tbuckley/cabot-search huggingface dataset:
Implementation of Validated Pharmacodynamic Assays in Multiple Laboratories: Challenges, Successes, and Limitations
Authors: Robert Kinders, Kate Ferry-Galow, Lihua Wang, Apurva K. Srivastava, Jiuping (Jay) Ji, Ralph E. Parchment
Journal: Clinical Cancer Research (2014)

Abstract There is a “life cycle” of pharmacodynamic (PD) biomarker assays that guides the development and clinical implementation in our laboratories. The well-recognized elements of analytical assay validation and demonstration of fitness-for-purpose of the biomarker, specimen collection, handling, and assay methods are only a part of the required activities. Assay transfer across laboratories and testing on actual human clinical specimens are vital for understanding assay performance and robustness. In our experience, this patient specimen-centered approach has required assay method modifications, some unexpected, but which were critical to successful implementation in clinical trials. In addition, dispersing assays throughout the National Cancer Institute's clinical trials network has required the development of calibrator and control materials as well as formal training courses for smooth implementation. One measure of success of this approach has been that a number of the assays developed at NCI's Frederick National Laboratory have ultimately reached the stage of commercialization, enabling wide accessibility of the PD biomarker assays by the research community. See all articles in this CCR Focus section, “Progress in Pharmacodynamic Endpoints.” Clin Cancer Res; 20(10); 2578–86. ©2014 AACR.
STUDIES IN THE BLOOD VOLUME OF EPILEPTICS
Authors: Morgan B. Hodskins, Riley H. Guthrie, James Z. Naurison
Journal: American Journal of Psychiatry (1932)

1. We have attempted to show that the cerebrospinal pathology in epilepsy is variable. 2. Dehydration is a factor in common in methods of treatment which modify the seizures in epilepsy. 3. The incidence of epilepsy is low in diseases in which there is present a low blood volume or a tendency to dehydration. 4. Alkalosis, edema, and decreased oxygen tension, conditions favoring convulsions are closely inter-related, as are acidosis, tissue dehydration and increased oxygen tension, conditions which decrease seizures. 5. A disturbance in the vasomotor control of the cerebral vessels is suggested as the precipitating factor of the epileptic convulsion. 6. A trend towards higher blood volume values was found in 78 epileptics as compared with 42 controls. 7. A low blood volume was found during convulsive seizures and during fainting attacks. 8. Acidosis, as is produced by ammonium nitrate therapy, is not sufficient to control seizures.
Abstract 1210: Activation of heterogeneous nuclear ribonucleoprotein K (HNRNPK) by ERBB2/ERBB3
Authors: Nirav M. Patel, Jie Xiang, Carmen Warren, Nurali Avliyakulov, Michael Haykinson, Ralf Landgraf
Journal: Cancer Research (2011)

Abstract ERBB2 (HER2/neu) amplification constitute one of the most prominent oncogenic amplification event in breast cancer, and ERBB2 overexpression is well established as a predominantly proliferation and metastasis favoring signaling input. It is consequently the object of different targeted therapies (e.g. Trastuzumab, Pertuzumab or Lapatinib). We carried out 2-D difference gel electrophoresis based proteomics studies (DIGE) of early posttranslational protein modifications in MCF7 breast cancer cells in response to ligand induced activation. These studies have identified heterogeneous nuclear ribonucleoprotein K (HNRNPK) as a target for rapid tyrosine phosphorylation after ERBB2/ERBB3 activation by neuregulin β1. Upregulation of protein levels coupled with cytoplasmic accumulation of HNRNPK has been found to be associated with its oncogenic role in several types of cancer, and HNRNPK overexpression enhances the tumorigenicity of breast cancer cells in cell culture models. Previous studies have shown that HNRNPK levels are reduced in breast cancer cells after prolonged treatment with EGFR or ERBB2 directed therapeutic antibodies. However, while molecular mechanistic data exist on HNRNPK from a variety of model systems, we currently lack a coherent mechanistic framework of the crosstalk of ERBB2 and HNRNPK signaling in breast cancer. Following our DIGE analysis, we found that ligand induced and ERBB2/ERBB3 mediated tyrosine phosphorylation of HNRNPK in MCF7 cells is mediated by members of the SRC kinase family. Following ligand dependent stimulation, activation of HNRNPK coincides with a cytoplasmic relocalization of a relatively small portion of the predominantly nuclear HNRNPK pool. We compared our observations of ligand induced activation with the status of HNRNPK in ERBB2 over expressing breast cancer cell lines in presence or absence of ERBB2 targeted inhibitors. These studies are aimed at elucidating the interplay of HNRNPK and constitutive ERBB2 signaling in breast cancer cells and its role in cellular transformation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1210. doi:10.1158/1538-7445.AM2011-1210
Validity of DSM-IV Conduct Disorder in 4½–5-Year-Old Children: A Longitudinal Epidemiological Study
Authors: Julia Kim-Cohen, Louise Arseneault, Avshalom Caspi, Mónica Polo Tomás, Alan Taylor, Terrie E. Moffitt
Journal: American Journal of Psychiatry (2005)

This longitudinal study of a nonreferred, population-based sample tested the concurrent, convergent, and predictive validity of DSM-IV conduct disorder in children 4(1/2)-5 years of age.In the Environmental Risk Longitudinal Twin Study, a representative birth cohort of 2,232 children, the children's mothers were interviewed and the teachers completed mailed questionnaires to assess the children's past 6-month conduct disorder symptoms. Children with three or more symptoms were diagnosed with conduct disorder, and a subset with five or more symptoms was diagnosed with "moderate-to-severe" conduct disorder.The prevalence of conduct disorder and moderate-to-severe conduct disorder were 6.6% and 2.5%, respectively. Children diagnosed with conduct disorder were significantly more likely than comparison subjects to self-report antisocial behaviors, to behave disruptively during observational assessment, and to have risk factors known to be associated with conduct disorder in older children (effect sizes ranging from 0.26 to 1.24). Five-year-olds diagnosed with conduct disorder were significantly more likely than comparison subjects to have behavioral and educational difficulties at age 7. Increased risk for educational difficulties at age 7 persisted after control for IQ and attention deficit hyperactivity disorder diagnosis at age 5.Behavioral problems of preschool-age children meeting diagnostic criteria for conduct disorder should not be ignored. Appropriate intervention should be provided to prevent ongoing behavioral and academic problems.
Cancer of the Gastrointestinal Tract
Authors: Philip Rubin
Journal: JAMA (1973)

The malignancy gradient of alimentary tract cancer increases as it ascends from the colon to the esophagus. The mortality and morbidity associated with tumors of the esophagus exceed that which is associated with lung cancer. Fortunately, esophageal cancer is not common in this country. Its incidence is highest in Japan, where 46.3 men per 100,000 men over 35 years of age are afflicted, compared to 10 men per 100,000 men in the United States. 1 It is primarily a disease of men, with a sex ratio of 3:1; but women account for 40% to 50% of esophageal cancer in Sweden and Finland. Certain conditions (ie, Plummer-Vinson syndrome) are associated with higher incidence, but the cause is obscure. Achalasia or hiatus hernia are more tenuously related. 2   Reprints are not available.  Cancer of the esophagus is rarely detected with screening procedures during its asymptomatic phase when it is localized. There is
Fifty years of violent war deaths from Vietnam to Bosnia: analysis of data from the world health survey programme
Authors: Ziad Obermeyer, Christopher J L Murray, Emmanuela Gakidou
Journal: BMJ (2008)

Objective To provide an accurate estimate of violent war deaths. Design Analysis of survey data on mortality, adjusted for sampling bias and censoring, from nationally representative surveys designed to measure population health. Estimated deaths compared with estimates in database of passive reports. Setting 2002-3 World health surveys, in which information was collected from one respondent per household about sibling deaths, including whether such deaths resulted from war injuries. Main outcome measure Estimated deaths from war injuries in 13 countries over 50 years. Results From 1955 to 2002, data from the surveys indicated an estimated 5.4 million violent war deaths (95% confidence interval 3.0 to 8.7 million) in 13 countries, ranging from 7000 in the Democratic Republic of Congo to 3.8 million in Vietnam. From 1995 to 2002 survey data indicate 36 000 war deaths annually (16 000 to 71 000) in the 13 countries studied. Data from passive surveillance, however, indicated a figure of only a third of this. On the basis of the relation between world health survey data and passive reports, we estimate 378 000 globalwar deaths annually from 1985-94, the last years for which complete passive surveillance data were available. Conclusions The use of data on sibling history from peacetime population surveys can retrospectively estimate mortality from war. War causes more deaths than previously estimated, and there is no evidence to support a recent decline in war deaths.
AB0324 Dose reduction of tocilizumab in rheumatoid arthritis patients with low disease activity: a pilot study
Authors: N. van Herwaarden, S. Herfkens-Hol, A. van der Maas, B. van den Bemt, R. van Vollenhoven, J. Bijlsma, A. den Broeder
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Tocilizumab, in the registered dose of 8 mg/kg, has proven to be an effective treatment in rheumatoid arthritis (RA) patients. However, RCT data show that a substantial proportion of patients can achieve low disease activity on a lower than registered (4 versus 8mg/kg) starting dose<sup>1</sup>. A lower dose might reduce dose-dependent side effects and costs. No data, however, are available on the feasibility of dose reduction to 4 mg/kg in RA patients who reached low disease activity on the registered dose of 8 mg/kg. <h3>Objectives</h3> To examine the proportion of RA patients with successful dose reduction of tocilizumab after achieving low disease activity, and to asses the frequency of secondary ineffectiveness after re-escalation. <h3>Methods</h3> According to the local treatment protocol, RA patients start with tocilizumab 8mg/kg every 4 weeks. After at least 6 months of successful treatment, the dose is reduced to 4 mg/kg if patients have low disease activity(DAS28&lt;3.2 and judgement of rheumatologist). In case of loss of disease control (DAS28&gt;3.2 and judgement of rheumatologist) the dose is increased again to 8mg/kg. In this observational pilot study, patient, disease and treatment characteristics were collected as well as data on disease activity before and after dose reduction and when applicable after dose re-escalation. <h3>Results</h3> In 19 patients tocilizumab dose was reduced because of low disease activity. The mean disease duration in those patients was 11 years (SD 8.4), rheumatoid factor positive 68%, anti-CCP positive 81% and erosive disease 58%. The mean DAS28 at time of dose reduction was 2.4 (SD 0.9). After 3 and 6 months follow up, respectively 73% (CI 49-90%) and 53% (CI 31-79%) of the patients still had low disease activity on the dose of 4mg/kg. The DAS28 at respectively 3 and 6 months was somewhat (ns) higher than baseline, 2.9 (SD 1.3) and 2.8 (SD 1.0). Most RA flares (78%) after dose reduction occurred in the first 16 weeks. All patients who experienced worsening of disease activity after dose reduction regained low disease activity after dose re-escalation. <h3>Conclusions</h3> Dose reduction of tocilizumab is feasible in a substantial proportion of patients. Dose re-escalation after flare was effective in all patients. <h3>References</h3> Kremer JM et al, <i>Arthritis&amp;Rheumatism</i> 2011;63(3):609-21 <h3>Disclosure of Interest</h3> N. van Herwaarden: None Declared, S. Herfkens-Hol: None Declared, A. van der Maas: None Declared, B. van den Bemt: None Declared, R. van Vollenhoven Grant/research support from: Abbott, BMS, GSK, MSD, Pfizer, Roche, UCB, Consultant for: Abbott, BMS, GSK, MSD, Pfizer, Roche, UCB, J. Bijlsma Consultant for: Abbott, Roche, BMS, UCB, Pfizer and Merck, A. den Broeder: None Declared
ROENTGEN RAY SKIAGRAPHY.
Authors: De FOREST WILLARD
Journal: JAMA (1897)

Professor Goodspeed has very properly emphasized the importance of the study of normal living anatomic delineations. Even surgeons are not familiar with the appearance of the living skeleton<i>in situ</i>, and for accurate comparison we assuredly require a series of skiagraphic normals. I was in my first efforts greatly puzzled in the interpretation of conditions either plainly or indistinctly seen in the skiagraph, and even after considerable experience am obliged to study with great care each representation in order to differentiate the abnormal from the normal conditions. Although skiagraphy is a most valuable assistant to the surgeon, yet a word of caution is necessary. It has been most conclusively shown that the position of the tube, the direction of the rays, the method and time of the exposure, the magnification of portions of an object not in contact with the plate, the elongation of shadows from distant portions of an
Dose‐response and time course of specific IgE and IgG after single and repeated topical skin exposure to dry trimellitic anhydride powder in a Brown Norway rat model
Authors: X. D. Zhang, D. K. Murray, D. M. Lewis, P. D. Siegel
Journal: Allergy (2002)

Background: Trimellitic anhydride (TMA)‐induced occupational asthma is thought to be associated with its ability to acylate proteins and to induce production of TMA‐specific immunoglobulin (Ig)E. Though the respiratory tract is considered to be a major exposure route leading to airway sensitization, the potential role of dermal exposure producing asthmatic sensitization is not known. The present study examines the ability of dry TMA powder to sensitize Brown Norway rats when applied, topically, to the skin. Methods: A patch of hair was carefully clipped with scissors on the rat's back. Dry TMA powder (0.3, 1.25, 5 and 20 mg) was administered on days 0, 7, 14 and 21, and the area occluded with surgical tape overnight after each application. Residual powder recovered from the occluded skin was analyzed by proton nuclear magnetic resonance and was still predominantly TMA. Circulating anti‐TMA IgE and IgG were measured by ELISA. Results: TMA elicited dose‐dependent production of specific IgE and IgG. Specific antibodies were detectable 2 weeks after the first TMA exposure and peaked between 3 and 4 weeks. Conclusion: The data suggest that topical skin exposure to dry TMA powder can induce allergic/immunological sensitization as demonstrated by the production of specific antibodies.
Aortic Diameter ≥5.5 cm Is Not a Good Predictor of Type A Aortic Dissection
Authors: Linda A. Pape, Thomas T. Tsai, Eric M. Isselbacher, Jae K. Oh, Patrick T. O’Gara, Arturo Evangelista, Rossella Fattori, Gabriel Meinhardt, Santi Trimarchi, Eduardo Bossone, Toru Suzuki, Jeanna V. Cooper, James B. Froehlich, Christoph A. Nienaber, Kim A. Eagle
Journal: Circulation (2007)

Background— Studies of aortic aneurysm patients have shown that the risk of rupture increases with aortic size. However, few studies of acute aortic dissection patients and aortic size exist. We used data from our registry of acute aortic dissection patients to better understand the relationship between aortic diameter and type A dissection. Methods and Results— We examined 591 type A dissection patients enrolled in the International Registry of Acute Aortic Dissection between 1996 and 2005 (mean age, 60.8 years). Maximum aortic diameters averaged 5.3 cm; 349 (59%) patients had aortic diameters &lt;5.5 cm and 229 (40%) patients had aortic diameters &lt;5.0 cm. Independent predictors of dissection at smaller diameters (&lt;5.5 cm) included a history of hypertension (odds ratio, 2.17; 95% confidence interval, 1.03 to 4.57; P =0.04), radiating pain (odds ratio, 2.08; 95% confidence interval, 1.08 to 4.0; P =0.03), and increasing age (odds ratio, 1.03; 95% confidence interval, 1.00 to 1.05; P =0.03). Marfan syndrome patients were more likely to dissect at larger diameters (odds ratio, 14.3; 95% confidence interval, 2.7 to 100; P =0.002). Mortality (27% of patients) was not related to aortic size. Conclusions— The majority of patients with acute type A acute aortic dissection present with aortic diameters &lt;5.5 cm and thus do not fall within current guidelines for elective aneurysm surgery. Methods other than size measurement of the ascending aorta are needed to identify patients at risk for dissection.
Diagnosis of cardiac tamponade by echocardiography: changes in mitral valve motion and ventricular dimensions, with special reference to paradoxical pulse.
Authors: I A D'Cruz, H C Cohen, R Prabhu, G Glick
Journal: Circulation (1975)

The echocardiographic findings in three patients who presented with pericardial effusion and cardiac tamponade are described. Cyclic respiratory changes affected the diastolic movement of the anterior mitral leaflet, viz., during inspiration its anterior excursion decreased in amplitude and the E-F slope diminished. This inspiratory alteration in mitral valve motion was accompanied by an increase in right ventricular dimensions and a reciprocal decrease in left ventricular dimensions. Pericardial paracentesis confirmed the presence of effusion and relieved cardiac tamponade in all the patients. Repeat echocardiography, performed in two of the patients immediately after the pericardial tap, showed that the E-F slope had become steeper and that phasic respiratory variations in the diastolic motion of the anterior mitral leaflet were no longer present. The compatibility of our observations with the theories which endeavor to explain the mechanism of the paradoxical pulse in pericardial effusion with cardiac tamponade is discussed. We suggest that the abnormalities in anterior mitral leaflet motion defined by echocardiography constitute a useful addition to the study of patients with suspected cardiac tamponade resulting from pericardial effusion.
Has psychiatric diagnosis labelled rather than enabled patients?
Authors: F. Callard, P. Bracken, A. S. David, N. Sartorius
Journal: BMJ (2013)

<h3>Abstract</h3> In northern Guinea, we sighted two groups of <i>Sousa teuszii</i> (n=25; n=40 dolphins) off the Tristao Islands during exploratory small-boat surveys in 2011–12. Based on these and recent (2013) observations in the contiguous Río Nuñez estuary, we propose a single 'Guineas stock', combining the former 'Rio do Jêba-Bijagos' and South Guinea stocks. Significant mortality of <i>S. teuszii</i> from fisheries interactions is widely recognised however not quantifiable as monitoring effort is sporadic. In Guinea, catches were documented in 2002 (n=1) and in 2011–12 (n=5). Landed specimens were recorded in Cameroon (n=2) and Nigeria (n=2). All individuals were killed in small-scale coastal fisheries, presumably as accidental net entanglements, though directed takes cannot be excluded. All landed dolphins were butchered for human consumption (marine bushmeat). Nigerian fishers indicated also an alternative use as shark bait. If local markets in cetacean bushmeat and bait develop, as in Ghana, that will exacerbate pressures by encouraging directed takes. Catch records in Nigeria and sightings in Togo authenticate both nations as (long-suspected) range states for <i>S. teuszii</i>, a belated documenting of the primary, historical distribution. The Gulf of Guinea stock ('Cameroon dolphins') extends at least from Togo to southern Cameroon, and probably into Equatorial Guinea. However, rare sightings of small groups point to remnant, not thriving, dolphin communities. We anticipate <i>de novo</i> distribution gaps emerging and consolidating, following decades of fisheries interactions and creeping encroachment on once pristine coastal habitat. Developed coastlines in Ghana and Côte d'Ivoire devoid of records may already constitute such gaps. As the lack or scarcity of records warn about formidable challenges to the long-term survival of <i>S. teuszii</i>, innovative, workable protection measures are needed, soonest. We recommend the implementation of several new border-straddling marine protected areas (cf. Saloum Delta-Niumi National Park Complex) which could bring forth a major conservation effect. Binational involvement bears obvious advantages, from sharing responsibilities and allowing for larger protected areas. Suggested dolphin sanctuary examples could include MPAs straddling borders between Cameroon/Equatorial Guinea and Guinea-Bissau/Guinea-Conakry.
The relationship between the metabolism of procainamide and sulfamethazine.
Authors: None Giardina E-GV, R M Stein, J T Bigger
Journal: Circulation (1977)

The metabolism of sulfamethazine (SMZ), which is acetylated by a binodally distributed enzyme, and procainamide (PA) was compared in 21 normal volunteers, each given a single oral dosted metabolites, N-acetyl-procainamide (NAPA) and Ac-SMZ, were measured. Subjects with less than 64% Ac-SMZ in the 0-8 hour collection were termed "slow" and those with more than 64% were termed "fast" SMZ acetylators. Slow SMZ acetylators had 9.8 to 43.8% (24.1 +/- 10.13) NAPA recovered, and fast SMZ acetylators, 22.0 to 42.6% (33.7 +/- 7.29) NAPA, P less than 0.01. In addition, the calculated half-life of PA metabolism for slow SMZ acetylators was 9.0 to 33.8 hours (18.4 +/- 8.82) and for fast SMZ acetylators was 8.1 to 14.4 hours (10.9 +/- 2.19), P less than 0.01. For four subjects, SMZ acetylation phenotype did not correlate with the half-life of SMZ or PA metabolism; and in two, SMZ acetylation phenotype and half-life of metabolism did not correlate with the same PA indices. Even though slow SMZ acetylators have less NAPA recovered than fast SMZ acetylators, it is not yet clear that procainamide is metabolized by a bimodally distributed enzyme as is sulfamethazine.
Cyclical variations in mood in normal women taking oral contraceptives.
Authors: A R Forrest
Journal: BMJ (1979)

non-binding fraction and the composition of amniotic fluid altered accordingly.This is apparently so.Since affinity chromatography is more complicated than con- ventional AFP assay it will probably be used on selected samples.If the method proves as reliable as suggested here, an appropriate strategy would be to lower the cut-off value to three standard devia- tions above the mean total AFP concentration and subject all samples with concentrations above this value to con-A-binding studies.Theoretically, this would give a high incidence of detection of open spina bifida with a specificity of nearly 100%.
Association between In Vitro Susceptibility to Natamycin and Voriconazole and Clinical Outcomes in Fungal Keratitis
Authors: Catherine Q. Sun, Prajna Lalitha, N. Venkatesh Prajna, Rajarathinam Karpagam, Manoharan Geetha, Kieran S. O'Brien, Catherine E. Oldenburg, Kathryn J. Ray, Stephen D. McLeod, Nisha R. Acharya, Thomas M. Lietman
Journal: Ophthalmology (2014)