tbuckley/cabot-search huggingface dataset:
Towards real-time 'biochemical endoscopy' for diagnosis of early barrett's neoplasia
Authors: M. Almond, J. Hutchings, C. Kendall, N. Stone, J. Day, N. Shepherd, H. Barr
Journal: Gut (2011)

<h3>Introduction</h3> Raman spectroscopy is a powerful analytical technique that can rapidly and accurately identify biochemical changes in cells that have become neoplastic. We aim to transfer this laboratory based technique to the bedside in order to identify high-grade dysplasia and early malignant change within Barrett9s oesophagus. Here we demonstrate the feasibility of a novel fibre-optic Raman probe to map the pathology encountered in a resected human distal oesophagus. <h3>Methods</h3> A novel Raman probe12 designed to fit through the 2.8 mm instrument channel of a standard endoscope was used to map a distal oesophagus ex vivo. Following Ivor-Lewis oesophagectomy (with curative intent in patients with oesophageal adenocarcinoma), a reproducible mapping grid was placed over the distal oesophagus and Raman spectra were measured at specified grid positions using 1 and 5 s acquisition times (Figure 1). A monochromatic 830 nm laser was used for excitation and a Renishaw system 100 spectrometer for the measurement of Raman spectra. <h3>Results</h3> Laboratory based Raman systems can delineate eight pathological groups in the distal oesophagus with sensitivities between 73% and 100%.3 To date we have measured 76 spectra from 3 oesophageal specimens using the novel endoscopic probe and data collection and analysis is currently on-going (Figure 2). Histopathological diagnosis has been confirmed by expert pathologists following point biopsy at each grid position in order to correlate the Raman signal with the gold standard. Multivariate analysis will be used to extract subtle spectral features to evaluate the accuracy of the probe for delineating between pathological groups. <h3>Conclusion</h3> Further data collection (currently on-going) is needed to generate a robust classification algorithm in order to delineate between Barrett9s metaplasia, low/high-grade dysplasia and cancer in the distal oesophagus. Preliminary spectra obtained using a novel endoscopic probe are consistent with laboratory data and suggest profound potential for in vivo endoscopic diagnosis using Raman spectroscopy.
Changes in Body Weight Predict CKD in Healthy Men
Authors: Seungho Ryu, Yoosoo Chang, Hee-Yeon Woo, Soo-Geun Kim, Dong-Il Kim, Won Sool Kim, Byung-Seong Suh, Nam-Kyong Choi, Jong-Tae Lee
Journal: Journal of the American Society of Nephrology (2008)

Several recent prospective studies have reported that obesity is associated with an increased risk for chronic kidney disease (CKD), but it is unknown whether weight gain increases the risk for CKD if one remains within the "normal" category of body mass index (BMI). We prospectively followed a cohort of 8792 healthy men who had no known risk factors for CKD and participated in a comprehensive health evaluation program at a large worksite. During 35,927 person-years of follow-up, 427 new incident cases of CKD (estimated GFR <64 ml/min per 1.73 m(2)) developed. Cox proportional hazards modeling revealed that in both the normal-weight and overweight groups, a U-shaped association between weight change categories and development of CKD was observed after adjustment for age, baseline GFR, baseline BMI, HDL, fasting blood glucose, uric acid, and exercise habits. The lowest risk for CKD was observed among those whose weight changed -0.25 to <0.25 kg/yr (P < 0.001 for quadratic term). Weight change as a time-dependent variable was significantly related to CKD incidence. These relationships remained significant even after further adjustment for Homeostasis Model Assessment of Insulin Resistance, high-sensitivity C-reactive protein, systolic BP, diastolic BP, metabolic syndrome, incident hypertension, or incident diabetes. In summary, increases in body weight are independently associated with an increased risk for CKD, even when the BMI remains within the normal range.
Canadian Medicare needs choice
Authors: K. Meloff
Journal: BMJ (2002)

EDITOR—Lewis et al accurately describe the intent of Medicare in Canada, but this does not represent the reality of day to day practice.1 Nor do they discuss the economic reality. In practice, the system is not portable. For example, Quebec does not pay physicians in Ontario their proper fees, and, as a result, many patients from Quebec have to pay the doctors they visit in Ontario with cash and then …
Quizartinib (AC220) is a potent second generation class III tyrosine kinase inhibitor that displays a distinct inhibition profile against mutant-FLT3, -PDGFRA and -KIT isoforms
Authors: Kerstin Maria Kampa-Schittenhelm, Michael Charles Heinrich, Figen Akmut, Hartmut Döhner, Konstanze Döhner, Marcus Matthias Schittenhelm
Journal: Molecular Cancer (2013)

Activating mutations of class III receptor tyrosine kinases (RTK) FLT3, PDGFR and KIT are associated with multiple human neoplasms including hematologic malignancies, for example: systemic mast cell disorders (KIT), non-CML myeloproliferative neoplasms (PDGFR) and subsets of acute leukemias (FLT3 and KIT). First generation tyrosine kinase inhibitors (TKI) are rapidly being integrated into routine cancer care. However, the expanding spectrum of TK-mutations, bioavailability issues and the emerging problem of primary or secondary TKI-therapy resistance have lead to the search for novel second generation TKIs to improve target potency and to overcome resistant clones.Quizartinib was recently demonstrated to be a selective FLT3 inhibitor with excellent pharmacokinetics and promising in vivo activity in a phase II study for FLT3 ITD + AML patients. In vitro kinase assays have suggested that in addition to FLT3, quizartinib also targets related class III RTK isoforms.Various FLT3 or KIT leukemia cell lines and native blasts were used to determine the antiproliferative and proapoptotic efficacy of quizartinib. To better compare differences between the mutant kinase isoforms, we generated an isogenic BaF3 cell line expressing different FLT3, KIT or BCR/ABL isoforms. Using immunoblotting, we examined the effects of quizartinib on activation of mutant KIT or FLT3 isoforms.Kinase inhibition of (mutant) KIT, PDGFR and FLT3 isoforms by quizartinib leads to potent inhibition of cellular proliferation and induction of apoptosis in in vitro leukemia models as well as in native leukemia blasts treated ex vivo. However, the sensitivity patterns vary widely depending on the underlying (mutant)-kinase isoform, with some isoforms being relatively insensitive to this agent (e.g. FLT3 D835V and KIT codon D816 mutations). Evaluation of sensitivities in an isogenic cellular background confirms a direct association with the underlying mutant-TK isoform--which is further validated by immunoblotting experiments demonstrating kinase inhibition consistent with the cellular sensitivity/resistance to quizartinib.Quizartinib is a potent second-generation class III receptor TK-inhibitor--but specific, mutation restricted spectrum of activity may require mutation screening prior to therapy.
Activation of EDTA-Resistant Gelatinases in Malignant Human Tumors
Authors: Donghai Chen, Alanna Kennedy, Jaw-Yuan Wang, Wei Zeng, Qiang Zhao, Michael Pearl, Mengzhen Zhang, Zhenhe Suo, Jahn M. Nesland, Yuhuan Qiao, Ah-Kau Ng, Naoko Hirashima, Tetsu Yamane, Yoshiyuki Mori, Masako Mitsumata, Giulio Ghersi, Wen-Tien Chen
Journal: Cancer Research (2006)

Abstract Among the many proteases associated with human cancer, seprase or fibroblast activation protein α, a type II transmembrane glycoprotein, has two types of EDTA-resistant protease activities: dipeptidyl peptidase and a 170-kDa gelatinase activity. To test if activation of gelatinases associated with seprase could be involved in malignant tumors, we used a mammalian expression system to generate a soluble recombinant seprase (r-seprase). In the presence of putative EDTA-sensitive activators, r-seprase was converted into 70- to 50-kDa shortened forms of seprase (s-seprase), which exhibited a 7-fold increase in gelatinase activity, whereas levels of dipeptidyl peptidase activity remained unchanged. In malignant human tumors, seprase is expressed predominantly in tumor cells as shown by in situ hybridization and immunohistochemistry. Proteins purified from experimental xenografts and malignant tumors using antibody- or lectin-affinity columns in the presence of 5 mmol/L EDTA were assayed for seprase activation in vivo. Seprase expression and activation occur most prevalently in ovarian carcinoma but were also detected in four other malignant tumor types, including adenocarcinoma of the colon and stomach, invasive ductal carcinoma of the breast, and malignant melanoma. Together, these data show that, in malignant tumors, seprase is proteolytically activated to confer its substrate specificity in collagen proteolysis and tumor invasion. (Cancer Res 2006; 66(20): 9977-85)
782 N-GLYCOSYLATION PATTERNS OF SERUM PROTEINS TO MAKE THE DISTINCTION BETWEEN STEATOSIS OF THE LIVER AND NON-ALCOHOLIC STEATOHEPATITIS IN OBESE PATIENTS SCHEDULED FOR BARIATRIC SURGERY
Authors: B. Blomme, L. Libbrecht, P. Pattyn, Y. Van Nieuwenhove, D. Van De Putte, A. Geerts, I. Colle, N. Callewaert, H. Van Vlierberghe
Journal: Journal of Hepatology (2010)
Serum Dioxin Concentrations and Bone Density and Structure in the Seveso Women’s Health Study
Authors: Brenda Eskenazi, Marcella Warner, Marcella Sirtori, Thomas Fuerst, Stephen A. Rauch, Paolo Brambilla, Paolo Mocarelli, Alessandro Rubinacci
Journal: Environmental Health Perspectives (2013)

Background: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a widespread environmental contaminant, is a known endocrine disruptor. In animal studies, TCDD exposure impairs bone metabolism and increases fragility. To our knowledge, no epidemiologic studies have examined this association.Objectives: On 10 July 1976, a chemical explosion in Seveso, Italy, resulted in the highest known residential exposure to TCDD. In 1996, we initiated the Seveso Women's Health Study, a retrospective cohort study of the health of the women. In 2008, we followed up the cohort. Here, we evaluated the association between TCDD exposure and bone structure and geometry in adulthood, and considered whether timing of TCDD exposure before achievement of peak bone mass (assumed to occur 2 years after onset of menarche) modified the association.Methods: Individual TCDD concentration was measured in archived serum collected soon after the explosion. In 2008, 350 women who were < 20 years old in 1976 underwent a dual-energy X-ray absorptiometry (DXA) bone scan. Bone mineral density was measured at the lumbar spine and hip, and hip geometry was extracted from hip DXA scans using the hip structural analysis method.Results: Among premenopausal women, TCDD serum levels were associated with some indexes indicating better bone structure in women exposed before peak bone mass (n = 219), with stronger associations in those exposed before 5 years of age (n = 46). In contrast, among postmenopausal women, TCDD levels were associated with evidence of better bone structure in women exposed after peak bone mass (n = 48) than in other women (n = 18).Conclusions: Our current results do not support the hypothesis that postnatal TCDD exposure adversely affects adult bone health. Continued follow-up of women who were youngest at exposure is warranted. Future studies should also focus on those exposed in utero.Citation: Eskenazi B, Warner M, Sirtori M, Fuerst T, Rauch SA, Brambilla P, Mocarelli P, Rubinacci A. 2014. Serum dioxin concentrations and bone density and structure in the Seveso Women's Health Study. Environ Health Perspect 122:51–57; http://dx.doi.org/10.1289/ehp.1306788
The 5A/6A Polymorphism of the Matrix Metalloproteinase 3 Gene Promoter and Breast Cancer
Authors: Peter Krippl, Uwe Langsenlehner, Wilfried Renner, Babak Yazdani-Biuki, Herwig Köppel, Andreas Leithner, Thomas C. Wascher, Bernhard Paulweber, Hellmut Samonigg
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The matrix metalloproteinase 3 (MMP3), also known as stromelysin-I, is a key-player for carcinogenesis and tumor growth. A 5A/6A promoter polymorphism is associated with differences in MMP3 activity and has been linked to cancer susceptibility in some studies. In the present study we evaluated the role of this polymorphism for breast cancer risk. Experimental Design: A case–control study was performed including 500 patients with histologically confirmed breast cancer and 500 female, age-matched, healthy control subjects from population-based screening studies. The MMP3 5A/6A polymorphism was determined by a 5′-nuclease (TaqMan) assay. Results: Prevalences of 5A/5A, 5A/6A, and 6A/6A genotypes were similar among patients (20.6, 51.8, and 27.6%, respectively) and controls (23.3, 47.3, and 29.4%, P = 0.34). The odds ratio of carriers of a MMP3 5A allele for breast cancer was 1.09 (95% confidence interval, 0.83–1.44). Patients with the 5A/5A genotype had a higher proportion of lymph-node metastases than those with a 5A/6A or 6A/6A genotype (P = 0.010). Conclusions: The MMP3 5A/6A promoter polymorphism does not appear to influence breast cancer susceptibility but may be linked to a higher risk for metastasizing among breast cancer patients.
Association of High Pulse Pressure With Proteinuria in Subjects With Diabetes, Prediabetes, or Normal Glucose Tolerance in a Large Japanese General Population Sample
Authors: Yuichiro Yano, Yuji Sato, Shouichi Fujimoto, Tsuneo Konta, Kunitoshi Iseki, Toshiki Moriyama, Kunihiro Yamagata, Kazuhiko Tsuruya, Hideaki Yoshida, Koichi Asahi, Issei Kurahashi, Yasuo Ohashi, Tsuyoshi Watanabe
Journal: Diabetes Care (2012)

To examine whether there is a difference in the association between high pulse pressure and proteinuria, independent of other blood pressure (BP) indices, such as systolic or diastolic BP, among subjects with diabetes, prediabetes, or normal glucose tolerance.Using a nationwide health checkup database of 228,778 Japanese aged ≥ 20 years (mean 63.2 years; 39.3% men; none had pre-existing cardiovascular disease), we examined the association between high pulse pressure, defined as the highest quintile of pulse pressure (≥ 63 mmHg, n = 40,511), and proteinuria (≥ 1+ on dipstick, n = 12,090) separately in subjects with diabetes (n = 27,913), prediabetes (n = 100,214), and normal glucose tolerance (n = 100,651).The prevalence of proteinuria was different among subjects with diabetes, prediabetes, and normal glucose tolerance (11.3 vs. 5.0 vs. 3.9%, respectively; P < 0.001). In subjects with diabetes, but not those with prediabetes or normal glucose tolerance, high pulse pressure was associated with proteinuria independently of significant covariates, including systolic BP (odds ratio 1.15 [95% CI 1.04-1.28]) or diastolic or mean BP (all P < 0.01). In patients with diabetes, a +1 SD increase of pulse pressure (+13 mmHg) was associated with proteinuria, even after adjustment for systolic BP (1.07 [1.00-1.13]) or diastolic or mean BP (all P < 0.05).Among the Japanese general population, there was a significant difference in the association between high pulse pressure and proteinuria among subjects with diabetes, prediabetes, and normal glucose tolerance. Only in diabetes was high pulse pressure associated with proteinuria independent of systolic, diastolic, or mean BP levels.
Cognitive Reserve Is a Determinant of Health-related Quality of Life in Patients With Cirrhosis, Independent of Covert Hepatic Encephalopathy and Model for End-Stage Liver Disease Score
Authors: Ankit V Patel, James B Wade, Leroy R Thacker, Richard K Sterling, Muhammad S Siddiqui, R Todd Stravitz, Arun J Sanyal, Velimir Luketic, Puneet Puri, Michael Fuchs, Scott Matherly, Melanie B White, Ariel Unser, Douglas M Heuman, Jasmohan S Bajaj
Journal: Clinical Gastroenterology and Hepatology (2014)
Relationship between different swimming styles and somatotype in national level swimmers
Authors: None Sonia, Shishir Nigam
Journal: British Journal of Sports Medicine (2010)

This study had been done to categorise the swimmers in India according to there somatotype in different swimming styles at an early age. This study aims to find out the somatotype of swimmers in different swimming styles and analyse the relationship between somatometric variables and swimming performance in competitive national swimmers under 19 years of age. Total of 96 swimmers (50 males and 46 females) aged younger than 19 years were picked up on their age-group championships and classification of the swimmers was done according to their primary swimming specialty, as self-reported. Method of selecting the subject was randomised. Ten anthropometric dimensions were needed to calculate the anthropometric somatotype:: height, weight, chest circumference, arm span, arm length, skinfolds (biceps, triceps, subscapular, supraspinale and calf), two biepicondylar bone breadth (humerus, femur) and two limb girths (arm flexed and tensed calf). By means of equations, anthropometric somatotype was obtained into which data were entered. Results showed that (1) sprint freestyle and backstroke swimmers were taller and heavier, compared with others, for both sexes. (2) Butterfly group swimmer had a distinct physical structure with lowest values for height and weight. (3) Significant correlations were obtained between swimming performance and somatometric variables such as height, weight, chest circumference, arm span, arm length, endomorphy, mesomorphy, ectomorphy and fat percentage. This study also concluded that swimmers in different swimming styles or events have variations in their body size and form at an early age. Early determination of somatotype of swimmers or athletes participating in different sports helps to improve their performance and development of body according to their requirement in particular sports or event.
Local Joint Inflammation and Histone Citrullination in a Murine Model of the Transition From Preclinical Autoimmunity to Inflammatory Arthritis
Authors: Dong Hyun Sohn, Christopher Rhodes, Kazuhiro Onuma, Xiaoyan Zhao, Orr Sharpe, Tal Gazitt, Rani Shiao, Justyna Fert‐Bober, Danye Cheng, Lauren J. Lahey, Heidi H. Wong, Jennifer Van Eyk, William H. Robinson, Jeremy Sokolove
Journal: Arthritis & Rheumatology (2015)

Objective Anti–citrullinated protein antibodies (ACPAs) are characteristic of rheumatoid arthritis (RA). However, their presence years before the onset of clinical RA is perplexing. Although multiple putative citrullinated antigens have been identified, no studies have demonstrated the specific capacity of these antigens to initiate inflammatory arthritis. This study was undertaken to recapitulate the transition from preclinical to clinical RA and to demonstrate the capacity of local citrullination to facilitate this transition. Methods We performed proteomic analysis of activated human neutrophils to identify citrullinated proteins, including those targeted as part of the RA immune response. Using enzyme‐linked immunosorbent assay, we compared RA and osteoarthritis synovial fluid for levels of citrullinated histone H2B and its immune complex. Using macrophage activation assays, we assessed the effect of histone citrullination on immunostimulatory capacity and evaluated the stimulatory capacity of native and citrullinated H2B immune complexes. Finally, we assessed the potential for anti–citrullinated H2B antibodies to mediate arthritis in vivo. Results We identified robust targeting of neutrophil‐derived citrullinated histones by the ACPA immune response. More than 90% of the RA patients had anti–citrullinated H2B antibodies. Histone citrullination increased innate immunostimulatory capacity, and immune complexes containing citrullinated histones activated macrophage cytokine production and propagated neutrophil activation. Finally, we demonstrated that immunization with H2B was arthritogenic, but only in the setting of underlying articular inflammation. Conclusion Our findings indicate that citrullinated histones, specifically citrullinated H2B, are an antigenic target of the ACPA immune response. Furthermore, local generation of citrullinated antigen during low‐grade articular inflammation provides a mechanistic model for the conversion from preclinical autoimmunity to inflammatory arthritis.
The role of altered intercellular coupling in arrhythmias induced by acute myocardial ischemia
Authors: D Lerner
Journal: Cardiovascular Research (2001)

Time for primary review 28 days. 

Sudden cardiac death occurs with unacceptably high incidence in patients with ischemic heart disease and cardiomyopathy. As Zipes and Wellens [1] have emphasized, sudden death arises from highly variable interactions between anatomic and/or functional myocardial substrates, transient initiating events and cellular/tissue arrhythmia mechanisms. In our view, a key strategy for developing mechanistic insights into sudden death is to first define the role of individual factors (including specific gene products) that contribute to arrhythmias, and to then understand how these factors interact to cause sudden death.

One of the most common disease settings leading to sudden cardiac death is the acute coronary syndromes. Acute ischemia is marked by alterations in cell metabolism, cell signaling, intercellular communication and electrical impulse propagation [2]. These changes produce a cascade of events that are adaptive in the sense that mechanisms are activated to mitigate injury, forestall cell death and isolate irreversibly injured myocytes from their viable neighbors, but also maladaptive in that they can create a substrate that supports the initiation and maintenance of malignant ventricular arrhythmias. Among the electrophysiologically relevant changes that occur rapidly after the onset of ischemia are reductions in tissue pH, increases in interstitial K+ and intracellular Ca2+ concentrations and changes in active and passive membrane properties, all of which interact in a complex milieu to slow conduction, alter excitability and refractoriness, promote electrical uncoupling, and generate spontaneous electrical activity [1–4].

In this review, we focus on the specific role of diminished intercellular electrical coupling in the pathogenesis of lethal arrhythmias induced by acute ischemia. Until recently, it has been difficult to isolate the contribution of diminished coupling per se to arrhythmogenesis in the complex setting of acute ischemia. However, the advent of techniques to manipulate gene expression and characterize cardiac …
Reflux patterns and related oesophageal motor activity in gastro-oesophageal reflux disease.
Authors: S Kruse-Andersen, L Wallin, T Madsen
Journal: Gut (1990)

Simultaneous intraoesophageal pH and pressure monitoring were performed for 12 hours in 20 patients with abnormal acid gastrooesophageal reflux or oesophagitis and in 10 healthy volunteers to determine characteristic reflux patterns with time. Increased acid exposure was not the only factor that characterised patients with oesophagitis. Indeed an overlap existed between patients with and without oesophagitis regarding total acid exposure time. Patients with oesophagitis suffered reflux nearly as much at night and in the morning as during the postprandial period. They also had as much reflux as a result of small and slow changes in pH around the pH limit of 4 as they had due to proper reflux episodes. This did not change over time after the postprandial period. More 12 hour acid exposure was related to more frequent night time reflux. In normal subjects compared with patients reflux triggered increased contractile activity, and contractile activity at a normal pH was greater in patients than in normal subjects.