tbuckley/cabot-search huggingface dataset:
Haplotypes of the Caspase-1 Gene, Plasma Caspase-1 Levels, and Cardiovascular Risk
Authors: Stefan Blankenberg, Tiphaine Godefroy, Odette Poirier, Hans J. Rupprecht, Sandrine Barbaux, Christoph Bickel, Viviane Nicaud, Renate Schnabel, Frank Kee, Caroline Morrison, Alun Evans, Karl J. Lackner, François Cambien, Thomas Münzel, Laurence Tiret
Journal: Circulation Research (2006)

Caspase-1 processes the interleukin (IL)-1beta and IL-18 inactive precursors to the biologically active cytokines that are known to have proatherogenic effects. The present study investigated the genetic variability of the CASP1 gene and plasma levels of caspase-1 in relation to cardiovascular risk. In Europeans, 3 tag SNPs captured 4 common haplotypes of the CASP1 gene. Among these, the A(in6) allele of the G+7/in6A polymorphism was less frequent in 246 cases with myocardial infarction and a parental history of disease than in 253 controls free of familial history of disease (0.13+/-0.02 versus 0.20+/-0.02; P=0.005). However, in a larger case/control study (n=1774), these effects are borderline restricted to the UK population. In a prospective cohort of 1168 patients with coronary artery disease followed up during a median period of 6.0 years, the A(in6) allele exhibited a borderline association with future cardiovascular death (hazard ratio [HR]: 0.64, 0.41 to 1.01; P=0.053) and was associated with lower serum IL-18 levels (P=0.014). Baseline caspase-1 levels in the top quartile of the distribution were predictive of cardiovascular deaths (HR=3.62, 1.81 to 7.27; P=0.0003 compared with the bottom quartile). Finally, in vitro assays of allelic imbalance showed that the CASP1 haplotype carrying the A(in6) allele was associated with a lower mRNA expression. These results indicate that caspase-1 levels are predictive of future cardiovascular death in patients with coronary artery disease. The role of CASP1 genetic variations in the susceptibility to myocardial infarction requires further investigation.
Chemosensitivity and p53–Bax pathway-mediated apoptosis in patients with uterine cervical cancer
Authors: H. Sultana, J. Kigawa, Y. Kanamori, H. Itamochi, T. Oishi, S. Sato, S. Kamazawa, M. Ohwada, M. Suzuki, N. Terakawa
Journal: Annals of Oncology (2003)
Short-Course Versus Split-Course Radiotherapy in Metastatic Spinal Cord Compression: Results of a Phase III, Randomized, Multicenter Trial
Authors: Ernesto Maranzano, Rita Bellavita, Romina Rossi, Verena De Angelis, Alessandro Frattegiani, Rita Bagnoli, Marcello Mignogna, Sara Beneventi, Marco Lupattelli, Pietro Ponticelli, Gian Paolo Biti, Paolo Latini
Journal: Journal of Clinical Oncology (2005)

Hypofractionated radiotherapy (RT) is often used in the treatment of metastatic spinal cord compression (MSCC). This randomized trial was planned to assess the clinical outcome and toxicity of two different hypofractionated RT regimens in MSCC.Three hundred patients with MSCC were randomly assigned to a short-course RT (8 Gy x 2 days) or to a split-course RT (5 Gy x 3; 3 Gy x 5). Only patients with a short life expectancy entered the protocol. Median follow-up was 33 months (range, 4 to 61 months).A total of 276 (92%) patients were assessable; 142 (51%) treated with the short-course and 134 (49%) treated with the split-course RT regimen. There was no significant difference in response, duration of response, survival, or toxicity found between the two arms. When short- versus split-course regimens were compared, after RT 56% and 59% patients had back pain relief, 68% and 71% were able to walk, and 90% and 89% had good bladder function, respectively. Median survival was 4 months and median duration of improvement was 3.5 months for both arms. Toxicity was equally distributed between the two arms: grade 3 esophagitis or pharyngitis was registered in four patients (1.5%), grade 3 diarrhea occurred in four patients (1.5%), and grade 3 vomiting or nausea occurred in 10 patients (6%). Late toxicity was never recorded.Both hypofractionated RT schedules adopted were effective and had acceptable toxicity. However, considering the advantages of the short-course regimen in terms of patient convenience and machine time, it could become the RT regimen of choice in the clinical practice for MSCC patients.
Withholding Resuscitation: A New Approach to Prehospital End-of-Life Decisions
Authors: Sylvia Feder, Roger L. Matheny, Robert S. Loveless, Thomas D. Rea
Journal: Annals of Internal Medicine (2006)

Background: Emergency medical services (EMS) personnel often are not permitted to honor requests to withhold resuscitation at the end of life, particularly if there is no written do-not-resuscitate (DNR) order. Objective: To determine whether EMS personnel from agencies implementing new guidelines would be more likely to withhold resuscitation from persons having out-of-hospital cardiac arrests than would personnel from agencies that did not implement the guidelines. Design: Observational study in which 16 of 35 local EMS agencies volunteered to implement new guidelines for withholding resuscitation. Setting: King County, Washington. Patients: 2770 patients with EMS-attended cardiac arrest. Intervention: New guidelines adopted by participating agencies permitted EMS personnel to withhold resuscitation if the patient had a terminal condition and if the patient, family, or caregivers indicated, in writing or verbally, that no resuscitation was desired. Measurements: Proportion of resuscitations withheld in agencies that implemented new guidelines compared with those that did not. Results: Emergency medical services personnel from agencies implementing new guidelines withheld resuscitation in 11.8% of patients (99 of 841 patients) having cardiac arrests, compared with an average of 5.3% (range, 4.2% to 5.9%) of patients (103 of 1929 patients) in 3 historical and contemporary control groups. Honoring verbal requests alone accounted for 53% of withheld resuscitations in the intervention group (52 of 99 patients) compared with an average of 8% (range, 7% to 9%) in the control groups (8 of 103 patients). Limitations: The study was not a randomized, controlled trial; individual agencies chose whether to implement the guidelines. Conclusions: Implementation of new guidelines was associated with an increase in the number of resuscitations withheld by EMS personnel. This increase was primarily due to honoring verbal requests.
Pulmonary Vascular Remodeling Correlates with Lung Eggs and Cytokines in Murine Schistosomiasis
Authors: Alexi Crosby, Frances M. Jones, Mark Southwood, Susan Stewart, Ralph Schermuly, Ghazwan Butrous, David W. Dunne, Nicholas W. Morrell
Journal: American Journal of Respiratory and Critical Care Medicine (2009)

Schistosomiasis is considered to be the most common worldwide cause of pulmonary hypertension. At present there is no well-characterized animal model to study the pathobiology of this important condition.To develop a mouse model of schistosomiasis, characterize the extent of pulmonary vascular remodeling, and determine the potential role of inflammatory cytokines.Mice (C57/Bl6) were infected transcutaneously with a high dose (approximately 75-100 cercariae) or a low dose (approximately 30 cercariae) of Schistosoma mansoni, and the development of lung and liver pathology was studied in the subacute (high-dose) and chronic (low-dose) settings.In the subacute setting, mice showed few eggs in the lungs and no evidence of pulmonary vascular remodeling. In contrast, chronically infected animals had a much greater lung egg burden and developed marked pulmonary vascular remodeling accompanied by perivascular inflammation from 12 weeks onwards. In addition, we observed the presence of plexiform-like lesions in these mice. Lung egg burden correlated with both liver egg burden and right ventricular (RV) index in the chronic group, although significant RV hypertrophy was lacking. Plasma Th1 and Th2 cytokines increased with time in the chronic group and correlated with the degree of pulmonary vascular remodeling.This study provides evidence for extensive pulmonary vascular remodeling, despite the absence of RV hypertrophy, in a mouse model of schistosomiasis, including the formation of plexiform-like lesions. Inflammatory cytokines and lung egg burden may contribute to vascular lesion formation.
The Guanine Nucleotide Exchange Factors Sec2 and PRONE: Candidate Synapomorphies for the Opisthokonta and the Archaeplastida
Authors: M. Elias
Journal: Molecular Biology and Evolution (2008)

Although recent multigene phylogenetic analyses support close relationship of Metazoa and Fungi (the eukaryotic supergroup Opisthokonta) and monophyly of eukaryotes with the primary plastid, that is, Chloroplastida, Rhodophyta, and Glaucophyta (the supergroup Archaeplastida or Plantae), some authors still challenge this scheme. I found that 2 particular types of guanine nucleotide exchange factors (GEFs, i.e., cofactors of GTPases) might provide a new piece of evidence to resolve this controversy. An exhaustive analysis of available sequence data revealed that Sec2-related proteins, known to serve as GEF for exocytic GTPases of the Rab8/Sec4 subfamily, are restricted to opisthokonts, whereas proteins with the PRONE domain, recently described as novel plant-specific GEFs for RHO family GTPases, occur only in Chloroplastida and Rhodophyta. The results thus point to possible evolutionary innovations in the exocytic apparatus of the ancestral opisthokonts and reveal the probably first plastid-independent trait (i.e., a unique mode of RHO GTPase regulation) exclusive for Chloroplastida + Rhodophyta, further supporting monophyly of these 2 groups.
Montelukast improves regional air-trapping due to small airways obstruction in asthma
Authors: M. R. Zeidler, E. C. Kleerup, J. G. Goldin, H. J. Kim, D. A. Truong, M. D. Simmons, J. W. Sayre, W. Liu, R. Elashoff, D. P. Tashkin
Journal: European Respiratory Journal (2006)

Quantitative image analysis of high-resolution computed tomography (HRCT) performed at residual volume, before and after methacholine, is a sensitive method of detecting small airways involvement in asthma and response to therapy targeted to the small airways. Since an oral anti-leukotriene reaches the small airways via the circulation, the present authors hypothesised that treatment with montelukast would lead to improved small airway patency. A double-blind crossover study compared the effect of montelukast versus placebo for 4 weeks in 16 mild-to-moderate steroid-naïve asthmatics. Small airways function was evaluated by HRCT at residual volume before and after methacholine to assess regional air-trapping and airways hyperresponsiveness, as well as by physiological studies of small airways. Montelukast treatment resulted in significantly less regional air-trapping on HRCT on the pre-methacholine images when compared with placebo, as well as improvement in total quality of life scores and symptom sub-scores. However, montelukast treatment had no effect on increases in regional air-trapping on HRCT in response to methacholine. No differences were noted in global measures of small airways physiology between placebo and montelukast. In conclusion, distal airways disease improves in asthmatic subjects treated with montelukast. This improvement can be detected with high-resolution computed tomography, but not with conventional physiological studies.
<i>HER2/neu</i> Expression and Hormonal Therapy in Early Breast Cancer: Can Muddy Waters Become Clear?
Authors: Gianluigi Ferretti, Serena Di Cosimo, Diana Giannarelli, Paolo Carlini, Paola Papaldo, Andrea Alimonti, Alessandra Fabi, Mario Mandalà, Michele Milella, Enzo Maria Ruggeri, Francesco Cognetti
Journal: Journal of Clinical Oncology (2004)

patients treated with preoperative prophylaxis.Because the prophylaxis regimen included a corticosteroid, we monitored our outcomes for wound complications.Although the complication rate was two-fold greater in patients receiving prophylaxis and dye compared with those receiving neither, this was not statistically significant.Several mechanisms of action behind adverse reactions to isosulfan blue dye have been postulated, but none have been confirmed.We are currently investigating the molecular basis of these adverse reactions.
Hyperactivation of P21ras and the Hematopoietic-Specific Rho Gtpase, Rac2, Cooperate to Alter the Proliferation of Neurofibromin-Deficient Mast Cells in Vivo and in Vitro
Authors: David A. Ingram, Kelly Hiatt, Alastair J. King, Lucy Fisher, Rama Shivakumar, Christina Derstine, Mary Jo Wenning, Bruce Diaz, Jeffrey B. Travers, Antoinette Hood, Mark Marshall, David A. Williams, D. Wade Clapp
Journal: The Journal of Experimental Medicine (2001)

Mutations in the NF1 tumor suppressor gene cause neurofibromatosis type I (NF1), a disease characterized by the formation of cutaneous neurofibromas infiltrated with a high density of degranulating mast cells. A hallmark of cell lines generated from NF1 patients or Nf1-deficient mice is their propensity to hyperproliferate. Neurofibromin, the protein encoded by NF1, negatively regulates p21ras activity by accelerating the conversion of Ras-GTP to Ras-GDP. However, identification of alterations in specific p21ras effector pathways that control proliferation in NF1-deficient cells is incomplete and critical for understanding disease pathogenesis. Recent studies have suggested that the proliferative effects of p21ras may depend on signaling outputs from the small Rho GTPases, Rac and Rho, but the physiologic importance of these interactions in an animal disease model has not been established. Using a genetic intercross between Nf1+/− and Rac2−/− mice, we now provide genetic evidence to support a biochemical model where hyperactivation of the extracellular signal–regulated kinase (ERK) via the hematopoietic-specific Rho GTPase, Rac2, directly contributes to the hyperproliferation of Nf1-deficient mast cells in vitro and in vivo. Further, we demonstrate that Rac2 functions as mediator of cross-talk between phosphoinositide 3-kinase (PI-3K) and the classical p21ras-Raf-Mek-ERK pathway to confer a distinct proliferative advantage to Nf1+/− mast cells. Thus, these studies identify Rac2 as a novel mediator of cross-talk between PI-3K and the p21ras-ERK pathway which functions to alter the cellular phenotype of a cell lineage involved in the pathologic complications of a common genetic disease.
Continuous Intrathecal Baclofen Infusion for Spasticity of Cerebral Origin
Authors: A. Leland Albright
Journal: JAMA (1993)

To determine if continuous intrathecal baclofen infusion (CIBI) would provide continuous relief of spasticity in patients with spasticity of cerebral origin, especially children with cerebral palsy.Prospective, unblinded trial, before and after CIBI.Children's Hospital of Pittsburgh (Pa).Thirty-seven patients, 5 to 27 years of age, with spasticity of cerebral origin.Continuous intrathecal baclofen infusion for 3 to 48 months.Muscle tone, range of motion, upper extremity timed tasks, activities of daily living (ADLs).Six and 12 months after CIBI, muscle tone was significantly decreased in the upper (P = .04) and lower (P = .001) extremities. There was a significant relationship between baclofen dosage and muscle tone in the upper (P = .02) and lower (P = .001) extremities. Hamstring motion, upper extremity function, and ADLs were significantly improved in 25 patients who were capable of self-care.Spasticity of cerebral origin can be effectively treated with CIBI. Because baclofen dosages can be titrated for the desired clinical response, CIBI is particularly useful for patients who need some spasticity to stand and ambulate.
Authors’ response to: How should we best determine the need for in-flight oxygen in patients with pulmonary arterial hypertension
Authors: Dinesh Shrikrishna, Luke Howard, Robina K Coker
Journal: Thorax (2013)

response to: How should we best determine the need for in-flight oxygen in patients with pulmonary arterial hypertensionWe thank Burns et al 1 for their comments on the updated British Thoracic Society recommendations for managing passengers with respiratory disease planning air travel. 2In particular, a central aim of the recommendations was to promote research in this field, and we therefore commend their recent study investigating hypoxaemia in patients with pulmonary arterial hypertension (PAH) during simulated air travel. 3The method of assessment which best serves a clinician in judging which patients with PAH require in-flight oxygen remains a challenge due to a lack of evidence.Indeed, the current recommendation that those PAH patients in New York Heart Association (NYHA) functional class III or IV should receive in-flight oxygen has only a grade D evidence base.Importantly, NYHA functional class does provide a key measure of the impact of the disease on patients and is a strong predictor of survival in PAH. 4 In this context, the successful completion of a hypoxic challenge test (HCT) alone does not always translate to an absence of symptoms in flight for these patients. 3he question of whether NYHA functional class III-IV or HCT better predicts the requirement for in-flight oxygen in PAH, clearly remains open to debate, and we hope this will only serve to encourage further high-quality research in this area to strengthen the evidence base for future air travel guidelines.
Acute Exposure to Cotton Dust
Authors: D. L. Holness
Journal: JAMA (1982)

EXPOSURE to cotton dust may cause several syndromes, the best known of which is byssinosis. 1 Another syndrome occurring principally in persons unaccustomed to cotton dust exposure is mill fever, which consists of fever, chills, cough, and malaise and which may recur with further exposures until tolerance develops over weeks or months. In 1940 Trice 2 described the symptoms of mill fever in persons carding low-grade cotton, but no measurements were included. In 1942 Neal and co-workers 3 described similar symptoms in rural mattress makers and proceeded to investigate the effects of low-grade cotton on exposed subjects under experimental conditions. Despite these early reports, mill fever has received scant attention in the scientific literature, and recent studies of cotton exposure have not drawn attention to the acute effects. 4,5 Moreover, the important relationship of mill fever to byssinosis remains poorly defined. Following a recent visit to a cotton garnett, by
Umbilical cord blood cells capable of engrafting in primary, secondary, and tertiary xenogeneic hosts are preserved after ex vivo culture in a noncontact system
Authors: Ian D. Lewis, Graca Almeida-Porada, Jingbo Du, Ihor R. Lemischka, Kateri A. Moore, Esmail D. Zanjani, Catherine M. Verfaillie
Journal: Blood (2001)
Structure and function of the ear and auditory nervous system.
Authors: M Lawrence
Journal: Environmental Health Perspectives (1982)

The transduction from sound vibrations to a nerve ending stimulus takes place in the organ of Corti. This process, resulting from fluid particle movement of a magnitude equivalent to the dimensions of the electron cloud around an atom, involves more than a simple deformation of the sensory cell. The fluid environment of these cells must be such that it provides sufficient oxygen and nutrients for the cells' survival and at the same time maintains a condition to enhance the biophysical process. The spiral capillaries beneath the tunnel of Corti furnish the metabolites for the Cortilymph surrounding the sensory cells. The capillaries of the stria vascularis provide this structure, an organ in its own right, so that it can maintain the high potassium concentration and positive potential of endolymph which are necessary for the transduction process. The stria vascularis itself and its blood supply and the sensory cells and their blood supply are all vulnerable to attack by various toxic agents, thus altering the homeostatic condition and resulting in a hearing loss.
Influence of Changes in pH on the Mechanical Activity of Cardiac Muscle
Authors: HRVOJE LORKOVIĆ
Journal: Circulation Research (1966)

In a comprehensive experimental study, the influence of changes in extra-and intracellular pH on the mechanical and electrical activity of frog heart ventricle preparations has been investigated. The twitch tension and potassium contracture tension were decreased in acid solutions, provided that the concentration of calcium or the frequency of stimulation was low. In solutions with a high calcium concentration, prolonged exposure to acid leads to an increase of the potassium contractures. The electrical activity, measured by intracellular microelectrodes, is abolished in acid solutions if the change of solution in the extracellular space is enforced by perpendicular jet superfusion; with slow perfusion it is well maintained except when [Ca] is high. The lowering of intracellular pH by applying a solution saturated with 80% CO 2 while keeping the extracellular pH constant causes a rapid drop in twitch tension followed by partial recovery. The relaxation phase of single twitches is prolonged and potassium contractures are markedly increased after the high CO 2 has acted for several minutes. When both intra- and extracellular pH are decreased, both twitches and potassium contractures are markedly decreased. The electrical activity is maintained. Some of the effects of variations in pH are discussed in terms of changes in the processes of mechanical activation and inactivation.
Mutant Mitochondrial Elongation Factor G1 and Combined Oxidative Phosphorylation Deficiency
Authors: Marieke J.H. Coenen, Hana Antonicka, Cristina Ugalde, Florin Sasarman, Rainer Rossi, J.G.A.M. Angelien Heister, Robert F. Newbold, Frans J.M.F. Trijbels, Lambert P. van den Heuvel, Eric A. Shoubridge, Jan A.M. Smeitink
Journal: New England Journal of Medicine (2004)

Although most components of the mitochondrial translation apparatus are encoded by nuclear genes, all known molecular defects associated with impaired mitochondrial translation are due to mutations in mitochondrial DNA. We investigated two siblings with a severe defect in mitochondrial translation, reduced levels of oxidative phosphorylation complexes containing mitochondrial DNA (mtDNA)-encoded subunits, and progressive hepatoencephalopathy. We mapped the defective gene to a region on chromosome 3q containing elongation factor G1 (EFG1), which encodes a mitochondrial translation factor. Sequencing of EFG1 revealed a mutation affecting a conserved residue of the guanosine triphosphate (GTP)-binding domain. These results define a new class of gene defects underlying disorders of oxidative phosphorylation.
Cerebellar neurodegeneration in the absence of microRNAs
Authors: Anne Schaefer, Dónal O'Carroll, Chan Lek Tan, Dean Hillman, Mutsuyuki Sugimori, Rodolfo Llinas, Paul Greengard
Journal: The Journal of Experimental Medicine (2007)

Genome-encoded microRNAs (miRNAs) are potent regulators of gene expression. The significance of miRNAs in various biological processes has been suggested by studies showing an important role of these small RNAs in regulation of cell differentiation. However, the role of miRNAs in regulation of differentiated cell physiology is not well established. Mature neurons express a large number of distinct miRNAs, but the role of miRNAs in postmitotic neurons has not been examined. Here, we provide evidence for an essential role of miRNAs in survival of differentiated neurons. We show that conditional Purkinje cell–specific ablation of the key miRNA-generating enzyme Dicer leads to Purkinje cell death. Deficiency in Dicer is associated with progressive loss of miRNAs, followed by cerebellar degeneration and development of ataxia. The progressive neurodegeneration in the absence of Dicer raises the possibility of an involvement of miRNAs in neurodegenerative disorders.