Targeting reactive nitrogen species: a promising therapeutic strategy for cerebral ischemia-reperfusion injury.

Science.gov (United States)

Chen, Xing-miao; Chen, Han-sen; Xu, Ming-jing; Shen, Jian-gang

2013-01-01

Ischemic stroke accounts for nearly 80% of stroke cases. Recanalization with thrombolysis is a currently crucial therapeutic strategy for re-building blood supply, but the thrombolytic therapy often companies with cerebral ischemia-reperfusion injury, which are mediated by free radicals. As an important component of free radicals, reactive nitrogen species (RNS), including nitric oxide (NO) and peroxynitrite (ONOO(-)), play important roles in the process of cerebral ischemia-reperfusion injury. Ischemia-reperfusion results in the production of nitric oxide (NO) and peroxynitrite (ONOO(-)) in ischemic brain, which trigger numerous molecular cascades and lead to disruption of the blood brain barrier and exacerbate brain damage. There are few therapeutic strategies available for saving ischemic brains and preventing the subsequent brain damage. Recent evidence suggests that RNS could be a therapeutic target for the treatment of cerebral ischemia-reperfusion injury. Herein, we reviewed the recent progress regarding the roles of RNS in the process of cerebral ischemic-reperfusion injury and discussed the potentials of drug development that target NO and ONOO(-) to treat ischemic stroke. We conclude that modulation for RNS level could be an important therapeutic strategy for preventing cerebral ischemia-reperfusion injury.

Therapeutic strategies to improve control of hypertension.

Science.gov (United States)

Armario, Pedro; Waeber, Bernard

2013-03-01

Blood pressure is poorly controlled in most European countries and the control rate is even lower in high-risk patients such as patients with chronic kidney disease, diabetic patients or previous coronary heart disease. Several factors have been associated with poor control, some of which involve the characteristic of the patients themselves, such as socioeconomic factors, or unsuitable life-styles, other factors related to hypertension or to associated comorbidity, but there are also factors directly associated with antihypertensive therapy, mainly involving adherence problems, therapeutic inertia and therapeutic strategies unsuited to difficult-to-control hypertensive patients. It is common knowledge that only 30% of hypertensive patients can be controlled using monotherapy; all the rest require a combination of two or more antihypertensive drugs, and this can be a barrier to good adherence and log-term persistence in patients who also often need to use other drugs, such as antidiabetic agents, statins or antiplatelet agents. The fixed combinations of three antihypertensive agents currently available can facilitate long-term control of these patients in clinical practice. If well tolerated, a long-term therapeutic regimen that includes a diuretic, an ACE inhibitor or an angiotensin receptor blocker, and a calcium channel blocker is the recommended optimal triple therapy.

Colorectal cancer: diagnostic and therapeutic strategies

International Nuclear Information System (INIS)

Vaillant, J.C.

1996-01-01

Technical advances that has been achieved during the past two decades have not dramatically improved the 35 % five-year rate observed in patients with colorectal cancer. These tumours remain one of the most challenging problems in public health policies in western countries. Screening applies to some subgroups of high-risk individuals and the general population aged over 50. In order to improve their efficacy, such screening programs imply large-scale information campaigns and a strong cooperation with the general physicians. The diagnosis is strongly suggested by any recent modification of bowel habits ad by rectal bleeding. It has to be confirmed by rectal examination and by colonoscopy which allows sampling to the tumour. Loco-regional and distant metastatic tumour spread must be assessed precisely before any therapeutic strategy is decided. Surgery, which resects the tumour en bloc with the corresponding lymphatic territories, is the only treatment that can achieve long term cure. In localized tumours, surgery alone can provide patients with 5-years survival rates close to 95 %. On the other hand, surgery alone is not sufficient to cure patients with advances cancers. In recent years, several adjuvant therapeutic modalities have been shown to improve the results of surgery in these cases (rectal cancer: pre-operative radiotherapy or post-operative radio-chemotherapy, colon cancer with nodal metastases: post-operative chemotherapy). There is a hope that a better use of our diagnostic and therapeutic armementarium would be able to avoid or to cure up to 75 % of the colorectal cancers we are dealing with. (author)

[Type 2 diabetes: what therapeutic strategy?].

Science.gov (United States)

Grimaldi, A; Hartemann-Heurtier, A

2001-02-17

GOAL OF TREATMENT: Prevention of diabetic micro and macroangiopathy is the goal of treatment in type 2 diabetes mellitus. A well-controlled glucose level is the key to prevention of microangiopathy; there is no threshold level. Antihypertensive treatment, with the goal of blood pressure below 130/80 mmHg is also beneficial in preventing aggravation of microangiopathy. For macroangiopathy, prevention is based in priority on treatment of other risk factors for cardiovascular disease; the threshold level for drug treatment and the therapeutic objective are those defined for secondary prevention in non-diabetic patients, i.e. blood pressure below 140/80 mmHg and LDL cholesterol under 1.30 g/l. The beneficial effect of lower glucose levels on preventing macrovascular risk was not formally demonstrated by the UKPDS, probably because the difference between the control and the treatment group HbA1c levels was minimal, 0.9 points. REVISITING STRATEGY: It is thus time to revisit the preventive strategy for type 2 diabetes mellitus, i.e. step-by-step increments, as currently proposed for worsening glucose levels. Metformine should be prescribed if the HbA1c is above normal in order to achieve the demonstrated benefit in prevention of microangiopathy and in the hope, motivated by pathophysiology data, of preventing insulin failure. Slow-release insulin at bedtime should be added to the oral hypoglycemiants if fasting glucose exceeds 1.60 or 1.80 g/l, even if the HbA1c remains below 8%. NEW HYPOGLYCEMIANTS: The role of these new agents in this more "aggressive" strategy remains to be defined. Glinides will have to demonstrate their superiority over sulfamides (fewer episodes of hypoglycemia with comparable efficacy) to justify their high cost. Glitazones will have to demonstrate a beneficial effect in second intention combination with metformine on cardiovascular morbidity mortality in type 2 diabetes patients with a metabolic insulin-resistance syndrome and visceral obesity

Using therapeutic cloning to fight human disease: a conundrum or reality?

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Hall, Vanessa J; Stojkovic, Petra; Stojkovic, Miodrag

2006-07-01

The development and transplantation of autologous cells derived from nuclear transfer embryonic stem cell (NT-ESC) lines to treat patients suffering from disease has been termed therapeutic cloning. Human NT is still a developing field, with further research required to improve somatic cell NT and human embryonic stem cell differentiation to deliver safe and effective cell replacement therapies. Furthermore, the implications of transferring mitochondrial heteroplasmic cells, which may harbor aberrant epigenetic gene expression profiles, are of concern. The production of human NT-ESC lines also remains plagued by ethical dilemmas, societal concerns, and controversies. Recently, a number of alternate therapeutic strategies have been proposed to circumvent the moral implications surrounding human nuclear transfer. It will be critical to overcome these biological, legislative, and moral restraints to maximize the potential of this therapeutic strategy and to alleviate human disease.

Co-immunization with DNA and protein mixture: a safe and efficacious immunotherapeutic strategy for Alzheimer's disease in PDAPP mice.

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Liu, Si; Shi, DanYang; Wang, Hai-Chao; Yu, Yun-Zhou; Xu, Qing; Sun, Zhi-Wei

2015-01-14

Active immunotherapy targeting β-amyloid (Aβ) is the most promising strategy to prevent or treat Alzheimer's disease (AD). Based on pre-clinical studies and clinical trials, a safe and effective AD vaccine requires a delicate balance between providing therapeutically adequate anti-Aβ antibodies and eliminating or suppressing unwanted adverse T cell-mediated inflammatory reactions. We describe here the immunological characterization and protective efficacy of co-immunization with a 6Aβ15-T DNA and protein mixture without adjuvant as an AD immunotherapeutic strategy. Impressively, this co-immunization induced robust Th2-polarized Aβ-specific antibodies while simultaneously suppressed unwanted inflammatory T cell reactions and avoiding Aβ42-specific T cell-mediated autoimmune responses in immunized mice. Co-immunization with the DNA + protein vaccine could overcome Aβ42-associated hypo-responsiveness and elicit long-term Aβ-specific antibody responses, which helped to maintain antibody-mediated clearance of amyloid and accordingly alleviated AD symptoms in co-immunized PDAPP mice. Our DNA and protein combined vaccine, which could induce an anti-inflammatory Th2 immune response with high level Aβ-specific antibodies and low level IFN-γ production, also demonstrated the capacity to inhibit amyloid accumulation and prevent cognitive dysfunction. Hence, co-immunization with antigen-matched DNA and protein may represent a novel and efficacious strategy for AD immunotherapy to eliminate T cell inflammatory reactions while retaining high level antibody responses.

Crosstalk between Apoptosis and Autophagy: Molecular Mechanisms and Therapeutic Strategies in Cancer

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Abdelouahid El-Khattouti

2013-01-01

Full Text Available Both apoptosis and autophagy are highly conserved processes that besides their role in the maintenance of the organismal and cellular homeostasis serve as a main target of tumor therapeutics. Although their important roles in the modulation of tumor therapeutic strategies have been widely reported, the molecular actions of both apoptosis and autophagy are counteracted by cancer protective mechanisms. While apoptosis is a tightly regulated process that is implicated in the removal of damaged or unwanted cells, autophagy is a cellular catabolic pathway that is involved in lysosomal degradation and recycling of proteins and organelles, and thereby is considered an important survival/protective mechanism for cancer cells in response to metabolic stress or chemotherapy. Although the relationship between autophagy and cell death is very complicated and has not been characterized in detail, the molecular mechanisms that control this relationship are considered to be a relevant target for the development of a therapeutic strategy for tumor treatment. In this review, we focus on the molecular mechanisms of apoptosis, autophagy, and those of the crosstalk between apoptosis and autophagy in order to provide insight into the molecular mechanisms that may be essential for the balance between cell survival and death as well as their role as targets for the development of novel therapeutic approaches.

Undergraduate nursing students writing therapeutic letters to families: an educational strategy.

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Erlingsson, Christen

2009-02-01

Writing therapeutic letters to families is discussed in this article as an educational strategy encouraging students to think reflectively about family nursing. At the University of Kalmar, Sweden, undergraduate nursing students in a primary care module interviewed families using the Calgary Family Assessment Model and wrote therapeutic letters to these families. This article describes (a) the examination process, which was the context for writing therapeutic letters, (b) results of analyses of the letters, and (c) student's post-examination evaluation comments. Results indicate that most students needed encouragement to focus on the family's strengths and resources instead of focusing on own feelings or problems they perceived the family as having. Students also needed support in relinquishing their hierarchical role of "expert nurse." Students' evaluation comments showed that writing therapeutic letters provided students with opportunities to reflect about the connections between family nursing theory and the family itself.

A Brief Overview of Tauopathy: Causes, Consequences, and Therapeutic Strategies.

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Orr, Miranda E; Sullivan, A Campbell; Frost, Bess

2017-07-01

There are currently no disease-modifying therapies for the treatment of tauopathies, a group of progressive neurodegenerative disorders that are pathologically defined by the presence of tau protein aggregates in the brain. Current challenges for the treatment of tauopathies include the inability to diagnose early and to confidently discriminate between distinct tauopathies in patients, alongside an incomplete understanding of the cellular mechanisms involved in pathogenic tau-induced neuronal death and dysfunction. In this review, we describe current diagnostic and therapeutic strategies, known drivers of pathogenic tau formation, recent contributions to our current mechanistic understanding of how pathogenic tau induces neuronal death, and potential diagnostic and therapeutic approaches. Copyright © 2017 Elsevier Ltd. All rights reserved.

Recent Advances in Stem Cell-Based Therapeutics for Stroke

OpenAIRE

Napoli, Eleonora; Borlongan, Cesar V.

2016-01-01

Regenerative medicine for central nervous system disorders, including stroke, has challenged the non-regenerative capacity of the brain. Among the many treatment strategies tailored towards repairing the injured brain, stem cell-based therapeutics have been demonstrated as safe and effective in animal models of stroke, and are being tested in limited clinical trials. We address here key lab-to-clinic translational research that relate to efficacy, safety, and mechanism of action underlying st...

An Integrated Data-Driven Strategy for Safe-by-Design Nanoparticles: The FP7 MODERN Project.

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Brehm, Martin; Kafka, Alexander; Bamler, Markus; Kühne, Ralph; Schüürmann, Gerrit; Sikk, Lauri; Burk, Jaanus; Burk, Peeter; Tamm, Tarmo; Tämm, Kaido; Pokhrel, Suman; Mädler, Lutz; Kahru, Anne; Aruoja, Villem; Sihtmäe, Mariliis; Scott-Fordsmand, Janeck; Sorensen, Peter B; Escorihuela, Laura; Roca, Carlos P; Fernández, Alberto; Giralt, Francesc; Rallo, Robert

2017-01-01

The development and implementation of safe-by-design strategies is key for the safe development of future generations of nanotechnology enabled products. The safety testing of the huge variety of nanomaterials that can be synthetized is unfeasible due to time and cost constraints. Computational modeling facilitates the implementation of alternative testing strategies in a time and cost effective way. The development of predictive nanotoxicology models requires the use of high quality experimental data on the structure, physicochemical properties and bioactivity of nanomaterials. The FP7 Project MODERN has developed and evaluated the main components of a computational framework for the evaluation of the environmental and health impacts of nanoparticles. This chapter describes each of the elements of the framework including aspects related to data generation, management and integration; development of nanodescriptors; establishment of nanostructure-activity relationships; identification of nanoparticle categories; hazard ranking and risk assessment.

Playing it safe: Patron safety strategies and experience of violence in night-time entertainment districts.

Science.gov (United States)

Zhou, Jin; Droste, Nicolas; Curtis, Ashlee; Zinkiewicz, Lucy; Miller, Peter

2018-03-01

Incidences of violence are elevated in night-time entertainment districts. Research suggests that safety-related behavioural strategies adopted while drinking can reduce negative alcohol-related outcomes. The current study investigates the use of safety strategies and its association with experiences of violence among patrons from the general population. Patron interviews (N = 3949) were conducted in and around licenced venues in Newcastle (New South Wales) and Geelong (Victoria) during peak trading hours (Friday and Saturday, 21:00-01:00 h). Participants (mean age = 24.3, SD = 5.8; male 54.4%) were asked to report what measures, if any, they used to keep safe when drinking and whether they had been involved in a violent incident in the last 12 months. After controlling for patron demographics and location, the use of multiple (more than one) safety strategies was significantly associated with reduced odds of involvement in a violent incident (odds ratio = 0.64, 95% confidence interval 0.49-0.85, P = 0.002). Significant gender differences were observed in the number and type of safety strategies reported. Increasing the number of safety-related behaviours during drinking occasions is associated with a small but significant reduction in experiencing alcohol-related harms, such as violence. [Zhou J, Droste N, Curtis A, Zinkiewicz L, Miller P. Playing it safe: Patron safety strategies and experience of violence in night-time entertainment districts. © 2017 Australasian Professional Society on Alcohol and other Drugs.

Design strategy for control of inherently safe reactors

International Nuclear Information System (INIS)

Chisholm, G.H.

1984-01-01

Reactor power plant safety is assured through a combination of engineered barriers to radiation release (e.g., reactor containment) in combination with active reactor safety systems to shut the reactor down and remove decay heat. While not specifically identified as safety systems, the control systems responsible for continuous operation of plant subsystems are the first line of defense for mitigating radiation releases and for plant protection. Inherently safe reactors take advantage of passive system features for decay-heat removal and reactor shutdown functions normally ascribed to active reactor safety systems. The advent of these reactors may permit restructuring of the present control system design strategy. This restructuring is based on the fact that authority for protection against unlikely accidents is, as much as practical, placed upon the passive features of the system instead of the traditional placement upon the PPS. Consequently, reactor control may be simplified, allowing the reliability of control systems to be improved and more easily defended

Manufacturing of Human Extracellular Vesicle-Based Therapeutics for Clinical Use

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Mario Gimona

2017-06-01

Full Text Available Extracellular vesicles (EVs derived from stem and progenitor cells may have therapeutic effects comparable to their parental cells and are considered promising agents for the treatment of a variety of diseases. To this end, strategies must be designed to successfully translate EV research and to develop safe and efficacious therapies, whilst taking into account the applicable regulations. Here, we discuss the requirements for manufacturing, safety, and efficacy testing of EVs along their path from the laboratory to the patient. Development of EV-therapeutics is influenced by the source cell types and the target diseases. In this article, we express our view based on our experience in manufacturing biological therapeutics for routine use or clinical testing, and focus on strategies for advancing mesenchymal stromal cell (MSC-derived EV-based therapies. We also discuss the rationale for testing MSC-EVs in selected diseases with an unmet clinical need such as critical size bone defects, epidermolysis bullosa and spinal cord injury. While the scientific community, pharmaceutical companies and clinicians are at the point of entering into clinical trials for testing the therapeutic potential of various EV-based products, the identification of the mode of action underlying the suggested potency in each therapeutic approach remains a major challenge to the translational path.

Endovenous treatment of primary varicose veins: an effective and safe therapeutic alternative to stripping?

International Nuclear Information System (INIS)

Kluner, C.; Fischer, T.; Filimonow, S.; Hamm, B.; Kroencke, T.

2005-01-01

Endovenous laser therapy (EVLT) is a new, minimally invasive therapeutic option for treating primary varicose veins and provides an effective and safe alternative to conventional surgical management (stripping). Short-term and intermediate-term outcome is comparable to surgical stripping in terms of elimination of venous reflux (90% - 98%), resolution of visible varices (85%), and improvement of subjective complaints such as sensations of heaviness and tension (96%). Complications occur in 1% - 3% of cases, which is markedly below the rate of conventional surgical management (up to 30%). The intermediate-term incidence of recurrent varicosis in a vein treated by EVLT depends on the laser fluence applied and is reported to range from 7% - 9% compared to 10% - 20% after surgical intervention. Based on a review of the current literature and our own experience, this survey article presents an overview of the indications and contraindications, the technique and pathophysiology of laser-induced venous occlusion, and the results and possible complications of EVLT. (orig.)

Hypoxia-regulated therapeutic gene as a preemptive treatment strategy against ischemia/reperfusion tissue injury.

Science.gov (United States)

Pachori, Alok S; Melo, Luis G; Hart, Melanie L; Noiseux, Nicholas; Zhang, Lunan; Morello, Fulvio; Solomon, Scott D; Stahl, Gregory L; Pratt, Richard E; Dzau, Victor J

2004-08-17

Ischemia and reperfusion represent major mechanisms of tissue injury and organ failure. The timing of administration and the duration of action limit current treatment approaches using pharmacological agents. In this study, we have successfully developed a preemptive strategy for tissue protection using an adenoassociated vector system containing erythropoietin hypoxia response elements for ischemia-regulated expression of the therapeutic gene human heme-oxygenase-1 (hHO-1). We demonstrate that a single administration of this vector several weeks in advance of ischemia/reperfusion injury to multiple tissues such as heart, liver, and skeletal muscle yields rapid and timely induction of hHO-1 during ischemia that resulted in dramatic reduction in tissue damage. In addition, overexpression of therapeutic transgene prevented long-term pathological tissue remodeling and normalized tissue function. Application of this regulatable system using an endogenous physiological stimulus for expression of a therapeutic gene may be a feasible strategy for protecting tissues at risk of ischemia/reperfusion injury.

Hypoxia-regulated therapeutic gene as a preemptive treatment strategy against ischemia/reperfusion tissue injury

Science.gov (United States)

Pachori, Alok S.; Melo, Luis G.; Hart, Melanie L.; Noiseux, Nicholas; Zhang, Lunan; Morello, Fulvio; Solomon, Scott D.; Stahl, Gregory L.; Pratt, Richard E.; Dzau, Victor J.

2004-08-01

Ischemia and reperfusion represent major mechanisms of tissue injury and organ failure. The timing of administration and the duration of action limit current treatment approaches using pharmacological agents. In this study, we have successfully developed a preemptive strategy for tissue protection using an adenoassociated vector system containing erythropoietin hypoxia response elements for ischemia-regulated expression of the therapeutic gene human heme-oxygenase-1 (hHO-1). We demonstrate that a single administration of this vector several weeks in advance of ischemia/reperfusion injury to multiple tissues such as heart, liver, and skeletal muscle yields rapid and timely induction of hHO-1 during ischemia that resulted in dramatic reduction in tissue damage. In addition, overexpression of therapeutic transgene prevented long-term pathological tissue remodeling and normalized tissue function. Application of this regulatable system using an endogenous physiological stimulus for expression of a therapeutic gene may be a feasible strategy for protecting tissues at risk of ischemia/reperfusion injury.

Targeting the Parasite's DNA with Methyltriazenyl Purine Analogs Is a Safe, Selective, and Efficacious Antitrypanosomal Strategy

NARCIS (Netherlands)

Rodenko, B.; Wanner, M.J.; Alkhaldi, A.A.M.; Ebiloma, G.U.; Barnes, R.L.; Kaiser, M.; Brun, R.; McCulloch, R.; Koomen, G.J.; de Koning, H.P.

2015-01-01

The human and veterinary disease complex known as African trypanosomiasis continues to inflict significant global morbidity, mortality, and economic hardship. Drug resistance and toxic side effects of old drugs call for novel and unorthodox strategies for new and safe treatment options. We designed

Therapeutic Symptomatic Strategies in the Parasomnias.

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Manni, Raffaele; Toscano, Gianpaolo; Terzaghi, Michele

2018-06-05

The purpose of this review was to discuss the currently available pharmacologic and non-pharmacologic treatment options for parasomnias. Recent pathophysiological findings about sleep structure in parasomnias helped understanding several drug mechanisms of action. Serotoninergic theory accounts for the effect of serotoninergic drugs. Study about spectral analysis of sleep showed the effect of clonazepam on spectral bands. Cannabinoids proved to be effective in some of parasomnias, as in many other neurological disorders. A series of therapeutic strategies were analyzed and compared. Benzodiazepines, antidepressant drugs, and L-5-hydroxytryptophan may be beneficial in DOA. SSRI and topiramate are effective in SRED. RBD responds to clonazepam, melatonin, and to a lesser extent to dopaminergic and anticholinergic agents. Prazosin and cannabinoids are effective in nightmare disorder. Sleep paralysis may respond to antidepressant agents. Tricyclic antidepressant may be effective in sleep-related hallucinations and exploding head syndrome. Sleep enuresis may be successfully treated with desmopressin, anticholinergic drugs, and imipramine.

Neuroprotective and Therapeutic Strategies against Parkinson’s Disease: Recent Perspectives

Directory of Open Access Journals (Sweden)

Sumit Sarkar

2016-06-01

Full Text Available Parkinsonism is a progressive motor disease that affects 1.5 million Americans and is the second most common neurodegenerative disease after Alzheimer’s. Typical neuropathological features of Parkinson’s disease (PD include degeneration of dopaminergic neurons located in the pars compacta of the substantia nigra that project to the striatum (nigro-striatal pathway and depositions of cytoplasmic fibrillary inclusions (Lewy bodies which contain ubiquitin and α-synuclein. The cardinal motor signs of PD are tremors, rigidity, slow movement (bradykinesia, poor balance, and difficulty in walking (Parkinsonian gait. In addition to motor symptoms, non-motor symptoms that include autonomic and psychiatric as well as cognitive impairments are pressing issues that need to be addressed. Several different mechanisms play an important role in generation of Lewy bodies; endoplasmic reticulum (ER stress induced unfolded proteins, neuroinflammation and eventual loss of dopaminergic neurons in the substantia nigra of mid brain in PD. Moreover, these diverse processes that result in PD make modeling of the disease and evaluation of therapeutics against this devastating disease difficult. Here, we will discuss diverse mechanisms that are involved in PD, neuroprotective and therapeutic strategies currently in clinical trial or in preclinical stages, and impart views about strategies that are promising to mitigate PD pathology.

Targeting lipid metabolism of cancer cells: A promising therapeutic strategy for cancer.

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Liu, Qiuping; Luo, Qing; Halim, Alexander; Song, Guanbin

2017-08-10

One of the most important metabolic hallmarks of cancer cells is deregulation of lipid metabolism. In addition, enhancing de novo fatty acid (FA) synthesis, increasing lipid uptake and lipolysis have also been considered as means of FA acquisition in cancer cells. FAs are involved in various aspects of tumourigenesis and tumour progression. Therefore, targeting lipid metabolism is a promising therapeutic strategy for human cancer. Recent studies have shown that reprogramming lipid metabolism plays important roles in providing energy, macromolecules for membrane synthesis, and lipid signals during cancer progression. Moreover, accumulation of lipid droplets in cancer cells acts as a pivotal adaptive response to harmful conditions. Here, we provide a brief review of the crucial roles of FA metabolism in cancer development, and place emphasis on FA origin, utilization and storage in cancer cells. Understanding the regulation of lipid metabolism in cancer cells has important implications for exploring a new therapeutic strategy for management and treatment of cancer. Copyright © 2017 Elsevier B.V. All rights reserved.

A readily applicable strategy to convert peptides to peptoid-based therapeutics.

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Minyoung Park

Full Text Available Incorporation of unnatural amino acids and peptidomimetic residues into therapeutic peptides is highly efficacious and commonly employed, but generally requires laborious trial-and-error approaches. Previously, we demonstrated that C20 peptide has the potential to be a potential antiviral agent. Herein we report our attempt to improve the biological properties of this peptide by introducing peptidomimetics. Through combined alanine, proline, and sarcosine scans coupled with a competitive fluorescence polarization assay developed for identifying antiviral peptides, we enabled to pinpoint peptoid-tolerant peptide residues within C20 peptide. The synergistic benefits of combining these (and other commonly employed methods could lead to a easily applicable strategy for designing and refining therapeutically-attractive peptidomimetics.

Ebola virus outbreak, updates on current therapeutic strategies.

Science.gov (United States)

Elshabrawy, Hatem A; Erickson, Timothy B; Prabhakar, Bellur S

2015-07-01

Filoviruses are enveloped negative-sense single-stranded RNA viruses, which include Ebola and Marburg viruses, known to cause hemorrhagic fever in humans with a case fatality of up to 90%. There have been several Ebola virus outbreaks since the first outbreak in the Democratic Republic of Congo in 1976 of which, the recent 2013-2015 epidemic in Guinea, Liberia, and Sierra Leone is the largest in recorded history. Within a few months of the start of the outbreak in December 2013, thousands of infected cases were reported with a significant number of deaths. As of March 2015, according to the Centers for Disease Control and Prevention, there have been nearly 25,000 suspected cases, with 15,000 confirmed by laboratory testing, and over 10,000 deaths. The large number of cases and the high mortality rate, combined with the lack of effective Food and Drug Administration-approved treatments, necessitate the development of potent and safe therapeutic measures to combat the current and future outbreaks. Since the beginning of the outbreak, there have been considerable efforts to develop and characterize protective measures including vaccines and antiviral small molecules, and some have proven effective in vitro and in animal models. Most recently, a cocktail of monoclonal antibodies has been shown to be highly effective in protecting non-human primates from Ebola virus infection. In this review, we will discuss what is known about the nature of the virus, phylogenetic classification, genomic organization and replication, disease transmission, and viral entry and highlight the current approaches and efforts, in the development of therapeutics, to control the outbreak. Copyright © 2015 John Wiley & Sons, Ltd.

Therapeutic strategies with oral fluoropyrimidine anticancer agent, S-1 against oral cancer.

Science.gov (United States)

Harada, Koji; Ferdous, Tarannum; Ueyama, Yoshiya

2017-08-01

Oral cancer has been recognized as a tumor with low sensitivity to anticancer agents. However, introduction of S-1, an oral cancer agent is improving treatment outcome for patients with oral cancer. In addition, S-1, as a main drug for oral cancer treatment in Japan can be easily available for outpatients. In fact, S-1 exerts high therapeutic effects with acceptable side effects. Moreover, combined chemotherapy with S-1 shows higher efficacy than S-1 alone, and combined chemo-radiotherapy with S-1 exerts remarkable therapeutic effects. Furthermore, we should consider the combined therapy of S-1 and molecular targeting agents right now as these combinations were reportedly useful for oral cancer treatment. Here, we describe our findings related to S-1 that were obtained experimentally and clinically, and favorable therapeutic strategies with S-1 against oral cancer with bibliographic considerations.

Safe abortion information hotlines: An effective strategy for increasing women's access to safe abortions in Latin America.

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Drovetta, Raquel Irene

2015-05-01

This paper describes the implementation of five Safe Abortion Information Hotlines (SAIH), a strategy developed by feminist collectives in a growing number of countries where abortion is legally restricted and unsafe. These hotlines have a range of goals and take different forms, but they all offer information by telephone to women about how to terminate a pregnancy using misoprostol. The paper is based on a qualitative study carried out in 2012-2014 of the structure, goals and experiences of hotlines in five Latin American countries: Argentina, Chile, Ecuador, Peru and Venezuela. The methodology included participatory observation of activities of the SAIH, and in-depth interviews with feminist activists who offer these services and with 14 women who used information provided by these hotlines to induce their own abortions. The findings are also based on a review of materials obtained from the five hotline collectives involved: documents and reports, social media posts, and details of public demonstrations and statements. These hotlines have had a positive impact on access to safe abortions for women whom they help. Providing these services requires knowledge and information skills, but little infrastructure. They have the potential to reduce the risk to women's health and lives of unsafe abortion, and should be promoted as part of public health policy, not only in Latin America but also other countries. Additionally, they promote women's autonomy and right to decide whether to continue or terminate a pregnancy. Copyright © 2015. Published by Elsevier Ltd.

A Synthetic-Biology-Inspired Therapeutic Strategy for Targeting and Treating Hepatogenous Diabetes.

Science.gov (United States)

Xue, Shuai; Yin, Jianli; Shao, Jiawei; Yu, Yuanhuan; Yang, Linfeng; Wang, Yidan; Xie, Mingqi; Fussenegger, Martin; Ye, Haifeng

2017-02-01

Hepatogenous diabetes is a complex disease that is typified by the simultaneous presence of type 2 diabetes and many forms of liver disease. The chief pathogenic determinant in this pathophysiological network is insulin resistance (IR), an asymptomatic disease state in which impaired insulin signaling in target tissues initiates a variety of organ dysfunctions. However, pharmacotherapies targeting IR remain limited and are generally inapplicable for liver disease patients. Oleanolic acid (OA) is a plant-derived triterpenoid that is frequently used in Chinese medicine as a safe but slow-acting treatment in many liver disorders. Here, we utilized the congruent pharmacological activities of OA and glucagon-like-peptide 1 (GLP-1) in relieving IR and improving liver and pancreas functions and used a synthetic-biology-inspired design principle to engineer a therapeutic gene circuit that enables a concerted action of both drugs. In particular, OA-triggered short human GLP-1 (shGLP-1) expression in hepatogenous diabetic mice rapidly and simultaneously attenuated many disease-specific metabolic failures, whereas OA or shGLP-1 monotherapy failed to achieve corresponding therapeutic effects. Collectively, this work shows that rationally engineered synthetic gene circuits are capable of treating multifactorial diseases in a synergistic manner by multiplexing the targeting efficacies of single therapeutics. Copyright © 2017 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Hydrogels for central nervous system therapeutic strategies.

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Russo, Teresa; Tunesi, Marta; Giordano, Carmen; Gloria, Antonio; Ambrosio, Luigi

2015-12-01

The central nervous system shows a limited regenerative capacity, and injuries or diseases, such as those in the spinal, brain and retina, are a great problem since current therapies seem to be unable to achieve good results in terms of significant functional recovery. Different promising therapies have been suggested, the aim being to restore at least some of the lost functions. The current review deals with the use of hydrogels in developing advanced devices for central nervous system therapeutic strategies. Several approaches, involving cell-based therapy, delivery of bioactive molecules and nanoparticle-based drug delivery, will be first reviewed. Finally, some examples of injectable hydrogels for the delivery of bioactive molecules in central nervous system will be reported, and the key features as well as the basic principles in designing multifunctional devices will be described. © IMechE 2015.

The arsenal of pathogens and antivirulence therapeutic strategies for disarming them

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Brannon JR

2016-05-01

Full Text Available John R Brannon,1 Maria Hadjifrangiskou1,21Division of Molecular Pathogenesis, Department of Pathology, Microbiology and Immunology, 2Department of Urologic Surgery, Vanderbilt University School of Medicine, Nashville, TN, USAAbstract: Pathogens deploy an arsenal of virulence factors (VFs to establish themselves within their infectious niche. The discovery of antimicrobial compounds and their development into therapeutics has made a monumental impact on human and microbial populations. Although humans have used antimicrobials for medicinal and agricultural purposes, microorganism populations have developed and shared resistance mechanisms to persevere in the face of classical antimicrobials. However, a positive substitute is antivirulence therapy; antivirulence therapeutics prevent or interrupt an infection by counteracting a pathogen’s VFs. Their application can reduce the use of broad-spectrum antimicrobials and dampen the frequency with which resistant strains emerge. Here, we summarize the contribution of VFs to various acute and chronic infections. In correspondence with this, we provide an overview of the research and development of antivirulence strategies.Keywords: virulence factors, antivirulence therapeutics, biofilms, regulation, Escherichia coli, quorum sensing, persister cells

Antimicrobial Peptides: A Promising Therapeutic Strategy in Tackling Antimicrobial Resistance.

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Nuti, Ramya; Goud, Nerella S; Saraswati, A Prasanth; Alvala, Ravi; Alvala, Mallika

2017-01-01

Antimicrobial resistance (AMR) has posed a serious threat to global public health and it requires immediate action, preferably long term. Current drug therapies have failed to curb this menace due to the ability of microbes to circumvent the mechanisms through which the drugs act. From the drug discovery point of view, the majority of drugs currently employed for antimicrobial therapy are small molecules. Recent trends reveal a surge in the use of peptides as drug candidates as they offer remarkable advantages over small molecules. Newer synthetic strategies like organometalic complexes, Peptide-polymer conjugates, solid phase, liquid phase and recombinant DNA technology encouraging the use of peptides as therapeutic agents with a host of chemical functions, and tailored for specific applications. In the last decade, many peptide based drugs have been successfully approved by the Food and Drug Administration (FDA). This success can be attributed to their high specificity, selectivity and efficacy, high penetrability into the tissues, less immunogenicity and less tissue accumulation. Considering the enormity of AMR, the use of Antimicrobial Peptides (AMPs) can be a viable alternative to current therapeutics strategies. AMPs are naturally abundant allowing synthetic chemists to develop semi-synthetics peptide molecules. AMPs have a broad spectrum of activity towards microbes and they possess the ability to bypass the resistance induction mechanisms of microbes. The present review focuses on the potential applications of AMPs against various microbial disorders and their future prospects. Several resistance mechanisms and their strategies have also been discussed to highlight the importance in the current scenario. Breakthroughs in AMP designing, peptide synthesis and biotechnology have shown promise in tackling this challenge and has revived the interest of using AMPs as an important weapon in fighting AMR. Copyright© Bentham Science Publishers; For any queries

Secular trends in mortality associated with new therapeutic strategies in surgical critical illness.

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Hartl, Wolfgang H; Wolf, Hilde; Schneider, Christian P; Küchenhoff, Helmut; Jauch, Karl-Walter

2007-10-01

Since 1999 randomized controlled trials have shown that new therapeutic strategies, such as strict glycemic control, increased use of noninvasive ventilation and of lung-protective ventilation, and early goal-oriented shock therapy, may reduce mortality in selected groups of critically ill patients. Whether these benefits can be translated to a surgical clinical setting is unclear. We wanted to evaluate longitudinally the successive routine implementation of new therapeutic measures and its effect on postsurgical patients admitted to the intensive care unit. We performed a retrospective analysis on data collected prospectively from March 1, 1993 through February 28, 2005. A cohort of 1,802 consecutive cases requiring intensive care therapy for more than 4 days was analyzed. A significant decrease in mortality was observed in the last years of the study. With adjustment for relevant covariates, treatment after the implementation of new therapeutic strategies was identified as an independent factor linked with a reduced risk of death (odds ratio [OR] .518; 95% confidence interval [CI] .337-.796), whereas older age (OR 1.030; 95% CI 1.015-1.045), a high severity score on admission (OR 1.155; 95% CI 1.113-1.198) or during intensive care unit stay (OR 1.187; 95% CI 1.145-1.231), a high number of failing organs (OR 1.918; 95% CI 1.635-2.250), and peritonitis (OR 3.277; 95% CI 2.046-5.246) were independently associated with death. Implementing of a variety of new therapeutic measures into routine care of critically ill surgical patients was associated with improved survival after 2001.

Emerging Therapeutic Strategies for Targeting Chronic Myeloid Leukemia Stem Cells

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Ahmad Hamad

2013-01-01

Full Text Available Chronic myeloid leukemia (CML is a clonal myeloproliferative disorder. Current targeted therapies designed to inhibit the tyrosine kinase activity of the BCR-ABL oncoprotein have made a significant breakthrough in the treatment of CML patients. However, CML remains a chronic disease that a patient must manage for life. Although tyrosine kinase inhibitors (TKI therapy has completely transformed the prognosis of CML, it has made the therapeutic management more complex. The interruption of TKI treatment results in early disease progression because it does not eliminate quiescent CML stem cells which remain a potential reservoir for disease relapse. This highlights the need to develop new therapeutic strategies for CML to achieve a permanent cure, and to allow TKI interruption. This review summarizes recent research done on alternative targeted therapies with a particular focus on some important signaling pathways (such as Alox5, Hedgehog, Wnt/b-catenin, autophagy, and PML that have the potential to target CML stem cells and potentially provide cure for CML.

Current therapeutic vaccination and immunotherapy strategies for HPV-related diseases.

Science.gov (United States)

Skeate, Joseph G; Woodham, Andrew W; Einstein, Mark H; Da Silva, Diane M; Kast, W Martin

2016-06-02

Carcinomas of the anogenital tract, in particular cervical cancer, remains one of the most common cancers in women, and represent the most frequent gynecological malignancies and the fourth leading cause of cancer death in women worldwide. Human papillomavirus (HPV)-induced lesions are immunologically distinct in that they express viral antigens, which are necessary to maintain the cancerous phenotype. The causal relationship between HPV infection and anogenital cancer has prompted substantial interest in the development of therapeutic vaccines against high-risk HPV types targeting the viral oncoproteins E6 and E7. This review will focus on the most recent clinical trials for immunotherapies for mucosal HPV-induced lesions as well as emerging therapeutic strategies that have been tested in pre-clinical models for HPV-induced diseases. Progress in peptide- and protein-based vaccines, DNA-based vaccines, viral/bacterial vector-based vaccines, immune checkpoint inhibition, immune response modifiers, and adoptive cell therapy for HPV will be discussed.

Strategy Escalation: An emerging paradigm for safe clinical development of T cell gene therapies

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Junghans Richard

2010-06-01

Full Text Available Abstract Gene therapy techniques are being applied to modify T cells with chimeric antigen receptors (CARs for therapeutic ends. The versatility of this platform has spawned multiple options for their application with new permutations in strategies continually being invented, a testimony to the creative energies of many investigators. The field is rapidly expanding with immense potential for impact against diverse cancers. But this rapid expansion, like the Big Bang, comes with a somewhat chaotic evolution of its therapeutic universe that can also be dangerous, as seen by recently publicized deaths. Time-honored methods for new drug testing embodied in Dose Escalation that were suitable for traditional inert agents are now inadequate for these novel "living drugs". In the following, I propose an approach to escalating risk for patient exposures with these new immuno-gene therapy agents, termed Strategy Escalation, that accounts for the molecular and biological features of the modified cells and the methods of their administration. This proposal is offered not as a prescriptive but as a discussion framework that investigators may wish to consider in configuring their intended clinical applications.

How safe is safe?

International Nuclear Information System (INIS)

Hughes, C.F.; Flood, M.

1996-01-01

Full text: The Australian Register of Therapeutic Goods lists over 25,000 medical device types currently supplied to Australian consumers. It is widely assumed that all goods listed on this register have been fully evaluated for safety and efficacy by the Therapeutic Goods Administration. However, only 1,010 devices are registered and thereby subject to full premarket evaluation. Five classes of registerable devices were arbitrarily assigned in 1986 based on overseas experience (Canada and the USA) and the work of several Advisory Panels convened by the then Minister of Health, Dr Neal Blewett. Some products have been removed from registerable categories, while others have been added. These decisions were made after reviewing device performance and problems. In May 1987, the Therapeutic Device Evaluation Committee (TDEC) and the Therapeutic Goods Administration introduced the Australian Therapeutic Device Problem Reporting Scheme. Under this scheme, any interested person can report medical device related problems to the Department for investigation. Each problem is investigated, a cause and/or outcome assigned and appropriate action is taken. Analysis of problem reports received indicates that no regulatory action was necessary in 34% of investigations. However, 24% of products required product improvement and recalls and/or safety alerts were issued for approximately 10% of problems investigated. In only 5% was the problem not confirmed by departmental investigation. The actual effect of the problem reported was temporary or minor injury in 10% of patients. In 2%, death or serious injury resulted. Forty-four percent of problems did not lead to patient injury at all and in 44% the problem was not related to the patient and/or his well being. However, the potential effect of death or serious injury was present in 17% of device problems. In 26% of reported events, temporary or minor injury could have occurred. Specific device related problems include the Bjork Shiley

Optimal Therapeutic Strategy for Non-small Cell Lung Cancer with Mutated Epidermal Growth Factor Receptor

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Zhong SHI

2015-02-01

Full Text Available Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs have been widely used in non-small cell lung cancer (NSCLC patients, it is still controversial about how to combine EGFR-TKI with chemotherapy and other targeted drugs. We have made a summary on the current therapeutic models of EGFR-TKI combined with chemotherapy/bevacizumab in this review and aimed to find the optimal therapeutic strategy for NSCLC patients with EGFR mutation.

Immune evasion in cancer: Mechanistic basis and therapeutic strategies.

Science.gov (United States)

Vinay, Dass S; Ryan, Elizabeth P; Pawelec, Graham; Talib, Wamidh H; Stagg, John; Elkord, Eyad; Lichtor, Terry; Decker, William K; Whelan, Richard L; Kumara, H M C Shantha; Signori, Emanuela; Honoki, Kanya; Georgakilas, Alexandros G; Amin, Amr; Helferich, William G; Boosani, Chandra S; Guha, Gunjan; Ciriolo, Maria Rosa; Chen, Sophie; Mohammed, Sulma I; Azmi, Asfar S; Keith, W Nicol; Bilsland, Alan; Bhakta, Dipita; Halicka, Dorota; Fujii, Hiromasa; Aquilano, Katia; Ashraf, S Salman; Nowsheen, Somaira; Yang, Xujuan; Choi, Beom K; Kwon, Byoung S

2015-12-01

Cancer immune evasion is a major stumbling block in designing effective anticancer therapeutic strategies. Although considerable progress has been made in understanding how cancers evade destructive immunity, measures to counteract tumor escape have not kept pace. There are a number of factors that contribute to tumor persistence despite having a normal host immune system. Immune editing is one of the key aspects why tumors evade surveillance causing the tumors to lie dormant in patients for years through "equilibrium" and "senescence" before re-emerging. In addition, tumors exploit several immunological processes such as targeting the regulatory T cell function or their secretions, antigen presentation, modifying the production of immune suppressive mediators, tolerance and immune deviation. Besides these, tumor heterogeneity and metastasis also play a critical role in tumor growth. A number of potential targets like promoting Th1, NK cell, γδ T cell responses, inhibiting Treg functionality, induction of IL-12, use of drugs including phytochemicals have been designed to counter tumor progression with much success. Some natural agents and phytochemicals merit further study. For example, use of certain key polysaccharide components from mushrooms and plants have shown to possess therapeutic impact on tumor-imposed genetic instability, anti-growth signaling, replicative immortality, dysregulated metabolism etc. In this review, we will discuss the advances made toward understanding the basis of cancer immune evasion and summarize the efficacy of various therapeutic measures and targets that have been developed or are being investigated to enhance tumor rejection. Copyright © 2015 Elsevier Ltd. All rights reserved.

Translational nanomedicine : Through the therapeutic window

NARCIS (Netherlands)

Pierce, Robin

2015-01-01

Translational nanomedicine occurs only through the successful integration of multiple inputs and iterative modifications. The therapeutic window plays a pivotal role in the trajectory of translational nanomedicine. Often defined in terms of the range of dosage for safe and effective therapeutic

Therapeutic strategies based on glucagon-like peptide 1

DEFF Research Database (Denmark)

Deacon, Carolyn F

2004-01-01

of factors influencing its metabolic stability and pharmacokinetic/pharmacodynamic profile, have therefore been the focus of intense research in both academia and the pharmaceutical industry. Such strategies include DPP-IV-resistant GLP-1 analogs and selective enzyme inhibitors to prevent in vivo degradation...... excursions. Furthermore, via its ability to enhance satiety, GLP-1 reduces food intake, thereby limiting weight gain, and may even cause weight loss. Taken together, these actions give GLP-1 a unique profile, considered highly desirable for an antidiabetic agent, particularly since the glucose dependency...... of its antihyperglycemic effects should minimize any risk of severe hypoglycemia. However, its pharmacokinetic/pharmacodynamic profile is such that native GLP-1 is not therapeutically useful. Thus, while GLP-1 is most effective when administered continuously, single subcutaneous injections have short...

Immunogenicity to therapeutic proteins: impact on PK/PD and efficacy.

Science.gov (United States)

Chirmule, Narendra; Jawa, Vibha; Meibohm, Bernd

2012-06-01

The development of therapeutic proteins requires the understanding of the relationship between the dose, exposure, efficacy, and toxicity of these molecules. Several intrinsic and extrinsic factors contribute to the challenges for measuring therapeutic proteins in a precise and accurate manner. In addition, induction of an immune response to therapeutic protein results in additional complexities in the analysis of the pharmacokinetic profile, toxicity, safety, and efficacy of this class of molecules. Assessment of immunogenicity of therapeutic proteins is a required aspect of regulatory filings for a licensing application and for the safe and efficacious use of these compounds. A systematic strategy and well-defined criteria for measuring anti-drug antibodies (ADA) have been established, to a large extent, through coordinated efforts. These recommendations are based on risk assessment and include the determination of ADA content (concentration/titer), affinity, immunoglobulin isotype/subtype, and neutralization capacity. This manuscript reviews the requirements necessary for understanding the nature of an ADA response in order to discern the impact of immunogenicity on pharmacokinetics/pharmacodynamics and efficacy.

Clinical reasoning in nursing: teaching strategies and assessment tools

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Emília Campos de Carvalho

Full Text Available ABSTRACT Objective: To present the concept and development of teaching strategies and the assessment tools regarding clinical reasoning for accurate practice. Method: This is a theoretical reflection based on scientific studies. Results: Comprehension of the essential concepts of the thought process and its articulation with the different teaching strategies and the assessment tools which has allowed presenting ways to improve the process of diagnostic or therapeutic clinical reasoning. Conclusion: The use of new strategies and assessment tools should be encouraged in order to contribute to the development of skills that lead to safe and effective decision making.

Safe communities in China as a strategy for injury prevention and safety promotion programmes in the era of rapid economic growth.

Science.gov (United States)

Wang, Shu-Mei; Dalal, Koustuv

2013-02-01

Due to its rapid economic development, China is facing a huge health, social, and economic burden resulting from injuries. The study's objective was to examine Safe Communities in China as a strategy for injury prevention and safety promotion programmes in the era of rapid economic growth. Literature searches in English and Chinese, which included grey literature, were performed on the Chinese Journal Full-text Search System and Medline, using the words "Safe Community", "injury", "economics", and "prevention". The results showed that the existing 35 recognized members of the International Safe Community Network have not placed due emphasis on suicide prevention, which is one of the leading problems in both rural and urban China. A few groups, such as children, the elderly, cyclists, and pedestrians, have received due emphasis, while other vulnerable groups, such as migrant workers, motorcyclists, students, players, and farmers have not received the necessary attention from the Safe Community perspective. As the evidence describes, Safe Communities in China can be a very effective strategy for injury prevention, but four aspects need to be strengthened in the future: (1) establish and strengthen the policy and regulations in terms of injury prevention at the national level; (2) create a system to involve professional organizations and personnel in projects; (3) consider the economic development status of different parts of China; and (4) intentional injury prevention should receive greater attention.

Modulating Neurotrophin Receptor Signaling as a Therapeutic Strategy for Huntington’s Disease

Science.gov (United States)

Simmons, Danielle A.

2017-01-01

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by CAG repeat expansions in the IT15 gene which encodes the huntingtin (HTT) protein. Currently, no treatments capable of preventing or slowing disease progression exist. Disease modifying therapeutics for HD would be expected to target a comprehensive set of degenerative processes given the diverse mechanisms contributing to HD pathogenesis including neuroinflammation, excitotoxicity, and transcription dysregulation. A major contributor to HD-related degeneration is mutant HTT-induced loss of neurotrophic support. Thus, neurotrophin (NT) receptors have emerged as therapeutic targets in HD. The considerable overlap between NT signaling networks and those dysregulated by mutant HTT provides strong theoretical support for this approach. This review will focus on the contributions of disrupted NT signaling in HD-related neurodegeneration and how targeting NT receptors to augment pro-survival signaling and/or to inhibit degenerative signaling may combat HD pathologies. Therapeutic strategies involving NT delivery, peptidomimetics, and the targeting of specific NT receptors (e.g., Trks or p75NTR), particularly with small molecule ligands, are discussed. PMID:29254102

Wharton’s Jelly-Derived Mesenchymal Stromal Cells as a Promising Cellular Therapeutic Strategy for the Management of Graft-versus-Host Disease

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Joseph P. McGuirk

2015-04-01

Full Text Available Allogeneic hematopoietic cell transplantation (allo-HCT, a treatment option in hematologic malignancies and bone marrow failure syndromes, is frequently complicated by Graft-versus-host disease (GVHD. The primary treatment for GVHD involves immune suppression by glucocorticoids. However, patients are often refractory to the steroid therapy, and this results in a poor prognosis. Therefore alternative therapies are needed to treat GVHD. Here, we review data supporting the clinical investigation of a novel cellular therapy using Wharton’s jelly (WJ-derived mesenchymal stromal cells (MSCs as a potentially safe and effective therapeutic strategy in the management of GVHD. Adult-derived sources of MSCs have demonstrated signals of efficacy in the management of GVHD. However, there are limitations, including: limited proliferation capacity; heterogeneity of cell sources; lengthy expansion time to clinical dose; expansion failure in vitro; and a painful, invasive, isolation procedure for the donor. Therefore, alternative MSC sources for cellular therapy are sought. The reviewed data suggests MSCs derived from WJ may be a safe and effective cellular therapy for GVHD. Laboratories investigated and defined the immune properties of WJ-MSCs for potential use in cellular therapy. These cells represent a more uniform cell population than bone marrow-derived MSCs, displaying robust immunosuppressive properties and lacking significant immunogenicity. They can be collected safely and painlessly from individuals at birth, rapidly expanded and stored cryogenically for later clinical use. Additionally, data we reviewed suggested licensing MSCs (activating MSCs by exposure to cytokines to enhance effectiveness in treating GVHD. Therefore, WJCs should be tested as a second generation, relatively homogeneous allogeneic cell therapy for the treatment of GVHD.

Therapeutic immunization strategies against cervical cancer : induction of cell-mediated immunity in murine models

NARCIS (Netherlands)

Bungener, Laura Barbara

2004-01-01

The aim of the study described in this thesis is the development of a therapeutic immunization strategy against cervical cancer and pre-malignant precursor lesions of cervical cancer (CIN lesions). Cervical cancer is caused by high risk human papillomavirus (HPV). Two of the early proteins of high

Music as a Therapeutic Assistant: Strategy to Reduce Work Stress

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Dereck Sena de Lima

2017-02-01

Full Text Available Objective: to understand the influence of music as a therapeutic assistant in reducing work stress of nursing professionals in a basic health unit. Method: it is an exploratory and descriptive research with a quantitative approach, developed with 9 nursing professionals from UBS Integrated Nova Esperança in João Pessoa, Paraíba. Data collection began after approval of the Research Ethics Committee of the Health Sciences Center of the Federal University of Paraíba, nº. 0508/16, CAAE: 58741916.6.0000.5188. Results: we identified that 33.3% of nursing professionals presented signs of stress, of the 33.3% who presented stress, 100% demonstrated to be in the resistance phase, 100% of the nursing professionals evaluated the musical strategy in a positive way. Conclusion: the musical strategy received extremely positive evaluations by the participants of the research, about 100% of professionals said that listening to music can reduce work stress.

Therapeutic strategies in Sickle Cell Anemia: The past present and future.

Science.gov (United States)

Fernandes, Queenie

2017-06-01

Sickle Cell Anemia (SCA) was one of the first hemoglobinopathies to be discovered. It is distinguished by the mutation-induced expression of a sickle cell variant of hemoglobin (HbS) that triggers erythrocytes to take a characteristic sickled conformation. The complex physiopathology of the disease and its associated clinical complications has initiated multi-disciplinary research within its field. This review attempts to lay emphasis on the evolution, current standpoint and future scope of therapeutic strategies in SCA. Copyright © 2017 Elsevier Inc. All rights reserved.

Investigation of therapeutic strategy for acute empyema

International Nuclear Information System (INIS)

Mochinaga, Koji; Akamine, Shinji; Muraoka, Masashi; Morino, Shigeyuki

2011-01-01

Recently, it has been reported that video-assisted thoracoscopic chest drainage is a useful treatment for acute empyema, but its indication has not been clarified. We retrospectively reviewed acute empyema patients by dividing them into 3 groups: operation group (7 patients), drainage group (6 patients), and antibiotic treatment group (9 patients), and then we evaluated the therapeutic strategy by examining the radiological findings, drainage period, and hospital stay. In the antibiotic treatment group, the ratio of pleural effusion on chest radiograph was under 1/4 in all patients. There were 5 patients who showed multilocular findings on chest CT, and all patients underwent an operation. Regarding the drainage period, the operation group showed a significantly shorter period than the drainage group. Concerning the hospital stay, the drainage group showed a significantly longer stay than the other 2 groups. The ratio of pleural effusion on chest radiograph was under 1/4, giving an indication for antibiotic treatment. With multilocular findings on CT, an indication for surgery is needed. Patients requiring drainage, which necessitates a long hospital stay, should be advised to consider surgery. (author)

Cell-based therapeutic strategies for multiple sclerosis.

Science.gov (United States)

Scolding, Neil J; Pasquini, Marcelo; Reingold, Stephen C; Cohen, Jeffrey A

2017-11-01

The availability of multiple disease-modifying medications with regulatory approval to treat multiple sclerosis illustrates the substantial progress made in therapy of the disease. However, all are only partially effective in preventing inflammatory tissue damage in the central nervous system and none directly promotes repair. Cell-based therapies, including immunoablation followed by autologous haematopoietic stem cell transplantation, mesenchymal and related stem cell transplantation, pharmacologic manipulation of endogenous stem cells to enhance their reparative capabilities, and transplantation of oligodendrocyte progenitor cells, have generated substantial interest as novel therapeutic strategies for immune modulation, neuroprotection, or repair of the damaged central nervous system in multiple sclerosis. Each approach has potential advantages but also safety concerns and unresolved questions. Moreover, clinical trials of cell-based therapies present several unique methodological and ethical issues. We summarize here the status of cell-based therapies to treat multiple sclerosis and make consensus recommendations for future research and clinical trials. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain.

Awareness tool for safe and responsible driving (OSCAR): a potential educational intervention for increasing interest, openness and knowledge about the abilities required and compensatory strategies among older drivers.

Science.gov (United States)

Levasseur, Mélanie; Audet, Thérèse; Gélinas, Isabelle; Bédard, Michel; Langlais, Marie-Ève; Therrien, France-Hélène; Renaud, Judith; Coallier, Jean-Claude; D'Amours, Monia

2015-01-01

This pilot study aimed to verify the impact of the awareness tool for safe and responsible driving (OSCAR) on older adults' (1) interest, openness, and knowledge about the abilities and compensatory strategies required for safe driving; (2) awareness of changes that have occurred in their own driving abilities; and (3) actual utilization of compensatory strategies. A preexperimental design, including a pretest (T0) and posttest (T1) 8 to 10 weeks after exposure to the intervention, was used with 48 drivers aged between 67 and 84. The participants had a valid driving license and drove at least once a week. Overall, the results demonstrate that OSCAR increased interest, openness, and knowledge about the abilities and compensatory strategies of older drivers (P driving, OSCAR also improved awareness of the changes that could negatively impact safe driving and enhanced utilization of compensatory strategies. While promoting safe driving and the prevention of crashes and injuries, this intervention could ultimately help older adults maintain or increase their transportation mobility. More studies are needed to further evaluate OSCAR and identify ways to improve its effectiveness.

The Assessment of the Colo-rectal Polyps in Order to the New Diagnostic and Therapeutic Strategies

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Raluca Diac Andreea

2015-09-01

Full Text Available Objective. Assessment of the histological and endoscopic features of the colo-rectal polyps is requered for the application of the new diagnostic and therapeutical strategies in the managment of the diminutive polyps.

Antioxidants as a Potential Preventive and Therapeutic Strategy for Cadmium.

Science.gov (United States)

Brzóska, Malgorzata M; Borowska, Sylwia; Tomczyk, Michal

2016-01-01

Epidemiological studies provide a growing number of evidences that chronic exposure to relatively low levels of cadmium (Cd), nowadays taking place in industrialized countries, may cause health hazard. Thus, growing interest has been focused on effective ways of protection from adverse effects of exposure to this heavy metal. Because numerous effects to Cd's toxic action result from its prooxidative properties, it seems reasonable that special attention should be directed to agents that can prevent or reduce this metal-induced oxidative stress and its consequences in tissues, organs and systems at risk of toxicity, including liver, kidneys, testes, ears, eyes, cardiovascular system and nervous system as well as bone tissue. This review discusses a wide range of natural (plant and animal origin) and synthetic antioxidants together with many plant extracts (e.g. black and green tea, Aronia melanocarpa, Allium sativum, Allium cepa, Ocimum sanctum, Phoenix dactylifera, Physalis peruviana, Zingiber officinale) that have been shown to prevent from Cd toxicity. Moreover, some attention has been focused on the fact that substances not possessing antioxidative potential may also prevent Cd-induced oxidative stress and its consequences. So far, most of the data on the protective effects of the natural and synthetic antioxidants and plant extracts come from studies in animals' models; however, numerous of them seem to be promising preventive/therapeutic strategies for Cd toxicity in humans. Further investigation of prophylactic and therapeutic use of antioxidants in populations exposed to Cd environmentally and occupationally is warranted, given that therapeutically effective chelation therapy for this toxic metal is currently lacking.

Therapeutic nuclear medicine

International Nuclear Information System (INIS)

Baum, Richard P.

2014-01-01

Discusses all aspects of radionuclide therapy, including basic principles, newly available treatments, regulatory requirements, and future trends. Provides the knowledge required to administer radionuclide therapy safely and effectively in the individual patient. Explains the role of the therapeutic nuclear physician in effectively coordinating a diverse multidisciplinary team. Written by leading experts. The recent revolution in molecular biology offers exciting new opportunities for targeted radionuclide therapy. The selective irradiation of tumor cells through molecular biological mechanisms is now permitting the radiopharmaceutical control of tumors that are unresectable and unresponsive to either chemotherapy or conventional radiotherapy. In this up-to-date, comprehensive book, world-renowned experts discuss the basic principles of radionuclide therapy, explore in detail the available treatments, explain the regulatory requirements, and examine likely future developments. The full range of clinical applications is considered, including thyroid cancer, hematological malignancies, brain tumors, liver cancer, bone and joint disease, and neuroendocrine tumors. The combination of theoretical background and practical information will provide the reader with all the knowledge required to administer radionuclide therapy safely and effectively in the individual patient. Careful attention is also paid to the important role of the therapeutic nuclear physician in delivering the effective coordination of a diverse multidisciplinary team that is essential to the safe provision of treatment.

Therapeutic nuclear medicine

Energy Technology Data Exchange (ETDEWEB)

Baum, Richard P. (ed.) [ENETS Center of Excellence, Bad Berka (Germany). THERANOSTICS Center for Molecular Radiotherapy and Molecular Imaging

2014-07-01

Discusses all aspects of radionuclide therapy, including basic principles, newly available treatments, regulatory requirements, and future trends. Provides the knowledge required to administer radionuclide therapy safely and effectively in the individual patient. Explains the role of the therapeutic nuclear physician in effectively coordinating a diverse multidisciplinary team. Written by leading experts. The recent revolution in molecular biology offers exciting new opportunities for targeted radionuclide therapy. The selective irradiation of tumor cells through molecular biological mechanisms is now permitting the radiopharmaceutical control of tumors that are unresectable and unresponsive to either chemotherapy or conventional radiotherapy. In this up-to-date, comprehensive book, world-renowned experts discuss the basic principles of radionuclide therapy, explore in detail the available treatments, explain the regulatory requirements, and examine likely future developments. The full range of clinical applications is considered, including thyroid cancer, hematological malignancies, brain tumors, liver cancer, bone and joint disease, and neuroendocrine tumors. The combination of theoretical background and practical information will provide the reader with all the knowledge required to administer radionuclide therapy safely and effectively in the individual patient. Careful attention is also paid to the important role of the therapeutic nuclear physician in delivering the effective coordination of a diverse multidisciplinary team that is essential to the safe provision of treatment.

Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

Science.gov (United States)

Gross, Christina; Berry-Kravis, Elizabeth M; Bassell, Gary J

2012-01-01

Fragile X syndrome (FXS) is an inherited neurodevelopmental disease caused by loss of function of the fragile X mental retardation protein (FMRP). In the absence of FMRP, signaling through group 1 metabotropic glutamate receptors is elevated and insensitive to stimulation, which may underlie many of the neurological and neuropsychiatric features of FXS. Treatment of FXS animal models with negative allosteric modulators of these receptors and preliminary clinical trials in human patients support the hypothesis that metabotropic glutamate receptor signaling is a valuable therapeutic target in FXS. However, recent research has also shown that FMRP may regulate diverse aspects of neuronal signaling downstream of several cell surface receptors, suggesting a possible new route to more direct disease-targeted therapies. Here, we summarize promising recent advances in basic research identifying and testing novel therapeutic strategies in FXS models, and evaluate their potential therapeutic benefits. We provide an overview of recent and ongoing clinical trials motivated by some of these findings, and discuss the challenges for both basic science and clinical applications in the continued development of effective disease mechanism-targeted therapies for FXS. PMID:21796106

Poly-S-Nitrosated Albumin as a Safe and Effective Multifunctional Antitumor Agent: Characterization, Biochemistry and Possible Future Therapeutic Applications

Directory of Open Access Journals (Sweden)

Yu Ishima

2013-01-01

Full Text Available Nitric oxide (NO is a ubiquitous molecule involved in multiple cellular functions. Inappropriate production of NO may lead to disease states. To date, pharmacologically active compounds that release NO within the body, such as organic nitrates, have been used as therapeutic agents, but their efficacy is significantly limited by unwanted side effects. Therefore, novel NO donors with better pharmacological and pharmacokinetic properties are highly desirable. The S-nitrosothiol fraction in plasma is largely composed of endogenous S-nitrosated human serum albumin (Mono-SNO-HSA, and that is why we are testing whether this albumin form can be therapeutically useful. Recently, we developed SNO-HSA analogs such as SNO-HSA with many conjugated SNO groups (Poly-SNO-HSA which were prepared using chemical modification. Unexpectedly, we found striking inverse effects between Poly-SNO-HSA and Mono-SNO-HSA. Despite the fact that Mono-SNO-HSA inhibits apoptosis, Poly-SNO-HSA possesses very strong proapoptotic effects against tumor cells. Furthermore, Poly-SNO-HSA can reduce or perhaps completely eliminate the multidrug resistance often developed by cancer cells. In this review, we forward the possibility that Poly-SNO-HSA can be used as a safe and effective multifunctional antitumor agent.

RNAi therapeutics and applications of microRNAs in cancer treatment.

Science.gov (United States)

Uchino, Keita; Ochiya, Takahiro; Takeshita, Fumitaka

2013-06-01

RNA interference-based therapies are proving to be powerful tools for combating various diseases, including cancer. Scientists are researching the development of safe and efficient systems for the delivery of small RNA molecules, which are extremely fragile in serum, to target organs and cells in the human body. A dozen pre-clinical and clinical trials have been under way over the past few years involving biodegradable nanoparticles, lipids, chemical modification and conjugation. On the other hand, microRNAs, which control the balance of cellular biological processes, have been studied as attractive therapeutic targets in cancer treatment. In this review, we provide an overview of RNA interference-based therapeutics in clinical trials and discuss the latest technology for the systemic delivery of nucleic acid drugs. Furthermore, we focus on dysregulated microRNAs in human cancer, which have progressed in pre-clinical trials as therapeutic targets, and describe a wide range of strategies to control the expression levels of endogenous microRNAs. Further development of RNA interference technologies and progression of clinical trials will contribute to the achievement of practical applications of nucleic acid drugs.

Factors associated with therapeutic strategies in patients with splanchnic vein thrombosis: Results of an international registry

NARCIS (Netherlands)

Riva, N.; Ageno, W.; Schulman, S.; Bang, S.M.; Sartori, M.T.; Grandone, E.; Beyer, J.; Barillari, G.; Di Minno, D.; Duce, R.; Malato, A.; Santoro, R.; Poli, D.; Verhamme, P.; Martinelli, I.; Kamphuisen, P.; Alatri, A.; Becattini, C.; Bucherini, E.; Piana, A.; De Stefano, V.; Dentali, F.

2012-01-01

Background Treatment of splanchnic vein thrombosis (SVT) is challenging due to the heterogeneous clinical presentation and the increased bleeding risk. We aimed to describe current treatment strategies and factors associated with therapeutic decisions. Materials and Methods Between May 2008 and

Molecular Strategies for Targeting Antioxidants to Mitochondria: Therapeutic Implications

Science.gov (United States)

2015-01-01

Abstract Mitochondrial function and specifically its implication in cellular redox/oxidative balance is fundamental in controlling the life and death of cells, and has been implicated in a wide range of human pathologies. In this context, mitochondrial therapeutics, particularly those involving mitochondria-targeted antioxidants, have attracted increasing interest as potentially effective therapies for several human diseases. For the past 10 years, great progress has been made in the development and functional testing of molecules that specifically target mitochondria, and there has been special focus on compounds with antioxidant properties. In this review, we will discuss several such strategies, including molecules conjugated with lipophilic cations (e.g., triphenylphosphonium) or rhodamine, conjugates of plant alkaloids, amino-acid- and peptide-based compounds, and liposomes. This area has several major challenges that need to be confronted. Apart from antioxidants and other redox active molecules, current research aims at developing compounds that are capable of modulating other mitochondria-controlled processes, such as apoptosis and autophagy. Multiple chemically different molecular strategies have been developed as delivery tools that offer broad opportunities for mitochondrial manipulation. Additional studies, and particularly in vivo approaches under physiologically relevant conditions, are necessary to confirm the clinical usefulness of these molecules. Antioxid. Redox Signal. 22, 686–729. PMID:25546574

Encapsulation Strategies of Bacteriophage (Felix O1) for Oral Therapeutic Application.

Science.gov (United States)

Islam, Golam S; Wang, Qi; Sabour, Parviz M

2018-01-01

Due to emerging antibiotic-resistant strains among the pathogens, a variety of strategies, including therapeutic application of bacteriophages, have been suggested as a possible alternative to antibiotics in food animal production. As pathogen-specific biocontrol agents, bacteriophages are being studied intensively. Primarily their applications in the food industry and animal production have been recognized in the USA and Europe, for pathogens including Salmonella, Campylobacter, Escherichia coli, and Listeria. However, the viability of orally administered phage may rapidly reduce under the harsh acidic conditions of the stomach, presence of enzymes and bile. It is evident that bacteriophages, intended for phage therapy by oral administration, require efficient protection from the acidic environment of the stomach and should remain active in the animal's gastrointestinal tract where pathogen colonizes. Encapsulation of phages by spray drying or extrusion methods can protect phages from the simulated hostile gut conditions and help controlled release of phages to the digestive system when appropriate formulation strategy is implemented.

Gene therapy for carcinoma of the breast: Therapeutic genetic correction strategies

International Nuclear Information System (INIS)

Obermiller, Patrice S; Tait, David L; Holt, Jeffrey T

2000-01-01

Gene therapy is a therapeutic approach that is designed to correct specific molecular defects that contribute to the cause or progression of cancer. Genes that are mutated or deleted in cancers include the cancer susceptibility genes p53 and BRCA1. Because mutational inactivation of gene function is specific to tumor cells in these settings, cancer gene correction strategies may provide an opportunity for selective targeting without significant toxicity for normal nontumor cells. Both p53 and BRCA1 appear to inhibit cancer cells that lack mutations in these genes, suggesting that the so-called gene correction strategies may have broader potential than initially believed. Increasing knowledge of cancer genetics has identified these and other genes as potential targets for gene replacement therapy. Initial patient trials of p53 and BRCA1 gene therapy have provided some indications of potential efficacy, but have also identified areas of basic and clinical research that are needed before these approaches may be widely used in patient care

TU-EF-210-00: Therapeutic Strategies and Image Guidance

Energy Technology Data Exchange (ETDEWEB)

NONE

2015-06-15

The use of therapeutic ultrasound to provide targeted therapy is an active research area that has a broad application scope. The invited talks in this session will address currently implemented strategies and protocols for both hyperthermia and ablation applications using therapeutic ultrasound. The role of both ultrasound and MRI in the monitoring and assessment of these therapies will be explored in both pre-clinical and clinical applications. Katherine Ferrara: High Intensity Focused Ultrasound, Drug Delivery, and Immunotherapy Rajiv Chopra: Translating Localized Doxorubicin Delivery to Pediatric Oncology using MRI-guided HIFU Elisa Konofagou: Real-time Ablation Monitoring and Lesion Quantification using Harmonic Motion Imaging Keyvan Farahani: AAPM Task Groups in Interventional Ultrasound Imaging and Therapy Learning Objectives: Understand the role of ultrasound in localized drug delivery and the effects of immunotherapy when used in conjunction with ultrasound therapy. Understand potential targeted drug delivery clinical applications including pediatric oncology. Understand the technical requirements for performing targeted drug delivery. Understand how radiation-force approaches can be used to both monitor and assess high intensity focused ultrasound ablation therapy. Understand the role of AAPM task groups in ultrasound imaging and therapies. Chopra: Funding from Cancer Prevention and Research Initiative of Texas (CPRIT), Award R1308 Evelyn and M.R. Hudson Foundation; Research Support from Research Contract with Philips Healthcare; COI are Co-founder of FUS Instruments Inc Ferrara: Supported by NIH, UCDavis and California (CIRM and BHCE) Farahani: In-kind research support from Philips Healthcare.

TU-EF-210-00: Therapeutic Strategies and Image Guidance

International Nuclear Information System (INIS)

2015-01-01

The use of therapeutic ultrasound to provide targeted therapy is an active research area that has a broad application scope. The invited talks in this session will address currently implemented strategies and protocols for both hyperthermia and ablation applications using therapeutic ultrasound. The role of both ultrasound and MRI in the monitoring and assessment of these therapies will be explored in both pre-clinical and clinical applications. Katherine Ferrara: High Intensity Focused Ultrasound, Drug Delivery, and Immunotherapy Rajiv Chopra: Translating Localized Doxorubicin Delivery to Pediatric Oncology using MRI-guided HIFU Elisa Konofagou: Real-time Ablation Monitoring and Lesion Quantification using Harmonic Motion Imaging Keyvan Farahani: AAPM Task Groups in Interventional Ultrasound Imaging and Therapy Learning Objectives: Understand the role of ultrasound in localized drug delivery and the effects of immunotherapy when used in conjunction with ultrasound therapy. Understand potential targeted drug delivery clinical applications including pediatric oncology. Understand the technical requirements for performing targeted drug delivery. Understand how radiation-force approaches can be used to both monitor and assess high intensity focused ultrasound ablation therapy. Understand the role of AAPM task groups in ultrasound imaging and therapies. Chopra: Funding from Cancer Prevention and Research Initiative of Texas (CPRIT), Award R1308 Evelyn and M.R. Hudson Foundation; Research Support from Research Contract with Philips Healthcare; COI are Co-founder of FUS Instruments Inc Ferrara: Supported by NIH, UCDavis and California (CIRM and BHCE) Farahani: In-kind research support from Philips Healthcare

Understanding HIV infection for the design of a therapeutic vaccine. Part II: Vaccination strategies for HIV.

Science.gov (United States)

de Goede, A L; Vulto, A G; Osterhaus, A D M E; Gruters, R A

2015-05-01

HIV infection leads to a gradual loss CD4(+) T lymphocytes comprising immune competence and progression to AIDS. Effective treatment with combined antiretroviral drugs (cART) decreases viral load below detectable levels but is not able to eliminate the virus from the body. The success of cART is frustrated by the requirement of expensive lifelong adherence, accumulating drug toxicities and chronic immune activation resulting in increased risk of several non-AIDS disorders, even when viral replication is suppressed. Therefore, there is a strong need for therapeutic strategies as an alternative to cART. Immunotherapy, or therapeutic vaccination, aims to increase existing immune responses against HIV or induce de novo immune responses. These immune responses should provide a functional cure by controlling viral replication and preventing disease progression in the absence of cART. The key difficulty in the development of an HIV vaccine is our ignorance of the immune responses that control of viral replication, and thus how these responses can be elicited and how they can be monitored. Part one of this review provides an extensive overview of the (patho-) physiology of HIV infection. It describes the structure and replication cycle of HIV, the epidemiology and pathogenesis of HIV infection and the innate and adaptive immune responses against HIV. Part two of this review discusses therapeutic options for HIV. Prevention modalities and antiretroviral therapy are briefly touched upon, after which an extensive overview on vaccination strategies for HIV is provided, including the choice of immunogens and delivery strategies. Copyright © 2014. Published by Elsevier Masson SAS.

Xeno-Free Strategies for Safe Human Mesenchymal Stem/Stromal Cell Expansion: Supplements and Coatings

Directory of Open Access Journals (Sweden)

M. Cimino

2017-01-01

Full Text Available Human mesenchymal stem/stromal cells (hMSCs have generated great interest in regenerative medicine mainly due to their multidifferentiation potential and immunomodulatory role. Although hMSC can be obtained from different tissues, the number of available cells is always low for clinical applications, thus requiring in vitro expansion. Most of the current protocols for hMSC expansion make use of fetal bovine serum (FBS as a nutrient-rich supplement. However, regulatory guidelines encourage novel xeno-free alternatives to define safer and standardized protocols for hMSC expansion that preserve their intrinsic therapeutic potential. Since hMSCs are adherent cells, the attachment surface and cell-adhesive components also play a crucial role on their successful expansion. This review focuses on the advantages/disadvantages of FBS-free media and surfaces/coatings that avoid the use of animal serum, overcoming ethical issues and improving the expansion of hMSC for clinical applications in a safe and reproducible way.

Dual targeting of MDM2 and BCL2 as a therapeutic strategy in neuroblastoma.

Science.gov (United States)

Van Goethem, Alan; Yigit, Nurten; Moreno-Smith, Myrthala; Vasudevan, Sanjeev A; Barbieri, Eveline; Speleman, Frank; Shohet, Jason; Vandesompele, Jo; Van Maerken, Tom

2017-08-22

Wild-type p53 tumor suppressor activity in neuroblastoma tumors is hampered by increased MDM2 activity, making selective MDM2 antagonists an attractive therapeutic strategy for this childhood malignancy. Since monotherapy in cancer is generally not providing long-lasting clinical responses, we here aimed to identify small molecule drugs that synergize with idasanutlin (RG7388). To this purpose we evaluated 15 targeted drugs in combination with idasanutlin in three p53 wild type neuroblastoma cell lines and identified the BCL2 inhibitor venetoclax (ABT-199) as a promising interaction partner. The venetoclax/idasanutlin combination was consistently found to be highly synergistic in a diverse panel of neuroblastoma cell lines, including cells with high MCL1 expression levels. A more pronounced induction of apoptosis was found to underlie the synergistic interaction, as evidenced by caspase-3/7 and cleaved PARP measurements. Mice carrying orthotopic xenografts of neuroblastoma cells treated with both idasanutlin and venetoclax had drastically lower tumor weights than mice treated with either treatment alone. In conclusion, these data strongly support the further evaluation of dual BCL2/MDM2 targeting as a therapeutic strategy in neuroblastoma.

Blockade of the intermediate-conductance calcium-activated potassium channel as a new therapeutic strategy for restenosis

DEFF Research Database (Denmark)

Köhler, Ralf; Wulff, Heike; Eichler, Ines

2003-01-01

hyperplasia was accompanied by decreased neointimal cell content, with no change in the rate of apoptosis or collagen content. CONCLUSIONS: The switch toward IKCa1 expression may promote excessive neointimal VSMC proliferation. Blockade of IKCa1 could therefore represent a new therapeutic strategy to prevent...

Translational nanomedicine--through the therapeutic window.

Science.gov (United States)

Pierce, Robin L

2015-01-01

Translational nanomedicine occurs only through the successful integration of multiple inputs and iterative modifications. The therapeutic window plays a pivotal role in the trajectory of translational nanomedicine. Often defined in terms of the range of dosage for safe and effective therapeutic effect, a second definition of the therapeutic window refers to the often narrow temporal window in which a therapeutic effect can be obtained. Expanding the second definition to explicitly include the spatial dimension, this article explores aspects of the therapeutic spaces created by nanomedicine that shift the traditional dimensions of symptom, sign and pathology. This article analyzes three aspects of the therapeutic window in nanomedicine - temporal, spatial and manner of construction and their impact on the dimensions of modern medicine.

Therapeutic strategies for spinal muscular atrophy: SMN and beyond

Directory of Open Access Journals (Sweden)

Melissa Bowerman

2017-08-01

Full Text Available Spinal muscular atrophy (SMA is a devastating neuromuscular disorder characterized by loss of motor neurons and muscle atrophy, generally presenting in childhood. SMA is caused by low levels of the survival motor neuron protein (SMN due to inactivating mutations in the encoding gene SMN1. A second duplicated gene, SMN2, produces very little but sufficient functional protein for survival. Therapeutic strategies to increase SMN are in clinical trials, and the first SMN2-directed antisense oligonucleotide (ASO therapy has recently been licensed. However, several factors suggest that complementary strategies may be needed for the long-term maintenance of neuromuscular and other functions in SMA patients. Pre-clinical SMA models demonstrate that the requirement for SMN protein is highest when the structural connections of the neuromuscular system are being established, from late fetal life throughout infancy. Augmenting SMN may not address the slow neurodegenerative process underlying progressive functional decline beyond childhood in less severe types of SMA. Furthermore, individuals receiving SMN-based treatments may be vulnerable to delayed symptoms if rescue of the neuromuscular system is incomplete. Finally, a large number of older patients living with SMA do not fulfill the present criteria for inclusion in gene therapy and ASO clinical trials, and may not benefit from SMN-inducing treatments. Therefore, a comprehensive whole-lifespan approach to SMA therapy is required that includes both SMN-dependent and SMN-independent strategies that treat the CNS and periphery. Here, we review the range of non-SMN pathways implicated in SMA pathophysiology and discuss how various model systems can serve as valuable tools for SMA drug discovery.

The strategies that peanut and nut-allergic consumers employ to remain safe when travelling abroad.

Science.gov (United States)

Barnett, Julie; Botting, Neil; Gowland, M Hazel; Lucas, Jane S

2012-07-09

An understanding of the management strategies used by food allergic individuals is needed as a prerequisite to improving avoidance and enhancing quality of life. Travel abroad is a high risk time for severe and fatal food allergic reactions, but there is paucity of research concerning foreign travel. This study is the first to investigate the experiences of, and strategies used by peanut and tree nut allergic individuals when travelling abroad. Thirty-two adults with a clinical history of reaction to peanuts or tree nuts consistent with IgE-mediated allergy participated in a qualitative interview study. Travel abroad was considered difficult with inherent risks for allergic individuals. Many participants recounted difficulties with airlines or restaurants. Inconsistency in managing allergen avoidance by airlines was a particular risk and a cause of frustration to participants. Individuals used a variety of strategies to remain safe including visiting familiar environments, limiting their activities, carrying allergy information cards in the host language, preparing their own food and staying close to medical facilities. Participants used a variety of allergen avoidance strategies, which were mostly extensions or modifications of the strategies that they use when eating at home or eating-out in the UK. The extended strategies reflected their recognition of enhanced risk during travel abroad. Their risk assessments and actions were generally well informed and appropriate. A need for airline policy regarding allergy to be declared and adhered to is needed, as is more research to quantify the true risks of airborne allergens in the cabin. Recommendations arising from our study are presented.

Goethe's anxieties, depressive episodes and (self-)therapeutic strategies: a contribution to method integration in psychotherapy.

Science.gov (United States)

Holm-Hadulla, Rainer M

2013-01-01

In psychiatry and psychotherapy, abstract scientific principles need to be exemplified by narrative case reports to gain practical precision. Goethe was one of the most creative writers, productive scientists, and effective statesmen that ever lived. His descriptions of feelings, emotions, and mental states related to anxieties, depressive episodes, dysthymia, and creativity are unique in their phenomenological precision and richness. His life and work can thus serve as an excellent example enhancing our understanding of the relationship between anxiety, depression and creativity. Furthermore, he described (self-)therapeutic strategies that reinforce and refine modern views. Goethe's self-assessments in his works and letters, and the descriptions by others are analyzed under the perspective of current psychiatric classification. His therapeutic techniques and recommendations are compared with cognitive-behavioral, psychodynamic, and existential psychotherapy to amplify modern concepts of psychotherapy. From a scientific perspective, several distinctive depressive episodes can be diagnosed in Goethe's life. They were characterized by extended depressive moods, lack of drive, and loss of interest and self-esteem combined with social retreat. Goethe displayed diffuse and phobic anxieties as well as dysthymia. His (self-)therapeutic strategies were: (a) the systematic use of helping alliances, (b) behavioral techniques, (c) cognitive reflection on meanings and beliefs, (d) psychodynamic and psychoanalytic remembering, repeating, and working through, and (e) existential striving for self-actualization, social commitment, meaning, and creativity. In Goethe's life, creative incubation, illumination, and elaboration appear to have been associated with psychic instability and dysthymia, sometimes with depressive episodes in a clinical sense. On the one hand, his creative work was triggered by anxieties, dysthymia, and depressive moods. On the other hand, his creativity

rAAV Vectors as Safe and Efficient Tools for the Stable Delivery of Genes to Primary Human Chondrosarcoma Cells In Vitro and In Situ

Directory of Open Access Journals (Sweden)

Henning Madry

2012-01-01

Full Text Available Treatment of chondrosarcoma remains a major challenge in orthopaedic oncology. Gene transfer strategies based on recombinant adenoassociated viral (rAAV vectors may provide powerful tools to develop new, efficient therapeutic options against these tumors. In the present study, we tested the hypothesis that rAAV is adapted for a stable and safe delivery of foreign sequences in human chondrosarcoma tissue by transducing primary human chondrosarcoma cells in vitro and in situ with different reporter genes (E. coli lacZ, firefly luc, Discosoma sp. RFP. The effects of rAAV administration upon cell survival and metabolic activities were also evaluated to monitor possibly detrimental effects of the gene transfer method. Remarkably, we provide evidence that efficient and prolonged expression of transgene sequences via rAAV can be safely achieved in all the systems investigated, demonstrating the potential of the approach of direct application of therapeutic gene vectors as a means to treat chondrosarcoma.

Effectiveness of multiple therapeutic strategies in neovascular glaucoma patients: A PRISMA-compliant network meta-analysis.

Science.gov (United States)

Dong, Zixian; Gong, Jianyang; Liao, Rongfeng; Xu, Shaojun

2018-04-01

Neovascular glaucoma (NVG) is a severe secondary glaucoma with uncontrolled intraocular pressure that leads to serious eye pain and vision loss. Presently, the therapeutic strategies for NVG are diverse, but the therapeutic effects are still not ideal. We performed a network analysis to assess the effect of multiple therapeutic strategies on the treatment of NVG patients. We searched public electronic databases through April 2017 using the following keywords "neovascular glaucoma," "iris neovascularization," "hemorrhagic glaucoma," and "random" without language restrictions. The outcome considered in the present analysis was treatment success rate. A network meta-analysis and multilevel mixed-effects logistic regression were used to compare regimens. We included 27 articles assessing a total of 1884 NVG patients in our analysis. According to the network analysis, interferon and mitomycin plus trabeculectomy (94.9%), glaucoma valve implantation (86.9%), and iris photocoagulation plus trabeculectomy (81.9%) were the most likely to improve treatment success rate in NVG patients. The multilevel logistic regression analysis showed that glaucoma valve, bevacizumab, interferon, cyclophotocoagulation, trabeculectomy, iris photocoagulation, ranibizumab, and mitomycin had advantages in terms of improving treatment success rate in NVG patients. However, the application of retinal photocoagulation and vitrectomy reduced patient treatment success rate. The regimen including mitomycin, interferon, and trabeculectomy was the most likely to improve the treatment success rate in NVG patients. The application of glaucoma valve and bevacizumab were more beneficial for improving patient treatment success rate as a surgery and as an agent, respectively.

Strategies and challenges for safe injection practice in developing countries

OpenAIRE

Gyawali, Sudesh; Rathore, Devendra Singh; Shankar, P Ravi; Kumar, KC Vikash

2013-01-01

Injection is one of the important health care procedures used globally to administer drugs. Its unsafe use can transmit various blood borne pathogens. This article aims to review the history and status of injection practices, its importance, interventions and the challenges for safe injection practice in developing countries. The history of injections started with the discovery of syringe in the early nineteenth century. Safe injection practice in developed countries was initiated in the earl...

Therapeutic HIV Peptide Vaccine

DEFF Research Database (Denmark)

Fomsgaard, Anders

2015-01-01

Therapeutic vaccines aim to control chronic HIV infection and eliminate the need for lifelong antiretroviral therapy (ART). Therapeutic HIV vaccine is being pursued as part of a functional cure for HIV/AIDS. We have outlined a basic protocol for inducing new T cell immunity during chronic HIV-1...... infection directed to subdominant conserved HIV-1 epitopes restricted to frequent HLA supertypes. The rationale for selecting HIV peptides and adjuvants are provided. Peptide subunit vaccines are regarded as safe due to the simplicity, quality, purity, and low toxicity. The caveat is reduced immunogenicity...

Cerebral collateral therapeutics in acute ischemic stroke: A randomized preclinical trial of four modulation strategies.

Science.gov (United States)

Beretta, Simone; Versace, Alessandro; Carone, Davide; Riva, Matteo; Dell'Era, Valentina; Cuccione, Elisa; Cai, Ruiyao; Monza, Laura; Pirovano, Silvia; Padovano, Giada; Stiro, Fabio; Presotto, Luca; Paternò, Giovanni; Rossi, Emanuela; Giussani, Carlo; Sganzerla, Erik P; Ferrarese, Carlo

2017-10-01

Cerebral collaterals are dynamically recruited after arterial occlusion and highly affect tissue outcome in acute ischemic stroke. We investigated the efficacy and safety of four pathophysiologically distinct strategies for acute modulation of collateral flow (collateral therapeutics) in the rat stroke model of transient middle cerebral artery (MCA) occlusion. A composed randomization design was used to assign rats (n = 118) to receive phenylephrine (induced hypertension), polygeline (intravascular volume load), acetazolamide (cerebral arteriolar vasodilation), head down tilt (HDT) 15° (cerebral blood flow diversion), or no treatment, starting 30 min after MCA occlusion. Compared to untreated animals, treatment with collateral therapeutics was associated with lower infarct volumes (62% relative mean difference; 51.57 mm 3 absolute mean difference; p Collateral therapeutics acutely increased cerebral perfusion in the medial (+40.8%; p collaterals is feasible and provides a tissue-saving effect in the hyperacute phase of ischemic stroke prior to recanalization therapy.

A therapeutic HIV vaccine using coxsackie-HIV recombinants: a possible new strategy.

Science.gov (United States)

Halim, S S; Collins, D N; Ramsingh, A I

2000-10-10

The ultimate goal in the treatment of HIV-infected persons is to prevent disease progression. A strategy to accomplish this goal is to use chemotherapy to reduce viral load followed by immunotherapy to stimulate HIV-specific immune responses that are observed in long-term asymptomatic individuals. An effective, live, recombinant virus, expressing HIV sequences, would be capable of inducing both CTL and CD4(+) helper T cell responses. To accomplish these goals, the viral vector must be immunogenic yet retain its avirulent phenotype in a T cell-deficient host. We have identified a coxsackievirus variant, CB4-P, that can induce protective immunity against a virulent variant. In addition, the CB4-P variant remains avirulent in mice lacking CD4(+) helper T cells, suggesting that CB4-P may be uniquely suited as a viral vector for a therapeutic HIV vaccine. Two strategies designed to elicit CTL and CD4(+) helper T cell responses were used to construct CB4-P/HIV recombinants. Recombinant viruses were viable, genetically stable, and retained the avirulent phenotype of the parental virus. In designing a viral vector for vaccine development, an issue that must be addressed is whether preexisting immunity to the vector would affect subsequent administration of the recombinant virus. Using a test recombinant, we showed that prior exposure to the parental CB4-P virus did not affect the ability of the recombinant to induce a CD4(+) T cell response against the foreign sequence. The results suggest that a "cocktail" of coxsackie/HIV recombinants may be useful as a therapeutic HIV vaccine.

Cell-based therapeutic strategies for replacement and preservation in retinal degenerative diseases

Science.gov (United States)

Jones, Melissa K.; Lu, Bin; Girman, Sergey; Wang, Shaomei

2017-01-01

Cell-based therapeutics offer diverse options for treating retinal degenerative diseases, such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP). AMD is characterized by both genetic and environmental risks factors, whereas RP is mainly a monogenic disorder. Though treatments exist for some patients with neovascular AMD, a majority of retinal degenerative patients have no effective therapeutics, thus indicating a need for universal therapies to target diverse patient populations. Two main cell-based mechanistic approaches are being tested in clinical trials. Replacement therapies utilize cell-derived retinal pigment epithelial (RPE) cells to supplant lost or defective host RPE cells. These cells are similar in morphology and function to native RPE cells and can potentially supplant the responsibilities of RPE in vivo. Preservation therapies utilize supportive cells to aid in visual function and photoreceptor preservation partially by neurotrophic mechanisms. The goal of preservation strategies is to halt or slow the progression of disease and maintain remaining visual function. A number of clinical trials are testing the safety of replacement and preservation cell therapies in patients; however, measures of efficacy will need to be further evaluated. In addition, a number of prevailing concerns with regards to the immune-related response, longevity, and functionality of the grafted cells will need to be addressed in future trials. This review will summarize the current status of cell-based preclinical and clinical studies with a focus on replacement and preservation strategies and the obstacles that remain regarding these types of treatments. PMID:28111323

[Psychic aspects of the premenstrual dysphoric disorders. New therapeutic strategies: our experience with Vitex agnus castus].

Science.gov (United States)

Ciotta, L; Pagano, I; Stracquadanio, M; Di Leo, S; Andò, A; Formuso, C

2011-06-01

The premenstrual dysphoric disorder (PMDD) is one of the main problems of the premenstrual phase. It consists of symptoms that sometimes invalidate the scope of employment, social and psycho-affective of patients, requiring thus a diagnostic and therapeutic approach as detailed and accurate as possible. The therapeutic strategies available for this disease are many, but recently the emphasis has been on Vitex agnus castus (VAC), considered by many as evidence drug of choice for both PMS and for the PMDD, being with satisfactory therapeutic properties and small side effects. Our study evaluated a group of patients suffering from PMDD and the clinical efficacy of treatment with VAC (and compared the effectiveness of the results of a more homogeneous group of patients treated with fluoxetine). This study confirms the data reported in the literature regarding the effectiveness of VAC therapy with no side effects.

Therapeutic Strategy for Chronic Headache in Children

Directory of Open Access Journals (Sweden)

H.O. Lezhenko

2016-05-01

Full Text Available The therapeutic efficacy of a combined homeopathic preparation Cefavora, which consists of alcoholic extracts of Ginkgo biloba, hawthorn (Crataegus and white mistletoe (Viscum album, has been studied in the treatment of chronic tension-type headache in children. It has been shown that alongside with elimination of headache manifestations, the use of homeopathic medicine has contributed to the normalization of adaptive mechanisms of autonomic regulation in children indicating its high therapeutic efficacy.

Nanotechnological strategies for nerve growth factor delivery: Therapeutic implications in Alzheimer's disease.

Science.gov (United States)

Faustino, Célia; Rijo, Patrícia; Reis, Catarina Pinto

2017-06-01

Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with amyloid-β peptide misfolding and aggregation. Neurotrophic factors, such as nerve growth factor (NGF), can prevent neuronal damage and rescue the cholinergic neurons that undergo cell death in AD, reverse deposition of extracellular amyloid plaques and improve cognitive deficits. However, NGF administration is hampered by the poor pharmacokinetic profile of the therapeutic protein and its inability to cross the blood-brain barrier, which requires specialised drug delivery systems (DDS) for efficient NGF delivery to the brain. This review covers the main therapeutic approaches that have been developed for NGF delivery targeting the brain, from polymeric implants to gene and cell-based therapies, focusing on the role of nanoparticulate systems for the sustained release of NGF in the brain as a neuroprotective and disease-modifying approach toward AD. Lipid- and polymer-based delivery systems, magnetic nanoparticles and quantum dots are specifically addressed as promising nanotechnological strategies to overcome the current limitations of NGF-based therapies. Copyright © 2017 Elsevier Ltd. All rights reserved.

The strategies that peanut and nut-allergic consumers employ to remain safe when travelling abroad

Directory of Open Access Journals (Sweden)

Barnett Julie

2012-07-01

Full Text Available Abstract Background An understanding of the management strategies used by food allergic individuals is needed as a prerequisite to improving avoidance and enhancing quality of life. Travel abroad is a high risk time for severe and fatal food allergic reactions, but there is paucity of research concerning foreign travel. This study is the first to investigate the experiences of, and strategies used by peanut and tree nut allergic individuals when travelling abroad. Methods Thirty-two adults with a clinical history of reaction to peanuts or tree nuts consistent with IgE-mediated allergy participated in a qualitative interview study. Results Travel abroad was considered difficult with inherent risks for allergic individuals. Many participants recounted difficulties with airlines or restaurants. Inconsistency in managing allergen avoidance by airlines was a particular risk and a cause of frustration to participants. Individuals used a variety of strategies to remain safe including visiting familiar environments, limiting their activities, carrying allergy information cards in the host language, preparing their own food and staying close to medical facilities. Conclusions Participants used a variety of allergen avoidance strategies, which were mostly extensions or modifications of the strategies that they use when eating at home or eating-out in the UK. The extended strategies reflected their recognition of enhanced risk during travel abroad. Their risk assessments and actions were generally well informed and appropriate. A need for airline policy regarding allergy to be declared and adhered to is needed, as is more research to quantify the true risks of airborne allergens in the cabin. Recommendations arising from our study are presented.

Strategies to optimize the biocompatibility of iron oxide nanoparticles – “SPIONs safe by design”

International Nuclear Information System (INIS)

Janko, Christina; Zaloga, Jan; Pöttler, Marina; Dürr, Stephan

2017-01-01

Various nanoparticle systems have been developed for medical applications in recent years. For constant improvement of efficacy and safety of nanoparticles, a close interdisciplinary interplay between synthesis, physicochemical characterizations and toxicological investigations is urgently needed. Based on combined toxicological data, we follow a “safe-by design” strategy for our superparamagnetic iron oxide nanoparticles (SPION). Using complementary interference-free toxicological assay systems, we initially identified agglomeration tendencies in physiological fluids, strong uptake by cells and improvable biocompatibility of lauric acid (LA)-coated SPIONs (SPION LA ). Thus, we decided to further stabilize those particles by an artificial protein corona consisting of serum albumin. This approach finally lead to increased colloidal stability, augmented drug loading capacity and improved biocompatibility in previous in vitro assays. Here, we show in whole blood ex vivo and on isolated red blood cells (RBC) that a protein corona protects RBCs from hemolysis by SPIONs. - Highlights: • Comparison of hemolytic properties between two SPION systems (with and without protein corona). • Protein corona increases the colloidal stability and hemocompatibility of SPIONs. • Close interaction between nanoparticle synthesis, physicochemical characterization and toxicology enables nanoparticle optimization (“safe by design”).

Strategies to optimize the biocompatibility of iron oxide nanoparticles – “SPIONs safe by design”

Energy Technology Data Exchange (ETDEWEB)

Janko, Christina, E-mail: christina.janko@uk-erlangen.de [Department of Otorhinolaryngology, Head and Neck Surgery, Section of Experimental Oncology and Nanomedicine (SEON), Else Kröner-Fresenius-Stiftung Professorship, University Hospital Erlangen, Glückstraße 10a, Erlangen, 91054 Germany (Germany); Zaloga, Jan, E-mail: jan.zaloga@uk-erlangen.de [Department of Otorhinolaryngology, Head and Neck Surgery, Section of Experimental Oncology and Nanomedicine (SEON), Else Kröner-Fresenius-Stiftung Professorship, University Hospital Erlangen, Glückstraße 10a, Erlangen, 91054 Germany (Germany); Pöttler, Marina, E-mail: marina.poettler@uk-erlangen.de [Department of Otorhinolaryngology, Head and Neck Surgery, Section of Experimental Oncology and Nanomedicine (SEON), Else Kröner-Fresenius-Stiftung Professorship, University Hospital Erlangen, Glückstraße 10a, Erlangen, 91054 Germany (Germany); Dürr, Stephan, E-mail: stephan.duerr@uk-erlangen.de [Department of Otorhinolaryngology, Head and Neck Surgery, Section of Experimental Oncology and Nanomedicine (SEON), Else Kröner-Fresenius-Stiftung Professorship, University Hospital Erlangen, Glückstraße 10a, Erlangen, 91054 Germany (Germany); Department of Otorhinolaryngology, Section of Phoniatrics & Pediatric Audiology, Head & Neck Surgery, University Hospital Erlangen, Bohlenplatz 21, Erlangen, 91054 Germany (Germany); and others

2017-06-01

Various nanoparticle systems have been developed for medical applications in recent years. For constant improvement of efficacy and safety of nanoparticles, a close interdisciplinary interplay between synthesis, physicochemical characterizations and toxicological investigations is urgently needed. Based on combined toxicological data, we follow a “safe-by design” strategy for our superparamagnetic iron oxide nanoparticles (SPION). Using complementary interference-free toxicological assay systems, we initially identified agglomeration tendencies in physiological fluids, strong uptake by cells and improvable biocompatibility of lauric acid (LA)-coated SPIONs (SPION{sup LA}). Thus, we decided to further stabilize those particles by an artificial protein corona consisting of serum albumin. This approach finally lead to increased colloidal stability, augmented drug loading capacity and improved biocompatibility in previous in vitro assays. Here, we show in whole blood ex vivo and on isolated red blood cells (RBC) that a protein corona protects RBCs from hemolysis by SPIONs. - Highlights: • Comparison of hemolytic properties between two SPION systems (with and without protein corona). • Protein corona increases the colloidal stability and hemocompatibility of SPIONs. • Close interaction between nanoparticle synthesis, physicochemical characterization and toxicology enables nanoparticle optimization (“safe by design”).

RNA interference-based therapeutics: new strategies to fight infectious disease.

Science.gov (United States)

López-Fraga, M; Wright, N; Jiménez, A

2008-12-01

For many years, there has been an ongoing search for new compounds that can selectively alter gene expression as a new way to treat human disease by addressing targets that are otherwise "undruggable" with traditional pharmaceutical approaches involving small molecules or proteins. RNA interference (RNAi) strategies have raised a lot of attention and several compounds are currently being tested in clinical trials. Viruses are the obvious target for RNAi-therapy, as most are difficult to treat with conventional drugs, they become rapidly resistant to drug treatment and their genes differ substantially from human genes, minimizing side effects. Antisense strategy offers very high target specificity, i.e., any viral sequence could potentially be targeted using the complementary oligonucleotide sequence. Consequently, new antisense-based therapeutics have the potential to lead a revolution in the anti-infective drug development field. Additionally, the relatively short turnaround for efficacy testing of potential RNAi molecules and that any pathogen is theoretically amenable to rapid targeting, make them invaluable tools for treating a wide range of diseases. This review will focus on some of the current efforts to treat infectious disease with RNAi-based therapies and some of the obstacles that have appeared on the road to successful clinical intervention.

Local Safety Toolkit: Enabling safe communities of opportunity

CSIR Research Space (South Africa)

Holtmann, B

2010-08-31

Full Text Available remain inadequate to achieve safety. The Local Safety Toolkit supports a strategy for a Safe South Africa through the implementation of a model for a Safe Community of Opportunity. The model is the outcome of work undertaken over the course of the past...

Targeting the renin-angiotensin system as novel therapeutic strategy for pulmonary diseases.

Science.gov (United States)

Tan, Wan Shun Daniel; Liao, Wupeng; Zhou, Shuo; Mei, Dan; Wong, Wai-Shiu Fred

2017-12-27

The renin-angiotensin system (RAS) plays a major role in regulating electrolyte balance and blood pressure. RAS has also been implicated in the regulation of inflammation, proliferation and fibrosis in pulmonary diseases such as asthma, acute lung injury (ALI), chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF) and pulmonary arterial hypertension (PAH). Current therapeutics suffer from some drawbacks like steroid resistance, limited efficacies and side effects. Novel intervention is definitely needed to offer optimal therapeutic strategy and clinical outcome. This review compiles and analyses recent investigations targeting RAS for the treatment of inflammatory lung diseases. Inhibition of the upstream angiotensin (Ang) I/Ang II/angiotensin receptor type 1 (AT 1 R) pathway and activation of the downstream angiotensin-converting enzyme 2 (ACE2)/Ang (1-7)/Mas receptor pathway are two feasible strategies demonstrating efficacies in various pulmonary disease models. More recent studies favor the development of targeting the downstream ACE2/Ang (1-7)/Mas receptor pathway, in which diminazene aceturate, an ACE2 activator, GSK2586881, a recombinant ACE2, and AV0991, a Mas receptor agonist, showed much potential for further development. As the pathogenesis of pulmonary diseases is so complex that RAS modulation may be used alone or in combination with existing drugs like corticosteroids, pirfenidone/nintedanib or endothelin receptor antagonists for different pulmonary diseases. Personalized medicine through genetic screening and phenotyping for angiotensinogen or ACE would aid treatment especially for non-responsive patients. This review serves to provide an update on the latest development in the field of RAS targeting for pulmonary diseases, and offer some insights into future direction. Copyright © 2017 Elsevier Ltd. All rights reserved.

Towards new therapeutic strategies in chondrosarcoma

NARCIS (Netherlands)

Schrage, Yvonne Maria

2009-01-01

This thesis presents the identification of new targets for therapeutic treatment of chondrosarcoma, tumours that are highly insensitive to conventional chemo- and radiation thearapy. A relatively new array technique to identify active kinases in chondrosarcoma cell cultures was used, which

Modulation of mitochondrial bioenergetics as a therapeutic strategy in Alzheimer's disease

Directory of Open Access Journals (Sweden)

Isaac G Onyango

2018-01-01

Full Text Available Alzheimer's disease (AD is an increasingly pressing worldwide public-health, social, political and economic concern. Despite significant investment in multiple traditional therapeutic strategies that have achieved success in preclinical models addressing the pathological hallmarks of the disease, these efforts have not translated into any effective disease-modifying therapies. This could be because interventions are being tested too late in the disease process. While existing therapies provide symptomatic and clinical benefit, they do not fully address the molecular abnormalities that occur in AD neurons. The pathophysiology of AD is complex; mitochondrial bioenergetic deficits and brain hypometabolism coupled with increased mitochondrial oxidative stress are antecedent and potentially play a causal role in the disease pathogenesis. Dysfunctional mitochondria accumulate from the combination of impaired mitophagy, which can also induce injurious inflammatory responses, and inadequate neuronal mitochondrial biogenesis. Altering the metabolic capacity of the brain by modulating/potentiating its mitochondrial bioenergetics may be a strategy for disease prevention and treatment. We present insights into the mechanisms of mitochondrial dysfunction in AD brain as well as an overview of emerging treatments with the potential to prevent, delay or reverse the neurodegenerative process by targeting mitochondria.

An evaluation of oligonucleotide-based therapeutic strategies for polyQ diseases

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Fiszer Agnieszka

2012-03-01

Full Text Available Abstract Background RNA interference (RNAi and antisense strategies provide experimental therapeutic agents for numerous diseases, including polyglutamine (polyQ disorders caused by CAG repeat expansion. We compared the potential of different oligonucleotide-based strategies for silencing the genes responsible for several polyQ diseases, including Huntington's disease and two spinocerebellar ataxias, type 1 and type 3. The strategies included nonallele-selective gene silencing, gene replacement, allele-selective SNP targeting and CAG repeat targeting. Results Using the patient-derived cell culture models of polyQ diseases, we tested various siRNAs, and antisense reagents and assessed their silencing efficiency and allele selectivity. We showed considerable allele discrimination by several SNP targeting siRNAs based on a weak G-G or G-U pairing with normal allele and strong G-C pairing with mutant allele at the site of RISC-induced cleavage. Among the CAG repeat targeting reagents the strongest allele discrimination is achieved by miRNA-like functioning reagents that bind to their targets and inhibit their translation without substantial target cleavage. Also, morpholino analog performs well in mutant and normal allele discrimination but its efficient delivery to cells at low effective concentration still remains a challenge. Conclusions Using three cellular models of polyQ diseases and the same experimental setup we directly compared the performance of different oligonucleotide-based treatment strategies that are currently under development. Based on the results obtained by us and others we discussed the advantages and drawbacks of these strategies considering them from several different perspectives. The strategy aimed at nonallele-selective inhibiting of causative gene expression by targeting specific sequence of the implicated gene is the easiest to implement but relevant benefits are still uncertain. The gene replacement strategy that

Strategies to optimize the biocompatibility of iron oxide nanoparticles - ;SPIONs safe by design;

Science.gov (United States)

Janko, Christina; Zaloga, Jan; Pöttler, Marina; Dürr, Stephan; Eberbeck, Dietmar; Tietze, Rainer; Lyer, Stefan; Alexiou, Christoph

2017-06-01

Various nanoparticle systems have been developed for medical applications in recent years. For constant improvement of efficacy and safety of nanoparticles, a close interdisciplinary interplay between synthesis, physicochemical characterizations and toxicological investigations is urgently needed. Based on combined toxicological data, we follow a ;safe-by design; strategy for our superparamagnetic iron oxide nanoparticles (SPION). Using complementary interference-free toxicological assay systems, we initially identified agglomeration tendencies in physiological fluids, strong uptake by cells and improvable biocompatibility of lauric acid (LA)-coated SPIONs (SPIONLA). Thus, we decided to further stabilize those particles by an artificial protein corona consisting of serum albumin. This approach finally lead to increased colloidal stability, augmented drug loading capacity and improved biocompatibility in previous in vitro assays. Here, we show in whole blood ex vivo and on isolated red blood cells (RBC) that a protein corona protects RBCs from hemolysis by SPIONs.

Inflammatory bowel disease: potential therapeutic strategies

DEFF Research Database (Denmark)

Nielsen, O H; Vainer, B; Bregenholt, S

1997-01-01

This review deals with potential and possibly primary therapeutics that, through insight into the inflammatory cascade, result in more rational treatment principles replacing the classical therapy of inflammatory bowel disease (IBD), i.e. Crohn's disease (CD) and ulcerative colitis (UC). These ne...

Oncogenic Human Papillomavirus: Application of CRISPR/Cas9 Therapeutic Strategies for Cervical Cancer

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Shuai Zhen

2017-12-01

Full Text Available Oncogenic human papillomaviruses (HPVs cause different types of cancer especially cervical cancer. HPV-associated carcinogenesis provides a classical model system for clustered regularly interspaced short palindromic repeats (CRISPR/Cas9 based cancer therapies since the viral oncogenes E6 and E7 are exclusively expressed in cancerous cells. Sequence-specific gene knockdown/knockout using CRISPR/Cas9 shows promise as a novel therapeutic approach for the treatment of a variety of diseases that currently lack effective treatments. However, CRISPR/Cas9-based targeting therapy requires further validation of its efficacy in vitro and in vivo to eliminate the potential off-target effects, necessitates verification of the delivery vehicles and the combinatory use of conventional therapies with CRISPR/Cas9 to ensure the feasibility and safety. In this review we discuss the potential of combining CRISPR/Cas9 with other treatment options as therapies for oncogenic HPVs-associated carcinogenesis. and present our assessment of the promising path to the development of CRISPR/Cas9 therapeutic strategies for clinical settings.

Emerging Strategies for Developing Next-Generation Protein Therapeutics for Cancer Treatment.

Science.gov (United States)

Kintzing, James R; Filsinger Interrante, Maria V; Cochran, Jennifer R

2016-12-01

Protein-based therapeutics have been revolutionizing the oncology space since they first appeared in the clinic two decades ago. Unlike traditional small-molecule chemotherapeutics, protein biologics promote active targeting of cancer cells by binding to cell-surface receptors and other markers specifically associated with or overexpressed on tumors versus healthy tissue. While the first approved cancer biologics were monoclonal antibodies, the burgeoning field of protein engineering is spawning research on an expanded range of protein formats and modifications that allow tuning of properties such as target-binding affinity, serum half-life, stability, and immunogenicity. In this review we highlight some of these strategies and provide examples of modified and engineered proteins under development as preclinical and clinical-stage drug candidates for the treatment of cancer. Copyright © 2016 Elsevier Ltd. All rights reserved.

Radiation Dosimetry considerations in the safe administration of therapeutic radiopharmaceuticals

International Nuclear Information System (INIS)

Turner, J.H.

1995-01-01

A set of eight questions was put to advanced nuclear medicine physicians-in-training participating in a continuing assessment exercise in practical therapeutic nuclear oncology. Using the particular example of 131 I-MIBG treatment of neuroblastoma in children, the questions were directed to the rationale of therapy and the contribution of other forms of treatment to toxic effects. The best answer to the questions are reproduced together with an introduction by the examiner, Dr. H. Turner. tabs

Managing Cassini Safe Mode Attitude at Saturn

Science.gov (United States)

Burk, Thomas A.

2010-01-01

The Cassini spacecraft was launched on October 15, 1997 and arrived at Saturn on June 30, 2004. It has performed detailed observations and remote sensing of Saturn, its rings, and its satellites since that time. In the event safe mode interrupts normal orbital operations, Cassini has flight software fault protection algorithms to detect, isolate, and recover to a thermally safe and commandable attitude and then wait for further instructions from the ground. But the Saturn environment is complex, and safety hazards change depending on where Cassini is in its orbital trajectory around Saturn. Selecting an appropriate safe mode attitude that insures safe operation in the Saturn environment, including keeping the star tracker field of view clear of bright bodies, while maintaining a quiescent, commandable attitude, is a significant challenge. This paper discusses the Cassini safe table management strategy and the key criteria that must be considered, especially during low altitude flybys of Titan, in deciding what spacecraft attitude should be used in the event of safe mode.

Current Therapeutic Strategies for Adipose Tissue Defects/Repair Using Engineered Biomaterials and Biomolecule Formulations

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Christopher M. Mahoney

2018-05-01

Full Text Available Tissue engineered scaffolds for adipose restoration/repair has significantly evolved in recent years. Patients requiring soft tissue reconstruction, caused by defects or pathology, require biomaterials that will restore void volume with new functional tissue. The gold standard of autologous fat grafting (AFG is not a reliable option. This review focuses on the latest therapeutic strategies for the treatment of adipose tissue defects using biomolecule formulations and delivery, and specifically engineered biomaterials. Additionally, the clinical need for reliable off-the-shelf therapies, animal models, and challenges facing current technologies are discussed.

Current Therapeutic Strategies for Adipose Tissue Defects/Repair Using Engineered Biomaterials and Biomolecule Formulations.

Science.gov (United States)

Mahoney, Christopher M; Imbarlina, Cayla; Yates, Cecelia C; Marra, Kacey G

2018-01-01

Tissue engineered scaffolds for adipose restoration/repair has significantly evolved in recent years. Patients requiring soft tissue reconstruction, caused by defects or pathology, require biomaterials that will restore void volume with new functional tissue. The gold standard of autologous fat grafting (AFG) is not a reliable option. This review focuses on the latest therapeutic strategies for the treatment of adipose tissue defects using biomolecule formulations and delivery, and specifically engineered biomaterials. Additionally, the clinical need for reliable off-the-shelf therapies, animal models, and challenges facing current technologies are discussed.

Therapeutic Strategies to Enhance the Anticancer Efficacy of Histone Deacetylase Inhibitors

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Claudia P. Miller

2011-01-01

Full Text Available Histone acetylation is a posttranslational modification that plays a role in regulating gene expression. More recently, other nonhistone proteins have been identified to be acetylated which can regulate their function, stability, localization, or interaction with other molecules. Modulating acetylation with histone deacetylase inhibitors (HDACi has been validated to have anticancer effects in preclinical and clinical cancer models. This has led to development and approval of the first HDACi, vorinostat, for the treatment of cutaneous T cell lymphoma. However, to date, targeting acetylation with HDACi as a monotherapy has shown modest activity against other cancers. To improve their efficacy, HDACi have been paired with other antitumor agents. Here, we discuss several combination therapies, highlighting various epigenetic drugs, ROS-generating agents, proteasome inhibitors, and DNA-damaging compounds that together may provide a therapeutic advantage over single-agent strategies.

Advanced Therapeutic Strategies for Chronic Lung Disease Using Nanoparticle-Based Drug Delivery

Directory of Open Access Journals (Sweden)

Ji Young Yhee

2016-09-01

Full Text Available Chronic lung diseases include a variety of obstinate and fatal diseases, including asthma, chronic obstructive pulmonary disease (COPD, cystic fibrosis (CF, idiopathic pulmonary fibrosis (IPF, and lung cancers. Pharmacotherapy is important for the treatment of chronic lung diseases, and current progress in nanoparticles offers great potential as an advanced strategy for drug delivery. Based on their biophysical properties, nanoparticles have shown improved pharmacokinetics of therapeutics and controlled drug delivery, gaining great attention. Herein, we will review the nanoparticle-based drug delivery system for the treatment of chronic lung diseases. Various types of nanoparticles will be introduced, and recent innovative efforts to utilize the nanoparticles as novel drug carriers for the effective treatment of chronic lung diseases will also be discussed.

Creatine metabolism and psychiatric disorders: Does creatine supplementation have therapeutic value?

Science.gov (United States)

Allen, Patricia J.

2012-01-01

Athletes, body builders, and military personnel use dietary creatine as an ergogenic aid to boost physical performance in sports involving short bursts of high-intensity muscle activity. Lesser known is the essential role creatine, a natural regulator of energy homeostasis, plays in brain function and development. Creatine supplementation has shown promise as a safe, effective, and tolerable adjunct to medication for the treatment of brain-related disorders linked with dysfunctional energy metabolism, such as Huntington’s Disease and Parkinson’s Disease. Impairments in creatine metabolism have also been implicated in the pathogenesis of psychiatric disorders, leaving clinicians, researchers and patients alike wondering if dietary creatine has therapeutic value for treating mental illness. The present review summarizes the neurobiology of the creatine-phosphocreatine circuit and its relation to psychological stress, schizophrenia, mood and anxiety disorders. While present knowledge of the role of creatine in cognitive and emotional processing is in its infancy, further research on this endogenous metabolite has the potential to advance our understanding of the biological bases of psychopathology and improve current therapeutic strategies. PMID:22465051

Data Analysis and Data-Driven Decision-Making Strategies Implemented by Elementary Teachers in Selected Exited Program Improvement Safe Harbor Schools in Southern California

Science.gov (United States)

Senger, Karen

2012-01-01

Purpose: The purposes of this study were to investigate and describe how elementary teachers in exited Program Improvement-Safe Harbor schools acquire student achievement data through assessments, the strategies and reflections utilized to make sense of the data to improve student achievement, ensure curriculum and instructional goals are aligned,…

Therapeutic strategy for granulomatous lobular mastitis: a clinicopathological study of 12 patients.

Science.gov (United States)

Akahane, Kazuhisa; Tsunoda, Nobuyuki; Kato, Masamichi; Noda, Sumiyo; Shimoyama, Yoshie; Ishigakis, Satoko; Satake, Hiroko; Nakamura, Shigeo; Nagino, Masato

2013-08-01

Granulomatous lobular mastitis (GLM) is a rare inflammatory pseudotumor. No therapeutic modality for this disease has been established because of its rarity. The purpose of this study is to evaluate the treatment strategies of GLM. Twelve women who met the histological criteria for GLM were retrospectively studied. The clinical data and the presentation, histopathology, and management of the disease were analyzed by reviewing the patients' medical records. The diagnosis of GLM was confirmed histologically by core needle biopsy in 9 cases, by vacuum-assisted biopsy in 2 cases, and by excisional biopsy in 1 case. Ten patients received corticosteroid treatment and another two patients were treated with local excision or incision and drainage. The median initial dosage of corticosteroid (Prednisolone) was 30 mg/day (range: 15-60 mg/day), and the dosages were tapered according to improvement. The median duration of corticosteroid treatment was 5 months (range: 1-12 months). The median follow-up period was 22 months (range: 6-104 months), and no patient treated with corticosteroid demonstrated recurrence. However, patients treated with excision or incision and drainage had recurrences. These results suggest that steroid treatment may be the first choice in treatment strategies for GLM.

Strategies for implementing and sustaining therapeutic lifestyle changes as part of hypertension management in African Americans.

Science.gov (United States)

Scisney-Matlock, Margaret; Bosworth, Hayden B; Giger, Joyce Newman; Strickland, Ora L; Harrison, R Van; Coverson, Dorothy; Shah, Nirav R; Dennison, Cheryl R; Dunbar-Jacob, Jacqueline M; Jones, Loretta; Ogedegbe, Gbenga; Batts-Turner, Marian L; Jamerson, Kenneth A

2009-05-01

African Americans with high blood pressure (BP) can benefit greatly from therapeutic lifestyle changes (TLC) such as diet modification, physical activity, and weight management. However, they and their health care providers face many barriers in modifying health behaviors. A multidisciplinary panel synthesized the scientific data on TLC in African Americans for efficacy in improving BP control, barriers to behavioral change, and strategies to overcome those barriers. Therapeutic lifestyle change interventions should emphasize patient self-management, supported by providers, family, and the community. Interventions should be tailored to an individual's cultural heritage, beliefs, and behavioral norms. Simultaneously targeting multiple factors that impede BP control will maximize the likelihood of success. The panel cited limited progress with integrating the Dietary Approaches to Stop Hypertension (DASH) eating plan into the African American diet as an example of the need for more strategically developed interventions. Culturally sensitive instruments to assess impact will help guide improved provision of TLC in special populations. The challenge of improving BP control in African Americans and delivery of hypertension care requires changes at the health system and public policy levels. At the patient level, culturally sensitive interventions that apply the strategies described and optimize community involvement will advance TLC in African Americans with high BP.

Photochemical internalisation, a minimally invasive strategy for light-controlled endosomal escape of cancer stem cell-targeting therapeutics.

Science.gov (United States)

Selbo, Pål Kristian; Bostad, Monica; Olsen, Cathrine Elisabeth; Edwards, Victoria Tudor; Høgset, Anders; Weyergang, Anette; Berg, Kristian

2015-08-01

Despite progress in radio-, chemo- and photodynamic-therapy (PDT) of cancer, treatment resistance still remains a major problem for patients with aggressive tumours. Cancer stem cells (CSCs) or tumour-initiating cells are intrinsically and notoriously resistant to conventional cancer therapies and are proposed to be responsible for the recurrence of tumours after therapy. According to the CSC hypothesis, it is imperative to develop novel anticancer agents or therapeutic strategies that take into account the biology and role of CSCs. The present review outlines our recent study on photochemical internalisation (PCI) using the clinically relevant photosensitiser TPCS2a/Amphinex® as a rational, non-invasive strategy for the light-controlled endosomal escape of CSC-targeting drugs. PCI is an intracellular drug delivery method based on light-induced ROS-generation and a subsequent membrane-disruption of endocytic vesicles, leading to cytosolic release of the entrapped drugs of interest. In different proof-of-concept studies we have demonstrated that PCI of CSC-directed immunotoxins targeting CD133, CD44, CSPG4 and EpCAM is a highly specific and effective strategy for killing cancer cells and CSCs. CSCs overexpressing CD133 are PDT-resistant; however, this is circumvented by PCI of CD133-targeting immunotoxins. In view of the fact that TPCS2a is not a substrate of the efflux pumps ABCG2 and P-glycoprotein (ABCB1), the PCI-method is a promising anti-CSC therapeutic strategy. Due to a laser-controlled exposure, PCI of CSC-targeting drugs will be confined exclusively to the tumour tissue, suggesting that this drug delivery method has the potential to spare distant normal stem cells.

Glyco-engineering strategies for the development of therapeutic enzymes with improved efficacy for the treatment of lysosomal storage diseases.

Science.gov (United States)

Oh, Doo-Byoung

2015-08-01

Lysosomal storage diseases (LSDs) are a group of inherent diseases characterized by massive accumulation of undigested compounds in lysosomes, which is caused by genetic defects resulting in the deficiency of a lysosomal hydrolase. Currently, enzyme replacement therapy has been successfully used for treatment of 7 LSDs with 10 approved therapeutic enzymes whereas new approaches such as pharmacological chaperones and gene therapy still await evaluation in clinical trials. While therapeutic enzymes for Gaucher disease have N-glycans with terminal mannose residues for targeting to macrophages, the others require N-glycans containing mannose-6-phosphates that are recognized by mannose-6-phosphate receptors on the plasma membrane for cellular uptake and targeting to lysosomes. Due to the fact that efficient lysosomal delivery of therapeutic enzymes is essential for the clearance of accumulated compounds, the suitable glycan structure and its high content are key factors for efficient therapeutic efficacy. Therefore, glycan remodeling strategies to improve lysosomal targeting and tissue distribution have been highlighted. This review describes the glycan structures that are important for lysosomal targeting and provides information on recent glyco-engineering technologies for the development of therapeutic enzymes with improved efficacy.

Gut microbiota role in irritable bowel syndrome: New therapeutic strategies.

Science.gov (United States)

Distrutti, Eleonora; Monaldi, Lorenzo; Ricci, Patrizia; Fiorucci, Stefano

2016-02-21

In the last decade the impressive expansion of our knowledge of the vast microbial community that resides in the human intestine, the gut microbiota, has provided support to the concept that a disturbed intestinal ecology might promote development and maintenance of symptoms in irritable bowel syndrome (IBS). As a correlate, manipulation of gut microbiota represents a new strategy for the treatment of this multifactorial disease. A number of attempts have been made to modulate the gut bacterial composition, following the idea that expansion of bacterial species considered as beneficial (Lactobacilli and Bifidobacteria) associated with the reduction of those considered harmful (Clostridium, Escherichia coli, Salmonella, Shigella and Pseudomonas) should attenuate IBS symptoms. In this conceptual framework, probiotics appear an attractive option in terms of both efficacy and safety, while prebiotics, synbiotics and antibiotics still need confirmation. Fecal transplant is an old treatment translated from the cure of intestinal infective pathologies that has recently gained a new life as therapeutic option for those patients with a disturbed gut ecosystem, but data on IBS are scanty and randomized, placebo-controlled studies are required.

Will Synergizing Vaccination with Therapeutics Boost Measles Virus Eradication?

Science.gov (United States)

Plemper, Richard K; Hammond, Anthea L

2014-01-01

Introduction Measles virus is a major human pathogen responsible for approximately 150,000 measles deaths annually. The disease is vaccine preventable and eradication of the virus is considered feasible in principle. However, a herd immunity exceeding 95% is required to prevent sporadic viral outbreaks in a population. Declining disease prevalence combined with public anxieties about vaccination safety has increased vaccine refusal especially in the European region, which has resulted in measles resurgence in some areas. Areas covered Here, we discuss whether synergizing effective measles therapeutics with vaccination could contribute to solving an endgame conundrum of measles elimination by accelerating the eradication effort. Based on an anticipated use for protection of high-risk contacts of confirmed measles cases through post-exposure prophylaxis, we identify key elements of the desirable drug profile, review current disease management strategies and the state of experimental inhibitor candidates, evaluate the risk associated with viral escape from inhibition, and consider the potential of measles therapeutics for the management of persistent viral infection of the CNS. Assuming a post-measles world with waning measles immunity, we contemplate the possible impact of therapeutics on controlling the threat imposed by closely related zoonotic pathogens of the same genus as measles virus. Expert opinion Efficacious therapeutics given for post-exposure prophylaxis of high-risk social contacts of confirmed index cases may aid measles eradication by closing herd immunity gaps due to vaccine refusal or failure in populations with overall good vaccination coverage. The envisioned primarily prophylactic application of measles therapeutics to a predominantly pediatric and/or adolescent patient population dictates the drug profile; the article must be safe and efficacious, orally available, shelf-stable at ambient temperature, and amenable to cost-effective manufacture

MSC transplantation: a promising therapeutic strategy to manage the onset and progression of diabetic nephropathy

Directory of Open Access Journals (Sweden)

Marcelo E Ezquer

2012-01-01

Full Text Available Currently, one of the main threats to public health is diabetes mellitus. Its most detrimental complication is diabetic nephropathy (DN, a clinical syndrome associated with kidney damage and an increased risk of cardiovascular disease. Irrespective of the type of diabetes, DN follows a well-known temporal course. The earliest detectable signs are microalbuminuria and histopathological changes including extracellular matrix deposition, glomerular basement membrane thickening, glomerular and mesangial expansion. Later on macroalbuminuria appears, followed by a progressive decline in glomerular filtration rate and the loss of glomerular podocytes, tubulointerstitial fibrosis, glomerulosclerosis and arteriolar hyalinosis. Tight glycemic and hypertension controls remain the key factors for preventing or arresting the progression of DN. Nevertheless, despite considerable educational effort to control the disease, a significant number of patients not only develop DN, but also progress to chronic kidney disease. Therefore, the availability of a strategy aimed to prevent, delay or revert DN would be highly desirable. In this article, we review the pathophysiological features of DN and the therapeutic mechanisms of multipotent mesenchymal stromal cells, also referred to as mesenchymal stem cells (MSCs. The perfect match between them, together with encouraging pre-clinical data available, allow us to support the notion that MSC transplantation is a promising therapeutic strategy to manage DN onset and progression, not only because of the safety of this procedure, but mainly because of the renoprotective potential of MSCs.

Induced-Decay of Glycine Decarboxylase Transcripts as an Anticancer Therapeutic Strategy for Non-Small-Cell Lung Carcinoma

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Jing Lin

2017-12-01

Full Text Available Self-renewing tumor-initiating cells (TICs are thought to be responsible for tumor recurrence and chemo-resistance. Glycine decarboxylase, encoded by the GLDC gene, is reported to be overexpressed in TIC-enriched primary non-small-cell lung carcinoma (NSCLC. GLDC is a component of the mitochondrial glycine cleavage system, and its high expression is required for growth and tumorigenic capacity. Currently, there are no therapeutic agents against GLDC. As a therapeutic strategy, we have designed and tested splicing-modulating steric hindrance antisense oligonucleotides (shAONs that efficiently induce exon skipping (half maximal inhibitory concentration [IC50] at 3.5–7 nM, disrupt the open reading frame (ORF of GLDC transcript (predisposing it for nonsense-mediated decay, halt cell proliferation, and prevent colony formation in both A549 cells and TIC-enriched NSCLC tumor sphere cells (TS32. One candidate shAON causes 60% inhibition of tumor growth in mice transplanted with TS32. Thus, our shAONs candidates can effectively inhibit the expression of NSCLC-associated metabolic enzyme GLDC and may have promising therapeutic implications.

Economics of place-based monitoring under the safe drinking water act, part II: design and development of place-based monitoring strategies.

Science.gov (United States)

Brands, Edwin; Rajagopal, R

2008-08-01

The goals of environmental legislation and associated regulations are to protect public health, natural resources, and ecosystems. In this context, monitoring programs should provide timely and relevant information so that the regulatory community can implement legislation in a cost-effective and efficient manner. The Safe Drinking Water Act (SDWA) of 1974 attempts to ensure that public water systems (PWSs) supply safe water to its consumers. As is the case with many other federal environmental statutes, SDWA monitoring has been implemented in relatively uniform fashion across the United States. In this three part series, spatial and temporal patterns in water quality data are utilized to develop, compare, and evaluate the economic performance of alternative place-based monitoring approaches to current monitoring practice. Part II: Several factors affect the performance of monitoring strategies, including: measurable objectives, required precision in estimates, acceptable confidence levels of such estimates, available budget for sampling. In this paper, we develop place-based monitoring strategies based on extensive analysis of available historical water quality data (1960-1994) of 19 Iowa community water systems. These systems supply potable water to over 350,000 people. In the context of drinking water, the objective is to protect public health by utilizing monitoring resources to characterize contaminants that are detectable, and are close to exceeding health standards. A place-based monitoring strategy was developed in which contaminants were selected based on their historical occurrence, rather than their appearance on the SDWA contaminant list. In a subset of the water systems, the temporal frequency of monitoring for one ubiquitous contaminant, nitrate, was tailored to patterns in its historical occurrence and concentration. Three sampling allocation models (linear, quadratic, and cubic) based on historic patterns in peak occurrence were developed and

Therapeutic applications of radiopharmaceuticals

International Nuclear Information System (INIS)

Baker, W.J.; Datz, F.L.; Beightol, R.W.

1987-01-01

Whether a radiopharmaceutical has diagnostic or therapeutic application depends on both the isotope and pharmaceutical used. For diagnostic applications, the isotope should undergo only γ-decay, since usually only γ-radiation is detected by nuclear medicine cameras. The half-life should be just long enough to allow the procedure to be performed. In contrast, the isotope needed for therapeutic purposes should have particulate radiation, such as a β-particle (electron), since these are locally absorbed an increase the local radiation dose. γ-Radiation, which penetrates the tissues, produces less radiation dose than do Β-particles. Several references dealing with radioactive decay, particulate interactions, and diagnostic and therapeutic applications of radiopharmaceuticals are available. Radiopharmaceuticals can legally be used only by physicians who are qualified by specific training in the safe handling of radionuclides. The experience and training of these physicians must be approved by the Nuclear Regulatory Commission or Agreement State Agency authorized to license the use of radiopharmaceuticals. A list of all byproduct material and procedures is available in the Code of Federal Regulations. Of the many radiopharmaceuticals available for diagnostic and therapeutic use, only those commonly used are discussed in this chapter

Verantwoording en kosteneffectiviet van therapeutic drug monitoring (1) : Betere behandeling voor minder geld

NARCIS (Netherlands)

Touw, D.J.; Neef, C.; Vinks, A.A.

2003-01-01

There are a number of effective but highly toxic drugs that exhibit a narrow therapeutic index and marked intersubject pharmacokinetic variability. Optimal therapy with such drugs requires therapeutic drug monitoring (TDM) in order to safely obtain the desired clinical effects. A systematic review

Altered cortical GABA neurotransmission in schizophrenia: insights into novel therapeutic strategies.

Science.gov (United States)

Stan, Ana D; Lewis, David A

2012-06-01

Altered markers of cortical GABA neurotransmission are among the most consistently observed abnormalities in postmortem studies of schizophrenia. The altered markers are particularly evident between the chandelier class of GABA neurons and their synaptic targets, the axon initial segment (AIS) of pyramidal neurons. For example, in the dorsolateral prefrontal cortex of subjects with schizophrenia immunoreactivity for the GABA membrane transporter is decreased in presynaptic chandelier neuron axon terminals, whereas immunoreactivity for the GABAA receptor α2 subunit is increased in postsynaptic AIS. Both of these molecular changes appear to be compensatory responses to a presynaptic deficit in GABA synthesis, and thus could represent targets for novel therapeutic strategies intended to augment the brain's own compensatory mechanisms. Recent findings that GABA inputs from neocortical chandelier neurons can be powerfully excitatory provide new ideas about the role of these neurons in the pathophysiology of cortical dysfunction in schizophrenia, and consequently in the design of pharmacological interventions.

New therapeutic approaches for treatment of tularaemia: a review

Directory of Open Access Journals (Sweden)

Sandrine eBOISSET

2014-03-01

Full Text Available Antibiotic treatment of tularaemia is based on a few drugs, including the fluoroquinolones, the tetracyclines and the aminoglycosides. Because no effective and safe vaccine is currently available, tularaemia prophylaxis following proven exposure to F. tularensis also relies on administration of antibiotics. A number of reasons make it necessary to search for new therapeutic alternatives: the potential toxicity of first-line drugs, especially in children and pregnant women; a high rate of treatment relapses and failures, especially for severe and/or suppurated forms of the disease; and the possible use of antibiotic-resistant strains in the context of a biological threat. This review presents novel therapeutic approaches that have been explored in recent years to improve tularaemia patients’ management and prognosis. First, the activities of newly available antibiotic compounds were evaluated against F. tularensis, including tigecycline (a glycylcycline, ketolides (telithromycin and cethromycin and fluoroquinolones (moxifloxacin, gatifloxacin, trovafloxacin and grepafloxacin. The liposome delivery of some antibiotics was evaluated. The effect of antimicrobial peptides against F. tularensis was also considered. Other drugs were evaluated for their ability to suppress the intracellular multiplication of F. tularensis. The effects of the modulation of the innate immune response (especially via TLR receptors on the course of F. tularensis infection were characterized. Another approach was the administration of specific antibodies to induce passive resistance to F. tularensis infection. All of these studies highlight the need to develop new therapeutic strategies to improve the management of patients with tularaemia. Many possibilities exist, some unexplored. Moreover, it is likely that new therapeutic alternatives that are effective against this intracellular pathogen could be, at least partially, extrapolated to other human pathogens.

Glioblastoma, a brief review of history, molecular genetics, animal models and novel therapeutic strategies.

Science.gov (United States)

Agnihotri, Sameer; Burrell, Kelly E; Wolf, Amparo; Jalali, Sharzhad; Hawkins, Cynthia; Rutka, James T; Zadeh, Gelareh

2013-02-01

Glioblastoma (GBM) is the most common and lethal primary brain tumor. Over the past few years tremendous genomic and proteomic characterization along with robust animal models of GBM have provided invaluable data that show that "GBM", although histologically indistinguishable from one another, are comprised of molecularly heterogenous diseases. In addition, robust pre-clinical models and a better understanding of the core pathways disrupted in GBM are providing a renewed optimism for novel strategies targeting these devastating tumors. Here, we summarize a brief history of the disease, our current molecular knowledge, lessons from animal models and emerging concepts of angiogenesis, invasion, and metabolism in GBM that may lend themselves to therapeutic targeting.

The effects of therapeutic touch on pain.

Science.gov (United States)

Monroe, Carolyn Magdalen

2009-06-01

To better understand how Therapeutic Touch can be used in today's health care arena, this integrative literature review will examine current research that will help answer the question, Does Therapeutic Touch reduce pain? An extensive search was conducted of the online databases MEDLINE, CINAHL, Cochrane Library, EMBASE, PsychLIT, and PubMed to retrieve research articles published from 1997 to 2007. Seven studies that were conducted between 1997 and 2004 were found and only five of the seven were included as pertinent evidence to answer the question. All of the research that was reviewed to answer whether Therapeutic Touch could significantly reduce pain revealed a majority of statistically significant positive results for implementing this intervention. Because there are no identified risks to Therapeutic Touch as a pain relief measure, it is safe to recommend despite the limitations of current research. Therapeutic Touch should be considered among the many possible nursing interventions for the treatment of pain.

Strategy to prime the host and cells to augment therapeutic efficacy of progenitor cells for patients with myocardial infarction

Directory of Open Access Journals (Sweden)

Jeehoon Kang

2016-11-01

Full Text Available Cell therapy in myocardial infarction (MI is an innovative strategy that is regarded as a rescue therapy to repair the damaged myocardium and to promote neovascularization for the ischemic border zone. Among several stem cell sources for this purpose, autologous progenitors from bone marrow or peripheral blood would be the most feasible and safest cell-source. Despite the theoretical benefit of cell therapy, this method is not widely adopted in the actual clinical practice due to its low therapeutic efficacy. Various methods have been used to augment the efficacy of cell therapy in MI, such as using different source of progenitors, genetic manipulation of cells, or priming of the cells or hosts (patients with agents. Among these methods, the strategy to augment the therapeutic efficacy of the autologous peripheral blood mononuclear cells by priming agents may be the most feasible and the safest method that can be applied directly to the clinic. In this review, we will discuss the current status and future directions of priming peripheral blood mononuclear cells or patients, as for cell therapy of MI.

Retinopathy of Prematurity: Therapeutic Strategies Based on Pathophysiology.

Science.gov (United States)

Cayabyab, Rowena; Ramanathan, Rangasamy

2016-01-01

retinal detachment. Long-term complications such as refractory errors, recurrence of ROP and risk of retinal detachment require continued follow-up with an ophthalmologist through adolescence and beyond. Optimal nutrition including adequate intake of omega-3 polyunsaturated fatty acids and decreasing infection/inflammation to promote normal vascularization are important strategies. Screening guidelines for ROP based on local incidence of ROP in different regions of the world are very important. Oxygen therapy is clearly a modifiable risk factor to decrease ROP that needs further study. Understanding the two phases of ROP will help to identify appropriate therapeutic strategies and improve visual outcomes in many preterm infants globally. © 2016 S. Karger AG, Basel.

The staying safe intervention: training people who inject drugs in strategies to avoid injection-related HCV and HIV infection.

Science.gov (United States)

Mateu-Gelabert, Pedro; Gwadz, Marya Viorst; Guarino, Honoria; Sandoval, Milagros; Cleland, Charles M; Jordan, Ashly; Hagan, Holly; Lune, Howard; Friedman, Samuel R

2014-04-01

This pilot study explores the feasibility and preliminary efficacy of the Staying Safe Intervention, an innovative, strengths-based program to facilitate prevention of infection with the human immunodeficiency virus and with the hepatitis C virus among people who inject drugs (PWID). The authors explored changes in the intervention's two primary endpoints: (a) frequency and amount of drug intake, and (b) frequency of risky injection practices. We also explored changes in hypothesized mediators of intervention efficacy: planning skills, motivation/self-efficacy to inject safely, skills to avoid PWID-associated stigma, social support, drug-related withdrawal symptoms, and injection network size and risk norms. A 1-week, five-session intervention (10 hours total) was evaluated using a pre- versus 3-month posttest design. Fifty-one participants completed pre- and posttest assessments. Participants reported significant reductions in drug intake and injection-related risk behavior. Participants also reported significant increases in planning skills, motivation/self-efficacy, and stigma management strategies, while reducing their exposure to drug withdrawal episodes and risky injection networks.

Threaded biliary inside stents are a safe and effective therapeutic option in cases of malignant hilar obstruction.

Science.gov (United States)

Inatomi, Osamu; Bamba, Shigeki; Shioya, Makoto; Mochizuki, Yosuke; Ban, Hiromitsu; Tsujikawa, Tomoyuki; Saito, Yasuharu; Andoh, Akira; Fujiyama, Yoshihide

2013-02-14

Although endoscopic biliary stents have been accepted as part of palliative therapy for cases of malignant hilar obstruction, the optimal endoscopic management regime remains controversial. In this study, we evaluated the safety and efficacy of placing a threaded stent above the sphincter of Oddi (threaded inside plastic stents, threaded PS) and compared the results with those of other stent types. Patients with malignant hilar obstruction, including those requiring biliary drainage for stent occlusion, were selected. Patients received either one of the following endoscopic indwelling stents: threaded PS, conventional plastic stents (conventional PS), or metallic stents (MS). Duration of stent patency and the incident of complication were compared in these patients. Forty-two patients underwent placement of endoscopic indwelling stents (threaded PS = 12, conventional PS = 17, MS = 13). The median duration of threaded PS patency was significantly longer than that of conventional PS patency (142 vs. 32 days; P = 0.04, logrank test). The median duration of threaded PS and MS patency was not significantly different (142 vs. 150 days, P = 0.83). Stent migration did not occur in any group. Among patients who underwent threaded PS placement as a salvage therapy after MS obstruction due to tumor ingrowth, the median duration of MS patency was significantly shorter than that of threaded PS patency (123 vs. 240 days). Threaded PS are safe and effective in cases of malignant hilar obstruction; moreover, it is a suitable therapeutic option not only for initial drainage but also for salvage therapy.

Therapeutic enhancement: nursing intervention category for patients diagnosed with Readiness for Therapeutic Regimen Management.

Science.gov (United States)

Kelly, Cynthia W

2008-04-01

To present a new nursing intervention category called therapeutic enhancement. Fewer than half of North Americans follow their physician's recommendations for diet and exercise, even when such are crucial to their health or recovery. It is imperative that nurses consider new ways to promote healthy behaviours. Therapeutic enhancement is intended to provide such a fresh approach. Traditional intervention techniques focusing on education, contracts, social support and more frequent interaction with physicians appear not to be effective when used alone. Successful strategies have been multidisciplinary; and have included interventions by professional nurses who assist patients to understand their disease and the disease process and that helps them to develop disease-management and self-management skills. Therapeutic enhancement incorporates The Stages of Change Theory, Commitment to Health Theory, Motivational Interviewing techniques and instrumentation specifically designed for process evaluation of health-promoting interventions. This is a critical review of approaches that, heretofore, have not been synthesised in a single published article. Based on the commonly used Stages of Change model, therapeutic enhancement is useful for patients who are at the action stage of change. Using therapeutic enhancement as well as therapeutic strategies identified in Stages of Change Theory, such as contingency management, helping relationships, counterconditioning, stimulus control and Motivational Interviewing techniques, nursing professionals can significantly increase the chances of patients moving from action to the maintenance stage of change for a specific health behaviour. Using the nursing intervention category, therapeutic enhancement can increase caregivers' success in helping patients maintain healthy behaviours.

Myasthenia gravis: subgroup classification and therapeutic strategies.

Science.gov (United States)

Gilhus, Nils Erik; Verschuuren, Jan J

2015-10-01

Myasthenia gravis is an autoimmune disease that is characterised by muscle weakness and fatigue, is B-cell mediated, and is associated with antibodies directed against the acetylcholine receptor, muscle-specific kinase (MUSK), lipoprotein-related protein 4 (LRP4), or agrin in the postsynaptic membrane at the neuromuscular junction. Patients with myasthenia gravis should be classified into subgroups to help with therapeutic decisions and prognosis. Subgroups based on serum antibodies and clinical features include early-onset, late-onset, thymoma, MUSK, LRP4, antibody-negative, and ocular forms of myasthenia gravis. Agrin-associated myasthenia gravis might emerge as a new entity. The prognosis is good with optimum symptomatic, immunosuppressive, and supportive treatment. Pyridostigmine is the preferred symptomatic treatment, and for patients who do not adequately respond to symptomatic therapy, corticosteroids, azathioprine, and thymectomy are first-line immunosuppressive treatments. Additional immunomodulatory drugs are emerging, but therapeutic decisions are hampered by the scarcity of controlled studies. Long-term drug treatment is essential for most patients and must be tailored to the particular form of myasthenia gravis. Copyright © 2015 Elsevier Ltd. All rights reserved.

The Medicinal Chemistry of Therapeutic Oligonucleotides.

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Wan, W Brad; Seth, Punit P

2016-11-10

Oligonucleotide-based therapeutics have made rapid progress in the clinic for treatment of a variety of disease indications. Unmodified oligonucleotides are polyanionic macromolecules with poor drug-like properties. Over the past two decades, medicinal chemists have identified a number of chemical modification and conjugation strategies which can improve the nuclease stability, RNA-binding affinity, and pharmacokinetic properties of oligonucleotides for therapeutic applications. In this perspective, we present a summary of the most commonly used nucleobase, sugar and backbone modification, and conjugation strategies used in oligonucleotide medicinal chemistry.

Mitomycin-treated undifferentiated embryonic stem cells as a safe and effective therapeutic strategy in a mouse model of Parkinson's disease.

Directory of Open Access Journals (Sweden)

Mariana eAcquarone

2015-04-01

Full Text Available Parkinson’s disease (PD is an incurable progressive neurodegenerative disorder. Clinical presentation of PD stems largely from the loss of dopaminergic neurons in the nigrostriatal dopaminergic pathway, motivating experimental strategies aimed at replacing dopaminergic innervation by cellular therapy. Transplantation of dopaminergic neurons derived from embryonic stem cells significantly improves motor functions in rodent and non-human primate models of PD. However, protocols to generate dopaminergic neurons from embryonic stem cells generally meet with low efficacy and high risk of teratoma development upon transplantation. To address these issues, we have pre-treated undifferentiated mouse embryonic stem cells (mESCs with the DNA alkylating agent mitomycin C (MMC before transplantation. MMC treatment of cultures prevented tumor formation in a 12-week follow-up after mESCs were injected in nude mice. In 6-OH-dopamine-lesioned mice, intrastriatal injection of MMC-treated mESCs markedly improved motor function without tumor formation for as long as 15 months. Furthermore, we show that halting mitotic activity of undifferentiated mESCs induces a four-fold increase in dopamine release following in vitro differentiation. Our findings indicate that treating mESCs with mitomycin C prior to intrastriatal transplant is an effective strategy that could be further investigated as a novel alternative for treatment of Parkinson's disease.

Interventional and surgical therapeutic strategies for pulmonary arterial hypertension: Beyond palliative treatments.

Science.gov (United States)

Sandoval, Julio; Gomez-Arroyo, Jose; Gaspar, Jorge; Pulido-Zamudio, Tomas

2015-10-01

Despite significant advances in pharmacological treatments, pulmonary arterial hypertension remains an incurable disease with an unreasonably high morbidity and mortality. Although specific pharmacotherapies have shifted the survival curves of patients and improved exercise endurance as well as quality of life, it is also true that these pharmacological interventions are not always accessible (particularly in developing countries) and, perhaps most importantly, not all patients respond similarly to these drugs. Furthermore, many patients will continue to deteriorate and will eventually require an additional, non-pharmacological, intervention. In this review we analyze the role of atrial septostomy and Potts anastomosis in the management of patients with pulmonary arterial hypertension, we summarize the current worldwide clinical experience (case reports and case series), and discuss why these interventional/surgical strategies might have a therapeutic role beyond that of a "bridge" to transplantation. Copyright © 2015 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

Neuropathic Pain and Lung Delivery of Nanoparticulate Drugs: An Emerging Novel Therapeutic Strategy.

Science.gov (United States)

Islam, Nazrul; Abbas, Muzaffar; Rahman, Shafiqur

2017-01-01

Neuropathic pain is a chronic neurological disorder affecting millions of people around the world. The currently available pharmacologic agents for the treatment of neuropathic pain have limited efficacy and are associated with dose related unwanted adverse effects. Due to the limited access of drug molecules across blood-brain barrier, a small percentage of drug that is administered systematically, reaches the central nervous system in active form. These therapeutic agents also require daily treatment regimen that is inconvenient and potentially impact patient compliance. Application of nanoparticulate drugs for enhanced delivery system has been explored extensively in the last decades. Pulmonary delivery of nanomedicines for the management of various diseases has become an emerging treatment strategy that ensures the targeted delivery of drugs both for systemic and local effects with low dose and limited adverse effects. To the best of our knowledge, there are no inhaled drug products available on market for the treatment of neuropathic pain. The advantages of delivering therapeutics into deep lungs include non-invasive drug delivery, higher bioavailability with low dose, lower systemic toxicity, and potentially greater blood-brain barrier penetration. This review discusses and highlights the important issues on the application of emerging nanoparticulate lung delivery of drugs for the effective treatment of neuropathic pain. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Therapeutic implications of curcumin in the prevention of diabetic retinopathy via modulation of anti-oxidant activity and genetic pathways

Science.gov (United States)

Aldebasi, Yousef H; Aly, Salah M; Rahmani, Arshad H

2013-01-01

Diabetic Retinopathy (DR) is one of the most common complications of diabetes mellitus that affects the blood vessels of the retina, leading to blindness. The current approach of treatment based on anti-inflammatory, anti-angiogenesis drugs and laser photocoagulation are effective but also shows adverse affect in retinal tissues and that can even worsen the visual abilities. Thus, a safe and effective mode of treatment is needed to control or delaying the DR. Based on the earlier evidence of the potentiality of natural products as anti-oxidants, anti-diabetic and antitumor, medicinal plants may constitute a good therapeutic approach in the prevention of DR. Curcumin, constituents of dietary spice turmeric, has been observed to have therapeutic potential in the inhibition or slow down progression of DR. In this review, we summarize the therapeutic potentiality of curcumin in the delaying the DR through antioxidant, anti-inflammatory, inhibition of Vascular Endothelial Growth and nuclear transcription factors. The strength of involvement of curcumin in the modulation of genes action creates a strong optimism towards novel therapeutic strategy of diabetic retinopathy and important mainstay in the management of diabetes and its complications DR. PMID:24379904

Diffusion MRI: A New Strategy for Assessment of Cancer Therapeutic Efficacy

OpenAIRE

Thomas L. Chenevert; Charles R. Meyer; Bradford A. Moffat; Alnawaz Rehemtulla; Suresh K. Mukherji; Stephen S. Gebarski; Douglas J. Quint; Patricia L. Robertson; Theodore S. Lawrence; Larry Junck; Jeremy M. G. Taylor; Timothy D. Johnson; Qian Dong; Karin M. Muraszko; James A. Brunberg

2002-01-01

The use of anatomical imaging in clinical oncology practice traditionally relies on comparison of patient scans acquired before and following completion of therapeutic intervention. Therapeutic success is typically determined from inspection of gross anatomical images to assess changes in tumor size. Imaging could provide significant additional insight into therapeutic impact if a specific parameter or combination of parameters could be identified which reflect tissue changes at the cellular ...

Impact of the scintigraphy of somatostatin receptors upon the therapeutic strategy in patients bearing digestive endocrine tumors

International Nuclear Information System (INIS)

Lebtahi, R.; Cadiot, G.; Genin, R.; Delahaye, N.; Faraggi, M.; Daou, D.; Peker, C.; Migon, M.; Le Guludec, D.

1997-01-01

The scintigraphy of somatostatin receptors (SSR) is a sensible method for detecting the gastroenteric-pancreatic endocrine tumors and their metastases. The aim of this study is to evaluate the clinical impact of the results of SSR in taking patients in therapeutic charge. A hundred and sixty patients bearing biologically and/or histologically proved digestive endocrine tumors were prospectively studied. The patients were classified in 3 groups: group I - 90 patients with no known metastases; group II - 59 patients with liver metastases and group III - 11 patients with known extra-hepatic metastases. The results of the scintigraphy were compared with those of conventional imaging. The following results were obtained: in group 1 (90 patients) the conventional imaging has allowed detecting 53 primitive tumors in 44 patients. The SSR visualized 68% of these sites and has detected 26 supplementary primitive sites in 20 patients and 29 metastatic sites in 25 patients. In group II the scintigraphy has detected 95% of hepatic metastases and revealed 23 new metastasis sites and 18/59 patients. In group III the scintigraphy has detected 11 new sites in 7 patients. The results of scintigraphy modified the patient's classification in 38 cases (24%). The therapeutic strategy was modified for 40 patients (25%). In conclusion, the scintigraphy of somatostatin receptors is able to detect a significant number of digestive endocrine tumors what has important implications for therapeutical planning of the treatment of patients. It must be carried out during pre-therapeutic extension examination of these tumors

Therapeutic cloning: The ethical limits

International Nuclear Information System (INIS)

Whittaker, Peter A.

2005-01-01

A brief outline of stem cells, stem cell therapy and therapeutic cloning is given. The position of therapeutic cloning with regard to other embryonic manipulations - IVF-based reproduction, embryonic stem formation from IVF embryos and reproductive cloning - is indicated. The main ethically challenging stages in therapeutic cloning are considered to be the nuclear transfer process including the source of eggs for this and the destruction of an embryo to provide stem cells for therapeutic use. The extremely polarised nature of the debate regarding the status of an early human embryo is noted, and some potential alternative strategies for preparing immunocompatible pluripotent stem cells are indicated

Safe sex

Science.gov (United States)

... sex; Sexually transmitted - safe sex; GC - safe sex; Gonorrhea - safe sex; Herpes - safe sex; HIV - safe sex; ... contact. STIs include: Chlamydia Genital herpes Genital warts Gonorrhea Hepatitis HIV HPV Syphilis STIs are also called ...

Therapeutic strategies in an animal model of neurodegeneration

NARCIS (Netherlands)

Borre, Y.E.

2013-01-01

Neurodegenerative diseases have complex and multifactorial etiologies, creating an enormous burden on society without an effective treatment. This thesis utilized olfactory bulbectomized rats to investigate therapeutic approaches to neurodegenerative disorders. Removal of the olfactory bulbs, leads

Expression of PFKFB3 and Ki67 in lung adenocarcinomas and targeting PFKFB3 as a therapeutic strategy.

Science.gov (United States)

Li, Xiaoli; Liu, Jian; Qian, Li; Ke, Honggang; Yao, Chan; Tian, Wei; Liu, Yifei; Zhang, Jianguo

2018-01-11

Phosphofructokinase-2/fructose-2, 6-bisphosphatase 3 (PFKFB3) catalyzes the synthesis of F2,6BP, which is an allosteric activator of 6-phosphofructo-1-kinase (PFK-1): the rate-limiting enzyme of glycolysis. During tumorigenesis, PFKFB3 increases glycolysis, angiogenesis, and tumor progression. In this study, our aim was to investigate the significance of PFKFB3 and Ki67 in human lung adenocarcinomas and to target PFKFB3 as a therapeutic strategy. In this study, we determined the expression levels of PFKFB3 mRNA and proteins in cancerous and normal lung adenocarcinomas by quantitative reverse transcription PCR (qRT-PCR), Western blot analysis, and tissue microarray immunohistochemistry analysis, respectively. In human adenocarcinoma tissues, PFKFB3 and Ki67 protein levels were related to the clinical characteristics and overall survival. Both PFKFB3 mRNA and protein were significantly higher in lung adenocarcinoma cells (all P targeting PFKFB3, it inhibited cell viability and glycolytic activity. It also caused apoptosis and induced cell cycle arrest. Furthermore, the migration and invasion of A549 cells was inhibited. We conclude that PFKFB3 bears an oncogene-like regulatory element in lung adenocarcinoma progression. In the treatment of lung adenocarcinoma, targeting PFKFB3 would be a promising therapeutic strategy.

Therapeutic Strategies for Hereditary Kidney Cancer.

Science.gov (United States)

Sidana, Abhinav; Srinivasan, Ramaprasad

2016-08-01

The study of hereditary forms of kidney cancer has vastly increased our understanding of metabolic and genetic pathways involved in the development of both inherited and sporadic kidney cancers. The recognition that diverse molecular events drive different forms of kidney cancers has led to the preclinical and clinical development of specific pathway-directed strategies tailored to treat distinct subgroups of kidney cancer. Here, we describe the molecular mechanisms underlying the pathogenesis of several different types of hereditary renal cancers, review their clinical characteristics, and summarize the treatment strategies for the management of these cancers.

No dry dock: safely strategy for avoiding unplanned dry dock and reducing safety, health and environment risks

Energy Technology Data Exchange (ETDEWEB)

Constantinis, Danny A.; Brett, David E. [EM and I Alliance, Cheshire (United Kingdom)

2012-07-01

There are currently over 150 operational FPUs with an expected increase of a further 100 units in the next 5 years. This results from several factors: increasing demand for hydrocarbons; new reserves in deep water; pipeline infrastructure is not required and FPU design fits many field requirements. FPUs are increasingly chosen for large, deep water, longer life developments. Units are bigger and more complex. Regulators and oil majors are imposing more stringent integrity requirements to protect against safety, environmental and operational risks related to loss of containment and loss of hull structure integrity which could lead to HSE risks, increased costs and production losses which would become particularly onerous should the unit have to dry dock. There are a number of other important components the context of asset integrity, e.g. mooring and sub sea systems, but these are outside the scope of this paper. The 'No Dry dock....Safely' approach is based on the principle of Criticality Based Integrity which identifies components whose integrity is critical to avoiding incidents and the risk of dry docking. Once critical components are identified the challenge is to establish integrity status and maintain fitness-for-service. Various JIPs e.g. the Hull Inspection Techniques and Strategies are looking at best practice inspection methodologies. The industry is progressing ways of maintaining and repairing critical items without going to dry dock. The challenges include coating maintenance, structural and pressure system repairs. Advances in cathodic protection and coating maintenance strategies are proving successful as are techniques for carrying out major structural repairs. The 'No Dry dock...Safely' methodology is a proven solution and case histories have been included. Technological advances will further improve integrity in the industry. There is no reason why FPUs cannot be kept on station and in production for 25 years or more whilst

USING THE SAFE SYSTEM APPROACH TO KEEP OLDER DRIVERS SAFELY MOBILE

Directory of Open Access Journals (Sweden)

Jim LANGFORD

2006-01-01

Full Text Available In 2003, Australian road transport jurisdictions collectively accepted that the greatest road safety gains would be achieved through adopting a Safe System approach, derived from Sweden's Vision Zero and the Netherlands' Sustainable Safety strategies. A key objective of all three approaches is to manage vehicles, the road infrastructure, speeds, road users and the interactions between these components, to ensure that in the event of crashes, crash energies will remain at levels that minimize the probability of death and serious injury. Older drivers pose a particular challenge to the Safe System approach, given particularly their greater physical frailty, their driving patterns and for some at least, their reduced fitness to drive. This paper has analyzed the so-called ‘older driver problem’ and identified a number of key factors underpinning their crash levels, for which countermeasures can be identified and implemented within a Safe System framework. The recommended countermeasures consist of: (1 safer roads, through a series of design improvements particularly governing urban intersections; (2 safer vehicles, through both the promotion of crashworthiness as a critical consideration when purchasing a vehicle and the wide use of developed and developing ITS technologies; (3 safer speeds especially at intersections; and (4 safer road users, through both improved assessment procedures to identify the minority of older drivers with reduced fitness to drive and educational efforts to encourage safer driving habits particularly but not only through self-regulation.

A safe strategy for addition of vitamins and minerals to foods

DEFF Research Database (Denmark)

Rasmussen, S.; Andersen, Niels Lyhne; Dragsted, L.O.

2006-01-01

Addition of vitamins and minerals to foods must be done without health risk to any consumer group. International expert groups have aimed at establishing tolerable upper intake levels (ULs) for vitamins and minerals although lack of solid data on their safety is a major obstacle to this work....... The levels are applied in a model for calculation of safe fortification levels for all ages.We have estimated the upper 95(th) percentile intake of vitamins and minerals from food in various Danish age and gender groups and suggest that a daily multivitaminmineral pill is included in the calculation of total...... dietary intake levels of all vitamins and minerals. By subtracting this dietary intake level from the UL, GL or TGL, we calculate the amount that can be safely used for fortification. Since safety must be assured for all age groups, the smallest difference relative to energy intake calculated for any age...

Targeting mitochondrial respiration as a therapeutic strategy for cervical cancer.

Science.gov (United States)

Tian, Shenglan; Chen, Heng; Tan, Wei

2018-05-23

Targeting mitochondrial respiration has been documented as an effective therapeutic strategy in cancer. However, the impact of mitochondrial respiration inhibition on cervical cancer cells are not well elucidated. Using a panel of cervical cancer cell lines, we show that an existing drug atovaquone is active against the cervical cancer cells with high profiling of mitochondrial biogenesis. Atovaquone inhibited proliferation and induced apoptosis with varying efficacy among cervical cancer cell lines regardless of HPV infection, cellular origin and their sensitivity to paclitaxel. We further demonstrated that atovaquone acts on cervical cancer cells via inhibiting mitochondrial respiration. In particular, atovaquone specifically inhibited mitochondrial complex III but not I, II or IV activity, leading to respiration inhibition and energy crisis. Importantly, we found that the different sensitivity of cervical cancer cell lines to atovaquone were due to their differential level of mitochondrial biogenesis and dependency to mitochondrial respiration. In addition, we demonstrated that the in vitro observations were translatable to in vivo cervical cancer xenograft mouse model. Our findings suggest that the mitochondrial biogenesis varies among patients with cervical cancer. Our work also suggests that atovaquone is a useful addition to cervical cancer treatment, particularly to those with high dependency on mitochondrial respiration. Copyright © 2018 Elsevier Inc. All rights reserved.

Therapeutic potential of systemic brain rejuvenation strategies for neurodegenerative disease [version 1; referees: 3 approved

Directory of Open Access Journals (Sweden)

Alana M. Horowitz

2017-08-01

Full Text Available Neurodegenerative diseases are a devastating group of conditions that cause progressive loss of neuronal integrity, affecting cognitive and motor functioning in an ever-increasing number of older individuals. Attempts to slow neurodegenerative disease advancement have met with little success in the clinic; however, a new therapeutic approach may stem from classic interventions, such as caloric restriction, exercise, and parabiosis. For decades, researchers have reported that these systemic-level manipulations can promote major functional changes that extend organismal lifespan and healthspan. Only recently, however, have the functional effects of these interventions on the brain begun to be appreciated at a molecular and cellular level. The potential to counteract the effects of aging in the brain, in effect rejuvenating the aged brain, could offer broad therapeutic potential to combat dementia-related neurodegenerative disease in the elderly. In particular, results from heterochronic parabiosis and young plasma administration studies indicate that pro-aging and rejuvenating factors exist in the circulation that can independently promote or reverse age-related phenotypes. The recent demonstration that human umbilical cord blood similarly functions to rejuvenate the aged brain further advances this work to clinical translation. In this review, we focus on these blood-based rejuvenation strategies and their capacity to delay age-related molecular and functional decline in the aging brain. We discuss new findings that extend the beneficial effects of young blood to neurodegenerative disease models. Lastly, we explore the translational potential of blood-based interventions, highlighting current clinical trials aimed at addressing therapeutic applications for the treatment of dementia-related neurodegenerative disease in humans.

Statin Intolerance: A Literature Review and Management Strategies.

Science.gov (United States)

Saxon, David R; Eckel, Robert H

Statin intolerance is a commonly encountered clinical problem for which useful management strategies exist. Although many patients report statin-related muscle symptoms, studies indicate that the majority of these patients can tolerate a statin upon re-challenge. Alternative statin dosing strategies are an effective way to modify and reintroduce statin therapy for patients reporting adverse symptoms. Correction of vitamin D deficiency and hypothyroidism may improve statin tolerability in some patients. CoQ10 supplementation has been found to be of no benefit for statin-related muscle symptoms in most recent clinical trials. PCSK9 inhibitors are a new therapeutic option that if confirmed as safe and effective by outcomes trials may be of substantial benefit to select patients at high ASCVD risk who are unable to achieve adequate low-density lipoprotein cholesterol (LDL-C) lowering on maximally tolerated statin therapy. Other available medications to lower LDL-C in statin intolerant patients include ezetimibe, bile acid sequestrants, niacin, and fibrates. Published by Elsevier Inc.

Therapeutic cloning in individual parkinsonian mice

Science.gov (United States)

Tabar, Viviane; Tomishima, Mark; Panagiotakos, Georgia; Wakayama, Sayaka; Menon, Jayanthi; Chan, Bill; Mizutani, Eiji; Al-Shamy, George; Ohta, Hiroshi; Wakayama, Teruhiko; Studer, Lorenz

2009-01-01

Cell transplantation with embryonic stem (ES) cell progeny requires immunological compatibility with host tissue. ‘Therapeutic cloning’ is a strategy to overcome this limitation by generating nuclear transfer (nt)ES cells that are genetically matched to an individual. Here we establish the feasibility of treating individual mice via therapeutic cloning. Derivation of 187 ntES cell lines from 24 parkinsonian mice, dopaminergic differentiation, and transplantation into individually matched host mice showed therapeutic efficacy and lack of immunological response. PMID:18376409

Biliary parasites: diagnostic and therapeutic strategies.

Science.gov (United States)

Khandelwal, Niraj; Shaw, Joanna; Jain, Mamta K

2008-04-01

Parasitic infections of the biliary tract are a common cause of biliary obstruction in endemic areas. This article focuses on primary biliary parasites: Ascaris lumbricoides, Clonorchis sinensis, Opisthorchis viverrini, Opisthorchis felineus, Dicrocoelium dendriticum, Fasciola hepatica, and Fasciola gigantica. Tropical and subtropical countries have the highest incidence and prevalence of these infections. Diagnosis is made primarily through direct microscopic examination of eggs in the stool, duodenal, or bile contents. Radiologic imaging may show intrahepatic ductal dilatation, whereas endoscopic retrograde cholangiopancreatography can be used diagnostically and therapeutically. However, oral treatment is inexpensive and effective for most of these parasites and can prevent untoward consequences. Primary and alternative treatments are available and are reviewed in this article.

Dysfunctional Hematopoietic Stem Cell Biology: Underlying Mechanisms and Potential Therapeutic Strategies

Directory of Open Access Journals (Sweden)

Anja Geiselhart

2012-01-01

Full Text Available Fanconi anemia (FA is the most common inherited bone marrow failure syndrome. FA patients suffer to varying degrees from a heterogeneous range of developmental defects and, in addition, have an increased likelihood of developing cancer. Almost all FA patients develop a severe, progressive bone marrow failure syndrome, which impacts upon the production of all hematopoietic lineages and, hence, is thought to be driven by a defect at the level of the hematopoietic stem cell (HSC. This hypothesis would also correlate with the very high incidence of MDS and AML that is observed in FA patients. In this paper, we discuss the evidence that supports the role of dysfunctional HSC biology in driving the etiology of the disease. Furthermore, we consider the different model systems currently available to study the biology of cells defective in the FA signaling pathway and how they are informative in terms of identifying the physiologic mediators of HSC depletion and dissecting their putative mechanism of action. Finally, we ask whether the insights gained using such disease models can be translated into potential novel therapeutic strategies for the treatment of the hematologic disorders in FA patients.

Empowering Staff Nurses With Essential Skills: Training Strategies for Success.

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Czekanski, Elizabeth

2016-01-01

Nurse leaders in the mental health field are challenged to ensure the mental health environment is safe and therapeutic. They must also continually evaluate whether nurses are effectively engaging therapeutically with patients in their care. Undergraduate nursing students and practicing nurses usually receive little or no training in facilitating nurse-led groups. Nurses who are trained and capable of facilitating groups may enhance therapeutic relationships and engage patients to improve treatment outcomes. Training staff and disseminating educational materials in an efficient manner are often challenges for nurse leaders. The Veterans Health Administration (VHA) Office of Nursing Services (ONS) Mental Health Field Advisory Committee (MH-FAC) developed a nursing guide for conducting psychoeducation groups. This was followed up with a complementary live virtual training with "on-demand" features that included discussion and demonstration of nurse-led group implementation strategies. Both products were disseminated to nurse leaders throughout the VHA ONS Web site. Responses to both the guide and video were overwhelmingly positive. This article discusses the importance of nurse-led psychoeducational groups and describes a project implemented by the ONS MH-FAC, which helped provide an essential training to more than 1100 RNs within the Veterans Affairs Health System nationally.

Mesenchymal stem cell-based gene therapy: A promising therapeutic strategy.

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Mohammadian, Mozhdeh; Abasi, Elham; Akbarzadeh, Abolfazl

2016-08-01

Mesenchymal stem cells (MSCs) are multipotent stromal cells that exist in bone marrow, fat, and so many other tissues, and can differentiate into a variety of cell types including osteoblasts, chondrocytes, and adipocytes, as well as myocytes and neurons. Moreover, they have great capacity for self-renewal while maintaining their multipotency. Their capacity for proliferation and differentiation, in addition to their immunomodulatory activity, makes them very promising candidates for cell-based regenerative medicine. Moreover, MSCs have the ability of mobilization to the site of damage; therefore, they can automatically migrate to the site of injury via their chemokine receptors following intravenous transplantation. In this respect, they can be applied for MSC-based gene therapy. In this new therapeutic method, genes of interest are introduced into MSCs via viral and non-viral-based methods that lead to transgene expression in them. Although stem cell-based gene therapy is a relatively new strategy, it lights a new hope for the treatment of a variety of genetic disorders. In the near future, MSCs can be of use in a vast number of clinical applications, because of their uncomplicated isolation, culture, and genetic manipulation. However, full consideration is still crucial before they are utilized for clinical trials, because the number of studies that signify the advantageous effects of MSC-based gene therapy are still limited.

Diffusion MRI: A New Strategy for Assessment of Cancer Therapeutic Efficacy

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Thomas L. Chenevert

2002-10-01

Full Text Available The use of anatomical imaging in clinical oncology practice traditionally relies on comparison of patient scans acquired before and following completion of therapeutic intervention. Therapeutic success is typically determined from inspection of gross anatomical images to assess changes in tumor size. Imaging could provide significant additional insight into therapeutic impact if a specific parameter or combination of parameters could be identified which reflect tissue changes at the cellular or physiologic level. This would provide an early indicator of treatment response/outcome in an individual patient before completion of therapy. Moreover, response of a tumor to therapeutic intervention may be heterogeneous. The use of imaging could assist in delineating therapeutic-induced spatial heterogeneity within a tumor mass by providing information related to specific regions that are resistant or responsive to treatment. Largely untapped potential resides in exploratory methods such as diffusion MRI, which is a non-volumetric intravoxel measure of tumor response based upon water molecular mobility. Alterations in water mobility reflect changes in tissue structure at the cellular level. While the clinical utility of diffusion MRI for oncologic practice is still under active investigation, this overview on the use of diffusion MRI for the evaluation of brain tumors will serve to introduce how this approach may be applied in the future for the management of patients with solid tumors.

Cellulose degradation: a therapeutic strategy in the improved treatment of Acanthamoeba infections.

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Lakhundi, Sahreena; Siddiqui, Ruqaiyyah; Khan, Naveed Ahmed

2015-01-14

Acanthamoeba is an opportunistic free-living amoeba that can cause blinding keratitis and fatal brain infection. Early diagnosis, followed by aggressive treatment is a pre-requisite in the successful treatment but even then the prognosis remains poor. A major drawback during the course of treatment is the ability of the amoeba to enclose itself within a shell (a process known as encystment), making it resistant to chemotherapeutic agents. As the cyst wall is partly made of cellulose, thus cellulose degradation offers a potential therapeutic strategy in the effective targeting of trophozoite encased within the cyst walls. Here, we present a comprehensive report on the structure of cellulose and cellulases, as well as known cellulose degradation mechanisms with an eye to target the Acanthamoeba cyst wall. The disruption of the cyst wall will make amoeba (concealed within) susceptible to chemotherapeutic agents, and at the very least inhibition of the excystment process will impede infection recurrence, as we bring these promising drug targets into focus so that they can be explored to their fullest.

Self-Assembly of pH-Responsive Microspheres for Intestinal Delivery of Diverse Lipophilic Therapeutics.

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Zhou, Xing; Zhao, Yang; Chen, Siyu; Han, Songling; Xu, Xiaoqiu; Guo, Jiawei; Liu, Mengyu; Che, Ling; Li, Xiaohui; Zhang, Jianxiang

2016-08-08

Targeted delivery of therapeutics to the intestine is preferred for the management of many diseases due to its diverse advantages. Currently, there are still challenges in creating cost-effective and translational pH-responsive microspheres for intestinal delivery of various hydrophobic drugs. Herein we report a multiple noncovalent interactions-mediated assembly strategy in which carboxyl-bearing compounds (CBCs) are guest molecules, while poly(N-isopropylacrylamide) (PNIPAm) serves as a host polymer. Formation of microparticles and therapeutic packaging can be achieved simultaneously by this assembly approach, leading to well-shaped microspheres with extremely higher drug loading capacity as compared to microspheres based on two FDA-approved materials of poly(d,l-lactide-co-glycolide) (PLGA) and an enteric coating polymer EudragitS 100 (S100). Also, carboxyl-deficient hydrophobic drugs can be effectively entrapped. These assembled microspheres, with excellent reconstitution capability as well as desirable scalability, could selectively release drug molecules under intestinal conditions. By significantly enhancing drug dissolution/release in the intestine, these pH-responsive assemblies may notably improve the oral bioavailability of loaded therapeutics. Moreover, the assembled microspheres possessed superior therapeutic performance in rodent models of inflammation and tumor over the control microspheres derived from PLGA and S100. Therapy with newly developed microspheres did not cause undesirable side effects. Furthermore, in vivo evaluation in mice revealed the carrier material PNIPAm was safe for oral delivery at doses as high as 10 g/kg. Collectively, our findings demonstrated that this type of pH-responsive microsphere may function as superior and translational intestine-directed delivery systems for a diverse array of therapeutics.

Pathophysiology and Therapeutic Strategies for Symptomatic Uncomplicated Diverticular Disease of the Colon.

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Scaioli, Eleonora; Colecchia, Antonio; Marasco, Giovanni; Schiumerini, Ramona; Festi, Davide

2016-03-01

Colonic diverticulosis imposes a significant burden on industrialized societies. The current accepted causes of diverticula formation include low fiber content in the western diet with decreased intestinal content and size of the lumen, leading to the transmission of muscular contraction pressure to the wall of the colon, inducing the formation of diverticula usually at the weakest point of the wall where penetration of the blood vessels occurs. Approximately 20 % of the patients with colonic diverticulosis develop abdominal symptoms (i.e., abdominal pain and discomfort, bloating, constipation, and diarrhea), a condition which is defined as symptomatic uncomplicated diverticular disease (SUDD). The pathogenesis of SUDD symptoms remains uncertain and even less is known about how to adequately manage bowel symptoms. Recently, low-grade inflammation, altered intestinal microbiota, visceral hypersensitivity, and abnormal colonic motility have been identified as factors leading to symptom development, thus changing and improving the therapeutic approach. In this review, a comprehensive search of the literature regarding on SUDD pathogenetic hypotheses and pharmacological strategies was carried out. The pathogenesis of SUDD, although not completely clarified, seems to be related to an interaction between colonic microbiota alterations, and immune, enteric nerve, and muscular system dysfunction (Cuomo et al. in United Eur Gastroenterol J 2:413-442, 2014). Greater understanding of the inflammatory pathways and gut microbiota composition in subjects affected by SUDD has increased therapeutic options, including the use of gut-directed antibiotics, mesalazine, and probiotics (Bianchi et al. in Aliment Pharmacol Ther 33:902-910, 2011; Comparato et al. in Dig Dis Sci 52:2934-2941, 2007; Tursi et al. in Aliment Pharmacol Ther 38:741-751, 2013); however, more research is necessary to validate the safety, effectiveness, and cost-effectiveness of these interventions.

Therapeutic Strategy for Targeting Aggressive Malignant Gliomas by Disrupting Their Energy Balance.

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Hegazy, Ahmed M; Yamada, Daisuke; Kobayashi, Masahiko; Kohno, Susumu; Ueno, Masaya; Ali, Mohamed A E; Ohta, Kumiko; Tadokoro, Yuko; Ino, Yasushi; Todo, Tomoki; Soga, Tomoyoshi; Takahashi, Chiaki; Hirao, Atsushi

2016-10-07

Although abnormal metabolic regulation is a critical determinant of cancer cell behavior, it is still unclear how an altered balance between ATP production and consumption contributes to malignancy. Here we show that disruption of this energy balance efficiently suppresses aggressive malignant gliomas driven by mammalian target of rapamycin complex 1 (mTORC1) hyperactivation. In a mouse glioma model, mTORC1 hyperactivation induced by conditional Tsc1 deletion increased numbers of glioma-initiating cells (GICs) in vitro and in vivo Metabolic analysis revealed that mTORC1 hyperactivation enhanced mitochondrial biogenesis, as evidenced by elevations in oxygen consumption rate and ATP production. Inhibition of mitochondrial ATP synthetase was more effective in repressing sphere formation by Tsc1-deficient glioma cells than that by Tsc1-competent glioma cells, indicating a crucial function for mitochondrial bioenergetic capacity in GIC expansion. To translate this observation into the development of novel therapeutics targeting malignant gliomas, we screened drug libraries for small molecule compounds showing greater efficacy in inhibiting the proliferation/survival of Tsc1-deficient cells compared with controls. We identified several compounds able to preferentially inhibit mitochondrial activity, dramatically reducing ATP levels and blocking glioma sphere formation. In human patient-derived glioma cells, nigericin, which reportedly suppresses cancer stem cell properties, induced AMPK phosphorylation that was associated with mTORC1 inactivation and induction of autophagy and led to a marked decrease in sphere formation with loss of GIC marker expression. Furthermore, malignant characteristics of human glioma cells were markedly suppressed by nigericin treatment in vivo Thus, targeting mTORC1-driven processes, particularly those involved in maintaining a cancer cell's energy balance, may be an effective therapeutic strategy for glioma patients. © 2016 by The American

Recent advances in therapeutic recruitment of mammalian RNAi and bacterial CRISPR-Cas DNA interference pathways as emerging antiviral strategies.

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Chin, Wei-Xin; Ang, Swee Kim; Chu, Justin Jang Hann

2017-01-01

In invertebrate eukaryotes and prokaryotes, respectively, the RNAi and clustered regularly interspaced short palindromic repeats-CRISPR-associated (CRISPR-Cas) pathways are highly specific and efficient RNA and DNA interference systems, and are well characterised as potent antiviral systems. It has become possible to recruit or reconstitute these pathways in mammalian cells, where they can be directed against desired host or viral targets. The RNAi and CRISPR-Cas systems can therefore yield ideal antiviral therapeutics, capable of specific and efficient viral inhibition with minimal off-target effects, but development of such therapeutics can be slow. This review covers recent advances made towards developing RNAi or CRISPR-Cas strategies for clinical use. These studies address the delivery, toxicity or target design issues that typically plague the in vivo or clinical use of these technologies. Copyright © 2016 Elsevier Ltd. All rights reserved.

Current Opinion on the Role of Neurogenesis in the Therapeutic Strategies for Alzheimer Disease, Parkinson Disease, and Ischemic Stroke; Considering Neuronal Voiding Function

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Myung-Hoon Han

2016-12-01

Full Text Available Neurological diseases such as Alzheimer, Parkinson, and ischemic stroke have increased in occurrence and become important health issues throughout the world. There is currently no effective therapeutic strategy for addressing neurological deficits after the development of these major neurological disorders. In recent years, it has become accepted that adult neural stem cells located in the subventricular and subgranular zones have the ability to proliferate and differentiate in order to replace lost or damaged neural cells. There have been many limitations in the clinical application of both endogenous and exogenous neurogenesis for neurological disorders. However, many studies have investigated novel mechanisms in neurogenesis and have shown that these limitations can potentially be overcome with appropriate stimulation and various approaches. We will review concepts related to possible therapeutic strategies focused on the perspective of neurogenesis for the treatment of patients diagnosed with Alzheimer disease, Parkinson disease, and ischemic stroke based on current reports.

Affinity-tuning leukocyte integrin for development of safe therapeutics

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Park, Spencer

Much attention has been given to the molecular and cellular pathways linking inflammation with cancer and the local tumor environment to identify new target molecules that could lead to improved diagnosis and treatment. Among the many molecular players involved in the complex response, central to the induction of inflammation is intercellular adhesion molecule (ICAM)-1, which is of particular interest for its highly sensitive and localized expression in response to inflammatory signals. ICAM-1, which has been implicated to play a critical role in tumor progression in various types of cancer, has also been linked to cancer metastases, where ICAM-1 facilitates the spread of metastatic cancer cells to secondary sites. This unique expression profile of ICAM-1 throughout solid tumor microenvironment makes ICAM-1 an intriguing molecular target, which holds great potential as an important diagnostic and therapeutic tool. Herein, we have engineered the ligand binding domain, or the inserted (I) domain of a leukocyte integrin, to exhibit a wide range of monovalent affinities to the natural ligand, ICAM-1. Using the resulting I domain variants, we have created drug and gene delivery nanoparticles, as well as targeted immunotherapeutics that have the ability to bind and migrate to inflammatory sites prevalent in tumors and the associated microenvironment. Through the delivery of diagnostic agents, chemotherapeutics, and immunotherapeutics, the following chapters demonstrate that the affinity enhancements achieved by directed evolution bring the affinity of I domains into the range optimal for numerous applications.

Radical surgery after chemotherapy: a new therapeutic strategy to envision in grade II glioma.

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Duffau, Hugues; Taillandier, Luc; Capelle, Laurent

2006-11-01

While surgery is proned in low-grade glioma (LGG), the invasion of functional areas frequently prevents a complete resection. We report the first case of a patient operated on for a left frontal LGG, diagnosed because of seizures, with partial resection due to an invasion of the controlateral hemisphere. Chemotherapy enabled a regression of this controlateral extension. Postchemotherapy surgery performed with intraoperative functional mapping then allowed a complete resection, without sequelae. The patient has a normal socio-professional life, with no seizure. No other treatment was given. There was no recurrence, with a follow-up of 2 years since the second surgery (3.5 years since the first symptom). We propose a new therapeutic strategy in unresectable LGG, with preoperative chemotherapy, to make a radical surgery possible in a second step, while preserving the quality of life.

Integrated Life Cycle Management: A Strategy for Plants to Extend Operating Lifetimes Safely with High Operational Reliability

International Nuclear Information System (INIS)

Esselman, Thomas; Bruck, Paul; Mengers, Charles

2012-01-01

Nuclear plant operators are studying the possibility of extending their existing generating facilities operating lifetime to 60 years and beyond. Many nuclear plants have been granted licenses to operate their facilities beyond the original 40 year term; however, in order to optimize the long term operating strategies, plant decision-makers need a consistent approach to support their options. This paper proposes a standard methodology to support effective decision-making for the long-term management of selected station assets. Methods detailed are intended to be used by nuclear plant site management, equipment reliability personnel, long term planners, capital asset planners, license renewal staff, and others that intend to look at operation between the current time and the end of operation. This methodology, named Integrated Life Cycle Management (ILCM), will provide a technical basis to assist decision makers regarding the timing of large capital investments required to get to the end of operation safely and with high plant reliability. ILCM seeks to identify end of life cycle failure probabilities for individual plant large capital assets and attendant costs associated with their refurbishment or replacement. It will provide a standard basis for evaluation of replacement and refurbishment options for these components. ILCM will also develop methods to integrate the individual assets over the entire plant thus assisting nuclear plant decision-makers in their facility long term operating strategies. (author)

Targeting methionine cycle as a potential therapeutic strategy for immune disorders.

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Li, Heng; Lu, Huimin; Tang, Wei; Zuo, Jianping

2017-08-23

Methionine cycle plays an essential role in regulating many cellular events, especially transmethylation reactions, incorporating the methyl donor S-adenosylmethionine (SAM). The transmethylations and substances involved in the cycle have shown complicated effects and mechanisms on immunocytes developments and activations, and exert crucial impacts on the pathological processes in immune disorders. Areas covered: Methionine cycle has been considered as an effective means of drug developments. This review discussed the role of methionine cycle in immune responses and summarized the potential therapeutic strategies based on the cycle, including SAM analogs, methyltransferase inhibitors, S-adenosylhomocysteine hydrolase (SAHH) inhibitors, adenosine receptors specific agonists or antagonists and homocysteine (Hcy)-lowering reagents, in treating human immunodeficiency virus (HIV) infections, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), systemic sclerosis (SSc) and other immune disorders. Expert opinion: New targets and biomarkers grown out of methionine cycle have developed rapidly in the past decades. However, impacts of epigenetic regulations on immune disorders are unclear and whether the substances in methionine cycle can be clarified as biomarkers remains controversial. Therefore, further elucidation on the role of epigenetic regulations and substances in methionine cycle may contribute to exploring the cycle-derived biomarkers and drugs in immune disorders.

Safe practices and financial considerations in using oral chemotherapeutic agents.

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Bartel, Sylvia B

2007-05-01

Safe handling practices and financial concerns associated with oral chemotherapy in non-traditional settings are discussed. Oral chemotherapy may pose a risk to patients because of a narrow therapeutic index, complex dosing regimen, dispensing by community pharmacists without prescription order review by an oncology pharmacist or nurse, or self-administration in the home or another nontraditional setting, where patient monitoring is infrequent. Errors in prescribing, dispensing, and administration and patient or caregiver misunderstandings are potential problems with the use of oral chemotherapy that need to be addressed when developing safe practices. Changes in Medicare pharmaceutical reimbursement rates and rules need to be monitored because they have the potential to affect patient care and outcomes. Patient assistance programs and advocacy groups can help alleviate financial concerns associated with oral chemotherapy. Consensus guidelines specific to safe handling of oral chemotherapy in the home or other nontraditional setting need to be developed. Also, healthcare providers must understand reimbursement and provide direction to patients when patient assistance programs or advocacy groups can assist with the financial challenges of oral chemotherapy.

Therapeutic Self-Disclosure within DBT, Schema Therapy, and CBASP: Opportunities and Challenges.

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Köhler, Stephan; Guhn, Anne; Betzler, Felix; Stiglmayr, Christian; Brakemeier, Eva-Lotta; Sterzer, Philipp

2017-01-01

In recent years, various therapeutic interventions have been established that extended behavior and cognitive behavior therapy (CBT) by so-called "third-wave" strategies. In order to address specific therapeutic challenges in certain subgroups of patients who do not sufficiently respond to "classical CBT," some of these third-wave strategies put particular emphasis on therapist self-disclosure. This article highlights therapeutic self-disclosure as a means to address interpersonal problems by comparing three third-wave strategies: (a) acceptance and change strategies as used in Dialectical Behavioral Therapy (DBT), (b) the concept of "limited reparenting" as used in Schema Therapy (ST), and (c) disciplined personal involvement as used in the Cognitive Behavioral Analysis System of Psychotherapy (CBASP). On the basis of a critical discussion on opportunities and challenges within these three concepts, self-disclosure is proposed to be a promising therapeutic tool that is worth to be investigated in more depth in future studies.

Therapeutic Self-Disclosure within DBT, Schema Therapy, and CBASP: Opportunities and Challenges

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Stephan Köhler

2017-11-01

Full Text Available In recent years, various therapeutic interventions have been established that extended behavior and cognitive behavior therapy (CBT by so-called “third-wave” strategies. In order to address specific therapeutic challenges in certain subgroups of patients who do not sufficiently respond to “classical CBT,” some of these third-wave strategies put particular emphasis on therapist self-disclosure. This article highlights therapeutic self-disclosure as a means to address interpersonal problems by comparing three third-wave strategies: (a acceptance and change strategies as used in Dialectical Behavioral Therapy (DBT, (b the concept of “limited reparenting” as used in Schema Therapy (ST, and (c disciplined personal involvement as used in the Cognitive Behavioral Analysis System of Psychotherapy (CBASP. On the basis of a critical discussion on opportunities and challenges within these three concepts, self-disclosure is proposed to be a promising therapeutic tool that is worth to be investigated in more depth in future studies.

Inhibition of thyroid hormone receptor locally in the retina is a therapeutic strategy for retinal degeneration.

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Ma, Hongwei; Yang, Fan; Butler, Michael R; Belcher, Joshua; Redmond, T Michael; Placzek, Andrew T; Scanlan, Thomas S; Ding, Xi-Qin

2017-08-01

Thyroid hormone (TH) signaling regulates cell proliferation, differentiation, and metabolism. Recent studies have implicated TH signaling in cone photoreceptor viability. Using mouse models of retinal degeneration, we demonstrated that antithyroid drug treatment and targeting iodothyronine deiodinases (DIOs) to suppress cellular tri-iodothyronine (T3) production or increase T3 degradation preserves cones. In this work, we investigated the effectiveness of inhibition of the TH receptor (TR). Two genes, THRA and THRB , encode TRs; THRB 2 has been associated with cone viability. Using TR antagonists and Thrb2 deletion, we examined the effects of TR inhibition. Systemic and ocular treatment with the TR antagonists NH-3 and 1-850 increased cone density by 30-40% in the Rpe65 -/- mouse model of Leber congenital amaurosis and reduced the number of TUNEL + cells. Cone survival was significantly improved in Rpe65 -/- and Cpfl1 (a model of achromatopsia with Pde6c defect) mice with Thrb2 deletion. Ventral cone density in Cpfl1/Thrb2 -/- and Rpe65 -/- / Thrb2 -/- mice was increased by 1- to 4-fold, compared with age-matched controls. Moreover, the expression levels of TR were significantly higher in the cone-degeneration retinas, suggesting locally elevated TR signaling. This work shows that the effects of antithyroid treatment or targeting DIOs were likely mediated by TRs and that suppressing TR protects cones. Our findings support the view that inhibition of TR locally in the retina is a therapeutic strategy for retinal degeneration management.-Ma, H., Yang, F., Butler, M. R., Belcher, J., Redmond, T. M., Placzek, A. T., Scanlan, T. S., Ding, X.-Q. Inhibition of thyroid hormone receptor locally in the retina is a therapeutic strategy for retinal degeneration. © FASEB.

Therapeutic Potency of Nanoformulations of siRNAs and shRNAs in Animal Models of Cancers

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Md. Emranul Karim

2018-05-01

Full Text Available RNA Interference (RNAi has brought revolutionary transformations in cancer management in the past two decades. RNAi-based therapeutics including siRNA and shRNA have immense scope to silence the expression of mutant cancer genes specifically in a therapeutic context. Although tremendous progress has been made to establish catalytic RNA as a new class of biologics for cancer management, a lot of extracellular and intracellular barriers still pose a long-lasting challenge on the way to clinical approval. A series of chemically suitable, safe and effective viral and non-viral carriers have emerged to overcome physiological barriers and ensure targeted delivery of RNAi. The newly invented carriers, delivery techniques and gene editing technology made current treatment protocols stronger to fight cancer. This review has provided a platform about the chronicle of siRNA development and challenges of RNAi therapeutics for laboratory to bedside translation focusing on recent advancement in siRNA delivery vehicles with their limitations. Furthermore, an overview of several animal model studies of siRNA- or shRNA-based cancer gene therapy over the past 15 years has been presented, highlighting the roles of genes in multiple cancers, pharmacokinetic parameters and critical evaluation. The review concludes with a future direction for the development of catalytic RNA vehicles and design strategies to make RNAi-based cancer gene therapy more promising to surmount cancer gene delivery challenges.

New Strategies for the Treatment of Solid Tumors with CAR-T Cells.

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Zhang, Hao; Ye, Zhen-Long; Yuan, Zhen-Gang; Luo, Zheng-Qiang; Jin, Hua-Jun; Qian, Qi-Jun

2016-01-01

Recent years, we have witnessed significant progresses in both basic and clinical studies regarding novel therapeutic strategies with genetically engineered T cells. Modification with chimeric antigen receptors (CARs) endows T cells with tumor specific cytotoxicity and thus induce anti-tumor immunity against malignancies. However, targeting solid tumors is more challenging than targeting B-cell malignancies with CAR-T cells because of the histopathological structure features, specific antigens shortage and strong immunosuppressive environment of solid tumors. Meanwhile, the on-target/off-tumor toxicity caused by relative expression of target on normal tissues is another issue that should be reckoned. Optimization of the design of CAR vectors, exploration of new targets, addition of safe switches and combination with other treatments bring new vitality to the CAR-T cell based immunotherapy against solid tumors. In this review, we focus on the major obstacles limiting the application of CAR-T cell therapy toward solid tumors and summarize the measures to refine this new cancer therapeutic modality.

A Comparison of Short- and Long-Term Therapeutic Outcomes of Infliximab- versus Tacrolimus-Based Strategies for Steroid-Refractory Ulcerative Colitis

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Katsuya Endo

2016-01-01

Full Text Available Background/Aims. Antitumor necrosis factor antibodies and calcineurin inhibitors have shown good therapeutic efficacy for steroid-refractory ulcerative colitis (UC. Although some studies have compared the efficacy of infliximab (IFX and cyclosporin A, there are no published studies comparing IFX and tacrolimus (Tac. This study aimed to compare therapeutic efficacies between IFX- and Tac-based strategies for steroid-refractory UC. Methods. Between July 2009 and August 2013, 95 patients with steroid-refractory UC received either IFX (n=48 or Tac (n=47 in our hospital. In the IFX group, the patients continued to receive maintenance treatment with IFX. In the Tac group, patients discontinued Tac treatment up to 3 months and subsequently received thiopurine. We retrospectively compared the therapeutic outcomes between the groups. Results. There was no significant difference in the colectomy-free rate, clinical remission rate, and clinical response rate at 2 months between the groups. However, relapse-free survival was significantly higher in the IFX group than in the Tac group (p<0.001; log-rank test. The proportions of serious adverse events did not differ between the groups. Conclusion. The findings of our study showed that IFX and Tac have similar short-term therapeutic efficacy for steroid-refractory UC. Maintenance treatment with IFX, however, yields better long-term outcomes than Tac-thiopurine bridging treatment.

Breast Cancer Stem Cell Therapeutics, Multiple Strategies Versus Using Engineered Mesenchymal Stem Cells With Notch Inhibitory Properties: Possibilities and Perspectives.

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Bose, Bipasha; Sen, Utsav; Shenoy P, Sudheer

2018-01-01

Relapse cases of cancers are more vigorous and difficult to control due to the preponderance of cancer stem cells (CSCs). Such CSCs that had been otherwise dormant during the first incidence of cancer gradually appear as radiochemoresistant cancer cells. Hence, cancer therapeutics aimed at CSCs would be an effective strategy for mitigating the cancers during relapse. Alternatively, CSC therapy can also be proposed as an adjuvant therapy, along-with the conventional therapies. As regenerative stem cells (RSCs) are known for their trophic effects, anti-tumorogenicity, and better migration toward an injury site, this review aims to address the use of adult stem cells such as dental pulp derived; cord blood derived pure populations of regenerative stem cells for targeting CSCs. Indeed, pro-tumorogenicity of RSCs is of concern and hence has also been dealt with in relation to breast CSC therapeutics. Furthermore, as notch signaling pathways are upregulated in breast cancers, and anti-notch antibody based and sh-RNA based therapies are already in the market, this review focuses the possibilities of engineering RSCs to express notch inhibitory proteins for breast CSC therapeutics. Also, we have drawn a comparison among various possibilities of breast CSC therapeutics, about, notch1 inhibition. J. Cell. Biochem. 119: 141-149, 2018. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Surgical management of spinal intramedullary tumors: radical and safe strategy for benign tumors.

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Takami, Toshihiro; Naito, Kentaro; Yamagata, Toru; Ohata, Kenji

2015-01-01

Surgery for spinal intramedullary tumors remains one of the major challenges for neurosurgeons, due to their relative infrequency, unknown natural history, and surgical difficulty. We are sure that safe and precise resection of spinal intramedullary tumors, particularly encapsulated benign tumors, can result in acceptable or satisfactory postoperative outcomes. General surgical concepts and strategies, technical consideration, and functional outcomes after surgery are discussed with illustrative cases of spinal intramedullary benign tumors such as ependymoma, cavernous malformation, and hemangioblastoma. Selection of a posterior median sulcus, posterolateral sulcus, or direct transpial approach was determined based on the preoperative imaging diagnosis and careful inspection of the spinal cord surface. Tumor-cord interface was meticulously delineated in cases of benign encapsulated tumors. Our retrospective functional analysis of 24 consecutive cases of spinal intramedullary ependymoma followed for at least 6 months postoperatively demonstrated a mean grade on the modified McCormick functional schema of 1.8 before surgery, deteriorating significantly to 2.6 early after surgery ( 6 months after surgery). The risk of functional deterioration after surgery should be taken into serious consideration. Functional deterioration after surgery, including neuropathic pain even long after surgery, significantly affects patient quality of life. Better balance between tumor control and functional preservation can be achieved not only by the surgical technique or expertise, but also by intraoperative neurophysiological monitoring, vascular image guidance, and postoperative supportive care. Quality of life after surgery should inarguably be given top priority.

Pharmacokinetics and toxicology of therapeutic proteins: Advances and challenges

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Vugmeyster, Yulia; Xu, Xin; Theil, Frank-Peter; Khawli, Leslie A; Leach, Michael W

2012-01-01

Significant progress has been made in understanding pharmacokinetics (PK), pharmacodynamics (PD), as well as toxicity profiles of therapeutic proteins in animals and humans, which have been in commercial development for more than three decades. However, in the PK arena, many fundamental questions remain to be resolved. Investigative and bioanalytical tools need to be established to improve the translation of PK data from animals to humans, and from in vitro assays to in vivo readouts, which would ultimately lead to a higher success rate in drug development. In toxicology, it is known, in general, what studies are needed to safely develop therapeutic proteins, and what studies do not provide relevant information. One of the major complicating factors in nonclinical and clinical programs for therapeutic proteins is the impact of immunogenicity. In this review, we will highlight the emerging science and technology, as well as the challenges around the pharmacokinetic- and safety-related issues in drug development of mAbs and other therapeutic proteins. PMID:22558487

Molecular Mechanisms of Diabetic Retinopathy, General Preventive Strategies, and Novel Therapeutic Targets

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Safi, Sher Zaman; Kumar, Selva; Ismail, Ikram Shah Bin

2014-01-01

The growing number of people with diabetes worldwide suggests that diabetic retinopathy (DR) and diabetic macular edema (DME) will continue to be sight threatening factors. The pathogenesis of diabetic retinopathy is a widespread cause of visual impairment in the world and a range of hyperglycemia-linked pathways have been implicated in the initiation and progression of this condition. Despite understanding the polyol pathway flux, activation of protein kinase C (KPC) isoforms, increased hexosamine pathway flux, and increased advanced glycation end-product (AGE) formation, pathogenic mechanisms underlying diabetes induced vision loss are not fully understood. The purpose of this paper is to review molecular mechanisms that regulate cell survival and apoptosis of retinal cells and discuss new and exciting therapeutic targets with comparison to the old and inefficient preventive strategies. This review highlights the recent advancements in understanding hyperglycemia-induced biochemical and molecular alterations, systemic metabolic factors, and aberrant activation of signaling cascades that ultimately lead to activation of a number of transcription factors causing functional and structural damage to retinal cells. It also reviews the established interventions and emerging molecular targets to avert diabetic retinopathy and its associated risk factors. PMID:25105142

76 FR 12719 - Safe Schools/Healthy Students Program; Office of Safe and Drug-Free Schools; Safe Schools/Healthy...

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2011-03-08

... DEPARTMENT OF EDUCATION Safe Schools/Healthy Students Program; Office of Safe and Drug- Free Schools; Safe Schools/Healthy Students Program; Catalog of Federal Domestic Assistance (CFDA) Numbers: 84... priorities, requirements, and definitions under the Safe Schools/Healthy Students (SS/HS) program. Since...

The Pathway to a Safe and Effective Medication Formulary for Exploration Spaceflight

Science.gov (United States)

Daniels, V. R.; Bayuse, T. M.; Mulcahy, R. A.; Mcguire, R. K. M.; Antonsen, E. L.

2017-01-01

PURPOSE: Exploration space missions pose several challenges to providing a comprehensive medication formulary designed to accommodate the size and space limitations of the spacecraft; while addressing the individual medications needs and preferences of the Crew; the negative outcome of a degrading inventory over time, the inability to resupply before expiration dates; and the need to properly forecast the best possible medication candidates to treat conditions that will occur in the future. METHODS: The Pharmacotherapeutics Discipline has partnered with the Exploration Medical Capabilities (ExMC) Element to develop and propose a research pathway that is comprehensively focused on evidence-based models and theories, as well as on new diagnostic tools and treatments or preventive measures aimed at closure of the Med02 “Pharmacy” Gap; defined in the Human Research Program’s (HRP) risk-based research strategy. The Med02 Gap promotes the challenge to identify a strategy to ensure that medications used to treat medical conditions during exploration space missions are available, safe, and effective. It is abundantly clear that pharmaceutical intervention is an essential component of risk management planning for astronaut healthcare during exploration space. However, the quandary still remains of how to assemble a formulary that is comprehensive enough to prevent or treat anticipated medical events; and is also chemically stable, safe, and robust enough to have sufficient potency to last for the duration of an exploration space mission. In cases where that is not possible, addressing this Gap requires exploration of novel drug development techniques, dosage forms, and dosage delivery platforms that enhance chemical stability as well as therapeutic effectiveness. RESULTS: The proposed research pathway outlines the steps, processes, procedures, and a research portfolio aimed at identifying a capability that will provide a safe and effective pharmacy for any specific

Preliminary results of M-VAC chemotherapy combined with mild hyperthermia, a new therapeutic strategy for advanced or metastatic transitional cell carcinoma of the urothelium.

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Yamada, Yoshiaki; Itoh, Youko; Aoki, Shigeyuki; Nakamura, Kogenta; Taki, Tomohiro; Naruse, Katsuya; Tobiume, Motoi; Zennami, Kenji; Katsuda, Remi; Kato, Yoshiharu; Watanabe, Masahito; Nishikawa, Genya; Minami, Miwako; Nakahira, Mariko; Ukai, Sayaka; Sawada, Masaki; Kitamura, Akiko; Honda, Nobuaki

2009-11-01

We evaluated the efficacy and safety of M-VAC chemotherapy combined with mild hyperthermia, a new therapeutic strategy for advanced metastatic transitional cell carcinoma of the urothelium. The subjects were 12 patients diagnosed with advanced metastatic transitional cell carcinoma of the urothelium. For mild hyperthermia, the patients' oral temperature was elevated to about 38 degrees C by heating for 20 min and retaining the heat for 20 min with a far-infrared heater. The antitumor effect was evaluated according to the RECIST, while adverse drug reactions were assessed based on the NCI-CTC. The antitumor effect was rated as partial remission (PR) in 10 of the 12 patients and stable disease in 2 patients, with an efficacy rate of 83% (10/12). All 10 patients who had achieved PR received three courses of treatment. Of the 12 patients, 5 died during the observation period, with survival for 9-23 months (mean: 15.6 months). Adverse drug reactions included myelosuppression in all patients (Grade 3 in 4 patients, Grade 4 in 8), and gastrointestinal toxicity, such as nausea or vomiting, which was mild (Grade 0 in 2 patients, Grade 1 in 8, Grade 2 in 1, Grade 3 in 1). The results of the present study suggest that M-VAC chemotherapy combined with mild hyperthermia, which potentiates the anticancer effect and reduces adverse drug reactions such as gastrointestinal symptoms, is a useful and safe method for the treatment of advanced transitional cell carcinoma of the urothelium.

A therapeutic-only versus prophylactic platelet transfusion strategy for preventing bleeding in patients with haematological disorders after myelosuppressive chemotherapy or stem cell transplantation

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Crighton, Gemma L; Estcourt, Lise J; Wood, Erica M; Trivella, Marialena; Doree, Carolyn; Stanworth, Simon

2015-01-01

Background Platelet transfusions are used in modern clinical practice to prevent and treat bleeding in thrombocytopenic patients with bone marrow failure. Although considerable advances have been made in platelet transfusion therapy in the last 40 years, some areas continue to provoke debate, especially concerning the use of prophylactic platelet transfusions for the prevention of thrombocytopenic bleeding. This is an update of a Cochrane review first published in 2004 and updated in 2012 that addressed four separate questions: therapeutic-only versus prophylactic platelet transfusion policy; prophylactic platelet transfusion threshold; prophylactic platelet transfusion dose; and platelet transfusions compared to alternative treatments. We have now split this review into four smaller reviews looking at these questions individually; this review is the first part of the original review. Objectives To determine whether a therapeutic-only platelet transfusion policy (platelet transfusions given when patient bleeds) is as effective and safe as a prophylactic platelet transfusion policy (platelet transfusions given to prevent bleeding, usually when the platelet count falls below a given trigger level) in patients with haematological disorders undergoing myelosuppressive chemotherapy or stem cell transplantation. Search methods We searched for randomised controlled trials (RCTs) in the Cochrane Central Register of Controlled Trials (Cochrane Library 2015, Issue 6), MEDLINE (from 1946), Embase (from 1974), CINAHL (from 1937), the Transfusion Evidence Library (from 1950) and ongoing trial databases to 23 July 2015. Selection criteria RCTs involving transfusions of platelet concentrates prepared either from individual units of whole blood or by apheresis, and given to prevent or treat bleeding in patients with malignant haematological disorders receiving myelosuppressive chemotherapy or undergoing HSCT. Data collection and analysis We used standard methodological procedures

Radioactive Waste Management Strategy

International Nuclear Information System (INIS)

2002-01-01

This strategy defines methods and means how collect, transport and bury radioactive waste safely. It includes low level radiation waste and high level radiation waste. In the strategy are foreseen main principles and ways of storage radioactive waste

MicroRNA modulation combined with sunitinib as a novel therapeutic strategy for pancreatic cancer

Directory of Open Access Journals (Sweden)

Passadouro M

2014-07-01

Full Text Available Marta Passadouro,1,2 Maria C Pedroso de Lima,1,2 Henrique Faneca11Center for Neuroscience and Cell Biology, 2Department of Life Sciences, Faculty of Science and Technology, University of Coimbra, Coimbra, PortugalAbstract: Pancreatic ductal adenocarcinoma (PDAC is a highly aggressive and mortal cancer, characterized by a set of known mutations, invasive features, and aberrant microRNA expression that have been associated with hallmark malignant properties of PDAC. The lack of effective PDAC treatment options prompted us to investigate whether microRNAs would constitute promising therapeutic targets toward the generation of a gene therapy approach with clinical significance for this disease. In this work, we show that the developed human serum albumin–1-palmitoyl-2-oleoyl-sn-glycero-3-ethylphosphocholine:cholesterol/anti-microRNA oligonucleotides (+/– (4/1 nanosystem exhibits the ability to efficiently deliver anti-microRNA oligonucleotides targeting the overexpressed microRNAs miR-21, miR-221, miR-222, and miR-10 in PDCA cells, promoting an almost complete abolishment of microRNA expression. Silencing of these microRNAs resulted in a significant increase in the levels of their targets. Moreover, the combination of microRNA silencing, namely miR-21, with low amounts of the chemotherapeutic drug sunitinib resulted in a strong and synergistic antitumor effect, showing that this combined strategy could be of great importance for therapeutic application in PDAC. Keywords: pancreatic cancer gene therapy, anti-microRNAs oligonucleotides, delivery nanosystems, albumin-associated lipoplexes

Potential antitumor therapeutic strategies of human amniotic membrane and amniotic fluid-derived stem cells.

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Kang, N-H; Hwang, K-A; Kim, S U; Kim, Y-B; Hyun, S-H; Jeung, E-B; Choi, K-C

2012-08-01

As stem cells are capable of self-renewal and can generate differentiated progenies for organ development, they are considered as potential source for regenerative medicine and tissue replacement after injury or disease. Along with this capacity, stem cells have the therapeutic potential for treating human diseases including cancers. According to the origins, stem cells are broadly classified into two types: embryonic stem cells (ESCs) and adult stem cells. In terms of differentiation potential, ESCs are pluripotent and adult stem cells are multipotent. Amnion, which is a membranous sac that contains the fetus and amniotic fluid and functions in protecting the developing embryo during gestation, is another stem cell source. Amnion-derived stem cells are classified as human amniotic membrane-derived epithelial stem cells, human amniotic membrane-derived mesenchymal stem cells and human amniotic fluid-derived stem cells. They are in an intermediate stage between pluripotent ESCs and lineage-restricted adult stem cells, non-tumorigenic, and contribute to low immunogenicity and anti-inflammation. Furthermore, they are easily available and do not cause any controversial issues in their recovery and applications. Not only are amnion-derived stem cells applicable in regenerative medicine, they have anticancer capacity. In non-engineered stem cells transplantation strategies, amnion-derived stem cells effectively target the tumor and suppressed the tumor growth by expressing cytotoxic cytokines. Additionally, they also have a potential as novel delivery vehicles transferring therapeutic genes to the cancer formation sites in gene-directed enzyme/prodrug combination therapy. Owing to their own advantageous properties, amnion-derived stem cells are emerging as a new candidate in anticancer therapy.

Imaging enabled platforms for development of therapeutics

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Celli, Jonathan; Rizvi, Imran; Blanden, Adam R.; Evans, Conor L.; Abu-Yousif, Adnan O.; Spring, Bryan Q.; Muzikansky, Alona; Pogue, Brian W.; Finkelstein, Dianne M.; Hasan, Tayyaba

2011-03-01

Advances in imaging and spectroscopic technologies have enabled the optimization of many therapeutic modalities in cancer and noncancer pathologies either by earlier disease detection or by allowing therapy monitoring. Amongst the therapeutic options benefiting from developments in imaging technologies, photodynamic therapy (PDT) is exceptional. PDT is a photochemistry-based therapeutic approach where a light-sensitive molecule (photosensitizer) is activated with light of appropriate energy (wavelength) to produce reactive molecular species such as free radicals and singlet oxygen. These molecular entities then react with biological targets such as DNA, membranes and other cellular components to impair their function and lead to eventual cell and tissue death. Development of PDT-based imaging also provides a platform for rapid screening of new therapeutics in novel in vitro models prior to expensive and labor-intensive animal studies. In this study we demonstrate how an imaging platform can be used for strategizing a novel combination treatment strategy for multifocal ovarian cancer. Using an in vitro 3D model for micrometastatic ovarian cancer in conjunction with quantitative imaging we examine dose and scheduling strategies for PDT in combination with carboplatin, a chemotherapeutic agent presently in clinical use for management of this deadly form of cancer.

Therapeutic Dancing for Parkinson's Disease

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Lorenna Pryscia Carvalho Aguiar

2016-06-01

Full Text Available Therapeutic dancing has been advocated as an effective adjunct to conventional physical therapies for people living with Parkinson's disease (PD. This systematic review evaluates studies on the outcomes of different dance genres on mobility and quality of life in PD. We searched databases including CINHAL (1982–2015, Medline (1922–2015, Scopus (1996–2015, Web of Science (2002–2015, Embase (2007–2015, PEDro (1999–2015 and the Cochrane Library (1996–2015. The key words were: Parkinson's disease, Parkinson*, Parkinsonism, dance, dance therapy, dance genres, safety, feasibility, and quality of life. Two independent investigators reviewed the texts. Only randomized controlled trials, quasirandomized controlled trials, and case series studies were included. There was emerging evidence that therapeutic dance can be safe and feasible for people with mild to moderately severe PD, with beneficial effects on walking, freezing of gait, and health related quality of life.

Recent advancement to prevent the development of allergy and allergic diseases and therapeutic strategy in the perspective of barrier dysfunction

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Osamu Natsume

2018-01-01

Full Text Available Therapeutic strategy in late 20th century to prevent allergic diseases was derived from a conceptual framework of allergens elimination which was as same as that of coping with them after their onset. Manifold trials were implemented; however, most of them failed to verify the effectiveness of their preventive measures. Recent advancement of epidemiological studies and cutaneous biology revealed epidermal barrier dysfunction plays a major role of allergen sensitization and development of atopic dermatitis which ignites the inception of allergy march. For this decade, therapeutic strategy to prevent the development of food allergy has been confronted with a paradigm shift from avoidance and delayed introduction of allergenic foods based on the theoretical concept to early introduction of them based on the clinical and epidemiological evidences. Especially, prevention of peanut allergy and egg allergy has been established with the highest evidence verified by randomized controlled trials, although application in clinical practice should be done with attention. This paradigm shift concerning food allergy was also due to the discovery of cutaneous sensitization risk of food allergens for an infant with eczema revealed by prospective studies. Here we have recognized the increased importance of prevention of eczema/atopic dermatitis in infancy. Two randomized controlled trials using emollients showed successful results in prevention of atopic dermatitis in infancy; however, longer term safety and prognosis including allergy march should be pursued. To establish more fundamental strategy for prevention of the development of allergy, further studies clarifying the mechanisms of interaction between barrier dysfunction and microbial milieu are needed with macroscope to understand the relationship between allergic diseases and a diversity of environmental influences.

Current therapeutic strategies of anti-HER2 treatment in advanced breast cancer patients

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Joanna Huszno

2016-03-01

Full Text Available The HER2/neu ( ERBB2 oncogene is amplified and/or overexpressed in approximately 20% of breast cancers, and is a strong prognostic factor for relapse and poor overall survival, particularly in node-positive patients. It is also an important predictor for response to trastuzumab, which has established efficacy against breast cancer with overexpression or amplification of the HER2 oncogene. Treatment with the anti-HER2 humanized monoclonal antibody – trastuzumab significantly improves progression-free and overall survival among patients with HER2-positive breast cancer. However, in most patients with HER2-positive metastatic breast cancer, the disease progresses occurred, what cause the need for new targeted therapies for advanced disease. In clinical trials, there are tested new drugs to improve the results of treatment for this group of patients. This paper presents new drugs introduced into clinical practice for treatment of advanced breast cancer, whose molecular target are receptors of the HER2 family. In addition, new therapeutic strategies and drugs that are currently in clinical researches are discussed.

Molecular docking studies of 3-bromopyruvate and its derivatives to metabolic regulatory enzymes: Implication in designing of novel anticancer therapeutic strategies.

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Yadav, Saveg; Pandey, Shrish Kumar; Singh, Vinay Kumar; Goel, Yugal; Kumar, Ajay; Singh, Sukh Mahendra

2017-01-01

Altered metabolism is an emerging hallmark of cancer, as malignant cells display a mammoth up-regulation of enzymes responsible for steering their bioenergetic and biosynthetic machinery. Thus, the recent anticancer therapeutic strategies focus on the targeting of metabolic enzymes, which has led to the identification of specific metabolic inhibitors. One of such inhibitors is 3-bromopyruvate (3-BP), with broad spectrum of anticancer activity due to its ability to inhibit multiple metabolic enzymes. However, the molecular characterization of its binding to the wide spectrum of target enzymes remains largely elusive. Therefore, in the present study we undertook in silico investigations to decipher the molecular nature of the docking of 3-BP with key target enzymes of glycolysis and TCA cycle by PatchDock and YASARA docking tools. Additionally, derivatives of 3-BP, dibromopyruvate (DBPA) and propionic acid (PA), with reported biological activity, were also investigated for docking to important target metabolic enzymes of 3-BP, in order to predict their therapeutic efficacy versus that of 3-BP. A comparison of the docking scores with respect to 3-BP indicated that both of these derivatives display a better binding strength to metabolic enzymes. Further, analysis of the drug likeness of 3-BP, DBPA and PA by Lipinski filter, admetSAR and FAF Drug3 indicated that all of these agents showed desirable drug-like criteria. The outcome of this investigation sheds light on the molecular characteristics of the binding of 3-BP and its derivatives with metabolic enzymes and thus may significantly contribute in designing and optimizing therapeutic strategies against cancer by using these agents.

Molecular docking studies of 3-bromopyruvate and its derivatives to metabolic regulatory enzymes: Implication in designing of novel anticancer therapeutic strategies.

Directory of Open Access Journals (Sweden)

Saveg Yadav

Full Text Available Altered metabolism is an emerging hallmark of cancer, as malignant cells display a mammoth up-regulation of enzymes responsible for steering their bioenergetic and biosynthetic machinery. Thus, the recent anticancer therapeutic strategies focus on the targeting of metabolic enzymes, which has led to the identification of specific metabolic inhibitors. One of such inhibitors is 3-bromopyruvate (3-BP, with broad spectrum of anticancer activity due to its ability to inhibit multiple metabolic enzymes. However, the molecular characterization of its binding to the wide spectrum of target enzymes remains largely elusive. Therefore, in the present study we undertook in silico investigations to decipher the molecular nature of the docking of 3-BP with key target enzymes of glycolysis and TCA cycle by PatchDock and YASARA docking tools. Additionally, derivatives of 3-BP, dibromopyruvate (DBPA and propionic acid (PA, with reported biological activity, were also investigated for docking to important target metabolic enzymes of 3-BP, in order to predict their therapeutic efficacy versus that of 3-BP. A comparison of the docking scores with respect to 3-BP indicated that both of these derivatives display a better binding strength to metabolic enzymes. Further, analysis of the drug likeness of 3-BP, DBPA and PA by Lipinski filter, admetSAR and FAF Drug3 indicated that all of these agents showed desirable drug-like criteria. The outcome of this investigation sheds light on the molecular characteristics of the binding of 3-BP and its derivatives with metabolic enzymes and thus may significantly contribute in designing and optimizing therapeutic strategies against cancer by using these agents.

New maintenance strategy of Tokyo Electric Power Company and Fukushima Dai-ichi Nuclear Power Plant for effective ageing management and safe long-term operation

International Nuclear Information System (INIS)

Inagaki, Takeyuki; Yamashita, Norimichi

2009-01-01

Fukushima Dai-ichi Nuclear Power Plant is the oldest among three nuclear power plants owned and operated by Tokyo Electric Power Company, which consists of six boiling water reactor units. The commercial operation of Unit 1 was commenced in 1971 (37 years old) and Unit 6 in 1978 (29 years old). Currently ageing degradations of systems, structures and components are managed through maintenance programs, component replacement/refurbishment programs and long-term maintenance plans. The long-term maintenance plans are established through ageing management component replacement/refurbishment programs reviews performed before the 30th year of operation and they are for safe and reliable operation after 30 years (long-term operation). However the past maintenance actions and past component replacement/refurbishment programs were not always proactive and past operational experience and maintenance practices suggest that effective/proactive ageing management programs be introduced in earlier stage of the plant operation. In this circumstance, Tokyo Electric Power Company and Fukushima Dai-ichi Nuclear Power Plant are setting up a new maintenance strategy that includes 1) improving the normal maintenance programs by using ageing degradation data, 2) effective use of information on internal/external operational experience and maintenance practices related to ageing, and 3) proactive component/equipment refurbishment programs during a refreshment outage for safe and reliable long-term operation. To accomplish the goal of this strategy, strengthening engineering capability of plant staff members is a crucial required for the plant. The objective of this paper is to briefly explain main results ageing management reviews, past and current significant ageing issues and management programs against them, and the new maintenance strategy established by Tokyo Electric Power Company and Fukushima Dai-ichi Nuclear Power Plant. (author)

Targeting miRNAs by polyphenols: Novel therapeutic strategy for cancer.

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Pandima Devi, Kasi; Rajavel, Tamilselvam; Daglia, Maria; Nabavi, Seyed Fazel; Bishayee, Anupam; Nabavi, Seyed Mohammad

2017-10-01

In the recent years, polyphenols have gained significant attention in scientific community owing to their potential anticancer effects against a wide range of human malignancies. Epidemiological, clinical and preclinical studies have supported that daily intake of polyphenol-rich dietary fruits have a strong co-relationship in the prevention of different types of cancer. In addition to direct antioxidant mechanisms, they also regulate several therapeutically important oncogenic signaling and transcription factors. However, after the discovery of microRNA (miRNA), numerous studies have identified that polyphenols, including epigallocatechin-3-gallate, genistein, resveratrol and curcumin exert their anticancer effects by regulating different miRNAs which are implicated in all the stages of cancer. MiRNAs are short, non-coding endogenous RNA, which silence the gene functions by targeting messenger RNA (mRNA) through degradation or translation repression. However, cancer associated miRNAs has emerged only in recent years to support its applications in cancer therapy. Preclinical experiments have suggested that deregulation of single miRNA is sufficient for neoplastic transformation of cells. Indeed, the widespread deregulation of several miRNA profiles of tumor and healthy tissue samples revealed the involvement of many types of miRNA in the development of numerous cancers. Hence, targeting the miRNAs using polyphenols will be a novel and promising strategy in anticancer chemotherapy. Herein, we have critically reviewed the potential applications of polyphenols on various human miRNAs, especially which are involved in oncogenic and tumor suppressor pathways. Copyright © 2017 Elsevier Ltd. All rights reserved.

Cool and Safe: Multiplicity in Safe Innovation at Unilever

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Penders, Bart

2011-01-01

This article presents the making of a safe innovation: the application of ice structuring protein (ISP) in edible ices. It argues that safety is not the absence of risk but is an active accomplishment; innovations are not "made safe afterward" but "safe innovations are made". Furthermore, there are multiple safeties to be accomplished in the…

Safe Reentry for False Aneurysm Operations in High-Risk Patients.

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Martinelli, Gian Luca; Cotroneo, Attilio; Caimmi, Philippe Primo; Musica, Gabriele; Barillà, David; Stelian, Edmond; Romano, Angelo; Novelli, Eugenio; Renzi, Luca; Diena, Marco

2017-06-01

In the absence of a standardized safe surgical reentry strategy for high-risk patients with large or anterior postoperative aortic false aneurysm (PAFA), we aimed to describe an effective and safe approach for such patients. We prospectively analyzed patients treated for PAFA between 2006 and 2015. According to the preoperative computed tomography scan examination, patients were divided into two groups according to the anatomy and extension of PAFA: in group A, high-risk PAFA (diameter ≥3 cm) developed in the anterior mediastinum; in group B, low-risk PAFA (diameter <3 cm) was situated posteriorly. For group A, a safe surgical strategy, including continuous cerebral, visceral, and coronary perfusion was adopted before resternotomy; group B patients underwent conventional surgery. We treated 27 patients (safe reentry, n = 13; standard approach, n = 14). Mean age was 60 years (range, 29 to 80); 17 patients were male. Mean interval between the first operation and the last procedure was 4.3 years. Overall 30-day mortality rate was 7.4% (1 patient in each group). No aorta-related mortality was observed at 1 and 5 years in either group. The Kaplan-Meier overall survival estimates at 1 and 5 years were, respectively, 92.3% ± 7.4% and 73.4% ± 13.4% in group A, and 92.9% ± 6.9% and 72.2% ± 13.9% in group B (log rank test, p = 0.830). Freedom from reoperation for recurrent aortic disease was 100% at 1 year and 88% at 5 years. The safe reentry technique with continuous cerebral, visceral, and coronary perfusion for high-risk patients resulted in early and midterm outcomes similar to those observed for low-risk patients undergoing conventional surgery. Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Therapeutic touch and agitation in individuals with Alzheimer's disease.

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Hawranik, Pamela; Johnston, Pat; Deatrich, Judith

2008-06-01

Limited effective strategies exist to alleviate or treat disruptive behaviors in people with Alzheimer's disease. Fifty-one residents of a long-term care facility with Alzheimer's disease were randomly assigned to one of three intervention groups. A multiple time series, blinded, experimental design was used to compare the effectiveness of therapeutic touch, simulated therapeutic touch, and usual care on disruptive behavior. Three forms of disruptive behavior comprised the dependent variables: physical aggression, physical nonaggression, and verbal agitation. Physical nonaggressive behaviors decreased significantly in those residents who received therapeutic touch compared with those who received the simulated version and the usual care. No significant differences in physically aggressive and verbally agitated behaviors were observed across the three study groups. The study provided preliminary evidence for the potential for therapeutic touch in dealing with agitated behaviors by people with dementia. Researchers and practitioners must consider a broad array of strategies to deal with these behaviors.

Inhibiting DNA Polymerases as a Therapeutic Intervention against Cancer

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Anthony J. Berdis

2017-11-01

Full Text Available Inhibiting DNA synthesis is an important therapeutic strategy that is widely used to treat a number of hyperproliferative diseases including viral infections, autoimmune disorders, and cancer. This chapter describes two major categories of therapeutic agents used to inhibit DNA synthesis. The first category includes purine and pyrmidine nucleoside analogs that directly inhibit DNA polymerase activity. The second category includes DNA damaging agents including cisplatin and chlorambucil that modify the composition and structure of the nucleic acid substrate to indirectly inhibit DNA synthesis. Special emphasis is placed on describing the molecular mechanisms of these inhibitory effects against chromosomal and mitochondrial DNA polymerases. Discussions are also provided on the mechanisms associated with resistance to these therapeutic agents. A primary focus is toward understanding the roles of specialized DNA polymerases that by-pass DNA lesions produced by DNA damaging agents. Finally, a section is provided that describes emerging areas in developing new therapeutic strategies targeting specialized DNA polymerases.

[Therapeutic strategies against myasthenia gravis].

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Utsugisawa, Kimiaki; Nagane, Yuriko

2013-05-01

Many patients with myasthenia gravis (MG) still find it difficult to maintain daily activities due to chronic residual fatigability and long-term side effects of oral corticosteroids, since full remission is not common. Our analysis demonstrated that disease severity, oral corticosteroids, and depressive state are the major factors negatively associated with QOL, and that QOL of MM status patients taking CSR and is a target of treatment. In order to achieve early MM or better status with prednisolne strategy that can achieve early improvement by performing an aggressive therapy using combined treatment with plasmapheresis and high-dose intravenous methylprednisolone and then maintain an improved status using low-dose oral corticosteroids and calcineurin inhibitors.

Transendothelial Transport and Its Role in Therapeutics

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Upadhyay, Ravi Kant

2014-01-01

Present review paper highlights role of BBB in endothelial transport of various substances into the brain. More specifically, permeability functions of BBB in transendothelial transport of various substances such as metabolic fuels, ethanol, amino acids, proteins, peptides, lipids, vitamins, neurotransmitters, monocarbxylic acids, gases, water, and minerals in the peripheral circulation and into the brain have been widely explained. In addition, roles of various receptors, ATP powered pumps, channels, and transporters in transport of vital molecules in maintenance of homeostasis and normal body functions have been described in detail. Major role of integral membrane proteins, carriers, or transporters in drug transport is highlighted. Both diffusion and carrier mediated transport mechanisms which facilitate molecular trafficking through transcellular route to maintain influx and outflux of important nutrients and metabolic substances are elucidated. Present review paper aims to emphasize role of important transport systems with their recent advancements in CNS protection mainly for providing a rapid clinical aid to patients. This review also suggests requirement of new well-designed therapeutic strategies mainly potential techniques, appropriate drug formulations, and new transport systems for quick, easy, and safe delivery of drugs across blood brain barrier to save the life of tumor and virus infected patients. PMID:27355037

International conference on safe decommissioning for nuclear activities: Assuring the safe termination of practices involving radioactive materials. Contributed papers

Energy Technology Data Exchange (ETDEWEB)

NONE

2002-07-01

Thousands of operations involving the use of radioactive substances will end during the current century. While there is considerable regulatory experience in the 'front end' of the regulatory system for practices, the experience at the back end is more limited as fewer practices have actually been terminated. When a practice is terminated because the facility has reached the end of its useful life, action has to betaken to ensure the safe shutdown of the facility and allow the removal of regulatory controls. There are many issues involved in the safe termination of practices. These include setting criteria for the release of material and sites from regulatory control; determining the suitability of the various options for decommissioning nuclear facilities, managing the waste and material released from control (recycling, reuse or disposal), and the eventual remediation of the site. Some countries have put in place regulatory infrastructures and have developed programmes to manage the associated decommissioning and remediation activities. Other countries are at the stage of assessing what is involved in terminating such practices. The purpose of this Conference is to foster an information exchange on the safe an orderly termination of practices that involve the use of radioactive substances, including both decommissioning and environmental remediation, and to promote improved coherence internationally on strategies and criteria for the safe termination of practices.

International conference on safe decommissioning for nuclear activities: Assuring the safe termination of practices involving radioactive materials. Contributed papers

International Nuclear Information System (INIS)

2002-01-01

Thousands of operations involving the use of radioactive substances will end during the current century. While there is considerable regulatory experience in the 'front end' of the regulatory system for practices, the experience at the back end is more limited as fewer practices have actually been terminated. When a practice is terminated because the facility has reached the end of its useful life, action has to betaken to ensure the safe shutdown of the facility and allow the removal of regulatory controls. There are many issues involved in the safe termination of practices. These include setting criteria for the release of material and sites from regulatory control; determining the suitability of the various options for decommissioning nuclear facilities, managing the waste and material released from control (recycling, reuse or disposal), and the eventual remediation of the site. Some countries have put in place regulatory infrastructures and have developed programmes to manage the associated decommissioning and remediation activities. Other countries are at the stage of assessing what is involved in terminating such practices. The purpose of this Conference is to foster an information exchange on the safe an orderly termination of practices that involve the use of radioactive substances, including both decommissioning and environmental remediation, and to promote improved coherence internationally on strategies and criteria for the safe termination of practices

A Zebrafish Heart Failure Model for Assessing Therapeutic Agents.

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Zhu, Xiao-Yu; Wu, Si-Qi; Guo, Sheng-Ya; Yang, Hua; Xia, Bo; Li, Ping; Li, Chun-Qi

2018-03-20

Heart failure is a leading cause of death and the development of effective and safe therapeutic agents for heart failure has been proven challenging. In this study, taking advantage of larval zebrafish, we developed a zebrafish heart failure model for drug screening and efficacy assessment. Zebrafish at 2 dpf (days postfertilization) were treated with verapamil at a concentration of 200 μM for 30 min, which were determined as optimum conditions for model development. Tested drugs were administered into zebrafish either by direct soaking or circulation microinjection. After treatment, zebrafish were randomly selected and subjected to either visual observation and image acquisition or record videos under a Zebralab Blood Flow System. The therapeutic effects of drugs on zebrafish heart failure were quantified by calculating the efficiency of heart dilatation, venous congestion, cardiac output, and blood flow dynamics. All 8 human heart failure therapeutic drugs (LCZ696, digoxin, irbesartan, metoprolol, qiliqiangxin capsule, enalapril, shenmai injection, and hydrochlorothiazide) showed significant preventive and therapeutic effects on zebrafish heart failure (p failure model developed and validated in this study could be used for in vivo heart failure studies and for rapid screening and efficacy assessment of preventive and therapeutic drugs.

Providing safe drinking water to 1.2 billion unserved people

Energy Technology Data Exchange (ETDEWEB)

Gadgil, Ashok J.; Derby, Elisabeth A.

2003-06-01

Despite substantial advances in the past 100 years in public health, technology and medicine, 20% of the world population, mostly comprised of the poor population segments in developing countries (DCs), still does not have access to safe drinking water. To reach the United Nations (UN) Millennium Goal of halving the number of people without access to safe water by 2015, the global community will need to provide an additional one billion urban residents and 600 million rural residents with safe water within the next twelve years. This paper examines current water treatment measures and implementation methods for delivery of safe drinking water, and offers suggestions for making progress towards the goal of providing a timely and equitable solution for safe water provision. For water treatment, based on the serious limitations of boiling water and chlorination, we suggest an approach based on filtration coupled with ultraviolet (UV) disinfection, combined with public education. Additionally, owing to the capacity limitations for non-governmental organizations (NGOs) to take on this task primarily on their own, we suggest a strategy based on financially sustainable models that include the private sector as well as NGOs.

Safeguards Automated Facility Evaluation (SAFE) methodology

International Nuclear Information System (INIS)

Chapman, L.D.; Grady, L.M.; Bennett, H.A.; Sasser, D.W.; Engi, D.

1978-08-01

An automated approach to facility safeguards effectiveness evaluation has been developed. This automated process, called Safeguards Automated Facility Evaluation (SAFE), consists of a collection of a continuous stream of operational modules for facility characterization, the selection of critical paths, and the evaluation of safeguards effectiveness along these paths. The technique has been implemented on an interactive computer time-sharing system and makes use of computer graphics for the processing and presentation of information. Using this technique, a comprehensive evaluation of a safeguards system can be provided by systematically varying the parameters that characterize the physical protection components of a facility to reflect the perceived adversary attributes and strategy, environmental conditions, and site operational conditions. The SAFE procedure has broad applications in the nuclear facility safeguards field as well as in the security field in general. Any fixed facility containing valuable materials or components to be protected from theft or sabotage could be analyzed using this same automated evaluation technique

Marketing therapeutic recreation services.

Science.gov (United States)

Thorn, B E

1984-01-01

The use of marketing strategies can enhance the delivery of therapeutic recreation services. This article discusses how agencies can adapt marketing techniques and use them to identify potential markets, improve image, evaluate external pressures, and maximize internal strengths. Four variables that can be controlled and manipulated in a proposed marketing plan are product, price, place and promotion.

Applying extracellular vesicles based therapeutics in clinical trials – an ISEV position paper

Science.gov (United States)

Lener, Thomas; Gimona, Mario; Aigner, Ludwig; Börger, Verena; Buzas, Edit; Camussi, Giovanni; Chaput, Nathalie; Chatterjee, Devasis; Court, Felipe A.; del Portillo, Hernando A.; O'Driscoll, Lorraine; Fais, Stefano; Falcon-Perez, Juan M.; Felderhoff-Mueser, Ursula; Fraile, Lorenzo; Gho, Yong Song; Görgens, André; Gupta, Ramesh C.; Hendrix, An; Hermann, Dirk M.; Hill, Andrew F.; Hochberg, Fred; Horn, Peter A.; de Kleijn, Dominique; Kordelas, Lambros; Kramer, Boris W.; Krämer-Albers, Eva-Maria; Laner-Plamberger, Sandra; Laitinen, Saara; Leonardi, Tommaso; Lorenowicz, Magdalena J.; Lim, Sai Kiang; Lötvall, Jan; Maguire, Casey A.; Marcilla, Antonio; Nazarenko, Irina; Ochiya, Takahiro; Patel, Tushar; Pedersen, Shona; Pocsfalvi, Gabriella; Pluchino, Stefano; Quesenberry, Peter; Reischl, Ilona G.; Rivera, Francisco J.; Sanzenbacher, Ralf; Schallmoser, Katharina; Slaper-Cortenbach, Ineke; Strunk, Dirk; Tonn, Torsten; Vader, Pieter; van Balkom, Bas W. M.; Wauben, Marca; Andaloussi, Samir El; Théry, Clotilde; Rohde, Eva; Giebel, Bernd

2015-01-01

Extracellular vesicles (EVs), such as exosomes and microvesicles, are released by different cell types and participate in physiological and pathophysiological processes. EVs mediate intercellular communication as cell-derived extracellular signalling organelles that transmit specific information from their cell of origin to their target cells. As a result of these properties, EVs of defined cell types may serve as novel tools for various therapeutic approaches, including (a) anti-tumour therapy, (b) pathogen vaccination, (c) immune-modulatory and regenerative therapies and (d) drug delivery. The translation of EVs into clinical therapies requires the categorization of EV-based therapeutics in compliance with existing regulatory frameworks. As the classification defines subsequent requirements for manufacturing, quality control and clinical investigation, it is of major importance to define whether EVs are considered the active drug components or primarily serve as drug delivery vehicles. For an effective and particularly safe translation of EV-based therapies into clinical practice, a high level of cooperation between researchers, clinicians and competent authorities is essential. In this position statement, basic and clinical scientists, as members of the International Society for Extracellular Vesicles (ISEV) and of the European Cooperation in Science and Technology (COST) program of the European Union, namely European Network on Microvesicles and Exosomes in Health and Disease (ME-HaD), summarize recent developments and the current knowledge of EV-based therapies. Aspects of safety and regulatory requirements that must be considered for pharmaceutical manufacturing and clinical application are highlighted. Production and quality control processes are discussed. Strategies to promote the therapeutic application of EVs in future clinical studies are addressed. PMID:26725829

Ebola virus (EBOV) infection: Therapeutic strategies.

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De Clercq, Erik

2015-01-01

Within less than a year after its epidemic started (in December 2013) in Guinea, Ebola virus (EBOV), a member of the filoviridae, has spread over a number of West-African countries (Guinea, Sierra Leone and Liberia) and gained allures that have been unprecedented except by human immunodeficiency virus (HIV). Although EBOV is highly contagious and transmitted by direct contact with body fluids, it could be counteracted by the adequate chemoprophylactic and -therapeutic interventions: vaccines, antibodies, siRNAs (small interfering RNAs), interferons and chemical substances, i.e. neplanocin A derivatives (i.e. 3-deazaneplanocin A), BCX4430, favipiravir (T-705), endoplasmic reticulum (ER) α-glucosidase inhibitors and a variety of compounds that have been found to inhibit EBOV infection blocking viral entry or by a mode of action that still has to be resolved. Much has to be learned from the mechanism of action of the compounds active against VSV (vesicular stomatitis virus), a virus belonging to the rhabdoviridae, that in its mode of replication could be exemplary for the replication of filoviridae. Copyright © 2014 Elsevier Inc. All rights reserved.

Therapeutic Targeting of AXL Receptor Tyrosine Kinase Inhibits Tumor Growth and Intraperitoneal Metastasis in Ovarian Cancer Models

Directory of Open Access Journals (Sweden)

Pinar Kanlikilicer

2017-12-01

Full Text Available Despite substantial improvements in the treatment strategies, ovarian cancer is still the most lethal gynecological malignancy. Identification of drug treatable therapeutic targets and their safe and effective targeting is critical to improve patient survival in ovarian cancer. AXL receptor tyrosine kinase (RTK has been proposed to be an important therapeutic target for metastatic and advanced-stage human ovarian cancer. We found that AXL-RTK expression is associated with significantly shorter patient survival based on the The Cancer Genome Atlas patient database. To target AXL-RTK, we developed a chemically modified serum nuclease-stable AXL aptamer (AXL-APTAMER, and we evaluated its in vitro and in vivo antitumor activity using in vitro assays as well as two intraperitoneal animal models. AXL-aptamer treatment inhibited the phosphorylation and the activity of AXL, impaired the migration and invasion ability of ovarian cancer cells, and led to the inhibition of tumor growth and number of intraperitoneal metastatic nodules, which was associated with the inhibition of AXL activity and angiogenesis in tumors. When combined with paclitaxel, in vivo systemic (intravenous [i.v.] administration of AXL-aptamer treatment markedly enhanced the antitumor efficacy of paclitaxel in mice. Taken together, our data indicate that AXL-aptamers successfully target in vivo AXL-RTK and inhibit its AXL activity and tumor growth and progression, representing a promising strategy for the treatment of ovarian cancer.

Contextual Challenges to Safe Surgery in a Resource-limited Setting: A Multicenter, Multiprofessional Qualitative Study.

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Scott, John W; Lin, Yihan; Ntakiyiruta, Georges; Mutabazi, Zeta A; Davis, William Austin; Morris, Megan A; Smink, Douglas S; Riviello, Robert; Yule, Steven

2018-03-01

Safe surgery should be available to all patients, no matter the setting. The purpose of this study was to explore the contextual-specific challenges to safe surgical care encountered by surgeons and surgical teams in many in low- and middle-income countries (LMICs), and to understand the ways in which surgical teams overcome them. Optimal surgical performance is highly complex and requires providers to integrate and communicate information regarding the patient, task, team, and environment to coordinate team-based care that is timely, effective, and safe. Resource limitations common to many LMICs present unique challenges to surgeons operating in these environments, but have never been formally described. Using a grounded theory approach, we interviewed 34 experienced providers (surgeons, anesthetists, and nurses) at the 4 tertiary referral centers in Rwanda, to understand the challenges to safe surgical care and strategies to overcome them. Interview transcripts were coded line-by-line and iteratively analyzed for emerging themes until thematic saturation was reached. Rwandan-described challenges related to 4 domains: physical resources, human resources, overall systems support, and communication/language. The majority of these challenges arose from significant variability in either the quantity or quality of these domains. Surgical providers exhibited examples of resilient strategies to anticipate, monitor, respond to, and learn from these challenges. Resource variability rather than lack of resources underlies many contextual challenges to safe surgical care in a LMIC setting. Understanding these challenges and resilient strategies to overcome them is critical for both LMIC surgical providers and surgeons from HICs working in similar settings.

Targeting activator protein 1 signaling pathway by bioactive natural agents: Possible therapeutic strategy for cancer prevention and intervention.

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Tewari, Devesh; Nabavi, Seyed Fazel; Nabavi, Seyed Mohammad; Sureda, Antoni; Farooqi, Ammad Ahmad; Atanasov, Atanas G; Vacca, Rosa Anna; Sethi, Gautam; Bishayee, Anupam

2018-02-01

Activator protein 1 (AP-1) is a key transcription factor in the control of several cellular processes responsible for cell survival proliferation and differentiation. Dysfunctional AP-1 expression and activity are involved in several severe diseases, especially inflammatory disorders and cancer. Therefore, targeting AP-1 has recently emerged as an attractive therapeutic strategy for cancer prevention and therapy. This review summarizes our current understanding of AP-1 biology and function as well as explores and discusses several natural bioactive compounds modulating AP-1-associated signaling pathways for cancer prevention and intervention. Current limitations, challenges, and future directions of research are also critically discussed. Copyright © 2017 Elsevier Ltd. All rights reserved.

Degradation of misfolded proteins in neurodegenerative diseases: therapeutic targets and strategies.

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Ciechanover, Aaron; Kwon, Yong Tae

2015-03-13

Mammalian cells remove misfolded proteins using various proteolytic systems, including the ubiquitin (Ub)-proteasome system (UPS), chaperone mediated autophagy (CMA) and macroautophagy. The majority of misfolded proteins are degraded by the UPS, in which Ub-conjugated substrates are deubiquitinated, unfolded and cleaved into small peptides when passing through the narrow chamber of the proteasome. The substrates that expose a specific degradation signal, the KFERQ sequence motif, can be delivered to and degraded in lysosomes via the CMA. Aggregation-prone substrates resistant to both the UPS and the CMA can be degraded by macroautophagy, in which cargoes are segregated into autophagosomes before degradation by lysosomal hydrolases. Although most misfolded and aggregated proteins in the human proteome can be degraded by cellular protein quality control, some native and mutant proteins prone to aggregation into β-sheet-enriched oligomers are resistant to all known proteolytic pathways and can thus grow into inclusion bodies or extracellular plaques. The accumulation of protease-resistant misfolded and aggregated proteins is a common mechanism underlying protein misfolding disorders, including neurodegenerative diseases such as Huntington's disease (HD), Alzheimer's disease (AD), Parkinson's disease (PD), prion diseases and Amyotrophic Lateral Sclerosis (ALS). In this review, we provide an overview of the proteolytic pathways in neurons, with an emphasis on the UPS, CMA and macroautophagy, and discuss the role of protein quality control in the degradation of pathogenic proteins in neurodegenerative diseases. Additionally, we examine existing putative therapeutic strategies to efficiently remove cytotoxic proteins from degenerating neurons.

[Premenstrual dysphoric disorder: diagnosis and therapeutic strategy].

Science.gov (United States)

Bianchi-Demicheli, F

2006-02-08

Prementrual dysphoric disorder (PMDD) is considered to be a very severe form of the premenstrual syndrome (PMS) that occurs regularly in the last week of the luteal phase of the cycle and begin to remit after the onset of follicular phase and is absent in the week postmenses. What sets PMDD apart from PMS is its severity and its dominant psychiatric symptoms. PMDD includes depression, anxiety, tension, irritability and moodiness. Moreover, women with PMDD find that it has a very disruptive effect on their everyday lives. Although, many treatments have been used for PMDD over the years, PMDD remains difficult to be cured. Until recently, only few of these treatments were evaluated in carefully designed research studies and even fewer were shown to be effective. Here, we discuss the different therapeutic options for PMDD.

Immunotherapeutic strategies for cervical squamous carcinoma

NARCIS (Netherlands)

van Driel, W. J.; Kenter, G. G.; Fleuren, G. J.; Melief, C. J.; Trimbos, B. J.

1999-01-01

Progress in developing preventive and therapeutic vaccines for HPV-associated diseases has been made in the last few years, but continued studies are needed to evaluate the clinical feasibility of different vaccination approaches and to determine a clinically effective and safe one. The perfect HPV

MicroRNA-targeted therapeutics for lung cancer treatment.

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Xue, Jing; Yang, Jiali; Luo, Meihui; Cho, William C; Liu, Xiaoming

2017-02-01

Lung cancer is one of the leading causes of cancer-related mortality worldwide. MicroRNAs (miRNAs) are endogenous non-coding small RNAs that repress the expression of a broad array of target genes. Many efforts have been made to therapeutically target miRNAs in cancer treatments using miRNA mimics and miRNA antagonists. Areas covered: This article summarizes the recent findings with the role of miRNAs in lung cancer, and discusses the potential and challenges of developing miRNA-targeted therapeutics in this dreadful disease. Expert opinion: The development of miRNA-targeted therapeutics has become an important anti-cancer strategy. Results from both preclinical and clinical trials of microRNA replacement therapy have shown some promise in cancer treatment. However, some obstacles, including drug delivery, specificity, off-target effect, toxicity mediation, immunological activation and dosage determination should be addressed. Several delivery strategies have been employed, including naked oligonucleotides, liposomes, aptamer-conjugates, nanoparticles and viral vectors. However, delivery remains a main challenge in miRNA-targeting therapeutics. Furthermore, immune-related serious adverse events are also a concern, which indicates the complexity of miRNA-based therapy in clinical settings.

Limited-Sampling Strategies for Therapeutic Drug Monitoring of Moxifloxacin in Patients With Tuberculosis

NARCIS (Netherlands)

Pranger, Arianna D.; Kosterink, Jos G. W.; van Altena, Richard; Aarnoutse, Rob E.; van der Werf, Tjip S.; Uges, Donald R. A.; Alffenaar, Jan-Willem C.

Background: Moxifloxacin (MFX) is a potent drug for multidrug resistant tuberculosis(TB) treatment and is also useful if first-line agents are not tolerated. Therapeutic drug monitoring may help to prevent treatment failure. Obtaining a full concentration-time curve of MFX for therapeutic drug

Limited-sampling strategies for therapeutic drug monitoring of moxifloxacin in patients with tuberculosis

NARCIS (Netherlands)

Pranger, A.D.; Kosterink, J.G.W.; Altena, R. van; Aarnoutse, R.E.; Werf, T.S. van der; Uges, D.R.A.; Alffenaar, J.W.C.

2011-01-01

BACKGROUND: Moxifloxacin (MFX) is a potent drug for multidrug resistant tuberculosis(TB) treatment and is also useful if first-line agents are not tolerated. Therapeutic drug monitoring may help to prevent treatment failure. Obtaining a full concentration-time curve of MFX for therapeutic drug

Solid lipid nanoparticles as attractive drug vehicles: Composition, properties and therapeutic strategies.

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Geszke-Moritz, Małgorzata; Moritz, Michał

2016-11-01

This work briefly reviews up-to-date developments in solid lipid nanoparticles (SLNs) as effective nanocolloidal system for drug delivery. It summarizes SLNs in terms of their preparation, surface modification and properties. The application of SLNs as a carrier system enables to improve the therapeutic efficacy of drugs from various therapeutic groups. Present uses of SLNs include cancer therapy, dermatology, bacterial infections, brain targeting and eye disorders among others. The usage of SLNs provides enhanced pharmacokinetic properties and modulated release of drugs. SLN ubiquitous application results from their specific features such as possibility of surface modification, increased permeation through biological barriers, resistance to chemical degradation, possibility of co-delivery of various therapeutic agents or stimuli-responsiveness. This paper will be useful to the scientists working in the domain of SLN-based drug delivery systems. Copyright © 2016 Elsevier B.V. All rights reserved.

Ocular Chlamydia trachomatis infection under the SAFE strategy in Amhara, Ethiopia, 2011-2015.

Science.gov (United States)

Nash, Scott D; Stewart, Aisha E P; Zerihun, Mulat; Sata, Eshetu; Gessese, Demelash; Melaku, Berhanu; Endeshaw, Tekola; Chanyalew, Melsew; Chernet, Ambahun; Bayissasse, Belay; Moncada, Jeanne; Lietman, Thomas M; Emerson, Paul M; King, Jonathan D; Tadesse, Zerihun; Callahan, E Kelly

2018-05-05

WHO recommendations for starting and stopping mass antibiotic distributions are based on a clinical sign of trachoma, which is indirectly related to actual infection with the causative agent, Chlamydia trachomatis. This study aimed to understand the effect of SAFE (surgery, antibiotics, facial cleanliness, and environmental improvement) interventions on ocular chlamydia in Amhara, Ethiopia by describing the infection prevalence in a population-based sample of children ages 1-5 years. Population-based trachoma surveys were conducted in all districts of Amhara, from 2011 to 2015 following approximately 5 years of SAFE. Ocular swabs were collected from randomly selected children whose households were included in the surveys to estimate the zonal prevalence of chlamydial infection. The Abbott Realtime PCR assay was used to detect C. trachomatis DNA using the m2000 system. A total of 15,632 samples were collected across the 10 zones of Amhara. The prevalence of chlamydial infection in children ages 1-5 years was 5.7% (95% Confidence Interval: 4.2-7.3), zonal range 1.0% to 18.5%. Chlamydial infection and trachomatous-inflammation intense (TI) among children ages 1-9 were highly correlated at the zonal level, Spearman correlation(r)= 0.93; P<0.001, while chlamydial infection and trachomatous-inflammation follicular (TF) among children ages 1-9 years were moderately correlated, r= 0.57; P=0.084. After 5 years of SAFE there is appreciable ocular chlamydial infection in children ages 1-5 years, indicating that transmission has not been interrupted, and that interventions should continue. The sign TI was highly correlated with chlamydial infection and can be used as a proxy indicator of infection.

Safe Human-Robot Cooperation in an Industrial Environment

Directory of Open Access Journals (Sweden)

Nicola Pedrocchi

2013-01-01

Full Text Available The standard EN ISO10218 is fostering the implementation of hybrid production systems, i.e., production systems characterized by a close relationship among human operators and robots in cooperative tasks. Human-robot hybrid systems could have a big economic benefit in small and medium sized production, even if this new paradigm introduces mandatory, challenging safety aspects. Among various requirements for collaborative workspaces, safety-assurance involves two different application layers; the algorithms enabling safe space-sharing between humans and robots and the enabling technologies allowing acquisition data from sensor fusion and environmental data analysing. This paper addresses both the problems: a collision avoidance strategy allowing on-line re-planning of robot motion and a safe network of unsafe devices as a suggested infrastructure for functional safety achievement.

The SafeCOP ECSEL Project: Safe Cooperating Cyber-Physical Systems Using Wireless Communication

DEFF Research Database (Denmark)

Pop, Paul; Scholle, Detlef; Hansson, Hans

2016-01-01

This paper presents an overview of the ECSEL project entitled "Safe Cooperating Cyber-Physical Systems using Wireless Communication" (SafeCOP), which runs during the period 2016 -- 2019. SafeCOP targets safety-related Cooperating Cyber-Physical Systems (CO-CPS) characterised by use of wireless...... detection of abnormal behaviour, triggering if needed a safe degraded mode. SafeCOP will also develop methods and tools, which will be used to produce safety assurance evidence needed to certify cooperative functions. SafeCOP will extend current wireless technologies to ensure safe and secure cooperation...

Safe motherhood at risk?

Science.gov (United States)

Thompson, A

1996-12-01

Health professionals' negative attitudes toward clients often exacerbate the problems women face in terms of health status and access to health care. Thus, the health professionals can themselves be obstacles to women seeking the health care they need. A key challenge to midwives, in addition to providing technically competent services, is gaining insight into the people for whom they are responsible so that childbirth traditions are treated with respect and women are offered dignity. Safe motherhood requires intersectoral collaboration. Many innovative approaches to safe motherhood are based on the community's participation in planning services that meet the needs of women. Other approaches are based on decentralization of services. For example, a large university teaching hospital in Lusaka, Zambia, set up birthing centers around the city to take the pressure off the hospital. Midwives head up these centers, which are close to the women's homes. Decentralization of delivery services has improved the physical and emotional outcomes for mothers and newborns. Midwives must be prepared to articulate concerns about inequalities and deficiencies in the health care system in order to persuade the government to change. Women, including midwives, need to form multidisciplinary alliances to work together to effect change. The front-line workers in maternity care are midwives. They should adopt the following strategies to become even more effective in their efforts to make motherhood safer. They should listen to what women say about their needs. They should scale services to a manageable, human scale. They should learn the skills to become politically active advocates. They should work with other midwives, women, leaders, and other professional groups. Motherhood can be safe when women have more control over their own decision making, the education to liberate themselves to make their own decisions, and access to skilled care.

When the Safe Alternative Is Not That Safe: Tramadol Prescribing in Children

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Frédérique Rodieux

2018-03-01

Full Text Available Children represent a vulnerable population in which management of nociceptive pain is complex. Drug responses in children differ from adults due to age-related differences. Moreover, therapeutic choices are limited by the lack of indication for a number of analgesic drugs due to the challenge of conducting clinical trials in children. Furthermore the assessment of efficacy as well as tolerance may be complicated by children’s inability to communicate properly. According to the World Health Organization, weak opioids such as tramadol and codeine, may be used in addition to paracetamol and ibuprofen for moderate nociceptive pain in both children and adults. However, codeine prescription has been restricted for the last 5 years in children because of the risk of fatal overdoses linked to the variable activity of cytochrome P450 (CYP 2D6 which bioactivates codeine. Even though tramadol has been considered a safe alternative to codeine, it is well established that tramadol pharmacodynamic opioid effects, efficacy and safety, are also largely influenced by CYP2D6 activity. For this reason, the US Food and Drug Administration recently released a boxed warning regarding the use of tramadol in children. To provide safe and effective tramadol prescription in children, a personalized approach, with dose adaptation according to CYP2D6 activity, would certainly be the safest method. We therefore recommend this approach in children requiring chronic or recurrent nociceptive pain treatment with tramadol. In case of acute inpatients nociceptive pain management, prescribing tramadol at the minimal effective dose, in a child appropriate dosage form and after clear instructions are given to the parents, remains reasonable based on current data. In all other situations, morphine should be preferred for moderate to severe nociceptive pain conditions.

Renal Sympathetic Denervation System via Intraluminal Ultrasonic Ablation: Therapeutic Intravascular Ultrasound Design and Preclinical Evaluation.

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Chernin, Gil; Szwarcfiter, Iris; Bausback, Yvonne; Jonas, Michael

2017-05-01

To assess the safety and performance of a nonfocused and nonballooned ultrasonic (US) catheter-based renal sympathetic denervation (RDN) system in normotensive swine. RDN with the therapeutic intravascular US catheter was evaluated in 3 experiments: (i) therapeutic intravascular US RDN vs a control group of untreated animals with follow-up of 30, 45, and 90 days (n = 6; n = 12 renal arteries for each group); (ii) therapeutic intravascular US RDN vs radiofrequency (RF) RDN in the contralateral artery in the same animal (n = 2; n = 4 renal arteries); and (iii) therapeutic intravascular US RDN in a recently stent-implanted renal artery (n = 2; n = 4 renal arteries). In the first experiment, therapeutic intravascular US RDN was safe, without angiographic evidence of dissection or renal artery stenosis. Neuronal tissue vacuolization, nuclei pyknosis, and perineuronal inflammation were evident after RDN, without renal artery wall damage. Norepinephrine levels were significantly lower after therapeutic intravascular US RDN after 30, 45, and 90 days compared with the control group (200.17 pg/mg ± 63.35, 184.75 pg/mg ± 44.51, and 203.43 pg/mg ± 58.54, respectively, vs 342.42 pg/mg ± 79.97). In the second experiment, deeper neuronal ablation penetrance was found with therapeutic intravascular US RDN vs RF RDN (maximal penetrance from endothelium of 7.0 mm vs 3.5 mm, respectively). There was less damage to the artery wall after therapeutic intravascular US RDN than with RF RDN, after which edema and injured endothelium were seen. In the third experiment, denervation inside the stent-implanted segments was feasible without damage to the renal artery wall or stent. The therapeutic intravascular US system performed safely and reduced norepinephrine levels. Deeper penetrance and better preservation of vessel wall were observed with therapeutic intravascular US RDN vs RF RDN. Neuronal ablations were observed in stent-implanted renal arteries. Copyright © 2017 SIR. Published

Combined Gemcitabine and Metronidazole Is a Promising Therapeutic Strategy for Cancer Stem-like Cholangiocarcinoma.

Science.gov (United States)

Kawamoto, Makoto; Umebayashi, Masayo; Tanaka, Hiroto; Koya, Norihiro; Nakagawa, Sinichiro; Kawabe, Ken; Onishi, Hideya; Nakamura, Masafumi; Morisaki, Takashi

2018-05-01

Metronidazole (MNZ) is a common antibiotic that exerts disulfiram-like effects when taken together with alcohol. However, the relationship between MNZ and aldehyde dehydrogenase (ALDH) activity remains unclear. This study investigated whether MNZ reduces cancer stemness by suppressing ALDH activity and accordingly reducing the malignancy of cholangiocarcinoma (CCA). We developed gemcitabine (GEM)-resistant TFK-1 cells and originally established CCA cell line from a patient with GEM-resistant CCA. Using these cell lines, we analyzed the impacts of MNZ for cancer stem cell markers, invasiveness, and chemosensitivity. MNZ reduced ALDH activity in GEM-resistant CCA cells, leading to decreased invasiveness and enhanced chemosensitivity. MNZ diminished the invasiveness by inducing mesenchymal-epithelial transition and enhancing chemosensitivity by increasing ENT1 (equilibrative nucleoside transporter 1) and reducing RRM1 (ribonucleotide reductase M1). MNZ reduced cancer stemness in GEM-resistant CCA cells. Combined GEM and MNZ would be a promising therapeutic strategy for cancer stem-like CAA. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Turmeric (Curcuma longa) and its major constituent (curcumin) as nontoxic and safe substances: Review.

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Soleimani, Vahid; Sahebkar, Amirhossein; Hosseinzadeh, Hossein

2018-02-26

Curcumin is the major constituent of turmeric (Curcuma longa). Turmeric has been widely used as a spice in foods and for therapeutic applications such as anti-inflammatory, antihyperlipidemic, and antimicrobial activities. Turmeric and curcumin are nonmutagenic and nongenotoxic. Oral use of turmeric and curcumin did not have reproductive toxicity in animals at certain doses. Studies on human did not show toxic effects, and curcumin was safe at the dose of 6 g/day orally for 4-7 weeks. However, some adverse effects such as gastrointestinal upsets may occur. Moreover, oral bioavailable formulations of curcumin were safe for human at the dose of 500 mg two times in a day for 30 days, but there are still few trials and more studies are needed specially on nanoformulations and it should be discussed in a separate article. In addition, curcumin is known as a generally recognized as safe substance. This review discusses the safety and toxicity of turmeric and curcumin in medicine. Turmeric and curcumin are nontoxic for human especially in oral administration. Turmeric and curcumin are also safe in animals. They are nonmutagenic and are safe in pregnancy in animals but more studies in human are needed. Copyright © 2018 John Wiley & Sons, Ltd.

Therapeutic bond judgments: Congruence and incongruence.

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Atzil-Slonim, Dana; Bar-Kalifa, Eran; Rafaeli, Eshkol; Lutz, Wolfgang; Rubel, Julian; Schiefele, Ann-Kathrin; Peri, Tuvia

2015-08-01

The present study had 2 aims: (a) to implement West and Kenny's (2011) Truth-and-Bias model to simultaneously assess the temporal congruence and directional discrepancy between clients' and therapists' ratings of the bond facet of the therapeutic alliance, as they cofluctuate from session to session; and (b) to examine whether symptom severity and a personality disorder (PD) diagnosis moderate congruence and/or discrepancy. Participants included 213 clients treated by 49 therapists. At pretreatment, clients were assessed for a PD diagnosis and completed symptom measures. Symptom severity was also assessed at the beginning of each session, using client self-reports. Both clients and therapists rated the therapeutic bond at the end of each session. Therapists and clients exhibited substantial temporal congruence in their session-by-session bond ratings, but therapists' ratings tended to be lower than their clients' across sessions. Additionally, therapeutic dyads whose session-by-session ratings were more congruent also tended to have a larger directional discrepancy (clients' ratings being higher). Pretreatment symptom severity and PD diagnosis did not moderate either temporal congruence or discrepancy at the dyad level; however, during sessions when clients were more symptomatic, therapist and client ratings were both farther apart and tracked each other less closely. Our findings are consistent with a "better safe than sorry" pattern, which suggests that therapists are motivated to take a vigilant approach that may lead both to underestimation and to attunement to fluctuations in the therapeutic bond. (c) 2015 APA, all rights reserved).

Novel Therapeutic Strategy for the Prevention of Bone Fractures

Science.gov (United States)

2015-02-01

therapeutic potential for improving muscle function in older adults , perhaps leading to the prevention of falls and fractures. Body Aim 1 (months 1-12...directly to postural instability, which in turn increases the risk for falls , and falls are the main etiolog ical factor inmore than 90% of bone...vitamin D supplementation (Girgis et al., 2013) may improve muscle strength and/or neuromuscular control and proprioception, perhaps reducing fall risk

Quercetin as an Emerging Anti-Melanoma Agent: A four-focus area therapeutic development strategy

Directory of Open Access Journals (Sweden)

Zoey Harris

2016-10-01

Full Text Available Replacing current refractory treatments for melanoma with new prevention and therapeutic approaches is crucial in order to successfully treat this aggressive cancer form. Melanoma develops from neural crest cells, which express tyrosinase -- a key enzyme in the pigmentation pathway. The tyrosinase enzyme is highly active in melanoma cells and metabolizes polyphenolic compounds; tyrosinase expression thus makes a feasible a target for polyphenol-based therapies. For example, quercetin (3,3′,4′,5,7-pentahydroxyflavone is a highly ubiquitous and well-classified dietary polyphenol found in various fruits, vegetables and other plant products including onions, broccoli, kale, oranges, blueberries, apples, and tea. Quercetin has demonstrated anti-proliferative and pro-apoptotic activity in various cancer cell types. Quercetin is readily metabolized by tyrosinase into various compounds that promote anti-cancer activity; additionally, given that tyrosinase expression increases during tumorigenesis, and its activity is associated with pigmentation changes in both early- and late-stage melanocytic lesions, it suggests that quercetin can be used to target melanoma. In this review we explore the potential of Quercetin as an anti-melanoma agent utilizing and extrapolating on evidence from previous in vitro studies in various human malignant cell lines and propose a four-focus area strategy to develop quercetin as a targeted anti-melanoma compound for use as either a preventative or therapeutic agent. The four areas of focus include utilizing quercetin to i modulate cellular bioreduction potential and associated signaling cascades, ii affect transcription of relevant genes, iii regulate epigenetic processes, and iv develop effective combination therapies and delivery modalities/protocols. In general, quercetin could be used to exploit tyrosinase activity to prevent, and/or treat, melanoma with minimal additional side effects.

Cancer chemopreventive and therapeutic effects of diosgenin, a food saponin.

Science.gov (United States)

Raju, Jayadev; Mehta, Rekha

2009-01-01

Cancer chemoprevention is a strategy taken to retard, regress, or resist the multistep process of carcinogenesis, including the blockage of its vital morphogenetic milestones viz. normal-preneoplasia-neoplasia-metastasis. For several reasons, including safety, minimal (or no) toxicity and side-effects, and better availability, alternatives such as naturally occurring phytochemicals that are found in foods are becoming increasingly popular over synthetic drugs. Food saponins have been used in complimentary and traditional medicine against a variety of diseases including several cancers. Diosgenin, a naturally occurring steroid saponin found abundantly in legumes and yams, is a well-known precursor of various synthetic steroidal drugs that are extensively used in the pharmaceutical industry. Over the past decade, a series of preclinical and mechanistic studies have been conducted to understand the role of diosgenin as a chemopreventive/therapeutic agent against several cancers. This review highlights the biological activity of diosgenin that contributes to cancer chemoprevention and control. The anticancer mode of action of diosgenin has been demonstrated via modulation of multiple cell signaling events involving critical molecular candidates associated with growth, differentiation, apoptosis, and oncogenesis. Altogether, these preclinical and mechanistic findings strongly implicate the use of diosgenin as a novel, multitarget-based chemopreventive or therapeutic agent against several cancer types. Future research in this field will help to establish not only whether diosgenin is safe and efficacious as a chemopreventive agent against several human cancers, but also to develop and evaluate standards of evidence for health claims for diosgenin-containing foods as they become increasingly popular and enter the marketplace labeled as functional foods and nutraceuticals.

Safe Kids Worldwide

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Protein Homeostasis Defects of Alanine-Glyoxylate Aminotransferase: New Therapeutic Strategies in Primary Hyperoxaluria Type I

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Angel L. Pey

2013-01-01

Full Text Available Alanine-glyoxylate aminotransferase catalyzes the transamination between L-alanine and glyoxylate to produce pyruvate and glycine using pyridoxal 5′-phosphate (PLP as cofactor. Human alanine-glyoxylate aminotransferase is a peroxisomal enzyme expressed in the hepatocytes, the main site of glyoxylate detoxification. Its deficit causes primary hyperoxaluria type I, a rare but severe inborn error of metabolism. Single amino acid changes are the main type of mutation causing this disease, and considerable effort has been dedicated to the understanding of the molecular consequences of such missense mutations. In this review, we summarize the role of protein homeostasis in the basic mechanisms of primary hyperoxaluria. Intrinsic physicochemical properties of polypeptide chains such as thermodynamic stability, folding, unfolding, and misfolding rates as well as the interaction of different folding states with protein homeostasis networks are essential to understand this disease. The view presented has important implications for the development of new therapeutic strategies based on targeting specific elements of alanine-glyoxylate aminotransferase homeostasis.

IL8-CXCR2 pathway inhibition as a therapeutic strategy against MDS and AML stem cells.

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Schinke, Carolina; Giricz, Orsolya; Li, Weijuan; Shastri, Aditi; Gordon, Shanisha; Barreyro, Laura; Barreryo, Laura; Bhagat, Tushar; Bhattacharyya, Sanchari; Ramachandra, Nandini; Bartenstein, Matthias; Pellagatti, Andrea; Boultwood, Jacqueline; Wickrema, Amittha; Yu, Yiting; Will, Britta; Wei, Sheng; Steidl, Ulrich; Verma, Amit

2015-05-14

Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are associated with disease-initiating stem cells that are not eliminated by conventional therapies. Novel therapeutic targets against preleukemic stem cells need to be identified for potentially curative strategies. We conducted parallel transcriptional analysis of highly fractionated stem and progenitor populations in MDS, AML, and control samples and found interleukin 8 (IL8) to be consistently overexpressed in patient samples. The receptor for IL8, CXCR2, was also significantly increased in MDS CD34(+) cells from a large clinical cohort and was predictive of increased transfusion dependence. High CXCR2 expression was also an adverse prognostic factor in The Cancer Genome Atlas AML cohort, further pointing to the critical role of the IL8-CXCR2 axis in AML/MDS. Functionally, CXCR2 inhibition by knockdown and pharmacologic approaches led to a significant reduction in proliferation in several leukemic cell lines and primary MDS/AML samples via induction of G0/G1 cell cycle arrest. Importantly, inhibition of CXCR2 selectively inhibited immature hematopoietic stem cells from MDS/AML samples without an effect on healthy controls. CXCR2 knockdown also impaired leukemic growth in vivo. Together, these studies demonstrate that the IL8 receptor CXCR2 is an adverse prognostic factor in MDS/AML and is a potential therapeutic target against immature leukemic stem cell-enriched cell fractions in MDS and AML. © 2015 by The American Society of Hematology.

Amyloid cascade hypothesis: Pathogenesis and therapeutic strategies in Alzheimer's disease.

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Barage, Sagar H; Sonawane, Kailas D

2015-08-01

Alzheimer's disease is an irreversible, progressive neurodegenerative disorder. Various therapeutic approaches are being used to improve the cholinergic neurotransmission, but their role in AD pathogenesis is still unknown. Although, an increase in tau protein concentration in CSF has been described in AD, but several issues remains unclear. Extensive and accurate analysis of CSF could be helpful to define presence of tau proteins in physiological conditions, or released during the progression of neurodegenerative disease. The amyloid cascade hypothesis postulates that the neurodegeneration in AD caused by abnormal accumulation of amyloid beta (Aβ) plaques in various areas of the brain. The amyloid hypothesis has continued to gain support over the last two decades, particularly from genetic studies. Therefore, current research progress in several areas of therapies shall provide an effective treatment to cure this devastating disease. This review critically evaluates general biochemical and physiological functions of Aβ directed therapeutics and their relevance. Copyright © 2015 Elsevier Ltd. All rights reserved.

IGF system targeted therapy: Therapeutic opportunities for ovarian cancer.

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Liefers-Visser, J A L; Meijering, R A M; Reyners, A K L; van der Zee, A G J; de Jong, S

2017-11-01

The insulin-like growth factor (IGF) system comprises multiple growth factor receptors, including insulin-like growth factor 1 receptor (IGF-1R), insulin receptor (IR) -A and -B. These receptors are activated upon binding to their respective growth factor ligands, IGF-I, IGF-II and insulin, and play an important role in development, maintenance, progression, survival and chemotherapeutic response of ovarian cancer. In many pre-clinical studies anti-IGF-1R/IR targeted strategies proved effective in reducing growth of ovarian cancer models. In addition, anti-IGF-1R targeted strategies potentiated the efficacy of platinum based chemotherapy. Despite the vast amount of encouraging and promising pre-clinical data, anti-IGF-1R/IR targeted strategies lacked efficacy in the clinic. The question is whether targeting the IGF-1R/IR signaling pathway still holds therapeutic potential. In this review we address the complexity of the IGF-1R/IR signaling pathway, including receptor heterodimerization within and outside the IGF system and downstream signaling. Further, we discuss the implications of this complexity on current targeted strategies and indicate therapeutic opportunities for successful targeting of the IGF-1R/IR signaling pathway in ovarian cancer. Multiple-targeted approaches circumventing bidirectional receptor tyrosine kinase (RTK) compensation and prevention of system rewiring are expected to have more therapeutic potential. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Targeting Glutathione-S Transferase Enzymes in Musculoskeletal Sarcomas: A Promising Therapeutic Strategy

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Michela Pasello

2011-01-01

Full Text Available Recent studies have indicated that targeting glutathione-S-transferase (GST isoenzymes may be a promising novel strategy to improve the efficacy of conventional chemotherapy in the three most common musculoskeletal tumours: osteosarcoma, Ewing's sarcoma, and rhabdomyosarcoma. By using a panel of 15 drug-sensitive and drug-resistant human osteosarcoma, Ewing's sarcoma, and rhabdomyosarcoma cell lines, the efficay of the GST-targeting agent 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthiohexanol (NBDHEX has been assessed and related to GST isoenzymes expression (namely GSTP1, GSTA1, GSTM1, and MGST. NBDHEX showed a relevant in vitro activity on all cell lines, including the drug-resistant ones and those with higher GSTs levels. The in vitro activity of NBDHEX was mostly related to cytostatic effects, with a less evident apoptotic induction. NBDHEX positively interacted with doxorubicin, vincristine, cisplatin but showed antagonistic effects with methotrexate. In vivo studies confirmed the cytostatic efficay of NBDHEX and its positive interaction with vincristine in Ewing's sarcoma cells, and also indicated a positive effect against the metastatisation of osteosarcoma cells. The whole body of evidence found in this study indicated that targeting GSTs in osteosarcoma, Ewing's sarcoma and rhabdomyosarcoma may be an interesting new therapeutic option, which can be considered for patients who are scarcely responsive to conventional regimens.

Human Mesenchymal Stem Cell Transfusion Is Safe and Improves Liver Function in Acute-on-Chronic Liver Failure Patients

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Shi, Ming; Zhang, Zheng; Xu, Ruonan; Lin, Hu; Fu, Junliang; Zou, Zhengsheng; Zhang, Aimin; Shi, Jianfei; Chen, Liming; Lv, Sa; He, Weiping; Geng, Hua; Jin, Lei; Liu, Zhenwen

2012-01-01

Acute-on-chronic liver failure (ACLF) is a severe, life-threatening complication, and new and efficient therapeutic strategies for liver failure are urgently needed. Mesenchymal stem cell (MSC) transfusions have been shown to reverse fulminant hepatic failure in mice and to improve liver function in patients with end-stage liver diseases. We assessed the safety and initial efficacy of umbilical cord-derived MSC (UC-MSC) transfusions for ACLF patients associated with hepatitis B virus (HBV) infection. A total of 43 ACLF patients were enrolled for this open-labeled and controlled study; 24 patients were treated with UC-MSCs, and 19 patients were treated with saline as controls. UC-MSC therapy was given three times at 4-week intervals. The liver function, adverse events, and survival rates were evaluated during the 48-week or 72-week follow-up period. No significant side effects were observed during the trial. The UC-MSC transfusions significantly increased the survival rates in ACLF patients; reduced the model for end-stage liver disease scores; increased serum albumin, cholinesterase, and prothrombin activity; and increased platelet counts. Serum total bilirubin and alanine aminotransferase levels were significantly decreased after the UC-MSC transfusions. UC-MSC transfusions are safe in the clinic and may serve as a novel therapeutic approach for HBV-associated ACLF patients. PMID:23197664

Safe, acceptable anti-microbial strategies for distillate fuels

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Hill, E.C. [ECHA Microbiology Ltd., Cardiff (United Kingdom)

1995-05-01

Microbiological fouling, spoilage and corrosion have for years been considered as end-user problems but they have now become endemic up-stream affecting cargoes, tank farms and terminals. Trading agreements to share storage and distribution facilities impose the need to mutually agree antimicrobial strategies which satisfy all health, safety and environmental regulations wherever that fuel is distributed and used. Also agreed must be the infection levels at which antimicrobial action is initiated. Physical decontamination methods are described and the use of biocides discussed in relation to increasing regulatory restrictions.

Targeting oncomiRNAs and mimicking tumor suppressor miRNAs: New trends in the development of miRNA therapeutic strategies in oncology (Review)

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GAMBARI, ROBERTO; BROGNARA, ELEONORA; SPANDIDOS, DEMETRIOS A.; FABBRI, ENRICA

2016-01-01

MicroRNA (miRNA or miR) therapeutics in cancer are based on targeting or mimicking miRNAs involved in cancer onset, progression, angiogenesis, epithelial-mesenchymal transition and metastasis. Several studies conclusively have demonstrated that miRNAs are deeply involved in tumor onset and progression, either behaving as tumor-promoting miRNAs (oncomiRNAs and metastamiRNAs) or as tumor suppressor miRNAs. This review focuses on the most promising examples potentially leading to the development of anticancer, miRNA-based therapeutic protocols. The inhibition of miRNA activity can be readily achieved by the use of miRNA inhibitors and oligomers, including RNA, DNA and DNA analogues (miRNA antisense therapy), small molecule inhibitors, miRNA sponges or through miRNA masking. On the contrary, the enhancement of miRNA function (miRNA replacement therapy) can be achieved by the use of modified miRNA mimetics, such as plasmid or lentiviral vectors carrying miRNA sequences. Combination strategies have been recently developed based on the observation that i) the combined administration of different antagomiR molecules induces greater antitumor effects and ii) some anti-miR molecules can sensitize drug-resistant tumor cell lines to therapeutic drugs. In this review, we discuss two additional issues: i) the combination of miRNA replacement therapy with drug administration and ii) the combination of antagomiR and miRNA replacement therapy. One of the solid results emerging from different independent studies is that miRNA replacement therapy can enhance the antitumor effects of the antitumor drugs. The second important conclusion of the reviewed studies is that the combination of anti-miRNA and miRNA replacement strategies may lead to excellent results, in terms of antitumor effects. PMID:27175518

Antisense targeting of 3' end elements involved in DUX4 mRNA processing is an efficient therapeutic strategy for facioscapulohumeral dystrophy: a new gene-silencing approach.

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Marsollier, Anne-Charlotte; Ciszewski, Lukasz; Mariot, Virginie; Popplewell, Linda; Voit, Thomas; Dickson, George; Dumonceaux, Julie

2016-04-15

Defects in mRNA 3'end formation have been described to alter transcription termination, transport of the mRNA from the nucleus to the cytoplasm, stability of the mRNA and translation efficiency. Therefore, inhibition of polyadenylation may lead to gene silencing. Here, we choose facioscapulohumeral dystrophy (FSHD) as a model to determine whether or not targeting key 3' end elements involved in mRNA processing using antisense oligonucleotide drugs can be used as a strategy for gene silencing within a potentially therapeutic context. FSHD is a gain-of-function disease characterized by the aberrant expression of the Double homeobox 4 (DUX4) transcription factor leading to altered pathogenic deregulation of multiple genes in muscles. Here, we demonstrate that targeting either the mRNA polyadenylation signal and/or cleavage site is an efficient strategy to down-regulate DUX4 expression and to decrease the abnormally high-pathological expression of genes downstream of DUX4. We conclude that targeting key functional 3' end elements involved in pre-mRNA to mRNA maturation with antisense drugs can lead to efficient gene silencing and is thus a potentially effective therapeutic strategy for at least FSHD. Moreover, polyadenylation is a crucial step in the maturation of almost all eukaryotic mRNAs, and thus all mRNAs are virtually eligible for this antisense-mediated knockdown strategy. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Safe Handling of Oral Antineoplastic Medications: Focus on Targeted Therapeutics in the Home Setting

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Cass, Yaakov; Connor, Thomas H.; Tabachnik, Alexander

2017-01-01

Introduction With the growing number of oral targeted therapies being approved for use in cancer therapy, the potential for long-term administration of these drugs to cancer patients is expanding. The use of these drugs in the home setting has the potential to expose family members and caregivers to them either through direct contact with the drugs or indirectly by exposure to the parent compounds and/or their active metabolites in contaminated patient's waste. Methods A systematic literature review was performed and the known adverse health effect of 32 oral targeted therapeutics is summarized. In particular, the carcinogenicity, genotoxicity, and embryo-foetal toxicity, along with the route of excretion were evaluated. Results Carcinogenicity testing has not been performed on most of the oral targeted therapeutics and the genotoxicity data are mixed. However, the majority of these drugs exhibit adverse reproductive effects, some of which are severe. Currently available data does not permit the possibility of a health hazard from inappropriate handling of drugs and contaminated patients waste to be ignored, especially in a long-term home setting. Further research is needed to understand these issues. Conclusions With the expanding use of targeted therapies in the home setting, family members and caregivers, especially those of reproductive risk age, are, potentially at risk. Overall basic education and related precautions should be taken to protect family members and caregivers from indirect or direct exposure from these drugs. Further investigations and discussion on this subject is warranted. PMID:27009803

Applying extracellular vesicles based therapeutics in clinical trials – an ISEV position paper

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Thomas Lener

2015-12-01

Full Text Available Extracellular vesicles (EVs, such as exosomes and microvesicles, are released by different cell types and participate in physiological and pathophysiological processes. EVs mediate intercellular communication as cell-derived extracellular signalling organelles that transmit specific information from their cell of origin to their target cells. As a result of these properties, EVs of defined cell types may serve as novel tools for various therapeutic approaches, including (a anti-tumour therapy, (b pathogen vaccination, (c immune-modulatory and regenerative therapies and (d drug delivery. The translation of EVs into clinical therapies requires the categorization of EV-based therapeutics in compliance with existing regulatory frameworks. As the classification defines subsequent requirements for manufacturing, quality control and clinical investigation, it is of major importance to define whether EVs are considered the active drug components or primarily serve as drug delivery vehicles. For an effective and particularly safe translation of EV-based therapies into clinical practice, a high level of cooperation between researchers, clinicians and competent authorities is essential. In this position statement, basic and clinical scientists, as members of the International Society for Extracellular Vesicles (ISEV and of the European Cooperation in Science and Technology (COST program of the European Union, namely European Network on Microvesicles and Exosomes in Health and Disease (ME-HaD, summarize recent developments and the current knowledge of EV-based therapies. Aspects of safety and regulatory requirements that must be considered for pharmaceutical manufacturing and clinical application are highlighted. Production and quality control processes are discussed. Strategies to promote the therapeutic application of EVs in future clinical studies are addressed.

Therapeutic strategies in the treatment of periodontitis

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Liljana Bogdanovska

2012-04-01

Full Text Available Periodontitis is a chronic inflammatory process which affects the tooth - supporting structures of the teeth. The disease is initiated by subgingival periopathogenic bacteria in susceptible periodontal sites. The host immune response towards periodontal pathogens helps to sustain periodontal disease and eventual alveolar bone loss. Although scaling and root planing is the standard treatment modality for periodontitis, it suffers from several drawbacks such as the inability to reach the base of deep pockets and doesn’t arrest migration of periodontal pathogens from other sites in the oral cavity. In order to overcome the limitations of scaling and root planning, adjunctive chemotherapeutics and host modulatory agents to the treatment are used. These therapeutic agents show substantial beneficial effects when compared to scaling and root planning alone. This review will cover an update on chemotherapeutic and past and future host immune modulatory agents used adjunctively to treat and manage periodontal diseases.

Novel therapeutic strategies to target leukemic cells that hijack compartmentalized continuous hematopoietic stem cell niches.

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Hira, Vashendriya V V; Van Noorden, Cornelis J F; Carraway, Hetty E; Maciejewski, Jaroslaw P; Molenaar, Remco J

2017-08-01

Acute myeloid leukemia and acute lymphoblastic leukemia cells hijack hematopoietic stem cell (HSC) niches in the bone marrow and become leukemic stem cells (LSCs) at the expense of normal HSCs. LSCs are quiescent and resistant to chemotherapy and can cause relapse of the disease. HSCs in niches are needed to generate blood cell precursors that are committed to unilineage differentiation and eventually production of mature blood cells, including red blood cells, megakaryocytes, myeloid cells and lymphocytes. Thus far, three types of HSC niches are recognized: endosteal, reticular and perivascular niches. However, we argue here that there is only one type of HSC niche, which consists of a periarteriolar compartment and a perisinusoidal compartment. In the periarteriolar compartment, hypoxia and low levels of reactive oxygen species preserve the HSC pool. In the perisinusoidal compartment, hypoxia in combination with higher levels of reactive oxygen species enables proliferation of progenitor cells and their mobilization into the circulation. Because HSC niches offer protection to LSCs against chemotherapy, we review novel therapeutic strategies to inhibit homing of LSCs in niches for the prevention of dedifferentiation of leukemic cells into LSCs and to stimulate migration of leukemic cells out of niches. These strategies enhance differentiation and proliferation and thus sensitize leukemic cells to chemotherapy. Finally, we list clinical trials of therapies that tackle LSCs in HSC niches to circumvent their protection against chemotherapy. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Therapeutic strategies in pulmonary hypertension

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Leonello eFuso

2011-04-01

Full Text Available Pulmonary hypertension (PH is a life-threatening condition characterized by elevated pulmonary arterial pressure. It is clinically classified into five groups: patients in the first group are considered to have pulmonary arterial hypertension (PAH whereas patients of the other groups have PH that is due to cardiopulmonary or other systemic diseases. The management of patients with PH has advanced rapidly over the last decade and the introduction of specific treatments especially for PAH has lead to an improved outcome. However, despite the progress in the treatment, the functional limitation and the survival of these patients remain unsatisfactory and there is no cure for PAH. Therefore the search for an ideal therapy still goes on. At present, two levels of treatment can be identified: primary and specific therapy. Primary therapy is directed at the underlying cause of the PH. It also includes a supportive therapy consisting in oxygen supplementation, diuretics, and anticoagulation which should be considered in all patients with PH. Specific therapy is directed at the PH itself and includes treatment with vasodilatators such as calcium channel blockers and with vasodilatator and pathogenetic drugs such as prostanoids, endothelin receptor antagonists and phosphodiesterase type-5 inhibitors. These drugs act in several pathogenetic mechanisms of the PH and are specific for PAH although they might be used also in the other groups of PH. Finally, atrial septostomy and lung transplantation are reserved for patients refractory to medical therapy. Different therapeutic approaches can be considered in the management of patients with PH. Therapy can be established on the basis of both the clinical classification and the functional class. It is also possible to adopt a goal-oriented therapy in which the timing of treatment escalation is determined by inadequate response to known prognostic indicators.

Complementary and Alternative Medicine Strategies for Therapeutic Gut Microbiota Modulation in Inflammatory Bowel Disease and their Next-Generation Approaches.

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Basson, Abigail R; Lam, Minh; Cominelli, Fabio

2017-12-01

The human gut microbiome exerts a major impact on human health and disease, and therapeutic gut microbiota modulation is now a well-advocated strategy in the management of many diseases, including inflammatory bowel disease (IBD). Scientific and clinical evidence in support of complementary and alternative medicine, in targeting intestinal dysbiosis among patients with IBD, or other disorders, has increased dramatically over the past years. Delivery of "artificial" stool replacements for fecal microbiota transplantation (FMT) could provide an effective, safer alternative to that of human donor stool. Nevertheless, optimum timing of FMT administration in IBD remains unexplored, and future investigations are essential. Copyright © 2017 Elsevier Inc. All rights reserved.

Structural and functional outcomes of a therapeutic strategy targeting low disease activity in patients with elderly-onset rheumatoid arthritis: a prospective cohort study (CRANE).

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Sugihara, Takahiko; Ishizaki, Tatsuro; Hosoya, Tadashi; Iga, Shoko; Yokoyama, Waka; Hirano, Fumio; Miyasaka, Nobuyuki; Harigai, Masayoshi

2015-05-01

The aim of this study was to evaluate structural damage and physical disability in patients with elderly-onset RA (EORA) who were treated in clinical practice with a therapeutic strategy targeting low disease activity (LDA). Data from 151 MTX-naive patients (mean age 74.9 years) with EORA from a prospective, monocentric registry were analysed. Treatment was adjusted every 3 months targeting LDA [28-joint DAS using ESR (DAS28-ESR) target strategy was observed in 83.4% of the 151 patients at week 24 and in 75.5% at week 52. At week 52, 67.6% of the patients were receiving a nbDMARD alone, 31.0% a TNFi with or without MTX and 1.4% tocilizumab. At week 52, structural remission (ΔmTSS/yr ≤0.5) was achieved in 49.7% of the patients, functional remission (HAQ-DI ≤0.5) in 63.4% and LDA in 51.0%. Clinical responses at weeks 12 and 24 were significant independent predictors of CRRP. Cumulative disease activity during the first 12 weeks predicted CRRP with a C-statistic of 0.888. Achieving structural remission, functional remission and LDA in clinical practice in EORA patients are realistic goals. Our results indicate significant benefits for a therapeutic strategy targeting LDA for EORA patients in clinical practice. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Multidisciplinary perspectives for Alzheimer's and Parkinson's diseases: hydrogels for protein delivery and cell-based drug delivery as therapeutic strategies.

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Giordano, Carmen; Albani, Diego; Gloria, Antonio; Tunesi, Marta; Batelli, Sara; Russo, Teresa; Forloni, Gianluigi; Ambrosio, Luigi; Cigada, Alberto

2009-12-01

This review presents two intriguing multidisciplinary strategies that might make the difference in the treatment of neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. The first proposed strategy is based on the controlled delivery of recombinant proteins known to play a key role in these neurodegenerative disorders that are released in situ by optimized polymer-based systems. The second strategy is the use of engineered cells, encapsulated and delivered in situ by suitable polymer-based systems, that act as drug reservoirs and allow the delivery of selected molecules to be used in the treatment of Alzheimer's and Parkinson's diseases. In both these scenarios, the design and development of optimized polymer-based drug delivery and cell housing systems for central nervous system applications represent a key requirement. Materials science provides suitable hydrogel-based tools to be optimized together with suitably designed recombinant proteins or drug delivering-cells that, once in situ, can provide an effective treatment for these neurodegenerative disorders. In this scenario, only interdisciplinary research that fully integrates biology, biochemistry, medicine and materials science can provide a springboard for the development of suitable therapeutic tools, not only for the treatment of Alzheimer's and Parkinson's diseases but also, prospectively, for a wide range of severe neurodegenerative disorders.

Pain and endometriosis: Etiology, impact, and therapeutics

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Robert N. Taylor

2012-12-01

Full Text Available The association of pain and endometriosis was recognized with the first definitive published reports of this disorder. Unfortunately, the precise etiologies and pathways leading to nociception and pain symptoms in endometriosis remain poorly understood, and as a result, effective therapeutic interventions are lacking with consequent profound effects on affected women’s quality of life. In this opinion paper we summarize selected proceedings presented at the 28th Annual Meeting of the European Society of Human Reproduction and Embryology (ESHRE in Istanbul, Turkey, and review the clinical and translational evidence of chronic pain, neurogenesis, and the pernicious impact of dyspareunia on women with symptomatic endometriosis. The effectiveness of medical treatments is critically assessed and the findings indicate that good therapeutic options are available with extant medications effective in some sub-groups of women with endometriosis, many of which are affordable globally. Nevertheless, new management strategies and drugs need to be developed to increase the options of all afflicted women to minimize and ideally eradicate painful symptoms of endometriosis. However, only by elucidating distinctions among sub-groups with specific symptoms, suggesting different mechanisms, are we likely to derive truly successful therapeutic strategies.

Cystic Fibrosis Transmembrane Conductance Regulator Potentiation as a Therapeutic Strategy for Pulmonary Edema: A Proof-of-Concept Study in Pigs.

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Li, Xiaopeng; Vargas Buonfiglio, Luis G; Adam, Ryan J; Stoltz, David A; Zabner, Joseph; Comellas, Alejandro P

2017-12-01

To determine the feasibility of using a cystic fibrosis transmembrane conductance regulator potentiator, ivacaftor (VX-770/Kalydeco, Vertex Pharmaceuticals, Boston, MA), as a therapeutic strategy for treating pulmonary edema. Prospective laboratory animal investigation. Animal research laboratory. Newborn and 3 days to 1 week old pigs. Hydrostatic pulmonary edema was induced in pigs by acute volume overload. Ivacaftor was nebulized into the lung immediately after volume overload. Grams of water per grams of dry lung tissue were determined in the lungs harvested 1 hour after volume overload. Ivacaftor significantly improved alveolar liquid clearance in isolated pig lung lobes ex vivo and reduced edema in a volume overload in vivo pig model of hydrostatic pulmonary edema. To model hydrostatic pressure-induced edema in vitro, we developed a method of applied pressure to the basolateral surface of alveolar epithelia. Elevated hydrostatic pressure resulted in decreased cystic fibrosis transmembrane conductance regulator activity and liquid absorption, an effect which was partially reversed by cystic fibrosis transmembrane conductance regulator potentiation with ivacaftor. Cystic fibrosis transmembrane conductance regulator potentiation by ivacaftor is a novel therapeutic approach for pulmonary edema.

"Same Room, Safe Place".

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Keene Woods, Nikki

2017-04-01

There are many different professional stances on safe sleep and then there is the reality of caring for a newborn. There is a debate among professionals regarding safe sleep recommendations. The continum of recommendations vary from the American Academy of Pediatrics (AAP) Safe Sleep Guidelines to the bed-sharing recommendations from the Mother-Baby Behavioral Sleep Laboratory. The lack of consistent and uniform safe sleep recommendations from health professionals has been confusing for families but has more recently raised a real professional ethical dilemma. Despite years of focused safe sleep community education and interventions, sleep-related infant deaths are on the rise in many communities. This commentary calls for a united safe sleep message from all health professionals to improve health for mothers and infants most at-risk, "Same Room, Safe Place."

Strategy for selecting nanotechnology carriers to overcome immunological and hematological toxicities challenging clinical translation of nucleic acid-based therapeutics.

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Dobrovolskaia, Marina A; McNeil, Scott E

2015-07-01

Clinical translation of nucleic acid-based therapeutics (NATs) is hampered by assorted challenges in immunotoxicity, hematotoxicity, pharmacokinetics, toxicology and formulation. Nanotechnology-based platforms are being considered to help address some of these challenges due to the nanoparticles' ability to change drug biodistribution, stability, circulation half-life, route of administration and dosage. Addressing toxicology and pharmacology concerns by various means including NATs reformulation using nanotechnology-based carriers has been reviewed before. However, little attention was given to the immunological and hematological issues associated with nanotechnology reformulation. This review focuses on application of nanotechnology carriers for delivery of various types of NATs, and how reformulation using nanoparticles affects immunological and hematological toxicities of this promising class of therapeutic agents. NATs share several immunological and hematological toxicities with common nanotechnology carriers. In order to avoid synergy or exaggeration of undesirable immunological and hematological effects of NATs by a nanocarrier, it is critical to consider the immunological compatibility of the nanotechnology platform and its components. Since receptors sensing nucleic acids are located essentially in all cellular compartments, a strategy for developing a nanoformulation with reduced immunotoxicity should first focus on precise delivery to the target site/cells and then on optimizing intracellular distribution.

Development of oral agent in the treatment of multiple sclerosis: how the first available oral therapy, Fingolimod will change therapeutic paradigm approach

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Gasperini C

2012-07-01

Full Text Available Claudio Gasperini,1 Serena Ruggieri21Department of Neurosciences, S Camillo Forlanini Hospital, 2Department of Neurology and Psychiatry, University of Rome “Sapienza,” Rome, ItalyAbstract: Multiple sclerosis (MS is a chronic inflammatory disorder of the central nervous system, traditionally considered to be an autoimmune, demyelinating disease. Based on this understanding, the initial therapeutic strategies were directed at immune modulation and inflammation control. At present, there are five licensed first-line disease-modifying drugs and two second-line treatments in MS. Currently available MS therapies have shown significant efficacy throughout many trials, but they produce different side-effect profiles in patients. Since they are well known and safe, they require regular and frequent parenteral administration and are associated with limited long-term treatment adherence. Thus, there is an important need for the development of new therapeutic strategies. Several oral compounds are in late-stage development for treating MS. Fingolimod (FTY720; Novartis, Basel, Switzerland is an oral sphingosine-1-phosphase receptor modulator which has demonstrated superior efficacy compared with placebo and interferon β-1a in Phase III studies and has been approved in the treatment of MS. We summarily review the oral compounds in study, focusing on the recent development, approval and the clinical experience with FTY720.Keywords: multiple sclerosis, oral compounds, fingolimod, fty720, sphingosine 1, phosphate, patient satisfaction

Intestinal parasite prevalence in an area of ethiopia after implementing the SAFE strategy, enhanced outreach services, and health extension program.

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Jonathan D King

Full Text Available BACKGROUND: The SAFE strategy aims to reduce transmission of Chlamydia trachomatis through antibiotics, improved hygiene, and sanitation. We integrated assessment of intestinal parasites into large-scale trachoma impact surveys to determine whether documented environmental improvements promoted by a trachoma program had collateral impact on intestinal parasites. METHODOLOGY: We surveyed 99 communities for both trachoma and intestinal parasites (soil-transmitted helminths, Schistosoma mansoni, and intestinal protozoa in South Gondar, Ethiopia. One child aged 2-15 years per household was randomly selected to provide a stool sample of which about 1 g was fixed in sodium acetate-acetic acid-formalin, concentrated with ether, and examined under a microscope by experienced laboratory technicians. PRINCIPAL FINDINGS: A total of 2,338 stool specimens were provided, processed, and linked to survey data from 2,657 randomly selected children (88% response. The zonal-level prevalence of Ascaris lumbricoides, hookworm, and Trichuris trichiura was 9.9% (95% confidence interval (CI 7.2-12.7%, 9.7% (5.9-13.4%, and 2.6% (1.6-3.7%, respectively. The prevalence of S. mansoni was 2.9% (95% CI 0.2-5.5% but infection was highly focal (range by community from 0-52.4%. The prevalence of any of these helminth infections was 24.2% (95% CI 17.6-30.9% compared to 48.5% as found in a previous study in 1995 using the Kato-Katz technique. The pathogenic intestinal protozoa Giardia intestinalis and Entamoeba histolytica/E. dispar were found in 23.0% (95% CI 20.3-25.6% and 11.1% (95% CI 8.9-13.2% of the surveyed children, respectively. We found statistically significant increases in household latrine ownership, use of an improved water source, access to water, and face washing behavior over the past 7 years. CONCLUSIONS: Improvements in hygiene and sanitation promoted both by the SAFE strategy for trachoma and health extension program combined with preventive chemotherapy

Intestinal parasite prevalence in an area of ethiopia after implementing the SAFE strategy, enhanced outreach services, and health extension program.

Science.gov (United States)

King, Jonathan D; Endeshaw, Tekola; Escher, Elisabeth; Alemtaye, Genetu; Melaku, Sileabatt; Gelaye, Woyneshet; Worku, Abebe; Adugna, Mitku; Melak, Berhanu; Teferi, Tesfaye; Zerihun, Mulat; Gesese, Demelash; Tadesse, Zerihun; Mosher, Aryc W; Odermatt, Peter; Utzinger, Jürg; Marti, Hanspeter; Ngondi, Jeremiah; Hopkins, Donald R; Emerson, Paul M

2013-01-01

The SAFE strategy aims to reduce transmission of Chlamydia trachomatis through antibiotics, improved hygiene, and sanitation. We integrated assessment of intestinal parasites into large-scale trachoma impact surveys to determine whether documented environmental improvements promoted by a trachoma program had collateral impact on intestinal parasites. We surveyed 99 communities for both trachoma and intestinal parasites (soil-transmitted helminths, Schistosoma mansoni, and intestinal protozoa) in South Gondar, Ethiopia. One child aged 2-15 years per household was randomly selected to provide a stool sample of which about 1 g was fixed in sodium acetate-acetic acid-formalin, concentrated with ether, and examined under a microscope by experienced laboratory technicians. A total of 2,338 stool specimens were provided, processed, and linked to survey data from 2,657 randomly selected children (88% response). The zonal-level prevalence of Ascaris lumbricoides, hookworm, and Trichuris trichiura was 9.9% (95% confidence interval (CI) 7.2-12.7%), 9.7% (5.9-13.4%), and 2.6% (1.6-3.7%), respectively. The prevalence of S. mansoni was 2.9% (95% CI 0.2-5.5%) but infection was highly focal (range by community from 0-52.4%). The prevalence of any of these helminth infections was 24.2% (95% CI 17.6-30.9%) compared to 48.5% as found in a previous study in 1995 using the Kato-Katz technique. The pathogenic intestinal protozoa Giardia intestinalis and Entamoeba histolytica/E. dispar were found in 23.0% (95% CI 20.3-25.6%) and 11.1% (95% CI 8.9-13.2%) of the surveyed children, respectively. We found statistically significant increases in household latrine ownership, use of an improved water source, access to water, and face washing behavior over the past 7 years. Improvements in hygiene and sanitation promoted both by the SAFE strategy for trachoma and health extension program combined with preventive chemotherapy during enhanced outreach services are plausible explanations for the

Targeting iodothyronine deiodinases locally in the retina is a therapeutic strategy for retinal degeneration.

Science.gov (United States)

Yang, Fan; Ma, Hongwei; Belcher, Joshua; Butler, Michael R; Redmond, T Michael; Boye, Sanford L; Hauswirth, William W; Ding, Xi-Qin

2016-12-01

Recent studies have implicated thyroid hormone (TH) signaling in cone photoreceptor viability. Using mouse models of retinal degeneration, we found that antithyroid treatment preserves cones. This work investigates the significance of targeting intracellular TH components locally in the retina. The cellular TH level is mainly regulated by deiodinase iodothyronine (DIO)-2 and -3. DIO2 converts thyroxine (T4) to triiodothyronine (T3), which binds to the TH receptor, whereas DIO3 degrades T3 and T4. We examined cone survival after overexpression of DIO3 and inhibition of DIO2 and demonstrated the benefits of these manipulations. Subretinal delivery of AAV5-IRBP/GNAT2-DIO3, which directs expression of human DIO3 specifically in cones, increased cone density by 30-40% in a Rpe65 -/- mouse model of Lebers congenital amaurosis (LCA) and in a Cpfl1 mouse with Pde6c defect model of achromatopsia, compared with their respective untreated controls. Intravitreal and topical delivery of the DIO2 inhibitor iopanoic acid also significantly improved cone survival in the LCA model mice. Moreover, the expression levels of DIO2 and Slc16a2 were significantly higher in the diseased retinas, suggesting locally elevated TH signaling. We show that targeting DIOs protects cones, and intracellular inhibition of TH components locally in the retina may represent a novel strategy for retinal degeneration management.-Yang, F., Ma, H., Belcher, J., Butler, M. R., Redmond, T. M., Boye, S. L., Hauswirth, W. W., Ding, X.-Q. Targeting iodothyronine deiodinases locally in the retina is a therapeutic strategy for retinal degeneration. © FASEB.

System Safety Program Plan for Project W-314, tank farm restoration and safe operations

International Nuclear Information System (INIS)

Boos, K.A.

1996-01-01

This System Safety Program Plan (SSPP) outlines the safety analysis strategy for project W-314, ''Tank Farm Restoration and Safe Operations.'' Project W-314 will provide capital improvements to Hanford's existing Tank Farm facilities, with particular emphasis on infrastructure systems supporting safe operation of the double-shell activities related to the project's conceptual Design Phase, but is planned to be updated and maintained as a ''living document'' throughout the life of the project to reflect the current safety analysis planning for the Tank Farm Restoration and Safe Operations upgrades. This approved W-314 SSPP provides the basis for preparation/approval of all safety analysis documentation needed to support the project

EBNA1: Oncogenic Activity, Immune Evasion and Biochemical Functions Provide Targets for Novel Therapeutic Strategies against Epstein-Barr Virus- Associated Cancers

Directory of Open Access Journals (Sweden)

Joanna B. Wilson

2018-04-01

Full Text Available The presence of the Epstein-Barr virus (EBV-encoded nuclear antigen-1 (EBNA1 protein in all EBV-carrying tumours constitutes a marker that distinguishes the virus-associated cancer cells from normal cells and thereby offers opportunities for targeted therapeutic intervention. EBNA1 is essential for viral genome maintenance and also for controlling viral gene expression and without EBNA1, the virus cannot persist. EBNA1 itself has been linked to cell transformation but the underlying mechanism of its oncogenic activity has been unclear. However, recent data are starting to shed light on its growth-promoting pathways, suggesting that targeting EBNA1 can have a direct growth suppressing effect. In order to carry out its tasks, EBNA1 interacts with cellular factors and these interactions are potential therapeutic targets, where the aim would be to cripple the virus and thereby rid the tumour cells of any oncogenic activity related to the virus. Another strategy to target EBNA1 is to interfere with its expression. Controlling the rate of EBNA1 synthesis is critical for the virus to maintain a sufficient level to support viral functions, while at the same time, restricting expression is equally important to prevent the immune system from detecting and destroying EBNA1-positive cells. To achieve this balance EBNA1 has evolved a unique repeat sequence of glycines and alanines that controls its own rate of mRNA translation. As the underlying molecular mechanisms for how this repeat suppresses its own rate of synthesis in cis are starting to be better understood, new therapeutic strategies are emerging that aim to modulate the translation of the EBNA1 mRNA. If translation is induced, it could increase the amount of EBNA1-derived antigenic peptides that are presented to the major histocompatibility (MHC class I pathway and thus, make EBV-carrying cancers better targets for the immune system. If translation is further suppressed, this would provide another

A virtual therapeutic environment with user projective agents.

Science.gov (United States)

Ookita, S Y; Tokuda, H

2001-02-01

Today, we see the Internet as more than just an information infrastructure, but a socializing place and a safe outlet of inner feelings. Many personalities develop aside from real world life due to its anonymous environment. Virtual world interactions are bringing about new psychological illnesses ranging from netaddiction to technostress, as well as online personality disorders and conflicts in multiple identities that exist in the virtual world. Presently, there are no standard therapy models for the virtual environment. There are very few therapeutic environments, or tools especially made for virtual therapeutic environments. The goal of our research is to provide the therapy model and middleware tools for psychologists to use in virtual therapeutic environments. We propose the Cyber Therapy Model, and Projective Agents, a tool used in the therapeutic environment. To evaluate the effectiveness of the tool, we created a prototype system, called the Virtual Group Counseling System, which is a therapeutic environment that allows the user to participate in group counseling through the eyes of their Projective Agent. Projective Agents inherit the user's personality traits. During the virtual group counseling, the user's Projective Agent interacts and collaborates to recover and increase their psychological growth. The prototype system provides a simulation environment where psychologists can adjust the parameters and customize their own simulation environment. The model and tool is a first attempt toward simulating online personalities that may exist only online, and provide data for observation.

Path Hopping: An MTD Strategy for Long-Term Quantum-Safe Communication

Directory of Open Access Journals (Sweden)

Reihaneh Safavi-Naini

2018-01-01

Full Text Available Moving target defense (MTD strategies have been widely studied for securing computer systems. We consider using MTD strategies to provide long-term cryptographic security for message transmission against an eavesdropping adversary who has access to a quantum computer. In such a setting, today’s widely used cryptographic systems including Diffie-Hellman key agreement protocol and RSA cryptosystem will be insecure and alternative solutions are needed. We will use a physical assumption, existence of multiple communication paths between the sender and the receiver, as the basis of security, and propose a cryptographic system that uses this assumption and an MTD strategy to guarantee efficient long-term information theoretic security even when only a single path is not eavesdropped. Following the approach of Maleki et al., we model the system using a Markov chain, derive its transition probabilities, propose two security measures, and prove results that show how to calculate these measures using transition probabilities. We define two types of attackers that we call risk-taking and risk-averse and compute our proposed measures for the two types of adversaries for a concrete MTD strategy. We will use numerical analysis to study tradeoffs between system parameters, discuss our results, and propose directions for future research.

Safe medication management in specialized home healthcare - an observational study.

Science.gov (United States)

Lindblad, Marléne; Flink, Maria; Ekstedt, Mirjam

2017-08-24

Medication management is a complex, error-prone process. The aim of this study was to explore what constitutes the complexity of the medication management process (MMP) in specialized home healthcare and how healthcare professionals handle this complexity. The study is theoretically based in resilience engineering. Data were collected during the MMP at three specialized home healthcare units in Sweden using two strategies: observation of workplaces and shadowing RNs in everyday work, including interviews. Transcribed material was analysed using grounded theory. The MMP in home healthcare was dynamic and complex with unclear boundaries of responsibilities, inadequate information systems and fluctuating work conditions. Healthcare professionals adapted their everyday clinical work by sharing responsibility and simultaneously being authoritative and preserving patients' active participation, autonomy and integrity. To promote a safe MMP, healthcare professionals constantly re-prioritized goals, handled gaps in communication and information transmission at a distance by creating new bridging solutions. Trade-offs and workarounds were necessary elements, but also posed a threat to patient safety, as these interim solutions were not systematically evaluated or devised learning strategies. To manage a safe medication process in home healthcare, healthcare professionals need to adapt to fluctuating conditions and create bridging strategies through multiple parallel activities distributed over time, space and actors. The healthcare professionals' strategies could be integrated in continuous learning, while preserving boundaries of safety, instead of being more or less interim solutions. Patients' and family caregivers' as active partners in the MMP may be an underestimated resource for a resilient home healthcare.

Protein based therapeutic delivery agents: Contemporary developments and challenges.

Science.gov (United States)

Yin, Liming; Yuvienco, Carlo; Montclare, Jin Kim

2017-07-01

As unique biopolymers, proteins can be employed for therapeutic delivery. They bear important features such as bioavailability, biocompatibility, and biodegradability with low toxicity serving as a platform for delivery of various small molecule therapeutics, gene therapies, protein biologics and cells. Depending on size and characteristic of the therapeutic, a variety of natural and engineered proteins or peptides have been developed. This, coupled to recent advances in synthetic and chemical biology, has led to the creation of tailor-made protein materials for delivery. This review highlights strategies employing proteins to facilitate the delivery of therapeutic matter, addressing the challenges for small molecule, gene, protein and cell transport. Copyright © 2017 Elsevier Ltd. All rights reserved.

Binge-eating disorder: Clinical and therapeutic advances.

Science.gov (United States)

Hutson, Peter H; Balodis, Iris M; Potenza, Marc N

2018-02-01

Binge-eating disorder (BED) is the most prevalent eating disorder with estimates of 2-5% of the general adult population. Nonetheless, its pathophysiology is poorly understood. Furthermore, there exist few therapeutic options for its effective treatment. Here we review the current state of binge-eating neurobiology and pharmacology, drawing from clinical therapeutic, neuroimaging, cognitive, human genetic and animal model studies. These studies, which are still in their infancy, indicate that while there are many gaps in our knowledge, several key neural substrates appear to underpin binge-eating and may be conserved between human and animals. This observation suggests that behavioral intermediate phenotypes or endophenotypes relevant to BED may be modeled in animals, facilitating the identification and testing of novel pharmacological targets. The development of novel, safe and effective pharmacological therapies for the treatment of BED will enhance the ability of clinicians to provide optimal care for people with BED. Copyright © 2017 Elsevier Inc. All rights reserved.

3D bioprinting: A new insight into the therapeutic strategy of neural tissue regeneration.

Science.gov (United States)

Hsieh, Fu-Yu; Hsu, Shan-hui

2015-01-01

Acute traumatic injuries and chronic degenerative diseases represent the world's largest unmet medical need. There are over 50 million people worldwide suffering from neurodegenerative diseases. However, there are only a few treatment options available for acute traumatic injuries and neurodegenerative diseases. Recently, 3D bioprinting is being applied to regenerative medicine to address the need for tissues and organs suitable for transplantation. In this commentary, the newly developed 3D bioprinting technique involving neural stem cells (NSCs) embedded in the thermoresponsive biodegradable polyurethane (PU) bioink is reviewed. The thermoresponsive and biodegradable PU dispersion can form gel near 37 °C without any crosslinker. NSCs embedded within the water-based PU hydrogel with appropriate stiffness showed comparable viability and differentiation after printing. Moreover, in the zebrafish embryo neural deficit model, injection of the NSC-laden PU hydrogels promoted the repair of damaged CNS. In addition, the function of adult zebrafish with traumatic brain injury was rescued after implantation of the 3D-printed NSC-laden constructs. Therefore, the newly developed 3D bioprinting technique may offer new possibilities for future therapeutic strategy of neural tissue regeneration.

Systematically Altering Bacterial SOS Activity under Stress Reveals Therapeutic Strategies for Potentiating Antibiotics.

Science.gov (United States)

Mo, Charlie Y; Manning, Sara A; Roggiani, Manuela; Culyba, Matthew J; Samuels, Amanda N; Sniegowski, Paul D; Goulian, Mark; Kohli, Rahul M

2016-01-01

The bacterial SOS response is a DNA damage repair network that is strongly implicated in both survival and acquired drug resistance under antimicrobial stress. The two SOS regulators, LexA and RecA, have therefore emerged as potential targets for adjuvant therapies aimed at combating resistance, although many open questions remain. For example, it is not well understood whether SOS hyperactivation is a viable therapeutic approach or whether LexA or RecA is a better target. Furthermore, it is important to determine which antimicrobials could serve as the best treatment partners with SOS-targeting adjuvants. Here we derived Escherichia coli strains that have mutations in either lexA or recA genes in order to cover the full spectrum of possible SOS activity levels. We then systematically analyzed a wide range of antimicrobials by comparing the mean inhibitory concentrations (MICs) and induced mutation rates for each drug-strain combination. We first show that significant changes in MICs are largely confined to DNA-damaging antibiotics, with strains containing a constitutively repressed SOS response impacted to a greater extent than hyperactivated strains. Second, antibiotic-induced mutation rates were suppressed when SOS activity was reduced, and this trend was observed across a wider spectrum of antibiotics. Finally, perturbing either LexA or RecA proved to be equally viable strategies for targeting the SOS response. Our work provides support for multiple adjuvant strategies, while also suggesting that the combination of an SOS inhibitor with a DNA-damaging antibiotic could offer the best potential for lowering MICs and decreasing acquired drug resistance. IMPORTANCE Our antibiotic arsenal is becoming depleted, in part, because bacteria have the ability to rapidly adapt and acquire resistance to our best agents. The SOS pathway, a widely conserved DNA damage stress response in bacteria, is activated by many antibiotics and has been shown to play central role in

Therapeutic Plasma Exchange in Critically Ill Children Requiring Intensive Care.

Science.gov (United States)

Cortina, Gerard; McRae, Rosemary; Chiletti, Roberto; Butt, Warwick

2018-02-01

To characterize the clinical indications, procedural safety, and outcome of critically ill children requiring therapeutic plasma exchange. Retrospective observational study based on a prospective registry. Tertiary and quaternary referral 30-bed PICU. Forty-eight critically ill children who received therapeutic plasma exchange during an 8-year period (2007-2014) were included in the study. Therapeutic plasma exchange. A total of 48 patients underwent 244 therapeutic plasma exchange sessions. Of those, therapeutic plasma exchange was performed as sole procedure in 193 (79%), in combination with continuous renal replacement therapy in 40 (16.4%) and additional extracorporeal membrane oxygenation in 11 (4.6%) sessions. The most common admission diagnoses were hematologic disorders (30%), solid organ transplantation (20%), neurologic disorders (20%), and rheumatologic disorders (15%). Complications associated with the procedure occurred in 50 (21.2%) therapeutic plasma exchange sessions. Overall, patient survival from ICU was 82%. Although patients requiring therapeutic plasma exchange alone (n = 31; 64%) had a survival rate of 97%, those with additional continuous renal replacement therapy (n = 13; 27%) and extracorporeal membrane oxygenation (n = 4; 8%) had survival rates of 69% and 50%, respectively. Factors associated with increased mortality were lower Pediatric Index of Mortality 2 score, need for mechanical ventilation, higher number of failed organs, and longer ICU stay. Our results indicate that, in specialized centers, therapeutic plasma exchange can be performed relatively safely in critically ill children, alone or in combination with continuous renal replacement therapy and extracorporeal membrane oxygenation. Outcome in children requiring therapeutic plasma exchange alone is excellent. However, survival decreases with the number of failed organs and the need for continuous renal replacement therapy and extracorporeal membrane oxygenation.

DroidSafe

Science.gov (United States)

2016-12-01

Massachusetts Avenue, Build E19-750 Cambridge , MA 02139-4307 8. PERFORMING ORGANIZATION REPORT NUMBER 9. SPONSORING/MONITORING AGENCY NAME(S) AND ADDRESS...Activity objects illustrating the challenges of points-to and information flow analysis...measure how many malicious flows Droid- Safe was able to detect). As these results illustrate , DroidSafe implements an analysis of unprece- dented

HIV-1 Immunogen: an overview of almost 30 years of clinical testing of a candidate therapeutic vaccine.

Science.gov (United States)

Graziani, Gina M; Angel, Jonathan B

2016-07-01

Although current antiretroviral therapy (ART) has transformed HIV infection into a chronic, manageable disease, ART does not cure HIV infection. Furthermore, the majority of the world's infected individuals live in resource-limited countries in which access to ART is limited. Thus, the development of an effective therapeutic HIV vaccine would be an invaluable treatment alternative. Developed by the late Dr. Jonas Salk, HIV-1 Immunogen (Remune®) is a candidate therapeutic vaccine that has been studied in thousands of HIV-infected individuals in more than a dozen clinical trials during almost three decades. This Drug Evaluation, which summarizes the results of these trials that have shown the vaccine to be safe and immunogenic, also discusses the contradictory and controversial conclusions drawn from the phases 2, 2/3 and 3 trials that assessed the clinical efficacy of this vaccine. Given the lack of unequivocal clinical benefits of HIV-1 Immunogen despite almost 30 years of extensive testing, it does not appear, in our view, that this vaccine is a clinically effective immunotherapy. However, inclusion of this vaccine in the newly proposed 'Kick/Shock and Kill' strategy for HIV eradication, or use as a prophylactic vaccine, could be considered for future trials.

Current Immunotherapeutic Strategies to Enhance Oncolytic Virotherapy

Directory of Open Access Journals (Sweden)

Daniel E. Meyers

2017-06-01

Full Text Available Oncolytic viruses (OV represent a promising strategy to augment the spectrum of cancer therapeutics. For efficacy, they rely on two general mechanisms: tumor-specific infection/cell-killing, followed by subsequent activation of the host’s adaptive immune response. Numerous OV genera have been utilized in clinical trials, ultimately culminating in the 2015 Food and Drug Administration approval of a genetically engineered herpes virus, Talminogene laherparepvec (T-VEC. It is generally accepted that OV as monotherapy have only modest clinical efficacy. However, due to their ability to elicit specific antitumor immune responses, they are prime candidates to be paired with other immune-modulating strategies in order to optimize therapeutic efficacy. Synergistic strategies to enhance the efficacy of OV include augmenting the host antitumor response through the insertion of therapeutic transgenes such as GM-CSF, utilization of the prime-boost strategy, and combining OV with immune-modulatory drugs such as cyclophosphamide, sunitinib, and immune checkpoint inhibitors. This review provides an overview of these immune-based strategies to improve the clinical efficacy of oncolytic virotherapy.

The Network Model of Depression as a Basis for New Therapeutic Strategies for Treating Major Depressive Disorder in Parkinson’s Disease

Science.gov (United States)

D’Ostilio, Kevin; Garraux, Gaëtan

2016-01-01

The high prevalence of major depressive disorder in people with Parkinson’s disease (PD), its negative impact on health-related quality of life and the low response rate to conventional pharmacological therapies call to seek innovative treatments. Here, we review the new approaches for treating major depressive disorder in patients with PD within the framework of the network model of depression. According to this model, major depressive disorder reflects maladaptive neuronal plasticity. Non-invasive brain stimulation (NIBS) using high frequency repetitive transcranial magnetic stimulation (rTMS) over the prefrontal cortex has been proposed as a feasible and effective strategy with minimal risk. The neurobiological basis of its therapeutic effect may involve neuroplastic modifications in limbic and cognitive networks. However, the way this networks reorganize might be strongly influenced by the environment. To address this issue, we propose a combined strategy that includes NIBS together with cognitive and behavioral interventions. PMID:27148016

Safe havens in Europe

DEFF Research Database (Denmark)

Paldam, Martin

2013-01-01

Eleven safe havens exist in Europe providing offshore banking and low taxes. Ten of these states are very small while Switzerland is moderately small. All 11 countries are richer than their large neighbors. It is shown that causality is from small to safe haven to wealth, and that theoretically...... equilibriums are likely to exist where a certain regulation is substantially lower in a small country than in its big neighbor. This generates a large capital inflow to the safe havens. The pool of funds that may reach the safe havens is shown to be huge. It is far in excess of the absorptive capacity...... of the safe havens, but it still explains, why they are rich. Microstates offer a veil of anonymity to funds passing through, and Switzerland offers safe storage of funds....

Molecular control of HIV-1 postintegration latency: implications for the development of new therapeutic strategies

Directory of Open Access Journals (Sweden)

Van Lint Carine

2009-12-01

Full Text Available Abstract The persistence of HIV-1 latent reservoirs represents a major barrier to virus eradication in infected patients under HAART since interruption of the treatment inevitably leads to a rebound of plasma viremia. Latency establishes early after infection notably (but not only in resting memory CD4+ T cells and involves numerous host and viral trans-acting proteins, as well as processes such as transcriptional interference, RNA silencing, epigenetic modifications and chromatin organization. In order to eliminate latent reservoirs, new strategies are envisaged and consist of reactivating HIV-1 transcription in latently-infected cells, while maintaining HAART in order to prevent de novo infection. The difficulty lies in the fact that a single residual latently-infected cell can in theory rekindle the infection. Here, we review our current understanding of the molecular mechanisms involved in the establishment and maintenance of HIV-1 latency and in the transcriptional reactivation from latency. We highlight the potential of new therapeutic strategies based on this understanding of latency. Combinations of various compounds used simultaneously allow for the targeting of transcriptional repression at multiple levels and can facilitate the escape from latency and the clearance of viral reservoirs. We describe the current advantages and limitations of immune T-cell activators, inducers of the NF-κB signaling pathway, and inhibitors of deacetylases and histone- and DNA- methyltransferases, used alone or in combinations. While a solution will not be achieved by tomorrow, the battle against HIV-1 latent reservoirs is well- underway.

Escola segura Safe school

Directory of Open Access Journals (Sweden)

Edson Ferreira Liberal

2005-11-01

Full Text Available OBJETIVO: Revisão das estratégias para tornar o ambiente escolar seguro. Inicialmente os autores contextualizam a violência e os acidentes no ambiente escolar e fazem recomendações, baseadas em dados da literatura, para a implantação de escolas seguras. FONTE DE DADOS: Artigos publicados entre 1993 e 2005 na base de dados MEDLINE. Dados nacionais epidemiológicos e da literatura também foram pesquisados. SÍNTESE DOS DADOS: Há evidência crescente de que a intervenção tem múltiplos componentes. O foco político é a prática em educação em saúde com o envolvimento de toda a comunidade. O norte dessas intervenções é ajudar estudantes e toda a comunidade a adotar um comportamento seguro e saudável. As escolas estão assumindo um envolvimento crescente na promoção da saúde, prevenção de doenças e prevenção de trauma. Nesse contexto de prevenção de causas externas de morbimortalidade, é importante reconhecer o risco ambiental, locais e comportamentos de risco como favoráveis ao trauma e à violência, além de um novo conceito de acidentes como algo que possa ser evitado. CONCLUSÃO: A implementação da escola segura representa uma nova direção promissora para o trabalho preventivo baseado na escola. É importante notar que uma escola segura deve intervir não meramente na sua estrutura física, mas também torná-la tão segura quanto possível, trabalhando com a comunidade escolar por meio de educação em saúde, discutindo principalmente o comportamento saudável.OBJECTIVE: To review the strategies to make school a safe environment. The paper first addresses the social context of accidents and violence in the school environment, and makes recommendations, based on the literature data, for the implementation of safe schools. SOURCE OF DATA: Articles published between 1993 and 2005 in the MEDLINE database. Brazilian epidemiological and literature data have also been searched. SUMMARY OF THE FINDINGS: There is

Traveling Safely with Medicines

Science.gov (United States)

... Medications Safely My Medicine List How to Administer Traveling Safely with Medicines Planes, trains, cars – even boats ... your trip, ask your pharmacist about how to travel safely with your medicines. Make sure that you ...

Regenerating the human heart: direct reprogramming strategies and their current limitations.

Science.gov (United States)

Ghiroldi, Andrea; Piccoli, Marco; Ciconte, Giuseppe; Pappone, Carlo; Anastasia, Luigi

2017-10-27

Cardiovascular diseases are the leading cause of death in the Western world. Unfortunately, current therapies are often only palliative, consequently essentially making heart transplantation necessary for many patients. However, several novel therapeutic approaches in the past two decades have yielded quite encouraging results. The generation of induced pluripotent stem cells, through the forced expression of stem cell-specific transcription factors, has inspired the most promising strategies for heart regeneration by direct reprogramming of cardiac fibroblasts into functional cardiomyocytes. Initial attempts at this reprogramming were conducted using a similar approach to the one used with transcription factors, but during years, novel strategies have been tested, e.g., miRNAs, recombinant proteins and chemical molecules. Although preliminary results on animal models are promising, the low reprogramming efficiency, as well as the incomplete maturation of the cardiomyocytes, still represents important obstacles. This review covers direct transdifferentiation strategies that have been proposed and developed and illustrates the pros and cons of each approach. Indeed, as described in the manuscript, there are still many unanswered questions and drawbacks that require a better understanding of the basic signaling pathways and transcription factor networks before functional cells, suitable for cardiac regeneration and safe for the patients, can be generated and used for human therapies.

Optimizing real time fMRI neurofeedback for therapeutic discovery and development

Science.gov (United States)

Stoeckel, L.E.; Garrison, K.A.; Ghosh, S.; Wighton, P.; Hanlon, C.A.; Gilman, J.M.; Greer, S.; Turk-Browne, N.B.; deBettencourt, M.T.; Scheinost, D.; Craddock, C.; Thompson, T.; Calderon, V.; Bauer, C.C.; George, M.; Breiter, H.C.; Whitfield-Gabrieli, S.; Gabrieli, J.D.; LaConte, S.M.; Hirshberg, L.; Brewer, J.A.; Hampson, M.; Van Der Kouwe, A.; Mackey, S.; Evins, A.E.

2014-01-01

While reducing the burden of brain disorders remains a top priority of organizations like the World Health Organization and National Institutes of Health, the development of novel, safe and effective treatments for brain disorders has been slow. In this paper, we describe the state of the science for an emerging technology, real time functional magnetic resonance imaging (rtfMRI) neurofeedback, in clinical neurotherapeutics. We review the scientific potential of rtfMRI and outline research strategies to optimize the development and application of rtfMRI neurofeedback as a next generation therapeutic tool. We propose that rtfMRI can be used to address a broad range of clinical problems by improving our understanding of brain–behavior relationships in order to develop more specific and effective interventions for individuals with brain disorders. We focus on the use of rtfMRI neurofeedback as a clinical neurotherapeutic tool to drive plasticity in brain function, cognition, and behavior. Our overall goal is for rtfMRI to advance personalized assessment and intervention approaches to enhance resilience and reduce morbidity by correcting maladaptive patterns of brain function in those with brain disorders. PMID:25161891

Safe current injection strategies for a STATCOM under asymmetrical grid faults

DEFF Research Database (Denmark)

Rodriguez, Pedro; Medeiros, Gustavo; Luna, Alvaro

2010-01-01

This paper explores different strategies to set the reference current of a STATCOM under unbalanced grid voltage conditions and determines the maximum deliverable reactive power in each case to guarantee the injected current is permanently within the STATCOM secure operation limits. The paper...... presents a comprehensive derivation of the proposed STATCOM control strategies to set the reactive current reference under unbalanced grid faults, together with an extensive evaluation using simulation and experimental results from a low-scale laboratory setup in order to verify and validate the dynamic...

Agmatine, a potential novel therapeutic strategy for depression.

Science.gov (United States)

Freitas, Andiara E; Neis, Vivian B; Rodrigues, Ana Lúcia S

2016-12-01

Major depressive disorder is the most common psychiatric disorder with lifetime prevalence of up to 20% worldwide. It is responsible for more years lost to disability than any other disorder. Despite the fact that current available antidepressant drugs are safe and effective, they are far from ideal. In addition to the need to administer the drugs for weeks or months to obtain clinical benefit, side effects are still a serious problem. Agmatine is an endogenous polyamine synthesized by the enzyme arginine decarboxylase. It modulates several receptors and is considered as a neuromodulator in the brain. In this review, studies demonstrating the antidepressant effects of agmatine are presented and discussed, as well as, the mechanisms of action related to these effects. Also, the potential beneficial effects of agmatine for the treatment of other neurological disorders are presented. In particular, we provide evidence to encourage future clinical studies investigating agmatine as a novel antidepressant drug. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

Therapeutic risk management of the suicidal patient: safety planning.

Science.gov (United States)

Matarazzo, Bridget B; Homaifar, Beeta Y; Wortzel, Hal S

2014-05-01

This column is the fourth in a series describing a model for therapeutic risk management of the suicidal patient. Previous columns presented an overview of the therapeutic risk management model, provided recommendations for how to augment risk assessment using structured assessments, and discussed the importance of risk stratification in terms of both severity and temporality. This final column in the series discusses the safety planning intervention as a critical component of therapeutic risk management of suicide risk. We first present concerns related to the relatively common practice of using no-suicide contracts to manage risk. We then present the safety planning intervention as an alternative approach and provide recommendations for how to use this innovative strategy to therapeutically mitigate risk in the suicidal patient.

Novel therapeutic approaches for chronic kidney disease due to glomerular disorders.

Science.gov (United States)

Del Nogal-Avila, Maria; Donoro-Blazquez, Hector; Saha, Manish K; Marshall, Caroline B; Clement, Lionel C; Macé, Camille E A; Chugh, Sumant S

2016-07-01

Improved understanding of glomerular disease mechanisms over the past decade has led to the emergence of new and targeted therapeutic strategies for chronic kidney disease (CKD). Most promising among these are the administration of recombinant mutated human angiopoietin-like 4, sialic acid-related sugars that induce sialylation in vivo, compounds related to Bis-T-23, and immune depletion of the soluble urokinase receptor from the circulation. Taking these therapeutic strategies into clinical trials will be the first step away from repurposed and relatively toxic drugs currently used for treating kidney disease. Copyright © 2016 the American Physiological Society.

It's Safe to Be Smart: Strategies for Creating a Supportive Classroom Environment

Science.gov (United States)

Hébert, Thomas P.; Corcoran, Jamie A.; Coté, John M.; Ene, Mihaela C.; Leighton, Elizabeth A.; Holmes, Ashley M.; Padula, Diane D.

2014-01-01

Gifted teenagers in middle and high school benefit from classroom environments that support their social and emotional development. Teachers of gifted adolescents may create classroom environments in which young people know it is safe to be smart and where they feel valued and respected for their intellect, creativity, and passions. By utilizing…

Creating Safe Growth Strategies for the San Francisco Bay Area

Science.gov (United States)

Report from a technical assistance project with the Association of Bay Area Governments to develop strategies to ensure that growth in the region is resilient to hazards such as earthquakes and sea level rise, but also affordable and transit accessible.

Economics of place-based monitoring under the safe drinking water act, part I: spatial and temporal patterns of contaminants, and design of screening strategies.

Science.gov (United States)

Brands, Edwin; Rajagopal, R

2008-08-01

The goals of environmental legislation and associated regulations are to protect public health, natural resources, and ecosystems. In this context, monitoring programs should provide timely and relevant information so that the regulatory community can implement legislation in a cost-effective and efficient manner. The Safe Drinking Water Act (SDWA) of 1974 attempts to ensure that public water systems (PWSs) supply safe water to its consumers. As is the case with many other federal environmental statutes, SDWA monitoring has been implemented in relatively uniform fashion across the USA. In this three part series, spatial and temporal patterns in water quality data are utilized to develop, compare, and evaluate the economic performance of alternative place-based monitoring approaches to current monitoring practice. Under the Safe Drinking Water Act (SDWA), a common list of over 90 contaminants is analyzed nationwide using EPA-authorized laboratory procedures. National and state-level summaries of SDWA data have shown that not all contaminants occur in all places at all times. This hypothesis is confirmed and extended by showing that only a few (less than seven) contaminants are of concern in any one of 19 Iowa surface water systems studied. These systems collectively serve about 350,000 people and their sizes vary between 1,200 and 120,000. The distributions of contaminants found in these systems are positively skewed, with many non-detect measurements. A screening strategy to identify such contaminants in individual systems is presented. These findings have significant implications not only for the design of alternative monitoring programs, but also in multi-billion-dollar decisions that influence the course of future drinking water infrastructure, repair, and maintenance investments.

Maintenance of whole-body therapeutic hypothermia during patient transport and magnetic resonance imaging

International Nuclear Information System (INIS)

Wu, Tai-Wei; McLean, Claire; Friedlich, Philippe; Seri, Istvan; Grimm, John; Bluml, Stefan

2014-01-01

Therapeutic hypothermia has become standard treatment for neonatal hypoxic-ischemic encephalopathy (HIE), with brain MRI commonly performed after the child has been rewarmed. However, early imaging during hypothermia might provide information important in designing clinical trials that refine and personalize therapeutic hypothermia. We tested a protocol to ensure safety and maintenance of hypothermia during in-hospital transport and MRI. MRI during therapeutic hypothermia was performed in 13 newborns on the 2nd-3rd postnatal days. Mean one-way transport time was 20.0 ± 3.3 min. Mean rectal temperatures ( C) leaving the unit, upon arrival at the MR suite, during MRI scan and upon return to the unit were 33.5 ± 0.3 C, 33.3 ± 0.3 C, 33.1 ± 0.4 C and 33.4 ± 0.3 C, respectively. Using our protocol therapeutic hypothermia was safely and effectively continued during in-hospital transport and MRI without adverse effects. (orig.)

Maintenance of whole-body therapeutic hypothermia during patient transport and magnetic resonance imaging

Energy Technology Data Exchange (ETDEWEB)

Wu, Tai-Wei; McLean, Claire; Friedlich, Philippe; Seri, Istvan [Children' s Hospital Los Angeles, Center for Fetal and Neonatal Medicine and the USC Division of Neonatal Medicine, Department of Pediatrics, Los Angeles, CA (United States); University of Southern California, LAC/USC Medical Center, Keck School of Medicine, Los Angeles, CA (United States); Grimm, John; Bluml, Stefan [University of Southern California, LAC/USC Medical Center, Keck School of Medicine, Los Angeles, CA (United States); Children' s Hospital Los Angeles, Department of Radiology, Los Angeles, CA (United States)

2014-05-15

Therapeutic hypothermia has become standard treatment for neonatal hypoxic-ischemic encephalopathy (HIE), with brain MRI commonly performed after the child has been rewarmed. However, early imaging during hypothermia might provide information important in designing clinical trials that refine and personalize therapeutic hypothermia. We tested a protocol to ensure safety and maintenance of hypothermia during in-hospital transport and MRI. MRI during therapeutic hypothermia was performed in 13 newborns on the 2nd-3rd postnatal days. Mean one-way transport time was 20.0 ± 3.3 min. Mean rectal temperatures ( C) leaving the unit, upon arrival at the MR suite, during MRI scan and upon return to the unit were 33.5 ± 0.3 C, 33.3 ± 0.3 C, 33.1 ± 0.4 C and 33.4 ± 0.3 C, respectively. Using our protocol therapeutic hypothermia was safely and effectively continued during in-hospital transport and MRI without adverse effects. (orig.)

Achieving pregnancy safely for HIV-serodiscordant couples: a social ecological approach.

Science.gov (United States)

Saleem, Haneefa T; Narasimhan, Manjulaa; Denison, Julie A; Kennedy, Caitlin E

2017-03-08

The recognition and fulfilment of the sexual and reproductive health and rights (SRHR) of all individuals and couples affected by HIV, including HIV-serodiscordant couples, requires intervention strategies aimed at achieving safe and healthy pregnancies and preventing undesired pregnancies. Reducing risk of horizontal and vertical transmission and addressing HIV-related infertility are key components of such interventions. In this commentary, we present challenges and opportunities for achieving safe pregnancies for serodiscordant couples through a social ecological lens. At the individual level, knowledge (e.g. of HIV status, assisted reproductive technologies) and skills (e.g. adhering to antiretroviral therapy or pre-exposure prophylaxis) are important. At the couple level, communication between partners around HIV status disclosure, fertility desires and safer pregnancy is required. Within the structural domain, social norms, stigma and discrimination from families, community and social networks influence individual and couple experiences. The availability and quality of safer conception and fertility support services within the healthcare system remains essential, including training for healthcare providers and strengthening integration of SRHR and HIV services. Policies, legislation and funding can improve access to SRHR services. A social ecological framework allows us to examine interactions between levels and how interventions at multiple levels can better support HIV-serodiscordant couples to achieve safe pregnancies. Strategies to achieve safer pregnancies should consider interrelated challenges at different levels of a social ecological framework. Interventions across multiple levels, implemented concurrently, have the potential to maximize impact and ensure the full SRHR of HIV-serodiscordant couples.

The struggle for safe nuclear expansion in China

International Nuclear Information System (INIS)

Xu, Y.C.

2014-01-01

After a temporary halt following the Fukushima nuclear disaster in March 2011, China resumed its fast, yet cautious, expansion of nuclear energy programme. Nuclear energy is considered as part of the general strategy to deal with the challenges of energy security and climate change and to advance with ‘state of the art’ technology in its development. This article briefly discusses recent development in and driving forces behind nuclear industry in China, and several challenges it has been facing: how to adopt, adapt, standardise and indigenise whose technologies, and how to address the shortage of qualified nuclear engineers, scientists, skilled labour force and qualified regulators. More importantly, it argues that safe and secure nuclear development requires consistent policies and effective regulations. Therefore, it is crucial to build policy and regulatory capacities based on coordination, planning and management of government agencies and the industry. - Highlights: • Nuclear energy development in China. • Nuclear technology selection. • Human capital. • Regulatory regime. • Safe and secure development

Therapeutic options to treat sulfur mustard poisoning--the road ahead.

Science.gov (United States)

Smith, William J

2009-09-01

For the past 15 years the international research community has conducted a basic and applied research program aimed at identifying a medical countermeasure against chemical threat vesicant, or blistering, agents. The primary emphasis of this program has been the development of therapeutic protection against sulfur mustard and its cutaneous pathology-blister formation. In addition to the work on a medical countermeasures, significant research has been conducted on the development of topical skin protectants and medical strategies for wound healing. This review will focus on the pharmacological strategies investigated, novel therapeutic targets currently under investigation and therapeutic approaches being considered for transition to advanced development. Additionally, we will review the expansion of our understanding of the pathophysiological mechanisms of mustard injury that has come from this research. While great strides have been made through these investigations, the complexity of the mustard insult demands that further studies extend the inroads made and point the way toward better understanding of cellular and tissue disruptions caused by sulfur mustard.

Therapeutic touch is not therapeutic for procedural pain in very preterm neonates: a randomized trial.

Science.gov (United States)

Johnston, Celeste; Campbell-Yeo, Marsha; Rich, Bonnie; Whitley, Julie; Filion, Francoise; Cogan, Jennifer; Walker, Claire-Dominique

2013-09-01

Preterm neonates below 30 weeks' gestational age undergo numerous painful procedures. Many management approaches are not appropriate for this population. Therapeutic Touch, an alternative approach based on the theory of energy medicine, has been shown to promote physiological stability in preterm neonates and reduce pain in some adult studies. The objective was to determine whether Therapeutic Touch is efficacious in decreasing pain in preterm neonates. Infants Touch (n = 27) with infant behind curtains, leaving the curtained area for the heel lance, performed by another. In the sham condition (n = 28), the therapist stood by the incubator with hands by her side. The Premature Infant Pain Profile was used for pain response and time for heart rate to return to baseline for recovery. Heart rate variability and stress response were secondary outcomes. There were no group differences in any of the outcomes. Mean Premature Infant Pain Profile scores across 2 minutes of heel lance procedure in 30-second blocks ranged from 7.92 to 8.98 in the Therapeutic Touch group and 7.64 to 8.46 in the sham group. Therapeutic Touch given immediately before and after heel lance has no comforting effect in preterm neonates. Other effective strategies involving actual touch should be considered.

Code of practice for the control and safe handling of radioactive sources used for therapeutic purposes (1988)

International Nuclear Information System (INIS)

1988-01-01

This Code is intended as a guide to safe practices in the use of sealed and unsealed radioactive sources and in the management of patients being treated with them. It covers the procedures for the handling, preparation and use of radioactive sources, precautions to be taken for patients undergoing treatment, storage and transport of radioactive sources within a hospital or clinic, and routine testing of sealed sources [fr

"Clicking" Gene Therapeutics: A Successful Union of Chemistry and Biomedicine for New Solutions

DEFF Research Database (Denmark)

Astakhova, Kira; Ray, Roslyn; Taskova, Maria

2018-01-01

The use of nucleic acid, DNA and RNA, based strategies to disrupt gene expression as a therapeutic is quickly emerging. Indeed, synthetic oligonucleotides represent a major component of modern gene therapeutics. However, the efficiency and specificity of intracellular uptake for nonmodified oligo...

Radiation protection and safety guide no. GRPB-G-5: safe use of x-rays

International Nuclear Information System (INIS)

Schandorf, C.; Darko, O.; Yeboah, J.; Osei, E.K.; Asiamah, S.D.

1998-01-01

If properly utilized, the use of x-rays can be instrumental in the improvement of the health and welfare of the public. This regulatory guide was developed to assist and encourage registrants in the safe and constructive use of x-rays and to prohibit and prevent exposure to ionizing radiation in amounts which are or may be detrimental to health. The present guide applies to the use of x-rays for diagnostic, therapeutic, and non medical purposes

Therapeutic Assessment of Complex Trauma: A Single-Case Time-Series Study.

Science.gov (United States)

Tarocchi, Anna; Aschieri, Filippo; Fantini, Francesca; Smith, Justin D

2013-06-01

The cumulative effect of repeated traumatic experiences in early childhood incrementally increases the risk of adjustment problems later in life. Surviving traumatic environments can lead to the development of an interrelated constellation of emotional and interpersonal symptoms termed complex posttraumatic stress disorder (CPTSD). Effective treatment of trauma begins with a multimethod psychological assessment and requires the use of several evidence-based therapeutic processes, including establishing a safe therapeutic environment, reprocessing the trauma, constructing a new narrative, and managing emotional dysregulation. Therapeutic Assessment (TA) is a semistructured, brief intervention that uses psychological testing to promote positive change. The case study of Kelly, a middle-aged woman with a history of repeated interpersonal trauma, illustrates delivery of the TA model for CPTSD. Results of this single-case time-series experiment indicate statistically significant symptom improvement as a result of participating in TA. We discuss the implications of these findings for assessing and treating trauma-related concerns, such as CPTSD.

Inherent Tumor Characteristics That Limit Effective and Safe Resection of Giant Nonfunctioning Pituitary Adenomas.

Science.gov (United States)

Nishioka, Hiroshi; Hara, Takayuki; Nagata, Yuichi; Fukuhara, Noriaki; Yamaguchi-Okada, Mitsuo; Yamada, Shozo

2017-10-01

Surgical treatment of giant pituitary adenomas is sometimes challenging. We present our surgical series of giant nonfunctioning adenomas to shed light on the limitations of effective and safe tumor resection. The preoperative tumor characteristics, surgical approaches, outcome, and histology of giant nonfunctioning adenoma (>40 mm) in 128 consecutive surgical patients are reviewed. The follow-up period ranged from 19 to 113 months (mean 62.2 months). A transsphenoidal approach was used in the treatment of 109 patients and a combined transsphenoidal transcranial approach in 19 patients. A total of 93 patients (72.7%) underwent total resection or subtotal resection apart from the cavernous sinus (CS). The degree of tumor resection, excluding the marked CS invasion, was lower in tumors that were larger (P = 0.0107), showed massive intracranial extension (P = 0.0352), and had an irregular configuration (P = 0.0016). Permanent surgical complications developed in 28 patients (22.0%). Long-term tumor control was achieved in all patients by single surgery, including 43 patients with adjuvant radiotherapy. Most tumors were histologically benign, with a low MIB-1 index (inherent factors that independently limit effective resection. These high-risk tumors require an individualized therapeutic strategy. Copyright © 2017 Elsevier Inc. All rights reserved.

Peroxisome Proliferator-Activated Receptor Ligands and Their Role in Chronic Myeloid Leukemia: Therapeutic Strategies.

Science.gov (United States)

Yousefi, Bahman; Samadi, Nasser; Baradaran, Behzad; Shafiei-Irannejad, Vahid; Zarghami, Nosratollah

2016-07-01

Imatinib therapy remains the gold standard for treatment of chronic myeloid leukemia; however, the acquired resistance to this therapeutic agent in patients has urged the scientists to devise modalities for overcoming this chemoresistance. For this purpose, initially therapeutic agents with higher tyrosine kinase activity were introduced, which had the potential for inhibiting even mutant forms of Bcr-Abl. Furthermore, coupling imatinib with peroxisome proliferator-activated receptor ligands also showed beneficial effects in chronic myeloid leukemia cell proliferation. These combination protocols inhibited cell growth and induced apoptosis as well as differentiation in chronic myeloid leukemia cell lines. In addition, peroxisome proliferator-activated receptors ligands increased imatinib uptake by upregulating the expression of human organic cation transporter 1. Taken together, peroxisome proliferator-activated receptors ligands are currently being considered as novel promising therapeutic candidates for chronic myeloid leukemia treatment, because they can synergistically enhance the efficacy of imatinib. In this article, we reviewed the potential of peroxisome proliferator-activated receptors ligands for use in chronic myeloid leukemia treatment. The mechanism of action of these therapeutics modalities are also presented in detail. © 2016 John Wiley & Sons A/S.

Generation of safe optimised execution strategies for uml models

DEFF Research Database (Denmark)

Herbert, Luke Thomas; Herbert-Hansen, Zaza Nadja Lee

When designing safety critical systems there is a need for verification of safety properties while ensuring system operations have a specific performance profile. We present a novel application of model checking to derive execution strategies, sequences of decisions at workflow branch points...... which optimise a set of reward variables, while simultaneously observing constraints which encode any required safety properties and accounting for the underlying stochastic nature of the system. By evaluating quantitative properties of the generated adversaries we are able to construct an execution...

EGFR conjunct FSCN1 as a Novel Therapeutic Strategy in Triple-Negative Breast Cancer.

Science.gov (United States)

Wang, Chao-Qun; Li, Yang; Huang, Bi-Fei; Zhao, Yong-Ming; Yuan, Hui; Guo, Dongfang; Su, Chen-Ming; Hu, Gui-Nv; Wang, Qian; Long, Tengyun; Wang, Yan; Tang, Chih-Hsin; Li, Xiaoni

2017-11-15

Emerging evidence indicates that Fascin-1 (FSCN1) may possess a causal role in the development of several types of cancers and serves as a novel biomarker of aggressiveness in certain carcinomas. However, the regulatory mechanism of FSCN1 in triple-negative breast cancer (TNBC) cell invasion and migration is still largely unknown. In our study, we observed that the FSCN1 expression rates were significantly higher in invasive ductal carcinoma, compared with both usual ductal hyperplasia and ductal carcinoma in situ. FSCN1 expression was significantly higher in cases of TNBC compared with the non-TNBC subtype. Overexpression of FSCN1 promoted TNBC cell migration and invasion. Epidermal growth factor induced the expression of FSCN1 through activation of MAPK, which subsequently promoted cell migration and invasion. A significant decrease in FSCN1 expression following the co-treatment of FSCN1 siRNA and Gefitinib, compared with the separate treatment of FSCN1 siRNA or Gefitinib. Furthermore, we found that there was a significant association between FSCN1 expression and poor relapse-free survival and overall survival. Therefore, we suggest that co-targeting epidermal growth factor receptor and FSCN1 dual biomarker may be used as a novel therapeutic strategy for TNBC.

Therapeutic navigations: National and transnational quests for fertility among Mozambican women and men

NARCIS (Netherlands)

Domingues Figueira de Faria, I.

2016-01-01

This thesis explores Mozambican women and couple’s processes of coping with infertility and their national and transnational therapeutic itineraries in the quest for a child. Based on the idea of therapeutic navigation, this work accounts for the manifold social and individual aspects and strategies

Ordeals of Chernobyl and the rejustification of the inherently safe reactors

International Nuclear Information System (INIS)

Lu, Y.

1989-01-01

This paper presents the necessity of developing inherently safe economic reactors (ISERs). Two characteristics which define inherent safety are discussed on the basis of various applications of such a principle in practice. Different design concepts of ISERs are then evaluated and their possible role in the future nuclear program of PRC discussed. A three-stage development strategy of ISERs in PRC is proposed

Humor: A Therapeutic Intervention for Child Counseling

Science.gov (United States)

Berg, Rachelle G.; Parr, Gerald; Bradley, Loretta J.; Berry, Jeremy J.

2009-01-01

Counselors utilize many strategies, techniques, and tools when building a therapeutic alliance or addressing children's issues. Due to the serious nature of discussing problems or perhaps because of the fear of seeming insensitive, counselors often overlook humor as a means to enhance therapy. Whether deliberate or spontaneous, humor can add…

Study and evaluation of radiometry in photo therapeutic treatment of the neonatal hyperbilirubinaemia

International Nuclear Information System (INIS)

Caly, Jose Pucci

2009-01-01

Phototherapy is a procedure established more than 50 years ago in the treatment of the newborn jaundice. However there is no a standard method to quantify the photo therapeutic dose in published clinical studies, hindering the comparison of previous studies on photo therapeutic effectiveness, as well as the establishment of safe and predictable doses. The photo therapeutic dose depends, among other factors, on the effective mean irradiance produced by the photo therapeutic unit. There are no standard procedures, however, neither to quantify the effective irradiance, nor to estimate the mean effective irradiance. As a consequence, large measurement variations in a same photo therapeutic unit are observed using different commercially available radiometers, as a consequence of the vast diversity of spectral responsivities of the instruments. An objective of this work was to adapt and to apply the bases of the wideband ultraviolet radiometry to quantify the available irradiance from photo therapeutic units, establishing procedures that allow us to compare measured irradiances from different sources, using radiometers presenting different spectral responsivities. Another objective was to characterize samples of photo therapeutic units commonly used, focusing the problem of the estimation of the effective mean irradiance from photo therapeutic units, proposing a method to estimate of the effective irradiance from focused sources. The experimental results allow us to conclude that it is not only necessary to standardize the photo therapeutic radiometry, but also the method of estimation of the effective mean irradiance. (author)

Therapeutic physical exercise in neural injury: friend or foe?

Science.gov (United States)

Park, Kanghui; Lee, Seunghoon; Hong, Yunkyung; Park, Sookyoung; Choi, Jeonghyun; Chang, Kyu-Tae; Kim, Joo-Heon; Hong, Yonggeun

2015-12-01

[Purpose] The intensity of therapeutic physical exercise is complex and sometimes controversial in patients with neural injuries. This review assessed whether therapeutic physical exercise is beneficial according to the intensity of the physical exercise. [Methods] The authors identified clinically or scientifically relevant articles from PubMed that met the inclusion criteria. [Results] Exercise training can improve body strength and lead to the physiological adaptation of skeletal muscles and the nervous system after neural injuries. Furthermore, neurophysiological and neuropathological studies show differences in the beneficial effects of forced therapeutic exercise in patients with severe or mild neural injuries. Forced exercise alters the distribution of muscle fiber types in patients with neural injuries. Based on several animal studies, forced exercise may promote functional recovery following cerebral ischemia via signaling molecules in ischemic brain regions. [Conclusions] This review describes several types of therapeutic forced exercise and the controversy regarding the therapeutic effects in experimental animals versus humans with neural injuries. This review also provides a therapeutic strategy for physical therapists that grades the intensity of forced exercise according to the level of neural injury.

SAFE Newsletter

OpenAIRE

2013-01-01

The Center of Excellence SAFE – “Sustainable Architecture for Finance in Europe” – is a cooperation of the Center for Financial Studies and Goethe University Frankfurt. It is funded by the LOEWE initiative of the State of Hessen (Landes-Offensive zur Entwicklung wissenschaftlich-ökonomischer Exzellenz). SAFE brings together more than 40 professors and just as many junior researchers who are all dedicated to conducting research in support of a sustainable financial architecture. The Center has...

Imbalanced pattern completion vs. separation in cognitive disease: network simulations of synaptic pathologies predict a personalized therapeutics strategy

Directory of Open Access Journals (Sweden)

Hanson Jesse E

2010-08-01

Full Text Available Abstract Background Diverse Mouse genetic models of neurodevelopmental, neuropsychiatric, and neurodegenerative causes of impaired cognition exhibit at least four convergent points of synaptic malfunction: 1 Strength of long-term potentiation (LTP, 2 Strength of long-term depression (LTD, 3 Relative inhibition levels (Inhibition, and 4 Excitatory connectivity levels (Connectivity. Results To test the hypothesis that pathological increases or decreases in these synaptic properties could underlie imbalances at the level of basic neural network function, we explored each type of malfunction in a simulation of autoassociative memory. These network simulations revealed that one impact of impairments or excesses in each of these synaptic properties is to shift the trade-off between pattern separation and pattern completion performance during memory storage and recall. Each type of synaptic pathology either pushed the network balance towards intolerable error in pattern separation or intolerable error in pattern completion. Imbalances caused by pathological impairments or excesses in LTP, LTD, inhibition, or connectivity, could all be exacerbated, or rescued, by the simultaneous modulation of any of the other three synaptic properties. Conclusions Because appropriate modulation of any of the synaptic properties could help re-balance network function, regardless of the origins of the imbalance, we propose a new strategy of personalized cognitive therapeutics guided by assay of pattern completion vs. pattern separation function. Simulated examples and testable predictions of this theorized approach to cognitive therapeutics are presented.

Children affected by HIV/AIDS: SAFE, a model for promoting their security, health, and development.

Science.gov (United States)

Betancourt, Theresa S; Fawzi, Mary K S; Bruderlein, Claude; Desmond, Chris; Kim, Jim Y

2010-05-01

A human security framework posits that individuals are the focus of strategies that protect the safety and integrity of people by proactively promoting children's well being, placing particular emphasis on prevention efforts and health promotion. This article applies this framework to a rights-based approach in order to examine the health and human rights of children affected by HIV/AIDS. The SAFE model describes sources of insecurity faced by children across four fundamental dimensions of child well-being and the survival strategies that children and families may employ in response. The SAFE model includes: Safety/protection; Access to health care and basic physiological needs; Family/connection to others; and Education/livelihoods. We argue that it is critical to examine the situation of children through an integrated lens that effectively looks at human security and children's rights through a holistic approach to treatment and care rather than artificially limiting our scope of work to survival-oriented interventions for children affected by HIV/AIDS. Interventions targeted narrowly at children, in isolation of their social and communal environment as outlined in the SAFE model, may in fact undermine protective resources in operation in families and communities and present additional threats to children's basic security. An integrated approach to the basic security and care of children has implications for the prospects of millions of children directly infected or indirectly affected by HIV/AIDS around the world. The survival strategies that young people and their families engage in must be recognized as a roadmap for improving their protection and promoting healthy development. Although applied to children affected by HIV/AIDS in the present analysis, the SAFE model has implications for guiding the care and protection of children and families facing adversity due to an array of circumstances from armed conflict and displacement to situations of extreme poverty.

Analysis of Control Strategies for Aircraft Flight Upset Recovery

Science.gov (United States)

Crespo, Luis G.; Kenny, Sean P.; Cox, David E.; Muri, Daniel G.

2012-01-01

This paper proposes a framework for studying the ability of a control strategy, consisting of a control law and a command law, to recover an aircraft from ight conditions that may extend beyond the normal ight envelope. This study was carried out (i) by evaluating time responses of particular ight upsets, (ii) by evaluating local stability over an equilibrium manifold that included stall, and (iii) by bounding the set in the state space from where the vehicle can be safely own to wings-level ight. These states comprise what will be called the safely recoverable ight envelope (SRFE), which is a set containing the aircraft states from where a control strategy can safely stabilize the aircraft. By safe recovery it is implied that the tran- sient response stays between prescribed limits before converging to a steady horizontal ight. The calculation of the SRFE bounds yields the worst-case initial state corresponding to each control strategy. This information is used to compare alternative recovery strategies, determine their strengths and limitations, and identify the most e ective strategy. In regard to the control law, the authors developed feedback feedforward laws based on the gain scheduling of multivariable controllers. In regard to the command law, which is the mechanism governing the exogenous signals driving the feed- forward component of the controller, we developed laws with a feedback structure that combines local stability and transient response considera- tions. The upset recovery of the Generic Transport Model, a sub-scale twin-engine jet vehicle developed by NASA Langley Research Center, is used as a case study.

Stem Cell Therapy: A Promising Therapeutic Method for Intracerebral Hemorrhage.

Science.gov (United States)

Gao, Liansheng; Xu, Weilin; Li, Tao; Chen, Jingyin; Shao, Anwen; Yan, Feng; Chen, Gao

2018-01-01

Spontaneous intracerebral hemorrhage (ICH) is one type of the most devastating cerebrovascular diseases worldwide, which causes high morbidity and mortality. However, efficient treatment is still lacking. Stem cell therapy has shown good neuroprotective and neurorestorative effect in ICH and is a promising treatment. In this study, our aim was to review the therapeutic effects, strategies, related mechanisms and safety issues of various types of stem cell for ICH treatment. Numerous studies had demonstrated the therapeutic effects of diverse stem cell types in ICH. The potential mechanisms include tissue repair and replacement, neurotrophy, promotion of neurogenesis and angiogenesis, anti-apoptosis, immunoregulation and anti-inflammation and so forth. The microenvironment of the central nervous system (CNS) can also influence the effects of stem cell therapy. The detailed therapeutic strategies for ICH treatment such as cell type, the number of cells, time window, and the routes of medication delivery, varied greatly among different studies and had not been determined. Moreover, the safety issues of stem cell therapy for ICH should not be ignored. Stem cell therapy showed good therapeutic effect in ICH, making it a promising treatment. However, safety should be carefully evaluated, and more clinical trials are required before stem cell therapy can be extensively applied to clinical use.

Vocational Education and Training and the Therapeutic Turn

Science.gov (United States)

Hyland, Terry

2006-01-01

The concept of "therapeutic education" is being increasingly used in contemporary education policy studies to identify learning initiatives which are dominated by objectives linked to personal and social skills, emotional intelligence and building self-esteem. Contemporary educational goals connected with such strategies have been…

Host-Directed Therapeutics as a Novel Approach for Tuberculosis Treatment.

Science.gov (United States)

Kim, Ye-Ram; Yang, Chul-Su

2017-09-28

Despite significant efforts to improve the treatment of tuberculosis (TB), it remains a prevalent infectious disease worldwide owing to the limitations of current TB therapeutic regimens. Recent work on novel TB treatment strategies has suggested that directly targeting host factors may be beneficial for TB treatment. Such strategies, termed host-directed therapeutics (HDTs), focus on host-pathogen interactions. HDTs may be more effective than the currently approved TB drugs, which are limited by the long durations of treatment needed and the emergence of drug-resistant strains. Targets of HDTs include host factors such as cytokines, immune checkpoints, immune cell functions, and essential enzyme activities. This review article discusses examples of potentially promising HDTs and introduces novel approaches for their development.

Independent Recruitment of a Flavin-Dependent Monooxygenase for Safe Accumulation of Sequestered Pyrrolizidine Alkaloids in Grasshoppers and Moths

OpenAIRE

Wang, Linzhu; Beuerle, Till; Timbilla, James; Ober, Dietrich

2012-01-01

Several insect lineages have developed diverse strategies to sequester toxic pyrrolizidine alkaloids from food-plants for their own defense. Here, we show that in two highly divergent insect taxa, the hemimetabolous grasshoppers and the holometabolous butterflies, an almost identical strategy evolved independently for safe accumulation of pyrrolizidine alkaloids. This strategy involves a pyrrolizidine alkaloid N-oxygenase that transfers the pyrrolizidine alkaloids to their respective N-oxide,...

Therapeutic strategy for the treatment of isolated spontaneous dissection of superior mesenteric arteries

International Nuclear Information System (INIS)

Xu Yongle; Xiong Jiang; Guo Wei; Liu Xiaoping; Liu Meng

2010-01-01

Objective: To summarize the treatment strategies of isolated superior mesenteric artery (SMA) dissection and to discuss the selection of therapeutic methods. Methods: The clinical data of ten patients, who were encountered during the period from Jan. 2007 to Feb. 2010 in General Hospital of Chinese PLA and diagnosed as isolated SMA dissection,were retrospectively analyzed. According to the presence or absence of intestinal ischemic necrosis and SMA rupture, the patients were divided into simple group (n = 9) and complicated group(n = 1). The treatments for different type of SMA dissection were discussed and the results and prognosis were analyzed. Results: Nine patients were divided into simple group and received conservative treatment, of which anticoagulation was not employed in 5. One patient was divided into complicated group and had to receive an iliomesenteric bypass surgery after the patient had failed to respond to conservative treatment. After the treatment the abdominal pain was relieved in all ten patients. Conclusion: With the wide use of computer tomography angiography and digital subtraction angiography, more and more isolated SMA dissections have been confirmed. For most patients with SMA dissection, especially for simple ones (i.e. without bowel ischemia or SMA rupture), excellent short-term results can be achieved by pure conservative treatment, even no anticoagulation needed. However, for the complicated isolated SMA dissections, vascular reconstruction procedure with various techniques, including open surgery, is necessary in order to obtain satisfactory short-term results. (authors)

Therapeutic Vaccination for HPV Induced Cervical Cancers

Directory of Open Access Journals (Sweden)

Joeli A. Brinkman

2007-01-01

Full Text Available Cervical Cancer is the second leading cause of cancer–related deaths in women worldwide and is associated with Human Papillomavirus (HPV infection, creating a unique opportunity to treat cervical cancer through anti-viral vaccination. Although a prophylactic vaccine may be available within a year, millions of women, already infected, will continue to suffer from HPV-related disease, emphasizing the need to develop therapeutic vaccination strategies. A majority of clinical trials examining therapeutic vaccination have shown limited efficacy due to examining patients with more advanced-stage cancer who tend to have decreased immune function. Current trends in clinical trials with therapeutic agents examine patients with pre-invasive lesions in order to prevent invasive cervical cancer. However, longer follow-up is necessary to correlate immune responses to lesion regression. Meanwhile, preclinical studies in this field include further exploration of peptide or protein vaccination, and the delivery of HPV antigens in DNA-based vaccines or in viral vectors. As long as pre-clinical studies continue to advance, the prospect of therapeutic vaccination to treat existing lesions seem good in the near future. Positive consequences of therapeutic vaccination would include less disfiguring treatment options and fewer instances of recurrent or progressive lesions leading to a reduction in cervical cancer incidence.

Could martial arts fall training be safe for persons with osteoporosis?: a feasibility study.

NARCIS (Netherlands)

Groen, B.E.; Smulders, E.; Duysens, J.E.J.; Lankveld, W.G.J.M. van; Weerdesteijn, V.G.M.

2010-01-01

ABSTRACT: BACKGROUND: Osteoporosis is a well-established risk factor for fall-related hip fractures. Training fall arrest strategies, such as martial arts (MA) fall techniques, might be useful to prevent hip fractures in persons with osteoporosis, provided that the training itself is safe. This

[Mantle cell lymphoma: Towards a personalized therapeutic strategy?].

Science.gov (United States)

Navarro Matilla, Belén; García-Marco, José A

2015-06-22

Mantle cell lymphoma (MCL) is a clinically heterogeneous non-Hodgkin lymphoma with an aggressive clinical behaviour and short survival in some cases and an indolent course in others. Advances in the biology and pathogenesis of MCL have unveiled several genes involved in deregulation of cell cycle checkpoints and the finding of subclonal populations with specific recurrent mutations (p53, ATM, NOTCH2) with an impact on disease progression and refractoriness to treatment. Prognostic stratification helps to distinguish between indolent and aggressive forms of MCL. Currently, younger fit patients benefit from more intensive front line chemotherapy regimens and consolidation with autologous transplantation, while older or frail patients are treated with less intensive regimens and rituximab maintenance. For relapsing disease, the introduction of bortezomib and lenalidomide containing regimens and B-cell receptor pathway inhibitors such as ibrutinib and idelalisib in combination with immunochemotherapy have emerged as therapeutic agents with promising clinical outcomes. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

Discovery and design of carbohydrate-based therapeutics.

Science.gov (United States)

Cipolla, Laura; Araújo, Ana C; Bini, Davide; Gabrielli, Luca; Russo, Laura; Shaikh, Nasrin

2010-08-01

Till now, the importance of carbohydrates has been underscored, if compared with the two other major classes of biopolymers such as oligonucleotides and proteins. Recent advances in glycobiology and glycochemistry have imparted a strong interest in the study of this enormous family of biomolecules. Carbohydrates have been shown to be implicated in recognition processes, such as cell-cell adhesion, cell-extracellular matrix adhesion and cell-intruder recognition phenomena. In addition, carbohydrates are recognized as differentiation markers and as antigenic determinants. Due to their relevant biological role, carbohydrates are promising candidates for drug design and disease treatment. However, the growing number of human disorders known as congenital disorders of glycosylation that are being identified as resulting from abnormalities in glycan structures and protein glycosylation strongly indicates that a fast development of glycobiology, glycochemistry and glycomedicine is highly desirable. The topics give an overview of different approaches that have been used to date for the design of carbohydrate-based therapeutics; this includes the use of native synthetic carbohydrates, the use of carbohydrate mimics designed on the basis of their native counterpart, the use of carbohydrates as scaffolds and finally the design of glyco-fused therapeutics, one of the most recent approaches. The review covers mainly literature that has appeared since 2000, except for a few papers cited for historical reasons. The reader will gain an overview of the current strategies applied to the design of carbohydrate-based therapeutics; in particular, the advantages/disadvantages of different approaches are highlighted. The topic is presented in a general, basic manner and will hopefully be a useful resource for all readers who are not familiar with it. In addition, in order to stress the potentialities of carbohydrates, several examples of carbohydrate-based marketed therapeutics are given

Leaving patients to their own devices? Smart technology, safety and therapeutic relationships.

Science.gov (United States)

Ho, Anita; Quick, Oliver

2018-03-06

This debate article explores how smart technologies may create a double-edged sword for patient safety and effective therapeutic relationships. Increasing utilization of health monitoring devices by patients will likely become an important aspect of self-care and preventive medicine. It may also help to enhance accurate symptom reports, diagnoses, and prompt referral to specialist care where appropriate. However, the development, marketing, and use of such technology raise significant ethical implications for therapeutic relationships and patient safety. Drawing on lessons learned from other direct-to-consumer health products such as genetic testing, this article explores how smart technology can also pose regulatory challenges and encourage overutilization of healthcare services. In order for smart technology to promote safer care and effective therapeutic encounters, the technology and its utilization must be safe. This article argues for unified regulatory guidelines and better education for both healthcare providers and patients regarding the benefits and risks of these devices.

Safe Grid

Science.gov (United States)

Chow, Edward T.; Stewart, Helen; Korsmeyer, David (Technical Monitor)

2003-01-01

The biggest users of GRID technologies came from the science and technology communities. These consist of government, industry and academia (national and international). The NASA GRID is moving into a higher technology readiness level (TRL) today; and as a joint effort among these leaders within government, academia, and industry, the NASA GRID plans to extend availability to enable scientists and engineers across these geographical boundaries collaborate to solve important problems facing the world in the 21 st century. In order to enable NASA programs and missions to use IPG resources for program and mission design, the IPG capabilities needs to be accessible from inside the NASA center networks. However, because different NASA centers maintain different security domains, the GRID penetration across different firewalls is a concern for center security people. This is the reason why some IPG resources are been separated from the NASA center network. Also, because of the center network security and ITAR concerns, the NASA IPG resource owner may not have full control over who can access remotely from outside the NASA center. In order to obtain organizational approval for secured remote access, the IPG infrastructure needs to be adapted to work with the NASA business process. Improvements need to be made before the IPG can be used for NASA program and mission development. The Secured Advanced Federated Environment (SAFE) technology is designed to provide federated security across NASA center and NASA partner's security domains. Instead of one giant center firewall which can be difficult to modify for different GRID applications, the SAFE "micro security domain" provide large number of professionally managed "micro firewalls" that can allow NASA centers to accept remote IPG access without the worry of damaging other center resources. The SAFE policy-driven capability-based federated security mechanism can enable joint organizational and resource owner approved remote

A Novel Therapeutic Strategy for the Treatment of Glioma, Combining Chemical and Molecular Targeting of Hsp90α

International Nuclear Information System (INIS)

Mehta, Adi; Shervington, Leroy; Munje, Chinmay; Shervington, Amal

2011-01-01

Hsp90α's vital role in tumour survival and progression, together with its highly inducible expression profile in gliomas and its absence in normal tissue and cell lines validates it as a therapeutic target for glioma. Hsp90α was downregulated using the post-transcriptional RNAi strategy (sihsp90α) and a post-translational inhibitor, the benzoquinone antibiotic 17-AAG. Glioblastoma U87-MG and normal human astrocyte SVGp12 were treated with sihsp90α, 17-AAG and concurrent sihsp90α/17-AAG (combined treatment). Both Hsp90α gene silencing and the protein inhibitor approaches resulted in a dramatic reduction in cell viability. Results showed that sihsp90α, 17-AAG and a combination of sihsp90α/17-AAG, reduced cell viability by 27%, 75% and 88% (p < 0.001), respectively, after 72 h. hsp90α mRNA copy numbers were downregulated by 65%, 90% and 99% after 72 h treatment with sihsp90α, 17-AAG and sihsp90α/17-AAG, respectively. The relationship between Hsp90α protein expression and its client Akt kinase activity levels were monitored following treatment with sihsp90α, 17-AAG and sihsp90α/17-AAG. Akt kinase activity was downregulated as a direct consequence of Hsp90α inhibition. Both Hsp90α and Akt kinase levels were significantly downregulated after 72 h. Although, 17-AAG when used as a single agent reduces the Hsp90α protein and the Akt kinase levels, the efficacy demonstrated by combinatorial treatment was found to be far more effective. Combination treatment reduced the Hsp90α protein and Akt kinase levels to 4.3% and 43%, respectively, after 72 h. hsp90α mRNA expression detected in SVGp12 was negligible compared to U87-MG, also, the combination treatment did not compromise the normal cell viability. Taking into account the role of Hsp90α in tumour progression and the involvement of Akt kinase in cell signalling and the anti-apoptotic pathways in tumours, this double targets treatment infers a novel therapeutic strategy

Recent progress in nanomedicine: therapeutic, diagnostic and theranostic applications

NARCIS (Netherlands)

Rizzo, L.Y.; Theek, B.; Storm, Gerrit; Kiessling, F.; Lammers, Twan Gerardus Gertudis Maria

2013-01-01

In recent years, the use of nanomedicine formulations for therapeutic and diagnostic applications has increased exponentially. Many different systems and strategies have been developed for drug targeting to pathological sites, as well as for visualizing and quantifying important (patho-)

Using Therapeutic Toys to Facilitate Venipuncture Procedure in Preschool Children.

Science.gov (United States)

da Silva, José Ronaldo Soares; Pizzoli, Lourdes Margareth Leite; Amorim, Amanda Regina do Prado; Pinheiros, Fernanda Tais; Romanini, Giovanna Chippari; da Silva, Jack Gomes; Joanete, Shirley; Alves, Silvana S M

2016-01-01

Intravenous access procedures in children are considered to be one of the most stressful because it is invasive, and the use of needles generates anxiety, insecurity, and fear. Playful strategies using dolls and even the materials used for venipuncture can assist children in understanding, accepting, and coping with the procedure. Field research was developed on the applicability of the therapeutic toy in the preparation of preschool children for venipuncture procedure based on the protocol developed by Martins, Ribeiro, Borba, and Silva (2001) and Kiche and Almeida (2009). The study was done in a private hospital in Greater São Paulo, Brazil, with 10 children ages 3 to 6 years. Data were gathered through observation and questionnaires completed by the children's adult guardians. Before the activity, the children showed fearful facial expressions, used monosyllabic responses, and avoided looking at the health care professional. After the strategy of using therapeutic toy dolls and puppets, 40% of the children calmly accepted the venipuncture procedure, and 100% showed a change to their initial negative reaction, became more communicative and cooperative, and participated and interacted with researchers, even after the end of the activity and procedure. The strategy of therapeutic toys helps make an unfamiliar environment, strangers, and a procedure characterized as painful and difficult less stressful. Pediatric nurses are in a good position to use this resource to offer more humanized care to children.

Emerging nanotechnology based strategies for diagnosis and therapeutics of urinary tract infections: A review.

Science.gov (United States)

Kumar, M S; Das, A P

2017-11-01

At present, various diagnostic and therapeutic approaches are available for urinary tract infections. But, still the quest for development of more rapid, accurate and reliable approach is an unending process. The pathogens, especially uropathogens are adapting to new environments and antibiotics day by day rapidly. Therefore, urinary tract infections are evolving as hectic and difficult to eradicate, increasing the economic burden to the society. The technological advances should be able to compete the adaptability characteristics of microorganisms to combat their growth in new environments and thereby preventing their infections. Nanotechnology is at present an extensively developing area of immense scientific interest since it has diverse potential applications in biomedical field. Nanotechnology may be combined with cellular therapy approaches to overcome the limitations caused by conventional therapeutics. Nanoantibiotics and drug delivery using nanotechnology are currently growing areas of research in biomedical field. Recently, various categories of antibacterial nanoparticles and nanocarriers for drug delivery have shown their potential in the treatment of infectious diseases. Nanoparticles, compared to conventional antibiotics, are more beneficial in terms of decreasing toxicity, prevailing over resistance and lessening costs. Nanoparticles present long term therapeutic effects since they are retained in body for relatively longer periods. This review focuses on recent advances in the field of nanotechnology, principally emphasizing diagnostics and therapeutics of urinary tract infections. Copyright © 2017 Elsevier B.V. All rights reserved.

Therapeutic apheresis for severe hypertriglyceridemia in pregnancy.

Science.gov (United States)

Basar, Rafet; Uzum, Ayse Kubat; Canbaz, Bulent; Dogansen, Sema Ciftci; Kalayoglu-Besisik, Sevgi; Altay-Dadin, Senem; Aral, Ferihan; Ozbey, Nese Colak

2013-05-01

During pregnancy, a progressive increase in serum triglyceride (TG) and cholesterol levels is observed whereas TG levels mostly remain hypertriglyceridemia, pregnancy may cause extremely elevated TG levels leading to potentially life-threatening pancreatitis attacks and chylomicronemia syndrome. The only safe medical treatment option during pregnancy is ω-3 fatty acids, which have moderate TG lowering effects. Therapeutic apheresis could be used as primary treatment approach during pregnancy. We reported the effect of double filtration apheresis in one pregnant women with severe hypertriglyceridemia, therapeutic plasmapheresis and double filtration methods in the other severe hypertriglyceridemic pregnant woman; a 32-year-old pregnant woman (patient 1) with a history of hypertriglyceridemia-induced acute pancreatitis during pregnancy and a 30-year-old pregnant woman with extremely high TG levels (12,000 mg/dl) leading to chylomicronemia syndrome (patient 2). Medical nutrition therapy and ω-3 fatty acids were also provided. Double filtration apheresis (patient 1) and plasmapheresis + double filtration apheresis (patient 2) were used. When we calculated the TG levels before and after therapeutic apheresis, maximum decrease achieved with double filtration apheresis was 46.3 % for patient 1 and 37.3 % for patient 2. However, with plasmapheresis TG level declined by 72 % in patient 2. Plasmapheresis seemed to be more efficient to decrease TG levels. Iron deficiency anemia was the main complication apart from technical difficulties by lipemic obstruction of tubing system. Healthy babies were born. Delivery led to decreases in TG levels. It is concluded that during pregnancy therapeutic apheresis is an effective method to decrease extremely high TG levels and risks of its potentially life-threatening complications.

Evolution of Therapeutic Antibodies, Influenza Virus Biology, Influenza, and Influenza Immunotherapy

Directory of Open Access Journals (Sweden)

Urai Chaisri

2018-01-01

Full Text Available This narrative review article summarizes past and current technologies for generating antibodies for passive immunization/immunotherapy. Contemporary DNA and protein technologies have facilitated the development of engineered therapeutic monoclonal antibodies in a variety of formats according to the required effector functions. Chimeric, humanized, and human monoclonal antibodies to antigenic/epitopic myriads with less immunogenicity than animal-derived antibodies in human recipients can be produced in vitro. Immunotherapy with ready-to-use antibodies has gained wide acceptance as a powerful treatment against both infectious and noninfectious diseases. Influenza, a highly contagious disease, precipitates annual epidemics and occasional pandemics, resulting in high health and economic burden worldwide. Currently available drugs are becoming less and less effective against this rapidly mutating virus. Alternative treatment strategies are needed, particularly for individuals at high risk for severe morbidity. In a setting where vaccines are not yet protective or available, human antibodies that are broadly effective against various influenza subtypes could be highly efficacious in lowering morbidity and mortality and controlling unprecedented epidemic/pandemic. Prototypes of human single-chain antibodies to several conserved proteins of influenza virus with no Fc portion (hence, no ADE effect in recipients are available. These antibodies have high potential as a novel, safe, and effective anti-influenza agent.

Safe and Effective Gene Therapy for Murine Wiskott-Aldrich Syndrome Using an Insulated Lentiviral Vector

Directory of Open Access Journals (Sweden)

Swati Singh

2017-03-01

Full Text Available Wiskott-Aldrich syndrome (WAS is a life-threatening immunodeficiency caused by mutations within the WAS gene. Viral gene therapy to restore WAS protein (WASp expression in hematopoietic cells of patients with WAS has the potential to improve outcomes relative to the current standard of care, allogeneic bone marrow transplantation. However, the development of viral vectors that are both safe and effective has been problematic. While use of viral transcriptional promoters may increase the risk of insertional mutagenesis, cellular promoters may not achieve WASp expression levels necessary for optimal therapeutic effect. Here we evaluate a self-inactivating (SIN lentiviral vector combining a chromatin insulator upstream of a viral MND (MPSV LTR, NCR deleted, dl587 PBS promoter driving WASp expression. Used as a gene therapeutic in Was−/− mice, this vector resulted in stable WASp+ cells in all hematopoietic lineages and rescue of T and B cell defects with a low number of viral integrations per cell, without evidence of insertional mutagenesis in serial bone marrow transplants. In a gene transfer experiment in non-human primates, the insulated MND promoter (driving GFP expression demonstrated long-term polyclonal engraftment of GFP+ cells. These observations demonstrate that the insulated MND promoter safely and efficiently reconstitutes clinically effective WASp expression and should be considered for future WAS therapy.

Peptide chemistry toolbox - Transforming natural peptides into peptide therapeutics.

Science.gov (United States)

Erak, Miloš; Bellmann-Sickert, Kathrin; Els-Heindl, Sylvia; Beck-Sickinger, Annette G

2018-06-01

The development of solid phase peptide synthesis has released tremendous opportunities for using synthetic peptides in medicinal applications. In the last decades, peptide therapeutics became an emerging market in pharmaceutical industry. The need for synthetic strategies in order to improve peptidic properties, such as longer half-life, higher bioavailability, increased potency and efficiency is accordingly rising. In this mini-review, we present a toolbox of modifications in peptide chemistry for overcoming the main drawbacks during the transition from natural peptides to peptide therapeutics. Modifications at the level of the peptide backbone, amino acid side chains and higher orders of structures are described. Furthermore, we are discussing the future of peptide therapeutics development and their impact on the pharmaceutical market. Copyright © 2018 Elsevier Ltd. All rights reserved.

Safe, secure, and clean disposal of final nuclear wastes using 'PyroGreen' strategies

International Nuclear Information System (INIS)

Jung, HyoSook; Choi, Sungyeol; Hwang, Il Soon

2011-01-01

Spent nuclear fuels (SNFs) present global challenges that must be overcome to pave way for safe, secure, peaceful and clean nuclear energy. As one of innovative solutions, we have proposed an innovative partitioning, transmutation, and disposal approach named as 'PyroGreen' that is designed to eliminate the need for high-level waste repositories. A flowsheet of pyrochemical partitioning process with technically achievable values of decontamination factors on long-living radionuclides has been established to enable all the final wastes to be disposed of as low and intermediate level wastes. The long-term performance of a geological repository was assessed by SAFE-ROCK code for the final wastes from the PyroGreen processing of entire 26,000 MTHM of SNFs arising from lifetime operation of 24 pressurized water reactors. The assessment results agree well with an earlier study in the fact that most harmful radionuclides dominating groundwater migration risk are shown to be long-living fission products including C-14, Cl-36, Se-79, I-129, and Cs-135, whereas most actinides including U, Pu, Np, Am, and Cm are shown to remain near the repository. It is shown that the final wastes can meet the radiological dose limit of current Korean regulation on the low and intermediate level waste repository. Long-living actinide concentration in wastes is comparable with those in wastes in Waste Isolation Pilot Plant that has proved adequately low risk of human intrusion. Overall decontamination factors required for PyroGreen are finally determined as 20,000 for uranium and all transuranic elements whereas much lower values in the range of 10-50 are required for important fission products including Se, Tc, I, Sr, and Cs in order to eliminate the need for any high-level waste repository. It has been shown that experimentally demonstrated recovery rate data for key process steps positively support the feasibility of PyroGreen. SAFE-ROCK code was used to evaluate the long-term performance

Stimuli-responsive nanomaterials for therapeutic protein delivery.

Science.gov (United States)

Lu, Yue; Sun, Wujin; Gu, Zhen

2014-11-28

Protein therapeutics have emerged as a significant role in treatment of a broad spectrum of diseases, including cancer, metabolic disorders and autoimmune diseases. The efficacy of protein therapeutics, however, is limited by their instability, immunogenicity and short half-life. In order to overcome these barriers, tremendous efforts have recently been made in developing controlled protein delivery systems. Stimuli-triggered release is an appealing and promising approach for protein delivery and has made protein delivery with both spatiotemporal- and dosage-controlled manners possible. This review surveys recent advances in controlled protein delivery of proteins or peptides using stimuli-responsive nanomaterials. Strategies utilizing both physiological and external stimuli are introduced and discussed. Copyright © 2014 Elsevier B.V. All rights reserved.

Therapeutic approaches for celiac disease

Science.gov (United States)

Plugis, Nicholas M.; Khosla, Chaitan

2015-01-01

Celiac disease is a common, lifelong autoimmune disorder for which dietary control is the only accepted form of therapy. A strict gluten-free diet is burdensome to patients and can be limited in efficacy, indicating there is an unmet need for novel therapeutic approaches to supplement or supplant dietary therapy. Many molecular events required for disease pathogenesis have been recently characterized and inspire most current and emerging drug-discovery efforts. Genome-wide association studies (GWAS) confirm the importance of human leukocyte antigen genes in our pathogenic model and identify a number of new risk loci in this complex disease. Here, we review the status of both emerging and potential therapeutic strategies in the context of disease pathophysiology. We conclude with a discussion of how genes identified during GWAS and follow-up studies that enhance susceptibility may offer insight into developing novel therapies. PMID:26060114

Safe genetic modification of cardiac stem cells using a site-specific integration technique.

Science.gov (United States)

Lan, Feng; Liu, Junwei; Narsinh, Kazim H; Hu, Shijun; Han, Leng; Lee, Andrew S; Karow, Marisa; Nguyen, Patricia K; Nag, Divya; Calos, Michele P; Robbins, Robert C; Wu, Joseph C

2012-09-11

Human cardiac progenitor cells (hCPCs) are a promising cell source for regenerative repair after myocardial infarction. Exploitation of their full therapeutic potential may require stable genetic modification of the cells ex vivo. Safe genetic engineering of stem cells, using facile methods for site-specific integration of transgenes into known genomic contexts, would significantly enhance the overall safety and efficacy of cellular therapy in a variety of clinical contexts. We used the phiC31 site-specific recombinase to achieve targeted integration of a triple fusion reporter gene into a known chromosomal context in hCPCs and human endothelial cells. Stable expression of the reporter gene from its unique chromosomal integration site resulted in no discernible genomic instability or adverse changes in cell phenotype. Namely, phiC31-modified hCPCs were unchanged in their differentiation propensity, cellular proliferative rate, and global gene expression profile when compared with unaltered control hCPCs. Expression of the triple fusion reporter gene enabled multimodal assessment of cell fate in vitro and in vivo using fluorescence microscopy, bioluminescence imaging, and positron emission tomography. Intramyocardial transplantation of genetically modified hCPCs resulted in significant improvement in myocardial function 2 weeks after cell delivery, as assessed by echocardiography (P=0.002) and MRI (P=0.001). We also demonstrated the feasibility and therapeutic efficacy of genetically modifying differentiated human endothelial cells, which enhanced hind limb perfusion (Pmodification system is a safe, efficient tool to enable site-specific integration of reporter transgenes in progenitor and differentiated cell types.

Treating ADHD With Suggestion: Neurofeedback and Placebo Therapeutics.

Science.gov (United States)

Thibault, Robert T; Veissière, Samuel; Olson, Jay A; Raz, Amir

2018-06-01

We propose that clinicians can use suggestion to help treat conditions such as ADHD. We use EEG neurofeedback as a case study, alongside evidence from a recent pilot experiment utilizing a sham MRI scanner to highlight the therapeutic potential of suggestion-based treatments. The medical literature demonstrates that many practitioners already prescribe treatments that hardly outperform placebo comparators. Moreover, the sham MRI experiment showed that, even with full disclosure of the procedure, suggestion alone can reduce the symptomatology of ADHD. Non-deceptive suggestion-based treatments, especially those drawing on accessories from neuroscience, may offer a safe complement and potential alternative to current standard of care for individuals with ADHD.

Current Status of Dengue Therapeutics Research and Development.

Science.gov (United States)

Low, Jenny G H; Ooi, Eng Eong; Vasudevan, Subhash G

2017-03-01

Dengue is a significant global health problem. Even though a vaccine against dengue is now available, which is a notable achievement, its long-term protective efficacy against each of the 4 dengue virus serotypes remains to be definitively determined. Consequently, drugs directed at the viral targets or critical host mechanisms that can be used safely as prophylaxis or treatment to effectively ameliorate disease or reduce disease severity and fatalities are still needed to reduce the burden of dengue. This review will provide a brief account of the status of therapeutics research and development for dengue. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America.

Therapeutic effects of hydrogen on chronic graft-versus-host disease.

Science.gov (United States)

Qian, Liren; Liu, Xiaopeng; Shen, Jianliang; Zhao, Defeng; Yin, Wenjie

2017-10-01

The incidence of chronic graft-versus-host disease (cGVHD) is rising recent years, which has been the leading cause of non-transplantation mortality post allogenetic hematopoietic stem cell transplantation (HSCT). Imbalance of inflammatory cytokines and fibrosis plays critical roles in the pathogenesis of cGVHD. Recent studies showed that molecular hydrogen has anti-inflammatory, antioxidant, anti-fibrosis effects. Therefore, we hypothesized that molecular hydrogen may have therapeutic effects on cGVHD. To determine whether hydrogen could protect mice from cGVHD in an MHC-incompatible murine bone marrow transplantation (BMT) model, survival rates of mice were calculated, and skin lesions were also evaluated after BMT. This article demonstrated that administration of hydrogen-rich saline increased survival rate of cGVHD mice. Administration of hydrogen-rich saline after transplantation also reduced skin lesions of cGVHD mice. Previously, we reported the therapeutic effects of hydrogen on acute GVHD. However, there was no report on the therapeutic effects of hydrogen on cGVHD mice. It is suggested that hydrogen has a potential as an effective and safe therapeutic agent on cGVHD. This study will provide new ideas on the treatment of cGVHD and has important theoretical values. © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Safe decommissioning of the Romanian VVR-S research reactor

International Nuclear Information System (INIS)

Garlea, C.; Garlea, I.; Kelerman, C.; Rodna, A.

2002-01-01

The VVR-S Romania research reactor was operated between 1957-1997, at 2 MW nominal power, for research and radioisotopical production. The detailed decommissioning plan was developed between 1995-1998, in the frame of the International Atomic Energy Agency Technical assistance project ROM/9/017. The proposed strategy agreed by the counterpart as well as international experts was stage 1. In 1997, an independent analysis performed by European Commission experts, in the frame of PHARE project PH04.1/1994 was dedicated to the 'Study of Soviet Design Research Reactors', had consolidated the development of the project emphasizing technical options of safe management for radioactive wastes and VVR-S spent fuel. The paper presents the main technical aspects as well as those of social impact, which lead to the establishment of strategy for safe management of decommissioning. Technical analysis of the VVR-S reactor and associated radwaste facilities (Radioactive Waste Treatment Plant - Magurele and National Repository Baita-Bihor) proved the possibility of the classical method utilization for dismantling of the facility and treatment-conditioning-disposal of the arrised wastes in safe conditions. The decommissioning plan at stage 2 has been developed based on radiological safety assessment, evaluation of radwaste inventory (removed as well as preserved on site), cost analysis and environmental impact. Technical data were provided by the R and D programme including neutron calculations and experiments, radiological characterizing (for facility and its influence area), seismic analysis and environmental balance during the operation and after shut down of the reactor. A special chapter is dedicated to regulatory issues concerning the development of decommissioning under nuclear safety. Based on the Fundamental Norms of Radiological Safety, the Regulatory Body defined the clearance levels and safety criteria for the process. The development of National Norms for the

Progresses towards safe and efficient gene therapy vectors.

Science.gov (United States)

Chira, Sergiu; Jackson, Carlo S; Oprea, Iulian; Ozturk, Ferhat; Pepper, Michael S; Diaconu, Iulia; Braicu, Cornelia; Raduly, Lajos-Zsolt; Calin, George A; Berindan-Neagoe, Ioana

2015-10-13

The emergence of genetic engineering at the beginning of the 1970's opened the era of biomedical technologies, which aims to improve human health using genetic manipulation techniques in a clinical context. Gene therapy represents an innovating and appealing strategy for treatment of human diseases, which utilizes vehicles or vectors for delivering therapeutic genes into the patients' body. However, a few past unsuccessful events that negatively marked the beginning of gene therapy resulted in the need for further studies regarding the design and biology of gene therapy vectors, so that this innovating treatment approach can successfully move from bench to bedside. In this paper, we review the major gene delivery vectors and recent improvements made in their design meant to overcome the issues that commonly arise with the use of gene therapy vectors. At the end of the manuscript, we summarized the main advantages and disadvantages of common gene therapy vectors and we discuss possible future directions for potential therapeutic vectors.

Diagnostic and therapeutic impact of MR enterography in Crohn's disease

Energy Technology Data Exchange (ETDEWEB)

Hafeez, R. [Department of Surgery, University College London Hospitals, NW1 2BU (United Kingdom); Punwani, S. [Centre for Medical Imaging, University College London (United Kingdom); Department of Specialist X-Ray, University College London Hospitals, NW1 2BU (United Kingdom); Boulos, P. [Department of Surgery, University College London Hospitals, NW1 2BU (United Kingdom); Bloom, S.; McCartney, S. [Department of Gastroenterology, University College London Hospitals, NW1 2BU (United Kingdom); Halligan, S. [Centre for Medical Imaging, University College London (United Kingdom); Department of Specialist X-Ray, University College London Hospitals, NW1 2BU (United Kingdom); Taylor, S.A., E-mail: csytaylor@yahoo.co.uk [Centre for Medical Imaging, University College London (United Kingdom); Department of Specialist X-Ray, University College London Hospitals, NW1 2BU (United Kingdom)

2011-12-15

Aim: To assess the impact of magnetic resonance enterography (MRE) on clinician diagnostic confidence and therapeutic strategy in patients under investigation for small bowel Crohn's disease. Material and methods: Gastroenterologists completed a proforma before and following MRE in 51 patients (mean age 35 years, 26 female) under investigation for small bowel Crohn's disease, indicating percentage confidence for presence/absence of small bowel involvement. In suspected disease, diagnostic confidence (using a scoring system from 1 = no to 6 = yes) was scored for subcategories: extent >30 cm (DE), terminal ileum (lTI), jejunal (JD), colonic disease (CoD), strictures (ST), activity (AD), extraluminal complications (EL), and surgical need (NS). Therapeutic strategy was recorded. Patients were divided into three groups: 1 = suspected disease, MRE normal (n = 15); 2 = suspected disease, MRE abnormal (n = 30); 3 = no suspected disease, MRE normal (n = 6). Binomial exact and paired t-tests were use to compare confidence pre and post-MRE. Results: Mean percentage confidence for the presence/absence of small bowel disease increased from 62 to 84% (p = 0.003), 87 to 98% (p = 0.0001), and 83 to 98% (p = 0.005) after MRE for groups 1, 2, and 3, respectively. In suspected disease, confidence changed significantly for all of the subcategories (p < 0.001) except EL in group 1. The percentage of patients with a confidence change ranged from 40% (CoD) to 87% (lTI; group 1) and from 7% (EL) to 93% (DE; group 2). Therapeutic strategy changed in 31/51 (61%, 95% CI 47-74%), 14 with a reduction in planned therapy and 17 with an increase. Conclusion: MRE had a positive diagnostic impact in patients under investigation for small bowel Crohn's disease and this influenced therapeutic strategy in 61% of the patients.

Therapeutic strategies after coronary stenting in chronically anticoagulated patients: the MUSICA study.

Science.gov (United States)

Sambola, A; Ferreira-González, I; Angel, J; Alfonso, F; Maristany, J; Rodríguez, O; Bueno, H; López-Minguez, J R; Zueco, J; Fernández-Avilés, F; San Román, A; Prendergast, B; Mainar, V; García-Dorado, D; Tornos, P

2009-09-01

To identify the therapeutic regimens used at discharge in patients receiving oral anticoagulant therapy (OAT) who undergo stenting percutaneous coronary intervention and stent implantation (PCI-S), and to assess the safety and efficacy associated with different therapeutic regimens according to thromboembolic risk. A prospective multicentre registry. In hospital, after discharge and follow-up by telephone call. 405 patients (328 male/77 female; mean (SD) age 71 (9) years) receiving OAT who underwent PCI-S between November 2003 and June 2006 from nine catheterisation laboratories of tertiary care teaching hospitals in Spain and one in the United Kingdom were included. Three therapeutic regimens were identified at discharge: triple therapy (TT) -- that is, any anticoagulant (AC) plus double antiplatelet therapy (DAT; 278 patients (68.6%); AC and a single antiplatelet (AC+AT; 46 (11.4%)) and DAT only (81 (20%)). At 6 months, patients receiving TT showed the greatest rate of bleeding events. No patients receiving DAT at low thromboembolic risk presented a bleeding event (14.8% receiving TT, 11.8% receiving AC+AT and 0% receiving DAT, p = 0.033) or cardiovascular event (6.7% receiving TT, 0% receiving AC+AT and 0% receiving DAT, p = 0.126). The combination of AC+AT showed the worst rate of adverse events in the whole cohort, especially in patients at moderate-high thromboembolic risk. In patients receiving OAT, TT was the most commonly used regimen after PCI-S. DAT was associated with the lowest rate of bleeding events and a similar efficacy to TT in patients at low thromboembolic risk. TT should probably be restricted to patients at moderate-high thromboembolic risk.

Therapeutic antibodies as a treatment option for dengue fever.

Science.gov (United States)

Chan, Kuan Rong; Ong, Eugenia Z; Ooi, Eng Eong

2013-11-01

Dengue fever is the most prevalent mosquito-borne viral disease globally with about 100 million cases of acute dengue annually. Severe dengue infection can result in a life-threatening illness. In the absence of either a licensed vaccine or antiviral drug against dengue, therapeutic antibodies that neutralize dengue virus (DENV) may serve as an effective medical countermeasure against severe dengue. However, therapeutic antibodies would need to effectively neutralize all four DENV serotypes. It must not induce antibody-dependent enhancement of DENV infection in monocytes/macrophages through Fc gamma receptor (FcγR)-mediated phagocytosis, which is hypothesized to increase the risk of severe dengue. Here, we review the strategies and technologies that can be adopted to develop antibodies for therapeutic applications. We also discuss the mechanism of antibody neutralization in the cells targeted by DENV that express Fc gamma receptor. These studies have provided significant insight toward the use of therapeutic antibodies as a potentially promising bulwark against dengue.

Nanoparticles for the delivery of therapeutic antibodies: Dogma or promising strategy?

Science.gov (United States)

Sousa, Flávia; Castro, Pedro; Fonte, Pedro; Kennedy, Patrick J; Neves-Petersen, Maria Teresa; Sarmento, Bruno

2017-10-01

Over the past two decades, therapeutic antibodies have demonstrated promising results in the treatment of a wide array of diseases. However, the application of antibody-based therapy implies multiple administrations and a high cost of antibody production, resulting in costly therapy. Another disadvantage inherent to antibody-based therapy is the limited stability of antibodies and the low level of tissue penetration. The use of nanoparticles as delivery systems for antibodies allows for a reduction in antibody dosing and may represent a suitable alternative to increase antibody stability Areas covered: We discuss different nanocarriers intended for the delivery of antibodies as well as the corresponding encapsulation methods. Recent developments in antibody nanoencapsulation, particularly the possible toxicity issues that may arise from entrapment of antibodies into nanocarriers, are also assessed. In addition, this review will discuss the alterations in antibody structure and bioactivity that occur with nanoencapsulation. Expert opinion: Nanocarriers can protect antibodies from degradation, ensuring superior bioavailability. Encapsulation of therapeutic antibodies may offer some advantages, including potential targeting, reduced immunogenicity and controlled release. Furthermore, antibody nanoencapsulation may aid in the incorporation of the antibodies into the cells, if intracellular components (e.g. intracellular enzymes, oncogenic proteins, transcription factors) are to be targeted.

Acceptance and Use of Eight Arsenic-Safe Drinking Water Options in Bangladesh

Science.gov (United States)

Inauen, Jennifer; Hossain, Mohammad Mojahidul; Johnston, Richard B.; Mosler, Hans-Joachim

2013-01-01

Arsenic contamination of drinking water is a serious public health threat. In Bangladesh, eight major safe water options provide an alternative to contaminated shallow tubewells: piped water supply, deep tubewells, pond sand filters, community arsenic-removal, household arsenic removal, dug wells, well-sharing, and rainwater harvesting. However, it is uncertain how well these options are accepted and used by the at-risk population. Based on the RANAS model (risk, attitudes, norms, ability, and self-regulation) this study aimed to identify the acceptance and use of available safe water options. Cross-sectional face-to-face interviews were used to survey 1,268 households in Bangladesh in November 2009 (n = 872), and December 2010 (n = 396). The questionnaire assessed water consumption, acceptance factors from the RANAS model, and socioeconomic factors. Although all respondents had access to at least one arsenic-safe drinking water option, only 62.1% of participants were currently using these alternatives. The most regularly used options were household arsenic removal filters (92.9%) and piped water supply (85.6%). However, the former result may be positively biased due to high refusal rates of household filter owners. The least used option was household rainwater harvesting (36.6%). Those who reported not using an arsenic-safe source differed in terms of numerous acceptance factors from those who reported using arsenic-safe sources: non-users were characterized by greater vulnerability; showed less preference for the taste and temperature of alternative sources; found collecting safe water quite time-consuming; had lower levels of social norms, self-efficacy, and coping planning; and demonstrated lower levels of commitment to collecting safe water. Acceptance was particularly high for piped water supplies and deep tubewells, whereas dug wells and well-sharing were the least accepted sources. Intervention strategies were derived from the results in order to

Metabolic Disorder, Inflammation, and Deregulated Molecular Pathways Converging in Pancreatic Cancer Development: Implications for New Therapeutic Strategies

International Nuclear Information System (INIS)

Motoo, Yoshiharu; Shimasaki, Takeo; Ishigaki, Yasuhito; Nakajima, Hideo; Kawakami, Kazuyuki; Minamoto, Toshinari

2011-01-01

Pancreatic cancer develops and progresses through complex, cumulative biological processes involving metabolic disorder, local inflammation, and deregulated molecular pathways. The resulting tumor aggressiveness hampers surgical intervention and renders pancreatic cancer resistant to standard chemotherapy and radiation therapy. Based on these pathologic properties, several therapeutic strategies are being developed to reverse refractory pancreatic cancer. Here, we outline molecular targeting therapies, which are primarily directed against growth factor receptor-type tyrosine kinases deregulated in tumors, but have failed to improve the survival of pancreatic cancer patients. Glycogen synthase kinase-3β (GSK3β) is a member of a serine/threonine protein kinase family that plays a critical role in various cellular pathways. GSK3β has also emerged as a mediator of pathological states, including glucose intolerance, inflammation, and various cancers (e.g., pancreatic cancer). We review recent studies that demonstrate the anti-tumor effects of GSK3β inhibition alone or in combination with chemotherapy and radiation. GSK3β inhibition may exert indirect anti-tumor actions in pancreatic cancer by modulating metabolic disorder and inflammation

Metabolic Disorder, Inflammation, and Deregulated Molecular Pathways Converging in Pancreatic Cancer Development: Implications for New Therapeutic Strategies

Energy Technology Data Exchange (ETDEWEB)

Motoo, Yoshiharu, E-mail: motoo@kanazawa-med.ac.jp [Department of Medical Oncology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa 920-0293 (Japan); Shimasaki, Takeo [Department of Medical Oncology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa 920-0293 (Japan); Division of Translational & Clinical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa (Japan); Ishigaki, Yasuhito [Medical Research Institute, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa 920-0293 (Japan); Nakajima, Hideo [Department of Medical Oncology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa 920-0293 (Japan); Kawakami, Kazuyuki; Minamoto, Toshinari [Division of Translational & Clinical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa (Japan)

2011-01-24

Pancreatic cancer develops and progresses through complex, cumulative biological processes involving metabolic disorder, local inflammation, and deregulated molecular pathways. The resulting tumor aggressiveness hampers surgical intervention and renders pancreatic cancer resistant to standard chemotherapy and radiation therapy. Based on these pathologic properties, several therapeutic strategies are being developed to reverse refractory pancreatic cancer. Here, we outline molecular targeting therapies, which are primarily directed against growth factor receptor-type tyrosine kinases deregulated in tumors, but have failed to improve the survival of pancreatic cancer patients. Glycogen synthase kinase-3β (GSK3β) is a member of a serine/threonine protein kinase family that plays a critical role in various cellular pathways. GSK3β has also emerged as a mediator of pathological states, including glucose intolerance, inflammation, and various cancers (e.g., pancreatic cancer). We review recent studies that demonstrate the anti-tumor effects of GSK3β inhibition alone or in combination with chemotherapy and radiation. GSK3β inhibition may exert indirect anti-tumor actions in pancreatic cancer by modulating metabolic disorder and inflammation.

Metabolic Disorder, Inflammation, and Deregulated Molecular Pathways Converging in Pancreatic Cancer Development: Implications for New Therapeutic Strategies

Directory of Open Access Journals (Sweden)

Toshinari Minamoto

2011-01-01

Full Text Available Pancreatic cancer develops and progresses through complex, cumulative biological processes involving metabolic disorder, local inflammation, and deregulated molecular pathways. The resulting tumor aggressiveness hampers surgical intervention and renders pancreatic cancer resistant to standard chemotherapy and radiation therapy. Based on these pathologic properties, several therapeutic strategies are being developed to reverse refractory pancreatic cancer. Here, we outline molecular targeting therapies, which are primarily directed against growth factor receptor-type tyrosine kinases deregulated in tumors, but have failed to improve the survival of pancreatic cancer patients. Glycogen synthase kinase-3β (GSK3β is a member of a serine/threonine protein kinase family that plays a critical role in various cellular pathways. GSK3β has also emerged as a mediator of pathological states, including glucose intolerance, inflammation, and various cancers (e.g., pancreatic cancer. We review recent studies that demonstrate the anti-tumor effects of GSK3β inhibition alone or in combination with chemotherapy and radiation. GSK3β inhibition may exert indirect anti-tumor actions in pancreatic cancer by modulating metabolic disorder and inflammation.

The recent fall in postperinatal mortality in New Zealand and the Safe Sleep programme.

Science.gov (United States)

Mitchell, Edwin A; Cowan, Stephanie; Tipene-Leach, David

2016-11-01

Postneonatal mortality rates changed very little from 2000 until recently. There has been a decrease in mortality in New Zealand from 2009 to 2015. This study describes an infant Safe Sleep programme and postulates it is the cause for the recent decrease in deaths. The Safe Sleep programme involved as follows: a focus on preventing accidental suffocation, a 'blitz' approach to SUDI education, the targeted provision of portable infant Safe Sleep devices (ISSD) and the development of Safe Sleep policy across all district health boards (DHBs). Participation in the education 'blitz' by health professionals exceeded one in 23 live births, distribution of Safe Sleep leaflets exceeded two for every live birth, and over 16 500 ISSDs have been distributed to vulnerable infants. Postperinatal mortality fell 29% from 2009 to 2015 (2.8 to 2.0/1000 live births). The fall has been greatest for Māori and in regions with the most intensive programmes. The recent fall in postperinatal mortality has not happened by chance. It is likely that the components of end-stage prevention strategy, a focus on preventing accidental suffocation, the education 'blitz', the targeted supply of ISSDs and strengthened health policy, have all contributed to varying degrees. ©2016 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.

Therapeutic intervention in violence against women in Colombia

Directory of Open Access Journals (Sweden)

Lina María Martínez González

2018-01-01

Full Text Available The article presents some reflections regarding the unspecified place of therapeutic intervention in the Colombian State’s strategies to address violence against women in the context of couple relationships. It focuses on professional intervention, concretely, therapeutic intervention, and states that despite its significant role in the potential transformation of the imaginaries and subjectivities that support that violence, this type of intervention occupies an unspecified place in the measures stipulated by the law, as well as in Colombian public policies aimed at countering that violence. The article also highlights some of the perspectives that therapists consider useful in the construction of non-violent functional conditions for couples.

Energy Efficient and Safe Weighted Clustering Algorithm for Mobile Wireless Sensor Networks

Directory of Open Access Journals (Sweden)

Amine Dahane

2015-01-01

Full Text Available The main concern of clustering approaches for mobile wireless sensor networks (WSNs is to prolong the battery life of the individual sensors and the network lifetime. For a successful clustering approach the need of a powerful mechanism to safely elect a cluster head remains a challenging task in many research works that take into account the mobility of the network. The approach based on the computing of the weight of each node in the network is one of the proposed techniques to deal with this problem. In this paper, we propose an energy efficient and safe weighted clustering algorithm (ES-WCA for mobile WSNs using a combination of five metrics. Among these metrics lies the behavioral level metric which promotes a safe choice of a cluster head in the sense where this last one will never be a malicious node. Moreover, the highlight of our work is summarized in a comprehensive strategy for monitoring the network, in order to detect and remove the malicious nodes. We use simulation study to demonstrate the performance of the proposed algorithm.

Are Detox Diets Safe?

Science.gov (United States)

... Safe Videos for Educators Search English Español Are Detox Diets Safe? KidsHealth / For Teens / Are Detox Diets ... seguras las dietas de desintoxicación? What Is a Detox Diet? The name sounds reassuring — everyone knows that ...

Biomedical applications of yeast- a patent view, part one: yeasts as workhorses for the production of therapeutics and vaccines.

Science.gov (United States)

Roohvand, Farzin; Shokri, Mehdi; Abdollahpour-Alitappeh, Meghdad; Ehsani, Parastoo

2017-08-01

Yeasts, as Eukaryotes, offer unique features for ease of growth and genetic manipulation possibilities, making it an exceptional microbial host. Areas covered: This review provides general and patent-oriented insights into production of biopharmaceuticals by yeasts. Patents, wherever possible, were correlated to the original or review articles. The review describes applications of major GRAS (generally regarded as safe) yeasts for the production of therapeutic proteins and subunit vaccines; additionally, immunomodulatory properties of yeast cell wall components were reviewed for use of whole yeast cells as a new vaccine platform. The second part of the review will discuss yeast- humanization strategies and innovative applications. Expert opinion: Biomedical applications of yeasts were initiated by utilization of Saccharomyces cerevisiae, for production of leavened (fermented) products, and advanced to serve to produce biopharmaceuticals. Higher biomass production and expression/secretion yields, more similarity of glycosylation patterns to mammals and possibility of host-improvement strategies through application of synthetic biology might enhance selection of Pichia pastoris (instead of S. cerevisiae) as a host for production of biopharmaceutical in future. Immunomodulatory properties of yeast cell wall β-glucans and possibility of intracellular expression of heterologous pathogen/tumor antigens in yeast cells have expanded their application as a new platform, 'Whole Yeast Vaccines'.

[Advances in Neurological Therapeutics for Friedreich Ataxia and Machado-Joseph Disease].

Science.gov (United States)

Yabe, Ichiro; Sasaki, Hidenao

2017-08-01

We reviewed advances in therapeutics for both Friedreich ataxia and Machado-Joseph disease. Various clinical trials have been carried out, mainly for Friedreich ataxia; however, the therapeutic reports from these trials have not provided much evidence for success. Some interesting clinical trials have been reported, and further developments are expected. Regenerative therapy using umbilical cord mesenchymal stem cells and a therapeutic study investigating a new pathomechanism in animal and/or cell culture studies were reported. We expect that these results will translate to therapeutic strategies for patients with these disorders. In addition, biomarkers play an important role when novel treatments are discovered and clinical trials are performed: hence at present, a number of biomarkers such as gait analysis by triaxial accelerometers and prism adaptation of hand-reaching movements, are being examined.

Epigenetic Mechanisms and Therapeutic Perspectives for Neurodevelopmental Disorders

Directory of Open Access Journals (Sweden)

Kunio Miyake

2012-04-01

Full Text Available The number of children with mild neurodevelopmental disorders, such as autism, has been recently increasing in advanced countries. This increase is probably caused by environmental factors rather than genetic factors, because it is unlikely that genetic mutation rates suddenly increased within a short period. Epigenetics is a mechanism that regulates gene expression, depending not on the underlying DNA sequence but on the chemical modifications of DNA and histone proteins. Because mental stress can alter the epigenetic status in neuronal cells, environmental factors may alter brain function through epigenetic changes. However, one advantage of epigenetic changes is their reversibility. Therefore, diseases due to abnormal epigenetic regulation are theoretically treatable. In fact, several drugs for treating mental diseases are known to have restoring effects on aberrant epigenetic statuses, and a novel therapeutic strategy targeting gene has been developed. In this review, we discuss epigenetic mechanisms of congenital and acquired neurodevelopmental disorders, drugs with epigenetic effects, novel therapeutic strategies for epigenetic diseases, and future perspectives in epigenetic medicine.

"When you carry condoms all the boys think you want it": negotiating competing discourses about safe sex.

Science.gov (United States)

Hillier, L; Harrison, L; Warr, D

1998-02-01

With the advent of HIV, sexual health campaigns and formal sex education in schools have worked to instil the concept of safe sex into the collective minds of Australia's youth. However the concept in its present guise is a fairly limited one. We argue in this paper that the predominant emphasis in education programmes on safe sex as condom use may be counter-productive for some young heterosexuals for two reasons. First, this strategy is male-focused and may not extrapolate well to young women who face special risks around pregnancy and rigid societal gender norms which govern sexual behaviour. Second, health promotion strategies aimed at young heterosexuals are based on an assumption of rational decision-making in sexual encounters and obscure the non-rational nature of arousal and desire, and the unequal power relations that exist between young men and women engaging in sex. Five hundred and twelve senior rural students participated in the study which included group discussions about sexuality and survey items which focused on the meanings of safe sex and the accessibility and use of condoms. The results showed that though most students identified condoms with safe sex, many were ambivalent about using them. Reasons given related to problems of negotiation, difficulties of access, and the risks which condoms gave no protection from, such as a sullied reputation. Perhaps, partly because of this, some students were looking to less secure methods of protection such as informal history-taking and monogamy. It is argued that successful sexual health promotion strategies must address the broad spectrum of concerns facing young men and women when they become sexually active and that consideration be given to the social context in which young people conduct their sexual lives.

Safe Anesthesia For Every Tot

DEFF Research Database (Denmark)

Weiss, Markus; Vutskits, Laszlo; Hansen, Tom G

2015-01-01

PURPOSE OF REVIEW: The term 'safe use of anesthesia in children is ill-defined and requires definition of and focus on the 'safe conduct of pediatric anesthesia'. RECENT FINDINGS: The Safe Anesthesia For Every Tot initiative (www.safetots.org) has been set up during the last year to focus...... on the safe conduct of pediatric anesthesia. This initiative aims to provide guidance on markers of quality anesthesia care. The introduction and implementation of national regulations of 'who, where, when and how' are required and will result in an improved perioperative outcome in vulnerable children....... The improvement of teaching, training, education and supervision of the safe conduct of pediatric anesthesia are the main goals of the safetots.org initiative. SUMMARY: This initiative addresses the well known perioperative risks in young children, perioperative causes for cerebral morbidity as well as gaps...

Strategy in Regulatory Decision-Making for Management of Progressive Multifocal Leukoencephalopathy.

Science.gov (United States)

Segec, A; Keller-Stanislawski, B; Vermeer, N S; Macchiarulo, C; Straus, S M; Hidalgo-Simon, A; De Bruin, M L

2015-11-01

Progressive multifocal leukoencephalopathy (PML) has been observed after the use of several medicines, including monoclonal antibodies. As these drugs play important roles in the therapeutic armamentarium, it is important to address the challenges that this severe adverse reaction poses to the safe use of medicines. Considering the need for consistent outcomes of regulatory decisions, the European Medicines Agency Pharmacovigilance Risk Assessment Committee (PRAC) used PML as an example to develop a systematic approach to labeling and risk minimization. © 2015 American Society for Clinical Pharmacology and Therapeutics.

PSA-selective activation of cytotoxic human serine proteases within the tumor microenvironment as a therapeutic strategy to target prostate cancer.

Science.gov (United States)

Rogers, Oliver C; Anthony, Lizamma; Rosen, D Marc; Brennen, W Nathaniel; Denmeade, Samuel R

2018-04-27

Prostate cancer is the most diagnosed malignancy and the second leading cause of cancer-related death in American men. While localized therapy is highly curative, treatments for metastatic prostate cancer are largely palliative. Thus, new innovative therapies are needed to target metastatic tumors. Prostate-Specific Antigen (PSA) is a chymotrypsin-like protease with a unique substrate specificity that is secreted by both normal and malignant prostate epithelial cells. Previous studies demonstrated the presence of high levels (μM-mM) of enzymatically active PSA is present in the extracellular fluid of the prostate cancer microenvironment. Because of this, PSA is an attractive target for a protease activated pro-toxin therapeutic strategy. Because prostate cancers typically grow very slowly, a strategy employing a proliferation-independent cytotoxic payload is preferred. Recently, it was shown that the human protease Granzyme B (GZMB), at low micromolar concentrations in the extracellular space, can cleave an array of extracellular matrix (ECM) proteins thus perturbing cell growth, signaling, motility, and integrity. It is also well established that other human proteases such as trypsin can induce similar effects. Because both enzymes require N-terminal proteolytic activation, we propose to convert these proteins into PSA-activated cytotoxins. In this study, we examine the enzymatic and cell targeting parameters of these PSA-activated cytotoxic serine proteases. These pro-enzymes were activated robustly by PSA and induced ECM damage that led to the death of prostate cancer cells in vitro thus supporting the potential use of this strategy as means to target metastatic prostate cancers.

[Therapeutic strategies. Evolution and current status of the European Guidelines on Cardiovascular disease prevention].

Science.gov (United States)

Guijarro, Carlos; García-Díaz, Juan de Dios

2013-01-01

The European Guidelines on Dyslipidaemias (2011) and Cardiovascular Prevention (2012) have incorporated important changes. Firstly, it highlights the identification of a group of "very high risk" patients: patients with atherosclerotic disease in any vascular area, diabetes with associated risk factors, advanced chronic renal failure, or a SCORE estimate >10%. Patients with diabetes and no other risk factors, moderate renal failure, severe hypertension, genetic dyslipidaemias, or a SCORE estimate 5-10%, are considered as "high risk". The HDL cholesterol and triglycerides levels are considered as modulators of risks, but not therapeutic objectives per se. The therapeutic objectives are set at LDL cholesterol levels < 70 mg/dl (or at least a reduction of at least 50%) for patients at very high risk, and an LDL < 100 mg/dl for high risk patients. As well as the changes in lifestyle, pharmacological treatment with statins is the focal point of lipid lowering treatments. Other pharmacological options may be considered if the treatment with the maximum tolerable doses of statins do not achieve the therapeutic objectives. Copyright © 2013 Elsevier España, S.L. y SEA. All rights reserved.

The Mammotome biopsy system is an effective treatment strategy for breast abscess.

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Wang, Keren; Ye, Yuqin; Sun, Guang; Xu, Zheli

2013-01-01

Although most breast abscesses can be treated with the current first-line treatment of antibiotics by needle aspiration, the therapeutic duration is lengthy and recurrences often occur. Therefore, we aimed to investigate the clinical efficacy of the Mammotome biopsy system (Johnson & Johnson Corp., New Brunswick, NJ) in a cohort of patients with breast abscesses. Forty lactating and 30 nonlactating breast abscess patients with unfavorable outcomes with antibiotic treatment and/or needle aspiration failure were recruited and treated with the Mammotome biopsy system. Skin inflammation of all patients disappeared within 6 days with no recurrence. The clinical outcomes in patients with an abscess size ≤ 3.5 cm was significantly better than those with an abscess size >3.5 cm (P = .025). The Mammotome biopsy system, an effective treatment strategy that is minimally invasive and less damaging, in combination with appropriate antibiotic therapy can be used safely as the first-line approach to breast abscess management. Copyright © 2013 Elsevier Inc. All rights reserved.

Cellular and molecular mechanisms of chronic rhinosinusitis and potential therapeutic strategies: review on cytokines, nuclear factor kappa B and transforming growth factor beta.

Science.gov (United States)

Phan, N T; Cabot, P J; Wallwork, B D; Cervin, A U; Panizza, B J

2015-07-01

Chronic rhinosinusitis is characterised by persistent inflammation of the sinonasal mucosa. Multiple pathophysiological mechanisms are likely to exist. Previous research has focused predominantly on T-helper type cytokines to highlight the inflammatory mechanisms. However, proteins such as nuclear factor kappa B and transforming growth factor beta are increasingly recognised to have important roles in sinonasal inflammation and tissue remodelling. This review article explores the roles of T-helper type cytokines, nuclear factor kappa B and transforming growth factor beta in the pathophysiological mechanisms of chronic rhinosinusitis. An understanding of these mechanisms will allow for better identification and classification of chronic rhinosinusitis endotypes, and, ultimately, improved therapeutic strategies.

Determinants of immunogenic response to protein therapeutics.

Science.gov (United States)

Singh, Satish K; Cousens, Leslie P; Alvarez, David; Mahajan, Pramod B

2012-09-01

Protein therapeutics occupy a very significant position in the biopharmaceutical market. In addition to the preclinical, clinical and post marketing challenges common to other drugs, unwanted immunogenicity is known to affect efficacy and/or safety of most biotherapeutics. A standard set of immunogenicity risk factors are routinely used to inform monitoring strategies in clinical studies. A number of in-silico, in vivo and in vitro approaches have also been employed to predict immunogenicity of biotherapeutics, but with limited success. Emerging data also indicates the role of immune tolerance mechanisms and impact of several product-related factors on modulating host immune responses. Thus, a comprehensive discussion of the impact of innate and adaptive mechanisms and molecules involved in induction of host immune responses on immunogenicity of protein therapeutics is needed. A detailed understanding of these issues is essential in order to fully exploit the therapeutic potential of this class of drugs. This Roundtable Session was designed to provide a common platform for discussing basic immunobiological and pharmacological issues related to the role of biotherapeutic-associated risk factors, as well as host immune system in immunogenicity against protein therapeutics. The session included overview presentations from three speakers, followed by a panel discussion with audience participation. Copyright © 2012. Published by Elsevier Ltd.. All rights reserved.

Safety Case for Safe-store

International Nuclear Information System (INIS)

Woollam, Paul B.

2002-01-01

Magnox Electric plc (Magnox), a wholly owned subsidiary of BNFL, owns 26 gas-cooled, graphite-moderated units on 11 sites in the UK. Eight units have been permanently shutdown and the remainder will shut this decade in a currently declared closure programme. The first of these reactors went to power in 1952 and the fleet has generated typically 9% of the UK's electricity during the last five decades. In accordance with UK Government policy, BNFL aims for a systematic and progressive reduction in hazards on its decommissioning sites. The end-point of the decommissioning process is that the reactors will be dismantled and their sites de-licensed. This will be done through minimising both the risks to the public, workers and the environment and also the lifetime cost, consistent with world class safety. There will be passive safe storage during deferment periods and it is BNFL's clear intent that the reactors will not be Safe-stored indefinitely. The main hazard associated with any decommissioned nuclear site is the spent fuel. Hence the reactors will be de-fuelled as soon as practicable after shutdown. After this work is complete, Cs-137 contaminated plant (e.g. fuel pools, effluent plant, and drains) will be dismantled when it is no longer needed. All other plant and buildings will also be dismantled when they are no longer needed, except for the reactor buildings which will be put into passive safe storage. Co-60 contaminated plant, such as steam generators, will be dismantled with the reactors. The reactors will be dismantled in a sequenced programme, with a notional start time around 100 years from shutdown. Magnox Electric is ensuring that the reactors and primary circuits on all its sites are well characterised. We have carried out a detailed, peer reviewed hazard identification on the lead site from which we have generated a rolling 25-year basic safety case. We have then searched for cliff edge effects and possible long-term changes to generate the 100-year

The safe home project.

Science.gov (United States)

Arphorn, Sara; Jiraniratisai, Sopaphan; Rungtakul, Rungsri; Phutta, Nikom

2011-12-01

The Thai Health Promotion Foundation supported the Improvement of Quality of Life of Informal Workers project in Ban Luang District, Amphur Photaram, Ratchaburi Province. There were many informal workers in Ban Luang District. Sweet-crispy fish producers in Ban Luang were the largest group among the sweet-crispy fish producers in Thailand. This project was aimed at improving living and working conditions of informal workers, with a focus on the sweet-crispy fish group. Good practices of improved living and working conditions were used to help informal workers build safe, healthy and productive work environments. These informal workers often worked in substandard conditions and were exposed to various hazards in the working area. These hazards included risk of exposure to hot work environment, ergonomics-related injuries, chemical hazards, electrical hazards etc. Ergonomics problems were commonly in the sweet-crispy fish group. Unnatural postures such as prolonged sitting were performed dominantly. One hundred and fifty informal workers participated in this project. Occupational health volunteers were selected to encourage occupational health and safety in four groups of informal workers in 2009. The occupational health volunteers trained in 2008 were farmers, beauty salon workers and doll makers. The occupational health and safety knowledge is extended to a new informal worker group: sweet-crispy fish producer, in 2009. The occupational health and safety training for sweet-crispy fish group is conducted by occupational health volunteers. The occupational health volunteers increased their skills and knowledge assist in to make safe home and safe community through participatory oriented training. The improvement of living and working condition is conducted by using a modified WISH, Work Improvement for Safe Home, checklist. The plans of improvement were recorded. The informal workers showed improvement mostly on material handling and storage. The safe uses and safe

Conclusion: imaging in strategy of endocrine diagnosis and therapeutics

International Nuclear Information System (INIS)

Mornex, R.

1995-01-01

Images in medicine have to help the doctor in a diagnostic or therapeutic aim. The choice must be made in function of pathology or organ as known (it is not necessary to ask for a computed tomography where we know that only an echography can give the answer to the question we ask ), the criteria must stay the best performance for the cheapest price, but the quality of interpretation is a more important thing. It is important to avoid a lot of examinations which do not give better informations but are heavy to endure for the patients. In conclusion, the aim of this kind of proceedings is to assure to the patients who come confidently to us, the best service at the less constraints price without forgetting that a conclusion depends on a given methodological situation and reminding of beside machines we have not to forget the men

Aware, motivated and striving for a 'safe tan': an exploratory mixed-method study of sun-protection during holidays.

Science.gov (United States)

Rodrigues, Angela M; Sniehotta, Falko F; Birch-Machin, Mark A; Araujo-Soares, Vera

2017-01-01

Background: This article presents an exploratory study, aiming to explore the correspondence between knowledge, motivation and sun-protection practices during holidays. Methods: Seventeen participants aged 21-62 years old, recruited from community settings took part in individual face-to-face semi-structured interviews, completed sun sensitivity questions and an objective assessment of sunscreen use. Holidaymakers' knowledge about sun-safe messages, intentions and perceptions of barriers and facilitators for sun-protection were assessed. Qualitative data were analysed using thematic analysis and integrated with quantitative data, using a pragmatic theory-informed approach to synthesise the findings. Results: Participants were well informed about sun-safe messages, highly motivated to protect themselves from solar UV radiation (UVR) and they perceived themselves as well protected. However, they did not seem to use effective protective practices. Sunscreen was the preferred method of sun-protection, but most participants used considerably less than the recommended amount and significantly overestimated the amount of time they could be safely exposed. Seeking shade was the least used method of sun-protection and covering-up strategies were mostly implemented as a partial protection (i.e. hats or sunglasses). The desire to reach an optimal balance between getting a tan and using sun-protection to avoid sunburns was preeminent. Several additional barriers and facilitators for sun-protection were identified. Conclusions: Holidaymakers might have a false sense of security when it comes to sun-exposure. They are aware of the need to protect from solar UVR, but the motive for a safe tan, the overreliance on sunscreen, the overestimation of the safe sun-exposure time for their skin type and the insufficient application of sunscreen leaves holidaymakers motivated to protect their skin at significant risk of overexposure, sunburn and skin cancer. Public health messages need to

The impact of state fire safe cigarette policies on fire fatalities, injuries, and incidents.

Science.gov (United States)

Folz, David H; Shults, Chris

Cigarettes are a leading cause of civilian deaths in home fires. Over the last decade, state fire service leaders and allied interest groups succeeded in persuading state lawmakers to require manufacturers to sell only low-ignition strength or "fire safe" cigarettes as a strategy to reduce these fatalities and the injuries and losses that stem from them. This article examines whether the states' fire safe cigarette laws actually helped to save lives, prevent injuries, and reduce the incidence of home fires ignited by cigarettes left unattended by smokers. Controlling for the effects of key demographic, social, economic, and housing variables, this study finds that the states' fire-safe cigarette policies had significant impacts on reducing the rate of smoking-related civilian fire deaths and the incidence of fires started by tobacco products. The findings also suggest that the states' fire safe cigarette policies may have helped to reduce the rate of smoking-related fire injuries. The study shows that collective actions by leaders in the fire service across the states can result in meaningful policy change that protects lives and advances public safety even when a political consensus for action is absent at the national level.

Development of a compassion-focused and contextual behavioural environment and validation of the Therapeutic Environment Scales (TESS).

Science.gov (United States)

Veale, David; Miles, Sarah; Naismith, Iona; Pieta, Maria; Gilbert, Paul

2016-02-01

Aims and method The aims of the study were to develop a scale sensitive enough to measure the interpersonal processes within a therapeutic environment, and to explore whether the new scale was sensitive enough to detect differences between settings, including a community based on compassionate mind and contextual behaviourism. The Therapeutic Environment Scales (TESS) were validated with 81 participants in three different settings: a specialist service for anxiety disorders, a specialist in-patient ward and a psychodynamic therapeutic community. Results TESS was found to be reliable and valid. Significant differences were seen between the services on the dimensions of compassion, belongingness, feeling safe, positive reinforcement of members' acts of courage, extinction and accommodation of unhelpful behaviours, inconsistency and high expressed emotion. These processes were over time associated with improved outcomes on a specialist service for anxiety disorders. Clinical implications The TESS offers a first step in exploring important interpersonal relationships in therapeutic environments and communities. An environment based on a compassionate mind and contextual behaviourism offers promise for the running of a therapeutic community.

Single Enteral Loading Dose of Phenobarbital for Achieving Its Therapeutic Serum Levels in Neonates

Science.gov (United States)

Turhan, Ali H.; Atici, Aytug; Okuyaz, Cetin; Uysal, Sercan

2010-01-01

Aim To investigate whether therapeutic serum drug levels may be achieved with a single enteral loading dose of phenobarbital. Methods The study was performed at the Mersin University Hospital in Turkey between April 2004 and August 2006, and included 29 newborn babies with seizure. After the acute treatment of the seizure with midazolam at a dose of 0.1 mg/kg, phenobarbital was administered by orogastric route at a loading dose of 20 mg/kg. Serum phenobarbital concentrations were measured at 0.5, 3, 6, and 12 hours after the loading. Serum phenobarbital levels between 10-30 μg/mL were considered as the therapeutic range. Results The serum phenobarbital levels reached therapeutic values in 9 (31%), 19 (66%), 21 (72%), and 23 (79%) patients at 0.5, 3, 6, and 12 hours after loading, respectively, while they did not reach therapeutic values in 6 patients (21%) after 12 hours. Four of the patients in whom there was no increase in serum phenobarbital levels had hypoxic-ischemic encephalopathy. Conclusion Enteral loading of phenobarbital can achieve therapeutic serum levels in the large majority of newborn babies with seizure and may be safely used in babies with the intact gastrointestinal tract. PMID:20564764

Clarification of Safe Delivery by Iranian Experts Based on Clinical Governance: A Qualitative Study

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Forozun Olfati

2015-10-01

Full Text Available Objective:To clarify the principles of a safe delivery based on Clinical Governance Criteria, as recommended by the pertinent experts.Materials and methods:The current study was part of a qualitative research conducted by content analysis method in 2013 and purposive sampling, performing 24 in-depth interviews based on semi-structured questions and analyzed using thematic content analysis. The participants in this research included midwives, obstetricians, managers, and hospital doctors. The data were under continuous consideration and comparative analysis in order to achieve data saturation.Results:The main concepts derived from interpretations of the pertinent experts include: Patient & Public involvement; Risk Management; Education; Clinical efficiency; Clinical audit; Personnel & Management.Conclusion:In a safe delivery, there is a vicious cycle of causes the elimination of which is only possible through benchmarking patterns that attend to most aspects of a safe delivery.Changes to services require utilization of appropriate change management strategies.

Nuclear data for the production of therapeutic radionuclides. Summary report of first research coordination meeting

International Nuclear Information System (INIS)

Sublet, J.-Ch.; Paviotti-Corcuera, R.

2003-06-01

Presentations, discussions and conclusions from the First Co-ordination Meeting on Nuclear Data for the Production of Therapeutic Radionuclides are summarised in this report. The main purpose of the meeting was to discuss scientific and technical matters related to the subject and to co-ordinate related tasks. Programmes of work were agreed and assigned, and deadlines were set. Participants emphasized the importance of the completeness and accuracy of the resulting nuclear data for the production of these radionuclides to appropriate specific activities and purity along with the relevant decay data. The recommended data from this Coordinated Research Project should meet the requirements for the safe and efficacious application of therapeutic treatments in nuclear medicine. (author)

Complex interactions between phytochemicals. The multi-target therapeutic concept of phytotherapy.

Science.gov (United States)

Efferth, Thomas; Koch, Egon

2011-01-01

Drugs derived from natural resources represent a significant segment of the pharmaceutical market as compared to randomly synthesized compounds. It is a goal of drug development programs to design selective ligands that act on single disease targets to obtain highly effective and safe drugs with low side effects. Although this strategy was successful for many new therapies, there is a marked decline in the number of new drugs introduced into clinical practice over the past decades. One reason for this failure may be due to the fact that the pathogenesis of many diseases is rather multi-factorial in nature and not due to a single cause. Phytotherapy, whose therapeutic efficacy is based on the combined action of a mixture of constituents, offers new treatment opportunities. Because of their biological defence function, plant secondary metabolites act by targeting and disrupting the cell membrane, by binding and inhibiting specific proteins or they adhere to or intercalate into RNA or DNA. Phytotherapeutics may exhibit pharmacological effects by the synergistic or antagonistic interaction of many phytochemicals. Mechanistic reasons for interactions are bioavailability, interference with cellular transport processes, activation of pro-drugs or deactivation of active compounds to inactive metabolites, action of synergistic partners at different points of the same signalling cascade (multi-target effects) or inhibition of binding to target proteins. "-Omics" technologies and systems biology may facilitate unravelling synergistic effects of herbal mixtures.

SAFE/SNAP application to shipboard security

International Nuclear Information System (INIS)

Grady, L.M.; Walker, J.L.; Polito, J.

1981-11-01

An application of the combined Safeguards Automated Facility Evaluation/Safeguards Network Analysis Procedure (SAFE/SNAP) modeling technique to a physical protection system (PPS) aboard a generic ship is described. This application was performed as an example of how the SAFE and SNAP techniques could be used. Estimates of probability of interruption and neutralization for the example shipboard PPS are provided by SAFE as well as an adversary scenario, which serves as input to SNAP. This adversary scenario is analyzed by SNAP through four cases which incorporate increasingly detailed security force tactics. Comparisons between the results of the SAFE and SNAP analyses are made and conclusions drawn on the validity of each technique. Feedback from SNAP to SAFE is described, and recommendations for upgrading the ship based on the results of the SAFE/SNAP application are also discussed

Review of knee arthroscopy performed under local anesthesia

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Law Billy

2009-01-01

Full Text Available Abstract Local anesthesia for knee arthroscopy is a well documented procedure with diagnostic and therapeutic role. Numerous therapeutic procedures including partial menisectomy, meniscus repair, abrasion chondroplasy, synovectomy, loose body removal can be performed safely and comfortably. Appropriate case selection, anesthetic strategy and technical expertise are the key to smooth and successful surgery.

Novel therapeutic strategies in human malignancy: combining immunotherapy and oncolytic virotherapy

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Sampath P

2015-06-01

Full Text Available Padma Sampath, Steve H Thorne Department of Surgery, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, USA Abstract: Results from randomized clinical trials over the last several years have finally begun to demonstrate the potential of oncolytic viral therapies to treat a variety of cancers. One reason for these successes has been the realization that this platform is most effective when considered primarily as an immunotherapy. Cancer immunotherapy has also made dramatic strides recently with antibodies capable of blocking immune checkpoint inhibitors and adoptive T-cell therapies, notably CAR T-cells, leading a panel of novel and highly clinically effective therapies. It is clear therefore that an understanding of how and when these complementary approaches can most effectively be combined offers the real hope of moving beyond simply treating the disease and toward starting to talk about curative therapies. In this review we discuss approaches to combining these therapeutic platforms, both through engineering the viral vectors to more beneficially interact with the host immune response during therapy, as well as through the direct combinations of different therapeutics. This primarily, but not exclusively focuses on strains of oncolytic vaccinia virus. Some of the results reported to date, primarily in pre-clinical models but also in early clinical trials, are dramatic and hold great promise for the future development of similar therapies and their translation into cancer therapies. Keywords: oncolytic virus, CAR T-cell, adoptive cell therapy, immune checkpoint inhibitor 

[Osteoarthritis and patient therapeutic education, learning to move more].

Science.gov (United States)

Coudeyre, Emmanuel; Gay, Chloé; Bareyre, Loïc; Coste, Nicolas; Chérillat, Marie-Sophie

2016-01-01

As part of the prevention strategies offered to people with osteoarthritis, therapeutic education plays a key role. It seeks to help the patient become a player in their own care and focuses in particular on the factors influencing regular participation in suitable physical activity. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Out-of-Hospital therapeutic hypothermia. A Systematic Review

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María Nélida Conejo Pérez

2012-07-01

Full Text Available Recent studies have demonstrated therapeutic mild hypothermia improves neurological outcome of patients after suffering an out-of-hospital cardiac arrest.Other studies in animals suggest that the sooner hypothermia is started after return of spontaneous circulation, the lower neurological symptoms are suffered by patients.The aim of this work is to know the efficiency of the therapeutic moderated hipotermia after the cardiopulmonar resuscitation realized extra hospitable.Methods: We made a literature search in Medline (Pubmed, Cinahl, Cuiden, Cochrane Library and the Joanna Briggs Institute, combining mesh and free terms; and searched in the journals Circulation, Resuscitation and Emergency Medicine Journal manually last year. We selected systematic reviews and randomized and nonrandomized clinical trials which had contrasted in-hospital and out-of-hospital TMH with over 18 years patients.Results: Only 5 articles met the inclusion criteria of the 35 selected: four randomized clinical trials and one nonrandomized. They were then subjected to a critical methodological evaluation (CASPe and statistic evaluation (IDIPaz.Conclusions: Pre hospital TMH is an effective and safe technique in comatose patients after being resuscitated from cardiac arrest, improving the neurological status at hospital discharge.

Understanding risk evaluation and mitigation strategies in organ transplantation.

Science.gov (United States)

Gabardi, Steven

2011-07-01

The United States Food and Drug Administration (FDA) Amendments Act of 2007 mandated that Risk Evaluation and Mitigation Strategies (REMS) be required of manufacturers. These REMS are strategies implemented to manage known or potential risks associated with drugs and to ensure ongoing pharmacovigilance throughout the life of a pharmaceutical product, including once the product becomes available as generic. The elements of an individual REMS program consist of three levels: medication guide or patient package insert, communication plan, and elements to assure safe use (ETASU). A medication guide or patient package insert is used to help prevent serious adverse events, aid in patient decision making, and enhance drug adherence. Communication plans are used to educate health care providers and to encourage their compliance with REMS. The ETASU is a restrictive process that is implemented when it is deemed necessary to ensure that patients have safe access to products with known serious risks that would otherwise be unavailable. To review the components of REMS and specifically assess their impact on health care providers practicing within the organ transplantation arena, a literature search of the MEDLINE database (January 2007-December 2010) was performed, and published materials from the FDA and its Web site were also reviewed. In transplantation, REMS programs exist for both everolimus (medication guide and communication plan) and sirolimus (medication guide). The FDA has stated that all mycophenolic acid derivatives will be subject to a proposed REMS that has not yet been approved; however, both branded mycophenolic acid agents already have approved medication guides. The REMS are a permanent fixture in the development and marketing of pharmaceutical agents, and their further implementation in solid organ transplantation is inevitable. Transplantation providers should take a proactive role in patient education and implementation of REMS within the therapeutic area

Mesenchymal Stem Cells as New Therapeutic Agents for the Treatment of Primary Biliary Cholangitis

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Aleksandar Arsenijevic

2017-01-01

Full Text Available Primary biliary cholangitis (PBC is a chronic autoimmune cholestatic liver disease characterized by the progressive destruction of small- and medium-sized intrahepatic bile ducts with resultant cholestasis and progressive fibrosis. Ursodeoxycholic acid and obethicholic acid are the only agents approved by the US Food and Drug Administration (FDA for the treatment of PBC. However, for patients with advanced, end-stage PBC, liver transplantation is still the most effective treatment. Accordingly, the alternative approaches, such as mesenchymal stem cell (MSC transplantation, have been suggested as an effective alternative therapy for these patients. Due to their immunomodulatory characteristics, MSCs are considered as promising therapeutic agents for the therapy of autoimmune liver diseases, including PBC. In this review, we have summarized the therapeutic potential of MSCs for the treatment of these diseases, emphasizing molecular and cellular mechanisms responsible for MSC-based effects in an animal model of PBC and therapeutic potential observed in recently conducted clinical trials. We have also presented several outstanding problems including safety issues regarding unwanted differentiation of transplanted MSCs which limit their therapeutic use. Efficient and safe MSC-based therapy for PBC remains a challenging issue that requires continuous cooperation between clinicians, researchers, and patients.

Summary report of the consultants' meeting on nuclear data for production of therapeutic radioisotopes

International Nuclear Information System (INIS)

Haight, R.C.; Paviotti-Corcuera, R.

2002-04-01

This report summarizes the presentations, recommendations and conclusions of the Consultants' Meeting on Nuclear Data for Production of Therapeutic Radioisotopes. The purpose of this meeting was to discuss scientific and technical matters related to the subject and to advise the IAEA Nuclear Data Section (NDS) on the need and possible formation of a Coordinated Research Programme (CRP). Accurate and complete knowledge of nuclear data are essential for the production of radionuclides for therapy to achieve the specific activity and purity required for efficient and safe clinical application. The Consultants recommended updating and completing the data for production of radionuclides that are recognized to be important in therapy. In addition, the consultants recommend investigating other radionuclides that have a potential interest and for which there exists a medical rationale for therapeutic use. To date no serious effort has been devoted to evaluation of nuclear data for the reactor and accelerator production of therapeutic radionuclides. The IAEA is in the unique and privileged position to address this important public health related problem. Therefore, the consultants highly recommend the formation of a CRP with the title: 'Nuclear Data for Production of Therapeutic Radionuclides.' (author)

Chernobyl new safe confinement

International Nuclear Information System (INIS)

Dodd, L.

2011-01-01

The author presents the new safe confinement that will be commissioned at Unit 4 of the Chernobyl NPP in 2015. The confinement will ensure that Chernobyl Unit 4 will be placed in an environmentally safe condition for at least next 100 years. The article highlights the current work status, future perspectives and the feasibility of confinement concept [ru

Asymptotically Safe Dark Matter

DEFF Research Database (Denmark)

Sannino, Francesco; Shoemaker, Ian M.

2015-01-01

We introduce a new paradigm for dark matter (DM) interactions in which the interaction strength is asymptotically safe. In models of this type, the coupling strength is small at low energies but increases at higher energies, and asymptotically approaches a finite constant value. The resulting...... searches are the primary ways to constrain or discover asymptotically safe dark matter....

Photochemical Internalization of Peptide Antigens Provides a Novel Strategy to Realize Therapeutic Cancer Vaccination

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Markus Haug

2018-04-01

Full Text Available Effective priming and activation of tumor-specific CD8+ cytotoxic T lymphocytes (CTLs is crucial for realizing the potential of therapeutic cancer vaccination. This requires cytosolic antigens that feed into the MHC class I presentation pathway, which is not efficiently achieved with most current vaccination technologies. Photochemical internalization (PCI provides an emerging technology to route endocytosed material to the cytosol of cells, based on light-induced disruption of endosomal membranes using a photosensitizing compound. Here, we investigated the potential of PCI as a novel, minimally invasive, and well-tolerated vaccination technology to induce priming of cancer-specific CTL responses to peptide antigens. We show that PCI effectively promotes delivery of peptide antigens to the cytosol of antigen-presenting cells (APCs in vitro. This resulted in a 30-fold increase in MHC class I/peptide complex formation and surface presentation, and a subsequent 30- to 100-fold more efficient activation of antigen-specific CTLs compared to using the peptide alone. The effect was found to be highly dependent on the dose of the PCI treatment, where optimal doses promoted maturation of immature dendritic cells, thus also providing an adjuvant effect. The effect of PCI was confirmed in vivo by the successful induction of antigen-specific CTL responses to cancer antigens in C57BL/6 mice following intradermal peptide vaccination using PCI technology. We thus show new and strong evidence that PCI technology holds great potential as a novel strategy for improving the outcome of peptide vaccines aimed at triggering cancer-specific CD8+ CTL responses.

Molecular Targets in Alzheimer’s Disease: From Pathogenesis to Therapeutics

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Xuan Cheng

2015-01-01

Full Text Available Alzheimer’s disease (AD is characterized by progressive cognitive decline usually beginning with impairment in the ability to form recent memories. Nonavailability of definitive therapeutic strategy urges developing pharmacological targets based on cell signaling pathways. A great revival of interest in nutraceuticals and adjuvant therapy has been put forward. Tea polyphenols for their multiple health benefits have also attracted the attention of researchers. Tea catechins showed enough potentiality to be used in future as therapeutic targets to provide neuroprotection against AD. This review attempts to present a concise map of different receptor signaling pathways associated with AD with an insight into drug designing based on the proposed signaling pathways, molecular mechanistic details of AD pathogenesis, and a scientific rationale for using tea polyphenols as proposed therapeutic agents in AD.

[Pathogenetic and therapeutic aspects of secondary anorexia].

Science.gov (United States)

Laviano, A; Cascino, A; Muscaritoli, M; Rossi Fanelli, F

2000-01-01

Anorexia is an often underrated symptom in the clinical management of patients suffering from chronic diseases. Moreover, the anorexia accompanying chronic diseases (secondary anorexia) is often confused with anorexia nervosa, a typically neuropsychiatric disorder involving completely different pathogenic mechanisms and therapeutic strategies. Secondary anorexia is one of the main factors responsible for the development of malnutrition, which in turn negatively affects patient morbidity and mortality. Different mechanisms have been proposed to explain the pathogenesis of secondary anorexia. However, consistent experimental and clinical evidence seems to point to hypothalamic serotonergic system hyperactivity as a preeminent cause; this hyperactivity appears to be triggered by enhanced brain availability of tryptophan, the aminoacid precursor of serotonin. The hyperactive hypothalamic serotonergic system might also represent the final effector where different regulatory and modulating pathways, including cytokines, converge. The involvement of tryptophan and the hypothalamic serotonergic system is further supported by the effectiveness of a therapeutic strategy, based on the inhibition of tryptophan entry into the brain, in increasing the food intake of anorectic patients. Although these results represent an encouraging approach to the treatment of secondary anorexia, with possible beneficial effects on the nutritional status of patients, they need to be validated in larger trials.

Novel strategies in glioblastoma surgery aim at safe, supra-maximum resection in conjunction with local therapies.

Science.gov (United States)

Wolbers, John G

2014-01-01

The biggest challenge in neuro-oncology is the treatment of glioblastoma, which exhibits poor prognosis and is increasing in incidence in an increasing aging population. Diverse treatment strategies aim at maximum cytoreduction and ensuring good quality of life. We discuss multimodal neuronavigation, supra-maximum tumor resection, and the postoperative treatment gap. Multimodal neuronavigation allows the integration of preoperative anatomic and functional data with intraoperative information. This approach includes functional magnetic resonance imaging (MRI) and diffusion tensor imaging in preplanning and ultrasound, computed tomography (CT), MRI and direct (sub)cortical stimulation during surgery. The practice of awake craniotomy decreases postoperative neurologic deficits, and an extensive supra-maximum resection appears to be feasible, even in eloquent areas of the brain. Intraoperative MRI- and fluorescence-guided surgery assist in achieving this goal of supra-maximum resection and have been the subject of an increasing number of reports. Photodynamic therapy and local chemotherapy are properly positioned to bridge the gap between surgery and chemoradiotherapy. The photosensitizer used in fluorescence-guided surgery persists in the remaining peripheral tumor extensions. Additionally, blinded randomized clinical trials showed firm evidence of extra cytoreduction by local chemotherapy in the tumor cavity. The cutting-edge promise is gene therapy although both the delivery and efficacy of the numerous transgenes remain under investigation. Issues such as the choice of (cell) vector, the choice of therapeutic transgene, the optimal route of administration, and biosafety need to be addressed in a systematic way. In this selective review, we present various evidence and promises to improve survival of glioblastoma patients by supra-maximum cytoreduction via local procedures while minimizing the risk of new neurologic deficit.

Liver cell-targeted delivery of therapeutic molecules.

Science.gov (United States)

Kang, Jeong-Hun; Toita, Riki; Murata, Masaharu

2016-01-01

The liver is the largest internal organ in mammals and is involved in metabolism, detoxification, synthesis of proteins and lipids, secretion of cytokines and growth factors and immune/inflammatory responses. Hepatitis, alcoholic or non-alcoholic liver disease, hepatocellular carcinoma, hepatic veno-occlusive disease, and liver fibrosis and cirrhosis are the most common liver diseases. Safe and efficient delivery of therapeutic molecules (drugs, genes or proteins) into the liver is very important to increase the clinical efficacy of these molecules and to reduce their side effects in other organs. Several liver cell-targeted delivery systems have been developed and tested in vivo or ex vivo/in vitro. In this review, we discuss the literature concerning liver cell-targeted delivery systems, with a particular emphasis on the results of in vivo studies.

Human Mesenchymal Stem Cell Transfusion Is Safe and Improves Liver Function in Acute-on-Chronic Liver Failure Patients

OpenAIRE

Shi, Ming; Zhang, Zheng; Xu, Ruonan; Lin, Hu; Fu, Junliang; Zou, Zhengsheng; Zhang, Aimin; Shi, Jianfei; Chen, Liming; Lv, Sa; He, Weiping; Geng, Hua; Jin, Lei; Liu, Zhenwen; Wang, Fu-Sheng

2012-01-01

This study assessed the safety and initial efficacy of umbilical cord-derived mesenchymal stem cell (UC-MSC) transfusions for acute-on-chronic liver failure (ACLF) patients associated with hepatitis B virus (HBV) infection. No significant side effects were observed, and the UC-MSC transfusions significantly increased the survival rates in ACLF patients. It was found that UC-MSC transfusions are safe in the clinic and may serve as a novel therapeutic approach for HBV-associated ACLF patients.

The Potential for Emerging Microbiome-Mediated Therapeutics in Asthma.

Science.gov (United States)

Ozturk, Ayse Bilge; Turturice, Benjamin Arthur; Perkins, David L; Finn, Patricia W

2017-08-10

In terms of immune regulating functions, analysis of the microbiome has led the development of therapeutic strategies that may be applicable to asthma management. This review summarizes the current literature on the gut and lung microbiota in asthma pathogenesis with a focus on the roles of innate molecules and new microbiome-mediated therapeutics. Recent clinical and basic studies to date have identified several possible therapeutics that can target innate immunity and the microbiota in asthma. Some of these drugs have shown beneficial effects in the treatment of certain asthma phenotypes and for protection against asthma during early life. Current clinical evidence does not support the use of these therapies for effective treatment of asthma. The integration of the data regarding microbiota with technologic advances, such as next generation sequencing and omics offers promise. Combining comprehensive bioinformatics, new molecules and approaches may shape future asthma treatment.

75 FR 1734 - Children’s Online Privacy Protection Rule Safe Harbor Proposed Self-Regulatory Guidelines; i-SAFE...

Science.gov (United States)

2010-01-13

... Proposed Self-Regulatory Guidelines; i-SAFE, Inc. Application for Safe Harbor AGENCY: Federal Trade... for public comment concerning proposed self-regulatory guidelines submitted by i-SAFE, Inc. under the... approval self-regulatory guidelines that would implement the Rule's protections.\\3\\ \\1\\ 64 FR 59888 (1999...

Aware, motivated and striving for a ‘safe tan’: an exploratory mixed-method study of sun-protection during holidays

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Rodrigues, Angela M.; Sniehotta, Falko F.; Birch-Machin, Mark A.; Araujo-Soares, Vera

2017-01-01

ABSTRACT Background: This article presents an exploratory study, aiming to explore the correspondence between knowledge, motivation and sun-protection practices during holidays. Methods: Seventeen participants aged 21–62 years old, recruited from community settings took part in individual face-to-face semi-structured interviews, completed sun sensitivity questions and an objective assessment of sunscreen use. Holidaymakers’ knowledge about sun-safe messages, intentions and perceptions of barriers and facilitators for sun-protection were assessed. Qualitative data were analysed using thematic analysis and integrated with quantitative data, using a pragmatic theory-informed approach to synthesise the findings. Results: Participants were well informed about sun-safe messages, highly motivated to protect themselves from solar UV radiation (UVR) and they perceived themselves as well protected. However, they did not seem to use effective protective practices. Sunscreen was the preferred method of sun-protection, but most participants used considerably less than the recommended amount and significantly overestimated the amount of time they could be safely exposed. Seeking shade was the least used method of sun-protection and covering-up strategies were mostly implemented as a partial protection (i.e. hats or sunglasses). The desire to reach an optimal balance between getting a tan and using sun-protection to avoid sunburns was preeminent. Several additional barriers and facilitators for sun-protection were identified. Conclusions: Holidaymakers might have a false sense of security when it comes to sun-exposure. They are aware of the need to protect from solar UVR, but the motive for a safe tan, the overreliance on sunscreen, the overestimation of the safe sun-exposure time for their skin type and the insufficient application of sunscreen leaves holidaymakers motivated to protect their skin at significant risk of overexposure, sunburn and skin cancer. Public health

Safeness of radiological machinery

International Nuclear Information System (INIS)

Yokoyama, Shun

1979-01-01

The human factors affecting the safeness of radiological machinery, which are often very big and complicated machines, are described from the stand point of handling. 20 to 50% of the troubles on equipments seem to be caused by men. This percentage will become even higher in highly developed equipments. Human factors have a great influence on the safeness of radiological equipments. As the human factors, there are sensory factors and knowledge factors as well as psychological factors, and the combination of these factors causes mishandling and danger. Medical services at present are divided in various areas, and consist of the teamwork of the people in various professions. Good human relationship, education and control are highly required to secure the safeness. (Kobatake, H.)

Failure of Chemotherapy in Hepatocellular Carcinoma Due to Impaired and Dysregulated Primary Liver Drug Metabolizing Enzymes and Drug Transport Proteins: What to Do?

Science.gov (United States)

Ul Islam, Salman; Ahmed, Muhammad Bilal; Shehzad, Adeeb; Ul-Islam, Mazhar; Lee, Young Sup

2018-05-28

Most of the drugs are metabolized in the liver by the action of drug metabolizing enzymes. In hepatocellular carcinoma (HCC), primary drug metabolizing enzymes are severely dysregulated, leading to failure of chemotherapy. Sorafenib is the only standard systemic drug available, but it still presents certain limitations, and much effort is required to understand who is responsive and who is refractory to the drug. Preventive and therapeutic approaches other than systemic chemotherapy include vaccination, chemoprevention, liver transplantation, surgical resection, and locoregional therapies. This review details the dysregulation of primary drug metabolizing enzymes and drug transport proteins of the liver in HCC and their influence on chemotherapeutic drugs. Furthermore, it emphasizes the adoption of safe alternative therapeutic strategies to chemotherapy. The future of HCC treatment should emphasize the understanding of resistance mechanisms and the finding of novel, safe, and efficacious therapeutic strategies, which will surely benefit patients affected by advanced HCC. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

The role of internationally educated nurses in a quality, safe workforce.

Science.gov (United States)

D Sherwood, Gwen; Shaffer, Franklin A

2014-01-01

Migration and globalization of the nursing workforce affect source countries and destination countries. Policies and regulations governing the movement of nurses from one country to another safeguard the public by ensuring educational comparability and competence. The global movement of nurses and other health care workers calls for quality and safety competencies that meet standards such as those defined by the Institute of Medicine. This article examines nurse migration and employment of internationally educated nurses (IENs) in the context of supporting and maintaining safe, quality patient care environments. Migration to the United States is featured as an exemplar to consider the following key factors: the impact of nurse migration on the nursing workforce; issues in determining educational comparability of nursing programs between countries; quality and safety concerns in transitioning IENs into the workforce; and strategies for helping IENs transition as safe, qualified members of the nursing workforce in the destination country. Copyright © 2014 Elsevier Inc. All rights reserved.

[Global brain metastases management strategy: a multidisciplinary-based approach].

Science.gov (United States)

Métellus, P; Tallet, A; Dhermain, F; Reyns, N; Carpentier, A; Spano, J-P; Azria, D; Noël, G; Barlési, F; Taillibert, S; Le Rhun, É

2015-02-01

Brain metastases management has evolved over the last fifteen years and may use varying strategies, including more or less aggressive treatments, sometimes combined, leading to an improvement in patient's survival and quality of life. The therapeutic decision is subject to a multidisciplinary analysis, taking into account established prognostic factors including patient's general condition, extracerebral disease status and clinical and radiological presentation of lesions. In this article, we propose a management strategy based on the state of current knowledge and available therapeutic resources. Copyright © 2015. Published by Elsevier SAS.

[Towards new therapeutic paradigms beyond symptom control in the management of inflammatory bowel diseases.

Science.gov (United States)

Festa, Stefano; Zerboni, Giulia; Aratari, Annalisa; Ballanti, Riccardo; Papi, Claudio

2018-01-01

Inflammatory bowel diseases, Crohn's disease and ulcerative colitis are chronic relapsing conditions that may result in progressive bowel damage, high risk of complications, surgery and permanent disability. The conventional therapeutic approach for inflammatory bowel diseases is based mainly on symptom control. Unfortunately, a symptom-based therapeutic approach has little impact on major long-term disease outcomes. In other chronic disabling conditions such as diabetes, hypertension and rheumatoid arthritis, the development of new therapeutic approaches has led to better outcomes. In this context a "treat to target" strategy has been developed. This strategy is based on identification of high-risk patients, regular assessment of disease activity by means of objective measures, adjustment of treatment to reach the pre-defined target. A treat to target approach has recently been proposed for inflammatory bowel disease with the aim at modifying the natural history of the disease. In this review, the evidence and the limitations of the treat to target paradigm in inflammatory bowel disease are analyzed and discussed.

Investigation of the clinical features and therapeutic methods for the ...

African Journals Online (AJOL)

Purpose: To establish if there are different classes of inflammatory lacrimal punctum diseases (ILPDs) and to examine the various strategies by which they can be managed therapeutically. Methods: Two hundred and fifty nine (259) patients with inflammatory punctum lacrimal disease were identified and used as subjects for ...

Administration of BMSCs with muscone in rats with gentamicin-induced AKI improves their therapeutic efficacy.

Directory of Open Access Journals (Sweden)

Pengfei Liu

Full Text Available The therapeutic action of bone marrow-derived mesenchymal stem cells (BMSCs in acute kidney injury (AKI has been reported by several groups. However, recent studies indicated that BMSCs homed to kidney tissues at very low levels after transplantation. The lack of specific homing of exogenously infused cells limited the effective implementation of BMSC-based therapies. In this study, we provided evidence that the administration of BMSCs combined with muscone in rats with gentamicin-induced AKI intravenously, was a feasible strategy to drive BMSCs to damaged tissues and improve the BMSC-based therapeutic effect. The effect of muscone on BMSC bioactivity was analyzed in vitro and in vivo. The results indicated that muscone could promote BMSC migration and proliferation. Some secretory capacity of BMSC still could be improved in some degree. The BMSC-based therapeutic action was ameliorated by promoting the recovery of biochemical variables in urine or blood, as well as the inhibition of cell apoptosis and inflammation. In addition, the up-regulation of CXCR4 and CXCR7 expression in BMSCs could be the possible mechanism of muscone amelioration. Thus, our study indicated that enhancement of BMSCs bioactivities with muscone could increase the BMSC therapeutic potential and further developed a new therapeutic strategy for the treatment of AKI.

An evaluation of the Adults and Children Together (ACT) Against Violence Parents Raising Safe Kids program.

Science.gov (United States)

Portwood, Sharon G; Lambert, Richard G; Abrams, Lyndon P; Nelson, Ellissa Brooks

2011-08-01

This study evaluated the effectiveness of the Adults and Children Together (ACT) Against Violence Parents Raising Safe Kids program, developed by the American Psychological Association in collaboration with the National Association for the Education of Young Children, as an economical primary prevention intervention for child maltreatment. Using an experimental design with random assignment to groups, program impact on participating parents' knowledge, behavior, and attitudes compared to those of a comparison group of parents receiving standard community-based support services was examined. As hypothesized, the ACT Parents Raising Safe Kids program achieved positive results in several areas related to effective parenting, including a reduction in the use of harsh verbal and physical discipline and an increase in nurturing behavior. Positive results were observable both at the conclusion of the ACT program and at three-month follow-up. Results further indicated a positive impact on parent expectations and social support for those parents with the greatest need in these areas. Qualitative data collected through focus groups demonstrated that parents themselves perceived numerous benefits to the ACT program, including assistance in controlling their anger, learning and implementing better parenting and discipline strategies, and recognizing when their child's behavior is developmentally appropriate. Overall, findings suggest that the ACT Parents Raising Safe Kids program is a promising primary prevention strategy that can be implemented across diverse community settings.

Therapeutic enhancement of newly derived bacteriocins against Giardia lamblia.

Science.gov (United States)

Amer, Eglal I; Mossallam, Shereen F; Mahrous, Hoda

2014-11-01

Trials for identifying efficient anti-giardial agents are still ongoing. Nowadays, bacteriocins have attracted the attention as potential antimicrobial compounds. For the first time, the current study evaluated the therapeutic efficacy of bacteriocins derived from newly isolated Egyptian strains of probiotics Lactobacilli; L. acidophilus (P106) and L. plantarum (P164) against Giardia lamblia. Bacteriocins' efficacy was evaluated both in vitro; by growth inhibition and adherence assays, and in vivo; through estimation of parasite density, intestinal histopathological examination and ultrastructural analysis of Giardia trophozoites. In vivo bacteriocins' clinical safety was assessed. In vitro results proved that 50 µg of L. acidophilus bacteriocin induced reduction of the mean Giardia lamblia trophozoites by 58.3 ± 4.04%, while at lower concentrations of 10 and 20 µg of both L. acidophilus and L. plantarum, non significant reduction of the mean parasite density was achieved. In vitro trophozoites adherence was susceptible to the tested bacteriocins at all studied concentrations with variable degrees, while the highest adherence reduction was demonstrated using 50 µg of L acidophilus bacteriocin. In vivo, oral inoculation of 50 µg/mouse L. acidophilus bacteriocin for 5 successive days resulted in a noteworthy decline of the intestinal parasite density, along with amelioration of intestinal pathology of infected mice. Ultrastructural examination proved thatfive doses of L. acidophilus bacteriocin showed marked changes in cellular architecture of the trophozoites with evident disorganization of the cell membrane, adhesive disc and cytoplasmic components. This is the first reported study of the safe anti-giardial efficacy of L. acidophilus (P106) derived bacteriocin, hence highlighting its great promise as a potential therapeutic safe alternative to existing commercial drugs. Copyright © 2014 Elsevier Inc. All rights reserved.

Feasibility of adjunct therapeutic hypothermia treatment for hyperammonemia and encephalopathy due to urea cycle disorders and organic acidemias.

Science.gov (United States)

Lichter-Konecki, Uta; Nadkarni, Vinay; Moudgil, Asha; Cook, Noah; Poeschl, Johannes; Meyer, Michael T; Dimmock, David; Baumgart, Stephen

2013-08-01

Children with urea cycle disorders (UCDs) or organic acidemias (OAs) and acute hyperammonemia and encephalopathy are at great risk for neurological injury, developmental delay, intellectual disability, and death. Nutritional support, intravenous alternative pathway therapy, and dialysis are used to treat severe hyperammonemia associated with UCDs and nutritional support and dialysis are used to treat severe hyperammonemia in OAs. Brain protective treatment while therapy is initiated may improve neurological and cognitive function for the lifetime of the child. Animal experiments and small clinical trials in hepatic encephalopathy caused by acute liver failure suggest that therapeutic hypothermia provides neuroprotection in hyperammonemia associated encephalopathy. We report results of an ongoing pilot study that assesses if whole body cooling during rescue treatment of neonates with acute hyperammonemia and encephalopathy is feasible and can be conducted safely. Adjunct whole body therapeutic hypothermia was conducted in addition to standard treatment in acutely encephalopathic, hyperammonemic neonates with UCDs and OAs requiring dialysis. Therapeutic hypothermia was initiated using cooling blankets as preparations for dialysis were underway. Similar to standard therapeutic hypothermia treatment for neonatal hypoxic ischemic encephalopathy, patients were maintained at 33.5°C±1°C for 72h, they were then slowly rewarmed by 0.5°C every 3h over 18h. In addition data of age-matched historic controls were collected for comparison. Seven patients were cooled using the pilot study protocol and data of seven historic controls were reviewed. All seven patients survived the initial rescue and cooling treatment, 6 patients were discharged home 2-4weeks after hospitalization, five of them feeding orally. The main complication observed in a majority of patients was hypotension. Adjunct therapeutic hypothermia for neonates with UCDs and OAs receiving standard treatment was

Scalable and fail-safe deployment of the ATLAS Distributed Data Management system Rucio

Science.gov (United States)

Lassnig, M.; Vigne, R.; Beermann, T.; Barisits, M.; Garonne, V.; Serfon, C.

2015-12-01

This contribution details the deployment of Rucio, the ATLAS Distributed Data Management system. The main complication is that Rucio interacts with a wide variety of external services, and connects globally distributed data centres under different technological and administrative control, at an unprecedented data volume. It is therefore not possible to create a duplicate instance of Rucio for testing or integration. Every software upgrade or configuration change is thus potentially disruptive and requires fail-safe software and automatic error recovery. Rucio uses a three-layer scaling and mitigation strategy based on quasi-realtime monitoring. This strategy mainly employs independent stateless services, automatic failover, and service migration. The technologies used for deployment and mitigation include OpenStack, Puppet, Graphite, HAProxy and Apache. In this contribution, the interplay between these components, their deployment, software mitigation, and the monitoring strategy are discussed.

Scalable and fail-safe deployment of the ATLAS Distributed Data Management system Rucio

CERN Document Server

Lassnig, Mario; The ATLAS collaboration; Beermann, Thomas Alfons; Barisits, Martin-Stefan; Garonne, Vincent; Serfon, Cedric

2015-01-01

This contribution details the deployment of Rucio, the ATLAS Distributed Data Management system. The main complication is that Rucio interacts with a wide variety of external services, and connects globally distributed data centres under different technological and administrative control, at an unprecedented data volume. It is therefore not possibly to create a duplicate instance of Rucio for testing or integration. Every software upgrade or configuration change is thus potentially disruptive and requires fail-safe software and automatic error recovery. Rucio uses a three-layer scaling and mitigation strategy based on quasi-realtime monitoring. This strategy mainly employs independent stateless services, automatic failover, and service migration. The technologies used for deployment and mitigation include OpenStack, Puppet, Graphite, HAProxy and Apache. In this contribution, the interplay between these component, their deployment, software mitigation, and the monitoring strategy are discussed.

Therapeutic management of acute pulmonary embolism.

Science.gov (United States)

Tromeur, Cécile; Van Der Pol, Liselotte M; Couturaud, Francis; Klok, Frederikus A; Huisman, Menno V

2017-08-01

Acute pulmonary embolism (PE) is a potentially fatal manifestation of venous thromboembolism. Prompt anticoagulant treatment is crucial for PE patients, which can decrease morbidity and mortality. Risk assessment is the cornerstone of the therapeutic management of PE. It guides physicians to the most appropriate treatment and selects patients for early discharge or home treatment. Areas covered: Here, we review the current treatments of acute PE according to contemporary risk stratification strategies, highlighting each step of PE therapeutic management. Expert commentary: Currently, direct oral anticoagulants (DOACs) represent the first-line therapy of patients presenting with non-high risk PE with a better risk-benefit ratios than vitamin K antagonists (VKAs) due to lower risk of major bleeding. Only high-risk patients with PE who present in shock should be treated with systematic thrombolysis, while surgical thrombectomy or catheter direct thrombolysis (CDT) should only be considered when thrombolysis is contraindicated because of too high bleeding risk.

NEW DATA ON THE CLINICAL AND THERAPEUTIC MANAGEMENT OF OCCLUSAL CARIES (III

Directory of Open Access Journals (Sweden)

Sorin ANDRIAN

2017-06-01

Full Text Available In the control of occlusal caries, the major challenges are related not only to the detection of non-cavitary lesions, but also to the establishment of the treatment strategies to be subsequently applied. Considering the objective of each treatment, that of helping the patient, it is essential to control the progression of carious lesions by means of nonsurgical, preventive/therapeutical methods, whenever necessary. The new strategies applied in caries management are based on the evaluation and predictibility of possible risks, a major aspect in the daily taking of therapeutical decisions. The management plan should include: (I patient’s level of risk, (II patient’s activity level and (III severity of the lesion. Various strategies for a most efficient management of patient’s problems, as well as of the carious lesions, have been elaborated by specialized medical organisms, such as: strategies established within ICDAS, CAMBRA, strategies of the caries management system (SMC and protocols indicated by the system of caries classification according to ADA (American Dental Association. The mission of any new model of caries management is first of all to preserve the dental tissues, and to restore them when only recommended – an idea to guide the decisions of practitioners, starting with the moment of anamnesis, clinical examination and estabishment of diagnosis, until the end of the treatment

Focus on Therapeutic Strategies of Nonalcoholic Fatty Liver Disease

Directory of Open Access Journals (Sweden)

Marilena Durazzo

2012-01-01

Full Text Available Nonalcoholic fatty liver disease (NAFLD is the most common chronic liver disease in the Western world (it affects 30% of the general adult population. The NAFLD encompasses a histological spectrum ranging from simple steatosis to nonalcoholic steatohepatitis (NASH, defined by steatosis, hepatocellular damage, and lobular inflammation in individuals without significant alcohol consumption and negative viral, congenital, and autoimmune liver disease markers. Currently, NAFLD is considered an emerging epidemic in light of the dramatic increase in obesity rates. With the progressive nature of NASH and its rising prevalence there is a significant need for a specific and targeted treatments since to date there has not been any validated therapies for NAFLD other than weight loss, which is well known to have a poor long-term success rate. In recent years, visceral adipose tissue has taken an important role in NAFLD pathogenesis, and current therapeutic approaches aim at reducing visceral obesity and free fatty acid overflow to the liver. This paper is focused on the treatments used for NAFLD and the potential new therapy.

Linezolid in the treatment of drug-resistant tuberculosis: the challenge of its narrow therapeutic index.

Science.gov (United States)

Wasserman, Sean; Meintjes, Graeme; Maartens, Gary

2016-10-01

Linezolid is an oxazolidinone with potent activity against M tuberculosis, and improves culture conversion and cure rates when added to treatment regimens for drug resistant tuberculosis. However, linezolid has a narrow therapeutic window, and the optimal dosing strategy that minimizes the substantial toxicity associated with linezolid's prolonged use in tuberculosis treatment has not been determined, limiting the potential impact of this anti-mycobacterial agent. This paper aims to review and summarize the current knowledge on linezolid for the treatment of drug-resistant tuberculosis. The focus is on the pharmacokinetic-pharmacodynamic determinants of linezolid's efficacy and toxicity in tuberculosis, and how this relates to defining an optimal dose. Mechanisms of linezolid toxicity and resistance, and the potential role of therapeutic drug monitoring are also covered. Expert commentary: Prospective pharmacokinetic-pharmacodynamic studies are required to define optimal therapeutic targets and to inform improved linezolid dosing strategies for drug-resistant tuberculosis.

Delivery of Therapeutic Proteins Using Electrospun Fibers-Recent Developments and Current Challenges.

Science.gov (United States)

Seif, Salem; Planz, Viktoria; Windbergs, Maike

2017-10-01

Proteins play a vital role within the human body by regulating various functions and even serving as structural constituent of many body parts. In this context, protein-based therapeutics have attracted a lot of attention in the last few decades as potential treatment of different diseases. Due to the steadily increasing interest in protein-based therapeutics, different dosage forms were investigated for delivering such complex macromolecules to the human body. Here, electrospun fibers hold a great potential for embedding proteins without structural damage and for controlled release of the protein for therapeutic applications. This review provides a comprehensive overview of the current state of protein-based carrier systems using electrospun fibers, with special emphasis on discussing their potential and key challenges in developing such therapeutic strategies, along with a prospective view of anticipated future directions. © 2017 Deutsche Pharmazeutische Gesellschaft.

Engineering responsive supramolecular biomaterials: Toward smart therapeutics.

Science.gov (United States)

Webber, Matthew J

2016-09-01

Engineering materials using supramolecular principles enables generalizable and modular platforms that have tunable chemical, mechanical, and biological properties. Applying this bottom-up, molecular engineering-based approach to therapeutic design affords unmatched control of emergent properties and functionalities. In preparing responsive materials for biomedical applications, the dynamic character of typical supramolecular interactions facilitates systems that can more rapidly sense and respond to specific stimuli through a fundamental change in material properties or characteristics, as compared to cases where covalent bonds must be overcome. Several supramolecular motifs have been evaluated toward the preparation of "smart" materials capable of sensing and responding to stimuli. Triggers of interest in designing materials for therapeutic use include applied external fields, environmental changes, biological actuators, applied mechanical loading, and modulation of relative binding affinities. In addition, multistimuli-responsive routes can be realized that capture combinations of triggers for increased functionality. In sum, supramolecular engineering offers a highly functional strategy to prepare responsive materials. Future development and refinement of these approaches will improve precision in material formation and responsiveness, seek dynamic reciprocity in interactions with living biological systems, and improve spatiotemporal sensing of disease for better therapeutic deployment.

Therapeutic approaches to preventing cell death in Huntington disease.

Science.gov (United States)

Kaplan, Anna; Stockwell, Brent R

2012-12-01

Neurodegenerative diseases affect the lives of millions of patients and their families. Due to the complexity of these diseases and our limited understanding of their pathogenesis, the design of therapeutic agents that can effectively treat these diseases has been challenging. Huntington disease (HD) is one of several neurological disorders with few therapeutic options. HD, like numerous other neurodegenerative diseases, involves extensive neuronal cell loss. One potential strategy to combat HD and other neurodegenerative disorders is to intervene in the execution of neuronal cell death. Inhibiting neuronal cell death pathways may slow the development of neurodegeneration. However, discovering small molecule inhibitors of neuronal cell death remains a significant challenge. Here, we review candidate therapeutic targets controlling cell death mechanisms that have been the focus of research in HD, as well as an emerging strategy that has been applied to developing small molecule inhibitors-fragment-based drug discovery (FBDD). FBDD has been successfully used in both industry and academia to identify selective and potent small molecule inhibitors, with a focus on challenging proteins that are not amenable to traditional high-throughput screening approaches. FBDD has been used to generate potent leads, pre-clinical candidates, and has led to the development of an FDA approved drug. This approach can be valuable for identifying modulators of cell-death-regulating proteins; such compounds may prove to be the key to halting the progression of HD and other neurodegenerative disorders. Copyright © 2012 Elsevier Ltd. All rights reserved.

Safe Cooperating Cyber-Physical Systems using Wireless Communication

DEFF Research Database (Denmark)

Pop, Paul; Scholle, Detlef; Sljivo, Irfan

2017-01-01

This paper presents an overview of the ECSEL project entitled ―Safe Cooperating Cyber-Physical Systems using Wireless Communication‖ (SafeCOP), which runs during the period 2016–2019. SafeCOP targets safety-related Cooperating Cyber-Physical Systems (CO-CPS) characterised by use of wireless...... detection of abnormal behaviour, triggering if needed a safe degraded mode. SafeCOP will also develop methods and tools, which will be used to produce safety assurance evidence needed to certify cooperative functions. SafeCOP will extend current wireless technologies to ensure safe and secure cooperation...

[Innovative therapeutic strategies for intravesical drug administration].

Science.gov (United States)

Moch, C; Salmon, D; Rome, P; Marginean, R; Pivot, C; Colombel, M; Pirot, F

2013-05-01

Perspectives for innovative pharmaceutical molecules and intravesical administration of pharmacological agents are presented in the present review carried out from a recent literature. This review of the literature was built by using the PubMed and ScienceDirect databases running 20keywords revealing 34publications between 1983 and 2012. The number of referenced articles on ScienceDirect has increased in recent years, highlighting the interest of scientists for intravesical drug administration and the relevance of innovating drug delivery systems. Different modalities of intravesical administration using physical (e.g., iontophoresis, electroporation) or chemical techniques (e.g., enzyme, solvent, nanoparticles, liposomes, hydrogels) based on novel formulation methods are reported. Finally, the development of biopharmaceuticals (e.g., bacillus Calmette-Guérin, interferon α) and gene therapies is also presented and analyzed in this review. The present review exhibits new development in the pipeline for emerging intravesical drug administration strategies. Knowledge of all these therapies allows practitioners to propose a specific and tailored treatment to each patient with limiting systemic side effects. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

SUNRAYCE 1993: Working safely with lead-acid batteries and photovoltaic power systems

Science.gov (United States)

Dephillips, M. P.; Moskowitz, P. D.; Fthenakis, V. M.

1992-11-01

The US Department of Energy (DOE) is sponsoring SUNRAYCE 93 to advance tile technology and use of photovoltaics and electric vehicles. Participants will use cars powered by photovoltaic modules and lead-acid storage batteries. This brochure, prepared for students and faculty participating in this race, outlines the health hazards presented by these electrical systems and gives guidance on strategies for their safe usage. At the outset, it should be noted that working with photovoltaic systems and batteries requires electric vehicle drivers and technicians to have 'hands-on' contact with the car on a daily basis. It is important that no one work near a photovoltaic energy system or battery, either in a vehicle or on the bench, unless they familiarize themselves with the components in use and know and observe safe work practices including the safety precautions described in the manuals provided by the various equipment vendors and this document.

InaSAFE applications in disaster preparedness

Science.gov (United States)

Pranantyo, Ignatius Ryan; Fadmastuti, Mahardika; Chandra, Fredy

2015-04-01

Disaster preparedness activities aim to reduce the impact of disasters by being better prepared to respond when a disaster occurs. In order to better anticipate requirements during a disaster, contingency planning activities can be undertaken prior to a disaster based on a realistic disaster scenario. InaSAFE is a tool that can inform this process. InaSAFE is a free and open source software that estimates the impact to people and infrastructure from potential hazard scenarios. By using InaSAFE, disaster managers can develop scenarios of disaster impacts (people and infrastructures affected) to inform their contingency plan and emergency response operation plan. While InaSAFE provides the software framework exposure data and hazard data are needed as inputs to run this software. Then InaSAFE can be used to forecast the impact of the hazard scenario to the exposure data. InaSAFE outputs include estimates of the number of people, buildings and roads are affected, list of minimum needs (rice and clean water), and response checklist. InaSAFE is developed by Indonesia's National Disaster Management Agency (BNPB) and the Australian Government, through the Australia-Indonesia Facility for Disaster Reduction (AIFDR), in partnership with the World Bank - Global Facility for Disaster Reduction and Recovery (GFDRR). This software has been used in many parts of Indonesia, including Padang, Maumere, Jakarta, and Slamet Mountain for emergency response and contingency planning.

Endogenous and Synthetic Cannabinoids as Therapeutics in Retinal Disease

Directory of Open Access Journals (Sweden)

Despina Kokona

2016-01-01

Full Text Available The functional significance of cannabinoids in ocular physiology and disease has been reported some decades ago. In the early 1970s, subjects who smoked Cannabis sativa developed lower intraocular pressure (IOP. This led to the isolation of phytocannabinoids from this plant and the study of their therapeutic effects in glaucoma. The main treatment of this disease to date involves the administration of drugs mediating either the decrease of aqueous humour synthesis or the increase of its outflow and thus reduces IOP. However, the reduction of IOP is not sufficient to prevent visual field loss. Retinal diseases, such as glaucoma and diabetic retinopathy, have been defined as neurodegenerative diseases and characterized by ischemia-induced excitotoxicity and loss of retinal neurons. Therefore, new therapeutic strategies must be applied in order to target retinal cell death, reduction of visual acuity, and blindness. The aim of the present review is to address the neuroprotective and therapeutic potential of cannabinoids in retinal disease.

[Identification, during development, of a methodology targeted at determining the positioning of new drugs for therapeutic strategies: examples of rheumatoid arthritis and cardiac insufficiency].

Science.gov (United States)

Le Jeunne, C; Plétan, Y; Boissel, J P

2002-01-01

The Marketing Authorization (MA) granted to a new molecular entity does not allow for proper anticipation of its future positioning within the therapeutic strategy. A specific methodology should be devised as early as during the pre-MA development phase that could result in an initial positioning that should be subjected to further reappraisal with regard to scientific advances, the arrival of new treatments and further developments with this molecule. A methodology is thus proposed, based on early optimisation of the development plan, the granting of subsequent MAs, and reappraisal of the positioning within the strategy, based on analysis of all available data. It should be possible to take into account the economic context, within an agreed system with pre-defined medico-economic criteria. This may in turn raise the issue of the role of the various parties involved in this assessment, as well as how to understand the respective opinions of stakeholders: authorities, sponsors, prescribers and patients, each of whom has a specific view of the definition of the strategic objective that should apply to the disease concerned.

Contact refusal by children following acrimonious separation: therapeutic approaches with children and parents.

Science.gov (United States)

Dejong, Margaret; Davies, Hilary

2013-04-01

This paper aims to build on the existing literature, by presenting some thoughts based on clinical experience with nine families of children referred for intractable contact refusal with one parent following marital separation. This particular group of high-conflict divorce cases engenders an inordinate amount of frustration both within the courts and therapeutic agencies. We outline here our assessment process and therapeutic strategies, as well as consideration of the role of the wider professional system and the courts. We conclude that whether or not direct contact with the rejected parent is achieved, useful therapeutic work can be carried out to assist children in moving on with their lives.

New Insights to Clathrin and Adaptor Protein 2 for the Design and Development of Therapeutic Strategies

Directory of Open Access Journals (Sweden)

Ebbe Toftgaard Poulsen

2015-12-01

Full Text Available The Amyloid Precursor Protein (APP has been extensively studied for its role as the precursor of the β-amyloid protein (Aβ in Alzheimer’s disease (AD. However, our understanding of the normal function of APP is still patchy. Emerging evidence indicates that a dysfunction in APP trafficking and degradation can be responsible for neuronal deficits and progressive degeneration in humans. We recently reported that the Y682 mutation in the 682YENPTY687 domain of APP affects its binding to specific adaptor proteins and leads to its anomalous trafficking, to defects in the autophagy machinery and to neuronal degeneration. In order to identify adaptors that influence APP function, we performed pull-down experiments followed by quantitative mass spectrometry (MS on hippocampal tissue extracts of three month-old mice incubated with either the 682YENPTY687 peptide, its mutated form, 682GENPTY687 or its phosphorylated form, 682pYENPTY687. Our experiments resulted in the identification of two proteins involved in APP internalization and trafficking: Clathrin heavy chain (hc and its Adaptor Protein 2 (AP-2. Overall our results consolidate and refine the importance of Y682 in APP normal functions from an animal model of premature aging and dementia. Additionally, they open the perspective to consider Clathrin hc and AP-2 as potential targets for the design and development of new therapeutic strategies.

Safe Minimum Internal Temperature Chart

Science.gov (United States)

... Internal Temperature Chart Safe steps in food handling, cooking, and storage are essential in preventing foodborne illness. You can't see, smell, or taste harmful bacteria that may cause illness. In every step of food preparation, follow the four guidelines to keep food safe: ...

The malignant niche: safe spaces for toxic stem cell marketing.

Science.gov (United States)

Sipp, Douglas

2017-01-01

Many tumors are sustained by microenvironments, or niches, that support and protect malignant cells, thus conferring a competitive advantage against both healthy cells and therapeutic interventions (for a brief review, see Yao and Link (Stem Cells 35: 3-8, 2017)). The global industry engaged in the commercial promotion of unproven and scientifically implausible cell-based "regenerative" therapies has developed a number of self-protective strategies that support its survival and growth in ways that are broadly analogous to the functions of the malignant niche.

Safe affordable fission engine (SAFE 30) module conductivity test thermal model correlation

International Nuclear Information System (INIS)

Roman, Jose

2001-01-01

The SAFE 30 is a simple, robust space fission power system that is comprised of several independent modules. Each module contains 4 fuel tubes bonded to a central heatpipe. Fission energy is conducted from the fuel tubes to the heatpipe, which in turn transfers the energy to a power conversion system. This paper benchmarks a thermal model of the SAFE 30 with actual test data from simulated SAFE 30 module tests. Two 'dummy' SAFE 30 modules were fabricated - each consisted of 4 1-inch dia. tubes (simulating the fuel tubes) bonded to a central '1' dia. tube (simulating the heatpipe). In the first module the fuel tubes were simply brazed to the heatpipe along the line of contact (leaving void space in the interstices), and in the second module the tubes and heatpipe were brazed via tri-cusps that completely fill the interstices between the tubes. In these tests, fission energy is simulated by placing resistance heaters within each of the 4 fuel tubes. The tests were conducted in a vacuum chamber in 4 configurations: tri-cusps filled with and without an outer insulation wrap, and no tri-cusps with and without an outer insulation wrap. The baseline SAFE 30 configuration uses the brazed tri-cusps. During the tests, the power applied to the heaters was varied in a stepwise fashion, until a steady-state temperature profile was reached. These temperature levels varied between 773 K and 1073 K. To benchmark the thermal model, the input energy and chamber surface temperature were used as boundary conditions for the model. The analytical results from the nodes at the same location as the test thermocouples were plotted again test data to determinate the accuracy of the analysis. The unknown variables on the analysis are the radiation emissivity of the pipe and chamber and the radiation view factor between the module and the chamber. A correlation was determined using a parametric analysis by varying the surface emissivity and view factor until a good match was reached. This

Steering teens safe: a randomized trial of a parent-based intervention to improve safe teen driving.

Science.gov (United States)

Peek-Asa, Corinne; Cavanaugh, Joseph E; Yang, Jingzhen; Chande, Vidya; Young, Tracy; Ramirez, Marizen

2014-07-31

Crashes are the leading cause of death for teens, and parent-based interventions are a promising approach. We assess the effectiveness of Steering Teens Safe, a parent-focused program to increase safe teen driving. Steering Teens Safe aimed to improve parental communication with teens about safe driving using motivational interviewing techniques in conjunction with 19 safe driving lessons. A randomized controlled trial involved 145 parent-teen dyads (70 intervention and 75 control). Intervention parents received a 45-minute session to learn the program with four follow-up phone sessions, a DVD, and a workbook. Control parents received a standard brochure about safe driving. Scores were developed to measure teen-reported quantity and quality of parental communication about safe driving. The main outcome measure was a previously validated Risky Driving Score reported by teens. Because the Score was highly skewed, a generalized linear model based on a gamma distribution was used for analysis. Intervention teens ranked their parent's success in talking about driving safety higher than control teens (p = 0.035) and reported that their parents talked about more topics (non-significant difference). The Risky Driving Score was 21% lower in intervention compared to control teens (85% CI = 0.60, 1.00). Interaction between communication quantity and the intervention was examined. Intervention teens who reported more successful communication had a 42% lower Risky Driving Score (95% CI = 0.37, 0.94) than control parents with less successful communication. This program had a positive although not strong effect, and it may hold the most promise in partnership with other programs, such as Driver's Education or Graduated Driver's License policies. ClinicalTrials.gov NCT01014923. Registered Nov. 16, 2009.

Staying Safe in the Water

Centers for Disease Control (CDC) Podcasts

In this podcast, Dr. Julie Gilchrist, a pediatrician and medical epidemiologist from CDC’s Injury Center, talks about staying safe in the water. Tips are for all audiences, with a focus on preventing drownings and keeping children safe in and around the pool, lake, or ocean.

Gene therapy prospects--intranasal delivery of therapeutic genes.

Science.gov (United States)

Podolska, Karolina; Stachurska, Anna; Hajdukiewicz, Karolina; Małecki, Maciej

2012-01-01

Gene therapy is recognized to be a novel method for the treatment of various disorders. Gene therapy strategies involve gene manipulation on broad biological processes responsible for the spreading of diseases. Cancer, monogenic diseases, vascular and infectious diseases are the main targets of gene therapy. In order to obtain valuable experimental and clinical results, sufficient gene transfer methods are required. Therapeutic genes can be administered into target tissues via gene carriers commonly defined as vectors. The retroviral, adenoviral and adeno-associated virus based vectors are most frequently used in the clinic. So far, gene preparations may be administered directly into target organs or by intravenous, intramuscular, intratumor or intranasal injections. It is common knowledge that the number of gene therapy clinical trials has rapidly increased. However, some limitations such as transfection efficiency and stable and long-term gene expression are still not resolved. Consequently, great effort is focused on the evaluation of new strategies of gene delivery. There are many expectations associated with intranasal delivery of gene preparations for the treatment of diseases. Intranasal delivery of therapeutic genes is regarded as one of the most promising forms of pulmonary gene therapy research. Gene therapy based on inhalation of gene preparations offers an alternative way for the treatment of patients suffering from such lung diseases as cystic fibrosis, alpha-1-antitrypsin defect, or cancer. Experimental and first clinical trials based on plasmid vectors or recombinant viruses have revealed that gene preparations can effectively deliver therapeutic or marker genes to the cells of the respiratory tract. The noninvasive intranasal delivery of gene preparations or conventional drugs seems to be very encouraging, although basic scientific research still has to continue.

Safe biodegradable fluorescent particles

Science.gov (United States)

Martin, Sue I [Berkeley, CA; Fergenson, David P [Alamo, CA; Srivastava, Abneesh [Santa Clara, CA; Bogan, Michael J [Dublin, CA; Riot, Vincent J [Oakland, CA; Frank, Matthias [Oakland, CA

2010-08-24

A human-safe fluorescence particle that can be used for fluorescence detection instruments or act as a safe simulant for mimicking the fluorescence properties of microorganisms. The particle comprises a non-biological carrier and natural fluorophores encapsulated in the non-biological carrier. By doping biodegradable-polymer drug delivery microspheres with natural or synthetic fluorophores, the desired fluorescence can be attained or biological organisms can be simulated without the associated risks and logistical difficulties of live microorganisms.

Safe Haven.

Science.gov (United States)

Bush, Gail

2003-01-01

Discusses school libraries as safe havens for teenagers and considers elements that foster that atmosphere, including the physical environment, lack of judgments, familiarity, leisure, and a welcoming nature. Focuses on the importance of relationships, and taking the time to listen to teens and encourage them. (LRW)

Innate heart regeneration: endogenous cellular sources and exogenous therapeutic amplification.

Science.gov (United States)

Malliaras, Konstantinos; Vakrou, Styliani; Kapelios, Chris J; Nanas, John N

2016-11-01

The -once viewed as heretical- concept of the adult mammalian heart as a dynamic organ capable of endogenous regeneration has recently gained traction. However, estimated rates of myocyte turnover vary wildly and the underlying mechanisms of cardiac plasticity remain controversial. It is still unclear whether the adult mammalian heart gives birth to new myocytes through proliferation of resident myocytes, through cardiomyogenic differentiation of endogenous progenitors or through both mechanisms. In this review, the authors discuss the cellular origins of postnatal mammalian cardiomyogenesis and touch upon therapeutic strategies that could potentially amplify innate cardiac regeneration. The adult mammalian heart harbors a limited but detectable capacity for spontaneous endogenous regeneration. During normal aging, proliferation of pre-existing cardiomyocytes is the dominant mechanism for generation of new cardiomyocytes. Following myocardial injury, myocyte proliferation increases modestly, but differentiation of endogenous progenitor cells appears to also contribute to cardiomyogenesis (although agreement on the latter point is not universal). Since cardiomyocyte deficiency underlies almost all types of heart disease, development of therapeutic strategies that amplify endogenous regeneration to a clinically-meaningful degree is of utmost importance.

Introduction to current and future protein therapeutics: a protein engineering perspective.

Science.gov (United States)

Carter, Paul J

2011-05-15

Protein therapeutics and its enabling sister discipline, protein engineering, have emerged since the early 1980s. The first protein therapeutics were recombinant versions of natural proteins. Proteins purposefully modified to increase their clinical potential soon followed with enhancements derived from protein or glycoengineering, Fc fusion or conjugation to polyethylene glycol. Antibody-based drugs subsequently arose as the largest and fastest growing class of protein therapeutics. The rationale for developing better protein therapeutics with enhanced efficacy, greater safety, reduced immunogenicity or improved delivery comes from the convergence of clinical, scientific, technological and commercial drivers that have identified unmet needs and provided strategies to address them. Future protein drugs seem likely to be more extensively engineered to improve their performance, e.g., antibodies and Fc fusion proteins with enhanced effector functions or extended half-life. Two old concepts for improving antibodies, namely antibody-drug conjugates and bispecific antibodies, have advanced to the cusp of clinical success. As for newer protein therapeutic platform technologies, several engineered protein scaffolds are in early clinical development and offer differences and some potential advantages over antibodies. Copyright © 2011 Elsevier Inc. All rights reserved.

SUNRAYCE 93: Working safely with lead-acid batteries and photovoltaic power systems

Energy Technology Data Exchange (ETDEWEB)

DePhillips, M.P.; Moskowitz, P.D.; Fthenakis, V.M.

1992-11-03

The US Department of Energy (DOE) is sponsoring SUNRAYCE 93 to advance tile technology and use of photovoltaics and electric vehicles. Participants will use cars powered by photovoltaic modules and lead-acid storage batteries. This brochure, prepared for students and faculty participating in this race, outlines the health hazards presented by these electrical systems, and gives guidance on strategies for their safe usage. At the outset, it should be noted that working with photovoltaic systems and batteries requires electric vehicle drivers and technicians to have {open_quotes}hands-on{close_quotes} contact with the car on a daily basis. It is important that no one work near a photovoltaic energy system or battery, either in a vehicle or on the bench, unless they familiarize themselves with the components in use, and know and observe safe work practices including the safety precautions described in the manuals provided by the various equipment vendors and this document.

Targeting endoplasmic reticulum and/or mitochondrial Ca2+ fluxes as therapeutic strategy for HCV infection

Science.gov (United States)

Scrima, Rosella; Piccoli, Claudia; Moradpour, Darius; Capitanio, Nazzareno

2018-03-01

Chronic hepatitis C is characterized by metabolic disorders and by a microenvironment in the liver dominated by oxidative stress, inflammation and regeneration processes that can in the long term lead to liver cirrhosis and hepatocellular carcinoma. Several lines of evidence suggest that mitochondrial dysfunctions play a central role in these processes. However, how these dysfunctions are induced by the virus and whether they play a role in disease progression and neoplastic transformation remains to be determined. Most in vitro studies performed so far have shown that several of the hepatitis C virus (HCV) proteins also localize to mitochondria, but the consequences of these interactions on mitochondrial functions remain contradictory and need to be confirmed in the context of productively replicating virus and physiologically relevant in vitro and in vivo model systems. In the past decade we have been proposing a temporal sequence of events in the HCV-infected cell whereby the primary alteration is localized at the mitochondria-associated ER membranes and causes release of Ca2+ from the ER, followed by uptake into mitochondria. This ensues successive mitochondrial dysfunction leading to the generation of reactive oxygen and nitrogen species and a progressive metabolic adaptive response consisting in decreased oxidative phosphorylation and enhanced aerobic glycolysis and lipogenesis. Here we resume the major results provided by our group in the context of HCV-mediated alterations of the cellular inter-compartmental calcium flux homeostasis and present new evidence suggesting targeting of ER and/or mitochondrial calcium transporters as a novel therapeutic strategy.

Targeting Endoplasmic Reticulum and/or Mitochondrial Ca2+ Fluxes as Therapeutic Strategy for HCV Infection.

Science.gov (United States)

Scrima, Rosella; Piccoli, Claudia; Moradpour, Darius; Capitanio, Nazzareno

2018-01-01

Chronic hepatitis C is characterized by metabolic disorders and by a microenvironment in the liver dominated by oxidative stress, inflammation and regeneration processes that can in the long term lead to liver cirrhosis and hepatocellular carcinoma. Several lines of evidence suggest that mitochondrial dysfunctions play a central role in these processes. However, how these dysfunctions are induced by the virus and whether they play a role in disease progression and neoplastic transformation remains to be determined. Most in vitro studies performed so far have shown that several of the hepatitis C virus (HCV) proteins also localize to mitochondria, but the consequences of these interactions on mitochondrial functions remain contradictory and need to be confirmed in the context of productively replicating virus and physiologically relevant in vitro and in vivo model systems. In the past decade we have been proposing a temporal sequence of events in the HCV-infected cell whereby the primary alteration is localized at the mitochondria-associated ER membranes and causes release of Ca 2+ from the ER, followed by uptake into mitochondria. This ensues successive mitochondrial dysfunction leading to the generation of reactive oxygen and nitrogen species and a progressive metabolic adaptive response consisting in decreased oxidative phosphorylation and enhanced aerobic glycolysis and lipogenesis. Here we resume the major results provided by our group in the context of HCV-mediated alterations of the cellular inter-compartmental calcium flux homeostasis and present new evidence suggesting targeting of ER and/or mitochondrial calcium transporters as a novel therapeutic strategy.

Prescribing knowledge in the light of undergraduate clinical pharmacology and therapeutics teaching in India: views of first-year postgraduate students

Directory of Open Access Journals (Sweden)

Upadhyaya P

2012-06-01

Full Text Available Prerna Upadhyaya,1 Vikas Seth,2 Monika Sharma,1 Mushtaq Ahmed,1 Vijay Vasant Moghe,1 Zafar Yab Khan,1 Vinay Kumar Gupta,1 Shipra Vikram Jain,1 Utkarsh Soni,1 Manohar Bhatia,1 Kumar Abhijit,1 Jaswant Goyal11Department of Pharmacology, Mahatma Gandhi Medical College, Jaipur, 2Department of Pharmacology, Hind Institute of Medical Sciences, Lucknow, IndiaObjectives: The study aimed to review the prescribing knowledge of first-year postgraduate doctors in a medical college in India, using the principles of good prescribing, to suggest strategies to improve rational prescribing, and to recommend what curriculum planners can do to accomplish this objective.Methods: Fifty first-year postgraduate doctors were asked to fill in a structured questionnaire that sought information regarding their undergraduate training in clinical pharmacology and therapeutics, prescribing habits, and commonly consulted drug information sources. Also, the questionnaire assessed any perceived deficiencies in their undergraduate clinical pharmacology teaching and sought feedback regarding improvement in the teaching.Results: Eighty-eight percent of residents said that they were taught prescription writing in undergraduate pharmacology teaching; 48% of residents rated their prescribing knowledge at graduation as average, 28% good, 4% excellent, 14% poor, and 4% very poor; 58% felt that their undergraduate training did not prepare them to prescribe safely, and 62% felt that their training did not prepare them to prescribe rationally. Fifty-eight percent of residents felt that they had some specific problems with writing a prescription during their internship training, while 92% thought that undergraduate teaching should be improved. Their suggestions for improving teaching methods were recorded.Conclusions: This study concludes that efforts are needed to develop a curriculum that encompasses important aspects of clinical pharmacology and therapeutics along with incorporation of

Derivation and validation of a novel risk score for safe discharge after acute lower gastrointestinal bleeding: a modelling study.

Science.gov (United States)

Oakland, Kathryn; Jairath, Vipul; Uberoi, Raman; Guy, Richard; Ayaru, Lakshmana; Mortensen, Neil; Murphy, Mike F; Collins, Gary S

2017-09-01

Acute lower gastrointestinal bleeding is a common reason for emergency hospital admission, and identification of patients at low risk of harm, who are therefore suitable for outpatient investigation, is a clinical and research priority. We aimed to develop and externally validate a simple risk score to identify patients with lower gastrointestinal bleeding who could safely avoid hospital admission. We undertook model development with data from the National Comparative Audit of Lower Gastrointestinal Bleeding from 143 hospitals in the UK in 2015. Multivariable logistic regression modelling was used to identify predictors of safe discharge, defined as the absence of rebleeding, blood transfusion, therapeutic intervention, 28 day readmission, or death. The model was converted into a simplified risk scoring system and was externally validated in 288 patients admitted with lower gastrointestinal bleeding (184 safely discharged) from two UK hospitals (Charing Cross Hospital, London, and Hammersmith Hospital, London) that had not contributed data to the development cohort. We calculated C statistics for the new model and did a comparative assessment with six previously developed risk scores. Of 2336 prospectively identified admissions in the development cohort, 1599 (68%) were safely discharged. Age, sex, previous admission for lower gastrointestinal bleeding, rectal examination findings, heart rate, systolic blood pressure, and haemoglobin concentration strongly discriminated safe discharge in the development cohort (C statistic 0·84, 95% CI 0·82-0·86) and in the validation cohort (0·79, 0·73-0·84). Calibration plots showed the new risk score to have good calibration in the validation cohort. The score was better than the Rockall, Blatchford, Strate, BLEED, AIMS65, and NOBLADS scores in predicting safe discharge. A score of 8 or less predicts a 95% probability of safe discharge. We developed and validated a novel clinical prediction model with good discriminative

Brain Insulin Resistance and Deficiency as Therapeutic Targets in Alzheimer's Disease

Science.gov (United States)

de la Monte, Suzanne M

2012-01-01

Alzheimer's disease [AD] is the most common cause of dementia in North America. Despite 30+ years of intense investigation, the field lacks consensus regarding the etiology and pathogenesis of sporadic AD, and therefore we still do not know the best strategies for treating and preventing this debilitating and costly disease. However, growing evidence supports the concept that AD is fundamentally a metabolic disease with substantial and progressive derangements in brain glucose utilization and responsiveness to insulin and insulin-like growth factor [IGF] stimulation. Moreover, AD is now recognized to be heterogeneous in nature, and not solely the end-product of aberrantly processed, misfolded, and aggregated oligomeric amyloid-beta peptides and hyperphosphorylated tau. Other factors, including impairments in energy metabolism, increased oxidative stress, inflammation, insulin and IGF resistance, and insulin/IGF deficiency in the brain should be incorporated into all equations used to develop diagnostic and therapeutic approaches to AD. Herein, the contributions of impaired insulin and IGF signaling to AD-associated neuronal loss, synaptic disconnection, tau hyperphosphorylation, amyloid-beta accumulation, and impaired energy metabolism are reviewed. In addition, we discuss current therapeutic strategies and suggest additional approaches based on the hypothesis that AD is principally a metabolic disease similar to diabetes mellitus. Ultimately, our ability to effectively detect, monitor, treat, and prevent AD will require more efficient, accurate and integrative diagnostic tools that utilize clinical, neuroimaging, biochemical, and molecular biomarker data. Finally, it is imperative that future therapeutic strategies for AD abandon the concept of uni-modal therapy in favor of multi-modal treatments that target distinct impairments at different levels within the brain insulin/IGF signaling cascades. PMID:22329651

More than a Safe Space

Science.gov (United States)

Sadowski, Michael

2016-01-01

Over the past three decades, much of the conversation about LGBTQ students in schools has centered on safety--anti-bullying policies, the "safe space" of gay-straight alliances, and "safe zones" marked by rainbow-colored stickers on classroom doors. In this article, Michael Sadowski argues that it's time to move beyond safety…

Summary of Session 2.A. Decommissioning strategies and regulations

International Nuclear Information System (INIS)

Schattke, H.

2003-01-01

The discussion focused largely on the decommissioning of large nuclear facilities. Equivalent strategies and procedures need to be developed for the safe decommissioning of the many other applications in medicine, industry and research involving radioactive materials. Planning for decommissioning should start early. Ideally, decommissioning considerations should have been taken into account at the design stage. Three basic decommissioning strategies are envisaged as possibilities for nuclear installations: immediate dismantling; safe enclosure prior to deferred dismantling; and entombment. All have advantages and disadvantages, but immediate dismantling is the generally preferred option. Immediate dismantling typically has the fewest uncertainties. It also eliminates the risks associated with the facility as promptly as possible, normally costs less than delaying and allows the retention of operational staff who know the facility and its history to contribute their expertise and experience during decommissioning. Approaches to regulating the implementation of decommissioning plans vary, but the common aim is to provide effective regulatory control to ensure safe decommissioning. The transition from operation to decommissioning will usually be accompanied by organizational changes, particularly reductions in staff. Such reductions may be inevitable, but the operator must manage the change so as to retain the expertise needed and to guard against a degradation of safety culture due to demotivation of the remaining staff. The absence of an available disposal route has been used as another argument for the safe enclosure strategy rather than immediate dismantling, the idea being that dismantling is delayed until a repository is available. The ultimate aim of decommissioning is to allow the removal of some or all regulatory control from a site, but internationally agreed criteria for the removal of such controls are needed

Safe injection procedures, injection practices, and needlestick ...

African Journals Online (AJOL)

Results: Safe injection procedures regarding final waste disposal were sufficiently adopted, while measures regarding disposable injection equipment, waste containers, hand hygiene, as well as injection practices were inadequately carried out. Lack of job aid posters that promote safe injection and safe disposal of ...

Frizzled Receptors as Potential Therapeutic Targets in Human Cancers

Directory of Open Access Journals (Sweden)

Chui-Mian Zeng

2018-05-01

Full Text Available Frizzled receptors (FZDs are a family of seven-span transmembrane receptors with hallmarks of G protein-coupled receptors (GPCRs that serve as receptors for secreted Wingless-type (WNT ligands in the WNT signaling pathway. Functionally, FZDs play crucial roles in regulating cell polarity, embryonic development, cell proliferation, formation of neural synapses, and many other processes in developing and adult organisms. In this review, we will introduce the basic structural features and review the biological function and mechanism of FZDs in the progression of human cancers, followed by an analysis of clinical relevance and therapeutic potential of FZDs. We will focus on the development of antibody-based and small molecule inhibitor-based therapeutic strategies by targeting FZDs for human cancers.

Toxoplasmosis Complications and Novel Therapeutic Synergism Combination of Diclazuril plus Atovaquone

Directory of Open Access Journals (Sweden)

Helieh S Oz

2014-09-01

Full Text Available Toxoplasmosis is a major cause of foodborne disease, congenital complication and morbidity. There is an urgent need for safe and effective therapies to encounter congenital and persisting toxoplasmosis. The hypothesis was: Combination Diclazuril plus Atovaquone to exert a novel therapeutic synergy to prevent toxoplasmosis syndromes. Methods. Pregnant dams were treated with Diclazuril and Atovaquone monotherapy or combination therapy and infected intraperitoneally with Toxoplasma tachyzoites (600. Results. Infected dams developed severe toxoplasmosis associated syndrome with increases in the abdominal adiposity surrounding uteri, gansterointestinal and other internal organs and excessive weight gain. Numerous organisms along with infiltration of inflammatory cells were detected scattered into adipose tissues. Combination therapy (p< 0.01 and to a lesser extent Diclazuril (p< 0.05 protected dams from inflammatory fat and excess weight gains. This was consistent with pancreatitis development in infected dams (versus normal p< 0.05 with infiltration of inflammatory cells, degeneration and necrosis of pancreatic cells followed by the degeneration and loss of islets. Combination and monotherapy protected dams from these inflammatory and pathological aspects of pancreatitis. Infected dams exhibited severe colitis, and colonic tissues significantly shortened in length. Brush border epithelial cells were replaced with infiltration of lymphocytes, granulocytes, and microabscess formations into cryptic microstructures. Combination therapy synergistically preserved colonic structure and normalized pathological damages (p< 0.001 and to a lesser degree Diclazuril monotherapy protected dams from colitis (p< 0.05 and gastrointestinal toxoplasmosis. Other complications included severe splenitis (p<0.001 and hepatitis (p<0.001 which were normalized with combination therapy. Conclusions. Combination Diclazuril plus Atovaquone was safe and with a novel therapeutic

Development of therapeutic antibodies to G protein-coupled receptors and ion channels: Opportunities, challenges and their therapeutic potential in respiratory diseases.

Science.gov (United States)

Douthwaite, Julie A; Finch, Donna K; Mustelin, Tomas; Wilkinson, Trevor C I

2017-01-01

The development of recombinant antibody therapeutics continues to be a significant area of growth in the pharmaceutical industry with almost 50 approved monoclonal antibodies on the market in the US and Europe. Therapeutic drug targets such as soluble cytokines, growth factors and single transmembrane spanning receptors have been successfully targeted by recombinant monoclonal antibodies and the development of new product candidates continues. Despite this growth, however, certain classes of important disease targets have remained intractable to therapeutic antibodies due to the complexity of the target molecules. These complex target molecules include G protein-coupled receptors and ion channels which represent a large target class for therapeutic intervention with monoclonal antibodies. Although these targets have typically been addressed by small molecule approaches, the exquisite specificity of antibodies provides a significant opportunity to provide selective modulation of these important regulators of cell function. Given this opportunity, a significant effort has been applied to address the challenges of targeting these complex molecules and a number of targets are linked to the pathophysiology of respiratory diseases. In this review, we provide a summary of the importance of GPCRs and ion channels involved in respiratory disease and discuss advantages offered by antibodies as therapeutics at these targets. We highlight some recent GPCRs and ion channels linked to respiratory disease mechanisms and describe in detail recent progress made in the strategies for discovery of functional antibodies against challenging membrane protein targets such as GPCRs and ion channels. Copyright © 2016 Elsevier Inc. All rights reserved.

Immunotherapeutic strategies in antiphospholipid syndrome.

Science.gov (United States)

Hoi, A Y; Ross, L; Day, J; Buchanan, R R C

2017-03-01

Antiphospholipid syndrome is an autoimmune condition, characterised by the persistent presence of antiphospholipid antibodies and either thrombosis or obstetric morbidity. The cornerstone of therapy is long-term anticoagulation to reduce morbidity and mortality; however, better understanding of the immunological pathways may direct us to develop future therapeutic strategies. We provide an overview of the current understanding of the immunopathogenesis of this perplexing condition and its associated morbidities and current evidence for some of the immunotherapeutic strategies. © 2017 Royal Australasian College of Physicians.

Strategies for Cancer Vaccine Development

Directory of Open Access Journals (Sweden)

Matteo Vergati

2010-01-01

Full Text Available Treating cancer with vaccines has been a challenging field of investigation since the 1950s. Over the years, the lack of effective active immunotherapies has led to the development of numerous novel strategies. However, the use of therapeutic cancer vaccines may be on the verge of becoming an effective modality. Recent phase II/III clinical trials have achieved hopeful results in terms of overall survival. Yet despite these encouraging successes, in general, very little is known about the basic immunological mechanisms involved in vaccine immunotherapy. Gaining a better understanding of the mechanisms that govern the specific immune responses (i.e., cytotoxic T lymphocytes, CD4 T helper cells, T regulatory cells, cells of innate immunity, tumor escape mechanisms elicited by each of the various vaccine platforms should be a concern of cancer vaccine clinical trials, along with clinical benefits. This review focuses on current strategies employed by recent clinical trials of therapeutic cancer vaccines and analyzes them both clinically and immunologically.

Therapeutic gene editing in CD34+ hematopoietic progenitors from Fanconi anemia patients.

Science.gov (United States)

Diez, Begoña; Genovese, Pietro; Roman-Rodriguez, Francisco J; Alvarez, Lara; Schiroli, Giulia; Ugalde, Laura; Rodriguez-Perales, Sandra; Sevilla, Julian; Diaz de Heredia, Cristina; Holmes, Michael C; Lombardo, Angelo; Naldini, Luigi; Bueren, Juan Antonio; Rio, Paula

2017-11-01

Gene targeting constitutes a new step in the development of gene therapy for inherited diseases. Although previous studies have shown the feasibility of editing fibroblasts from Fanconi anemia (FA) patients, here we aimed at conducting therapeutic gene editing in clinically relevant cells, such as hematopoietic stem cells (HSCs). In our first experiments, we showed that zinc finger nuclease (ZFN)-mediated insertion of a non-therapeutic EGFP-reporter donor in the AAVS1 "safe harbor" locus of FA-A lymphoblastic cell lines (LCLs), indicating that FANCA is not essential for the editing of human cells. When the same approach was conducted with therapeutic FANCA donors, an efficient phenotypic correction of FA-A LCLs was obtained. Using primary cord blood CD34 + cells from healthy donors, gene targeting was confirmed not only in in vitro cultured cells, but also in hematopoietic precursors responsible for the repopulation of primary and secondary immunodeficient mice. Moreover, when similar experiments were conducted with mobilized peripheral blood CD34 + cells from FA-A patients, we could demonstrate for the first time that gene targeting in primary hematopoietic precursors from FA patients is feasible and compatible with the phenotypic correction of these clinically relevant cells. © 2017 The Authors. Published under the terms of the CC BY 4.0 license.

A gamma-ray therapeutic system applied to treatment of body

International Nuclear Information System (INIS)

Huang Yu; Duan Zhengcheng; Zhu Guoli; Gong Shihua; Li Xiaoping

2004-01-01

In order to treat malignant tumors in human body, a stereotactic gamma-ray whole-body therapeutic system has been developed. This system is a typical large mechatronics treatment machine. In this paper, its main working principles and characteristics are introduced. This system comprises a special gallows frame with an open vertical structure, a changeable collimator device by which the size of convergence center can be chosen, and a 3D treatment couch. A computer brings the couch to target position automatically. Therefore precise and dynamic rotary converging therapy for tumors located anywhere in the body has been realized. The system's performance has been proved in practice, which includes good curative effect, reliable automation, and safe and secure operation. (authors)

Inherently safe light water reactors

International Nuclear Information System (INIS)

Ise, Takeharu

1987-01-01

Today's large nuclear power reactors of world-wise use have been designed based on the philosophy. It seems that recent less electricity demand rates, higher capital cost and the TMI accident let us acknowledge relative small and simplified nuclear plants with safer features, and that Chernobyl accident in 1983 underlines the needs of intrinsic and passive safety characteristics. In such background, several inherently safe reactor concepts have been presented abroad and domestically. First describing 'Can inherently safe reactors be designed,' then I introduce representative reactor concepts of inherently safe LWRs advocated abroad so far. All of these innovative reactors employ intrinsic and passive features in their design, as follows: (1) PIUS, an acronym for Process Inherent Ultimate Safety, or an integral PWR with passive heat sink and passive shutdown mechanism, advocated by ASEA-ATOM of Sweden. (2) MAP(Minimum Attention Plant), or a self-pressurized, natural circulation integral PWR, promoted by CE Inc. of the U.S. (3) TPS(TRIGA Power System), or a compact PWR with passive heat sink and inherent fuel characteristics of large prompt temperature coefficient, prompted by GA Technologies Inc. of the U.S. (4) PIUS-BWR, or an inherently safe BWR employing passively actuated fluid valves, in competition with PIUS, prompted by ORNL of the U.S. Then, I will describe the domestic trends in Japan and the innovative inherently safe LWRs presented domestically so far. (author)

A new therapeutic strategy for lengthening severe short nose.

Science.gov (United States)

Rikimaru, Hideaki; Kiyokawa, Kensuke; Watanabe, Koichi; Koga, Noriyuki; Nishi, Yukiko

2010-03-01

Correction of severe short nose is a distressing problem for plastic surgeons. It is difficult to simultaneously lengthen the 3 components of the nose, which are the outer skin envelope, the framework, and the mucosal lining. We developed a new method to lengthen the nose more than 10 mm definitively and safely, which was performed using the technique of distraction osteogenesis. The procedure involves a 2-stage operation. At the first stage, boat-shaped iliac bone is grafted on the dorsum. More than 6 months later, the second-stage operation is performed. The grafted bone is cut horizontally in the center, and the distraction device is applied to it. Distraction osteogenesis is started after a latency period of 14 days and performed at a rate of 0.6 mm once daily. The distraction device is replaced by a special attachment (Ribbond; Ribbond Inc) during the 3-month consolidation period. Our method was applied for 2 patients with congenitally and posttraumatic severe short nose, respectively. The total amount of distraction osteogenesis was 12.6 and 13.8 mm, respectively. The profiles of both of the patients improved, and they were satisfied with the results. The method we developed is an entirely new approach to the correction of severe short nose. Furthermore, it was determined that nonvascularized grafted iliac bone could be lengthened by distraction osteogenesis. Our new method was a very effective and definitive technique and could become a mainstream procedure for the correction of severe short nose.

Dementia - keeping safe in the home

Science.gov (United States)

... this page: //medlineplus.gov/ency/patientinstructions/000031.htm Dementia - keeping safe in the home To use the ... make sure the homes of people who have dementia are safe for them. Safety Tips for the ...

Improving lithium therapeutics by crystal engineering of novel ionic cocrystals.

Science.gov (United States)

Smith, Adam J; Kim, Seol-Hee; Duggirala, Naga K; Jin, Jingji; Wojtas, Lukasz; Ehrhart, Jared; Giunta, Brian; Tan, Jun; Zaworotko, Michael J; Shytle, R Douglas

2013-12-02

Current United States Food and Drug Administration (FDA)-approved lithium salts are plagued with a narrow therapeutic window. Recent attempts to find alternative drugs have identified new chemical entities, but lithium's polypharmacological mechanisms for treating neuropsychiatric disorders are highly debated and are not yet matched. Thus, re-engineering current lithium solid forms in order to optimize performance represents a low cost and low risk approach to the desired therapeutic outcome. In this contribution, we employed a crystal engineering strategy to synthesize the first ionic cocrystals (ICCs) of lithium salts with organic anions. We are unaware of any previous studies that have assessed the biological efficacy of any ICCs, and encouragingly we found that the new speciation did not negatively affect established bioactivities of lithium. We also observed that lithium ICCs exhibit modulated pharmacokinetics compared to lithium carbonate. Indeed, the studies detailed herein represent an important advancement in a crystal engineering approach to a new generation of lithium therapeutics.

Safeguards Automated Facility Evaluation (SAFE) methodology

International Nuclear Information System (INIS)

Chapman, L.D.; Grady, L.M.; Bennett, H.A.; Sasser, D.W.; Engi, D.

1978-01-01

The SAFE procedure is an efficient method of evaluating the physical protection system of a nuclear facility. Since the algorithms used in SAFE for path generation and evaluation are analytical, many paths can be evaluated with a modest investment in computer time. SAFE is easy to use because the information required is well-defined and the interactive nature of this procedure lends itself to straightforward operation. The modular approach that has been taken allows other functionally equivalent modules to be substituted as they become available. The SAFE procedure has broad applications in the nuclear facility safeguards field as well as in the security field in general. Any fixed facility containing valuable materials or components to be protected from theft or sabotage could be analyzed using this same automated evaluation technique

Immunogenicity of biologically-derived therapeutics: assessment and interpretation of nonclinical safety studies.

Science.gov (United States)

Ponce, Rafael; Abad, Leslie; Amaravadi, Lakshmi; Gelzleichter, Thomas; Gore, Elizabeth; Green, James; Gupta, Shalini; Herzyk, Danuta; Hurst, Christopher; Ivens, Inge A; Kawabata, Thomas; Maier, Curtis; Mounho, Barbara; Rup, Bonita; Shankar, Gopi; Smith, Holly; Thomas, Peter; Wierda, Dan

2009-07-01

An evaluation of potential antibody formation to biologic therapeutics during the course of nonclinical safety studies and its impact on the toxicity profile is expected under current regulatory guidance and is accepted standard practice. However, approaches for incorporating this information in the interpretation of nonclinical safety studies are not clearly established. Described here are the immunological basis of anti-drug antibody formation to biopharmaceuticals (immunogenicity) in laboratory animals, and approaches for generating and interpreting immunogenicity data from nonclinical safety studies of biotechnology-derived therapeutics to support their progression to clinical evaluation. We subscribe that immunogenicity testing strategies should be adapted to the specific needs of each therapeutic development program, and data generated from such analyses should be integrated with available clinical and anatomic pathology, pharmacokinetic, and pharmacodynamic data to properly interpret nonclinical studies.

Breastfeeding FAQs: Safely Storing Breast Milk

Science.gov (United States)

... Search English Español Breastfeeding FAQs: Safely Storing Breast Milk KidsHealth / For Parents / Breastfeeding FAQs: Safely Storing Breast ... may have. How do I store my breast milk? You can freeze and/or refrigerate your pumped ( ...

Ayahuasca: Pharmacology, neuroscience and therapeutic potential.

Science.gov (United States)

Domínguez-Clavé, Elisabet; Soler, Joaquim; Elices, Matilde; Pascual, Juan C; Álvarez, Enrique; de la Fuente Revenga, Mario; Friedlander, Pablo; Feilding, Amanda; Riba, Jordi

2016-09-01

Ayahuasca is the Quechua name for a tea obtained from the vine Banisteriopsis caapi, and used for ritual purposes by the indigenous populations of the Amazon. The use of a variation of the tea that combines B. caapi with the leaves of the shrub Psychotria viridis has experienced unprecedented expansion worldwide for its psychotropic properties. This preparation contains the psychedelic 5-HT 2A receptor agonist N,N-dimethyltryptamine (DMT) from P. viridis, plus β-carboline alkaloids with monoamine-oxidase-inhibiting properties from B. caapi. Acute administration induces a transient modified state of consciousness characterized by introspection, visions, enhanced emotions and recollection of personal memories. A growing body of evidence suggests that ayahuasca may be useful to treat substance use disorders, anxiety and depression. Here we review the pharmacology and neuroscience of ayahuasca, and the potential psychological mechanisms underlying its therapeutic potential. We discuss recent findings indicating that ayahuasca intake increases certain mindfulness facets related to acceptance and to the ability to take a detached view of one's own thoughts and emotions. Based on the available evidence, we conclude that ayahuasca shows promise as a therapeutic tool by enhancing self-acceptance and allowing safe exposure to emotional events. We postulate that ayahuasca could be of use in the treatment of impulse-related, personality and substance use disorders and also in the handling of trauma. More research is needed to assess the full potential of ayahuasca in the treatment of these disorders. Copyright © 2016 Elsevier Inc. All rights reserved.

Ecological therapeutic opportunities for oral diseases

Science.gov (United States)

Hoare, Anilei; Marsh, Philip D.; Diaz, Patricia I.

2017-01-01

SUMMARY The three main oral diseases of humans, that is caries, periodontal diseases and oral candidiasis, are associated with microbiome shifts initiated by changes in the oral environment and/or decreased effectiveness of mucosal immune surveillance. In this review we discuss the role that microbial-based therapies may have in the control of these conditions. Most investigations on the use of microorganisms for management of oral disease have been conducted with probiotic strains with some positive but very discrete clinical outcomes. Other strategies such as whole oral microbiome transplantation or modification of community function by enrichment with health-promoting indigenous oral strains may offer more promise but research in this field is still in its infancy. Any microbial-based therapeutics for oral conditions, however, are likely to be only one component within a holistic preventive strategy that should also aim at modification of the environmental influences responsible for the initiation and perpetuation of microbiome shifts associated with oral dysbiosis. PMID:28840820

Curiosity's Autonomous Surface Safing Behavior Design

Science.gov (United States)

Neilson, Tracy A.; Manning, Robert M.

2013-01-01

The safing routines on all robotic deep-space vehicles are designed to put the vehicle in a power and thermally safe configuration, enabling communication with the mission operators on Earth. Achieving this goal is made a little more difficult on Curiosity because the power requirements for the core avionics and the telecommunication equipment exceed the capability of the single power source, the Multi-Mission Radioisotope Thermoelectric Generator. This drove the system design to create an operational mode, called "sleep mode", where the vehicle turns off most of the loads in order to charge the two Li-ion batteries. The system must keep the vehicle safe from over-heat and under-heat conditions, battery cell failures, under-voltage conditions, and clock failures, both while the computer is running and while the system is sleeping. The other goal of a safing routine is to communicate. On most spacecraft, this simply involves turning on the receiver and transmitter continuously. For Curiosity, Earth is above the horizon only a part of the day for direct communication to the Earth, and the orbiter overpass opportunities only occur a few times a day. The design must robustly place the Rover in a communicable condition at the correct time. This paper discusses Curiosity's autonomous safing behavior and describes how the vehicle remains power and thermally safe while sleeping, as well as a description of how the Rover communicates with the orbiters and Earth at specific times.

Strategies for safe exploitation of fresh water through multi-strainer skimming wells in saline groundwater areas

International Nuclear Information System (INIS)

Alam, M.M.; Jaffery, H.M.; Hanif, M.

2005-01-01

Indus Basin of Pakistan to develop strategies for the safe exploitation of fresh upper groundwater layer through multi-strainer skimming wells in the areas having deeper saline groundwater. Results of detailed investigations are given in this paper. A methodology was designed for investigations and to study the movement of saline-fresh water interface. For this purpose deep observation wells were installed and water samples from various depths over a period of wells operational hours have been collected. Water quality of these samples was tested to evaluate the movement of saline-fresh water interface. Results indicated that there exists a relatively fresh water aquifer above the depth of 20m. Relatively impervious layer and clay lenses of variable thickness exists at various locations in the area. There is relatively less contribution from the lower aquifer as compared to the lateral movement of water to the well above the impervious layers. The skimming wells were operated for a different number of hours and water quality evaluated. The results show that the quality and quantity of the pumped groundwater can be improved with intermittent pumping for 4-6 hours per day under drought conditions and recovery of the water-table is quick. Moreover, the intermittent pumping maintained a minimum suction lift that helped get a relatively good discharge. Continuous long term pumping proved to be dangerous which can cause saline water intrusion. It is recommended to avoid long term pumping of skimming wells. Intermittent short hours operation can be helpful for safe exploitation of fresh water and make skimming well operation more cost effective. It is further added that 4-6 strainers make these skimming wells cost effective as compared to having a large number of strainers in a skimming well. (author)

Supporting safe driving with arthritis: developing a driving toolkit for clinical practice and consumer use.

Science.gov (United States)

Vrkljan, Brenda H; Cranney, Ann; Worswick, Julia; O'Donnell, Siobhan; Li, Linda C; Gélinas, Isabelle; Byszewski, Anna; Man-Son-Hing, Malcolm; Marshall, Shawn

2010-01-01

We conducted a series of focus groups to explore the information needs of clinicians and consumers related to arthritis and driving. An open coding analysis identified common themes across both consumer and clinician-based focus groups that underscored the importance of addressing driving-related concerns and the challenges associated with assessing safety. The results revealed that although driving is critical for maintaining independence and community mobility, drivers with arthritis experience several problems that can affect safe operation of a motor vehicle. Findings from this study are part of a broader research initiative that will inform the development of the Arthritis and Driving toolkit. This toolkit outlines strategies to support safe mobility for people with arthritis and will be an important resource in the coming years given the aging population.

Therapeutic Use of Prebiotics, Probiotics, and Postbiotics to Prevent Necrotizing Enterocolitis: What is the Current Evidence?

Science.gov (United States)

Patel, Ravi Mangal; Denning, Patricia Wei

2013-01-01

Synopsis Necrotizing enterocolitis (NEC) is a leading cause of neonatal morbidity and mortality and preventative therapies that are both effective and safe are urgently needed. Current evidence from therapeutic trials suggests that probiotics are effective in decreasing NEC in preterm infants and probiotics are currently the most promising therapy on the horizon for this devastating disease. However, concerns regarding safety and optimal dosing have limited the widespread adoption of routine clinical use of probiotics in preterm infants. In addition, prebiotics and postbiotics may be potential alternatives or adjunctive therapies to the administration of live microorganisms, although studies demonstrating their clinical efficacy in preventing NEC are lacking. This review summarizes the current evidence regarding the use of probiotics, prebiotics and postbiotics in the preterm infant, including its therapeutic role in preventing NEC. PMID:23415261

Removing Hair Safely

Science.gov (United States)

... For Consumers Home For Consumers Consumer Updates Removing Hair Safely Share Tweet Linkedin Pin it More sharing ... related to common methods of hair removal. Laser Hair Removal In this method, a laser destroys hair ...

Therapeutically targeting cyclin D1 in primary tumors arising from loss of Ini1

Science.gov (United States)

Smith, Melissa E.; Cimica, Velasco; Chinni, Srinivasa; Jana, Suman; Koba, Wade; Yang, Zhixia; Fine, Eugene; Zagzag, David; Montagna, Cristina; Kalpana, Ganjam V.

2011-01-01

Rhabdoid tumors (RTs) are rare, highly aggressive pediatric malignancies with poor prognosis and with no standard or effective treatment strategies. RTs are characterized by biallelic inactivation of the INI1 tumor suppressor gene. INI1 directly represses CCND1 and activates cyclin-dependent kinase (cdk) inhibitors p16Ink4a and p21CIP. RTs are exquisitely dependent on cyclin D1 for genesis and survival. To facilitate translation of unique therapeutic strategies, we have used genetically engineered, Ini1+/− mice for therapeutic testing. We found that PET can be used to noninvasively and accurately detect primary tumors in Ini1+/− mice. In a PET-guided longitudinal study, we found that treating Ini1+/− mice bearing primary tumors with the pan-cdk inhibitor flavopiridol resulted in complete and stable regression of some tumors. Other tumors showed resistance to flavopiridol, and one of the resistant tumors overexpressed cyclin D1, more than flavopiridol-sensitive cells. The concentration of flavopiridol used was not sufficient to down-modulate the high level of cyclin D1 and failed to induce cell death in the resistant cells. Furthermore, FISH and PCR analyses indicated that there is aneuploidy and increased CCND1 copy number in resistant cells. These studies indicate that resistance to flavopiridol may be correlated to elevated cyclin D1 levels. Our studies also indicate that Ini1+/− mice are valuable tools for testing unique therapeutic strategies and for understanding mechanisms of drug resistance in tumors that arise owing to loss of Ini1, which is essential for developing effective treatment strategies against these aggressive tumors. PMID:21173237

Clinical Practice Guideline: Safe Medication Use in the ICU.

Science.gov (United States)

Kane-Gill, Sandra L; Dasta, Joseph F; Buckley, Mitchell S; Devabhakthuni, Sandeep; Liu, Michael; Cohen, Henry; George, Elisabeth L; Pohlman, Anne S; Agarwal, Swati; Henneman, Elizabeth A; Bejian, Sharon M; Berenholtz, Sean M; Pepin, Jodie L; Scanlon, Mathew C; Smith, Brian S

2017-09-01

To provide ICU clinicians with evidence-based guidance on safe medication use practices for the critically ill. PubMed, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, CINAHL, Scopus, and ISI Web of Science for relevant material to December 2015. Based on three key components: 1) environment and patients, 2) the medication use process, and 3) the patient safety surveillance system. The committee collectively developed Population, Intervention, Comparator, Outcome questions and quality of evidence statements pertaining to medication errors and adverse drug events addressing the key components. A total of 34 Population, Intervention, Comparator, Outcome questions, five quality of evidence statements, and one commentary on disclosure was developed. Subcommittee members were assigned selected Population, Intervention, Comparator, Outcome questions or quality of evidence statements. Subcommittee members completed their Grading of Recommendations Assessment, Development, and Evaluation of the question with his/her quality of evidence assessment and proposed strength of recommendation, then the draft was reviewed by the relevant subcommittee. The subcommittee collectively reviewed the evidence profiles for each question they developed. After the draft was discussed and approved by the entire committee, then the document was circulated among all members for voting on the quality of evidence and strength of recommendation. The committee followed the principles of the Grading of Recommendations Assessment, Development, and Evaluation system to determine quality of evidence and strength of recommendations. This guideline evaluates the ICU environment as a risk for medication-related events and the environmental changes that are possible to improve safe medication use. Prevention strategies for medication-related events are reviewed by medication use process node (prescribing, distribution, administration, monitoring). Detailed

Endothelial progenitor cells from human dental pulp-derived iPS cells as a therapeutic target for ischemic vascular diseases.

Science.gov (United States)

Yoo, Chae Hwa; Na, Hee-Jun; Lee, Dong-Seol; Heo, Soon Chul; An, Yuri; Cha, Junghwa; Choi, Chulhee; Kim, Jae Ho; Park, Joo-Cheol; Cho, Yee Sook

2013-11-01

Human dental pulp cells (hDPCs) are a valuable source for the generation of patient-specific human induced pluripotent stem cells (hiPSCs). An advanced strategy for the safe and efficient reprogramming of hDPCs and subsequent lineage-specific differentiation is a critical step toward clinical application. In present research, we successfully generated hDPC-iPSCs using only two non-oncogenic factors: Oct4 and Sox2 (2F hDPC-hiPSCs) and evaluated the feasibility of hDPC-iPSCs as substrates for endothelial progenitor cells (EPCs), contributing to EPC-based therapies. Under conventional differentiation conditions, 2F hDPC-hiPSCs showed higher differentiation efficiency, compared to hiPSCs from other cell types, into multipotent CD34(+) EPCs (2F-hEPCs) capable to differentiate into functional endothelial and smooth muscle cells. The angiogenic and neovasculogenic activities of 2F-hEPCs were confirmed using a Matrigel plug assay in mice. In addition, the therapeutic effects of 2F-hEPC transplantation were confirmed in mouse models of hind-limb ischemia and myocardial infarction. Importantly, 2F-EPCs effectively integrated into newly formed vascular structures and enhanced neovascularization via likely both direct and indirect paracrine mechanisms. 2F hDPC-hiPSCs have a robust capability for the generation of angiogenic and vasculogenic EPCs, representing a strategy for patient-specific EPC therapies and disease modeling, particularly for ischemic vascular diseases. Copyright © 2013 Elsevier Ltd. All rights reserved.

Nuclear data for production of therapeutic radionuclides. Summary report of second research coordination meeting

International Nuclear Information System (INIS)

Sublet, J.-Ch.; Capote Noy, R.

2004-11-01

A summary is given of the Second Research Coordination Meeting on Nuclear Data for Production of Therapeutic Radionuclides. The new library of evaluated cross section will cover the reactor and/or accelerator production of therapeutic radionuclides to appropriate specific activities and purity along with the relevant decay data. There are a significant number of radioisotopes in use or being proposed for therapeutic applications. As a consequence of the work undertaken during the course of this CRP, the resulting completeness and accuracy of the nuclear data for the production of these nuclides to appropriate specific activities and purity along with the re-definition of their decay data should be adequate for safe and efficient medical applications. The radioisotopes to be considered in the CRP were divided into two categories: Established Radioisotopes (therapeutic radioisotopes that have established clinical uses) and Emerging Radioisotopes (less-commonly used but potentially interesting radioisotopes for which medical applications have been demonstrated). Experimental data compilations and selection and preliminary evaluations for each of the reactions were extensively discussed during the meeting. The recommendations for both established and emerging radionuclides, and validation/testing of the cross section library are summarized. Technical discussions and the resulting work plan of the Coordinated Research Programme are summarized for every reaction path to be evaluated, along with actions and deadlines. Participants' contributions to the RCM are also attached. (author)

Application in the STRATHE trial of a score system to compare the efficacy and the tolerability of different therapeutic strategies in the management of hypertension

Directory of Open Access Journals (Sweden)

Bernard Waeber

2008-02-01

Full Text Available Bernard Waeber1, Jean-Jacques Mourad21Division de Physiopathologie Clinique, Centre Hospitalier Universitaire Vaudois et Université de Lausanne, Lausanne, Switzerland; 2Hôpital Avicienne, Bobigny, FranceAbstract: A score system integrating the evolution of efficacy and tolerability over time was applied to a subpopulation of the STRATHE trial, a trial performed according to a parallel group design, with a double-blind, random allocation to either a fixed-dose combination strategy (perindopril/indapamide 2 mg/0.625 mg, with the possibility to increase the dose to 3 mg/0.935 mg, and 4 mg/1.250 mg if needed, n = 118, a sequential monotherapy approach (atenolol 50 mg, followed by losartan 50 mg and amlodipine 5 mg if needed, n = 108, or a stepped-care strategy (valsartan 40 mg, followed by valsartan 80 mg and valsartan 80 mg+ hydrochlorothiazide 12.5 mg if needed, n = 103. The aim was to lower blood pressure below 140/90 mmHg within a 9-month period. The treatment could be adjusted after 3 and 6 months. Only patients in whom the study protocol was strictly applied were included in this analysis. At completion of the trial the total score averaged 13.1 ± 70.5 (mean ± SD using the fixed-dose combination strategy, compared with –7.2 ± 81.0 using the sequential monotherapy approach and –17.5 ± 76.4 using the stepped-care strategy. In conclusion, the use of a score system allows the comparison of antihypertensive therapeutic strategies, taking into account at the same time efficacy and tolerability. In the STRATHE trial the best results were observed with the fixed-dose combination containing low doses of an angiotensin enzyme converting inhibitor (perindopril and a diuretic (indapamide.Keywords: antihypertensive therapy, tolerability, antihypertensive efficacy, fixed-dose combination, sequential monotherapy, stepped-care treatment

Surface-functionalized nanoparticles for biosensing and imaging-guided therapeutics

Science.gov (United States)

Jiang, Shan; Win, Khin Yin; Liu, Shuhua; Teng, Choon Peng; Zheng, Yuangang; Han, Ming-Yong

2013-03-01

In this article, the very recent progress of various functional inorganic nanomaterials is reviewed including their unique properties, surface functionalization strategies, and applications in biosensing and imaging-guided therapeutics. The proper surface functionalization renders them with stability, biocompatibility and functionality in physiological environments, and further enables their targeted use in bioapplications after bioconjugation via selective and specific recognition. The surface-functionalized nanoprobes using the most actively studied nanoparticles (i.e., gold nanoparticles, quantum dots, upconversion nanoparticles, and magnetic nanoparticles) make them an excellent platform for a wide range of bioapplications. With more efforts in recent years, they have been widely developed as labeling probes to detect various biological species such as proteins, nucleic acids and ions, and extensively employed as imaging probes to guide therapeutics such as drug/gene delivery and photothermal/photodynamic therapy.

Herbs-are they safe enough? an overview.

Science.gov (United States)

Singh, Divya; Gupta, Rajiv; Saraf, Shubhini A

2012-01-01

Drugs based on herbs have become a common form of therapy as well as for prophylaxis because they are often perceived as being natural and therefore harmless. Today they are one of the hottest trends and most sought after in the field of nutrition or herbal therapeutics. As the use of complementary medicine grows, so does the knowledge that many compounds in common use not only have a significant effect on the body but may also interact with pharmaceuticals and also with other alternative products. Concurrent use of herbs with drugs may mimic, magnify, or oppose the effect of drugs leading to herb-drug interactions. Currently, there is very little information published on herb-herb or herb-drug interactions as compared to the use of herbs which is progressively growing across the world. Many reports of herb-drug interactions are sketchy and lack laboratory analysis of suspect preparations. Health-care practitioners should caution patients against mixing herbs and pharmaceutical drugs. The article reviews the recent literature on the adverse effects of herbal remedies including the most widely sold herbal medicinal products, like liquorice, garlic, ginger, green tea, and turmeric, etc., and reinforce the safety aspect of herbal products, which are considered to be relatively safe by common people.

Safety Outreach and Incident Response Stakeholder Strategy

Energy Technology Data Exchange (ETDEWEB)

Rosewater, David Martin [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Conover, David [Pacific Northwest National Lab. (PNNL), Richland, WA (United States)

2016-06-01

The objective of this document is to set out a strategy to reach all stakeholders that can impact the timely deployment of safe stationary energy storage systems in the built environment with information on ESS technology and safety that is relevant to their role in deployment of the technology.

Strategies in the treatment for intracranial venous sinus thrombosis

Directory of Open Access Journals (Sweden)

JIA Qiang

2013-03-01

It was probable to subdivide CVST into mild type and severe type according to the features of symptoms, signs, lumbar puncture pressure and imaging. Different therapeutic strategies were proved to be safe and effective in the treatment of different types.

Specific transfection of inflamed brain by macrophages: a new therapeutic strategy for neurodegenerative diseases.

Directory of Open Access Journals (Sweden)

Matthew J Haney

Full Text Available The ability to precisely upregulate genes in inflamed brain holds great therapeutic promise. Here we report a novel class of vectors, genetically modified macrophages that carry reporter and therapeutic genes to neural cells. Systemic administration of macrophages transfected ex vivo with a plasmid DNA (pDNA encoding a potent antioxidant enzyme, catalase, produced month-long expression levels of catalase in the brain resulting in three-fold reductions in inflammation and complete neuroprotection in mouse models of Parkinson's disease (PD. This resulted in significant improvements in motor functions in PD mice. Mechanistic studies revealed that transfected macrophages secreted extracellular vesicles, exosomes, packed with catalase genetic material, pDNA and mRNA, active catalase, and NF-κb, a transcription factor involved in the encoded gene expression. Exosomes efficiently transfer their contents to contiguous neurons resulting in de novo protein synthesis in target cells. Thus, genetically modified macrophages serve as a highly efficient system for reproduction, packaging, and targeted gene and drug delivery to treat inflammatory and neurodegenerative disorders.

Prevention of postoperative atrial fibrillation: novel and safe strategy based on the modulation of the antioxidant system

Directory of Open Access Journals (Sweden)

Ramón eRodrigo

2012-04-01

Full Text Available Postoperative atrial fibrillation (AF is the most common arrhythmia following cardiac surgery with extracorporeal circulation. The pathogenesis of postoperative AF is multifactorial. Oxidative stress, caused by the unavoidable ischemia-reperfusion event occurring in this setting, is a major contributory factor. ROS-derived effects could result in lipid peroxidation, protein carbonylation or DNA oxidation of cardiac tissue, thus leading to functional and structural myocardial remodeling. The vulnerability of myocardial tissue to the oxidative challenge is also dependent on the activity of the antioxidant system. High ROS levels, overwhelming this system, should result in deleterious cellular effects, such as the induction of necrosis, apoptosis or autophagy. Nevertheless, tissue exposure to low to moderate ROS levels could trigger a survival response with a trend to reinforce the antioxidant defense system. Administration of n-3 polyunsaturated fatty acids (PUFA, known to involve a moderate ROS production, is consistent with a diminished vulnerability to the development of postoperative AF. Accordingly, supplementation of n-3 PUFA successfully reduced the incidence of postoperative AF after coronary bypass grafting. This response is due to an up-regulation of antioxidant enzymes, as shown in experimental models. In turn, non-enzymatic antioxidant reinforcement through vitamin C administration prior to cardiac surgery has also reduced the postoperative AF incidence. Therefore, it should be expected that a mixed therapy result in an improvement of the cardioprotective effect by modulating both components of the antioxidant system. We present available evidence supporting the view of an effective prevention of postoperative AF including a 2-step therapeutic strategy: n-3 PUFA followed by vitamin C supplementation to patients scheduled for cardiac surgery with extracorporeal circulation. The present study should encourage the design of clinical

Oxidative Stress: A Unifying Mechanism for Cell Damage Induced by Noise, (Water-Pipe) Smoking, and Emotional Stress-Therapeutic Strategies Targeting Redox Imbalance.

Science.gov (United States)

Golbidi, Saeid; Li, Huige; Laher, Ismail

2018-03-20

Modern technologies have eased our lives but these conveniences can impact our lifestyles in destructive ways. Noise pollution, mental stresses, and smoking (as a stress-relieving solution) are some environmental hazards that affect our well-being and healthcare budgets. Scrutinizing their pathophysiology could lead to solutions to reduce their harmful effects. Recent Advances: Oxidative stress plays an important role in initiating local and systemic inflammation after noise pollution, mental stress, and smoking. Lipid peroxidation and release of lysolipid by-products, disturbance in activation and function of nuclear factor erythroid 2-related factor 2 (Nrf2), induction of stress hormones and their secondary effects on intracellular kinases, and dysregulation of intracellular Ca 2+ can all potentially trigger other vicious cycles. Recent clinical data suggest that boosting the antioxidant system through nonpharmacological measures, for example, lifestyle changes that include exercise have benefits that cannot easily be achieved with pharmacological interventions alone. Indiscriminate manipulation of the cellular redox network could lead to a new series of ailments. An ideal approach requires meticulous scrutiny of redox balance mechanisms for individual pathologies so as to create new treatment strategies that target key pathways while minimizing side effects. Extrapolating our understanding of redox balance to other debilitating conditions such as diabetes and the metabolic syndrome could potentially lead to devising a unifying therapeutic strategy. Antioxid. Redox Signal. 28, 741-759.

Therapeutic Potential of Cell Penetrating Peptides (CPPs) and Cationic Polymers for Chronic Hepatitis B

DEFF Research Database (Denmark)

Ndeboko, Bénédicte; Lemamy, Guy Joseph; Nielsen, Peter E

2015-01-01

, such as chitosan (CS), appear of particular interest as nonviral vectors due to their capacity to facilitate cellular delivery of bioactive cargoes including peptide nucleic acids (PNAs) or DNA vaccines. We have investigated the ability of a PNA conjugated to different CPPs to inhibit the replication of duck......-modified CS and cationic nanoparticles. The results showed that these nonviral vectors considerably increased plasmid DNA uptake and expression. Collectively promising results obtained in preclinical studies suggest the usefulness of these safe delivery systems for the development of novel therapeutics...

A safe and reliable neutralization assay based on pseudovirus to measure neutralizing antibody titer against poliovirus.

Science.gov (United States)

Liu, Shaohua; Song, Dongmei; Bai, Han; Lu, Weiwei; Dai, Xinxian; Hao, Chunsheng; Zhang, Zhongyang; Guo, Huijie; Zhang, Yue; Li, Xiuling

2017-12-01

With the promotion of inactivated poliomyelitis vaccine (IPV) and live attenuated oral poliomyelitis vaccine (OPV), the global reported cases of poliomyelitis have reduced sharply from 0.35 million in 1988 to 74 in 2015. The Polio Eradication & Endgame Strategic Plan published by WHO in 2013 included the strategy of implementation of poliovirus safe handling and containment measures to minimize the risks of facility-associated reintroduction of virus into the polio-free community to prevent the re-import of poliovirus. Toward this strategy, we produced replication-incompetent pseudovirus of poliovirus type 1, 2, 3 attenuated strains by constructing poliovirus capsid expression vectors and poliovirus replicon then transfecting HEK293T cells and developed a pseudovirus-based neutralization assay (pNA) to determine neutralizing antibody titer which is more secure, time-saving and reliable than conventional neutralization assay (cNA). By using anti-poliovirus rat serum, we demonstrated excellent correlation between neutralizing antibody titers measured by cNA and pNA. It was concluded that pNA can be a potential alternative to replace cNA as a safe and time-saving system for titer determination after live poliovirus's safekeeping. © 2017 Wiley Periodicals, Inc.

Safe and competent opioid prescribing education: Increasing dissemination with a train-the-trainer program.

Science.gov (United States)

Zisblatt, Lara; Hayes, Sean M; Lazure, Patrice; Hardesty, Ilana; White, Julie L; Alford, Daniel P

2017-01-01

Due to the high prevalence of prescription opioid misuse, the US Food and Drug Administration (FDA) mandated a Risk Evaluation and Mitigation Strategy (REMS) requiring manufacturers of extended-release/long-acting (ER/LA) opioids to fund continuing education based on an FDA curricular Blueprint. This paper describes the Safe and Competent Opioid Prescribing Education (SCOPE of Pain) train-the-trainer program and its impact on (1) disseminating the SCOPE of Pain curriculum and (2) knowledge, confidence, attitudes, and performance of the participants of trainer-led compared with expert-led meetings. SCOPE of Pain is a 3-hour ER/LA opioid REMS education. In addition to expert-led live statewide meetings, a 2-hour train-the-trainer (TTT) workshop was developed to increase dissemination nationally. The trainers were expected to conduct SCOPE of Pain meetings at their institutions. Participants of both the trainer-led and expert-led SCOPE of Pain programs were surveyed immediately post and 2 months post meetings to assess improvements in knowledge, confidence, attitudes, and self-reported safe opioid prescribing practices. During 9 months (May 2013 to February 2014), 89 trainers were trained during 9 TTT workshops in 9 states. Over 24 months (May 2013 to April 2015), 33% of the trainers conducted at least 1 SCOPE of Pain training, with a total of 79 meetings that educated 1419 participants. The average number of meetings of those who conducted at least 1 meeting was 2.8 (range: 1-19). The participants of the trainer-led programs were significantly more likely to be practicing in rural settings than those who participated in the expert-led meetings (39% vs. 26%, P strategy to increase guideline-based safe opioid prescribing knowledge, confidence, attitudes, and self-reported practices.

Developing Safe Schools Partnerships with Law Enforcement

Science.gov (United States)

Rosiak, John

2009-01-01

Safe schools are the concern of communities throughout the world. If a school is safe, and if children feel safe, students "are better able to learn. But what are the steps to make" this happen? First, it is important to understand the problem: What are the threats to school safety? These include crime-related behaviors that find their way to…

Decommissioning strategy selection

International Nuclear Information System (INIS)

Warnecke, E.

2005-01-01

At the end of their useful life nuclear facilities have to be decommissioned. The strategy selection on how to decommission a facility is a highly important decision at the very beginning of decommissioning planning. Basically, a facility may be subject to (a) immediate dismantling; (b) deferred dismantling after a period of ''safe enclosure'' or (c) entombment where a facility is turned into a near surface disposal facility. The first two strategies are normally applied. The third one may be accepted in countries without significant nuclear activities and hence without disposal facilities for radioactive waste. A large number of factors has to be taken into account when a decision on the decommissioning strategy is being made. Many of the factors cannot be quantified. They may be qualitative or subject to public opinion which may change with time. At present, a trend can be observed towards immediate dismantling of nuclear facilities, mainly because it is associated with less uncertainty, less local impact, a better public acceptance, and the availability of operational expertise and know how. A detailed evaluation of the various factors relevant to strategy selection and a few examples showing the situation regarding decommissioning strategy in a number of selected countries are presented in the following article. (orig.)

Coronary Computed Tomographic Angiography-Derived Fractional Flow Reserve for Therapeutic Decision Making.

Science.gov (United States)

Tesche, Christian; Vliegenthart, Rozemarijn; Duguay, Taylor M; De Cecco, Carlo N; Albrecht, Moritz H; De Santis, Domenico; Langenbach, Marcel C; Varga-Szemes, Akos; Jacobs, Brian E; Jochheim, David; Baquet, Moritz; Bayer, Richard R; Litwin, Sheldon E; Hoffmann, Ellen; Steinberg, Daniel H; Schoepf, U Joseph

2017-12-15

This study investigated the performance of coronary computed tomography angiography (cCTA) with cCTA-derived fractional flow reserve (CT-FFR) compared with invasive coronary angiography (ICA) with fractional flow reserve (FFR) for therapeutic decision making in patients with suspected coronary artery disease (CAD). Seventy-four patients (62 ± 11 years, 62% men) with at least 1 coronary stenosis of ≥50% on clinically indicated dual-source cCTA, who had subsequently undergone ICA with FFR measurement, were retrospectively evaluated. CT-FFR values were computed using an on-site machine-learning algorithm to assess the functional significance of CAD. The therapeutic strategy (optimal medical therapy alone vs revascularization) and the appropriate revascularization procedure (percutaneous coronary intervention vs coronary artery bypass grafting) were selected using cCTA-CT-FFR. Thirty-six patients (49%) had a functionally significant CAD based on ICA-FFR. cCTA-CT-FFR correctly identified a functionally significant CAD and the need of revascularization in 35 of 36 patients (97%). When revascularization was deemed indicated, the same revascularization procedure (32 percutaneous coronary interventions and 3 coronary artery bypass grafting) was chosen in 35 of 35 patients (100%). Overall, identical management strategies were selected in 73 of the 74 patients (99%). cCTA-CT-FFR shows excellent performance to identify patients with and without the need for revascularization and to select the appropriate revascularization strategy. cCTA-CT-FFR as a noninvasive "one-stop shop" has the potential to change diagnostic workflows and to directly inform therapeutic decision making in patients with suspected CAD. Copyright © 2017 Elsevier Inc. All rights reserved.

Prediction of safe driving Behaviours based on health belief model: the case of taxi drivers in Bandar Abbas, Iran.

Science.gov (United States)

Razmara, Asghar; Aghamolaei, Teamur; Madani, Abdoulhossain; Hosseini, Zahra; Zare, Shahram

2018-03-20

Road accidents are among the main causes of mortality. As safe and secure driving is a key strategy to reduce car injuries and offenses, the present research aimed to explore safe driving behaviours among taxi drivers based on the Health Belief Model (HBM). This study was conducted on 184 taxi drivers in Bandar Abbas who were selected based on a multiple stratified sampling method. Data were collected by a questionnaire comprised of a demographic information section along with the constructs of the HBM. Data were analysed by SPSS ver19 via a Pearson's correlation coefficient and multiple regressions. The mean age of the participants was 45.1 years (SD = 11.1). They all had, on average, 10.3 (SD = 7/5) years of taxi driving experience. Among the HBM components, cues to action and perceived benefits were shown to be positively correlated with safe driving behaviours, while perceived barriers were negatively correlated. Cues to action, perceived barriers and perceived benefits were shown to be the strongest predictors of a safe drivers' behaviour. Based on the results of this study in designing health promotion programmes to improve safe driving behaviours among taxi drivers, cues to action, perceived benefits and perceived barriers are important. Therefore, advertising, the design of information campaigns, emphasis on the benefits of safe driving behaviours and modification barriers are recommended.

The effect of therapeutic horseback riding on balance in community-dwelling older adults: a pilot study.

Science.gov (United States)

Homnick, Tamara D; Henning, Kim M; Swain, Charlene V; Homnick, Douglas N

2015-02-01

Equine assisted activities (hippotherapy and therapeutic riding) improve balance in patients with disabilities such as cerebral palsy, but have not been systematically studied in older adults, at risk of falls due to balance deficits. We conducted a 10-week, single blind, controlled trial of the effect of a therapeutic horseback riding course on measures of balance in community-dwelling adults 65 years and older. Nine riders and six controls completed the trial. Controls were age matched to riders and all participants were recruited from the local community. Both groups showed improvements in balance during the trial, but did not reach statistical significance. Sample size was small, participants had relatively high initial balance scores, and controls tended to increase their physical activities, likely influencing outcomes. No adverse events occurred and the supervised therapeutic riding program appeared to be a safe and effective form of exercise to improve balance in older adults. A power analysis was performed to estimate numbers of participants needed for a larger study. © The Author(s) 2012.

Can triptans safely be used for airplane headache?

Science.gov (United States)

Ipekdal, H Ilker; Karadaş, Ömer; Öz, Oğuzhan; Ulaş, Ümit H

2011-12-01

A few cases of airplane headache (AH) have been reported in the literature. Treatment strategies of AHs are also controversial. We followed-up five patients with AH. They were symptom-free during the daytime. Their physical, neurological, and ear-nose-throat examinations were all normal. Blood chemistries, cerebral magnetic resonance imaging, cerebral magnetic resonance imaging angiography, and paranasal sinus tomography studies of the patients were also normal. We preferred triptans because of the possible effect on the mechanism of AH. Patients were recommended to use single-dose of their drugs half an hour prior to flights. All of the patients had a good response to single dose triptan treatment and became headache-free during flights. This is the first study which puts forward the usefulness of the triptans as a safe treatment choice for airplane AH.

A Potential Therapeutic Strategy for Malignant Mesothelioma with Gene Medicine

Directory of Open Access Journals (Sweden)

Yuji Tada

2013-01-01

Full Text Available Malignant mesothelioma, closely linked with occupational asbestos exposure, is relatively rare in the frequency, but the patient numbers are going to increase in the next few decades all over the world. The current treatment modalities are not effective in terms of the overall survival and the quality of life. Mesothelioma mainly develops in the thoracic cavity and infrequently metastasizes to extrapleural organs. A local treatment can thereby be beneficial to the patients, and gene therapy with an intrapleural administration of vectors is one of the potential therapeutics. Preclinical studies demonstrated the efficacy of gene medicine for mesothelioma, and clinical trials with adenovirus vectors showed the safety of an intrapleural injection and a possible involvement of antitumor immune responses. Nevertheless, low transduction efficiency remains the main hurdle that hinders further clinical applications. Moreover, rapid generation of antivector antibody also inhibits transgene expressions. In this paper, we review the current status of preclinical and clinical gene therapy for malignant mesothelioma and discuss potential clinical directions of gene medicine in terms of a combinatory use with anticancer agents and with immunotherapy.

Overcoming the Challenges of siRNA Delivery: Nanoparticle Strategies.

Science.gov (United States)

Shajari, Neda; Mansoori, Behzad; Davudian, Sadaf; Mohammadi, Ali; Baradaran, Behzad

2017-01-01

Despite therapeutics based on siRNA have an immense potential for the treatment of incurable diseases such as cancers. However, the in vivo utilization of siRNA and also the delivery of this agent to the target site is one of the most controversial challenges. The helpful assistance by nanoparticles can improve stable delivery and also enhance efficacy. More nanoparticle-based siRNA therapeutics is expected to become available in the near future. The search strategy followed the guidelines of the Centre of Reviews and Dissemination. The studies were identified from seven databases (Scopus, Web of Science, Academic Search Premiere, CINAHL, Medline Ovid, Eric and Cochrane Library). Studies was selected based on titles, abstracts and full texts. One hundred twenty nine papers were included in the review. These papers defined hurdles in RNAi delivery and also strategies to overcome these hurdles. This review discussed the existing hurdles for systemic administration of siRNA as therapeutic agents and highlights the various strategies to overcome these hurdles, including lipid-based nanoparticles and polymeric nanoparticles, and we also briefly reviewed chemical modification. Delivery of siRNA to the target site is the biggest challenge for its application in the clinic. The findings of this review confirmed by encapsulation siRNA in the nanoparticles can overcome these challenges. The rapid progress in nanotechnology has enabled the development of effective nanoparticles as the carrier for siRNA delivery. However, our data about siRNA-based therapeutics and also nanomedicine are still limited. More clinical data needs to be completely understood in the benefits and drawbacks of siRNA-based therapeutics. Prospective studies must pay attention to the in vivo safety profiles of the different delivery systems, including uninvited immune system stimulation and cytotoxicity. In essence, the development of nontoxic, biocompatible, and biodegradable delivery systems for

Towards Safe Robotic Surgical Systems

DEFF Research Database (Denmark)

Sloth, Christoffer; Wisniewski, Rafael

2015-01-01

a controller for motion compensation in beating-heart surgery, and prove that it is safe, i.e., the surgical tool is kept within an allowable distance and orientation of the heart. We solve the problem by simultaneously finding a control law and a barrier function. The motion compensation system is simulated...... from several initial conditions to demonstrate that the designed control system is safe for every admissible initial condition....

Safe use of ionizing radiations

Energy Technology Data Exchange (ETDEWEB)

1973-01-01

Based on the ''Code of Practice for the protection of persons against ionizing radiations arising from medical and dental use'' (CIS 74-423), this handbook shows how hospital staff can avoid exposing themselves and others to these hazards. It is designed particularly for junior and student nurses. Contents: ionizing radiations, their types and characteristics; their uses and dangers; basic principles in their safe use; safe use in practice; explanation of terms.

Staying Safe in the Water

Centers for Disease Control (CDC) Podcasts

2008-05-15

In this podcast, Dr. Julie Gilchrist, a pediatrician and medical epidemiologist from CDC’s Injury Center, talks about staying safe in the water. Tips are for all audiences, with a focus on preventing drownings and keeping children safe in and around the pool, lake, or ocean.  Created: 5/15/2008 by National Center for Injury Prevention and Control (NCIPC).   Date Released: 5/19/2008.

Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE)

DEFF Research Database (Denmark)

Peyrin-Biroulet, L; Sandborn, W; Sands, B E

2015-01-01

OBJECTIVES: The Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) program was initiated by the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD). It examined potential treatment targets for inflammatory bowel disease (IBD) to be used for a "treat-t...... target. CONCLUSIONS: Evidence- and consensus-based recommendations for selecting the goals for treat-to-target strategies in patients with IBD are made available. Prospective studies are needed to determine how these targets will change disease course and patients' quality of life....

Safe prescribing: a titanic challenge

Science.gov (United States)

Routledge, Philip A

2012-01-01

The challenge to achieve safe prescribing merits the adjective ‘titanic’. The organisational and human errors leading to poor prescribing (e.g. underprescribing, overprescribing, misprescribing or medication errors) have parallels in the organisational and human errors that led to the loss of the Titanic 100 years ago this year. Prescribing can be adversely affected by communication failures, critical conditions, complacency, corner cutting, callowness and a lack of courage of conviction, all of which were also factors leading to the Titanic tragedy. These issues need to be addressed by a commitment to excellence, the final component of the ‘Seven C's’. Optimal prescribing is dependent upon close communication and collaborative working between highly trained health professionals, whose role is to ensure maximum clinical effectiveness, whilst also protecting their patients from avoidable harm. Since humans are prone to error, and the environments in which they work are imperfect, it is not surprising that medication errors are common, occurring more often during the prescribing stage than during dispensing or administration. A commitment to excellence in prescribing includes a continued focus on lifelong learning (including interprofessional learning) in pharmacology and therapeutics. This should be accompanied by improvements in the clinical working environment of prescribers, and the encouragement of a strong safety culture (including reporting of adverse incidents as well as suspected adverse drug reactions whenever appropriate). Finally, members of the clinical team must be prepared to challenge each other, when necessary, to ensure that prescribing combines the highest likelihood of benefit with the lowest potential for harm. PMID:22738396

Does Your Department Have a Technology Innovation Strategy?

Science.gov (United States)

Felkey, Bill G; Fox, Brent I

2016-11-01

There are ways to facilitate the successful implementation of technological innovations. These are especially important in a time of rapid development of new tools to support safe and effective medication therapy. This installment addresses some of the key components of a successful technology innovation strategy.

Ventilation Guidance To Promote the Safe Use of Spray Polyurethane Foam (SPF) Insulation, Incluyendo la Versión de Español

Science.gov (United States)

This guidance describes basic ventilation principles and strategies to help protect workers and building occupants and promote the safe use of spray polyurethane foam (SPF) insulation. Guia para la ventilacion sobre la application del aerosol de espuma.

From Islands to Networks: A Blueprint for a Comprehensive US Security Strategy in the Asia-Pacific Region

National Research Council Canada - National Science Library