tbuckley/cabot-search huggingface dataset:
Antihypertensive effects of ACE2 in the paraventricular nucleus: a consequence of reduced neuroinflammation?
Authors: O. Grisk
Journal: Cardiovascular Research (2011)

This editorial refers to ‘ACE2 overexpression in the paraventricular nucleus attenuates angiotensin II-induced hypertension’ by S. Sriramula et al ., pp. 401–408, this issue. 

Angiotensin II increases arterial pressure through its multiple actions on the nervous system, the adrenal glands, the vasculature, and renal epithelial transport. In recent years, evidence has accumulated that the activation of proinflammatory mechanisms contributes to the pathogenesis of arterial hypertension by causing inflammation of tissues and organs, such as the vasculature, the kidneys, and the central nervous system (CNS).1 Angiotensin II is a potent stimulator of proinflammatory activity in hypertension.1,2

The paraventricular nucleus (PVN) of the hypothalamus is intimately involved in neuroendocrine regulatory processes that affect arterial pressure.3 It receives inputs from osmosensitive neurons, arterial baroreceptors, and stretch receptors in the large veins and in the atria.3,4 The PVN effector neurons project to the posterior pituitary where they release oxytocin or vasopressin and to the anterior pituitary where they secrete releasing hormones into the portal circulation. Other neurons of the PVN project to CNS target neurons outside the pituitary that determine sympathetic and parasympathetic output.3,5 Stimulation of PVN neurons by circulating angiotensin II increases vasopressin release, elevates sympathetic activity, …
Montelukast Added to Inhaled Beclomethasone in Treatment of Asthma
Authors: MICHEL LAVIOLETTE, KERSTIN MALMSTROM, SUSAN LU, PAUL CHERVINSKY, JEAN-CLAUDE PUJET, IZABELLA PESZEK, JI ZHANG, THEODORE F. REISS
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

The primary objective of this study was to determine whether montelukast, an oral leukotriene receptor antagonist, provides additional clinical benefit to the effect of inhaled corticosteroids. A total of 642 patients with chronic asthma (FEV1 50 to 85% of predicted value and at least a predefined level of asthma symptoms) incompletely controlled with inhaled beclomethasone, 200 μ g twice daily using a spacer device, during the 4-wk run-in period were randomly allocated, in a double-blind, double-dummy manner to one of four treatment groups: (1) montelukast 10 mg plus continuing inhaled beclomethasone; (2) placebo tablet plus continuing inhaled beclomethasone; (3) montelukast 10 mg and inhaled placebo (after blind beclomethasone removal); and (4) placebo tablet and inhaled placebo (after blind beclomethasone removal). The primary endpoints were FEV1 and daytime asthma symptoms score. Montelukast provided significant (p < 0.05) clinical benefit in addition to inhaled beclomethasone by improving FEV1, daytime asthma symptom scores, and nocturnal awakenings. Blind removal of beclomethasone in the presence of placebo tablets caused worsening of asthma control, demonstrating that patients received clinical benefit from inhaled corticosteroids. Blind removal of beclomethasone in the presence of montelukast resulted in less asthma control but not to the level of the placebo group. All treatments were well tolerated; clinical and laboratory adverse experiences were generally similar to placebo treatment in this study. In conclusion, montelukast provided additional asthma control to patients benefitting from, but incompletely controlled on, inhaled beclomethasone. Laviolette M, Malmstrom K, Lu S, Chervinsky P, Pujet J-C, Peszek I, Zhang J, Reiss TF for the Montelukast/Beclomethasone Additivity Group. Montelukast added to inhaled beclomethasone in treatment of asthma.
The Effects of Hypoxia on pH <sub>i</sub> in Porcine Coronary Artery Endothelium and Smooth Muscle
Authors: Robyn A. Foy, Shunichi Shimizu, Richard J. Paul
Journal: Circulation Research (1997)

Endothelium-dependent relaxation of porcine coronary arteries is attenuated under hypoxic conditions. Recent evidence also indicates that pH i may modulate the release of the endothelium-derived relaxing factor. We tested the hypothesis that hypoxia-induced attenuation of endothelium-dependent relaxation is mediated by alterations in pH i . We developed a novel method for loading surface cells, whereby endothelial cell pH i could be measured in situ on the intact porcine coronary artery. Endothelial cells of arterial ring segments were selectively loaded with the fluorescent indicator BCECF-AM. Differential loading of the endothelial cell layer was verified by confocal microscopy. pH i of the endothelial cells in situ and of endothelium-denuded arteries was measured with a Photon Technology International spectrofluorimeter. The functional integrity of the endothelium was assessed by the endothelium-dependent relaxation to substance P in a paired adjacent ring. In the experimental protocol for pH i measurements, preparations were perfused with a physiological bicarbonate buffer (pH 7.4), stimulated with KCl (29 mmol/L), and then subjected to hypoxia and reoxygenation. The mean basal pH i in endothelial cells on the intact six arteries was 6.92±0.07. Addition of KCl to the perfusion medium decreased ( P =.025) pH i to 6.79±0.07. Subsequent bubbling with N 2 increased ( P =.009) pH i to 7.00±0.06, which was reversed by reoxygenation. In contrast to the in situ endothelium, pH i of the smooth muscle was not significantly altered from its basal value of 7.24±0.06 (n=5) by either KCl or hypoxia. This differential behavior corroborated the confocal data indicating differential dye loading. These data thus suggest that oxygen-sensitive alterations in pH i may be an important mechanism of signal transduction in endothelial cells.
Mechanisms and Management of Diabetic Painful Distal Symmetrical Polyneuropathy
Authors: Solomon Tesfaye, Andrew J.M. Boulton, Anthony H. Dickenson
Journal: Diabetes Care (2013)

Although a number of the diabetic neuropathies may result in painful symptomatology, this review focuses on the most common: chronic sensorimotor distal symmetrical polyneuropathy (DSPN). It is estimated that 15–20% of diabetic patients may have painful DSPN, but not all of these will require therapy. In practice, the diagnosis of DSPN is a clinical one, whereas for longitudinal studies and clinical trials, quantitative sensory testing and electrophysiological assessment are usually necessary. A number of simple numeric rating scales are available to assess the frequency and severity of neuropathic pain. Although the exact pathophysiological processes that result in diabetic neuropathic pain remain enigmatic, both peripheral and central mechanisms have been implicated, and extend from altered channel function in peripheral nerve through enhanced spinal processing and changes in many higher centers. A number of pharmacological agents have proven efficacy in painful DSPN, but all are prone to side effects, and none impact the underlying pathophysiological abnormalities because they are only symptomatic therapy. The two first-line therapies approved by regulatory authorities for painful neuropathy are duloxetine and pregabalin. α-Lipoic acid, an antioxidant and pathogenic therapy, has evidence of efficacy but is not licensed in the U.S. and several European countries. All patients with DSPN are at increased risk of foot ulceration and require foot care, education, and if possible, regular podiatry assessment.
Mental Disorders and Access to Medical Care in the United States
Authors: Benjamin G. Druss, Robert A. Rosenheck
Journal: American Journal of Psychiatry (1998)

Objective:The authors examined the barriers to receipt of medical services among people reporting mental disorders in a representative sample of U.S. adults.Method:The sample was drawn from adults who responded to the 1994 National Health Interview Survey (N=77,183). The authors studied the association between report of a mental disorder and 1) access to health insurance and a primary provider, and 2) actual receipt of medical care. Multivariate techniques were used to model problems with access as a function of mental disorders, controlling for demographic, insurance, and health variables.Results:While people who reported mental disorders showed no difference from those without mental disorders in likelihood of being uninsured or of having a primary care provider, they were twice as likely to report having been denied insurance because of a preexisting condition or having stayed in their job for fear of losing their health benefits. Among respondents with insurance, those who reported mental illness were no less likely to have a primary care provider but were about two times more likely to report having delayed seeking needed medical care because of cost or having been unable to obtain needed medical care.Conclusions:People who reported mental disorders experienced significant barriers to receipt of medical care. Efforts to measure and improve access to health care for this population may need to go beyond simply providing insurance benefits or access to general medical providers. Am J Psychiatry 1998; 155: 1775-1777
Circulating Tumor Cell Number and Prognosis in Progressive Castration-Resistant Prostate Cancer
Authors: Daniel C. Danila, Glenn Heller, Gretchen A. Gignac, Rita Gonzalez-Espinoza, Aseem Anand, Erika Tanaka, Hans Lilja, Lawrence Schwartz, Steven Larson, Martin Fleisher, Howard I. Scher
Journal: Clinical Cancer Research (2007)

Abstract Purpose: The development of tumor-specific markers to select targeted therapies and to assess clinical outcome remains a significant area of unmet need. We evaluated the association of baseline circulating tumor cell (CTC) number with clinical characteristics and survival in patients with castrate metastatic disease considered for different hormonal and cytotoxic therapies. Experimental Design: CTC were isolated by immunomagnetic capture from 7.5-mL samples of blood from 120 patients with progressive clinical castrate metastatic disease. We estimated the probability of survival over time by the Kaplan-Meier method. The concordance probability estimate was used to gauge the discriminatory strength of the informative prognostic factors. Results: Sixty-nine (57%) patients had five or more CTC whereas 30 (25%) had two cells or less. Higher CTC numbers were observed in patients with bone metastases relative to those with soft tissue disease and in patients who had received prior cytotoxic chemotherapy relative to those who had not. CTC counts were modestly correlated to measurements of tumor burden such as prostate-specific antigen and bone scan index, reflecting the percentage of boney skeleton involved with tumor. Baseline CTC number was strongly associated with survival, without a threshold effect, which increased further when baseline prostate-specific antigen and albumin were included. Conclusions: Baseline CTC was predictive of survival, with no threshold effect. The shedding of cells into the circulation represents an intrinsic property of the tumor, distinct from extent of disease, and provides unique information relative to prognosis.
Involvement of vascular endothelial growth factor receptor-3 in maintenance of integrity of endothelial cell lining during tumor angiogenesis
Authors: Hajime Kubo, Takashi Fujiwara, Lotta Jussila, Hiroyuki Hashi, Minetaro Ogawa, Kenji Shimizu, Masaaki Awane, Yoshiharu Sakai, Arimichi Takabayashi, Kari Alitalo, Yoshio Yamaoka, Shin-Ichi Nishikawa
Journal: Blood (2000)
Isolation of murine pluripotent hemopoietic stem cells.
Authors: J W Visser, J G Bauman, A H Mulder, J F Eliason, A M de Leeuw
Journal: The Journal of Experimental Medicine (1984)

A method described to purify pluripotent hemopoietic stem cells ( PHSC ) from adult mouse bone marrow. The method consists of three separation steps. First, bone marrow cells are centrifuged in a discontinuous metrizamide gradient and simultaneously labeled with wheat germ agglutinin-fluorescein isothiocyanate (WGA-FITC). Second, the low density cells are analyzed by a fluorescence-activated cell sorter (FACS) and the WGA-positive cells with medium forward and low perpendicular light scatter intensities are sorted. The WGA-FITC is removed from the cells by incubation with N-acetyl-D-glucosamine. Finally, the sorted cells are incubated with anti-H-2K-biotin and avidin-FITC and sorted a second time to enrich cells with high H-2K density. The sorted cells gave rise to 2 spleen colonies per 100 injected cells at 8 d and 6.6 colonies per 100 cells at 12 d after transplantation into lethally irradiated syngeneic recipients. The average enrichment factor for day 12 CFU-S (colony-forming unit/spleen) was 135 (range, 90--230; n = 15) and was similar to that for the cell type that provides radioprotection (180 +/- 70), indicating that these functional properties were copurified. Indirect evidence suggests that the spleen-seeding efficiency (f factor) of these cells is 0.10 and, therefore, the average purity of the sorted PHSC was 65% (range in 15 experiments, 35--110%). The sorted cells were all in the G1 or G0 phase of the cell cycle. They appeared to be undifferentiated blasts by morphological criteria. Electron microscopy revealed that the sorted cells consisted primarily of two cell types, possibly representing G0 and G1 cells. The FACS was used to deposit single selected cells into individual microwells of Terasaki trays. 32% of the sorted cells could be induced to form myeloid progeny in vitro. This procedure should be useful for direct studies on the regulation of hemopoietic cell differentiation.
Angiotensin II Stimulates p90 <sup>rsk</sup> in Vascular Smooth Muscle Cells
Authors: Eiichi Takahashi, Jun-ichi Abe, Bradford C. Berk
Journal: Circulation Research (1997)

Angiotensin II is a multifunctional agonist for vascular smooth muscle cells (VSMCs), stimulating increases in signal events, cell growth, and ion flux. We previously defined protein kinase C (PKC)-dependent and -independent mechanisms by which angiotensin II stimulated activity of the Na(+)-H+ exchanger isoform-1 (NHE-1) and identified a 90-kD kinase that exhibited increased activity in VSMCs isolated from genetically hypertensive rats. To determine whether this 90-kD kinase was p90rsk (RSK), VSMCs were stimulated with 100 nmol/L angiotensin II, and NHE-1 kinase activity was measured by phosphorylation of recombinant NHE-1 (a glutathione S-transferase fusion protein containing amino acids 516 to 815 of the cytoplasmic carboxyl tail) in vitro. NHE-1 kinase (90 kD) activity was markedly decreased by immunodepletion of RSK. Characterization of RSK activation by angiotensin II revealed many similarities to the 90-kD NHE-1 kinase, including time course and NHE-1 domain phosphorylation, as well as regulation by extracellular signal-regulated kinases (ERK1/2), intracellular Ca2+, and PKC. Specifically, angiotensin II stimulated a rapid and transient (peak, 5 minutes) increase in RSK activity. Analysis of several NHE-1 fusion proteins revealed that only proteins containing amino acids 670 to 714 were phosphorylated by RSK. Inhibiting ERK1/2 (30 mumol/L PD098059 for 30 minutes) or chelating intracellular Ca2+ prevented RSK activation. In contrast, downregulating PKC (1 mumol/L phorbol dibutyrate for 24 hours) had little effect. These findings establish RSK as a putative NHE-1 kinase and potential mediator of increased Na(+)-H+ exchange in hypertension.
Why We Need Medical Savings Accounts
Authors: Phil Gramm
Journal: New England Journal of Medicine (1994)

There are two propositions on which everyone involved in the health care debate should be able to agree. First, for all the talk about our problems, Americans enjoy the greatest medical care in the world. Whether you are the richest or the poorest person on the planet, if you were going to get very sick today, you would want to be treated in the United States. Second, for all our spectacular success in developing lifesaving technology and training health care professionals to use it, every serious attempt to control medical costs in the past quarter-century has been a disappointing failure. . . .
Violence and Severe Mental Illness: The Effects of Substance Abuse and Nonadherence to Medication
Authors: Marvin S. Swartz, Jeffrey W. Swanson, Virginia A. Hiday, Randy Borum, H. Ryan Wagner, Barbara J. Burns
Journal: American Journal of Psychiatry (1998)

Violent behavior among individuals with severe mental illness has become an important focus in community-based care. This study examines the joint effect of substance abuse and medication noncompliance on the greater risk of serious violence among persons with severe mental illness.Involuntarily admitted inpatients with severe mental illness who were awaiting a period of outpatient commitment were enrolled in a longitudinal outcome study. At baseline, 331 subjects underwent an extensive face-to-face interview. Complementary data were gathered by a review of hospital records and a telephone interview with a family member or other informant. These data included subjects' sociodemographic characteristics, illness history, clinical status, medication adherence, substance abuse, insight into illness, and violent behavior during the 4 months that preceded hospitalization. Associations between serious violent acts and a range of individual characteristics and problems were analyzed by using multivariable logistic regression.The combination of medication noncompliance and alcohol or substance abuse problems was significantly associated with serious violent acts in the community, after sociodemographic and clinical characteristics were controlled.Alcohol or other drug abuse problems combined with poor adherence to medication may signal a higher risk of violent behavior among persons with severe mental illness. Reduction of such risk may require carefully targeted community interventions, including integrated mental health and substance abuse treatment.
Current Therapies for ANCA-Associated Vasculitis
Authors: Lindsay Lally, Robert Spiera
Journal: Annual Review of Medicine (2014)

The ANCA-associated vasculitides, granulomatosis with polyangiitis (GPA, formerly Wegener's), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-Strauss), are a group of multisystem autoimmune diseases characterized by necrotizing small- to medium-vessel vasculitis and the presence of anti-neutrophil cytoplasmic antibodies. Current therapeutic strategies consist of glucocorticoids in conjunction with either conventional or biologic agents for both induction of remission and remission maintenance. Treatment goals include reducing toxicity of induction therapy, preventing disease relapse, and limiting overall accrual of both disease-related damage and treatment-related morbidity. Future research directions include investigation of the optimal duration and frequency of maintenance therapy as well as development of targeted therapeutic agents, which is enhanced by emerging insights into disease pathogenesis.
β1-Integrin: A Potential Therapeutic Target in the Battle against Cancer Recurrence
Authors: Dalit Barkan, Ann F. Chambers
Journal: Clinical Cancer Research (2011)

Primary cancer treatment, involving both local and often systemic adjuvant therapy, is often successful, especially if the cancer is detected at an early stage of progression. However, for some patients, the cancer may recur either locally or as distant metastases, in some cases many years after apparently successful primary treatment. Significant tumor dormancy has been documented in several cancers, such as breast, melanoma, and renal cancer. Tumor dormancy has long been recognized as an important problem in management of cancer patients. Recent work has clarified biologic aspects of tumor dormancy and has shown that dormant tumor cells may be resistant to cytotoxic chemotherapy and radiation. This work has led to recognition of a key role for β1-integrin in regulating the switch from a dormant state to active proliferation and metastasis. Here we discuss the role of β1-integrin and its signaling partners in regulating the dormant phenotype. We also consider possible therapeutic approaches, such as small molecules or antibodies (ATN-161, volociximab, and JSM6427), directed against β1-integrin signaling to target dormant cancer cells and to prevent metastatic recurrence.
Autoimmunity in a cohort of 130 pediatric patients with partial DiGeorge syndrome
Authors: Brian E. Tison, Sarah K. Nicholas, Stuart L. Abramson, Imelda C. Hanson, Mary E. Paul, Filiz O. Seeborg, William T. Shearer, Maria D. Perez, Lenora M. Noroski, Javier Chinen
Journal: Journal of Allergy and Clinical Immunology (2011)
Understanding the complexity of IgE-related phenotypes from childhood to young adulthood: A Mechanisms of the Development of Allergy (MeDALL) Seminar
Authors: Josep M. Antó, Mariona Pinart, Mübeccel Akdis, Charles Auffray, Claus Bachert, Xavier Basagaña, Kai-Håkon Carlsen, Stefano Guerra, Leena von Hertzen, Sabina Illi, Francine Kauffmann, Thomas Keil, James P. Kiley, Gerard H. Koppelman, Christian Lupinek, Fernando D. Martinez, Martijn C. Nawijn, Dirkje S. Postma, Valérie Siroux, Henriette A. Smit, Peter J. Sterk, Jordi Sunyer, Rudolf Valenta, Sergio Valverde, Cezmi A. Akdis, Isabella Annesi-Maesano, Ferran Ballester, Marta Benet, Anne Cambon-Thomsen, Leda Chatzi, Jonathan Coquet, Pascal Demoly, Weiniu Gan, Judith Garcia-Aymerich, Elena Gimeno-Santos, Chantal Guihenneuc-Jouyaux, Tari Haahtela, Joachim Heinrich, Marie Herr, Cynthia Hohmann, Bénédicte Jacquemin, Jocelyne Just, Marjan Kerkhof, Manolis Kogevinas, Marek L. Kowalski, Bart N. Lambrecht, Susanne Lau, Karin C. Lødrup Carlsen, Dieter Maier, Isabelle Momas, Patricia Noel, Sam Oddie, Susanna Palkonen, Isabelle Pin, Daniela Porta, Antonello Punturieri, Fanny Rancière, Robert A. Smith, Barbara Stanic, Renato T. Stein, Willem van de Veen, Antoon J.M. van Oosterhout, Raphaelle Varraso, Magnus Wickman, Cisca Wijmenga, John Wright, Gorkem Yaman, Torsten Zuberbier, Jean Bousquet
Journal: Journal of Allergy and Clinical Immunology (2012)
New Insights into the Evolution of Metazoan Cadherins
Authors: P. Hulpiau, F. van Roy
Journal: Molecular Biology and Evolution (2010)

Mining newly sequenced genomes of basal metazoan organisms reveals the evolutionary origin of modern protein families. Specific cell–cell adhesion and intracellular communication are key processes in multicellular animals, and members of the cadherin superfamily are essential players in these processes. Mammalian genomes contain over 100 genes belonging to this superfamily. By a combination of tBLASTn and profile hidden Markov model analyses, we made an exhaustive search for cadherins and compiled the cadherin repertoires in key organisms, including Branchiostoma floridae (amphioxus), the sea anemone Nematostella vectensis, and the placozoan Trichoplax adhaerens. Comparative analyses of multiple protein domains within known and novel cadherins enabled us to reconstruct the complex evolution in metazoa of this large superfamily. Five main cadherin branches are represented in the primitive metazoan Trichoplax: classical (CDH), flamingo (CELSR), dachsous (DCHS), FAT, and FAT-like. Classical cadherins, such as E-cadherin, arose from an Urmetazoan cadherin, which progressively lost N-terminal extracellular cadherin repeats, whereas its cytoplasmic domain, which binds the armadillo proteins p120ctn and β-catenin, remained quite conserved from placozoa to man. The origin of protocadherins predates the Bilateria and is likely rooted in an ancestral FAT cadherin. Several but not all protostomians lost protocadherins. The emergence of chordates coincided with a great expansion of the protocadherin repertoire. The evolution of ancient metazoan cadherins points to their unique and crucial roles in multicellular animal life.