tbuckley/cabot-search huggingface dataset:
Retinoids Regulate the Repairing Process of the Podocytes in Puromycin Aminonucleoside-induced Nephrotic Rats
Authors: Akira Suzuki, Takahito Ito, Enyu Imai, Masaya Yamato, Hirotsugu Iwatani, Hiroshi Kawachi, Masatsugu Hori
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. The foot processes forming the slit diaphragm are disrupted in diseases associated with proteinuria. Although they are often repairable, regulators for the repairing process remain unknown. By extrapolating from the fact that vitamin A is essential for the nephrogenesis, this study examined whether or not injured podocytes in the middle of the repairing process require retinaldehyde dehydrogenase type 2 (RALDH2), one of the key enzymes to produce all-trans-retinoic acid (ATRA). RALDH2 was dramatically upregulated in podocytes of puromycin aminonucleoside-induced nephrosis (PAN nephrosis) rats. On day 5 of PAN nephrosis, RALDH2 showed the remarkable induction, whereas glomerular expression levels of nephrin and midkine, one of the ATRA target genes, were downregulated. Daily administration of ATRA ameliorated proteinuria, which was accompanied by the improvement in the effacement of the foot processes and by the induction of nephrin and midkine. In contrast, recovery from PAN nephrosis was delayed in rats fed with a vitamin A-deficient diet. Consistently, the promoter region of human nephrin gene (NPHS1) contained three putative retinoic acid response elements (RARE) and showed the enhancer activity in response to ATRA in a dose-dependent manner. This transcriptional activation was regulated through the receptors for retinoids because BMS-189453, an antagonist to the retinoid receptors, counteracted it in a dose-dependent manner. In conclusion, active metabolites of vitamin A, especially ATRA produced by RALDH2 play relevant roles during the repairing process of injured podocytes. The results obtained from PAN nephrosis rats might be applicable to human renal diseases. E-mail: [email protected]
Differential rates of replacement of human dermal dendritic cells and macrophages during hematopoietic stem cell transplantation
Authors: Muzlifah Haniffa, Florent Ginhoux, Xiao-Nong Wang, Venetia Bigley, Michal Abel, Ian Dimmick, Sarah Bullock, Marcos Grisotto, Trevor Booth, Peter Taub, Catharien Hilkens, Miriam Merad, Matthew Collin
Journal: The Journal of Experimental Medicine (2009)

Animal models of hematopoietic stem cell transplantation have been used to analyze the turnover of bone marrow-derived cells and to demonstrate the critical role of recipient antigen-presenting cells (APC) in graft versus host disease (GVHD). In humans, the phenotype and lineage relationships of myeloid-derived tissue APC remain incompletely understood. It has also been proposed that the risk of acute GVHD, which extends over many months, is related to the protracted survival of certain recipient APC. Human dermis contains three principal subsets of CD45(+)HLA-DR(+) cells: CD1a(+)CD14(-) DC, CD1a(-)CD14(+) DC, and CD1a(-)CD14(+)FXIIIa(+) macrophages. In vitro, each subset has characteristic properties. After transplantation, both CD1a(+) and CD14(+) DC are rapidly depleted and replaced by donor cells, but recipient macrophages can be found in GVHD lesions and may persist for many months. Macrophages isolated from normal dermis secrete proinflammatory cytokines. Although they stimulate little proliferation of naive or memory CD4(+) T cells, macrophages induce cytokine expression in memory CD4(+) T cells and activation and proliferation of CD8(+) T cells. These observations suggest that dermal macrophages and DC are from distinct lineages and that persistent recipient macrophages, although unlikely to initiate alloreactivity, may contribute to GVHD by sustaining the responses of previously activated T cells.
cGMP signalling in pre- and post-conditioning: the role of mitochondria
Authors: A. D.T. Costa, S. V. Pierre, M. V. Cohen, J. M. Downey, K. D. Garlid
Journal: Cardiovascular Research (2007)

Much of cell death from ischaemia/reperfusion in heart and other tissues is generally thought to arise from mitochondrial permeability transition (MPT) in the first minutes of reperfusion. In ischaemic pre-conditioning, agonist binding to Gi protein-coupled receptors prior to ischaemia triggers a signalling cascade that protects the heart from MPT. We believe that the cytosolic component of this trigger pathway terminates in activation of guanylyl cyclase resulting in increased production of cGMP and subsequent activation of protein kinase G (PKG). PKG phosphorylates a protein on the mitochondrial outer membrane (MOM), which then causes the mitochondrial KATP channel (mitoKATP) on the mitochondrial inner membrane to open, leading to increased production of reactive oxygen species (ROS) by the mitochondria. This implies that the protective signal is somehow transmitted from the MOM to its inner membrane. This is accomplished by a series of intermembrane signalling steps that includes protein kinase C (PKCε) activation. The resulting ROS then activate a second PKC pool which, through another signal transduction pathway termed the mediator pathway, causes inhibition of MPT and reduction in cell death.
Primary biliary cirrhosis: geographical clustering and symptomatic onset seasonality.
Authors: A N Hamlyn, A F Macklon, O James
Journal: Gut (1983)

Patients with primary biliary cirrhosis (primary non-suppurative destructive cholangitis) in the north east region of England were studied over a five year period and, to evaluate epidemicity, compared with two contemporaneous disease series of known occurrence. These were: terminal renal failure, all causes (low or absent epidemicity n = 106) and an outbreak of echovirus 19 disease (high epidemicity n = 201). Eight primary biliary cirrhosis-affected men and 109 women from an estimated catchment population of 2.08 million were identified. The current diagnosis rate was 1.0/100 000 (1.8/100 000 for women of 15 or more). There were 18 deaths, mean survival from diagnosis 4.0 years. Within the region prevalence varied from 3.7/100 000 in rural areas to 14.4/100 000 in industrial urban areas. In the conurbation, prevalence rates varied insignificantly. Here, most cases were concentrated in central districts, where the proportion of asymptomatic presentations was 50%. Outside the conurbation the asymptomatic proportion fell to 21%, suggesting low incidental diagnosis rates. When compared with echovirus 19, primary biliary cirrhosis was of low or absent epidemicity, and similar to renal failure in its uniform geographical distribution and lack of clustering. Forty three patients (37% of the total), however, had significantly seasonal symptomatic presentations (p less than 0.01), although scan statistic testing failed to show clustering of onset in time. Apparently provocative factors associated with primary biliary cirrhosis symptomatic onset were identified in only 11 (9.4%) of patients. Age-specific onset rates rose linearly between ages 35 and 65, and nearly one third of patients presented after 65 years, two thirds of deaths occurring in this age group. There is thus no evidence in north east England of geographical anomalies in the distribution of primary biliary cirrhosis. International differences may be partly explained by environmental factors influencing seasonal presentation, such as sunlight. Diagnosis rates are profoundly influenced by increased medical awareness, especially in the elderly, of this now relatively common disease and increased use of the mitochondrial (AMA) antibody test.
Self-Efficacy, Problem Solving, and Social-Environmental Support Are Associated With Diabetes Self-Management Behaviors
Authors: Diane K. King, Russell E. Glasgow, Deborah J. Toobert, Lisa A. Strycker, Paul A. Estabrooks, Diego Osuna, Andrew J. Faber
Journal: Diabetes Care (2010)

OBJECTIVE To evaluate associations between psychosocial and social-environmental variables and diabetes self-management, and diabetes control. RESEARCH DESIGN AND METHODS Baseline data from a type 2 diabetes self-management randomized trial with 463 adults having elevated BMI (M = 34.8 kg/m2) were used to investigate relations among demographic, psychosocial, and social-environmental variables; dietary, exercise, and medication-taking behaviors; and biologic outcomes. RESULTS Self-efficacy, problem solving, and social-environmental support were independently associated with diet and exercise, increasing the variance accounted for by 23 and 19%, respectively. Only diet contributed to explained variance in BMI (β = −0.17, P = 0.0003) and self-rated health status (β = 0.25, P &amp;lt; 0.0001); and only medication-taking behaviors contributed to lipid ratio (total–to–HDL) (β = −0.20, P = 0.0001) and A1C (β = −0.21, P &amp;lt; 0.0001). CONCLUSIONS Interventions should focus on enhancing self-efficacy, problem solving, and social-environmental support to improve self-management of diabetes.
Association of oestrogen receptor gene polymorphisms with age at onset of rheumatoid arthritis
Authors: T. Ushiyama, K. Mori, K. Inoue, J. Huang, J. Nishioka, S. Hukuda
Journal: Annals of the Rheumatic Diseases (1999)

<h3>OBJECTIVE</h3> In view of the possible role of oestrogens in the pathogenesis of rheumatoid arthritis (RA), this study investigated the association between oestrogen receptor (OR) gene polymorphisms and RA. <h3>METHODS</h3> Pvu II and Xba I restriction fragment length polymorphisms of the OR gene were analysed in 70 male and 240 female patients with RA, and in 300 male and 350 female controls. The absence or presence of restriction sites were represented as P, p (Pvu II ) or X, x (Xba I ). The distribution of OR genotypes was compared between the RA and control subjects by sex. RA patients were divided into subgroups according to their OR genotypes, then the age at onset, seropositivity, and rheumatoid nodule positivity were compared between the subgroups. <h3>RESULTS</h3> The OR genotype frequency of distribution did not have significant differences between the male RA and male controls nor between the female RA and female controls. In women with RA, there was a significant difference of age at onset between the subgroups (uncorrected p=0.047, corrected p=0.94). Female patients with the OR genotype PPxx (homozygote of Px) tended to have developed RA at a younger age, whereas those with PPXX and ppxx (lack of Px haplotype) developed RA at an older age. In men with RA, there was no association between the OR genotype and age at onset. In seropositivity and rheumatoid nodule positivity, there was no significant difference between subgroups for either sex. <h3>CONCLUSIONS</h3> Some variants of the OR gene are related to the onset of RA in women in certain age periods, suggesting the role of the interaction between the OR gene and serum concentrations of oestrogen at the onset of the disease.
Role of Endothelial Nitric Oxide Synthase in the Regulation of SREBP Activation by Oxidized Phospholipids
Authors: Nima M. Gharavi, Nancy A. Baker, Kevin P. Mouillesseaux, Winnie Yeung, Henry M. Honda, Xavier Hsieh, Michael Yeh, Eric J. Smart, Judith A. Berliner
Journal: Circulation Research (2006)

Oxidized-1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine (Ox-PAPC), found in atherosclerotic lesions and other sites of chronic inflammation, activates endothelial cells (EC) to synthesize chemotactic factors, such as interleukin (IL)-8. Previously, we demonstrated that the sustained induction of IL-8 transcription by Ox-PAPC was mediated through the activation of sterol regulatory element-binding protein (SREBP). We now present evidence for the role of endothelial nitric oxide synthase (eNOS) in the activation of SREBP by Ox-PAPC. Ox-PAPC treatment of EC induced a dose- and time-dependent activation of eNOS, as measured by phosphorylation of serine 1177, dephosphorylation of threonine 495, and the conversion of L-arginine to L-citrulline. Activation of eNOS by Ox-PAPC was regulated through a phosphatidylinositol-3-kinase/Akt-mediated mechanism. These studies also demonstrated that pretreatment of EC with NOS inhibitor, Nomega-nitro-L-arginine-methyl ester (L-NAME), significantly inhibited Ox-PAPC-induced IL-8 synthesis. Because SREBP activation had been previously shown to regulate IL-8 transcription by Ox-PAPC, we examined the effects of L-NAME on Ox-PAPC-induced SREBP activation. Our data demonstrated that Ox-PAPC-induced SREBP activation and expression of SREBP target genes were significantly reduced by pretreatment with L-NAME. Interestingly, treatment of EC with NO donor, S-nitroso-N-acetylpenicillamine, did not activate SREBP, suggesting that NO alone was not sufficient for SREBP activation. Rather, our findings indicated that superoxide (O2*-), in combination with NO, regulated SREBP activation by Ox-PAPC. We found that Ox-PAPC treatment generated O2*- through an eNOS-mediated mechanism and that mercaptoethylguanidine, a peroxynitrite scavenger, reduced SREBP activation by Ox-PAPC. Taken together, these findings propose a novel role for eNOS in the activation of SREBP and SREBP-mediated inflammatory processes.
Pulmonary hyperinflation and ventilator-dependent patients
Authors: A Rossi, A Ganassini, G Polese, V Grassi
Journal: European Respiratory Journal (1997)

Pulmonary hyperinflation is a major medical problem in patients with advanced chronic obstructive pulmonary disease (COPD) or acute asthma. The apparent beneficial effects of pulmonary hyperinflation on lung mechanics, such as an increased airway patency and lung elastic recoil, are by far overwhelmed by the deleterious effects on the pressure generating capacity of the respiratory muscles. Moreover, the ventilatory workload can be remarkably increased: 1) by the displacement of the respiratory system toward the upper, flat portion of the pressure-volume curve; 2) by the need to expand the chest wall and not only the lungs; and 3) by the intrinsic positive end-expiratory pressure (PEEPi) systematically associated with dynamic hyperinflation. In mechanically ventilated patients, the mechanisms underlying pulmonary hyperinflation as well as its pathophysiological consequences do not differ from those described in spontaneously breathing patients. However, there are some specific issues that should be taken into account, namely the effect of the endotracheal tube and the mode and setting of the ventilator. In mechanically ventilated patients, pulmonary hyperinflation increases the risk of barotrauma and may hamper weaning due to the excessive burden of PEEPi, which can even lead to ineffective inspiratory efforts. Because of its harmful consequences, pulmonary hyperinflation must be treated aggressively by pharmacological therapy and, when needed, by ventilatory treatment. The setting of the ventilator must be predetermined to ensure the longest possible time for expiration, and positive end-expiratory pressure can be applied to prevent an excessive workload for the patient and ineffective inspiratory efforts.
Role in nitric oxide in Kupffer cell-mediated hepatoma cell cytotoxicity in vitro and ex vivo
Authors: D Fukumura
Journal: Hepatology (1996)

The metabolic change in tumor cells (AH70, a rat hepatoma cell line) cocultured with isolated rat Kupffer cells were visualized and analyzed by a laser scanning confocal imaging system. When AH70 cells were cocultured with Kupffer cells, fluorescence intensity of rhodamine 123 (Rh123) decreased, indicating the reduction of mitochondrial function. The reduction in Rh123 was eliminated by NG-monomethyl-L-arginine (L- NMMA), an analogue of L-arginine, suggesting the involvement of nitric oxide (NO). Two hour after the cells were cocultured, membrane compromised AH70 cells which were observed as propidium from 2.8% to 25%. This increase was also attenuated by L-NMMA, suggesting that Kupffer cell-mediated injury of tumor cells largely depends on NO. The concentrations of NO-2 + NO-3 in the culture medium markedly increased after coculture of AH70 cells with Kupffer cells. Moreover, NO synthase (NOS) activity in Kupffer cells significantly increased after coculture. These in vitro results suggest that NO mediates Kupffer cell- induced tumor cell damage characterized by reduced mitochondrial function and diminished barrier function. In the ex vivo study of the perfused liver to which AH70 cells were injected via the catheter inserted into the portal vein, some AH70 cells were arrested in the upper stream of sinusoid and the fluorescence intensity of Rh123 in adherent AH70 cells decreased in a time-dependent manner within 2 hours. The number of PI-positive AH70 cells also increased 2 hours after the injection of AH70 cells. These changes were inhibited by either administration of N omega-L-nitroarginine-methylester (L-NAME) to perfusate or pretreatment of the rat liver with GdCl3, which is known to deplete Kupffer cell function. Thus, the present study suggests that NO from Kupffer cells induces mitochondrial dysfunction in tumor cells followed by membrane barrier dysfunction in the liver sinusoid. (Hepatology 1996 Jul;24(1):141-9)
Phase I Multidose-Escalation Study of the Anti-CD19 Maytansinoid Immunoconjugate SAR3419 Administered by Intravenous Infusion Every 3 Weeks to Patients With Relapsed/Refractory B-Cell Lymphoma
Authors: Anas Younes, Stella Kim, Jorge Romaguera, Amanda Copeland, Silvana de Castro Farial, Larry W. Kwak, Luis Fayad, Frederick Hagemeister, Michelle Fanale, Sattva Neelapu, John M. Lambert, Rodica Morariu-Zamfir, Sandrine Payrard, Leo I. Gordon
Journal: Journal of Clinical Oncology (2012)

Purpose We determine the maximum-tolerated dose (MTD), pharmacokinetics, safety, and preliminary efficacy of SAR3419, an antibody-drug conjugate targeting CD19, in a first-in-man phase I clinical trial in patients with relapsed lymphoma. Patients and Methods Patients with relapsed CD19+ B-cell lymphoma were treated with escalating doses of SAR3419 given by intravenous infusion once every 21 days. Results Thirty-nine patients were treated on seven dose levels ranging from 10 to 270 mg/m 2 . The median number of prior treatment regimens was four (range, 1 to 9), and 11 patients had prior autologous or allogeneic stem-cell transplantation. The dose-limiting toxicities were reversible severe blurred vision associated with microcystic epithelial corneal changes reported in six patients and neuropathy in one patient. The MTD was 160 mg/m 2 once every 21 days. Hematologic and hepatic toxicities were predominantly grade 1 or 2 in severity. A total of 35 patients have completed at least two cycles of treatment and were evaluable for tumor response. Twenty-six patients (74%) demonstrated reduction in their tumor size; six of those patients achieved partial or complete remissions. Seven (47%) of 15 patients with rituximab-refractory disease demonstrated reduction in their tumor sizes. The pharmacokinetic profile of SAR3419 is characterized by linear kinetics, low clearance from 0.2 to 0.6 L/d/m 2 , and an elimination half-life in the range of 3 to 7 days. Conclusion Using an every 3-week-schedule of SAR3419 for six cycles, the MTD is 160 mg/m 2 . SAR3419 can be safely administered to patients with relapsed B-cell lymphoma and demonstrates promising clinical activity, including patients who were refractory to rituximab.
unity in the wild variety of nature, or just variety?
Authors: i. c. mcmanus
Journal: Behavioral and Brain Sciences (2005)

although there are some common underlying mechanisms for many nonhuman behavioural asymmetries, the evidence at present is not compelling for commonalities in cerebral organisation across vertebrates. phylogenetic analysis of detour behaviour in fish suggests that more closely related species are not particularly similar in the direction of turning; contingency and demands of ecological niches may better explain such asymmetries.
Barriers to Immediate Breast Reconstruction in the Canadian Universal Health Care System
Authors: Toni Zhong, Kimberly A. Fernandes, Refik Saskin, Rinku Sutradhar, Jennica Platt, Brett A. Beber, Christine B. Novak, David R. McCready, Stefan O.P. Hofer, Jonathan C. Irish, Nancy N. Baxter
Journal: Journal of Clinical Oncology (2014)

Purpose To describe the population-based rates of immediate breast reconstruction (IBR) for all women undergoing mastectomy for treatment or prophylaxis of breast cancer in the past decade, and to evaluate geographic, institutional, and patient factors that influence use in the publically funded Canadian health care system. Methods This population-based retrospective cohort study used administrative data that included 28,176 women who underwent mastectomy (25,141 mastectomy alone and 3,035 IBR) between April 1, 2002, and March 31, 2012, in Ontario, Canada. We evaluated factors associated with IBR by using a multivariable logistic regression model with the generalized estimating equation approach. Results The population-based, age-adjusted IBR rate increased from 5.1 procedures to 8.7 in 100,000 adult women (43.7%; P &lt; .001), and the increase was greatest for prophylactic mastectomy or therapeutic mastectomy for in situ breast cancer (78.6%; P &lt; .001). Women who lived in neighborhoods with higher median income had significantly increased odds of IBR compared with mastectomy alone (odds ratio [OR], 1.71; 95% CI, 1.47 to 2.00), and immigrant women had significantly lower odds (OR, 0.59; 95% CI, 0.44 to 0.78). A patient had nearly twice the odds of receiving IBR when she was treated at a teaching hospital (OR, 1.84; 95% CI, 1.1 to 3.06) or at a hospital with two or more available plastic surgeons (OR, 2.01; 95% CI, 1.53 to 2.65). Patients who received IBR traveled significantly farther compared with those who received mastectomy alone (OR, 1.04; 95% CI, 1.02 to 1.05 for every 10 km increase). Conclusion IBR is available to select patients with favorable clinical and demographic characteristics who travel farther to undergo surgery at teaching hospitals with two or more available plastic surgeons.
Osteosarcoma in Patients Older Than 65 Years
Authors: Alessandra Longhi, Costantino Errani, Daniel Gonzales-Arabio, Cristina Ferrari, Mario Mercuri
Journal: Journal of Clinical Oncology (2008)

We reviewed the outcome of osteosarcoma patients older than 65 years, an age group usually excluded from protocols, to determine the different clinical features and prognostic factors in this age group compared with younger patients.Patients treated at our institute who had high-grade osteosarcoma and were older than 65 years were observed.Forty-three patients were eligible to be enrolled onto this study; of these, 22 were male and 21 were female. The median age of this group was 69 years (range, 65 to 80 years). Of the 43 patients, 29 patients had localized disease, and 14 patients had metastatic disease. Localizations were appendicular in 33 patients, and axial in 10 patients. Twenty-nine patients had a primary osteosarcoma, 13 patients (30%) had a sarcoma in Paget's disease, and one patient had postradiotherapy (RT) osteosarcoma. The median interval from onset of symptoms to diagnosis was 4 months (range, 0 to 73 months).Thirty-two of 43 patients received surgery for a primary tumor. Of these, 18 patients had limb salvage, 13 patients had an amputation, and one patient had palliative surgery; the remaining 11 patients received palliative RT. Fourteen patients received chemotherapy; two deaths related to chemotherapy were observed. Median overall survival (OS) for all 43 patients was 19 months (range, 3 to 229 months); 5-year OS was 22% (SE = 3%) for the whole group, and 45% OS for those patients with localized primary osteosarcoma. Multivariate analysis demonstrated that stage, volume, and surgery were significant prognostic factors. Insignificant prognostic factors were sex, type of surgery, chemotherapy, and Paget's disease.Patients older than 65 years with osteosarcoma have a worse prognosis compared with younger patients. This older age group is characterized by a longer time lapse from the onset of symptoms to diagnosis, more metastatic cases at diagnosis, less use of limb salvage, fewer patients receiving chemotherapy, and more patients excluded from clinical trials than a younger age group.