tbuckley/cabot-search huggingface dataset:
Paediatric origins of adult lung diseases bullet 2: Prevention of adult asthma by early intervention during childhood: potential value of new generation immunomodulatory drugs
Authors: P G Holt
Journal: Thorax (2000)

Current treatment regimens for asthma are based principally upon active suppression of inflammatory processes within airway tissues of sufferers, and one of the major thrusts of research in this area is towards development of increasingly more selective and more potent anti-inflammatory drugs. The impetus for much of the recent activity in relation to drug development in this field stems from an increased understanding of the contribution of immunologically mediated mechanisms towards inflammation induced tissue damage in the asthmatic airway, and this has led to the identification of a new spectrum of drug targets associated specifically with T helper 2 (Th2) cell functions.

However, we argue below that this overall drug development/testing process may be conceptually flawed, not in relation to drug design per se, but at the key stage of selection of subjects for subsequent clinical studies. In brief, we suggest that the practice of testing new selective anti-inflammatory and/or immunomodulatory drugs exclusively in adult asthmatic subjects with established disease inadvertently selects for equivocal or, at worst, negative results in relation to efficacy because the disease process in these patients will frequently have progressed beyond a stage at which it is susceptible to such agents. If so, the potential value of newly developed therapeutic agents which may be efficacious at earlier stages of the disease, including those capable of blocking the progression from trivial allergy to persistent asthma, is unlikely to be recognised unless the testing process is redesigned specifically to address this important possibility.

On the basis of studies from our group and others on the immunology and epidemiology of asthma in early life, we have developed a general working model for the relationship between respiratory allergy and persistent asthma which is summarised in fig1.1-3 This model envisages the development of asthma occurring in multiple stages …
Metagenomic Frameworks for Monitoring Antibiotic Resistance in Aquatic Environments
Authors: Jesse A. Port, Alison C. Cullen, James C. Wallace, Marissa N. Smith, Elaine M. Faustman
Journal: Environmental Health Perspectives (2013)

High-throughput genomic technologies offer new approaches for environmental health monitoring, including metagenomic surveillance of antibiotic resistance determinants (ARDs). Although natural environments serve as reservoirs for antibiotic resistance genes that can be transferred to pathogenic and human commensal bacteria, monitoring of these determinants has been infrequent and incomplete. Furthermore, surveillance efforts have not been integrated into public health decision making.We used a metagenomic epidemiology-based approach to develop an ARD index that quantifies antibiotic resistance potential, and we analyzed this index for common modal patterns across environmental samples. We also explored how metagenomic data such as this index could be conceptually framed within an early risk management context.We analyzed 25 published data sets from shotgun pyrosequencing projects. The samples consisted of microbial community DNA collected from marine and freshwater environments across a gradient of human impact. We used principal component analysis to identify index patterns across samples.We observed significant differences in the overall index and index subcategory levels when comparing ecosystems more proximal versus distal to human impact. The selection of different sequence similarity thresholds strongly influenced the index measurements. Unique index subcategory modes distinguished the different metagenomes.Broad-scale screening of ARD potential using this index revealed utility for framing environmental health monitoring and surveillance. This approach holds promise as a screening tool for establishing baseline ARD levels that can be used to inform and prioritize decision making regarding management of ARD sources and human exposure routes.Port JA, Cullen AC, Wallace JC, Smith MN, Faustman EM. 2014. Metagenomic frameworks for monitoring antibiotic resistance in aquatic environments. Environ Health Perspect 122:222–228; http://dx.doi.org/10.1289/ehp.1307009
The Pharmacologic Principles of Regional Pain Relief
Authors: J Adriani, M Naraghi
Journal: The Annual Review of Pharmacology and Toxicology (1977)

The Pharmacologic Principles of Regional Pain Relief, Page 1 of 1 < Previous page | Next page > /docserver/preview/fulltext/pharmtox/17/1/annurev.pa.17.040177.001255-1.gif
Multicenter, Placebo-Controlled Trial of Lorcaserin for Weight Management
Authors: Steven R. Smith, Neil J. Weissman, Christen M. Anderson, Matilde Sanchez, Emil Chuang, Scott Stubbe, Harold Bays, William R. Shanahan
Journal: New England Journal of Medicine (2010)

Lorcaserin is a selective serotonin 2C receptor agonist that could be useful in reducing body weight.
Treatment of Young People With Antipsychotic Medications in the United States
Authors: Mark Olfson, Marissa King, Michael Schoenbaum
Journal: JAMA Psychiatry (2015)

Despite concerns about rising treatment of young people with antipsychotic medications, little is known about trends and patterns of their use in the United States.To describe antipsychotic prescription patterns among young people in the United States, focusing on age and sex.A retrospective descriptive analysis of antipsychotic prescriptions among patients aged 1 to 24 years was performed with data from calendar years 2006 (n = 765,829), 2008 (n = 858,216), and 2010 (n = 851,874), including a subset from calendar year 2009 with service claims data (n = 53,896). Data were retrieved from the IMS LifeLink LRx Longitudinal Prescription database, which includes approximately 60% of all retail pharmacies in the United States. Denominators were adjusted to generalize estimates to the US population.The percentage of young people filling 1 or more antipsychotic prescriptions during the study year by sex and age group (younger children, 1-6 years; older children, 7-12 years; adolescents, 13-18 years; and young adults, 19-24 years) was calculated. Among young people with antipsychotic use, percentages with specific clinical psychiatric diagnoses and 1 or more antipsychotic prescriptions from a psychiatrist and from a child and adolescent psychiatrist were also determined.The percentages of young people using antipsychotics in 2006 and 2010, respectively, were 0.14% and 0.11% for younger children, 0.85% and 0.80% for older children, 1.10% and 1.19% for adolescents, and 0.69% and 0.84% for young adults. In 2010, males were more likely than females to use antipsychotics, especially during childhood and adolescence: 0.16% vs 0.06% for younger children, 1.20% vs 0.44% for older children, 1.42% vs 0.95% for adolescents, and 0.88% vs 0.81% for young adults. Among young people treated with antipsychotics in 2010, receiving a prescription from a psychiatrist was less common among younger children (57.9%) than among other age groups (range, 70.4%-77.9%). Approximately 29.3% of younger children treated with antipsychotics in 2010 received 1 or more antipsychotic prescriptions from a child and adolescent psychiatrist. Among young people with claims for mental disorders in 2009 who were treated with antipsychotics, the most common diagnoses were attention-deficit/hyperactivity disorder in younger children (52.5%), older children (60.1%), and adolescents (34.9%) and depression in young adults (34.5%).Antipsychotic use increased from 2006 to 2010 for adolescents and young adults but not for children aged 12 years or younger. Peak antipsychotic use in adolescence, especially among boys, and clinical diagnosis patterns are consistent with management of developmentally limited impulsive and aggressive behaviors rather than psychotic symptoms.
Prevalence of Thyroid Cancer in Familial Adenomatous Polyposis Syndrome and the Role of Screening Ultrasound Examinations
Authors: Maite Herraiz, Giuseppe Barbesino, William Faquin, Gayun Chan–Smutko, Devanshi Patel, Kristen M. Shannon, Gilbert H. Daniels, Daniel C. Chung
Journal: Clinical Gastroenterology and Hepatology (2007)
Bile acid patterns in meconium are influenced by cholestasis of pregnancy and not altered by ursodeoxycholic acid treatment
Authors: C M P Rodrigues, J J G Marín, D Brites
Journal: Gut (1999)

BACKGROUND Data on meconium bile acid composition in newborn babies of patients with intrahepatic cholestasis of pregnancy (ICP) are relatively scant, and changes that occur on ursodeoxycholic acid (UDCA) administration have not been evaluated. AIMS To investigate bile acid profiles in meconium of neonates from untreated and UDCA treated patients with ICP. Maternal serum bile acid composition was also analysed both at diagnosis and delivery to determine whether this influences the concentration and proportion of bile acids in the meconium. PATIENTS/METHODS The population included eight healthy pregnant women and 16 patients with ICP, nine of which received UDCA (12.5–15.0 mg/kg body weight/day) for 15±4 days until parturition. Bile acids were assessed in the meconium by gas chromatography-mass spectrometry and in maternal serum by high performance liquid chromatography. RESULTS Total bile acid and cholic acid concentrations in the meconium were increased (p&lt;0.01) in newborns from patients with ICP (13.5 (5.1) and 8.4 (4.1) μmol/g respectively; mean (SEM)) as compared with controls (2.0 (0.5) and 0.8 (0.3) μmol/g respectively), reflecting the total bile acid and cholic acid levels in the maternal serum ( r = 0.85 and r = 0.84, p&lt;0.01). After UDCA administration, total bile acid concentrations decreased in the mother (∼3-fold, p&lt;0.05) but not in the meconium. UDCA concentration in the meconium showed only a 2-fold increase after treatment, despite the much greater increase in the maternal serum (p&lt;0.01). Lithocholic acid concentration in the meconium was not increased by UDCA treatment. CONCLUSIONS UDCA administration does not influence the concentration and proportion of bile acids in the meconium, which in turn are altered by ICP. Moreover, this beneficial treatment for the mother does not increase meconium levels of potentially toxic metabolites of UDCA such as lithocholic acid.
A quality by design (QbD) case study on enteric-coated pellets: Screening of critical variables and establishment of design space at laboratory scale
Authors: Shuling Kan, Jing Lu, Jianping Liu, Junlin Wang, Yi Zhao
Journal: Asian Journal of Pharmaceutical Sciences (2014)

The study aims to prepare naproxen enteric-coated pellets (NAP-ECPs) by fluid-bed coating using QbD principle. Risk assessment was firstly performed by using failure mode and effect analysis (FMEA) methodology. A Plackett–Burman design was then used for assessment of the most important variables affecting enteric-coated pellets characteristics. A Box–Behnken design was subsequently used for investigating the main, interactive, and quadratic effects of these variables on the response. By FMEA we discovered that eight factors should be considered to be high/important risk variables as compared with others. The responses of acid resistance and cumulative drug release were taken as critical quality attributes (CQAs). Pareto ranking analyses indicated that the coating weight gain (X7), triethyl citrate percentage (X1) and glycerol monostearate percentage (X2) were the most significant factors affecting the selected responses out of the eight high-risk variables. Optimization with response surface method (RSM) further fully clarified the relationship between X7, X1, X2 and CQAs, and design space was established based on the constraints set on the responses. Due to the extreme coincidence of the predicted value generated by model with the observed value, the accuracy and robustness of the model were confirmed. It could be concluded that a promising NAP-ECPs was successfully designed using QbD approach in a laboratory scale.
Preliminary evaluation of the first international reference preparation for anticitrullinated peptide antibodies
Authors: Nicola Bizzaro, Francesca Pregnolato, Martin A M van Boekel, Danilo Villalta, Renato Tozzoli, Elio Tonutti, Antonio Antico, Maria Orietta Borghi, Allan Wiik, Pier Luigi Meroni
Journal: Annals of the Rheumatic Diseases (2012)

A lyophilised reference serum from one patient with rheumatoid arthritis (RA) diluted with serum samples from healthy subjects was evaluated as a possible first international standard for anticitrullinated peptide antibodies (ACPAs).The authors used 12 commercial ELISAs for ACPA detection in the reference serum and for testing the linearity of the assays by studying twofold serial dilutions. To test the effectiveness of the standardisation, sera from 20 RA patients with variable antibody concentrations were analysed, and the relative concentrations were calculated using both the kit's own curve and the six dilutions of the reference serum as a calibration curve. Fifty sera from normal healthy subjects were used to calculate cut-off values for the reference serum using each commercial kit.The calibration curve obtained for each of the 12 methods using the reference sample dilutions as calibrator allowed harmonisation of the ACPA concentration of the 20 RA serum samples, significantly reducing the dispersion of the values. The mean coefficient of variation (CV) was reduced from 76.4% to 27.9% (p=0.018) and from 85.9% to 33.5% (p=0.028) for the medium/high and negative samples, respectively. Low positive sera CV was also reduced, but to a smaller degree, from 82.5% to 55.5% (p=0.043).This first evaluation of the behaviour of the ACPA reference serum demonstrated that it tested positive in all the assays and that it may be used as a reference standard for establishing calibration curves, reducing the dispersion of antibody values and better comparing results obtained from different methods/laboratories.
Marine pyridoacridine alkaloids and synthetic analogues as antitumor agents
Authors: Evelyne Delfourne, Jean Bastide
Journal: Medicinal Research Reviews (2002)

Abstract Pyrido[4,3,2‐mn]acridines are of major interest as metabolites in sponges and ascidians. During the last few years, numerous additional compounds of this family were isolated, some of them being polycyclic structures already reported with different substituents (shermilamine or kuanoniamine‐derivatives), others, such as neoamphimedine, arnoamines and styelsamines having original structures. The synthesis of these compounds and analogues have been performed in order to allow their biological evaluation. In most of the cases, the cytotoxicity of analogues was improved compared to the natural product, specially in ascididemin or meridine series. The pyridoacridines have not a sole mode of action, but it seems that the reductive DNA cleavage mediated by reactive oxygen species is a potential general mode of action. © 2002 Wiley Periodicals, Inc. Med Res Rev, 23, No. 2, 234–252, 2003
Effect of Duration of Treatment on Treatment Outcome for Patients With Clear-Cell Sarcoma of the Kidney: A Report From the National Wilms' Tumor Study Group
Authors: Nita L. Seibel, Sierra Li, Norman E. Breslow, J. Bruce Beckwith, Daniel M. Green, Gerald M. Haase, Michael L. Ritchey, Patrick R.M. Thomas, Paul E. Grundy, Jerry Z. Finklestein, Tae Kim, Stephen J. Shochat, Panayotis P. Kelalis, Giulio J. D'Angio
Journal: Journal of Clinical Oncology (2004)

Purpose To evaluate the effect of conventional and standard (ST) versus pulse-intensive (PI) chemotherapy and short-duration versus long-duration chemotherapy on relapse-free survival (RFS) and overall survival rates of patients with clear-cell sarcoma of the kidney (CCSK) entered onto the National Wilms' Tumor Study (NWTS)-4. Patients and Methods The 5-year and 8-year RFS rates were determined for patients with CCSK treated on the NWTS-4. After August 6, 1986, 40 previously untreated children younger than 16 years with CCSK were randomly assigned, after the completion of 6 months of chemotherapy, to discontinue (short) or continue 9 additional months (long) of treatment with chemotherapy regimens that included vincristine and either divided-dose (ST) courses (5 days) or single-dose (PI) treatment with dactinomycin and divided-dose (ST) courses (3 days) or single-dose (PI) treatment with doxorubicin. Results For patients with CCSK, the 5- and 8-year RFS rates were 65.2% and 60.6%, respectively, for patients randomly assigned to the short chemotherapy and 87.8% (both 5- and 8-year RFS) for patients randomly assigned to the long chemotherapy (P = .08). The overall survival rates for patients at 5 and 8 years were 95.5% and 85.9%, respectively, for the short chemotherapy and 87.5% (both 5- and 8-year overall survival) for the long chemotherapy (P = .99). In NWTS-4, the overall survival rates for patients with CCSK improved from NWTS-3 (83% v 66.9% at 8 years, respectively; P &lt; .01). Conclusion CCSK patients exhibit an improved RFS from a longer course of therapy when using vincristine, doxorubicin, and dactinomycin, but their long-term survival is unchanged compared with patients receiving 6 months of therapy. The overall survival rates for patients with CCSK have improved from NWTS-3.
Intercontinental dissemination of azithromycin-resistant shigellosis through sexual transmission: a cross-sectional study
Authors: Kate S Baker, Timothy J Dallman, Philip M Ashton, Martin Day, Gwenda Hughes, Paul D Crook, Victoria L Gilbart, Sandra Zittermann, Vanessa G Allen, Benjamin P Howden, Takehiro Tomita, Mary Valcanis, Simon R Harris, Thomas R Connor, Vitali Sintchenko, Peter Howard, Jeremy D Brown, Nicola K Petty, Malika Gouali, Duy Pham Thanh, Karen H Keddy, Anthony M Smith, Kaisar A Talukder, Shah M Faruque, Julian Parkhill, Stephen Baker, François-Xavier Weill, Claire Jenkins, Nicholas R Thomson
Journal: The Lancet Infectious Diseases (2015)
Detection of tumor progression in optic pathway glioma with and without neurofibromatosis type 1
Authors: J. P. Kelly, A. H. Weiss
Journal: Neuro-Oncology (2013)

We wanted to determine the sensitivity and specificity of serial changes in visual acuity and visual evoked potentials (VEPs) to detect radiological progression of tumor volume in children with optic pathway gliomas. From a retrospective review of a cohort of 69 patients, 54 patients met inclusion criteria (31 with primary chemotherapy, 4 with primary radiotherapy, and 19 with stable tumor volume and no treatment). Age at presentation ranged from 0.3 to 13 years. Patients were serially followed by MRI, age-corrected visual acuity in log minimum angle of resolution (logMAR), and pattern VEP. Longitudinal data averaged 7.9 years (range 0.5–16 y). Visual assessments were aligned with MRI data within 6-month intervals. Tumor progression was defined by 25% or greater increase in volume. Visual acuity in the better eye had poor sensitivity and specificity for detecting tumor volume progression (0.5 and 0.5, respectively). Visual acuity in the worse eye showed worse sensitivity and specificity because false positives (visual decline without tumor progression) were more frequent than true positives (visual decline with tumor progression). VEPs showed slightly better sensitivity and specificity (0.69 and 0.58, respectively). In patients with stable tumors, visual acuity fluctuated ±0.55 logMAR (SD = 0.15) between examinations. VEP amplitude fluctuated −0.74 to 0.48 log units (SD = 0.19) between examinations. Serial changes in visual function do not reliably detect tumor progression. Conversely, tumor progression does not reliably indicate decreased visual function. Objective visual function and serial MRIs are complementary in management of optic pathway gliomas.
Prices for NHS services can change by 10% every year, finds study
Authors: A. O'Dowd
Journal: BMJ (2012)

Many prices for NHS services set by the current Payment by Results system can change by 10% or more every year, claims a new report commissioned by the NHS’s regulator of foundation trusts.

The report from Monitor analyses pricing in the NHS and the reimbursement system for NHS funded care and suggests that there is much room for improvement in the way that providers of NHS services are paid.

It found that more than 40% of prices set under the current Payment by Results framework—the national tariff system in which prices are set for certain services—change by 10% or more each year.

Such changes undermine the confidence that providers and …
Epidermal Growth Factor Receptor Messenger RNA Expression, Gene Dosage, and Gefitinib Sensitivity in Non–Small Cell Lung Cancer
Authors: Rafal Dziadziuszko, Samir E. Witta, Federico Cappuzzo, Seongjin Park, Koji Tanaka, Peter V. Danenberg, Anna E. Barón, Lucio Crino, Wilbur A. Franklin, Paul A. Bunn, Marileila Varella-Garcia, Kathleen D. Danenberg, Fred R. Hirsch
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Epidermal growth factor receptor (EGFR) mRNA expression and EGFR gene dosage by quantitative PCR in tumor samples obtained from patients with gefitinib-treated non–small cell lung cancer were analyzed in order to determine the association with treatment outcome, clinical, and biological features [EGFR copy number by fluorescent in situ hybridization (FISH), EGFR tyrosine kinase mutations, and EGFR protein expression]. Experimental Design: EGFR mRNA expression was measured by real-time quantitative reverse transcription-PCR in 64 patients, and EGFR gene dosage was analyzed by real-time quantitative PCR in 82 patients from paraffin-embedded specimens. Results: EGFR mRNA expression was higher in responders to gefitinib as compared with nonresponders (P = 0.012). Patients with high EGFR mRNA expression (&amp;gt;5.01) had 43% response probability, whereas patients with low EGFR mRNA expression had 8% response probability (P = 0.006). Patients with high EGFR mRNA expression had longer median progression-free (5.3 versus 2.8 months, P = 0.028) but not overall survival (13.8 versus 10.9 months, P = 0.87). EGFR mRNA expression was higher in FISH-positive patients (P = 0.001) and in patients with positive EGFR immunostaining (P &amp;lt; 0.001) but not in patients with EGFR mutations (P = 0.19). EGFR gene dosage did not predict response (P = 0.54), progression-free (P = 0.73), or overall survival (P = 0.89). EGFR gene dosage was not associated with FISH positivity (P = 0.15), relative mRNA expression (P = 0.27), EGFR mutation status (P = 0.39), and EGFR protein expression (P = 0.35). Conclusion: EGFR mRNA expression is a predictive biomarker for response to gefitinib and to progression-free survival after gefitinib treatment. EGFR gene dosage is neither predictive for response nor progression-free nor overall survival.
The ring-infected erythrocyte surface antigen (RESA) of Plasmodium falciparum stabilizes spectrin tetramers and suppresses further invasion
Authors: Xinhong Pei, Xinhua Guo, Ross Coppel, Souvik Bhattacharjee, Kasturi Haldar, Walter Gratzer, Narla Mohandas, Xiuli An
Journal: Blood (2007)