tbuckley/cabot-search huggingface dataset:
Natural killer cell in systemic lupus erythematosus. Defects in effector lytic activity and response to interferon and interferon inducers.
Authors: W L Sibbitt, P M Mathews, A D Bankhurst
Journal: Journal of Clinical Investigation (1983)

Spontaneous cytotoxicity mediated by natural killer (NK) cells is impaired in several human diseases including systemic lupus erythematosus (SLE). The precise mechanism(s) by which NK activity is suppressed in patients with SLE is generally unknown. The present study was designed to focus on cellular defects per se in NK cells from patients with SLE. It was observed that the usual enhancing effect of interferon (IF) and IF inducers was markedly impaired in SLE patients. Of 24 SLE patients studied, 17 had significantly decreased NK activity relative to controls. NK activity had a significant negative correlation with clinical activity score (r = -0.56, P less than 0.005) but was not correlated with corticosteroid dose, antinuclear antibody titers, total hemolytic complement (CH50), or sedimentation rate. Furthermore, significant depressions in NK activity correlated with variations in disease activity in six patients followed serially. Depressed NK function could not be reversed by prolonged in vitro incubation at 37 degrees C or with protease treatment. Furthermore, depressed NK activity was not altered by removal of glass adherent cells nor was a suppression of NK activity in normal controls seen by the addition of SLE peripheral mononuclear cells. No reversal of depressed activity to normal levels was seen by the addition of indomethacin nor did the supernatants from SLE cell cultures cause a suppression of normal NK function. NK activity in SLE patients did not respond normally to IF inducers (poly-I:C and concanavalin A) even if the SLE patients had normal NK function. The response of SLE cells to exogenous IF was also impaired. The number of effector-target conjugates was quantitated with several target cells (K562, Yac-1, Fravel) in SLE patients and controls. A significant correlation between the proportion of glass nonadherent mononuclear cells that formed effector-target conjugates with these various targets and the magnitude of NK lysis was observed. However, SLE and normal subjects had equal numbers of effector-target conjugates independent of NK function. Release of a soluble cytotoxic factor was induced with concanavalin A, and was markedly impaired in SLE patients relative to normal controls. Thus, impaired NK cell function in SLE does not appear to be related to cell-mediated suppressive mechanisms or to the deletion of effector cells; rather, the decreased NK activity may be related to an impaired release of a soluble cytotoxic factor.
Body composition and plasma levels of inflammatory biomarkers in COPD
Authors: T.M.L. Eagan, P. Aukrust, T. Ueland, J.A. Hardie, A. Johannessen, T.E. Mollnes, J.K. Damås, P.S. Bakke, P.D. Wagner
Journal: European Respiratory Journal (2010)

Previous studies suggest a relationship between systemic inflammation and body composition in chronic obstructive pulmonary disease (COPD). We examined the relationships between body composition (fat free mass index (FFMI) kg·m −2 and fat mass index (FMI) kg·m −2 ) and three plasma inflammatory markers C-reactive Protein (CRP), soluble tumour necrosis factor receptor 1 (sTNF-R1) and osteoprotegerin (OPG) in 409 stable COPD patients (aged 40–75 yrs, Global Initiative for Obstructive Chronic Lung Disease (GOLD) categories II-IV, 249 male) from the Bergen COPD Cohort Study in Norway. FFMI and FMI were measured by bioelectrical impedance. Plasma CRP (μg·mL −1 ), sTNF-R1 (pg·mL −1 ) and OPG (ng·mL −1 ) were determined by enzyme immunoassays. Correlations and Kruskal–Wallis tests were used for bivariate analyses. Linear regression models were fitted for each of the three markers, CRP, sTNF-R1 and OPG, with FFMI and FMI as explanatory variables including sex, age, smoking habits, GOLD category, hypoxaemia, Charlson Comorbidity Index and inhaled steroid use as potential confounders. CRP and sTNF-R1 levels correlated positively with both FFMI and FMI. The adjusted regression coefficients for an increase in logCRP per unit increase in FFMI was 1.23 (1.14–1.33) kg·m −2 and 24.9 (11.8–38.1) kg·m −2 for sTNF-R1. Higher FMI was associated with a lower OPG, with adjusted regression coefficient -0.14 (-0.23– -0.04), whereas FFMI was unrelated to OPG. In conclusion, COPD patients with low FFMI had lower not higher plasma levels of CRP and sTNF-R1, whereas higher fat mass was associated with higher CRP and sTNF-R1 and lower OPG.
The effect of the nitric oxide synthase inhibitor, l‐NMMA, on sodium metabisulphite‐induced bronchoconstriction and refractoriness in asthma
Authors: A.m. Hamad, A. Wisniewski, S.p. Range, T. Small, F. Holland, A.j. Knox
Journal: European Respiratory Journal (1999)

Refractoriness to indirect bronchoconstrictor stimuli, is a feature of asthma but the mechanism is poorly understood. This study tested the hypothesis that endogenous nitric oxide (NO) produced during a first bronchoconstrictor challenge protects against subsequent challenge and therefore has a role in the refractory process. The effect of an NO synthase inhibitor, N(G)-mono-methyl-L-arginine (L-NMMA), on refractoriness to sodium metabisulphite (MBS) was investigated in 20 subjects with mild asthma. On visit one, the dose of MBS which caused a 20% fall in forced expiratory volume in one second (FEV1) (PD20) was determined. On visit two, the refractory index (RI) to MBS was determined by challenging the subjects twice with their PD20 of MBS, the second challenge proceeding after recovery from the first. Those showing a refractory index of approximately 30% (10 subjects) inhaled either L-NMMA or placebo followed 5 min later by two challenges with their PD20 of MBS in a double-blind cross over study at two further visits. The dose of L-NMMA used was shown to reduce exhaled NO for a duration sufficient to cover the second MBS challenge However, no significant difference was found between L-NMMA and placebo in maximum fall in FEV1% and area under the curve (AUC) during first or second MBS challenges or in RI on the two study days. It is concluded that subjects with mild asthma show refractoriness to sodium metabisulphite, but that endogenous nitric oxide is unlikely to be involved either in the refractory process or in the response to sodium metabisulphite per se.
Nonesterified Fatty Acids as Mediators of Glucose Intolerance in Indian Asian Populations
Authors: Jeetesh V. Patel, Avni Vyas, Dorairaj Prabhakaran, Deepak Bhatnagar, Paul N. Durrington, Adrien Heald, Elizabeth A. Hughes, Michael I. Mackness, K. Srinath Reddy, J. Kennedy Cruickshank
Journal: Diabetes Care (2005)

In India, diabetes is endemic, linked to urbanization (1), and its dispersed migrant populations show a particular vulnerability (2,3). For example, in Britain, diabetes is more frequent among Indian migrants than in the general population (4,5), but reported rates appear to equal those in India (6), although diverse dietary and cultural habits across India are also likely to have an impact (7). Rates of glucose intolerance seem to be similar between particular Indian communities living in East Africa, and British population studies provide increasing support for a causal role of nonesterified fatty acids (NEFAs) in the etiology of type 2 diabetes (8,9). Here, using a standardized comparison of culturally specific Gujarati communities between India and Britain, we hypothesized that factors associated with disordered NEFA suppression following glucose challenge would confer greater glucose intolerance in these populations.

We compared a Gujarati community who had migrated to Sandwell (West Midlands, Britain) from rural villages around Navsari (Gujarat) with age-, sex-, and caste-matched contemporaries still living in those villages in India (as described elsewhere [10]). Randomly sampled participants from electoral rolls were invited to clinic sessions (beginning 8:30–10:00 a.m.). Participants without known diabetes had glucose tolerance testing (GTT) using …
Homeobox Protein Hex Induces SMemb/Nonmuscle Myosin Heavy Chain-B Gene Expression Through the cAMP-Responsive Element
Authors: Kenichi Sekiguchi, Masahiko Kurabayashi, Yuko Oyama, Yasushi Aihara, Toru Tanaka, Hironosuke Sakamoto, Yoichi Hoshino, Tsugiyasu Kanda, Tomoyuki Yokoyama, Yukio Shimomura, Hirokazu Iijima, Yoshio Ohyama, Ryozo Nagai
Journal: Circulation Research (2001)

Abstract —Recent studies have shown that the homeobox gene Hex plays an important role in inducing differentiation of vascular endothelial cells. In this study, we examined the expression of Hex in vascular smooth muscle cells (VSMCs) in vitro and in vivo. Immunohistochemistry showed a marked induction of Hex protein in neointimal VSMCs after balloon injury in rat aorta. Western and reverse transcriptase–polymerase chain reaction analyses demonstrated that Hex was abundantly expressed in cultured VSMCs, whereas it was undetectable in other cell types or in normal aorta. The expression pattern of Hex was similar to that of SMemb/NMHC-B, a nonmuscle isoform of myosin heavy chain that we have previously reported to be a molecular marker of dedifferentiated VSMCs. We next examined the role of Hex in SMemb gene transcription. Promoter analysis demonstrated that the sequence identical to consensus cAMP-responsive element (CRE) located at −481 of the SMemb promoter was critical for Hex responsiveness. Mutant Hex expression vector, which lacks the homeodomain, failed to stimulate SMemb gene transcription, suggesting the requirement of the homeodomain for its transactivation. Elecrophoretic mobility shift assay showed that Hex binds to a consensus binding sequence for homeobox proteins, but not to CRE. Cotransfection of protein kinase A expression vector increased the ability of Hex to stimulate SMemb promoter activity in a CRE-dependent manner. Overexpression of CRE binding protein (CREB), but not Mut-CREB which contains mutation at Ser133, strongly activated Hex-induced SMemb promoter activity. These results suggest that Hex mediates transcriptional induction of the SMemb/NMHC-B gene via its homeodomain, and Hex can function as a transcriptional modulator of CRE-dependent transcription in VSMCs.
Phase II Trial of Infusional Cyclophosphamide, Doxorubicin, and Etoposide in Patients With HIV-Associated Non-Hodgkin’s Lymphoma: An Eastern Cooperative Oncology Group Trial (E1494)
Authors: Joseph A. Sparano, Sandra Lee, Michael G. Chen, Tipu Nazeer, Avi Einzig, Richard F. Ambinder, David H. Henry, Jane Manalo, Tianhong Li, Jamie H. Von Roenn
Journal: Journal of Clinical Oncology (2004)

Purpose To determine the effectiveness of an infusional chemotherapy regimen in patients with HIV-associated lymphoma treated before and after the use of highly active antiretroviral therapy (HAART) in routine clinical practice. Patients and Methods Ninety-eight assessable patients with HIV-associated intermediate- or high-grade non-Hodgkin’s lymphoma received cyclophosphamide 200 mg/m 2 /d, doxorubicin 12.5 mg/m 2 /d, and etoposide 60 mg/m 2 /d (CDE) given by continuous intravenous infusion for 4 days (96 hours) every 4 weeks plus filgrastim. Concurrent antiretroviral treatment consisted of the nucleoside analog didanosine in the first 43 patients enrolled before December 1996 (pre-HAART group), or HAART in the remaining 55 patients enrolled after that time (HAART group). Results Complete response occurred in 44 patients (45%; 95% CI, 35% to 55%). Failure-free survival and overall survival (OS) at 2 years was 36% (95% CI, 26% to 46%) and 43% (95% CI, 33% to 53%), respectively. At the time of the analysis, 30% in the pre-HAART group were alive compared with 47% in the HAART group; when adjusted for varying length of follow-up, patients in the HAART group had improved OS (P = .039). Patients in the HAART group experienced less grade 4 nonhematologic toxicity (22% v 42%; P = .037), thrombocytopenia (31% v 52%; P = .033), and anemia (9% v 27%; P = .021), and had fewer treatment-associated deaths (0% v 10%; P = .013). Conclusion Infusional CDE is an effective and potentially curative regimen for patients with HIV-associated lymphoma. Patients treated in the HAART era have less chemotherapy-associated toxicity and improved survival.
Smooth Muscle Protein 22α–Mediated Patchy Deletion of <i>Bmpr1a</i> Impairs Cardiac Contractility but Protects Against Pulmonary Vascular Remodeling
Authors: Nesrine El-Bizri, Lingli Wang, Sandra L. Merklinger, Christophe Guignabert, Tushar Desai, Takashi Urashima, Ahmad Y. Sheikh, Russell H. Knutsen, Robert P. Mecham, Yuji Mishina, Marlene Rabinovitch
Journal: Circulation Research (2007)

Vascular expression of bone morphogenetic type IA receptor (Bmpr1a) is reduced in lungs of patients with pulmonary arterial hypertension, but the significance of this observation is poorly understood. To elucidate the role of Bmpr1a in the vascular pathology of pulmonary arterial hypertension and associated right ventricular (RV) dysfunction, we deleted Bmpr1a in vascular smooth muscle cells and in cardiac myocytes in mice using the SM22alpha;TRE-Cre/LoxP;R26R system. The LacZ distribution reflected patchy deletion of Bmpr1a in the lung vessels, aorta, and heart of SM22alpha;TRE-Cre;R26R;Bmpr1a(flox/+) and flox/flox mutants. This reduction in BMPR-IA expression was confirmed by Western immunoblot and immunohistochemistry in the flox/flox group. This did not affect pulmonary vasoreactivity to acute hypoxia (10% O2) or the increase in RV systolic pressure and RV hypertrophy following 3 weeks in chronic hypoxia. However, both SM22alpha;TRE-Cre;R26R;Bmpr1a(flox/+) and flox/flox mutant mice had fewer muscularized distal pulmonary arteries and attenuated loss of peripheral pulmonary arteries compared with age-matched control littermates in hypoxia. When Bmpr1a expression was reduced by short interference RNA in cultured pulmonary arterial smooth muscle cells, serum-induced proliferation was attenuated explaining decreased hypoxia-mediated muscularization of distal vessels. When Bmpr1a was reduced in cultured microvascular pericytes by short interference RNA, resistance to apoptosis was observed and this could account for protection against hypoxia-mediated vessel loss. The similar elevation in RV systolic pressure and RV hypertrophy, despite the attenuated remodeling with chronic hypoxia in the flox/flox mutants versus controls, was not a function of elevated left ventricular end diastolic pressure but was associated with increased periadventitial deposition of elastin and collagen, potentially influencing vascular stiffness.
Botulism from Chopped Garlic: Delayed Recognition of a Major Outbreak
Authors: M E St Louis, S H Peck, D Bowering, G B Morgan, J Blatherwick, S Banerjee, G D Kettyls, W A Black, M E Milling, A H Hauschild
Journal: Annals of Internal Medicine (1988)

Diagnosis of botulism in two teenaged sisters in Montreal led to the identification of 36 previously unrecognized cases of type B botulism in persons who had eaten at a restaurant in Vancouver, British Columbia, during the preceding 6 weeks. A case-control study implicated a new vehicle for botulism, commercial chopped garlic in soybean oil (P less than 10(-4)). Relatively mild and slowly progressive illness, dispersion of patients over at least eight provinces and states in three countries, and a previously unsuspected vehicle had contributed to prolonged misdiagnoses, including myasthenia gravis (six patients), psychiatric disorders (four), stroke (three), and others. Ethnic background influenced severity of illness: 60% of Chinese patients but only 4% of others needed mechanical ventilation (P less than 10(-3]. Trypsinization of serum was needed to show toxemia in one patient. Electromyography results with high-frequency repetitive stimulation corroborated the diagnosis of botulism up to 2 months after onset. Although botulism is a life-threatening disease, misdiagnosis may be common and large outbreaks can escape recognition completely.
The PI3-Kinase-Akt Pathway Promotes Mesangial Cell Survival and Inhibits Apoptosis In Vitro via NF-κB and Bad
Authors: Haruko Shimamura, Yoshio Terada, Tomokazu Okado, Hiroyuki Tanaka, Seiji Inoshita, Sei Sasaki
Journal: Journal of the American Society of Nephrology (2003)

While the serine/threonine protein kinase Akt has attracted attention as a mediator of survival (anti-apoptotic) signal, the regulation and function of the PI3-kinase-Akt pathway in mesangial cells is not well known. To explore the significance of the PI3-kinase-Akt pathway, this study used PI3-kinase inhibitors (Wortmannin and LY294002) and recombinant adenoviruses encoding a dominant-active mutant of Akt (AxCAmyrAkt) and a dominant-negative mutant of Akt (AxCAAkt-AA) in cultured rat mesangial cells. Apoptotic signals were measured by nucleosomal laddering of DNA, caspase 3 assay, and cell death detection ELISA. The PI3 kinase inhibitors and dominant-negative mutant of Akt increased the apoptotic signals in the presence of platelet-derived growth factor (PDGF), while the dominant-active mutant of Akt prevented apoptosis induced by a serum-free medium. In separate experiments, we further investigated downstream signals of Akt in mesangial cells. While PDGF activated NF-kappa B and phosphorylated Bad, these reactions were inhibited by overexpression of the dominant-negative mutant of Akt as well as the PI3-kinase inhibitors. These data indicate, firstly, that Akt is phosphorylated by PDGF, and secondly, that the activated Akt prevents apoptotic changes via activation of NF-kappa B and phosphorylation of Bad in mesangial cells. This study investigated whether it is Bad phosphorylation or NF-kappa B activation that provides the anti-apoptotic effects of Akt, and the data suggested that NF-kappa B is probably the principal contributor to the downstream activation of the PI3-kinase-Akt pathway. The findings suggest that the PI3-kinase-Akt pathway acts as a survival signal and plays a key role in the regulation of apoptotic change in mesangial cells principally via NF-kappa B.
Drug Dosing and Pharmacokinetics in Children With Obesity
Authors: Margreet W. Harskamp-van Ginkel, Kevin D. Hill, Kristian C. Becker, Daniela Testoni, Michael Cohen-Wolkowiez, Daniel Gonzalez, Jeffrey S. Barrett, Daniel K. Benjamin, David A. Siegel, Patricia Banks, Kevin M. Watt
Journal: JAMA Pediatrics (2015)

Obesity affects nearly one-sixth of US children and results in alterations to body composition and physiology that can affect drug disposition, possibly leading to therapeutic failure or toxic side effects. The depth of available literature regarding obesity's effect on drug safety, pharmacokinetics, and dosing in obese children is unknown.
EHMT1 and EHMT2 inhibition induces fetal hemoglobin expression
Authors: Aline Renneville, Peter Van Galen, Matthew C. Canver, Marie McConkey, John M. Krill-Burger, David M. Dorfman, Edward B. Holson, Bradley E. Bernstein, Stuart H. Orkin, Daniel E. Bauer, Benjamin L. Ebert
Journal: Blood (2015)
Changes in cerebrovascular prostaglandins and thromboxane as a function of systemic blood pressure. Cerebral blood flow autoregulation of the newborn.
Authors: S Chemtob, K Beharry, J Rex, D R Varma, J V Aranda
Journal: Circulation Research (1990)

Cerebrovascular concentrations of prostaglandin E (PGE), prostaglandin F2 alpha (PGF2 alpha), 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha), and thromboxane B2 (TXB2) were determined over a blood pressure range of 17-117 mm Hg (induced by inflation of balloon-tipped catheters placed in the thoracic descending aorta and at the aortic root) in eight newborn piglets to access the role of prostanoids in cerebral blood flow (CBF; measured using radioactive microspheres) autoregulation. Basal systemic blood pressure, heart rate, blood gases, total CBF, and prostanoid concentrations were stable. CBF was constant between 50 and 90 mm Hg, but beyond this range CBF varied directly with blood pressure (tau = 0.48; p less than 0.05). Sagittal sinus concentrations of PGE, PGF2 alpha, and 6-keto-PGF1 alpha varied with blood pressure according to a quadratic function (R2 = 0.92 to 0.96; p less than 0.0001), exhibiting lowest values between mean blood pressures of 60 and 90 mm Hg. During hypotension (17-49 mm Hg), there was a greater relative increase in sagittal sinus concentrations of TXB2 than of PGE, PGF2 alpha, and 6-keto-PGF1 alpha; at the lowest blood pressures, TXB2 increased by 658 +/- 44%, and prostaglandins increased on the average by 331 +/- 49% (p less than 0.01) from their values during normotension (50-90 mm Hg). During hypertension (91-117 mm Hg), cerebrovascular production and concentrations of prostaglandins increased by 142 +/- 31% and 45 +/- 10%, respectively, but did not change for TXB2.(ABSTRACT TRUNCATED AT 250 WORDS)
Toll-like receptors in the pathogenesis of human B cell malignancies
Authors: Johana M Isaza-Correa, Zheng Liang, Anke van den Berg, Arjan Diepstra, Lydia Visser
Journal: Journal of Hematology & Oncology (2014)

Toll-like receptors (TLRs) are important players in B-cell activation, maturation and memory and may be involved in the pathogenesis of B-cell lymphomas. Accumulating studies show differential expression in this heterogeneous group of cancers. Stimulation with TLR specific ligands, or agonists of their ligands, leads to aberrant responses in the malignant B-cells. According to current data, TLRs can be implicated in malignant transformation, tumor progression and immune evasion processes. Most of the studies focused on multiple myeloma and chronic lymphocytic leukemia, but in the last decade the putative role of TLRs in other types of B-cell lymphomas has gained much interest. The aim of this review is to discuss recent findings on the role of TLRs in normal B cell functioning and their role in the pathogenesis of B-cell malignancies.
Contribution of the initial features of systemic lupus erythematosus to the clinical evolution and survival of a cohort of Mediterranean patients
Authors: S Bujan
Journal: Annals of the Rheumatic Diseases (2003)

<b>Background:</b> Systemic lupus erythematosus has a wide spectrum of immunological and clinical manifestations. Its course is characterised by exacerbations which may result in mortality or morbidity to vital organs/systems. <b>Objective:</b> To determine clear and early prognostic markers to avoid further complications. <b>Methods:</b> 245 adult patients diagnosed between January 1978 and March 2001 were studied. Clinical manifestations and laboratory findings both at onset and during the clinical course were collected. The number, type, and severity of the flares were also noted. Statistical analyses between disease features at onset, subsequent flares, and mortality were performed. <b>Results:</b> 239 patients entered the study. Their mean age at onset was 30 years. The mean time between onset and diagnosis was 36 months and the mean evolution time was 114 months. 205 patients developed 915 flares; 205 (22.4%) of these flares were major flares, and affected 110 patients. Cardiac, neurological, or renal affection at onset were associated with a higher probability of developing cardiac (p=0.022), neurological (p&lt;0.001), and renal (p&lt;0.001) exacerbations, respectively, during the evolution. Lupus anticoagulant (LA) and anticardiolipin antibodies (aCL) were predictors of stroke (aCL, p=0.000; LA, p=0.001). Age at diagnosis (p=0.003) and valvular disease at onset (p=0.008) were independent predictors of low survival. <b>Conclusions:</b> Renal, cardiac, or neurological involvement and the presence of LA or aCL positivity at onset were predictors of renal, cardiac, or neurological flares, respectively. Age and valvular involvement at onset were found to be independent adverse outcome predictors for low survival.
Was the prevalence of Japanese childhood atopic eczema symptoms overestimated in the ISAAC study?
Authors: Yoshihiro Miyake, Yukihiro Ohya, Satoshi Sasaki, Shoichi Miyamoto, Ichiro Matsunaga, Toshiaki Yoshida, Yoshio Hirota, Hajime Oda
Journal: Journal of Allergy and Clinical Immunology (2004)