tbuckley/cabot-search huggingface dataset:
Gα <sub>s</sub> -Biased β <sub>2</sub> -Adrenergic Receptor Signaling from Restoring Synchronous Contraction in the Failing Heart
Authors: Khalid Chakir, Charlene Depry, Veronica L. Dimaano, Wei-Zhong Zhu, Marc Vanderheyden, Jozef Bartunek, Theodore P. Abraham, Gordon F. Tomaselli, Shu-bai Liu, Yang K. Xiang, Manling Zhang, Eiki Takimoto, Nickolai Dulin, Rui Ping Xiao, Jin Zhang, David A. Kass
Journal: Science Translational Medicine (2011)

Cardiac resynchronization therapy (CRT), in which both ventricles are paced to recoordinate contraction in hearts that are dyssynchronous from conduction delay, is the only heart failure (HF) therapy to date to clinically improve acute and chronic function while also lowering mortality. CRT acutely enhances chamber mechanical efficiency but chronically alters myocyte signaling, including improving β-adrenergic receptor reserve. We speculated that the latter would identify unique CRT effects that might themselves be effective for HF more generally. HF was induced in dogs by 6 weeks of atrial rapid pacing with (HFdys, left bundle ablated) or without (HFsyn) dyssynchrony. We used dyssynchronous followed by resynchronized tachypacing (each 3 weeks) for CRT. Both HFdys and HFsyn myocytes had similarly depressed rest and β-adrenergic receptor sarcomere and calcium responses, particularly the β2-adrenergic response, whereas cells subjected to CRT behaved similarly to those from healthy controls. CRT myocytes exhibited suppressed Gαi signaling linked to increased regulator of G protein (heterotrimeric guanine nucleotide-binding protein) signaling (RGS2, RGS3), yielding Gαs-biased β2-adrenergic responses. This included increased adenosine cyclic AMP responsiveness and activation of sarcoplasmic reticulum-localized protein kinase A. Human CRT responders also showed up-regulated myocardial RGS2 and RGS3. Inhibition of Gαi (with pertussis toxin, RGS3, or RGS2 transfection), stimulation with a Gαs-biased β2 agonist (fenoterol), or transient (2-week) exposure to dyssynchrony restored β-adrenergic receptor responses in HFsyn to the values obtained after CRT. These results identify a key pathway that is triggered by restoring contractile synchrony and that may represent a new therapeutic approach for a broad population of HF patients.
A remarkably simple genome underlies highly malignant pediatric rhabdoid cancers
Authors: Ryan S. Lee, Chip Stewart, Scott L. Carter, Lauren Ambrogio, Kristian Cibulskis, Carrie Sougnez, Michael S. Lawrence, Daniel Auclair, Jaume Mora, Todd R. Golub, Jaclyn A. Biegel, Gad Getz, Charles W.M. Roberts
Journal: Journal of Clinical Investigation (2012)

Cancer is principally considered a genetic disease, and numerous mutations are thought essential to drive its growth. However, the existence of genomically stable cancers and the emergence of mutations in genes that encode chromatin remodelers raise the possibility that perturbation of chromatin structure and epigenetic regulation are capable of driving cancer formation. Here we sequenced the exomes of 35 rhabdoid tumors, highly aggressive cancers of early childhood characterized by biallelic loss of SMARCB1, a subunit of the SWI/SNF chromatin remodeling complex. We identified an extremely low rate of mutation, with loss of SMARCB1 being essentially the sole recurrent event. Indeed, in 2 of the cancers there were no other identified mutations. Our results demonstrate that high mutation rates are dispensable for the genesis of cancers driven by mutation of a chromatin remodeling complex. Consequently, cancer can be a remarkably genetically simple disease.
STUDIES ON THE PSITTACOSIS-LYMPHOGRANULOMA GROUP
Authors: Anthony J. Girardi, Emma G. Allen, M. Michael Sigel
Journal: The Journal of Experimental Medicine (1952)

The pattern of growth of meningopneumonitis virus in vitro seemed to be similar to that occurring in ovo and thus the initial stages of development, the adsorption and the latent periods, were investigated by the use of tissue culture procedures. The initial increment of infectivity in allantoic membrane suspensions following virus inoculation in ovo was due to prolonged adsorption of virus and not to immediate virus reproduction. The length of the adsorption period varied with the virus dilution employed. The reduction of virus titer in allantoic membrane suspensions subsequent to adsorption was due to a change of infectious virus to a non-infectious form and this seemed to be a part of the normal developmental cycle of the virus. The possible causes for both prolonged virus adsorption and for the subsequent development of a non-infectious form are discussed.
Treatment of autoimmune hepatitis: what is the optimal end point on follow-up biopsy?
Authors: H. K. Dhaliwal, B. S. Hoeroldt, A. Dube, E. McFarlane, M. A. Karajeh, D. C. Gleeson
Journal: Gut (2011)

<h3>Introduction</h3> The authors have reported1 that following immunosuppressive treatment of Autoimmune Hepatitis (AIH), many patients fail to achieve histological remission (necro-inflammatory score (NIS) ≥3), despite attaining biochemical remission (normal serum ALT). A recent report2 suggests that, following treatment, a NIS≥5 is not associated with fibrosis progression and hence, may be an acceptable treatment outcome.2 The authors therefore aimed to assess the associations of NIS on follow-up biopsy within the range 0–5, with change in fibrosis and survival. <h3>Methods</h3> The authors studied 114 patients with AIH by IAIHG criteria (81 definite, 94 female, mean age 48.7±1.7 years), treated initially with reducing dose prednisolone and 1 mg/kg azathioprine, who had achieved normal serum ALT and a NIS between 0 and 5 on follow-up biopsy (performed at median (range) 2.16 (0.65–13.67) years) after diagnosis (paired diagnostic and follow-up biopsies available in 93 patients). Biopsies were graded using the Ishak system. <h3>Results</h3> Fibrosis score between baseline and follow-up biopsy decreased in patients with follow-up NIS 0–3 (mean 3.4±0.24 to 2.7±0.21, n=59 p=0.001) but was unchanged in those with follow-up NIS of 4 or 5 (3.5±0.3 to 3.4±0.3, n=34 p=0.846). Fibrosis score on follow-up biopsy was higher in patients with NIS 4–5 (n=40) than with NIS 0–3 (n=72) (mean 3.3±0.3 vs 2.4±0.2, p=0.014). Regression of fibrosis was independently associated with lower NIS (p=0.014) and less portal inflammation (p=0.006) on follow-up biopsy, and with longer interval between the two biopsies (p=0.001). All cause death/transplantation rate was higher in those with NIS of 4–5 than in those with NIS 0–3 (18% vs 6% and 64% vs 24% after 10 and 20 years respectively; p&lt;0.001) and this categorisation was independently associated with survival (p=0.001). A similar trend for liver death/transplantation just failed to reach significance (p=0.07). <h3>Conclusion</h3> In patients with AIH treated with immunosupression, even mild histological activity (NIS 4 or 5) on follow-up biopsy is associated with more fibrosis and with reduced survival and hence may not be an optimal end point of treatment.
Preventing coronary heart disease: High baseline risk strategy and cost effectiveness of guidelines
Authors: D Graham Mackenzie, John Forbes, Sarah Wild, Philip Rutledge
Journal: BMJ (2006)

Eosinophilic airway inflammation is one of the hallmarks of asthma. Sputum eosinophilia has been suggested as a predictor of the response to inhaled corticosteroids in asthma. This study sought to investigate the proportion of steroid-naive uncontrolled asthmatics without significant sputum eosinophilia (≤1%) and to examine whether sputum eosinophilia could predict the response to inhaled corticosteroids. A total of 51 mild uncontrolled steroid-naive asthmatics who had not been treated with oral or inhaled corticosteroids for at least 3 months were investigated. The evaluation included a spirometry, methacholine inhalation challenge and sputum induction on two occasions, one at baseline and the other after 1 month of treatment with 250 µg twice-daily fluticasone propionate. Of the 51 subjects, 15 had an eosinophil count ≤1%, and 46 completed the two visits. Patients with baseline sputum eosinophils ≤1% (n=14) were compared with those with sputum eosinophils &gt;1% (n=32). The baseline characteristics of these two groups were similar. After 1 month of treatment, respiratory symptoms, quality of life, forced expiratory volume in one second (FEV<sub>1</sub>) and provocative concentration causing a 20% fall in FEV<sub>1</sub> improved in both groups. The absence of sputum eosinophilia does not seem to be an indicator of poor response to inhaled corticosteroid treatment in steroid-naive asthmatics. However, this finding needs to be investigated further in a double-blind, placebo-controlled study, entirely designed to answer this question.
Secondary Causes of Low Bone Mass in Patients With Breast Cancer: A Need for Greater Vigilance
Authors: G. Bruce Mann, Y. Chiu Kang, Caroline Brand, Peter R. Ebeling, Julie A. Miller
Journal: Journal of Clinical Oncology (2009)

An observational study to assess the prevalence of secondary causes of low bone density in patients with breast cancer.Female patients within 5 years of breast cancer diagnosis and age older than 50 years at diagnosis were recruited. Consenting patients completed a questionnaire and had blood taken for serum calcium, vitamin D, parathyroid hormone (PTH), and thyroid function testing. Bone mineral density (BMD) was assessed. Abnormalities were additionally investigated and treated.Two hundred patients were recruited. The median age at diagnosis was 62 years. One hundred sixty-nine patients had hormone receptor (HR) -positive cancer. Vitamin D and thyroid function were assessed in 200 patients; PTH was assessed in 197 patients; and BMD was assessed in 187 patients. Eighty-seven patients (46.5%) had osteopenia, and 24 patients (12.8%) had osteoporosis. Vitamin D levels were insufficient (ie, 50 to 75 nmol/L) in 74 patients (37%) and were deficient (ie, < 50 nmol/L) in 54 patients (27%). Only 24 of 65 patients taking vitamin D supplements were replete (ie, > 75 nmol/L). Thirty-nine (21%) of 197 patients had PTH concentrations greater than the normal range. Six had primary hyperparathyroidism (PHPT), and two more had recent surgery for PHPT. Twenty-seven had secondary hyperparathyroidism (HPT) from vitamin D deficiency and six had normocalcemic HPT. Of 90 patients with low BMD and HR-positive cancer, 8% (seven of 90 patients) had new or recent PHPT, and 63% (57 of 90 patients) had insufficient or deficient vitamin D. More patients with HR-positive cancer than with HR-negative cancer had elevated PTH (38 of 167 v three of 30 patients, respectively; P = .10).Secondary causes of low BMD are common in postmenopausal women. Identification and management of secondary causes should be included in bone health management algorithms.
Mometasone furoate is a less specific glucocorticoid than fluticasone propionate
Authors: R.J.H. Austin, B. Maschera, A. Walker, L. Fairbairn, E. Meldrum, S.N. Farrow, I.J. Uings
Journal: European Respiratory Journal (2002)

Fluticasone propionate (FP) and mometasone furoate (MF) are potent synthetic corticosteroids that are widely used as anti-inflammatory agents to treat respiratory diseases. As part of the assessment of the potential for side-effects associated with their use, their activities, not only at the glucocorticoid receptor (GR) but also at the other members of the steroid nuclear receptor family, have been compared. Cell-based functional systems were established to measure different aspects of GR function, as well as the activity at all the other steroid nuclear receptors. The effects of MF and FP on the GR were potent and indistinguishable. Neither corticosteroid showed any activity at the oestrogen receptor, while both were weak antagonists of the androgen receptor. FP was a relatively weak agonist of the progesterone receptor but MF was a very potent agonist of the progesterone receptor, giving activity at similar concentrations to those that stimulate the GR (concentration generating 50% maximal effect (EC 50 )=50 pM). Moreover, while FP was a weak antagonist of the mineralocorticoid receptor (concentration generating 50% maximal inhibitory effect=80 nM), MF displayed potent partial agonist activity (EC 50 =3 nM, 30%). Mometasone furoate is considerably less specific for the glucocorticoid receptor than fluticasone propionate, showing significant activity at other nuclear steroid receptors.
The potential roles for embryotrophic ligands in preimplantation embryo development
Authors: Chris O’Neill
Journal: Human Reproduction Update (2008)

Identification of the role(s) extracellular ligands play in regulating the development of the mammalian preimplantation embryo is a controversial area. Unequivocal evidence for their role is complicated by the apparent overlapping actions of multiple ligands. The discovery that the embryo also releases its own repertoire of ligands and expresses their corresponding receptors has further constrained analysis of their roles. Conventional ligand ablation strategies have limited utility when the cell responding to multiple ligands also produces them. The application of methods for identifying signal transduction events that occur in the early embryo in response to ligands has allowed direct assessment of the actions of these putative trophic ligands. A range of ligands induce phosphatidylinositol-3-kinase mediated survival signalling, and this is required for normal embryo development. Survival signalling maintains apoptotic pathways in a latent state within normal somatic cells, and they may fulfill the same role in the early embryo. Survival signals can also mitigate the adverse response of embryos to genotoxic and non-genotoxic stressors. Currently, there is no unequivocal evidence for a direct role of these ligands in the induction of mitosis in the early embryo. Embryotrophic ligands, acting via their specific receptors, to activate a network of effectors to create pro-survival, anti-apoptotic settings within the preimplantation embryo and these are required for normal embryo survival.
Effects of heart rate and diltiazem hydrochloride on alternans of ST segment elevation and ventricular arrhythmia during acute myocardial ischaemia in dogs
Authors: T. HAYAKAWA, Y. NAGAMOTO, K. NINOMIYA, S. ABE, T. FUKUMOTO, A. KUROIWA
Journal: Cardiovascular Research (1989)

Although the incidence of ventricular arrhythmias following myocardial ischaemia lessens as ischaemia improves, it is not clear whether this is correlated with a reduction in the degree of ST segment elevation. To explore this further we examined the effects of change in heart rate and the administration of the calcium antagonist diltiazem, 0.02 mg.kg-1.min-1, on ST segment elevation and the alternans of ST segment elevation (STA) and on serious ventricular arrhythmia induced by 10 min occlusion of the left anterior descending coronary artery in 86 mongrel dogs. The dogs were divided into three groups: 26 dogs paced at a rate of 180 beats.min-1 (group A); 44 dogs paced at a rate of 120 beats.min-1 (group B); and 16 dogs paced at a rate of 180 beats.min-1 and given diltiazem intravenously from 25 min before the coronary occlusion (group C). The degree of ST segment elevation and STA within 3 min of ischaemia was significantly lower in group B than in group A. There was no marked difference in the degree of ST segment elevation between groups A and C, but the STA was lower in group C than in group A. Incidence of ventricular tachycardia and ventricular fibrillation was significantly lower in groups B and C than in group A, and the timing of their first appearance was 4.5 (SEM 0.6), 4.2(0.9) and 3.0(0.4) min, respectively. We suggest that the reduction in serious ventricular arrhythmias associated with the decrease in heart rate was caused by the improvement of STA secondary to the improvement of ST segment elevation.(ABSTRACT TRUNCATED AT 250 WORDS)
Tacrolimus versus ciclosporin as primary immunosuppression for kidney transplant recipients: meta-analysis and meta-regression of randomised trial data
Authors: Angela C Webster, Rebecca C Woodroffe, Rod S Taylor, Jeremy R Chapman, Jonathan C Craig
Journal: BMJ (2005)

<h3>Abstract</h3> <b>Objective</b> To compare the positive and negative effects of tacrolimus and ciclosporin as initial treatment for renal transplant recipients. <b>Design</b> Systematic review. <b>Data sources and study selection</b> Reports of comparative randomised trials of tacrolimus and ciclosporin identified by searches of Medline, Embase, the Cochrane Register of Controlled Trials, the Cochrane Renal Group Specialist Register, and conference proceedings. <b>Data extraction and synthesis</b> Two reviewers assessed trials for eligibility and quality and extracted data independently. Data were synthesised (random effects model) and results expressed as relative risk (RR), with values &lt; 1 favouring tacrolimus. Subgroup analysis and meta-regression were used to examine potential effect modification by differences in trial design and immunosuppressive co-interventions. <b>Results</b> 123 reports from 30 trials (4102 patients) were included. At six months, graft loss was significantly reduced in tacrolimus treated recipients (RR = 0.56, 95% confidence interval 0.36 to 0.86), and this effect persisted up to three years. The relative reduction in graft loss with tacrolimus diminished with higher concentrations of tacrolimus (P = 0.04) but did not vary with ciclosporin formulation (P = 0.97) or ciclosporin concentration (P = 0.38). At one year, tacrolimus treated patients had less acute rejection (RR = 0.69, 0.60 to 0.79) and less steroid resistant rejection (RR = 0.49, 0.37 to 0.64) but more diabetes mellitus requiring insulin (RR = 1.86, 1.11 to 3.09), tremor, headache, diarrhoea, dyspepsia, and vomiting. The relative excess of diabetes increased with higher concentrations of tacrolimus (P = 0.003). Ciclosporin treated recipients had significantly more constipation and cosmetic side effects. No differences were seen in infection or malignancy. <b>Conclusions</b> Treating 100 recipients with tacrolimus instead of ciclosporin for the first year after transplantation avoids 12 patients having acute rejection and two losing their graft but causes an extra five patients to develop insulin dependent diabetes. Optimal drug choice may vary between patients.
Molecular features of non-B, non-C hepatocellular carcinoma: a PCR-array gene expression profiling study
Authors: Yukinori Kurokawa, Ryo Matoba, Ichiro Takemasa, Shoji Nakamori, Masanori Tsujie, Hiroaki Nagano, Keizo Dono, Koji Umeshita, Masato Sakon, Noriko Ueno, Hiroko Kita, Shigeyuki Oba, Shin Ishii, Kikuya Kato, Morito Monden
Journal: Journal of Hepatology (2003)
Accelerated Partial Breast Irradiation: Where Do We Stand?
Authors: Frederick M. Dirbas
Journal: Journal of the National Comprehensive Cancer Network (2009)

Accelerated partial breast irradiation (APBI) is a new form of postlumpectomy radiotherapy delivered over 1 to 5 days. Early trials showed high local recurrence rates. More recent single and multiinstitutional studies, as well as a single phase III trial, have shown local control more comparable to whole breast radiotherapy. Patient selection and surgical technique are important variables preparatory to irradiation, which is delivered using 1 of 4 accelerated radiotherapy methods. Phase I/II studies have produced most of the information currently available regarding APBI. Additional phase III studies are underway to determine whether any or all of these accelerated radiotherapy approaches may safely substitute for whole breast radiotherapy in women seeking breast conservation.
Decreased elastin in vessel walls puts the pressure on
Authors: Jeanine D’Armiento
Journal: Journal of Clinical Investigation (2003)

Mice haploinsufficient for elastin develop structural changes in vessel walls similar to those seen in patients with mutations in the elastin gene. A new study demonstrates that due to mechanical changes in the vessel wall, these animals exhibit increased mean arterial pressures. The results evoke the possibility that alterations in elastin may contribute to the development of essential hypertension in patients.
Interventions to Improve the Management of Diabetes in Primary Care, Outpatient, and Community Settings
Authors: Carry M. Renders, Gerlof D. Valk, Simon J. Griffin, Edward H. Wagner, Jacques ThM. Eijk van, Willem J.J. Assendelft
Journal: Diabetes Care (2001)

OBJECTIVE—To review the effectiveness of interventions targeted at health care professionals and/or the structure of care in order to improve the management of diabetes in primary care, outpatient, and community settings. RESEARCH DESIGN AND METHODS—A systematic review of controlled trials evaluating the effectiveness of interventions targeted at health care professionals and aimed at improving the process of care or patient outcomes for patients with diabetes was performed. Standard search methods of the Cochrane Effective Practice and Organization of Care Group were used. RESULTS—A total of 41 studies met the inclusion criteria. The studies identified were heterogeneous in terms of interventions, participants, settings, and reported outcomes. In all studies, the interventions were multifaceted. The interventions were targeted at health care professionals only in 12 studies, at the organization of care only in 9 studies, and at both in 20 studies. Complex professional interventions improved the process of care, but the effect on patient outcomes remained less clear because such outcomes were rarely assessed. Organizational interventions that facilitated the structured and regular review of patients also showed a favorable effect on process measures. Complex interventions in which patient education was added and/or the role of a nurse was enhanced led to improvements in patient outcomes as well as the process of care. CONCLUSIONS—Multifaceted professional interventions and organizational interventions that facilitate structured and regular review of patients were effective in improving the process of care. The addition of patient education to these interventions and the enhancement of the role of nurses in diabetes care led to improvements in patient outcomes and the process of care.
Effect of fetal adrenalectomy on catecholamine release and physiologic adaptation at birth in sheep.
Authors: J Padbury, Y Agata, J Ludlow, M Ikegami, B Baylen, J Humme
Journal: Journal of Clinical Investigation (1987)

Plasma catecholamine levels increase dramatically at birth. To determine the contribution of adrenal catecholamine secretion to the surge in catecholamines at birth and the role in newborn adaptation, we performed surgical adrenalectomy or sham operation on near-term ovine fetuses. After recovery in utero, the animals were delivered and supported by mechanical ventilation. Plasma catecholamine levels, heart rate, blood pressure, cardiac output, pulmonary function, surfactant secretion, and release of free fatty acids (FFA) and glucose were compared in control and adrenalectomized animals. Plasma epinephrine increased rapidly at birth in controls but was undetectable in adrenalectomized animals. Norepinephrine levels were not statistically different. Heart rate, blood pressure, cardiac output and contractility increased abruptly after cord cutting in controls but did not increase in adrenalectomized animals. Lung compliance, pulmonary function, surfactant pool size, glucose and FFA levels were significantly decreased in adrenalectomized animals. These results suggest that adrenal epinephrine secretion is vital to many of the adaptive events at birth.
'The only constant is change': UKSEM, ISEM, Twitter, Podcasts and YouTube reflect the dynamic nature of sport and exercise medicine
Authors: Karim M Khan
Journal: British Journal of Sports Medicine (2010)

Warm upDavid Bowie's 1971 classic song 'Changes' includes the lines 'Time may change me, but I can't trace time'.As a lapsed BASM (as it was then) member, I believe he was suggesting we could be heroes and that we should dance to the major changes we see today in BASEM, UKSEM, ISEM, Twitter and YouTube.