tbuckley/cabot-search huggingface dataset:
NPC1 repression contributes to lipid accumulation in human macrophages exposed to environmental aryl hydrocarbons
Authors: N. Podechard, E. Le Ferrec, A. Rebillard, O. Fardel, V. Lecureur
Journal: Cardiovascular Research (2008)

Aryl hydrocarbons (AHs), such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and benzo(a)pyrene (BP), are environmental contaminants promoting the development of atherosclerosis-related cardiovascular diseases. In order to identify molecular mechanisms involved in these effects, we have analysed AH-mediated regulation of the lipid trafficking Niemann–Pick type C1 protein (NPC1) and its contribution to AH-induced macrophage lipid accumulation. Exposure of primary human macrophages to TCDD and BP decreased NPC1 mRNA expression in a time-dependent manner. NPC1 protein expression and NPC1-related acid sphingomyelinase activity were reduced in parallel. NPC1 was also similarly down-regulated in mice exposed to BP. Moreover, TCDD and BP were demonstrated to trigger lipid accumulation in human macrophages, as assessed by Oil Red O and Nile Red staining and cholesterol determination. Such lipid loading occurred at least partly in endosomal/lysosomal compartments as demonstrated by immunolabelling of lipid vesicles by the lysosome-associated membrane protein 1. These cellular phenotypic effects were found to be similar to those triggered by knock-down of NPC1 expression using siRNAs and were counteracted by NPC1 overexpression, thus supporting the contribution of NPC1 to AH-mediated lipid accumulation in macrophages. Finally, both NPC1 down-expression and lipid accumulation in response to TCDD were found to be abolished through knock-down of the AH receptor (AHR), a ligand-activated transcription factor mediating many effects of AHs. Our data have shown that contaminants such as TCDD and BP repress NPC1 expression in macrophages in an AHR-dependent manner, which likely contributes to macrophage lipid accumulation caused by these environmental chemicals. Thus, NPC1 appears to be a new molecular target regulated by environmental AHs and putatively involved in their deleterious cardiovascular effects.
Prolonged Endoplasmic Reticulum Stress in Hypertrophic and Failing Heart After Aortic Constriction
Authors: Ken-ichiro Okada, Tetsuo Minamino, Yoshitane Tsukamoto, Yulin Liao, Osamu Tsukamoto, Seiji Takashima, Akio Hirata, Masashi Fujita, Yoko Nagamachi, Takeshi Nakatani, Chikao Yutani, Kentaro Ozawa, Satoshi Ogawa, Hitonobu Tomoike, Masatsugu Hori, Masafumi Kitakaze
Journal: Circulation (2004)

The endoplasmic reticulum (ER) is recognized as an organelle that participates in folding secretory and membrane proteins. The ER responds to stress by upregulating ER chaperones, but prolonged and/or excess ER stress leads to apoptosis. However, the potential role of ER stress in pathophysiological hearts remains unclear.Mice were subjected to transverse aortic constriction (TAC) or sham operation. Echocardiographic analysis demonstrated that mice 1 and 4 weeks after TAC had cardiac hypertrophy and failure, respectively. Cardiac expression of ER chaperones was significantly increased 1 and 4 weeks after TAC, indicating that pressure overload by TAC induced prolonged ER stress. In addition, the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells increased, and caspase-3 was cleaved in failing hearts. The antagonism of angiotensin II type 1 receptor prevented upregulation of ER chaperones and apoptosis in failing hearts. On the other hand, angiotensin II upregulated ER chaperones and induced apoptosis in cultured adult rat cardiac myocytes. We also investigated possible signaling pathways for ER-initiated apoptosis. The CHOP- (a transcription factor induced by ER stress), but not JNK- or caspase-12-, dependent pathway was activated in failing hearts by TAC. Pharmacological ER stress inducers upregulated ER chaperones and induced apoptosis in cultured cardiac myocytes. Finally, mRNA levels of ER chaperones were markedly increased in failing hearts of patients with elevated brain natriuretic peptide levels.These findings suggest that pressure overload by TAC induces prolonged ER stress, which may contribute to cardiac myocyte apoptosis during progression from cardiac hypertrophy to failure.
3,3′,4,4′-Tetrabromobiphenyl sensitizes rats to the hepatotoxic effects of endotoxin by a mechanism that involves more than tumor necrosis factor
Authors: Steven I. Shedlofsky, Niel C. Hoglen, Larry E. Rodman, Ron Honchel, Farrel R. Robinson, Alice T. Swim, Craig J. McClain, Larry W. Robertson
Journal: Hepatology (1991)

To determine whether the cytokine tumor necrosis factor/cachectin might be a mediator of hepatotoxicity seen after exposure to polyhalogenated aromatic hydrocarbons, rats treated with a single dose of 3,3',4,4'-tetrabromobiphenyl (150 mumol/kg intraperitoneally) or corn oil vehicle were studied. The 3,3',4,4'-tetrabromobiphenyl caused the expected anorexia, alterations in organ weights and changes in cytochromes P-450 over 21 days. Although tumor necrosis factor could not be detected in the serum of rats at any time after 3,3',4,4'-tetrabromobiphenyl treatment alone (from 90 min to 21 days), 3,3',4,4'-tetrabromobiphenyl treatment significantly increased peak serum tumor necrosis factor concentrations after intravenous bacterial endotoxin (lipopolysaccharide, 1 mg/kg). This effect was seen with lipopolysaccharide given 24 hr, 48 hr, and 20 days after 3,3',4,4'-tetrabromobiphenyl treatment and increases in peak serum tumor necrosis factor levels ranged from threefold to eightfold over controls in various experiments with no significant differences between the three time points. However, a synergistic increase in hepatic damage (assessed by serum enzymes and liver histological findings 24 hr after lipopolysaccharide injection) was seen in rats given lipopolysaccharide 24 hr and 48 hr after 3,3',4,4'-tetrabromobiphenyl administration, with 75% and 25% lethality, respectively. There was no lethality with lipopolysaccharide given 20 days after 3,3',4,4'-tetrabromobiphenyl administration or with simultaneous administration. A lower dose of lipopolysaccharide (0.1 mg/kg) given 24 hr after 3,3',4,4'-tetrabromobiphenyl also enhanced hepatotoxicity and serum tumor necrosis factor but without lethality. Lipopolysaccharide decreased cytochromes P-450 concentrations and activities to similar extents at all time points tested in both control and 3,3'4,4'-tetrabromobiphenyl-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Appendicitis after appendicectomy
Authors: K H R. Kumar
Journal: Journal of the Royal Society of Medicine (2005)

Dr McNaught is right to point out examples of racism in the NHS (December 2004 JRSM 1 ).But what to do about it?Maybe we can learn some lessons from the past.Today there is an over-representation of black people in the mental health system but in the 1960s Irish people were over-represented. 2 Psychiatrists thought that the prevalence of schizophrenia was high in people from the west of Ireland and invented a new syndrome 'western seaboard psychosis'. 3 Anthropologists descended on the unsuspecting immigrants to ask them if their Catholic faith caused their minds to unbalance and psychiatrists followed to dole out antipsychotics.But then some proper research was done and it showed no excess of schizophrenia in Irish immigrants. 4 The methods of case collection in the early studies were poor and cross-cultural comparisons were not properly thought through. 3 Today Irish people are no more likely to be diagnosed with schizophrenia than anyone else.How did this happen?I would love to say that it was because of the new research or because of government initiatives.The research helped a bit but the main cures for anti-Irish discrimination were that the new immigrants were richer, better educated, better informed and more questioning.They would not be fobbed off with a misdiagnosis.An increasing understanding and appreciation of Irish culture also helped reduce anti-Irish discrimination generally.The most effective cure of all was time.A cynic would add that, nowadays, people have a new batch of immigrants (such as asylum seekers) to discriminate against.So we need fewer new policy drives and more changes of heart.These will only come from changes in society.Blaming individuals or even the NHS will not help.
Phospholipase activity in human bile
Authors: Toru Nakano, Jiro Yanagisawa, Fumio Nakayama
Journal: Hepatology (1988)

To investigate the importance of bacterial infection in the formation of free fatty acids found in brown pigment gallstones, free fatty acids and phospholipase activity in hepatic bile, with or without the presence of bacterial infection, were compared. The concentration of free fatty acids in bile with bacterial infection [0.467 +/- 0.447 mg per ml (mean +/- S.D.)] was significantly higher than when bacterial infection was absent (0.073 +/- 0.041 mg per ml; p less than 0.01). However, there was no significant difference in the composition of free fatty acids in hepatic bile when bacterial infection was present. Biliary phospholipase activity was determined by counting [14C] palmitic acid released from [14C]dipalmitoyl phosphatidylcholine that was incubated with native bile. The biliary phospholipase activity was significantly higher when bacterial infection was present. Furthermore, a positive correlation (p less than 0.001) was found between the activity of biliary phospholipases and the concentration of free fatty acids in hepatic bile. Most bacterial strains isolated from bile were shown to have both phospholipase A1 and A2 activity. On the other hand, human pancreatic juice and human gallbladder epithelial cells contained mainly phospholipase A2. Since fatty acids in the gallstone are mainly palmitic acid and must have been cleaved from first position in the biliary phosphatidylcholine molecule, bacterial phospholipase A1 seems to play an important role in the formation of calcium palmitate found in brown pigment gallstones.
Evidence for mouse Th1- and Th2-like helper T cells in vivo. Selective reduction of Th1-like cells after total lymphoid irradiation.
Authors: H Bass, T Mosmann, S Strober
Journal: The Journal of Experimental Medicine (1989)

Purified CD4+ BALB/c spleen T cells obtained 4-6 wk after total lymphoid irradiation (TLI) helped normal syngeneic B cells to produce a vigorous antibody response to TNP keyhole limpet hemocyanin in adoptive cell transfer experiments. However, the same cells failed to transfer delayed-type hypersensitivity to the adoptive hosts as measured by a foot pad swelling assay. In addition, purified CD4+ cells from TLI-treated mice were unable to induce graft vs. host disease in lethally irradiated allogeneic C57BL/Ka recipient mice. In response to mitogen stimulation, unfractionated spleen cells obtained from TLI mice secreted normal levels of IL-4 and IL-5, but markedly reduced levels of IL-2 and INF-gamma. A total of 229 CD4+ clones from spleen cells of both normal and TLI-treated mice were established, and the cytokine secretion pattern from each clone was analyzed. The results demonstrate that the ratio of Th1- and Th2-like clones in the spleens of normal BALB/c mice is 1:0.6, whereas the ratio in TLI mice is approximately 1:7. These results suggest that Th2-like cells recover rapidly (at approximately 4-6 wk) after TLI treatment and account for the early return of antibody helper activity and secretion of IL-4 and IL-5, but Th1-like cells recover more slowly (in approximately 3 mo) after irradiation, and this accounts for the deficit in cell-mediated immunity and the reduced amount of IL-2 and IFN-gamma secretion.
Users' Guides to the Medical Literature&lt;SUBTITLE&gt;XVI. How to Use a Treatment Recommendation&lt;/SUBTITLE&gt;
Authors: Gordon H. Guyatt
Journal: JAMA (1999)

Clinicians can often find treatment recommendations in traditional narrative reviews and the discussion sections of original articles and meta-analyses. Making a treatment recommendation involves framing a question, identifying management options and outcomes, collecting and summarizing evidence, and applying value judgments or preferences to arrive at an optimal course of action. Each step in this process can be conducted systematically (thus protecting against bias) or unsystematically (leaving the process open to bias). Clinicians faced with a plethora of recommendations may wish to attend to those that are less likely to be biased. Therefore, we propose a hierarchy of rigor of recommendations to guide clinicians when judging the usefulness of particular recommendations. Recommendations with the highest rigor consider all relevant options and outcomes, include a comprehensive collection of the methodologically highest quality data with an explicit strategy for summarizing the data (that is, a systematic review), and make an explicit statement of the values or preferences involved in moving from evidence to action. High rigor recommendations come from systematically developed, evidence-based practice guidelines or rigorously conducted decision analyses. Systematic reviews, which typically do not consider all relevant options and outcomes or make the preferences underlying recommendations explicit, offer intermediate rigor recommendations. Traditional approaches in which the collection and assessment of evidence remains unsystematic, all relevant options and outcomes may not be considered, and values remain implicit, provide recommendations of weak rigor. In an era in which clinicians are barraged by recommendations as to how to manage their patients, this hierarchy provides a potentially useful set of guides.
Endothelial dysfunction in a rat model of endotoxic shock. Importance of the activation of poly (ADP-ribose) synthetase by peroxynitrite.
Authors: C Szabó, S Cuzzocrea, B Zingarelli, M O'Connor, A L Salzman
Journal: Journal of Clinical Investigation (1997)

DNA single strand breakage and activation of the nuclear enzyme poly (ADP-ribose) synthetase (PARS) contribute to peroxynitrite-induced cellular injury. We investigated the role of PARS activation in the pathogenesis of endothelial dysfunction. In human umbilical vein endothelial cells (HUVEC), DNA strand breakage (alkaline unwinding assay), PARS activation (incorporation or radiolabeled NAD+ into proteins), mitochondrial respiration [conversion of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide to formazan] and apoptotic index (cytoplasmatic release of histones) were measured. Endotoxin shock was induced in rats by bacterial lipopolysaccharide. Vascular reactivity of thoracic aortic rings were measured in organ chambers. In HUVEC, peroxynitrite caused a dose-dependent suppression of mitochondrial respiration, induced DNA strand breakage and caused an activation of PARS. Pharmacological inhibition of PARS reduced the acute and delayed suppression of mitochondrial respiration when cells were exposed to intermediate, but not high doses of peroxynitrite. Similarly, protection against the intermediate, but not high doses of peroxynitrite was seen in fibroblasts from the PARS-/- mice, when compared to wild-type controls. These data suggest that PARS plays a role in peroxynitrite-induced cytotoxicity, but at very high levels of oxidant exposure, PARS-independent cytotoxic mechanisms become predominant. Peroxynitrite-induced apoptosis was not affected by PARS inhibition. Vascular rings exposed to peroxynitrite and rings taken from rats subjected to endotoxic shock exhibited reduced endothelium-dependent relaxant responses in response to acetylcholine. The development of this endothelial dysfunction was ameliorated by the PARS inhibitor 3-aminobenzamide. Activation of PARS by peroxynitrite, therefore, may be involved in the development of endothelial dysfunction in endotoxemia.
Endothelin induces diuresis and natriuresis in the rat by acting on proximal tubular cells through a mechanism mediated by lipoxygenase products.
Authors: N Perico, R P Cornejo, A Benigni, B Malanchini, J R Ladny, G Remuzzi
Journal: Journal of the American Society of Nephrology (1991)

Besides being a potent renal vasoconstrictor, endothelin causes diuresis and natriuresis. At which site along the nephron and how endothelin alters water and sodium handling in the tubule remain to be clarified. It was found that endothelin (75 pmol) given as an i.v. infusion in vivo to rats caused diuresis and urinary sodium excretion to double but did not affect glomerular filtration rate and renal plasma flow. On raising the dose of endothelin to 150 pmol, a further increase in diuresis and natriuresis was found, whereas glomerular filtration rate fell 33% and renal plasma flow fell 36%; 300 pmol of endothelin reduced glomerular filtration rate by 73% and renal plasma flow by 77% but did not significantly affect diuresis and absolute sodium excretion. It did, however, increase fractional sodium excretion eightfold. Lithium clearance studies of changes in tubular handling of water and sodium indicated that infusion of 150 pmol of endothelin to rats caused a reduction in absolute (pre, 84.7 +/- 5.9; post, 47.9 +/- 6.1 microEq/min/100 g) and fractional (pre, 85.7 +/- 3.0; post, 64.7 +/- 6.4%) proximal reabsorption of sodium. Endothelin infusion (150 pmol) was not associated with any significant change in plasma atrial natriuretic peptide levels, which on average remained comparable to those in rats given the vehicle alone (49.7 +/- 8.4 versus 46.3 +/- 5.6 pg/mL). In the isolated perfused rat kidney preparation, exposure to 150 pmol of endothelin significantly increased fractional sodium excretion over preinjection values (pre, 2.2 +/- 0.2; post, 7.3 +/- 1.0%) despite a marked decrease in glomerular filtration rate and renal perfusate flow. Additional in vivo experiments showed that oral administration of the specific 5-lipoxygenase inhibitor L-651,392 to rats prevented the increase in urine flow rate (pre, 5.7 +/- 0.1; post, 6.6 +/- 0.8 microL/min), and in absolute (pre, 0.33 +/- 0.04; post, 0.37 +/- 0.05 microEq/min) and fractional (pre, 0.10 +/- 0.02; post, 0.11 +/- 0.03%) sodium excretion caused by bolus i.v. infusion of endothelin (150 pmol). Similarly, a specific leukotriene C4/D4 receptor antagonist, L-649,923, also prevented the diuretic and natriuretic effect of 150 pmol of endothelin i.v. infusion. These findings show that (1) endothelin has a diuretic and natriuretic effect that is independent of its action on renal hemodynamics; (2) this effect depends on a direct action on the proximal tubules; (3) atrial natriuretic peptide does not appear to be involved in this effect; and (4) the diuretic and natriuretic responses to endothelin are mediated by 5-lipoxygenase products.
The perfect pelvic pouch--what makes the difference?
Authors: W G Lewis, A S Miller, M E Williamson, P M Sagar, P J Holdsworth, A T Axon, D Johnston
Journal: Gut (1995)

The aim of this study was to determine what factors are important for the achievement of perfect anal continence after restorative proctocolectomy. One hundred patients underwent paired studies of anorectal physiology before and one year after restorative proctocolectomy with pelvic ileal reservoir (11 S, 25 J, 64 W) with stapled ileoanal anastomosis, without mucosectomy. Fifty seven patients attained perfect anal continence and were able to discriminate flatus from faeces with such confidence that they were able to release flatus safely without fear of faecal soiling. The remaining 43 patients experienced minor problems in this regard. Four factors were found to correlate significantly with a perfect functional result (median, perfect v imperfect): maximum resting anal pressure (72 v 57 cm H2O, p < 0.02), the sensory threshold in the upper and mid-anal canal (7.3 v 8.6 and 5.3 v 7.0 mA, p < 0.05 and p < 0.02), compliance of the ileal reservoir (12.4 v 7.6 ml/cm H2O, p < 0.01), and the presence of a pouch-anal inhibitory reflex (56 of 57 patients v 29 of 43 patients, p < 0.01). The quality of anal continence depends on several factors: a complaint ileal reservoir, a strong sensitive anal sphincter, and normal reflex coordination of the activities of the reservoir and the sphincter. Excellent pouch-anal coordination is obtainable irrespective of the design of the reservoir, provided that these criteria are satisfied.
Fluoroquinolones and Theophylline Toxicity: Norfloxacin
Authors: Lanh Green
Journal: JAMA (1989)

To the Editor.—  Many drugs, including the new broad-spectrum fluoroquinolone anti-infective agents, are known to interfere with theophylline metabolism by the hepatic cytochrome P450 system, causing toxic reactions to theophylline. Wijnands et al1reported increases in plasma theophylline concentrations during coadministration of enoxacin (110.9%) and to a lesser degree during coadministration of ciprofloxacin (22.8%) and pefloxacin (19.6%). Although two recent pharmacokinetic studies2,3suggest that a drug-drug interaction between norfloxacin and theophylline also exists, we are not aware of any case reports of elevated theophylline levels associated with this drug in the medical literature.  Three cases have been reported to the Food and Drug Administration that suggest theophylline toxic effects in patients taking norfloxacin. Each patient had a baseline steady-state theophylline level that was increased by at least 50% after starting norfloxacin therapy. A judgment was made that concomitant drugs or diseases were not likely to be responsible. All
Accelerated Partial Breast Irradiation Using Brachytherapy for Breast Cancer: Patterns in Utilization and Guideline Concordance
Authors: J. A. Hattangadi, N. Taback, B. A. Neville, J. R. Harris, R. S. Punglia
Journal: JNCI Journal of the National Cancer Institute (2011)

Accelerated partial breast irradiation using brachytherapy (APBIb) is an alternative to whole-breast irradiation (WBI) after breast-conserving surgery. We evaluated patterns of APBIb use with respect to 2009 American Society for Radiation Oncology consensus guidelines (ASTRO-G) in a population-based cohort. From Surveillance, Epidemiology, and End Results data, we identified 138 815 American women with breast cancer diagnosed between January 1, 2000, and December 31, 2007, who underwent WBI or APBIb after breast-conserving surgery and classified them as suitable, cautionary, or unsuitable for APBIb according to ASTRO-G criteria. Logistic regression was applied to study APBIb use overall and within each guideline category. All P values are from two-sided tests. Overall, 2.6% of patients received APBIb, and 65.8% of them were classified as cautionary or unsuitable. APBIb was used by 5% of suitable, 3.4% of cautionary, and 1.6% of unsuitable patients by ASTRO-G criteria ( P < .001). APBIb use increased from 0.4% in 2000 to 6.6% in 2007 and varied widely (0%–7%) between localities. Variables associated with APBIb use among suitable patients included other vs white race (odds ratio [OR] = 0.51, P < .001), region (OR = 2.60–8.62, P < .001), and more recent year (OR = 20.3, P < .001). Among cautionary patients, variables associated with APBIb use included black vs white race (OR = 0.76, P = .027), other vs white race (OR = 0.57, P < .001), Hispanic ethnicity (OR = 0.75, P = .036), region (OR = 3.10–10.2, P < .001), nonmetropolitan or rural location (OR = 0.53, P = .012), and more recent year (OR = 17.6, P < .001). Among unsuitable patients, black vs white race (OR = 0.77, P = .008), other vs white race (OR = 0.46, P < .001), region (OR = 3.33–21.6, P < .001), and more recent year (OR = 12.7, P < .001) were associated with APBIb use. APBIb after breast-conserving surgery has been rapidly adopted in the United States. Use varied by race, ethnicity, and widely by region, especially among patients who may not be suitable for this radiation technique.