tbuckley/cabot-search huggingface dataset:
Inflammasome Activation by Cystine Crystals
Authors: Giusi Prencipe, Ivan Caiello, Stephanie Cherqui, Thomas Whisenant, Stefania Petrini, Francesco Emma, Fabrizio De Benedetti
Journal: Journal of the American Society of Nephrology (2014)

Intralysosomal cystine crystal accumulation, due to mutations in the CTNS gene, is a hallmark of nephropathic cystinosis, but the role of these crystals in disease pathogenesis remains unclear. We hypothesized that, similar to other host-derived crystalline moieties, cystine crystals can induce IL-1β production through inflammasome activation. Thus, we investigated the proinflammatory effects of cystine crystals in primary human PBMCs. LPS-primed PBMCs stimulated with cystine crystals secreted IL-1β in a dose-dependent manner. Similarly to IL-1β secretion induced by other crystalline inflammasome activators, cystine crystal-induced IL-1β secretion required activation of caspase-1. Additionally, exogenous cystine crystals were internalized by monocytes, and inhibition of phagocytosis, cathepsin B leakage, generation of reactive oxygen species, and potassium efflux reduced cystine crystal-induced IL-1β secretion. Patients with cystinosis had higher levels of circulating IL-1β and IL-18 compared with controls. Analysis of inflammasome-related gene expression in PBMCs from patients with cystinosis revealed a significant increase in IL-1β and CASP-1 transcript levels compared with controls. Moreover, knockout of cystinosin in mice led to significant increases in serum IL-18 levels and kidney expression of inflammasome-related genes (Casp-1, Pycard, Il-18, Il18r1, Il1r1, and Il1rl2). Taken together, these data demonstrate that cystine crystals are endogenous inflammasome-activating stimuli, suggesting a novel role for cystine crystals in the pathogenesis of nephropathic cystinosis.
Lupine allergy: Not simply cross-reactivity with peanut or soy
Authors: Kim A.B.M. Peeters, Julie A. Nordlee, André H. Penninks, Lingyun Chen, Richard E. Goodman, Carla A.F.M. Bruijnzeel-Koomen, Sue L. Hefle, Steve L. Taylor, André C. Knulst
Journal: Journal of Allergy and Clinical Immunology (2007)
The role of a soluble TNF receptor fusion protein (etanercept) in corticosteroid refractory asthma: a double blind, randomised, placebo controlled trial
Authors: J B Morjaria, A J Chauhan, K S Babu, R Polosa, D E Davies, S T Holgate
Journal: Thorax (2008)

Tumour necrosis factor alpha (TNFalpha) is a cytokine recognised as a therapeutic target in chronic inflammatory diseases.A randomised, double blind, placebo controlled parallel group trial is reported of etanercept (an IgG1-TNF p75 receptor fusion protein), administered once weekly for 12 weeks in 39 patients with severe corticosteroid refractory asthma. Efficacy was measured by change from the pretreatment baseline in Asthma Related Quality of Life (AQLQ) and Asthma Control (ACQ) Questionnaire scores (the primary endpoints), lung function, peak expiratory flow (PEF) and bronchial hyperresponsiveness (BHR). Sputum and serum inflammatory cells and cytokines, serum albumin and C reactive protein (CRP) as biomarkers of inflammation were also assessed.There was a small but significant difference in reduction of ACQ scores between treatment and placebo (-1.11 (95% CI -1.56 to -0.75) and -0.52 (95% CI -0.97 to -0.07), respectively, p = 0.037). There was no significant difference in improvements in AQLQ scores, lung function, PEF, BHR or exacerbation rates between the groups. Minor adverse events, including injection site pain and skin rashes, were more frequent with etanercept. There was a significant reduction in sputum macrophages and CRP, and increases in serum TNFalpha and albumin following treatment, but not in other laboratory parameters.Etanercept therapy over 12 weeks demonstrated only a small but significant improvement in asthma control and systemic inflammation, as measured by serum albumin and CRP. Larger randomised, placebo controlled trials are required to clarify the role of TNFalpha antagonism in subjects with severe refractory asthma.
Sublingual Immunotherapy With Honeybee Venom Is Effective In Patients With Large Local Reactions Due To Bee Sting. A Randomised, Double Blind Placebo Controlled Trial
Authors: G. Passalacqua, M.G. Severino, G. Cortellini, P. Bonadonna, E. Francescato, I. Panzini, D. Macchia, P. Campi, I. Spadolini, G.W. Canonica
Journal: Journal of Allergy and Clinical Immunology (2008)
Global burden of respiratory infections due to seasonal influenza in young children: a systematic review and meta-analysis
Authors: Harish Nair, W Abdullah Brooks, Mark Katz, Anna Roca, James A Berkley, Shabir A Madhi, James Mark Simmerman, Aubree Gordon, Masatoki Sato, Stephen Howie, Anand Krishnan, Maurice Ope, Kim A Lindblade, Phyllis Carosone-Link, Marilla Lucero, Walter Ochieng, Laurie Kamimoto, Erica Dueger, Niranjan Bhat, Sirenda Vong, Evropi Theodoratou, Malinee Chittaganpitch, Osaretin Chimah, Angel Balmaseda, Philippe Buchy, Eva Harris, Valerie Evans, Masahiko Katayose, Bharti Gaur, Cristina O'Callaghan-Gordo, Doli Goswami, Wences Arvelo, Marietjie Venter, Thomas Briese, Rafal Tokarz, Marc-Alain Widdowson, Anthony W Mounts, Robert F Breiman, Daniel R Feikin, Keith P Klugman, Sonja J Olsen, Bradford D Gessner, Peter F Wright, Igor Rudan, Shobha Broor, Eric AF Simões, Harry Campbell
Journal: The Lancet (2011)
Variability in languages, variability in learning?
Authors: Bob McMurray, Edward Wasserman
Journal: Behavioral and Brain Sciences (2009)

Abstract In documenting the dizzying diversity of human languages, Evans &amp; Levinson (E&amp;L) highlight the lack of universals. This suggests the need for complex learning. Yet, just as there is no universal structure, there may be no universal learning mechanism responsible for language. Language is a behavior assembled by many processes, an assembly guided by the language being learned.
VENTRICULAR TWIST AND STRAIN ALTERATIONS IN PATIENTS WITH COARCTATION OF THE AORTA: A NOVEL GRADIENT CINE MRI WITH STRAINS COMPUTED BY VECTOR VELOCITY IMAGING
Authors: David J. Sahn, Petra S. Niemann, Helene Houle, Craig S. Broberg, Michael Silberbach, Muhammad Ashraf
Journal: Journal of the American College of Cardiology (2011)
DIABETES CONTROL AND COMPLICATIONS
Authors: Oscar B. Crofford, M.D
Journal: Annual Review of Medicine (1995)

▪ Abstract The Diabetes Control and Complications Trial (DCCT) demonstrated that intensive treatment of patients with insulin-dependent diabetes mellitus (IDDM) can substantially reduce the onset and progression of diabetic retinopathy, nephropathy, and neuropathy. The major risk associated with intensive treatment is recurrent hypoglycemia. Implementation of intensive treatment recommendations is difficult but should be considered and probably recommended to most patients with IDDM. If intensive treatment is impractical, any improvement in glycemic control is probably beneficial. Improved glycemic control should be recommended to most patients with non-insulin-dependent diabetes mellitus (NIDDM). The use of insulin in patients with NIDDM is controversial, especially in patients who are overweight, overeating, and minimally symptomatic.
Cardiomyocyte-Restricted Overexpression of Endothelial Nitric Oxide Synthase ( <i>NOS3</i> ) Attenuates β-Adrenergic Stimulation and Reinforces Vagal Inhibition of Cardiac Contraction
Authors: Paul B. Massion, Chantal Dessy, Fanny Desjardins, Michel Pelat, Xavier Havaux, Catharina Belge, Pierre Moulin, Yves Guiot, Olivier Feron, Stefan Janssens, Jean-Luc Balligand
Journal: Circulation (2004)

In the heart, nitric oxide synthases (NOS) modulate cardiac contraction in an isoform-specific manner, which is critically dependent on their cellular and subcellular localization. Defective NO production by NOS3 (endothelial NOS [eNOS]) in the failing heart may precipitate cardiac failure, which could be reversed by overexpression of NOS3 in the myocardium.We studied the influence of NOS3 in relation to its subcellular localization on the function of cardiomyocytes isolated from transgenic mice overexpressing NOS3 under the alpha-myosin heavy chain promoter (NOS3-TG). Immunoblot analysis demonstrated moderate (5-fold) NOS3 overexpression in cardiomyocytes from NOS3-TG heterozygotes. Caveolar localization of transgenic eNOS was demonstrated by immunofluorescence, coimmunoprecipitation with caveolin-3, sucrose gradient fractionation, and immunogold staining revealed by electron microscopy. Compared with wild-type littermate, contractility of NOS3-TG cardiomyocytes analyzed by videomicroscopy revealed a lower incidence of spontaneous arrhythmic contractions (n=32, P<0.001); an attenuation of the beta-adrenergic positive inotropic response (isoproterenol, 10(-7) mol/L: 62.1+/-7.8% versus 90.8+/-8.0% of maximum Ca2+ response; n=10 to 17; P<0.05); a potentiation of the muscarinic negative chronotropic response (carbamylcholine, 3.10(-8) mol/L: -63.9+/-14% versus -27.7+/-5.6% of basal rate; n=8 to 10; P<0.05), confirmed by telemetry in vivo; and an attenuation of the accentuated antagonism of beta-adrenergically stimulated contraction (-14.6+/-1.5% versus -3.5+/-1.5; n=7 to 11; P<0.05). Cardiomyocyte NOS inhibition reversed all 4 effects (P<0.05).Moderate overexpression of NOS3, targeted to caveolae in murine cardiomyocytes, potentiates the postsynaptic muscarinic response and attenuates the effect of high concentrations of catecholamines. Cardiomyocyte NOS3 may represent a promising therapeutic target to restore the sympathovagal balance and protect the heart against arrhythmia.
Nebulizer therapy in cystic fibrosis: An overview
Authors: Nicola Collins
Journal: Journal of the Royal Society of Medicine (2009)

The word nebulizer comes from the Latin ‘nebula’ meaning mist, and was first used in 1872. However, the principles of nebulizer therapy date back over 4000 years. Even Hippocrates supported the use of hot vapours to help the diseases of the throat and chest.1

Nebulizer therapy has altered vastly over the years and cystic fibrosis (CF) caregivers are often bombarded with a large, and often, confusing array of nebulizer systems to choose from.2 The British Thoracic Society and European Respiratory Society formulated nebulizer guidelines in 1994 and 2001, respectively, aiming to give guidance to clinicians prescribing and delivering treatment with nebulizers.3,4

The purpose of this paper is to present practical information regarding the different nebulizer systems available. The aim is to assist the CF clinician to choose the most appropriate nebulizer device for the drug to be nebulized and the individual patient receiving therapy. Where possible information is referenced or taken from the nebulizer device handbooks. However, on occasion, observations are made based on the author's clinical experiences working with adults and children with CF.

Most therapeutic aerosols are heterodisperse, consisting of a range of particle sizes.5 They can be described by the mass median aerodynamic diameter (MMAD) above and below which 50% of the mass of the drug is contained.6

The therapeutic effectiveness of an inhaled drug depends on a number of factors but in particular how much bypasses the oropharynx and deposits in the lungs. There are three main mechanisms of deposition. Inertial impaction occurs in the upper airway and in the first few generations of bronchi where airflow is faster and more turbulent. Impaction also occurs at bends and branches of the airway. Further distally, as the cross‐sectional area of the airways increases, the velocity of airflow decreases and becomes more laminar. In these peripheral airways, particularly if the tidal breath is slow and deep (increasing dwell time), gravitational sedimentation is the main method of deposition. Submicronic particles are more likely to deposit via diffusion providing they are not exhaled.7

Based on industrial hygiene models, particles greater than 10 μm in diameter are demonstrated to deposit in mouth and throat, 5–10 μm deposit in the large conducting airways and oropharanyx, and those between 1–5 μm deposit in the smaller airways and alveoli.8 However, accurately predicting aerosol deposition in real life is challenging, particularly as there are so many patient factors to consider (Table 1).

Table 1

Factors determining aerosol delivery6
The Curious Case of Dr Alabone—Heterodoxy in 19th Century Medicine
Authors: Michael Vaile, Sally Gilbert
Journal: Journal of the Royal Society of Medicine (2005)

The year 1910 saw publication of a book entitled Poly-cycloepicycloidal and other Geometric Curves,1 written by Dr E W Alabone, ex-mrcs but with mds from two American institutions. Previous works of the author included The Cure of Consumption2 and Infamous Conduct.3 The story of Alabone illustrates the struggle to regulate doctors and eliminate professional quackery that was underway a century ago.
Capacity for Moderate Exercise in Obese Subjects after Adaptation to a Hypocaloric, Ketogenic Diet
Authors: Stephen D. Phinney, Edward S. Horton, Ethan A. H. Sims, John S. Hanson, Elliot Danforth, Betty M. Lagrange
Journal: Journal of Clinical Investigation (1980)

To study the capacity for moderate endurance exercise and change in metabolic fuel utilization during adaptation to a ketogenic diet, six moderately obese, untrained subjects were fed a eucaloric, balanced diet (base line) for 2 wk, followed by 6 wk of a protein-supplemented fast (PSF), which provided 1.2 g of protein/kg ideal body wt, supplemented with minerals and vitamins. The mean weight loss was 10.6 kg. The duration of treadmill exercise to subjective exhaustion was 80% of base line after 1 wk of the PSF, but increased to 155% after 6 wk. Despite adjusting up to base line, with a backpack, the subjects' exercise weight after 6 wk of dieting, the final exercise test was performed at a mean of 60% of maximum aerobic capacity, whereas the base-line level was 76%. Resting vastus lateralis glycogen content fell to 57% of base line after 1 wk of the PSF, but rose to 69% after 6 wk, at which time no decrement in muscle glycogen was measured after >4 h of uphill walking. The respiratory quotient (RQ) during steady-state exercise was 0.76 during base line, and fell progressively to 0.66 after 6 wk of the PSF. Blood glucose was well maintained during exercise in ketosis. The sum of acetoacetate and beta hydroxybutyrate rose from 3.28 to 5.03 mM during exercise after 6 wk of the PSF, explaining in part the low exercise RQ. The low RQ and the fact that blood glucose and muscle glycogen were maintained during exhausting exercise after 6 wk of a PSF suggest that prolonged ketosis results in an adaptation, after which lipid becomes the major metabolic fuel, and net carbohydrate utilization is markedly reduced during moderate but ultimately exhausting exercise.
Global Trends in Rates of Peritoneal Dialysis
Authors: Arsh K. Jain, Peter Blake, Peter Cordy, Amit X. Garg
Journal: Journal of the American Society of Nephrology (2012)

Although there is a perception that the use of peritoneal dialysis is declining worldwide, compilations of global data are unavailable to test this hypothesis. We assessed longitudinal trends in the use of peritoneal dialysis from 1997 to 2008 in 130 countries. The preferred data sources were renal registries, followed by nephrology societies, health ministries, academic centers, national experts, and industry affiliates. In 2008, there were approximately 196,000 peritoneal dialysis patients worldwide, representing 11% of the dialysis population. In total, 59% were treated in developing countries and 41% in developed countries. Over 12 years, the number of peritoneal dialysis patients increased in developing countries by 24.9 patients per million population and in developed countries by 21.8 per million population. The proportion of all dialysis patients treated with peritoneal dialysis did not change in developing countries but significantly declined in developed countries by 5.3%. The use of automated peritoneal dialysis increased by 14.5% in developing countries and by 30.3% in developed countries. In summary, the number of patients treated with peritoneal dialysis rose worldwide from 1997 to 2008, with a 2.5-fold increase in the prevalence of peritoneal dialysis patients in developing countries. The proportion of all dialysis patients treated with this modality continues to decline in developed countries.
Mineralocorticoid Receptor Mutations and a Severe Recessive Pseudohypoaldosteronism Type 1
Authors: Edwige-Ludiwyne Hubert, Raphaël Teissier, Fábio L. Fernandes-Rosa, Michel Fay, Marie-Edith Rafestin-Oblin, Xavier Jeunemaitre, Chantal Metz, Brigitte Escoubet, Maria-Christina Zennaro
Journal: Journal of the American Society of Nephrology (2011)

Pseudohypoaldosteronism type 1 (PHA1) is a rare genetic disease of mineralocorticoid resistance characterized by salt wasting and failure to thrive in infancy. Here we describe the first case of a newborn with severe recessive PHA1 caused by two heterozygous mutations in NR3C2, gene coding for the mineralocorticoid receptor (MR). Independent segregation of the mutations occurred in the family, with p.Ser166X being transmitted from the affected father and p.Trp806X from the asymptomatic mother Whereas the truncated MR(166X) protein was degraded, MR(806X) was expressed both at the mRNA and protein level. Functional studies demonstrated that despite its inability to bind aldosterone, MR(806X) had partial ligand-independent transcriptional activity. Partial nuclear localization of MR(806X) in the absence of hormone was identified as a prerequisite to initiate transcription. This exceptional case broadens the spectrum of clinical phenotypes of PHA1 and demonstrates that minimal residual activity of MR is compatible with life. It also suggests that rare hypomorphic NR3C2 alleles may be more common than expected from the prevalence of detected PHA1 cases. This might prove relevant for patient's care in neonatal salt losing disorders and may affect renal salt handling and blood pressure in the general population.
Needle Biopsy of Bone
Authors: J. Ted Hartman
Journal: JAMA (1967)

We have reviewed a series of 146 biopsies of bone performed with the Craig needle by closed technique since 1961. This method has proved superior to previous methods of needle biopsy and has been particularly helpful in establishing a correct diagnosis in patients with neoplasm metastatic to bone. We believe a proved pathologic diagnosis in these patients is of more than academic interest since it has allowed us, in many instances, to initiate an appropriate therapeutic program without delay. Furthermore, these needle biopsies have changed our preoperative diagnosis in some cases from neoplasm to sepsis, or vice versa. The determination of the etiologic agent in cases of sepsis has also proved of great therapeutic value. A needle biopsy, especially in a patient with vertebral involvement, may effectively exclude a suspected disease process.
Recruitment of PKC-βII to lipid rafts mediates apoptosis-resistance in chronic lymphocytic leukemia expressing ZAP-70
Authors: C Meyer zum Büschenfelde, M Wagner, G Lutzny, M Oelsner, Y Feuerstacke, T Decker, C Bogner, C Peschel, I Ringshausen
Journal: Leukemia (2009)
The Somatostatin Analogue Octreotide Confers Sensitivity to Rapamycin Treatment on Pituitary Tumor Cells
Authors: Vesna Cerovac, Jose Monteserin-Garcia, Hadara Rubinfeld, Michael Buchfelder, Marco Losa, Tullio Florio, Marcelo Paez-Pereda, Günter K. Stalla, Marily Theodoropoulou
Journal: Cancer Research (2010)

Abstract Rapamycin and its analogues have significant antiproliferative action against a variety of tumors. However, sensitivity to rapamycin is reduced by Akt activation that results from the ablative effects of rapamycin on a p70 S6K–induced negative feedback loop that blunts phosphoinositide 3-kinase (PI3K)–mediated support for Akt activity. Thus, sensitivity to rapamycin might be increased by imposing an upstream blockade to the PI3K/Akt pathway. Here, we investigated this model using the somatostatin analogue octreotide as a tool to decrease levels of activated Ser473-phosphorylated Akt (pAkt-Ser473) in pituitary tumor cells that express somatostatin receptors. Octreotide increased levels of phosphorylated insulin receptor substrate-1 that were suppressed by rapamycin, subsequently decreasing levels of pAkt-Ser473 through effects on phosphotyrosine phosphatase SHP-1. Octreotide potentiated the antiproliferative effects of rapamycin in immortalized pituitary tumor cells or human nonfunctioning pituitary adenoma cells in primary cell culture, sensitizing tumor cells even to low rapamycin concentrations. Combined treatment of octreotide and rapamycin triggered G1 cell cycle arrest, decreasing E2F transcriptional activity and cyclin E levels by increasing levels of p27/Kip1. These findings show that adjuvant treatment with a somatostatin analogue can sensitize pituitary tumor cells to the antiproliferative effects of rapamycin. Cancer Res; 70(2); 666–74
THE INFLUENCE OF SEXUAL MATURITY UPON THE REACTIVITY OF RABBITS TO HORSE SERUM
Authors: Mark P. Schultz
Journal: The Journal of Experimental Medicine (1934)

1. Normal rabbits in the course of their development, after infancy, vary in their responses to minute doses of horse serum given intracutaneously. 2. There is increased reactivity in males as they mature, beginning, in the stock employed in these experiments, at about the age of 13 weeks when a weight of 1,700 gm. has been attained. 3. The reactivity of normal females remains at a constant level and the increase demonstrated in males does not take place. 4. The divergence in degree of reactivity between males and females, beginning with the establishment of estrus, indicates that factors associated with sexual maturity in females are responsible for their low reactivity. 5. The suppression of estrus by operative removal of the ovaries results in an increase of reactivity which, however, in the experiments reported here is probably not great enough to account entirely for the difference in reactivity between mature males and females.