joints adjusted for disease duration and disease-modifying antirheumatic treatments.HLA-Cw6 was found to be in linkage disequilibrium with HLA-DRB1*07 (r(2) = 0.46). Patients with PsA who carried both HLA-Cw6 and HLA-DRB1*07 had fewer damaged or involved joints (41% fewer damaged (95% CI 23% to 55%, p = 0.02) and 31% fewer involved joints (95% CI 16% to 44%, p<0.001)) compared with those who carried neither HLA-Cw6 nor HLA-DRB1*07 alleles. Those who carried either HLA-Cw6 or HLA-DRB1*07 alleles alone had no evidence of a reduction in joint involvement. The SE, HLA-DRB1*03 and HLA-DRB1*04 alleles did not predict severity using these outcome measures.Patients with PsA carrying both HLA-Cw6 and HLA-DRB1*07 alleles have a less severe course of arthritis. This suggests that a protective locus lies on a haplotype marked by these alleles. No association was detected with disease severity and SE status.
The Influence of Growth Hormone Status on Physical Impairments, Functional Limitations, and Health-Related Quality of Life in Adults
Authors: Linda J. Woodhouse, Annice Mukherjee, Stephen M. Shalet, Shereen Ezzat
Journal: Endocrine Reviews (2006)

The availability of recombinant human GH and somatostatin analogs has resulted in widespread treatment for adults with GH deficiency (GHD) and those with GH excess (acromegaly). Despite being at opposite ends of the spectrum in terms of their GH/IGF-I axis, both of these populations experience overlapping somatic impairments. Adults with untreated GHD have low circulating levels of IGF-I that manifest as altered body composition with increased fat and reduced lean body and skeletal muscle mass. At the other end of the spectrum, adults with GH excess, who have elevated levels of IGF-I, also have altered body composition. Impairments that result from disorders of either GHD or GH excess are both associated with increased functional limitations, such as reduced ability to walk quickly for prolonged periods, and poorer health-related quality of life (HR-QoL). Adults with untreated GHD and GH excess both commonly complain of excessive fatigue that seems to be associated more with impaired aerobic than muscular performance.
Transcription, Translation, and the Evolution of Specialists and Generalists
Authors: S. Zhong, S. P. Miller, D. E. Dykhuizen, A. M. Dean
Journal: Molecular Biology and Evolution (2009)

We used DNA microarrays to measure transcription and iTRAQ 2D liquid chromatography-mass spectrometry/mass spectrometry (a mass-tag labeling proteomic technique) to measure protein expression in 14 strains of Escherichia coli adapted for hundreds of generations to growth-limiting concentrations of either lactulose, methylgalactoside, or a 72:28 mixture of the two. The two ancestors, TD2 and TD10, differ only in their lac operons and have similar transcription and protein expression profiles. Changes in transcription and protein expression are observed at 30–250 genes depending on the evolved strain. Lactulose specialists carry duplications of the lac operon and show increased transcription and translation at lac. Methylgalactoside specialists are galS– and so constitutively transcribe and translate mgl, which encodes a transporter of methylgalactoside. However, there are two strains that carry lac duplications, are galS–, and show increased transcription and translation at both operons. One is a generalist, the other a lactulose specialist. The generalist fails to sweep to fixation because its lac+, galS+ competitor expresses the csg adhesin and sticks to the chemostat wall, thereby preventing complete washout. Transcription and translation are sometimes decoupled. Lactulose-adapted strains show increased protein expression at fru, a fructose transporter, without evidence of increased transcription. This suggests that fructose, produced by the action of β-galactosidase on lactulose, may leach from cells before being recouped. Reduced expression, at "late" flagella genes and the constitutive gat operon, is an adaptation to starvation. A comparison with two other long-term evolution experiments suggests that certain aspects of adaptation are predictable, some are characteristic of an experimental system, whereas others seem erratic.
Risk of pancreatic adenocarcinoma in chronic pancreatitis
Authors: D Malka
Journal: Gut (2002)

<b>Background:</b> The risk of pancreatic cancer in patients with chronic pancreatitis (CP) is difficult to assess. Previous studies, mostly case control studies or studies relying on data case registers, reported relative risks varying from 2.3 to 18.5. <b>Methods:</b> We studied a prospective, single centre, medical-surgical cohort of 373 consecutive patients (322 (86%) men, median age 40 years) with proven CP (alcoholic origin 85%) and a follow up of at least two years (median follow up 9.2 years; range 2.0–34.8) in order to exclude pancreatitis revealing pancreatic cancer. We calculated the age and sex standardised incidence ratio (SIR) as the ratio of the number of observed cases of pancreatic cancer in this cohort to the number of expected cases, as provided by the French National Cancer Register. <b>Results:</b> Four cases of pancreatic adenocarcinoma (1.1% of patients) were observed in 3437 patient years (expected number of cases 0.15; SIR 26.7, 95% confidence interval (CI) 7.3–68.3; p=0.00002). In a second analysis in which patients lost to follow up were considered to be followed up until the end point without having developed pancreatic adenocarcinoma (4762 patient years), SIR was 19.0 (CI 5.2–48.8; p=0.00007). <b>Conclusion:</b> Patients with CP have a markedly increased risk of pancreatic cancer compared with the general population.
Liver Fibrosis Progression in Hepatitis C Virus Infection After Seroconversion
Authors: Adeel A. Butt, Peng Yan, Vincent Lo Re, David Rimland, Matthew B. Goetz, David Leaf, Matthew S. Freiberg, Marina B. Klein, Amy C. Justice, Kenneth E. Sherman
Journal: JAMA Internal Medicine (2014)

Knowing the rate of liver fibrosis progression in hepatitis C virus (HCV)-infected persons can help inform patients and providers (clinicians, medical institutions or organizations, and third-party payers) in making treatment decisions.To determine the rate and factors associated with liver fibrosis progression and hepatic decompensation in persons after acquiring HCV infection.Secondary data analysis of persons in the Electronically Retrieved Cohort of HCV Infected Veterans (ERCHIVES), a national Veterans Affairs (VA) database, between 2002 and 2012. Among 610 514 persons in ERCHIVES (half were HCV positive), we identified those with an initial negative and subsequent positive test result for HCV antibody and positive HCV RNA test result (HCV+). Controls had 2 negative HCV antibody test results (HCV-) in a comparable time frame and were matched 1:1 on age (in 5-year blocks), race, and sex. We excluded persons with human immunodeficiency virus, hepatitis B, less than 24 months of follow-up, hepatocellular carcinoma, and cirrhosis at baseline.Progression of liver fibrosis as estimated by the Fibrosis-4 (FIB-4) index; development of cirrhosis, defined by a FIB-4 score greater than 3.5; and development of hepatic decompensation.The evaluable data set consisted of 1840 persons who were HCV+ and 1840 HCV- controls. The HCV+ persons were younger and had a lower mean (SD) body mass index (27.39 [5.51] vs 29.49 [6.16]; P < .001), a higher prevalence of alcohol and drug abuse and dependence diagnoses, and higher serum aminotransferase levels, but had a lower prevalence of diabetes and hypertension. Fibrosis progression started early after infection among HCV+ persons and tapered off after 5 years. A total of 452 cirrhosis and 85 hepatic decompensation events were recorded. After 10 years of follow-up, HCV+ persons were more likely to have a diagnosis of cirrhosis compared with HCV- controls (18.4% vs 6.1%). Nine years after diagnosis of cirrhosis, hepatic decompensation events were uncommon but had a higher rate in the HCV+ group (1.79% vs 0.33%).Persons who seroconverted for HCV have a more rapid progression of liver fibrosis and accelerated time to development of cirrhosis after seroconversion compared with HCV- controls. Fibrosis progression occurs early after infection; however, hepatic decompensation is uncommon after diagnosis of cirrhosis.
Active euthanasia in The Netherlands
Authors: M. A. de Wachter
Journal: JAMA (1989)

Active euthanasia in the Netherlands remains a topic for both professional and public debate. However, many aspects of the medical practice of active euthanasia remain unclear, and no figures on the actual incidence of this practice exist. Legally, active euthanasia is a criminal offense, but a pattern of jurisprudence has developed since the first court case in 1973 that has allowed physicians to practice euthanasia under certain strict conditions. Two proposals, one from the Royal Dutch Medical Association and one from a government-appointed state commission, have advised that the current law be changed. While the debate continues, a number of Dutch institutions have developed procedures and policies to enable physicians and health care providers to participate in active euthanasia in an acceptable and controllable manner. However, many Dutch physicians remain uncomfortable with the professional and public tolerance of this practice.A Dutch bioethicist discusses the status of voluntary, active euthanasia as it is practiced currently in the Netherlands, and traces the medical, legal, and public policy developments in the issue from the early 1970s to the late 1980s. While Dutch courts have allowed physicians to practice euthanasia under certain strict conditions, legally the act is a criminal offense and carries the risk of prosecution. De Wachter emphasizes that many questions about active euthanasia remain unresolved, and maintains that the several thousand deaths by euthanasia believed to take place each year in the Netherlands occur without a moral, social, legal, and medical framework.
A Multicenter Study of Glucocerebrosidase Mutations in Dementia With Lewy Bodies
Authors: Michael A. Nalls, Raquel Duran, Grisel Lopez, Marzena Kurzawa-Akanbi, Ian G. McKeith, Patrick F. Chinnery, Christopher M. Morris, Jessie Theuns, David Crosiers, Patrick Cras, Sebastiaan Engelborghs, Peter Paul De Deyn, Christine Van Broeckhoven, David M. A. Mann, Julie Snowden, Stuart Pickering-Brown, Nicola Halliwell, Yvonne Davidson, Linda Gibbons, Jenny Harris, Una-Marie Sheerin, Jose Bras, John Hardy, Lorraine Clark, Karen Marder, Lawrence S. Honig, Daniela Berg, Walter Maetzler, Kathrin Brockmann, Thomas Gasser, Fabiana Novellino, Aldo Quattrone, Grazia Annesi, Elvira Valeria De Marco, Ekaterina Rogaeva, Mario Masellis, Sandra E. Black, Juan M. Bilbao, Tatiana Foroud, Bernardino Ghetti, William C. Nichols, Nathan Pankratz, Glenda Halliday, Suzanne Lesage, Stephan Klebe, Alexandra Durr, Charles Duyckaerts, Alexis Brice, Benoit I. Giasson, John Q. Trojanowski, Howard I. Hurtig, Nahid Tayebi, Claudia Landazabal, Melanie A. Knight, Margaux Keller, Andrew B. Singleton, Tyra G. Wolfsberg, Ellen Sidransky
Journal: JAMA Neurology (2013)

<h3>Importance</h3>While mutations in glucocerebrosidase (GBA1) are associated with an increased risk for Parkinson disease (PD), it is important to establish whether such mutations are also a common risk factor for other Lewy body disorders.<h3>Objective</h3>To establish whether GBA1 mutations are a risk factor for dementia with Lewy bodies (DLB).<h3>Design</h3>We compared genotype data on patients and controls from 11 centers. Data concerning demographics, age at onset, disease duration, and clinical and pathological features were collected when available. We conducted pooled analyses using logistic regression to investigate GBA1 mutation carrier status as predicting DLB or PD with dementia status, using common control subjects as a reference group. Random-effects meta-analyses were conducted to account for additional heterogeneity.<h3>Setting</h3>Eleven centers from sites around the world performing genotyping.<h3>Participants</h3>Seven hundred twenty-one cases met diagnostic criteria for DLB and 151 had PD with dementia. We compared these cases with 1962 controls from the same centers matched for age, sex, and ethnicity.<h3>Main Outcome Measures</h3>Frequency of GBA1 mutations in cases and controls.<h3>Results</h3>We found a significant association between GBA1 mutation carrier status and DLB, with an odds ratio of 8.28 (95% CI, 4.78-14.88). The odds ratio for PD with dementia was 6.48 (95% CI, 2.53-15.37). The mean age at diagnosis of DLB was earlier in GBA1 mutation carriers than in noncarriers (63.5 vs 68.9 years; P &lt; .001), with higher disease severity scores.<h3>Conclusions and Relevance</h3>Mutations in GBA1 are a significant risk factor for DLB. GBA1 mutations likely play an even larger role in the genetic etiology of DLB than in PD, providing insight into the role of glucocerebrosidase in Lewy body disease.
Cell Cycle/Apoptosis Molecule Expression Correlates with Imatinib Response in Patients with Advanced Gastrointestinal Stromal Tumors
Authors: Salvatore Romeo, Maria Debiec-Rychter, Martine Van Glabbeke, Heidi Van Paassen, Paola Comite, Ronald Van Eijk, Jan Oosting, Jaap Verweij, Philippe Terrier, Ulrike Schneider, Raf Sciot, Jean Yves Blay, Pancras C.W. Hogendoorn
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Altered expression of cell cycle/apoptosis key regulators may promote tumor progression, reflect secondary genetic/epigenetic events, and impair the effectiveness of therapy. Their expression pattern might then identify gastrointestinal stromal tumor (GIST) patient subgroups with different response to imatinib and elucidate novel therapeutic targets. Experimental Design: Immunohistochemical evaluation of expression of p53, p16, p21, CHK2, CCND1, BCL2, CDK4, and MDM2 was done on 353 histologically validated GIST patients enrolled into a European/Australasian phase III trial. TP53 was screened for mutations in cases with presumptive nonfunctional protein; that is, high p53 and low expression of the two downstream molecules p21 and MDM2. Results were correlated with clinicopathologic data, KIT/PDGFRA mutation status, and imatinib dosage. Results: Frequent impaired expression was found for BCL2 (78%), CHK2 (53%), p53 (50%), and p16 (47%). Stomach-originating GISTs showed significantly lower expression of p21, p16, and BCL2. KIT/PDGFRA wild-type GISTs had significant lower expression of CDK4. Eighty-eight percent of the high p53 expressers show low downstream target activation, indicating a nonfunctional p53 route. Of these high p53 expressers, 16.4% harbor a detectable TP53 mutation. Multivariate analysis, including previously identified markers, showed an independent effect of p53 and p16 on progression-free survival (PFS). Patients with high level of CHK2 and p21 showed significantly better PFS upon a high-dose regimen. Conclusions: Impaired p53, p16, BCL2, and CHK2 expression is common in advanced GISTs. Distinct patterns of expression correlate with tumor site, genotype, and PFS. Cell cycle/apoptosis maintenance is instrumental for optimal response to imatinib.
Integrin Targeted Delivery of Gene Therapeutics
Authors: Rudy L Juliano, Xin Ming, Osamu Nakagawa, Rongzuo Xu, Hoon Yoo
Journal: Theranostics (2011)

Integrins have become key targets for molecular imaging and for selective delivery of anti-cancer agents.Here we review recent work concerning the targeted delivery of antisense and siRNA oligonucleotides via integrins.A variety of approaches have been used to link oligonucleotides to ligands capable of binding integrins with high specificity and affinity.This includes direct chemical conjugation, incorporating oligonucleotides into lipoplexes, and use of various polymeric nanocarriers including dendrimers.The ligand-oligonucleotide conjugate or complex associates selectively with the integrin, followed by internalization into endosomes and trafficking through subcellular compartments.Escape of antisense or siRNA from the endosome to the cytosol and nucleus may come about through endogenous trafficking mechanisms, or because of membrane disrupting capabilities built into the conjugate or complex.Thus a variety of useful strategies are available for using integrins to enhance the pharmacological efficacy of therapeutic oligonucleotides.
Osteonecrosis of the Jaw in Cancer After Treatment With Bisphosphonates: Incidence and Risk Factors
Authors: Aristotle Bamias, Efstathios Kastritis, Christina Bamia, Lia A. Moulopoulos, Ioannis Melakopoulos, George Bozas, Vassiliki Koutsoukou, Dimitra Gika, Athanasios Anagnostopoulos, Christos Papadimitriou, Evagelos Terpos, Meletios A. Dimopoulos
Journal: Journal of Clinical Oncology (2005)

Purpose Osteonecrosis of the jaw (ONJ) has been associated recently with the use of pamidronate and zoledronic acid. We studied the incidence, characteristics, and risk factors for the development of ONJ among patients treated with bisphosphonates for bone metastases. Patients and Methods ONJ was assessed prospectively since July 2003. The first bisphosphonate treatment among patients with ONJ was administered in 1997. Two hundred fifty-two patients who received bisphosphonates since January 1997 were included in this analysis. Results Seventeen patients (6.7%) developed ONJ: 11 of 111 (9.9%) with multiple myeloma, two of 70 (2.9%) with breast cancer, three of 46 (6.5%) with prostate cancer, and one of 25 (4%) with other neoplasms (P = .289). The median number of treatment cycles and time of exposure to bisphosphonates were 35 infusions and 39.3 months for patients with ONJ compared with 15 infusions (P &lt; .001) and 19 months (P = .001), respectively, for patients with no ONJ. The incidence of ONJ increased with time to exposure from 1.5% among patients treated for 4 to 12 months to 7.7% for treatment of 37 to 48 months. The cumulative hazard was significantly higher with zoledronic acid compared with pamidronate alone or pamidronate and zoledronic acid sequentially (P &lt; .001). All but two patients with ONJ had a history of dental procedures within the last year or use of dentures. Conclusion The use of bisphosphonates seems to be associated with the development of ONJ. Length of exposure seems to be the most important risk factor for this complication. The type of bisphosphonate may play a role and previous dental procedures may be a precipitating factor.