tbuckley/cabot-search huggingface dataset:
NASH may be trash
Authors: D. Cassiman, J. Jaeken
Journal: Gut (2008)

The liver is a stupid organ. It has only limited abilities to express itself. It can necrotise, swell, inflame, clot and scarify. The liver can become leaky, it can sometimes hurt and its plumbing can clog. And then the liver can be fatty. For some time already, we know that, for example, several viruses can cause the inflammation, and that drugs, viruses and autoimmunity cause most of the necrosis, etc. Luckily, for the majority of these causes, we have more or less reliable methods to pin them down. Not so for the fatty sign because, when turning fatty, the liver is at its most stupid. On a communication scale and compared with the eloquent monologue of a viral hepatitis, turning fatty would rate as a grunt. It is never entirely clear what causes a grunt or what is meant by grunting, as it is never clear what provokes fatty infiltration of the liver or what the liver wants to convey by turning fatty. A grunt can be an expression of pain, but also of pleasure. Is it time to expand the liver’s vocabulary, or could there also be something wrong with us, the audience?

> When turning fatty, the liver is at its most stupid

When fatty liver is not associated with moderate to severe alcohol intake and the most prevalent liver diseases are excluded, it is called “non-alcoholic fatty liver disease” (NAFLD). When the fatty liver is also inflamed, we call it “non-alcoholic steatohepatitis” (NASH). However, there is a very long and ever-expanding list of causes of fatty livers, which cannot simply be named NAFLD/NASH (table 1). Also on a more theoretical level, there is a problem with NAFLD and NASH: they are “non”-diseases, exclusion diagnoses: it’s not a bird, it’s not a plane, so it must be Superman. Therefore, …
Human Artificial Chromosomes for Gene Delivery and the Development of Animal Models
Authors: Yasuhiro Kazuki, Mitsuo Oshimura
Journal: Molecular Therapy (2011)

Random integration of conventional gene delivery vectors such as viruses, plasmids, P1 phage-derived artificial chromosomes, bacterial artificial chromosomes and yeast artificial chromosomes can be associated with transgene silencing. Furthermore, integrated viral sequences can activate oncogenes adjacent to the insertion site resulting in cancer. Various human artificial chromosomes (HACs) exhibit several potential characteristics desired for an ideal gene delivery vector, including stable episomal maintenance and the capacity to carry large genomic loci with their regulatory elements, thus allowing the physiological regulation of the introduced gene in a manner similar to that of native chromosomes. HACs have been generated mainly using either a "top-down approach" (engineered chromosomes), or a "bottom-up approach" (de novo artificial chromosomes). The recent emergence of stem cell–based tissue engineering has opened up new avenues for gene and cell therapies. This review describes the lessons learned and prospects identified mainly from studies in the construction of HACs and HAC-mediated gene expression systems in cultured cells, as well as in animals. Random integration of conventional gene delivery vectors such as viruses, plasmids, P1 phage-derived artificial chromosomes, bacterial artificial chromosomes and yeast artificial chromosomes can be associated with transgene silencing. Furthermore, integrated viral sequences can activate oncogenes adjacent to the insertion site resulting in cancer. Various human artificial chromosomes (HACs) exhibit several potential characteristics desired for an ideal gene delivery vector, including stable episomal maintenance and the capacity to carry large genomic loci with their regulatory elements, thus allowing the physiological regulation of the introduced gene in a manner similar to that of native chromosomes. HACs have been generated mainly using either a "top-down approach" (engineered chromosomes), or a "bottom-up approach" (de novo artificial chromosomes). The recent emergence of stem cell–based tissue engineering has opened up new avenues for gene and cell therapies. This review describes the lessons learned and prospects identified mainly from studies in the construction of HACs and HAC-mediated gene expression systems in cultured cells, as well as in animals.
Nucleotide Bias Causes a Genomewide Bias in the Amino Acid Composition of Proteins
Authors: Gregory A. C. Singer, Donal A. Hickey
Journal: Molecular Biology and Evolution (2000)

We analyzed the nucleotide contents of several completely sequenced genomes, and we show that nucleotide bias can have a dramatic effect on the amino acid composition of the encoded proteins. By surveying the genes in 21 completely sequenced eubacterial and archaeal genomes, along with the entire Saccharomyces cerevisiae genome and two Plasmodium falciparum chromosomes, we show that biased DNA encodes biased proteins on a genomewide scale. The predicted bias affects virtually all genes within the genome, and it could be clearly seen even when we limited the analysis to sets of homologous gene sequences. Parallel patterns of compositional bias were found within the archaea and the eubacteria. We also found a positive correlation between the degree of amino acid bias and the magnitude of protein sequence divergence. We conclude that mutational bias can have a major effect on the molecular evolution of proteins. These results could have important implications for the interpretation of protein-based molecular phylogenies and for the inference of functional protein adaptation from comparative sequence data.
[18F]-FDG–PET in clinical stage I/II non-seminomatous germ cell tumours: results of the German multicentre trial
Authors: M. de Wit, W. Brenner, M. Hartmann, J. Kotzerke, D. Hellwig, J. Lehmann, C. Franzius, S. Kliesch, M. Schlemmer, K. Tatsch, R. Heicappell, L. Geworski, H. Amthauer, B.M. Dohmen, H. Schirrmeister, U. Cremerius, C. Bokemeyer, R. Bares
Journal: Annals of Oncology (2008)
Maternal Obesity and Risk of Preterm Delivery
Authors: Sven Cnattingius, Eduardo Villamor, Stefan Johansson, Anna-Karin Edstedt Bonamy, Martina Persson, Anna-Karin Wikström, Fredrik Granath
Journal: JAMA (2013)

Preterm birth is a leading cause of infant mortality, morbidity, and long-term disability, and these risks increase with decreasing gestational age. Obesity increases the risk of preterm delivery, but the associations between overweight and obesity and subtypes of preterm delivery are not clear.To study the associations between early pregnancy body mass index (BMI) and risk of preterm delivery by gestational age and by precursors of preterm delivery.Population-based cohort study of women with live singleton births in Sweden from 1992 through 2010. Maternal and pregnancy characteristics were obtained from the nationwide Swedish Medical Birth Register.Risks of preterm deliveries (extremely, 22-27 weeks; very, 28-31 weeks; and moderately, 32-36 weeks). These outcomes were further characterized as spontaneous (related to preterm contractions or preterm premature rupture of membranes) and medically indicated preterm delivery (cesarean delivery before onset of labor or induced onset of labor). Risk estimates were adjusted for maternal age, parity, smoking, education, height, mother's country of birth, and year of delivery.Among 1,599,551 deliveries with information on early pregnancy BMI, 3082 were extremely preterm, 6893 were very preterm, and 67,059 were moderately preterm. Risks of extremely, very, and moderately preterm deliveries increased with BMI and the overweight and obesity-related risks were highest for extremely preterm delivery. Among normal-weight women (BMI 18.5-<25), the rate of extremely preterm delivery was 0.17%. As compared with normal-weight women, rates (%) and adjusted odds ratios (ORs [95% CIs]) of extremely preterm delivery were as follows: BMI 25 to less than 30 (0.21%; OR, 1.26; 95% CI, 1.15-1.37), BMI 30 to less than 35 (0.27%; OR, 1.58; 95% CI, 1.39-1.79), BMI 35 to less than 40 (0.35%; OR, 2.01; 95% CI, 1.66-2.45), and BMI of 40 or greater (0.52%; OR, 2.99; 95% CI, 2.28-3.92). Risk of spontaneous extremely preterm delivery increased with BMI among obese women (BMI≥30). Risks of medically indicated preterm deliveries increased with BMI among overweight and obese women.In Sweden, maternal overweight and obesity during pregnancy were associated with increased risks of preterm delivery, especially extremely preterm delivery. These associations should be assessed in other populations.
Primary Prevention of Cardiovascular Disease with a Mediterranean Diet
Authors: Ramón Estruch, Emilio Ros, Jordi Salas-Salvadó, Maria-Isabel Covas, Dolores Corella, Fernando Arós, Enrique Gómez-Gracia, Valentina Ruiz-Gutiérrez, Miquel Fiol, José Lapetra, Rosa Maria Lamuela-Raventos, Lluís Serra-Majem, Xavier Pintó, Josep Basora, Miguel Angel Muñoz, José V Sorlí, José Alfredo Martínez, Miguel Angel Martínez-González
Journal: New England Journal of Medicine (2013)

Observational cohort studies and a secondary prevention trial have shown an inverse association between adherence to the Mediterranean diet and cardiovascular risk. We conducted a randomized trial of this diet pattern for the primary prevention of cardiovascular events.In a multicenter trial in Spain, we randomly assigned participants who were at high cardiovascular risk, but with no cardiovascular disease at enrollment, to one of three diets: a Mediterranean diet supplemented with extra-virgin olive oil, a Mediterranean diet supplemented with mixed nuts, or a control diet (advice to reduce dietary fat). Participants received quarterly individual and group educational sessions and, depending on group assignment, free provision of extra-virgin olive oil, mixed nuts, or small nonfood gifts. The primary end point was the rate of major cardiovascular events (myocardial infarction, stroke, or death from cardiovascular causes). On the basis of the results of an interim analysis, the trial was stopped after a median follow-up of 4.8 years.A total of 7447 persons were enrolled (age range, 55 to 80 years); 57% were women. The two Mediterranean-diet groups had good adherence to the intervention, according to self-reported intake and biomarker analyses. A primary end-point event occurred in 288 participants. The multivariable-adjusted hazard ratios were 0.70 (95% confidence interval [CI], 0.54 to 0.92) and 0.72 (95% CI, 0.54 to 0.96) for the group assigned to a Mediterranean diet with extra-virgin olive oil (96 events) and the group assigned to a Mediterranean diet with nuts (83 events), respectively, versus the control group (109 events). No diet-related adverse effects were reported.Among persons at high cardiovascular risk, a Mediterranean diet supplemented with extra-virgin olive oil or nuts reduced the incidence of major cardiovascular events. (Funded by the Spanish government's Instituto de Salud Carlos III and others; Controlled-Trials.com number, ISRCTN35739639.).
Heterogeneous ventilation and perfusion: a sensitive indicator of lung impairment in nonsmoking coal miners
Authors: H Susskind, JC Acevedo, J Iwai, DL Rasmussen, DK Heydinger, HR Pate, WH Harold, AB Brill
Journal: European Respiratory Journal (1988)

Twenty life-long nonsmoking West Virginia coal-miners participated in a study to amplify the role of focal irregularities on regional ventilation (V) and perfusion (Q) and to develop an improved method for the early detection of coal-workers' pneumoconiosis. Their mean age was 59.3 yr and they averaged 35.2 years' exposure to coal dust. Conventional pulmonary function tests were supplemented by measurement of V, Q and lung volume (V), using radioactive Kr-81m, Tc-99m MAA and Xe-127, respectively, to determine regional abnormalities in lung function. A computer analysis of the regional distributions of V/V, Q/V and V/Q was performed, and their topographical distributions and indices of heterogeneity (HI) computed. V/V and Q/V were significantly reduced in the lower third, and increased in the upper two-thirds of the miners' lungs; V/Q was reduced in the upper half. The miners' V/V and Q/V were more heterogeneous (p less than 0.001) than that of eleven age-matched controls, with mean ventilation HI values of 0.190 +/- 0.027 and 0.133 +/- 0.011, respectively, and mean perfusion HI values of 0.206 +/- 0.022 and 0.164 +/- 0.041, respectively. P(A-a)O2 correlated positively (r = 0.72; p less than 0.001) with ventilation HI. Gas exchange was the most significant functional measurement, being abnormal in 19/20 subjects. In contrast, conventional spirometric measurements were within the predicted normal limits in all but four miners.
Pulmonary Cell Biology
Authors: ROBERT J. MASON, RONALD G. CRYSTAL
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

The purpose of this review is to relate developments in lung cell biology to our understanding and treatment of pulmonary diseases. The authors’ careers in pulmonary biology began when we came to the Heart Institute of the National Institutes of Health in 1968 (R.J.M.) and 1970 (R.G.C.). This was before the creation of the Heart, Lung and Blood Institute in 1973. At that time, there was also no active basic or clinical investigation of pulmonary disease in the intramural Heart Institute at NIH. The focus of the pulmonary investigation had been on tuberculosis and had turned to pulmonary physiology, and investigations of pulmonary cell biology were just beginning. This review will focus on surfactant and alveolar type II cell biology and on the molecular basis of a 1-antitrypsin ( a 1AT) deficiency. The type II cell has been chosen to represent advances in cell biology and a 1AT to represent advances in genetics and molecular biology. These recollections highlight the collaboration and achievements in the intramural and extramural programs of the NHLBI.
Shouldn't We See the White Flag Before We Cry Victory?
Authors: I. C. Henderson
Journal: JNCI Journal of the National Cancer Institute (1990)

Journal Article Shouldn't We See the White Flag Before We Cry Victory? Get access I. Craig Henderson I. Craig Henderson Breast Evaluation Center, Division of Clinical Oncology, Dana-Farber Cancer Institute44 Binney St., Boston MA 02115 Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 82, Issue 2, 17 January 1990, Pages 103–105, https://doi.org/10.1093/jnci/82.2.103 Published: 17 January 1990 Article history Received: 13 December 1989 Accepted: 14 December 1989 Published: 17 January 1990
Immunoglobulin-mediated signal transduction in B cells from CD45-deficient mice.
Authors: T Benatar, R Carsetti, C Furlonger, N Kamalia, T Mak, C J Paige
Journal: The Journal of Experimental Medicine (1996)

CD45 expression is essential for immunoglobulin (Ig)-mediated B cell activation. Treatments with either anti-Ig or anti-CD45 suggest that CD45 may facilitate early signaling events such as calcium mobilization, and phosphoinositide hydrolyis as well as later events leading to transcription of genes such as c-myc. To examine the role of CD45 more extensively, CD45-deficient mice were generated by disruption of exon 6. Although normal numbers of B cells were found in peripheral lymphoid tissues, CD45-deficient cells failed to proliferate upon IgM crosslinking. In the present study, we demonstrate that the fraction of high buoyant density B cells is reduced while low buoyant density cells are increased. Moreover, there is a significant decline in the number of splenic B cells of the mature IgDhi, IgMlo phenotype. Although both the basal and anti-Ig-induced levels of phosphorylation of Ig-alpha and phospholipase C gamma 2 are indistinguishable from that observed in CD45+ control B cells, a major distinction was found in Ca2+ mobilization. While anti-Ig-induced mobilization of intracellular Ca2+ stores was normal, influx from extracellular sources was abrogated. This finding reveals a novel pathway of regulating B cell responses mediated by CD45.
844-1 Doppler tissue imaging assessment of dyssynchronicity is a powerful predictor of mortality in severe congestive heart failure with normal QRS duration
Authors: Goo-Yeong Cho, Woo-Jung Park, Sung-Woo Han, Seung-Hyuk Choi, Young-Cheoul Doo, Dong-Jin Oh, Chong-Yun Rhim, Yung Lee
Journal: Journal of the American College of Cardiology (2004)
Documenting and Comparing Medical Students' Clinical Experiences
Authors: S L Rattner, D Z Louis, C Rabinowitz, J E Gottlieb, T J Nasca, F W Markham, R P Gottlieb, J W Caruso, J L Lane, J Veloski, M Hojat, J S Gonnella
Journal: JAMA (2001)

The decentralization of clinical teaching networks over the past decade calls for a systematic way to record the case-mix of patients, the severity of diseases, and the diagnostic procedures that medical students encounter in clinical clerkships.To demonstrate a system that documents medical students' clinical experiences across clerkships.Evaluation of a method for recording student-patient clinical encounters using a pocket-sized computer-read patient encounter card at a US university hospital and its 16 teaching affiliates during academic years 1997-1998 through 1999-2000.A total of 647 third-year medical students who completed patient encounter cards in 3 clerkships: family medicine, pediatrics, and internal medicine.Number of patient encounters, principal and secondary diagnoses, severity of diseases, and diagnostic procedures as recorded on patient encounter cards; concordance of patient encounter card data with medical records.Students completed 86 011 patient encounter cards: 48 367 cards by 582 students in family medicine, 22 604 cards by 469 students in pediatrics, and 15 040 cards by 531 students in internal medicine. Significant differences were found in students' case-mix of patients, the level of disease severity, and the number of diagnostic procedures performed across the 3 clerkships. Stability of the findings within each clerkship across 3 academic years and the 77% concordance of students' reports of principal diagnosis with faculty's confirmation of diagnosis support the reliability and validity of the findings.An instrument that facilitates students' documentation of clinical experiences can provide data on important differences among students' clerkship experiences. Data from this instrument can be used to assess the nature of students' clinical education.
Pilot Trial of Unlabeled and Indium-111–Labeled Anti–Prostate-Specific Membrane Antigen Antibody J591 for Castrate Metastatic Prostate Cancer
Authors: Michael J. Morris, Chaitanya R. Divgi, Neeta Pandit-Taskar, Maria Batraki, Nyasha Warren, Angelo Nacca, Peter Smith-Jones, Lawrence Schwartz, W. Kevin Kelly, Susan Slovin, David Solit, Jennifer Halpern, Anthony Delacruz, Tracy Curley, Ronald Finn, Joseph A. O'Donoghue, Philip Livingston, Steven Larson, Howard I. Scher
Journal: Clinical Cancer Research (2005)

Abstract Background: Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein primarily expressed on benign and malignant prostatic epithelial cells. J591 is an IgG1 monoclonal antibody that targets the external domain of the PSMA. The relationship among dose, safety, pharmacokinetics, and antibody-dependent cellular cytotoxicity (ADCC) activation for unlabeled J591 has not been explored. Patients and Methods: Patients with progressive metastatic prostate cancer despite androgen deprivation were eligible. Each patient received 10, 25, 50, and 100 mg of J591. Two milligrams of antibody, conjugated with the chelate 1,4,7,10-tetraazacyclododecane-N, N′,N″,N‴-tetraacetic acid, were labeled with 5 mCi indium-111 (111In) as a tracer. One group of patients received unlabeled J591 before the labeled antibody; the other received both together. Toxicities, pharmacokinetic properties, biodistribution, ADCC induction, immunogenicity, and clinical antitumor effects were assessed. Results: Fourteen patients were treated (seven in each group). Treatment was well tolerated. Biodistribution of 111In-labeled J591 was comparable in both groups. The mean T1/2 was .96, 1.9, 2.75, and 3.47 days for the 10, 25, 50, and 100 mg doses, respectively. Selective targeting of 111In-labeled J591 to tumor was seen. Hepatic saturation occurred by the 25-mg dose. ADCC activity was proportional to dose. One patient showed a &amp;gt;50% prostate-specific antigen decline. Conclusions: J591 is well tolerated in repetitive dose-escalating administrations. The rate of serum clearance decreases with increasing antibody mass. ADCC activation is proportional to antibody mass. The optimal dose is 25 mg for radioimmunotherapy and 100 mg for immunotherapy. Phase II studies using J591 as a radioconjugate are under way.
Hypoglycemia-associated autonomic failure in insulin-dependent diabetes mellitus. Recent antecedent hypoglycemia reduces autonomic responses to, symptoms of, and defense against subsequent hypoglycemia.
Authors: S E Dagogo-Jack, S Craft, P E Cryer
Journal: Journal of Clinical Investigation (1993)

We hypothesize that in patients with insulin-dependent diabetes mellitus (IDDM), recent antecedent iatrogenic hypoglycemia is a major cause of hypoglycemia-associated autonomic failure, a disorder distinct from classical diabetic autonomic neuropathy (CDAN), and that hypoglycemia-associated autonomic failure, by reducing both symptoms of and defense against developing hypoglycemia, results in recurrent iatrogenic hypoglycemia, thus creating a vicious cycle. We used the hyperinsulinemic (12.0 pmol.kg-1.min-1) stepped hypoglycemic clamp technique to assess autonomic and symptomatic responses to hypoglycemia and the insulin infusion test (4.0 pmol.kg-1.min-1) to assess defense against hypoglycemia on mornings before and after clamped afternoon hypoglycemia (approximately 2.8 mmol/liter) and hyperglycemia (approximately 11.1 mmol/liter) in patients with IDDM. Compared with nondiabetic subjects, IDDM with or without CDAN exhibited reduced epinephrine (P = 0.0222 and 0.0040) and pancreatic polypeptide (P = 0.0083 and 0.0056) responses to hypoglycemia. After afternoon hypoglycemia, lower plasma glucose concentrations were required to elicit autonomic and symptomatic responses during morning hypoglycemic clamps in patients without CDAN. At the 2.8 mmol/liter step, mean (+/- SE) epinephrine levels were 1,160 +/- 270 and 2,040 +/- 270 pmol/liter (P = 0.0060), pancreatic and total symptom scores were 22 +/- 3 and 41 +/- 7 (P = 0.0475) after afternoon hypoglycemia and hyperglycemia, respectively. During morning insulin infusion tests after afternoon hypoglycemia, nadir plasma glucose concentrations were 2.6 +/- 0.2 mmol/liter compared with 3.3 +/- 0.3 mmol/liter (P < 0.001) at the corresponding time points after afternoon hyperglycemia. Thus, we conclude: (a) elevated glycemic thresholds for autonomic responses to hypoglycemia are a feature of IDDM per se, not classical diabetic autonomic neuropathy; and (b) a single episode of afternoon hypoglycemia results in both elevated glycemic thresholds for autonomic and symptomatic responses to hypoglycemia and impaired physiological defense against hypoglycemia the next morning in IDDM.
Probiotics in inflammatory bowel disease
Authors: S V. Karthik
Journal: Journal of the Royal Society of Medicine (2003)

Reviewing the possible value of probiotics in inflammatory bowel disease, Dr Jonkers and Dr Stockbrugger conclude that clearcut evidence is lacking (April 2003 JRSM1). The most impressive effects with probiotics so far are in children with acute infectious diarrhoea, particularly of viral causation. A meta-analysis revealed that probiotics lessened both duration of diarrhoea and stool frequency.2 The value of probiotics in inflammatory bowel disease is more difficult to assess because patients need to continue with existing mainstay medications. A multicentre trial in children with Crohn's disease, now underway in the USA, may provide further insight.3