tbuckley/cabot-search huggingface dataset:
Sphingomyelinases: their regulation and roles in cardiovascular pathophysiology
Authors: Catherine Pavoine, Françoise Pecker
Journal: Cardiovascular Research (2009)

Sphingomyelinases (SMases) hydrolyse sphingomyelin, releasing ceramide and creating a cascade of bioactive lipids. These lipids include sphingosine and sphingosine-1-phosphate, all of which have a specific signalling capacity. Sphingomyelinase activation occurs in different cardiovascular system cell types, namely cardiac myocytes, endothelial and vascular smooth muscle cells, mediating cell proliferation, cell death, and contraction of cardiac and vascular myocytes. Three main types of SMases contribute to cardiovascular physiology: the lysosomal and secreted acidic SMases (L- and S-ASMases, respectively) and the membrane neutral SMase (NSMase). These three enzymes have common activators, including ischaemia/reperfusion stress and proinflammatory cytokines, but they differ in their enzymatic properties and subcellular locations that determine the final effect of enzyme activation. This review focuses on the recent advances in the understanding of ASMase and NSMase pathways and their specific contribution to cardiovascular pathophysiology. Current knowledge indicates that the inhibitors of the different SMase types are potential tools for the treatment of cardiovascular diseases. Acid SMase inhibitors could be tools against post-ischaemia reperfusion injury and in the treatment of atherosclerosis. Neutral SMase inhibitors could be tools for the treatment of atherosclerosis, heart failure, and age-related decline in vasomotion. However, the design of bioavailable and more specific SMase-type inhibitors remains a challenge.
Effect of Octreotide on Refractory AIDS-associated Diarrhea
Authors: John P. Cello, James H. Grendell, Paul Basuk, Douglas Simon, Louis Weiss, Murray Wittner, Richard P. Rood, C. Mel Wilcox, Chris E. Forsmark, Alexandra E. Read, Julie A. Satow, Cynthia S. Weikel, Cheryl Beaumont
Journal: Annals of Internal Medicine (1991)

▪ Objective: To determine the efficacy and safety of octreotide for treatment of refractory, profuse diarrhea in patients with the acquired immunodeficiency syndrome (AIDS). ▪ Design: A prospective, open-label study. ▪ Setting: Inpatient metabolic units of four university medical centers. ▪ Patients: Fifty-one patients infected with human immunodeficiency virus (HIV) who had uncontrolled diarrhea (≥ 500-mL liquid stool per day) despite treatment with maximally tolerable doses of antidiarrheal medications. ▪ Intervention: After initial baseline studies, patients received octreotide, 50 µg every 8 hours for 48 hours. If stool volume was not reduced to < 250 mL/d, the dose of octreotide was increased stepwise to 100, 250, and 500 µg. ▪ Main Results: Fifty men and one woman (mean age, 36.3 ± 1.1 years) entered and completed the 28-day protocol (14 days of inpatient therapy and 14 days of outpatient therapy). Stool frequency and volume decreased significantly (6.5 ± 0.5 stools per day on day 0 compared with 3.8 ± 0.3 stools per day on day 21 [P < 0.001] and 1604 ± 180 mL/d on day 0 compared with 1084 ± 162 mL/d on day 14 [P < 0.001], respectively). Twenty-one patients (41.2%) were considered to be partial or complete responders (reduction in daily stool volume by ≥ 50% of initial collections or reduction to ≤ 250 mL/d). Of the 21 responders, 14 (67%) had no identifiable pathogens at initial screening compared with 9 of 30 (30%) nonresponders (P < 0.01). ▪ Conclusion: Patients with AIDS-associated refractory watery diarrhea, especially those without identifiable pathogens, may respond favorably to subcutaneously administered octreotide. This drug deserves further study in a randomized, placebo-controlled trial.
Breakfast Frequency and Development of Metabolic Risk
Authors: Andrew O. Odegaard, David R. Jacobs, Lyn M. Steffen, Linda Van Horn, David S. Ludwig, Mark A. Pereira
Journal: Diabetes Care (2013)

The relation of breakfast intake frequency to metabolic health is not well studied. The aim of this study was to examine breakfast intake frequency with incidence of metabolic conditions.We performed an analysis of 3,598 participants from the community-based Coronary Artery Risk Development in Young Adults (CARDIA) study who were free of diabetes in the year 7 examination when breakfast and dietary habits were assessed (1992-1993) and participated in at least one of the five subsequent follow-up examinations over 18 years.Relative to those with infrequent breakfast consumption (0-3 days/week), participants who reported eating breakfast daily gained 1.9 kg less weight over 18 years (P=0.001). In a Cox regression analysis, there was a stepwise decrease in risk across conditions in frequent breakfast consumers (4-6 days/week) and daily consumers. The results for incidence of abdominal obesity, obesity, metabolic syndrome, and hypertension remained significant after adjustment for baseline measures of adiposity (waist circumference or BMI) in daily breakfast consumers. Hazard ratios (HRs) and 95% CIs for daily breakfast consumption were as follows: abdominal obesity HR 0.78 (95% CI 0.66-0.91), obesity 0.80 (0.67-0.96), metabolic syndrome 0.82 (0.69-0.98), and hypertension 0.84 (0.72-0.99). For type 2 diabetes, the corresponding estimate was 0.81 (0.63-1.05), with a significant stepwise inverse association in black men and white men and women but no association in black women. There was no evidence of differential results for high versus low overall dietary quality.Daily breakfast intake is strongly associated with reduced risk of a spectrum of metabolic conditions.
Intracranial Granulocytic Sarcoma After Chemotherapy for Pineal Germinoma and Testicular Cancer
Authors: Maria Grazia Passarin, Emanuela Vattemi, Anna Maria Musso, Silvia Romito, Giuseppe Moretto, Claudio Ghimenton, Paolo Iuzzolino, Claudio Doglioni, Rebecca Pedersini
Journal: Journal of Clinical Oncology (2008)
Control of Renin Secretion From Rat Juxtaglomerular Cells by cAMP-Specific Phosphodiesterases
Authors: Ulla G. Friis, Boye L. Jensen, Shala Sethi, Ditte Andreasen, Pernille B. Hansen, Ole Skøtt
Journal: Circulation Research (2002)

We tested the hypothesis that cGMP stimulates renin release through inhibition of the cAMP-specific phosphodiesterase 3 (PDE3) in isolated rat juxtaglomerular (JG) cells. In addition, we assessed the involvement of PDE4 in JG-cell function. JG cells expressed PDE3A and PDE3B, and the PDE3 inhibitor trequinsin increased cellular cAMP content, enhanced forskolin-induced cAMP formation, and stimulated renin release from incubated and superfused JG cells. Trequinsin-mediated stimulation of renin release was inhibited by the permeable protein kinase A antagonist Rp-8-CPT-cAMPS. PDE4C was also expressed, and the PDE4 inhibitor rolipram enhanced cellular cAMP content. Dialysis of single JG cells with cAMP in whole-cell patch-clamp experiments led to concentration-dependent, biphasic changes in cell membrane capacitance (C(m)) with a marked increase in C(m) at 1 micromol/L, no net change at 10 micromol/L, and a decrease at 100 micromol/L cAMP. cGMP also had a dual effect on C(m) at 10-fold higher concentration compared with cAMP. Trequinsin, milrinone, and rolipram mimicked the effect of cAMP on C(m). Trequinsin, cAMP, and cGMP enhanced outward current 2- to 3-fold at positive membrane potentials. The effects of cAMP, cGMP, and trequinsin on C(m) and cell currents were abolished by inhibition of protein kinase A with Rp-cAMPs. We conclude that degradation of cAMP by PDE3 and PDE4 contributes to regulation of renin release from JG cells. Our data provide evidence at the cellular level that stimulation of renin release by cGMP involves inhibition of PDE3 resulting in enhanced cAMP formation and activation of the cAMP sensitive protein kinase.
Combined Steroid Treatment for Congenital Heart Surgery Improves Oxygen Delivery and Reduces Postbypass Inflammatory Mediator Expression
Authors: Valerie A. Schroeder, Jeffery M. Pearl, Steven M. Schwartz, Thomas P. Shanley, Peter B. Manning, David P. Nelson
Journal: Circulation (2003)

Background— Steroid administration during cardiopulmonary bypass is thought to improve cardiopulmonary function by modulating bypass-related inflammation. This study was designed to compare preoperative and intraoperative methylprednisolone (MP) to intraoperative MP alone with respect to postbypass inflammation and clinical outcome. Methods and Results— Twenty-nine pediatric patients undergoing bypass procedures were randomly assigned to receive preoperative and intraoperative MP (30 mg/kg 4 hours before bypass and in bypass prime, n=14) or intraoperative MP only (30 mg/kg, n=15). Myocardial inflammatory mediator mRNA expression was determined in paired atrial biopsies (before and after bypass) by ribonuclease protection. Before and after bypass, serum IL-6 and IL-10 were measured by ELISA. Postoperative outcome was assessed by intubation time, CICU length of stay, fluid balance, arterio-venous O 2 difference (ΔA−V o 2 ), and inotrope requirements. Compared with intraoperative MP alone, combined preoperative and intraoperative MP was associated with reduced myocardial mRNA expression for IL-6, MCP-1, and ICAM-1 both before and after bypass ( P &lt;0.05). Patients who received combined steroids had lower serum IL-6 and increased IL-10 at end-bypass ( P &lt;0.05), although differences were negligible by 24 hours. Combined MP treatment was associated with reduced fluid requirements, lower body temperature, and lower ΔA−V o 2 for the first 24 hours after surgery ( P &lt;0.05), along with trends toward improvement in other clinical outcomes. Conclusions— Compared with intraoperative steroid treatment, combined preoperative and intraoperative steroid administration attenuates inflammatory mediator expression more effectively and is associated with improved indexes of O 2 delivery in the first 24 hours after congenital heart surgery. These findings need to be confirmed in a larger multicenter trial.
Immunomodulation by interference with co-stimulatory molecules: therapeutic perspectives in asthma
Authors: S. E Burastero, G. A Rossi
Journal: Thorax (1999)

In allergic asthma, allergen specific T lymphocytes of the CD4 subset (T helper or Th cells) control the cellular and molecular events underlying the establishment and chronic maintenance of airway inflammation that characterises the disease. The basic immunological event is the shift of allergen reactive CD4 Th lymphocytes towards a Th2 phenotype with the production of Th2 cytokines such as interleukin (IL)-4, IL-13, and IL-5. Th2 cells can support both allergen specific IgE production and eosinophil recruitment.

Recognition of allergen via the T cell receptor (TcR) provides the trigger for a specific T cell response; as any antigen, allergen is seen by Th cells as one of a few possible peptides derived from proteolytic processing. Immunogenic peptides are presented on major histocompatibility complex (MHC) molecules expressed on the membrane of antigen presenting cells. However, antigen recognition can follow such opposite events as anergy or activation of T cells—that is, induction of tolerance versus establishment of an effective immune response. Current concepts recognise that the outcome of antigen recognition is dependent, at least in part, on the complex interaction between MHC molecule associated membrane proteins (collectively known as co-stimulatory molecules) on the antigen presenting cells and their ligands on the T cells. Moreover, when the immune response is activated, co-stimulation is also involved in determining which effector profile will be acquired by the T cells—that is, a Th1 or a Th2 phenotype.

We will briefly review the experimental evidence supporting the concept that interference with the proper co-stimulatory molecules may allow the design of pharmaceutical products which cause immune deviation that could quantitatively and qualitatively change the T cell response. This approach could interfere with the chronic amplification of allergic inflammation at the level of the target organ in atopic individuals.

Alveolar macrophages and dendritic cells are resident phagocytes in the …
c-Src Activation Mediates Erlotinib Resistance in Head and Neck Cancer by Stimulating c-Met
Authors: Laura P. Stabile, Guoqing He, Vivian Wai Yan Lui, Sufi M. Thomas, Cassandra Henry, Christopher T. Gubish, Sonali Joyce, Kelly M. Quesnelle, Jill M. Siegfried, Jennifer R. Grandis
Journal: Clinical Cancer Research (2012)

Strategies to inhibit the EGF receptor (EGFR) using the tyrosine kinase inhibitor erlotinib have been associated with limited clinical efficacy in head and neck squamous cell carcinoma (HNSCC). Co-activation of alternative kinases may contribute to erlotinib resistance.We generated HNSCC cells expressing dominant-active c-Src (DA-Src) to determine the contribution of c-Src activation to erlotinib response.Expression of DA-Src conferred resistance to erlotinib in vitro and in vivo compared with vector-transfected control cells. Phospho-Met was strongly upregulated by DA-Src, and DA-Src cells did not produce hepatocyte growth factor (HGF). Knockdown of c-Met enhanced sensitivity to erlotinib in DA-Src cells in vitro, as did combining a c-Met or c-Src inhibitor with erlotinib. Inhibiting EGFR resulted in minimal reduction of phospho-Met in DA-Src cells, whereas complete phospho-Met inhibition was achieved by inhibiting c-Src. A c-Met inhibitor significantly sensitized DA-Src tumors to erlotinib in vivo, resulting in reduced Ki67 labeling and increased apoptosis. In parental cells, knockdown of endogenous c-Src enhanced sensitivity to erlotinib, whereas treatment with HGF to directly induce phospho-Met resulted in erlotinib resistance. The level of endogenous phospho-c-Src in HNSCC cell lines was also significantly correlated with erlotinib resistance.Ligand-independent activation of c-Met contributes specifically to erlotinib resistance, not cetuximab resistance, in HNSCC with activated c-Src, where c-Met activation is more dependent on c-Src than on EGFR, providing an alternate survival pathway. Addition of a c-Met or c-Src inhibitor to erlotinib may increase efficacy of EGFR inhibition in patients with activated c-Src.
Effect of air pollution on lung cancer: a Poisson regression model based on vital statistics.
Authors: T Tango
Journal: Environmental Health Perspectives (1994)

This article describes a Poisson regression model for time trends of mortality to detect the long-term effects of common levels of air pollution on lung cancer, in which the adjustment for cigarette smoking is not always necessary. The main hypothesis to be tested in the model is that if the long-term and common-level air pollution had an effect on lung cancer, the death rate from lung cancer could be expected to increase gradually at a higher rate in the region with relatively high levels of air pollution than in the region with low levels, and that this trend would not be expected for other control diseases in which cigarette smoking is a risk factor. Using this approach, we analyzed the trend of mortality in females aged 40 to 79, from lung cancer and two control diseases, ischemic heart disease and cerebrovascular disease, based on vital statistics in 23 wards of the Tokyo metropolitan area for 1972 to 1988. Ward-specific mean levels per day of SO2 and NO2 from 1974 through 1976 estimated by Makino (1978) were used as the ward-specific exposure measure of air pollution. No data on tobacco consumption in each ward is available. Our analysis supported the existence of long-term effects of air pollution on lung cancer.
<i>RUNX1</i> Mutations in Acute Myeloid Leukemia: Results From a Comprehensive Genetic and Clinical Analysis From the AML Study Group
Authors: Verena I. Gaidzik, Lars Bullinger, Richard F. Schlenk, Andreas S. Zimmermann, Jürgen Röck, Peter Paschka, Andrea Corbacioglu, Jürgen Krauter, Brigitte Schlegelberger, Arnold Ganser, Daniela Späth, Andrea Kündgen, Ingo G.H. Schmidt-Wolf, Katharina Götze, David Nachbaur, Michael Pfreundschuh, Heinz A. Horst, Hartmut Döhner, Konstanze Döhner
Journal: Journal of Clinical Oncology (2011)

The tet oncogene family member 2 (TET2) gene was recently identified to be mutated in myeloid disorders including acute myeloid leukemia (AML). To date, there is increasing evidence for a functional role of TET2 mutations (TET2(mut)) in AML. Thus, we explored the frequency, gene-expression pattern, and clinical impact of TET2(mut) in a large cohort of patients with AML in the context of other AML-associated aberrations.Samples from 783 younger adult patients with AML were analyzed for the presence of TET2(mut) (coding exons 3 to 11), and results were correlated with data from molecular genetic analyses, gene-expression profiling, and clinical outcome.In total, 66 TET2(mut) were found in 60 patients (60 of 783 patients; 7.6%), including missense (n = 37), frameshift (n = 16), and nonsense (n = 13) mutations, which, with one exception, were all heterozygous. TET2(mut) were not correlated with distinct clinical features or genetic alterations, except for isocitrate dehydrogenase mutations (IDH(mut)) that were almost mutually exclusive with TET2(mut) (P < .001). TET2(mut) were characterized by only a weak gene-expression pattern, which, nevertheless, reflected TET2(mut)-associated biology. TET2(mut) did not impact the response to induction therapy and clinical outcome; the combination of patients who exhibited TET2(mut) and/or IDH(mut) revealed shorter overall survival (P = .03), although this association was not independent from known risk factors.TET2(mut) were identified in 7.6% of younger adult patients with AML and did not impact the response to therapy and survival. Mutations were mutually exclusive with IDH(mut), which supported recent data on a common mechanism of action that might obscure the impact of TET2(mut) if compared against all other patients with AML.
Multiple Sclerosis: A Review
Authors: Marvin M Goldenberg
Journal: BMJ (1973)

5and 50% of patients will need help walking within 15 years after the onset of the disease. 6 Twice as many women are affected as men, and persons of Northern European descent appear to be at highest risk for MS. 2,7 The disease is diagnosed on the basis of clinical findings and supporting evidence from ancillary tests, such as magnetic resonance imaging (MRI) of the brain and examination of the cerebrospinal fluid (CSF). MS typically presents in adults 20 to 45 years of age; occasionally, it presents in childhood or late middle age. 7
Behavior of Vascular Beds In the Human Upper Limb at Low Perfusion Pressure
Authors: GEOFFREY M. COLLINS, JOHN LUDBROOK
Journal: Circulation Research (1967)

A technique of venous occlusion pressure plethysmography was used to examine the behavior of blood flow in the hand and forearm during reduced perfusion pressure. The trend of flow following sudden reduction in perfusion pressure was recorded, and steady-state pressure-flow curves were constructed. Epinephrine iontophoresis allowed discrimination between forearm skin and muscle blood flow. Pressure-flow curves for the hand were parabolic, convex to the pressure axis, and passing close to the zero point. There was no progressive change in flow once perfusion pressure and flow were initially reduced. Autoregulation was evident in forearm muscle and was more marked in chronically sympathectomized limbs. When perfusion pressure was reduced, blood flow fell, then rose to a new, steady level. Pressure-flow curves were concave to the pressure axis and intersected it at close to zero.
C-1027, A Radiomimetic Enediyne Anticancer Drug, Preferentially Targets Hypoxic Cells
Authors: Terry A. Beerman, Loretta S. Gawron, Seulkih Shin, Ben Shen, Mary M. McHugh
Journal: Cancer Research (2009)

Abstract The hypoxic nature of cells within solid tumors limits the efficacy of anticancer therapies such as ionizing radiation and conventional radiomimetics because their mechanisms require oxygen to induce lethal DNA breaks. For example, the conventional radiomimetic enediyne neocarzinostatin is 4-fold less cytotoxic to cells maintained in low oxygen (hypoxic) compared with normoxic conditions. By contrast, the enediyne C-1027 was nearly 3-fold more cytotoxic to hypoxic than to normoxic cells. Like other radiomimetics, C-1027 induced DNA breaks to a lesser extent in cell-free, or cellular hypoxic, compared with normoxic environments. However, the unique DNA interstrand cross-linking ability of C-1027 was markedly enhanced under the same hypoxic conditions that reduced its DNA break induction. Although the unique chemistry of C-1027 allows it to concurrently generate both DNA breaks and cross-links in normoxic cells, a low oxygen environment represses the former and promotes the latter. Thus, treatment with C-1027 offers a facile approach for overcoming the radioresistance associated with poorly oxygenated cells. [Cancer Res 2009;69(2):OF593–6]
A Method of Treating Infundibular Pulmonary Stenosis
Authors: A. Temesvari
Journal: Thorax (1958)

Valvular and infundibular stenosis of the pulmonary outflow tract can be treated by open resection of the obstructing tissue. In consequence operations of the type devised by Blalock are not as popular as they were. The desired results can be obtained, by techniques similar to that described by Brock, whether the circulation is temporarily arrested or not. But the most successful cases are those in which the obstruction is muscular and only involves a short segment of the outflow tract. In the latter the stenosis can be relieved by opening the right ventricle, and by removing the bar of muscle adjacent to the ventricular septum. This obstructing diaphragm can also be eliminated by cutting through its anterior wall. Kirklin, operating in 1953, was the first surgeon to succeed in this way (Kirklin, Openshaw, and Tompkins, 1953). He cut through the stenosis by using a wire which disrupted the continuity of the muscle fibres. Kirklin's method has the disadvantage that it leaves a scar after the wound in the heart has been closed, and this becomes undesirable if a long segment of the infundibular muscle is involved. Indeed, in the latter circumstances the method is not feasible. To meet these difficulties we have developed a technique (Temesvdri, 1955a and b), the essentials of which are that we cut out a piece of the obstructing ventricular wall, 3 to 4 mm. in width, and cover the defect thus created with a fullthickness skin graft. The stenosis is alleviated not only because some of the obstructing tissue is removed but also because the grafted area expands during systole. Before trying this operation in man, we carried out many animal experiments to determine how much of the right ventricular wall could be removed without impairing its function as a pump, and we found that excisions of the dimensions described had no injurious effect. We also compared the healing qualities of free and attached grafts and came to the conclusion that free grafts healed well. In some of these experiments the pulmonary artery was partially occluded to raise the pressure in the right ventricle, and under these circumstances the grafts healed well and aneurysms did not form. None of the grafts ruptured.
THE PHYSICAL AND PSYCHOLOGICAL ASPECTS OF ENVIRONMENT ESSENTIAL TO THE TREATMENT OF TRAUMATIC NEUROSES OF WAR
Authors: HOWARD W. POTTER
Journal: American Journal of Psychiatry (1943)

The treatment of traumatic neuroses of war should be conceived as a total therapy designed to affect, regulate or modulate all aspects of the psycho-biological organism and its environmental relationships and impacts. Any and every individual, physician, nurse, social worker and others should clearly understand that these patients are suffering from a most complex form of insecurity which has its medical, psychological and social symptomalologies. These patients are best treated in an environment which combines the atmosphere of a home, a personally supervised work-recreation program, prompt personal attention to everything that promotes good mental and physical health and a genuine sensible personal interest in each patient by every person in contact with them regularly during their stay in the convalescent center.