tbuckley/cabot-search huggingface dataset:
Angiotensinogen Gene Promoter Region Variant Modifies Body Size–Ambulatory Blood Pressure Relations in Hypertension
Authors: Armindo D. Tiago, Nilesh J. Samani, Geoffrey P. Candy, Richard Brooksbank, Elena N. Libhaber, Pinhas Sareli, Angela J. Woodiwiss, Gavin R. Norton
Journal: Circulation (2002)

The extent to which genes modify the relationship between risk factors for hypertension and blood pressure (BP) is unclear. As angiotensinogen is expressed in adipose tissue and angiotensinogen (AGT) gene promoter variants influence the production of angiotensinogen, we evaluated the role of AGT gene variants as potential modifiers of body size-BP relations.Five hundred twenty-one hypertensives of African origin sampled from a group with a high mean body mass index (BMI) had 24-hour ambulatory BP (ABP) measurements determined off therapy and were genotyped for the AGT -6G-->A, -532C-->T, -20A-->C, and 704T-->C (M235T) gene variants. Genotypes were also determined in 547 control subjects of African origin who had a normal clinic BP. The -6A and -532C alleles were concordant with the M235T variant. Although AGT gene variants had no independent effects on either the presence of hypertension or ABP values in hypertensives, the -20A-->C polymorphism had a marked influence on the relation between ambulatory systolic BP and BMI. This relation was present in patients homozygous for the -20A allele (n=399, r=0.23, P<0.0001), but absent in those with at least one copy of the -20C allele (n=122, r=0.01, P=0.89). The M235T polymorphism did not impact on the BMI-BP relation. Specificity of the -20A-->C polymorphism effect on the BMI-BP relation is further indicated by the lack of effect on the systolic BP-age relation.An AGT gene promoter region variant is an important modifier of the relation between body size and BP. Hence, these data corroborate the notion that genetic modifiers can produce a profound impact on BP-phenotypic relations.
Brand-Name Prescription Drug Use Among Veterans Affairs and Medicare Part D Patients With Diabetes
Authors: Walid F. Gellad, Julie M. Donohue, Xinhua Zhao, Maria K. Mor, Carolyn T. Thorpe, Jeremy Smith, Chester B. Good, Michael J. Fine, Nancy E. Morden
Journal: Annals of Internal Medicine (2015)

The use of generic instead of brand-name drugs could reduce health care costs. This study compared the use of brand-name diabetes drugs within Medicare Part D and the U.S. Department of Veterans Af...
Tyrosine Kinase Inhibition in Leukemia Induces an Altered Metabolic State Sensitive to Mitochondrial Perturbations
Authors: Francesca Alvarez-Calderon, Mark A. Gregory, Catherine Pham-Danis, Deborah DeRyckere, Brett M. Stevens, Vadym Zaberezhnyy, Amanda A. Hill, Lelisa Gemta, Amit Kumar, Vijay Kumar, Michael F. Wempe, Daniel A. Pollyea, Craig T. Jordan, Natalie J. Serkova, Douglas K. Graham, James DeGregori
Journal: Clinical Cancer Research (2014)

Although tyrosine kinase inhibitors (TKI) can be effective therapies for leukemia, they fail to fully eliminate leukemic cells and achieve durable remissions for many patients with advanced BCR-ABL(+) leukemias or acute myelogenous leukemia (AML). Through a large-scale synthetic lethal RNAi screen, we identified pyruvate dehydrogenase, the limiting enzyme for pyruvate entry into the mitochondrial tricarboxylic acid cycle, as critical for the survival of chronic myelogenous leukemia (CML) cells upon BCR-ABL inhibition. Here, we examined the role of mitochondrial metabolism in the survival of Ph(+) leukemia and AML upon TK inhibition.Ph(+) cancer cell lines, AML cell lines, leukemia xenografts, cord blood, and patient samples were examined.We showed that the mitochondrial ATP-synthase inhibitor oligomycin-A greatly sensitized leukemia cells to TKI in vitro. Surprisingly, oligomycin-A sensitized leukemia cells to BCR-ABL inhibition at concentrations of 100- to 1,000-fold below those required for inhibition of respiration. Oligomycin-A treatment rapidly led to mitochondrial membrane depolarization and reduced ATP levels, and promoted superoxide production and leukemia cell apoptosis when combined with TKI. Importantly, oligomycin-A enhanced elimination of BCR-ABL(+) leukemia cells by TKI in a mouse model and in primary blast crisis CML samples. Moreover, oligomycin-A also greatly potentiated the elimination of FLT3-dependent AML cells when combined with an FLT3 TKI, both in vitro and in vivo.TKI therapy in leukemia cells creates a novel metabolic state that is highly sensitive to particular mitochondrial perturbations. Targeting mitochondrial metabolism as an adjuvant therapy could therefore improve therapeutic responses to TKI for patients with BCR-ABL(+) and FLT3(ITD) leukemias.
Real-Time Hypoglycemia Prediction Suite Using Continuous Glucose Monitoring
Authors: Eyal Dassau, Fraser Cameron, Hyunjin Lee, B. Wayne Bequette, Howard Zisser, Lois Jovanovič, H. Peter Chase, Darrell M. Wilson, Bruce A. Buckingham, Francis J. Doyle
Journal: Diabetes Care (2010)

The purpose of this study was to develop an advanced algorithm that detects pending hypoglycemia and then suspends basal insulin delivery. This approach can provide a solution to the problem of nocturnal hypoglycemia, a major concern of patients with diabetes.This real-time hypoglycemia prediction algorithm (HPA) combines five individual algorithms, all based on continuous glucose monitoring 1-min data. A predictive alarm is issued by a voting algorithm when a hypoglycemic event is predicted to occur in the next 35 min. The HPA system was developed using data derived from 21 Navigator studies that assessed Navigator function over 24 h in children with type 1 diabetes. We confirmed the function of the HPA using a separate dataset from 22 admissions of type 1 diabetic subjects. During these admissions, hypoglycemia was induced by gradual increases in the basal insulin infusion rate up to 180% from the subject's own baseline infusion rate. RESULTS Using a prediction horizon of 35 min, a glucose threshold of 80 mg/dl, and a voting threshold of three of five algorithms to predict hypoglycemia (defined as a FreeStyle plasma glucose readings <60 mg/dl), the HPA predicted 91% of the hypoglycemic events. When four of five algorithms were required to be positive, then 82% of the events were predicted.The HPA will enable automated insulin-pump suspension in response to a pending event that has been detected prior to severe immediate complications.
Impaired canine coronary vasodilator response to acetylcholine and bradykinin after occlusion-reperfusion.
Authors: J L Mehta, W W Nichols, W H Donnelly, D L Lawson, T G Saldeen
Journal: Circulation Research (1989)

Previous studies indicate impairment of coronary arterial ring relaxation in response to acetylcholine (ACh) following coronary reperfusion, mediated via loss of endothelium-derived relaxing factor (EDRF). To examine if coronary vasodilator reserve is reduced following coronary occlusion-reperfusion in intact animals, 16 open-chest mongrel dogs were subjected to 1 hour of total left circumflex (Cx) coronary artery occlusion followed by reperfusion for 1 hour. Prior to Cx occlusion, coronary blood flow increased and vascular resistance decreased (both p less than or equal to 0.01) in response to ACh and bradykinin (BK). Following reperfusion, increase in Cx coronary flow in response to both vasodilators was significantly (p less than or equal to 0.01) impaired. Myocardial histology showed extensive neutrophil infiltration and capillary plugging by neutrophils in the Cx compared with the left anterior descending coronary artery-supplied myocardium. Myocardial myeloperoxidase activity was also increased in the Cx compared with the left anterior descending region (p less than or equal to 0.02). Pretreatment of four dogs with indomethacin partially reduced the vasodilator response to BK but not to ACh. However, indomethacin did not affect reperfusion-induced attenuation of BK or ACh's coronary vasodilator effects. To determine if calcium blocker verapamil would modify reperfusion-induced impairment in coronary vasodilator reserve, six dogs were treated with verapamil. Although verapamil enhanced coronary vasodilator effects of ACh and BK, it did not modify reperfusion-induced attenuation of coronary vasodilator reserve. Myocardial neutrophil accumulation and myeloperoxidase activity was also similar in control, indomethacin, and verapamil-treated dogs. These observations suggest that coronary reperfusion impairs coronary vasodilator reserve in intact dogs. This impairment is not modified by prostaglandin inhibition or by calcium blockade. Besides loss of EDRF, capillary plugging by neutrophils may contribute to the altered coronary flow reserve observed in the immediate post-reperfusion period. Furthermore, indomethacin or verapamil are not effective in modifying the reperfusion-related impairment of coronary vasodilator reserve.
Variants at the promoter of the interleukin-6 gene are associated with severity and outcome of pneumococcal community-acquired pneumonia
Authors: Ignacio Martín-Loeches, Jordi Solé-Violán, Felipe Rodríguez de Castro, M. Isabel García-Laorden, Luis Borderías, José Blanquer, Olga Rajas, M. Luisa Briones, Javier Aspa, Estefanía Herrera-Ramos, José Alberto Marcos-Ramos, Ithaisa Sologuren, Nereida González-Quevedo, José María Ferrer-Agüero, Judith Noda, Carlos Rodríguez-Gallego
Journal: Intensive Care Medicine (2011)
Acute ischaemic hemispheric stroke is associated with impairment of reflex in addition to voluntary cough
Authors: K. Ward, J. Seymour, J. Steier, C.J. Jolley, M.I. Polkey, L. Kalra, J. Moxham
Journal: European Respiratory Journal (2010)

Cough function is impaired after stroke; this may be important for protection against chest infection. Reflex cough (RC) intensity indices have not been described after stroke. RC, voluntary cough (VC) and respiratory muscle strength were studied in patients within 2 weeks of hemispheric infarct. The null hypotheses were that patients with cortical hemisphere stroke would show the same results as healthy controls on: 1) objective indices of RC and VC intensity; and 2) respiratory muscle strength tests. Peak cough flow rate (PCFR) and gastric pressure ( P ga ) were measured during maximum VC and RC. Participants also underwent volitional and nonvolitional respiratory muscle testing. Nonvolitional expiratory muscle strength was assessed by measuring P ga increase after magnetic stimulation over the T 10 nerve roots (twitch T 10 P ga ). Stroke severity was scored using the National Institutes of Health Stroke Scale (NIHSS; maximum = 31). 18 patients (mean± sd age 62±15 yrs and NIHSS score 14±8) and 20 controls (56±16 yrs) participated. VC intensity was impaired in patients (PCFR 287±171 versus 497±122 L·min −1 ) as was VC P ga (98.5±61.6 versus 208.5±61.3 cmH 2 O; p&lt;0.001 for both). RC PCFR was reduced in patients (204±111 versus 379±110 L·min −1 ; p&lt;0.001), but RC P ga was not significantly different from that of controls (179.0±78.0 versus 208.0±77.4 cmH 2 O; p = 0.266). Patients exhibited impaired volitional respiratory muscle tests, but twitch T 10 P ga was normal. VC and RC are both impaired in hemispheric stroke patients, despite preserved expiratory muscle strength. Cough coordination is probably cortically modulated and affected by hemispheric stroke.
Role of Genetic Analyses in Cardiology
Authors: Silvia G. Priori, Carlo Napolitano
Journal: Circulation (2006)

Genetic analysis can be performed to identify the molecular substrate of inherited arrhythmogenic diseases; however, the role of this information in helping the management of patients is still debated. Here, we support the view that the practical value of genetic analysis is different in the various inherited conditions and that it is strongly influenced by the amount of information available in each disease about genotype-phenotype correlations. In some diseases, clinical management of patients is profoundly affected by the type of the underlying genetic defect; therefore, in these conditions, there is a high priority to introduce genetic analysis into clinical practice. In the absence of genotype-phenotype correlations, genetic testing still can be very useful when there is a clinical advantage in establishing presymptomatic diagnosis or when screening of family members may point to reproductive counseling. Finally, there is a high priority for introducing genetic testing for those genetic diseases in which a limited number of genes allow a high yield of successfully genotyped patients. We have developed a "score" to compare the value of genetic testing in arrhythmogenic diseases and to convey our view that the clinical role of genetic analysis is different in the various inherited cardiomyopathies and channelopathies. Healthcare authorities should become responsive to the advancement of knowledge in this field and should help facilitate access to genotyping for families affected by those conditions in which genetic analysis provides useful information for clinical management.
Comprehensive geriatric care for patients with hip fractures: a prospective, randomised, controlled trial
Authors: Anders Prestmo, Gunhild Hagen, Olav Sletvold, Jorunn L Helbostad, Pernille Thingstad, Kristin Taraldsen, Stian Lydersen, Vidar Halsteinli, Turi Saltnes, Sarah E Lamb, Lars G Johnsen, Ingvild Saltvedt
Journal: The Lancet (2015)
Nuclear protein 1 promotes pancreatic cancer development and protects cells from stress by inhibiting apoptosis
Authors: Tewfik Hamidi, Hana Algül, Carla Eliana Cano, Maria José Sandi, Maria Inés Molejon, Marc Riemann, Ezequiel Luis Calvo, Gwen Lomberk, Jean-Charles Dagorn, Falk Weih, Raul Urrutia, Roland Michael Schmid, Juan Lucio Iovanna
Journal: Journal of Clinical Investigation (2012)

Pancreatic ductal adenocarcinoma (PDAC) has the lowest survival rate of all cancers and shows remarkable resistance to cell stress. Nuclear protein 1 (Nupr1), which mediates stress response in the pancreas, is frequently upregulated in pancreatic cancer. Here, we report that Nupr1 plays an essential role in pancreatic tumorigenesis. In a mouse model of pancreatic cancer with constitutively expressed oncogenic Kras(G12D), we found that loss of Nupr1 protected from the development of pancreatic intraepithelial neoplasias (PanINs). Further, in cultured pancreatic cells, nutrient deprivation activated Nupr1 expression, which we found to be required for cell survival. We found that Nupr1 protected cells from stress-induced death by inhibiting apoptosis through a pathway dependent on transcription factor RelB and immediate early response 3 (IER3). NUPR1, RELB, and IER3 proteins were coexpressed in mouse PanINs from Kras(G12D)-expressing pancreas. Moreover, pancreas-specific deletion of Relb in a Kras(G12D) background resulted in delayed in PanIN development associated with a lack of IER3 expression. Thus, efficient PanIN formation was dependent on the expression of Nupr1 and Relb, with likely involvement of IER3. Finally, in patients with PDAC, expression of NUPR1, RELB, and IER3 was significantly correlated with a poor prognosis. Cumulatively, these results reveal a NUPR1/RELB/IER3 stress-related pathway that is required for oncogenic Kras(G12D)-dependent transformation of the pancreas.
Faster Brain Shrinkage in the ACCORD MIND Study
Authors: Rong Zhang, Wanpen Vongpatanasin, Benjamin D. Levine
Journal: JAMA Internal Medicine (2015)

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Validation of a Proliferation-Based Expression Signature as Prognostic Marker in Early Stage Lung Adenocarcinoma
Authors: Ignacio I. Wistuba, Carmen Behrens, Francesca Lombardi, Susanne Wagner, Junya Fujimoto, M. Gabriela Raso, Lorenzo Spaggiari, Domenico Galetta, Robyn Riley, Elisha Hughes, Julia Reid, Zaina Sangale, Steven G. Swisher, Neda Kalhor, Cesar A. Moran, Alexander Gutin, Jerry S. Lanchbury, Massimo Barberis, Edward S. Kim
Journal: Clinical Cancer Research (2013)

Abstract Purpose: New prognostic markers to guide treatment decisions in early stage non–small cell lung cancer are necessary to improve patient outcomes. In this report, we assess the utility of a predefined mRNA expression signature of cell-cycle progression genes (CCP score) to define 5-year risk of lung cancer–related death in patients with early stage lung adenocarcinoma. Experimental Design: A CCP score was calculated from the mRNA expression levels of 31 proliferation genes in stage I and stage II tumor samples from two public microarray datasets [Director's Consortium (DC) and GSE31210]. The same gene set was tested by quantitative PCR in 381 formalin-fixed paraffin-embedded (FFPE) primary tumors. Association of the CCP score with outcome was assessed by Cox proportional hazards analysis. Results: In univariate analysis, the CCP score was a strong predictor of cancer-specific survival in both the Director's Consortium cohort (P = 0.00014; HR = 2.08; 95% CI, 1.43–3.02) and GSE31210 (P = 0.0010; HR = 2.25; 95% CI, 1.42–3.56). In multivariate analysis, the CCP score remained the dominant prognostic marker in the presence of clinical variables (P = 0.0022; HR = 2.02; 95% CI, 1.29–3.17 in Director's Consortium, P = 0.0026; HR = 2.16; 95% CI, 1.32–3.53 in GSE31210). On a quantitative PCR platform, the CCP score maintained highly significant prognostic value in FFPE-derived mRNA from clinical samples in both univariate (P = 0.00033; HR = 2.10; 95% CI, 1.39–3.17) and multivariate analyses (P = 0.0071; HR = 1.92; 95% CI, 1.18–3.10). Conclusions: The CCP score is a significant predictor of lung cancer death in early stage lung adenocarcinoma treated with surgery and may be a valuable tool in selecting patients for adjuvant treatment. Clin Cancer Res; 19(22); 6261–71. ©2013 AACR.
Barriers to Human Papillomavirus Vaccination Among US Adolescents
Authors: Dawn M. Holman, Vicki Benard, Katherine B. Roland, Meg Watson, Nicole Liddon, Shannon Stokley
Journal: JAMA Pediatrics (2013)

Since licensure of the human papillomavirus (HPV) vaccine in 2006, HPV vaccine coverage among US adolescents has increased but remains low compared with other recommended vaccines.To systematically review the literature on barriers to HPV vaccination among US adolescents to inform future efforts to increase HPV vaccine coverage.We searched PubMed and previous review articles to identify original research articles describing barriers to HPV vaccine initiation and completion among US adolescents. Only articles reporting data collected in 2009 or later were included. Findings from 55 relevant articles were summarized by target populations: health care professionals, parents, underserved and disadvantaged populations, and males.Health care professionals cited financial concerns and parental attitudes and concerns as barriers to providing the HPV vaccine to patients. Parents often reported needing more information before vaccinating their children. Concerns about the vaccine's effect on sexual behavior, low perceived risk of HPV infection, social influences, irregular preventive care, and vaccine cost were also identified as potential barriers among parents. Some parents of sons reported not vaccinating their sons because of the perceived lack of direct benefit. Parents consistently cited health care professional recommendations as one of the most important factors in their decision to vaccinate their children.Continued efforts are needed to ensure that health care professionals and parents understand the importance of vaccinating adolescents before they become sexually active. Health care professionals may benefit from guidance on communicating HPV recommendations to patients and parents. Further efforts are also needed to reduce missed opportunities for HPV vaccination when adolescents interface with the health care system. Efforts to increase uptake should take into account the specific needs of subgroups within the population. Efforts that address system-level barriers to vaccination may help to increase overall HPV vaccine uptake.
The effects of cocaine and metanephrine on the cardiac responses to sympathetic nerve stimulation in dogs.
Authors: Y Matsuda, Y Masuda, M N Levy
Journal: Circulation Research (1979)

The effects of infusions of cocaine (COC) and metanephrine (MET) on the inotropic and chronotropic responses to cardiac sympathetic nerve stimulation were studied in open-chest, anesthetized dogs. COC blocks the neuronal uptake of norepinephrine (NE), whereas MET blocks the extraneuronal uptake. Both blocking agents slightly enhanced the inotropic but not the chronotropic responses. COC prolonged the cardiac responses significantly, particularly the chronotropic responses, whereas MET had no appreciable effect on the durations of these responses. Hence, it appears that the neuronal uptake mechanism plays a major role in the dissipation of neurally released NE in the heart, but that the extra-neuronal uptake mechanism plays only a minor role in its dissipation. In contrast to the results in certain other tissues, the combined effects of COC and MET on the cardiac responses were no greater or more prolonged than the sum of the effects produced by each agent acting alone.