tbuckley/cabot-search huggingface dataset:
Blockade of Inflammation and Airway Hyperresponsiveness in Immune-sensitized Mice by Dominant-Negative Phosphoinositide 3-Kinase–TAT
Authors: Shigeharu Myou, Alan R. Leff, Saori Myo, Evan Boetticher, Jiankun Tong, Angelo Y. Meliton, Jie Liu, Nilda M. Munoz, Xiangdong Zhu
Journal: The Journal of Experimental Medicine (2003)

Phosphoinositide 3-kinase (PI3K) is thought to contribute to the pathogenesis of asthma by effecting the recruitment, activation, and apoptosis of inflammatory cells. We examined the role of class IA PI3K in antigen-induced airway inflammation and hyperresponsiveness by i.p. administration into mice of Deltap85 protein, a dominant negative form of the class IA PI3K regulatory subunit, p85alpha, which was fused to HIV-TAT (TAT-Deltap85). Intraperitoneal administration of TAT-Deltap85 caused time-dependent transduction into blood leukocytes, and inhibited activated phosphorylation of protein kinase B (PKB), a downstream target of PI3K, in lung tissues in mice receiving intranasal FMLP. Antigen challenge elicited pulmonary infiltration of lymphocytes, eosinophils and neutrophils, increase in mucus-containing epithelial cells, and airway hyperresponsiveness to methacholine. Except for modest airway neutrophilia, these effects all were blocked by treatment with 3-10 mg/kg of TAT-Deltap85. There was also significant reduction in IL-5 and IL-4 secretion into the BAL. Intranasal administration of IL-5 caused eosinophil migration into the airway lumen, which was attenuated by systemic pretreatment with TAT-Deltap85. We conclude that PI3K has a regulatory role in Th2-cell cytokine secretion, airway inflammation, and airway hyperresponsiveness in mice.
Magnetic Meters: Effects of Electrical Resistance in Tissues on Flow Measurements, and an Improved Calibration for Square-Wave Circuits
Authors: DONALD J. FERGUSON, HERBERT D. LANDAHL
Journal: Circulation Research (1966)

Apparent sensitivity of magnetic meters applied to intact vessels can be altered by changes in conductivity of vessel walls or of the contained fluid, and by variable contact of the vessel with surrounding tissue or fluid. An experimental study of these problems was begun by designing a built-in magnetometer for complete electrical calibration of the square-wave meter. It was then found that flow of mercury, saline or blood of various hematocrits through nonconductive tubes gave signals equal to those calculated on the basis of Faraday's principle, providing that the magnetic field was practically uniform across the electrodes. Adequate uniformity was obtained with parallel pole faces at least 1.3 times as wide as the gap. Variable loss of signal (up to 50%), owing to contact of conductive vessels with surrounding tissue or fluid, could be practically eliminated by an electrical shield extending 2.6 times the diameter along the vessel at the electrodes. Specific conductances of canine aortas were from 0.52 to 0.73 times the conductances of blood from the same animals. Alterations in this ratio, readily produced by changes in composition of vessel or fluid, can result in significant changes of flow signal. Indirect flow calibrations require matching of the conductance ratio to that occurring at the time of measurement.
Validity of Meta-analysis in Diabetes: Meta-analysis Is an Indispensable Tool in Evidence Synthesis
Authors: Sherita Hill Golden, Eric B. Bass
Journal: Diabetes Care (2013)

To deliver high-quality clinical care to patients with diabetes and other chronic conditions, clinicians must understand the evidence available from studies that have been performed to address important clinical management questions. In an evidence-based approach to clinical care, the evidence from clinical research should be integrated with clinical expertise, pathophysiological knowledge, and an understanding of patient values. As such, in an effort to provide information from many studies, the publication of diabetes meta-analyses has increased markedly in the recent past, using either observational or clinical trial data. In this regard, guidelines have been developed to direct the performance of meta-analysis to provide consistency among contributions. Thus, when done appropriately, meta-analysis can provide estimates from clinically and statistically homogeneous but underpowered studies and is useful in supporting clinical decisions, guidelines, and cost-effectiveness analysis. However, often these conditions are not met, the data considered are unreliable, and the results should not be assumed to be any more valid than the data underlying the included studies. To provide an understanding of both sides of the argument, we provide a discussion of this topic as part of this two-part point-counterpoint narrative. In the point narrative preceding the counterpoint narrative below, Dr. Home provides his opinion and review of the data to date showing that we need to carefully evaluate meta-analysis, and we need to learn what results are reliable. In the counterpoint narrative here, Drs. Golden and Bass emphasize that an effective system exists to guide meta-analysis and that rigorously conducted, high-quality systematic reviews and meta-analyses using established guidelines are an indispensable tool in evidence synthesis despite their limitations. —William T. Cefalu, MD Editor in Chief, Diabetes Care
Chronic metabolic acidosis decreases albumin synthesis and induces negative nitrogen balance in humans.
Authors: P E Ballmer, M A McNurlan, H N Hulter, S E Anderson, P J Garlick, R Krapf
Journal: Journal of Clinical Investigation (1995)

Chronic metabolic acidosis has been previously shown to stimulate protein degradation. To evaluate the effects of chronic metabolic acidosis on nitrogen balance and protein synthesis we measured albumin synthesis rates and urinary nitrogen excretion in eight male subjects on a constant metabolic diet before and during two different degrees of chronic metabolic acidosis (NH4Cl 2.1 mmol/kg body weight, low dose group, and 4.2 mmol/kg body weight, high dose group, orally for 7 d). Albumin synthesis rates were measured by intravenous injection of [2H5ring]phenylalanine (43 mg/kg body weight, 7.5 atom percent and 15 atom percent, respectively) after an overnight fast. In the low dose group, fractional synthesis rates of albumin decreased from 9.9 +/- 1.0% per day in the control period to 8.4 +/- 0.7 (n.s.) in the acidosis period, and from 8.3 +/- 1.3% per day to 6.3 +/- 1.1 (P < 0.001) in the high dose group. Urinary nitrogen excretion increased significantly in the acidosis period (sigma delta 634 mmol in the low dose group, 2,554 mmol in the high dose group). Plasma concentrations of insulin-like growth factor-I, free thyroxine and tri-iodothyronine were significantly lower during acidosis. In conclusion, chronic metabolic acidosis causes negative nitrogen balance and decreases albumin synthesis in humans. The effect on albumin synthesis may be mediated, at least in part, by a suppression of insulin-like growth factor-I, free thyroxine and tri-iodothyronine.
Effective Photothermal Chemotherapy Using Doxorubicin-Loaded Gold Nanospheres That Target EphB4 Receptors in Tumors
Authors: Jian You, Rui Zhang, Chiyi Xiong, Meng Zhong, Maritess Melancon, Sanjay Gupta, Alpa M. Nick, Anil K. Sood, Chun Li
Journal: Cancer Research (2012)

Abstract Photothermal ablation (PTA) is an emerging technique that uses near-infrared (NIR) laser light–generated heat to destroy tumor cells. However, complete tumor eradication by PTA therapy alone is difficult because heterogeneous heat distribution can lead to sublethal thermal dose in some areas of the tumor. Successful PTA therapy requires selective delivery of photothermal conducting nanoparticles to mediate effective PTA of tumor cells, and the ability to combine PTA with other therapy modalities. Here, we synthesized multifunctional doxorubicin (DOX)-loaded hollow gold nanospheres (DOX@HAuNS) that target EphB4, a member of the Eph family of receptor tyrosine kinases overexpressed on the cell membrane of multiple tumors and angiogenic blood vessels. Increased uptake of targeted nanoparticles T-DOX@HAuNS was observed in three EphB4-positive tumors both in vitro and in vivo. In vivo release of DOX from DOX@HAuNS, triggered by NIR laser, was confirmed by dual-radiotracer technique. Treatment with T-DOX@HAuNS followed by NIR laser irradiation resulted in significantly decreased tumor growth when compared with treatments with nontargeted DOX@HAuNS plus laser or HAuNS plus laser. The tumors in 6 of the 8 mice treated with T-DOX@HAuNS plus laser regressed completely with only residual scar tissue by 22 days following injection, and none of the treatment groups experienced a loss in body weight. Together, our findings show that concerted chemo-photothermal therapy with a single nanodevice capable of mediating simultaneous PTA and local drug release may have promise as a new anticancer therapy. Cancer Res; 72(18); 4777–86. ©2012 AACR.
Clinical application of a systems model of apoptosis execution for the prediction of colorectal cancer therapy responses and personalisation of therapy
Authors: Suzanne Hector, Markus Rehm, Jasmin Schmid, Joan Kehoe, Niamh McCawley, Patrick Dicker, Frank Murray, Deborah McNamara, Elaine W Kay, Caoimhin G Concannon, Heinrich J Huber, Jochen H M Prehn
Journal: Gut (2011)

<h3>Objective</h3> Key to the clinical management of colorectal cancer is identifying tools which aid in assessing patient prognosis and determining more effective and personalised treatment strategies. We evaluated whether an experimental systems biology strategy which analyses the susceptibility of cancer cells to undergo caspase activation can be exploited to predict patient responses to 5-fluorouracil-based chemotherapy and to case-specifically identify potential alternative targeted treatments to reactivate apoptosis. <h3>Design</h3> We quantified five essential apoptosis-regulating proteins (Pro-Caspases 3 and 9, APAF-1, SMAC and XIAP) in samples of Stage II (n=13) and III (n=17) tumour and normal colonic (n=8) tissue using absolute quantitative immunoblotting and employed systems simulations of apoptosis signalling to predict the susceptibility of tumour cells to execute apoptosis. Additional systems analyses assessed the efficacy of novel apoptosis-inducing therapeutics such as XIAP antagonists, proteasome inhibitors and Pro-Caspase-3-activating compounds in restoring apoptosis execution in apoptosis-incompetent tumours. <h3>Results</h3> Comparisons of caspase activity profiles demonstrated that the likelihood of colorectal tumours to undergo apoptosis decreases with advancing disease stage. Systems-level analysis correctly predicted positive or negative outcome in 85% (p=0.004) of colorectal cancer patients receiving 5-fluorouracil based chemotherapy and significantly outperformed common uni- and multi-variate statistical approaches. Modelling of individual patient responses to novel apoptosis-inducing therapeutics revealed markedly different inter-individual responses. <h3>Conclusions</h3> Our study represents the first proof-of-concept example demonstrating the significant clinical potential of systems biology-based approaches for predicting patient outcome and responsiveness to novel targeted treatment paradigms.
High Risk for Hyperlipidemia and the Metabolic Syndrome after an Episode of Hypertriglyceridemia during 13-<i>cis</i> Retinoic Acid Therapy for Acne: A Pharmacogenetic Study
Authors: Nicolas Rodondi, Roger Darioli, Albert-Adrien Ramelet, Daniel Hohl, Vincent Lenain, Jean Perdrix, Vincent Wietlisbach, Walter F. Riesen, Thomas Walther, Laurent Medinger, Pascal Nicod, Béatrice Desvergne, Vincent Mooser
Journal: Annals of Internal Medicine (2002)

Administration of 13-cis retinoic acid (isotretinoin) for acne is occasionally accompanied by hyperlipidemia. It is not known why some persons develop this side effect.To determine whether isotretinoin triggers a familial susceptibility to hyperlipidemia and the metabolic syndrome.Cross-sectional comparison.University hospital in Lausanne, Switzerland.102 persons in whom triglyceride levels increased at least 1.0 mmol/L (> or =89 mg/dL) (hyperresponders) and 100 persons in whom triglyceride levels changed 0.1 mmol/L (< or =9 mg/dL) or less (nonresponders) during isotretinoin therapy for acne. Parents of 71 hyperresponders and 60 nonresponders were also evaluated.Waist-to-hip ratio; fasting glucose, insulin, and lipid levels; and apoE genotype.Hyperresponders and nonresponders had similar pretreatment body weight and plasma lipid levels. When reevaluated approximately 4 years after completion of isotretinoin therapy, hyperresponders were more likely to have hypertriglyceridemia (triglyceride level > 2.0 mmol/L [>177 mg/dL]; odds ratio [OR], 4.8 [95% CI, 1.6 to 13.8]), hypercholesterolemia (cholesterol level > 6.5 mmol/L [>252 mg/dL]; OR, 9.1 [CI, 1.9 to 43]), truncal obesity (waist-to-hip ratio > 0.90 [OR, 11.0 (CI, 2.0 to 59]), and hyperinsulinemia (insulin-glucose ratio > 7.2; OR, 3.0 [CI, 1.6 to 5.7]). In addition, more hyperresponders had at least one parent with hypertriglyceridemia (OR, 2.6 [CI, 1.2 to 5.7]) or a ratio of total to high-density lipoprotein cholesterol that exceeded 4.0 (OR, 3.5 [CI, 1.5 to 8.0]). Lipid response to isotretinoin was closely associated with the apoE gene.Persons who develop hypertriglyceridemia during isotretinoin therapy for acne, as well as their parents, are at increased risk for future hyperlipidemia and the metabolic syndrome.
Pruritus in the Older Patient
Authors: Timothy G. Berger, Melissa Shive, G. Michael Harper
Journal: JAMA (2013)

<h3>Importance</h3> Pruritus is a common problem among elderly people and, when severe, causes as much discomfort as chronic pain. Little evidence supports pruritus treatment, limiting therapeutic possibilities and resulting in challenging management problems. <h3>Objectives</h3> To present the evidence on the etiology, diagnosis, and treatment of pruritus in the elderly and, using the best available evidence, provide an approach for generalist physicians caring for older patients with pruritus. <h3>Evidence Review</h3> PubMed and EMBASE databases were searched (1946–August 2013).The Cochrane Database of Systematic Reviews and the Agency for Healthcare Research and Quality Systematic Review Data Repository were also searched from their inception to August 2013. References from retrieved articles were evaluated. <h3>Findings</h3> More than 50% of elderly patients have xerosis (dry skin). Xerosis treatment should be included in the initial therapy for pruritus in all elderly patients. Calcium channel blockers and hydrochlorothiazide are important causes of pruritic skin eruptions in older patients. Neuropathic pruritus is infrequently considered but may cause localized itching (especially in the genital area) and generalized truncal pruritus (especially in patients with diabetes mellitus). Certain skin conditions are more common in elderly patients, including scabies, bullous pemphigoid, transient acantholytic dermatosis, and mycosis fungoides, and should be considered in elderly patients with pruritus. <h3>Conclusions and Relevance</h3> It is important to evaluate elderly patients for dermatological, systemic, and neurological etiologies of itch. A simple-to-apply diagnostic and therapeutic algorithm can be used. Xerosis, drug reactions, and neuropathy should be considered when evaluating pruritus.
Association of the Interleukin-1 Receptor Antagonist Gene with Asthma
Authors: Henning Gohlke, Thomas Illig, Margret Bahnweg, Norman Klopp, Elisabeth André, Janine Altmüller, Nicole Herbon, Monika Werner, Michael Knapp, Lydia Pescollderungg, Attilio Boner, Giovanni Malerba, Pier Franco Pignatti, Matthias Wjst
Journal: American Journal of Respiratory and Critical Care Medicine (2004)

The interleukin-1 cluster on human chromosome 2q12-2q14 harbors various promising candidate genes for asthma and other inflammatory diseases. We conducted a systematic association study with single-nucleotide polymorphisms (SNPs) located in candidate genes situated in this cluster. Single-marker, two-locus and three-locus haplotype analysis of SNPs yielded several significant results (p < 0.05-0.0021) for the human IL1RN gene encoding the IL-1 receptor antagonist protein, an antiinflammatory cytokine that plays an important role in maintaining the balance between inflammatory and antiinflammatory cytokines. These findings were replicated and confirmed in an independent Italian family sample in which significant, although weaker, association with asthma was detected. A sequencing approach to the coding region of the human IL1RN gene revealed additional DNA variants, from which a selection was also associated with the disease in German and Italian samples. Calculation of the linkage disequilibrium for the human IL1RN gene showed strong linkage disequilibrium for nearly all analyzed SNPs. Further haplotype analysis indicated that six SNPs are sufficient for tagging all haplotypes with a prevalence of more than 1%. The most frequent haplotype constructed from these SNPs was 1.4-fold overtransmitted in the German family sample.
Association of Cerebrospinal Fluid Prion Protein Levels and the Distinction Between Alzheimer Disease and Creutzfeldt-Jakob Disease
Authors: Aline Dorey, Yannick Tholance, Alain Vighetto, Armand Perret-Liaudet, Ingolf Lachman, Pierre Krolak-Salmon, Uta Wagner, Hanne Struyfs, Peter P. De Deyn, Benaissa El-Moualij, Willy Zorzi, David Meyronet, Nathalie Streichenberger, Sebastiaan Engelborghs, Gabor G. Kovacs, Isabelle Quadrio
Journal: JAMA Neurology (2015)

Although typical forms of Alzheimer disease (AD) and Creutzfeldt-Jakob disease (CJD) are clinically distinguishable, atypical AD phenotypes may pose a diagnostic challenge. The major biological diagnostic biomarker for identifying CJD, 14-3-3 protein in cerebrospinal fluid (CSF), unfortunately lacks specificity when confronting a rapid dementia presentation.To assess the relevance of total CSF prion protein (t-PrP) levels in the differential biological diagnosis between atypical AD phenotypes and CJD.A retrospective study in an autopsy-confirmed cohort of 82 patients was performed to evaluate the relevance of CSF t-PrP to distinguish 30 definite cases of AD from 52 definite cases of CJD. Next, CSF t-PrP concentration was measured in a cohort of 104 patients including 55 patients with probable AD, 26 with probable sporadic CJD, and 23 control patients for whom 14-3-3 protein, total tau, phosphorylated tau 181 (P-tau181), and Aβ1-42 were available. We investigated 46 patients diagnosed as having probable AD who presented atypical phenotypes. A diagnosis strategy was proposed to classify atypical AD phenotypes with suspicion of CJD based on a decision tree combining CSF biomarkers.We determined CSF t-PrP levels for all patients. We calculated the ratio of total tau and P-tau181 and determined the diagnostic accuracy of each biomarker alone or in combination. We calculated the misclassification rate for each biomarker that corresponded to the percentage of patients within the group of atypical AD phenotypes wrongly classified as CJD.In patients with CJD, CSF t-PrP concentrations were decreased compared with control participants and patients with AD. When considering the differential diagnosis of CJD compared with atypical AD phenotypes, CSF t-PrP determination reached 82.1% sensitivity and 91.3% specificity. The misclassification rate of atypical AD phenotypes decreased from 43.5%, obtained when using the CSF 14-3-3 protein determination alone, to only 4.3% when calculating the ratio total tau/(P-tau181 × t-PrP). The proposed classification tree permitted correct classification of 98.4% of the patients.For unusual phenotypes of AD, especially cases presenting with a biological ambiguity suggesting CJD, determination of CSF t-PrP levels increased diagnostic accuracy. The use of CSF t-PrP levels may be beneficial in clinical practice in addition to the current classic biomarkers.
Comparative study of hydrogen and methane production in the human colon using caecal and faecal homogenates.
Authors: B Flourie, F Etanchaud, C Florent, P Pellier, Y Bouhnik, J C Rambaud
Journal: Gut (1990)

Rates of hydrogen and methane production were compared in caecal and faecal homogenates in six methane producers. Faecal homogenates produced hydrogen and methane in the absence of and after the addition of lactulose, whereas caecal homogenates produced hydrogen but little methane.
H1N1 2009 influenza virus infection during pregnancy in the USA
Authors: Denise J Jamieson, Margaret A Honein, Sonja A Rasmussen, Jennifer L Williams, David L Swerdlow, Matthew S Biggerstaff, Stephen Lindstrom, Janice K Louie, Cara M Christ, Susan R Bohm, Vincent P Fonseca, Kathleen A Ritger, Daniel J Kuhles, Paula Eggers, Hollianne Bruce, Heidi A Davidson, Emily Lutterloh, Meghan L Harris, Colleen Burke, Noelle Cocoros, Lyn Finelli, Kitty F MacFarlane, Bo Shu, Sonja J Olsen
Journal: The Lancet (2009)
BRAK/CXCL14 Is a Potent Inhibitor of Angiogenesis and a Chemotactic Factor for Immature Dendritic Cells
Authors: Thomas D. Shellenberger, Mary Wang, Manu Gujrati, Arumugam Jayakumar, Robert M. Strieter, Marie D. Burdick, Constantin G. Ioannides, Clayton L. Efferson, Adel K. El-Naggar, Dianna Roberts, Gary L. Clayman, Mitchell J. Frederick
Journal: Cancer Research (2004)

Abstract BRAK/CXCL14 is a CXC chemokine constitutively expressed at the mRNA level in certain normal tissues but absent from many established tumor cell lines and human cancers. Although multiple investigators cloned BRAK, little is known regarding the physiologic function of BRAK or the reason for decreased expression in cancer. To understand the possible significance associated with loss of BRAK mRNA in tumors, we examined the pattern of BRAK protein expression in normal and tumor specimens from patients with squamous cell carcinoma (SCC) of the tongue and used recombinant BRAK (rBRAK) to investigate potential biological functions. Using a peptide-specific antiserum, abundant expression of BRAK protein was found in suprabasal layers of normal tongue mucosa but consistently was absent in tongue SCC. Consistent with previous in situ mRNA studies, BRAK protein also was expressed strongly by stromal cells adjacent to tumors. In the rat corneal micropocket assay, BRAK was a potent inhibitor of in vivo angiogenesis stimulated by multiple angiogenic factors, including interleukin 8, basic fibroblast growth factor, and vascular endothelial growth factor. In vitro, rBRAK blocked endothelial cell chemotaxis at concentrations as low as 1 nmol/L, suggesting this was a major mechanism for angiogenesis inhibition. Although only low affinity receptors for BRAK could be found on endothelial cells, human immature monocyte-derived dendritic cells (iDCs) bound rBRAK with high affinity (i.e., Kd, ∼2 nmol/L). Furthermore, rBRAK was chemotactic for iDCs at concentrations ranging from 1 to 10 nmol/L. Our findings support a hypothesis that loss of BRAK expression from tumors may facilitate neovascularization and possibly contributes to immunologic escape.
1369 TELAPREVIR SUBSTANTIALLY IMPROVED SVR RATES ACROSS ALL IL28B GENOTYPES IN THE ADVANCE TRIAL
Authors: I.M. Jacobson, I. Catlett, P. Marcellin, N.H. Bzowej, A.J. Muir, N. Adda, L. Bengtsson, S. George, S. Seepersaud, R. Ramachandran, K. Sussky, R.S. Kauffman, M. Botfield
Journal: Journal of Hepatology (2011)