tbuckley/cabot-search huggingface dataset:
Primary Myelofibrosis: Update on Definition, Pathogenesis, and Treatment
Authors: Omar I. Abdel-Wahab, Ross L. Levine
Journal: Annual Review of Medicine (2008)

Primary myelofibrosis (PMF) is a clonal stem cell disorder that manifests clinically as anemia, splenomegaly due to extramedullary hematopoiesis, leukoerythroblastosis, and constitutional symptoms, which are the clinical hallmarks of PMF. Within the past three years it has been determined that a single, recurrent, somatic mutation in the gene encoding the cytoplasmic tyrosine kinase Janus kinase 2 (JAK2) occurs in the majority of patients with PMF, and more recently, activating mutations in the gene encoding the thrombopoietin receptor MPL have also been identified in a subset of PMF patients. These discoveries have yielded important insights into the pathogenesis of PMF and have brought about the first opportunity for rationally targeted therapy for this disorder. Here we present an updated review of the pathogenesis, definition, and treatment of PMF in light of the discovery of JAK2 and MPL mutations, as well as other recent work in the myeloproliferative neoplasm field.
Autophagy and Lipid Droplets in the Liver
Authors: Nuria Martinez-Lopez, Rajat Singh
Journal: Annual Review of Nutrition (2015)

Autophagy is a conserved quality-control pathway that degrades cytoplasmic contents in lysosomes. Autophagy degrades lipid droplets through a process termed lipophagy. Starvation and an acute lipid stimulus increase autophagic sequestration of lipid droplets and their degradation in lysosomes. Accordingly, liver-specific deletion of the autophagy gene Atg7 increases hepatic fat content, mimicking the human condition termed nonalcoholic fatty liver disease. In this review, we provide insights into the molecular regulation of lipophagy, discuss fundamental questions related to the mechanisms by which autophagosomes recognize lipid droplets and how ATG proteins regulate membrane curvature for lipid droplet sequestration, and comment on the possibility of cross talk between lipophagy and cytosolic lipases in lipid mobilization. Finally, we discuss the contribution of lipophagy to the pathophysiology of human fatty liver disease. Understanding how lipophagy clears hepatocellular lipid droplets could provide new ways to prevent fatty liver disease, a major epidemic in developed nations.
Differential Effects of Metformin and Troglitazone on Cardiovascular Risk Factors in Patients With Type 2 Diabetes
Authors: Neelima V. Chu, Alice P. S. Kong, Dennis D. Kim, Debra Armstrong, Sunita Baxi, Reena Deutsch, Michael Caulfield, Sunder R. Mudaliar, Richard Reitz, Robert R. Henry, Peter D. Reaven
Journal: Diabetes Care (2002)

OBJECTIVE—Traditional cardiovascular risk factors (CVRF) only partly explain the excessive risk of cardiovascular disease in patients with type 2 diabetes. There is now an increasing appreciation for many novel CVRF that occur largely as a result of insulin resistance and hyperinsulinemia. Therefore, we investigated whether diabetes medications that vary in their mechanism of action and ability to reduce insulin resistance may differ in their effects on both traditional and novel CVRF. RESEARCH DESIGN AND METHODS—We compared the addition of metformin or troglitazone therapy on CVRF in 22 subjects with type 2 diabetes who remained in poor glycemic control (with HbA1c &amp;gt;8.5%) while taking glyburide 10 mg twice daily. Subjects were initially randomized to either metformin 850 mg once daily or troglitazone 200 mg once daily. Both medications were then titrated upward as needed to achieve fasting plasma glucose &amp;lt;120 mg/dl. Measures of glucose control, insulin resistance, and CVRF (blood pressure, lipids, plasminogen activator inhibitor-1, C-reactive protein, fibrinogen, and small dense LDL) were assessed both before and after therapy. RESULTS—After 4 months of treatment, both metformin and troglitazone led to similar decreases in fasting plasma glucose and HbA1c. The reduction in insulin resistance determined by hyperinsulinemic-euglycemic clamp was nearly twofold greater with troglitazone than metformin. Metformin did not induce significant changes in blood pressure, LDL cholesterol, LDL size, HDL cholesterol, triglycerides, or plasminogen activator inhibitor-1. However, C-reactive protein did decrease by 33% (6± 1 to 4± 1 ng/l; P &amp;lt; 0.01). Troglitazone therapy was associated with increases in LDL size (26.21± 0.22 to 26.56 ±0.25 nm; P=0.04) and HDL cholesterol (33 ±3 to 36± 3 mg/dl; P=0.05) and decreases in triglycerides (197± 19 to 155± 23 mg/dl; P=0.07) and C-reactive protein by 60% (8± 3 to 3± 1 ng/l, P &amp;lt; 0.01). CONCLUSIONS—For patients with type 2 diabetes in whom maximal sulfonylurea therapy failed, the addition of the insulin sensitizer troglitazone seemed to have greater benefits on several traditional and novel CVRF than metformin therapy. These differences were not related to glycemic improvement but reflected, in part, the greater reduction in insulin resistance obtained with addition of troglitazone. These data suggest that medications that more effectively address this underlying metabolic defect may be more beneficial in reducing cardiovascular risk in type 2 diabetes.
A Prospective Population-Based Study of Microalbuminuria as a Predictor of Mortality in NIDDM
Authors: Andrew Neil, Michael Hawkins, Michael Potok, Margaret Thorogood, David Cohen, Jim Mann
Journal: Diabetes Care (1993)

To assess prospectively the relationship between microalbuminuria and mortality in a geographically defined population of NIDDM patients and to determine the relative importance of microalbuminuria as a risk factor for mortality.A survey of known diabetes undertaken in 1982 identified a cohort of 249 NIDDM patients. Follow-up information was available for 246 patients who contributed 1498 person-yr exposure and were followed up for a mean period of 6.1 yr. The median age of the cohort at entry was 68 yr (range 28-89 yr), and the median duration of diabetes was 7 yr (range 1-41 yr). At baseline, a clinical examination was performed and a random daytime urine specimen was obtained for measurement of urinary albumin concentration.UAC results were available for 236 patients: 45 (19%) patients had a UAC > 15- < 40 mg/L; 36 (15%) had a UAC 40-200 mg/L; 10 (4%) had a UAC > 200 mg/L; and 145 (61%) had a normal UAC < or = 15 mg/L. During the follow-up period, 93 patients died. All-causes mortality, expressed as standardized mortality ratio (SMR = 149) and coronary heart disease mortality (CHD SMR = 166) were significantly increased. This excess mortality was significant in women (all-causes SMR = 194, CHD SMR = 234) but not in men (all-causes SMR = 118, CHD SMR = 128). On univariate analysis, systolic blood pressure was the only significant association with albumin concentration (P = 0.0002). An age-stratified log-rank test was conducted to determine the effect of potential explanatory variables on survival. Survival distributions were significantly different for known duration of diabetes (P = 0.045), intermittent claudication (P = 0.012), severity of retinopathy, lens opacity (P < 0.001) and UAC (P = 0.013) and diastolic blood pressure approached significance (P = 0.051). After adjusting for the effects of these potentially confounding variables identified by the log-rank analysis, significant predictors of early mortality on multivariate survival analysis were age, UAC of 40-200 mg/L (relative risk = 2.2, 95% confidence interval 1.3-3.7), more severe retinopathy (relative risk = 3.4, 95% confidence interval 1.9-6.0), and lens opacity (relative risk = 2.4, 95% confidence interval 1.6-3.8).The findings from this population-based cohort confirm the predictive power of microalbuminuria as a risk factor for mortality in NIDDM. In contrast to prospective studies of conventional cardiovascular risk factors in NIDDM, consistent evidence indicates that microalbuminuria is an independent predictor of excess mortality regardless of the collection procedure used.
Long-term performance of a hand held spirometer.
Authors: A. Dirksen, F. Madsen, O. F. Pedersen, A. M. Vedel, A. Kok-Jensen
Journal: Thorax (1996)

BACKGROUND: A study was undertaken to test the long term performance of a small hand held spirometer for self-administered serial spirometric testing. METHODS: Thirty turbine pocket spirometers (MicroMedical DiaryCard) were used in a clinical trial on 22 emphysematous patients with severe alpha 1-antitrypsin deficiency. The spirometers were able to store the date, time, forced expiratory volume in one second (FEV1), forced vital capacity (FVC), peak expiratory flow (PEF), and flow-volume loop for each blow. Every four weeks when the patients came for alpha 1-antitrypsin infusions the performance of their spirometer was checked before and after retrieval of the data from the spirometer. Calibration checks were threefold and included volume calibration with a 1.0 litre and 3.0 litre syringe, and flow calibration with a decompression calibrator. RESULTS: After two years of study the mean number of spirometric recordings performed per spirometer was 693 (range 237-1178), and the mean number of calibration checks was 33 (range 2-57). The coefficient of variation of the calibration signal was 1-2% for syringes and 0.5-1% for the decompression calibrator. The bearings of one turbine exhibited excessive friction after 17 months. None of the other 29 instruments showed drift, and a general drift of all spirometers towards larger or smaller readings could not be shown. However, unforeseen problems in the stability of the calibrating devices were observed. CONCLUSIONS: The small hand held turbine spirometers are suitable for long term patient-administered serial spirometric testing. The two year durability is acceptable and the long term reproducibility excellent.
MicroRNAs: a potential interface between the circadian clock and human health
Authors: Katelin F Hansen, Kensuke Sakamoto, Karl Obrietan
Journal: Genome Medicine (2011)

The biochemical activity of a stunning diversity of cell types and organ systems is shaped by a 24-hour (circadian) clock. This rhythmic drive to a good deal of the transcriptome (up to 15% of all coding genes) imparts circadian modulation over a wide range of physiological and behavioral processes (from cell division to cognition). Further, dysregulation of the clock has been implicated in the pathogenesis of a large and diverse array of disorders, such as hypertension, cancer and depression. Indeed, the possibility of utilizing therapeutic approaches that target clock physiology (that is, chronotherapy) has gained broad interest. However, a deeper understanding of the underlying molecular mechanisms that modulate the clock, and give rise to organ-specific clock transcriptomes, will be required to fully realize the power of chronotherapies. Recently, microRNAs have emerged as significant players in circadian clock timing, thus raising the possibility that clock-controlled microRNAs could contribute to disorders of the human circadian timing system. Here, we highlight recent work revealing a key role for microRNAs in clock physiology, and discuss potential approaches to unlocking their utility as effectors of circadian physiology and pathophysiology.
Patent Foramen Ovale: Current Pathology, Pathophysiology, and Clinical Status
Authors: Hidehiko Hara, Renu Virmani, Elena Ladich, Shannon Mackey-Bojack, Jack Titus, Mark Reisman, William Gray, Masato Nakamura, Michael Mooney, Anil Poulose, Robert S. Schwartz
Journal: Journal of the American College of Cardiology (2005)
Effect of editors' implementation of CONSORT guidelines on the reporting of abstracts in high impact medical journals: interrupted time series analysis
Authors: S. Hopewell, P. Ravaud, G. Baron, I. Boutron
Journal: BMJ (2012)

To investigate the effect of the CONSORT for Abstracts guidelines, and different editorial policies used by five leading general medical journals to implement the guidelines, on the reporting quality of abstracts of randomised trials.Interrupted time series analysis.We randomly selected up to 60 primary reports of randomised trials per journal per year from five high impact, general medical journals in 2006-09, if indexed in PubMed with an electronic abstract. We excluded reports that did not include an electronic abstract, and any secondary trial publications or economic analyses. We classified journals in three categories: those not mentioning the guidelines in their instructions to authors (JAMA and New England Journal of Medicine), those referring to the guidelines in their instructions to authors but with no specific policy to implement them (BMJ), and those referring to the guidelines in their instructions to authors with an active policy to implement them (Annals of Internal Medicine and Lancet). Two authors extracted data independently using the CONSORT for Abstracts checklist.Mean number of CONSORT items reported in selected abstracts, among nine items reported in fewer than 50% of the abstracts published across the five journals in 2006.We assessed 955 reports of abstracts of randomised trials. Journals with an active policy to enforce the guidelines showed an immediate increase in the level of mean number of items reported (increase of 1.50 items; P=0.0037). At 23 months after publication of the guidelines, the mean number of items reported per abstract for the primary outcome was 5.41 of nine items, a 53% increase compared with the expected level estimated on the basis of pre-intervention trends. The change in level or trend did not increase in journals with no policy to enforce the guidelines (BMJ, JAMA, and New England Journal of Medicine).Active implementation of the CONSORT for Abstracts guidelines by journals can lead to improvements in the reporting of abstracts of randomised trials.
Differential Proteolytic Enzyme Activity in Eosinophilic and Neutrophilic Asthma
Authors: Jodie L. Simpson, Rodney J. Scott, Michael J. Boyle, Peter G. Gibson
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

Asthma is characterized by both chronic inflammation and remodeling of the airways. Proteases are important mediators of inflammation, cytokine activation, and tissue remodeling.This study investigated matrix metalloproteinase-9 (MMP-9) and neutrophil elastase (NE) enzyme activity in the sputum of subjects with different inflammatory phenotypes of asthma (eosinophilic, neutrophilic, and paucigranulocytic asthma) and in healthy control subjects.Nonsmoking adults with asthma and healthy control subjects underwent hypertonic saline challenge and sputum induction. Selected sputum portions were dispersed with dithiothreitol and assayed for MMP-9 and NE enzyme activity.Subjects with eosinophilic asthma had significantly more active MMP-9 (39 ng/ml) compared with those with neutrophilic asthma (10 ng/ml) and control subjects (2.5 ng/ml, p < 0.01). Although there were high levels of total MMP-9 in neutrophilic asthma (5,273 ng/ml), most (> 99%) was inactivated (and bound to tissue inhibitor of metalloproteinase-1). In neutrophilic asthma, more subjects had NE activity (39%) compared with both healthy control subjects (0%), subjects with eosinophilic asthma (6%), or subjects with paucigranulocytic asthma (0%, p < 0.05). There were strong and consistent positive correlations between interleukin-8, neutrophils, and proteolytic enzymes. MMP-9 was inversely correlated with NE (r = -0.93).Proteolytic enzyme activity in asthma is dependent on the underlying inflammatory phenotype and is differentially regulated with MMP-9 activity a feature of eosinophilic inflammation, and active NE in neutrophilic inflammation.
Association of Depressive Symptoms During Abstinence With the Subjective High Produced by Cocaine
Authors: Jason Uslaner, Ari Kalechstein, Todd Richter, Walter Ling, Thomas Newton
Journal: American Journal of Psychiatry (1999)

During early abstinence, many cocaine-dependent individuals experience symptoms such as anhedonia, craving, fatigue, insomnia, and dysphoria. While several studies have shown an association between depressive symptoms and negative treatment outcome, the reasons for this association are unclear. The authors conducted this study in order to determine the association between severity of depressive symptoms during early abstinence and subjective effects of experimentally administered cocaine.Seventeen cocaine-dependent individuals achieved 5 days of abstinence in a hospital setting. Forty mg of cocaine was given intravenously on the fifth day of abstinence, and participants were asked to rate the subjective effects produced by the cocaine. The relationship between the subjective high produced by cocaine and the symptoms experienced during the 5 days of abstinence was evaluated.Individuals experiencing more intense depressive symptoms experienced a significantly greater high from the 40-mg cocaine infusion than individuals who did not.These data suggest that the severity of depressive symptoms experienced during initial abstinence is associated with the intensity of the subsequent high produced by cocaine. This finding could help explain why individuals who experience greater levels of depression-like symptoms during abstinence appear to be at greater risk for unsuccessful treatment outcome.
Aberrant maturation of mutant perforin underlies the clinical diversity of hemophagocytic lymphohistiocytosis
Authors: K. A. Risma
Journal: Journal of Clinical Investigation (2005)

Missense mutations in perforin, a critical effector of lymphocyte cytotoxicity, lead to a spectrum of diseases, from familial hemophagocytic lymphohistiocytosis to an increased risk of tumorigenesis. Understanding of the impact of mutations has been limited by an inability to express human perforin in vitro. We have shown, for the first time to our knowledge, that recombinant human perforin is expressed, processed appropriately, and functional in rat basophilic leukemia (RBL) cells following retroviral transduction. Subsequently, we have addressed how perforin missense mutations lead to absent perforin detection and impaired cytotoxicity by analyzing 21 missense mutations by flow cytometry, immunohistochemistry, and immunoblot. We identified perforin missense mutations with partial maturation (class 1), no apparent proteolytic maturation (class 2), and no recognizable forms of perforin (class 3). Class 1 mutations exhibit lytic function when expressed in RBL cells and are associated with residual protein detection and variable cytotoxic function in affected individuals, suggesting that carriers of class 1 alleles may exhibit more subtle immune defects. By contrast, class 3 mutations cause severely diminished perforin detection and cytotoxicity, while class 2 mutations have an intermediate phenotype. Thus, the pathologic mechanism of perforin missense mutation likely involves a protein dosage effect of the mature protein.
Relationship between Blood Glucose Control, Pathogenesis and Progression of Diabetic Nephropathy
Authors: Romano Nosadini, Giancarlo Tonolo
Journal: Journal of the American Society of Nephrology (2004)

ABSTRACT. The present review briefly discusses evidence that the risk of a rapid decline of glomerular function abruptly increases when glycated hemoglobin is steadily higher than 7.5% and postprandial blood glucose is >200 mg/dl. The capacity to accomplish and to maintain steadily tightly controlled blood glucose levels is scanty using the currently implemented hypoglycemic drugs. Moreover, it must be highlighted that most patients with type 2 diabetes, particularly when renal damage does occur, have arterial hypertension. Several studies suggested that the development of ESRD is prevented significantly better by drugs that modulate the renin angiotensin system than by other compounds in patients with type 1 and 2 diabetes with overt diabetic nephropathy. However, a recent trial, the study Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), which compared lisinopril, chlorthalidone, and amlodipine in a large population of patients with arterial hypertension, either associated or not with diabetes, demonstrated that the development of both coronary heart diseases and renal complications was equally prevented by the three drugs. One word of caveat, however, needs to be raised concerning one of the results of the ALLHAT study: the higher risk of developing new-onset diabetes among hypertensive patients who are not treated with lisinopril. Even if it is true that this latter side effect was not accompanied by a worse outcome of macrovascular and renal complications during the 5-yr follow-up period, one cannot rule out the possibility that this might be the case during more prolonged periods of follow-up in the future. Thus, the advantage of a lower cost in the treatment of hypertension with diuretics as compared with other drugs, with similar degree of success in the prevention of vascular complications, should be weighed also taking into consideration the burden of a higher rate of occurrence of new-onset diabetes.
The purified protein derivative of turberculin, a B-cell mitogen that distinguishes in its action resting, small B cells from activated B-cell blasts.
Authors: J Andersson, W Lernhardt, F Melchers
Journal: The Journal of Experimental Medicine (1979)

The purified protein derivative of tuberculin (PPD tuberculin) stimulates approximately one of two lipopolysaccharide (LPS)-activated B-cell blasts of C57BL/6J nu/nu spleen cells to continued clonal growth and maturation to IgM and IgG secretion. It alwo stimulates background, in vivo-activated large cells of normal C57BL/6J nu/nu spleen to growth and Ig secretion, at a frequency of approximately 1 of 100 large spleen cells. PPD tuberculin, therefore, is a polyclonal B-cell activator for B-cell blasts. Many single murine splenic B cells (approximately 50%) appear to have reactivities, and therefore probably receptors, for LPS and PPD tuberculin. PPD tuberculin does not stimulate small, resting B cells to growth as measured by the number of cells in culture and by thymidine uptake. However, it stimulates approximately one-fourth of all spleen cells to blast transformation. The large-size blast cells secrete IgM and, therefore, form plaques in the protein A plaque assay. IgG-secreting, plaque-forming cells develop at later stages of stimulation, indicating that the switch from IgM to IgG may occur without division in single, stimulated B cells. Stimulation of resting B cells to maturation by PPD tuberculin is polyclonal. Thus, approximately 1 in 10(2) IgM-secreting plaque-forming cells form plaques with trinitrophenyl-substituted sheep erythrocytes, 1 in 450 do so with horse erythrocytes, and 1 in 10(3) with sheep erythrocytes. Furthermore, the number of Ig-secreting cells developing from small, resting cells without growth in cultures with or without filler thymus cells suggests polyclonal activation by PPD tuberculin to maturation only of at least one out of four small, splenic B cells.