tbuckley/cabot-search huggingface dataset:
Formoterol Restores Mitochondrial and Renal Function after Ischemia-Reperfusion Injury
Authors: Sean R. Jesinkey, Jason A. Funk, L. Jay Stallons, Lauren P. Wills, Judit K. Megyesi, Craig C. Beeson, Rick G. Schnellmann
Journal: Journal of the American Society of Nephrology (2014)

Mitochondrial biogenesis may be an adaptive response necessary for meeting the increased metabolic and energy demands during organ recovery after acute injury, and renal mitochondrial dysfunction has been implicated in the pathogenesis of AKI. We proposed that stimulation of mitochondrial biogenesis 24 hours after ischemia/reperfusion (I/R)-induced AKI, when renal dysfunction is maximal, would accelerate recovery of mitochondrial and renal function in mice. We recently showed that formoterol, a potent, highly specific, and long-acting β2-adrenergic agonist, induces renal mitochondrial biogenesis in naive mice. Animals were subjected to sham or I/R-induced AKI, followed by once-daily intraperitoneal injection with vehicle or formoterol beginning 24 hours after surgery and continuing through 144 hours after surgery. Treatment with formoterol restored renal function, rescued renal tubules from injury, and diminished necrosis after I/R-induced AKI. Concomitantly, formoterol stimulated mitochondrial biogenesis and restored the expression and function of mitochondrial proteins. Taken together, these results provide proof of principle that a novel drug therapy to treat AKI, and potentially other acute organ failures, works by restoring mitochondrial function and accelerating the recovery of renal function after injury has occurred.
Factors associated with toxicity, final dose, and efficacy of methotrexate in patients with rheumatoid arthritis
Authors: M Hoekstra
Journal: Annals of the Rheumatic Diseases (2003)

<b>Objective:</b> To study factors associated with toxicity, final dose, and efficacy of methotrexate (MTX) in patients with rheumatoid arthritis (RA). <b>Methods:</b> Data were used from a randomised clinical 48 week trial on 411 patients with RA all treated with MTX, comparing folates and placebo. Logistic regression was used to study the relation between baseline variables and various dependent factors, including hepatotoxicity (alanine aminotransferase ⩾3×upper limit of normal), MTX withdrawal, final MTX dose ⩾15 mg/week, and MTX efficacy. <b>Results:</b> Addition of folates to MTX treatment was strongly related to the lack of hepatotoxicity. Next to this, high body mass index was related to the occurrence of hepatotoxicity. Prior gastrointestinal (GI) events and younger age were related to the adverse event, diarrhoea. Hepatotoxicity and GI adverse events were the main reason for MTX withdrawal, which in turn was associated with the absence of folate supplementation, body mass index, prior GI events, and female sex. Renal function (creatinine clearance ⩾50 ml/min) was not associated with toxicity. Reaching a final dose of MTX of ⩾15 mg/week was related to folate supplementation and the absence of prior GI events. Efficacy of MTX treatment was associated with low disease activity at baseline, male sex, use of non-steroidal anti-inflammatory drugs (NSAIDs), and lower creatinine clearance. <b>Conclusions:</b> MTX toxicity, final dose, and efficacy are influenced by folate supplementation. Baseline characteristics predicting the outcome of MTX treatment are mainly prior GI events, body mass index, sex, use of NSAIDs, and creatinine clearance.
Aerosolized Ebola vaccine protects primates and elicits lung-resident T cell responses
Authors: Michelle Meyer, Tania Garron, Ndongala M. Lubaki, Chad E. Mire, Karla A. Fenton, Curtis Klages, Gene G. Olinger, Thomas W. Geisbert, Peter L. Collins, Alexander Bukreyev
Journal: Journal of Clinical Investigation (2015)

Direct delivery of aerosolized vaccines to the respiratory mucosa elicits both systemic and mucosal responses. This vaccine strategy has not been tested for Ebola virus (EBOV) or other hemorrhagic fever viruses. Here, we examined the immunogenicity and protective efficacy of an aerosolized human parainfluenza virus type 3–vectored vaccine that expresses the glycoprotein (GP) of EBOV (HPIV3/EboGP) delivered to the respiratory tract. Rhesus macaques were vaccinated with aerosolized HPIV3/EboGP, liquid HPIV3/EboGP, or an unrelated, intramuscular, Venezuelan equine encephalitis replicon vaccine expressing EBOV GP. Serum and mucosal samples from aerosolized HPIV3/EboGP recipients exhibited high EBOV-specific IgG, IgA, and neutralizing antibody titers, which exceeded or equaled titers observed in liquid recipients. The HPIV3/EboGP vaccine induced an EBOV-specific cellular response that was greatest in the lungs and yielded polyfunctional CD8+ T cells, including a subset that expressed CD103 (αE integrin), and CD4+ T helper cells that were predominately type 1. The magnitude of the CD4+ T cell response was greater in aerosol vaccinees. The HPIV3/EboGP vaccine produced a more robust cell-mediated and humoral immune response than the systemic replicon vaccine. Moreover, 1 aerosol HPIV3/EboGP dose conferred 100% protection to macaques exposed to EBOV. Aerosol vaccination represents a useful and feasible vaccination mode that can be implemented with ease in a filovirus disease outbreak situation.
New MLLT10 gene recombinations in pediatric T-acute lymphoblastic leukemia
Authors: Lucia Brandimarte, Valentina Pierini, Danika Di Giacomo, Chiara Borga, Filomena Nozza, Paolo Gorello, Marco Giordan, Giovanni Cazzaniga, Geertruy te Kronnie, Roberta La Starza, Cristina Mecucci
Journal: Blood (2013)
Normal lung function in infants with cystic fibrosis shortly after birth
Authors: Elisabeth Kieninger, Sophie Yammine, Elena Proietti, Carmen Casaulta, Nicolas Regamey, Urs Frey, Philipp Latzin
Journal: European Respiratory Journal (2013)

Background  In children with cystic fibrosis (CF) small airway disease can occur early in life.   Objective  To assess ventilation heterogeneity, a marker of small-airway function, shortly after birth in infants with CF diagnosed by newborn screening.   Methods  We performed multiple-breath washout (MBW) using 4% sulfur hexafluoride and tidal breathing measurements in 23 infants with CF, aged median (range) 6.3 (3.9 – 12.6) weeks and compared it to a previously reported equipment and tracer-gas specific normative data population of 305 healthy infants, aged median 5.0 (3.6 – 8.7) weeks (Fuchs et al, ERJ 2011). We compared lung clearance index (LCI), functional residual capacity (FRC) and the following tidal breathing parameters: Tidal volume, respiratory rate, minute ventilation, mean and peak tidal inspiratory and expiratory flow and the ratio of time to peak tidal expiratory flow to expiratory time.   Results  Compared to controls, and after adjustment for body weight and age, LCI was normal in infants with CF (mean difference (95% CI) 0.28 (-0.19 to 0.74) z-scores, p = 0.24), as was FRC (mean difference (95% CI) 0.40 (-0.05 to 0.85) z-scores, p = 0.08) and tidal breathing parameters. Only one infant with CF had elevated LCI (> 1.96 z-scores), while none showed elevated FRC.   Conclusions  CF infants show normal LCI values shortly after birth and thus no sign of ventilation inhomogeneity. The fact that all other parameters are also normal reflects the still undamaged state of the lungs. This highlights the importance of early therapy to maintain normal lung function as long as possible.
Cytokine Requirements for Acute and Basal Homeostatic Proliferation of Naive and Memory CD8+ T Cells
Authors: Ananda W. Goldrath, Pallavur V. Sivakumar, Moira Glaccum, Mary K. Kennedy, Michael J. Bevan, Christophe Benoist, Diane Mathis, Eric A. Butz
Journal: The Journal of Experimental Medicine (2002)

Both naive and memory T cells undergo antigen-independent proliferation after transfer into a T cell–depleted environment (acute homeostatic proliferation), whereas only memory T cells slowly divide in a full T cell compartment (basal proliferation). We show, first, that naive and memory CD8+ T cells have different cytokine requirements for acute homeostatic proliferation. Interleukin (IL)-7 receptor(R)α–mediated signals were obligatory for proliferation of naive T cells in lymphopenic hosts, whereas IL-15 did not influence their division. Memory T cells, on the other hand, could use either IL-7Rα– or IL-15–mediated signals for acute homeostatic proliferation: their proliferation was delayed when either IL-7Rα was blocked or IL-15 removed, but only when both signals were absent was proliferation ablated. Second, the cytokine requirements for basal and acute homeostatic proliferation of CD8+ memory T cells differ, as basal division of memory T cells was blocked completely in IL-15–deficient hosts. These data suggest a possible mechanism for the dearth of memory CD8+ T cells in IL-15– and IL-15Rα–deficient mice is their impaired basal proliferation. Our results show that naive and memory T lymphocytes differ in their cytokine dependence for acute homeostatic proliferation and that memory T lymphocytes have distinct requirements for proliferation in full versus empty compartments.
Rising trends in the prevalence of wheezing, rhinitis and eczema in 5- to 8- year old Maltese children over a decade (ISAAC - Malta)
Authors: Eleanor Gerada, Hugo Agius Muscat, Stephen Montefort
Journal: European Respiratory Journal (2014)

The prevalence of asthma, rhinitis and eczema has been increasing worldwide, as a result of which, these allergic conditions became some of the most common conditions of childhood. The International Study of Asthma and Allergies in Childhood (ISAAC) was the largest standardised worldwide epidemiological research programme ever undertaken on allergies in children.

The aim of our study was to investigate the current prevalence and severity of childhood allergic conditions in Malta, and analyze time trends by comparing the results with data obtained from phase 3 of the ISAAC study in 2001, in which Malta participated. The same validated standardized ISAAC questionnaire and protocol was used. Data was obtained from 3071 5- to 8-year-olds in 60 randomly sampled primary state schools over 2013 and 2014.52.4% were boys while 47.6% were girls. The trends in prevalence are shown in Table 1.

![Figure][1] 



These results indicate a rise in both the cumulative and current prevalence of wheezing, rhinitis and eczema in Maltese children over a span of 11 years. This has important implications in terms of: quality of life, economic burden and mortality.

 [1]: pending:yes
Electrophysiological Findings During Ablation of Persistent Atrial Fibrillation With Electroanatomic Mapping and Double Lasso Catheter Technique
Authors: Feifan Ouyang, Sabine Ernst, Julian Chun, Dietmar Bänsch, Yigang Li, Anselm Schaumann, Hercules Mavrakis, Xingpeng Liu, Florian T. Deger, Boris Schmidt, Yumei Xue, Jiang Cao, Detlef Hennig, He Huang, Karl-Heinz Kuck, Matthias Antz
Journal: Circulation (2005)

Pulmonary veins (PVs) can be completely isolated with continuous circular lesions (CCLs) around the ipsilateral PVs. However, electrophysiological findings have not been described in detail during ablation of persistent atrial fibrillation (AF).Forty patients with symptomatic persistent AF underwent complete isolation of the right-sided and left-sided ipsilateral PVs guided by 3D mapping and double Lasso technique during AF. Irrigated ablation was initially performed in the right-sided CCLs and subsequently in the left-sided CCLs. After complete isolation of both lateral PVs, stable sinus rhythm was achieved after AF termination in 12 patients; AF persisted and required cardioversion in 18 patients. In the remaining 10 patients, AF changed to left macroreentrant atrial tachycardia in 6 and common-type atrial flutter in 4 patients. All atrial tachycardias were successfully terminated during the procedure. Atrial tachyarrhythmias recurred in 15 of 40 patients at a median of 4 days after the initial ablation. A repeat ablation was performed at a median of 35 days after the initial procedure in 14 patients. During the repeat study, recovered PV conduction was found in 13 patients and successfully abolished by focal ablation of the conduction gap of the previous CCLs. After a mean of 8+/-2 months of follow-up, 38 (95%) of the 40 patients were free of AF.In patients with persistent AF, CCLs can result in either AF termination or conversion to macroreentrant atrial tachycardia in 55% of the patients. In addition, recovered PV conduction after the initial procedure is a dominant finding in recurrent atrial tachyarrhythmias and can be successfully abolished.
Correction of glutathione deficiency in the lower respiratory tract of HIV seropositive individuals by glutathione aerosol treatment.
Authors: K J Holroyd, R Buhl, Z Borok, J H Roum, A D Bokser, G J Grimes, D Czerski, A M Cantin, R G Crystal
Journal: Thorax (1993)

BACKGROUND--Concentrations of glutathione, a ubiquitous tripeptide with immune enhancing and antioxidant properties, are decreased in the blood and lung epithelial lining fluid of human immunodeficiency virus (HIV) seropositive individuals. Since the lung is the most common site of infection in those who progress to AIDS it is rational to consider whether it is possible to safely augment glutathione levels in the epithelial lining fluid of HIV seropositive individuals, thus potentially improving local host defence. METHODS--Purified reduced glutathione was delivered by aerosol to HIV seropositive individuals (n = 14) and the glutathione levels in lung epithelial lining fluid were compared before and at one, two, and three hours after aerosol administration. RESULTS--Before treatment total glutathione concentrations in the epithelial lining fluid were approximately 60% of controls. After three days of twice daily doses each of 600 mg reduced glutathione, total glutathione levels in the epithelial lining fluid increased and remained in the normal range for at least three hours after treatment. Strikingly, even though &gt; 95% of the glutathione in the aerosol was in its reduced form, the percentage of oxidised glutathione in epithelial lining fluid increased from 5% before treatment to about 40% three hours after treatment, probably reflecting the use of glutathione as an antioxidant in vivo. No adverse effects were observed. CONCLUSIONS--It is feasible and safe to use aerosolised reduced glutathione to augment the deficient glutathione levels of the lower respiratory tract of HIV seropositive individuals. It is rational to evaluate further the efficacy of this tripeptide in improving host defence in HIV seropositive individuals.
Preventing childhood obesity by reducing consumption of carbonated drinks: cluster randomised controlled trial
Authors: Janet James, Peter Thomas, David Cavan, David Kerr
Journal: BMJ (2004)

<h3>Abstract</h3> <b>Objective</b> To determine if a school based educational programme aimed at reducing consumption of carbonated drinks can prevent excessive weight gain in children. <b>Design</b> Cluster randomised controlled trial. <b>Setting</b> Six primary schools in southwest England. <b>Participants</b> 644 children aged 7-11 years. <b>Intervention</b> Focused educational programme on nutrition over one school year. <b>Main outcome measures</b> Drink consumption and number of overweight and obese children. <b>Results</b> Consumption of carbonated drinks over three days decreased by 0.6 glasses (average glass size 250 ml) in the intervention group but increased by 0.2 glasses in the control group (mean difference 0.7, 95% confidence interval 0.1 to 1.3). At 12 months the percentage of overweight and obese children increased in the control group by 7.5%, compared with a decrease in the intervention group of 0.2% (mean difference 7.7%, 2.2% to 13.1%). <b>Conclusion</b> A targeted, school based education programme produced a modest reduction in the number of carbonated drinks consumed, which was associated with a reduction in the number of overweight and obese children.
First trimester prenatal screening among women pregnant after IVF/ICSI
Authors: A. C. Gjerris, A. Tabor, A. Loft, M. Christiansen, A. Pinborg
Journal: Human Reproduction Update (2012)

Prenatal screening and diagnosis of chromosomal abnormalities especially Down's syndrome in IVF pregnancies are complicated by higher maternal age, a high multiple pregnancy rate, a high risk of a vanishing twin and an increased risk of chromosomal abnormalities, particularly in pregnancies after ICSI. The aim of the present systematic review was to evaluate the findings of first trimester screening for chromosomal abnormalities in IVF/ICSI singleton and twin pregnancies.A systematic MESH-term search in MEDLINE using PubMed and the Cochrane Library was performed until May 2011, with no earlier date limit.The electronic search retrieved 562 citations, 96 of which were evaluated in detail and 57 were then excluded for not meeting the selection criteria. A total of 61 articles were finally selected for review. Our analysis of the data shows that, for IVF/ICSI singletons, combined first trimester prenatal screening based on maternal age, nuchal translucency scan and biomarkers is appropriate. However, biomarkers seem to be altered, causing a higher false-positive rate, in IVF/ICSI singleton gestations. Correction factors have been developed and should be used when screening for Down's syndrome in singleton pregnancies. With regard to IVF/ICSI twin pregnancies, biomarker values seem to be dependent on chorionicity as well as gestational age. Whether the use of a correction factor for mode of conception in the risk calculations for Down's syndrome in twin pregnancies is valid has not been fully elucidated. In vanishing twin pregnancies with a second gestational sac with a dead fetus, first trimester screening should be based solely on the maternal age and the nuchal translucency scan as biomarkers are significantly altered in these cases.First trimester prenatal screening after IVF/ICSI treatment requires specific precautions in both singleton and twin pregnancies.
Treatment of murine lupus with cDNA encoding IFN-γR/Fc
Authors: Brian R. Lawson, Gerald J. Prud’homme, Yigang Chang, Humphrey A. Gardner, Jason Kuan, Dwight H. Kono, Argyrios N. Theofilopoulos
Journal: Journal of Clinical Investigation (2000)

IFN-gamma, a pleiotropic cytokine, is a key effector molecule in the pathogenesis of several autoimmune diseases, including lupus. Importantly, deletion of IFN-gamma or IFN-gammaR in several lupus-predisposed mouse strains resulted in significant disease reduction, suggesting the potential for therapeutic intervention. We evaluated whether intramuscular injections of plasmids with cDNA encoding IFN-gammaR/Fc can retard lupus development and progression in MRL-Fas(lpr) mice. Therapy significantly reduced serum levels of IFN-gamma, as well as disease manifestations (autoantibodies, lymphoid hyperplasia, glomerulonephritis, mortality), when treatment was initiated at the predisease stage, particularly when IFN-gammaR/Fc expression was enhanced by electroporation at the injection site. Remarkably, disease was arrested and even ameliorated when this treatment was initiated at an advanced stage. This therapy represents a rare example of disease reversal and makes application of this nonviral gene therapy in humans with lupus (and perhaps other autoimmune/inflammatory conditions) highly promising.
Clinical Relevance of <i>Mycobacterium tuberculosis plcD</i> Gene Mutations
Authors: Zhenhua Yang, Dong Yang, Ying Kong, Lixin Zhang, Carl F. Marrs, Betsy Foxman, Joseph H. Bates, Frank Wilson, M. Donald Cave
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

To identify Mycobacterium tuberculosis virulence factors, we integrated comparative genomics and epidemiologic data analysis to investigate the relationship between certain genomic insertions and deletions in the phospholipase-C gene D (plcD) with the clinical presentation of tuberculosis (TB). Four hundred ninety-six well-characterized M. tuberculosis clinical isolates were studied. Approximately 30% (147) of the isolates had an interruption of the plcD gene. Patients infected with the plcD mutant were twice as likely to have extrathoracic disease as those infected by a strain without an interruption (adjusted odds ratio, 2.19; 95% confidence interval, 1.27, 3.76). When we limited the analysis to the 275 isolates with distinct DNA fingerprint patterns, we observed the same association (adjusted odds ratio, 2.74; 95% confidence interval, 1.35, 5.56). Furthermore, the magnitude of the association appeared to differ with the type of extrathoracic TB. Our findings suggest that the plcD gene of M. tuberculosis is potentially involved in the pathogenesis of TB, and the clinical presentation of the disease may be influenced by the genetic variability of the plcD region.
IL-17 Family Cytokines and the Expanding Diversity of Effector T Cell Lineages
Authors: Casey T. Weaver, Robin D. Hatton, Paul R. Mangan, Laurie E. Harrington
Journal: Annual Review of Immunology (2007)

Since its conception two decades ago, the Th1-Th2 paradigm has provided a framework for understanding T cell biology and the interplay of innate and adaptive immunity. Naive T cells differentiate into effector T cells with enhanced functional potential for orchestrating pathogen clearance largely under the guidance of cytokines produced by cells of the innate immune system that have been activated by recognition of those pathogens. This secondary education of post-thymic T cells provides a mechanism for appropriately matching adaptive immunity to frontline cues of the innate immune system. Owing in part to the rapid identification of novel cytokines of the IL-17 and IL-12 families using database searches, the factors that specify differentiation of a new effector T cell lineage-Th17-have now been identified, providing a new arm of adaptive immunity and presenting a unifying model that can explain many heretofore confusing aspects of immune regulation, immune pathogenesis, and host defense.
Pathogenesis of Mantle-Cell Lymphoma: All Oncogenic Roads Lead to Dysregulation of Cell Cycle and DNA Damage Response Pathways
Authors: Veronica Fernàndez, Elena Hartmann, German Ott, Elias Campo, Andreas Rosenwald
Journal: Journal of Clinical Oncology (2005)

Mantle-cell lymphoma (MCL) is a well-defined subtype of B-cell non-Hodgkin's lymphomas (B-NHL), accounts for approximately 6% of all lymphoid neoplasms, and has a median survival of 3 to 4 years. The genetic hallmark of MCL is the chromosomal translocation t(11;14)(q13;q32) that leads to deregulation and upregulation of Cyclin D1, an important regulator of the G1 phase of the cell cycle. This genetic event is present in virtually all cases of MCL, whereas additional genetic alterations that occur in subsets of MCL have been described. Most of these alterations appear to disturb the cell cycle machinery/interfere with the cellular response to DNA damage, thus making MCL a paradigm for cell cycle and DNA damage response dysregulation in cancer in general. In particular, Cyclin D1 upregulation, genomic amplification of the cyclin-dependent kinase (CDK) -4, deletions of the CDK inhibitor p16(INK4a) and overexpression of BMI-1, a transcriptional repressor of the p16(INK4a) locus, are associated with dysregulation of the cell cycle machinery in MCL. The DNA damage response pathway is affected by frequent alterations of the ataxia-telangiectasia mutated (ATM) kinase as well as occasional inactivation of checkpoint kinase (CHK)-1 and CHK2 that are kinases that act downstream of ATM in response to detection of DNA damage. Moreover, p53 is frequently targeted by alterations in MCL. A recent gene expression profiling study defined the proliferation signature, a quantitative measure of gene expression of proliferation-associated genes as the strongest survival predictor available to date allowing the definition of prognostic MCL subgroups that differ in median survival by more than 5 years.