tbuckley/cabot-search huggingface dataset:
Gut barrier function in malnourished patients
Authors: F K S Welsh, S M Farmery, K MacLennan, M B Sheridan, G R Barclay, P J Guillou, J V Reynolds
Journal: Gut (1998)

The integrity of the gastrointestinal mucosa is a key element in preventing systemic absorption of enteric toxins and bacteria. In the critically ill, breakdown of gut barrier function may fuel sepsis. Malnourished patients have an increased risk of postoperative sepsis; however, the effects of malnutrition on intestinal barrier function in man are unknown.To quantify intestinal barrier function, endotoxin exposure, and the acute phase cytokine response in malnourished patients.Malnourished and well nourished hospitalised patients.Gastrointestinal permeability was measured in malnourished patients and well nourished controls using the lactulose:mannitol test. Endoscopic biopsy specimens were stained and morphological and immunohistochemical features graded. The polymerase chain reaction was used to determine mucosal cytokine expression. The immunoglobulin G antibody response to endotoxin and serum interleukin 6 were measured by enzyme linked immunosorbent assay.There was a significant increase in intestinal permeability in the malnourished patients in association with phenotypic and molecular evidence of activation of lamina propria mononuclear cells and enterocytes, and a heightened acute phase response.Intestinal barrier function is significantly compromised in malnourished patients, but the clinical significance is unclear.
Decreased glutathione and low catalase activity contribute to oxidative stress in children with α-1 antitrypsin deficiency: Table 1
Authors: Amparo Escribano, Mónica Amor, Sara Pastor, Silvia Castillo, Francisco Sanz, Pilar Codoñer-Franch, Francisco Dasí
Journal: Thorax (2014)

<h3>Background</h3> Recent investigations in animal models have revealed oxidative stress and oxidative damage in the pathogenesis of alpha-1 antitrypsin deficiency (AATD). However, no data are available on the oxidative stress status and antioxidant enzyme activity in these patients. This study was aimed to analyse the oxidative stress profile and enzymatic antioxidant defence mechanisms in children with AATD. <h3>Methods</h3> Oxidative stress parameters and the activity of the main antioxidant enzymes were prospectively measured in serum of fifty-one children diagnosed with AATD and thirty-eight control individuals. <h3>Results</h3> Oxidative stress was increased in the serum of children with intermediate- (MZ; SZ) and high-risk (ZZ) phenotypes for developing AATD-related emphysema and/or liver disease. When compared with the control group, intermediate- and high-risk groups showed significantly lower total glutathione and reduced glutathione levels, decreased catalase activity and increased glutathione peroxidase activity leading to an accumulation of hydrogen peroxide that would explain the significantly increased levels of oxidative stress biomarkers observed in these patients. No differences were observed between the control (MM) and the low-risk (MS; SS) groups. A gradation in oxidative stress parameters was observed when patients were compared among themselves, in that the expression of the Z allele produces a higher oxidative stress status in homozygous (ZZ) than in heterozygous (MZ; SZ) patients. <h3>Conclusions</h3> Increased oxidative stress, together with reduced antioxidant defence are involved in the pathophysiology of AATD at early stages, opening up a new rationale for the use of antioxidant therapies in the treatment of the disease.
Inverted (Endophytic) Noninvasive Lesions and Neoplasms of the Urothelium: The Cinderella Group Has Yet to Be Fully Exploited
Authors: Rodolfo Montironi, Liang Cheng, Antonio Lopez-Beltran, Marina Scarpelli, Roberta Mazzucchelli, Gregor Mikuz, Ziya Kirkali, Francesco Montorsi
Journal: European Urology (2010)
Analysis of the Overdispersed Clock in the Short-Term Evolution of Hepatitis C Virus: Using the E1/E2 Gene Sequences to Infer Infection Dates in a Single Source Outbreak
Authors: B. Wrobel
Journal: Molecular Biology and Evolution (2006)

The assumption of a molecular clock for dating events from sequence information is often frustrated by the presence of heterogeneity among evolutionary rates due, among other factors, to positively selected sites. In this work, our goal is to explore methods to estimate infection dates from sequence analysis. One such method, based on site stripping for clock detection, was proposed to unravel the clocklike molecular evolution in sequences showing high variability of evolutionary rates and in the presence of positive selection. Other alternatives imply accommodating heterogeneity in evolutionary rates at various levels, without eliminating any information from the data. Here we present the analysis of a data set of hepatitis C virus (HCV) sequences from 24 patients infected by a single individual with known dates of infection. We first used a simple criterion of relative substitution rate for site removal prior to a regression analysis. Time was regressed on maximum likelihood pairwise evolutionary distances between the sequences sampled from the source individual and infected patients. We show that it is indeed the fastest evolving sites that disturb the molecular clock and that these sites correspond to positively selected codons. The high computational efficiency of the regression analysis allowed us to compare the site-stripping scheme with random removal of sites. We demonstrate that removing the fast-evolving sites significantly increases the accuracy of estimation of infection times based on a single substitution rate. However, the time-of-infection estimations improved substantially when a more sophisticated and computationally demanding Bayesian method was used. This method was used with the same data set but keeping all the sequence positions in the analysis. Consequently, despite the distortion introduced by positive selection on evolutionary rates, it is possible to obtain quite accurate estimates of infection dates, a result of especial relevance for molecular epidemiology studies.
Maternal Modification of Responsiveness in the Ova-Transfer Substrain DBA/2eB
Authors: Delta E. Uphoff
Journal: JNCI Journal of the National Cancer Institute (1972)

Bone marrow transplantation in lethally irradiated recipients demonstrated differences in the functional capacity of the immunologically competent cells of the ancestral DBA/2 strain and its ova-transfer substrain DBA/2eB. Marrow from both DBA/2 and DBA/2eB donors produced equally good survival in lethally irradiated DBA/2 recipients. Marrow from DBA/2eB donors caused a more severe (P<0.02) graft-versus-host reaction in lethally irradiated (DBA/2 × C57BL/Ka)F1 recipients than did DBA/2 marrow. Although DBA/2eB marrow produced a less severe reaction than C57BL/De marrow, this difference lacked statistical significance (P>0.10). The genetic disparity between strains of the H-2b and H-2d genotypes favors the greater responsiveness of the C57BL/De. The graft-versus-host reactions produced in (C57BL/Ka × DBA/2)F1 recipients by C57BL/De and DBA/-2eB marrow were similar and only slightly more severe than the reaction of DBA/2 marrow. C57BL/De marrow inoculation resulted in significantly (P<0.01) more severe reaction in (DBA/2 × C57BL/Ka)F1than in (C57BL/-Ka × DBA/2)F1, whereas DBA/2 marrow produced a similar (P>0.70) response in both hybrids, and DBA/2eB marrow caused an intermediate response that lacked significance (P<0.50). The difference between substrain DBA/2 and DBA/2eB appears to be a shift in the innate ability to respond to alloantigens, which was apparently transferred from the C57BL/De foster mother and vertically transmitted to all progeny of the ova-transfer substrain.
Current issues concerning thrombolytic therapy for acute myocardial infarction
Authors: Charles H. Hennekens, Christopher J. O'Donnell, Paul M. Ridker, Victor J. Marder
Journal: Journal of the American College of Cardiology (1995)

Data are now available from three large-scale randomized trials that directly compare the risks and benefits of thrombolytic agents in acute myocardial infarction. In the interpretation of results from the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI-2) trial and its International Extension, the Third International Study of Infarct Survival (ISIS-3), and the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-1) trial, there are areas of both agreement and controversy. It is generally agreed that the agents most commonly used in the United States—tissue-type plasminogen activator (t-PA), streptokinase and anisoylated plasminogen streptokinase activator complex (APSAC)—all reduce mortality when given to patients with acute evolving myocardial infarction. Further, it is clear that thrombolytic therapy given to such patients presenting up to 12 h after onset of symptoms reduces the mortality rate by ∼20%, that aspirin therapy for patients presenting up to 24 h reduces the mortality rate by ∼23% and that the benefits of thrombolytic therapy and aspirin are additive. Finally, and of most importance, the earlier administration as well as the more widespread use of thrombolytic therapy and aspirin would save many more lives. The totality of evidence clearly indicates that streptokinase produces significantly fewer strokes and cerebral hemorrhages than either t-PA or APSAC. Whether or not accelerated t-PA has a small advantage for mortality is less conclusive. At present, any small differences in safety, efficacy and ease of administration of different thrombolytic agents are far outweighed by the large benefits that would accrue from earlier administration and wider utilization of any of these drugs.
Effects of Acute Insulin-Induced Hypoglycemia on Indices of Inflammation
Authors: Rohana J. Wright, David E. Newby, David Stirling, Christopher A. Ludlam, Ian A. Macdonald, Brian M. Frier
Journal: Diabetes Care (2010)

To examine the effects of acute insulin-induced hypoglycemia on inflammation, endothelial dysfunction, and platelet activation in adults with and without type 1 diabetes.We studied 16 nondiabetic adults and 16 subjects with type 1 diabetes during euglycemia (blood glucose 4.5 mmol/l) and hypoglycemia (blood glucose 2.5 mmol/l). Markers of inflammation, thrombosis, and endothelial dysfunction (soluble P-selectin, interleukin-6, von Willebrand factor [vWF], tissue plasminogen activator [tPA], high-sensitivity C-reactive protein [hsCRP], and soluble CD40 ligand [sCD40L]) were measured; platelet-monocyte aggregation and CD40 expression on monocytes were determined using flow cytometry.In nondiabetic participants, platelet activation occurred after hypoglycemia, with increments in platelet-monocyte aggregation and P-selectin (P <or= 0.02). Inflammation was triggered with CD40 expression increasing maximally at 24 h (3.13 +/- 2.3% vs. 2.06 +/- 1.0%) after hypoglycemia (P = 0.009). Both sCD40L and hsCRP (P = 0.02) increased with a nonsignificant rise in vWF and tPA, indicating a possible endothelial effect. A reduction in sCD40L, tPA, and P-selectin occurred during euglycemia (P = 0.03, P <or= 0.006, and P = 0.006, respectively). In type 1 diabetes, both CD40 expression (5.54 +/- 4.4% vs. 3.65 +/- 1.8%; P = 0.006) and plasma sCD40L concentrations increased during hypoglycemia (peak 3.41 +/- 3.2 vs. 2.85 +/- 2.8 ng/ml; P = 0.03). Platelet-monocyte aggregation also increased significantly at 24 h after hypoglycemia (P = 0.03). A decline in vWF and P-selectin occurred during euglycemia (P <or= 0.04).Acute hypoglycemia may provoke upregulation and release of vasoactive substances in adults with and without type 1 diabetes. This may be a putative mechanism for hypoglycemia-induced vascular injury.
Circulating suPAR in Two Cohorts of Primary FSGS
Authors: Changli Wei, Howard Trachtman, Jing Li, Chuanhui Dong, Aaron L. Friedman, Jennifer J. Gassman, June L. McMahan, Milena Radeva, Karsten M. Heil, Agnes Trautmann, Ali Anarat, Sevinc Emre, Gian M. Ghiggeri, Fatih Ozaltin, Dieter Haffner, Debbie S. Gipson, Frederick Kaskel, Dagmar-Christiane Fischer, Franz Schaefer, Jochen Reiser
Journal: Journal of the American Society of Nephrology (2012)

Overexpression of soluble urokinase receptor (suPAR) causes pathology in animal models similar to primary FSGS, and one recent study demonstrated elevated levels of serum suPAR in patients with the disease. Here, we analyzed circulating suPAR levels in two cohorts of children and adults with biopsy-proven primary FSGS: 70 patients from the North America–based FSGS clinical trial (CT) and 94 patients from PodoNet, the Europe-based consortium studying steroid-resistant nephrotic syndrome. Circulating suPAR levels were elevated in 84.3% and 55.3% of patients with FSGS patients in the CT and PodoNet cohorts, respectively, compared with 6% of controls (P<0.0001); inflammation did not account for this difference. Multiple regression analysis suggested that lower suPAR levels associated with higher estimated GFR, male sex, and treatment with mycophenolate mofetil. In the CT cohort, there was a positive association between the relative reduction of suPAR after 26 weeks of treatment and reduction of proteinuria, with higher odds for complete remission (P=0.04). In the PodoNet cohort, patients with an NPHS2 mutation had higher suPAR levels than those without a mutation. In conclusion, suPAR levels are elevated in geographically and ethnically diverse patients with FSGS and do not reflect a nonspecific proinflammatory milieu. The associations between a change in circulating suPAR with different therapeutic regimens and with remission support the role of suPAR in the pathogenesis of FSGS.
PME-1 Protects Extracellular Signal-Regulated Kinase Pathway Activity from Protein Phosphatase 2A–Mediated Inactivation in Human Malignant Glioma
Authors: Pietri Puustinen, Melissa R. Junttila, Sari Vanhatupa, Anna A. Sablina, Melissa E. Hector, Kaisa Teittinen, Olayinka Raheem, Kirsi Ketola, Shujun Lin, Juergen Kast, Hannu Haapasalo, William C. Hahn, Jukka Westermarck
Journal: Cancer Research (2009)

Extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase pathway activity is regulated by the antagonist function of activating kinases and inactivating protein phosphatases. Sustained ERK pathway activity is commonly observed in human malignancies; however, the mechanisms by which the pathway is protected from phosphatase-mediated inactivation in the tumor tissue remain obscure. Here, we show that methylesterase PME-1-mediated inhibition of the protein phosphatase 2A promotes basal ERK pathway activity and is required for efficient growth factor response. Mechanistically, PME-1 is shown to support ERK pathway signaling upstream of Raf, but downstream of growth factor receptors and protein kinase C. In malignant gliomas, PME-1 expression levels correlate with both ERK activity and cell proliferation in vivo. Moreover, PME-1 expression significantly correlates with disease progression in human astrocytic gliomas (n=222). Together, these observations identify PME-1 expression as one mechanism by which ERK pathway activity is maintained in cancer cells and suggest an important functional role for PME-1 in the disease progression of human astrocytic gliomas.
Chronic Synovitis in Gout Simulating Rheumatoid Arthritis
Authors: E. D. Trentham, Alfonse T. Masi
Journal: JAMA (1976)

A PATIENT had gouty arthritis closely simulating rheumatoid arthritis clinically and on plain-film examination. Serial arthrographic study showed persistent, generalized, synovial corrugation of the wrists and large popliteal cysts of both knees. These arthrographic features, typically associated with rheumatoid arthritis,<sup>1-3</sup>provide evidence for a rheumatoid-like chronic uratic synovitis in gout. Chronic synovial inflammation, rather than tophus deposition in avascular paraarticular structures,<sup>4</sup>may account for instances of roentgenographic mimicry of rheumatoid arthritis by gout,<sup>5</sup>and this mechanism should be considered in determining the pathogenesis of joint lesions typically associated with gout. Finally, this case illustrates the occasional difficulty, especially in older patients, in distinguishing clinically as well as roentgenographically these two synovial inflammatory diseases that are believed to be mutually exclusive, almost without exception.<sup>4</sup> <h3>Report of a Case</h3> A 66-year-old retired soldier reported a chronic, symmetrical, progressive polyarthritis of his knees, wrists, elbows, and proximal interphalangeal joints
CD36 gene transfer confers capacity for phagocytosis of cells undergoing apoptosis.
Authors: Y Ren, R L Silverstein, J Allen, J Savill
Journal: The Journal of Experimental Medicine (1995)

Phagocyte recognition and ingestion of intact cells undergoing apoptosis are key events in this generally important program of cell death. Insufficient phagocyte capacity for apoptotic cells can result in failure to clear dying cells before membrane integrity is lost, resulting in leakage of noxious cell contents and severe tissue damage. However, no means has been available to increase phagocytic clearance of apoptotic cells. We now report that transfection of the macrophage adhesion molecule CD36 into human Bowes melanoma cells specifically conferred greatly increased capacity to ingest apoptotic neutrophils, lymphocytes, and fibroblasts, comparable to that exhibited by macrophages. Furthermore, when CD36 was transfected into another cell type with limited capacity to take up apoptotic bodies, the monkey COS-7 cell, similar effects were observed. Therefore, CD36 gene transfer can confer "professional" capacity to ingest apoptotic cells upon "amateur" phagocytes.
Genetic Testing for Children and Adolescents
Authors: Leo Uzych
Journal: JAMA (1995)

To the Editor.  —The article by Dr Wertz and colleagues 1 on genetic testing observes correctly that genetic testing of minors presents issues of privacy and disclosure. It is noted, in a similar vein, that minors who request testing should be informed prior to testing that third-party entities, including employers, insurers, and schools, may be able to coerce their consent for access to test results by withholding employment, insurance, or school admission.  It is probably true that various third parties may be quite interested in access to genetic testing results, whether they involve children, adolescents, or adults. Insurers, for example, may be interested in knowing the results of genetic tests that have been done by others, for cause, on persons applying for insurance. 2 If access to such data are obtained, however, the affected individual may be severely disadvantaged. There have been instances of persons with phenylketonuria being denied health
Does the Association of Habitual Physical Activity With the Metabolic Syndrome Differ by Level of Cardiorespiratory Fitness?
Authors: Paul W. Franks, Ulf Ekelund, Søren Brage, Man-Yu Wong, Nicholas J. Wareham
Journal: Diabetes Care (2004)

Cardiovascular fitness (VO(2max)) and physical activity are both related to risk of metabolic disease. It is unclear, however, whether the metabolic effects of sedentary living are the same in fit and unfit individuals. The purpose of this study was, therefore, to describe the association between physical activity and the metabolic syndrome and to test whether fitness level modifies this relationship.Physical activity was measured objectively using individually calibrated heart rate against energy expenditure. VO(2max) was predicted from a submaximal exercise stress test. Fat mass and fat-free mass (FFM) were calculated using impedance biometry. A metabolic syndrome score was computed by summing the standardized values for obesity, hypertension, hyperglycemia, insulin resistance, hypertriglyceridemia, and the inverse level of HDL cholesterol and was expressed as a continuously distributed outcome. To correct for exposure measurement error, a random subsample (22% of cohort) re-attended for three repeat measurements in the year following the first assessment.The relationship of VO(2max) (ml O2.kg(FFM)(-1).min(-1)) and the metabolic syndrome score was of borderline significance after adjusting for age, sex, physical activity, and measurement error (beta = -0.58, P = 0.06). The magnitude of the association between physical activity (kJ.d(-1).kg(FFM)(-1)) and the metabolic syndrome was more than three times greater than for VO(2max) (standardized beta = -1.83, P = 0.0042). VO(2max), however, modified the relationship between physical activity energy expenditure and metabolic syndrome (P = 0.036).This study demonstrates a strong inverse association between physical activity and metabolic syndrome, an association that is much steeper in unfit individuals. Thus, prevention of metabolic disease may be most effective in the subset of unfit inactive people.
Nuclear Factor-κB Nuclear Localization Is Predictive of Biochemical Recurrence in Patients with Positive Margin Prostate Cancer
Authors: Vincent Fradet, Laurent Lessard, Louis R. Bégin, Pierre Karakiewicz, Anne-Marie Mes Masson, Fred Saad
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Radical prostatectomy (RP) patients with positive surgical margins are at increased risk for recurrence, emphasizing the need for prognostic markers to stratify probable outcome for optimal patient management decisions. We tested the hypothesis that nuclear localization of nuclear factor (NF)-κB, a transcription factor involved in the regulation of cell growth, angiogenesis, invasion, and apoptosis, is associated with an increased risk of biochemical recurrence after RP. Experimental Design: Analyses addressed data from 42 patients (age range, 52–72 years; mean age, 63.7 years) who exhibited positive surgical margins after RP. Immunohistochemical analysis of NF-κB (p65) was performed on the positive margin tissue. A nuclear staining cutoff of &amp;gt;5% was considered positive. The relation between nuclear NF-κB expression and biochemical recurrence (prostate-specific antigen &amp;gt;0.3 ng/mL and rising) after RP was tested in univariate and multivariate Cox regression models. Results: Biochemical recurrence was recorded in 23 patients (54.8%; median follow-up, 3.2 years). Univariate Cox regression demonstrated a 4.9-fold (95% confidence interval, 1.5–16.7; P = 0.01) higher rate of recurrence in men with NF-κB &amp;gt; 5%. In the multivariate model, after controlling for primary (P = 0.004) and secondary (P = 0.7) Gleason patterns, lymph node (P = 0.06) and seminal vesicle invasion (P = 0.2), and preoperative prostate-specific antigen (P = 0.009), NF-κB &amp;gt; 5% was associated with a 6.2-fold higher risk of biochemical recurrence (95% confidence interval, 1.7–23.5; P = 0.007). Conclusions: In univariate and multivariate analysis, NF-κB nuclear expression was strongly predictive of biochemical recurrence in patients with positive surgical margins after RP. We propose that nuclear NF-κB may serve as a useful independent molecular marker for stratifying patients at risk for recurrence.