tbuckley/cabot-search huggingface dataset:
GA<sup>2</sup>LEN skin test study II: clinical relevance of inhalant allergen sensitizations in Europe
Authors: G. J. Burbach, L. M. Heinzerling, G. Edenharter, C. Bachert, C. Bindslev‐Jensen, S. Bonini, J. Bousquet, L. Bousquet‐Rouanet, P. J. Bousquet, M. Bresciani, A. Bruno, G. W. Canonica, U. Darsow, P. Demoly, S. Durham, W. J. Fokkens, S. Giavi, M. Gjomarkaj, C. Gramiccioni, T. Haahtela, M. L. Kowalski, P. Magyar, G. Muraközi, M. Orosz, N. G. Papadopoulos, C. Röhnelt, G. Stingl, A. Todo‐Bom, E. Von Mutius, A. Wiesner, S. Wöhrl, T. Zuberbier
Journal: Allergy (2009)

Skin prick testing is the standard for diagnosing IgE-mediated allergies. A positive skin prick reaction, however, does not always correlate with clinical symptoms. A large database from a Global Asthma and Allergy European Network (GA(2)LEN) study with data on clinical relevance was used to determine the clinical relevance of sensitizations against the 18 most frequent inhalant allergens in Europe. The study population consisted of patients referred to one of the 17 allergy centres in 14 European countries (n = 3034, median age = 33 years). The aim of the study was to assess the clinical relevance of positive skin prick test reactions against inhalant allergens considering the predominating type of symptoms in a pan-European population of patients presenting with suspected allergic disease.Clinical relevance of skin prick tests was recorded with regard to patient history and optional additional tests. A putative correlation between sensitization and allergic disease was assessed using logistic regression analysis.While an overall rate of >or=60% clinically relevant sensitizations was observed in all countries, a differential distribution of clinically relevant sensitizations was demonstrated depending on type of allergen and country where the prick test was performed. Furthermore, a significant correlation between the presence of allergic disease and the number of sensitizations was demonstrated.This study strongly emphasizes the importance of evaluating the clinical relevance of positive skin prick tests and calls for further studies, which may, ultimately, help increase the positive predictive value of allergy testing.
Ionizing Radiation Activates the Nrf2 Antioxidant Response
Authors: J. Tyson McDonald, Kwanghee Kim, Andrew J. Norris, Erina Vlashi, Tiffany M. Phillips, Chann Lagadec, Lorenza Della Donna, Josephine Ratikan, Heather Szelag, Lynn Hlatky, William H. McBride
Journal: Cancer Research (2010)

The transcription factor NF-E2-related factor 2 (Nrf2) binds the antioxidant DNA response element (ARE) to activate important cellular cytoprotective defense systems. Recently several types of cancers have been shown to overexpress Nrf2, but its role in the cellular response to radiation therapy has yet to be fully determined. In this study, we report that single doses of ionizing radiation from 2 to 8 Gy activate ARE-dependent transcription in breast cancer cells in a dose-dependent manner, but only after a delay of five days. Clinically relevant daily dose fractions of radiation also increased ARE-dependent transcription, but again only after five days. Downstream activation of Nrf2-ARE-dependent gene and protein markers, such as heme oxygenase-1, occurred, whereas Nrf2-deficient fibroblasts were incapable of these responses. Compared with wild-type fibroblasts, Nrf2-deficient fibroblasts had relatively high basal levels of reactive oxygen species that increased greatly five days after radiation exposure. Further, in vitro clonogenic survival assays and in vivo sublethal whole body irradiation tests showed that Nrf2 deletion increased radiation sensitivity, whereas Nrf2-inducing drugs did not increase radioresistance. Our results indicate that the Nrf2-ARE pathway is important to maintain resistance to irradiation, but that it operates as a second-tier antioxidant adaptive response system activated by radiation only under specific circumstances, including those that may be highly relevant to tumor response during standard clinical dose-fractionated radiation therapy.
Propagated Endothelial Ca <sup>2+</sup> Waves and Arteriolar Dilation In Vivo
Authors: Yvonne N. Tallini, Johan Fredrik Brekke, Bo Shui, Robert Doran, Seong-min Hwang, Junichi Nakai, Guy Salama, Steven S. Segal, Michael I. Kotlikoff
Journal: Circulation Research (2007)

To study endothelial cell (EC)- specific Ca(2+) signaling in vivo we engineered transgenic mice in which the Ca(2+) sensor GCaMP2 is placed under control of endogenous connexin40 (Cx40) transcription regulatory elements within a bacterial artificial chromosome (BAC), resulting in high sensor expression in arterial ECs, atrial myocytes, and cardiac Purkinje fibers. High signal/noise Ca(2+) signals were obtained in Cx40(BAC)-GCaMP2 mice within the ventricular Purkinje cell network in vitro and in ECs of cremaster muscle arterioles in vivo. Microiontophoresis of acetylcholine (ACh) onto arterioles triggered a transient increase in EC Ca(2+) fluorescence that propagated along the arteriole with an initial velocity of approximately 116 microm/s (n=28) and decayed over distances up to 974 microm. The local rise in EC Ca(2+) was followed (delay, 830+/-60 ms; n=8) by vasodilation that conducted rapidly (mm/s), bidirectionally, and into branches for distances exceeding 1 mm. At intermediate distances (300 to 600 microm), rapidly-conducted vasodilation occurred without changing EC Ca(2+), and additional dilation occurred after arrival of a Ca(2+) wave. In contrast, focal delivery of sodium nitroprusside evoked similar local dilations without Ca(2+) signaling or conduction. We conclude that in vivo responses to ACh in arterioles consists of 2 phases: (1) a rapidly-conducted vasodilation initiated by a local rise in EC Ca(2+) but independent of EC Ca(2+) signaling at remote sites; and (2) a slower complementary dilation associated with a Ca(2+) wave that propagates along the endothelium.
On Real-Time Estimates of Blood Glucose Levels: Response to Garg et al. and Deiss et al.
Authors: George Trevin̄o
Journal: Diabetes Care (2007)

Recent articles (1–3) have emphasized the need for real-time assessment of blood glucose levels. Real-time analysis is motivated by the belief that the random time series being analyzed manifests average properties that change with the passage of time. Results of such analyses are presented to patients as means (μ) ± SD. Farmer et al. (3) report that their statistical analysis is carried out using SPSS version 11; …
P67 Electronic prescribing alerts significantly increase oxygen prescribing
Authors: CL Peplow, L Ward, D Thickett, R Thompson
Journal: Thorax (2013)

<h3>Introduction</h3> In 2011, the number of patients using oxygen without a prescription within a teaching hospital in the West Midlands was higher than the national average (local 11.3% vs national 7.1%). Following this, an electronic alert was incorporated into a bespoke prescribing system to remind doctors to prescribe oxygen. This alert was triggered whenever the oxygen saturations of a patient were recorded on supplemental oxygen without an oxygen prescription. <h3>Method</h3> Data was collected using the standard BTS oxygen prescribing audit proforma in October 2011 and October 2012. In 2012, 215 patients from six medical and respiratory wards were included; 40 were on supplemental oxygen. We used Fisher exact test to analyse our data. <h3>Results</h3> The number of patients using oxygen with a valid prescription increased significantly from 42.9% in 2011 to 72.5% in 2012 (p = 0.023). The national average for oxygen prescriptions in 2012 was 52.3%. Oxygen is being signed for on drug round s more often, 64.1% of the time compared with 13.5% the previous year. Despite the number of oxygen prescriptions increasing significantly, the proportion of patients with saturations in their target range actually decreased. <h3>Conclusions</h3> The number of oxygen prescriptions have increased significantly with the introduction of an electronic alert system. Potential development s for the future would include an automatic prescription with ‘opt out’ facility and an alert for nursing staff when oxygen saturations are out of range to allow better titration of oxygen. This study shows that use of information technology and prescribing alerts and reminders can have a significant effect on number of prescriptions. What remains to be seen is if this will have an effect on patient outcomes. <h3>References</h3> O9Driscoll BR <i>et al</i>. BTS guideline for emergency oxygen use in adult patients., <i>Thorax</i>. 2008 Oct;63 Suppl 6:vi1–68 O9Driscoll BR Emergency oxygen use. 2012 <i>BMJ</i>;345:e6856. Brent Mollon <i>et al.</i> Features predicting the success of computerized decision support for prescribing: a systematic review of randomized controlled trials. <i>BMC Medical Informatics and Decision Making</i> 2009, <b>9</b>:11
USEFULNESS OF THE INDEX OF MICROCIRCULATORY RESISTANCE FOR PREDICTING LATE LEFT VENTRICULAR REMODELING AND RECOVERY IMMEDIATELY AFTER PRIMARY ANGIOPLASTY IN ANTERIOR MYOCARDIAL INFARCTION
Authors: Hong-Seok Lim, Myeong-Ho Yoon, Seung Jea Tahk, Hyoung-Mo Yang, Kyoung Woo Seo, Byoung-Joo Choi, So-Yeon Choi, Jin-Sun Park, Gyo-Seung Hwang, Joon-Han Shin
Journal: Journal of the American College of Cardiology (2012)
Adaptation of HIV-1 to Its Human Host
Authors: Louise V. Wain, Elizabeth Bailes, Frederic Bibollet-Ruche, Julie M. Decker, Brandon F. Keele, Fran Van Heuverswyn, Yingying Li, Jun Takehisa, Eitel Mpoudi Ngole, George M. Shaw, Martine Peeters, Beatrice H. Hahn, Paul M. Sharp
Journal: Molecular Biology and Evolution (2007)

Human immunodeficiency virus type 1 (HIV-1) originated from three independent cross-species transmissions of simian immunodeficiency virus (SIVcpzPtt) infecting chimpanzees (Pan troglodytes troglodytes) in west central Africa, giving rise to pandemic (group M) and non-pandemic (groups N and O) clades of HIV-1. To identify host-specific adaptations in HIV-1 we compared the inferred ancestral sequences of HIV-1 groups M, N and O to 12 full length genome sequences of SIVcpzPtt and four of the outlying but closely related SIVcpzPts (from P. t. schweinfurthii). This analysis revealed a single site that was completely conserved among SIVcpzPtt strains but different (due to the same change) in all three groups of HIV-1. This site, Gag-30, lies within p17, the gag-encoded matrix protein. It is Met in SIVcpzPtt, underwent a conservative replacement by Leu in one lineage of SIVcpzPts but changed radically to Arg on all three lineages leading to HIV-1. During subsequent diversification this site has been conserved as a basic residue (Arg or Lys) in most lineages of HIV-1. Retrospective analysis revealed that Gag-30 had reverted to Met in a previous experiment in which HIV-1 was passaged through chimpanzees. To examine whether this substitution conferred a species specific growth advantage, we used site-directed mutagenesis to generate variants of these chimpanzee-adapted HIV-1 strains with Lys at Gag-30, and tested their replication in both human and chimpanzee CD4+ T lymphocytes. Remarkably, viruses encoding Met replicated to higher titers than viruses encoding Lys in chimpanzee T cells, but the opposite was found in human T cells. Taken together, these observations provide compelling evidence for host-specific adaptation during the emergence of HIV-1 and identify the viral matrix protein as a modulator of viral fitness following transmission to the new human host.
Accelerated Insulin Pharmacokinetics and Improved Postprandial Glycemic Control in Patients With Type 1 Diabetes After Coadministration of Prandial Insulins With Hyaluronidase
Authors: Marcus Hompesch, Douglas B. Muchmore, Linda Morrow, Daniel E. Vaughn
Journal: Diabetes Care (2011)

To compare the pharmacokinetics, pharmacodynamics, and safety of insulin lispro or regular human insulin (RHI) with or without recombinant human hyaluronidase (rHuPH20) administered before a standardized meal.In this four-way, crossover study, 22 patients with type 1 diabetes received injections of individually optimized doses of lispro or RHI with and without rHuPH20 before a liquid meal.With rHuPH20 coadministration, early insulin exposure (0-60 min) increased by 54% (P = 0.0011) for lispro and 206% (P < 0.0001) for RHI compared with the respective insulin alone. Peak blood glucose decreased 26 mg/dL for lispro (P = 0.002) and 24 mg/dL for RHI (P = 0.017), reducing hyperglycemic excursions (area under the curve for blood glucose >140 mg/dL) by 79% (P = 0.09) and 85% (P = 0.049), respectively. Rates of hypoglycemia were comparable for lispro with or without rHuPH20, whereas coadministration of RHI and rHuPH20 reduced hypoglycemia.Lispro or RHI with rHuPH20 produced earlier and greater peak insulin concentrations and improved postprandial glycemic control.
All Bariatric Surgeries Are Not Created Equal: Insights from Mechanistic Comparisons
Authors: Margaret A. Stefater, Hilary E. Wilson-Pérez, Adam P. Chambers, Darleen A. Sandoval, Randy J. Seeley
Journal: Endocrine Reviews (2012)

Despite considerable scientific progress on the biological systems that regulate energy balance, we have made precious little headway in providing new treatments to curb the obesity epidemic. Diet and exercise are the most popular treatment options for obesity, but rarely are they sufficient to produce long-term weight loss. Bariatric surgery, on the other hand, results in dramatic, sustained weight loss and for this reason has gained increasing popularity as a treatment modality for obesity. At least some surgical approaches also reduce obesity-related comorbidities including type 2 diabetes and hyperlipidemia. This success puts a premium on understanding how these surgeries exert their effects. This review focuses on the growing human and animal model literature addressing the underlying mechanisms. We compare three common procedures: Roux-en-Y Gastric Bypass (RYGB), vertical sleeve gastrectomy (VSG), and adjustable gastric banding (AGB). Although many would group together VSG and AGB as restrictive procedures of the stomach, VSG is more like RYGB than AGB in its effects on a host of endpoints including intake, food choice, glucose regulation, lipids and gut hormone secretion. Our strong belief is that to advance our understanding of these procedures, it is necessary to group bariatric procedures not on the basis of surgical similarity but rather on how they affect key physiological variables. This will allow for greater mechanistic insight into how bariatric surgery works, making it possible to help patients better choose the best possible procedure and to develop new therapeutic strategies that can help a larger portion of the obese population.
Experiments on the Nervous System
Authors: E D ADRIAN
Journal: BMJ (1950)

DBRITJo NAL 1385 (7) B.C.G.Vaccination.-Itsadoption in this country for certain susceptible groups is welcomed.(8) Examination of Contacts.-Contactexamination is extremely important and is comparable to mass radiography in that it discovers tuberculosis in persons who do not admit to being ill.The local health authority should assist through health visitors in encouraging contacts to be examined.
Long-term Effectiveness of Adjuvant Goserelin in Premenopausal Women With Early Breast Cancer
Authors: A. Hackshaw, M. Baum, T. Fornander, B. Nordenskjold, A. Nicolucci, K. Monson, S. Forsyth, K. Reczko, U. Johansson, H. Fohlin, M. Valentini, R. Sainsbury
Journal: JNCI Journal of the National Cancer Institute (2009)

Systematic reviews have found that luteinizing hormone-releasing hormone (LHRH) agonists are effective in treating premenopausal women with early breast cancer.We conducted long-term follow-up (median 12 years) of 2706 women in the Zoladex In Premenopausal Patients (ZIPP), which evaluated the LHRH agonist goserelin (3.6 mg injection every 4 weeks) and tamoxifen (20 or 40 mg daily), given for 2 years. Women were randomly assigned to receive each therapy alone, both, or neither, after primary therapy (surgery with or without radiotherapy/chemotherapy). Hazard ratios and absolute risk differences were used to assess the effect of goserelin treatment on event-free survival (breast cancer recurrence, new tumor or death), overall survival, risk of recurrence of breast cancer, and risk of dying from breast cancer, in the presence or absence of tamoxifen.Fifteen years after the initiation of treatment, for every 100 women not given tamoxifen, there were 13.9 (95% confidence interval [CI] = 17.5 to 19.4) fewer events among those who were treated with goserelin compared with those who were not treated with goserelin. However, among women who did take tamoxifen, there were 2.8 fewer events (95% CI = 7.7 fewer to 2.0 more) per 100 women treated with goserelin compared with those not treated with goserelin. The risk of dying from breast cancer was also reduced at 15 years: For every 100 women given goserelin, the number of breast cancer deaths was lower by 2.6 (95% CI = 6.6 fewer to 2.1 more) and 8.5 (95% CI = 2.2 to 13.7) in those who did and did not take tamoxifen, respectively, although in the former group the difference was not statistically significant.Two years of goserelin treatment was as effective as 2 years of tamoxifen treatment 15 years after starting therapy. In women who did not take tamoxifen, there was a large benefit of goserelin treatment on survival and recurrence, and in women who did take tamoxifen, there was a marginal potential benefit on these outcomes when goserelin was added.
TGF-β–Activated Kinase 1 Is Crucial in Podocyte Differentiation and Glomerular Capillary Formation
Authors: Sung Il Kim, So-Young Lee, Zhibo Wang, Yan Ding, Nadeem Haque, Jiwang Zhang, Jing Zhou, Mary E. Choi
Journal: Journal of the American Society of Nephrology (2014)

TGF-β-activated kinase 1 (TAK1) is a key intermediate in signal transduction induced by TGF-β or inflammatory cytokines, such as TNF-α and IL-1, which are potent inducers of podocyte injury responses that lead to proteinuria and glomerulosclerosis. Nevertheless, little is known about the physiologic and pathologic roles of TAK1 in podocytes. To examine the in vivo role of TAK1, we generated podocyte-specific Tak1 knockout mice (Nphs2-Cre(+):Tak1(fx/fx); Tak1(∆/∆)). Targeted deletion of Tak1 in podocytes resulted in perinatal lethality, with approximately 50% of animals dying soon after birth and 90% of animals dying within 1 week of birth. Tak1(∆/∆) mice developed proteinuria from P1 and exhibited delayed glomerulogenesis and reduced expression of Wilms' tumor suppressor 1 and nephrin in podocytes. Compared with Tak1(fx/fx) mice, Tak1(∆/∆) mice exhibited impaired formation of podocyte foot processes that caused disruption of the podocyte architecture with prominent foot process effacement. Intriguingly, Tak1(∆/∆) mice displayed increased expression of vascular endothelial growth factor within the glomerulus and abnormally enlarged glomerular capillaries. Furthermore, 4- and 7-week-old Tak1(∆/∆) mice with proteinuria had increased collagen deposition in the mesangium and the adjacent tubulointerstitial area. Thus, loss of Tak1 in podocytes is associated with the development of proteinuria and glomerulosclerosis. Taken together, our data show that TAK1 regulates the expression of Wilms' tumor suppressor 1, nephrin, and vascular endothelial growth factor and that TAK1 signaling has a crucial role in podocyte differentiation and attainment of normal glomerular microvasculature during kidney development and glomerular filtration barrier homeostasis.
Fes Tyrosine Kinase Expression in the Tumor Niche Correlates with Enhanced Tumor Growth, Angiogenesis, Circulating Tumor Cells, Metastasis, and Infiltrating Macrophages
Authors: Shengnan Zhang, Violeta Chitu, E. Richard Stanley, Bruce E. Elliott, Peter A. Greer
Journal: Cancer Research (2010)

Fes is a protein tyrosine kinase with cell autonomous oncogenic activities that are well established in cell culture and animal models, but its involvement in human cancer has been unclear. Abundant expression of Fes in vascular endothelial cells and myeloid cell lineages prompted us to explore roles for Fes in the tumor microenvironment. In an orthotopic mouse model of breast cancer, we found that loss of Fes in the host correlated with reductions in engrafted tumor growth rates, metastasis, and circulating tumor cells. The tumor microenvironment in Fes-deficient mice also showed reduced vascularity and fewer macrophages. In co-culture with tumor cells, Fes-deficient macrophages also poorly promoted tumor cell invasive behavior. Taken together, our observations argue that Fes inhibition might provide therapeutic benefits in breast cancer, in part by attenuating tumor-associated angiogenesis and the metastasis-promoting functions of tumor-associated macrophages.
Evolution of Genes and Repeats in the Nimrod Superfamily
Authors: K. Somogyi, B. Sipos, Z. Penzes, E. Kurucz, J. Zsamboki, D. Hultmark, I. Ando
Journal: Molecular Biology and Evolution (2008)

The recently identified Nimrod superfamily is characterized by the presence of a special type of EGF repeat, the NIM repeat, located right after a typical CCXGY/W amino acid motif. On the basis of structural features, nimrod genes can be divided into three types. The proteins encoded by Draper-type genes have an EMI domain at the N-terminal part and only one copy of the NIM motif, followed by a variable number of EGF-like repeats. The products of Nimrod B-type and Nimrod C-type genes (including the eater gene) have different kinds of N-terminal domains, and lack EGF-like repeats but contain a variable number of NIM repeats. Draper and Nimrod C-type (but not Nimrod B-type) proteins carry a transmembrane domain. Several members of the superfamily were claimed to function as receptors in phagocytosis and/or binding of bacteria, which indicates an important role in the cellular immunity and the elimination of apoptotic cells. In this paper, the evolution of the Nimrod superfamily is studied with various methods on the level of genes and repeats. A hypothesis is presented in which the NIM repeat, along with the EMI domain, emerged by structural reorganizations at the end of an EGF-like repeat chain, suggesting a mechanism for the formation of novel types of repeats. The analyses revealed diverse evolutionary patterns in the sequences containing multiple NIM repeats. Although in the Nimrod B and Nimrod C proteins show characteristics of independent evolution, many internal NIM repeats in Eater sequences seem to have undergone concerted evolution. An analysis of the nimrod genes has been performed using phylogenetic and other methods and an evolutionary scenario of the origin and diversification of the Nimrod superfamily is proposed. Our study presents an intriguing example how the evolution of multigene families may contribute to the complexity of the innate immune response.
New Therapies for Coronary Artery Disease: Genetics Provides a Blueprint
Authors: Daniel J. Rader
Journal: Science Translational Medicine (2014)

The development of new therapies for coronary artery disease (CAD) poses a substantial challenge, and several recent approaches have failed for lack of efficacy. Human genetics has the potential to identify new targets for which the likelihood of therapeutic success is considerably greater. The intense focus on the genetics of CAD will revitalize the field and lead to future therapies for this common disease.