tbuckley/cabot-search huggingface dataset:
Reports of Pathological Gambling, Hypersexuality, and Compulsive Shopping Associated With Dopamine Receptor Agonist Drugs
Authors: Thomas J. Moore, Joseph Glenmullen, Donald R. Mattison
Journal: JAMA Internal Medicine (2014)

Severe impulse control disorders involving pathological gambling, hypersexuality, and compulsive shopping have been reported in association with the use of dopamine receptor agonist drugs in case series and retrospective patient surveys. These agents are used to treat Parkinson disease, restless leg syndrome, and hyperprolactinemia.To analyze serious adverse drug event reports about these impulse control disorders received by the US Food and Drug Administration (FDA) and to assess the relationship of these case reports with the 6 FDA-approved dopamine receptor agonist drugs.We conducted a retrospective disproportionality analysis based on the 2.7 million serious domestic and foreign adverse drug event reports from 2003 to 2012 extracted from the FDA Adverse Event Reporting System.Cases were selected if they contained any of 10 preferred terms in the Medical Dictionary for Regulatory Activities (MedDRA) that described the abnormal behaviors. We used the proportional reporting ratio (PRR) to compare the proportion of target events to all serious events for the study drugs with a similar proportion for all other drugs.We identified 1580 events indicating impulse control disorders from the United States and 21 other countries:710 fordopamine receptor agonist drugs and 870 for other drugs. The dopamine receptor agonist drugs had a strong signal associated with these impulse control disorders (n = 710; PRR = 277.6, P < .001). The association was strongest for the dopamine agonists pramipexole (n = 410; PRR = 455.9, P < .001) and ropinirole (n = 188; PRR = 152.5, P < .001), with preferential affinity for the dopamine D3 receptor. A signal was also seen for aripiprazole, an antipsychotic classified as a partial agonist of the D3 receptor (n = 37; PRR = 8.6, P < .001).Our findings confirm and extend the evidence that dopamine receptor agonist drugs are associated with these specific impulse control disorders. At present, none of the dopamine receptor agonist drugs approved by the FDA have boxed warnings as part of their prescribing information. Our data, and data from prior studies, show the need for more prominent warnings.
Novel 1,2,5-Oxadiazole 2-Oxide Derivatives with Analgesic and Fetal Hemoglobin Induced Properties Designed As Drug Candidate to Treat Sickle Cell Disease Symptoms
Authors: Jean Leandro Santos, Carolina Lanaro, Sheley Gambero, Rafael Chelucci, Lidia Moreira Lima, Hugo Cerecetto, Mercedes Gonzalez, Fernando Ferreira Costa, Chung Man Chin
Journal: Blood (2011)
Understanding of Prognosis and Goals of Care Among Couples Whose Child Died of Cancer
Authors: Kelly E. Edwards, Bridget A. Neville, Earl F. Cook, Sarah H. Aldridge, Veronica Dussel, Joanne Wolfe
Journal: Journal of Clinical Oncology (2008)

Purpose Little is known about how couples care for the terminally ill child with cancer. We assessed both parents’ understanding of prognosis and treatment goals for children with cancer and explored whether sex mediates these views. We also investigated whether discordance within couples regarding treatment goals was related to parental perception of the child's end-of-life (EOL) experience. Methods We surveyed mothers and fathers of children who died of cancer and were cared for at Children's Hospital (Boston, MA) and the Dana-Farber Cancer Institute (Boston, MA) between 2000 and 2004. Our sample included 38 couples (response rate, 56%). Results Willingness to participate did not differ by sex. At diagnosis, fathers and mothers held a similar understanding of the child's prognosis, and 58% of couples agreed on the goal of cure. During the EOL period, a majority of fathers and mothers reported lessening suffering as the primary goal. However, within couples there was poor agreement about the primary goal of care (κ = 0.07). When parents did not agree on the primary goal of lessening suffering, both parents were more likely to report that the child suffered significantly from cancer-directed treatment (P = .03). Conclusion Though parent goals are often concurrent at diagnosis, they frequently differ during the EOL period. Parent disagreement about the goal of lessening suffering at the EOL appears to impact how parents describe their child's experience of suffering. Creating opportunities for parents to work through their goals together may lead to improvements in the child's EOL experience.
Improvement of Sleep Apnea in Patients with Chronic Renal Failure Who Undergo Nocturnal Hemodialysis
Authors: Patrick J. Hanly, Andreas Pierratos
Journal: New England Journal of Medicine (2001)

Sleep apnea is common in patients with chronic renal failure and is not improved by either conventional hemodialysis or peritoneal dialysis. With nocturnal hemodialysis, patients undergo hemodialysis seven nights per week at home, while sleeping. We hypothesized that nocturnal hemodialysis would correct sleep apnea in patients with chronic renal failure because of its greater effectiveness.
Interaction between heptad repeat 1 and 2 regions in spike protein of SARS-associated coronavirus: implications for virus fusogenic mechanism and identification of fusion inhibitors
Authors: Shuwen Liu, Gengfu Xiao, Yibang Chen, Yuxian He, Jinkui Niu, Carlos R Escalante, Huabao Xiong, James Farmar, Asim K Debnath, Po Tien, Shibo Jiang
Journal: The Lancet (2004)
Conservative surgery for mitral valve disease: clinical and echocardiographic analysis of results.
Authors: O A Adebo, J K Ross
Journal: Thorax (1983)

Eighty-five patients underwent mitral valve reconstruction by the Carpentier method from January 1976 to December 1981. Concomitant procedures were performed in 30 patients (aortic valve replacement in 23, coronary revascularisation in six, and tricuspid valve repair in seven). Before operation 76 patients (89%) were in clinical class II or III (New York Heart Association) and atrial fibrillation was present in 50. Thirty-six patients had valvular incompetence, while 26 had pure stenosis. The aetiology was rheumatic in 57 cases and dysplastic in 21. The patients were assessed for clinical improvement, durability of valve repair, thromboembolism, and survival. There was one death, an operative mortality rate of 1.2%, and 63 of 74 patients followed for one to six years were in clinical class I after operation. The actuarial survival was 92% with a 93% incidence of freedom from thromboemboli at five years. Six patients had embolic episodes, four of whom had aortic valve replacement. Three patients had a repeat operation 16-20 months later, a valve failure rate of 6.7%. Nineteen patients with ruptured chordae had postoperative echocardiographic assessment of myocardial and mitral valve functions; the peak rates of dimension changes of the left ventricular cavity (indicative of flow across the mitral valve) fell to normal in most patients, and the left ventricular end-diastolic dimensions decreased significantly from 6.4 (1.53) to 5.09 (1.31) cm (mean and SD)--p less than 0.05. Our results confirm that reconstructive mitral surgery is able to restore and maintain normal valve function in addition to providing satisfactory relief of symptoms.
The Genetic Basis of Phenotypic Convergence in Beach Mice: Similar Pigment Patterns but Different Genes
Authors: C. C. Steiner, H. Rompler, L. M. Boettger, T. Schoneberg, H. E. Hoekstra
Journal: Molecular Biology and Evolution (2008)

Convergent evolution is a widespread phenomenon seen in diverse organisms inhabiting similar selective environments. However, it is unclear if similar phenotypes are produced by the same or different genes and mutations. Here we analyze the molecular mechanisms underlying convergent pigment pattern among subspecies of the beach mouse (Peromyscus polionotus) inhabiting the Gulf and Atlantic coasts of Florida. In these two geographic regions, separated by more than 300 km, "beach mice" have lighter colored coats than do their mainland counterparts, produced by natural selection for camouflage against the pale coastal sand dunes. We measured color pattern in eight beach mouse subspecies and showed that three of the Gulf Coast subspecies are more phenotypically similar to an Atlantic coast subspecies than to their Gulf Coast neighbors. However, light-colored beach mice do not form a monophyletic group. Previous results implicated a single derived amino acid change in the melanocortin-1 receptor (Mc1r) as a major contributor to pigment pattern in the Gulf Coast beach mice; despite phenotypic similarities, the derived Mc1r allele was not found in the Atlantic coast beach mouse populations. Here we show that Atlantic coast beach mice have high levels of Mc1r polymorphism but they lack unique alleles. Functional assays revealed that single amino acid mutations segregating in Atlantic coast beach mice do not cause any change in Mc1r activity compared with the activity of Mc1r from dark-colored mice. These joint results show that convergent pigment patterns in recently diverged beach mouse subspecies—whose developmental constraints are presumably similar—have evolved through a diversity of genetic mechanisms.
Peripheral airways as a determinant of ventilatory function in the human lung.
Authors: D E Niewoehner, J D Knoke, J Kleinerman
Journal: Journal of Clinical Investigation (1977)

We have investigated the morphological differences responsible for the variability in two tests of pulmonary function, maximal expiratory flow rates (MEF) and the frequency dependence of dynamic compliance (CDYN ratio). Functional measurements were obtained from 53 normal and minimally diseased postmortem human lungs. Morphological measurements performed on these same lungs included airway diameter at three levels in the bronchial tree, the amount of bronchial gland mass, and the alveolar surface to volume ratio. Multiple regression analysis suggests that the diameter of the peripheral conduction airways (membranous bronchioles) is the major morphological determinant for both MEF and the CDYN ratio in lungs at any particular age. Age-dependent changes in both functional tests were associated primarily with differences in the alveolar surface to volume ratio. Minimal emphysema and a lesion associated with cigarette smoking, respiratory bronchiolitis, have no demonstrable effect on either MEF or the CDYN ratio. These studies provide further evidence that the peripheral conducting airways are a major determinant of ventilatory function in the normal human lung.
Prediagnosis Smoking, Obesity, Insulin Resistance, and Second Primary Cancer Risk in Male Cancer Survivors: National Health Insurance Corporation Study
Authors: Sang Min Park, Min Kyung Lim, Kyu Won Jung, Soon Ae Shin, Keun-Young Yoo, Young Ho Yun, Bong Yul Huh
Journal: Journal of Clinical Oncology (2007)

Smoking, obesity, and insulin resistance are well-known risk factors for cancer, yet few epidemiology studies evaluate their role as risk factors for a second primary cancer (SPC).We identified 14,181 men with a first cancer from the National Health Insurance Corporation Study cohort. We obtained data on fasting glucose level, body mass index (BMI), and smoking history from an enrollment interview (1996). We obtained SPC incidence data for 1996 through 2002 from the Korean Central Cancer Registry. We used the standard Poisson regression model to estimate the age- and multivariate-adjusted relative risk (RR) for SPCs in relation to smoking history, BMI, and insulin resistance before diagnosis.We observed 204 patients with SPC. The overall age-standardized incidence rate of SPC was 603.2 occurrences per 100,000 person-years, which was about 2.3 times higher than that of first cancer in the general male population. Multivariate regression revealed that lung (RR, 3.69; 95% CI, 1.35 to 10.09) and smoking-related (RR, 2.02; 95% CI, 1.02 to 4.03) SPCs were significantly associated with smoking. Obese patients (BMI > or = 25 kg/m2) had significantly elevated RRs for colorectal (RR, 3.45; 95% CI, 1.50 to 7.93) and genitourinary (RR, 3.61; 95% CI, 1.36 to 9.54) SPCs. Patients with a fasting serum glucose concentration > or = 126 mg/dL had a higher RR for hepatopancreatobiliary (RR, 3.33; 95% CI, 1.33 to 8.37) and smoking-related (1.93; 95% CI, 1.01 to 3.68) SPCs.Prediagnosis smoking history, obesity, and insulin resistance were risk factors for several SPCs. These findings suggest that more thorough surveillance and screening for SPCs is needed for the cancer survivors with these risk factors.
Abnormalities of lung mechanics in young asthmatic children.
Authors: A Greenough, B G Loftus, J Pool, J F Price
Journal: Thorax (1987)

Measurements of total compliance of the respiratory system by the weighted spirometer technique and of the functional residual capacity by helium gas dilution were attempted in 86 asthmatic children aged 2.2-7.9 years. In all but six of the 86 children reliable measurements could be obtained. Significantly raised functional residual capacity was detected in children with asthma of all degrees of severity. The compliance of the respiratory system was significantly abnormal (reduced) only in children who had symptoms at the time of measurement or who had chronic persistent asthma. The results indicate that these measurements are well tolerated in young asthmatic children. Further work needs to be undertaken to assess the value of this technique in following the response to treatment.
T-Tubule Remodeling During Transition From Hypertrophy to Heart Failure
Authors: Sheng Wei, Ang Guo, Biyi Chen, William Kutschke, Yu-Ping Xie, Kathy Zimmerman, Robert M. Weiss, Mark E. Anderson, Heping Cheng, Long-Sheng Song
Journal: Circulation Research (2010)

The transverse tubule (T-tubule) system is the ultrastructural substrate for excitation-contraction coupling in ventricular myocytes; T-tubule disorganization and loss are linked to decreased contractility in end stage heart failure (HF).We sought to examine (1) whether pathological T-tubule remodeling occurs early in compensated hypertrophy and, if so, how it evolves during the transition from hypertrophy to HF; and (2) the role of junctophilin-2 in T-tubule remodeling.We investigated T-tubule remodeling in relation to ventricular function during HF progression using state-of-the-art confocal imaging of T-tubules in intact hearts, using a thoracic aortic banding rat HF model. We developed a quantitative T-tubule power (TT(power)) index to represent the integrity of T-tubule structure. We found that discrete local loss and global reorganization of the T-tubule system (leftward shift of TT(power) histogram) started early in compensated hypertrophy in left ventricular (LV) myocytes, before LV dysfunction, as detected by echocardiography. With progression from compensated hypertrophy to early and late HF, T-tubule remodeling spread from the LV to the right ventricle, and TT(power) histograms of both ventricles gradually shifted leftward. The mean LV TT(power) showed a strong correlation with ejection fraction and heart weight to body weight ratio. Over the progression to HF, we observed a gradual reduction in the expression of a junctophilin protein (JP-2) implicated in the formation of T-tubule/sarcoplasmic reticulum junctions. Furthermore, we found that JP-2 knockdown by gene silencing reduced T-tubule structure integrity in cultured adult ventricular myocytes.T-tubule remodeling in response to thoracic aortic banding stress begins before echocardiographically detectable LV dysfunction and progresses over the development of overt structural heart disease. LV T-tubule remodeling is closely associated with the severity of cardiac hypertrophy and predicts LV function. Thus, T-tubule remodeling may constitute a key mechanism underlying the transition from compensated hypertrophy to HF.
Prevalence of hbeag and anti-hbe in chronic active hepatitis, cirrhosis and primary hepatocellular carcinoma in korea
Authors: Chung-Yong Kim, Soon-Kee Bae, Hie-Won L. Hann, Thomas W. London, Baruch S. Blumberg
Journal: Hepatology (1985)

The prevalence of HBeAg was studied in Korean patients with chronic active hepatitis, cirrhosis and primary hepatocellular carcinoma. There is an independent association of HBeAg prevalence with age and diagnosis. These findings are discussed in terms of a developmental model for primary hepatocellular carcinoma which could explain the lower frequency of HBeAg in the cancer cases.
Transgenic kallikrein 5 mice reproduce major cutaneous and systemic hallmarks of Netherton syndrome
Authors: Laetitia Furio, Simon de Veer, Madeleine Jaillet, Anais Briot, Aurelie Robin, Celine Deraison, Alain Hovnanian
Journal: The Journal of Experimental Medicine (2014)

Netherton syndrome (NS) is a severe genetic skin disease in which absence of a key protease inhibitor causes congenital exfoliative erythroderma, eczematous-like lesions, and atopic manifestations. Several proteases are overactive in NS, including kallikrein-related peptidase (KLK) 5, KLK7, and elastase-2 (ELA2), which are suggested to be part of a proteolytic cascade initiated by KLK5. To address the role of KLK5 in NS, we have generated a new transgenic murine model expressing human KLK5 in the granular layer of the epidermis (Tg-KLK5). Transgene expression resulted in increased proteolytic activity attributable to KLK5 and its downstream targets KLK7, KLK14, and ELA2. Tg-KLK5 mice developed an exfoliative erythroderma with scaling, growth delay, and hair abnormalities. The skin barrier was defective and the stratum corneum was detached through desmosomal cleavage. Importantly, Tg-KLK5 mice displayed cutaneous and systemic hallmarks of severe inflammation and allergy with pruritus. The skin showed enhanced expression of inflammatory cytokines and chemokines, infiltration of immune cells, and markers of Th2/Th17/Th22 T cell responses. Moreover, serum IgE and Tslp levels were elevated. Our study identifies KLK5 as an important contributor to the NS proteolytic cascade and provides a new and viable model for the evaluation of future targeted therapies for NS or related diseases such as atopic dermatitis.
PTU-154 Sirt2 Modulates the Inflammatory Response in Oesophageal Adenocarcinoma
Authors: L K E Schulz, P Lao-Sirieix, M O’ Donovan, R C Fitzgerald
Journal: Gut (2013)

<h3>Introduction</h3> Gastro-oesophageal reflux disease is the main risk factor for Barrett’s oesophagus (BE), the precursor lesion to oesophageal adenocarcinoma. In BE, GORD leads to chronic inflammation and to NF-κB pathway activation. SIRT2 is a histone deacetylase involved in deacetylation of key players in the cell, including p65, one subunit of the NF-κB transcription complex. SIRT2 is part of our previously published gene signatures in which loss of SIRT2 confers a poor prognosis and over-expression a good prognosis in keeping with its known role as a tumour suppressor. We hypothesised that exerts its protective effect through recruitment of inflammatory cells to the tumour site via the NF-κB pathway The aim of this study was to assess the inflammatory infiltrate in positive tumoursto assess the relationship betweenthe NF-κB pathway. <h3>Methods</h3> 76 surgical resection specimen of oesophageal adenocarcinoma were immunostained for SIRT2. An in-depth analysis of the nature of inflammatory cells localised to high SIRT2 areas was done in 5 cases using immune cell markers (CD3, CD4, CD8, CD20, CD56 and CD68). NF- κB and SIRT2 luciferase reporter assays were used with SIRT2 overexpression and TNFα stimulation to study the interplay between the NF- κB pathway and SIRT2. A panel of SIRT2 promoter mutants with mutations of one or two or both NF-κB putative binding sites, identified through an <i>in silico</i> analysis, were also used. <h3>Results</h3> 32% of the cases were strongly positive for SIRT2 (+3 and +2 on a scale from 0 to +3 where 0 is negative). A higher number of inflammatory cells were identified in SIRT2-positive cases compared to SIRT2 negative cases. In particular, SIRT2 positive cases showed strong staining for CD68 indicating an enrichment in the number of macrophages. SIRT2 overexpression significantly down-regulated NF-κB activity (p = 0.0011). Immunoblotting suggests that this downregulation is probably conferred by the deacetylation of Lysine 310 at the p65 subunit of NF- κB. Luciferase assays with the full-length SIRT2-promoter reporter revealed that the SIRT2 promoter was induced by TNFα stimulation (activates NF- κB pathway). This stimulation resulted in decreased luciferase activity when the NF- κB binding sites mutants were used, suggesting a direct action of NF- κB on SIRT2. <h3>Conclusion</h3> In oesophageal adenocarcinoma, SIRT2 expression is linked with an increased inflammatory infiltrate, especially macrophages. Luciferase reporter assays suggest that SIRT2 and NF-κB regulate each other. Taken together, downregulation of NF- κB by SIRT2 could be an explanation for the protective effect of SIRT2 overexpression in oesophageal adenocarcinoma. Further work is required to confirm these findings. <h3>Disclosure of Interest</h3> None Declared
The balance between severe cardiovascular and gastrointestinal events among users of selective and non-selective non-steroidal anti-inflammatory drugs
Authors: M W van der Linden, S van der Bij, P Welsing, E J Kuipers, R M C Herings
Journal: Annals of the Rheumatic Diseases (2008)

To simultaneously assess cardiovascular (CV) and gastrointestinal (GI) risk with traditional non-steroidal anti-inflammatory drugs (tNSAIDs) and cyclo-oxygenase 2 (COX-2) inhibitors.Using the PHARMO Record Linkage System, including drug-dispensing and hospitalisation data of >2 million residents of The Netherlands, subjects with first hospitalisation for acute myocardial infarction (AMI), CV and GI events were identified. Use of COX-2 inhibitors and traditional non-selective NSAIDs was classified into remote, recent and current. Cases were matched to controls in a 1:4 ratio on age and event date. Multivariate analyses adjusted for gender, history of hospitalisations and medications.Compared to remote use, AMI risk was increased among current users of COX-2 inhibitors combined (adjusted odds ratio (OR) 1.73, 95% CI 1.37 to 2.19) and tNSAIDs combined (OR 1.41, 95% CI 1.23 to 1.61). AMI risk with celecoxib (OR 2.53, 95% CI 1.53 to 4.18), rofecoxib (OR 1.60, 95% CI 1.22 to 2.10), ibuprofen (OR 1.56, 95% CI 1.19 to 2.05) and diclofenac (OR 1.51, 95% CI 1.22 to 1.87) was significantly increased. CV risk with current use of individual COX-2 inhibitors and tNSAIDs was significantly increased (OR from 1.17 to 1.64), as was GI risk with current use of rofecoxib (OR 1.99, 95% CI 1.51 to 2.63), naproxen (OR 4.44, 95% CI 3.36 to 5.86), ibuprofen (OR 1.90, 95% CI 1.40 to 2.58), diclofenac (OR 4.77, 95% CI 3.94 to 5.76), other tNSAIDs (OR 2.59, 95% CI 2.08 to 3.21), but not celecoxib (OR 1.36, 95% CI 0.70 to 2.66). Compared to current use of celecoxib and AMI risk was significantly decreased with current use of naproxen (OR 0.48, 95% CI 0.26 to 0.87) only. GI risk was increased with current naproxen (OR 3.26, 95% CI 1.59 to 6.70) and diclofenac (OR 3.50, 95% CI 1.76 to 6.98).AMI and CV risk increased similarly with individual COX-2 inhibitors and tNSAIDs, whereas GI risk was found to be greater with naproxen and diclofenac. Residual confounding and "channelling" cannot be excluded.