tbuckley/cabot-search huggingface dataset:
Comparing histological activity indexes in UC
Authors: Aude Bressenot, Julia Salleron, Claire Bastien, Silvio Danese, Camille Boulagnon-Rombi, Laurent Peyrin-Biroulet
Journal: Gut (2014)

<h3>Background</h3> Assessment of disease activity in UC is important for designing an optimal therapeutic strategy. No single histology score is considered optimum. The aim of this study was to compare intraobserver reproducibility and the interobserver agreement of available histological UC activity indexes. <h3>Methods</h3> One hundred and two biopsy specimens (collected between 2003 and 2014) were scored blindly by three pathologists by determining Geboes, Riley, Gramlich and Gupta indexes and global visual evaluation (GVE). Intraobserver reproducibility and interobserver agreements for index and items of index were studied by intraclass correlation coefficient for quantitative parameter and by κ values and Krippendorff index for qualitative parameters. Relationship between indexes was studied by computation of Pearson9s and Spearman9s correlation coefficients. <h3>Results</h3> Geboes, Riley, Gramlich and Gupta indexes and GVE showed good intraobserver reproducibility and a good interobserver agreement. Histological items that showed the best interobserver agreement were ‘erosion/ulceration or surface epithelial integrity’ and ‘acute inflammatory cells infiltrate/neutrophils in lamina propria’. The five scores were strongly correlated. <h3>Conclusions</h3> Correlation between indexes is strong. Intraobserver reproducibility and interobserver agreement for all indexes is very good. Histological items that showed the best interobserver agreement are ‘erosion/ulceration’ and ‘acute inflammatory cells infiltrate/neutrophils in lamina propria’.
Silencing of Epidermal Growth Factor Receptor Suppresses Hypoxia-Inducible Factor-2–Driven <i>VHL</i>−/− Renal Cancer
Authors: Karlene Smith, Lakshman Gunaratnam, Melissa Morley, Aleksandra Franovic, Karim Mekhail, Stephen Lee
Journal: Cancer Research (2005)

Loss of skeletal muscle is an important determinant of survival in patients with cancer-induced weight loss. The effect of the leucine metabolite beta-hydroxy-beta-methylbutyrate (HMB) on the reduction of body weight loss and protein degradation in the MAC16 model of cancer-induced weight loss has been compared with that of eicosapentaenoic acid (EPA), a recognized inhibitor of protein degradation. HMB was found to attenuate the development of weight loss at a dose greater than 0.125 g/kg accompanied by a small reduction in tumor growth rate. When EPA was used at a suboptimal dose level (0.6 g/kg) the combination with HMB seemed to enhance the anticachectic effect. Both treatments caused an increase in the wet weight of soleus muscle and a reduction in protein degradation, although there did not seem to be a synergistic effect of the combination. Proteasome activity, determined by the "chymotrypsin-like" enzyme activity, was attenuated by both HMB and EPA. Protein expression of the 20S alpha or beta subunits was reduced by at least 50%, as were the ATPase subunits MSS1 and p42 of the 19S proteasome regulatory subunit. This was accompanied by a reduction in the expression of E2(14k) ubiquitin-conjugating enzyme. The combination of EPA and HMB was at least as effective or more effective than either treatment alone. Attenuation of proteasome expression was reflected as a reduction in protein degradation in gastrocnemius muscle of cachectic mice treated with HMB. In addition, HMB produced a significant stimulation of protein synthesis in skeletal muscle. These results suggest that HMB preserves lean body mass and attenuates protein degradation through down-regulation of the increased expression of key regulatory components of the ubiquitin-proteasome proteolytic pathway, together with stimulation of protein synthesis.
Absence of vacuolar H(+)-ATPase pump in the collecting duct of a patient with hypokalemic distal renal tubular acidosis and Sjögren's syndrome.
Authors: P E DeFranco, L Haragsim, P G Schmitz, B Bastani
Journal: Journal of the American Society of Nephrology (1995)

Distal renal tubular acidosis (dRTA) is a common complication of autoimmune connective tissue diseases. The underlying pathophysiology of renal tubular acidosis in these syndromes is frequently characterized by impaired hydrogen ion secretion, i.e., secretory defect dRTA. However, the precise molecular events leading to this disturbance remain poorly understood. An opportunity was recently afforded to examine the ultrastructural features of the collecting duct in a patient with Sjögren's syndrome and secretory defect dRTA. Immunocytochemical analysis of a renal biopsy obtained 12 months after the patient's initial presentation demonstrated a complete absence of vacuolar H(+)-ATPase in the collecting duct. Antibodies to the 31- and 56-kd kidney-specific subunits of the H(+)-ATPase pump were used to characterize pump distribution. Interestingly, although antiserum to the CI-:HCO3- anion exchanger (band-3 protein) reacted strongly with normal human kidney and the patient's red blood cells, no immunoreactivity was observed in the patient's collecting duct epithelium. Importantly, electron microscopy of the patient's renal biopsy specimen disclosed cells that ultrastructurally were indistinguishable from intercalated cells. These results suggest that the functional basis of impaired hydrogen ion secretion in this patient was secondary to the absence of intact H(+)-ATPase pumps rather than defective pump function or distribution. The presence of intercalated cells ultrastructurally, but the absence of discernible staining for band-3 protein and H(+)-ATPase, also suggests that the defect in proton secretion may represent a defect involving the assembly of at least two of the ion transport pumps essential for the normal maintenance of acid-base homeostasis by the intercalated cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Altered Interhemispheric Connectivity in Individuals With Tourette's Disorder
Authors: Kerstin J Plessen, Tore Wentzel-Larsen, Kenneth Hugdahl, Patricia Feineigle, Joel Klein, Lawrence H Staib, James F Leckman, Ravi Bansal, Bradley S Peterson
Journal: American Journal of Psychiatry (2004)

OBJECTIVE: The corpus callosum is the major commissure connecting the cerebral hemispheres. Prior evidence suggests involvement of the corpus callosum in the pathophysiology of Tourette's disorder. The authors assessed corpus callosum size and anatomical connectivity across the cerebral hemispheres in persons with Tourette's disorder. METHOD: The size of the corpus callosum was determined on the true midsagittal slices of reformatted, high-resolution magnetic resonance imaging scans and compared across groups in a cross-sectional case-control study of 158 subjects with Tourette's disorder and 121 healthy comparison subjects, ages 5–65 years. RESULTS: In the context of increasing midsagittal corpus callosum area from childhood to age 30 years, children with Tourette's disorder had smaller overall corpus callosum size, whereas adults with Tourette's disorder on average had larger corpus callosum size, yielding a prominent interaction of diagnosis with age. Corpus callosum size correlated positively with tic severity. Corpus callosum size also correlated inversely with dorsolateral prefrontal and orbitofrontal cortical volumes in both the subjects with Tourette's disorder and the comparison subjects, but the magnitudes of the correlations were significantly greater in the group with Tourette's disorder. The effects of medication and comorbid illnesses had no appreciable influence on the findings. CONCLUSIONS: Given prior evidence for the role of prefrontal hypertrophy in the regulation of tic symptoms, the current findings suggest that neural plasticity may contribute to smaller corpus callosum size in persons with Tourette's disorder, which thereby limits neuronal trafficking across the cerebral hemispheres and reduces input to cortical inhibitory interneurons within the prefrontal cortices. Reduced inhibitory input may in turn enhance prefrontal excitation, thus helping to control tics and possibly contributing to the cortical hyperexcitatibility reported previously in patients with Tourette's disorder.
Randomized, Double-Blind, Multicenter Study of the Endeavor Zotarolimus-Eluting Phosphorylcholine-Encapsulated Stent for Treatment of Native Coronary Artery Lesions
Authors: Jean Fajadet, William Wijns, Gert-Jan Laarman, Karl-Heinz Kuck, John Ormiston, Thomas Münzel, Jeffrey J. Popma, Peter J. Fitzgerald, Raoul Bonan, Richard E. Kuntz
Journal: Circulation (2006)

Background— The use of the Endeavor stent might reduce restenosis and stent thrombosis at 9 months. Methods and Results— Patients (n=1197) treated for single coronary artery stenosis were enrolled in a prospective, randomized, double-blind study and randomly assigned to receive the Endeavor zotarolimus-eluting phosphorylcholine polymer–coated stent (n=598) or the same bare metal stent but without the drug or the polymer coating (n=599). The 2 groups were well matched in baseline characteristics. Diabetes was present in 20.1% of patients; the mean reference vessel diameter was 2.75 mm; and the mean lesion length was 14.2 mm. The primary end point of target vessel failure at 9 months was reduced from 15.1% with the bare metal stent to 7.9% with the Endeavor ( P =0.0001), and the rate of major adverse cardiac events was reduced from 14.4% with the bare metal stent to 7.3% with the Endeavor ( P =0.0001). Target lesion revascularization was 4.6% with Endeavor compared with 11.8% with the bare metal stent ( P =0.0001). The rate of stent thrombosis was 0.5% with the Endeavor, which was not significantly different from 1.2% with the bare metal stent. In 531 patients submitted to angiographic follow-up, late loss was reduced from 1.03±0.58 to 0.61±0.46 ( P &lt;0.001) in stent and from 0.72±0.61 to 0.36±0.46 ( P &lt;0.001) in segment. The rate of in-segment restenosis was reduced from 35.0% to 13.2% with Endeavor ( P &lt;0.0001). There was no excessive edge stenosis, aneurysm formation, or late acquired malapposition by intravascular ultrasound imaging. Differences in clinical outcome were maintained at 12 and 24 months ( P &lt;0.0001). Conclusions— Compared with bare metal stents, the Endeavor stent is safe and reduces the rates of clinical and angiographic restenosis at 9, 12, and 24 months.
Clinical, radiographic and immunogenic effects after 1 year of tocilizumab-based treatment strategies in rheumatoid arthritis: the ACT-RAY study
Authors: Maxime Dougados, Karsten Kissel, Philip G Conaghan, Emilio Martin Mola, Georg Schett, Roberto Gerli, Michael Sejer Hansen, Howard Amital, Ricardo M Xavier, Orrin Troum, Corrado Bernasconi, T W J Huizinga
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Objective</h3> To assess the 1-year efficacy and safety of a regimen of tocilizumab plus methotrexate or placebo, which was augmented by a treat-to-target strategy from week 24. <h3>Methods</h3> ACT-RAY was a double-blind, 3-year trial. Adults with active rheumatoid arthritis despite methotrexate were randomised to add tocilizumab to ongoing methotrexate (add-on strategy) or to switch to tocilizumab plus placebo (switch strategy). Tocilizumab 8 mg/kg was administered every 4 weeks. Conventional open-label disease-modifying antirheumatic drugs (DMARDs) other than methotrexate were added at week 24 or later in patients with DAS28&gt;3.2. <h3>Results</h3> 556 patients were randomised; 85% completed 52 weeks. The proportion of patients receiving open-label DMARDs was comparable in the add-on (29%) and switch (33%) arms. Overall, week 24 results were maintained or further improved at week 52 in both arms. Some endpoints favoured the add-on strategy. Mean changes in Genant-modified Sharp scores were small; more add-on (92.8%) than switch patients (86.1%) had no radiographic progression. At week 52, comparable numbers of patients had antidrug antibodies (ADAs; 1.5% and 2.2% of add-on and switch patients, respectively) and neutralising ADAs (0.7% and 1.8%). Rates of serious adverse events and serious infections per 100 patient-year (PY) were 11.3 and 4.5 in add-on and 16.8 and 5.5 in switch patients. In patients with normal baseline values, alanine aminotransferase elevations &gt;3× upper limit of normal were observed in 11% of add-on and 3% of switch patients. <h3>Conclusions</h3> Despite a trend favouring the add-on strategy, these data suggest that both tocilizumab add-on and switch strategies led to meaningful clinical and radiographic responses.
Abstract 202: Dysregulation of the Small Organic Carnitine Transporter and Carnitine in Heart Failure
Authors: Kenneth C Bedi, Nathaniel W Snyder, Jeff Brandimarto, Clementina Mesaros, Ian A Blair, Kenneth B Margulies, J. E Rame
Journal: Circulation Research (2014)

Introduction: Advanced heart failure (HF) is characterized by metabolic abnormalities. We have recently shown myocardial lipid species to be significantly decreased in non-diabetic HF. The finding of deficient carnitine species has directed us to examine a key gene SLC22A5 the high-affinity carnitine transporter. Known mutations of this gene lead to primary carnitine deficiency and cardiomyopathy. Methods: Left ventricular samples procured at the time of orthotopic heart transplantation (OHT) from non-diabetic idiopathic dilated cardiomyopathy (DCM) n=16, and brain-dead organ donors without a history of diabetes or HF (NF) n=18 formed the study sample. All hearts received in situ cold cardioplegia. Lipids including carnitines were quantitated with liquid chromatography and high-resolution mass spectrometry (LC-HRMS) following the Folch extraction method. mRNA expression data of target genes including SLC22A5 from a separate study of n=117 DCM patients and n=67 NF patients p≤0.05 were analyzed. Results: Representative trends for all carnitine species assayed were shown to be significantly reduced in DCM. The figure below represents the mRNA expression between DCM and NF patients. There was a statistically significant reduction of SLC22A5 expression in the DCM population (Figure: ***p≤ 0.0001, dots 95 th percentiles). Conclusions: A statistically significant deficiency of carnitine species and a reduction in the expression of the carnitine transporter SLC22A5 was demonstrated in non-diabetic HF. Future studies will attempt to resolve the mechanisms behind these observations.
Comparison of anthropometric and physical variables among kho-kho and handball players of Andhra Pradesh School Games teams
Authors: Ramu Pilli
Journal: British Journal of Sports Medicine (2010)

The purpose of the study was to compare the anthropometric and physical variables among kho-kho and hand ball players of Andhra Pradesh School Games teams. To achieve this purpose of the study, 40 male players of kho-kho and hand ball were selected as subjects from Andhra Pradesh State School Games teams. The players who were selected as subjects for the studies have participated at national level competition. The age of the subjects were ranged between 16 and 20 years. The following variables such as speed, endurance, explosive strength, muscular endurance, height, weight, sitting height, body fat and somatotype were selected as criterion variables. The analysis of ‘t’ ratio was used to analyse the significant differences if any between the groups. The level of significance was fixed at 0.05 level of confidence, which was considered to be appropriate. The result of the study shows that hand ball players were better in six variables such as explosive strength, muscular endurance, height, weight, body fat, somatotype, further the study indicates that kho-kho players were better in speed and endurance.
The Pathobiology of Glioma Tumors
Authors: Candece L. Gladson, Richard A. Prayson, Wei Michael Liu
Journal: Annual Review of Pathology Mechanisms of Disease (2009)

The ongoing characterization of the genetic and epigenetic alterations in the gliomas has already improved the classification of these heterogeneous tumors and enabled the development of rodent models for analysis of the molecular pathways underlying their proliferative and invasive behavior. Effective application of the targeted therapies that are now in development will depend on pathologists' ability to provide accurate information regarding the genetic alterations and the expression of key receptors and ligands in the tumors. Here we review the mechanisms that have been implicated in the pathogenesis of the gliomas and provide examples of the cooperative nature of the pathways involved, which may influence the initial therapeutic response and the potential for development of resistance.
Chemotherapy Is More Effective in Patients with Breast Cancer Not Expressing Steroid Hormone Receptors
Authors: Marco Colleoni, Giuseppe Viale, David Zahrieh, Giancarlo Pruneri, Oreste Gentilini, Paolo Veronesi, Richard D. Gelber, Giuseppe Curigliano, Rosalba Torrisi, Alberto Luini, Mattia Intra, Viviana Galimberti, Giuseppe Renne, Franco Nolè, Giulia Peruzzotti, Aron Goldhirsch
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The purpose of this research was to identify factors predicting response to preoperative chemotherapy. Experimental Design: In a large volume laboratory using standard immunohistochemical methods, we reviewed the pretreatment biopsies and histologic specimens at final surgery of 399 patients with large or locally advanced breast cancer (cT2-T4, N0–2, M0) who were treated with preoperative chemotherapy. The incidence of pathological complete remission and the incidence of node-negative status at final surgery were assessed with respect to initial pathological and clinical findings. Menopausal status, estrogen receptor status, progesterone receptor status [absent (0% of the cells positive) versus expressed], clinical tumor size, histologic grade, Ki-67, Her-2/neu expression, and type and route of chemotherapy were considered. Results: High rates of pathological complete remission were associated with absence of estrogen receptor and progesterone receptor expression (P &amp;lt; 0.0001), and grade 3 (P = 0.001). Significant predictors of node-negative status at surgery were absence of estrogen receptor and progesterone receptor expression (P &amp;lt; 0.0001), clinical tumor size &amp;lt;5 cm (P &amp;lt; 0.001), and use of infusional regimens (P = 0.003). The chance of obtaining pathological complete remission or node-negative status for patients with endocrine nonresponsive tumors compared with those having some estrogen receptor or progesterone receptor expression was 4.22 (95% confidence interval, 2.20–8.09, 33.3% versus 7.5%) and 3.47 (95% confidence interval, 2.09–5.76, 42.9% versus 21.7%), respectively. Despite the significantly higher incidence of pathological complete remission and node-negative status achieved by preoperative chemotherapy for patients with estrogen receptor and progesterone receptor absent disease, the disease-free survival was significantly worse for this cohort compared with the low/positive expression cohort (4-year disease-free survival %: 41% versus 74%; hazard ratio 3.22; 95% confidence interval, 2.28–4.54; P &amp;lt; 0.0001). Conclusions: Response to preoperative chemotherapy is significantly higher for patients with endocrine nonresponsive tumors. New chemotherapy regimens or combinations should be explored in this cohort of patients with poor outcome. For patients with endocrine responsive disease, the role of preoperative endocrine therapies should be studied.
Population aging and health
Authors: R. N Butler
Journal: BMJ (1997)

Old age has always been with us.The ancient Egyptians and the author of the 12th chapter of Ecclesiastes were familiar with the common disabilities of later life.Survival into what we still regard as old age was not unusual in classical Greece (table).The average length of human life has increased over the centuries as living conditions have improved and childhood mortality has fallen; the maximum lifespan of our species is determined largely by our genes and will be the same as it ever was.Doctors and philosophers of antiquity commented on age associated illness.Hippocrates noted conditions common in later life, and Aristotle offered a theory of aging based on loss of heat.Two thousand years were to pass before anything better was written on the subject.Francis Bacon proposed a scientific programme of epidemiological investigations into the longevity of people living in different places and under different conditions. 1 He also noted that the pursuit of knowledge depended on "the fresh examination of particulars," advice that underlaid the systematic observation of nature that complemented the active experimentation advocated by his contemporary William Harvey.During the 18th and 19th centuries several physicians wrote specifically about the diseases of later life and their treatment.These included Cheyne 2 and Day 3 in Britain and Rush 4 in the United States.Charcot's lectures on the medicine of old age aroused scientific interest in the field and became available in English translation in 1881. 5 The word "geriatrics" was invented by Ignatz L Nascher, a Vienna-born immigrant to the United States in 1909. 6(It is not clear who is to blame for the barbarous miscoining of "gerontology"-the study of old men-for "geratology"-the study of old age.)Nascher's initiative provided a stimulus for social and biological research on aging, 7 but clinical geriatrics did not flourish in the United States.The American Geriatrics Society was founded in 1942, but as a thriving and influential medical specialty geriatric medicine was essentially a product of the British NHS. Old age in classical Greece
Pharmacology and Signaling of MAS-Related G Protein–Coupled Receptors
Authors: Hans Jürgen Solinski, Thomas Gudermann, Andreas Breit
Journal: Pharmacological Reviews (2014)

Signaling by heptahelical G protein–coupled receptors (GPCR) regulates many vital body functions. Consequently, dysfunction of GPCR signaling leads to pathologic states, and approximately 30% of all modern clinical drugs target GPCR. One decade ago, an entire new GPCR family was discovered, which was recently named MAS-related G protein–coupled receptors (MRGPR) by the HUGO Gene Nomenclature Committee. The MRGPR family consists of ∼40 members that are grouped into nine distinct subfamilies (MRGPRA to -H and -X) and are predominantly expressed in primary sensory neurons and mast cells. All members are formally still considered "orphan" by the Committee on Receptor Nomenclature and Drug Classification of the International Union of Basic and Clinical Pharmacology. However, several distinct peptides and amino acids are discussed as potential ligands, including <i>β</i>-alanine, angiotensin-(1–7), alamandine, GABA, cortistatin-14, and cleavage products of proenkephalin, pro-opiomelanocortin, prodynorphin, or proneuropeptide-FF-A. The full spectrum of biologic roles of all MRGPR is still ill-defined, but there is evidence pointing to a role of distinct MRGPR subtypes in nociception, pruritus, sleep, cell proliferation, circulation, and mast cell degranulation. This review article summarizes findings published in the last 10 years on the phylogenetic relationships, pharmacology, signaling, physiology, and agonist-promoted regulation of all MRGPR subfamilies. Furthermore, we highlight interactions between MRGPR and other hormonal systems, paying particular attention to receptor multimerization and morphine tolerance. Finally, we discuss the challenges the field faces presently and emphasize future directions of research.