tbuckley/cabot-search huggingface dataset:
LL-02 * TEMOZOLOMIDE IN PRIMARY CENTRAL NERVOUS SYSTEM POST-TRANSPLANT LYMPHOPROLIFERATIVE DISORDER (CNS-PTLD): A CASE SERIES
Authors: J. Krishnamurthy, T. Greiner, V. Bhatt, M. White, P. Bierman
Journal: Neuro-Oncology (2014)

BACKGROUND: CNS-PTLD is associated with inferior survival, compared to other forms of PTLD. Rituximab, high-dose methotrexate (HD-MTX) or cytarabine along with reduction of immunosuppression is the current standard of care. Although temozolomide has been used successfully in primary CNS lymphoma, its role in CNS-PTLD is unclear. METHODS: We retrospectively analyzed data for patients with CNS-PTLD, at the University of Nebraska Medical Center. RESULTS: We identified five females and one male. The median age was 53 years (range 18-67). Two had kidney transplants; two had kidney-pancreas transplants; one had a heart transplant and one had a heart-liver transplant. The immunosuppressive regimens included prednisone with either cyclosporine, tacrolimus, mycophenolate mofetil or sirolimus. The median interval between the transplant and CNS-PTLD diagnosis was 24 months (range 9-108). Patients presented with altered mental status (50%) or focal neurological deficits (83%). The radiographic appearance was solitary (33%) or multiple (66%) masses. Histology was polymorphic (33%) or monomorphic (66%). Tumor cells were positive for Epstein-Barr virus (EBV) and CD20 in all cases. Quantitative EBV DNA in blood was detected in five patients (<2.70 to 14000 copies/ml). Two patients underwent total and subtotal resection respectively. In addition to reduction of immunosuppression, all patients received rituximab (mean = 4.5 cycles, range 1-6) and temozolomide (mean = 6 cycles, range 1-12). Three patients received HD-MTX also. Temozolomide was used either as a second line agent due to worsening renal function or as a first line agent if baseline renal function was poor. The complete remission rate was 50% with no disease progression in any of the patients. At a median follow-up of 17 months (range 1-54), overall survival was 100%. CONCLUSIONS: Our study indicates a promising role for temozolomide in CNS-PTLD. There may also be a role for surgical resection when feasible, as described for PTLD at other sites.
Antiangiogenic Concentrations of Vinflunine Increase the Interphase Microtubule Dynamics and Decrease the Motility of Endothelial Cells
Authors: Bertrand Pourroy, Stéphane Honoré, Eddy Pasquier, Véronique Bourgarel-Rey, Anna Kruczynski, Claudette Briand, Diane Braguer
Journal: Cancer Research (2006)

Angiogenesis is a key event in tumor progression and metastasis. This complex process, which constitutes a potent target for cancer therapy, is inhibited by very low concentrations of microtubule-targeting drugs (MTD). However, the intimate mechanisms of the antiangiogenic activity of MTDs remain unclear. Recently, we have shown that low antiangiogenic and noncytotoxic concentrations of paclitaxel induced an unexpected increase in microtubule dynamics in endothelial cells. In this study, we showed that vinflunine, the newest Vinca alkaloid, increased microtubule dynamic instability in human endothelial cells after 4-hour incubation at low concentrations (29% and 54% at 0.1 and 2 nmol/L). The growth and shortening rates were increased, and the percentage of time spent in pause and the mean duration of pauses were decreased, as previously observed with paclitaxel. As opposed to paclitaxel, the transition frequencies were not significantly disturbed by vinflunine. Moreover, low concentrations of vinflunine did not affect mitotic index and anaphase/metaphase ratio. Interestingly, these low vinflunine concentrations that increased microtubule dynamics exhibited an antiangiogenic effect through the inhibition of both morphogenesis and random motility. Capillary tube formation on Matrigel was decreased up to 44%. The cell speed and the random motility coefficient were decreased (13% and 19% and 13% and 33% at 0.1 and 2 nmol/L, respectively) and the persistent time was statistically increased. Altogether, our results confirm that the increase in microtubule dynamics is involved in MTD antiangiogenic activity and highlight the crucial role of interphase microtubule dynamics in angiogenesis.
Independent appraiser assessment of the quality, methodological rigour and transparency of the development of the 2008 international consensus statement on concussion in sport
Authors: Peta E White, Anna Wong Shee, Caroline F Finch
Journal: British Journal of Sports Medicine (2013)

In recent years, considerable effort has been devoted to the development and revisions to an international consensus statement on concussion in sport (ICSCS). The aim of this study was to obtain expert views on the methodological rigour and transparency with which the 2008 ICSCS was developed, as a precursor to the development of the 2012 update.Delegates registered for the 2012 fourth International Conference on Concussion in Sport, selected local concussion researchers not involved in any prior international consensus meetings, and all authors of the 2008 ICSCS published paper were invited to assess the methodological rigour and transparency with which the 2008 ICSCS was developed. The online Appraisal of Guidelines for Research and Evaluation (AGREE) II assessment tool, with six quality domains, was used and domain scores were expressed as a percentage of the maximum possible score for that domain.18 appraisers completed the online AGREE II assessment. Ten appraisers said they would recommend the 2008 ICSCS for use (without modification) and seven said they would recommend its use with some modification. The 'scope and purpose' and 'clarity of presentation' were rated highest, both scoring 78%. The lowest scoring domain was 'applicability' with a score of 55%.The quality of the ICSCS is important because it is used to guide return-to-play decisions and the management of sport-related concussions. This appraisal of the 2008 ICSCS suggests that a greater focus is needed on the actual implementation of future ICSCS and the relationship between implementation and desired health outcomes.
Prognostic significance of the early course of minimal change nephrotic syndrome
Authors: P Tarshish, J N Tobin, J Bernstein, C M Edelmann
Journal: Journal of the American Society of Nephrology (1997)

The ability to predict the course in children with newly diagnosed minimal change nephrotic syndrome (MCNS) may have significant therapeutic implications. Previous attempts based on data available at disease onset have not been successful. Therefore, it was investigated whether characterization of the initial response to adrenocortical steroids and the course during the early months of disease are predictive of the subsequent outcome. Three hundred-eighty-nine children with MCNS, diagnosed at onset, were treated with standard prednisone regimens and monitored for up to 17 yr (mean, 9.4 yr). They were classified, after 8 wk of therapy, as initial responders (complete remission) or initial nonresponders (continued proteinuria). Subsequent classifications included nonrelapsers, infrequent relapsers, and frequent relapsers. At 8 yr of follow-up, 80% of patients were in remission. Three-fourths of initial responders who remained in remission during the first 6-month period after initial therapy (nonrelapsers; 40% of the entire series) either continued in remission during their entire course or relapsed rarely. In contrast, initial relapsers, both frequent and infrequent, achieved a nonrelapsing course only after an average of 3 yr. Unremitting proteinuria during the initial 8 wk of treatment was followed by progression to ESRD in 21%. When proteinuria during the initial 8 wk continued through the subsequent 6 months, progression to renal failure occurred for 35%. Although 95% of children with MCNS do well, 4 to 5% die from complications or undergo progression to ESRD. Documentation of the early course aids in identifying those at increased risk for a poor outcome. More aggressive therapy may be indicated for these individuals.
Pacing-induced heart failure causes a reduction of delayed rectifier potassium currents along with decreases in calcium and transient outward currents in rabbit ventricle
Authors: Yukiomi Tsuji, Tobias Opthof, Kaichiro Kamiya, Kenji Yasui, Weiran Liu, Zhibo Lu, Itsuo Kodama
Journal: Cardiovascular Research (2000)

Objective: Heart failure in patients and in animal models is associated with action potential prolongation of the ventricular myocytes. Changes in several membrane currents have been already demonstrated to underlie this prolongation. However, information on the two components (IKr and IKs) of the delayed rectifier potassium current (IK) in rapid pacing induced heart failure is lacking. Methods and results: Action potentials and whole-cell currents, IK, Ito1, IK1, and ICa-L were recorded in apical myocytes of left ventricle from 10 rabbits subjected to left ventricular pacing at 350–380 beats/min for 3–4 weeks and 10 controls with sham operation. Action potential duration at 90% repolarization (APD90) was prolonged in myocytes from failing hearts compared to controls at both cycle lengths of 333 and 1000 ms. Both E-4031-sensitive and -resistant components of IK (IKr, IKs) in myocytes from failing hearts were significantly less than those of control hearts; tail current densities of IKr and IKs following depolarization to +50 mV were 0.62±0.05 vs. 0.96±0.12 pA/pF (P<0.05), and 0.27±0.08 vs. 0.52±0.08 pA/pF (P<0.05), respectively. There was no significant difference between control and failing myocytes in the voltage- and time-dependence of activation of total IK, IKr and IKs. The peak of L-type Ca2+ current (ICa-L) was significantly reduced in myocytes from failing hearts (at +10 mV, −9.29±0.52 vs. −12.28±1.63 pA/pF, P<0.05), as was the Ca2+-independent transient outward current (Ito1; at +40 mV, 4.8±0.9 vs. 9.6±1.3 pA/pF, P<0.05). Steady state I–V curve for IK1 was similar in myocytes from failing and control hearts. Conclusions: Decrease of IK (both IKr and IKs) in addition to reduced Ito1, may underly action potential prolongation at physiological cycle length and thereby contribute to arrhythmogenesis in heart failure.
Long-term survivors of leukemia treated in infancy: factors associated with neuropsychologic status.
Authors: R K Mulhern, E Kovnar, J Langston, M Carter, D Fairclough, L Leigh, L E Kun
Journal: Journal of Clinical Oncology (1992)

PURPOSE Because of concerns about late toxicities of treatment among infants diagnosed with acute lymphoblastic leukemia (ALL), and especially the effects of cranial radiation therapy (CRT), we compared the functional and neuropsychologic status of 26 long-term survivors of ALL who were diagnosed in the first 24 months of life versus 26 children who were treated previously for Wilms' tumor. PATIENTS AND METHODS Of the children with ALL, CNS prophylaxis included no CRT in six, 18 Gy CRT in five, 20 Gy CRT in seven, and 24 Gy CRT in five. Three additional children experienced CNS relapse and received total CRT doses of 24, 40, and 44 Gy. All children received neuropsychologic testing; children with ALL also participated in diagnostic imaging studies. RESULTS As a group, the children who were treated for ALL did not differ significantly from those who were treated for Wilms' tumor on objective measures of global functional status. However, children treated for ALL had a significantly lower mean intelligence quotient (IQ) (87 v 96), poorer performance on four of six measures of visual and auditory memory, lower achievement with regard to arithmetic skills, and a greater frequency of special educational intervention than those who were treated for Wilms' tumor. IQ and auditory memory performance in the ALL group was correlated inversely with time since the completion of therapy and total CRT dose. CONCLUSIONS These results reinforce the contemporary trend of prophylactic CRT omission in very young children except for those who are at risk for CNS relapse. For infants and very young children who require CRT, evidence is presented that supports the approach for the delay of CRT until the child is older.
In vivo characterization of vasodilating muscarinic-receptor subtypes in humans.
Authors: T A Bruning, M G Hendriks, P C Chang, E A Kuypers, P A van Zwieten
Journal: Circulation Research (1994)

The role of muscarinic (M)-receptor subtypes in the regulation of vascular tone has not yet been defined in humans. To analyze the role of M-receptor subtypes in the forearm resistance vasculature of normotensive volunteers (n = 20), we infused acetylcholine (ACh) and methacholine (MCh) in the presence of saline and the antagonists atropine (nonselective), pirenzepine (M1 selective), and AF-DX 116 (M2 selective), using automated R-wave-triggered venous occlusion plethysmography. Schild analysis was applied by calculating plasma concentrations of the infused compounds and determining EC50 values. ACh and MCh both caused dose-dependent vasodilation, with EC50 values of 537 and 52 nmol/L, respectively. The apparent 10-fold higher potency of MCh compared with ACh may be explained by rapid degradation of ACh in plasma. The concentration-response curve of MCh was shifted to the right by atropine, pirenzepine, and AF-DX 116, with apparent pA2 values of 8.03 +/- 0.03, 6.71 +/- 0.08, and 5.32 +/- 0.05, respectively, and slopes not different from unity. The present technique enabled us to perform M-receptor characterization by Schild analysis in humans. The affinity constants and rank order of potency--atropine > pirenzepine > AF-DX 116-suggest that cholinergic vasodilation in this vascular bed is predominantly mediated by the M3-receptor subtype. The EC50 value of MCh and the pA2 values of pirenzepine and AF-DX 116 are comparable to values reported for in vitro experiments.
STUDIES OF UROBILIN ELIMINATION IN THE NORMAL AND ANEMIC DOG
Authors: Harry Dubin
Journal: The Journal of Experimental Medicine (1918)

1. The output of urobilin is increased in experimental trypanosome anemia presumably as a result of the increased blood destruction. 2. The administration of salvarsan (arsenobenzol) during the anemic period, if it checks the blood destruction, reduces the urobilin elimination, but this result does not follow unless the blood picture improves. 3. Following splenectomy in the normal dog an increase in the urobilin elimination of varying degree occurs, the significance of which is doubtful. 4. Splenectomy during the period of anemia does not cause a decrease in urobilin elimination. The experiments support the view that the elimination of urobilin may be considered as an index of blood destruction, but they do not explain the decrease in the elimination occurring in man in certain forms of hemolytic anemia following splenectomy.
Polyarticular psoriatic arthritis is more like oligoarticular psoriatic arthritis, than rheumatoid arthritis
Authors: P S Helliwell, G Porter, W J Taylor
Journal: Annals of the Rheumatic Diseases (2006)

<b>Background and objective:</b> Since the original description of psoriatic arthritis (PsA) subgroups by Moll and Wright, there has been some discrepancy in the precise prevalence of the different subgroups and in particular the proportion of patients with polyarthritis. The higher prevalence of the polyarthritis subgroup may be due to the inclusion of patients with seronegative rheumatoid arthritis with coincidental psoriasis. The classification of psoriatic arthritis (CASPAR) study database provided an opportunity to examine this question. <b>Methods:</b> The CASPAR study collected clinical, radiological and laboratory data on 588 patients with physician-diagnosed PsA and 525 controls with other inflammatory arthritis, 70% of whom had rheumatoid arthritis. Patients with PsA were divided into two groups: polyarthritis and non-polyarthritis (which included the Moll and Wright subgroups of spinal disease, distal interphalangeal predominant and arthritis mutilans) and were compared with patients with rheumatoid arthritis. Comparisons were made between all three groups and, if a significant difference occurred, between the two groups with PsA. <b>Results:</b> The three groups differed significantly with regard to all clinical and laboratory variables except duration of disease. Significant differences were also found between the two groups of PsA in terms of age, sex, total number of involved joints, disability score and symmetry. However, no differences were found between the groups of patients with PsA in terms of seropositivity for rheumatoid factor and antibodies to cyclic citrullinated peptide, enthesitis, and spinal pain and stiffness. Further, dactylitis was commonly seen in patients with PsA (57% in the polyarticular group and 45% in non-polyarticular group), and uncommonly found in patients with rheumatoid arthritis (5%). With the exception of entheseal changes, syndesmophytes and osteolysis, typical radiological features of PsA could not be used to distinguish between the PsA subgroups. <b>Conclusions:</b> The evidence suggests that the changing prevalence of the polyarticular subgroup of PsA is not because doctors include patients with seronegative rheumatoid arthritis with coincidental psoriasis.
Vitamin D receptor regulates TGF-β signalling in systemic sclerosis
Authors: Pawel Zerr, Stefan Vollath, Katrin Palumbo-Zerr, Michal Tomcik, Jingang Huang, Alfiya Distler, Christian Beyer, Clara Dees, Kolja Gela, Oliver Distler, Georg Schett, Jörg H W Distler
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Vitamin D receptor (VDR) is a member of the nuclear receptor superfamily. Its ligand, 1,25-(OH)<sub>2</sub>D, is a metabolically active hormone derived from vitamin D<sub>3</sub>. The levels of vitamin D<sub>3</sub> are decreased in patients with systemic sclerosis (SSc). Here, we aimed to analyse the role of VDR signalling in fibrosis. <h3>Methods</h3> VDR expression was analysed in SSc skin, experimental fibrosis and human fibroblasts. VDR signalling was modulated by siRNA and with the selective agonist paricalcitol. The effects of VDR on Smad signalling were analysed by reporter assays, target gene analyses and coimmunoprecipitation. The effects of paricalcitol were evaluated in the models of bleomycin-induced fibrosis and fibrosis induced by overexpression of a constitutively active transforming growth factor-β (TGF-β) receptor I (TBRI<sup>CA</sup>). <h3>Results</h3> VDR expression was decreased in fibroblasts of SSc patients and murine models of SSc in a TGF-β-dependent manner. Knockdown of VDR enhanced the sensitivity of fibroblasts towards TGF-β. In contrast, activation of VDR by paricalcitol reduced the stimulatory effects of TGF-β on fibroblasts and inhibited collagen release and myofibroblast differentiation. Paricalcitol stimulated the formation of complexes between VDR and phosphorylated Smad3 in fibroblasts to inhibit Smad-dependent transcription. Preventive and therapeutic treatment with paricalcitol exerted potent antifibrotic effects and ameliorated bleomycin- as well as TBRI<sup>CA</sup>-induced fibrosis. <h3>Conclusions</h3> We characterise VDR as a negative regulator of TGF-β/Smad signalling. Impaired VDR signalling with reduced expression of VDR and decreased levels of its ligand may thus contribute to hyperactive TGF-β signalling and aberrant fibroblast activation in SSc.
Neutrophil Migration Mechanisms, with an Emphasis on the Pulmonary Vasculature
Authors: James G. Wagner, Robert A. Roth
Journal: Pharmacological Reviews (2000)

Leukocyte trafficking into pulmonary tissue and airspaces is a critical component of the host defense response. Activation and migration of polymorphonuclear leukocytes (PMNs) into lungs also contribute to inflammatory tissue injury and remodeling of tissue architecture. There have been considerable advances in our understanding of the mechanisms that control PMN adhesion and transendothelial migration (TEM). Mechanisms of migration unique to the lungs have been described with regard to the profile of adhesion molecules, cytokines, and chemokines elicited during PMN emigration from blood vessels. This work reviews general mechanisms of TEM of PMNs and discusses the nature of PMN recruitment in several models of airway inflammation that illustrate how various stimuli elicit different responses. Pharmacologic manipulation of adhesive interactions between PMNs and endothelial cells is a current area of research aimed at developing pharmacologic agents to control inflammation during pulmonary and other inflammatory diseases. A summary of some of these agents and their actions is presented.
Glycolipids of the mouse peritoneal macrophage. Alterations in amount and surface exposure of specific glycolipid species occur in response to inflammation and tumoricidal activation.
Authors: A M Mercurio, G A Schwarting, P W Robbins
Journal: The Journal of Experimental Medicine (1984)

We have characterized the major glycolipid constituents of the mouse peritoneal macrophage, and have demonstrated that alterations in the amount and in the accessibility of specific glycolipid species to galactose oxidase/NaB3H4 labeling, an indicator of glycolipid surface exposure, occur in response to inflammation and as a consequence of activation to a tumoricidal state. The key findings are: (a) Asialo GM1, a major neutral glycolipid constituent of all macrophage populations examined, is accessible to galactose oxidase/NaB3H4 labeling on the surface of TG-elicited and BCG-activated macrophages but not on resident macrophages; (b) GM1 is the predominant ganglioside constituent of the mouse macrophage. Resident macrophages contain two distinct GM1 species, as determined by cholera toxin binding, while TG-elicited and BCG-activated macrophages contain an additional GM1 species. Differences in the relative amounts of these GM1 species, as well as in their accessibility to galactose oxidase/NaB3H4 labeling, exist among the macrophage populations. These observations suggest that both a chemical and spatial reorganization of surface glycolipids occurs in response to inflammation and tumoricidal activation.
Chemical Studies on Tobacco Smoke. XXXIII. N'-Nitrosonornicotine in Tobacco: Analysis of Possible Contributing Factors and Biologic Implications2
Authors: Stephen S. Hecht, Raphael M. Ornaf, Dietrich Hoffman
Journal: JNCI Journal of the National Cancer Institute (1975)

Journal Article Chemical Studies on Tobacco Smoke. XXXIII. N'-Nitrosonornicotine in Tobacco: Analysis of Possible Contributing Factors and Biologic Implications Get access Stephen S. Hecht, Stephen S. Hecht Search for other works by this author on: Oxford Academic PubMed Google Scholar Raphael M. Ornaf, Raphael M. Ornaf Search for other works by this author on: Oxford Academic PubMed Google Scholar Dietrich Hoffman Dietrich Hoffman Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 54, Issue 5, May 1975, Pages 1237–1244, https://doi.org/10.1093/jnci/54.5.1237 Published: 01 May 1975 Article history Received: 10 December 1974 Accepted: 31 January 1975 Published: 01 May 1975