tbuckley/cabot-search huggingface dataset:
Requirement of Fas for the Development of Autoimmune Diabetes in Nonobese Diabetic Mice
Authors: Naoto Itoh, Akihisa Imagawa, Toshiaki Hanafusa, Masako Waguri, Koji Yamamoto, Hiromi Iwahashi, Makoto Moriwaki, Hiromu Nakajima, Junichiro Miyagawa, Mitsuyoshi Namba, Susumu Makino, Shigekazu Nagata, Norio Kono, Yuji Matsuzawa
Journal: The Journal of Experimental Medicine (1997)

Insulin-dependent diabetes mellitus (IDDM) is assumed to be a T cell–mediated autoimmune disease. To investigate the role of Fas-mediated cytotoxicity in pancreatic β cell destruction, we established nonobese diabetic (NOD)-lymphoproliferation (lpr)/lpr mice lacking Fas. Out of three genotypes, female NOD-+/+ and NOD-+/lpr developed spontaneous diabetes by the age of 10 mo with the incidence of 68 and 62%, respectively. In contrast, NOD-lpr/lpr did not develop diabetes or insulitis. To further explore the role of Fas, adoptive transfer experiments were performed. When splenocytes were transferred from diabetic NOD, male NOD-+/+ and NOD-+/lpr developed diabetes with the incidence of 89 and 83%, respectively, whereas NOD-lpr/lpr did not show glycosuria by 12 wk after transfer. Severe mononuclear cell infiltration was revealed in islets of NOD-+/+ and NOD-+/lpr, whereas islet morphology remained intact in NOD-lpr/lpr. These results suggest that Fas-mediated cytotoxicity is required to initiate β cell autoimmunity in NOD mice. Fas–Fas ligand system might be critical for autoimmune β cell destruction leading to IDDM.
MB-05 * PHARMACOLOGICAL INHIBITION OF MRK/ZAK KINASE FOR THE TREATMENT OF MEDULLOBLASTOMA
Authors: R. Ruggieri, D. Markowitz, C. Powell, N. Tran, M. Vanan, M. He, Y. Al Abed, M. Symons
Journal: Neuro-Oncology (2015)

Medulloblastoma is a cerebellar tumor and the most common pediatric brain malignancy. Radiation therapy is part of the standard care for this tumor, but its effectiveness is accompanied by significant neurocognitive sequelae due to the deleterious effects of radiation on the developing brain. We have previously shown that the protein kinase MRK/ZAK protects tumor cells from radiation-induced cell death by regulating cell cycle arrest after ionizing radiation. Here, we show that siRNA-mediated MRK depletion sensitizes medulloblastoma primary cells to radiation. We have, therefore, designed and tested a small molecule inhibitor of MRK, M443, which binds to MRK in an irreversible fashion and inhibits its activity. We found that M443 strongly radio-sensitizes UW228 medulloblastoma cells as well as IMB226 patient-derived primary cells. M443 also inhibits radiation-induced activation of both p38 and Chk2, two proteins that act downstream of MRK and are involved in DNA damage-induced cell cycle arrest. We also tested the effect of M443 in an animal model of medulloblastoma that employs orthotopic implantation of IMB226 medulloblastoma cells in nude mice. Intra-tumoral delivery of M443 alone significantly extended animal survival by 5 days compared to vehicle treatment. Combination treatment of M443 with radiation at 2 x 3 Gy, that is not effective on its own (1 day of additional survival over control), achieved a synergistic increase in survival (15 days over the control survival time). Western blotting of tumor lysates demonstrated strong inhibition of MRK activity. In conclusion, we have developed a new small molecule inhibitor of MRK/ZAK that radio-sensitizes medulloblastoma cells. We hypothesize that combining radio-therapy with M443 will allow us to lower the radiation dose while maintaining therapeutic efficacy, thereby minimizing radiation-induced side effects.
Hospitalisations for sport-related concussions in US children aged 5 to 18 years during 2000–2004
Authors: J Yang, G Phillips, H Xiang, V Allareddy, E Heiden, C Peek-Asa
Journal: British Journal of Sports Medicine (2008)

Objectives: To describe patient and hospital characteristics associated with hospitalisation for a diagnosis of non-fatal sport-related concussion, and to determine factors associated with these hospitalisations. Methods: Children aged 5–18 years with a primary diagnosis of a sport-related concussion in the Nationwide Inpatient Sample (2000–2004) were identified. Length of stay and hospital charges for sport-related concussions were documented. Logistic regression was used to assess the association of patient or hospital characteristics with hospitalisations for sport-related concussion. Results: Between 2000 and 2004, a total of 755 non-fatal paediatric sport-related hospitalisations for concussion were identified. Nationwide, this represents 3712 hospitalisations and over US$29 million total hospital charges, with nearly US$6 million in total hospital charges per year. Over half (52.3%) of patients with concussion experienced loss of consciousness. Over 80% of the patients hospitalised for concussion received no procedures during their average 1.1 day (median 0.8 day) of hospital stay. Older age, but not gender, was associated with increased odds of sport-related hospitalisations for concussion. Non-teaching hospitals or hospitals in rural areas had significantly greater odds of admitting sport-related concussions versus other sport-related traumatic brain injuries compared with teaching or urban hospitals. Conclusions: Management of paediatric sport-related concussions varied, depending on the patient and the hospital. Better guidelines are needed for the identification and management of sport-related concussions. Standardised procedures for hospitals treating concussive injuries may also be warranted.
Characterization of a cis-acting regulatory element which silences expression of the class II-A beta gene in epithelium.
Authors: S E Albert, F Strutz, K Shelton, T Haverty, M J Sun, S R Li, A Denham, R A Maki, E G Neilson
Journal: The Journal of Experimental Medicine (1994)

Class II major histocompatibility complex (MHC) genes encode for alpha/beta chain pairs that are constitutively expressed principally on mature B cells and dendritic cells in mice. These gene products are easily induced on macrophages with cytokines, and may also aberrantly appear on the surface of epithelium during immune injury. The appearance of class II determinants in parenchymal tissue potentially renders these somatic cells capable of antigen presentation to circulating CD4+ T lymphocytes, and their absence may be protective for normal tissues expressing self-antigens. The low surface class II expression observed on parenchymal cells generally correlates with low levels of mRNA, suggesting that transcription rate is a major element in class II regulation. To understand the transcriptional mechanism maintaining low basal surface expression of class II in somatic cells, we transiently transfected mini-gene reporter constructs to study the regulation of the murine A beta promoter in a cultured renal epithelial cell line. We describe here a negative cis-acting regulatory region located between -552 and -489 bp upstream of the A beta cap site that silences the transcriptional activity of the A beta promoter in epithelial cells in an orientation-dependent manner, and is also able to silence a heterologous promoter. This region is not active in class II-expressing B cells (BAL-17) in culture, but is functional in two other murine class II-negative cell lines, fibroblasts and thymoma T cells. Using competition electrophoretic mobility shift assays, we have localized the core protein binding site within this region to an 8-10-bp response element, designated A beta NRE, at -543 to -534 bp. A nuclear extract from BAL-17 cells does not bind to this element. Mutation of this site abrogates the transcriptional silencing activity of the region. We conclude that the transcription of class II-A beta in parenchymal cells, and some lymphocytes, can be actively repressed by an upstream silencing element.
Coagulase-Negative Staphylococci: Role as Pathogens
Authors: Johannes Huebner, MD, Donald A. Goldmann, MD
Journal: Annual Review of Medicine (1999)

Coagulase-negative staphylococci have long been regarded as apathogenic but their important role as pathogens and their increasing incidence have been recognized and studied in recent years. Although specific virulence factors are not as clearly established as they are in Staphylococcus aureus, it seems clear that factors such as bacterial polysaccharide components are involved in attachment and/or persistence of bacteria on foreign materials. Coagulase-negative staphylococci are by far the most common cause of bacteremia related to indwelling devices. Most of these infections are hospital-acquired, and studies over the past several years suggest that they are often caused by strains that are transmitted among hospitalized patients. Other important infections due to coagulase-negative staphylococci include central nervous system shunt infections, native or prosthetic valve endocarditis, urinary tract infections, and endophthalmitis. Intravenous treatment of systemic infections is usually required because coagulase-negative staphylococci have become increasingly resistant to multiple antibiotics.
Arginine Vasopressin–Induced Potentiation of Unitary L-Type Ca <sup>2+</sup> Channel Current in Guinea Pig Ventricular Myocytes
Authors: Shetuan Zhang, Yuji Hirano, Masayasu Hiraoka
Journal: Circulation Research (1995)

Abstract The effects of arginine vasopressin (AVP) on L-type Ca 2+ channels were studied by recording single-channel activity from cell-attached patches on isolated guinea pig ventricular myocytes, with 100 mmol/L Ba 2+ used as the charge carrier. Bath application of AVP (100 nmol/L) reversibly increased channel open probability by a factor of 2.92±1.43 (n=15) because of the increased number of channel openings and increased open times. AVP did not change the amplitudes of single-channel currents (1.17±0.10 pA in the control condition and 1.12±0.11 pA after AVP, at +20 mV; n=6). In our experimental conditions, in which myocytes were bathed in Ca 2+ -free high-potassium solutions, AVP-induced potentiation was observed without changes in [Ca 2+ ] i measured by fura 2 fluorescence signals (estimated [Ca 2+ ] i , ≈80 nmol/L). The AVP-induced increase in channel open probability was abolished by OPC-21268 (8 μmol/L), a specific blocker of V 1 receptor, but not by a V 2 blocker, OPC-31260 (5 μmol/L). AVP-induced potentiation was also suppressed by a broad-spectrum protein kinase inhibitor, H7 (100 μmol/L, bath application), but not by H89 (1 μmol/L), a blocker with high specificity to protein kinase A. AVP application after the treatment by phorbol ester (phorbol 12-myristate 13-acetate, 100 nmol/L for 1 hour) failed to potentiate the channel activity. These results raised the possibility that protein kinase C might be involved during signal transduction. Our results provide direct evidence that AVP potentiates cardiac L-type Ca 2+ currents via V 1 receptor stimulation.
LEGIONNAIRES' DISEASE IN RENAL-TRANSPLANT RECIPIENTS
Authors: BonnieV. Bock, PaulH. Edelstein, KimM. Snyder, CaroleM. Hatayama, RobertP. Lewis, BarbaraD. Kirby, WilliamL. George, MiltonL. Owens, CharlesE. Haley, RichardD. Meyer, SydneyM. Finegold
Journal: The Lancet (1978)
Poor Outcome for Children and Adolescents With Progressive Disease or Relapse of Lymphoblastic Lymphoma: A Report From the Berlin-Frankfurt-Muenster Group
Authors: Birgit Burkhardt, Alfred Reiter, Eva Landmann, Peter Lang, Lisa Lassay, Roswitha Dickerhoff, Max Lakomek, Günter Henze, Arend von Stackelberg
Journal: Journal of Clinical Oncology (2009)

Little is known about the outcome of pediatric patients with lymphoblastic lymphoma (LBL) who suffer from progressive disease or relapse.We analyzed the pattern of LBL relapses after current non-Hodgkin's lymphoma Berlin-Frankfurt-Muenster (BFM) frontline therapy between April 1990 and March 2003. Relapse therapy was according to acute lymphoblastic leukemia (ALL) -Relapse-BFM protocols or ALL-BFM protocols for high-risk patients.Twenty-eight (11%) of 251 registered patients with precursor T-cell LBL (T-LBL) and six (8%) of 73 patients with precursor B-cell LBL (pB-LBL) suffered from relapse. Of the 28 patients with T-LBL, one died from infection during relapse chemotherapy, 18 failed to achieve stable remission and died from disease progression, and nine reached allogeneic stem-cell transplantation (SCT). Two of these nine patients who underwent SCT died from transplantation-associated toxicity, three died from disease progression, and four are still alive. These four patients are in second remission of their lymphoma for 48, 68, 125, and 131 months, respectively, after allogeneic SCT. One of the four patients developed colon adenocarcinoma 47 months after SCT. Of the six patients with pB-LBL who experienced relapse, one patient died as a result of toxicity of relapse chemotherapy, two died from disease progression after chemotherapy, and three received allogeneic SCT. Of these, two died from subsequent disease progression, and one is still alive 57 months after allogeneic SCT.Using modern conventional therapy in the frontline treatment of LBL, 10% of patients suffer from progressive disease or relapse. Because of the extremely poor reinduction success, the salvage rate for these patients is poor, with only a 14% (SE = 6%) overall survival. Long-term survival was only achieved in those few patients who were able to undergo an allogeneic SCT.
The Relation of Size to the Relative Rates of Degradation of Intestinal Brush Border Proteins
Authors: David H. Alpers
Journal: Journal of Clinical Investigation (1972)

Proteins associated with intestinal brush borders and their various fractions were solubilized with sodium dodecyl sulfate and beta-mercaptoethanol, and separated by electrophoresis on acrylamide gels containing sodium dodecyl sulfate. Brush borders contain at least 15 proteins or subunits, ranging in molecular weight from 19,000 to 270,000. The largest proteins (170-270,000 mol wt), including the disaccharidases, are removed from the brush borders by papain. Proteins belonging to the remaining membrane, including alkaline phosphatase, have an intermediate size (53-140,000 mol wt). The proteins corresponding to the filamentous "core" of the microvilli are the smallest (19-45,000). The relative rates of degradation of these proteins were studied by following the rate of decline of (14)C-labeled leucine activity in specific proteins, and by the double isotope technique of Schimke in which leucine-(14)C was given to intact rats intraluminally 10 hr before an intraluminal dose of leucine-(3)H. Heterogeneity of (3)H/(14)C ratios and thus of rates of turnover of brush border proteins was noted. In general, the largest proteins (including the disaccharidases), were turning over the fastest. Other membrane proteins (i.e. alkaline phosphatase) had an intermediate rate of degradation, and "core" proteins turned over slowly. Thus, there was a general correlation between relative degradation rate and size.
Diagnostic yield of image guided Abrams needle versus Tru-cut needle pleural biopsies for non-granulomatous pleural disease: A large tertiary centre experience
Authors: Deepak Jayaram, Liju Ahmed, Milos Prica, Peter Mezes, Irfan Ahmed
Journal: European Respiratory Journal (2012)

Aim:   To compare the diagnostic yield of physician led image guided Abrams pleural biopsies versus interventional radiologist led Tru-cut.   Methodology:   Retrospective analysis of image guided pleural biopsies from 2006 to 2011 in a large tertiary centre. Granulomatous disease was excluded.   Results:   We analysed 27 Abrams and 33 Tru-cut biopsies. The median (IQR) of the size (volume) of specimens for Abrams vs Tru-cut were 14mm 3  (2 - 12) vs 8mm 3  (4 - 12). Comparing both types using Mann-Whitney U test showed statistically significant difference  p =0.030.  Analysis of the yield of pleural tissue and diagnosis by Chi-Sqaured or Fischer9s exact test in Abrams vs Tru-cut were 93.8% vs 86.7% (p= 0.339) and 89.6% vs 88.3% (p=0.837) respectively.   Conclusion:   Physician led image guided Abrams biopsies had larger size specimens. The diagnostic yield of Abrams technique is statistically similar to the Tru-cut method. The diagnostic yield with Abrams is superior to published literature. To the best of our knowledge this is the first data series comparing image guided Abrams vs Tru-cut pleural biopsies.
RAP80 Acts Independently of BRCA1 in Repair of Topoisomerase II Poison-Induced DNA Damage
Authors: Junko Iijima, Zhihong Zeng, Shunichi Takeda, Yoshihito Taniguchi
Journal: Cancer Research (2010)

Abstract The tumor suppressor BRCA1 functions in DNA homologous recombination, and mutations in BRCA1 increase the risk of breast and ovarian cancers. RAP80 is a component of BRCA1-containing complexes that is required for recruitment of BRCA1 to sites of DNA damage. To evaluate the role of RAP80 in DNA damage repair, we genetically disrupted both RAP80 alleles in the recombinogenic avian DT40 cell line. The resulting RAP80−/− cells were proficient at homologous recombination and nonhomologous end-joining (NHEJ), but were specifically sensitized to the topoisomerase II inhibitor etoposide. Notably, doubly mutant RAP80−/−BRCA1−/− cells were more sensitive to etoposide than were BRCA1−/− cells, revealing that RAP80 performs a BRCA1-independent repair function. Moreover, jointly impairing the function of CtIP, a distinct BRCA1 effector protein, rendered RAP80−/− cells more sensitive to etoposide compared with singly mutant cells, again illustrating a BRCA1-independent role of RAP80. Based on our findings, we propose that RAP80 exerts a specific function in repair of the topoisomerase-cleavage complex, such as the removal of covalently bound polypeptides from double-strand break ends independently of BRCA1. Cancer Res; 70(21); 8467–74. ©2010 AACR.
Relationship Between Organotropism and Leukemogenicity of Type C RNA Viruses as Demonstrated in NIH Swiss Mice Inoculated at Birth With Gross Murine Leukemia Virus2
Authors: Kenji Nagao, Yuso Kadama, Katsutomo Hamada, Kenji Yokoro
Journal: JNCI Journal of the National Cancer Institute (1978)

The relationship of the organ distribution pattern of ecotropic murine leukemia virus and leukemogenesis was examined by XC plaque assay in NIH Swiss mice infected at birth with Gross murine leukemia virus (G-MuLV), and the data obtained were compared with those in rats infected at birth with G-MuLV adapted for rats (G-MuLV-AR). All G-MuLV-infected mice developed T-cell leukemia with a short latency period. The virus infectivity was detected not only in lymphoid tissues but also in various other tissues such as muscle, testis, and uterus in which no overt leukemia cell infiltration was found. Infectivity was first detected in the thymus and other tissues as early as 7 days after infection, and the titers steadily increased thereafter in many tissues up to the manifestation of leukemia. In noninfected controls, no virus was expressed in any tissues at any age up to 18 months after birth. These findings were different from those obtained from rats infected with G-MuLV-AR in which the site of the virus replication and the leukemogenic process was confined to the thymus. Cell-free extracts (CFE) were prepared from the thymuses, spleens, muscles, testes, and uteri of G-MuLV-infected mice in preleukemic and leukemic stages and inoculated into newborn syngeneic mice to examine their leukemogenic activity. CFE from the thymus and spleen showed prominent leukemogenicity, whereas CFE from the muscle, testis, and uterus either were much less leukemogenic or lacked leukemogenicity. These results indicated that G-MuLV contained leukemogenic and non leukemogenic viruJies as two subpopulations and that lymphoid organs, especially the thymus, seem the most favored sites for the replication of oncogenic viruses and nonlymphoid tissues seem the most favored sites for nononcogenic viruses.
IN VITRO AND IN VIVO DRUG INTERACTIONS INVOLVING HUMAN CYP3A
Authors: K. E. Thummel, G. R. Wilkinson
Journal: The Annual Review of Pharmacology and Toxicology (1998)

▪ Abstract Cytochrome P4503A (CYP3A) is importantly involved in the metabolism of many chemically diverse drugs administered to humans. Moreover, its localization in high amounts both in the small intestinal epithelium and liver makes it a major contributor to presystemic elimination following oral drug administration. Drug interactions involving enzyme inhibition or induction are common following the coadministration of two or more CYP3A substrates. Studies using in vitro preparations are useful in identifying such potential interactions and possibly permitting extrapolation of in vitro findings to the likely in vivo situation. Even if accurate quantitative predictions cannot be made, several classes of drugs can be expected to result in a drug interaction based on clinical experience. In many instances, the extent of such drug interactions is sufficiently pronounced to contraindicate the therapeutic use of the involved drugs.
Opportunistic screening for Chlamydia at a community based contraceptive service for young people
Authors: V Moens
Journal: BMJ (2003)

<h3>Abstract</h3> <b>Problem</b> The suspected high prevalence of <i>Chlamydia</i> infection that is undiagnosed and untreated among high risk women who attend a contraceptive service for young people. <b>Design</b> Cross sectional study from a community screening service. <b>Background and setting</b> An inner city contraceptive and psychotherapy service for young people aged 12–21 years. <b>Key measure for improvement</b> Prevalence of infection commensurate with or above findings from the national screening pilot (13.8% for &gt; 16 year olds, 10.5% for 16–19 year olds, and 7.2% for 20 to 24 year olds). <b>Strategies for change</b> Offering testing (of a first catch urine sample) for <i>Chlamydia</i> to all young people using the contraceptive service who were not previously screened; launching a publicity campaign about the new service; training medical staff and reception staff to deliver the service to maximise take up of screening and of treatment by infected cases; and surveying results from testing to monitor significant patterns of infection requiring further action. <b>Effects of change</b> Percentage of clients with infection exceeded targets for each age group, 76% with a positive or equivocal result returned for treatment, 87% of those treated returned for a test of cure, and 99% of tests of cure were negative. Prevention work was initiated in a school with a particularly heavy concentration of infected clients. <b>Lessons learnt</b> A contraceptive service for young women is a highly acceptable location for effective <i>Chlamydia</i> screening.
Immunoregulation of a viral model of multiple sclerosis using the synthetic cannabinoid R(+)WIN55,212
Authors: J. Ludovic Croxford, Stephen D. Miller
Journal: Journal of Clinical Investigation (2003)

Theiler murine encephalomyelitis virus–induced demyelinating disease (TMEV-IDD) is a mouse model of chronic-progressive multiple sclerosis (MS) characterized by Th1-mediated CNS demyelination and spastic hindlimb paralysis. Existing MS therapies reduce relapse rates in 30% of relapsing-remitting MS patients, but are ineffective in chronic-progressive disease, and their effects on disability progression are unclear. Experimental studies demonstrate cannabinoids are useful for symptomatic treatment of spasticity and tremor in chronic-relapsing experimental autoimmune encephalomyelitis. Cannabinoids, however, have reported immunosuppressive properties. We show that the cannabinoid receptor agonist, R(+)WIN55,212, ameliorates progression of clinical disease symptoms in mice with preexisting TMEV-IDD. Amelioration of clinical disease is associated with downregulation of both virus and myelin epitope-specific Th1 effector functions (delayed-type hypersensitivity and IFN-γ production) and the inhibition of CNS mRNA expression coding for the proinflammatory cytokines, TNF-α, IL1-β, and IL-6. Clinical trials investigating the therapeutic potential of cannabinoids for the symptomatic treatment of MS are ongoing, and this study demonstrates that they may also have potent immunoregulatory properties.