tbuckley/cabot-search huggingface dataset:
Liver transplantation alcohol related liver disease: (deliberately) stirring a hornet's nest!
Authors: J G O'Grady
Journal: Gut (2006)

Outcomes after liver transplantation for alcohol related liver disease compare very favourably with those documented for other causes of cirrhosis. Despite this, 5% or less of patients with advanced alcohol related liver disease are considered for transplantation. The reasons for this are complex but include professional reluctance to refer these patients for formal assessment as well as a limited and dwindling number of organs available for transplantation. Demonstrating abstinence from alcohol consumption remains central to the assessment of candidates for transplantation. Return to alcohol consumption after transplantation can follow a pattern of abuse with consequences for health and survival but may also be controlled and of little clinical significance. A better understanding of the issues influencing these outcomes should decrease the tension that currently exists between patient expectations, professional opinion, and the attitude of the general public who gift organs for donation.
Codon Usage Bias and Effective Population Sizes on the X Chromosome versus the Autosomes in Drosophila melanogaster
Authors: Jose L. Campos, Kai Zeng, Darren J. Parker, Brian Charlesworth, Penelope R. Haddrill
Journal: Molecular Biology and Evolution (2012)

Codon usage bias (CUB) in Drosophila is higher for X-linked genes than for autosomal genes. One possible explanation is that the higher effective recombination rate for genes on the X chromosome compared with the autosomes reduces their susceptibility to Hill–Robertson effects, and thus enhances the efficacy of selection on codon usage. The genome sequence of D. melanogaster was used to test this hypothesis. Contrary to expectation, it was found that, after correcting for the effective recombination rate, CUB remained higher on the X than on the autosomes. In contrast, an analysis of polymorphism data from a Rwandan population showed that mean nucleotide site diversity at 4-fold degenerate sites for genes on the X is approximately three-quarters of the autosomal value after correcting for the effective recombination rate, compared with approximate equality before correction. In addition, these data show that selection for preferred versus unpreferred synonymous variants is stronger on the X than the autosomes, which accounts for the higher CUB of genes on the X chromosome. This difference in the strength of selection does not appear to reflect the effects of dominance of mutations affecting codon usage, differences in gene expression levels between X and autosomes, or differences in mutational bias. Its cause therefore remains unexplained. The stronger selection on CUB on the X chromosome leads to a lower rate of synonymous site divergence compared with the autosomes; this will cause a stronger upward bias for X than A in estimates of the proportion of nonsynonymous mutations fixed by positive selection, for methods based on the McDonald–Kreitman test.
Intellectual aptitude tests and A levels for selecting UK school leaver entrants for medical school
Authors: I C McManus, David A Powis, Richard Wakeford, Eamonn Ferguson, David James, Peter Richards
Journal: BMJ (2005)

An extension of A level grades is the most promising alternative to intellectual aptitude tests for selecting students for medical school How to make the selection of medical students effective, fair, and open has been contentious for many years.w1 A levels are a major component of selection for entry of school-leavers into UK universities and medical schools, w2 but intellectual aptitude tests for the selection of medical students are burgeoning-they include the Oxford medicine admissions test 1 and the Australian graduate medical school admissions test 2 (table).Tests such as the thinking skills assessment w3 are being promoted for student selection generally.The reasons include a political climate in which government ministers are advocating alternatives to A levels, some support for them in the Schwartz report on admissions to higher education, 3 lobbying from organisations such as the Sutton Trust, w4 and the difficulty of distinguishing between the growing numbers of students achieving three A grades at A level.We examine the problems that intellectual aptitude tests are addressing, their drawbacks, any evidence that they are helpful, and alternatives.Medical schools need selection procedures that are evidence based and legally defensible.We therefore explored a series of questions around these developments.Many UK school leavers apply to university with other educational qualifications, including the international Baccalaureat and Scottish highers.Medical schools are increasingly admitting entrants other than directly from school.These different mechanisms of entry require separate study.We discuss the main school-leaver route through A levels.
The Future of Psychiatric Education
Authors: LOUIS JOLYON WEST
Journal: American Journal of Psychiatry (1973)

The psychiatrist of tomorrow, while retaining his hardwon expertise in psychodynamics and psychotherapy, will be considerably more of a neurobiologist, endocrinologist, behavioral scientist, even mathematician, than is common today. He will be expected to integrate advances in research on both brain and behavior, and to apply the amalgam in a truly biosocial approach to the field of mental health and the practice of medicine. Therefore the psychiatrist's education must provide him with a great variety of knowledge without sacrificing depth, scholarship, or humanity. Four years of college, four of medical school (with the emphasis on breadth and enrichment rather than on early specialization and shortcuts), and four of rigorous postdoctoral education will not be considered irrelevant or excessive. Furthermore, psychiatry and the behavioral sciences will become increasingly important in the education of all physicians and other health professionals. Thus liaison teaching will be a major responsibility of psychiatric educators in the future.
Effect of arterial impedance changes on the end-systolic pressure-volume relation.
Authors: W L Maughan, K Sunagawa, D Burkhoff, K Sagawa
Journal: Circulation Research (1984)

To study the end-systolic pressure-volume relationship of left ventricle ejection against physiological afterload, we imposed seven simulated arterial impedances on excised canine left ventricles connected to a newly developed servo-pump system. We set each of the impedance parameters (resistance, capacitance, and characteristic impedance) to 50, 100, and 200% of normal value (resistance: 3 mm Hg sec/ml; capacitance: 0.4 ml/mm Hg; characteristic impedance: 0.2 mm Hg sec/ml), while leaving the other parameters normal. Under a given impedance, the end-systolic pressure-volume relationship was determined by preloading the ventricle at four different end-diastolic volumes. There was no significant change in the slope of the end-systolic pressure-volume relationship with changes in any of the afterloading impedance parameters. However, the volume intercept of the end-systolic pressure-volume relationship decreased significantly with resistance from 5.5 +/- 1.0 (SE) ml at resistance equal to 1.5 mm Hg sec/ml to 0.6 +/- 1.8 ml at resistance equal to 6 mm Hg sec/ml (P less than 0.01). The volume axis intercept also decreased with characteristic impedance, from 5.9 +/- 2.0 ml at a characteristic impedance of 0.1 mm Hg sec/ml to 5.4 +/- 2.1 ml at a characteristic impedance of 0.4 mm Hg sec/ml, (P less than 0.05). We conclude that the slope of the end-systolic pressure-volume relationship is insensitive to a wide range of changes in afterload impedance, but its volume intercept is dependent on resistance and characteristic impedance.
The Efficacy and Safety of Saxagliptin When Added to Metformin Therapy in Patients With Inadequately Controlled Type 2 Diabetes With Metformin Alone
Authors: Ralph A. DeFronzo, Miguel N. Hissa, Alan J. Garber, Jorge Luiz Gross, Raina Yuyan Duan, Shoba Ravichandran, Roland S. Chen
Journal: Diabetes Care (2009)

OBJECTIVE This 24-week trial assessed the efficacy and safety of saxagliptin as add-on therapy in patients with type 2 diabetes with inadequate glycemic control with metformin alone. RESEARCH DESIGN AND METHODS This was a randomized, double-blind, placebo-controlled study of saxagliptin (2.5, 5, or 10 mg once daily) or placebo plus a stable dose of metformin (1,500–2,500 mg) in 743 patients (A1C ≥7.0 and ≤10.0%). Efficacy analyses were performed using an ANCOVA model using last observation carried forward methodology on primary (A1C) and secondary (fasting plasma glucose [FPG] and postprandial glucose [PPG] area under the curve [AUC]) end points. RESULTS Saxagliptin (2.5, 5, and 10 mg) plus metformin demonstrated statistically significant adjusted mean decreases from baseline to week 24 versus placebo in A1C (−0.59, −0.69, and −0.58 vs. +0.13%; all P &amp;lt; 0.0001), FPG (−14.31, −22.03, and −20.50 vs. +1.24 mg/dl; all P &amp;lt; 0.0001), and PPG AUC (−8,891, −9,586, and −8,137 vs. −3,291 mg · min/dl; all P &amp;lt; 0.0001). More than twice as many patients achieved A1C &amp;lt;7.0% with 2.5, 5, and 10 mg saxagliptin versus placebo (37, 44, and 44 vs. 17%; all P &amp;lt; 0.0001). β-Cell function and postprandial C-peptide, insulin, and glucagon AUCs improved in all saxagliptin treatment groups at week 24. Incidence of hypoglycemic adverse events and weight reductions were similar to those with placebo. CONCLUSIONS Saxagliptin once daily added to metformin therapy was generally well tolerated and led to statistically significant improvements in glycemic indexes versus placebo added to metformin in patients with type 2 diabetes inadequately controlled with metformin alone.
HLA-mismatched unrelated donors are a viable alternate graft source for allogeneic transplantation following alemtuzumab-based reduced-intensity conditioning
Authors: Adam J. Mead, Kirsty J. Thomson, Emma C. Morris, Sajir Mohamedbhai, Shari Denovan, Guillermo Orti, Adele K. Fielding, Panagiotis D. Kottaridis, Rachael Hough, Ronjon Chakraverty, David C. Linch, Stephen Mackinnon, Karl S. Peggs
Journal: Blood (2010)
Modification of the international primary care airways group (IPAG)-questionnaire for Japanese
Authors: Go Tsukuya, Takuya Samukawa, Tsutomu Hamada, Kaoru Oketani, Masatada Soejima, Hiroyuki Nagahama, Hirohito Tsubouchi, Hiromasa Inoue
Journal: European Respiratory Journal (2011)

Background:  Several reports showed the IPAG- Questionnaire (Q) is useful for screening COPD, but may require modification for Japanese. However its modification hasn9t been reported yet.   Objective:  The aim of this study was to establish a modified IPAG-Q for Japanese.   Method:  Smokers (excepting those with a history of bronchial asthma) aged 40 and over who underwent a screening CT and had given written informed consent were enrolled. They were classified into two groups based on the results of respiratory function tests (FEV 1 % ≥ or    Results:  A total of 268 subjects (control-smokers/COPD: 244/24) were enrolled. We described the receiver operating characteristic (ROC) curve about the original IPAG-Q: the area under the ROC curve (AUC) was 0.764, cut-off was 18.5/total 56 (score), sensitivity was 0.750 and specificity was 0.615. Logistic regression analysis revealed only “wheeze frequency” was useful in the “symptoms/history”, so we deleted “symptoms/history” except for this parameter. And we improved the stratification for age, BMI, and pack/year: age ≥ or    Conclusion:  Our modified IPAG-Q is of greater use for screening COPD among Japanese than the original one.
Randomized Phase II Study of Docetaxel and Prednisone With or Without OGX-011 in Patients With Metastatic Castration-Resistant Prostate Cancer
Authors: Kim N. Chi, Sebastien J. Hotte, Evan Y. Yu, Dongsheng Tu, Bernhard J. Eigl, Ian Tannock, Fred Saad, Scott North, Jean Powers, Martin E. Gleave, Elizabeth A. Eisenhauer
Journal: Journal of Clinical Oncology (2010)

To determine the clinical activity of OGX-011, an antisense inhibitor of clusterin, in combination with docetaxel/prednisone in patients with metastatic castration-resistant prostate cancer.Patients were randomly assigned 1:1 to receive docetaxel/prednisone either with (arm A) or without (arm B) OGX-011 640 mg intravenously weekly. The primary end point was the proportion of patients with a prostate-specific antigen (PSA) decline of ≥ 50% from baseline, with the experimental therapy being considered of interest if the proportion of patients with a PSA decline was more than 60%. Secondary end points were objective response rate, progression-free survival (PFS), overall survival (OS), and changes in serum clusterin.Eighty-two patients were accrued, 41 to each arm. OGX-011 adverse effects included rigors and fevers. After cycle 1, median serum clusterin decreased by 26% in arm A and increased by 0.9% in arm B (P < .001). PSA declined by ≥ 50% in 58% of patients in arm A and 54% in arm B. Partial response occurred in 19% and 25% of patients in arms A and B, respectively. Median PFS and OS times were 7.3 months (95% CI, 5.3 to 8.8 months) and 23.8 months (95% CI, 16.2 months to not reached), respectively, in arm A and 6.1 months (95% CI, 3.7 to 8.6 months) and 16.9 months (95% CI, 12.8 to 25.8 months), respectively, in arm B. Baseline factors associated with improved OS on exploratory multivariate analysis were an Eastern Cooperative Oncology Group performance status of 0 (hazard ratio [HR], 0.27; 95% CI, 0.14 to 0.51), presence of bone or lymph node metastases only (HR, 0.45; 95% CI, 0.25 to 0.79), and treatment assignment to OGX-011 (HR, 0.50; 95% CI, 0.29 to 0.87).Treatment with OGX-011 and docetaxel was well tolerated with evidence of biologic effect and was associated with improved survival. Further evaluation is warranted.
Outcome of high-dose therapy and autologous transplantation in non-Hodgkin's lymphoma based on the presence of tumor in the marrow or infused hematopoietic harvest.
Authors: J G Sharp, A Kessinger, S Mann, D A Crouse, J O Armitage, P Bierman, D D Weisenburger
Journal: Journal of Clinical Oncology (1996)

To evaluate the outcomes in 65 consecutive patients with non-Hodgkin's lymphoma (NHL) undergoing high-dose therapy (HDT) and autologous transplantation based on initial marrow involvement and the presence or absence of minimal disease in the hematopoietic harvests.Patients with any history of histologic evidence of marrow tumor underwent autologous peripheral-blood stem-cell transplantation (PSCT), whereas others underwent autologous bone marrow transplantation (ABMT). Patients who underwent ABMT were further segregated retrospectively into two groups depending on whether there was evidence by cell culture and/or Southern analysis of minimal tumor in the marrow harvest.Comparable proportions (58% to 60%) of patients in each of the two groups (PSCT and ABMT) achieved a complete clinical remission (CR) at 100 days. For patients who achieve a CR, the actuarial relapse-free survival rate at 5 years for PSCT patients who received a tumor-negative apheresis harvest was 64%, compared with 57% for patients who received a tumor-negative bone marrow harvest and 17% for patients who received a histologically negative but minimally contaminated bone marrow harvest. Lymphoma grade and phenotype were not significant predictors of outcome.The observation that survival was significantly better in the groups of patients who received tumor-negative harvests and worse for patients who received minimally contaminated harvests suggests that tumor cells, even at minimal levels, reinfused in the transplanted harvest are responsible for progression in a proportion of patients who achieve a CR following HDT, although other biologic characteristics of the tumor could also be important. A relatively good outcome can be achieved with HDT and PSCT, even in patients with a significant marrow tumor burden.
Durable responses and reversible toxicity of high-dose interleukin-2 treatment of melanoma and renal cancer in a Community Hospital Biotherapy Program
Authors: Roxanne Payne, Lyn Glenn, Helena Hoen, Beverley Richards, John W Smith, Robert Lufkin, Todd S Crocenzi, Walter J Urba, Brendan D Curti
Journal: Journal for ImmunoTherapy of Cancer (2014)

High-dose interleukin-2 (IL-2) has been FDA-approved for over 20 years, but it is offered only at a small number of centers with expertise in its administration. We analyzed the outcomes of patients receiving high-dose IL-2 in relation to the severity of toxicity to ascertain if response or survival were adversely affected.A retrospective analysis of the outcomes of 500 patients with metastatic renal cell carcinoma (RCC) (n = 186) or melanoma (n = 314) treated with high-dose IL-2 between 1997 and 2012 at Providence Cancer Center was performed. IL-2 was administered at a dose of 600,000 international units per kg by IV bolus every 8 hours for up to 14 doses. A second cycle was administered 16 days after the first and patients with tumor regression could receive additional cycles. Survival and anti-tumor response were analyzed by diagnosis, severity of toxicity, number of IL-2 cycles and subsequent therapy.The objective response rate in melanoma was 28% (complete 12% and partial 16%), and in RCC was 24% (complete 7% and partial 17%). The 1-, 2- and 3-year survivals were 59%, 41% and 31%, for melanoma and 75%, 56% and 44%, for RCC, respectively. The proportion of patients with complete or partial response in both melanoma and RCC was higher in patients who a) required higher phenylephrine doses to treat hypotension (p < 0.003), b) developed acidosis (bicarbonate < 19 mmol (p < 0.01)), or c) thrombocytopenia (<50, 50-100, >100,000 platelets; p < 0.025). The proportion achieving a complete or partial response was greater in patients with melanoma who received 5 or more compared with 4 or fewer IL-2 cycles (p < 0.0001). The incidence of death from IL-2 was less than 1% and was not higher in patients who required phenylephrine.High-dose IL-2 can be administered safely; severe toxicity including hypotension is reversible and can be managed in a community hospital. The tumor response and survival reported here are superior to the published literature and support treating patients to their individualized maximum tolerated dose. IL-2 should remain part of the treatment paradigm in selected patients with melanoma and RCC.
Minor local alveolar edema in an in vivo human model can be detected by changes in respiratory mechanics by impulse oscillometry (IOS)
Authors: Manuela Bartesaghi, Egidio Beretta, Alberto Pesci, Andrea Aliverti, Giuseppe Miserocchi
Journal: European Respiratory Journal (2011)

Aim: We assessed the sensitivity of the impulse oscillometry methods (IOS) to detect residual alveolar edema in a lung segment after broncho- alveolar lavage (BAL).

Methods: 15 patients of both sexes undergoing BAL in different lobes for diagnosis of interstitial lung disease were studied. IOS was applied before and after withdrawal of BAL fluid, leaving in the alveoli a volume (V) of 86.6ml ± 23.6 (mean ± DS), and continued up to 150 min. From IOS data we derived the corresponding values of respiratory resistance ( Rrs ) and reactance ( Xrs ) at frequencies from 5 to 35 Hz. We also estimated the “area of reactance” ( AXrs) as defined in Fig. 1A.

Results: After withdrawal of BAL fluid, the remaining V caused a 30% significant increase of Rrs at 5Hz; a significant increase in resonance frequency ( fres ) from 11.9 Hz ± 3.3 to 15.2 Hz ± 4.9; and minor changes in Xrs . The increase in fres led to a significant 90% increase in AXrs . Rrs , fres and AXrs returned towards baseline values through an exponential decay function within 150 min (data of AXrs and regression equation are shown in Fig. 1B).

![Figure][1] 



Conclusion: IOS technique is sensible enough to detect minor localized increase in extravascular lung water.

 [1]: pending:yes
Endothelin A Receptor Blockade Prevents Capillary/Myocyte Mismatch in the Heart of Uremic Animals
Authors: KERSTIN AMANN, KLAUS MÜNTER, SABINE WESSELS, JÜRGEN WAGNER, VITALI BALAJEW, STEFAN HERGENRÖDER, GERHARD MALL, EBERHARD RITZ
Journal: Journal of the American Society of Nephrology (2000)

Abstract. In the heart of uremic animals and patients, the number of capillaries per volume of myocardium is reduced. Immunohistochemical studies demonstrated increased cardiac endothelin-1 (ET-1) expression in the left ventricle of uremic animals. Therefore, whether treatment with a selective ET A -receptor antagonist prevented such capillary-myocyte mismatch was investigated. Twenty-four h after subtotal nephrectomy, rats were left untreated or started on treatment with the ET A -receptor antagonist LU 135252 (20 mg/kg per d) and with the angiotensin-converting enzyme (ACE) inhibitor trandolapril (0.3 mg/kg per d), respectively. BP was monitored by telemetry. Myocardial capillary length density was analyzed by stereologic techniques that avoid anisotropy artifacts. In addition, cardiac ET-1 protein and mRNA were measured using immunohistochemistry, in situ hybridization, and quantitative reverse transcription—PCR. Changes in cardiac ET A -and ET B -PCR. receptor mRNA were measured using reverse transcription—PCR. Fifteen wk after subtotal nephrectomy, significantly reduced left ventricular capillary length density (3307 ± 535 mm/mm 3 ) was found compared with sham-operated controls (3995 ± 471 mm/mm 3 ); this was also seen in animals that were treated with trandolapril (3503 ± 533 mm/mm 3 ) but not in animals that were treated with LU 135252 (3800 ± 303 mm/mm 3 ). The results support a role of ET-1 in the genesis of left ventricular capillary/myocyte mismatch in uremia.
Gene Transfer-Induced Local Heme Oxygenase-1 Overexpression Protects Rat Kidney Transplants From Ischemia/Reperfusion Injury
Authors: Tom D. Blydt-Hansen, Masamichi Katori, Charles Lassman, Bibo Ke, Ana J. Coito, Suhasani Iyer, Roland Buelow, Robert Ettenger, Ronald W. Busuttil, Jerzy W. Kupiec-Weglinski
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Heme oxygenase-1 (HO-1) overexpression using gene transfer protects rat livers against ischemia/reperfusion (I/R) injury. This study evaluates the effects of Ad-HO-1 gene transfer in a rat renal isograft model. Donor LEW kidneys were perfused with Ad-HO-1, Ad-β-gal, or PBS, stored at 4°C for 24 h, and transplanted orthotopically into LEW recipients, followed by contralateral native nephrectomy. Serum creatinine, urine protein/creatinine ratios, severity of histologic changes, HO-1 mRNA/protein expression, and HO enzymatic activity were analyzed. Ad-HO-1 gene transfer conferred a survival advantage when compared with PBS– and Ad-β-gal–treated controls, with median survival of 100, 7, and 7 d, respectively (<i>P</i> &lt; 0.01). Serum creatinine levels were elevated at day 7 in all groups (range, 2.2 to 5.8 mg/dl) but recovered to 1.0 mg/dl by day 14 (<i>P</i> &lt; 0.01) in Ad-HO-1 group, which was sustained thereafter. Urine protein/creatinine ratio at day 7 was elevated in both PBS and Ad-β-gal, as compared with the Ad-HO-1 group (12.0 and 9.8 <i>versus</i> 5.0; <i>P</i> &lt; 0.005); histologically, ATN and glomerulosclerosis was more severe in Ad-β-gal group at all time points. Reverse transcriptase-PCR–based HO-1 gene expression was significantly increased before reperfusion (<i>P</i> &lt; 0.001) and remained increased in the Ad-HO-1–treated group for 3 d after transplantation. Concomitantly, HO enzymatic activity was increased at transplantation and at 3 d posttransplant in the Ad-HO-1 group, compared with Ad-β-gal controls (<i>P</i> &lt; 0.05); tubular HO-1 expression was discernible early posttransplant in the Ad-HO-1 group alone. These findings are consistent with protective effects of HO-1 overexpression using a gene transfer approach against severe renal I/R injury, with reduced mortality and attenuation of tissue injury. E-mail: jkupiec@mednet.ucla.edu