tbuckley/cabot-search huggingface dataset:
Meta-Analysis: Surgical Treatment of Obesity
Authors: Melinda A. Maggard, Lisa R. Shugarman, Marika Suttorp, Margaret Maglione, Harvey J. Sugerman, Edward H. Livingston, Ninh T. Nguyen, Zhaoping Li, Walter A. Mojica, Lara Hilton, Shannon Rhodes, Sally C. Morton, Paul G. Shekelle
Journal: Annals of Internal Medicine (2005)

Background: Controversy exists regarding the effectiveness of surgery for weight loss and the resulting improvement in health-related outcomes. Purpose: To perform a meta-analysis of effectiveness and adverse events associated with surgical treatment of obesity. Data Sources: MEDLINE, EMBASE, Cochrane Controlled Trials Register, and systematic reviews. Study Selection: Randomized, controlled trials; observational studies; and case series reporting on surgical treatment of obesity. Data Extraction: Information about study design, procedure, population, comorbid conditions, and adverse events. Data Synthesis: The authors assessed 147 studies. Of these, 89 contributed to the weight loss analysis, 134 contributed to the mortality analysis, and 128 contributed to the complications analysis. The authors identified 1 large, matched cohort analysis that reported greater weight loss with surgery than with medical treatment in individuals with an average body mass index (BMI) of 40 kg/m2 or greater. Surgery resulted in a weight loss of 20 to 30 kg, which was maintained for up to 10 years and was accompanied by improvements in some comorbid conditions. For BMIs of 35 to 39 kg/m2, data from case series strongly support superiority of surgery but cannot be considered conclusive. Gastric bypass procedures result in more weight loss than gastroplasty. Bariatric procedures in current use (gastric bypass, laparoscopic adjustable gastric band, vertical banded gastroplasty, and biliopancreatic diversion and switch) have been performed with an overall mortality rate of less than 1%. Adverse events occur in about 20% of cases. A laparoscopic approach results in fewer wound complications than an open approach. Limitations: Only a few controlled trials were available for analysis. Heterogeneity was seen among studies, and publication bias is possible. Conclusions: Surgery is more effective than nonsurgical treatment for weight loss and control of some comorbid conditions in patients with a BMI of 40 kg/m2 or greater. More data are needed to determine the efficacy of surgery relative to nonsurgical therapy for less severely obese people. Procedures differ in efficacy and incidence of complications.
The Hypercholesterolemia-Risk Gene SORT1 Facilitates PCSK9 Secretion
Authors: Camilla Gustafsen, Mads Kjolby, Mette Nyegaard, Manuel Mattheisen, Jesper Lundhede, Henriette Buttenschøn, Ole Mors, Jacob F. Bentzon, Peder Madsen, Anders Nykjaer, Simon Glerup
Journal: Cell Metabolism (2014)

Circulating PCSK9 destines low-density lipoprotein receptor for degradation in lysosomes, resulting in increased LDL cholesterol. Accordingly, it is an attractive drug target for hypercholesterolemia, and results from clinical trials are promising. While the physiological role of PCSK9 in cholesterol metabolism is well described, its complex mechanism of action remains poorly understood, although it is known to depend on intracellular trafficking. We here identify sortilin, encoded by the hypercholesterolemia-risk gene SORT1, as a high-affinity sorting receptor for PCSK9. Sortilin colocalizes with PCSK9 in the trans-Golgi network and facilitates its secretion from primary hepatocytes. Accordingly, sortilin-deficient mice display decreased levels of circulating PCSK9, while sortilin overexpression in the liver confers increased plasma PCSK9. Furthermore, circulating PCSK9 and sortilin were positively correlated in a human cohort of healthy individuals, suggesting that sortilin is involved in PCSK9 secretion in humans. Taken together, our findings establish sortilin as a critical regulator of PCSK9 activity.
Muscle-Specific F-Box Only Proteins Facilitate BK Channel β <sub>1</sub> Subunit Downregulation in Vascular Smooth Muscle Cells of Diabetes Mellitus
Authors: Dai-min Zhang, Tongrong He, Zvonimir S. Katusic, Hon-Chi Lee, Tong Lu
Journal: Circulation Research (2010)

activity of the large conductance Ca(2+)-activated K(+) (BK) channels is profoundly modulated by its β(1) subunit (BK-β(1)). However, BK-β(1) expression is downregulated in diabetic vessels. The ubiquitin-proteasome system (UPS) is a major mechanism of intracellular protein degradation. Whether UPS participates in BK-β(1) downregulation in diabetic vessels is unknown.we hypothesize that UPS facilitates vascular BK-β(1) degradation in diabetes.using patch clamp and molecular biological approaches, we found that BK-β(1)-mediated channel activation and BK-β(1) protein expression were reduced in aortas of streptozotocin-induced diabetic rats and in human coronary arterial smooth muscle cells (CASMCs) cultured in high glucose. This was accompanied by upregulation of F-box only protein (FBXO)-9 and FBXO-32 (atrogin-1), the key components of the Skp1-Cullin-F-box (SCF) type ubiquitin ligase complex. BK-β(1) expression was suppressed by the FBXO activator doxorubicin but enhanced by FBXO-9 small interfering RNA or by the proteasome inhibitor MG-132. Cotransfection of atrogin-1 in HEK293 cells significantly reduced Flag-hSlo-β(1) expression by 2.16-fold, compared with expression of Flag-hSlo-β(1)V146A (a mutant without the PDZ-binding motif). After cotransfection with atrogin-1, the ubiquitination of Flag-hSlo-β(1) was increased by 1.91-fold, compared with that of hSlo-β(1)V146A, whereas cotransfection with atrogin-1ΔF (a nonfunctional mutant without the F-box motif) had no effect. Moreover, inhibition of Akt signaling attenuated the phosphorylation of forkhead box O transcription factor (FOXO)-3a and enhanced atrogin-1 expression, which in turn suppressed BK-β(1) protein levels in human CASMCs.downregulation of vascular BK-β(1) expression in diabetes and in high-glucose culture conditions was associated with FOXO-3a/FBXO-dependent increase in BK-β(1) degradation.
Cytoprotection against neutrophil derived hypochlorous acid: a potential mechanism for the therapeutic action of 5-aminosalicylic acid in ulcerative colitis.
Authors: F Dallegri, L Ottonello, A Ballestrero, F Bogliolo, F Ferrando, F Patrone
Journal: Gut (1990)

The aim of the present study was to investigate the effects of 5-aminosalicyclic acid (5-ASA) on the cell injury mediated by activated neutrophils. We used a system constituted of neutrophils, triggered with phorbol myristate acetate, and 51Cr-labelled Daudi cells as targets. The results show that 5-ASA is capable of efficiently preventing neutrophil-mediated lysis. 5-ASA was up to 10-fold more effective than taurine, which acts as an hypochlorous acid scavenger. Moreover, 5-ASA was found to compete with taurine for the neutrophil derived hypochlorous acid. The results are consistent with the conclusion that 5-ASA is capable of limiting the neutrophil mediated cell damage by scavenging the generated hypochlorous acid. This may represent a potential mechanism for the therapeutic action of 5-ASA in ulcerative colitis.
Refractoriness to inhaled sodium metabisulphite in subjects with mild asthma
Authors: ID Pavord, A Wisniewski, AE Tattersfield
Journal: European Respiratory Journal (1994)

Refractoriness occurs after challenges causing mediator release in asthma, by a mechanism which may involve inhibitory prostaglandins. Bronchoconstriction due to inhaled sodium metabisulphite is thought to involve neural pathways and to be independent of mediator release; whether it shows refractoriness is uncertain. We have sought evidence of refractoriness to the bronchoconstrictor response to inhaled sodium metabisulphite in subjects with mild asthma, and have tested the hypothesis that the development of refractoriness involves inhibitory prostaglandins. Twelve subjects were challenged twice with a dose of sodium metabisulphite, previously shown to cause a 20% fall in forced expiratory volume in one second (FEV1); the second challenge proceeded after recovery from the first. The response to sodium metabisulphite was expressed as the maximum % fall in FEV1 and area under the change in FEV1 curve over 20 min (AUC). Nine subjects were studied after double-blind treatment with oral indomethacin, 50 mg t.d.s., or placebo, for 3 days. The second sodium metabisulphite challenge caused significantly less bronchoconstriction than the first (mean maximum fall in FEV1 13.1 and 24.3%, respectively). Nine subjects showed a greater than 50% reduction in the response to the second challenge (mean reduction in AUC 73.7%). In these subjects, indomethacin did not alter the response to the first sodium metabisulphite challenge, or the mean maximum fall in FEV1 in response to the second challenge (placebo 9.7%, indomethacin 11.2%), but significantly increased the AUC of the second challenge (placebo 55, indomethacin 114). The mean reduction in AUC from first to second challenge was 78% with placebo and 48% with indomethacin.(ABSTRACT TRUNCATED AT 250 WORDS)
Taxol Increases the Amount and T Cell–Activating Ability of Self-Immune Stimulatory Multimolecular Complexes Found in Ovarian Cancer Cells
Authors: Naotake Tsuda, David Z. Chang, Takashi Mine, Clay Efferson, Adolfo García-Sastre, Xinhui Wang, Soldano Ferrone, Constantin G. Ioannides
Journal: Cancer Research (2007)

Abstract It has been proposed that chemotherapy enhances tumor antigen (TA)–specific immunity. The molecular form of TA from ovarian tumor that activates cellular immunity is unknown. We report here identification of a novel molecular form of immunogenic TA for CD8+ cells named self-immune stimulatory multimolecular complexes (ISMMC). ISMMC consist of a molecular complex of polyosome/ribosome-bound ubiquitinated nascent HER-2 polypeptides. This complex is chaperoned by heat shock protein Gp96, which mediates ISMMC uptake by antigen-presenting cells through the scavenger receptor CD91. RNAs in ISMMC stimulate immature dendritic cells to secrete interleukin 12 and induce IFN-γ in peripheral blood mononuclear cells. ISMMC dissociate, retrotranslocate from the lysosome to cytoplasm, and are processed to peptides by the proteasome. At subpharmacologic doses, Taxol increased the amount of ISMMC by three to four times and modified their composition by inducing the attachment of cochaperones of HSP70, such as the mitotic-phase phosphoprotein 11J. On a total protein basis, Taxol induced ISMMC, expanded more CD8+ cells, activated more CD56+ NKG2D+ cells to produce IFN-γ, and were more potent inducers of high T-cell receptor density Perforin+ cells than native ISMMC and peptide E75. Elucidation of the composition of ISMMC and identification of adducts formed by Taxol should be important for developing molecular cancer vaccines. [Cancer Res 2007;67(17):8378–87]
Well-defined, reversible disulfide cross-linked micelles for on-demand paclitaxel delivery
Authors: Yuanpei Li, Kai Xiao, Juntao Luo, Wenwu Xiao, Joyce S. Lee, Abby M. Gonik, Jason Kato, Tiffany A. Dong, Kit S. Lam
Journal: Biomaterials (2011)
Resident CD141 (BDCA3)+ dendritic cells in human skin produce IL-10 and induce regulatory T cells that suppress skin inflammation
Authors: Chung-Ching Chu, Niwa Ali, Panagiotis Karagiannis, Paola Di Meglio, Ania Skowera, Luca Napolitano, Guillermo Barinaga, Katarzyna Grys, Ehsan Sharif-Paghaleh, Sophia N. Karagiannis, Mark Peakman, Giovanna Lombardi, Frank O. Nestle
Journal: The Journal of Experimental Medicine (2012)

Human skin immune homeostasis, and its regulation by specialized subsets of tissue-residing immune sentinels, is poorly understood. In this study, we identify an immunoregulatory tissue-resident dendritic cell (DC) in the dermis of human skin that is characterized by surface expression of CD141, CD14, and constitutive IL-10 secretion (CD141+ DDCs). CD141+ DDCs possess lymph node migratory capacity, induce T cell hyporesponsiveness, cross-present self-antigens to autoreactive T cells, and induce potent regulatory T cells that inhibit skin inflammation. Vitamin D3 (VitD3) promotes certain phenotypic and functional properties of tissue-resident CD141+ DDCs from human blood DCs. These CD141+ DDC-like cells can be generated in vitro and, once transferred in vivo, have the capacity to inhibit xeno-graft versus host disease and tumor alloimmunity. These findings suggest that CD141+ DDCs play an essential role in the maintenance of skin homeostasis and in the regulation of both systemic and tumor alloimmunity. Finally, VitD3-induced CD141+ DDC-like cells have potential clinical use for their capacity to induce immune tolerance.
Activation of cytokines as a mechanism of disease progression in heart failure
Authors: B. Bozkurt
Journal: Annals of the Rheumatic Diseases (2000)

The scientific quest for the basic mechanism(s) responsible for the development and progression of congestive heart failure in humans has been practically exhaustive; none the less, the mechanisms responsible for the decompensation of myocardial function after myocardial injury or haemodynamic overloading, or both, have remained elusive. Initially clinicians viewed heart failure as a problem of excessive salt and water retention that was caused by abnormalities of renal blood flow (the cardiorenal model). As clinicians began to perform careful haemodynamic measurements, it also became apparent that heart failure was accompanied by reduced cardiac output and excessive peripheral vasoconstriction. This led to the development of a cardiocirculatory or haemodynamic model for heart failure, in which heart failure was thought to arise from abnormalities of the pumping capacity of the heart. Neither of these models explained the progression of heart failure. Subsequently neurohormones were considered to lead to disease progression through myocyte loss, progressive myocardial fibrosis, as well as salt and water retention. More recently, it has become evident that another class of biologically active molecules, generally referred to as cytokines are also important in heart failure.1-8 

The term cytokine is applied to a group of relatively small molecular weight protein molecules (generally 15–30 kDa) that are secreted by cells in response to a variety of different inducing stimuli. Classically, cytokines are thought to be secreted by neighbouring “producer cells” and to act in an autocrine, juxtacrine or paracrine manner to influence the biological behaviour of neighbouring “target cells” (see Mann and Young8 for a brief review). However, when cytokines are overproduced they can “spill over” into the peripheral circulation where they can exert endocrine-like effects. It should be recognised that although cytokines are similar in many respects to polypeptide hormones, cytokines can be produced by a variety of different cell …
Walking Strategy in Diabetic Patients With Peripheral Neuropathy
Authors: Claudia Giacomozzi, Antonella Caselli, Velio Macellari, Laura Giurato, Lina Lardieri, Luigi Uccioli
Journal: Diabetes Care (2002)

Diabetic neuropathic patients show a peculiar loading pattern of the foot, which led us to hypothesize that a substantial modification exists in their deambulatory strategy. The aim of the present study was to support this hypothesis by quantifying the changes of the loading patterns and by monitoring the excursion of center of pressure (COP) during gait.-A total of 21 healthy volunteers (C) and 61 diabetic patients were evaluated: 27 diabetic subjects without neuropathy (D), 19 with neuropathy (DN), and 15 with previous neuropathic ulcer (DPU). A piezo-dynamometric platform was used to record the foot-to-floor interaction by measuring loading time and the instantaneous COP position during the stance phase of gait.Loading time was significantly longer in neuropathic patients than in control subjects (DPU: 816.8 +/- 150 ms; DN: 828.6 +/- 152 ms; D: 766.5 +/- 89.9 ms; C: 723.7 +/- 65.7 ms; P < 0.05). COP excursion along the medio-lateral axis of the foot clearly decreased from C to DPU groups (C: 6.41 +/- 0.1 cm; D: 4.88 +/- 0.2 cm; DN: 4.57 +/- 0.1 cm; DPU: 3.36 +/- 0.1 cm; P < 0.05) as well as COP excursion along the longitudinal axis for the DPU group only (C: 26.6 +/- 1 cm; D: 26.9 +/- 1 cm; DN: 27.2 +/- 1 cm; DPU: 24.2 +/- 1 cm; P < 0.05). COP integrals were significantly reduced for all pathological classes (DPU: 14.2 +/- 8 cm(2); DN: 25.8 +/- 6 cm(2); D: 27.7 +/- 3 cm(2); C: 38.6 +/- 6 cm(2); P < 0.05).The accurate quantification of loading patterns and of COP excursions and integrals highlights changes of foot-to-floor interaction in diabetic neuropathic patients. The decreased medio-lateral and longitudinal COP excursions and corresponding changes of loading times and patterns support our hypothesis that a change in the walking strategy of diabetic patients with peripheral neuropathy does occur.
Nitric oxide modulates ventilatory responses to hypoxia in the developing rat.
Authors: D Gozal, E Gozal, J E Torres, Y M Gozal, T J Nuckton, P J Hornby
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

Nitric oxide (NO) is an important excitatory neurotransmitter in the central nervous system. In the adult rat, both selective and nonselective blockers of constitutive nitric oxide synthase (NOS) induce marked ventilatory reductions during sustained hypoxia, thereby enhancing ventilatory roll-off. Since hypoxic ventilatory depression is greater in developing mammals during the late phases of hypoxic exposure, we hypothesized that limited NOS activity may play a role in the late arm of the ventilatory response. To test our hypothesis, 5-d-, 10-d-, and 15-d-old rat pups underwent a 30-min hypoxic challenge (10% O2) before and after administration of 100 mg/kg N-nitro-L-arginine methyl ester (L-NAME), a competitive NOS inhibitor. Minute ventilation (VE) was measured using whole-body plethysmography. In 5-d-old pups, early VE hypoxic responses were enhanced, and late VE were similar after administration of L-NAME. In contrast, in 15-d-old hypoxic pups, L-NAME administration was associated with smaller early VE increments and significantly larger VE reductions when compared with pretreatment conditions. The role of central nervous system NO in the development of these ventilatory changes was further assessed by Western blots of protein equivalents from the nucleus tractus solitarius (NTS), the first central relay for peripheral chemoreceptor afferent input, which revealed increasing neuronal NOS expression with age. Furthermore, NADPH-diaphorase immunohistochemical staining of neurons in the NTS revealed increased positively labeled neuronal populations within subnuclei of this structure with advancing postnatal age. Current findings suggest that NOS activity mediates both excitatory and inhibitory components of the hypoxic ventilatory response. Furthermore, in brainstem respiratory regions, NO may play a role in modulating the prominent second phase of the biphasic response to hypoxia typically seen in early postnatal life.
Dominant Role of Prostaglandin E2 EP4 Receptor in Furosemide-Induced Salt-Losing Tubulopathy
Authors: Rolf M. Nu[Combining Diaeresis]sing, Antje Treude, Christian Weissenberger, Boye Jensen, Martin Bek, Charlotte Wagner, Shuh Narumiya, Hannsjo[Combining Diaeresis]rg W. Seyberth
Journal: Journal of the American Society of Nephrology (2005)

Increased formation of prostaglandin E2 (PGE2) is a key part of hyperprostaglandin E syndrome/antenatal Bartter syndrome (HPS/aBS), a renal disease characterized by NaCl wasting, water loss, and hyperreninism. Inhibition of PGE2 formation by cyclo-oxygenase inhibitors significantly lowers patient mortality and morbidity. However, the pathogenic role of PGE2 in HPS/aBS awaits clarification. Chronic blockade of the Na-K-2Cl co-transporter NKCC2 by diuretics causes symptoms similar to HPS/aBS and provides a useful animal model. In wild-type (WT) mice and in mice lacking distinct PGE2 receptors (EP1-/-, EP2-/-, EP3-/-, and EP4-/-), the effect of chronic furosemide administration (7 d) on urine output, sodium and potassium excretion, and renin secretion was determined. Furthermore, furosemide-induced diuresis and renin activity were analyzed in mice with defective PGI2 receptors (IP-/-). In all animals studied, furosemide stimulated a rise in diuresis and electrolyte excretion. However, this effect was blunted in EP1-/-, EP3-/-, and EP4-/- mice. Compared with WT mice, no difference was observed in EP2-/- and IP-/- mice. The furosemide-induced increase in plasma renin concentration was significantly decreased in EP4-/- mice and to a lesser degree also in IP-/- mice. Pharmacologic inhibition of EP4 receptors in furosemide-treated WT mice with the specific antagonist ONO-AE3-208 mimicked the changes in renin mRNA expression, plasma renin concentration, diuresis, and sodium excretion seen in EP4-/- mice. The GFR in EP4-/- mice was not changed compared with that in WT mice, which indicated that blunted diuresis and salt loss seen in EP4-/- mice were not a consequence of lower GFR. In summary, these findings demonstrate that the EP4 receptor mediates PGE2-induced renin secretion and that EP1, EP3, and EP4 receptors all contribute to enhanced PGE2-mediated salt and water excretion in the HPS/aBS model.
Delayed effects of sublethal ischemia on the acquisition of tolerance to ischemia.
Authors: T Kuzuya, S Hoshida, N Yamashita, H Fuji, H Oe, M Hori, T Kamada, M Tada
Journal: Circulation Research (1993)

The infarct-limiting effect of ischemic preconditioning is believed to be a transient phenomenon. We examined the delayed effects of repetitive brief ischemia on limiting infarct size in an open-chest dog model by an occlusion (90 minutes) of the left anterior descending coronary artery (LAD) followed by reperfusion (5 hours). The dogs were preconditioned with four brief repeated ischemic episodes induced by 5-minute LAD occlusions with subsequent reperfusion. The size of infarcts initiated by a sustained occlusion immediately or 24 hours after preconditioning was significantly smaller when compared with infarcts in sham-operated dogs (for the immediate occlusion, 14.4 +/- 2.0% versus 39.0 +/- 3.7%, respectively [p &lt; 0.01]; and for the delayed occlusion, 18.8 +/- 3.4% versus 35.1 +/- 4.6%, respectively [p &lt; 0.05]); however, when the infarction was induced 3 hours (31.2 +/- 3.7% versus 37.5 +/- 4.2%, respectively) or 12 hours (25.4 +/- 4.8% versus 35.0 +/- 5.3%, respectively) after repetitive ischemia, the infarct size did not differ. No differences were seen in regional myocardial blood flow or rate-pressure products between the two groups. These results indicate that an infarct-limiting effect of brief repeated ischemia can be observed 24 hours after sublethal preconditioning.