tbuckley/cabot-search huggingface dataset:
STUDIES ON THE MECHANISM OF HYPERSENSITIVITY PHENOMENA
Authors: Abraham G. Osler, Harry G. Randall, Betsy M. Hill, Zoltan Ovary
Journal: The Journal of Experimental Medicine (1959)

The interaction of fresh rat and guinea pig serum with washed preformed immune aggregates has been studied with respect to the loss in hemolytic potency of the serum, diminution of the C'(3); activity, and appearance of anaphylatoxin. It has been found that the formation of anaphylatoxin, as judged by its effect on capillary permeability and smooth muscle contraction, is coincident with or subsequent to the fixation of all the known C' components. Less anaphylatoxin is formed by aggregates formed with excess antigen than those in equivalence ratio combination. C' fixation, as well as anaphylatoxin production, may be inhibited by chelation of the divalent cations, presumably by interfering with the fixation of C'(1), C'(4), and C'(2). Phlorizin suppresses the utilization of C'(3) in immune hemolysis, C' fixation by antigen-antibody aggregates, and the production of anaphylatoxin. The biological activities associated with the fixation of C' are not manifest unless C'(3) participates in this process at 37 degrees C. It is concluded that the formation of anaphylatoxin may be regarded as a product of C' fixation.
Targeting glucose metabolism for cancer therapy
Authors: Robert B. Hamanaka, Navdeep S. Chandel
Journal: The Journal of Experimental Medicine (2012)

Cellular transformation is associated with the reprogramming of cellular pathways that control proliferation, survival, and metabolism. Among the metabolic changes exhibited by tumor cells is an increase in glucose metabolism and glucose dependence. It has been hypothesized that targeting glucose metabolism may provide a selective mechanism by which to kill cancer cells. In this minireview, we discuss the benefits that high levels of glycolysis provide for tumor cells, as well as several key enzymes required by cancer cells to maintain this high level of glucose metabolism. It is anticipated that understanding which metabolic enzymes are particularly critical for tumor cell proliferation and survival will identify novel therapeutic targets.
Peripheral blood T and B lymphocytes during acute rheumatic fever.
Authors: R D Lueker, Z H Abdin, R C Williams
Journal: Journal of Clinical Investigation (1975)

Proportions and total numbers of thymus-derived (T) and bone marrow-derived (B) peripheral blood lymphocytes were studied in 53 patients with acute rheumatic fever, diagnosed on the basis of modifified Jones criteria. An elevation in both proportions and absolute numbers of cells bearing surface Ig was found in most patients, particularly during the first 7 days after onset. Conversely, T-cell proportions and numbers were often found to be depressed early in the acue phases of rheumatic fever. Proportions of cells bearing surface Ig did not correlate with another B-cell marker, the aggregated gamma globulin receptor, suggesting that such cells bearing surface Ig were not all B lymphocytes. Incuvation for 20 h at 37 per cent C of cells showing high proportions of surface Ig-bearing surface Ig in both normal and rheumatic fever subjects, although there was no appreciable increment in proportions of lymphocytes expressing T-cell markers. Patients with initial attacks showed higher percentages and total numbers of Ig-bearing lymphocytes (P smaller than 0.01) than did those with rneumatic fever recurrences. Elevations in numbers and proportions of peripheral blood lymphocytes bearing Ig appeared to correlate with the relative acute nature of the rheumatic fever attack.
Increased thromboxane biosynthesis during coronary thrombolysis. Evidence that platelet activation and thromboxane A2 modulate the response to tissue-type plasminogen activator in vivo.
Authors: D J Fitzgerald, F Wright, G A FitzGerald
Journal: Circulation Research (1989)

Platelet activation is markedly increased during coronary thrombolysis and limits the response to thrombolytic therapy. A possible mediator of platelet activation in this setting is thromboxane (TX) A2, a potent platelet agonist formed in greatly increased amounts during coronary thrombolysis in man. To address this hypothesis, we examined the role of TXA2 in modulating the response to intravenous tissue-type plasminogen activator (t-PA) in a chronic canine model of coronary thrombosis. Reperfusion occurred in 60 +/- 5 minutes and was complicated by spontaneous reocclusion. The times to reperfusion and reocclusion were platelet-dependent. Consistent with a role for TXA2 in this process, TXA2 biosynthesis, determined a excretion of its enzymatic metabolite, 2,3-dinor-TXB2, was markedly increased during coronary thrombolysis. Furthermore, inhibition of TXA2 by aspirin, given alone or in combination with a TXA2/prostaglandin endoperoxide receptor antagonist, accelerated reperfusion and partly inhibited cyclic flow variations during reperfusion. The delay in reperfusion and reocclusion induced by TXA2 appeared to be mediated by platelet aggregation since the F(ab')2 fragment of 7E3, a monoclonal antibody to the platelet GPIIb/IIIa, also accelerated reperfusion and prevented reocclusion without altering TXA2 biosynthesis. These finding suggest that platelet aggregation limits the response to coronary thrombolysis and that platelet activation in this setting is partly TXA2-dependent.
International Union of Pharmacology. LXX. Subtypes of γ-Aminobutyric Acid<sub>A</sub>Receptors: Classification on the Basis of Subunit Composition, Pharmacology, and Function. Update
Authors: Richard W. Olsen, Werner Sieghart
Journal: Pharmacological Reviews (2008)

In this review we attempt to summarize experimental evidence on the existence of defined native GABA<sub>A</sub> receptor subtypes and to produce a list of receptors that actually seem to exist according to current knowledge. This will serve to update the most recent classification of GABA<sub>A</sub> receptors (<i>Pharmacol Rev</i> 50:291–313, 1998) approved by the Nomenclature Committee of the International Union of Pharmacology. GABA<sub>A</sub> receptors are chloride channels that mediate the major form of fast inhibitory neurotransmission in the central nervous system. They are members of the Cys-loop pentameric ligand-gated ion channel (LGIC) superfamily and share struc-tural and functional homology with other members of that family. GABA<sub>A</sub> receptors are assembled from a family of 19 homologous subunit gene products and form numerous, mostly hetero-oligomeric, pentamers. Such receptor subtypes with properties that depend on subunit composition vary in topography and ontogeny, in cellular and subcellular localization, in their role in brain circuits and behaviors, in their mechanisms of regulation, and in their pharmacology. We propose several criteria, which can be applied to all the members of the LGIC superfamily, for including a receptor subtype on a list of native hetero-oligomeric subtypes. With these criteria, we develop a working GABA<sub>A</sub> receptor list, which currently includes 26 members, but will undoubtedly be modified and grow as information expands. The list is divided into three categories of native receptor subtypes: "identified," "existence with high probability," and "tentative."
PMS2 mutations in childhood cancer
Authors: D T Bonthron
Journal: Gut (2005)

Pitfalls in diagnosing acute pancreatitisWe thank Jolobe for his letter (Gut 2005;54:1207-8) which mentions the difficulty of establishing the diagnosis of acute pancreatitis in patients with diabetic ketoacidosis.We did not address diagnostic tests and medical intensive care treatment of acute pancreatitis in our article, 1 but reviewed the interventional and surgical treatment strategies in acute pancreatitis.There is no doubt that treatment of acute pancreatitis, including organ failure in its early phase, is solely supportive. 2 Due to improvements in inten- sive care medicine, mortality of severe disease has decreased dramatically over the past decades.However, to treat patient adequately, the correct diagnosis has to be made.Therefore, the first step in the diagnostic process of acute pancreatitis is to think of this disease.According to the latest classification from Atlanta, 3 acute pancreatitis is an acute inflammatory process of the pancreas with variable involvement of other regional tissues or remote organ systems.From a clinical point of view, acute upper abdominal pain and elevated pancreatic enzyme levels are needed to diagnose acute pancreatitis.As pointed out by Jolobe in his letter, acute pancreatitis is still underdiagnosed under certain clinical conditions, including diabetic ketoacidosis, but also in other clinical situations, such as shock of unknown origin, patients under intensive care treatment, as well as rare causes of the disease.As acute pancreatitis can be associated with diabetic ketoacidosis and the association between these two is a two way cause-and-effect relationship, early imaging of the pancreas is recommended in these patients to establish the correct diagnosis.Our article focused on the surgical and interventional treatment of severe acute pancreatitis.
Endoscopic Ultrasound As a First Test for Diagnosis and Staging of Lung Cancer
Authors: Pankaj Singh, Brian Camazine, Yashodeep Jadhav, Rahul Gupta, Phalguni Mukhopadhyay, Ahmed Khan, Rama Reddy, Qi Zheng, David D. Smith, Renu Khode, Bankim Bhatt, Sanjay Bhat, Yasir Yaqub, Rajnikant S. Shah, Ashish Sharma, Pawan Sikka, Richard A. Erickson
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Rationale: Multiple tests are required for the management of lung cancer.Objectives: Endoscopic ultrasound–guided fine needle aspiration (EUS-FNA) was evaluated as a single test for the diagnosis and staging (thoracic and extrathoracic) of lung cancer.Methods: Consecutive subjects with computed tomography (CT) findings of a lung mass were enrolled for EUS and results were compared with those from CT and positron emission tomography scans.Results: Of 113 subjects with lung cancer, EUS was performed as a first test (after CT scan) for diagnosis in 93 (82%) of them. EUS-FNA established tissue diagnosis in 70% of cases. EUS-FNA, CT, and positron emission tomography detected metastases to the mediastinal lymph nodes with accuracies of 93, 81, and 83%, respectively. EUS-FNA was significantly better than CT at detecting distant metastases (accuracies of 97 and 89%, respectively; p = 0.02). Metastases to lymph nodes at the celiac axis (CLNs) were observed in 11% of cases. The diagnostic yields of EUS-FNA and CT for detection of metastases to the CLNs were 100 and 50%, respectively (p < 0.05). EUS was able to detect small metastases (less than 1 cm) often missed by CT. Metastasis to the CLNs was a predictor of poor survival of subjects with non–small cell lung cancer, irrespective of the size of the CLNs. Of 44 cases with resectable tumor on CT scan, EUS-FNA avoided thoracotomy in 14% of cases.Conclusions: EUS-FNA as a first test (after CT) has high diagnostic yield and accuracy for detecting lung cancer metastases to the mediastinum and distant sites. Metastasis to the CLNs is associated with poor prognosis. EUS-FNA is able to detect occult metastasis to the CLNs and thus avoids thoracotomy.
Comparison of oral prednisolone and intramuscular depot triamcinolone in patients with severe chronic asthma.
Authors: R F Willey, R J Fergusson, D J Godden, G K Crompton, I W Grant
Journal: Thorax (1984)

Grid cells in the rat medial entorhinal cortex fire (periodically) over the entire environment. These cells provide input to hippocampal granule cells whose output is characterized by one or more small place fields. We sought to understand how this input–output transformation occurs. Available information allows simulation of this process with no freely adjustable parameters. We first examined the spatial distribution of excitation in granule cells produced by the convergence of excitatory inputs from randomly chosen grid cells. Because the resulting summation depends on the number of inputs, it is necessary to use a realistic number (∼1200) and to take into consideration their 20-fold variation in strength. The resulting excitation maps have only modest peaks and valleys. To analyze how this excitation interacts with inhibition, we used an <i>E</i>%-max (percentage of maximal suprathreshold excitation) winner-take-all rule that describes how gamma-frequency inhibition affects firing. We found that simulated granule cells have firing maps that have one or more place fields whose size and number approximates those observed experimentally. A substantial fraction of granule cells have no place fields, as observed experimentally. Because the input firing rates and synaptic properties are known, the excitatory charge into granule cells could be calculated (2–3 pC) and was found to be only somewhat larger than required to fire granule cells (1 pC). We conclude that the input–output transformation of dentate granule does not depend strongly on synaptic modification; place field formation can be understood in terms of simple summation of randomly chosen excitatory inputs, in conjunction with a winner-take-all network mechanism.
Thrombocytopenia identifies a severe familial phenotype of systemic lupus erythematosus and reveals genetic linkages at 1q22 and 11p13
Authors: R. Hal Scofield, Gail R. Bruner, Jennifer A. Kelly, Jeff Kilpatrick, Debra Bacino, Swapan K. Nath, John B. Harley
Journal: Blood (2003)
Enhanced expression of the protein kinase substrate annexin in human hepatocellular carcinoma
Authors: T Masaki
Journal: Hepatology (1996)

Annexin (AX) constitutes a new family of Ca2+-dependent membrane-binding proteins; 13 of them have been described. Among these, annexin-1 (AX-I) has displayed many biological functions in vitro. Its actual role in vivo, however, remains unknown. We already reported that AX-I was expressed in proliferating (regenerating) hepatocytes at both protein and messenger RNA (mRNA) levels. The role of AX-I in human hepatocellular carcinoma (HCC) remains obscure. In this study, the amounts of AX-I at protein and mRNA levels, as well as its localization, have been determined in the normal human liver, chronic hepatitis liver, and nontumorous and tumorous portions of HCC. AX-I was rarely found in normal and chronic liver tissues, whereas it is overexpressed at both the transcriptional and translational levels in tumorous and nontumorous regions of HCC. In addition, more AX-I was expressed in the tumorous portion than the nontumorous portion of HCC. AX-I was present in the hepatocytes and HCC cells, localized mainly in the cytoplasm. AX-I was expressed in poorly differentiated cancer cells. Furthermore, AX-I was tyrosine-phosphorylated in HCC. We also found that some of the AX-I-positive hepatocytes in the nontumorous tissues were derived from a particular subset of parenchymal cells (stem or oval cells). These results indicate that AX-I plays an important role in the malignant transformation process leading to HCC and that it is closely related to the histological grade of HCC. HCC would offer a novel tool with which to study the function of AX-I in malignant transformation. (Hepatology 1996 Jul;24(1):72-81)
Psychiatry in Australia
Authors: E. CUNNINGHAM DAX
Journal: American Journal of Psychiatry (1967)

In 1951 the government of Victoria took steps toward a major reform of its mental health services which set the example for comparable advances in other parts of Australia. In the following 16 years much has been done to overcome the serious deficiencies in the country's psychiatric services. The author concludes that greater federal participation is needed to coordinate present efforts and to close the existing gap between treatment of the physically ill and treatment of the mentally ill.
Tristetraprolin Down-regulates Interleukin-8 and Vascular Endothelial Growth Factor in Malignant Glioma Cells
Authors: Esther Suswam, Yanyan Li, Xiaowen Zhang, G. Yancey Gillespie, Xuelin Li, John J. Shacka, Liang Lu, Lei Zheng, Peter H. King
Journal: Cancer Research (2008)

Abstract Malignant gliomas are highly aggressive tumors of the central nervous system that rely on production of growth factors for tumor progression. Vascular endothelial growth factor (VEGF), interleukin-8 (IL-8), and tumor necrosis factor-α, for example, are up-regulated in these tumors to promote angiogenesis and proliferation. RNA stability, mediated through adenine and uridine-rich elements (ARE) in the 3′ untranslated region, is a critical control point for regulating these growth factors. RNA half-life is predominantly governed by a balance between stabilizing and destabilizing factors that bind to ARE. We have previously shown that the stabilizing factor HuR is overexpressed in malignant gliomas and linked to RNA stabilization of angiogenic growth factors. Here, we report that the destabilizing factor tristetraprolin (TTP) is also ubiquitously expressed in primary malignant glioma tissues and cell lines. In contrast to benign astrogliotic tissues, however, the protein was hyperphosphorylated, with evidence implicating the p38/mitogen-activated protein kinase (MAPK) pathway. Conditional overexpression of TTP as a transgene in malignant glioma cells led to RNA destabilization of IL-8 and VEGF and down-regulation of protein production. Analysis of in vivo RNA binding indicated a shift of mRNA toward ectopic TTP and away from endogenous HuR. This biochemical phenotype was associated with a decrease in cell proliferation, loss of cell viability, and apoptosis. We postulate that hyperphosphorylation of TTP via p38/MAPK promotes progression of malignant gliomas by negatively regulating its RNA destabilizing function. [Cancer Res 2008;68(3):674–82]
Postsystolic Shortening in Ischemic Myocardium
Authors: Helge Skulstad, Thor Edvardsen, Stig Urheim, Stein Inge Rabben, Marie Stugaard, Erik Lyseggen, Halfdan Ihlen, Otto A. Smiseth
Journal: Circulation (2002)

Background — Postsystolic shortening in ischemic myocardium has been proposed as a marker of tissue viability. Our objectives were to determine if postsystolic shortening represents active fiber shortening or passive recoil and if postsystolic shortening may be quantified by strain Doppler echocardiography (SDE). Methods and Results — In 15 anesthetized dogs, we measured left ventricular (LV) pressure, myocardial long-axis strains by SDE, and segment lengths by sonomicrometry before and during LAD stenosis and occlusion. Active contraction was defined as elevated LVP and stress during postsystolic shortening when compared with the fully relaxed ventricle at similar segment lengths. LAD stenosis decreased systolic shortening from 10.4±1.2% to 5.9±0.9% ( P &lt;0.05), whereas postsystolic shortening increased from 1.1±0.3% to 4.2±0.7% ( P &lt;0.05). In hypokinetic and akinetic segments, LV pressure–segment length and LV stress–segment length loop analysis indicated that postsystolic shortening was active. LAD occlusion resulted in dyskinesis, and postsystolic shortening increased additionally to 8.2±1.0% ( P &lt;0.05). After 3 to 5 minutes with LAD occlusion, the dyskinetic segment generated no active stress, and the postsystolic shortening was attributable to passive recoil. Elevation of afterload caused hypokinetic segments to become dyskinetic, and postsystolic shortening remained partly active. Postsystolic shortening by SDE correlated well with sonomicrometry ( r =0.83, P &lt;0.01). Conclusions — Postsystolic shortening is a relatively nonspecific feature of ischemic myocardium and may occur in dyskinetic segments by an entirely passive mechanism. However, in segments with systolic hypokinesis or akinesis, postsystolic shortening is a marker of actively contracting myocardium. SDE was able to quantify postsystolic shortening and might represent a clinical method for identifying actively contracting and hence viable myocardium.
EVIDENCE OF SUPPRESSOR CELL ACTIVITY IN SPLEENS OF MICE BEARING PRIMARY TUMORS INDUCED BY MOLONEY SARCOMA VIRUS
Authors: H. Kirchner, T. M. Chused, R. B. Herberman, H. T. Holden, D. H. Lavrin
Journal: The Journal of Experimental Medicine (1974)

Spleens from Moloney sarcoma virus (MSV) tumor-bearing C57BL/6N mice contained four times the normal number of mononuclear cells and displayed a markedly elevated "spontaneous" (mitogen-independent) DNA synthesis on a per cell basis. The number of macrophages were increased three-fold while there was a slight reduction in the percentage of T lymphocytes. The phytohemagglutinin (PHA) response on a per cell basis of spleens from tumor-bearing mice was decreased about 90% when compared with normal control mice. The primary in vitro immune response to sheep red blood cells was also suppressed to levels of less than 10% of normals. The PHA response could be restored by purification of MSV spleen cells by rayon adherence columns and by removal of phagocytic cells by an iron/magnet technique. The activity of suppressor cells in MSV spleens was demonstrated in mixtures with syngeneic normal spleen cells where a marked impairment of the PHA response was observed. Spleen cells from tumor-free nude mice and normal spleen cells treated by anti-theta serum plus guinea pig complement (C'), both totally unreactive to PHA, had no such effect. The inhibitor cell in MSV spleens was shown to be insensitive to inactivation by anti-theta plus C', but could be removed by the adherence columns and the iron/magnet technique. These data suggest that this suppressor cell is a cell of the monocyte/macrophage series. Suggestive evidence was also presented that the suppressor cells belong to a proliferating population in MSV spleens. Similar suppressor cells have been previously demonstrated in spleens of mice during a variety of immune responses. Our data show, that a tumor, although stimulating the immune system, nevertheless may be suppressive on certain immune functions through the activation of suppressor cells.
Impact of Clopidogrel Plus Aspirin Versus Aspirin Alone on the Progression of Native Coronary Artery Disease After Bypass Surgery
Authors: Dai Une, Talal Al-Atassi, Alexander Kulik, Pierre Voisine, Michel Le May, Marc Ruel
Journal: Circulation (2014)

Background— The effects of dual antiplatelet therapy with aspirin and clopidogrel on the progression of native coronary artery disease after coronary artery bypass grafting are unknown. Methods and Results— In the Clopidogrel After Surgery for Coronary Artery DiseasE (CASCADE) trial, a total of 113 patients were randomized to receive aspirin plus clopidogrel or aspirin plus placebo for 1 year after coronary artery bypass grafting. In this secondary analysis, the 92 patients who underwent preoperative and 1-year postoperative angiograms at 2 centers had each of their coronary stenoses graded serially by using 6 thresholds (grade 0 [0%–24%], grade 1 [25%–37%], grade 2 [38%–62%], grade 3 [63%–82%], grade 4 [83%–98%], and grade 5 [99%–100%]). We compared the incidence and degree of evolving coronary artery disease between the 2 treatment groups. A total of 543 preoperative stenoses and occlusions were quantified and followed. At 1-year postoperatively, there were 103 evolving (94 worsened, 9 improved) and 22 new lesions. The right coronary artery territory and sites proximal to a graft were more commonly associated with worsening coronary artery disease ( P ≤0.02). There were no differences in clinical events between treatment groups, and the proportion of patients with evolving or new lesions was also similar (70% versus 74%, aspirin–clopidogrel versus aspirin–placebo, respectively; P =0.8). However, in evolving or new lesions, the mean grade change (1.1±1.0 versus 1.6±1.1, respectively; P =0.01) and the proportion of new occlusions (7% versus 22%; P =0.02) were lower in the aspirin–clopidogrel group. Conclusions— The addition of clopidogrel to aspirin correlates with less worsening of native coronary artery disease 1 year after coronary artery bypass grafting. These findings may help guide post–coronary artery bypass grafting antiplatelet therapy. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00228423.