tbuckley/cabot-search huggingface dataset:
Cytotoxic mechanisms in vitro against Epstein-Barr virus infected lymphoblastoid cell lines in rheumatoid arthritis.
Authors: M B McChesney, A D Bankhurst
Journal: Annals of the Rheumatic Diseases (1986)

Impaired regulation of latent infection with Epstein-Barr virus (EBV) may contribute to the pathogenesis of rheumatoid arthritis (RA) by allowing uncontrolled polyclonal B cell activation. The control of EBV infection in vitro is dependent on several cytotoxic lymphoid cell populations. The present report examines the suppression of early lymphoblastoid outgrowth by natural killer (NK) like cells and the ability to form cytotoxic T lymphocytes (CTLs) specific for EBV in vitro. The latter was measured by a regression assay of EBV induced lymphoblastoid transformation. In this assay the regression of B cell outgrowth at four and six weeks is due to the generation of CTLs specific for EBV. Patients with RA were defective in this ability to generate CTLs. Eight out of nine patients with RA had a geometric mean at the 50% regression end point equal to or greater than 20 X 10(5) cells/ml. In contrast, the geometric mean for all control donors was less than 4 X 10(5) cell/ml. NK activity was measured by a conventional 51Cr release assay with K562 targets. Patients with RA did not have significantly different activity from that of controls (RA patients, n = 4, 45.6 +/- 19.7% (means +/- SD) at 50:1, effector:target; normals, n = 5, 56.6 +/- 5.7%). No spontaneous NK activity was detected against allogeneic or autologous EBV infected B cell targets. When peripheral mononuclear cells from patients were incubated for six days with interleukin-2, lysis of EBV infected targets was seen. No difference in this activity was seen between RA and control studies. Overall, these studies show that patients with RA are defective in their ability to generate CTLs specific for EBV in vitro.
Myeloid-derived suppressor cell accumulation and function in patients with newly diagnosed glioblastoma
Authors: B. Raychaudhuri, P. Rayman, J. Ireland, J. Ko, B. Rini, E. C. Borden, J. Garcia, M. A. Vogelbaum, J. Finke
Journal: Neuro-Oncology (2011)

To assess the accumulation of myeloid-derived suppressor cells (MDSCs) in the peripheral blood of patients with glioma and to define their heterogeneity and their immunosuppressive function. Peripheral blood mononuclear cells (PBMCs) from healthy control subjects and from patients with newly diagnosed glioma were stimulated with anti-CD3/anti-CD28 and T cells assessed for intracellular expression of interferon (IFN)–γ. Antibody staining of PBMCs from glioma patients and healthy donors (CD33, HLADR, CD15, and CD14) followed by 4-color flow cytometry analysis–defined MDSC levels in the peripheral blood. To assess the role of MDSCs in suppressing T cell IFNγ production, PBMCs were depleted of MDSCs using anti-CD33 and anti-CD15 antibody-coated beads prior to T cell stimulation. Enzyme-linked immunosorbent assays were used to assess plasma arginase activity and the level of granulocyte colony-stimulating factor (G-CSF). Patients with glioblastoma have increased MDSC counts (CD33+HLADR−) in their blood that are composed of neutrophilic (CD15+; >60%), lineage-negative (CD15−CD14−; 31%), and monocytic (CD14+; 6%) subsets. After stimulation, T cells from patients with glioblastoma had suppressed IFN-γ production when compared with healthy, age-matched donor T cells. Removal of MDSCs from the PBMCs with anti-CD33/CD15–coated beads significantly restored T cell function. Significant increases in arginase activity and G-CSF levels were observed in plasma specimens obtained from patients with glioblastoma. The accumulation of MDSCs in peripheral blood in patients with glioma likely promotes T cell immune suppression that is observed in this patient population. Increased plasma levels of arginase and G-CSF may relate to MDSC suppressor function and MDSC expansion, respectively, in patients with glioma.
Understanding early serum hepatitis D virus and hepatitis B surface antigen kinetics during pegylated interferon‐alpha therapy via mathematical modeling
Authors: Jeremie Guedj, Yaron Rotman, Scott J. Cotler, Christopher Koh, Peter Schmid, Jeff Albrecht, Vanessa Haynes‐Williams, T. Jake Liang, Jay H. Hoofnagle, Theo Heller, Harel Dahari
Journal: Hepatology (2014)

There is little information on the early kinetics of hepatitis delta virus (HDV) and hepatitis B surface antigen (HBsAg) during interferon-α therapy. Here a mathematical model was developed and fitted to frequent HDV and HBsAg kinetic data from 10 patients during the first 28 weeks of pegylated-interferon-α2a (peg-IFN) therapy. Three patients achieved a complete virological response (CVR), defined as undetectable HDV 6 months after treatment stopped with loss of HBsAg and anti-HBsAg seroconversion. After initiation of therapy, a median delay of 9 days (interquartile range [IQR]: 5-15) was observed with no significant changes in HDV level. Thereafter, HDV declined in a biphasic manner, where a rapid first phase lasting for 25 days (IQR: 23-58) was followed by a slower or plateau second phase. The model predicts that the main effect of peg-IFN is to reduce HDV production/release with a median effectiveness of 96% (IQR: 93-99.8). Median serum HDV half-life (t1/2 ) was estimated as 2.9 days (IQR: 1.5-5.3) corresponding to a pretreatment production and clearance of about 10(10) (IQR: 10(9.7) -10(10.7) ) virions/day. None of the patients with flat second phase in HDV achieved CVR. HBsAg kinetics of decline paralleled the second phase of HDV decline consistent with HBsAg-productive-infected cells being the main source of production of HDV, with a median t1/2 of 135 days (IQR: 20-460). The interferon lambda-3 polymorphism (rs12979860) was not associated with kinetic parameters.
NICE tells local authorities to involve public in health decisions or risk judicial review
Authors: N. Hawkes
Journal: BMJ (2014)

Axonal degeneration contributes to permanent neurological disability in inherited and acquired diseases of myelin. Mitochondrial dysfunction has been proposed as a major contributor to this axonal degeneration. It remains to be determined, however, if myelination, demyelination, or remyelination alter the size and distribution of axonal mitochondrial stationary sites or the rates of axonal mitochondrial transport. Using live myelinated rat dorsal root ganglion (DRG) cultures, we investigated whether myelination and lysolecithin-induced demyelination affect axonal mitochondria. Myelination increased the size of axonal stationary mitochondrial sites by 2.3-fold. After demyelination, the size of axonal stationary mitochondrial sites was increased by an additional 2.2-fold and the transport velocity of motile mitochondria was increased by 47%. These measures returned to the levels of myelinated axons after remyelination. Demyelination induced activating transcription factor 3 (ATF3) in DRG neurons. Knockdown of neuronal ATF3 by short hairpin RNA abolished the demyelination-induced increase in axonal mitochondrial transport and increased nitrotyrosine immunoreactivity in axonal mitochondria, suggesting that neuronal ATF3 expression and increased mitochondrial transport protect demyelinated axons from oxidative damage. In response to insufficient ATP production, demyelinated axons increase the size of stationary mitochondrial sites and thereby balance ATP production with the increased energy needs of nerve conduction.
Second-line platinum therapy in patients with ovarian cancer previously treated with cisplatin.
Authors: M Markman, R Rothman, T Hakes, B Reichman, W Hoskins, S Rubin, W Jones, L Almadrones, J L Lewis
Journal: Journal of Clinical Oncology (1991)

In an effort to critically define the incidence and clinical characteristics of secondary responses to cisplatin-based therapy in patients with ovarian cancer previously treated with a cisplatin-based program, a retrospective review was undertaken of patients at the Memorial Sloan-Kettering Cancer Center who received greater than or equal to two cisplatin/carboplatin-based programs. Eighty-two patients were identified who met the entry criteria of having had a cisplatin-free interval (CFI) of more than 4 months between the completion of their first regimen and the institution of a second cisplatin/carboplatin program. Of the 72 assessable patients (10 had no measurable disease, and a laparotomy was not performed to assess response), 31 (43%) responded, including 10 surgically defined complete responses (S-CRs). The overall response rates (and S-CR rate), based on duration of CFI, were 5 to 12 months, 27% (5%); 13 to 24 months, 33% (11%); and more than 24 months, 59% (22%). Twenty-nine patients (35%) received noncisplatin/carboplatin-containing treatments between the cisplatin programs. Patients without any treatment for more than 24 months from the completion of their initial therapy experienced a 77% (17 of 22) response rate and a 32% (seven of 22) S-CR rate. In conclusion, secondary responses to cisplatin/carboplatin-based treatment are common in patients with ovarian cancer who have previously responded to the agents and increase in frequency with greater distance from the initial therapy.
Physical Activity and Screen-Time Viewing Among Elementary School–Aged Children in the United States From 2009 to 2010
Authors: Tala H. I. Fakhouri, Jeffery P. Hughes, Debra J. Brody, Brian K. Kit, Cynthia L. Ogden
Journal: JAMA Pediatrics (2013)

OBJECTIVES To describe the percentage of children who met physical activity and screen-time recommendations and to examine demographic differences. Recommendations for school-aged children include 60 minutes of daily moderate-to-vigorous physical activity and no more than 2 hours per day of screen-time viewing. DESIGN Cross-sectional study. SETTING Data from the 2009-2010 National Health and Nutrition Examination Survey, a representative sample of the US population. PARTICIPANTS Analysis included 1218 children 6 to 11 years of age. MAIN EXPOSURES Age, race/ethnicity, sex, income, family structure, and obesity status. MAIN OUTCOME MEASURES Proxy-reported adherence to physical activity and screen-time recommendations, separately and concurrently. RESULTS Based on proxy reports, overall, 70% of children met physical activity recommendations, and 54% met screen-time viewing recommendations. Although Hispanics were less likely to meet physical activity recommendations (adjusted odds ratio [aOR], 0.60 [95% CI, 0.38-0.95]), they were more likely to meet screen-time recommendations compared with non-Hispanic whites (aOR, 1.69 [95% CI, 1.18-2.43]). Only 38% met both recommendations concurrently. Age (9-11 years vs 6-8 years: aOR, 0.57 [95% CI, 0.38-0.85]) and obesity (aOR, 0.53 [95% CI, 0.38-0.73]) were inversely associated with concurrent adherence to both recommendations. CONCLUSIONS Fewer than 4 in 10 children met both physical activity and screen-time recommendations concurrently. The prevalence of sedentary behavior was higher in older children. Low levels of screen-time viewing may not necessarily predict higher levels of physical activity.
Improved hepatocytein vitro maintenance in a culture model with woven multicompartment capillary systems: Electron microscopy studies
Authors: Jörg C. Gerlach, Norbert Schnoy, Jens Encke, Mark D. Smith, Christian Müller, Peter Neuhaus
Journal: Hepatology (1995)

Primary pig hepatocytes form a tissuelike structure in an in vitro culture model that has provision for three-dimensional cell orientation, cell aggregation, decentralized cell perfusion with low metabolite gradients, integral oxygenation, and nonparenchymal cell coculture. Scanning electron microscopy (SEM) has shown that hepatocytes spontaneously form aggregates in a three-dimensional structure between and on the surface of artificial capillaries. Transmission electron microscopy (TEM) has shown that after 7 weeks of in vitro perfusion, the cell ultrastructure remains similar to that of the parenchyma in vivo. Golgi complexes, active membrane processes, reorganization of cell junctions, and bile canaliculi-like intercellular spaces were demonstrated.
Disruption of IFT Complex A Causes Cystic Kidneys without Mitotic Spindle Misorientation
Authors: Julie A. Jonassen, Jovenal SanAgustin, Stephen P. Baker, Gregory J. Pazour
Journal: Journal of the American Society of Nephrology (2012)

Intraflagellar transport (IFT) complexes A and B build and maintain primary cilia. In the mouse, kidney-specific or hypomorphic mutant alleles of IFT complex B genes cause polycystic kidneys, but the influence of IFT complex A proteins on renal development is not well understood. In the present study, we found that HoxB7-Cre–driven deletion of the complex A gene Ift140 from collecting ducts disrupted, but did not completely prevent, cilia assembly. Mutant kidneys developed collecting duct cysts by postnatal day 5, with rapid cystic expansion and renal dysfunction by day 15 and little remaining parenchymal tissue by day 20. In contrast to many models of polycystic kidney disease, precystic Ift140-deleted collecting ducts showed normal centrosomal positioning and no misorientation of the mitotic spindle axis, suggesting that disruption of oriented cell division is not a prerequisite to cyst formation in these kidneys. Precystic collecting ducts had an increased mitotic index, suggesting that cell proliferation may drive cyst expansion even with normal orientation of the mitotic spindle. In addition, we observed significant increases in expression of canonical Wnt pathway genes and mediators of Hedgehog and tissue fibrosis in highly cystic, but not precystic, kidneys. Taken together, these studies indicate that loss of Ift140 causes pronounced renal cystic disease and suggest that abnormalities in several different pathways may influence cyst progression.
Impact of Office Systems and Improvement Strategies on Costs of Care for Adults With Diabetes
Authors: Todd P. Gilmer, Patrick J. O’Connor, William A. Rush, A. Lauren Crain, Robin R. Whitebird, Anne M. Hanson, Leif I. Solberg
Journal: Diabetes Care (2006)

OBJECTIVE—To assess the impact of organizational features and improvement strategies of primary care clinics on health care costs of adults with diabetes. RESEARCH DESIGN AND METHODS—This study included a prospective cohort study of 1,628 adults with diabetes in a large, health care organization receiving care in 84 clinics within 18 medical groups. Data from surveys of patients, clinic medical directors and managers, and medical record reviews were merged with 3 years of medical claims. Costs were estimated using health plan data on resource use and common Medicare payment methodologies. Generalized linear regression models were used to analyze costs related to clinic characteristics, adjusting for individual patient comorbidity, demographic, and socioeconomic factors. RESULTS—Clinics with regular clinician meetings to discuss patient care problems and clinics that used diabetes registries to prioritize patients based on cardiovascular risk were associated with lower 3-year costs: −$3,962 (P = 0.002) and −$2,916 (P = 0.019), respectively. The use of databases to monitor lab results was associated with higher costs ($2,439, P = 0.038). Quality improvement strategies focused on resource use related to diabetes care (−$2,883, P = 0.017) or heart disease care (−$3,228, P = 0.014) were associated with lowered costs, whereas quality improvement strategies that emphasized pharmacy use for patients with heart disease ($3,059, P = 0.029) or depression ($2,962, P = 0.038) were associated with increased costs. CONCLUSIONS—Several organizational features of primary care offices were significant predictors of future health care costs for adults with diabetes. The mechanism by which such factors affect costs of care and the relationship of costs to clinical outcomes merits further evaluation.
Total and Regional Coronary Blood Flow Measured by Radioactive Microspheres in Conscious and Anesthetized Dogs
Authors: RAUL J. DOMENECH, JULIEN I. HOFFMAN, MARK I. NOBLE, KENNETH B. SAUNDERS, JAMES R. HENSON, SUJANTO SUBIJANTO
Journal: Circulation Research (1969)

Total and regional coronary blood flow were measured in dogs by left atrial injection of carbonized microspheres labeled with different radioactive isotopes (mean diameter 14 to 61µ). Simultaneously blood was collected at 20 ml/min from a catheter tied into a peripheral artery. The ratios of flow to radioactivity in myocardium and arterial blood should be equal if microspheres are well mixed in the aortic root and are distributed regionally in proportion to flow. This was proved in seven right heart by-pass experiments where coronary venous drainage was measured directly. Also, less than 0.1% of total myocardial radioactivity appeared in coronary venous blood, even with hypoxemia and small microspheres. Total coronary flow in seven conscious dogs averaged 95 to 150 ml/min/100 g heart; and flow to the left ventricle was 111 to 169 ml/100 g. Although not validated independently, there was evidence that values for flow to each ventricle, the atria and the septum were correct. The radioactivity per gram of left ventricular subendocardial muscle was 2.5 times that of subepicardial muscle using microspheres 51 to 61µ in diameter, but the ratios were 1.4 and 1.3 using microspheres of mean diameters 20 to 23µ and 14µ, respectively. It is unlikely that any of these microspheres measure blood flow to small portions of the ventricle.
Comparative cardiovascular actions of verapamil and its major metabolites in the anaesthetised dog
Authors: G. NEUGEBAUER
Journal: Cardiovascular Research (1978)

After intracoronary administration in 12 dogs verapamil exhibited considerably greater vasodilator efficacy than the metabolites nor-verapamil (D 591, N-demethylated form of verapamil), D 617 (N-dealkylated form by removal of the dimethoxyphenylethyl moiety), and D 620 (the N-demethylated analogue of D 617), relative potencies being 1, 0.22, 0.03, and 0.04 respectively. According to their coronary activity equipotent doses of the drugs were administered i.v. in another group of 24 animals and haemodynamic variables were measured. Verapamil exhibited significant effects on LVSP (−17%), systolic, mean and diastolic blood pressures (−18, −20, −24%), cardiac output (+66%), stroke volume (+ 18%), heart rate (+40%), peripheral (−51%), and coronary resistance (−60%), coronary flow (+98%), and P-Q interval (+ 15%, P-Qc+56%). Contractility was not influenced as judged from mean values. D 591 produced significant but smaller haemodynamic effects on coronary flow (+42%), cardiac output (+25%), stroke volume (+ 18%), peripheral (−20%), and coronary resistance (−31%). Heart rate and consequently left ventricular contractility increased gradually with a time effect course different from the other variables. The only significant effects after D 617 were a reduction in contractility (−20%) and an increase in coronary resistance (+ 18%). D 620 exhibited no statistically significant haemodynamic changes. It is concluded that of the metabolites investigated D 591 may partly contribute to the haemodynamic actions of verapamil, whereas D 617 and 620 appear to play no role. None of the metabolites seems to contribute to verapamil's prolongation of nodal conduction.
Sophora Flavescens Alkaloid-Rich Fraction Induction of IL-10 Production and Prevention of Dexamethasone Suppression of Asthma Patient PBMC IL-10 Production Is Associated with Altered DNA Methylation at foxp3 Gene Promoter
Authors: Ying Song, Li Xin Wang, Changda Liu, Lauren Lisann, David Weir, Ching-feng Huang, Paula J. Busse, Xiu-Min Li
Journal: Journal of Allergy and Clinical Immunology (2015)
The steady state concentration gradients of an electron-dense marker (ferritin in the three-layered hemochorial placenta of the rabbit.
Authors: K L Thornburg, J J Faber
Journal: Journal of Clinical Investigation (1976)

Ferritin was injected into the fetal or the maternal circulation of 27-29-day-pregnant rabbits. After the occurrence of a quasi-steady state, the placentas were prepared for electron microscopy. Ferritin particles were counted in the electron micrographs in the fetal capillaries, in the maternal blood spaces, and in the two interstitial compartments of the three-layered placenta. Under the circumstances of the experiments (excessively elevated plasma ferritin concentrations), no evidence was found for nondiffusional transport of radiolabeled ferritin. Comparison of the standing concentration gradients in the placentas, recorded after maternal and after fetal injection, showed that the interstitial spaces "excluded" ferritin; the plasma-interstitial space ferritin partition coefficients were 10 in the basement membrane space and 3 in the space between the cyto- and syncytiotrophoblasts. 55% of the total concentration gradient across the rabbit placenta occurred across the fetal endothelium, about 45% across the cytotrophoblast, and less than 5% across the syncytiotrophoblast. These figures are believed to reflect the relative contributions of these three layers to the total diffusional resistance in the rabbit placenta. When compared to previous data on the relative contributions of these three layers for small ions and molecules, the present data lead to the conclusion that discrimination of molecular size is a function of the fetal capillary endothelium alone.
Photodermatoses: classification, evaluation and management
Authors: M. Bylaite, J. Grigaitiene, G.S. Lapinskaite
Journal: British Journal of Dermatology (2009)

Photodermatoses are skin disorders induced or exacerbated by light. They can be broadly classified into four groups: (i) immunologically mediated photodermatoses (idioapathic); (ii) drug- and chemical-induced photosensitivity; (iii) defective DNA repair disorders; and (iv) photoaggravated dermatoses. The exact pathomechanism of those diverse skin reactions to light radiation remains unclear. Immunologically mediated photodermatoses are the most common dermatoses among all photosesnsitive disorders. The management of photodermatoses starts with clinical recognition of characteristic lesions localized predominantly in light exposed skin. Detailed history-taking, phototesting and photopatch testing are required to establish a correct diagnosis, especially if patients present in disease-free intervals. Classification and short description of distinctive clinical features of most common photodermatoses, several practical aspects of evaluation and management of the patient with photosensitivity will be outlined.
Efficacy of lower-limb muscle training modalities in severely dyspnoeic individuals with COPD and quadriceps muscle weakness: results from the DICES trial
Authors: Emma Chaplin, Lorna Latimer
Journal: Thorax (2014)

Finding an effective rehabilitative modality that does not evoke severe dyspnoea is indeed of great interest to clinicians. The DICES trial aims to identify the optimal training modality by studying the efficacy of high-frequency neuromuscular electrical stimulation (NMES), and low-frequency NMES or strength training in severely dyspnoeic individuals with COPD with quadriceps muscle weakness at baseline. We have some queries regarding the data analysis employed by Sillen et al .1

A power calculation is described in the online supplement which is based …
ARSACS, a spastic ataxia common in northeastern Québec, is caused by mutations in a new gene encoding an 11.5-kb ORF
Authors: James C. Engert, Pierre Bérubé, Jocelyne Mercier, Carole Doré, Pierre Lepage, Bing Ge, Jean-Pierre Bouchard, Jean Mathieu, Serge B. Melançon, Martin Schalling, Eric S. Lander, Kenneth Morgan, Thomas J. Hudson, Andrea Richter
Journal: Nature Genetics (2000)