tbuckley/cabot-search huggingface dataset:
Assessment of problematic severe asthma in children
Authors: K. C. Lodrup Carlsen, G. Hedlin, A. Bush, G. Wennergren, F. M. de Benedictis, J. C. De Jongste, E. Baraldi, C. Pedroletti, A. Barbato, K. Malmstrom, P. Pohunek, S. Pedersen, G. L. Piacentini, R. J. M. Middelveld, K. H. Carlsen
Journal: European Respiratory Journal (2010)

Assessment of problematic severe asthma in children should be performed in a step-wise manner to ensure an optimal approach. A four-step assessment scheme is proposed. First, a full diagnostic work-up is performed to exclude other diseases which mimic asthma. Secondly, a multi-disciplinary assessment is performed to identify issues that may need attention, including comorbidities. Thirdly, the pattern of inflammation is assessed, and finally steroid responsiveness is documented. Based upon these four steps an optimal individualised treatment plan is developed. In this article the many gaps in our current knowledge in all these steps are highlighted, and recommendations for current clinical practice and future research are made. The lack of good data and the heterogeneity of problematic severe asthma still limit our ability to optimise the management on an individual basis in this small, but challenging group of patients.
High Levels of a Major Histocompatibility Complex II–Self Peptide Complex on Dendritic Cells from the T Cell Areas of Lymph Nodes
Authors: Kayo Inaba, Maggie Pack, Muneo Inaba, Hiraki Sakuta, Frank Isdell, Ralph M. Steinman
Journal: The Journal of Experimental Medicine (1997)

T lymphocytes recirculate continually through the T cell areas of peripheral lymph nodes. During each passage, the T cells survey the surface of large dendritic cells (DCs), also known as interdigitating cells. However, these DCs have been difficult to release from the lymph node. By emphasizing the use of calcium-free media, as shown by Vremec et al. (Vremec, D., M. Zorbas, R. Scollay, D.J. Saunders, C.F. Ardavin, L. Wu, and K. Shortman. 1992. J. Exp. Med. 176:47–58.), we have been able to release and enrich DCs from the T cell areas. The DCs express the CD11c leukocyte integrin, the DEC-205 multilectin receptor for antigen presentation, the intracellular granule antigens which are recognized by monoclonal antibodies M342, 2A1, and MIDC-8, very high levels of MHC I and MHC II, and abundant accessory molecules such as CD40, CD54, and CD86. When examined with the Y-Ae monoclonal which recognizes complexes formed between I-Ab and a peptide derived from I-Eα, the T cell area DCs expressed the highest levels. The enriched DCs also stimulated a T-T hybridoma specific for this MHC II–peptide complex, and the hybridoma underwent apoptosis. Therefore DCs within the T cell areas can be isolated. Because they present very high levels of self peptides, these DCs should be considered in the regulation of self reactivity in the periphery.
Patient died after out of hours care firm ignored doctor's warnings
Authors: A. O'Dowd
Journal: BMJ (2010)

The out of hours company that employed the German locum Daniel Ubani, who killed a patient during his first shift in England, ignored a prior warning that it was a “matter of time” before a patient was killed by an overdose.

The regulator of the NHS, the Care Quality Commission, has published a highly critical report after investigating Take Care Now, the company that employed Dr Ubani at the time of the incident.

The investigation was triggered by the case of David Gray, a patient killed by an overdose of 100 mg diamorphine in February 2008. The drug was administered by Dr …
Retooling the Creatinine Clearance Equation to Estimate Kinetic GFR when the Plasma Creatinine Is Changing Acutely
Authors: Sheldon Chen
Journal: Journal of the American Society of Nephrology (2013)

It is often desirable to estimate the GFR (eGFR) at the bedside to assess AKI or renal recovery. Current eGFR equations estimate kidney function when the plasma creatinine is stable, but do not work if the plasma creatinine is changing rapidly. To analyze kidney function in the acute setting, a simple formula is proposed that requires only a modest number of inputs that are readily obtainable from clinical laboratory data. The so-called kinetic eGFR (KeGFR) formula is derived from the initial creatinine content, volume of distribution, creatinine production rate, and the quantitative difference between consecutive plasma creatinines over a given time. For that period, the deciphered creatinine excretion then yields the creatinine clearance rate. The additional formula variables needed are any steady-state plasma creatinine, the corresponding eGFR by an empirical formula, and the maximum increase in creatinine per day if anuric. The kinetic formula complements clinical intuition but also adds a quantitative and visual dimension to the assessment of kidney function, demonstrated by its analysis of GFRs underlying the plasma creatinine fluctuations in several scenarios of AKI or renal recovery. Deduced from first principles regarding the physiology of creatinine balance, the KeGFR formula enhances the fundamental clearance equation with the power and versatility to estimate the kidney function when the plasma creatinine is varying acutely.
Viral infection prevents diabetes by inducing regulatory T cells through NKT cell–plasmacytoid dendritic cell interplay
Authors: Julien Diana, Vedran Brezar, Lucie Beaudoin, Marc Dalod, Andrew Mellor, Anna Tafuri, Matthias von Herrath, Christian Boitard, Roberto Mallone, Agnès Lehuen
Journal: The Journal of Experimental Medicine (2011)

Type 1 diabetes (T1D) is an autoimmune disease resulting from T cell–mediated destruction of insulin-producing β cells, and viral infections can prevent the onset of disease. Invariant natural killer T cells (iNKT cells) exert a regulatory role in T1D by inhibiting autoimmune T cell responses. As iNKT cell–plasmacytoid dendritic cell (pDC) cooperation controls viral replication in the pancreatic islets, we investigated whether this cellular cross talk could interfere with T1D development during viral infection. Using both virus-induced and spontaneous mouse models of T1D, we show that upon viral infection, iNKT cells induce TGF-β–producing pDCs in the pancreatic lymph nodes (LNs). These tolerogenic pDCs convert naive anti-islet T cells into Foxp3+ CD4+ regulatory T cells (T reg cells) in pancreatic LNs. T reg cells are then recruited into the pancreatic islets where they produce TGF-β, which dampens the activity of viral- and islet-specific CD8+ T cells, thereby preventing T1D development in both T1D models. These findings reveal a crucial cooperation between iNKT cells, pDCs, and T reg cells for prevention of T1D by viral infection.
Strain-specific silencing of a predominant antidextran clonotype family.
Authors: B G Froscher, N R Klinman
Journal: The Journal of Experimental Medicine (1985)

The immune response to dextran is characterized by marked phenotypic differences among murine strains. In particular, Igha strains, as opposed to strains of other Igh haplotypes, respond relatively vigorously to dextran B1355 fraction S (DEX), producing predominantly antibodies bearing the lambda light chain, and specific for the alpha(1----3) glucose linkage. We have investigated this disparity in BALB/c (Igha) vs. C.B20 (Ighb) mice at the individual precursor cell level. Consistent with previous findings (7-9, 35, 40, 42, 43), there was a 10-fold higher frequency of lambda-bearing splenic B cells specific for the alpha(1----3) linkage in Igha mice. As with previously studied (25-27) predominant specificities, the origin of this high frequency of lambda-bearing alpha(1----3) DEX-specific B cells appears to be a reflection of a high expression of this specificity in surface Ig (sIg)-negative cells emerging from the bone marrow generative cell pool. Surprisingly, although C.B20 mice (Ighb) have a low frequency of lambda-bearing alpha(1----3) DEX-specific B cells in their mature primary splenic population, the frequency of precursor cells of this clonotype in their sIg- bone marrow cell population is equivalent to that of BALB/c sIg- cells. These cells could only be stimulated in allotype allogeneic (Igha), as opposed to allotype syngeneic (Ighb), carrier-primed irradiated recipients. This finding was confirmed by the finding that a high proportion of antidextran hybridoma cell lines derived from C.B20 bone marrow cells produced lambda-bearing alpha(1----3) DEX-specific antibodies that were IdX+. These findings have led us to conclude that the well-established phenotypic difference between Igha and Ighb mice with respect to the expression of lambda-bearing alpha(1----3) DEX-specific antibody responses is not, as previously assumed, the result of an inability of Ighb mice to generate B cells of this clonotype, but rather, is the product of environmental, possibly antiidiotypic, silencing of cells of this clonotype as they mature in Ighb mice.
Apparent lack of 2 adrenergic receptors in porcine myocardium
Authors: R. BJORNERHEIM, S. GOLF, V. HANSSON
Journal: Cardiovascular Research (1989)

The aim of this study was to investigate the relative numbers of myocardial beta 1 and beta 2 receptors in pigs. Membrane particles from left ventricular porcine and mixed ventricular rat myocardium were examined for subtypes of beta adrenergic receptors with a radioligand binding technique using [125I]-cyanopindolol (ICYP) as trace, and the new highly beta 1 selective antagonist Sandoz 204 545 and the beta 2 selective antagonist ICI 118 551 for displacement. Radioligand displacement experiments were also performed using propranolol, isoprenaline and terbutaline. The displacement curves obtained with the subtype selective antagonists and agonist revealed biphasic inhibition of specific ICYP binding in rat preparations, indicating a beta 1/beta 2 ratio of approximately 2/1. In porcine preparations displacement of specific ICYP binding with all agents resulted in monophasic curves, thus sharply contrasting the rat preparations. Affinity constants of displacing drugs derived from these monophasic curves indicated that the specific binding site was a beta 1 receptor. No displacement compatible with beta 2 affinity was found. In the same rat preparations we found that adenylate cyclase activation and inhibition by beta receptor subtype specific agonists and antagonists were mediated by two receptor subtypes, whereas in the pig, adenylate cyclase activation and its inhibition seemed to occur via only one receptor subtype, the beta 1 adrenoceptor.
Side-effect of Phenindione
Authors: I. M. Baird
Journal: BMJ (1963)

EDICALJOURNASide-effect of Phenindione SIR,-I would like to bring to the attention of other physicians a brownish-yellow discoloration of the finger- nails which became evident in one of my patients who was treated with long-term anticoagulants for coronary disease.This patient was started on phenindione in April, 1962, and put on a long-term maintenance dose on May 2, 1962, but in August, 1962, he noted that the peripheral third of every finger-nail in the hands had become brownish-yellow in colour, and this has persisted up to the present date.He is still on a maintenance therapy of "dindevan " (phenindione) 75 mg.daily.I would be very interested to learn if other physicians have noted this unusual side-effect of phenindione.-
Nonlinear Dynamics in Cardiology
Authors: Trine Krogh-Madsen, David J. Christini
Journal: Annual Review of Biomedical Engineering (2012)

The dynamics of many cardiac arrhythmias, as well as the nature of transitions between different heart rhythms, have long been considered evidence of nonlinear phenomena playing a direct role in cardiac arrhythmogenesis. In most types of cardiac disease, the pathology develops slowly and gradually, often over many years. In contrast, arrhythmias often occur suddenly. In nonlinear systems, sudden changes in qualitative dynamics can, counterintuitively, result from a gradual change in a system parameter-this is known as a bifurcation. Here, we review how nonlinearities in cardiac electrophysiology influence normal and abnormal rhythms and how bifurcations change the dynamics. In particular, we focus on the many recent developments in computational modeling at the cellular level that are focused on intracellular calcium dynamics. We discuss two areas where recent experimental and modeling work has suggested the importance of nonlinearities in calcium dynamics: repolarization alternans and pacemaker cell automaticity.
Thyroid Hormone Inhibition of the Prolactin Response to Thyrotropin-Releasing Hormone
Authors: Peter J. Snyder, Laurence S. Jacobs, Robert D. Utiger, William H. Daughaday
Journal: Journal of Clinical Investigation (1973)

The influence of serum triiodothyronine (T3) and thyroxine (T4) concentrations on the release of prolactin in man was studied by determining the prolactin response to synthetic thyrotropin-releasing hormone (TRH) in hypothyroid and hyperthyroid patients before and after correction of their serum thyroid hormone abnormalities. The maximum increment in serum prolactin above the basal level (maximum Δ prolactin) was used as the index of response to TRH.
Not All Side Effects Associated With Tricyclic Antidepressant Therapy Are True Side Effects
Authors: Syed Thiwan, Douglas A. Drossman, Carolyn B. Morris, Chris Dalton, Brenda B. Toner, Nicholas E. Diamant, J.B. Hu, William E. Whitehead, Jane Leserman, Shrikant I. Bangdiwala
Journal: Clinical Gastroenterology and Hepatology (2008)
β-Adrenergic Regulation of Cardiac Progenitor Cell Death Versus Survival and Proliferation
Authors: Mohsin Khan, Sadia Mohsin, Daniele Avitabile, Sailay Siddiqi, Jonathan Nguyen, Kathleen Wallach, Pearl Quijada, Michael McGregor, Natalie Gude, Roberto Alvarez, Douglas G. Tilley, Walter J. Koch, Mark A. Sussman
Journal: Circulation Research (2012)

Short-term β-adrenergic stimulation promotes contractility in response to stress but is ultimately detrimental in the failing heart because of accrual of cardiomyocyte death. Endogenous cardiac progenitor cell (CPC) activation may partially offset cardiomyocyte losses, but consequences of long-term β-adrenergic drive on CPC survival and proliferation are unknown.We sought to determine the relationship between β-adrenergic activity and regulation of CPC function.Mouse and human CPCs express only β2 adrenergic receptor (β2-AR) in conjunction with stem cell marker c-kit. Activation of β2-AR signaling promotes proliferation associated with increased AKT, extracellular signal-regulated kinase 1/2, and endothelial NO synthase phosphorylation, upregulation of cyclin D1, and decreased levels of G protein-coupled receptor kinase 2. Conversely, silencing of β2-AR expression or treatment with β2-antagonist ICI 118, 551 impairs CPC proliferation and survival. β1-AR expression in CPC is induced by differentiation stimuli, sensitizing CPC to isoproterenol-induced cell death that is abrogated by metoprolol. Efficacy of β1-AR blockade by metoprolol to increase CPC survival and proliferation was confirmed in vivo by adoptive transfer of CPC into failing mouse myocardium.β-adrenergic stimulation promotes expansion and survival of CPCs through β2-AR, but acquisition of β1-AR on commitment to the myocyte lineage results in loss of CPCs and early myocyte precursors.
Quantification of circulating endothelial progenitor cells in systemic sclerosis: a direct comparison of protocols
Authors: Masataka Kuwana, Yuka Okazaki
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Background</h3> It has been proposed that dysfunctional endothelial progenitor cells (EPCs) play a role in pathogenic vasculopathy in systemic sclerosis (SSc). However, there is some debate as to whether the EPC count is reduced in SSc. The European League Against Rheumatism Scleroderma Trials and Research (EUSTAR) group recently proposed recommendations for evaluating EPCs. <h3>Objective</h3> To validate the proposed EUSTAR recommendations by a side-by-side comparison of methods for quantifying EPCs. <h3>Methods</h3> Peripheral blood samples were obtained from 11 patients with SSc and 11 age-matched healthy controls. EPCs were simultaneously quantified by two methods: flow cytometry combined with immunomagnetic CD34+ cell enrichment or rosette-based lineage-negative (Lin−) cell enrichment. EPCs, defined as CD34+CD133+VEGFR2+ cells, were counted with and without fluorosphere calibration. <h3>Results</h3> EPC counts measured with fluorosphere calibration correlated well with each other, regardless of the enrichment procedure used. In contrast, EPC counts from protocols that did not use fluorospheres correlated poorly with results from other protocols. <h3>Conclusions</h3> The EUSTAR recommendations are valid when they are combined with fluorosphere calibration.
Maintenance therapy with budesonide and formoterol in chronicobstructive pulmonary disease
Authors: P.M. Calverley, W. Boonsawat, Z. Cseke, N. Zhong, S. Peterson, H. Olsson
Journal: European Respiratory Journal (2003)

Lung function in chronic obstructive pulmonary disease (COPD) can be improved acutely by oral corticosteroids and bronchodilators. Whether clinical improvement can be maintained by subsequent inhaled therapy is unknown. COPD patients (n=1,022, mean prebronchodilator forced expiratory volume in one second (FEV 1 ) 36% predicted) initially received formoterol (9 µg b.i.d. ) and oral prednisolone (30 mg o.d. ) for 2 weeks. After this time, patients were randomised to b.i.d. inhaled budesonide/formoterol 320/9 µg, budesonide 400 µg, formoterol 9 µg or placebo for 12 months. Postmedication FEV 1 improved by 0.21 L and health-related quality of life using the St George's Respiratory Questionnaire (SGRQ) by 4.5 units after run-in. Fewer patients receiving budesonide/formoterol withdrew from the study than those receiving budesonide, formoterol or placebo. Budesonide/formoterol patients had a prolonged time to first exacerbation (254 versus 96 days) and maintained higher FEV 1 (99% versus 87% of baseline), both primary variables versus placebo. They had fewer exacerbations (1.38 versus 1.80 exacerbations per patient per year), had higher prebronchodilator peak expiratory flow, and showed clinically relevant improvements in SGRQ versus placebo (−7.5 units). Budesonide/formoterol was more effective than either monocomponent in both primary variables. Budesonide/formoterol in a single inhaler (Symbicort®) maintains the benefit of treatment optimisation, stabilising lung function and delaying exacerbations more effectively than either component drug alone or placebo.
Disulfide Bond Acquisition through Eukaryotic Protein Evolution
Authors: Jason W. H. Wong, Simon Y. W. Ho, Philip J. Hogg
Journal: Molecular Biology and Evolution (2010)

Disulfide bonds play critical roles in protein stability and function. They are generally considered to be strongly conserved among species. Although there is compelling evidence in the literature for this conservation on a case-by-case basis, comparative genomic analyses of disulfide conservation have in the past been limited. By analyzing the conservation of all structurally validated disulfide bonds from the Protein Data Bank across 29 completely sequenced eukaryotic genomes, we observe elevated conservation of disulfide-bonded cysteines (half-cystines) compared with unpaired cysteines and other amino acids. Remarkably, half-cystines are even more conserved than tryptophan—the most conserved amino acid. Overall, once disulfide bonds are acquired in proteins, they are rarely lost. Moreover, the acquisition of disulfide bonds shows a strong positive correlation (R2 = 0.74) with organismal complexity. Although the correlation weakens (R2 = 0.59) when yeast is excluded from the analysis, this trend is still apparent when compared with the slightly negative correlation of unpaired cysteine acquisition with organismal complexity. The accrual of disulfide bonds is likely to reflect the demand for greater sophistication in protein function in complex species. Our findings provide further support for the increasing usage of cysteines in modern proteomes and suggest that there has been positive selection for disulfide bonds through eukaryotic evolution. Finally, we show that the acquisition of the functionally relevant disulfide bond in domain 2 of the CD4 protein occurred independently in primates and rodents.
Anaplastic Wilms' tumor: clinical and pathologic studies.
Authors: J F Bonadio, B Storer, P Norkool, V T Farewell, J B Beckwith, G J D'Angio
Journal: Journal of Clinical Oncology (1985)

A review of almost 1,200 children participating in the first and second National Wilms' Tumor Study (NWTS-1 and -2) has demonstrated a number of significant differences in the clinical presentation and response to therapy of anaplastic and nonanaplastic Wilms' tumor. Compared to their counterparts, children with anaplastic Wilms' tumor were generally one to two years older at diagnosis, more were non-white, and more had lymph node metastases at diagnosis. Consistent with previous studies, children with anaplastic Wilms' tumor survived for a significantly shorter time than those with non-anaplastic Wilms' tumor. A hopeful outlook, however, was suggested by the NWTS-2 experience since the more aggressive chemotherapies used in this study appear to have substantially improved the survival of patients with diffusely anaplastic tumors. Also, the survival of NWTS-2 patients with anaplastic Wilms' tumor was determined in part by clinicopathologic stage. It may be possible therefore to refine therapy according to stage so as to provide children with localized disease a chance for cure with fewer untoward treatment-related sequelae.
Montelukast as add-on therapy to inhaled corticosteroids in the treatment of mild to moderate asthma: a systematic review
Authors: S Joos, A Miksch, J Szecsenyi, B Wieseler, U Grouven, T Kaiser, A Schneider
Journal: Thorax (2008)

To systematically review the evidence for the medium to long term benefits and risks of montelukast as add-on therapy to inhaled corticosteroids (ICS) in comparison with placebo and active controls in mild to moderate asthma.Medline, Embase, Cochrane Register of Controlled Trials, reference lists of retrieved articles, clinical trial registries and study results databases.Systematic review of randomised controlled trials (duration > or = 12 weeks) in adolescents and adults comparing montelukast/ICS versus ICS monotherapy or montelukast/ICS versus active control/ICS. Meta-analyses were conducted where feasible. The main focus was on clinical outcomes (eg, exacerbations). Adverse events were also assessed.13 studies meeting all of the inclusion criteria were identified: 7 studies, including constant or tapered doses of ICS, compared montelukast/ICS with ICS monotherapy. Six studies compared add-on montelukast with an add-on active control (salmeterol). Overall, the data indicated that montelukast/ICS was clinically more effective than ICS monotherapy. The ICS sparing potential of montelukast was clearly demonstrated in one study. Montelukast/ICS and ICS monotherapy showed similar safety profiles. In the active controlled studies, montelukast/ICS was clinically less effective than salmeterol/ICS in the 12 week trials (pooled proportion of patients with > or = 1 exacerbation: p = 0.006). However, separate analysis of active controlled 48 week trials showed comparable proportions for patients with > or = 1 exacerbation in both groups.Montelukast as add-on therapy to ICS improves control of mild to moderate asthma compared with ICS monotherapy. Although the addition of salmeterol to ICS is clinically as effective as or even more effective than the addition of montelukast, montelukast may have a better long term safety profile and offer a treatment alternative for asthma patients.