tbuckley/cabot-search huggingface dataset:
Exome sequencing identifies ACSF3 as a cause of combined malonic and methylmalonic aciduria
Authors: Jennifer L Sloan, Jennifer J Johnston, Irini Manoli, Randy J Chandler, Caitlin Krause, Nuria Carrillo-Carrasco, Suma D Chandrasekaran, Justin R Sysol, Kevin O'Brien, Natalie S Hauser, Julie C Sapp, Heidi M Dorward, Marjan Huizing, Bruce A Barshop, Susan A Berry, Philip M James, Neena L Champaigne, Pascale de Lonlay, Vassilli Valayannopoulos, Michael D Geschwind, Dimitar K Gavrilov, William L Nyhan, Leslie G Biesecker, Charles P Venditti
Journal: Nature Genetics (2011)
T<scp>HE</scp> B<scp>IOLOGY OF</scp> E<scp>PILEPSY</scp> G<scp>ENES</scp>
Authors: Jeffrey L. Noebels
Journal: Annual Review of Neuroscience (2003)

▪ Abstract Mutations in over 70 genes now define biological pathways leading to epilepsy, an episodic dysrhythmia of the cerebral cortex marked by abnormal network synchronization. Some of the inherited errors destabilize neuronal signaling by inflicting primary disorders of membrane excitability and synaptic transmission, whereas others do so indirectly by perturbing critical control points that balance the developmental assembly of inhibitory and excitatory circuits. The genetic diversity is now sufficient to discern short- and long-range functional convergence of epileptogenic molecular pathways, reducing the broad spectrum of primary molecular defects to a few common processes regulating cortical synchronization. Synaptic inhibition appears to be the most frequent target; however, each gene mutation retains unique phenotypic features. This review selects exemplary members of several gene families to illustrate principal categories of the disease and trace the biological pathways to epileptogenesis in the developing brain.
Assessments for oxygen therapy in COPD: are we under correcting arterial oxygen tensions?
Authors: K. Dheda, K. Lim, B. Ollivere, J. Leftley, F.C. Lampe, A. Salisbury, J.P. Dilworth, R.K. Rajakulasingum
Journal: European Respiratory Journal (2004)

There is little data about the use of different oxygen sources during assessment for long-term oxygen therapy (LTOT) and how this impacts upon blood oxygen tensions and prescribed flow rates. Patients with chronic obstructive pulmonary disease (COPD), n=30, had assessments for LTOT using both an oxygen-concentrator and piped hospital oxygen (wall-oxygen) as supply sources. In addition, a random survey of 64 hospitals was conducted to determine what source of oxygen supply was used during assessments. Wall-oxygen was used by 89% of hospitals to perform assessments. During assessments, the median oxygen flow required to achieve an arterial oxygen tension ( P a,O 2 ) &gt;8 kPa was significantly greater for an oxygen-concentrator than for wall-oxygen, with a median difference (range) in flow of 1 (0–3) L. This difference was most likely in those with an forced expiratory volume &lt;30% of predicted. At an oxygen flow of 1 L·min −1 , the mean P a,O 2 using an oxygen-concentrator was significantly lower than that of the wall-oxygen value, with a difference of 1.32±1.19 kPa (mean± sd ). The common practice of using wall-oxygen to perform assessments significantly underestimates the required oxygen-concentrator flow rate. This may have implications for the long-term effect of domiciliary oxygen therapy.
Comparative Evolutionary Analysis of the Major Structural Subunit of Vibrio vulnificus Type IV Pili
Authors: S. Chattopadhyay, R. N. Paranjpye, D. E. Dykhuizen, E. V. Sokurenko, M. S. Strom
Journal: Molecular Biology and Evolution (2009)

Type IV pili contribute to virulence in Vibrio vulnificus, the bacterium responsible for the majority of fatal seafood-related infections. Here, we performed within- and between-species evolutionary analysis of the gene that encodes the major structural subunit of the pilus, pilA, by comparing it with pilD and gyrB, the genes encoding the type IV prepilin peptidase and beta subunit of DNA gyrase, respectively. Although the diversity in pilD and gyrB is similar to each other and likely to have accumulated after speciation of V. vulnificus, pilA is several times more diverse at both nonsynonymous and synonymous levels. Also, in contrast to pilD and gyrB, there are virtually unrestricted and highly localized horizontal movements of pilA alleles between the major phylogenetic groups of V. vulnificus. The frequent movement of pilA involves homologous recombination of the entire gene with no evidence for intragenic recombination between the alleles. We propose that pilA allelic diversity and horizontal movement is maintained in the population by both diversifying and frequency-dependent selection most likely to escape shellfish innate immunity defense or lytic phages. Other possibilities leading to such selection dynamics of V. vulnificus pilA could involve adaptation to diverse host populations or within-host compartments, or natural DNA uptake and transformation. We show that the history of nucleotide diversification in pilA predates V. vulnificus speciation and this diversification started at or before the time of the last common ancestor for V. vulnificus, Vibrio parahaemolyticus, and Vibrio cholerae. At the same time, it appears that within the various pilA groups of V. vulnificus, there is no positive selection for structural mutations and consequently no evidence for source-sink selection. In contrast, pilD has accumulated a number of apparently adaptive mutations in the regions encoding the membrane-spanning portions of the prepilin peptidase, possibly affecting fimbrial expression and/or function, and is being subjected to source-sink selection dynamics.
A solitary amyloid nodule in the lung
Authors: M. R. Chaudhuri, D. J. Parker
Journal: Thorax (1970)

Solitary primary amyloid nodule of the lung is rare. Only eight cases have been reported. Our patient was a 66-year-old retired furnaceman who had an asymptomatic, smooth, round shadow in the right lower lobe, discovered accidentally on routine chest radiography. Right lower lobectomy was performed and a firm round nodule was found in the lateral basal segment. Its cut surface had a yellow-grey tinge and stained mahogany brown with Lugol9s iodine. Microscopically the nodule consisted of uniformly eosinophilic-staining material with scattered multi-nucleate giant cells and groups of lymphocytes, plasma cells, and mononuclear cells at the edge. As the material stained with Congo red and gave typical greenish birefringence under polarized light it was evidently amyloid.
Pulmonary sarcoidosis: excess of helper T lymphocytes and T cell subset imbalance at sites of disease activity.
Authors: G A Rossi, O Sacco, E Cosulich, G Damiani, G Corte, A Bargellesi, C Ravazzoni
Journal: Thorax (1984)

Different lymphocyte subpopulations have been evaluated in bronchoalveolar fluid and blood obtained from six patients with active and six with inactive pulmonary sarcoidosis and from six normal subjects by means of two recently described monoclonal antibodies, 5/9 and MLR4. The percentages of OKT4 positive (helper) and OKT8 positive (suppressor) T cells were also determined. Patients with active sarcoidosis had significantly higher proportions of 5/9 positive T cells in the bronchoalveolar fluid than patients with inactive disease (p less than 0.01) or normal subjects (p less than 0.001). In contrast, the proportions of 5/9 positive blood T cells were similar in the three groups studied. Patients with active sarcoidosis had also a greater proportion proportion of MLR4 positive T lymphocytes in bronchoalveolar fluid than patients with inactive disease or normal subjects (p less than 0.01 for each comparison), but similar proportions of MLR4 positive blood T cells were found in each group. The ratio of 5/9 positive to MLR4 positive T cells was higher in the bronchoalveolar fluid (but not in the blood) in patients with either active or inactive sarcoidosis than in normal subjects. These observations suggest that the MLR4 negative fraction rather than the MLR4 positive fraction of the 5/9 positive T cells is preferentially expanded in the lungs of patients with pulmonary sarcoidosis and may indicate a secondary role for the MLR4 positive T cells in producing lung injury in this disorder. Comparisons of the OKT4 positive and 5/9 positive T cells showed that in patients with active disease most of the lung T lymphocytes expressed both the OKT4 and the 5/9 surface antigens, so the 5/9 monoclonal antibody may be considered a good marker of activity in this disorder. Pulmonary sarcoidosis may be characterised by the preferential expansion of helper T cell subsets at sites of disease activity.
Small airways: a time to revisit?
Authors: D. J EVANS, M. GREEN
Journal: Thorax (1998)

The branching network of airways in the lung poses a complex challenge to both physiologists and physicians. Measurements of lung function have been made for nearly 200 years. Davy (1800) and Hutchinson (1844) were amongst the first to recognise and measure lung volumes. Despite these early discoveries, progress in understanding pulmonary physiology was intermittent. Rohrer (1925) and Rahn (1946) established the concepts of pressure and volume relationships in the lung and Rohrer alluded to the possibility of volume dependent airways resistance, although he did not live long enough to make these measurements himself.1 2 In fact, it was not until the 1960s that the issue of airways resistance was resolved and the distinction drawn between the large and small airways.3 4Small airways are usually defined as those airways of less than 2 mm internal diameter and equate to generations 12–23 of Weibel’s model of lung architecture.3 Although the small airways are themselves tiny, the dichotomously branching pattern of the tracheobronchial tree results in increasingly large numbers of airways in peripheral generations. This results in very low resistance of each generation of small airways, so that in total they contribute only about 10% of the total airway resistance of the tracheobronchial tree.5 6 Thus, most of the small airways can be damaged or destroyed before symptoms occur and before any of the conventional tests of lung function, in particular measurements of airway resistance, show loss of function. This led …
START Trial
Authors: Niels van Royen, Stephan H. Schirmer, Bektas Atasever, Casper Y.H. Behrens, Dirk Ubbink, Eva E. Buschmann, Michiel Voskuil, Pieter Bot, Imo Hoefer, Reinier O. Schlingemann, Bart J. Biemond, J.G. Tijssen, Christoph Bode, Wolfgang Schaper, Jacques Oskam, Dink A. Legemate, Jan J. Piek, Ivo Buschmann
Journal: Circulation (2005)

Granulocyte-macrophage colony-stimulating factor (GM-CSF) was recently shown to increase collateral flow index in patients with coronary artery disease. Experimental models showed beneficial effects of GM-CSF on collateral artery growth in the peripheral circulation. Thus, in the present study, we evaluated the effects of GM-CSF in patients with peripheral artery disease.A double-blinded, randomized, placebo-controlled study was performed in 40 patients with moderate or severe intermittent claudication. Patients were treated with placebo or subcutaneously applied GM-CSF (10 microg/kg) for a period of 14 days (total of 7 injections). GM-CSF treatment led to a strong increase in total white blood cell count and C-reactive protein. Monocyte fraction initially increased but thereafter decreased significantly as compared with baseline. Both the placebo group and the treatment group showed a significant increase in walking distance at day 14 (placebo: 127+/-67 versus 184+/-87 meters, P=0.03, GM-CSF: 126+/-66 versus 189+/-141 meters, P=0.04) and at day 90. Change in walking time, the primary end point of the study, was not different between groups. No change in ankle-brachial index was found on GM-CSF treatment at day 14 or at day 90. Laser Doppler flowmetry measurements showed a significant decrease in microcirculatory flow reserve in the control group (P=0.03) and no change in the GM-CSF group.The present study does not support the use of GM-CSF for treatment of patients with moderate or severe intermittent claudication. Issues that need to be addressed are dosing, the selection of patients, and potential differences between GM-CSF effects in the coronary and the peripheral circulation.
Surfactant apoprotein A modulates interleukin-8 and monocyte chemotactic peptide-1 production
Authors: F. Meloni, A. Alberti, A. Bulgheroni, A. Lupi, E. Paschetto, A. Marone Bianco, G. Rodi, A. Fietta, M. Luisetti, A. Baritussio
Journal: European Respiratory Journal (2002)

Previous studies have shown that surfactant apoprotein A (SP-A) and natural or synthetic surfactant can modulate the release of pro-inflammatory cytokines from alveolar mononuclear phagocytes. The aim of this study was to assess whether SP-A or Surfactant (Surf) from patients with pulmonary alveolar proteinosis (PAP) can affect the release of two chemokines (interleukin (IL)-8 and monocyte chemtactic peptide (MCP)-1) from human monocytes and rat lung type-II cells. In addition IL-8 and MCP-1 levels were assessed in the brochoalveolar lavage fluid (BALF) of seven patients with PAP and compared with those in a group of control subjects (n=5). SP-A, tested over a wide range of concentrations, significantly increased IL-8 and MCP-1 release from monocytes. SP-A retained its activity after collagenase digestion, but was not active after heat treatment. The release of IL-8 by monocytes was also stimulated by Surf. Finally, median BALF IL-8 and MCP-1 levels in PAP patients were significantly higher than in controls (9.50 and 9.51 pg·mL −1 in controls versus 151.95 and 563.70 pg·mL −1 in PAP, respectively) and significantly correlated with SP-A concentrations in BALF. Overall the results of this study support the view that the high content of alveolar surfactant apoprotein A may contribute to the upregulation of chemokine release in pulmonary alveolar proteinosis, thus contributing to airway inflammation.
From transcriptome analysis to therapeutic anti-CD40L treatment in the SOD1 model of amyotrophic lateral sclerosis
Authors: John M Lincecum, Fernando G Vieira, Monica Z Wang, Kenneth Thompson, Gerald S De Zutter, Joshua Kidd, Andrew Moreno, Ricardo Sanchez, Isarelis J Carrion, Beth A Levine, Bashar M Al-Nakhala, Shawn M Sullivan, Alan Gill, Steven Perrin
Journal: Nature Genetics (2010)
Insulin-Sensitizing Antihyperglycemic Drugs and Mortality After Acute Myocardial Infarction
Authors: Silvio E. Inzucchi, Frederick A. Masoudi, Yongfei Wang, Mikhail Kosiborod, Joanne M. Foody, John F. Setaro, Edward P. Havranek, Harlan M. Krumholz
Journal: Diabetes Care (2005)

OBJECTIVE—Thiazolidinediones (TZDs) and metformin are insulin-sensitizing antihyperglycemic agents with reported benefits on atherosclerosis. Despite extensive use in patients with diabetes and cardiovascular disease, there is a paucity of outcomes data with metformin and none yet with TZDs. We sought to determine the impact of these insulin sensitizers on outcomes in diabetic patients after hospitalization with acute myocardial infarction (AMI). RESEARCH DESIGN AND METHODS—We conducted a retrospective cohort study of 24,953 Medicare beneficiaries with diabetes discharged after hospitalization with AMI between April 1998 and March 1999 or July 2000 and June 2001. The independent association between discharge prescription for metformin, TZD, or both agents and outcomes at 1 year was assessed in multivariable Cox proportional hazards models, adjusting for patient, physician, and hospital variables. The primary outcome was time to death within 1 year of discharge; secondary outcomes were time to first rehospitalization within 1 year of discharge for AMI, heart failure, and all causes. RESULTS—There were 8,872 patients discharged on an antihyperglycemic agent, of which 819 were prescribed a TZD, 1,273 metformin, and 139 both drugs. After multivariable analysis, compared with patients prescribed an antihyperglycemic regimen that included no insulin sensitizer, mortality rates were not significantly different in patients treated with either metformin (hazard ratio [HR] 0.92 [95% CI 0.81–1.06]) or a TZD (0.92 [0.80–1.05]) but were lower in those prescribed both drugs (0.52 [0.34–0.82]). The results were similar among patients with heart failure. The prescription of a TZD was associated with a borderline higher risk of all-cause readmission (1.09[1.00–1.20]), predominately due to a higher risk for heart failure readmission (1.17 [1.05–1.30]). CONCLUSIONS—Individually, prescription of insulin-sensitizing drugs is not associated with a significantly different risk of death in older diabetic patients within 1 year following AMI compared with other antihyperglycemic agents. Combined, however, metformin and TZDs may exert benefit. TZD prescription is associated with a higher risk of readmission for heart failure after myocardial infarction.
Activity Patterns of Patients With Diabetic Foot Ulceration
Authors: David G. Armstrong, Lawrence A. Lavery, Heather R. Kimbriel, Brent P. Nixon, Andrew J.M. Boulton
Journal: Diabetes Care (2003)

To evaluate the activity of patients with diabetic foot ulcerations and their adherence to their pressure off-loading device.We enrolled 20 subjects treated for neuropathic diabetic foot wounds corresponding to University of Texas grade 1 stage A. All were off-loaded using a removable cast walker (RCW). We recorded the total activity (measured in activity steps per day) taken on a waist-worn computerized accelerometer. We subsequently correlated this to activity recorded on an RCW-mounted accelerometer, which was not readily accessible to the patient.There were a mean 1219.1 +/- 821.2 activity units (steps) taken per patient per day. Patients logged significantly more daily activity units with the protective RCW off than with it on (873.7 +/- 828.0 vs. 345.3 +/- 219.1, P = 0.01). This amounts to only 28% of total daily activity recorded while patients were wearing their RCW. Although a total of 30% of the patients in the study recorded more daily activity units while wearing the device, this subset most adherent to their off-loading regimen still only wore the device for a total of 60% of their total daily activity.Subjects with diabetic foot ulcerations appear to wear their off-loading devices for only a minority of steps taken each day. This may partially explain the poor results reported from many trials of agents designed to help speed the healing of these wounds. Control of this important aspect of care with less easily removable devices may increase the prevalence of healing.
Permanent Alteration of PCSK9 With In Vivo CRISPR-Cas9 Genome Editing
Authors: Qiurong Ding, Alanna Strong, Kevin M. Patel, Sze-Ling Ng, Bridget S. Gosis, Stephanie N. Regan, Chad A. Cowan, Daniel J. Rader, Kiran Musunuru
Journal: Circulation Research (2014)

Individuals with naturally occurring loss-of-function proprotein convertase subtilisin/kexin type 9 (PCSK9) mutations experience reduced low-density lipoprotein cholesterol levels and protection against cardiovascular disease.
Management of asthma in patients supervised by primary care physicians or by specialists
Authors: L. Laforest, E. Van Ganse, G. Devouassoux, S. Chretin, L. Osman, G. Bauguil, Y. Pacheco, G. Chamba
Journal: European Respiratory Journal (2005)

French asthma patients may be supervised by general practitioners (GPs) and/or specialists. Therefore, this study examined asthma management in patients exclusively supervised by specialists (SPE), GPs, (GP) and both (GP+SPE group), and compared the findings. Asthma patients were consecutively recruited in 348 pharmacies. Each patient completed a questionnaire providing data on personal characteristics, asthma management, perception of disease and asthma supervision. Asthma control was measured using the Asthma Control Test. Questionnaires were linked to computerised records of medications which had been dispensed before inclusion in the study. From the 1,256 patients (mean age = 36.1 yrs, 54.3% females), 11.4, 36.6, and 52.0% were placed in the SPE, GP, and GP+SPE groups, respectively. During the previous 4 weeks, most patients in the SPE group were properly controlled (52.2 versus 26.4 and 21.5% in GP and GP+SPE groups, respectively). The SPE group made more use of fixed combinations of long-acting beta agonist and inhaled corticosteroid, while receiving less short-acting beta agonists, antitussives and antibiotics. Striking differences in symptoms and asthma management were observed according to the type of asthma supervision. The current results strongly support the need to improve the management of asthma in primary care, and the coordination of care between general practitioners and specialists.
Periostin promotes renal cyst growth and interstitial fibrosis in polycystic kidney disease
Authors: Darren P. Wallace, Corey White, Lyudmyla Savinkova, Emily Nivens, Gail A. Reif, Cibele S. Pinto, Archana Raman, Stephen C. Parnell, Simon J. Conway, Timothy A. Fields
Journal: Kidney International (2013)
The Efficacy of “Distant Healing”
Authors: John A. Astin, Elaine Harkness, Edzard Ernst
Journal: Annals of Internal Medicine (2000)

Purpose: To conduct a systematic review of the available data on the efficacy of any form of "distant healing" (prayer, mental healing, Therapeutic Touch, or spiritual healing) as treatment for any medical condition. Data Sources: Studies were identified by an electronic search of the MEDLINE, PsychLIT, EMBASE, CISCOM, and Cochrane Library databases from their inception to the end of 1999 and by contact with researchers in the field. Study Selection: Studies with the following features were included: random assignment, placebo or other adequate control, publication in peer-reviewed journals, clinical (rather than experimental) investigations, and use of human participants. Data Extraction: Two investigators independently extracted data on study design, sample size, type of intervention, type of control, direction of effect (supporting or refuting the hypothesis), and nature of the outcomes. Data Synthesis: A total of 23 trials involving 2774 patients met the inclusion criteria and were analyzed. Heterogeneity of the studies precluded a formal meta-analysis. Of the trials, 5 examined prayer as the distant healing intervention, 11 assessed noncontact Therapeutic Touch, and 7 examined other forms of distant healing. Of the 23 studies, 13 (57%) yielded statistically significant treatment effects, 9 showed no effect over control interventions, and 1 showed a negative effect. Conclusions: The methodologic limitations of several studies make it difficult to draw definitive conclusions about the efficacy of distant healing. However, given that approximately 57% of trials showed a positive treatment effect, the evidence thus far merits further study.
Renal Organogenesis from Transplanted Metanephric Primordia
Authors: Marc R. Hammerman
Journal: Journal of the American Society of Nephrology (2004)

ABSTRACT. One novel solution to the shortage of human organs available for transplantation envisions growing new organs <i>in situ</i> via xenotransplantation of developing primordia from animal embryos. It has been shown that renal primordia (metanephroi) transplanted into animal hosts undergo organogenesis <i>in situ</i>, become vascularized by blood vessels of host origin, and exhibit excretory function. Metanephroi can be stored for up to 3 d <i>in vitro</i> before transplantation with no impairment in growth or function post-implantation. Metanephroi can be transplanted across both concordant (rat to mouse) and highly disparate (pig to rodent) xenogeneic barriers. This is a review of studies exploring the therapeutic potential for renal organogenesis posttransplantation of kidney primordia.