tbuckley/cabot-search huggingface dataset:
AAV2 Gene Therapy Readministration in Three Adults with Congenital Blindness
Authors: Jean Bennett, Manzar Ashtari, Jennifer Wellman, Kathleen A. Marshall, Laura L. Cyckowski, Daniel C. Chung, Sarah McCague, Eric A. Pierce, Yifeng Chen, Jeannette L. Bennicelli, Xiaosong Zhu, Gui-shuang Ying, Junwei Sun, J. Fraser Wright, Alberto Auricchio, Francesca Simonelli, Kenneth S. Shindler, Federico Mingozzi, Katherine A. High, Albert M. Maguire
Journal: Science Translational Medicine (2012)

Demonstration of safe and stable reversal of blindness after a single unilateral subretinal injection of a recombinant adeno-associated virus (AAV) carrying the RPE65 gene (AAV2-hRPE65v2) prompted us to determine whether it was possible to obtain additional benefit through a second administration of the AAV vector to the contralateral eye. Readministration of vector to the second eye was carried out in three adults with Leber congenital amaurosis due to mutations in the RPE65 gene 1.7 to 3.3 years after they had received their initial subretinal injection of AAV2-hRPE65v2. Results (through 6 months) including evaluations of immune response, retinal and visual function testing, and functional magnetic resonance imaging indicate that readministration is both safe and efficacious after previous exposure to AAV2-hRPE65v2.
Shrinking central nervous system in systemic lupus erythematosus
Authors: C C Mok
Journal: Annals of the Rheumatic Diseases (2004)

Neuropsychiatric manifestations of systemic lupus erythematosus (SLE) are diverse and heterogeneous.1 We report a patient who experienced a flare of SLE with subacute transverse myelopathy. Magnetic resonance imaging (MRI) showed atrophy of the entire central nervous system (CNS). Apart from psychosis at SLE onset, there had not been any neuropsychiatric relapses. Progressive atrophy of the CNS should be recognised as an evolving feature of SLE, which may occur without overt neurological symptoms.

A 22 year old Chinese woman with SLE was admitted because of a 2 month history of progressive weakness in her legs and bladder dysfunction. Her SLE had been diagnosed 5 years previously when she presented with polyarthritis, malar rash, cytopenia, psychosis, positive anti-dsDNA, and anti-Ro. A computed tomographic (CT) scan of the brain and cerebrospinal fluid (CSF) findings were unremarkable. Steroid and cyclophosphamide were given, with complete response. She remained well while receiving prednisone and azathioprine maintenance. …
Cell Biology of Ureter Development
Authors: Adrian S. Woolf, Jamie A. Davies
Journal: Journal of the American Society of Nephrology (2012)

The mammalian ureter contains two main cell types: a multilayered water-tight epithelium called the urothelium, surrounded by smooth muscle layers that, by generating proximal to distal peristaltic waves, pump urine from the renal pelvis toward the urinary bladder. Here, we review the cellular mechanisms involved in the development of these tissues, and the molecules that control the process. We consider the relevance of these biologic findings for understanding the pathogenesis of human ureter malformations.
Specific incremental test in elite squash players
Authors: O Girard, P Sciberras, M Habrard, P Hot, R Chevalier, G P Millet
Journal: British Journal of Sports Medicine (2005)

Objectives: To compare cardiorespiratory responses between incremental treadmill (non-specific) and field (sport specific) tests in elite squash players. Methods: Seven elite players (ranked 1 to 25 in their national federation including the World number 1) randomly performed an incremental treadmill test (TT) and a squash specific graded test (ST) to exhaustion. The ST consisted of repeated displacements replicating the game of squash, at increasing speed on the court. In both tests, ventilatory variables and heart rate were determined at the ventilatory threshold, respiratory compensation point, and maximal loads (max). Results: Heart rate and percentage maximal oxygen uptake (V˙ o 2 max ) at the ventilatory threshold and respiratory compensation point were not different between the ST and TT, whereas V˙ o 2 max was higher in the ST than in the TT (63.6 (3.0) v 54.9 (2.5) ml/kg/min; p&lt;0.001). Time to exhaustion was not different between the ST and TT (1056 (180) v 962 (71) seconds) but correlated with the ranking of the players only in the ST ( r = −0.96, p&lt;0.001). Conclusions: V˙ o 2 max values derived from laboratory testing were not relevant for accurately estimating fitness in elite squash players. So the ST may be used as an additional test for determination of training intensity. Improved training advice for prescribing aerobic exercise or perfecting stroke technique may result from these results.
Development of B-1 cells: segregation of phosphatidyl choline-specific B cells to the B-1 population occurs after immunoglobulin gene expression.
Authors: L W Arnold, C A Pennell, S K McCray, S H Clarke
Journal: The Journal of Experimental Medicine (1994)

Adult mice have two easily recognizable subsets of B cells: the predominant resting population of the spleen, called B-2, and those called B-1, which predominate in coelomic cavities and can express CD5. Some antibody specificities appear to be unique to the B-1 population. Cells expressing antibody specific for phosphatidyl choline (PtC) are the most frequent, comprising 2-10% of peritoneal B cells in normal mice. To understand the basis for the segregation of the anti-PtC specificity to this population, we have produced transgenic (Tg) mice expressing the rearranged VH12 and V kappa 4 genes of a PtC-specific B-1 cell lymphoma. We find that VH12-Tg and VH12/V kappa 4 double-Tg mice develop very high numbers of PtC-specific peritoneal and splenic B cells. These cells have the characteristics of B-1 cells; most are CD5+, and are all IgMhi, B220lo, and CD23-. In the peritoneum these cells are also CD11b+. In addition, adult mice have many splenic B cells (up to one third of Tg+ cells) that express the VH12 Tg but do not bind PtC, presumably because they express a V kappa gene other than V kappa 4. These cells appear to be B-2 cells; they are CD23+, CD11b-, IgMlo, B220hi, and CD5-. Thus, mice given either the VH12 Tg alone or together with the V kappa 4 Tg develop a large population of PtC-specific B cells which belong exclusively to the B-1 population. Since B-2 cells can express the VH12 and V kappa 4 gene separately, we interpret these data to indicate that the events leading to the segregation of PtC-specific B cells to the B-1 population in normal mice are initiated after Ig gene rearrangement and expression. These data are discussed with regard to hypotheses of the origin of B-1 cells. We also find that VH12-Tg mice have a marked decrease in the generation of Tg-expressing B cells in adult bone marrow, but not newborn liver. We speculate that this may be related to positive selection of VH12-expressing B cells during differentiation.
Epinephrine QT Stress Testing in the Evaluation of Congenital Long-QT Syndrome
Authors: Himeshkumar Vyas, Joseph Hejlik, Michael J. Ackerman
Journal: Circulation (2006)

A paradoxical increase in the uncorrected QT interval during infusion of low-dose epinephrine appears pathognomonic for type 1 long-QT syndrome (LQT1). We sought to determine the diagnostic accuracy of this response among patients referred for clinical evaluation of congenital long-QT syndrome (LQTS).From 1999 to 2002, 147 genotyped patients (125 untreated and 22 undergoing beta-blocker therapy) had an epinephrine QT stress test that involved a 25-minute infusion protocol (0.025 to 0.3 microg.kg(-1).min(-1)). A 12-lead ECG was monitored continuously, and repolarization parameters were measured. The sensitivity, specificity, and positive and negative predictive values for the paradoxical QT response (defined as a > or =30-ms increase in QT during infusion of < or =0.1 microg.kg(-1).min(-1) epinephrine) was determined. The 125 untreated patients (44 genotype negative, 40 LQT1, 30 LQT2, and 11 LQT3) constituted the primary analysis. The median baseline corrected QT intervals (QTc) were 444 ms (gene negative), 456 ms (LQT1), 486 ms (LQT2), and 473 ms (LQT3). The median change in QT interval during low-dose epinephrine infusion was -23 ms in the gene-negative group, 78 ms in LQT1, -4 ms in LQT2, and -58 ms in LQT3. The paradoxical QT response was observed in 37 (92%) of 40 patients with LQT1 compared with 18% (gene-negative), 13% (LQT2), and 0% (LQT3; P<0.0001) of the remaining patients. Overall, the paradoxical QT response had a sensitivity of 92.5%, specificity of 86%, positive predictive value of 76%, and negative predictive value of 96% for LQT1 status. Secondary analysis of the subset undergoing beta-blocker therapy indicated inferior diagnostic utility in this setting.The epinephrine QT stress test can unmask concealed type 1 LQTS with a high level of accuracy.
Scintigraphic Assessment of Regionalized Defects in Myocardial Sympathetic Innervation and Blood Flow Regulation in Diabetic Patients With Autonomic Neuropathy
Authors: Martin J Stevens, Firat Dayanikli, David M Raffel, Kevin C Allman, Tracy Sandford, Eva L Feldman, Donald M Wieland, James Corbett, Marcus Schwaiger
Journal: Journal of the American College of Cardiology (1998)
Programmed death ligand 1 expression and tumor-infiltrating lymphocytes in glioblastoma
Authors: Anna Sophie Berghoff, Barbara Kiesel, Georg Widhalm, Orsolya Rajky, Gerda Ricken, Adelheid Wöhrer, Karin Dieckmann, Martin Filipits, Anita Brandstetter, Michael Weller, Sebastian Kurscheid, Monika E. Hegi, Christoph C. Zielinski, Christine Marosi, Johannes A. Hainfellner, Matthias Preusser, Wolfgang Wick
Journal: Neuro-Oncology (2014)

Immune checkpoint inhibitors targeting programmed cell death 1 (PD1) or its ligand (PD-L1) showed activity in several cancer types. We performed immunohistochemistry for CD3, CD8, CD20, HLA-DR, phosphatase and tensin homolog (PTEN), PD-1, and PD-L1 and pyrosequencing for assessment of the O6-methylguanine-methyltransferase (MGMT) promoter methylation status in 135 glioblastoma specimens (117 initial resection, 18 first local recurrence). PD-L1 gene expression was analyzed in 446 cases from The Cancer Genome Atlas. Diffuse/fibrillary PD-L1 expression of variable extent, with or without interspersed epithelioid tumor cells with membranous PD-L1 expression, was observed in 103 of 117 (88.0%) newly diagnosed and 13 of 18 (72.2%) recurrent glioblastoma specimens. Sparse-to-moderate density of tumor-infiltrating lymphocytes (TILs) was found in 85 of 117 (72.6%) specimens (CD3+ 78/117, 66.7%; CD8+ 52/117, 44.4%; CD20+ 27/117, 23.1%; PD1+ 34/117, 29.1%). PD1+ TIL density correlated positively with CD3+ (P < .001), CD8+ (P < .001), CD20+ TIL density (P < .001), and PTEN expression (P = .035). Enrichment of specimens with low PD-L1 gene expression levels was observed in the proneural and G-CIMP glioblastoma subtypes and in specimens with high PD-L1 gene expression in the mesenchymal subtype (P = 5.966e-10). No significant differences in PD-L1 expression or TIL density between initial and recurrent glioblastoma specimens or correlation of PD-L1 expression or TIL density with patient age or outcome were evident. TILs and PD-L1 expression are detectable in the majority of glioblastoma samples but are not related to outcome. Because the target is present, a clinical study with specific immune checkpoint inhibitors seems to be warranted in glioblastoma.
Enhanced myelotoxicity due to granulocyte colony-stimulating factor administration until 48 hours before the next chemotherapy course in patients with small-cell lung carcinoma.
Authors: V C Tjan-Heijnen, B Biesma, J Festen, T A Splinter, A Cox, D J Wagener, P E Postmus
Journal: Journal of Clinical Oncology (1998)

PURPOSE To evaluate the impact of granulocyte colony-stimulating factor (G-CSF) priming on peripheral-blood cell counts during standard-dose chemotherapy. PATIENTS AND METHODS Twelve patients with relapsed small-cell lung carcinoma (SCLC) were treated with two chemotherapy courses. Six patients received G-CSF priming only before the first course (group A) and the other six patients only before the second course (group B). Each patient served as his own control. Patients were treated with cyclophosphamide, epirubicin, and etoposide (CEE), or with vincristine, ifosfamide, mesna, and carboplatin (VIMP) every 4 weeks. G-CSF was administered subcutaneously 5 microg/kg/d for 6 days until 48 hours before the first or second chemotherapy course. RESULTS Priming caused a lowering of the WBC nadir, with a median value of 0.95 x 10(9)/L (P = .004), and of absolute neutrophil nadir, with a median value of 0.48 x 10(9)/L (P = .03). There was a trend for a lower platelet (PLT) nadir after G-CSF priming (P = .09). G-CSF priming resulted in a prolonged duration of WBC count less than 3.0 x 10(9)/L of +4.25 days (P = .04), and of WBC count less than 1.0 x 10(9)/L of +0.50 days (P = .03). The duration of neutropenia less than 0.5 x 10(9)/L seemed longer in primed courses (+3.75 days, P = .18). The duration of PLT counts less than 100 x 10(9)/L was prolonged by 1.5 days (P = .04). Hemoglobin (Hgb) levels were not influenced by G-CSF priming. CONCLUSION G-CSF administration until 48 hours before the next chemotherapy course increases chemotherapy-associated leukocytopenia and thrombocytopenia. This may be of special concern when G-CSF is administered during dose-densified chemotherapy.
The Safety and Immunogenicity of a Human Immunodeficiency Virus Type 1 (HIV-1) Recombinant gp160 Candidate Vaccine in Humans
Authors: Raphael Dolin, Barney S. Graham, Stephen B. Greenberg, Carol O. Tacket, Robert B. Belshe, Karen Midthun, Mary Lou Clements, Geoffrey J. Gorse, Brian W. Horgan, Robert L. Atmar, David T. Karzon, William Bonnez, Bruce F. Fernie, David C. Montefiori, Donald M. Stablein, Gale E. Smith, Wayne C. Koff
Journal: Annals of Internal Medicine (1991)

Objective: To evaluate the safety and immunogenicity of a human immunodeficiency virus type 1 (HIV-1) recombinant envelope glycoprotein (rgp160) candidate vaccine in humans. Subjects: Healthy adults (72) who were seronegative for HIV-1 were randomly assigned to one of four groups. Interventions: The subjects were randomly assigned to receive 40 or 80 µg of rgp160,10 µg of hepatitis B vaccine, or placebo in three doses (on days 0, 30, and 180), with an elective, nonblinded administration of a fourth dose on day 540. Measurements and Main Results: Neither clinical nor laboratory toxicity was encountered during a follow-up period exceeding 21 months. No effect of immunization was noted on lymphocyte counts, mitogenic responses, or delayed-type hypersensitivity. Serum anti-body responses to HIV envelope proteins detected by Western blot were seen in 30 of 33 subjects (91%; 95% CI, 71% to 97%) receiving either 40- or 80-µg doses of rgp160 and were most commonly of weakly reactive intensity. Responses were first noted by Western blot after the second dose. They markedly increased in frequency after the third dose and declined over the next 12 to 18 months. The administration of a fourth dose resulted in homologous neutralizing activity in sera from 5 of 24 subjects (21%; CI, 7% to 37%) as well as in complement-mediated antibody-dependent enhancement in sera from 6 of 24 subjects (25%; CI, 10% to 42%). Antibody responses were detected by enzyme-linked immunosorbent assay (ELISA) less frequently than by Western blot, and these responses persisted for a shorter time. Conclusions: The administration of rgp160 was well tolerated and safe, resulted in a high rate of antibody response by Western blot after the administration of the third and fourth doses, and generated serum neutralizing activity and complement-mediated antibody-dependent enhancement in some subjects after the fourth dose.
Immune Tolerance After Delivery of Dying Cells to Dendritic Cells In Situ
Authors: Kang Liu, Tomonori Iyoda, Marzena Saternus, Yukino Kimura, Kayo Inaba, Ralph M. Steinman
Journal: The Journal of Experimental Medicine (2002)

Peripheral immune tolerance is believed to be induced by the processing and presentation of self-tissues that die during physiologic tissue turnover. To examine the mechanism that mediates tolerance, we injected mice with dying syngeneic TAP−/− splenocytes loaded with small amounts of the protein antigen, ovalbumin (OVA). After ingestion and presentation of cell-associated OVA by the CD8+ subset of dendritic cells in situ, large numbers of antigen-reactive, CD8+ T cell receptor (TCR) transgenic T lymphocytes were driven into cell cycle, but then the T cells were deleted. The animals were also tolerant to challenge with OVA in complete Freund's adjuvant. An agonistic anti-CD40 monoclonal antibody was then administered together with the OVA-loaded splenocytes, so that the dendritic cells in the recipient mice would mature. In contrast to observations made in the steady state, the antigen-reactive T cells expanded in numbers for 1–2 wk and produced large amounts of interleukin 2 and interferon γ, while the animals retained responsiveness to antigen rechallenge. The specific tolerance that develops when dendritic cells process self tissues in the steady state should prevent or reduce the development of autoimmunity when dying cells are subsequently processed during infection.
A phase I study of sunitinib in combination with FOLFIRI in patients with untreated metastatic colorectal cancer
Authors: N Starling, F Vázquez-Mazón, D Cunningham, I Chau, J Tabernero, F J Ramos, T J Iveson, M P Saunders, E Aranda, A M Countouriotis, A Ruiz-Garcia, G Wei, J M Tursi, C Guillen-Ponce, A Carrato
Journal: Annals of Oncology (2011)
Trends in Bariatric Surgical Procedures
Authors: Heena P. Santry
Journal: JAMA (2005)

ContextThe increasing prevalence and associated sociodemographic disparities of morbid obesity are serious public health concerns. Bariatric surgical procedures provide greater and more durable weight reduction than behavioral and pharmacological interventions for morbid obesity.ObjectiveTo examine trends for elective bariatric surgical procedures, patient characteristics, and in-hospital complications from 1998 to 2003 in the United States.Design, Setting, and PatientsThe Nationwide Inpatient Sample was used to identify bariatric surgery admissions from 1998-2002 (with preliminary data for 12 states from 2003) using International Classification of Diseases, Ninth Revision, codes for foregut surgery with a confirmatory diagnosis of obesity or by diagnosis related group code for obesity surgery. Annual estimates and trends were determined for procedures, patient characteristics, and adjusted complication rates.Main Outcome MeasuresTrends in bariatric surgical procedures, patient characteristics, and complications.ResultsThe estimated number of bariatric surgical procedures increased from 13 365 in 1998 to 72 177 in 2002 (P&lt;.001). Based on preliminary state-level data (1998-2003), the number of bariatric surgical procedures is projected to be 102 794 in 2003. Gastric bypass procedures accounted for more than 80% of all bariatric surgical procedures. From 1998 to 2002, there were upward trends in the proportion of females (81% to 84%; P = .003), privately insured patients (75% to 83%; P = .001), patients from ZIP code areas with highest annual household income (32% to 60%, P&lt;.001), and patients aged 50 to 64 years (15% to 24%; P&lt;.001). Length of stay decreased from 4.5 days in 1998 to 3.3 days in 2002 (P&lt;.001). The adjusted in-hospital mortality rate ranged from 0.1% to 0.2%. The rates of unexpected reoperations for surgical complications ranged from 6% to 9% and pulmonary complications ranged from 4% to 7%. Rates of other in-hospital complications were low.ConclusionsThese findings suggest that use of bariatric surgical procedures increased substantially from 1998 to 2003, while rates of in-hospital complications were stable and length of stay decreased. However, disparities in the use of these procedures, with disproportionate and increasing use among women, those with private insurance, and those in wealthier ZIP code areas should be explored further.
Investigations of Cigarette Smoke Dosages in Inhalation Experiments With Syrian Hamsters. I. Concentration of Cigarette Smoke in the Inhalation Chamber and of Carbon Monoxide in the Blood
Authors: H.-J. Klimisch, W. Dontenwill
Journal: JNCI Journal of the National Cancer Institute (1977)

Journal Article Investigations of Cigarette Smoke Dosages in Inhalation Experiments With Syrian Hamsters. I. Concentration of Cigarette Smoke in the Inhalation Chamber and of Carbon Monoxide in the Blood Get access H.-J. Klimisch, H.-J. Klimisch Search for other works by this author on: Oxford Academic PubMed Google Scholar W. Dontenwill W. Dontenwill Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 58, Issue 4, April 1977, Pages 931–933, https://doi.org/10.1093/jnci/58.4.931 Published: 01 April 1977 Article history Received: 03 March 1976 Revision received: 08 July 1976 Accepted: 28 September 1976 Published: 01 April 1977
A spastic paraplegia mouse model reveals REEP1-dependent ER shaping
Authors: Christian Beetz, Nicole Koch, Mukhran Khundadze, Geraldine Zimmer, Sandor Nietzsche, Nicole Hertel, Antje-Kathrin Huebner, Rizwan Mumtaz, Michaela Schweizer, Elisabeth Dirren, Kathrin N. Karle, Andrey Irintchev, Victoria Alvarez, Christoph Redies, Martin Westermann, Ingo Kurth, Thomas Deufel, Michael M. Kessels, Britta Qualmann, Christian A. Hübner
Journal: Journal of Clinical Investigation (2013)

Axonopathies are a group of clinically diverse disorders characterized by the progressive degeneration of the axons of specific neurons. In hereditary spastic paraplegia (HSP), the axons of cortical motor neurons degenerate and cause a spastic movement disorder. HSP is linked to mutations in several loci known collectively as the spastic paraplegia genes (SPGs). We identified a heterozygous receptor accessory protein 1 (REEP1) exon 2 deletion in a patient suffering from the autosomal dominantly inherited HSP variant SPG31. We generated the corresponding mouse model to study the underlying cellular pathology. Mice with heterozygous deletion of exon 2 in Reep1 displayed a gait disorder closely resembling SPG31 in humans. Homozygous exon 2 deletion resulted in the complete loss of REEP1 and a more severe phenotype with earlier onset. At the molecular level, we demonstrated that REEP1 is a neuron-specific, membrane-binding, and membrane curvature-inducing protein that resides in the ER. We further show that Reep1 expression was prominent in cortical motor neurons. In REEP1-deficient mice, these neurons showed reduced complexity of the peripheral ER upon ultrastructural analysis. Our study connects proper neuronal ER architecture to long-term axon survival.
Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs)
Authors: Carole Peyssonnaux, Annelies S. Zinkernagel, Reto A. Schuepbach, Erinn Rankin, Sophie Vaulont, Volker H. Haase, Victor Nizet, Randall S. Johnson
Journal: Journal of Clinical Investigation (2007)

Iron is essential for many biological processes, including oxygen delivery, and its supply is tightly regulated. Hepcidin, a small peptide synthesized in the liver, is a key regulator of iron absorption and homeostasis in mammals. Hepcidin production is increased by iron overload and decreased by anemia and hypoxia; but the molecular mechanisms that govern the hepcidin response to these stimuli are not known. Here we establish that the von Hippel–Lindau/hypoxia-inducible transcription factor (VHL/HIF) pathway is an essential link between iron homeostasis and hepcidin regulation in vivo. Through coordinate downregulation of hepcidin and upregulation of erythropoietin and ferroportin, the VHL-HIF pathway mobilizes iron to support erythrocyte production.