tbuckley/cabot-search huggingface dataset:
Similar colds in subjects with allergic asthma and nonatopic subjects after inoculation with rhinovirus-16
Authors: Jennifer P. DeMore, Elizabeth H. Weisshaar, Rose F. Vrtis, Cheri A. Swenson, Michael D. Evans, Allison Morin, Elizabeth Hazel, Jack A. Bork, Sujani Kakumanu, Ronald Sorkness, William W. Busse, James E. Gern
Journal: Journal of Allergy and Clinical Immunology (2009)
Lower Expression of Glutamic Acid Decarboxylase 67 in the Prefrontal Cortex in Schizophrenia: Contribution of Altered Regulation by Zif268
Authors: Sohei Kimoto, H. Holly Bazmi, David A. Lewis
Journal: American Journal of Psychiatry (2014)

Objective Cognitive deficits of schizophrenia may be due at least in part to lower expression of the 67-kDa isoform of glutamic acid decarboxylase (GAD67), a key enzyme for GABA synthesis, in the dorsolateral prefrontal cortex of individuals with schizophrenia. However, little is known about the molecular regulation of lower cortical GAD67 levels in schizophrenia. The GAD67 promoter region contains a conserved Zif268 binding site, and Zif268 activation is accompanied by increased GAD67 expression. Thus, altered expression of the immediate early gene Zif268 may contribute to lower levels of GAD67 mRNA in the dorsolateral prefrontal cortex in schizophrenia. Method The authors used polymerase chain reaction to quantify GAD67 and Zif268 mRNA levels in dorsolateral prefrontal cortex area 9 from 62 matched pairs of schizophrenia and healthy comparison subjects, and in situ hybridization to assess Zif268 expression at laminar and cellular levels of resolution. The effects of potentially confounding variables were assessed in human subjects, and the effects of antipsychotic treatments were tested in antipsychotic-exposed monkeys. The specificity of the Zif268 findings was assessed by quantifying mRNA levels for other immediate early genes. Results GAD67 and Zif268 mRNA levels were significantly lower and were positively correlated in the schizophrenia subjects. Both Zif268 mRNA-positive neuron density and Zif268 mRNA levels per neuron were significantly lower in the schizophrenia subjects. These findings were robust to the effects of the confounding variables examined and differed from other immediate early genes. Conclusions Deficient Zif268 mRNA expression may contribute to lower cortical GAD67 levels in schizophrenia, suggesting a potential mechanistic basis for altered cortical GABA synthesis and impaired cognition in schizophrenia.
A comparison of clinical assessments of disease activity in rheumatoid arthritis.
Authors: V M Rhind, H A Bird, V Wright
Journal: Annals of the Rheumatic Diseases (1980)

Six clinical assessments of disease activity, including a new summated change scale (SCS), have been compared in a group of 30 patients with rheumatoid arthritis seen on 8 separate occasions during their first 6 months of therapy with either D-penicillamine or hydroxychloroquine. Articular index and grip strength correlate best with erythrocyte sedimentation rate and C-reactive protein, pain score and early morning stiffness less well, and summated change score and joint circumference least well. Articular index and grip strength also correlated well with the other clinical parameters and are therefore judged to be the best clinical indices of change in treatment with these drugs.
Acute intensive insulin therapy exacerbates diabetic blood-retinal barrier breakdown via hypoxia-inducible factor-1α and VEGF
Authors: Vassiliki Poulaki, Wenying Qin, Antonia M. Joussen, Peter Hurlbut, Stanley J. Wiegand, John Rudge, George D. Yancopoulos, Anthony P. Adamis
Journal: Journal of Clinical Investigation (2002)

Acute intensive insulin therapy is an independent risk factor for diabetic retinopathy. Here we demonstrate that acute intensive insulin therapy markedly increases VEGF mRNA and protein levels in the retinae of diabetic rats. Retinal nuclear extracts from insulin-treated rats contain higher hypoxia-inducible factor-1α (HIF-1α) levels and demonstrate increased HIF-1α–dependent binding to hypoxia-responsive elements in the VEGF promoter. Blood-retinal barrier breakdown is markedly increased with acute intensive insulin therapy but can be reversed by treating animals with a fusion protein containing a soluble form of the VEGF receptor Flt; a control fusion protein has no such protective effect. The insulin-induced retinal HIF-1α and VEGF increases and the related blood-retinal barrier breakdown are suppressed by inhibitors of p38 mitogen-activated protein kinase (MAPK) and phosphatidylinositol (PI) 3-kinase, but not inhibitors of p42/p44 MAPK or protein kinase C. Taken together, these findings indicate that acute intensive insulin therapy produces a transient worsening of diabetic blood-retinal barrier breakdown via an HIF-1α–mediated increase in retinal VEGF expression. Insulin-induced VEGF expression requires p38 MAPK and PI 3-kinase, whereas hyperglycemia-induced VEGF expression is HIF-1α–independent and requires PKC and p42/p44 MAPK. To our knowledge, these data are the first to identify a specific mechanism for the transient worsening of diabetic retinopathy, specifically blood-retinal barrier breakdown, that follows the institution of intensive insulin therapy.
Abstract 1441: Adapting the Syngraft mouse model to study metastatic recurrence of pancreatic cancer
Authors: Crissy Dudgeon, Ashley Tsang, Neil Campbell, Eric Collisson, Darren Carpizo
Journal: Cancer Research (2015)

Abstract Pancreatic cancer is one of the most aggressive human malignancies with a 5-year survival rate for all stages of only 6%. While surgery remains the most effective treatment for pancreatic cancer, the majority of patients that undergo resection go on to die of pancreatic cancer recurrence. The biology of pancreatic recurrence is poorly understood due to the lack of sufficient mouse models to study this aspect of the disease. Our laboratory has adapted the Syngraft mouse model in order to study metastatic recurrence of pancreatic cancer. The Syngraft model is an orthotopic syngeneic mouse model using a pancreatic tumor cell line derived from the genetically engineered model (KrasG12D/+; Ink4a flox/flox) that has been modified with lentiviral vectors expressing mCherry and luciferase. After orthotopic injection, tumor formation was detected with the IVIS Spectrum using injected luciferin. Mice underwent distal pancreatectomy with spleenectomy when the primary pancreatic tumor measured ∼107 photons/sec/cm2, with a mean time to surgical resection at 19 days. Mice were then followed for metastatic recurrence to the liver using the IVIS Spectrum, with a mean time to recurrence of 23 days. We were able to establish a rate of metastatic recurrence in the Syngraft mouse model of 41% to the liver. Research is ongoing to enhance the metastatic efficiency of the injected cell lines and to further characterize the model for evidence of single cell and micrometastases in the liver. This model holds potential to be a useful tool to study the cell and molecular biology of pancreatic cancer recurrence. Citation Format: Crissy Dudgeon, Ashley Tsang, Neil Campbell, Eric Collisson, Darren Carpizo. Adapting the Syngraft mouse model to study metastatic recurrence of pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1441. doi:10.1158/1538-7445.AM2015-1441
Response gene to complement 32 deficiency causes impaired placental angiogenesis in mice
Authors: Xiao-Bing Cui, Xia Guo, Shi-You Chen
Journal: Cardiovascular Research (2013)

The objectives of this study are to determine the role of response gene to complement 32 (RGC-32) in the placental angiogenesis during pregnancy and explore the underlying mechanisms. RGC-32-deficient (RGC32−/−) mice were generated from C57BL/6 embryonic stem cells with deletion of exon 2 and 3 of the RGC-32 gene. Most of the RGC32−/− mice can survive. However, their body sizes were much smaller compared with their wild-type littermates when they were born. By examining the embryo development and placentas at 16.5 days post-coitum, we found that RGC32−/− embryos and foetal placentas were significantly smaller than the wild-type. Further analysis showed that the labyrinth zone of RGC32−/− placenta was smaller with defective angiogenesis. Mechanistically, vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) and placental growth factor (PlGF) were significantly down-regulated in RGC32−/− placentas, suggesting that VEGFR2 and PlGF may mediate RGC-32 function in placental angiogenesis. Indeed, knockdown of RGC-32 by shRNA inhibited VEGF-induced endothelial cell proliferation, migration, and tube formation while blocking VEGFR2 expression. RGC-32 appeared to regulate VEGFR2 expression via activation of NF-kB. Moreover, RGC-32 regulated trophoblasts proliferation via control of PlGF expression. Absence of RGC-32 caused foetal growth restriction through interrupting the placental angiogenesis, which was due to the decrease in VEGFR2 expression through the NF-kB-dependent pathway in endothelial cells and PlGF expression in trophoblasts.
S139 The K+ channel KCa3.1 is a novel target for the treatment of idiopathic pulmonary fibrosis
Authors: M. C. Shepherd, S. R. Sabir, C. McSharry, H. Wulff, P. Bradding
Journal: Thorax (2010)

<h3>Introduction and objectives</h3> Idiopathic pulmonary fibrosis (IPF) is common, largely unresponsive to treatment with a median survival of 3 years. New therapies are urgently required. IPF is characterised by proliferation of pulmonary mesenchymal cells through epithelial mesenchymal transition, resident fibroblast proliferation and circulating fibrocyte recruitment. We have previously demonstrated that the potassium channel K<sub>Ca</sub>3.1 regulates lung mesenchymal cell proliferation, is up-regulated by TGFβ, an important driver of IPF, and is present in fibrocytes in peripheral blood. We tested the hypotheses that K<sub>Ca</sub>3.1 is up-regulated in IPF using the bleomycin-induced pulmonary fibrosis murine model and that K<sub>Ca</sub>3.1 inhibition reduces pulmonary fibrosis. <h3>Methods</h3> Prophylactic (Day -3) and daily thereafter, sub-cutaneous TRAM-34, a specific K<sub>Ca</sub>3.1 inhibitor, was administered to C57BL/6 mice later exposed to nasal bleomycin (Day 0) and culled on day +21. Mice exposed to PBS or bleomycin acted as negative and positive controls. The primary endpoint was histological fibrosis score. Inflammation was assessed by bronchoalveolar lavage. Collagen deposition and K<sub>Ca</sub>3.1 expression were assessed by Masson9s trichrome staining and qPCR. <h3>Results</h3> Bleomycin-induced pulmonary fibrosis characterised by thickened alveolar septae, architectural destruction and collagen deposition. Co-administration of TRAM-34 significantly reduced pulmonary fibrosis (Modified Ashcroft9s score +/− SEM: 4.8+/−0.8 bleomycin group vs 2.6+/−0.6 TRAM-34 group: p=0.02). Bleomycin increased lung K<sub>Ca</sub>3.1 (55-fold versus PBS control) and collagen Iα mRNA (fourfold) expression (n=3 in each case). Mice receiving bleomycin lost more weight (2.39 vs 0 g) and had greater mortality than those co-administered TRAM-34. BAL cellularity did not differ between the groups. Collagen staining was reduced in the TRAM-34 group. <h3>Conclusions</h3> K<sub>Ca</sub>3.1 expression is increased in a model of pulmonary fibrosis and inhibition with TRAM-34 significantly improves pathological outcome. The mechanism is likely to involve the modulation of cells involved in the fibrotic process. Previous clinical studies have shown KCa3.1 inhibition to be safe in humans and our study provides a rationale for a clinical trial of K<sub>Ca</sub>3.1 inhibitors in human IPF.
MICROVASCULAR PERSPECTIVE OF OXYGEN-CARRYING AND -NONCARRYING BLOOD SUBSTITUTES
Authors: Marcos Intaglietta, Pedro Cabrales, Amy G. Tsai
Journal: Annual Review of Biomedical Engineering (2006)

The development of an alternative to natural blood has evolved from the initial goal of replicating blood properties to the current objective of formulating a fluid that can be used to replace blood while preserving microvascular function and delivering oxygen. The properties of this fluid are counterintuitive and different from blood because it has high viscosity, oxygen affinity, and a low oxygen carrier concentration when compared with blood. The optimal oxygen carrier devised presently is poly-ethylene-conjugated human hemoglobin, a material demonstrated to be vasoinactive and void of the toxicities present in previous hemoglobin formulations. A feature of this material is that it is effective in small quantities, and therefore amplifies the equivalent supply of blood derived from blood donations.
SF-36 and Diabetes Outcome Measures
Authors: Mayer B. Davidson
Journal: Diabetes Care (2005)

In a recent issue of Diabetes Care, Hill-Briggs et al. (1) found that the Medical Outcomes Study 36-item short form (SF-36) did not improve in a population whose outcome measures (HbA1c, triglycerides, and diastolic blood pressure) showed modest improvement. We found a similar lack of change in the standard SF-36 in a group of patients whose HbA1c levels, measured in a boronate affinity assay in …
Attributional Style and Depression in Pregnant Teenagers
Authors: Karen Dineen Wagner, Abbey Berenson, Olayinka Harding, Thomas Joiner
Journal: American Journal of Psychiatry (1998)

Objective: Study 1 evaluated whether pregnancy is a stressful life event for teenagers and is associated with depression for teenagers with a pessimistic attributional style but not for those with an optimistic attributional style. Study 2 replicated unexpected findings from study 1. Study 3 evaluated whether pregnant teenagers with a pessimistic attributional style will be more depressed after childbirth than optimistic pregnant teenagers. Method: In study 1, 122 pregnant and 96 nonpregnant teenagers completed questionnaires assessing depression and attributional style. In study 2, 43 pregnant teenagers and 49 nonpregnant teenagers completed the same questionnaires. In study 3, subjects from studies 1 and 2 were contacted by mail and asked to complete the same questionnaires; 63 (38%) did so.Results: In studies 1 and 2, pregnant teenagers with a pessimistic attributional style were less depressed than those with an optimistic attributional style and the nonpregnant group. In study 3, pessimistic teenagers experienced a higher level of depression than nonpessimistic adolescents following childbirth.Conclusions: Pregnancy may serve to protect pessimistic teenagers from experiencing depression. The subsequent demands of motherhood may remove any protection from depression afforded by the pregnancy. The experience of depression being relieved by another pregnancy may be a previously unidentified risk factor for repeated pregnancies in teenagers. Am J Psychiatry 1998; 155: 1227-1233
Effects of Tolvaptan, a Vasopressin Antagonist, in Patients Hospitalized With Worsening Heart Failure&lt;SUBTITLE&gt;A Randomized Controlled Trial&lt;/SUBTITLE&gt;
Authors: Mihai Gheorghiade, Wendy A. Gattis, Christopher M. O'Connor, Kirkwood F. Adams, Uri Elkayam, Alejandro Barbagelata, Jalal K. Ghali, Raymond L. Benza, Frank A. McGrew, Marc Klapholz, John Ouyang, Cesare Orlandi
Journal: JAMA (2004)

ContextNearly 1 million hospitalizations for chronic heart failure occur yearly in the United States, with most related to worsening systemic congestion. Diuretic use, the mainstay therapy for congestion, is associated with electrolyte abnormalities and worsening renal function. In contrast to diuretics, the vasopressin antagonist tolvaptan may increase net volume loss in heart failure without adversely affecting electrolytes and renal function.ObjectiveTo evaluate the short- and intermediate-term effects of tolvaptan in patients hospitalized with heart failure.Design, Setting, and ParticipantsRandomized, double-blind, placebo-controlled, parallel-group, dose-ranging, phase 2 trial conducted at 45 centers in the United States and Argentina and enrolling 319 patients with left ventricular ejection fraction of less than 40% and hospitalized for heart failure with persistent signs and symptoms of systemic congestion despite standard therapy.InterventionAfter admission, patients were randomized to receive 30, 60, or 90 mg/d of oral tolvaptan or placebo in addition to standard therapy, including diuretics. The study drug was continued for up to 60 days.Main Outcome MeasuresIn-hospital outcome was change in body weight at 24 hours after randomization; outpatient outcome was worsening heart failure (defined as death, hospitalization, or unscheduled visits for heart failure) at 60 days after randomization.ResultsMedian (interquartile range) body weight at 24 hours after randomization decreased by −1.80 (−3.85 to −0.50), −2.10 (−3.10 to −0.85), −2.05 (−2.80 to −0.60), and −0.60 (−1.60 to 0.00) kg in the groups receiving tolvaptan 30, 60, and 90 mg/d, and placebo, respectively (P≤.008 for all tolvaptan groups vs placebo). The decrease in body weight with tolvaptan was not associated with changes in heart rate or blood pressure, nor did it result in hypokalemia or worsening renal function. There were no differences in worsening heart failure at 60 days between the tolvaptan and placebo groups (P = .88 for trend). In post hoc analysis, 60-day mortality was lower in tolvaptan-treated patients with renal dysfunction or severe systemic congestion.ConclusionTolvaptan administered in addition to standard therapy may hold promise for management of systemic congestion in patients hospitalized for heart failure.
Inhibition of Mannose-Binding Lectin Reduces Postischemic Myocardial Reperfusion Injury
Authors: James E. Jordan, Michael C. Montalto, Gregory L. Stahl
Journal: Circulation (2001)

Complement consists of a complex cascade of proteins involved in innate and adaptive immunity. The cascade can be activated through 3 distinct mechanisms, designated the classical, alternative, and lectin pathways. Although complement is widely accepted as participating in the pathophysiology of ischemia-reperfusion injury, the specific role of the lectin pathway has not been addressed.Monoclonal antibodies (mAbs; P7E4 and 14C3.74, IgG1kappa isotypes) were raised against rat mannose-binding lectin (rMBL). Both mAbs recognized rMBL-A by Western analysis or surface plasmon resonance. P7E4, but not 14C3.74, exhibited a concentration-dependent inhibition of the lectin pathway, with maximal effect at 10 microg/mL. In vivo, rats were subjected to 30 minutes of left coronary artery occlusion and 4 hours of reperfusion. Complement C3 deposition was greatly attenuated in hearts pretreated with P7E4 compared with 14C3.74-treated hearts. Pretreatment with P7E4 (1 mg/kg) significantly reduced myocardial creatine kinase loss (48%), infarct size (39%), and neutrophil infiltration (47%) compared with 14C3.74-treated animals. In addition, P7E4 pretreatment significantly attenuated the expression of proinflammatory genes (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and interleukin-6) after ischemia-reperfusion.The lectin complement pathway is activated after myocardial ischemia-reperfusion and leads to tissue injury. Blockade of the lectin pathway with inhibitory mAbs protects the heart from ischemia-reperfusion by reducing neutrophil infiltration and attenuating proinflammatory gene expression.
ApoER2 expression increases Aβ production while decreasing Amyloid Precursor Protein (APP) endocytosis: Possible role in the partitioning of APP into lipid rafts and in the regulation of γ-secretase activity
Authors: Rodrigo A Fuentealba, Maria Ines Barría, Jiyeon Lee, Judy Cam, Claudia Araya, Claudia A Escudero, Nibaldo C Inestrosa, Francisca C Bronfman, Guojun Bu, Maria-Paz Marzolo
Journal: Molecular Neurodegeneration (2007)

The generation of the amyloid-beta peptide (Abeta) through the proteolytic processing of the amyloid precursor protein (APP) is a central event in the pathogenesis of Alzheimer's disease (AD). Recent studies highlight APP endocytosis and localization to lipid rafts as important events favoring amyloidogenic processing. However, the precise mechanisms underlying these events are poorly understood. ApoER2 is a member of the low density lipoprotein receptor (LDL-R) family exhibiting slow endocytosis rate and a significant association with lipid rafts. Despite the important neurophysiological roles described for ApoER2, little is known regarding how ApoER2 regulates APP trafficking and processing.Here, we demonstrate that ApoER2 physically interacts and co-localizes with APP. Remarkably, we found that ApoER2 increases cell surface APP levels and APP association with lipid rafts. The increase of cell surface APP requires the presence of ApoER2 cytoplasmic domain and is a result of decreased APP internalization rate. Unexpectedly, ApoER2 expression correlated with a significant increase in Abeta production and reduced levels of APP-CTFs. The increased Abeta production was dependent on the integrity of the NPxY endocytosis motif of ApoER2. We also found that expression of ApoER2 increased APP association with lipid rafts and increased gamma-secretase activity, both of which might contribute to increased Abeta production.These findings show that ApoER2 negatively affects APP internalization. However, ApoER2 expression stimulates Abeta production by shifting the proportion of APP from the non-rafts to the raft membrane domains, thereby promoting beta-secretase and gamma-secretase mediated amyloidogenic processing and also by incrementing the activity of gamma-secretase.
Angle dependence of ultrasonic backscatter in arterial tissues: a study in vitro.
Authors: E Picano, L Landini, A Distante, M Salvadori, F Lattanzi, M Masini, A L'Abbate
Journal: Circulation (1985)

The object of this study was to obtain quantitative data on the angle dependence of reflected ultrasound signals in freshly excised normal human arterial walls and those with different degrees of atherosclerotic involvement (fatty, fibrofatty, fibrous, or calcified). Fifteen specimens were evaluated in each pathologic subset. The backscatter coefficient (BS, expressed as cm-1 X steradians -1), measured at the single frequency of 10 MHz, was evaluated at a normal angle of incidence of the interrogating beam to the tissue sample and over an angular span of 60 degrees (+/- 30 degrees around normal incidence, 2 degree steps). BS measured at normal incidence separated normal (10(-2) X 0.155 +/- 0.018; mean +/- SE) from fibrofatty (10(-1) X 0.0103 +/- 0.008), fibrous (10(-1) X 0.182 +/- 0.016), and calcified (0.202 +/- 0.016) specimens; normal and fatty (10(-3) X 0.759 +/- 0.142) and fibrofatty and fibrous samples could not be distinguished from each other in a statistically significant way. Angular scattering measurements identified two patterns: A "directive" pattern, characterized by a strongly angle-dependent BS that falls abruptly when the beam is moved slightly away from normal incidence. This pattern was typical of calcified, fibrous, and less markedly, fibrofatty and normal samples. A "nondirective" pattern, characterized by a BS that is not significantly angle dependent and fluctuates throughout the entire angular range. This was typical of fatty samples.