tbuckley/cabot-search huggingface dataset:
Drotrecogin Alfa (Activated) for Adults with Severe Sepsis and a Low Risk of Death
Authors: Edward Abraham, Pierre-François Laterre, Rekha Garg, Howard Levy, Deepak Talwar, Benjamin L. Trzaskoma, Bruno François, Jeffrey S. Guy, Martina Brückmann, Álvaro Rea-Neto, Rolf Rossaint, Dominique Perrotin, Armin Sablotzki, Nancy Arkins, Barbara G. Utterback, William L. Macias
Journal: New England Journal of Medicine (2005)

In November 2001, the Food and Drug Administration (FDA) approved drotrecogin alfa (activated) (DrotAA) for adults who had severe sepsis and a high risk of death. The FDA required a study to evaluate the efficacy of DrotAA for adults who had severe sepsis and a low risk of death.We randomly assigned adult patients with severe sepsis and a low risk of death (defined by an Acute Physiology and Chronic Health Evaluation [APACHE II] score <25 or single-organ failure) to receive an intravenous infusion of placebo or DrotAA (24 microg per kilogram of body weight per hour) for 96 hours in a double-blind, placebo-controlled, multicenter trial. The prospectively defined primary end point was death from any cause and was assessed 28 days after the start of the infusion. In-hospital mortality within 90 days after the start of the infusion was measured, and safety information was collected.Enrollment in the trial was terminated early because of a low likelihood of meeting the prospectively defined objective of demonstrating a significant reduction in the 28-day mortality rate with the use of DrotAA. The study enrolled 2640 patients and collected data on 2613 (1297 in the placebo group and 1316 in the DrotAA group) at the 28-day follow-up. There were no statistically significant differences between the placebo group and the DrotAA group in 28-day mortality (17.0 percent in the placebo group vs. 18.5 percent in the DrotAA group; P=0.34; relative risk, 1.08; 95 percent confidence interval, 0.92 to 1.28) or in in-hospital mortality (20.5 percent vs. 20.6 percent; P=0.98; relative risk, 1.00; 95 percent confidence interval, 0.86 to 1.16). The rate of serious bleeding was greater in the DrotAA group than in the placebo group during both the infusion (2.4 percent vs. 1.2 percent, P=0.02) and the 28-day study period (3.9 percent vs. 2.2 percent, P=0.01).The absence of a beneficial treatment effect, coupled with an increased incidence of serious bleeding complications, indicates that DrotAA should not be used in patients with severe sepsis who are at low risk for death, such as those with single-organ failure or an APACHE II score less than 25.
Personalized management of cirrhosis by non-invasive tests of liver fibrosis
Authors: Grace Lai-Hung Wong, Wendell Zaragoza Espinosa, Vicnent Wai-Sun Wong
Journal: Clinical and Molecular Hepatology (2015)

Owing to the high prevalence of various chronic liver diseases, cirrhosis is one of the leading causes of morbidity and mortality worldwide. In recent years, the development of non-invasive tests of fibrosis allows accurate diagnosis of cirrhosis and reduces the need for liver biopsy. In this review, we discuss the application of these non-invasive tests beyond the diagnosis of cirrhosis. In particular, their role in the selection of patients for hepatocellular carcinoma surveillance and varices screening is highlighted. Keywords: Transient elastography; FibroScan; FibroTest; Hepatocellular carcinoma; Varices
Role of perforin in controlling B-cell hyperactivity and humoral autoimmunity
Authors: Andrei Shustov, Irina Luzina, Phuong Nguyen, John C. Papadimitriou, Barry Handwerger, Keith B. Elkon, Charles S. Via
Journal: Journal of Clinical Investigation (2000)

To determine the role of perforin-mediated cytotoxic T lymphocyte (CTL) effector function in immune regulation, we studied a well-characterized mouse model of graft-versus-host disease (GVHD). Induction of acute GVHD using perforin-deficient donor T cells (pfp→F1) initially resulted in features of acute GVHD, e.g., engraftment of both donor CD4+ and CD8+ T cells, upregulation of Fas and FasL, production of antihost CTL, and secretion of both Th1 and Th2 cytokines. Despite fully functional FasL activity, pfp donor cells failed to totally eliminate host B cells, and, by 4 weeks of disease, cytokine production in pfp→F1 mice had polarized to a Th2 response. Pfp→F1 mice eventually developed features of chronic GVHD, such as increased numbers of B cells, persistence of donor CD4 T cells, autoantibody production, and lupuslike renal disease. We conclude that in the setting of B- and T-cell activation, perforin plays an important immunoregulatory role in the prevention of humoral autoimmunity through the elimination of both autoreactive B cells and ag-specific T cells. Moreover, an ineffective initial CTL response can evolve into a persistent antibody-mediated response and, with it, the potential for sustained humoral autoimmunity.
A Threefold Dose Intensity Treatment With Ifosfamide, Carboplatin, and Etoposide for Patients With Small Cell Lung Cancer: A Randomized Trial
Authors: S. Leyvraz, S. Pampallona, G. Martinelli, F. Ploner, L. Perey, S. Aversa, S. Peters, P. Brunsvig, A. Montes, A. Lange, U. Yilmaz, G. Rosti
Journal: JNCI Journal of the National Cancer Institute (2008)

The dose intensity of chemotherapy can be increased to the highest possible level by early administration of multiple and sequential high-dose cycles supported by transfusion with peripheral blood progenitor cells (PBPCs). A randomized trial was performed to test the impact of such dose intensification on the long-term survival of patients with small cell lung cancer (SCLC). Patients who had limited or extensive SCLC with no more than two metastatic sites were randomly assigned to high-dose (High, n = 69) or standard-dose (Std, n = 71) chemotherapy with ifosfamide, carboplatin, and etoposide (ICE). High-ICE cycles were supported by transfusion with PBPCs that were collected after two cycles of treatment with epidoxorubicin at 150 mg/m 2 , paclitaxel at 175 mg/m 2 , and filgrastim. The primary outcome was 3-year survival. Comparisons between response rates and toxic effects within subgroups (limited or extensive disease, liver metastases or no liver metastases, Eastern Cooperative Oncology Group performance status of 0 or 1, normal or abnormal lactate dehydrogenase levels) were also performed. Median relative dose intensity in the High-ICE arm was 293% (range = 174%–392%) of that in the Std-ICE arm. The 3-year survival rates were 18% (95% confidence interval [CI] = 10% to 29%) and 19% (95% CI = 11% to 30%) in the High-ICE and Std-ICE arms, respectively. No differences were observed between the High-ICE and Std-ICE arms in overall response (n = 54 [78%, 95% CI = 67% to 87%] and n = 48 [68%, 95% CI = 55% to 78%], respectively) or complete response (n = 27 [39%, 95% CI = 28% to 52%] and n = 24 [34%, 95% CI = 23% to 46%], respectively). Subgroup analyses showed no benefit for any outcome from High-ICE treatment. Hematologic toxicity was substantial in the Std-ICE arm (grade ≥ 3 neutropenia, n = 49 [70%]; anemia, n = 17 [25%]; thrombopenia, n = 17 [25%]), and three patients (4%) died from toxicity. High-ICE treatment was predictably associated with severe myelosuppression, and five patients (8%) died from toxicity. The long-term outcome of SCLC was not improved by raising the dose intensity of ICE chemotherapy by threefold.
The asthmatic patient and inhaler treatment devices profile in Turkey: Asthma inhaler treatment study
Authors: Fusun Yildiz, Nese Dursunoglu, Serap Duru
Journal: European Respiratory Journal (2012)

AIM

Factors such as severity, duration of asthma, concomitant diseases, smoking habits, influence asthma control, besides compliance to inhaler devices. In this study, we aimed to profile contributing factors and conditions and inhaler devices in Turkey.

METHODS

In this non-interventional study asthma patients were surveyed at baseline for asthma history, demographics, concomitant medical conditions and smoking habits,with possible impact on asthma and its prognosis, including exacerbation rates. The profile of treatment agents and devices were also evaluated.

RESULTS

A total of 572 patients were enrolled at 31 centers. The majority of asthma patients registered to the study was female (76%) and mean age was 42.7±12.1, the mean asthma age was 7.98 ± 8.28 years. BMI was 28.0 kg/m2.During enrolment, asthma symptoms were under control in 22% of patients enrolled, in 38% was not under control and 40% was partially controlled. During enrolment 56% of patients had co-morbid conditions, and 65.5% had rhinosinusitis, 12.8% had GERD, with high percentage of uncontrolled asthma. One in every five patient (18.2%) was current smokers and 49% had uncontrolled asthma during baseline.

View this table:

Table 1. Asthma treatment at baseline (n=572)





CONCLUSION

Patient profile of asthmatics receiving inhaler treatment showed that one out of every five patients enrolled were effectively controlled, despite smokers and presence of complicating concomitant medical conditions. Fixed combinations are the main stay of therapy in Turkey, with all types of inhaler devices.
Honest smiles as a costly signal in social exchange
Authors: Samuele Centorrino, Elodie Djemai, Astrid Hopfensitz, Manfred Milinski, Paul Seabright
Journal: Behavioral and Brain Sciences (2010)

Abstract Smiling can be interpreted as a costly signal of future benefits from cooperation between the individual smiling and the individual to whom the smile is directed. The target article by Niedenthal et al. gives little attention to the possible mechanisms by which smiling may have evolved. In our view, there are strong reasons to think that smiling has the key characteristics of a costly signal.
Tamoxifen Treatment After Adjuvant Chemotherapy Has Opposite Effects on Bone Mineral Density in Premenopausal Patients Depending on Menstrual Status
Authors: Leena Vehmanen, Inkeri Elomaa, Carl Blomqvist, Tiina Saarto
Journal: Journal of Clinical Oncology (2006)

Adjuvant chemotherapy followed by tamoxifen is a standard treatment option for women with intermediate or high-risk hormone receptor-positive breast cancer. Premenopausal women treated with chemotherapy often develop early menopause and thus, enter a period of accelerated bone loss. We conducted a prospective study of the effect of sequential adjuvant therapy with chemotherapy followed by tamoxifen on bone mineral density (BMD) in premenopausal patients.One hundred eleven premenopausal women with early breast cancer were treated with adjuvant chemotherapy. Patients with hormone receptor-positive tumors went on to tamoxifen 6 months after the beginning of the chemotherapy (tamoxifen group), while those with hormone receptor-negative tumors received no further therapy (control group). The effect of tamoxifen and menstrual status on BMD was studied.Tamoxifen treatment and menopausal status correlated significantly with the changes in lumbar spine BMD (P < .0001). A significant bone loss was noted in those tamoxifen-treated patients who continued to menstruate after chemotherapy. At 3 years of follow-up, menstruating patients on tamoxifen had lost -4.6% of their baseline BMD values, while a modest gain of +0.6% was noted in the control group. In contrast, bone loss was reduced among tamoxifen-treated women as compared with controls in patients who developed chemotherapy-induced early menopause. In amenorrheic patients, the lumbar spine BMD values decreased -6.8% in tamoxifen users and -9.5% in the controls, respectively.We conclude that tamoxifen usage was associated with bone loss in patients who continued to menstruate after adjuvant chemotherapy. On the contrary, tamoxifen decreased bone loss in those women who developed chemotherapy-induced amenorrhea.
Pressure–Volume Curves and Compliance in Acute Lung Injury
Authors: BJÖRN JONSON, JEAN-CHRISTOPHE RICHARD, CHRISTIAN STRAUS, JORDI MANCEBO, FRANÇOIS LEMAIRE, LAURENT BROCHARD
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

Measuring elastic pressure–volume (Pel-V) curves of the respiratory system and the volume recruited by a positive end-expiratory pressure (PEEP) allows one to study the pressure range over which recruitment occurs in acute lung injury (ALI), and to explain how recruitment affects the compliance. Pel-V curves were measured with the low flow inflation technique in 11 patients mechanically ventilated for ALI. Curve I was recorded during inflation from the volume attained after a prolonged expiration (6 s) at PEEP (9.0 ± 2.2 cm H2O), and Curve II after expiration to the elastic equilibrium volume at zero end-expiratory pressure (ZEEP). By using the end-expiratory volume of the breaths, the curves were aligned on a common volume axis to determine the effect of a single complete expiration. In each patient, Curve II (from ZEEP) was shifted toward lower volumes than Curve I. The volume shift, probably due to derecruitment, was 205 ± 100 ml at 15 cm H2O (p < 0.01) and 78 ± 93 ml at 30 cm H2O (p < 0.01); thus, during inflation from ZEEP, the volume deficit was successively regained over a pressure range up to at least 30 cm H2O. At any pressure, compliance was higher on the curve from ZEEP than from PEEP, by 10.0 ± 8.7 ml/cm H2O at 15 cm H2O (p < 0.01), and by 5.4 ± 5.5 at 30 cm H2O (p < 0.01). It is concluded that in ALI, a single expiration to ZEEP leads to lung collapse. High compliance during insufflation from ZEEP indicates that lung recruitment happens far above the lower inflection point of the Pel-V curve.
Suppression of dynamin GTPase decreases α-synuclein uptake by neuronal and oligodendroglial cells: a potent therapeutic target for synucleinopathy
Authors: Masatoshi Konno, Takafumi Hasegawa, Toru Baba, Emiko Miura, Naoto Sugeno, Akio Kikuchi, Fabienne C Fiesel, Tsutomu Sasaki, Masashi Aoki, Yasuto Itoyama, Atsushi Takeda
Journal: Molecular Neurodegeneration (2012)

Abstract Background The intracellular deposition of misfolded proteins is a common neuropathological hallmark of most neurodegenerative disorders. Increasing evidence suggests that these pathogenic proteins may spread to neighboring cells and induce the propagation of neurodegeneration. Results In this study, we have demonstrated that α-synuclein (αSYN), a major constituent of intracellular inclusions in synucleinopathies, was taken up by neuronal and oligodendroglial cells in both a time- and concentration-dependent manner. Once incorporated, the extracellular αSYN was immediately assembled into high-molecular-weight oligomers and subsequently formed cytoplasmic inclusion bodies. Furthermore, αSYN uptake by neurons and cells of the oligodendroglial lineage was markedly decreased by the genetic suppression and pharmacological inhibition of the dynamin GTPases, suggesting the involvement of the endocytic pathway in this process. Conclusions Our findings shed light on the mode of αSYN uptake by neuronal and oligodendroglial cells and identify therapeutic strategies aimed at reducing the propagation of protein misfolding.
Use of Fluorine-19 Nuclear Magnetic Resonance Spectroscopy and Hydralazine for Measuring Dynamic Changes in Blood Perfusion Volume in Tumors in Mice
Authors: C. Thomas, C. Counsell, P. Wood, G. E. Adams
Journal: JNCI Journal of the National Cancer Institute (1992)

Background : One method of evaluating the mechanism of action of agents which alter tumor oxygenation is to determine their effects on tumor blood flow. Purpose : This study tests applicability of a new approach using an emulsion of the inert fluorocarbon perfluorooctylbromide (PFOB) at nontoxic doses as a tracer in fluorine-19 ( 19 F) nuclear magnetic resonance (NMR) spectroscopy to evaluate dynamic changes in vascular perfusion volume in transplanted tumors. Methods : The PFOB emulsion (100% wt/vol) was injected into the tail vein in tumor-bearing C3H/He or nu/nu mice immobilized in a magnet interfaced to a spectrometer, either as a single bolus injection of 8 mL/kg body weight or in multiple injections to a total dose of 24 mL/kg. A 7-mm external surface coil was placed over the tumor. Signal from the PFOB in the tumor volume seen by the coil rapidly reached equilibrium and was maintained for at least 2 hours, and multiple doses of PFOB emulsion resulted in a linear increase in 19 F signal strength. Since the 19 F signal strength was directly proportional to the perfusion volume of the tumor vasculature, reduction of signal intensity should correspond directly to any reduction in volume caused by a change in the tumor blood flow. To investigate this hypothesis, the vasoactive agent hydralazine (5 mg/kg) was injected intravenously after administering the PFOB emulsion to induce changes in tumor blood supply. KHT and RIF-1 murine sarcomas, the HT29 human colon carcinoma, and the HX118 human melanoma tumors were studied. In a comparative analysis of changes in blood flow induced by hydralazine, we studied Xe-133 clearance in KHT murine sarcoma and SCCVII/Ha (SCCVII) murine squamous cell carcinoma. Results : Hydralazine significantly reduced the 19 F signal intensity in the murine tumors RIF-1 and KHT and in the HT29 human tumor, with little reduction in the SCCVII/Ha murine and HX118 human tumors. Hydralazine induced a statistically significant 64% decrease in mean clearance rate in the KHT tumor, while SCCVII/Ha tumors showed no significant change, indicating that hydralazine restricted blood flow to a greater extent in the tumor type that showed reduced 19 F signal from the PFOB emulsion. Conclusion : These data demonstrate the potential of PFOB emulsion as a tracer in NMR spectroscopy for studying tumor vasculature. [J Natl Cancer Inst 84: 174–180, 1992]
Atrial natriuretic polypeptide inhibits hypertrophy of vascular smooth muscle cells.
Authors: H Itoh, R E Pratt, V J Dzau
Journal: Journal of Clinical Investigation (1990)

Vascular remodeling is central to the pathophysiology of hypertension and atherosclerosis. Recent evidence suggests that vasoconstrictive substances, such as angiotensin II (AII), may function as a vascular smooth muscle growth promoting substance. To explore the role of the counterregulatory hormone, atrial natriuretic polypeptide (ANP) in this process, we examined the effect of ANP (alpha-rat ANP [1-28]) on the growth characteristics of cultured rat aortic smooth muscle (RASM) cells. ANP (10(-7) M) significantly suppressed the proliferative effect of 1% and 5% serum as measured by 3H-thymidine incorporation and cell number, confirming ANP as an antimitogenic factor. In quiescent RASM cells, ANP (10(-7), 10(-6) M) significantly suppressed the basal incorporations of 3H-uridine and leucine by 50 and 30%, respectively. ANP (10(-7), 10(-6) M) also suppressed AII-induced RNA and protein syntheses (by 30-40%) with the concomitant reduction of the cell size. Furthermore, ANP also significantly attenuated the increase of 3H-uridine and leucine incorporations caused by transforming growth factor-beta (4 x 10(-11), 4 x 10(-10) M), a potent hypertrophic factor. These results indicate that ANP possesses an antihypertrophic action on vascular smooth muscle cells. Down-regulation of protein kinase C by 24-h treatment with phorbol 12,13-dibutyrate did not inhibit ANP-induced suppression on 3H-uridine incorporation. Based on the observation that ANP was more potent than a ring-deleted analogue of ANP on inhibiting 3H-uridine incorporation, we conclude that the ANP's inhibitory effect is primarily mediated via the activation of a guanylate cyclase-linked ANP receptor(s). Indeed 8-bromo cGMP mimicked the antihypertrophic action of ANP. Accordingly, we speculate that in addition to its vasorelaxant and natriuretic effects, the antihypertrophic action of ANP observed in the present study may serve as an additional compensatory mechanism of ANP in hypertension.
Tension Developed by Papillary Muscles from Hypertrophied Rat Hearts
Authors: ANDREW KERR, ALAN R. WINTERBERGER, MARY GIAMBATTISTA
Journal: Circulation Research (1961)

Papillary muscle strips from hypertrophied left ventricles of 17 rats were tested for tension developed in response to electrical stimulation in a perfused, oxygenated, isometric muscle chamber. The maximum tension developed was significantly greater per unit weight than that developed by papillary muscles from normal ventricles. Greater tension was also developed by the papillary muscles from hypertrophied hearts when tested with an anaerobic perfusate.
Effect of Ruboxistaurin on Urinary Transforming Growth Factor-β in Patients With Diabetic Nephropathy and Type 2 Diabetes
Authors: Richard E. Gilbert, Sandra A. Kim, Katherine R. Tuttle, George L. Bakris, Robert D. Toto, Janet B. McGill, Douglas J. Haney, Darren J. Kelly, Pamela W. Anderson
Journal: Diabetes Care (2007)

Excessive protein kinase C-β (PKC-β) activity has been implicated in the pathogenesis of diabetic nephropathy (1–5) such that its selective inhibition might be a useful strategy in treating patients with this complication.

Ruboxistaurin mesylate, a bisindolylmaleimide, is a specific and selective inhibitor of PKC-β isoforms that, in preclinical studies, attenuates overexpression of transforming growth factorβ (TGF-β) (6), a key mediator of the glomerulosclerosis and tubulointerstitial fibrosis characterizing diabetic nephropathy (7).

In contrast with albuminuria, thought to derive largely from plasma filtrate, urinary TGF-β mostly reflects its intrarenal production (8). In untreated patients with diabetic nephropathy, urinary TGF-β is increased (8), parallels the magnitude of proteinuria (9), correlates with glycemia (10), and decreases with angiotensin receptor blocker (ARB) therapy (10). The effects of agents beyond those that block the renin-angiotensin system (RAS), such as PKC-β inhibition, on urinary TGF-β are unknown.

We obtained urine from participants in a prospective, double-blind, placebo-controlled study of the effects of ruboxistaurin 32 mg/day in patients with diabetic nephropathy (11), in which the effect on urinary TGF-β was a prespecified secondary objective. Patients were ≥30 years old with type 2 diabetes and urinary albumin–to–creatinine ratio (ACR) 200-2000 mg/g despite stable blockade of the RAS with ACE inhibitors and/or ARBs. Urine was collected before randomization (baseline) and …