tbuckley/cabot-search huggingface dataset:
The unique hypusine modification of eIF5A promotes islet β cell inflammation and dysfunction in mice
Authors: Bernhard Maier, Takeshi Ogihara, Anthony P. Trace, Sarah A. Tersey, Reiesha D. Robbins, Swarup K. Chakrabarti, Craig S. Nunemaker, Natalie D. Stull, Catherine A. Taylor, John E. Thompson, Richard S. Dondero, Eli C. Lewis, Charles A. Dinarello, Jerry L. Nadler, Raghavendra G. Mirmira
Journal: Journal of Clinical Investigation (2010)

In both type 1 and type 2 diabetes, pancreatic islet dysfunction results in part from cytokine-mediated inflammation. The ubiquitous eukaryotic translation initiation factor 5A (eIF5A), which is the only protein to contain the amino acid hypusine, contributes to the production of proinflammatory cytokines. We therefore investigated whether eIF5A participates in the inflammatory cascade leading to islet dysfunction during the development of diabetes. As described herein, we found that eIF5A regulates iNOS levels and that eIF5A depletion as well as the inhibition of hypusination protects against glucose intolerance in inflammatory mouse models of diabetes. We observed that following knockdown of eIF5A expression, mice were resistant to beta cell loss and the development of hyperglycemia in the low-dose streptozotocin model of diabetes. The depletion of eIF5A led to impaired translation of iNOS-encoding mRNA within the islet. A role for the hypusine residue of eIF5A in islet inflammatory responses was suggested by the observation that inhibition of hypusine synthesis reduced translation of iNOS-encoding mRNA in rodent beta cells and human islets and protected mice against the development of glucose intolerance the low-dose streptozotocin model of diabetes. Further analysis revealed that hypusine is required in part for nuclear export of iNOS-encoding mRNA, a process that involved the export protein exportin1. These observations identify the hypusine modification of eIF5A as a potential therapeutic target for preserving islet function under inflammatory conditions.
Head of NHS praises GPs' plans for commissioning
Authors: A. O'Dowd
Journal: BMJ (2012)

Caloric restriction (CR) reduces the pathological effects of aging and extends the lifespan in many species, including nonhuman primates, although the effect on the brain is less well characterized. We used two common indicators of aging, motor performance speed and brain iron deposition measured <i>in vivo</i> using MRI, to determine the potential effect of CR on elderly rhesus macaques eating restricted (<i>n</i> = 24; 13 males, 11 females) and standard diets (<i>n</i> = 17; 8 males, 9 females). Both the CR and control monkeys showed age-related increases in iron concentrations in globus pallidus (GP) and substantia nigra (SN), although the CR group had significantly less iron deposition in the GP, SN, red nucleus, and temporal cortex. A diet × age interaction revealed that CR modified age-related brain changes, evidenced as attenuation in the rate of iron accumulation in basal ganglia and parietal, temporal, and perirhinal cortex. Additionally, control monkeys had significantly slower fine motor performance on the Movement Assessment Panel, which was negatively correlated with iron accumulation in left SN and parietal lobe, although CR animals did not show this relationship. Our observations suggest that the CR-induced benefit of reduced iron deposition and preserved motor function may indicate neural protection similar to effects described previously in aging rodent and primate species.
Pharmacokinetic Modeling of Tumor Bioluminescence Implicates Efflux, and Not Influx, as the Bigger Hurdle in Cancer Drug Therapy
Authors: Hoon Sim, Kristin Bibee, Samuel Wickline, David Sept
Journal: Cancer Research (2010)

In vivo bioluminescence imaging is a powerful tool for assessing tumor burden and quantifying therapeutic response in xenograft models. However, this technique exhibits significant variability as a consequence of differences in substrate administration, as well as the tumor size, type, and location. Here, we present a novel pharmacokinetic (PK) approach that utilizes bioluminescence image data. The sample data are taken from mice implanted with a melanoma tumor cell line that was transfected to express the firefly (Photinus pyralis) luciferase gene. At 5, 7, and 10 days postimplant, intraperitoneal injections of D-luciferin were given to monitor the uptake into the tumor, and the tumor volume was measured using ultrasound. A multicompartment PK model was used to simultaneously fit all experiments for each mouse. We observed that the rates of luciferin transport in and out of the tumor exhibited a clear dependence on the tumor volume. Also, the rate of tumor influx increased faster than did the efflux, resulting in a shortening of the time to peak-luciferin concentration as the tumor grows. The time of the peak concentration correlated poorly with the tumor volume, but the peak bioluminescence signal and the area under the curve both exhibited a dependence on the tumor surface area. These results agree with Starling's hypothesis relating the higher interstitial fluid pressure in the tumor with flux across the boundary, and suggest that drug transport may depend more strongly on the surface area of the tumor than its volume. These observations provide a quantitative physical rationale for molecular targeting of therapeutics that enhance trapping and overcome the accelerated efflux kinetics.
Leg Scanning With Radioisotope-Labeled Fibrinogen in Patients Undergoing Hip Surgery
Authors: J. Richard LeMoine
Journal: JAMA (1980)

To establish whether radioisotope-labeled fibrinogen leg scanning is of value in the context of hip surgery, we prospectively studied 21 consecutive patients undergoing either total hip replacement (14) or open repair of a hip fracture (seven) with leg scans, contrast phlebography, and ventilation and perfusion lung scans. We found that in eight patients (38%), venous thromboembolism developed postoperatively. Agreement between phlebographic and leg scanning results was excellent. In no patient was venous thrombosis limited to the thigh on the operated-on side, a vital consideration in application of fibrinogen leg scanning to this patient population. Two patients had lung scan changes indicative of embolism; both had thrombi extending into thigh veins. Leg scanning with radioisotope-labeled fibrinogen appears to be a useful method for monitoring patients undergoing hip surgery, if the upper three counting points on the operated-on side are excluded. (<i>JAMA</i>243:2035-2037, 1980)
Low-Level Lead Exposure, Metabolic Syndrome, and Heart Rate Variability: The VA Normative Aging Study
Authors: Sung Kyun Park, Joel Schwartz, Marc Weisskopf, David Sparrow, Pantel S. Vokonas, Robert O. Wright, Brent Coull, Huiling Nie, Howard Hu
Journal: Environmental Health Perspectives (2006)

Altered heart rate variability (HRV), a marker of poor cardiac autonomic function, has been associated with sudden cardiac death and heart failure.We examined the association of low-level lead exposure measured in bone by K-X-ray fluorescence with alterations in HRV, and whether metabolic syndrome (MetS) or its individual components modify those associations.HRV measures [power in high-frequency (HFnorm) and low-frequency (LFnorm) in normalized units, and LF/HF] were taken among 413 elderly men from the Normative Aging Study. MetS was defined as subjects having three or more of the following criteria: abdominal obesity, hypertriglyceridemia, low high-density lipoprotein, high blood pressure, and high fasting glucose.Of the subjects, 32% were identified as having MetS. Inverse but nonstatistically significant associations of both tibia and patella lead levels with HFnorm and nonstatistically significant positive relations with LFnorm and LF/HF were found in the entire cohort. There was a graded, statistically significant reduction in HFnorm and increases in LFnorm and LF/HF in association with an increase in patella lead as the number of metabolic abnormalities increased. We also observed that higher patella lead was consistently associated with lower HFnorm and higher LFnorm and LF/HF among subjects with MetS or its individual components. No statistically significant interaction between MetS and tibia lead was observed.The results suggest that elderly men with MetS were more susceptible to autonomic dysfunction in association with chronic lead exposure as measured in patella. The modification by MetS is consistent with a role for oxidative stress in lead toxicity on the cardiovascular system.
A Systematic Review and Meta-Analysis of Hypoglycemia and Cardiovascular Events
Authors: Azim S. Gangji, Tali Cukierman, Hertzel C. Gerstein, Charles H. Goldsmith, Catherine M. Clase
Journal: Diabetes Care (2007)

Glyburide is the most widely used sulfonylurea but has unique pharmacodynamic properties that may increase harm. We hypothesized that glyburide causes more hypoglycemia and cardiovascular events than other secretagogues or insulin.Data sources were Medline, Embase, Cochrane, and three other web-based clinical trial registers (1966-2005). Parallel, randomized, controlled trials in people with type 2 diabetes comparing glyburide monotherapy with monotherapy using secretagogues or insulin were selected. Outcomes were hypoglycemia, glycemic control, cardiovascular events, body weight, and death. Titles and abstracts of 1,806 publications were reviewed in duplicate and 21 relevant articles identified. Data on patient characteristics, interventions, outcomes, and validity were extracted in duplicate using predefined criteria.Glyburide was associated with a 52% greater risk of experiencing at least one episode of hypoglycemia compared with other secretagogues (relative risk 1.52 [95% CI 1.21-1.92]) and with 83% greater risk compared with other sulfonylureas (1.83 [1.35-2.49]). Glyburide was not associated with an increased risk of cardiovascular events (0.84 [0.56-1.26]), death (0.87 [0.70-1.07]), or end-of-trial weight (weighted mean difference 1.69 kg [95% CI -0.41 to 3.80]) compared with other secretagogues. Limitations included suboptimal reporting of original trials. Loss to follow-up exceeded 20% in some studies, and major hypoglycemia was infrequently reported.Glyburide caused more hypoglycemia than other secretagogues and other sulfonylureas. Glyburide was not associated with an increased risk of cardiovascular events, death, or weight gain.
Further explorations of the empirical and theoretical aspects of the emulation theory
Authors: Rick Grush
Journal: Behavioral and Brain Sciences (2004)

The emulation theory of representation articulated in the target article is further explained and explored in this response to commentaries. Major topics include: the irrelevance of equilibrium-point and related models of motor control to the theory; clarification of the particular sense of “representation” which the emulation theory of representation is an account of; the relation between the emulation framework and Kalman filtering; and addressing the empirical data considered to be in conflict with the emulation theory. In addition, I discuss the further empirical support for the emulation theory provided by some commentators, as well as a number of suggested theoretical applications.
The chemotherapy of metastatic gastric adenocarcinomas with hypersecretion of α-fetoprotein or β-human chorionic gonadotrophin: report of two cases
Authors: N. Germann, M. Gross-Goupil, E. Wasserman, J.-F. Emile, J.-L. Misset, M. Reynes, F. Goldwasser
Journal: Annals of Oncology (2002)
Interdisciplinary management of EGFR-inhibitor-induced skin reactions: a German expert opinion
Authors: K. Potthoff, R. Hofheinz, J.C. Hassel, M. Volkenandt, F. Lordick, J.T. Hartmann, M. Karthaus, H. Riess, H.P. Lipp, A. Hauschild, T. Trarbach, A. Wollenberg
Journal: Annals of Oncology (2010)
Skin Manifestations, Multiple Aneurysms, and Carotid-Cavernous Fistula in Ehlers-Danlos Syndrome Type IV
Authors: Jay-Hyun Koh, Joo Sung Kim, Seung-Chyul Hong, Yeon Hyeon Choe, Young Soo Do, Hong Sik Byun, Won Ro Lee, Duk-Kyung Kim
Journal: Circulation (1999)
Insulin Delivery Systems: Do They Need a Glucose Sensor?
Authors: A M Albisser
Journal: Diabetes Care (1982)

New systems are being developed for continuous insulin infusion in diabetes mellitus. Of these, the bedside closed-loop system (artificial B-cell) normalizes measured blood glucose in the fasting and fed states, while favorably altering other fuel substrates and hormone levels in short-term studies of 1-2 days. More recent portable, external open-loop insulin delivery systems have been developed which can be programmed to achieve similar results in long-term studies in animals and humans. This is accomplished without the need for continuous glucose sensing. The partial metabolic normalization achieved is not compromised by physical exercise, and unacceptably low blood glucose levels are rarely observed. Further development and application of these new systems will enable researchers to establish whether the achievement of ideal metabolic control in diabetes can be realized with or without sensors for glucose or other metabolites.
Nuclear factors that mediate intrathymic signals are developmentally regulated.
Authors: J Sen, Y Shinkai, F W Alt, R Sen, S J Burakoff
Journal: The Journal of Experimental Medicine (1994)

Thymocytes mature through several stages of development, defined by cell surface markers such as CD3, CD4, and CD8, in response to environmental cues. Signal transduction resulting from lymphocyte-stromal cell interactions is likely to activate inducible transcription factors which in turn govern stage-specific gene expression. In this report we show that inducible transcription factors such as AP-1 and NF-AT are constitutively nuclear, in response to intrathymic signals, in freshly isolated thymocytes at all stages of maturation. In CD4+CD8+ double positive (DP), but not in the more immature CD4-CD8- double negative (DN) thymocytes, constant stimulus from the thymic environment is required to maintain nuclear AP-1. Thus, disruption of the thymus and incubation of thymocytes at 37 degrees C downregulates DNA binding by nuclear factors AP-1 and NF-AT. Similar treatment of thymocytes has previously been shown to downregulate CD3 zeta chain phosphorylation and increase T cell receptor CD3 expression on DP thymocytes, which is a feature of repertoire selection. Since mature T cells maintain inducible nuclear factors in an inactive form until an encounter with antigen, we propose that downregulation of nuclear DNA binding proteins may reflect another feature of this stage of T cell maturation.
Phase I and Pharmacokinetic Study of Cetuximab and Irinotecan in Children With Refractory Solid Tumors: A Study of the Pediatric Oncology Experimental Therapeutic Investigators' Consortium
Authors: Tanya M. Trippett, Cynthia Herzog, James A. Whitlock, Johannes Wolff, John Kuttesch, Rochelle Bagatell, Stephen P. Hunger, Jessica Boklan, Amy A. Smith, Robert J. Arceci, Howard M. Katzenstein, Christopher Harbison, Xiaofei Zhou, Haolan Lu, Christiane Langer, Martin Weber, Lia Gore
Journal: Journal of Clinical Oncology (2009)

Purpose To determine the dose of cetuximab that can be safely combined with irinotecan for treatment of pediatric and adolescent patients with refractory solid tumors. Patients and Methods This open-label, phase I study enrolled patients ages 1 to 18 years with advanced refractory solid tumors, including tumors of the CNS. Patient cohorts by age group (children, ages 1 to 12 years; adolescents, ages 13 to 18 years) received escalating weekly doses of cetuximab (75, 150, 250 mg/m 2 ) in a 3 + 3 design, plus irinotecan (16 or 20 mg/m 2 /d) for 5 days for 2 consecutive weeks every 21 days. The primary end points were establishing the maximum-tolerated dose (MTD), recommended phase II dose (RPIID), and pharmacokinetics of the combination. Preliminary safety and efficacy data were also collected. Results Twenty-seven children and 19 adolescents received a median of 7.1 and 6.0 weeks of cetuximab therapy, respectively. Cetuximab 250 mg/m 2 weekly plus irinotecan 16 mg/m 2 /d (pediatric) or 20 mg/m 2 /d (adolescent) have been established as the MTD/RPIID. Dose-limiting toxicities included diarrhea and neutropenia. Mild to moderate (grade 1 to 2) acneiform rash occurred in a majority of patients; no grade 3 to 4 rashes were observed. Cetuximab demonstrated dose-dependent clearance in both children and adolescents, similar to that in adults. There were two confirmed partial responses, both in patients with CNS tumors. Stable disease was achieved in 18 patients overall, including 10 patients with CNS tumors (38.5%). Conclusion The cetuximab/irinotecan combination can be given safely to children and adolescents with cancer. Promising activity, particularly in CNS tumors, warrants phase II evaluation of this regimen.
Type II secretory phospholipase A2 in cardiovascular disease: a mediator in atherosclerosis and ischemic damage to cardiomyocytes?
Authors: H Niessen
Journal: Cardiovascular Research (2003)

Inflammatory reactions contribute to the pathogenesis of cardiovascular conditions such as atherosclerosis and ischemic damage in acute myocardial infarction (AMI). Among the mediators involved in inflammation are secretory phospholipase A2 group II (sPLA2-II) enzymes. Though some cells constitutively express sPLA2-II, the synthesis by cells such as hepatocytes is typical for an acute-phase reactant. Recent literature suggests multiple roles for sPLA2-II in cardiovascular disease. In this review we discuss the role of sPLA2-II in various in vivo and in vitro models of atherosclerosis or AMI, including the therapeutic perspective of sPLA2-II inhibitors. It was concluded that sPLA2-II appears to be an important inflammatory mediator of cardiovascular disease.
Impact of Total Lymph Node Count on Staging and Survival After Gastrectomy for Gastric Cancer: Data From a Large US-Population Database
Authors: David D. Smith, Rebecca R. Schwarz, Roderich E. Schwarz
Journal: Journal of Clinical Oncology (2005)

Prognosis of potentially curable (M0), completely resected gastric cancer is primarily determined by pathologic T and N staging criteria. The optimal regional dissection extent during gastrectomy for gastric adenocarcinoma continues to be debated.A gastric cancer data set was created through structured queries to the Surveillance, Epidemiology, and End Results database (1973 to 1999). Relationships between the number of lymph nodes (LNs) examined and survival were analyzed for the stage subgroups T1/2N0, T1/2N1, T3N0, and T3N1.In every stage subgroup, overall survival was highly dependent on the number of LNs examined. Multivariate prognostic variables in the T1/2N0M0 subgroup were number of LNs examined, age (for both, P < .0001), race (P = .0004), sex (P = .0006), and tumor size (P = .02). A linear trend for superior survival based on more LNs examined could be confirmed for all four stage subgroups. Baseline model-predicted 5-year survival with only one LN examined was 56% (T1/2N0), 35% (T1/2N1), 29% (T3N0), or 13% (T3N1). For every 10 extra LNs dissected, survival improved by 7.6% (T1/2N0), 5.7% (T1/2N1), 11% (T3N0), or 7% (T3N1). A cut-point analysis yielded the greatest survival difference at 10 LNs examined but continued to detect significantly superior survival differences for cut points at up to 40 LNs, always in favor of more LNs examined.Although the impact of stage migration versus improved regional disease control cannot be separated on basis of the available information, the data provide support in favor of extended lymphadenectomy during potentially curative gastrectomy for gastric cancer.
Hospital Readmission With Feeding-Related Problems After Early Postpartum Discharge of Normal Newborns
Authors: M. Bruce Edmonson
Journal: JAMA (1997)

Increasingly short postpartum hospital stays in the United States precipitated a policy debate that culminated in passage of the Newborns' and Mothers' Health Protection Act of 1996. The debate occurred without population-based evidence for adverse health effects in newborns who are discharged early.To determine whether early postpartum hospital discharge of normal newborns increases their risk for hospital readmission with feeding-related problems.Nested case-control analysis of 1991 to 1994 Wisconsin birth certificate and hospital discharge data.A total of 210 readmitted case patients and 630 control subjects selected from a cohort of 120 290 normal newborns who weighed at least 2500 g, were delivered vaginally of mothers with uncomplicated medical and obstetrical histories, and were discharged from the hospital either early (day of life 1 or 2) or conventionally (day 3).Readmission at age 4 to 28 days with discharge diagnoses indicating a primary feeding problem, secondary dehydration, or inadequate weight gain.Early discharges increased 3-fold (reaching 521/1000 discharges) during the study period, but feeding-related readmissions (1.7/1000) remained stable. Most readmitted newborns (53.8%) were 4 to 7 days old, many (34.3%) had concurrent dehydration and jaundice, and 29% were admitted through emergency departments. Readmitted newborns were significantly (P<.05) more likely to have been breast-fed, firstborn, or preterm or to have mothers who were poorly educated (<12th grade), unmarried, or receiving Medicaid. Readmission was not associated with early discharge (adjusted odds ratio, 1.05; 95% confidence interval, 0.71-1.53).Although several neonatal and maternal factors increase the risk that a normal newborn will be rehospitalized with a feeding-related problem, early discharge following an uncomplicated postpartum hospital stay appears to have little or no independent effect on this risk.
Antiapoptotic Effect of Growth Factors in Leukemia
Authors: Wai M. Liu, Richard Baird, Debashis Sarker, Thomas Powles
Journal: Journal of Clinical Oncology (2005)

We have read with great interest the article by Ringden et al, 1 who reported on the risk of graftversus-host disease (GVHD) and death in patients with acute leukemia receiving granulocyte-colony-stimulating factor (G-CSF) after allogeneic bone marrow (BM) transplantation.In this retrospective analysis, patients received bone marrow or peripheral blood stem cells (PBSC), and were administered phrophylatic G-CSF post-transplantation.An increase in GVHD and treatment-related mortality (TRM) was observed only in patients receiving G-CSF after BM transplantation.Similarly, overall and leukemia-free survival rates were significantly reduced (relative to control risks: 0.59, P Ͻ .0001;0.64, P ϭ .0003,respectively).The results of this study differ from the recently published meta-analyses examining the effect of growth factors on GVHD after allogeneic transplantation. 2 In addition, as discussed in the accompanying editorial, there were significant differences between the two arms in terms of patient characteristics, GVHD prophylaxis, and disease stage.However, although the authors emphasized the possibility of center effect or bias and discussed their rationale in disregarding interpatient or interstudy variability, no clear hypotheses to explain the negative effects of G-CSF in the GVHD-sensitive cohort were mooted.There are fundamental differences in the leukocyte profiles of PBSC and BM that need to be considered, which could explain the differences in response to G-CSF.It is already known that 85% of PBSC are composed of granulocytes that undergo apoptosis more readily. 3Therefore, G-CSF would have minimal effects on these cells.Conversely, BM is rich in pluripotent cells highly expressing functional G-CSF receptors, and would respond to the ligand more effectively.This could easily promote the immunogenic cells responsible for the GVHD.We have recently reported granulocyte-macrophage colony-stimulating factor, a growth factor with similar function and target to G-CSF 4,5 that could potentiate antiapoptotic function in cells expressing the receptor, thereby maintaining the cell viability. 6Consequently, it would have been useful to know the G-CSF receptor expression of the bone marrow and PBSCs.It is intriguing to speculate that G-CSF-mediated GVHD was compounded by this feature.