tbuckley/cabot-search huggingface dataset:
Acetaminophen (Paracetamol) Improves Pain and Well-Being in People With Advanced Cancer Already Receiving a Strong Opioid Regimen: A Randomized, Double-Blind, Placebo-Controlled Cross-Over Trial
Authors: Martin Stockler, Janette Vardy, Avinesh Pillai, David Warr
Journal: Journal of Clinical Oncology (2004)

To determine whether adding regular acetaminophen (paracetamol) could improve pain and well-being in people with advanced cancer and pain despite strong opioids.Participants took acetaminophen for 48 hours and placebo for 48 hours. The order (acetaminophen or placebo first) was randomly allocated. Pain was the primary outcome. Preferences, number of opioid breakthrough doses, overall well-being, nausea and vomiting, drowsiness, constipation, and cold sweats were secondary outcomes. Patients rated themselves daily with visual analog scales (VAS) and a verbal numeric scale (VNS) for pain, all scaled from 0 to 10.Thirty patients completed the trial. The oral opioid was morphine in 23 patients and hydromorphone in seven patients. The median daily opioid dose in oral morphine equivalents was 200 mg (range, 20 to 2,100 mg). Nonsteroidal anti-inflammatory drugs, corticosteroids, or both were used by 16 patients. Pain and overall well-being were better for patients receiving acetaminophen than for those receiving placebo. The mean difference was 0.4 (95% CI, 0.1 to 0.8; P =.03) in VNS for pain, 0.6 (95% CI, -0.1 to 1.3; P =.09) in VAS for pain, and 0.7 (95% CI, 0.0 to 1.4; P =.05) in VAS for overall well-being. More patients preferred the period they took acetaminophen (n = 14) than the period they took placebo (n = 8), but many had no preference (n = 8). There were no differences in the other outcomes.Acetaminophen improved pain and well-being without major side effects in patients with cancer and persistent pain despite a strong opioid regimen. Its addition is worth considering in all such patients.
Endogenous p53 Protects Vascular Smooth Muscle Cells From Apoptosis and Reduces Atherosclerosis in ApoE Knockout Mice
Authors: John Mercer, Nichola Figg, Victoria Stoneman, Denise Braganza, Martin R. Bennett
Journal: Circulation Research (2005)

Recent studies have indicated that the tumor suppressor gene p53 limits atherosclerosis in animal models; p53 expression is also increased in advanced human plaques compared with normal vessels, where it may induce growth arrest and apoptosis. However, controversy exists as to the role of endogenous levels of p53 in different cell types that comprise plaques. We examined atherosclerotic plaque development and composition in brachiocephalic arteries and aortas of p53-/-/ApoE-/- mice versus wild type p53 controls. p53-/- mice demonstrated increased aortic plaque formation, with increased rates of cell proliferation and reduced rates of apoptosis in brachiocephalic arteries. Although most proliferating cells were monocyte/macrophages, apoptotic cells were both vascular smooth muscle cells (VSMCs) and macrophages. Transplant of p53 bone marrow to p53-/-/ApoE-/- mice reduced aortic plaque formation and cell proliferation in brachiocephalic plaques, but also markedly reduced apoptosis. To examine p53 regulation of these processes, we studied proliferation and apoptosis in macrophages, bone marrow stromal cells and VSMCs cultured from these mice. Although endogenous p53 promoted apoptosis in macrophages, it protected VSMCs and stromal cells from death, a hitherto unknown function in these cells, in part by inhibiting DNA damage response enzymes. p53 also inhibited stromal cell expression of VSMC markers. We conclude that endogenous levels of p53 protect VSMCs and stromal cells against apoptosis, while promoting apoptosis in macrophages, and protect against atherosclerosis development.
Accumulation of carbonyls accelerates the formation of pentosidine, an advanced glycation end product
Authors: T Miyata, Y Ueda, Y Yamada, Y Izuhara, T Wada, M Jadoul, A Saito, K Kurokawa, C van Ypersele de Strihou
Journal: Journal of the American Society of Nephrology (1998)

Advanced glycation end product (AGE) formation is related to hyperglycemia in diabetes but not in uremia, because plasma AGE levels do not differ between diabetic and nondiabetic hemodialysis patients. The mechanism of this phenomenon remains elusive. Previously, it was suggested that elevation of AGE levels in uremia might result from the accumulation of unknown AGE precursors. The present study evaluates the in vitro generation of pentosidine, a well identified AGE structure. Plasma samples from healthy subjects and nondiabetic hemodialysis patients were incubated under air for several weeks. Pentosidine levels were determined at intervals by HPLC assay. Pentosidine rose to a much larger extent in uremic than in control plasma. Pentosidine yield, i.e., the change in pentosidine level between 0 and 4 wk divided by 28 d, averaged 0.172 nmol/ml per d in uremic versus 0.072 nmol/ml per d in control plasma (P < 0.01). The difference in pentosidine yield between uremic and control plasma was maintained in samples ultrafiltrated through a filter with a 5000-Da cutoff value and fortified with human serum albumin (0.099 versus 0.064 nmol/ml per d; P < 0.05). Pentosidine yield was higher in pre- than in postdialysis plasma samples (0.223 versus 0.153 nmol/ml per d; P < 0.05). These results suggest that a large fraction of the pentosidine precursors accumulated in uremic plasma have a lower than 5000 Da molecular weight. Addition of aminoguanidine and OPB-9195, which inhibit the Maillard reaction, lowered pentosidine yield in both uremic and control plasma. When ultrafiltrated plasma was exposed to 2,4-dinitrophenylhydrazine, the yield of hydrazones, formed by interaction with carbonyl groups, was markedly higher in uremic than in control plasma. These observations strongly suggest that the pentosidine precursors accumulated in uremic plasma are carbonyl compounds. These precursors are unrelated to glucose or ascorbic acid, whose concentration is either normal or lowered in uremic plasma. They are also unrelated to 3-deoxyglucosone, a glucose-derived dicarbonyl compound whose level is raised in uremic plasma: Its addition to normal plasma fails to increase pentosidine yield. This study reports an elevated level of reactive carbonyl compounds ("carbonyl stress") in uremic plasma. Most have a lower than 5000 Da molecular weight and are thus partly removed by hemodialysis. Their effect on pentosidine generation can be inhibited by aminoguanidine or OPB-9195. Carbonyl stress might contribute to AGE modification of proteins and thus to clinically relevant complications of uremia.
Coupling of the antiviral drug ara-AMP to lactosaminated albumin leads to specific uptake in rat and human hepatocytes
Authors: Robert W. Jansen, Johan K. Kruijt, THEO J. C. van Berkel, Dirk K. F. Meije
Journal: Hepatology (1993)

We covalently coupled 9-beta-D-arabinofuranosyladenine 5'-monophosphate (ara-AMP) to the carrier molecule lactosaminated human serum albumin using a water-soluble carbodiimide with a two-step conjugation method (pH 4.5 and pH 7.5) instead of the commonly used single-step conjugation at pH 7.5. This resulted in a predominantly monomeric conjugate (lac27-HSA-ara-AMP9). The conjugate was stable in buffer (pH 7.4) and blood plasma. After in vivo injection, the carrier and the monomeric conjugate were subjected to selective endocytosis in rat hepatocytes, as shown on immunohistochemical study and cell-separation techniques using 125I-labeled material. In competition experiments with other ligands for the asialoglycoprotein receptor N-acetylgalactosamine and asialofetuin, we showed that both lactosaminated human serum albumin and lac27-HSA-ara-AMP9 are subject to endocytosis by this receptor system. Although the coupling of ara-AMP significantly increased the net negative charge of the conjugate compared with the native carrier, liver uptake was not affected by coadministration of an excess of succinylated human serum albumin (suc-HSA), a negatively charged ligand for the scavenger receptor. Incubation studies with purified rat liver lysosomes showed that in this acidic and proteolytic environment, mainly ara-AMP and, to a much lesser extent, ara-A itself were released from the carrier. After injection into the rat in vivo and in isolated perfused rat liver, no free ara-AMP or 9-B-D-arabinofuranosyladenine (ara-A) could be detected in plasma and perfusate, respectively, indicating proper retention of the virally active components in hepatocytes.(ABSTRACT TRUNCATED AT 250 WORDS)
Fas/Fas Ligand–mediated Apoptosis Promotes Hypersensitivity Pneumonitis in Mice by Enhancing Maturation of Dendritic Cells
Authors: Su Jin Hwang, Hye Sung Kim, Doo Hyun Chung
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

Fas/Fas ligand (FasL)-mediated apoptosis has been implicated in various lung diseases, but whether Fas/FasL-mediated apoptosis in the lungs plays a critical role in the development of hypersensitivity pneumonitis (HP) is unclear.To explore the functional roles of Fas/FasL-mediated apoptosis in HP.Fas-deficient (lpr/lpr), FasL-deficient (gld/gld), and B6 mice were challenged with Saccharopolyspora rectivirgula (SR) antigen intranasally.lpr/lpr and gld/gld mice exhibited attenuation of HP in terms of histological alterations, influx of immune cells in bronchoalveolar lavage fluid (BALF), and SR-specific immune responses compared with B6 mice, similar to the effects of SR in B6 mice given a caspase inhibitor. The lungs of lpr/lpr and gld/gld mice showed high IL-4 production and low IFN-gamma, IL-8, macrophage inflammatory protein-2, IL-1beta, and tumor necrosis factor-alpha production compared with those of B6 mice. Moreover, mice with chimeric B6 and lpr/lpr bone marrow revealed that apoptosis of nonhematopoietic and BALF immune cells of the lungs enhanced immune responses against SR antigen. Gr-1(+) granulocytes in BALF expressed annexin V and their depletion in B6 mice attenuated HP. Apoptosis of nonhematopoietic cells and Gr-1(+) granulocytes in the lungs enhanced the maturation of pulmonary CD11c(+) dendritic cells and their production of macrophage inflammatory protein-1alpha and monocyte chemoattractant protein-1, resulting in recruitment of immune cells into the lungs during HP.These results suggest that apoptosis in nonhematopoietic cells and Gr-1(+) granulocytes of the lungs promotes HP by enhancing maturation and chemokine production of CD11c(+) dendritic cells.
The Conserved Scavenger Receptor Cysteine-Rich Superfamily in Therapy and Diagnosis
Authors: Vanesa Gabriela Martínez, Søren Kragh Moestrup, Uffe Holmskov, Jan Mollenhauer, Francisco Lozano
Journal: Pharmacological Reviews (2011)

The scavenger receptor cysteine-rich (SRCR) superfamily of soluble or membrane-bound protein receptors is characterized by the presence of one or several repeats of an ancient and highly conserved protein module, the SRCR domain. This superfamily (SRCR-SF) has been in constant and progressive expansion, now up to more than 30 members. The study of these members is attracting growing interest, which parallels that in innate immunity. No unifying function has been described to date for the SRCR domains, this being the result of the limited knowledge still available on the physiology of most members of the SRCR-SF, but also of the sequence versatility of the SRCR domains. Indeed, involvement of SRCR-SF members in quite different functions, such as pathogen recognition, modulation of the immune response, epithelial homeostasis, stem cell biology, and tumor development, have all been described. This has brought to us new information, unveiling the possibility that targeting or supplementing SRCR-SF proteins could result in diagnostic and/or therapeutic benefit for a number of physiologic and pathologic states. Recent research has provided structural and functional insight into these proteins, facilitating the development of means to modulate the activity of SRCR-SF members. Indeed, some of these approaches are already in use, paving the way for a more comprehensive use of SRCR-SF members in the clinic. The present review will illustrate some available evidence on the potential of well known and new members of the SRCR-SF in this regard.
Community Clinical Oncology Program Celebrates 20 Years of Trials and a Few Tribulations
Authors: G. Moulton
Journal: JNCI Journal of the National Cancer Institute (2003)

Cancer Institute's Community Clinical Oncology Program (CCOP), the underlying collegiality and collaboration of people networked across the country in 61 community programs known as CCOPs and 14 national research bases, have not waned.The program was established in 1983 to provide a mechanism for community physicians at large to be involved in cancer clinical trials, to bring the benefits of clinical research to patients in their own communities."The CCOP legacy is that they've contributed to the cooperative groups' ability to start trials, complete trials, and affect the way physicians care for patients and individuals at risk for cancer," said Leslie Ford, M.D., associate director for clinical research in NCI's Division of Cancer Prevention.Administrators and investigators celebrated the 20th anniversary of CCOP last month at the annual meeting of the National Surgical Adjuvant Breast and Bowel Project, an NCIsponsored clinical trials cooperative group, and recalled the program's trials and tribulations over the years.
Effect of medium chain triglycerides (MCT) on jejunal mucosa mass and protein synthesis.
Authors: S Schwartz, M Farriol, E Garcia-Arumi, A L Andreu, J Lopez Hellin, M A Arbos
Journal: Gut (1994)

The effects of medium chain triglycerides (MCT) on jejunal mucosa mass and protein synthesis were compared with results from previous experiments with rats fed by parenteral nutrition or enteral nutrition. Other published studies have also been analysed. Three experimental models were studied. In the traumatic model, production of a femoral fracture was followed by Kirschner pin insertion into the medullary canal of both fragments at reduction. (Forty ras were fed enteral nutrition and 93 were given parenteral nutrition.) A second model entailed resection under ether anaesthesia using the technique described by Higgins. (Fifty five rats were fed enteral nutrition and 28 with parenteral nutrition.) A third model entailed a terminolateral portocaval shunt under anaesthesia with pentobarbital. (Sixty nine rats were treated this way and then given enteral nutrition.) Proportions of medium chain/long chain triglycerides (LCT) were as follows: 0/100, 20/80, 40/60, 50/50, and 92/8 for enteral nutrition and 0/100, 30/70, 50/50, and 70/30 for parenteral nutrition. Faecal losses of alpha amino nitrogen, protein, total fats, and free fatty acids were analysed together with the quantitative intake, weight gain of the rats, jejunal mucosal mass, and protein synthesis in relation to the MCT proportion ingested or given by enteral nutrition or parenteral nutrition. From analysis of our results and those of others, several conclusions could be drawn. Firstly, the route of administration of MCT is extremely important and enterocytes might be considered one of the main target sites. Secondly, a high proportion of MCT (more than 80%) offers no advantage for jejunal mucosa and produces undesirable side effects. Thirdly, the effect of MCT on jejunal mucosal protein synthesis depends on the metabolic state. Finally, an increase in jejunal mucosal mass directly correlated with MCT concentrations, but no correlation was found between mass and protein synthesis. A positive correlation, however, between MCT proportion and enzyme activity (alkaline phosphatase and sucrase) in the brush border membrane was seen as well as a positive correlation with the concentration of phospholipids in the microvilli.
Dysfunctional Attitudes and 5-HT<sub>2</sub> Receptors During Depression and Self-Harm
Authors: Jeffrey H. Meyer, Shelley McMain, Sidney H. Kennedy, Lorne Korman, Gregory M. Brown, Jean N. DaSilva, Alan A. Wilson, Thomas Blak, Rahel Eynan-Harvey, Verdell S. Goulding, Sylvain Houle, Paul Links
Journal: American Journal of Psychiatry (2002)

OBJECTIVE: Dysfunctional attitudes are negatively biased assumptions and beliefs regarding oneself, the world, and the future. In healthy subjects, increasing serotonin (5-HT) agonism with a single dose of d-fenfluramine lowered dysfunctional attitudes. To investigate whether the converse, a low level of 5-HT agonism, could account for the higher levels of dysfunctional attitudes observed in patients with major depression or with self-injurious behavior, cortex 5-HT2 receptor binding potential and dysfunctional attitudes were measured in patients with major depressive disorder, patients with a history of self-injurious behavior, and healthy comparison subjects (5-HT2 receptor density increases during 5-HT depletion). METHOD: Twenty-nine healthy subjects were recruited to evaluate the effect of d-fenfluramine or of clonidine (control condition) on dysfunctional attitudes. Dysfunctional attitudes were assessed with the Dysfunctional Attitude Scale 1 hour before and 1 hour after drug administration. In a second experiment, dysfunctional attitudes and 5-HT2 binding potential were measured in 22 patients with a major depressive episode secondary to major depressive disorder, 18 patients with a history of self-injurious behavior occurring outside of a depressive episode, and another 29 age-matched healthy subjects. Cortex 5-HT2 binding potential was measured with [18F]setoperone positron emission tomography. RESULTS: In the first experiment, dysfunctional attitudes decreased after administration of d-fenfluramine. In the second experiment, in the depressed group, dysfunctional attitudes were positively associated with cortex 5-HT2 binding potential, especially in Brodmann's area 9 (after adjustment for age). Depressed subjects with extremely dysfunctional attitudes had higher 5-HT2 binding potential, compared to healthy subjects, particularly in Brodmann's area 9. CONCLUSIONS: Low levels of 5-HT agonism in the brain cortex may explain the severely pessimistic, dysfunctional attitudes associated with major depression.
Mycobacterial PE_PGRS Proteins Contain Calcium-Binding Motifs with Parallel <i>β</i>-Roll Folds
Authors: Nandita Bachhawat, Balvinder Singh
Journal: Genomics Proteomics & Bioinformatics (2007)

Abstract The PE_PGRS family of proteins unique to mycobacteria is demonstrated to contain multiple calcium-binding and glycine-rich sequence motifs GGXGXD/NXUX. This sequence repeat constitutes a calcium-binding parallel β-roll or parallel β-helix structure and is found in RTX toxins secreted by many Gram-negative bacteria. It is predicted that the highly homologous PE_PGRS proteins containing multiple copies of the nona-peptide motif could fold into similar calcium-binding structures. The implication of the predicted calcium-binding property of PE_PGRS proteins in the light of macrophage-pathogen interaction and pathogenesis is presented.
RELATIONSHIP BETWEEN THE CEREBROSPINAL FLUID SUGAR AND BLOOD SUGAR IN UNTREATED NEUROSYPHILIS
Authors: Purcell G. Schube
Journal: American Journal of Psychiatry (1936)

A study of the simultaneous fasting cerebrospinal fluid sugar and blood sugar in untreated neurosyphilis is presented. The cerebrospinal fluid sugar was within normal range in 88.2 per cent of the cases and the blood sugar in 89.2 per cent. The ratio existing between the cerebrospinal fluid sugar and the blood sugar was within the normal range in only 51.2 per cent of the cases of neurosyphilis: 51.5 per cent of the cases of general paresis, 55 per cent of the cases of cerebrospinal syphilis with psychosis, and in 41.7 per cent of the cases of tabes without psychosis. This ratio was below normal in 13.2 per cent of the cases of neurosyphilis: 12.7 per cent of the cases of general paresis, 15.0 per cent of the cases of cerebrospinal syphilis with psychosis, and 16.6 per cent of the cases of tabes without psychosis. And the ratio was above normal in 35.6 per cent of the cases of neurosyphilis: 35.8 per cent of the cases of general paresis, 30.0 per cent of the cases of cerebrospinal syphilis with psychosis, and 41.7 per cent of the cases of tabes without psychosis. Therefore, in 48.8 per cent of the cases of untreated neurosyphilis there is definite evidence of some abnormality in the hemato-encephalic barrier to the passage of sugar.
Noninvasive, real-time monitoring of renal function during critical care.
Authors: C A Rabito, F Panico, R Rubin, N Tolkoff-Rubin, R Teplick
Journal: Journal of the American Society of Nephrology (1994)

The inadequacy of the current techniques to monitor renal function has been the most important limitation for determining the appropriateness of a particular form of therapy in acute renal failure. The objective of this study was to determine the advantage offered by a new method of accurate, noninvasive, and real-time monitoring of renal function during the critical care of patients. A radiation detector attached to a miniature data logger was used to monitor the clearance of the glomerular filtration agent 99mTc-diethylene triamine pentaacetic acid from the extracellular space in 20 patients admitted into an intensive care unit. The rate constant for this clearance was calculated online from 5-min epoch lengths of activity versus time. Changes in this constant were compared with changes in plasma creatinine and timed urine output. The results showed that the ambulatory renal monitor could accurately measure rapid changes in renal function during the critical care of patients who are at risk of acute renal failure with a resolution time of 5 to 10 min. The sensitivity and specificity of the technique are also superior to plasma creatinine and urine output because it can detect minimal and transient changes in renal function that otherwise may have gone undetected by these parameters. This unique approach should allow for the immediate institution and/or adjustment of the appropriate therapeutic procedure to preserve or improve the renal function.
Extracellular accumulation of potently microbicidal bactericidal/permeability-increasing protein and p15s in an evolving sterile rabbit peritoneal inflammatory exudate.
Authors: Y Weinrauch, A Foreman, C Shu, K Zarember, O Levy, P Elsbach, J Weiss
Journal: Journal of Clinical Investigation (1995)

To what extent the host defense role of granule-associated antibacterial proteins and peptides of PMN includes extracellular action has not been established. To address this question, we have analyzed the antibacterial activity of cell-free (ascitic) fluid (AF) obtained from glycogen-induced sterile inflammatory rabbit peritoneal exudates in which > 95% of the accumulating cells are PMN. AF, but not plasma collected in parallel, exhibits potent activity toward serum-resistant Gram-negative and Gram-positive bacteria. Total and specific antibacterial activity of AF increases during the first 12 h after injection of glycogen in parallel with the influx of PMN. At maximum, > 99% of 10(7) encapsulated Escherichia coli and Staphylococcus aureus are killed in 30 min/ml of AF. Neutralizing antibodies against the bactericidal/permeability-increasing protein (BPI) of PMN abolishes activity of AF toward encapsulated E. coli but has no effect on activity vs staphylococci. However, BPI alone (approximately 1 microgram/ml in AF) can only account for < or = 20% of AF activity toward E. coli. AF also contains 15 kD PMN proteins (p15s) that act in synergy with BPI. Purified BPI and p15s, in amounts present in AF, reconstitute the growth-inhibitory activity of AF toward encapsulated E. coli. These findings show for the first time an extracellular function of endogenous BPI, providing, together with the p15s, a potent microbicidal system toward Gram-negative bacteria resistant to plasma-derived proteins and phagocytes in inflammatory exudates.