Current treatments to control pathological or unwanted immune responses often use broadly immunosuppressive drugs. New approaches to induce antigen-specific immunological tolerance that control both ...cellular and humoral immune responses are desirable. Here we describe the use of synthetic, biodegradable nanoparticles carrying either protein or peptide antigens and a tolerogenic immunomodulator, rapamycin, to induce durable and antigen-specific immune tolerance, even in the presence of potent Toll-like receptor agonists. Treatment with tolerogenic nanoparticles results in the inhibition of CD4+ and CD8+ T-cell activation, an increase in regulatory cells, durable B-cell tolerance resistant to multiple immunogenic challenges, and the inhibition of antigen-specific hypersensitivity reactions, relapsing experimental autoimmune encephalomyelitis, and antibody responses against coagulation factor VIII in hemophilia A mice, even in animals previously sensitized to antigen. Only encapsulated rapamycin, not the free form, could induce immunological tolerance. Tolerogenic nanoparticle therapy represents a potential novel approach for the treatment of allergies, autoimmune diseases, and prevention of antidrug antibodies against biologic therapies.
Significance Synthetic nanoparticles containing either protein or peptide antigen and the immunosuppressant rapamycin are capable of inducing durable and specific resistance to mounting immune responses toward the antigen. This immunological tolerance operates on lymphocytes even after multiple immunogenic challenges with the antigen and adding enhancers of immune responses (adjuvants). As a result, the animals treated with these tolerogenic nanoparticles (tNPs) show reduced allergic hypersensitivity disorders, protection from disease relapse in a model of multiple sclerosis, and prevention of inhibitory antidrug antibody responses in an animal model of hemophilia A. These results show the potential for nanocarriers to modify the immunoreactivity of a given molecule by providing tolerogenic instructions to the immune system, thereby preventing or reversing pathological and neutralizing immune responses.
Why do governance reforms in developing democracies so often fail, and when might they succeed? When Democracies Deliver offers a dynamic framework for assessing the effectiveness and durability of ...policy change. Drawing on detailed analyses of public sector reforms in Brazil and Argentina, this book challenges conventional wisdom to reveal that incremental changes sequenced over time prove more effective in promoting accountability, increasing transparency, and strengthening institutions than comprehensive overhauls pushed through by political will. Developing an innovative theory that integrates cognitive-psychological insights about decision making with research on institutional change, Katherine Bersch shows how political and organizational factors can shape reform strategies and information processing. Through extensive interviews and field research, Bersch traces how two competing strategies have determined the different trajectories of institutions responsible for government contracting in health care and transportation. When Democracies Deliver offers a fresh insight on the perils of powering and the benefits of gradual reform.
Docetaxel-based chemotherapy is effective in metastatic gastric and gastro-oesophageal junction adenocarcinoma. This study reports on the safety and efficacy of the docetaxel-based triplet FLOT ...(fluorouracil plus leucovorin, oxaliplatin and docetaxel) as a perioperative therapy for patients with locally advanced, resectable tumours.
In this controlled, open-label, phase 2/3 trial, we randomly assigned 716 patients with histologically-confirmed advanced clinical stage cT2 or higher or nodal positive stage (cN+), or both, resectable tumours, with no evidence of distant metastases, via central interactive web-based-response system, to receive either three pre-operative and three postoperative 3-week cycles of 50 mg/m2 epirubicin and 60 mg/m2 cisplatin on day 1 plus either 200 mg/m2 fluorouracil as continuous intravenous infusion or 1250 mg/m2 capecitabine orally on days 1 to 21 (ECF/ECX; control group) or four preoperative and four postoperative 2-week cycles of 50 mg/m2 docetaxel, 85 mg/m2 oxaliplatin, 200 mg/m2 leucovorin and 2600 mg/m2 fluorouracil as 24-h infusion on day 1 (FLOT; experimental group). The primary outcome of the trial was overall survival (superiority) analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01216644.
Between Aug 8, 2010, and Feb 10, 2015, 716 patients were randomly assigned to treatment in 38 German hospitals or with practice-based oncologists. 360 patients were assigned to ECF/ECX and 356 patients to FLOT. Overall survival was increased in the FLOT group compared with the ECF/ECX group (hazard ratio HR 0·77; 95% confidence interval CI; 0.63 to 0·94; median overall survival, 50 months 38·33 to not reached vs 35 months 27·35 to 46·26). The number of patients with related serious adverse events (including those occurring during hospital stay for surgery) was similar in the two groups (96 27% in the ECF/ECX group vs 97 27% in the FLOT group), as was the number of toxic deaths (two <1% in both groups). Hospitalisation for toxicity occurred in 94 patients (26%) in the ECF/ECX group and 89 patients (25%) in the FLOT group.
In locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma, perioperative FLOT improved overall survival compared with perioperative ECF/ECX.
The German Cancer Aid (Deutsche Krebshilfe), Sanofi-Aventis, Chugai, and Stiftung Leben mit Krebs Foundation.
This article describes the pharmacology of approved parenteral anticoagulants. These include the indirect anticoagulants, unfractionated heparin (UFH), low-molecular-weight heparins (LMWHs), ...fondaparinux, and danaparoid, as well as the direct thrombin inhibitors hirudin, bivalirudin, and argatroban. UFH is a heterogeneous mixture of glycosaminoglycans that bind to antithrombin via a unique pentasaccharide sequence and catalyze the inactivation of thrombin, factor Xa, and other clotting enzymes. Heparin also binds to cells and plasma proteins other than antithrombin causing unpredictable pharmacokinetic and pharmacodynamic properties and triggering nonhemorrhagic side effects, such as heparin-induced thrombocytopenia (HIT) and osteoporosis. LMWHs have greater inhibitory activity against factor Xa than thrombin and exhibit less binding to cells and plasma proteins than heparin. Consequently, LMWH preparations have more predictable pharmacokinetic and pharmacodynamic properties, have a longer half-life than heparin, and are associated with a lower risk of nonhemorrhagic side effects. LMWHs can be administered once daily or bid by subcutaneous injection, without coagulation monitoring. Based on their greater convenience, LMWHs have replaced UFH for many clinical indications. Fondaparinux, a synthetic pentasaccharide, catalyzes the inhibition of factor Xa, but not thrombin, in an antithrombin-dependent fashion. Fondaparinux binds only to antithrombin. Therefore, fondaparinux-associated HIT or osteoporosis is unlikely to occur. Fondaparinux exhibits complete bioavailability when administered subcutaneously, has a longer half-life than LMWHs, and is given once daily by subcutaneous injection in fixed doses, without coagulation monitoring. Three additional parenteral direct thrombin inhibitors and danaparoid are approved as alternatives to heparin in patients with HIT.
Abstract Objectives The aim of this review was to evaluate current literature for dosing recommendations for the use of antiepileptic medications in patients receiving renal replacement therapy ...(RRT). Data Sources With the assistance of an experienced medical librarian specialized in pharmacy and toxicology, we searched MEDLINE, EMBASE, CINAHL, Web of Science, WorldCat, and Scopus through May 2016. Study Selection and Data Extraction 403 articles were screened for inclusion, of which 130 were identified as potentially relevant. Micromedex® DRUGDEX as well as package inserts were used to obtain known pharmacokinetic properties and dosage adjustment recommendations in RRT if known. Data Synthesis Data regarding antiepileptic drug (AED) use in RRT are limited and mostly consist of case reports limiting our proposed dosing recommendations. Known pharmacokinetic parameters should guide dosing, and recommendations are provided where possible. Conclusion Additional studies are necessary before specific dosing recommendations can be made for most AEDs in critically ill patients receiving RRT, specifically with newer agents.
•Chitosan-based composite hydrogel was designed for the synergistic photothermal- and chemotherapy of colon cancer.•The temperature-sensitive hydrogel could release drug in an on-demand ...manner.•Localized therapy with no harm to normal tissues and organs was achieved.•The chitosan-based hydrogel had antibacterial effects.
The purpose of this study was to design an injectable hydrogel with temperature-sensitive property for safe and high efficient in vivo colon cancer hyperthermia and chemotherapy. Chitosan (CS) solution was injected into the tumor at room temperature and automatically gelled after warming to body temperature in the present of β-glycerophosphate (β-GP). Combined localized tumor photothermal and chemotherapy were achieved by dissolving photothermal material MoS2/Bi2S3-PEG (MBP) nanosheets and drug molecule doxorubicin (DOX) into the hydrogel, and the gel system could encapsulate DOX and MBP nanosheets and prevent them from entering the blood circulation and damaging normal tissues and cells. More importantly, the CS/MBP/DOX (CMD) hydrogel exhibited a photothermal efficiency of 22.18% and 31.42% in the first and second near infrared light (NIR I and NIR II) biowindows respectively at a low MBP concentration (0.5 mg/mL). Besides, the release of the DOX from CMD hydrogel was controllable since the gel temperature could be governed by NIR laser irradiation. Moreover, the chitosan-based hydrogel had antibacterial effects. The designed composite hydrogel is anticipated to act as a platform for the high efficient treatment of tumors owing to the different penetration depths of NIR I and NIR II.
Resilient health care Hollnagel, Erik; Braithwaite, Jeffrey; Wears, Robert L
2013., 2013, 2013-08-01, 2013-09-28
eBook
Health care is everywhere under tremendous pressure with regard to efficiency, safety, and economic viability - to say nothing of having to meet various political agendas - and has responded by ...eagerly adopting techniques that have been useful in other industries, such as quality management, lean production, and high reliability. This has on the whole been met with limited success because health care as a non-trivial and multifaceted system differs significantly from most traditional industries. In order to allow health care systems to perform as expected and required, it is necessary to have concepts and methods that are able to cope with this complexity. Resilience engineering provides that capacity because its focus is on a system's overall ability to sustain required operations under both expected and unexpected conditions rather than on individual features or qualities. Resilience engineering's unique approach emphasises the usefulness of performance variability, and that successes and failures have the same aetiology. This book contains contributions from acknowledged international experts in health care, organisational studies and patient safety, as well as resilience engineering. Whereas current safety approaches primarily aim to reduce or eliminate the number of things that go wrong, Resilient Health Care aims to increase and improve the number of things that go right. Just as the WHO argues that health is more than the absence of illness, so does Resilient Health Care argue that safety is more than the absence of risk and accidents. This can be achieved by making use of the concrete experiences of resilience engineering, both conceptually (ways of thinking) and practically (ways of acting).
The ALK inhibitor crizotinib as first-line therapy was associated with a significantly better response rate, longer progression-free survival, and greater improvement in quality of life measures than ...standard chemotherapy in patients with
ALK
-positive lung cancer.
Rearrangements of the anaplastic lymphoma kinase (
ALK
) gene are present in 3 to 5% of non–small-cell lung cancers (NSCLCs).
1
,
2
They define a distinct subgroup of NSCLC that typically occurs in younger patients who have never smoked or have a history of light smoking and that has adenocarcinoma histologic characteristics.
3
–
5
Crizotinib is an oral small-molecule tyrosine kinase inhibitor of ALK, MET, and ROS1 kinases.
6
In phase 1 and 2 studies, crizotinib treatment resulted in objective tumor responses in approximately 60% of patients with
ALK
-positive NSCLC and in progression-free survival of 7 to 10 months.
7
–
9
In . . .
Patients with myocardial infarction 1 to 3 years previously were assigned to ticagrelor, 90 or 60 mg twice daily, or to placebo, in addition to low-dose aspirin. At 3 years, ticagrelor reduced the ...risk of cardiovascular death, MI, or stroke but increased the risk of major bleeding.
Myocardial infarction is a global problem.
1
In the United States alone, nearly 8 million people have a history of myocardial infarction.
2
Patients who have had a myocardial infarction are at heightened risk for recurrent ischemic events,
3
–
5
which suggests that this population may derive particular benefit from intensive secondary prevention.
A key element in the pathobiology of cardiovascular ischemic events is the activated platelet.
6
Aspirin reduces the risk of ischemic events both among patients who present with an acute coronary syndrome and in secondary prevention for patients with a history of myocardial infarction.
7
The addition of a P2Y
12
receptor . . .
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