tbuckley/cabot-search huggingface dataset:
Variability in the severity of colonic disease in familial adenomatous polyposis results from differences in tumour initiation rather than progression and depends relatively little on patient age
Authors: M D Crabtree
Journal: Gut (2001)

<h3>INTRODUCTION</h3> As large scale genetic analysis becomes increasingly efficient, attention is turning to problems arising from inaccurate measurement of the phenotype. We have investigated the underlying basis of variation in disease severity in the large intestine of familial adenomatous polyposis (FAP) patients. The development of objective and reproducible measures may have future use in genetic studies, such as analysis of modifier genes. <h3>METHODS</h3> We examined the ratio of adenomas to crypts from microscopic slides taken from all parts of the colon of 44 resected FAP specimens. These findings were compared with a carefully reported macroscopic polyp count. Age dependency of adenoma counts (in the period around colectomy) was also analysed. <h3>RESULTS</h3> The adenoma:crypt ratio strongly correlated with reported macroscopic polyp count (<i>r</i>=0.82, p&lt;0.001) with no significant residual variation. Polyp density measured using the adenoma: crypt ratio did not vary significantly within an individual colon. Apparent visible variation in polyp density within any colon was not found at the microscopic level. There was no detectable age related increase in macroscopic adenoma count between siblings over the age range at which colectomies were performed. <h3>DISCUSSION</h3> The severity of colonic polyposis in FAP can be determined accurately by counting the adenoma:crypt ratio in sections derived from stored tissue blocks. Variation between patients—dependent on APC genotype and, probably, modifier genes—is manifest at both the microscopic and macroscopic levels. Thus variation in disease severity is more likely to result from different rates of tumour initiation than from differences in progression of microadenomas to macroscopic tumours. The absence of a detectable relationship between adenoma number and age (over the range studied) suggests that most tumours may be initiated relatively early in the patient9s life, perhaps at a time of particular susceptibility.
Circulating antibodies to lung protein(s) in patients with cryptogenic fibrosing alveolitis.
Authors: W A Wallace, S N Roberts, H Caldwell, E Thornton, A P Greening, D Lamb, S E Howie
Journal: Thorax (1994)

BACKGROUND--It has been hypothesised that cryptogenic fibrosing alveolitis has an immunological pathogenesis mediated by T lymphocytes. It is, however, recognised that patients may show dysregulation of the humoral immune system and that the presence of large numbers of B lymphocytes in open lung biopsies may be associated with a poor prognosis. Evidence of a role for the humoral immune system in the pathogenesis of cryptogenic fibrosing alveolitis has been suggested, but attempts to demonstrate circulating immunoglobulin to antigen within the lung have been inconclusive. METHODS--Plasma samples from 22 patients with cryptogenic fibrosing alveolitis, 22 patients with sarcoidosis, and 17 healthy controls were screened by SDS-PAGE and Western blotting for the presence of autoantibodies to lung proteins derived from cryptogenic fibrosing alveolitis, sarcoid and control lung tissue, as well as four normal non-pulmonary tissues. Possible site(s) of target protein(s) within the lung tissue were identified by immunohistochemical examination using IgG purified from the plasma of six patients and two controls. RESULTS--Eighteen of the plasma samples from patients with cryptogenic fibrosing alveolitis had reactive IgG to lung protein(s) in the 70-90 kDa molecular weight range compared with five of 18 plasma samples from patients with sarcoidosis and one of 17 controls. Plasma from patients with cryptogenic fibrosing alveolitis recognised antigen(s) of the same molecular weight in control and sarcoid lung tissue, but not non-pulmonary tissues, with a similar frequency. Immunohistochemical staining of cryptogenic fibrosing alveolitis biopsy material using IgG purified from plasma samples from patients with cryptogenic fibrosing alveolitis, but not control samples, revealed fine linear positivity in the lung parenchyma in a pattern suggestive of reaction with alveolar lining cells. The pattern was cytoplasmic/membranous and not nuclear. CONCLUSIONS--Patients with cryptogenic fibrosing alveolitis have a high frequency of plasma IgG autoantibodies to protein(s) within lung tissue associated with alveolar lining cells. This is believed to be the site where immunological injury occurs in cryptogenic fibrosing alveolitis, but the significance of these antibodies to the aetiology and pathogenesis is as yet unclear.
Cardiac Glycosides Exert Anticancer Effects by Inducing Immunogenic Cell Death
Authors: Laurie Menger, Erika Vacchelli, Sandy Adjemian, Isabelle Martins, Yuting Ma, Shensi Shen, Takahiro Yamazaki, Abdul Qader Sukkurwala, Mickaël Michaud, Grégoire Mignot, Frederic Schlemmer, Eric Sulpice, Clara Locher, Xavier Gidrol, François Ghiringhelli, Nazanine Modjtahedi, Lorenzo Galluzzi, Fabrice André, Laurence Zitvogel, Oliver Kepp, Guido Kroemer
Journal: Science Translational Medicine (2012)

Cardiac glycosides kill cancer cells in a way that stimulates the immune response.
Staphylococcal Nasal Carriage and Subsequent Infection in Peritoneal Dialysis Patients
Authors: C. Mack Sewell
Journal: JAMA (1982)

Thirty patients undergoing long-term home-based peritoneal dialysis were monitored for 13 months for carriage of Staphylococcus aureus in the nares and for the development of infectious complications. The patients could be divided into three groups with regard to S aureus carriage: chronic, intermittent, and noncarriers. Twenty-five episodes of peritonitis and 20 episodes of catheter exit-site infections occurred during 268 patient-months of observation. Staphylococcus aureus accounted for eight episodes of peritonitis and 12 episodes of exit-site infection. Chronic and intermittent carriers of S aureus were found to be at higher risk of development of infection than noncarriers.
Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study
Authors: Javier Cortes, Joyce O'Shaughnessy, David Loesch, Joanne L Blum, Linda T Vahdat, Katarina Petrakova, Philippe Chollet, Alexey Manikas, Veronique Diéras, Thierry Delozier, Vladimir Vladimirov, Fatima Cardoso, Han Koh, Philippe Bougnoux, Corina E Dutcus, Seth Seegobin, Denis Mir, Nicole Meneses, Jantien Wanders, Chris Twelves
Journal: The Lancet (2011)
Surfactant function affected by airway inflammation and cooling: possible impact on exercise-induced asthma
Authors: G Enhorning, J. Hohlfeld, N. Krug, G Lema, R.c Welliver
Journal: European Respiratory Journal (2000)

Pulmonary surfactant maintains patency of narrow conducting airways. An inflammation, with a leakage of plasma proteins into the airway lumen, causes surfactant to lose some of this ability. Will a lowering of temperature aggravate the deteriorating effect of an inflammation? Calf lung surfactant extract (CLSE) with proteins added was studied with a capillary surfactometer (CS) at temperatures of 25-42 degrees C. BALB/c mice were infected with respiratory syncytial virus (RSV). Six days later the lungs were lavaged and the surfactant in the lavage fluid was studied with the CS at temperatures of 25-42 degrees C. Lavage fluid from allergen challenged asthmatics was examined for its content of surfactant inhibitors at reduced temperatures. It was shown that CLSE with proteins gradually lost its ability to maintain patency as the temperature was lowered. Lavage fluid from the RSV infected mice showed a similar dysfunction at low temperatures. Lavage fluid from the airways of human asthmatics, when challenged with antigen but not with saline, contained agents inhibiting surface activity, particularly at reduced temperatures. Airway inflammation causes surfactant to lose its ability to maintain patency, particularly as the temperature is reduced. That might be a reason for the increased airway resistance observed in asthma patients hyperventilating in cold weather.
SICKLING PHENOMENON PRODUCED BY HYPERTONIC SOLUTIONS: A POSSIBLE EXPLANATION FOR THE HYPOSTHENURIA OF SICKLEMIA*
Authors: Pasquale E. Perillie, Franklin H. Epstein
Journal: Journal of Clinical Investigation (1963)

Hyposthenuria and recurrent episodes of hema- turia are well-known complications of the sickle- cell disorders (1).Although it has been sug- gested that the defect in renal concentrating ability results from the presence of sickle hemoglobin within the circulating erythrocytes, there has been no satisfactory explanation for the special vulner- ability of the kidney to the presence of such cells.A physiological characteristic differentiating the kidney from all other organs of the body is the high concentration of solutes normally attained in blood traversing the capillaries of the renal medulla (2, 3).It seemed worthwhile, therefore, to examine the effects of hypertonic solutions upon erythrocytes from patients with sickle-cell dis- ease.The sickling phenomenon was found to be enhanced by concentrated solutions of sodium salts, and these results have suggested an ex- planation for the hyposthenuria associated with sickle-cell anemia. METHODSPaticnts.Ten hematologically normal white and Negro subjects and a group of ten patients with hemoglobinopathies other than sickle-cell disease served as controls in the present investigation.The disorders represented in the latter group were hemoglobin C disease, hemoglobin C trait, thalassemia major, and thalassemia minor.The main study group consisted of 16 patients with sickle-cell disease as listed in Table I.Sickling phenomenon.A drop of capillary blood was mixed with 2 drops of solutions of NaCl having osmolali- ties ranging from 300 to 2,000 mOsm per kg.The mix- tures were immediately examined microscopically for the presence of sickling.Standard metabisulfite sickle prepa- rations were also performed in the usual manner (4).The percentage of sickled cells present in varying con-
A UFLC/MS/MS method for simultaneous quantitation of alisol A and alisol B 23-acetate from Alisma orientale (Sam.) Juz. in rat plasma
Authors: Yaowen Zhang, Qing Li, Chunxiao Lv, Yidi Yin, Kaishun Bi
Journal: Asian Journal of Pharmaceutical Sciences (2014)

A sensitive and reliable ultra fast liquid chromatography tandem mass spectrometry (UFLC-MS/MS) method has been developed and validated for simultaneous quantitation of alisol A and alisol B 23-acetate from Alisma orientale (Sam.) Juz. in rat plasma using diazepam as an internal standard (IS). The plasma samples were extracted by liquid–liquid extraction with methyl tert-butyl ether and separated on a Venusil MP C18 column (100 mm × 2.1 mm, 3.0 mm) (Venusil, China) using gradient elution with the mobile phase consisting of methanol and 0.1% acetic acid in water at a flow rate of 0.4 ml/min. The two analytes were monitored with positive electrospray ionization by multiple reaction monitoring mode (MRM). The lower limit of quantitation was 5.00 ng/ml for alisol A and 5.00 ng/ml for alisol B 23-acetate. The calibration curves were linear in the range of 5.00–2500 ng/ml for alisol A and 5–2500 ng/ml for alisol B 23-acetate. The mean extraction recoveries were above 63.8% for alisol A and 68.0% for alisol B 23-acetate from biological matrixes. Both intra-day and inter-day precision and accuracy of analytes were well within acceptance criteria (15%). The validated method was successfully applied to the pharmacokinetic study of alisol A and alisol B 23-acetate in rat plasma after oral administration of alcohol extract of Alismatis Rhizoma.
c-Jun N-Terminal Kinases Mediate Reactivation of Akt and Cardiomyocyte Survival After Hypoxic Injury In Vitro and In Vivo
Authors: Zhili Shao, Kausik Bhattacharya, Eileen Hsich, Larry Park, Brian Walters, Ursula Germann, Yow-Ming Wang, John Kyriakis, Ramon Mohanlal, Keisuke Kuida, Mark Namchuk, Francesco Salituro, Yung-mae Yao, Wei-min Hou, Xin Chen, Mark Aronovitz, Philip N. Tsichlis, Susmita Bhattacharya, Thomas Force, Heiko Kilter
Journal: Circulation Research (2005)

Akt is a central regulator of cardiomyocyte survival after ischemic injury in vitro and in vivo, but the mechanisms regulating Akt activity in the postischemic cardiomyocyte are not known. Furthermore, although much is known about the detrimental role that the c-Jun N-terminal kinases (JNKs) play in promoting death of cells exposed to various stresses, little is known of the molecular mechanisms by which JNK activation can be protective. We report that JNKs are necessary for the reactivation of Akt after ischemic injury. We identified Thr450 of Akt as a residue that is phosphorylated by JNKs, and the phosphorylation status of Thr450 regulates reactivation of Akt after hypoxia, apparently by priming Akt for subsequent phosphorylation by 3-phosphoinositide–dependent protein kinase. The reduction in Akt activity that is induced by JNK inhibition may have significant biological consequences, as we find that JNKs, acting via Akt, are critical determinants of survival in posthypoxic cardiomyocytes in culture. Furthermore, in contrast to selective p38–mitogen-activated protein kinase inhibition, which was cardioprotective in vivo, concurrent inhibition of both JNKs and p38–mitogen-activated protein kinases increased ischemia/reperfusion injury in the heart of the intact rat. These studies demonstrate that reactivation of Akt after resolution of hypoxia and ischemia is regulated by JNKs and suggest that this is likely a central mechanism of the myocyte protective effect of JNKs.
Matrix Metalloproteinase-2 Dysregulation in Type 1 Diabetes
Authors: Kathryn M. Thrailkill, Robert C. Bunn, Cynthia S. Moreau, Gael E. Cockrell, Pippa M. Simpson, Hannah N. Coleman, J. Paul Frindik, Stephen F. Kemp, John L. Fowlkes
Journal: Diabetes Care (2007)

OBJECTIVE—Dysregulation of matrix metalloproteinase (MMP)-2 may contribute pathologically to the development of diabetes complications, including diabetic retinopathy and coronary and peripheral arterial disease. Our objective was to explore whether systemic MMP-2 dysregulation could be demonstrated in type 1 diabetes and to determine how MMP-2 concentration relates to disease status. RESEARCH DESIGN AND METHODS—In this cross-sectional study, MMP-2 concentrations and MMP-2 activity were measured in plasma and timed urine samples from 93 type 1 diabetic and 50 healthy control subjects, aged 14–40 years. Relationships between MMP-2 concentrations in these biological fluids and subject characteristics (sex, age, and duration of type 1 diabetes), indexes of glycemic control (A1C, fasting plasma glucose, and continuous glucose monitoring system average daily glucose), and measurements of renal function (urinary albumin excretion and glomerular filtration rate) were examined. RESULTS—Urine and plasma MMP-2 concentrations and plasma MMP-2 activity were all significantly elevated in type 1 diabetic subjects compared with those in control subjects. Urine MMP-2 concentrations, in particular, were correlated with several clinical parameters that infer increased risk for diabetic comorbidity and specifically for diabetic nephropathy, including higher A1C, longer duration of disease, evidence of renal hyperfiltration, and the presence of microalbuminuria. CONCLUSIONS—Urine and plasma MMP-2 concentrations are dysregulated in type 1 diabetes; urinary excretion of MMP-2, in particular, might provide a unique biomarker of diabetes-induced intrarenal pathologic processes.
Role of Structural Barriers in the Mechanism of Alternans-Induced Reentry
Authors: Joseph M. Pastore, David S. Rosenbaum
Journal: Circulation Research (2000)

Abstract —Previously, using an animal model of T-wave alternans in structurally normal myocardium, we demonstrated that repolarization can alternate with opposite phase between neighboring myocytes (ie, discordant alternans), causing spatial dispersions of repolarization that form the substrate for functional block and reentrant ventricular fibrillation (VF). However, the mechanisms responsible for cellular discordant alternans and its electrocardiographic manifestation (ie, T-wave alternans) in patients with structural heart disease are unknown. We hypothesize that electrotonic uncoupling between neighboring regions of cells by a structural barrier (SB) is a mechanism for discordant alternans. Using voltage-sensitive dyes, ventricular action potentials were recorded from 26 Langendorff-perfused guinea pig hearts in the absence (ie, control) and presence of an insulating SB produced by an epicardial laser lesion. Quantitative analysis of magnitude and phase of cellular alternans revealed that in controls, action potential duration alternated in phase at all ventricular sites above a critical heart rate (269±17 bpm), ie, concordant alternans. Also, above a faster critical heart rate threshold (335±24 bpm), action potential duration alternated with opposite phase between sites, ie, discordant alternans. In contrast, only discordant but not concordant alternans was observed in 80% of hearts with the SB, and discordant alternans always occurred at a significantly slower heart rate (by 68±28 bpm) compared with controls. Therefore, the SB had a major effect on the alternans–heart rate relation, which served to facilitate the development of discordant alternans. Whether a SB was present or not, discordant alternans produced considerable increases (by ≈170%) in the maximum spatial gradient of repolarization, which in turn formed the substrate for unidirectional block and reentry. However, by providing a structural anchor for stable reentry, discordant alternans in the presence of a SB led most often to sustained monomorphic ventricular tachycardia rather than to VF, whereas in the absence of a SB discordant alternans caused VF. SBs facilitate development of discordant alternans between cells with different ionic properties by electrotonically uncoupling neighboring regions of myocardium. This may explain why arrhythmia-prone patients with structural heart disease exhibit T-wave alternans at lower heart rates. These data also suggest a singular mechanism by which T-wave alternans forms a substrate for initiation of both VF and sustained monomorphic ventricular tachycardia.
Prognostic significance of the aggregative perivascular growth pattern of tumor cells in primary central nervous system diffuse large B-cell lymphoma
Authors: Miaoxia He, Changjing Zuo, Jianjun Wang, Jianmin Liu, Binghua Jiao, Jianmin Zheng, Zailong Cai
Journal: Neuro-Oncology (2013)

Primary central nervous system lymphomas, predominantly diffuse large B-cell lymphomas (PCNS-DLBCL), are aggressive malignancies, and no histopathological variables with independent prognostic value are currently available. The aim of this study is to determine the prognostic value of histopathological variables of PCNS-DLBCL. Aggregative perivascular tumor cells (APVTs) and reactive perivascular T cell infiltrates (RPVIs) in tumor samples from 62 immunocompetent patients with PCNS-DLBCL were histopathologically and immunohistochemically studied. A mouse brain DLBCL model was established to confirm the special morphological features of PCNS-DLBCL. The therapy, overall response rate (ORR), and overall survival (OS) among patients were followed up. APVT was present in 54 (87%) of the 62 cases, whereas RPVI was present in 20 (32%). Patients with APVT-positive lesions exhibited significantly worse OS, with intermediate to high International Extranodal Lymphoma Study Group (IELSG) scores, compared with patients with RPVI-positive lesions. Among cases of APVT-positive lymphoma, the semiquantitative score of immunostaining of X-box–binding protein (XBP1) and CD44 demonstrated prognostic significance. Multivariate analysis confirmed independent associations between APVT and XBP1 and between CD44 staining and survival. The presence of APVT and staining of XBP1 and CD44 are independently associated with survival among patients with PCNS-DLBCL. These features could be routinely assessed in histopathological and immunohistochemical specimens.
Assessment of Autonomic Function in Patients with a Parkinsonian Syndrome
Authors: M. J. Aminoff, C. S. Wilcox
Journal: BMJ (1971)

The integrity of the autonomic nervous system was assessed in 11 Parkinsonian patients with symptoms suggestive of autonomic dysfunction. Three had the additional clinical features of the Shy-Drager variant of idiopathic orthostatic hypotension and were found to have a gross disturbance of vasomotor, sudomotor, pilomotor, and bladder function; assessment indicated that a lesion was present at sympathetic ganglionic level or beyond in two cases, though a more centrally placed lesion may well have been present also, as in the third case. In the remaining eight patients with paralysis agitans no unequivocal functional disturbance was found except in the bladder; nevertheless, the low resting blood pressure and the supersensitivity to intravenously infused L-noradrenaline in the three patients in whom it was tested is taken to imply defective regulation from higher centres, with a consequent reduction in impulse traffic at sympathetic nerve terminals. Such a concept is supported by experimental studies in animals and would account for the low renin and aldosterone secretion rates and reduced noradrenaline formation reported by others in patients with paralysis agitans.
Using criteria-based interview models for assessing clinical expertise to select physiotherapists at major multisport games
Authors: Nicola Phillips, Marie-Elaine Grant, Lynn Booth, Philip Glasgow
Journal: British Journal of Sports Medicine (2015)

Background Benchmarking is an established means of identifying levels of specialist practice and competence-based interviews are a tool used to facilitate this. The London 2012 Olympic and Paralympic Games (LOCOG) provided an opportunity to introduce a pragmatic approach to assess expert behaviour in large numbers of volunteer physiotherapists. Aim To test inter-tester repeatability of an assessment matrix used to score clinical expertise in a sporting context, followed by reporting on the findings for physiotherapy selection. Methods Four volunteers were videoed answering an identical sport-specific clinical scenario. Recordings were initially scored by two experienced assessors (gold standard). Subsequently, nine assessors scored the same videos then compared with the gold standard. 602 physiotherapists were assessed during volunteer interviews for LOCOG. Scores were compared to those based on self-reported clinical experience. Cross-tabulation was used to determine levels of agreement for the initial scoring matrix and the relationship between the two scoring systems was analysed. Results Levels of agreement ranged from 22% to 88%. A good correlation (r=0.754 p&gt;0.001) was found between self-reported clinical experience and scenario scores. Marginal data points in the correlational analysis indicated that only 52% of participants attained the same score across assessments. Conclusions A tool to facilitate assessment for large scale selection could be used for Host Nation physiotherapist selection for Major Games. There is a need to train assessors in this environment, as well as provide detailed matrices, specific to each context being assessed, to ensure that observations can be made on domain-specific and general, non-technical aspects.