tbuckley/cabot-search huggingface dataset:
Nkx2-5 mutation causes anatomic hypoplasia of the cardiac conduction system
Authors: Patrick Y. Jay, Brett S. Harris, Colin T. Maguire, Antje Buerger, Hiroko Wakimoto, Makoto Tanaka, Sabina Kupershmidt, Dan M. Roden, Thomas M. Schultheiss, Terrence X. O’Brien, Robert G. Gourdie, Charles I. Berul, Seigo Izumo
Journal: Journal of Clinical Investigation (2004)

Heterozygous mutations of the cardiac transcription factor Nkx2-5 cause atrioventricular conduction defects in humans by unknown mechanisms. We show in KO mice that the number of cells in the cardiac conduction system is directly related to Nkx2-5 gene dosage. Null mutant embryos appear to lack the primordium of the atrioventricular node. In Nkx2-5 haploinsufficiency, the conduction system has half the normal number of cells. In addition, an entire population of connexin40(-)/connexin45(+) cells is missing in the atrioventricular node of Nkx2-5 heterozygous KO mice. Specific functional defects associated with Nkx2-5 loss of function can be attributed to hypoplastic development of the relevant structures in the conduction system. Surprisingly, the cellular expression of connexin40, the major gap junction isoform of Purkinje fibers and a putative Nkx2-5 target, is unaffected, consistent with normal conduction times through the His-Purkinje system measured in vivo. Postnatal conduction defects in Nkx2-5 mutation may result at least in part from a defect in the genetic program that governs the recruitment or retention of embryonic cardiac myocytes in the conduction system.
Do non-steroidal anti-inflammatory drugs have a significant effect on detection and grading of ultrasound-detected synovitis in patients with rheumatoid arthritis? Results from a randomised study
Authors: Ahmed S Zayat, Philip G Conaghan, Mohammad Sharif, Jane E Freeston, Claire Wenham, Elizabeth M A Hensor, Paul Emery, Richard J Wakefield
Journal: Annals of the Rheumatic Diseases (2011)

Objectives To determine whether non-steroidal anti-inflammatory drugs (NSAIDs) have a significant effect on ultrasonographic (US) grey scale (GS) and power Doppler (PD) assessment of synovitis in rheumatoid arthritis (RA). Methods Patients with RA taking NSAIDs were randomised to either stopping (for a minimum of 5 drug half-lives) or continuing the drug. All patients had a clinical assessment and US examination of both hands and wrists before and after stopping/continuing the NSAID. Changes at follow-up were compared between groups using Mann–Whitney U tests. Results A total of 58 patients with RA were recruited. All the clinical assessment parameters (including disease activity, pain, general state of health and physician global visual analogue score and tender and swollen joints count) showed an increase in the group who stopped their NSAID treatment. The total GS and PD score showed median (first to third quartiles) increase of 9.5 (5.75 to 19.0) and 4.0 (2.0 to 6.0) per patient, respectively, in the patients who stopped their NSAID in comparison with 1.0 (–1.0 to 2.25) and 0.0 (–2.0 to 3.0), respectively, in the patients who continued their NSAID (p&lt;0.001). There was an increase in the number of joints scoring &gt;0 for GS and PD in the patients who stopped the NSAID. The inter- and intrareader agreement was good to excellent for the US examination. Conclusion NSAID usage may mask the GS and PD signal and result in lower scoring despite continuing disease activity. Consideration should be given to the NSAID effect in designing clinical studies which use US to assess response to therapeutic.
Genetic Variations in Epigenetic Genes Are Predictors of Recurrence in Stage I or II Non–Small Cell Lung Cancer Patients
Authors: Klaus W. Wagner, Yuanqing Ye, Jie Lin, Ara A. Vaporciyan, Jack A. Roth, Xifeng Wu
Journal: Clinical Cancer Research (2012)

Abstract Purpose: Early-stage non–small cell lung cancer (NSCLC) is potentially curable, however, many patients develop recurrent disease. Therefore, identification of biomarkers that can be used to predict patient's risk of recurrence and survival is critical. Genetic polymorphisms or single-nucleotide polymorphisms (SNP) of DNA- and histone-modifying genes, particularly those of O6-methylguanine DNA-methyltransferase (MGMT), have been linked to an increased risk of lung cancer as well as treatment outcomes in other tumors. Experimental Design: We assessed the association of 165 SNPs in selected epigenetic enzyme genes, DNA methyltransferases, and methyl-CpG–binding proteins with cancer recurrence in 467 patients with stage I or II NSCLC treated with either surgery alone (N = 340) or surgery plus (neo)-adjuvant chemotherapy (N = 127). Results: We found several SNPs to be strongly correlated with tumor recurrence. We identified 10 SNPs that correlated with the outcome in patients treated with surgery alone but not in patients treated with surgery and adjuvant chemotherapy, which suggested that the addition of platinum-based chemotherapy could reverse the high genetic risk of recurrence. We also identified 10 SNPs that predicted the risk of recurrence in patients treated with surgery plus adjuvant chemotherapy but not in patients treated with surgery alone. The cumulative effect of these SNPs significantly predicted outcomes with P-values of 10−9 and 10−6, respectively. Conclusions: The first set of genotypes may be used as novel predictive biomarkers to identify patients with stage I NSCLC, who could benefit from adjuvant chemotherapy, and the second set of SNPs might predict response to adjuvant chemotherapy. Clin Cancer Res; 18(2); 585–92. ©2012 AACR.
Performance of a predictive model to identify undiagnosed diabetes in a health care setting.
Authors: C A Baan, J B Ruige, R P Stolk, J C Witteman, J M Dekker, R J Heine, E J Feskens
Journal: Diabetes Care (1999)

OBJECTIVE: To develop a predictive model to identify individuals with an increased risk for undiagnosed diabetes, allowing for the availability of information within the health care system. RESEARCH DESIGN AND METHODS: A sample of participants from the Rotterdam Study (n = 1,016), aged 55-75 years, not known to have diabetes completed a questionnaire on diabetes-related symptoms and risk factors and underwent a glucose tolerance test. Predictive models were developed using stepwise logistic regression analyses with the absence or presence of newly diagnosed diabetes as the dependent variable and various items with a plausible connection to diabetes as the independent variables. The models were evaluated in another Dutch population-based study, the Hoorn Study (n = 2,364), in which the participants were aged 50-74 years. Performances of the predictive models were compared by using receiver-operator characteristics (ROC) curves. RESULTS: We developed three predictive models (PMs), PM1 contained information routinely collected by the general practitioner, while PM2 also contained variables obtainable by additional questions. The third predictive model, PM3, included variables that had to be obtained from a physical examination. These latter variables did not have additive predictive value, resulting in a PM3 similar to PM2. The area under the ROC curve was higher for PM2 than for PM1, but the 95% Cls overlapped (0.74 [0.70-0.78] and 0.68 [0.64-0.72], respectively). CONCLUSIONS: Using only information normally present in the files of a general practitioner, a predictive model was developed that performed similarly to one supplemented by information obtained from additional questions. The simplicity of PM1 makes it easy to implement in the current health care setting.
Antisense oligodeoxynucleotide to the cystic fibrosis transmembrane conductance regulator inhibits cyclic AMP-activated but not calcium-activated cell volume reduction in a human pancreatic duct cell line.
Authors: H Kopelman, C Gauthier, M Bornstein
Journal: Journal of Clinical Investigation (1993)

Cystic fibrosis (CF) is characterized by a defect in cAMP-regulated chloride channels in epithelial cells. The CF gene product CF transmembrane conductance regulator (CFTR) is expressed in the apical membrane of pancreatic duct cells, and mutant CFTR accounts for the pathology in the CF pancreas. PANC 1, a pancreatic duct cell line, has not been considered a good model for studying CFTR and pancreatic chloride transport because CFTR mRNA and protein are undetectable using standard methods. Using electronic cell sizing and cell volume reduction under isotonic conditions, PANC 1 cells were found to possess both cAMP and calcium-activated chloride conductances. Using CFTR antisense oligodeoxynucleotides, the cAMP-activated conductance could be specifically inhibited in a concentration- and time-dependent manner. These findings demonstrate that PANC 1 cells express CFTR and a CFTR-independent calcium-activated chloride channel. With electronic cell sizing and CFTR antisense oligodeoxynucleotides, PANC 1 cells can provide an ideal system for the study of pancreatic duct cell physiology and pathophysiology with respect to the role of CFTR in the pancreas. These findings also suggest that antisense oligodeoxynucleotides may provide a more sensitive yet highly specific means of detecting low levels of expression of CFTR than currently available.
The longitudinal determinants of decline in COPD and asthma-COPD overlap in an Australian population
Authors: Vanessa McDonald, Juanjuan Fu, Jodie Simpson, Peter Gibson
Journal: European Respiratory Journal (2012)

Longitudinal examination of the characteristics of COPD and asthma-COPD overlap will improve our understanding of these conditions and help identify the role of systemic inflammation (SI). We hypothesised that overlap and SI are associated with the greatest decline in FEV 1  and health status.  Aim:  To determine the association between the decline of FEV 1  and other clinical outcomes over time.  Methods:  A prospective cohort study with 4 year follow up. Participants with COPD and asthma-COPD overlap, underwent an assessment of spirometry, health status, and biomarkers of CRP and sputum cell counts at baseline and 4 years.  Results:  84 (84%) of the original cohort were contactable, 41(41%) were reassessed, and there were 15 deaths. The mean (SD) age at follow up was 72.2 (6.8) years. COPD and overlap diagnosis was 57.5% and 42.5% respectively. The mean difference in FEV 1  was -.08mls (0.3). 6MWD decreased by 42 (44)m and there was a 2.2 (11.4) unit decrement in SGRQ. Changes did not differ by diagnosis. Those with SI (CRP >3mg/l) at baseline had the greatest decline in SGRQ [diff 5.7 (2.4) versus -2.2 (2.5); p=0.03], but there was no difference in FEV 1  decline. Mean (SD) baseline FEV 1 % pred (41.6 (12.3) V 59.5 (18); p=0.0007), 6MWD (319 (100) V 440 (97); p=0.0001) and SGRQ (55 (16) V 42 (17.7); p=0.009) was worse in the group that died compared to survivors.  Conclusions:  Overlap asthma-COPD is not associated with increased functional decline. SI is associated with declining health status, suggesting a need to target treatment to low grade SI. Overall there was only slight health status and functional decline over 4 years, however the 15% that died had the greatest baseline impairment.
Lung disease with chronic obstruction in opium smokers in Singapore: Clinical, electrocardiographic, radiological, functional, and pathological features
Authors: J. L. Da Costa, E. P. C. Tock, H. K. Boey
Journal: Thorax (1971)

Fifty-four opium smokers with chronic obstructive lung disease were studied for two-and-a-half years. Forty-eight patients had a cough for at least two years before the onset of inappropriate exertional dyspnoea. Fine, bubbling adventitious sounds suggesting small airway disease were heard on auscultation over the middle and lower lobes in 38 patients. The prevalence of inflammatory lung disease and chronic respiratory failure in this series is suggested as the main cause for the frequent finding of right ventricular hypertrophy and congestive heart failure. Physiological studies revealed moderate to severe airways obstruction with gross over-inflation and, in 32 patients, an additional restrictive defect probably due to peribronchiolar fibrosis. Radiological evidence of chronic bronchitis and bronchiolitis was observed in 45 patients, `pure9 chronic bronchiolitis in six patients, and `widespread9 emphysema in 25 patients respectively. Necropsy examinations in nine patients, however, showed destructive emphysema of variable severity in all. Chronic bronchiolitis often associated with striking bronchiolectasis was present in six cases. More severe bronchiolar rather than bronchial inflammation was noted. The heavy opium smokers had characteristic nodular shadows on chest radiography, sometimes associated with a striking reticular pattern not seen in `pure9 cigarette smokers. This was due to gross pigmented dust (presumably carbon) deposition in relation to blood vessels, lymphatics, and bronchioles, and also within the alveoli. It is speculated that the initial lesion is an acquired bronchiolitis. Opium smoking induces an irritative bronchopathy favouring repeated attacks of acute bronchiolitis and eventually resulting in obliterative bronchiolitis, peribronchiolar fibrosis, chronic bronchitis, and destructive emphysema.
Changes in Brain Function (Quantitative EEG Cordance) During Placebo Lead-In and Treatment Outcomes in Clinical Trials for Major Depression
Authors: Aimee M. Hunter, Andrew F. Leuchter, Melinda L. Morgan, Ian A. Cook
Journal: American Journal of Psychiatry (2006)

Objective: Decreases in prefrontal electroencephalogram (EEG) cordance that are detectable as early as 48 hours after the start of medication have been related to clinical outcome in treatment trials for major depressive disorder. The relationship between brain changes during the placebo lead-in phase and medication treatment outcome is unknown. The authors hypothesized that decreases in prefrontal cordance during the placebo lead-in phase would be associated with better clinical outcome in subjects treated with antidepressants. Method: Data were pooled examining 51 adults with major depressive disorder from two independent double-blind placebo-controlled trials. A 1-week single-blind placebo lead-in phase preceded 8 weeks of randomized treatment with medication (fluoxetine 20 mg or venlafaxine 150 mg) or placebo. The authors obtained quantitative EEG cordance measures at baseline and at the end of the placebo lead-in period. Relationships between regional cordance changes at the end of the placebo lead-in period and clinical outcome (the final 17-item Hamilton Rating Scale for Depression scores) were examined using multiple linear regression analysis. Results: As hypothesized, decreases in prefrontal cordance during the placebo lead-in period were associated with lower final Hamilton depression scale scores in subjects randomly assigned to medication. Prefrontal changes explained 19% of the variance in final Hamilton depression scale scores. Conclusions: Neurophysiological changes during a placebo lead-in period may serve as nonpharmacodynamic biomarkers of eventual treatment outcomes in clinical trials for major depressive disorder.
Degradation of Tob1 Mediated by SCFSkp2-Dependent Ubiquitination
Authors: Yoshihiro Hiramatsu, Kyoko Kitagawa, Toru Suzuki, Chiharu Uchida, Takayuki Hattori, Hirotoshi Kikuchi, Toshiaki Oda, Shigetsugu Hatakeyama, Keiichi I. Nakayama, Tadashi Yamamoto, Hiroyuki Konno, Masatoshi Kitagawa
Journal: Cancer Research (2006)

Abstract Tob1, a member of the Tob/BTG family, is involved in the control of G1-S progression by suppressing cyclin D1 expression and acts as a tumor suppressor gene. Tob1 was reported to have a quick turnover through the ubiquitin-proteasome pathway, but proteins involved in this process are still unknown. We showed that Skp2, a substrate-targeting subunit of the SCF (Skp1/Cul1/F-box protein) ubiquitin ligase complex, was involved in ubiquitin-dependent degradation of Tob1. Skp2 interacted with Tob1 and facilitated ubiquitination of Tob1 in intact cells as well as in vitro. Skp2 mutants without the F-box or leucine rich repeat were not able to bind to Tob1 and did not enhance ubiquitination of Tob1. Tob1 was stabilized in both Skp2−/− mouse fibroblasts and Skp2 knockdown HeLa cells. Moreover, cyclin D1 expression was suppressed in Skp2 knockdown HeLa cells. These data suggest that Tob1 is a novel target for degradation by the SCF-Skp2 ubiquitin ligase. (Cancer Res 2006; 66(17): 8477-83)
Pulmonary veno-occlusive disease and Hodgkin's lymphoma
Authors: GL Swift, A Gibbs, IA Campbell, CA Wagenvoort, D Tuthill
Journal: European Respiratory Journal (1993)

Pulmonary veno-occlusive disease (PVOD) is a rare cause of pulmonary hypertension, and is of unknown aetiology. It has seldom been described in association with malignant disease and cytotoxic chemotherapy, and there have been only two previous reports of an association with Hodgkin's disease [1, 2]. We report a third case which developed 14 yrs after Hodgkin's disease had been diagnosed and treated, initially with radiotherapy and subsequently with chemotherapy.
McDonald's profits drop and Mars abandons king size bars
Authors: Rebecca Coombes
Journal: BMJ (2004)

The profits of McDonald's UK arm have slumped to the lowest level in the fast food giant's 30 year history after a stream of bad publicity about the ill effects to health of eating junk food.

The chain's pretax profits fell by nearly three quarters in the United Kingdom last year, to £23.6m ($42.1m; €34.3m), it emerged last week.

The figures—which also show that sales have dropped—follow claims that the high fat and salt content of food from McDonald's have contributed to the United Kingdom's rising incidence of obesity in children.

The film Super Size Me —a documentary currently on release in the United …
Biological significance and development of practical synthesis of biotin
Authors: Masahiko Seki
Journal: Medicinal Research Reviews (2006)

Abstract Biotin ( 1 ), a water‐soluble B series vitamin, distributes widely in microorganisms, plants, and animals. Biosynthesis of 1 involves five steps sequence starting from pimelic acid. The last step, a transformation from dethiobiotin (DTB) to 1 , includes an iron clusters‐mediated radical process. The compound 1 is a cofactor of carboxylation enzymes and plays crucial roles in the metabolism of fatty acids, sugars, and α‐amino acids. In addition to the increasing application to feed additives, recent reports have revealed that 1 enhances insulin secretion in animals, suggesting it for a promising therapeutic candidate for an anti‐diabetes drug. The remarkably strong affinity of 1 with avidin and streptavidin has been extensively applied for such technologies as photoaffinity labeling. Among the number of approaches to 1 so far developed in 50 years, a synthesis using L ‐cysteine and thiolactone as a starting material and a key intermediate, respectively, represents one of the best routes leading to 1 , because of short steps, high yield, use of inexpensive reagents, and ease of operation. © 2006 Wiley Periodicals, Inc. Med Res Rev, 26, No. 4, 434–482, 2006
Sudden Death Associated With Short-QT Syndrome Linked to Mutations in HERG
Authors: Ramon Brugada, Kui Hong, Robert Dumaine, Jonathan Cordeiro, Fiorenzo Gaita, Martin Borggrefe, Teresa M. Menendez, Josep Brugada, Guido D. Pollevick, Christian Wolpert, Elena Burashnikov, Kiyotaka Matsuo, Yue Sheng Wu, Alejandra Guerchicoff, Francesca Bianchi, Carla Giustetto, Rainer Schimpf, Pedro Brugada, Charles Antzelevitch
Journal: Circulation (2003)

Background— Sudden cardiac death takes the lives of more than 300 000 Americans annually. Malignant ventricular arrhythmias occurring in individuals with structurally normal hearts account for a subgroup of these sudden deaths. The present study describes the genetic basis for a new clinical entity characterized by sudden death and short-QT intervals in the ECG. Methods and Results— Three families with hereditary short-QT syndrome and a high incidence of ventricular arrhythmias and sudden cardiac death were studied. In 2 of them, we identified 2 different missense mutations resulting in the same amino acid change (N588K) in the S5-P loop region of the cardiac I Kr channel HERG (KCNH2). The mutations dramatically increase I Kr , leading to heterogeneous abbreviation of action potential duration and refractoriness, and reduce the affinity of the channels to I Kr blockers. Conclusions— We demonstrate a novel genetic and biophysical mechanism responsible for sudden death in infants, children, and young adults caused by mutations in KCNH2. The occurrence of sudden cardiac death in the first 12 months of life in 2 patients suggests the possibility of a link between KCNH2 gain of function mutations and sudden infant death syndrome. KCNH2 is the binding target for a wide spectrum of cardiac and noncardiac pharmacological compounds. Our findings may provide better understanding of drug interaction with KCNH2 and have implications for diagnosis and therapy of this and other arrhythmogenic diseases.
Tiotropium reduction of lung inflammation in a model of chronic gastro-oesophageal reflux
Authors: Y. Cui, P. Devillier, X. Kuang, H. Wang, L. Zhu, Z. Xu, Z. Xia, L. Zemoura, C. Advenier, H. Chen
Journal: European Respiratory Journal (2009)

Gastro-oesophageal reflux is frequent in chronic airway diseases and is considered a trigger for symptoms. In animal models, bilateral vagotomy or muscarinic antagonists prevent the increase in airway resistance and the microvascular leakage induced by acute oesophageal acid instillation. The present study investigates lung inflammation and remodelling in an animal model of chronic gastro-oesophageal reflux disease (GORD), and the effectiveness of pretreatments with tiotropium, atropine and dexamethasone. Mice were exposed to twice-daily intra-oesophageal HCl instillations for 21 days. Exposure to HCl causes: marked infiltration by inflammatory cells of the airways and of peribronchial areas; an increase in epithelial thickness; histological features of interstitial pneumonitis; an increase in cell numbers and in the levels of interleukin-8; and soluble intercellular adhesion molecule in bronchoalveolar lavage fluids, as well as of in vitro tracheal contractility. The administration of nebulised tiotropium or intraperitoneal atropine prior to each instillation of HCl, considerably inhibited all these changes. These results indicate a major role of acetylcholine in airway inflammation and remodelling in a GORD model, and demonstrate that tiotropium and atropine can prevent lung inflammation with an effectiveness similar to intraperitoneal dexamethasone, providing additional evidence that anticholinergics might contribute to the control of inflammatory processes in airway diseases.
Live attenuated yellow fever 17D infects human DCs and allows for presentation of endogenous and recombinant T cell epitopes
Authors: Giovanna Barba-Spaeth, Randy S. Longman, Matthew L. Albert, Charles M. Rice
Journal: The Journal of Experimental Medicine (2005)

The yellow fever (YF) 17D vaccine is one of the most successful live attenuated vaccines available. A single immunization induces both long-lasting neutralizing antibody and YF-specific T cell responses. Surprisingly, the mechanism for this robust immunity has not been addressed. In light of several recent reports suggesting flavivirus interaction with dendritic cells (DCs), we investigated the mechanism of YF17D interaction with DCs and the importance of this interaction in generating T cell immunity. Our results show that YF17D can infect immature and mature human DCs. Viral entry is Ca2+ dependent, but it is independent of DC-SIGN as well as multiple integrins expressed on the DC surface. Similar to infection of cell lines, YF infection of immature DCs is cytopathic. Although infection itself does not induce DC maturation in vitro, TNF-α–induced maturation protects DCs from YF-induced cytopathogenicity. Furthermore, we show that DCs infected with YF17D or YF17D carrying a recombinant epitope can process and present antigens for CD8+ T cell stimulation. These findings offer insight into the immunologic mechanisms associated with the highly capable YF17D vaccine that may guide effective vaccine design.