tbuckley/cabot-search huggingface dataset:
Hemodynamic effects of blood volume restitution following a hemorrhage in rats with portal hypertension due to cirrhosis of the liver: Influence of the extent of portal-systemic shunting
Authors: David Kravetz, Jaime Bosch, Maite Arderiu, Pilar M. Pizcueta, Juan Rodés
Journal: Hepatology (1989)

The present study investigated whether, in rats with portal hypertension due to cirrhosis of the liver induced by carbon tetrachloride, blood volume restitution following a hemorrhage produces an increase of portal pressure beyond control values, as observed in rats with prehepatic portal hypertension. Since carbon tetrachloride-induced cirrhosis caused mild portal-systemic shunting, in some of the cirrhotic rats (12 of 29 rats) portal-systemic shunting was enhanced by a transient (4 days) partial constriction of the portal vein, which was removed 1 week prior to the study. After baseline measurements of portal pressure and arterial pressure, 15 ml per kg of blood were withdrawn at a rate of 0.3 ml per min and reinfused 15 min later. After blood reinfusion, portal pressure and arterial pressure were measured again, and cardiac output, regional blood flows and portal-systemic shunting were determined using radioactive microspheres. Portal-systemic shunting was 78 ± 11% of total blood flow in the cirrhotic rats that had temporary portal vein constriction, but only 5 ± 2% (p &lt; 0.001) in those that did not. Blood volume restitution in low-portal-systemic shunting rats did not produce any significant modification in splanchnic or systemic hemodynamics. However, in rats with high portal-systemic shunting, blood volume restitution produced a significant increase in portal pressure (from 9.9 ± 0.9 to 13.5 ± 0.9 mmHg, p &lt; 0.02). This increase in portal pressure after blood reinfusion was due to a significant increase in portal vascular resistance (from 1.3 ± 0.2 to 1.9 ± 0.2 mmHg per ml per min per 100 gm, p &lt; 0.05), since no significant changes were observed in either portal blood flow or systemic hemodynamics. Our results show that blood volume restitution after a hemorrhage worsens the portal hypertension syndrome in cirrhotic rats with high portal-systemic shunting but not in those with low portal-systemic shunting, thus demonstrating that the extent of portal-systemic shunting is an important mediator of this deleterious effect.
Theory of Schizophrenia
Authors: I. I. Gottesman
Journal: BMJ (1965)

<h3>Introduction</h3> Eosinophilic Oesophagitis (EoE) is an increasing clinical problem. Patients with EoE commonly present with dysphagia, food impaction, chest pain unresponsive to antacids, and gastro-oesophageal reflux disease (GORD) like symptoms. To confirm a diagnosis of EoE, it is highly recommended to obtain oesophageal biopsies following trial of high-dose proton pump inhibitor therapy (to exclude GORD which may also have microscopic eosinophilia). Sampling from both normal and abnormal appearing areas with a minimum of 4 biopsies (each proximal and distal oesophagus) is recommended. Doing 6–9 biopsies increases the sensitivity of detecting EoE to 100%. Histologically, the diagnosis of EoE is made in presence of at least 15 eosinophils per high-power field (hpf) and should be documented in the microscopic histopathology report. <h3>Method</h3> A single centre, retrospective analysis, of patients with a diagnosis of EoE at a large NHS Hospital Trust in north London over 4 years from 2010 was performed. The database of patients was obtained from histology department. The endoscopy and histology report of the patients were analysed for the number of biopsies obtained (protocol recommends 8), site at which biopsies were obtained (protocol recommends proximal and distal oesophagus) and presence of &gt; 15 eosinophils per hpf within the histology report. <h3>Results</h3> During the study period, 29 patients with EoE were identified. The number of biopsies obtained varied from 1–8 (mean 3.5). One patient had 8 biopsies. 28/29 patients had 7 or less biopsies obtained. No patient had at least 4 biopsies from 2 different sites, with 15 (52%) having biopsy from lower oesophagus, 10 (30%) from mid oesophagus, 2 (7%) from middle and upper oesophagus and 1 (3%) from upper and lower oesophagus, One had biopsies fromupper, middle and lower oesophagus. In 6 of 29 (20%),the histopathology report explicitly mentioned the presence of &gt;15 eosinophils per hpf. <h3>Conclusion</h3> From this study, we conclude that biopsy protocol for diagnosis of EoE falls short of the consensus recommendations, not only in the total number of oesophageal biopsies obtained but also location from which biopsies are obtained. In only 83% of patients was the recommended diagnostic criteria of &gt;15 eosinophils per hpf used. If biopsy and reporting protocol is not followed there is a risk that patients with another cause of raised eosinophils (eg GORD) may be incorrectly diagnosed with EoE. We recommend a greater awareness and observation of the protocol for obtaining biopsies and its histology reporting in EoE. <h3>Disclosure of interest</h3> None Declared.
Abstract 4483: SR13668, a selective 12-lipoxygenase inhibitor, suppresses tumor growth by modulating the Akt signaling pathway
Authors: Ling Jong, Wan-Ru Chao, Carol Green, Izet Kapetanovic, Lidia Sambucetti, Nathan Collins
Journal: Cancer Research (2011)

Abstract SR13668, an orally active cancer therapeutic agent, exhibits potent antitumor activity against various human cancer xenografts (e.g., breast, prostate, lung and ovarian cancer) without significant toxicity. An exploratory IND study of SR13668 has been completed with a two-stage design to compare the bioavailability of five SR13668 formulations, and the preferred formulation will be subjected to investigation in subsequent phase I testing. SR13668 inhibits growth factor-stimulated phosphorylation of Akt and its downstream target GSK3β in PC-3 prostate and high pAkt expressing MDA-MB-468 breast cancer cells in a dose-dependent manner. SR13668 was also shown to block FGF- and IGF-stimulated Akt activation. Screening a broad selection of kinase targets, including Akt(1,2,3), PI3K, and PDK1, indicated that SR13668 is not a kinase inhibitor. Preliminary mechanistic studies showed that SR13668 selectively inhibits 12-lipoxygenase (12-LOX), but does not affect other lipoxygenases (5-LOX and 15-LOX), or cyclooxygenases (COX-1 and COX-2). 12-LOX plays a major role in promoting cancer progression, invasion and metastasis as well as tumor angiogenesis. 12-LOX has been regarded as a novel target for cancer therapy, since it is generally absent in normal epithelia and is often constitutively expressed in various epithelial cancers. Unlike direct inhibitors of PI3K or Akt, SR13668 has no adverse effects on fasting glucose levels or body weights after 14 days of oral treatment with SR13668 at 500 mg/kg/day, a dose more than 10 times higher than that needed for antitumor activity. Pharmacologic intervention studies with lipoxygenase inhibitors for the prevention or inhibition of cancers have been difficult to interpret, as there are very few isoform-selective LOX inhibitors available. SR13668 is a highly specific 12-LOX inhibitor. No off-target activities were observed, when screened against a broad collection of 40 diverse enzymes and 80 transmembrane and soluble receptors, ion channels and monoamine transporters. The Phase 0 clinical study showed that SR13668 has long half-life (11.2 ± 3.1 hours), and patients did not experience significant adverse events related to SR13668 treatment; thus SR13668 is a promising candidate for further clinical investigation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4483. doi:10.1158/1538-7445.AM2011-4483
UNCONSCIOUS MOTIVATION AND THE POLYGRAPH TEST
Authors: H. B. DEARMAN, B. M. SMITH
Journal: American Journal of Psychiatry (1963)

A case has been presented which illustrates some of the psychological, ethical, and possibly legal problems associated with the use of the polygraph examination (lie detector) in commercial establishments. The polygraph technique only provides measures of various autonomic responses. The stimuli that elicit these responses, the intervening variables (constitutional predisposition, past learning, conscious and unconscious motivation, etc.) and the interpretations made of the resulting graphs are highly complex and are inferences made from more or less incomplete data. In any event, these instruments do not identify lying per se. The interpretation of the polygraph record is based on inferences of varying levels of remoteness. Inference is subjective; hence, polygraph examiners can, and do, make different interpretations of the same record. It is our conclusion that the application of the polygraph technique as a lie detector is fraught with too many variables and sources of error for it to be used as it is currently being used in business and industry. Its use in criminal investigations and in other situations involving the commonweal (such as screening employees for sensitive government positions) should be carefully and continually scrutinized, lest we find that George Orwell's 1984 is upon us.
Repair-related activation of hedgehog signaling promotes cholangiocyte chemokine production
Authors: Alessia Omenetti, Wing‐Kin Syn, Youngmi Jung, Heather Francis, Alessandro Porrello, Rafal P. Witek, Steve S. Choi, Liu Yang, Marlyn J. Mayo, M. Eric Gershwin, Gianfranco Alpini, Anna Mae Diehl
Journal: Hepatology (2009)

The mechanisms mediating hepatic accumulation of inflammatory cells in cholestatic liver disease remain enigmatic. Our thesis is that Hedgehog (Hh) pathway activation promotes hepatic accumulation of immune cells that interact with cholangiocytes. We believe that myofibroblastic hepatic stellate cells (MF-HSCs) release soluble Hh ligands that stimulate cholangiocytes to express chemokines that recruit mononuclear cell types with cognate receptors for these chemokines, thereby orchestrating a repair-related mechanism for liver inflammation. To address this thesis, we used three experimental systems that allow the definition of Hh-dependent mechanisms that induce phenotypic changes in cholangiocytes. First, cholangiocytes were cultured alone or in the presence of Hh-producing MF-HSCs in a transwell coculture system and/or treated with MF-HSC-conditioned medium with or without Hh-neutralizing antibodies. Changes in the cholangiocyte phenotype were then evaluated by microarray analysis, quantitative reverse-transcriptase polymerase chain reaction (QRT-PCR), and/or enzyme-linked immunosorbent assay for chemokine (C-X-C) motif ligand 16 (Cxcl16). Bile duct ligation was chosen to model biliary fibrosis in mice with an overly active Hh pathway, control littermates, and healthy rats, and the gene profile was evaluated by QRT-PCR in whole liver tissue. Second, a transwell chemotaxis assay was used to examine natural killer T (NKT) cell migration in response to cholangiocytes and particularly cholangiocyte-derived Cxcl16. Finally, we studied liver samples from primary biliary cirrhosis patients and controls by QRT-PCR to compare differences in the Hh pathway and Cxcl16. Co-immunostaining of cytokeratin-7 and Cxcl16 was then performed to localize the phenotypic source of Cxcl16. We found that MF-HSCs release soluble Hh ligands that stimulate cholangiocytes to produce Cxcl16 and recruit NKT cells. Hh pathway activation during cholestatic liver injury also induces cholangiocyte expression of Cxcl16.During biliary injury, Hh pathway activation induces cholangiocyte production of chemokines that recruit NKT cells to portal tracts.
Effect of soluble products from lectin-stimulated lymphocytes on the growth, adhesiveness, and glycosaminoglycan synthesis of cultured synovial fibroblastic cells.
Authors: T P Anastassiades, A Wood
Journal: Journal of Clinical Investigation (1981)

Human blood mononuclear cells exposed to concanavalin A or phytohemagglutinin secrete a soluble factor that arrests the growth of human synovial fibroblastic cells in culture. Once the growth-inhibitory effect is initiated it cannot be reversed by washing the fibroblastic cells, by refeeding with nonconditioned fresh serum-containing medium, by trypsinization, EDTA treatment, or a combination of these procedures. Media from nonstimulated mononuclear cells, fibroblastic cells, or the lectins themselves do not contain similar inhibitory activity that can be detected by the present culture systems. This lectin-dependent, growth-inhibitory activity does not have a cytotoxic effect on the fibroblasts but increases their adhesiveness to plastic or glass surfaces, and the cells tend to assume a less fibroblastic morphology. The growth-inhibitory activity is stable in the cold and is nondialyzable or ultrafilterable, but the activity is rapidly lost at temperature between 60 degrees and 70 degrees C and at pH 2.0. The growth-arrested cells secrete more glycosaminoglycan per cell in the medium and synthesize more cell surface glycosaminoglycan than the controls. However, the increased glycosaminoglycan synthesis cannot be explained as being entirely secondary to a cell density effect as it is also observed when adjustments are made for the differences in growth rates.
The future of community medicine.
Authors: G M Reynolds
Journal: BMJ (1971)

1 Hawkey, J. K., Loudon, I. S. L., Bungay, G. T., and Greenhalgh, G. P., British Medical Journal, 1968, 2, 699. * Tunbridge, R. E., The Standardization of Hospital Medical Records. London, H.M.S.O., 1965. 8 Central Health Services Council, Committee on Field of Work of the Family Doctor. London, H.M.S.O., 1963. 4 Wallace, B. B., and Havard Davies, R., Journal of the Royal College of General Practitioners, 1970, 20, 163. 6 Cormack, J. J. C, Journal of the Royal College of General Practitioners, 1970, 20, 333. Coulay, R., Modern Management, 1970, 1, 5. 7 Taylor, B., London Doctor, 1970, 1, 4. 8 Cormack, J. J. C, Scottish Health Service Studies, No. 15, Edinburgh, H.M.S.O., 1971.
Abstract S2-1: Obesity at Diagnosis Is Associated with Inferior Outcomes in Hormone Receptor Positive Breast Cancer
Authors: JA Sparano, M Wang, S Martino, V Jones, EA Perez, T Saphner, AC Wolff, GW Sledge, WC Wood, J Fetting, NE. Davidson
Journal: Cancer Research (2010)

Abstract Background: Obesity has been associated with worse outcomes in operable breast cancer. We evaluated the effect of obesity on outcomes in several adjuvant trials coordinated by the ECOG which included doxorubicin/cyclophosphamide plus other agents, including E1199 (NEJM 2008; 358: 1663), E5188 (JCO 2005; 23: 5973) and E3189 (JCO 10998; 16: 2382). Methods: The relationship between body mass index (BMI in kg/m2) and disease free survival (DFS) and overall survival (OS) was evaluated in multivariate models adjusted for covariates including age, tumor size, nodal status, race (black vs. other), surgery type, prior RT, menopausal status, treatment arm, and treatment adherence. Results are expressed as hazard ratios (HR) from Cox's proportional hazards models (HR &amp;gt; 1 indicates a worse outcome). All p-values are two sided. Results: The study characteristics and results are shown in the table below. We first evaluated results for the E1199 trial (for the 75% of those with BMI data available) and found a non-significant trend toward inferior DFS (HR 1.10, 95% CI 0.96, 1.26, p=0.18) and OS (HR 1.13, 95% CI 0.96, 1.33, p=0.15) for obese subjects compared with others. When evaluated by breast cancer subtype, however, obese subjects with ER and/or PR-positive/HER2-negative disease had significantly inferior DFS (HR 1.24, p=0.026) and OS (HR 1.42, p=0.003), an effect that was not seen for HER2-positive and triple negative disease. In a model including obesity, ER and/or PR-pos/HER2-neg disease, and their interaction, the interaction term was significant for OS (p=0.017) but not DFS (p=0.21). There was no evidence for differing chemotherapy delivery or endocrine therapy adherence, or differences in toxicity for obese subjects in the E1199 trial. We then evaluated the relationship between obesity and outcomes in two prior ECOG studies which included only premenopausal women with ER positive, node positive breast cancer (E5188) and women of any age with ER/PR negative, node positive disease (E3189), and confirmed a relationship between obesity and poor outcomes only in women with hormone receptor positive disease. HR-hazard ratio; ER/PR-estrogen/progesterone receptor Conclusions: Obesity was associated with significantly inferior DFS and OS in hormone receptor positive operable breast cancer treated with adjuvant chemotherapy. These findings suggest that hyperinsulinemia or other factors associated with obesity may predispose to recurrence specifically in hormone receptor positive disease, and requires further evaluation in prospective studies in order to identify modifiable factors contributing to this effect. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S2-1.
Nonprescription Sale of Inhaled Metaproterenol — Déjà Vu
Authors: Leslie Hendeles, Miles Weinberger
Journal: New England Journal of Medicine (1984)

IN the October 25, 1982, issue of the Federal Register, the Food and Drug Administration announced its intention to change the status of metaproterenol in metered-dose inhalers from a prescription to a nonprescription medication.1 In March 1983, over-the-counter sales began and were accompanied by an intensive television advertising campaign that encouraged self-medication of asthma with "prescription strength" Alupent. The FDA initiated this change on the basis of the safety and efficacy of the medication during its use by prescription in the United States over the previous nine years. In support, they cited studies in which inhaled metaproterenol had been . . .
Review: bDMARDs are linked to increased risk for infection compared with conventional synthetic DMARDs in RA
Authors: Ami Schattner
Journal: Annals of Internal Medicine (2014)

Source Citation Ramiro S, Gaujoux-Viala C, Nam JL, et al. Safety of synthetic and biological DMARDs: a systematic literature review informing the 2013 update of the EULAR recommendations for management of rheumatoid arthritis. Ann Rheum Dis. 2014;73:529-35. 24401994
Diagnosis of deep vein thrombosis by plasma-soluble fibrin or D-dimer
Authors: Satoshi Ota, Hideo Wada, Tsutomu Nobori, Toshihiko Kobayashi, Midori Nishio, Yukiko Nishioka, Maki Noda, Akane Sakaguchi, Yasunori Abe, Junji Nishioka, Ken Ishikura, Norikazu Yamada, Takeshi Nakano
Journal: American Journal of Hematology (2005)

The present study was designed to determine the cutoff values of D-dimer and soluble fibrin (SF) for the diagnosis of deep venous thrombosis (DVT) and pulmonary embolism (PE) in Japanese patients. Plasma levels of these molecules were measured in 243 patients suspected of having DVT and 100 healthy volunteers (controls). Out of 243 patients, 20 patients were diagnosed with DVT. In the control group, plasma levels of D-dimer and SF did not show normal distribution, and the 95% confidence intervals (CI) of D-dimer and SF were 2.45 μg/mL and 6.92 μg/mL, respectively. Plasma levels of D-dimer and SF of patients with DVT were significantly higher than of those without DVT. In patients with DVT, the minimum values of D-dimer and SF were 1.71 and 1.44 μg/mL, respectively. When the cutoff value was set at the average + 1 SD of those of the control (D-dimer, about 1.8 μg/mL; SF, about 1.4 μg/mL), 1 and 0 patient with DVT was overlooked, respectively. The sensitivity and specificity of D-dimer and SF for DVT were 95% and 100%, and 61.9% and 53.8%, respectively. When the cutoff value was set at 95% CI of the control (D-dimer, 2.5 μg/mL; SF, 6.9 μg/mL), 2 and 9 patients with DVT were overlooked, respectively. The sensitivity and specificity of D-dimer and SF were 90% and 50%, and 77.6% and 88.3%, respectively. When the cutoff values set at 2.5 μg/mL of D-dimer or 6.9 μg/mL of SF, 1 DVT patient was overlooked, with sensitivity and specificity of 95% and 69.5%. Our data suggest that both D-dimer and SF are useful markers for the diagnosis of DVT and that measurement of both D-dimer and SF increases the sensitivity and specificity for the diagnosis of DVT/PE. Am. J. Hematol. 79:274–280, 2005. © 2005 Wiley-Liss, Inc.
Molecular sieving of albumin by the ascending vasa recta wall.
Authors: T L Pallone
Journal: Journal of Clinical Investigation (1992)

Molecular sieving of albumin by ascending vasa recta. Evidence exists to support the presence of an extravascular pool of albumin in the renal medullary interstitium. This study used microperfusion in vivo to measure the transport of 125I-labeled albumin from descending (DVR) and ascending vasa recta (AVR) to the papillary interstitium. Perfusions were performed during furosemide diuresis with a buffer containing FITC-labeled dextran (FITC-Dx) 2 x 10(6) mol wt and 125I-albumin. Perfusate albumin and collection pressure were adjusted to induce either zero transcapillary volume flux (Jv) or high volume flux. When Jv was zero, the collectate-to-perfusate ratios of FITC-Dx (RDX) and 125I-albumin (Ralb) in the DVR and AVR were identical implying that diffusive efflux of albumin was immeasurably small. In contrast, when Jv was increased, paired comparison of Ralb and RDX in the same AVR revealed a difference, 1.58 +/- 0.06 vs 1.72 +/- 0.08, respectively (P less than 0.01). AVR perfusions in hydropenic animals showed similar results, Ralb = 1.70 +/- 0.07 and RDX = 2.00 +/- 0.07 (P less than 0.01). These data suggest that albumin transport across vasa recta in vivo is likely to be governed by solvent drag. The reflection coefficient of the AVR wall to 125I-albumin is estimated to be 0.78.
Heart Failure and Sudden Death in Patients With Tachycardia-Induced Cardiomyopathy and Recurrent Tachycardia
Authors: Pamela Nerheim, Sally Birger-Botkin, Lubna Piracha, Brian Olshansky
Journal: Circulation (2004)

Background— Tachycardia-induced cardiomyopathy is a reversible cause of heart failure. We hypothesized that although left ventricular ejection fraction measurements normalize after heart rate or rhythm control in patients with tachycardia-induced cardiomyopathy, recurrent tachycardia may have abrupt and deleterious consequences. Methods and Results— Patients with tachycardia-induced cardiomyopathy that developed over years were evaluated and treated. Tachycardia episodes and outcomes were assessed. Twenty-four patients were identified. All had NYHA functional class III heart failure or greater on presentation. One third were heart transplant candidates. There were 17 men and 7 women with a mean age of 46±16 years and mean left ventricular ejection fraction of 0.26±0.09 at the index visit. The cause was atrial fibrillation (n=13), atrial flutter (n=4), atrial tachycardia (n=3), idiopathic ventricular tachycardia (n=1), permanent junctional reciprocating tachycardia (n=2), and bigeminal ventricular premature contractions (n=1). Within 6 months of rate control or correction of the rhythm, left ventricular ejection fraction improved or normalized and symptoms abated in all. Five patients had tachycardia recur. In these patients, left ventricular ejection fraction dropped precipitously and heart failure ensued within 6 months, even though the initial impairment took years. Rate control eliminated heart failure and improved or normalized ejection fraction in 6 months. Three of 24 patients died suddenly and unexpectedly. Conclusions— Tachycardia-induced cardiomyopathy develops slowly and appears reversible by left ventricular ejection fraction improvement, but recurrent tachycardia causes rapid decline in left ventricular function and development of heart failure. Sudden death is possible.