tbuckley/cabot-search huggingface dataset:
Viral vectors expressing immunoregulatory cytokines to treat inflammatory bowel disease
Authors: T. T MACDONALD
Journal: Gut (1998)

Inflammatory bowel disease (IBD) is characterised by altered immunoregulation and augmented synthesis of nitric oxide. The purpose of this study was to determine the effects of exogenous IL-4, introduced by a recombinant human type 5 adenovirus (Ad5) vector, on the tissue injury associated with an experimental model of colonic immune activation and inflammation. Colitis was induced in rats by the intrarectal administration of trinitrobenzene sulfonic acid (TNB) dissolved in 50% ethanol, and control rats received saline via the same route. 1 h later, all rats were randomized into two groups. The first group was injected intraperitoneally (i.p.) with 3.0 x 10(6) plaque forming units (PFUs) of Ad5 transfected with murine interleukin-4 (Ad5IL-4) and the second group was injected i.p. with the same amount of Ad5 expressing the Escherichia coli Lac Z gene (Ad5LacZ). One-half of the colitic and controls rats were injected again with 3.0 x 10(6) PFUs of Ad5IL-4 or Ad5LacZ on day 3 of the 6-d study. When introduced once or twice via the peritoneal route into control rats Ad5LacZ was localised to the serosal lining of the peritoneal cavity, the diaphragm and the liver on day 6. One or two injections of Ad5IL-4 into rats also produced measurable levels of circulating IL-4. TNB-colitis in both Ad5LacZ-treated groups was associated with pronounced elevations in serum IFN-gamma, and mucosal ulceration of the distal colon. Myeloperoxidase and inducible nitric oxide synthase II (NOS II) synthetic activity were also increased by 30- and fivefold, respectively, above control levels in the distal colon. However, two injections of AD5IL-4 into colitic rats caused the overexpression of IL-4, and significantly inhibited tissue damage, serum and colon IFN-gamma levels and myeloperoxidase activity in the distal colon. In addition, NOS II gene expression and NOS II nitric oxide synthesis was significantly inhibited. No therapeutic effect was observed in rats injected once with AD5IL-4. Thus, IL-4, introduced by Ad5, is therapeutic during acute inflammation in the rat colon. The therapeutic effect of IL-4 was associated with an inhibition of inducible nitric oxide expression and a reduction in nitric oxide synthesis.
Upregulation of Heat Shock Transcription Factor 1 Plays a Critical Role in Adaptive Cardiac Hypertrophy
Authors: Masaya Sakamoto, Tohru Minamino, Haruhiro Toko, Yosuke Kayama, Yunzeng Zou, Masanori Sano, Eiichi Takaki, Teruhiko Aoyagi, Katsuyoshi Tojo, Naoko Tajima, Akira Nakai, Hiroyuki Aburatani, Issei Komuro
Journal: Circulation Research (2006)

Exercise-induced cardiac hypertrophy has been reported to have better prognosis than pressure overload-induced cardiac hypertrophy. Cardiac hypertrophy induced by exercise was associated with less cardiac fibrosis and better systolic function, suggesting that the adaptive mechanisms may exist in exercise-induced hypertrophy. Here, we showed a critical role of heat shock transcription factor 1 (HSF1), an important transcription factor for heat shock proteins, in the adaptive mechanism of cardiac hypertrophy. We examined expression of 8800 genes in the heart of exercise-induced hypertrophy model using DNA chip technique and compared with pressure overload-induced hypertrophy. Expression of HSF1 and its target molecule heat shock proteins was significantly upregulated in the heart by exercise but not by chronic pressure overload. Constitutive activation of HSF1 in the heart significantly ameliorated death of cardiomyocytes and cardiac fibrosis and thereby prevented cardiac dysfunction as well as hypertrophy induced by chronic pressure overload. Conversely, decreased activity of HSF1 in the heart promoted cardiac dysfunction in response to exercise, a load that normally leads to adaptive hypertrophy with preserved systolic function. Likewise, cardiac function was significantly impaired from the early phase of pressure overload, when HSF1 activation was inhibited. These results suggest that HSF1 plays a critical role in the transition between adaptive and maladaptive hypertrophy.
Survival in hemodialysis patients
Authors: P L Kimmel, K Weihs, R A Peterson
Journal: Journal of the American Society of Nephrology (1993)

Depression has been identified at the most prevalent psychologic problem in patients with ESRD treated with hemodialysis (HD). Depression has been associated with mortality in HD patients; however, the similarity of the symptoms of depressive disorders to those of uremia and the difficulties in measuring depression and dissociating psychologic from physical aspects of depression in such patients render these studies difficult to evaluate. Conflicting data regarding the effects of depression on survival in HD patients may be the result of using somatic symptoms in quantifying the extent of depression. In this review, studies regarding the diagnosis of depression in HD patients, the association of depression and survival in HD patients in light of recent work on factors related to the morbidity and mortality in the ESRD population, and aspects of therapy for depression in HD patients are considered. Specifically, depression may affect immunologic function, nutrition, and compliance factors that may affect the prescription and delivery of dialysis, which may, in turn, influence outcome. Alternatively, depression may be an independent factor in influencing survival. Cognitive depression measures may be more useful in predicting outcome in HD patients than standard measures used in nonmedically ill populations. Although there are few studies of the effect of treatment of depression on outcome in HD patients, it is reasonable to hypothesize that treatment of depressive disorders in HD patients might effect outcome. Further studies on the association of depression and its treatment and mortality in ESRD patients are warranted.
Upper-Extremity Deep Vein Thrombosis
Authors: Hylton V. Joffe, Samuel Z. Goldhaber
Journal: Circulation (2002)

U pper-extremity deep vein thrombosis (UEDVT) is an increasingly important clinical entity with potential for considerable morbidity.Pulmonary embolism (PE) is present in up to one third of patients with UEDVT. 1 Other complications, such as persistent upper-extremity pain and swelling, the superior vena cava (SVC) syndrome, and loss of vascular access, can be disabling and devastating. 2Although once considered rare, UEDVT has become more common over the past several decades.This is directly related to the increasing use of central venous catheters for chemotherapy, bone marrow transplantation, dialysis, and parenteral nutrition.UEDVT has been reported in up to one fourth of patients with these catheters. 3For these reasons, it is imperative that physicians understand UEDVT risk factors, diagnostic options, treatment alternatives, and prophylaxis regimens. PathogenesisUEDVT most commonly refers to thrombosis of the axillary and/or subclavian veins.UEDVT is classified as primary or secondary on the basis of pathogenesis.
Polymethylene tetraamine backbone as template for the development of biologically active polyamines
Authors: Carlo Melchiorre, Alessandra Antonello, Rita Banzi, Maria Laura Bolognesi, Anna Minarini, Michela Rosini, Vincenzo Tumiatti
Journal: Medicinal Research Reviews (2002)

Abstract The concept that polyamines may represent a universal template in the receptor recognition process is embodied in the design of ligands for different biological targets. As a matter of fact, the insertion of different pharmacophores onto the polymethylene tetraamine backbone can tune both affinity and selectivity for any given receptor. The application of this approach provided a prospect of modifying benextramine ( 1 ) structure to achieve specific recognition of muscarinic receptors that led to the discovery of methoctramine ( 2 ), which is widely used as a pharmacological tool for muscarinic receptor characterization. In turn, appropriate structural modifications performed on the structure of methoctramine led to the discovery of new polyamines endowed with high affinity and selectivity for (a) muscarinic receptor subtypes, (b) G i proteins, and (c) muscle‐type nicotinic receptors. Thus, polyamines tripitramine ( 9 ) and spirotramine ( 33 ), among others, were designed, which were shown to be highly selective for muscarinic M 2 and M 1 receptors, respectively. Several polyamines have been discovered, which inhibit noncompetitively a closed state of the nicotinic receptor. These ligands, such as 66 , resulted in important tools for elucidating the mode and site of interaction of polyamines with the ion channel. It was discovered that reducing the flexibility of the diaminohexane spacer of methoctramine led to polyamines, such as 70 , which are endowed with a biological profile significantly different from that of the prototype. Most likely, tetraamine ( 70 ) is a potent activator of G i proteins. Finally, the universal template approach formed the basis for modifying benextramine ( 1 ) structure to the design of ligands, which display affinity for acetylcholinesterase and muscarinic M 2 receptors. Thus, these polyamines, such as caproctamine ( 78 ), could have potential in the investigation of Alzheimer disease. © 2002 Wiley Periodicals, Inc. Med Res Rev, 23, No. 2, 200–233, 2003
Interleukin 6 promotes murine lupus in NZB/NZW F1 mice.
Authors: B K Finck, B Chan, D Wofsy
Journal: Journal of Clinical Investigation (1994)

To investigate the role of IL-6 in systemic lupus erythematosus (SLE), we selectively inhibited IL-6 in lupus-prone NZB/NZW F1(B/W) mice by chronic administration of a rat mAb to mouse IL-6. Anti-IL-6 alone elicited an anti-rat response that blocked its biologic effects. To circumvent this problem, we rendered B/W mice tolerant to the rat mAb by administration of anti-CD4 concurrent with the first dose of anti-IL-6. Thereafter, the mice received weekly injections of anti-IL-6 alone. There were two control groups: one group received the tolerizing regimen of anti-CD4 along with a control rat IgG1 mAb (GL113) instead of anti-IL-6; the other control group received PBS. Mice that received anti-CD4 were tolerant to the rat mAb for 6 mo. Throughout this period, treatment with anti-IL-6 prevented production of anti-dsDNA, significantly reduced proteinuria, and prolonged life. Mice that received anti-IL-6 without anti-CD4 developed an immune response to the rat mAb and then developed anti-dsDNA antibodies, proteinuria, and mortality comparable with control mice. These findings establish that IL-6 promotes autoimmunity in B/W mice. They further indicate that, although mAb to IL-6 can suppress murine lupus, the development of host immunity to the mAb abrogates its beneficial effects. Finally, this is the first study to demonstrate that a brief course of anti-CD4 can induce tolerance to another therapeutic mAb, in this case an anti-cytokine mAb.
Mode and place of delivery, gastrointestinal microbiota, and their influence on asthma and atopy
Authors: Frederika A. van Nimwegen, John Penders, Ellen E. Stobberingh, Dirkje S. Postma, Gerard H. Koppelman, Marjan Kerkhof, Naomi E. Reijmerink, Edward Dompeling, Piet A. van den Brandt, Isabel Ferreira, Monique Mommers, Carel Thijs
Journal: Journal of Allergy and Clinical Immunology (2011)
Ditiocarb Sodium (Diethyldithiocarbamate) Therapy in Patients With Symptomatic HIV Infection and AIDS
Authors: Evan M. Hersh
Journal: JAMA (1991)

We randomized 389 symptomatic patients with human immunodeficiency virus (HIV) infection to ditiocarb sodium (400 mg/m2 orally for 24 weeks) or a placebo. Patients were well balanced according to Centers for Disease Control (CDC) group, CD4+ cell number, and duration of disease prior to entry. Ten new acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections occurred in the treated patients and 21 in the controls. Reduction of new opportunistic infections in the ditiocarb group was significant in all patients (relative risk [RR], 0.44) and in patients with AIDS (CDC groups IV-C1 and IV-D) (RR, 0.12). The size of the effect of ditiocarb was maintained when data were reanalyzed after exclusion of a patient who progressed to Pneumocystis carinii pneumonia who was not strictly CDC-defined (RR, 0.46), or when considering as new opportunistic infections three events, which were clinically active at entry, but for which the definitive diagnosis was made during study (RR, 0.49). The administration of ditiocarb did not induce any major adverse clinical or biological reactions. We conclude that, in this study, ditiocarb was safe and reduced the incidence of opportunistic infections in patients with symptomatic HIV infection.
Thinking About the Human Neuron Mouse
Authors: Henry T. Greely, Mildred K. Cho, Linda F. Hogle, Debra M. Satz
Journal: The American Journal of Bioethics (2007)

Click to increase image sizeClick to decrease image size Acknowledgment: The authors wish to thank Professor Bill Newsome, our colleague on the working group and an extremely valuable contributor to the initial report; Dr. Irving Weissman, for giving us this opportunity and for his subsequent comments; an anonymous (and kind) referee; and Professor Greely's research assistant, Sean Rodriguez.
Evaluation of early abdominopelvic computed tomography in patients with acute abdominal pain of unknown cause: prospective randomised study
Authors: Chaan S Ng, Christopher J E Watson, Christopher R Palmer, Teik Choon See, Nigel A Beharry, Barbara A Housden, J Andrew Bradley, Adrian K Dixon
Journal: BMJ (2002)

<h3>Abstract</h3> <b>Objectives:</b> To evaluate the impact of early abdominopelvic computed tomography in patients with acute abdominal pain of unknown cause on length of hospital stay and accuracy of diagnosis. <b>Design:</b> Randomised, prospective controlled trial. <b>Setting:</b> Teaching hospital in England. <b>Participants:</b> 120 patients admitted with acute abdominal pain for which no immediate surgical intervention or computed tomography was indicated. <b>Intervention:</b> 55 participants were prospectively randomised to early computed tomography (within 24 hours of admission) and 65 to standard practice (radiological investigations as indicated). <b>Main outcome measures:</b> Length of hospital stay, accuracy of diagnosis, and, owing to a possible effect on inpatient mortality, deaths during the study. <b>Results:</b> Early computed tomography reduced the length of hospital stay by 1.1 days (geometric mean 5.3 days (range 1 to 31) <i>v</i> 6.4 days (1 to 60)), but the difference was non-significant (95% confidence interval, 8% shorter stay to 56% longer stay, P=0.17). Early computed tomography missed significantly fewer serious diagnoses. Seven inpatients in the standard practice arm died. Only 50% (59 of 118) of diagnoses on admission were correct at follow up at 6 months, but this improved to 76% (90) of diagnoses after 24 hours. <b>Conclusions:</b> Early abdominopelvic computed tomography for acute abdominal pain may reduce mortality and length of hospital stay. It can also identify unforeseen conditions and potentially serious complications. <h3>What is already known on this topic</h3> Computed tomography improves the accuracy of diagnosis of several acute abdominal conditions Uncontrolled studies have shown improvements in accuracy of diagnosis after computed tomography; none have described an effect on mortality <h3>What this study adds</h3> Early abdominopelvic computed tomography for acute abdominal pain can identify unforeseen serious abdominal conditions It may also reduce length of hospital stay and might reduce inpatient mortality
Apoptosis in podocytes induced by TGF-β and Smad7
Authors: Mario Schiffer, Markus Bitzer, Ian S.D. Roberts, Jeffrey B. Kopp, Peter ten Dijke, Peter Mundel, Erwin P. Böttinger
Journal: Journal of Clinical Investigation (2001)

Primary and secondary forms of focal segmental glomerulosclerosis (FSGS) are characterized by depletion of podocytes and constitute a central manifestation of chronic progressive glomerular diseases. Here we report that podocytes undergo apoptosis at early stages in the course of progressive glomerulosclerosis in TGF-β1 transgenic mice. Apoptosis is associated with progressive depletion of podocytes and precedes mesangial expansion. Smad7 protein expression is strongly induced specifically in damaged podocytes of transgenic mice and in cultured murine podocytes treated with TGF-β. TGF-β1 and Smad7 each induce apoptosis in podocytes, and their coexpression has an additive effect. Activation of p38 MAP kinase and caspase-3 is required for TGF-β–mediated apoptosis, but not for apoptosis induced by Smad7. Unlike TGF-β, Smad7 inhibits nuclear translocation and transcriptional activity of the cell survival factor NF-κB. Our results suggest a novel functional role for Smad7 as amplifier of TGF-β−induced apoptosis in podocytes and a new pathomechanism for podocyte depletion in progressive glomerulosclerosis.
Population-Based Study of Incidence and Outcome of Acute Aortic Dissection and Premorbid Risk Factor Control
Authors: Dominic P.J. Howard, Amitava Banerjee, Jack F. Fairhead, Jeremy Perkins, Louise E. Silver, Peter M. Rothwell
Journal: Circulation (2013)

Background— Acute aortic dissection is a preventable life-threatening condition. However, there have been no prospective population-based studies of incidence or outcome to inform an understanding of risk factors, strategies for prevention, or projections for future clinical service provision. Methods and Results— We prospectively determined incidence and outcomes of all acute aortic dissections in a population of 92 728 in Oxfordshire, United Kingdom, from 2002 to 2012. Among 155 patients with 174 acute aortic events, 54 patients had 59 thoracoabdominal aortic dissections (52 incident events: 6/100 000, 95% confidence interval, 4–7; 37 Stanford type A, 15 Stanford type B; 31 men, mean age=72.0 years). Among patients with type A incident events, 18 (48.6%) died before hospital assessment (61.1% women). The 30-day fatality rate was 47.4% for patients with type A dissections who survived to hospital admission and 13.3% for patients with type B dissections, although subsequent 5-year survival rates were high (85.7% for type A; 83.3% for type B). Even though 67.3% of patients were on antihypertensive drugs, 46.0% of all patients had at least 1 systolic BP ≥180 mm Hg in their primary care records over the preceding 5 years, and the proportion of blood pressures in the hypertensive range (&gt;140/90 mm Hg) averaged 56.0%. Premorbid blood pressure was higher in patients with type A dissections that were immediately fatal than in those who survived to admission (mean/standard deviation pre-event systolic blood pressure=151.2/19.3 versus 137.9/17.9; P &lt;0.001). Conclusions— Uncontrolled hypertension remains the most significant treatable risk factor for acute aortic dissection. Prospective population-based ascertainment showed that hospital-based registries will underestimate not only incidence and case fatality, but also the association with premorbid hypertension.
Neurocognitive functioning in adult WHO grade II gliomas: impact of old and new treatment modalities
Authors: M. Klein
Journal: Neuro-Oncology (2012)

In the treatment of patients with low-grade glioma, there still is controversy on how surgical intervention, radiation therapy, and chemotherapy contribute to an ameliorated progression-free survival, overall survival, and treatment-related neurotoxicity. With the ongoing changes in treatment options for these patients, neurocognitive functioning is an increasingly important outcome measure, because neurocognitive impairments can have a large impact on self-care, social and professional functioning, and consequently, health-related quality of life. Many factors contribute to neurocognitive outcome, such as direct and indirect tumor effects, seizures, medication, and oncological treatment. Although the role of radiotherapy has been studied extensively, the adverse effects on neurocognitive function of other treatment-related factors remain elusive. This holds for both resective surgery, in which the use of intraoperative stimulation mapping has a high potential benefit concerning survival and patient functioning, and the use of chemotherapy that might have some interesting new applications, such as the facilitation of total resection for initially primary or recurrent diffuse low-grade glioma tumors. This article will discuss these treatment options in patients with low-grade glioma and their potential effects on neurocognitive functioning.
Antiviral treatment of hepatitis C
Authors: E. R. Feeney, R. T. Chung
Journal: BMJ (2014)

Hepatitis C virus (HCV) infection is a substantial health problem worldwide. Most patients infected with HCV remain chronically infected, with an increased risk of cirrhosis and hepatocellular carcinoma. Although they are associated with toxicities and low sustained viral response rates, interferon alfa and ribavirin have been the mainstay of treatment until recently. New direct acting antivirals, specifically designed to inhibit three viral proteins (the NS3/4A protease, the NS5A protein, and the NS5B RNA dependent RNA polymerase) are now becoming available. The NS3/4A inhibitor simeprevir and NS5B inhibitor sofosbuvir have recently been licensed and can reduce the length of antiviral treatment, improve response rates, and allow for interferon-free regimens for some HCV genotypes. Several other newer direct acting antivirals have shown promise in clinical studies and are likely to be licensed soon. These agents seem to facilitate the use of shortened courses of combination interferon-free therapy, which are associated with high (&gt;95%) sustained response rates and relatively few toxicities. These regimens have also been successful in patients who were previously difficult to treat, including those with cirrhosis, HIV coinfection, and those who have undergone liver transplantation. The high cost of these agents may be the biggest challenge to their implementation worldwide.
Quantitative Analysis of Biomarkers Defines an Optimal Biological Dose for Recombinant Human Endostatin in Primary Human Tumors
Authors: Darren W. Davis, Yu Shen, Nizar A. Mullani, Sijin Wen, Roy S. Herbst, Michael O’Reilly, James L. Abbruzzese, David J. McConkey
Journal: Clinical Cancer Research (2004)

Abstract Purpose: In a recent study, we presented preliminary evidence for biological activity in a Phase I dose-finding study (15–600 mg/m2) of recombinant human endostatin in patients with refractory solid tumors. Here, we conducted additional biomarker analyses to correlate changes in tumor biology with dose. Experimental Design: Excisional tumor biopsies were obtained at baseline and after 56 days of endostatin therapy. Laser scanning cytometry (LSC) was used to quantify biomarker levels in whole tissue sections. Apoptosis in tumor cells (TCs) and tumor-associated endothelial cells (ECs) was quantified by fluorescent three-color anti-CD31/terminal deoxynucleotidyl transferase-mediated nick end labeling staining. Microvessel densities were measured by LSC-guided vessel contouring. Levels of tumor-associated EC BCL-2 and hypoxia-inducible factor 1α were determined by immunofluorescence and LSC quantification. The results, including tumor blood flow measured by positron emission tomography, were analyzed using a quadratic polynomial model. Results: Significant increases in EC death and decreases in tumor microvessel density were observed, with maximal effects of endostatin at a dose of 249 mg/m2 (95% confidence interval, 159–338) and 257 mg/m2 (95% confidence interval, 183–331), respectively. In contrast, levels of TC death were uniformly low and did not correlate with endostatin dose. Maximal nuclear hypoxia-inducible factor 1α and minimal EC Bcl-2 levels were observed at ∼250 mg/m2, although the changes did not reach statistical significance. Conclusions: The data suggest that endostatin had optimal biological activity at doses ∼250 mg/m2 in our cohort of patients. Endostatin’s failure to induce high levels of TC death may explain its lack of significant clinical activity in this Phase I trial.