tbuckley/cabot-search huggingface dataset:
Enhanced prostacyclin synthesis in endothelial cells by retrovirus-mediated transfer of prostaglandin H synthase cDNA.
Authors: X M Xu, K Ohashi, S K Sanduja, K H Ruan, L H Wang, K K Wu
Journal: Journal of Clinical Investigation (1993)

A retroviral vector (BAG) was used to transfer human prostaglandin H synthase (PGHS-1) gene into a human endothelial cell line for enhancement of PGI2 synthesis. Cells infected with BAG containing PGHS-1 cDNA in the sense orientation relative to the retroviral promoter (PGHS(S)) expressed a 30-fold increase in mRNA but, due to a reading frame shift, did not show an increase in PGHS protein or in PGI2 synthesis, while those with PGHS-1 in reverse orientation relative to the viral promoter (PGHS(R)), produced a > 10-fold increase in PGHS mRNA over the control (169 +/- 22 vs 14.8 +/- 1.2 amol/micrograms RNA) with a concordant increase in PGHS protein (5.82 +/- 1.07 vs 0.23 +/- 0.04 ng/mg protein) and enzyme activity. Primer extension analysis of PGHS(R) revealed two transcription start sites located in the SV40 late promoter region adjacent to PGHS-1 cDNA. PGHS(R) cells produced a high basal PGI2 level which was increased by several-fold in response to stimulation by ionophore, arachidonic acid, and thrombin. Kinetic analysis revealed the PGI2 synthetic rate to be 14 ng/min-1 per million cells and t1/2 of PGI2 synthesis, 13.3 min. These findings indicate that transfer of PGHS-1 gene into vascular cells enhances PGI2 synthesis and may be a useful strategy for restoring thromboprotective property of damaged blood vessels.
Fludarabine in Combination With Alemtuzumab Is Effective and Feasible in Patients With Relapsed or Refractory B-Cell Chronic Lymphocytic Leukemia: Results of a Phase II Trial
Authors: Thomas Elter, Peter Borchmann, Holger Schulz, Marcel Reiser, Sven Trelle, Roland Schnell, Markus Jensen, Peter Staib, Timo Schinköthe, Hartmut Stützer, Jürgen Rech, Martin Gramatzki, Walter Aulitzky, Ibrahim Hasan, Andreas Josting, Michael Hallek, Andreas Engert
Journal: Journal of Clinical Oncology (2005)

To determine the efficacy and safety of a newly developed concomitant administration of fludarabine and alemtuzumab (FluCam) in patients with relapsed or refractory B-cell chronic lymphocytic leukemia (B-CLL).A total of 36 patients were treated in this phase II study (median age, 61.47 years; mean number of prior chemotherapies, 2.6; Binet stage C, n = 28). After an initial dose escalation of alemtuzumab over 3 days, alemtuzumab 30 mg and fludarabine 30 mg/m2 were administered on 3 consecutive days. Treatment was repeated after 28 days for up to six cycles. Restaging (following National Cancer Institute criteria) was carried out after cycles 2 and 4 and 1 month after the end of treatment.The overall response rate was 83% (11 complete responses, 19 partial responses, one stable disease, and five progressive diseases). Two patients with progressive disease developed fungal pneumonias, and one patient died as a result of Escherichia coli sepsis. Two subclinical cytomegalovirus reactivations occurred.The new FluCam regimen is effective and feasible in patients with relapsed and refractory B-CLL.
Haematopoietic stem cell transplantation and gene therapy in the fetus: ready for clinical use?
Authors: D. V. Surbek
Journal: Human Reproduction Update (2001)

Allogeneic haematopoietic stem cell transplantation in utero has been successfully used for the prenatal treatment of severe combined immunodefiency syndrome. However, this treatment has not been successful in the therapy of other conditions in which the fetus is immunologically competent. The main obstacles to success are lack of competitive advantage of donor versus host stem cells, preventing stable engraftment and graft rejection. Several strategies are being explored to overcome these problems, and some of them have been successful in animal studies. Prenatal gene therapy, using ex-vivo transduced autologous haematopoietic cells or direct gene targeting in utero, is another potential approach in the treatment of immunocompetent fetal recipients. Although this has been shown to be feasible in animal models, safety concerns regarding transduction of fetal germ cells or maternal cells should be addressed in preclinical experiments prior to initiation of clinical trials.
Efficacy of Risk-Reduction Counseling to Prevent Human Immunodeficiency Virus and Sexually Transmitted Diseases
Authors: M L Kamb, M Fishbein, J M Douglas, F Rhodes, J Rogers, G Bolan, J Zenilman, T Hoxworth, C K Malotte, M Iatesta, C Kent, A Lentz, S Graziano, R H Byers, T A Peterman
Journal: JAMA (1998)

The efficacy of counseling to prevent infection with the human immunodeficiency virus (HIV) and other sexually transmitted diseases (STDs) has not been definitively shown.To compare the effects of 2 interactive HIV/STD counseling interventions with didactic prevention messages typical of current practice.Multicenter randomized controlled trial (Project RESPECT), with participants assigned to 1 of 3 individual face-to-face interventions.Five public STD clinics (Baltimore, Md; Denver, Colo; Long Beach, Calif; Newark, NJ; and San Francisco, Calif) between July 1993 and September 1996.A total of 5758 heterosexual, HIV-negative patients aged 14 years or older who came for STD examinations.Arm 1 received enhanced counseling, 4 interactive theory-based sessions. Arm 2 received brief counseling, 2 interactive risk-reduction sessions. Arms 3 and 4 each received 2 brief didactic messages typical of current care. Arms 1, 2, and 3 were actively followed up after enrollment with questionnaires at 3, 6, 9, and 12 months and STD tests at 6 and 12 months. An intent-to-treat analysis was used to compare interventions.Self-reported condom use and new diagnoses of STDs (gonorrhea, chlamydia, syphilis, HIV) defined by laboratory tests.At the 3- and 6-month follow-up visits, self-reported 100% condom use was higher (P<.05) in both the enhanced counseling and brief counseling arms compared with participants in the didactic messages arm. Through the 6-month interval, 30% fewer participants had new STDs in both the enhanced counseling (7.2%; P= .002) and brief counseling (7.3%; P= .005) arms compared with those in the didactic messages arm (10.4%). Through the 12-month study, 20% fewer participants in each counseling intervention had new STDs compared with those in the didactic messages arm (P = .008). Consistently at each of the 5 study sites, STD incidence was lower in the counseling intervention arms than in the didactic messages intervention arm. Reduction of STD was similar for men and women and greater for adolescents and persons with an STD diagnosed at enrollment.Short counseling interventions using personalized risk reduction plans can increase condom use and prevent new STDs. Effective counseling can be conducted even in busy public clinics.
Ghrelin enhances gastric emptying in diabetic gastroparesis: a double blind, placebo controlled, crossover study
Authors: C D R Murray
Journal: Gut (2005)

<b>Background:</b> Diabetic gastroparesis is a disabling condition with no consistently effective treatment. In animals, ghrelin increases gastric emptying and reverses postoperative ileus. We present the results of a double blind, placebo controlled, crossover study of ghrelin in gastric emptying in patients with diabetic gastroparesis. <b>Methods:</b> Ten insulin requiring diabetic patients (five men, six type I) referred with symptoms indicative of gastroparesis received a two hour infusion of either ghrelin (5 pmol/kg/min) or saline on two occasions. Blood glucose was controlled by euglycaemic clamp. Gastric emptying rate (GER) was calculated by real time ultrasound following a test meal. Blood was sampled for ghrelin, growth hormone (GH), and pancreatic polypeptide (PP) levels. Cardiovagal neuropathy was assessed using the Mayo Clinic composite autonomic severity score (range 0 (normal)–3). <b>Results:</b> Baseline ghrelin levels were mean 445 (SEM 36) pmol/l. Ghrelin infusion achieved a peak plasma level of 2786 (188) pmol/l at 90 minutes, corresponding to a peak GH of 70.9 (19.8) pmol/l. Ghrelin increased gastric emptying in seven of 10 patients (30 (6)% to 43 (5)%; p = 0.04). Impaired cardiovagal tone correlated inversely with peak postprandial PP values (p&lt;0.05) but did not correlate with GER. <b>Conclusions:</b> Ghrelin increases gastric emptying in patients with diabetic gastroparesis. This is independent of vagal tone. We propose that analogues of ghrelin may represent a new class of prokinetic agents.
Human endothelial cells derived from circulating progenitors display specific functional properties compared with mature vessel wall endothelial cells
Authors: Heidi Bompais, Jalila Chagraoui, Xavier Canron, Mihaela Crisan, Xu Hui Liu, Aurora Anjo, Carine Tolla-Le Port, Marylene Leboeuf, Pierre Charbord, Andreas Bikfalvi, Georges Uzan
Journal: Blood (2003)
Rapid induction of clinical remission by low-dose interleukin-2 in a patient with refractory SLE
Authors: Jens Y Humrich, Caroline von Spee-Mayer, Elise Siegert, Tobias Alexander, Falk Hiepe, Andreas Radbruch, Gerd-Rüdiger Burmester, Gabriela Riemekasten
Journal: Annals of the Rheumatic Diseases (2015)

Interleukin-2 (IL-2) is crucial for the growth and survival of regulatory T cells (Treg) and, thus, for the control of autoimmunity.1 ,2 In previous studies, we have proven a causal relationship between an acquired IL-2-deficiency, defects in Treg biology and the development of systemic lupus erythematosus (SLE).3 Accordingly, we showed that compensation of IL-2 deficiency by IL-2 therapy corrects associated Treg defects and ameliorates already established disease in lupus-prone mice.3 In line with this, two independent clinical studies showed recently that low-dose IL-2 induced expansion of the Treg pool and reduced clinical symptoms in two different immunological diseases without known IL-2 deficiency.4 ,5 These promising clinical findings in conjunction with preclinical data3 ,6 ,7 provide strong rationales for an IL-2-based immunotherapy of SLE in order to restore Treg activity and, thus, to re-establish endogenous mechanisms of tolerance that can counteract autoimmunity.

Here we report a rapid and robust reduction of disease activity in parallel with a remarkable expansion of the Treg population by low-dose IL-2 therapy in one patient with a long-term history of SLE and increased disease activity refractory …
The New Worldwide Definition of Metabolic Syndrome Is Not a Better Diagnostic Predictor of Cardiovascular Disease in Japanese Diabetic Patients Than the Existing Definitions: Additional analysis from the Japan Diabetes Complications Study 
Authors: H. Sone
Journal: Diabetes Care (2006)

We previously reported (1) the limited clinical significance for Japanese diabetic patients of the widely used World Health Organization (WHO) (2) and National Cholesterol Education Program (NCEP) (3) definitions of metabolic syndrome and suggested that an international definition of metabolic syndrome that was applicable regardless of ethnicity was necessary (1).

Recently, the International Diabetes Federation published a long-awaited new worldwide definition of metabolic syndrome (4) that is intended to be applicable to various ethnic groups. The new definition is similar to the NCEP definition (3) but has several important differences. Notably, most components of the new definition now include subjects who are receiving specific treatments for the abnormalities that comprise metabolic syndrome. Also, central obesity (defined by waist circumference with ethnic modification in its thresholds) has become a mandatory component in the new definition. In this report, we evaluated the predictive power of the new international definition for cardiovascular disease (CVD), as compared with that of previous definitions, in Japanese diabetic patients.

The Japan Diabetes Complications Study (JDCS) has been described in detail elsewhere (1, 5). The same dataset was used for evaluation so that the new definition of metabolic syndrome could be directly compared with the WHO and NCEP definitions (1–4). A total of 1,424 Japanese patients (771 men and 653 women, age 58.4 ± 7.4 years [means ± SD]) with previously diagnosed type 2 diabetes but without known CVD were …
Farming practices and the respiratory health risks of swine confinement buildings
Authors: Y Cormier, E Israel-Assayag, G Racine, C Duchaine
Journal: European Respiratory Journal (2000)

This study investigated whether clean swine confinement buildings (SCB) are less harmful to the respiratory system than older and dirtier facilities. Eight healthy volunteers were exposed for 4 h, at 1 week intervals, to eight SCB representing the widest possible range of cleanliness. Each volunteer and a technician rated the SCB for cleanliness from 1-10, 1 being the cleanest possible. Airborne dust, bacteria, endotoxin levels, molds, and ammonia were measured. For each volunteer measured, before and after each exposure, forced expiratory flows (forced expiratory volume in one second (FEV1), and forced vital capacity), white cells in nasal wash and venous blood, and nasal lavage levels of interleukin (IL)-8 and serum levels of IL-6. A methacholine challenge was obtained at baseline and following each exposure. Cleanliness scores ranged 1.5-8.25. Mean airborne levels were: dust 3.54 mg x m(-3) bacteria 4.25 x 10(5) CFU x m(-3); endotoxins 404 EU x m(-3); molds 883 CFU x m(-3); ammonia 20.7 parts per million (ppm). Expiratory flows decreased after exposure (FEV1 from 4.8+/-0.7 to 4.4+/-0.7, p&lt;0.001), neutrophils in the nasal wash and white blood cells increased (28.5+/-37 to 424+/-207 x 10(3), 5.4+/-1.0 to 7.4+/-1.7 x 10(9) cells x mL(-1) respectively), IL-8 increased from 158+/-311 to 2679+/-639 pg x mL(-1), IL-6 from 0.15+/-0.26 to 2.34+/-0.92 pg x mL(-1), (p&lt;0.001). All SCB were similarly harmful. In conclusion, modern farming has not succeeded in making swine confinement buildings inoffensive to exposed subjects.
Enhanced Contractile Response and Protein Kinase Activation to Threshold Levels of β-Adrenergic Stimulation in Hyperthyroid Rat Heart
Authors: Thomas Guarnieri, Charles R. Filburn, Elsie S. Beard, Edward G. Lakatta
Journal: Journal of Clinical Investigation (1980)

The contractile response measured as maximum rate of force development to a near threshold concentration of isoproterenol (1 nM) was enhanced in perfused interventricular septa from hyperthyroid (128+/-4% control) compared with euthyroid rats (105+/-2%, P < 0.01). This enhanced contractile response was accompanied by a significant activation of cyclic (c)AMP-dependent protein kinase (protein kinase activity ratio increased from 0.159+/-0.008 to 0.218+/-0.019, P < 0.005, although no significant changes from base line occurred in euthyroid septa, 0.152+/-0.007-0.179+/-0.012). No difference between hyperthyroid and euthyroid hearts was observed in the contractile response to 0.1 mM dibutyryl cAMP (126.5+/-2.5% and 122.0+/-9.2% in hyperthyroid and euthyroid, respectively), and the magnitude of the response to dibutyryl cAMP was comparable with that observed in the hyperthyroid group with 1 nM isoproterenol. These results suggest that the mechanism for enhanced protein kinase activation and contractile response to low concentrations of isoproterenol in the hyperthyroid heart is at or proximal to cAMP generation. The maximum contractile response to isoproterenol (0.5 muM), however, was decreased in hyperthyroid myocardium (192+/-13%) compared with euthyroid (291+/-37%, P < 0.05). Both protein kinase activity ratio (0.356+/-0.017 and 0.344+/-0.013) and the maximum contractile response to Ca(++) (335+/-15 and 340+/-12% control in hyperthyroid and euthyroid, respectively) were similar, suggesting that the mechanism of the diminished maximum response was distal to protein kinase activation but not a function of an altered Ca(++)-troponin interaction. The diminished maximum rate of force development response in the hyperthyroid hearts was accompanied by significantly less shortening of the contraction duration that was 85.6+/-2.1% control in hyperthyroid vs. 66+/-2.8% control in euthyroid, P < 0.001. Although the basal rate of Ca(++) accumulation was greater in microsomes isolated from hyperthyroid than from euthyroid hearts, there was significantly less additional stimulation of Ca(++) accumulation in response to exogenous cAMP and protein kinase in hyperthyroid compared with euthyroid hearts. This reduction may explain the diminished effect of isoproterenol on the shortening of contraction duration in hyperthyroid compared with the euthyroid myocardium, and may explain, at least in part, the diminished maximum contractile response to isoproterenol.
Randomized Phase II Study of Bortezomib, Thalidomide, and Dexamethasone With or Without Cyclophosphamide As Induction Therapy in Previously Untreated Multiple Myeloma
Authors: Heinz Ludwig, Luisa Viterbo, Richard Greil, Tamas Masszi, Ivan Spicka, Ofer Shpilberg, Roman Hajek, Anna Dmoszynska, Bruno Paiva, María-Belén Vidriales, Graca Esteves, Anne Marie Stoppa, Don Robinson, Deborah Ricci, Andrew Cakana, Christopher Enny, Huaibao Feng, Helgi van de Velde, Jean-Luc Harousseau
Journal: Journal of Clinical Oncology (2012)

Purpose Bortezomib-thalidomide-dexamethasone (VTD) is an effective induction therapy in multiple myeloma (MM). This phase II, noncomparative study sought to determine whether addition of cyclophosphamide to this regimen (VTDC) could further increase efficacy without compromising safety. Patients and Methods Patients age 18 to 70 years with previously untreated, measurable MM, who were eligible for high-dose chemotherapy–autologous stem-cell transplantation (HDCT-ASCT), were randomly assigned to bortezomib 1.3 mg/m 2 , thalidomide 100 mg, and dexamethasone 40 mg, with (n = 49) or without (n = 49) cyclophosphamide 400 mg/m 2 for four 21-day cycles, followed by HDCT-ASCT. The primary end point was postinduction combined rate of near-complete response (nCR) or better (including complete response [CR] with normalized serum κ:λ free light chain ratio, CR, and nCR). Results Postinduction, 51% (VTD) and 44% (VTDC) of patients achieved combined CR/nCR, with bone marrow–confirmed CR in 29% and 31%, overall response rates of 100% and 96%, respectively, and very good partial response or better rates of 69% per arm. Post–HDCT-ASCT, combined CR/nCR rates were 85% (VTD) and 77% (VTDC). In all, 35% (VTD) and 27% (VTDC) of patients were negative for minimal residual disease (MRD) during induction and postinduction. Three-year overall survival was 80% (both arms). Grade 3 to 4 adverse events (AEs) and serious AEs were observed in 47% and 22% (VTD) and 57% and 41% (VTDC) of patients, respectively. The primary health-related quality of life end point (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 [EORTC QLQ-C30] Global Health score) steadily increased with VTD during induction and reached a clinically relevant difference post-transplantation versus baseline. Conclusion Both VTD and VTDC are highly active induction regimens producing high combined CR/nCR and MRD-negative rates; however, VTDC was associated with increased toxicity and suggestion of transient decreases in Global Health score, without an increase in activity.
Treatment of Acute Otitis Media in Children under 2 Years of Age
Authors: Alejandro Hoberman, Jack L. Paradise, Howard E. Rockette, Nader Shaikh, Ellen R. Wald, Diana H. Kearney, D. Kathleen Colborn, Marcia Kurs-Lasky, Sonika Bhatnagar, Mary Ann Haralam, Lisa M. Zoffel, Carly Jenkins, Marcia A. Pope, Tracy L. Balentine, Karen A. Barbadora
Journal: New England Journal of Medicine (2011)

Recommendations vary regarding immediate antimicrobial treatment versus watchful waiting for children younger than 2 years of age with acute otitis media.We randomly assigned 291 children 6 to 23 months of age, with acute otitis media diagnosed with the use of stringent criteria, to receive amoxicillin-clavulanate or placebo for 10 days. We measured symptomatic response and rates of clinical failure.Among the children who received amoxicillin-clavulanate, 35% had initial resolution of symptoms by day 2, 61% by day 4, and 80% by day 7; among children who received placebo, 28% had initial resolution of symptoms by day 2, 54% by day 4, and 74% by day 7 (P=0.14 for the overall comparison). For sustained resolution of symptoms, the corresponding values were 20%, 41%, and 67% with amoxicillin-clavulanate, as compared with 14%, 36%, and 53% with placebo (P=0.04 for the overall comparison). Mean symptom scores over the first 7 days were lower for the children treated with amoxicillin-clavulanate than for those who received placebo (P=0.02). The rate of clinical failure--defined as the persistence of signs of acute infection on otoscopic examination--was also lower among the children treated with amoxicillin-clavulanate than among those who received placebo: 4% versus 23% at or before the visit on day 4 or 5 (P<0.001) and 16% versus 51% at or before the visit on day 10 to 12 (P<0.001). Mastoiditis developed in one child who received placebo. Diarrhea and diaper-area dermatitis were more common among children who received amoxicillin-clavulanate. There were no significant changes in either group in the rates of nasopharyngeal colonization with nonsusceptible Streptococcus pneumoniae.Among children 6 to 23 months of age with acute otitis media, treatment with amoxicillin-clavulanate for 10 days tended to reduce the time to resolution of symptoms and reduced the overall symptom burden and the rate of persistent signs of acute infection on otoscopic examination. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT00377260.).
Multidrug resistance protein 1 protects the choroid plexus epithelium and contributes to the blood-cerebrospinal fluid barrier
Authors: Jan Wijnholds, Elizabeth C.M. de Lange, George L. Scheffer, Dirk-Jan van den Berg, Carla A.A.M. Mol, Martin van der Valk, Alfred H. Schinkel, Rik J. Scheper, Douwe D. Breimer, Piet Borst
Journal: Journal of Clinical Investigation (2000)

Multidrug resistance protein 1 (MRP1) is a transporter protein that helps to protect normal cells and tumor cells against the influx of certain xenobiotics. We previously showed that Mrp1 protects against cytotoxic drugs at the testis-blood barrier, the oral epithelium, and the kidney urinary collecting duct tubules. Here, we generated Mrp1/Mdr1a/Mdr1b triple-knockout (TKO) mice, and used them together with Mdr1a/Mdr1b double-knockout (DKO) mice to study the contribution of Mrp1 to the tissue distribution and pharmacokinetics of etoposide. We observed increased toxicity in the TKO mice, which accumulated etoposide in brown adipose tissue, colon, salivary gland, heart, and the female urogenital system. Immunohistochemical staining revealed the presence of Mrp1 in the oviduct, uterus, salivary gland, and choroid plexus (CP) epithelium. To explore the transport function of Mrp1 in the CP epithelium, we used TKO and DKO mice cannulated for cerebrospinal fluid (CSF). We show here that the lack of Mrp1 protein causes etoposide levels to increase about 10-fold in the CSF after intravenous administration of the drug. Our results indicate that Mrp1 helps to limit tissue distribution of certain drugs and contributes to the blood-CSF drug-permeability barrier.