tbuckley/cabot-search huggingface dataset:
PTH-136 Faecal Calprotectin - Is it Requested Appropriately and is it Cost Effective?
Authors: E Derbyshire, C Wells, J Hancock, D Dwarakanath
Journal: Gut (2013)

<h3>Introduction</h3> Faecal calprotectin is a neutrophil derived protein that can be detected by quantitative enzyme linked immunosorbant assay in stool samples. It reliably predicts the level of mucosal inflammation in the lower gastrointestinal tract (1). The high negative predictive value of faecal calprotectin should lead to invasive investigation being avoided with a subsequent reduction in cost and demand on already stretched endoscopy services (2). We reviewed the use of faecal calprotectin in the trust to establish if current practise confirms this. <h3>Methods</h3> The hospital numbers of all patients who had a faecal calprotectin processed at North Tees &amp; Hartlepool NHS Foundation Trust from 01/04/2011 to 31/12/2011 were collected from the biochemistry department’s database. These patients’ case notes were then analysed to record the indication for faecal calprotectin, its result, subsequent investigation and management. <h3>Results</h3> Faecal calprotectin was requested in 2 groups of patients: 68 with lower gastrointestinal symptoms and 44 with Inflammatory Bowel Disease (IBD). Of the 68 patients with lower gastrointestinal symptoms, faecal calprotectin was normal in 48 patients: 13 (9 males, 4 females, median age 30 years, commonest symptom abdominal pain) at initial presentation had no further investigation, 23 (11 males, 12 females, median age 41, commonest symptom abdominal pain) went onto have further investigations (12 colonoscopies, 3 flexible sigmoidoscopies and 1 small bowel meal and follow through; all normal); in 12(3 males, 9 females, median age 45, commonest symptom chronic diarrhoea) the negative faecal calprotectin was as a second line following initial investigation including 8 normal colonoscopies and 1 normal flexible sigmoidoscopy. Of those patients with IBD, faecal calprotectin was normal in 9 patients. In 7 patients management decisions were taken on the basis of its result alone. These included commencement of Infliximab (n = 2), 6-mercaptopurine (n = 1), azathoprine (n = 1), pentasa (n = 2) and prednisolone (n = 1) without further investigation. <h3>Conclusion</h3> A negative faecal calprotectin led directly to the avoidance of a colonoscopy in 12 patients and of small bowel investigation in 11 patients. Given the trust’s current tariffs for faecal calprotectin, colonoscopy and small bowel meal and follow through, a total cost saving of £7,194.59 was made. Avoiding further investigation by waiting for a negative faecal calprotectin would have resulted in a greater cost saving. <h3>Disclosure of Interest</h3> None Declared. <h3>References</h3> CA Lamb, JC Mansfield. Measurement of faecal calprotectin and lactoferrin in inflammatory bowel disease. Frontline Gastroenterol 2011; 2:13–18. James Turvill. High negative predictive value of a normal faecal calprotectin in patients with symptomatic intestinal disease. Frontline Gastroenterol 2012; 3:21–28.
Prominent Role of P-Selectin in the Development of Advanced Atherosclerosis in ApoE-Deficient Mice
Authors: Zhao Ming Dong, Allison A. Brown, Denisa D. Wagner
Journal: Circulation (2000)

Background —Adhesive interactions between leukocytes and endothelial cells are characteristic of the development of atherosclerotic lesions, but the receptors involved remain to be defined. P-selectin is an adhesion receptor expressed on activated endothelial cells or platelets and was shown to be involved in fatty streak formation in LDL receptor–deficient mice on an atherogenic diet. The main purpose of this study is to examine the role of P-selectin in the spontaneous development of advanced atherosclerosis in apoE-deficient mice. Methods and Results —We intercrossed P-selectin–deficient mice with mice lacking apoE and compared lesion development in apoE-deficient mice with P-selectin (apoE −/− P +/+ ) and without P-selectin (apoE −/− P −/− ) that were fed normal mouse chow. At 4 months of age, apoE −/− P −/− mice had 3.5-fold smaller aortic sinus lesions than apoE −/− P +/+ mice. These were limited to fatty streaks in the apoE −/− P −/− mice, whereas 70% of apoE −/− P +/+ lesions contained smooth muscle cells. Significantly more of the aortic sinus circumference was covered by lesions in the apoE −/− P +/+ animals. The P-selectin genotype affected macrophage recruitment, because twice as many mononuclear cells were present in the P-selectin–positive lesions. At 15 months, the lesions progressed to the fibrous plaque stage in both genotypes and spread throughout the aorta, but this process was delayed in apoE −/− P −/− mice. In the aortic sinus, the lesions of the apoE −/− P −/− mice were 2.6-fold smaller and less calcified. Conclusions —P-selectin appears to be a key adhesion receptor mediating leukocyte recruitment into lesions and promoting advanced atherosclerosis in apoE-deficient mice.
Mitochondria and Cardiovascular Aging
Authors: Dao-Fu Dai, Peter S. Rabinovitch, Zoltan Ungvari
Journal: Circulation Research (2012)

Old age is a major risk factor for cardiovascular diseases. Several lines of evidence in experimental animal models have indicated the central role of mitochondria both in lifespan determination and in cardiovascular aging. In this article we review the evidence supporting the role of mitochondrial oxidative stress, mitochondrial damage and biogenesis as well as the crosstalk between mitochondria and cellular signaling in cardiac and vascular aging. Intrinsic cardiac aging in the murine model closely recapitulates age-related cardiac changes in humans (left ventricular hypertrophy, fibrosis and diastolic dysfunction), while the phenotype of vascular aging include endothelial dysfunction, reduced vascular elasticity, and chronic vascular inflammation. Both cardiac and vascular aging involve neurohormonal signaling (eg, renin–angiotensin, adrenergic, insulin-IGF1 signaling) and cell-autonomous mechanisms. The potential therapeutic strategies to improve mitochondrial function in aging and cardiovascular diseases are also discussed, with a focus on mitochondrial-targeted antioxidants, calorie restriction, calorie restriction mimetics, and exercise training.
The Ins and Outs of CCR7 in the Thymus
Authors: Colleen M. Witt, Ellen A. Robey
Journal: The Journal of Experimental Medicine (2004)

Although it is widely supposed that chemokines play a role in the thymus, most existing evidence is circumstantial. In this issue, two groups provide direct evidence that the chemokine receptor CCR7 is required for normal thymocyte migration (Ueno, T., F. Saito, D. Gray, S. Kuse, K. Hieshima, H. Nakano, T. Kakiuchi, M. Lipp, R. Boyd, and Y. Takahama. 2004. J. Exp. Med. 200:493–505; Misslitz, A., O. Pabst, G. Hintzen, L. Ohl, E. Kremmer, H. T. Petrie, and R. Forster. 2004. J. Exp. Med. 200:481–491). The two papers focus on distinct and opposite migration events, an early outward migration and a later inward migration. Together these papers provide a fascinating picture of the complex role of CCR7 in orchestrating thymocyte migration.
Cutaneous reactive hyperaemia: racial differences induced by corticoid application
Authors: E. BERARDESCA, H. MAIBACH
Journal: British Journal of Dermatology (1989)

The postocclusive hyperaemic reaction before and after a single 1 h application of a potent corticoid (clobetasol 0.05% in ointment) was recorded by means of laser Doppler velocimetry in order to elucidate different racial responses in skin vasoconstriction. Fourteen young male subjects entered the study (eight Caucasians, six Blacks). Reactive hyperaemia was recorded after 4 min of occlusion of the forearm blood flow. The following parameters of the hyperaemic reaction were investigated: area under the curve response, peak response, rise of blood flow slope to peak and decay of blood flow slope after peak. Different responses were recorded in the Black subjects after the vasoconstrictive stimulus compared to the Caucasians, namely: decreased area under the curve response (P < 0.04); decreased peak response (P < 0.01); decreased decay slope after peak blood flow (P < 0.04). These data are consistent with a different reactivity of blood vessels in black skin and possibly not related to the transcutaneous penetration of the chemical compound.
Neuregulins Regulate Cardiac Parasympathetic Activity
Authors: Katashi Okoshi, Masaharu Nakayama, Xinhua Yan, Marina P. Okoshi, Adam J.T. Schuldt, Mark A. Marchionni, Beverly H. Lorell
Journal: Circulation (2004)

Neuregulins are required for maintenance of acetylcholine receptor-inducing activity of nicotinic receptors in neurons and skeletal muscle, but effects of neuregulins on muscarinic receptors are not known. In the normal heart, parasympathetic activation counterbalances beta-adrenergic activation. To test the hypothesis that neuregulins modify parasympathetic function in the heart, we studied cardiomyocytes from mice heterozygous for neuregulin-1 gene deletion (NRG-1+/-) and examined the effects of beta-adrenergic stimulation on contractility in the presence and absence of the muscarinic agonist carbachol.We evaluated contraction and intracellular Ca2+ transients ([Ca2+]i) in left ventricular (LV) myocytes loaded with Fluo-3 from NRG-1+/- and wild-type (WT) mice. Under baseline conditions (0.5 Hz, 1.5 mmol/L [Ca2+]o, 25 degrees C), characteristics of myocyte contraction/relengthening and systolic/diastolic [Ca2+]i were not different between WT and NRG-1+/- mice. The steady-state increases in fractional shortening (FS) and peak-systolic [Ca2+]i in response to isoproterenol were similar in both groups. In WT myocytes stimulated with isoproterenol, carbachol decreased FS, peak-systolic [Ca2+]i, and cAMP levels. In NRG-1+/- myocytes, carbachol did not attenuate either FS or peak-systolic [Ca2+]i, associated with the failure to decrease cAMP levels. Investigation of muscarinic receptor signaling showed no difference of LV protein levels of muscarinic M2 receptors or G protein Galpha(i1,2), Galpha(i3), and Galpha(o) subunits.Cardiomyocytes deficient in neuregulin signaling are unable to adequately counterbalance beta-adrenergic activation by inhibitory parasympathetic activity. This mechanism may contribute to the known increased risk of heart failure in injured human hearts when neuregulin signaling is suppressed.
Behavioural therapy (biofeedback) for solitary rectal ulcer syndrome improves symptoms and mucosal blood flow
Authors: M E D Jarrett
Journal: Gut (2004)

<b>Aims:</b> The aim of the study was to determine if there is a permanent disorder of mucosal blood flow in patients with solitary rectal ulcer syndrome (SRUS) or a disorder related to autonomic gut innervation and physiological function that is reversible concomitant with successful treatment. Rectal mucosal blood flow was used as a validated measure of extrinsic autonomic nerve function. <b>Methods:</b> Sixteen consecutive patients with SRUS (12 women; mean age 35 years) and 26 healthy controls (17 women; mean age 36 years) were studied. Laser Doppler mucosal flowmetry was performed before and after biofeedback treatment. Symptoms were documented before and after biofeedback treatment using a standardised prospectively applied questionnaire. <b>Results:</b> Twelve of 16 patients (75%) reported subjective symptomatic improvement after treatment. Five of the 16 patients (31%) had sigmoidoscopic ulcer resolution. Pretreatment rectal mucosal blood flow was significantly lower in patients with SRUS compared with controls (163 (27) <i>v</i> 186 (14) flux units (FU) (mean (SD)); p&lt;0.01). Biofeedback resulted in a significant improvement in rectal mucosal blood flow in subjects who felt subjectively better after biofeedback (p = 0.001), from 165 (30) FU to 190 (40) FU. <b>Conclusion:</b> Gut directed biofeedback is an effective behavioural treatment for the majority of patients with SRUS. Mucosal blood flow is reduced to a similar level seen in normal transit constipation, suggesting similar impaired extrinsic autonomic cholinergic nerve activity. Successful outcome following biofeedback is associated with increased rectal mucosal blood flow, suggesting that improved extrinsic innervation to the gut may be partially responsible for the response to treatment.
Comparative Testing of DNA Segmentation Algorithms Using Benchmark Simulations
Authors: Eran Elhaik, Dan Graur, Krešimir Josić
Journal: Molecular Biology and Evolution (2009)

Numerous segmentation methods for the detection of compositionally homogeneous domains within genomic sequences have been proposed. Unfortunately, these methods yield inconsistent results. Here, we present a benchmark consisting of two sets of simulated genomic sequences for testing the performances of segmentation algorithms. Sequences in the first set are composed of fixed-sized homogeneous domains, distinct in their between-domain guanine and cytosine (GC) content variability. The sequences in the second set are composed of a mosaic of many short domains and a few long ones, distinguished by sharp GC content boundaries between neighboring domains. We use these sets to test the performance of seven segmentation algorithms in the literature. Our results show that recursive segmentation algorithms based on the Jensen–Shannon divergence outperform all other algorithms. However, even these algorithms perform poorly in certain instances because of the arbitrary choice of a segmentation-stopping criterion.
Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies
Authors: R. Chowdhury, S. Kunutsor, A. Vitezova, C. Oliver-Williams, S. Chowdhury, J. C. Kiefte-de-Jong, H. Khan, C. P. Baena, D. Prabhakaran, M. B. Hoshen, B. S. Feldman, A. Pan, L. Johnson, F. Crowe, F. B. Hu, O. H. Franco
Journal: BMJ (2014)

<h3>Summary</h3> Sister chromatid exchanges (SCEs) are products of joint DNA molecule resolution, and are considered to form through homologous recombination (HR). Indeed, upon generation of irradiation-induced DNA breaks, SCE induction was compromised in cells deficient for canonical HR factors BRCA1, BRCA2 and RAD51. Contrarily, replication-blocking agents, including PARP inhibitors, induced SCEs independently of BRCA1, BRCA2 and RAD51. PARP inhibitor-induced SCEs were enriched at common fragile sites (CFSs), and were accompanied by post-replicative single-stranded DNA (ssDNA) gaps. Moreover, PARP inhibitor-induced replication lesions were transmitted into mitosis, suggesting that SCEs originate from mitotic processing of under-replicated DNA. We found that DNA polymerase theta (POLQ) was recruited to mitotic DNA lesions, and loss of POLQ resulted in reduced SCE numbers and severe chromosome fragmentation upon PARP inhibition in HR-deficient cells. Combined, our data show that PARP inhibition generates under-replicated DNA, which is transferred into mitosis and processed into SCEs, independently of canonical HR factors.
Continuous Lenalidomide Treatment for Newly Diagnosed Multiple Myeloma
Authors: Antonio Palumbo, Roman Hajek, Michel Delforge, Martin Kropff, Maria Teresa Petrucci, John Catalano, Heinz Gisslinger, Wiesław Wiktor-Jędrzejczak, Mamia Zodelava, Katja Weisel, Nicola Cascavilla, Genadi Iosava, Michele Cavo, Janusz Kloczko, Joan Bladé, Meral Beksac, Ivan Spicka, Torben Plesner, Joergen Radke, Christian Langer, Dina Ben Yehuda, Alessandro Corso, Lindsay Herbein, Zhinuan Yu, Jay Mei, Christian Jacques, Meletios A. Dimopoulos
Journal: New England Journal of Medicine (2012)

Lenalidomide has tumoricidal and immunomodulatory activity against multiple myeloma. This double-blind, multicenter, randomized study compared melphalan-prednisone-lenalidomide induction followed by lenalidomide maintenance (MPR-R) with melphalan-prednisone-lenalidomide (MPR) or melphalan-prednisone (MP) followed by placebo in patients 65 years of age or older with newly diagnosed multiple myeloma.We randomly assigned patients who were ineligible for transplantation to receive MPR-R (nine 4-week cycles of MPR followed by lenalidomide maintenance therapy until a relapse or disease progression occurred [152 patients]) or to receive MPR (153 patients) or MP (154 patients) without maintenance therapy. The primary end point was progression-free survival.The median follow-up period was 30 months. The median progression-free survival was significantly longer with MPR-R (31 months) than with MPR (14 months; hazard ratio, 0.49; P<0.001) or MP (13 months; hazard ratio, 0.40; P<0.001). Response rates were superior with MPR-R and MPR (77% and 68%, respectively, vs. 50% with MP; P<0.001 and P=0.002, respectively, for the comparison with MP). The progression-free survival benefit associated with MPR-R was noted in patients 65 to 75 years of age but not in those older than 75 years of age (P=0.001 for treatment-by-age interaction). After induction therapy, a landmark analysis showed a 66% reduction in the rate of progression with MPR-R (hazard ratio for the comparison with MPR, 0.34; P<0.001) that was age-independent. During induction therapy, the most frequent adverse events were hematologic; grade 4 neutropenia was reported in 35%, 32%, and 8% of the patients in the MPR-R, MPR, and MP groups, respectively. The 3-year rate of second primary tumors was 7% with MPR-R, 7% with MPR, and 3% with MP.MPR-R significantly prolonged progression-free survival in patients with newly diagnosed multiple myeloma who were ineligible for transplantation, with the greatest benefit observed in patients 65 to 75 years of age. (Funded by Celgene; MM-015 ClinicalTrials.gov number, NCT00405756.).
Interleukin 1B gene (IL-1B) and interleukin 1 receptor antagonist gene (IL-1RN) polymorphisms in Helicobacter pylori-negative gastric cancer of intestinal and diffuse histotype
Authors: A. Ruzzo, F. Graziano, F. Pizzagalli, D. Santini, V. Battistelli, S. Panunzi, E. Canestrari, V. Catalano, B. Humar, R. Ficarelli, I. Bearzi, S. Cascinu, N. Naldi, E. Testa, M. Magnani
Journal: Annals of Oncology (2005)
Speculations on the Functional Anatomy of Basal Ganglia Disorders
Authors: J B Penney, A B Young
Journal: Annual Review of Neuroscience (1983)

The brain's default mode network consists of discrete, bilateral and symmetrical cortical areas, in the medial and lateral parietal, medial prefrontal, and medial and lateral temporal cortices of the human, nonhuman primate, cat, and rodent brains. Its ...Read More
The Immunohistopathology of Glomerular Antigens THE GLOMERULAR BASEMENT MEMBRANE, COLLAGEN, AND ACTOMYOSIN ANTIGENS IN NORMAL AND DISEASED KIDNEYS
Authors: Jon I. Scheinman, Alfred J. Fish, Alfred F. Michael
Journal: Journal of Clinical Investigation (1974)

The immunofluorescent localization of antisera to human glomerular basement membrane (GBM), collagen, and smooth muscle actomyosin was examined in 15 specimens of normal renal tissue and 98 specimens from patients with renal disease. The anti-GBM and anticollagen antisera normally localize to GBM, while antiactomyosin localizes to the mesangium. Diabetic nephropathy revealed a striking expansion of mesangial material reacting with antiactomyosin. In contrast, the expanded mesangium in membranoproliferative glomerulonephritis did not react with antiactomyosin, and the GBM localization of anti-GBM and anticollagen sera was similarly lost. The thickened GBM in diabetes mellitus and membranous nephropathy reacted with anti-GBM and anticollagen, but with accentuation of staining on the inner aspect of the GBM. In proliferative glomerulonephritis there was a moderate increase in the distribution of actomyosin. Glomerular sclerosis and hyalinization in all diseases studied was accompanied by a loss of immunofluorescent staining for all glomerular antigens, including collagen.
Autoregulation of an antibody response via network-induced auto-anti-idiotype
Authors: JC Brown, LS Rodkey
Journal: The Journal of Experimental Medicine (1979)

The antibody response of a single outbred rabbit was studied throughout three rounds of injections with Micrococcus lysodeikticus vaccine over a 31-mo period. The first-round response was characterized by a vigorous anti- micrococcus response and a strong anti-IgG rheumatoid factor response. The second-round response consisted of a triad of interacting molecules: anti- micrococcal antibodies, autoanti-idiotypic antibodies specific for distinct clonotypes of the first-round anti-micrococcal antibodies, and Fc-specific anti-IgG rheumatoid factor. The interacting triple complex was detected because of the formation of an immune complex that became insoluble upon dilution of the serum. Complex formation was inhibited in the presence of saccharide compounds known to be major immunodominant determinants of the micrococcal cell-wall carbohydrate polymer. The same saccharides did not affect the reaction of rheumatoid factor with IgG. Direct-binding radioimmunoassays ruled out mediation of the dilution-precipitation reaction by soluble micrococcal antigens. Specific absorption of rheumatoid factor inhibited the dilution-precipitation reaction. Auto-anti-idiotypic antibodies were specifically purified from second-round sera, directly confirming the presence of these antibodies. Suppressive effects of auto-anti-idiotypic antibodies on distinct antibody clonotypes were shown by gel isoelectric focusing of first-, second-, and third-round sera. Clonotypes expressed in the first round of immunizations were reduced in quantity or absent when auto-anti-idiotypic antibodies were detectable. Greatly enhanced levels or initial synthesis of new clonotypes of anti-micrococcal antibodies were detected during the period of auto-anti-idiotype synthesis. The third-round sera, devoid of detectable auto-anti-idiotype, contained clonotypes characteristic of both first- and second-round antisera. Thus, auto-anti- idiotypic-mediated suppression appeared to be reversible. The data are interpreted as lending strong support for concepts of autoregulation of immune processes in normal outbred animals via an idiotypic network.
Risk Equation Determining Unsuccessful Cannulation Events and Failure to Maturation in Arteriovenous Fistulas (REDUCE FTM I)
Authors: Charmaine E. Lok, Michael Allon, Louise Moist, Matthew J. Oliver, Hemal Shah, Deborah Zimmerman
Journal: Journal of the American Society of Nephrology (2006)

Fistulas are the preferred permanent hemodialysis vascular access but a significant obstacle to increasing their prevalence is the fistula's high "failure to mature" (FTM) rate. This study aimed to (1) identify preoperative clinical characteristics that are predictive of fistula FTM and (2) use these predictive factors to develop and validate a scoring system to stratify the patient's risk for FTM. From a derivation set of 422 patients who had a first fistula created, a prediction rule was created using multivariate stepwise logistic regression. The model was internally validated using split-half cross-validation and bootstrapping techniques. A simple scoring system was derived and externally validated on 445 different, prospective patients who received a new fistula at five large North American dialysis centers. The clinical predictors that were associated with FTM were aged > or =65 yr (odds ratio [OR] 2.23; 95% confidence interval [CI] 1.25 to 3.96), peripheral vascular disease (OR 2.97; 95% CI 1.34 to 6.57), coronary artery disease (OR 2.83; 95% CI 1.60 to 5.00), and white race (OR 0.43; 95% CI 0.24 to 0.75). The resulting scoring system, which was externally validated in 445 patients, had four risk categories for fistula FTM: low (24%), moderate (34%), high (50%), and very high (69%; trend P < 0.0001). A preoperative, clinical prediction rule to determine fistulas that are likely to fail maturation was created and rigorously validated. It was found to be simple and easily reproducible and applied to predictive risk categories. These categories predicted risk of FTM to be 24, 34, 50, and 69% and are dependent on age, coronary artery disease, peripheral vascular disease, and race. The clinical utility of these risk categories in increasing rates of permanent accesses requires further clinical evaluation.