tbuckley/cabot-search huggingface dataset:
An evaluation of two aerosol delivery systems for rhDNase
Authors: PL Shah, SF Scott, DM Geddes, S Conway, A Watson, T Nazir, SB Carr, C Wallis, C Marriott, ME Hodson
Journal: European Respiratory Journal (1997)

Increasingly, proteins are delivered to the respiratory tract as an aerosol, and clinical efficacy is dependent on optimal delivery of the protein in an intact form. The object of this study was to compare the in vivo and in vitro results of two aerosol delivery systems for the aerosolization of recombinant human deoxyribonuclease I (rhDNase) in patients with cystic fibrosis (CF). Patients with CF who were to be initiated on rhDNase were randomized either to the Hudson nebulizer and Pulmo-Aide compressor or to the Sidestream nebulizer driven by the CR50 air compressor. An in vitro study was performed in six sets of the two aerosol delivery systems. One hundred and seventy three patients were randomized in this open study, where rhDNase was administered for 7 days. Improvements in pulmonary function were observed in both groups following 1 week of therapy with rhDNase. Changes in the Sidestream/CR50 and Hudson/Pulmo-Aide groups, respectively, were: 16 and 11% for forced expiratory volume in one second (p=0.14); 12 and 10% for forced vital capacity (p=0.70); and 14 and 7% for forced expiratory flow at 25-75% of expiration (FEF(25-75)) (p=0.18). A greater proportion of patients in the Sidestream/CR50 group (58%) had a &gt;10% response in FEF(25-75) compared to the Hudson/Pulmo-Aide group (42%; p=0.03). The Sidestream nebulizer had a faster nebulization rate (p&lt;0.05), lower mass median diameter for the aerosol mass produced (p&lt;0.001), higher percentage of particles in the respirable range (p&lt;0.001) and greater respirable output (p&lt;0.005), compared to the Hudson nebulizer. The Sidestream/CR50 combination is a quicker, more efficient system in vitro than the Hudson/Pulmo-Aide combination, whereas the in vivo study only suggested a difference. Clinically, the two systems have similar efficacy.
PTH-082 Serum Calprotectin: A Novel Biomarker to Predict Outcome in Acute Severe Ulcerative Colitis?
Authors: N C Hare, N A Kennedy, K Kingstone, I D Arnott, A G Shand, K R Palmer, I D Penman, C W Lees, J Satsangi
Journal: Gut (2013)

<h3>Introduction</h3> Acute severe ulcerative colitis (ASUC) remains an important clinical problem and is associated with significant morbidity and requirement for colectomy. Faecal calprotectin and C-reactive protein (CRP) have previously been shown to predict the need for colectomy but there is an unmet need for further biomarkers. Serum calprotectin has not previously been analysed for this purpose and may provide a novel way of determining disease activity and outcome. The aim of this study was to assess how serum calprotectin relates to faecal calprotectin and other blood markers of inflammation, and to determine whether serum calprotectin on admission predicts colectomy. <h3>Methods</h3> Blood samples were collected prospectively from patients who presented with ASUC as defined by the Truelove and Witts criteria. Blood samples were taken within the first 24 hours of admission. Faecal samples were pre-processed using PhiCal™ extraction buffer. Samples were stored at –80°C and analysed in duplicate using the PhiCal™ calprotectin ELISA according to manufacturer's instructions. Samples with a calprotectin result of &gt; 2500 µg/g were diluted and retested. Statistical comparisons were made between serum calprotectin and other markers of inflammation using Spearman's correlation coefficient, and ROC curve analysis was performed to determine how well each test performed in predicting colectomy. <h3>Results</h3> There were 45 patients recruited to the study with ASUC, of which 22 (49%) were female. Median age on admission was 40 years (interquartile range [IQR] 26–62). Median disease duration was 12 years (IQR 0–59). 26 of the 45 patients had a paired faecal sample for calprotectin analysis. There was no difference in sex, age or disease extent between those with or without faecal calprotectin. Serum calprotectin correlated significantly with CRP (R2 = 0.46, p &lt; 0.0001) and with albumin (R2 = 0.12, p = 0.023) but not with faecal calprotectin (R2 = 0.02, p = 0.450). ROC analysis gave an AUC of 0.69 for serum calprotectin compared with 0.71 for CRP and 0.58 for faecal calprotectin. A cut off for serum calprotectin of 400 µg/g gave a sensitivity of 0.68 and a specificity of 0.69. <h3>Conclusion</h3> In the setting of acute severe ulcerative colitis, serum calprotectin is comparable with serum CRP in predicting outcome. Further work is needed to establish if it may be a useful predictor of outcome in patients with ulcerative colitis who fail to mount a high CRP response despite endoscopic assessment confirming severe active inflammation. Work is also ongoing to establish its utility in the outpatient setting both in Crohn's disease and ulcerative colitis. <h3>Disclosure of Interest</h3> None Declared.
Murine macrophages and pancreatic beta cells. Chemotactic properties of insulin and beta-cytostatic action of interleukin 1.
Authors: E H Leiter
Journal: The Journal of Experimental Medicine (1987)

This study has used in vitro techniques to investigate the potential interactions between mouse pancreatic islet cells and syngeneic macrophages (M phi). Islets strongly stimulated M phi migration from agarose microdroplets; insulin was the only one of four islet cell hormones tested that was effective individually. Chronic exposure of islet monolayers to recombinant mouse IL-1, an M phi secretory product, was not cytolytic, but inhibited insulin secretion, reduced intracellular insulin content, and produced beta cell-specific degranulation. These effects were unique to IL-1; another monokine, tumor necrosis factor, as well as the lymphokine IL-2, and lymphotoxin were all without effect on insulin secretion or monolayer viability at the concentrations tested. The potential pathological consequences of the chemoattractive action of insulin on M phi, and the inhibitory effect of IL-1 on insulin secretion, are discussed.
PTEN Activity Is Modulated During Ischemia and Reperfusion
Authors: Zheqing Cai, Gregg L. Semenza
Journal: Circulation Research (2005)

Ischemic preconditioning (IPC), a brief period of ischemia and reperfusion (I/R), generates profound but transient protection against a subsequent prolonged ischemic episode. The serine-threonine kinase Akt has been shown to mediate IPC, and Akt activation is negatively regulated by the phosphatase PTEN, but whether PTEN activity is modulated by IPC has not been investigated. When isolated, perfused rat hearts were subjected to an IPC stimulus consisting of 15-minute ischemia and 30-minute reperfusion (I-15/R-30), PTEN protein levels and activity were decreased, and levels of phospho-AKT were increased, relative to nonischemic hearts. Hearts subjected to IPC demonstrated improved recovery of cardiac function when subsequently subjected to I-30/R-45 as compared with hearts subjected to I-30/R-45 without prior IPC. When hearts were subjected to I-15 followed by R-30, R-60, or R-120, PTEN reaccumulated gradually and its activity was restored. Phospho-Akt levels at R-120 were decreased and these hearts were no longer protected against injury when subjected to I-30/R-45. Wortmannin administration during reperfusion blocked Akt activation and PTEN reaccumulation. In ischemic hearts, PTEN was rapidly degraded. Pretreatment with proteasome inhibitor MG132 blocked ischemia-induced degradation of PTEN and blocked IPC. Reperfusion following I-15 induced oxidation of the remaining PTEN, leading to Akt activation. Perfusion of H 2 O 2 was sufficient to induce Akt activation. Thus, loss of PTEN activity leads to induction of IPC and feedback mechanisms designed to ensure that Akt activation is transient are responsible for decay of IPC.
Effectiveness of diabetes and hypertension management by rural primary health-care workers (Behvarz workers) in Iran: a nationally representative observational study
Authors: Farshad Farzadfar, Christopher JL Murray, Emmanuela Gakidou, Thomas Bossert, Hengameh Namdaritabar, Siamak Alikhani, Ghobad Moradi, Alireza Delavari, Hamidreza Jamshidi, Majid Ezzati
Journal: The Lancet (2011)
Positive and Negative Symptom Response to Clozapine in Schizophrenic Patients With and Without the Deficit Syndrome
Authors: R W Buchanan, A Breier, B Kirkpatrick, P Ball, W T Carpenter
Journal: American Journal of Psychiatry (1998)

In a preliminary report, the authors observed that clozapine was superior to haloperidol in the treatment of positive and negative symptoms in stable outpatients with schizophrenia. In this final report, they examine the effects of clozapine on positive and negative symptoms in patients with and without the deficit syndrome to determine which patients receive the positive symptom advantage of clozapine and the extent of clozapine's therapeutic effects on negative symptoms. In addition, they examine the long-term effects of clozapine on positive, negative, and affective symptoms, social and occupational functioning, and quality of life.Seventy-five outpatients with schizophrenia, who met retrospective and prospective criteria for residual positive or negative symptoms, were entered into a 10-week double-blind, parallel-groups comparison of clozapine and haloperidol. Patients who completed the double-blind study were then entered into a 1-year open-label clozapine study.For patients who completed the 10-week double-blind study, clozapine was superior to haloperidol in treating positive symptoms. This effect was not observed in the intent-to-treat analyses. There was no evidence of any superior efficacy or long-term effect of clozapine on primary or secondary negative symptoms. Long-term clozapine treatment was associated with significant improvements in social and occupational functioning but not in overall quality of life.For schizophrenic patients who are able to tolerate clozapine therapy, clozapine has superior efficacy for positive symptoms but not negative symptoms and is associated with long-term improvements in social and occupational functioning for patients with and without the deficit syndrome.
Investigating and managing pyrexia of unknown origin in adults
Authors: G. M. Varghese, P. Trowbridge, T. Doherty
Journal: BMJ (2010)

Few clinical problems generate such a wide differential diagnosis as pyrexia (fever) of unknown origin. The initial definition proposed by Petersdorf and Beeson in 1961,¹ later revised, is "a fever of 38.3°C (101°F) or more lasting for at least three weeks for which no cause can be identified after three days of investigation in hospital or after three or more outpatient visits." ²⁻⁴Essentially the term refers to a prolonged febrile illness without an obvious cause despite reasonable evaluation and diagnostic testing. A fever that is not self limiting for which no cause can be found can become a source of frustration for both patient and doctor. There is little consensus on how such patients should be investigated, although recent prospective studies have evaluated diagnostic protocols to suggest approaches to investigation. ³⁵⁶ We discuss evidence from epidemiological and diagnostic studies and suggest an approach to investigating and managing pyrexia of unknown origin. Immunocompromised individuals, those with HIV infection, and patients admitted to hospital for other reasons with persistent or unexplained fever represent distinct subgroups in which the likely causes, diagnosis, and treatment of pyrexia usually differ from those in patients who are not immunocompromised. We do not discuss these subgroups in this review other than to provide definitions of pyrexia of unknown origin in different groups of patients (see box 1).
Gene Transfer of Extracellular Superoxide Dismutase Reduces Arterial Pressure in Spontaneously Hypertensive Rats
Authors: Yi Chu, Shinichiro Iida, Donald D. Lund, Robert M. Weiss, Gerald F. DiBona, Yoshimasa Watanabe, Frank M. Faraci, Donald D. Heistad
Journal: Circulation Research (2003)

Oxidative stress may contribute to hypertension. The goals of this study were to determine whether extracellular superoxide dismutase (ECSOD) reduces arterial pressure in spontaneously hypertensive rats (SHR) and whether its heparin-binding domain (HBD), which is responsible for cellular binding, is necessary for the function of ECSOD. Three days after intravenous injection of an adenoviral vector expressing human ECSOD (AdECSOD), mean arterial pressure (MAP) decreased from 165+/-4 mm Hg (mean+/-SE, n=7) to 124+/-3 mm Hg (n=7) in adult anesthetized SHR (P<0.01) but was not altered in normotensive Wistar-Kyoto rats. Cardiac output was not changed in SHR 3 days after AdECSOD. Gene transfer of ECSOD with deletion of the HBD (AdECSODDeltaHBD) had no effect on SHR MAP, even though plasma SOD activity was greater after AdECSODDeltaHBD than after AdECSOD. Immunohistochemistry revealed intense staining for ECSOD in blood vessels and kidneys after AdECSOD but not after AdECSODDeltaHBD. Impaired relaxation of the carotid artery to acetylcholine in SHR was significantly improved after AdECSOD. Cumulative sodium balance in SHR was reduced by AdECSOD compared with AdECSODDeltaHBD. Gene transfer of ECSOD also reduced MAP in conscious SHR, although the effect was not as profound as in anesthetized SHR. In summary, gene transfer of ECSOD, with a strict requirement for its HBD, reduces systemic vascular resistance and arterial pressure in a genetic model of hypertension. This reduction in arterial pressure may be mediated by vasomotor and/or renal mechanisms.
KiSS-1, a Novel Human Malignant Melanoma Metastasis-Suppressor Gene
Authors: J.-H. Lee, M. E. Miele, D. J. Hicks, K. K. Phillips, J. M. Trent, B. E. Weissman, D. R. Welch
Journal: JNCI Journal of the National Cancer Institute (1996)

Microcell-mediated transfer of chromosome 6 into human C8161 and MelJuSo melanoma cells suppresses their ability to metastasize by at least 95% without affecting their tumorigenicity. This observation demonstrates that the ability to metastasize is a phenotype distinct from tumor formation and suggests that tumorigenic cells acquire meta-static capability only after accumulating additional genetic defects. These results also imply that mutations of genes on chromosome 6 are among those late genetic changes responsible for metastatic potential. They further suggest that a melanoma metastasis-suppressor gene(s) is encoded on chromosome 6 or is regulated by genes on chromosome 6. Our objective was to identify the gene(s) responsible for the suppression of metastasis in chromosome 6/melanoma cell hybrids A modified subtractive hybridization technique was used to compare the expression of messenger RNAs (mRNAs), via an analysis of complementary DNAs (cDNAs), in metastatic cells (C8161 or MelJuSo) and nonmetastatic hybrid clones (neo6/C8161 or neo6/MelJuSo). A novel cDNA, designated KiSS-1, was isolated from malignant melanoma cells that had been suppressed for metastatic potential by the introduction of human chromosome 6. Northern blot analyses comparing mRNAs from a panel of human melanoma cells revealed that KiSS-1 mRNA expression occurred only in nonmetastatic melanoma cells. Expression of this mRNA in normal heart, brain, liver, lung, and skeletal muscle was undetect-able by northern blot analysis. Weak expression was found in the kidney and pancreas, but the highest expression was observed in the placenta. The KiSS-1 cDNA encodes a predominantly hydrophilic, 164 amino acid protein with a polyproline-rich domain indicative of an SH3 ligand (binds to the homology 3 domain of the oncoprotein Src) and a putative protein kinase C-α phosphorylation site. Transfection of a full-length KiSS-1 cDNA into C8161 melanoma cells suppressed metastasis in an expression-dependent manner These data strongly suggest that KiSS-1 expression may suppress the metastatic potential of malignant melanoma cells. KiSS-1 may be a useful marker for distinguishing metastatic melanomas from nonmetastatic melanomas. [J Natl Cancer Inst 1996;88: 1731–7]
Positive and Negative Selection in Murine Ultraconserved Noncoding Elements
Authors: Daniel L. Halligan, Fiona Oliver, Jack Guthrie, Kathryn C. Stemshorn, Bettina Harr, Peter D. Keightley
Journal: Molecular Biology and Evolution (2011)

There are many more selectively constrained noncoding than coding nucleotides in the mammalian genome, but most mammalian noncoding DNA is subject to weak selection, on average.One of the most striking discoveries to have emerged from comparisons among mammalian genomes is the hundreds of noncoding elements of more than 200 bp in length that show absolute conservation among mammalian orders.These elements represent the tip of the iceberg of a much larger class of conserved noncoding elements (CNEs).Much evidence suggests that CNEs are selectively constrained and not mutational cold-spots, and there is evidence that some CNEs play a role in the regulation of development.Here, we quantify negative and positive selection acting in murine CNEs by analyzing within-species nucleotide variation and between-species divergence of CNEs that we identified using a phylogenetically independent comparison.The distribution of fitness effects of new mutations in CNEs, inferred from within-species polymorphism, suggests that CNEs receive a higher number of strongly selected deleterious mutations and many fewer nearly neutral mutations than amino acid sites of protein-coding genes or regulatory elements close to genes.However, we also show that CNEs experience a far higher proportion of adaptive substitutions than any known category of genomic sites in murids.The absolute rate of adaptation of CNEs is similar to that of amino acid sites of proteins.This result suggests that there is widespread adaptation in mammalian conserved noncoding DNA elements, some of which have been implicated in the regulation of crucially important processes, including development.
Ischemia–reperfusion associated myocardial contractile dysfunction may depend on Ca2+-activated cytoskeleton protein degradation
Authors: L Rappaport
Journal: Cardiovascular Research (2000)

See article by Papp et al. [9] (pages 981–993) in this issue. 

Postischemic dysfunction, or myocardial stunning, is defined as ‘the mechanical dysfunction that persists after reperfusion despite the absence of irreversible damage and restoration of normal or near normal coronary flow’ (for a review, see Ref. [1]). Myocardial stunning may be considered as a relatively mild, sublethal injury that must be distinguished from myocardial infarction. It is generally admitted that myocardial stunning is a multifactorial process, that mostly depends on two major mechanisms: (1) generation of oxygen radicals, (2) calcium overload, both being probably involved in the process (for review, see Ref. [1]).

The calcium hypothesis may explain many key features of the stunned myocardium. It has been postulated that calcium overload during reflow triggers myofilament dysfunction which uncouples excitation from contraction, so that for any given calcium transient, the myocardium generates less force [2].

A variety of biochemical abnormalities have been reported to explain the sustained, but reversible, myocardial contractile dysfunction that occurs after reperfusion. Immunonoblotting and SDS–PAGE analysis have permitted the identification of subtle Ca2+-dependent changes in the amount of myofibrillar proteins. Elevated [Ca2+]i during ischemia and during the initial reperfusion period have long-lasting after effects by activating Ca2+-dependent proteases, which could partially degrade contractile proteins [3]. Myofilament dysfunction would depend on protein degradation, the extent to which increases with the severity of injury, the major functional damage occurring on reperfusion [2]. Indeed, in stunned rat myocardium depression of myofilament function has been associated with a Ca2+-dependent degradation of α-actinin, a myofilament-associated scaffolding protein distributed at the level of the Z line [4] and of a thin filament regulatory protein, troponin I (TnI) [5]. The exact role of these changes in force generation … 

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Ischaemic postconditioning protects against reperfusion injury via the SAFE pathway
Authors: Lydia Lacerda, Sarin Somers, Lionel H. Opie, Sandrine Lecour
Journal: Cardiovascular Research (2009)

Ischaemic postconditioning (IPostC) is a powerful protective phenomenon that activates prosurvival intrinsic signalling cascades to limit reperfusion injury. We propose that IPostC confers its infarct-sparing effect via activation of the newly described prosurvival Survivor Activating Factor Enhancement (SAFE) pathway, which involves the activation of the cytokine tumour necrosis factor alpha (TNFalpha) and signal transducer and activator of transcription-3 (STAT-3).Isolated ischaemic/reperfused hearts from TNF knockout, TNF receptor-1 knockout, TNF receptor-2 knockout, cardiomyocyte-specific STAT-3-deficient mice or their respective wild-type, (TNF-WT) or (STAT-3-WT), were postconditioned by ischaemic episodes (IPostC) or with exogenous TNFalpha (0.5 microg/L) (TNF-PostC) at the onset of reperfusion. IPostC reduced infarct size (IS) in TNF-WT and TNFR1(-/-) hearts (by 33 and 27%, respectively, P < 0.05), whereas hearts from TNF(-/-) or TNFR2(-/-) failed to be postconditioned. TNF-PostC reduced IS by 37% (P < 0.05) in STAT-3-WT hearts but failed to protect cardiac-specific STAT-3(-/-) hearts. Administration of wortmannin, an inhibitor of PI-3 kinase/Akt, or PD98059, an inhibitor of extracellular regulated kinase 1/2 (Erk1/2), during the postconditioning stimulus did not abolish the infarct-sparing effect of TNF-PostC. AG490, an inhibitor of STAT-3, abrogated the protective effect of TNFalpha. Western blot analysis did not demonstrate the involvement of Akt or Erk1/2 in TNF-PostC, whereas STAT-3 phosphorylation was increased in both IPostC and TNF-PostC.The protective effect of the SAFE pathway is shown in IPostC, with the activation of TNFalpha, its receptor type 2, and STAT-3. This signalling cascade is activated independently of the well-known Reperfusion Injury Salvage Kinases (RISK) pathway, which involves the kinases Akt and Erk1/2.
How do shared circuits develop?
Authors: Lindsay M. Oberman, Vilayanur S. Ramachandran
Journal: Behavioral and Brain Sciences (2008)

Abstract The target article discusses a model of how brain circuits mediate social behaviors such as imitation and mindreading. Hurley suggests potential mechanisms for development of shared circuits. We propose that empirical studies can be designed to differentiate the influence of genetic and learning-based factors on the development of shared circuits. We use the mirror neuron system as a model system.