tbuckley/cabot-search huggingface dataset:
Arrhythmogenic left atrial cellular electrophysiology in a murine genetic long QT syndrome model
Authors: Marc D. Lemoine, James Elber Duverger, Patrice Naud, Denis Chartier, Xiao Yan Qi, Philippe Comtois, Larissa Fabritz, Paulus Kirchhof, Stanley Nattel
Journal: Cardiovascular Research (2011)

Increasing evidence indicates that congenital long QT syndromes (LQTSs) promote atrial fibrillation. The atrial action potential (AP) has a short plateau, and whether LQTS atrial cardiomyocytes generate triggered activity via early afterdepolarizations (EADs) is unclear. Atrial cellular arrhythmia mechanisms have not been defined in congenital LQTS. Therefore, we studied atrial cardiomyocyte electrophysiology in mice with an LQTS3 SCN5A inactivation-impairing mutation (ΔKPQ heterozygotes). Peak and late Na(+) current (I(NaP) and I(NaL)) were measured with whole-cell patch clamp in left atrial (LA) cardiomyocytes. APs were recorded in multicellular LA preparations with floating microelectrodes. I(NaL) was increased by 110% in LA cardiomyocytes of ΔKPQ mice, whereas I(NaP) was unchanged. AP duration (APD) was prolonged over all frequencies in ΔKPQ mice, but particularly at lower frequencies [e.g. APD(90) at 0.5 Hz: 197 ± 8 ms vs. wild-type (WT) 82 ± 2 ms, P< 0.001]. EADs occurred at 0.5 Hz in 10/18 ΔKPQ (56%) vs. 1/10 WT (10%) atria (P< 0.05). EADs immediately preceded premature APs in other LA regions, suggesting triggered activity. Ranolazine preferentially inhibited I(NaL) (50% inhibitory concentration: 12.5 vs. 151.8 µM for I(NaP)) in ΔKPQ myocytes. At 10 µM, ranolazine shortened APD (e.g. APD(90) at 0.5 Hz to 122 ± 4 ms, P= 0.01) without changing APD in WT and suppressed EAD occurrence and triggered activity (from 10/18 to 1/9 preparations, 11%, P< 0.05). This study implicates increased I(NaL) in excessive atrial APD prolongation and arrhythmic EAD occurrence in a congenital LQTS3 mouse model. Our observations provide the first direct demonstration of atrial EADs and triggered activity in a genetically defined animal model of human LQTS and have potential clinically-relevant mechanistic and therapeutic implications.
The importance of bronchoscopy with transbronchial biopsy and bronchoalveolar lavage in the management of lung transplant recipients.
Authors: R A Guilinger, I L Paradis, J H Dauber, S A Yousem, P A Williams, R J Keenan, B P Griffith
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

Medical and surgical advances have made lung transplantation a feasible therapy for end-stage lung disease. Fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) and transbronchial lung biopsy (TBBx) is an accepted technique for detecting clinically evident rejection and infection in the allograft of symptomatic recipients. The role of TBBx and BAL in managing asymptomatic recipients is less defined. We retrospectively examined the role of bronchoscopy with TBBx and BAL in 1124 bronchoscopy procedures that were performed on 161 lung transplant recipients between January 1, 1988, and December 31, 1993. Bronchoscopy was performed when there was a change in the recipient's clinical condition, to assess the response of the allograft to a prior therapy, and under a surveillance protocol for detecting asymptomatic rejection or infection. Surveillance bronchoscopy was performed according to the following schedule: 10-14 days after transplantation, every 3 mo during the first year, every 4 mo during the second year, and at 6-mo intervals thereafter. Surveillance bronchoscopies were defined as procedures where the physician felt that there was no infection or rejection in the allograft on the basis of a standardized clinical evaluation, which excluded the results of the TBBx and BAL. We compared the clinical impression recorded by the physician on the day of the procedure with the final diagnosis determined after the results of the TBBx and BAL were known. We found unsuspected rejection and/or infection that required therapy in 25% (90/355) of all surveillance bronchoscopy procedures. Most episodes (61/90, 68%) of unsuspected rejection and/or infection occurred in the first 6 mo after transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)
Chemogenetics—A Transformational and Translational Platform
Authors: Justin G. English, Bryan L. Roth
Journal: JAMA Neurology (2015)

Neurologic disorders are frequently a result of inappropriate electrical and/or chemical signaling of neurons and glia. Ultimate remediation would necessitate reprogramming these signals. Historically, correcting neuronal and glial signaling is accomplished via drug therapy/administration, although they frequently fail to effectively and fully treat the underlying disorder. Developments in basic research have produced several new classes of potential therapeutics to directly and precisely control neuron activity at the single-cell level. We review one such technology, Designer Receptors Exclusively Activated by Designer Drugs, and suggest its potential as a powerful tool for augmenting neuronal and glial signaling and activity for basic and translational applications.
Increased 90-kDa ribosomal S6 kinase (Rsk) activity is protective against mutant huntingtin toxicity
Authors: Xavier Xifró, Marta Anglada-Huguet, Laura Rué, Ana Saavedra, Esther Pérez-Navarro, Jordi Alberch
Journal: Molecular Neurodegeneration (2011)

Abstract Background The 90-kDa ribosomal S6 kinase (Rsk) family is involved in cell survival. Rsk activation is regulated by sequential phosphorylations controlled by extracellular signal-regulated kinase (ERK) 1/2 and 3-phosphoinositide-dependent protein kinase 1 (PDK1). Altered ERK1/2 and PDK1 phosphorylation have been described in Huntington's disease (HD), characterized by the expression of mutant huntingtin (mhtt) and striatal degeneration. However, the role of Rsk in this neurodegenerative disease remains unknown. Here, we analyzed the protein levels, activity and role of Rsk in in vivo and in vitro HD models. Results We observed increased protein levels of Rsk1 and Rsk2 in the striatum of Hdh Q111/Q111 and R6/1 mice, STHdh Q111/Q111 cells and striatal cells transfected with full-length mhtt. Analysis of the phosphorylation of Rsk in Hdh mice and STHdh cells showed reduced levels of phospho Ser-380 (dependent on ERK1/2), whereas phosphorylation at Ser-221 (dependent on PDK1) was increased. Moreover, we found that elevated Rsk activity in STHdh Q111/Q111 cells was mainly due to PDK1 activity, as assessed by transfection with Rsk mutant constructs. The increase of Rsk in STHdh Q111/Q111 cells occurred in the cytosol and in the nucleus, which results in enhanced phosphorylation of both cytosolic and nuclear Rsk targets. Finally, pharmacological inhibition of Rsk, knock-down and overexpression experiments indicated that Rsk activity exerts a protective effect against mhtt-induced cell death in STHdh Q7/Q7 cells transfected with mhtt. Conclusion The increase of Rsk levels and activity would act as a compensatory mechanism with capacity to prevent mhtt-mediated cell death. We propose Rsk as a good target for neuroprotective therapies in HD.
Integrating stakeholder perspectives into the translation of cell-free fetal DNA testing for aneuploidy
Authors: Lauren C Sayres, Megan Allyse, Mildred K Cho
Journal: Genome Medicine (2012)

The translation of novel genomic technologies from bench to bedside enjoins the comprehensive consideration of the perspectives of all stakeholders who stand to influence, or be influenced by, the translational course. Non-invasive prenatal aneuploidy testing that utilizes cell-free fetal DNA (cffDNA) circulating in maternal blood is one example of an innovative technology that promises significant benefits for its intended end users; however, it is currently uncertain whether it will achieve widespread clinical implementation. We conducted qualitative interviews with 18 diverse stakeholders in this domain, including prospective users of the technology and healthcare personnel, researchers and developers, and experts in social, legal, and regulatory aspects of genetic technology, and a pilot survey of 62 obstetric healthcare providers. Analysis of interview and survey data was combined with a review of the proceedings of a full-day, multidisciplinary conference on the topic and published scientific and ethics literature surrounding this and other relevant technologies.We constructed potential pathways for technological implementation, identified broad stakeholder classes party to these translational processes, and performed a preliminary assessment of the viewpoints and interrelations among these diverse stakeholders. Some of the stakeholders whose priorities are critical to understand and integrate into translation include pregnant women and their families; healthcare providers; scientists, their institutions or companies, and the funding agencies that support them; regulatory and judicial bodies; third-party payers; professional societies; educational systems; disability rights communities; and other representatives from civil society. Stakeholder interviews, survey findings, and conference proceedings add complexity to these envisioned pathways and also demonstrate a paramount need to incorporate an iterative stakeholder analysis early and throughout the translational endeavor. We believe that the translational framework that we have developed will help guide crucial future stakeholder mapping and engagement activities for cffDNA aneuploidy testing and inform novel methods of technology assessment for other developments in the growing field of genomic medicine.Mapping potential pathways for implementation and exploring the attitudes and interrelations of diverse stakeholders may lead to more effective translation of a novel method of prenatal aneuploidy testing.
Trapidil protects ischemic hearts from reperfusion injury by stimulating PKAII activity
Authors: Oliver J Sichelschmidt, Claudia Hahnefeld, Thomas Hohlfeld, Friedrich W Herberg, Karsten Schrör
Journal: Cardiovascular Research (2003)

Objective: The cardioprotective effects of trapidil on ischemic reperfused (I/R) rabbit hearts were studied. Recently, we had shown that trapidil might activate protein kinase A (PKA). In this study, we examined the exact mode of PKA stimulating activity of trapidil. Finally, we investigated the effect of trapidil on the phosphorylation state of phospholamban (PLB), a major PKA target in the heart and key regulator of Ca2+ sequestration via the sarcoplasmic reticulum Ca2+-ATPase. Methods: Langendorff-hearts of New Zealand White rabbits were perfused at constant volume and subjected to global low-flow ischemia for 2 h, followed by 1 h of reperfusion. Subsequently, hearts were used for Western blot analysis of PLB phosphorylation. Furthermore, three different regulatory subunits and one catalytic subunit of PKA were overexpressed in E. coli. These PKA subunits were purified and used in an in vitro assay system to test the impact of trapidil on PKA activities in the absence and presence of cAMP. Results: I/R resulted in a significant increase in left ventricular end-diastolic pressure and creatine kinase efflux in the hearts. Trapidil (10 μM) prevented these alterations. Using recombinant cAMP-free PKA isoforms, it was found that trapidil specifically stimulated PKAII but only did so in the presence of small amounts of added cAMP. Furthermore, the PKA-dependent 16Ser phosphorylation of PLB was markedly reduced in I/R. Trapidil largely normalized the 16Ser phosphorylation of PLB. Conclusions: The data demonstrate cardioprotective actions of trapidil in I/R and show a PKAII-dependent cAMP sensitizing effect of the compound. They also indicate PKA-dependent PLB phosphorylation as a target, suggesting an improved Ca2+ uptake by the sarcoplasmic reticulum. This action might be involved in the cardioprotective effects of trapidil.
PMO-080 Home enteral tube feeding via percutaneous jejunostomy: a 5-year UK regional study of trends and outcomes: Abstract PMO-080 Table 1
Authors: L Eyles, K Henderson, J Mackel, R McLean
Journal: Gut (2012)

<h3>Introduction</h3> NHS Lothian home enteral tube feeding (HETF) point prevalence figures reveal that of the 328 adults on HETF in the Lothian region, 18 (5.4%) are being fed via jejunostomy. The aims of this study were to establish the trends in jejunostomy feeding over a 5-year period and to identify the associated complications. <h3>Methods</h3> A retrospective review of the regional HETF database was carried out to identify all adults discharged home to the Lothian region on jejunal feeding between 01 January 2007 and 31 December 2011. <h3>Results</h3> Ninety adults were discharged on jejunal feeding within the study period. The number of adults receiving jejunostomy feeding at home had increased with an average of 11 per year from 2007 to 2009 rising to an average of 28 per year from 2010 to 2011. Patient age at start of feeding ranged from 17 years old to 79 years old with a median age of 61.6. The most common reason for home jejunal feeding was post-oesophagectomy for oesophageal cancer (65%), followed by gastrectomy (8%) and oesophageal rupture (6%). Length of time on home jejunal feeding ranged from 7 days to 999 days with an average of 165 days, equivalent to 23.6 weeks. The most common clinical outcome was discontinuation of HETF and a return to normal oral diet (64%), 16% died due to underlying disease, and 14% continued on jejunostomy feeding. A review of the complications associated with use of a jejunostomy feeding tube revealed that 55% had documented complications and of this number, 36% had more than one complication documented. In practice, this incidence may be higher as not all patient records had tube site examination documented. A summary of the most common jejunostomy-related complications is shown in the Abstract PMO-080 table 1 below. <h3>Conclusion</h3> This study has shown that the number of patients discharged home on jejunostomy feeding over a 5-year period has increased significantly. Average length of time on jejunostomy feeding was almost 6 months therefore the availability of ongoing and timely follow-up in the community is essential. Of particular note is the high rate of tube-related complications, some of which required admission to hospital or treatment at specialist clinics. This incidence could be reduced by improving training and information on prevention and early detection of complications for community based health care professionals as well as for patients. These findings have direct implications for practice in highlighting the need for dedicated, specialist and individualised care for patients at home on jejunostomy feeding. <h3>Competing interests</h3> None declared.
Anti-arrhythmic protection by ischaemic preconditioning in isolated rat hearts is not due to depletion of endogenous catecholamines
Authors: C.S Lawson, D.J Hearse
Journal: Cardiovascular Research (1996)

Objectives: The present study addresses whether the mechanism of anti-arrhythmic protection by ischaemic preconditioning involves depletion of myocardial catecholamines. Methods: In a randomised series of studies isolated rat hearts, perfused with whole blood, underwent episodes of regional ischaemia and reperfusion induced with a snare around the left coronary artery. Control hearts (Group 1, n = 12) were subjected to 40 min aerobic perfusion, 30 min ischaemia and 10 min reperfusion. Preconditioned hearts (Group 2, n = 12) were subjected to 10 min aerobic perfusion, three cycles of ischaemia and reperfusion (5 min each), 30 min ischaemia and 10 min reperfusion. Cardiac rhythm was recorded continuously and arrhythmias quantified during the final periods of ischaemia and reperfusion. At the end of the experiment samples of right ventricular (RV; non-ischaemic) and left ventricular (LV; ischaemic territory) tissue were separated and frozen. In 5 additional groups (n = 6/group) tissue samples were taken after 10 min aerobic perfusion, after 10 min aerobic perfusion followed by 1, 2 or 3 preconditioning cycles and after 40 min of aerobic perfusion. All tissue samples were analysed for catecholamine content. Results: Preconditioning resulted in reductions in the incidence of ischaemia-induced VF from 67% in Group 1 to 8% in Group 2, the incidence of ischaemia-induced VT from 100% to 17% and the number of ischaemia-induced VPBs from 246 ± 25 to 59 ± 19 (each P < 0.05). The mean content of noradrenaline and adrenaline was consistently higher in RV than LV tissue. Within the LV, however, neither preconditioning nor prolonged ischaemia had any significant effect upon tissue catecholamine content at any time in the experimental protocol. Conclusions: Depletion of myocardial catecholamines is not involved in the mechanism of anti-arrhythmic protection by ischaemic preconditioning in isolated rat hearts.
Acute tryptophan depletion affects brain-gut responses in irritable bowel syndrome patients and controls
Authors: T O C Kilkens
Journal: Gut (2004)

<b>Background:</b> Serotonin, a key denominator of the brain-gut axis, is involved in the regulation of gastrointestinal motility, secretion, and perception as well as cognition and mood. <b>Aim:</b> To assess the effects of an acutely lowered serotonin synthesis, using the acute tryptophan depletion (ATD) method, on visceral perception, affective memory performance, and mood in diarrhoea predominant irritable bowel syndrome patients (d-IBS) and controls. <b>Methods:</b> In a randomised, double blind, crossover design, 14 d-IBS patients and fourteen matched controls were studied under ATD and placebo conditions, respectively. Perception of urge and pain was scored during rectal distensions. Affective memory performance, mood, and biochemical parameters of serotonergic metabolism were simultaneously assessed. <b>Results:</b> ATD significantly decreased plasma tryptophan (67.0 (2.0) <i>v</i> 24.9 (2.0) μmol/l) and 5-hydroxyindole acetic acid concentrations (29.9 (1.0) <i>v</i> 15.8 (0.6) nmol/l). ATD was associated with significantly increased urge scores specifically in the lower pressure range and overall increased pain scores. ATD significantly lowered the perceptual threshold for first perception compared with placebo (patients 10.6 (1.2) <i>v</i> 13.6 (0.8) mm Hg, controls 12.6 (1.3) <i>v</i> 15.7 (1.2) mm Hg) but not for maximal tolerable discomfort (patients 50.5 (3.6) <i>v</i> 51.6 (3.3) mm Hg, controls 50.9 (3.3) <i>v</i> 48.8 (2.9) mm Hg). ATD induced a significant shift in affective memory bias towards preferential loss of positive material but no significant changes in mood. ATD did not differentially affect the patient or control group. <b>Conclusions:</b> We have provided evidence that serotonergic modulation by ATD affects both visceral perception as well as cognition in d-IBS and controls. Simultaneous measurement of brain and gut function and the application of ATD contribute to the elucidation of the complex pathophysiology of IBS.
The I2020T Leucine-rich repeat kinase 2 transgenic mouse exhibits impaired locomotive ability accompanied by dopaminergic neuron abnormalities
Authors: Tatsunori Maekawa, Sayuri Mori, Yui Sasaki, Takashi Miyajima, Sadahiro Azuma, Etsuro Ohta, Fumiya Obata
Journal: Molecular Neurodegeneration (2012)

Abstract Background Leucine-rich repeat kinase 2 (LRRK2) is the gene responsible for autosomal-dominant Parkinson’s disease (PD), PARK8, but the mechanism by which LRRK2 mutations cause neuronal dysfunction remains unknown. In the present study, we investigated for the first time a transgenic (TG) mouse strain expressing human LRRK2 with an I2020T mutation in the kinase domain, which had been detected in the patients of the original PARK8 family. Results The TG mouse expressed I2020T LRRK2 in dopaminergic (DA) neurons of the substantia nigra, ventral tegmental area, and olfactory bulb. In both the beam test and rotarod test, the TG mice exhibited impaired locomotive ability in comparison with their non-transgenic (NTG) littermates. Although there was no obvious loss of DA neurons in either the substantia nigra or striatum, the TG brain showed several neurological abnormalities such as a reduced striatal dopamine content, fragmentation of the Golgi apparatus in DA neurons, and an increased degree of microtubule polymerization. Furthermore, the tyrosine hydroxylase-positive primary neurons derived from the TG mouse showed an increased frequency of apoptosis and had neurites with fewer branches and decreased outgrowth in comparison with those derived from the NTG controls. Conclusions The I2020T LRRK2 TG mouse exhibited impaired locomotive ability accompanied by several dopaminergic neuron abnormalities. The TG mouse should provide valuable clues to the etiology of PD caused by the LRRK2 mutation.
A randomized, double-blind, placebo-controlled, phase 2 study of RMP-7 in combination with carboplatin administered intravenously for the treatment of recurrent malignant glioma
Authors: Michael D. Prados, S. Clifford Schold, Howard A. Fine, Kurt Jaeckle, Fred Hochberg, Laszlo Mechtler, Michael R. Fetell, Surasak Phuphanich, Lynn Feun, Todd J. Janus, Kathleen Ford, William Graney
Journal: Neuro-Oncology (2003)

RMP-7, a bradykinin analog, temporarily increases the permeability of the blood-brain tumor barrier to chemotherapy drugs like carboplatin. We conducted a randomized, controlled trial of carboplatin and RMP-7 versus carboplatin and placebo in patients with recurrent malignant glioma. The primary outcome measure was time to tumor progression (TTP). Adults with recurrent glioblastoma multiforme or anaplastic glioma were randomized in a 1:1 ratio to receive carboplatin and either RMP-7 or placebo. Radiation therapy had failed in all patients, and they may have received prior chemotherapy. Carboplatin (dosed to achieve an area under the curve of 5 mg/ml x time for patients who had received prior chemotherapy, or 7 mg/ml x time for those who had not) was given intravenously every 4 weeks, followed by intravenous infusion of either RMP-7 or placebo (300 ng/kg). TTP, tumor response, neuropsychological assessments, functional independence, and quality of life assessments were analyzed every 4 weeks. There were 122 patients enrolled, 62 in the RMP-7 and carboplatin group and 60 in the placebo and carboplatin group. Median TTP was 9.7 weeks (95% CI, 8.3-12.6 weeks) for the RMP-7 and carboplatin group and 8.0 weeks (95% CI, 7.4-12.6 weeks) for the placebo and carboplatin group. Median survival times were 26.9 weeks (95% CI, 21.3-37.6 weeks) for the RMP-7 group and 19.9 weeks (95% CI, 15.0-31.3 weeks) for the placebo group. No differences were noted for time to worsening of neuropsychological assessments, functional independence, or quality of life assessments. The use of RMP-7 had no effect on the pharmacokinetics or toxicity of carboplatin. At the dose and schedule used in this trial, RMP-7 did not improve the efficacy of carboplatin. Recent preclinical pharmacokinetic modeling of RMP-7 suggests that higher doses of RMP-7 may be required to increase carboplatin delivery to tumor.