WorldWideScience

Sample records for therapeutic strategy comparison

  1. [Hepatitis C infection: Therapeutic strategies].

    Science.gov (United States)

    Diatta, Thierno; Chavade, Delphine; Degos, Françoise; d'Andon, Anne; Guillevin, Loïc

    2016-05-01

    The development of new direct acting antivirals has significantly modified strategies to treat chronic hepatitis C. Treatments were previously made of an interferon-based combination. This article aims to review the direct acting antivirals clinical data and to discuss the new regimens for the management of chronic hepatitis C. Direct acting antivirals combinations - with or without ribavirin - are the new chronic hepatitis C standard treatment regimen. These combinations often result in sustained viral response rate (>90%, including in patients with uncomplicated cirrhosis) after a 12-week treatment for most patients. The innovation could represent a new era for patients with unmet medical need (especially ineligible or non-responders to interferon and/or ribavirin patients). Further investigations are required to confirm the efficacy in specific population (complicated cirrhosis, pre- or post-transplantation, chronic renal failure, comorbidities, etc.) where clinical data are still limited. Other treatments are currently being developed and might lead to new perspectives, especially in terms of treatment duration or therapeutic simplification. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  2. Indirect comparisons of therapeutic interventions

    Directory of Open Access Journals (Sweden)

    Boulkhemair, Dalila

    2009-07-01

    Full Text Available Health political background: The comparison of the effectiveness of health technologies is not only laid down in German law (Social Code Book V, § 139 and § 35b but also constitutes a central element of clinical guidelines and decision making in health care. Tools supporting decision making (e. g. Health Technology Assessments (HTA are therefore in need of a valid methodological repertoire for these comparisons. Scientific background: Randomised controlled head-to-head trials which directly compare the effects of different therapies are considered the gold standard methodological approach for the comparison of the efficacy of interventions. Because this type of trial is rarely found, comparisons of efficacy often need to rely on indirect comparisons whose validity is being controversially debated. Research questions: Research questions for the current assessment are: Which (statistical methods for indirect comparisons of therapeutic interventions do exist, how often are they applied and how valid are their results in comparison to the results of head-to-head trials? Methods: In a systematic literature research all medical databases of the German Institute of Medical Documentation and Information (DIMDI are searched for methodological papers as well as applications of indirect comparisons in systematic reviews. Results of the literature analysis are summarized qualitatively for the characterisation of methods and quantitatively for the frequency of their application. The validity of the results from indirect comparisons is checked by comparing them to the results from the gold standard – a direct comparison. Data sets from systematic reviews which use both direct and indirect comparisons are tested for consistency by of the z-statistic. Results: 29 methodological papers and 106 applications of indirect methods in systematic reviews are being analysed. Four methods for indirect comparisons can be identified: 1. Unadjusted indirect comparisons

  3. Therapeutic strategies in pulmonary hypertension

    Directory of Open Access Journals (Sweden)

    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.

  4. Therapeutic Strategies in Pulmonary Hypertension

    Science.gov (United States)

    Fuso, Leonello; Baldi, Fabiana; Perna, Alessandra Di

    2011-01-01

    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. PMID:21687513

  5. [Therapeutic strategies for systemic lupus erythematosus].

    Science.gov (United States)

    Schneider, M

    2015-04-01

    Therapeutic strategy means the definition of a long-term target, which should be reached by a chosen management. As for rheumatoid arthritis, the treat to target initiative recommends remission as the target for systemic lupus erythematosus (SLE) but the command variables of remission are not yet defined. The basis of a therapeutic strategy is first the analysis of those factors that may influence the achievement of the objectives: SLE disease activity, the differentiation of damage, organ manifestations, comorbidities, genetics, sex, age of onset and considering the pathophysiological basis are some of these factors. The next step is the analysis of the available substances and concepts that allow the target to be reached. Finally, rules for management (e.g. guidelines) are needed that enrich the possibility to reach the target and improve the prognosis of patients suffering from SLE.

  6. [Hodgkin lymphoma: Current and future therapeutic strategies].

    Science.gov (United States)

    Turpin, Anthony; Michot, Jean-Marie; Kempf, Emmanuelle; Mazeron, Renaud; Dartigues, Peggy; Terroir, Marie; Boros, Angela; Bonnetier, Serge; Castilla-Llorente, Cristina; Coman, Tereza; Danu, Alina; Ghez, David; Pilorge, Sylvain; Arfi-Rouche, Julia; Dercle, Laurent; Soria, Jean-Charles; Carde, Patrice; Ribrag, Vincent; Fermé, Christophe; Lazarovici, Julien

    2018-01-01

    Hodgkin lymphoma (HL) is a cancer that mostly affects young people, in which modern therapeutic strategies using chemotherapy and radiotherapy result in a cure rate exceeding 80%. Survivors are exposed to long-term consequences of treatments, such as secondary malignancies and cardiovascular diseases, whose mortality exceeds the one of the disease itself, with long-term follow-up. The current therapeutic strategy in HL, based on the assessment of initial risk factors, is the result of large clinical trials led by the main international cooperating groups. More recently, several groups have tried to develop treatment strategies adapted to the response to chemotherapy, evaluated by interim PET/CT scan. However to date, the combined treatment with chemotherapy followed by radiation therapy remains a standard in most of the above-diaphragmatic localized forms. Immune checkpoint inhibitors, and especially anti-PD1 antibodies, have shown dramatic results in some serious forms of relapsed or refractory HL, with limited toxicity, and may contribute in the future to reduce the toxicities of treatments. Copyright © 2017 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

  7. Creutzfeldt-Jakob disease: therapeutic strategies.

    Science.gov (United States)

    Beringue, V; Deslys, J P; Adjou, K T; Dormont, D

    1997-04-01

    Creutzfeldt-Jakob disease (CJD) is a rare neurodegenerative illness which belongs to the group of transmissible subacute spongiform encephalopathies (TSSE). Today, no treatment is available for TSSE. The appearance of a new variant of CJD, which affects young people and could be linked to so-called ;mad cow disease', has stimulated researchers to develop new therapies against CJD. A few drugs have already been shown to delay the onset of experimental TSSE. They could contribute to the understanding of the pathogenic mechanisms involved in TSSE and, therefore, could be the basis for therapeutic strategies against CJD.

  8. Mustard Gas Inhalation Injury: Therapeutic Strategy.

    Science.gov (United States)

    Keyser, Brian M; Andres, Devon K; Holmes, Wesley W; Paradiso, Danielle; Appell, Ashley; Letukas, Valerie A; Benton, Betty; Clark, Offie E; Gao, Xiugong; Ray, Prabhati; Anderson, Dana R; Ray, Radharaman

    2014-07-01

    Mustard gas (sulfur mustard [SM], bis-[2-chloroethyl] sulfide) is a vesicating chemical warfare agent and a potential chemical terrorism agent. Exposure of SM causes debilitating skin blisters (vesication) and injury to the eyes and the respiratory tract; of these, the respiratory injury, if severe, may even be fatal. Therefore, developing an effective therapeutic strategy to protect against SM-induced respiratory injury is an urgent priority of not only the US military but also the civilian antiterrorism agencies, for example, the Homeland Security. Toward developing a respiratory medical countermeasure for SM, four different classes of therapeutic compounds have been evaluated in the past: anti-inflammatory compounds, antioxidants, protease inhibitors and antiapoptotic compounds. This review examines all of these different options; however, it suggests that preventing cell death by inhibiting apoptosis seems to be a compelling strategy but possibly dependent on adjunct therapies using the other drugs, that is, anti-inflammatory, antioxidant, and protease inhibitor compounds. © The Author(s) 2014.

  9. 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)

  10. Hydrogels for central nervous system therapeutic strategies.

    Science.gov (United States)

    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.

  11. [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

  12. [Therapeutic strategies in the first psychotic episode].

    Science.gov (United States)

    Douki, S; Taktak, M J; Ben Zineb, S; Cheour, M

    1999-11-01

    A first psychotic episode includes a wide range of disorders with different outcomes: schizophrenia, bipolar disorder, schizophreniform disorder, schizoaffective disorder, drug-induced psychosis, brief reactive psychosis, organic psychoses and delusional disorder. The course and outcome of a first psychotic episode is greatly dependent on its initial management. Major clinical, etiopathogenic and therapeutic advances have been achieved in this field and have allowed specific management strategies to be adopted. The primary task of therapists involved in the management of patients who have experienced a first episode of psychosis is promotion of recovery and prevention of secondary morbidity, relapse and persistent disability. The main guidelines of an early psychosis management are:--to keep in mind that early psychosis is not early schizophrenia. Thus, clinicians and therapists should avoid an early diagnosis of schizophrenia. Diagnosis in early psychosis can be highly unstable. A diagnosis of schizophrenia, with its implications of pessimism, relapse and disability, does not contribute anything positive in terms of guiding treatment. On the contrary, such a diagnosis may damage the patient and family by stigmatizing them and affecting the way they are viewed and managed by healthcare professionals.--To integrate biological, psychological and social interventions: effective medications is useful in reducing the risk of relapse, but is not a guarantee against it. Psychological and social interventions can greatly help promote recovery.--To tailor the various strategies to met the needs of an individual: as an example, it is important to formulate appropriate strategies for the different stages of the illness (prodromal phase, acute phase, early recovery phase and late recovery phase) because patients have different therapeutic needs at each stage.--In the acute treatment, not to concentrate on short-term goals in indicating antipsychotic treatment: prescribing

  13. The therapeutic strategies against Naegleria fowleri.

    Science.gov (United States)

    Bellini, Natália Karla; Santos, Thomás Michelena; da Silva, Marco Túlio Alves; Thiemann, Otavio Henrique

    2018-04-01

    Naegleria fowleri is a pathogenic amoeboflagellate most prominently known for its role as the etiological agent of the Primary Amoebic Meningoencephalitis (PAM), a disease that afflicts the central nervous system and is fatal in more than 95% of the reported cases. Although being fatal and with potential risks for an increase in the occurrence of the pathogen in populated areas, the organism receives little public health attention. A great underestimation in the number of PAM cases reported is assumed, taking into account the difficulty in obtaining an accurate diagnosis. In this review, we summarize different techniques and methods used in the identification of the protozoan in clinical and environmental samples. Since it remains unclear whether the protozoan infection can be successfully treated with the currently available drugs, we proceed to discuss the current PAM therapeutic strategies and its effectiveness. Finally, novel compounds for potential treatments are discussed as well as research on vaccine development against PAM. Copyright © 2018 Elsevier Inc. All rights reserved.

  14. Sterile Neuroinflammation and Strategies for Therapeutic Intervention

    Directory of Open Access Journals (Sweden)

    Manoj Banjara

    2017-01-01

    Full Text Available Sterile neuroinflammation is essential for the proper brain development and tissue repair. However, uncontrolled neuroinflammation plays a major role in the pathogenesis of various disease processes. The endogenous intracellular molecules so called damage-associated molecular patterns or alarmins or damage signals that are released by activated or necrotic cells are thought to play a crucial role in initiating an immune response. Sterile inflammatory response that occurs in Alzheimer’s disease (AD, Parkinson’s disease (PD, stroke, hemorrhage, epilepsy, or traumatic brain injury (TBI creates a vicious cycle of unrestrained inflammation, driving progressive neurodegeneration. Neuroinflammation is a key mechanism in the progression (e.g., AD and PD or secondary injury development (e.g., stroke, hemorrhage, stress, and TBI of multiple brain conditions. Hence, it provides an opportunity for the therapeutic intervention to prevent progressive tissue damage and loss of function. The key for developing anti-neuroinflammatory treatment is to minimize the detrimental and neurotoxic effects of inflammation while promoting the beneficial and neurotropic effects, thereby creating ideal conditions for regeneration and repair. This review outlines how inflammation is involved in the pathogenesis of major nonpathogenic neuroinflammatory conditions and discusses the complex response of glial cells to damage signals. In addition, emerging experimental anti-neuroinflammatory drug treatment strategies are discussed.

  15. Delta hedging strategies comparison

    DEFF Research Database (Denmark)

    De Giovanni, Domenico; Ortobelli, S.; Rachev, S.T.

    2008-01-01

    In this paper we implement dynamic delta hedging strategies based on several option pricing models. We analyze different subordinated option pricing models and we examine delta hedging costs using ex-post daily prices of S&P 500. Furthermore, we compare the performance of each subordinated model...

  16. Therapeutic vaccination strategies to treat nasopharyngeal carcinoma.

    Science.gov (United States)

    Taylor, Graham S; Steven, Neil M

    2016-04-01

    Epstein-Barr virus (EBV) infects most people worldwide. EBV has oncogenic potential and is strongly associated with several lymphomas and carcinomas, including nasopharyngeal carcinoma (NPC), that together total 200,000 cases of cancer each year. All EBV-associated cancers express viral proteins that allow highly selective immunotherapeutic targeting of the malignant cells. A number of therapeutic EBV vaccines have been tested in clinical trials with evidence of immune boosting and clinical responses in NPC patients. Therapeutic vaccination could be used after adoptive T-cell transfer to increase and sustain the number of infused T-cells or combined with immunotherapies acting at different stages of the cancer immunity cycle to increase efficacy. The therapeutic EBV vaccines tested to date have been well tolerated with minimal off-target toxicity. A safe therapeutic vaccine that was also able to be mass produced could, in principle, be used to vaccinate large numbers of patients after first line therapy to reduce recurrence.

  17. 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.

  18. 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...

  19. Diagnostic efficacy of gadoxetic acid (Primovist)-enhanced MRI and spiral CT for a therapeutic strategy: comparison with intraoperative and histopathologic findings in focal liver lesions

    International Nuclear Information System (INIS)

    Hammerstingl, Renate; Vogl, Thomas J.; Huppertz, Alexander; Breuer, Josy; Balzer, Thomas; Blakeborough, Anthony; Carter, Rick; Castells Fuste, Lluis; Heinz-Peer, Gertraud; Judmaier, Werner; Laniado, Michael; Manfredi, Riccardo M.; Mathieu, Didier G.; Mueller, Dieter; Mortele, Koenraad; Reimer, Peter; Reiser, Maximilian F.; Robinson, Philip J.; Shamsi, Kohkan; Strotzer, Michael; Taupitz, Matthias; Tombach, Bernd; Valeri, Gianluca; Beers, Bernhard E. van

    2008-01-01

    A multicenter study has been employed to evaluate the diagnostic efficacy of magnetic resonance imaging (MRI) using the new liver-specific contrast agent gadoxetic acid (Gd-EOB-DTPA, Primovist), as opposed to contrast-enhanced biphasic spiral computed tomography (CT), in the diagnosis of focal liver lesions, compared with a standard of reference (SOR). One hundred and sixty-nine patients with hepatic lesions eligible for surgery underwent Gd-EOB-DTPA-enhanced MRI as well as CT within 6 weeks. Pathologic evaluation of the liver specimen combined with intraoperative ultrasound established the SOR. Data sets were evaluated on-site (14 investigators) and off-site (three independent blinded readers). Gd-EOB-DTPA was well tolerated. Three hundred and two lesions were detected in 131 patients valid for analysis by SOR. The frequency of correctly detected lesions was significantly higher on Gd-EOB-DTPA-enhanced MRI compared with CT in the clinical evaluation [10.44%; 95% confidence interval (CI): 4.88, 16.0]. In the blinded reading there was a trend towards Gd-EOB-DTPA-enhanced MRI, not reaching statistical significance (2.14%; 95% CI: -4.32, 8.6). However, the highest rate of correctly detected lesions with a diameter below 1 cm was achieved by Gd-EOB-DTPA-enhanced MRI. Differential diagnosis was superior for Gd-EOB-DTPA-enhanced MRI (82.1%) versus CT (71.0%). A change in surgical therapy was documented in 19 of 131 patients (14.5%) post Gd-EOB-DTPA-enhanced MRI. Gd-EOB-DTPA-enhanced MRI was superior in the diagnosis and therapeutic management of focal liver lesions compared with CT. (orig.)

  20. Diagnostic efficacy of gadoxetic acid (Primovist)-enhanced MRI and spiral CT for a therapeutic strategy: comparison with intraoperative and histopathologic findings in focal liver lesions

    Energy Technology Data Exchange (ETDEWEB)

    Hammerstingl, Renate; Vogl, Thomas J. [Johann Wolfgang Goethe-Univ., Inst. of Diagnostic and Interventional Radiology, Frankfurt am Main (Germany); Huppertz, Alexander [Imaging Science Inst., Charite - Siemens, Berlin (Germany); Breuer, Josy; Balzer, Thomas [Gobal Clinical Development Diagnostics, Bayer Schering Pharma AG, Berlin (Germany); Blakeborough, Anthony [Royal Hallamshire Hospital, Dept. of Radiology, Sheffield (United Kingdom); Carter, Rick [Bayer Health Care Ltd., Burgess Hill, West Sussex (United Kingdom); Castells Fuste, Lluis [Hospital Vall d' Hebron, Liver Unit, Dept. of Internal Medicine, Barcelona (Spain); Heinz-Peer, Gertraud [Universitaetsklinik fuer Radiodiagnostik, Allg. Krankenhaus der Stadt Wien, Wien (Germany); Judmaier, Werner [Univ. Hospital Innsbruck, Dept. of Magnetic Resonance Imaging and Spectroscopy, Innsbruck (Austria); Laniado, Michael [Universitaetsklinikum Carl Gustav Carus, Technische Univ. Dresden, Inst. for Diagnostic Radiology, Dresden (Germany); Manfredi, Riccardo M. [Univ. of Verona, Dept. of Radiology, Verona (Italy); Mathieu, Didier G. [Centre d' Imagerie, Aix en Provence (France); Mueller, Dieter [Georg-August Univ., Dept. of Radiology, Goettingen (Germany); Mortele, Koenraad [Brigham and Women' s Hospital, Dept. of Radiology (L1), Boston, MA (United States); Reimer, Peter [Klinikum Karlsruhe, Dept. of Radiology, Karlsruhe (Germany); Reiser, Maximilian F. [Ludwig-Maximilians-Univ. Munich - Klinikum Grosshadern, Inst. of Clinical Radiology, Munich (Germany); Robinson, Philip J. [St James' s Univ. Hospital, Dept. of Clinical Radiology, Leeds (United Kingdom); Shamsi, Kohkan [Berlex Labs. Inc., Montville, NJ (United States); Strotzer, Michael [Univ. Hospital, Dept. of Diagnostic Radiology, Regensburg (Germany); Taupitz, Matthias [Universitaetsklinikum Charite, Med. Fakultaet der Humboldt-Univ., Dept. of Radiology, Berlin (Germany); Tombach, Bernd; Valeri, Gianluca; Beers, Bernhard E. van [and others

    2008-03-15

    A multicenter study has been employed to evaluate the diagnostic efficacy of magnetic resonance imaging (MRI) using the new liver-specific contrast agent gadoxetic acid (Gd-EOB-DTPA, Primovist), as opposed to contrast-enhanced biphasic spiral computed tomography (CT), in the diagnosis of focal liver lesions, compared with a standard of reference (SOR). One hundred and sixty-nine patients with hepatic lesions eligible for surgery underwent Gd-EOB-DTPA-enhanced MRI as well as CT within 6 weeks. Pathologic evaluation of the liver specimen combined with intraoperative ultrasound established the SOR. Data sets were evaluated on-site (14 investigators) and off-site (three independent blinded readers). Gd-EOB-DTPA was well tolerated. Three hundred and two lesions were detected in 131 patients valid for analysis by SOR. The frequency of correctly detected lesions was significantly higher on Gd-EOB-DTPA-enhanced MRI compared with CT in the clinical evaluation [10.44%; 95% confidence interval (CI): 4.88, 16.0]. In the blinded reading there was a trend towards Gd-EOB-DTPA-enhanced MRI, not reaching statistical significance (2.14%; 95% CI: -4.32, 8.6). However, the highest rate of correctly detected lesions with a diameter below 1 cm was achieved by Gd-EOB-DTPA-enhanced MRI. Differential diagnosis was superior for Gd-EOB-DTPA-enhanced MRI (82.1%) versus CT (71.0%). A change in surgical therapy was documented in 19 of 131 patients (14.5%) post Gd-EOB-DTPA-enhanced MRI. Gd-EOB-DTPA-enhanced MRI was superior in the diagnosis and therapeutic management of focal liver lesions compared with CT. (orig.)

  1. 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.

  2. New therapeutic strategies for malignant pleural mesothelioma.

    Science.gov (United States)

    Bonelli, Mara A; Fumarola, Claudia; La Monica, Silvia; Alfieri, Roberta

    2017-01-01

    Malignant pleural mesothelioma (MPM) is a rare and aggressive malignant disease affecting the mesothelium, commonly associated to asbestos exposure. Therapeutic actions are limited due to the late stage at which most patients are diagnosed and the intrinsic chemo-resistance of the tumor. The recommended systemic therapy for MPM is cisplatin/pemetrexed regimen with a mean overall survival of about 12months and a median progression free survival of less than 6months. Considering that the incidence of this tumor is expected to increase in the next decade and that its prognosis is poor, novel therapeutic approaches are urgently needed. For some tumors, such as lung cancer and breast cancer, druggable oncogenic alterations have been identified and targeted therapy is an important option for these patients. For MPM, clinical guidelines do not recommend biological targeted therapy, mainly because of poor target definition or inappropriate trial design. Further studies are required for a full comprehension of the molecular pathogenesis of MPM and for the development of new target agents. This review updates pre-clinical and clinical data on the efficacy of targeted therapy and immune checkpoint inhibition in the treatment of mesothelioma. Finally, future perspectives in this deadly disease are also discussed. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. 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.

  4. 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.

  5. Therapeutic strategies in the treatment of periodontitis

    Directory of Open Access Journals (Sweden)

    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.

  6. Therapeutic Strategies and Intellectualism in On Anger by Seneca

    Directory of Open Access Journals (Sweden)

    Rodrigo Sebastián Braicovich

    2015-08-01

    Full Text Available I try to show that a the treatise On Anger by Seneca includes not one but two therapeutic strategies designed to avoid anger and that b the second of these strategies –which has been neglected in the secondary literature– presents unsolvable problems when we contrast it with the Stoic theory of action, which is rooted in intellectualist premises.

  7. Novel therapeutic strategies against AIDS progression based on the ...

    African Journals Online (AJOL)

    Novel therapeutic strategies against AIDS progression based on the pathogenic effects of HIV-1 and V pr Proteins. Ahmed A Azad. Abstract. No Abstract. Discovery and Innovation Vol. 17, 2005: 52-60. Full Text: EMAIL FULL TEXT EMAIL FULL TEXT · DOWNLOAD FULL TEXT DOWNLOAD FULL TEXT. Article Metrics.

  8. Biofilms in chronic rhinosinusitis: Pathophysiology and therapeutic strategies

    Directory of Open Access Journals (Sweden)

    Judd H. Fastenberg

    2016-12-01

    Full Text Available Background: There is increasing evidence that biofilms are critical to the pathophysiology of chronic infections including chronic rhinosinusitis (CRS. Until relatively recently, our understanding of biofilms was limited. Recent advances in methods for biofilm identification and molecular biology have offered new insights into the role of biofilms in CRS. With these insights, investigators have begun to investigate novel therapeutic strategies that may disrupt or eradicate biofilms in CRS. Objective: This review seeks to explore the evidence implicating biofilms in CRS, discuss potential anti-biofilm therapeutic strategies, and suggest future directions for research. Results: The existing evidence strongly supports the role of biofilms in the pathogenesis of CRS. Several anti-biofilm therapies have been investigated for use in CRS and these are at variable stages of development. Generally, these strategies: 1 neutralize biofilm microbes; 2 disperse existing biofilms; or 3 disrupt quorum sensing. Several of the most promising anti-biofilm therapeutic strategies are reviewed. Conclusions: A better understanding of biofilm function and their contribution to the CRS disease process will be pivotal to the development of novel treatments that may augment and, potentially, redefine the CRS treatment paradigm. There is tremendous potential for future research. Keywords: Sinusitis, Biofilms, Anti-bacterial agents, Quorum sensing, Surface-active agents, Active immune response, Innate immune response

  9. Therapeutic and prevention strategies against human enterovirus 71 infection

    Science.gov (United States)

    Kok, Chee Choy

    2015-01-01

    Human enterovirus 71 (HEV71) is the cause of hand, foot and mouth disease and associated neurological complications in children under five years of age. There has been an increase in HEV71 epidemic activity throughout the Asia-Pacific region in the past decade, and it is predicted to replace poliovirus as the extant neurotropic enterovirus of highest global public health significance. To date there is no effective antiviral treatment and no vaccine is available to prevent HEV71 infection. The increase in prevalence, virulence and geographic spread of HEV71 infection over the past decade provides increasing incentive for the development of new therapeutic and prevention strategies against this emerging viral infection. The current review focuses on the potential, advantages and disadvantages of these strategies. Since the explosion of outbreaks leading to large epidemics in China, research in natural therapeutic products has identified several groups of compounds with anti-HEV71 activities. Concurrently, the search for effective synthetic antivirals has produced promising results. Other therapeutic strategies including immunotherapy and the use of oligonucleotides have also been explored. A sound prevention strategy is crucial in order to control the spread of HEV71. To this end the ultimate goal is the rapid development, regulatory approval and widespread implementation of a safe and effective vaccine. The various forms of HEV71 vaccine designs are highlighted in this review. Given the rapid progress of research in this area, eradication of the virus is likely to be achieved. PMID:25964873

  10. Therapeutic strategies based on glucagon-like peptide 1

    DEFF Research Database (Denmark)

    Deacon, Carolyn F

    2004-01-01

    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......-lasting effects. GLP-1 is highly susceptible to enzymatic degradation in vivo, and cleavage by dipeptidyl peptidase IV (DPP-IV) is probably the most relevant, since this occurs rapidly and generates a noninsulinotropic metabolite. Strategies for harnessing GLP-1's therapeutic potential, based on an understanding...... 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...

  11. Comparison of the Therapeutic Efficacy of Double-Modality Therapy ...

    African Journals Online (AJOL)

    Comparison of the Therapeutic Efficacy of Double-Modality Therapy, Phonophoresis and Cryotherapy in the Management of Musculoskeletal Injuries in Adult ... Ultrasound at an intensity of 1.5 W/cm² and frequency of 1MHz was used to apply methyl salicylate while intermittent cryotherapy was the mode of application.

  12. Which therapeutic strategy will achieve a cure for HIV-1?

    Science.gov (United States)

    Cillo, Anthony R; Mellors, John W

    2016-06-01

    Strategies to achieve a cure for HIV-1 infection can be broadly classified into three categories: eradication cure (elimination of all viral reservoirs), functional cure (immune control without reservoir eradication), or a hybrid cure (reservoir reduction with improved immune control). The many HIV-1 cure strategies being investigated include modification of host cells to resist HIV-1, engineered T cells to eliminate HIV-infected cells, broadly HIV-1 neutralizing monoclonal antibodies, and therapeutic vaccination, but the 'kick and kill' strategy to expose latent HIV-1 with latency reversing agents (LRAs) and kill the exposed cells through immune effector functions is currently the most actively pursued. It is unknown, however, whether LRAs can deplete viral reservoirs in vivo or whether current LRAs are sufficiently safe for clinical use. Copyright © 2016. Published by Elsevier B.V.

  13. Therapeutic Potential of Stem Cells Strategy for Cardiovascular Diseases

    Directory of Open Access Journals (Sweden)

    Chang Youn Lee

    2016-01-01

    Full Text Available Despite development of medicine, cardiovascular diseases (CVDs are still the leading cause of mortality and morbidity worldwide. Over the past 10 years, various stem cells have been utilized in therapeutic strategies for the treatment of CVDs. CVDs are characterized by a broad range of pathological reactions including inflammation, necrosis, hyperplasia, and hypertrophy. However, the causes of CVDs are still unclear. While there is a limit to the currently available target-dependent treatments, the therapeutic potential of stem cells is very attractive for the treatment of CVDs because of their paracrine effects, anti-inflammatory activity, and immunomodulatory capacity. Various studies have recently reported increased therapeutic potential of transplantation of microRNA- (miRNA- overexpressing stem cells or small-molecule-treated cells. In addition to treatment with drugs or overexpressed miRNA in stem cells, stem cell-derived extracellular vesicles also have therapeutic potential because they can deliver the stem cell-specific RNA and protein into the host cell, thereby improving cell viability. Here, we reported the state of stem cell-based therapy for the treatment of CVDs and the potential for cell-free based therapy.

  14. Future-Focused Therapeutic Strategies for Integrative Health.

    Science.gov (United States)

    Torem, Moshe S

    2017-01-01

    For many years, the therapy field was dominated by a focus on the past. In this context, many clinicians were trained to use hypnosis as a tool to explore the past, and there is a rich literature documenting the use of hypnosis as a tool to induce age regression and the uncovering of traumatic memories. This article presents a therapeutic paradigm that focuses on the future. Hypnosis is used to induce creativity, flexibility, and openness to the future. In the context of health care, hypnosis is used to explore the best possible treatment outcome, which may be pharmacological, surgical, or a combination of both as well as other nonsurgical interventions. This article elaborates on the effective use of a therapeutic hypnosis strategy and technique focused on the future.

  15. T cell avidity and tumor recognition: implications and therapeutic strategies

    Directory of Open Access Journals (Sweden)

    Roszkowski Jeffrey J

    2005-09-01

    Full Text Available Abstract In the last two decades, great advances have been made studying the immune response to human tumors. The identification of protein antigens from cancer cells and better techniques for eliciting antigen specific T cell responses in vitro and in vivo have led to improved understanding of tumor recognition by T cells. Yet, much remains to be learned about the intricate details of T cell – tumor cell interactions. Though the strength of interaction between T cell and target is thought to be a key factor influencing the T cell response, investigations of T cell avidity, T cell receptor (TCR affinity for peptide-MHC complex, and the recognition of peptide on antigen presenting targets or tumor cells reveal complex relationships. Coincident with these investigations, therapeutic strategies have been developed to enhance tumor recognition using antigens with altered peptide structures and T cells modified by the introduction of new antigen binding receptor molecules. The profound effects of these strategies on T cell – tumor interactions and the clinical implications of these effects are of interest to both scientists and clinicians. In recent years, the focus of much of our work has been the avidity and effector characteristics of tumor reactive T cells. Here we review concepts and current results in the field, and the implications of therapeutic strategies using altered antigens and altered effector T cells.

  16. Therapeutic strategies of urinary disorders in MS. Practice and algorithms.

    Science.gov (United States)

    Denys, P; Phe, V; Even, A; Chartier-Kastler, E

    2014-07-01

    Review the literature on therapeutic strategies and guidelines for the treatment of neurogenic bladder in multiple sclerosis. A search on available articles on consensus, recommendations guidelines and algorithm of treatment of urinary tract dysfunction in multiple sclerosis. Five national consensus guidelines were recently published and proposed guidelines for the first and second line treatments. Multiple sclerosis patients suffering from lower urinary tract disorders must benefit from an early diagnosis and simple first line evaluation and treatment. More complex and invasive evaluation in the neuro-urology unit is appropriate for patients who failed to first line treatment or in case of complications. Copyright © 2014. Published by Elsevier Masson SAS.

  17. Strategy Use and Strategy Choice in Fraction Magnitude Comparison

    Science.gov (United States)

    Fazio, Lisa K.; DeWolf, Melissa; Siegler, Robert S.

    2016-01-01

    We examined, on a trial-by-trial basis, fraction magnitude comparison strategies of adults with more and less mathematical knowledge. College students with high mathematical proficiency used a large variety of strategies that were well tailored to the characteristics of the problems and that were guaranteed to yield correct performance if executed…

  18. 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.

  19. TNF biology, pathogenic mechanisms and emerging therapeutic strategies

    Science.gov (United States)

    Kalliolias, George D.; Ivashkiv, Lionel B.

    2016-01-01

    TNF is a pleiotropic cytokine with important functions in homeostasis and disease pathogenesis. Recent discoveries have provided insights into TNF biology that introduce new concepts for the development of therapeutics for TNF-mediated diseases. The model of TNF receptor signalling has been extended to include linear ubiquitination and the formation of distinct signalling complexes that are linked with different functional outcomes, such as inflammation, apoptosis and necroptosis. Our understanding of TNF-induced gene expression has been enriched by the discovery of epigenetic mechanisms and concepts related to cellular priming, tolerization and induction of ‘short-term transcriptional memory’. Identification of distinct homeostatic or pathogenic TNF-induced signalling pathways has introduced the concept of selectively inhibiting the deleterious effects of TNF while preserving its homeostatic bioactivities for therapeutic purposes. In this Review, we present molecular mechanisms underlying the roles of TNF in homeostasis and inflammatory disease pathogenesis, and discuss novel strategies to advance therapeutic paradigms for the treatment of TNF-mediated diseases. PMID:26656660

  20. Current therapeutic strategies for anal squamous cell carcinoma in Japan

    International Nuclear Information System (INIS)

    Takashima, Atsuo; Shimada, Yasuhiro; Hamaguchi, Tetsuya

    2009-01-01

    In Western countries, chemoradiotherapy (CRT) is well established as the standard therapy for stages II/III anal squamous cell carcinoma (ASCC). In Japan, the therapeutic modalities for and outcomes of this disease have not been clarified because ASCC is quite rare. The Colorectal Cancer Study Group of the Japan Clinical Oncology Group (JCOG-CCSG) conducted a survey to determine the current therapeutic strategies for ASCC in Japan. In July 2006, a questionnaire was sent to 49 institutions affiliated with the JCOG-CCSG to gather information on numbers of cases, therapeutic modalities, and outcomes. The target subjects were patients with stages II/III ASCC, diagnosed from January 2000 to December 2004, who were 20-80 years of age with normal major organ function and no severe complications. Replies were received from 40 institutions. A total of 59 patients satisfied the subject criteria. Detailed information was obtained for 55 subjects; 25 (45%) had stage II ASCC and 30 (55%) had stage III ASCC. CRT was performed in 25 patients (45%); surgery in 17 (31%); surgery combined with radiotherapy (RT), chemotherapy, or CRT in 8 (15%); and RT in 5 (9%). Complete response rate in CRT was 80% (20/25). The 3-year progression-free survival rates for all subjects and for CRT-only subjects were 67% and 77%, respectively. From 2000 to 2004, only 59 patients with ASCC were identified in the JCOG-CCSG survey and about half of them underwent CRT. (author)

  1. Therapeutic targeting strategies using endogenous cells and proteins.

    Science.gov (United States)

    Parayath, Neha N; Amiji, Mansoor M

    2017-07-28

    Targeted drug delivery has become extremely important in enhancing efficacy and reducing the toxicity of therapeutics in the treatment of various disease conditions. Current approaches include passive targeting, which relies on naturally occurring differences between healthy and diseased tissues, and active targeting, which utilizes various ligands that can recognize targets expressed preferentially at the diseased site. Clinical translation of these mechanisms faces many challenges including the immunogenic and toxic effects of these non-natural systems. Thus, use of endogenous targeting systems is increasingly gaining momentum. This review is focused on strategies for employing endogenous moieties, which could serve as safe and efficient carriers for targeted drug delivery. The first part of the review involves cells and cellular components as endogenous carriers for therapeutics in multiple disease states, while the second part discusses the use of endogenous plasma components as endogenous carriers. Further understanding of the biological tropism with cells and proteins and the newer generation of delivery strategies that exploits these endogenous approaches promises to provide better solutions for site-specific delivery and could further facilitate clinical translations. Copyright © 2017 Elsevier B.V. All rights reserved.

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

    Science.gov (United States)

    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

  3. Patent documentation - comparison of two MT strategies

    DEFF Research Database (Denmark)

    Offersgaard, Lene; Povlsen, Claus

    2007-01-01

    This paper focuses on two matters: A comparison of how two different MT strategies manage translating the text type of patent documentation and a survey of what is needed to transform a MT research prototype system to a translation application for patent texts. The two MT strategies is represented...

  4. Therapeutic potential of systemic brain rejuvenation strategies for neurodegenerative disease.

    Science.gov (United States)

    Horowitz, Alana M; Villeda, Saul A

    2017-01-01

    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.

  5. Cell-based therapeutic strategies for multiple sclerosis

    DEFF Research Database (Denmark)

    Scolding, Neil J; Pasquini, Marcelo; Reingold, Stephen C

    2017-01-01

    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 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....

  6. STAT3 targeting by polyphenols: Novel therapeutic strategy for melanoma.

    Science.gov (United States)

    Momtaz, Saeideh; Niaz, Kamal; Maqbool, Faheem; Abdollahi, Mohammad; Rastrelli, Luca; Nabavi, Seyed Mohammad

    2017-05-06

    Melanoma or malignant melanocytes appear with the low incidence rate, but very high mortality rate worldwide. Epidemiological studies suggest that polyphenolic compounds contribute for prevention or treatment of several cancers particularly melanoma. Such findings motivate to dig out novel therapeutic strategies against melanoma, including research toward the development of new chemotherapeutic and biologic agents that can target the tumor cells by different mechanisms. Recently, it has been found that signal transducer and activator of transcription 3 (STAT3) is activated in many cancer cases surprisingly. Different evidences supply the aspect that STAT3 activation plays a vital role in the metastasis, including proliferation of cells, survival, invasion, migration, and angiogenesis. This significant feature plays a vital role in various cellular processes, such as cell proliferation and survival. Here, we reviewed the mechanisms of the STAT3 pathway regulation and their role in promoting melanoma. Also, we have evaluated the emerging data on polyphenols (PPs) specifically their contribution in melanoma therapies with an emphasis on their regulatory/inhibitory actions in relation to STAT3 pathway and current progress in the development of phytochemical therapeutic techniques. An understanding of targeting STAT3 by PPs brings an opportunity to melanoma therapy. © 2016 BioFactors, 43(3):347-370, 2017. © 2016 International Union of Biochemistry and Molecular Biology.

  7. Music as a Therapeutic Assistant: Strategy to Reduce Work Stress

    Directory of Open Access Journals (Sweden)

    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.

  8. 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

  9. [Therapeutic strategies and systemic treatment of brain melanoma metastases].

    Science.gov (United States)

    Durando, Xavier; Mansard, Sandrine; Daste, Amaury; Gimbergues, Pierre; Brocard, Laura; Magné, Nicolas; Thivat, Emilie

    2013-01-01

    Brain metastases affect 37% of patients suffering from metastatic melanoma, and their prognosis remains poor, with an overall survival lower than six months. At the moment, there is no standard therapeutic strategy for management of melanoma brain metastases. In some cases, having recourse to a systemic treatment is justified, for example, when brain metastases are combined with a progressive peripheral disease, or with unresecable brain lesions. In France, the use of fotemustine, which received the AMM approval, for metastatic melanoma treatment, is one of the treatments recommended in the case of brain metastases as this chemotherapy, that is active on the melanoma passes the blood-brain barrier. Temozolomide also shows some activity in the brain metastases treatment of melanoma that remains modest in monotherapy but seems interesting when it is combined with radiotherapy. The place of new drugs, in particular ipilimumab and vemurafenib, in the strategy of melanoma brain metastases treatment, still has to be defined and may improve the prognosis of these patients and their quality of life. The new targeted therapies, the widespread use of stereotactic radiosurgery and the improvement in neurosurgical operations would need a prospective clinical assessment, all the more so, in most of clinical studies, the presence of metastases is an exclusion criterion.

  10. 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.

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

    Science.gov (United States)

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

    2016-01-01

    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. PMID:26900286

  12. Therapeutic strategies for secondary hyperparathyroidism in dialysis patients.

    Science.gov (United States)

    Ogata, Hiroaki; Koiwa, Fumihiko; Ito, Hidetoshi; Kinugasa, Eriko

    2006-08-01

    Secondary hyperparathyroidism (SHPT) leads not only to bone disorders, but also to cardiovascular complications in long-term dialysis patients. Conventional treatment with calcium (Ca) supplement, phosphate (P) binders and active vitamin D analogs lead in part to amelioration of SHPT, but are simultaneously associated with unacceptable side-effects, including hypercalcemia, hyperphosphatemia, and increased Ca x P products, which are the risk factors for cardiovascular disease in dialysis patients. Conventional treatment has been unable to facilitate the attainment of optimal management of SHPT proposed in the K/DOQI guidelines. Cinacalcet HCl (cinacalcet), a novel calcimimetic compound, restores the sensitivity of the Ca-sensing receptor in parathyroid cells, and decreases serum parathyroid hormone (PTH) without introducing hypercalcemia or hyperphosphatemia. Cinacalcet treatment enables a significant number of patients to achieve the K/DOQI guideline. Based on experimental data, calcimimetics could ameliorate cardiovascular calcification and remodeling in uremic rats with SHPT. Clinical trials have shown that cinacalcet significantly reduced the risks of parathyroidectomy, fracture and cardiovascular hospitalization among long-term dialysis patients with SHPT. Parathyroid intervention therapy (parathyroidectomy and percutaneous direct injection) is also a useful alternative. In the present article, we review novel therapeutic strategies for SHPT.

  13. 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.

  14. 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.

  15. Patent documentation - comparison of two MT strategies

    DEFF Research Database (Denmark)

    Offersgaard, Lene; Povlsen, Claus

    2007-01-01

    This paper focuses on two matters: A comparison of how two different MT strategies manage translating the text type of patent documentation and a survey of what is needed to transform a MT research prototype system to a translation application for patent texts. The two MT strategies is represented....... The distinctive text type of patents pose special demands for machine translation and these aspects are discussed based on linguistic observations with focus on the users point of view. Two main demands are automatic pre processing of the documents and implementation of a module which in a flexible and user......-friendly manner offers the opportunity to extend the lexical coverage of the system. These demands and the comparison of the two MT strategies are discussed on the basis of proofread patents....

  16. 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

  17. Indications of hematopoietic stem cell transplantations and therapeutic strategies of accidental irradiations

    International Nuclear Information System (INIS)

    2003-01-01

    Produced by a group of experts, this document first discusses the issue of accidental irradiations in terms of medical management. They notably outline the peculiar characteristics of these irradiations with respect to therapeutic irradiations. They agreed on general principles regarding casualty sorting criteria and process, and their medical treatment (systematic hematopoiesis stimulation, allogeneic transplantation of hematopoietic stem cells). They discuss some practical aspects of these issues: casualty sorting within a therapeutic perspective (actions to be performed within 48 hours), therapeutic strategies (support therapy, use of cytokines, and therapy by hematopoietic stem cell transplant). They state a set of recommendations regarding the taking into care and diagnosis, therapeutic strategies, research perspectives, and teaching

  18. Extracellular vesicles: A new therapeutic strategy for joint conditions.

    Science.gov (United States)

    Tofiño-Vian, Miguel; Guillén, Maria Isabel; Alcaraz, Maria José

    2018-02-07

    Extracellular vesicles (EVs) are attracting increasing interest since they might represent a more convenient therapeutic tool with respect to their cells of origin. In the last years much time and effort have been expended to determine the biological properties of EVs from mesenchymal stem cells (MSCs) and other sources. The immunoregulatory, anti-inflammatory and regenerative properties of MSC EVs have been demonstrated in in vitro studies and animal models of rheumatoid arthritis or osteoarthritis. This cell-free approach has been proposed as a possible better alternative to MSC therapy in autoimmune conditions and tissue regeneration. In addition, EVs show great potential as biomarkers of disease or delivery systems for active molecules. The standardization of isolation and characterization methods is a key step for the development of EV research. A better understanding of EV mechanisms of action and efficacy is required to establish the potential therapeutic applications of this new approach in joint conditions. Copyright © 2018 Elsevier Inc. All rights reserved.

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

    Science.gov (United States)

    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.

  20. Personalized therapeutic strategies for patients with retinitis pigmentosa.

    Science.gov (United States)

    Zheng, Andrew; Li, Yao; Tsang, Stephen H

    2015-03-01

    Retinitis pigmentosa (RP) encompasses many different hereditary retinal degenerations that are caused by a vast array of different gene mutations and have highly variable disease presentations and severities. This heterogeneity poses a significant therapeutic challenge, although an answer may eventually be found through two recent innovations: induced pluripotent stem cells (iPSCs) and clustered regularly interspaced short palindromic repeats (CRISPR)/Cas genome editing. This review discusses the wide-ranging applications of iPSCs and CRISPR-including disease modelling, diagnostics and therapeutics - with an ultimate view towards understanding how these two technologies can come together to address disease heterogeneity and orphan genes in a novel personalized medicine platform. An extensive literature search was conducted in PubMed and Google Scholar, with a particular focus on high-impact research published within the last 1 - 2 years and centered broadly on the subjects of retinal gene therapy, iPSC-derived outer retina cells, stem cell transplantation and CRISPR/Cas gene editing. For the retinal pigment epithelium, autologous transplantation of gene-corrected grafts derived from iPSCs may well be technically feasible in the near future. Photoreceptor transplantation faces more significant unresolved technical challenges but remains an achievable, if more distant, goal given the rapid pace of advancements in the field.

  1. Transgenic plants for therapeutic proteins: linking upstream and downstream strategies.

    Science.gov (United States)

    Cramer, C L; Boothe, J G; Oishi, K K

    1999-01-01

    We have described two very different and innovative plant-based production systems--postharvest production and recovery of recombinant product from tobacco leaves using an inducible promoter and oleosin-mediated recovery of recombinant product from oilseeds using a seed-specific promoter. Both base technologies are broadly applicable to numerous classes of pharmaceutical and industrial proteins. As with any emerging technology, the key to success may lie in identifying those products and applications that would most benefit from the unique advantages offered by each system. The postharvest tobacco leaf system appears effective for proteins requiring complex posttranslational processing and endomembrane targeting. Because of the remarkable fecundity and biomass production capacity of tobacco, biomass scale-up is very rapid and production costs are low. Clearly the development of equally cost-effective extraction and purification technologies will be critical for full realization of the commercial opportunities afforded by transgenic plant-based bioproduction. The recovery of protein from tobacco leaves or oleosin-partitioned proteins by oil-body separations represent significant break-throughs for cost-effective commercialization strategies. Additional low-cost, high-affinity separation technologies need to be developed for effective scale-up purification of plant-synthesized recombinant proteins. Clearly successful commercialization of plant-synthesized biopharmaceuticals must effectively link upstream strategies involving gene and protein design with downstream strategies for reproducible GMP-level recovery of bioactive recombinant protein. Both the tobacco and oilseed systems are uniquely designed to address issues of biomass storage, product recovery, quality assurance, and regulatory scrutiny in addition to issues of transgene expression and protein processing.

  2. Management of constipation in the elderly: emerging therapeutic strategies.

    Science.gov (United States)

    Kapoor, Shailendra

    2008-09-07

    A number of new, novel strategies for managing constipation in the elderly have emerged over the past few years. Prucalopride is one such new agent that is highly efficacious in managing chronic constipation. In fact, Camilleri et al in a recent study reported that the average number of bowel movements increased by at least one in nearly 47% of the patients who were administered a dose of 4 mg. Lubiprostone is another new agent recently approved by the FDA that shows efficacy in managing the symptoms of constipation. Neostigmine has also been successfully used for the management of recalcitrant constipation. Most of these studies have used subcutaneous neostigmine. Symbiotic yogurt containing components, such as Bifidobacterium and fructoligosaccharide, have also been recently shown to be highly effective in improving symptoms of constipation. Elderly patients especially those in hospices and nursing homes are often on opioids for pain management. Constipation secondary to opioid use is extremely common in nursing homes. Subcutaneous methylnaltrexone has recently been shown to be highly effective in the management of opioid-related constipation, and was recently approved by the FDA. Sacral nerve stimulation is another emerging strategy. A recent analysis by Mowatt et al supports the efficacy of this technique. Botulinum toxin is another agent that has already been successfully used for the management of chronic, refractory constipation in children and may be very effective for elderly constipation. Further larger studies are needed to confirm the findings noted in these studies. Constipation is clearly a major issue in the elderly and these new, emerging strategies will hopefully improve the quality of life and relieve the symptoms of constipation in this population.

  3. Management of constipation in the elderly: Emerging therapeutic strategies

    OpenAIRE

    Kapoor, Shailendra

    2008-01-01

    A number of new, novel strategies for managing constipation in the elderly have emerged over the past few years. Prucalopride is one such new agent that is highly efficacious in managing chronic constipation. In fact, Camilleri et al in a recent study reported that the average number of bowel movements increased by at least one in nearly 47% of the patients who were administered a dose of 4 mg. Lubiprostone is another new agent recently approved by the FDA that shows efficacy in managing the ...

  4. [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.

  5. Therapeutic strategies utilizing SDF-1α in ischaemic cardiomyopathy.

    Science.gov (United States)

    Ziff, Oliver J; Bromage, Daniel I; Yellon, Derek M; Davidson, Sean M

    2018-03-01

    Heart failure is rapidly increasing in prevalence and will redraw the global landscape for cardiovascular health. Alleviating and repairing cardiac injury associated with myocardial infarction (MI) is key to improving this burden. Homing signals mobilize and recruit stem cells to the ischaemic myocardium where they exert beneficial paracrine effects. The chemoattractant cytokine SDF-1α and its associated receptor CXCR4 are upregulated after MI and appear to be important in this context. Activation of CXCR4 promotes both cardiomyocyte survival and stem cell migration towards the infarcted myocardium. These effects have beneficial effects on infarct size, and left ventricular remodelling and function. However, the timing of endogenous SDF-1α release and CXCR4 upregulation may not be optimal. Furthermore, current ELISA-based assays cannot distinguish between active SDF-1α, and SDF-1α inactivated by dipeptidyl peptidase 4 (DPP4). Current therapeutic approaches aim to recruit the SDF-1α-CXCR4 pathway or prolong SDF-1α life-time by preventing its cleavage by DPP4. This review assesses the evidence supporting these approaches and proposes SDF-1α as an important confounder in recent studies of DPP4 inhibitors.

  6. Advances in therapeutic strategies for the treatment of pruritus.

    Science.gov (United States)

    Stull, Carolyn; Lavery, Michael J; Yosipovitch, Gil

    2016-01-01

    Chronic pruritus is a common symptom that arises from both dermatologic and non-dermatologic conditions including chronic kidney disease, cholestasis, lymphoma and neuropathy. Over the past decade, research has elucidated many of the receptors, neuropeptides and cytokines involved in itch sensation and transmission. In addition, the first biomarker for cholestatic itch has been discovered. These findings have led to the development of a host of novel antipruritic medications, both on the market and in the pipeline. A summary of new and emerging treatments for pruritus, as well as possible targets for future therapeutic development is provided. At present, there is no universally effective treatment available for all types of chronic pruritus. A combination of topical and systemic therapies addressing peripheral mediators, and a top-down approach targeting the brain and spinal cord, seems preferable to a single agent approach. Neural hypersensitization plays a significant role in many forms of chronic pruritus and may be downregulated by new treatments. In addition, specific neuropeptides are now targeted by novel antipruritic therapies. Furthermore, targeted biologic agents are anticipated to play a significant role in treating pruritus of inflammatory origin.

  7. A Potential Therapeutic Strategy for Malignant Mesothelioma with Gene Medicine

    Science.gov (United States)

    Tada, Yuji; Shimada, Hideaki; Hiroshima, Kenzo; Tagawa, Masatoshi

    2013-01-01

    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. PMID:23484132

  8. Plasma cells in immunopathology: concepts and therapeutic strategies.

    Science.gov (United States)

    Tiburzy, Benjamin; Kulkarni, Upasana; Hauser, Anja Erika; Abram, Melanie; Manz, Rudolf Armin

    2014-05-01

    Plasma cells are terminally differentiated B cells that secrete antibodies, important for immune protection, but also contribute to any allergic and autoimmune disease. There is increasing evidence that plasma cell populations exhibit a considerable degree of heterogeneity with respect to their immunophenotype, migration behavior, lifetime, and susceptibility to immunosuppressive drugs. Pathogenic long-lived plasma cells are refractory to existing therapies. In contrast, short-lived plasma cells can be depleted by steroids and cytostatic drugs. Therefore, long-lived plasma cells are responsible for therapy-resistant autoantibodies and resemble a challenge for the therapy of antibody-mediated autoimmune diseases. Both lifetime and therapy resistance of plasma cells are supported by factors produced within their microenviromental niches. Current results suggest that plasma cell differentiation and survival factors such as IL-6 also signal via mammalian miRNAs within the plasma cell to modulate downstream transcription factors. Recent evidence also suggests that plasma cells and/or their immediate precursors (plasmablasts) can produce important cytokines and act as antigen-presenting cells, exhibiting so far underestimated roles in immune regulation and bone homeostasis. Here, we provide an overview on plasma cell biology and discuss exciting, experimental, and potential therapeutic approaches to eliminate pathogenic plasma cells.

  9. Therapeutic strategies to prevent contrast-induced acute kidney injury.

    Science.gov (United States)

    Quintavalle, Cristina; Donnarumma, Elvira; Fiore, Danilo; Briguori, Carlo; Condorelli, Gerolama

    2013-11-01

    Contrast-induced acute kidney injury (CI-AKI) accounts for approximately 10% of all causes of hospital-acquired renal failure, causes a prolonged in-hospital stay, and represents a powerful predictor of poor early and late outcome. Here, we highlight endpoints used to assess major strategies to prevent CI-AKI. A general consensus exists on the beneficial prophylactic effect of hydration. This seems to act by increasing urine flow rate and, thereby, by limiting the time of contact between the contrast media and the epithelial tubular cells. On the contrary, both observational trials and randomized studies are often controversial in their conclusions on the efficacy of several drugs tested to prevent CI-AKI. Compounds evaluated include diuretics (furosemide), antioxidants (i.e., N-acetylcysteine and statins), and vasodilators (i.e., calcium antagonists, dopamine, and fenoldopam). Due to the negative and/or controversial clinical results, none of these drugs has been currently recommended to prevent CI-AKI. More reliable markers of acute kidney injury and new prophylactic strategies are warranted to prevent the incidence of CI-AKI.

  10. [Complications and postoperative therapeutic strategies in cross-linking].

    Science.gov (United States)

    Kohlhaas, M

    2017-08-01

    The reduced corneal mechanical stability in keratoconus and similar collagen diseases can lead to a progressive and irregular corneal shape and decrease of visual acuity. A progression of keratectatic diseases can be shown with corneal topography. Keratoconus can be treated by photo-oxidative cross-linking of the corneal collagen. In order to achieve a high absorption of irradiation energy in the cornea, riboflavin at a concentration of 0.1% and UVA light at a wavelength of 370 nm corresponding to the relative maximum absorption of riboflavin (vitamin B2) are used. Evidence for corneal cross-linking are the increase of biomechanical stiffness, the increased resistance against enzymatic degradation, a higher shrinkage temperature, a lower swelling rate and an increased diameter of collagen fibers. The currently available data demonstrate that the therapeutic cross-linking procedure is safe when respecting the important theoretical and clinical parameters and that a progression of the keratoconus can be avoided. In 80% of cases an average levelling of the curvature of approximately 2 dpt can be achieved, which leads not only to stabilization but also to an increase in visual acuity of approximately 1.2 lines. In a Cochrane review from 2015 publications about complications and results were reviewed. Complication rates ranged from 1-10% depending on the initial situation, comorbidities and stage of the keratoconus. The most important complications are early epithelial wound healing problems as well as extremely rare perforations. Corneal cross-linking is a well-established and safe procedure but is not free of complications.

  11. Role of inflammatory response in liver diseases: Therapeutic strategies.

    Science.gov (United States)

    Del Campo, José A; Gallego, Paloma; Grande, Lourdes

    2018-01-27

    Inflammation and tumorigenesis are tightly linked pathways impacting cancer development. Inflammasomes are key signalling platforms that detect pathogenic microorganisms, including hepatitis C virus (HCV) infection, and sterile stressors (oxidative stress, insulin resistance, lipotoxicity) able to activate pro-inflammatory cytokines interleukin-1β and IL-18. Most of the inflammasome complexes that have been described to date contain a NOD-like receptor sensor molecule. Redox state and autophagy can regulate inflammasome complex and, depending on the conditions, can be either pro- or anti-apoptotic. Acute and chronic liver diseases are cytokine-driven diseases as several proinflammatory cytokines (IL-1α, IL-1β, tumor necrosis factor-alpha, and IL-6) are critically involved in inflammation, steatosis, fibrosis, and cancer development. NLRP3 inflammasome gain of function aggravates liver disease, resulting in severe liver fibrosis and highlighting this pathway in the pathogenesis of non-alcoholic fatty liver disease. On the other hand, HCV infection is the primary catalyst for progressive liver disease and development of liver cancer. It is well established that HCV-induced IL-1β production by hepatic macrophages plays a critical and central process that promotes liver inflammation and disease. In this review, we aim to clarify the role of the inflammasome in the aggravation of liver disease, and how selective blockade of this main pathway may be a useful strategy to delay fibrosis progression in liver diseases.

  12. Current Research Therapeutic Strategies for Alzheimer’s Disease Treatment

    Directory of Open Access Journals (Sweden)

    Jaume Folch

    2016-01-01

    Full Text Available Alzheimer’s disease (AD currently presents one of the biggest healthcare issues in the developed countries. There is no effective treatment capable of slowing down disease progression. In recent years the main focus of research on novel pharmacotherapies was based on the amyloidogenic hypothesis of AD, which posits that the beta amyloid (Aβ peptide is chiefly responsible for cognitive impairment and neuronal death. The goal of such treatments is (a to reduce Aβ production through the inhibition of β and γ secretase enzymes and (b to promote dissolution of existing cerebral Aβ plaques. However, this approach has proven to be only modestly effective. Recent studies suggest an alternative strategy centred on the inhibition of the downstream Aβ signalling, particularly at the synapse. Aβ oligomers may cause aberrant N-methyl-D-aspartate receptor (NMDAR activation postsynaptically by forming complexes with the cell-surface prion protein (PrPC. PrPC is enriched at the neuronal postsynaptic density, where it interacts with Fyn tyrosine kinase. Fyn activation occurs when Aβ is bound to PrPC-Fyn complex. Fyn causes tyrosine phosphorylation of the NR2B subunit of metabotropic glutamate receptor 5 (mGluR5. Fyn kinase blockers masitinib and saracatinib have proven to be efficacious in treating AD symptoms in experimental mouse models of the disease.

  13. Advances in genetic therapeutic strategies for Duchenne muscular dystrophy.

    Science.gov (United States)

    Guiraud, Simon; Chen, Huijia; Burns, David T; Davies, Kay E

    2015-12-01

    What is the topic of this review? This review highlights recent progress in genetically based therapies targeting the primary defect of Duchenne muscular dystrophy. What advances does it highlight? Over the last two decades, considerable progress has been made in understanding the mechanisms underlying Duchenne muscular dystrophy, leading to the development of genetic therapies. These include manipulation of the expression of the gene or related genes, the splicing of the gene and its translation, and replacement of the gene using viral approaches. Duchenne muscular dystrophy is a lethal X-linked disorder caused by mutations in the dystrophin gene. In the absence of the dystrophin protein, the link between the cytoskeleton and extracellular matrix is destroyed, and this severely compromises the strength, flexibility and stability of muscle fibres. The devastating consequence is progressive muscle wasting and premature death in Duchenne muscular dystrophy patients. There is currently no cure, and despite exhaustive palliative care, patients are restricted to a wheelchair by the age of 12 years and usually succumb to cardiac or respiratory complications in their late 20s. This review provides an update on the current genetically based therapies and clinical trials that target or compensate for the primary defect of this disease. These include dystrophin gene-replacement strategies, genetic modification techniques to restore dystrophin expression, and modulation of the dystrophin homologue, utrophin, as a surrogate to re-establish muscle function. © 2015 The Authors. Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.

  14. Strategies to Target Matrix Metalloproteinases as Therapeutic Approach in Cancer.

    Science.gov (United States)

    Piperigkou, Zoi; Manou, Dimitra; Karamanou, Konstantina; Theocharis, Achilleas D

    2018-01-01

    Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that are capable of degrading numerous extracellular matrix (ECM) components thus participating in physiological and pathological processes. Apart from the remodeling of ECM, they affect cell-cell and cell-matrix interactions and are implicated in the development and progression of various diseases such as cancer. Numerous studies have demonstrated that MMPs evoke epithelial to mesenchymal transition (EMT) of cancer cells and affect their signaling, adhesion, migration and invasion to promote cancer cell aggressiveness. Various studies have suggested MMPs as suitable targets for treatment of malignancies, and several MMP inhibitors (MMPIs) have been developed. Although initial trials have failed to establish MMPIs as anticancer agents due to lack of specificity and side effects, new MMPIs have been developed with improved action that are currently being investigated. Furthermore, novel strategies that target MMPs for improving drug delivery and regulating their activity in tumors are presented. This review summarizes the implication of MMPs in cancer progression and discusses the advancements in their targeting.

  15. Myeloid-Derived Suppressor Cells and Therapeutic Strategies in Cancer

    Directory of Open Access Journals (Sweden)

    Hiroshi Katoh

    2015-01-01

    Full Text Available Development of solid cancer depends on escape from host immunosurveillance. Various types of immune cells contribute to tumor-induced immune suppression, including tumor associated macrophages, regulatory T cells, type 2 NKT cells, and myeloid-derived suppressor cells (MDSCs. Growing body of evidences shows that MDSCs play pivotal roles among these immunosuppressive cells in multiple steps of cancer progression. MDSCs are immature myeloid cells that arise from myeloid progenitor cells and comprise a heterogeneous immune cell population. MDSCs are characterized by the ability to suppress both adaptive and innate immunities mainly through direct inhibition of the cytotoxic functions of T cells and NK cells. In clinical settings, the number of circulating MDSCs is associated with clinical stages and response to treatment in several cancers. Moreover, MDSCs are reported to contribute to chemoresistant phenotype. Collectively, targeting MDSCs could potentially provide a rationale for novel treatment strategies in cancer. This review summarizes recent understandings of MDSCs in cancer and discusses promissing clinical approaches in cancer patients.

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

    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

  18. Dreams and Psychedelics: Neurophenomenological Comparison and Therapeutic Implications.

    Science.gov (United States)

    Kraehenmann, Rainer

    2017-01-01

    A resurgence of neurobiological and clinical research is currently underway into the therapeutic potential of serotonergic or 'classical' psychedelics, such as the prototypical psychedelic drug lysergic acid diethylamide (LSD), psilocybin (4-phosphoryloxy-N,Ndimethyltryptamine), and ayahuasca - a betacarboline- and dimethyltryptamine (DMT)-containing Amazonian beverage. The aim of this review is to introduce readers to the similarities and dissimilarities between psychedelic states and night dreams, and to draw conclusions related to therapeutic applications of psychedelics in psychiatry. Research literature related to psychedelics and dreaming is reviewed, and these two states of consciousness are systematically compared. Relevant conclusions with regard to psychedelicassisted therapy will be provided. Common features between psychedelic states and night dreams include perception, mental imagery, emotion activation, fear memory extinction, and sense of self and body. Differences between these two states are related to differential perceptual input from the environment, clarity of consciousness and meta-cognitive abilities. Therefore, psychedelic states are closest to lucid dreaming which is characterized by a mixed state of dreaming and waking consciousness. The broad overlap between dreaming and psychedelic states supports the notion that psychedelics acutely induce dreamlike subjective experiences which may have long-term beneficial effects on psychosocial functioning and well-being. Future clinical studies should examine how therapeutic outcome is related to the acute dreamlike effects of psychedelics. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  19. Dreams and Psychedelics: Neurophenomenological Comparison and Therapeutic Implications

    Science.gov (United States)

    Kraehenmann, Rainer

    2017-01-01

    Background: A resurgence of neurobiological and clinical research is currently underway into the therapeutic potential of serotonergic or ‘classical’ psychedelics such as the prototypical psychedelic drug lysergic acid diethylamide (LSD) psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) and ayahuasca – a betacarboline- and dimethyltryptamine (DMT)-containing Amazonian beverage. The aim of this review is to introduce readers to the similarities and dissimilarities between psychedelic states and night dreams and to draw conclusions related to therapeutic applications of psychedelics in psychiatry. Methods: Research literature related to psychedelics and dreaming is reviewed and these two states of consciousness are systematically compared. Relevant conclusions with regard to psychedelic-assisted therapy will be provided. Results: Common features between psychedelic states and night dreams include perception mental imagery emotion activation fear memory extinction and sense of self and body. Differences between these two states are related to differential perceptual input from the environment clarity of consciousness and meta-cognitive abilities. Therefore psychedelic states are closest to lucid dreaming which is characterized by a mixed state of dreaming and waking consciousness Conclusion: The broad overlap between dreaming and psychedelic states supports the notion that psychedelics acutely induce dreamlike subjective experiences which may have long-term beneficial effects on psychosocial functioning and well-being. Future clinical studies should examine how therapeutic outcome is related to the acute dreamlike effects of psychedelics. PMID:28625125

  20. Therapeutic Strategies to Attenuate Hemorrhagic Transformation After Tissue Plasminogen Activator Treatment for Acute Ischemic Stroke.

    Science.gov (United States)

    Kanazawa, Masato; Takahashi, Tetsuya; Nishizawa, Masatoyo; Shimohata, Takayoshi

    2017-03-01

    This review focuses on the mechanisms and emerging concepts of stroke and therapeutic strategies for attenuating hemorrhagic transformation (HT) after tissue plasminogen activator (tPA) treatment for acute ischemic stroke (AIS). The therapeutic time window for tPA treatment has been extended. However, the patients who are eligible for tPA treatment are still <5% of all patients with AIS. The risk of serious or fatal symptomatic hemorrhage increases with delayed initiation of treatment. HT is thought to be caused by 1) ischemia/reperfusion injury; 2) the toxicity of tPA itself; 3) inflammation; and/or 4) remodeling factor-mediated effects. Modulation of these pathophysiologies is the basis of direct therapeutic strategies to attenuate HT after tPA treatment. Several studies have revealed that matrix metalloproteinases and free radicals are potential therapeutic targets. In addition, we have demonstrated that the inhibition of the vascular endothelial growth factor-signaling pathway and supplemental treatment with a recombinant angiopoietin-1 protein might be a promising therapeutic strategy for attenuating HT after tPA treatment through vascular protection. Moreover, single-target therapies could be insufficient for attenuating HT after tPA treatment and improving the therapeutic outcome of patients with AIS. We recently identified progranulin, which is a growth factor and a novel target molecule with multiple therapeutic effects. Progranulin might be a therapeutic target that protects the brain through suppression of vascular remodeling (vascular protection), neuroinflammation, and/or neuronal death (neuroprotection). Clinical trials which evaluate the effects of anti-VEGF drugs or PGRN-based treatment with tPA will be might worthwhile.

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

    Science.gov (United States)

    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.

  2. 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

  3. 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.

  4. [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.

  5. 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.

  6. [Work-related musculoskeletal disorders in dentistry professionals. 2. Prevention, ergonomic strategies and therapeutic programs].

    Science.gov (United States)

    Sartorio, F; Franchignoni, F; Ferriero, G; Vercelli, S; Odescalchi, L; Augusti, D; Migliario, M

    2005-01-01

    In dental professionals the risk of developing work-related musculoskeletal disorders (WMSD) can be minimized through a combination of prevention, ergonomic strategies, and specific therapeutic programs. Prevention includes early identification of symptoms, analysis of working posture and activity, and the evaluation of equipment (such as dental instruments, position of the dental unit, patient and operator chairs, and lighting). The ergonomic strategies are based on identifying the best daily timetable (including periodic pauses) and most efficient team organization, as well as establishing the correct position that should be held at the patient chair. Finally specific therapeutic programs are very important in preventing or treating WMSD. In fact, fitness exercises such as mobilization, stretching or muscular and cardiovascular training are recognized as fundamental for dental professionals, and when WMSD occurs physiatric care and physical therapy are recommended.

  7. Human Papillomavirus: Current and Future RNAi Therapeutic Strategies for Cervical Cancer

    Directory of Open Access Journals (Sweden)

    Hun Soon Jung

    2015-05-01

    Full Text Available Human papillomaviruses (HPVs are small DNA viruses; some oncogenic ones can cause different types of cancer, in particular cervical cancer. HPV-associated carcinogenesis provides a classical model system for RNA interference (RNAi based cancer therapies, because the viral oncogenes E6 and E7 that cause cervical cancer are expressed only in cancerous cells. Previous studies on the development of therapeutic RNAi facilitated the advancement of therapeutic siRNAs and demonstrated its versatility by siRNA-mediated depletion of single or multiple cellular/viral targets. Sequence-specific gene silencing using RNAi shows promise as a novel therapeutic approach for the treatment of a variety of diseases that currently lack effective treatments. However, siRNA-based targeting requires further validation of its efficacy in vitro and in vivo, for its potential off-target effects, and of the design of conventional therapies to be used in combination with siRNAs and their drug delivery vehicles. In this review we discuss what is currently known about HPV-associated carcinogenesis and the potential for combining siRNA with other treatment strategies for the development of future therapies. Finally, we present our assessment of the most promising path to the development of RNAi therapeutic strategies for clinical settings.

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

    Directory of Open Access Journals (Sweden)

    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.

  9. Ten national cyber security strategies: A comparison

    NARCIS (Netherlands)

    Luiijf, H.A.M.; Besseling, K. van; Spoelstra, M.; Graaf, P. de

    2013-01-01

    A number of nations developed and published a national cyber security strategy (NCSS). Most of them were published in the period 2009 - 2011. Despite the fact that each of these NCSS intends to address the cyber security threat, large differences exist between the NCSS approaches. This paper

  10. Novel therapeutic strategies for patients with triple-negative breast cancer

    Directory of Open Access Journals (Sweden)

    Zhang J

    2016-10-01

    Full Text Available Jun-Fei Zhang,1 Jia Liu,1,2 Yu Wang,1,2 Bin Zhang1,2 1Affiliated Hospital of Inner Mongolia University for the Nationalities, Tongliao, Inner Mongolia, People’s Republic of China; 2Medicinal Chemistry and Pharmacology Institute, Inner Mongolia University for the Nationalities, Tongliao, Inner Mongolia, People’s Republic of China Abstract: Triple-negative breast cancer (TNBC represents a very heterogeneous group of breast diseases. Currently, the backbone of therapy for TNBC is mainly chemotherapy as there are no effective specific targeted agents approved to treat TNBC. Despite initial responses to chemotherapy, resistance frequently and rapidly develops and metastatic TNBC has a poor prognosis. Therefore, new targeted strategies are, accordingly, urgently needed. This article discusses the recent developments in targeted agents explored for TNBC, aiming to offer novel therapeutic strategies that can potentially assist in designing personalized therapeutics in the future as well as provide the basis for further research in an attempt to target TNBC. Keywords: therapeutic strategies, TNBC, targeted agents

  11. Eye movements reflect and shape strategies in fraction comparison.

    Science.gov (United States)

    Ischebeck, Anja; Weilharter, Marina; Körner, Christof

    2016-01-01

    The comparison of fractions is a difficult task that can often be facilitated by separately comparing components (numerators and denominators) of the fractions--that is, by applying so-called component-based strategies. The usefulness of such strategies depends on the type of fraction pair to be compared. We investigated the temporal organization and the flexibility of strategy deployment in fraction comparison by evaluating sequences of eye movements in 20 young adults. We found that component-based strategies could account for the response times and the overall number of fixations observed for the different fraction pairs. The analysis of eye movement sequences showed that the initial eye movements in a trial were characterized by stereotypical scanning patterns indicative of an exploratory phase that served to establish the kind of fraction pair presented. Eye movements that followed this phase adapted to the particular type of fraction pair and indicated the deployment of specific comparison strategies. These results demonstrate that participants employ eye movements systematically to support strategy use in fraction comparison. Participants showed a remarkable flexibility to adapt to the most efficient strategy on a trial-by-trial basis. Our results confirm the value of eye movement measurements in the exploration of strategic adaptation in complex tasks.

  12. Development of fraction comparison strategies: A latent transition analysis.

    Science.gov (United States)

    Rinne, Luke F; Ye, Ai; Jordan, Nancy C

    2017-04-01

    The present study investigated the development of fraction comparison strategies through a longitudinal analysis of children's responses to a fraction comparison task in 4th through 6th grades (N = 394). Participants were asked to choose the larger value for 24 fraction pairs blocked by fraction type. Latent class analysis of performance over item blocks showed that most children initially exhibited a "whole number bias," indicating that larger numbers in numerators and denominators produce larger fraction values. However, some children instead chose fractions with smaller numerators and denominators, demonstrating a partial understanding that smaller numbers can yield larger fractions. Latent transition analysis showed that most children eventually adopted normative comparison strategies. Children who exhibited a partial understanding by choosing fractions with smaller numbers were more likely to adopt normative comparison strategies earlier than those with larger number biases. Controlling for general math achievement and other cognitive abilities, whole number line estimation accuracy predicted the probability of transitioning to normative comparison strategies. Exploratory factor analyses showed that over time, children appeared to increasingly represent fractions as discrete magnitudes when simpler strategies were unavailable. These results support the integrated theory of numerical development, which posits that an understanding of numbers as magnitudes unifies the process of learning whole numbers and fractions. The findings contrast with conceptual change theories, which propose that children must move from a view of numbers as counting units to a new view that accommodates fractions to overcome whole number bias. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  13. A comparison of WEC control strategies

    Energy Technology Data Exchange (ETDEWEB)

    Wilson, David G. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Bacelli, Giorgio [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Coe, Ryan Geoffrey [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Bull, Diana L. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Abdelkhalik, Ossama [Michigan Technological Univ., Houghton, MI (United States); Korde, Umesh A. [South Dakota School of Mines and Technology, Rapid City, SD (United States); Robinett, Rush D. [Michigan Technological Univ., Houghton, MI (United States)

    2016-04-01

    The operation of Wave Energy Converter (WEC) devices can pose many challenging problems to the Water Power Community. A key research question is how to significantly improve the performance of these WEC devices through improving the control system design. This report summarizes an effort to analyze and improve the performance of WEC through the design and implementation of control systems. Controllers were selected to span the WEC control design space with the aim of building a more comprehensive understanding of different controller capabilities and requirements. To design and evaluate these control strategies, a model scale test-bed WEC was designed for both numerical and experimental testing (see Section 1.1). Seven control strategies have been developed and applied on a numerical model of the selected WEC. This model is capable of performing at a range of levels, spanning from a fully-linear realization to varying levels of nonlinearity. The details of this model and its ongoing development are described in Section 1.2.

  14. Novel therapeutic strategies for degenerative disc disease: Review of cell biology and intervertebral disc cell therapy.

    Science.gov (United States)

    Fernandez-Moure, Joseph; Moore, Caitlyn A; Kim, Keemberly; Karim, Azim; Smith, Kevin; Barbosa, Zonia; Van Eps, Jeffrey; Rameshwar, Pranela; Weiner, Bradley

    2018-01-01

    Intervertebral disc degeneration is a disease of the discs connecting adjoining vertebrae in which structural damage leads to loss of disc integrity. Degeneration of the disc can be a normal process of ageing, but can also be precipitated by other factors. Literature has made substantial progress in understanding the biological basis of intervertebral disc, which is reviewed here. Current medical and surgical management strategies have shortcomings that do not lend promise to be effective solutions in the coming years. With advances in understanding the cell biology and characteristics of the intervertebral disc at the molecular and cellular level that have been made, alternative strategies for addressing disc pathology can be discovered. A brief overview of the anatomic, cellular, and molecular structure of the intervertebral disc is provided as well as cellular and molecular pathophysiology surrounding intervertebral disc degeneration. Potential therapeutic strategies involving stem cell, protein, and genetic therapy for intervertebral disc degeneration are further discussed.

  15. Delivery of growth factor-based therapeutics in vascular diseases: Challenges and strategies.

    Science.gov (United States)

    Xu, He-Lin; Yu, Wen-Ze; Lu, Cui-Tao; Li, Xiao-Kun; Zhao, Ying-Zheng

    2017-05-01

    Either cardiovascular or peripheral vascular diseases have become the major cause of morbidity and mortality worldwide. Recently, growth factors therapeutics, whatever administrated in form of exogenous growth factors or their relevant genes have been discovered to be an effective strategy for the prevention and therapy of vascular diseases, because of their promoting angiogenesis. Besides, as an alternative, stem cell-based therapy has been also developed in view of their paracrine-mediated effect or ability of differentiation toward angiogenesis-related cells under assistance of growth factors. Despite of being specific and potent, no matter growth factors or stem cells-based therapy, their full clinical transformation is limited from bench to bedside. In this review, the potential choices of therapeutic modes based on types of different growth factors or stem cells were firstly summarized for vascular diseases. The confronted various challenges such as lack of non-invasive delivery method, the physiochemical challenge, the short half-life time, and poor cell survival, were carefully analyzed for these therapeutic modes. Various strategies to overcome these limitations are put forward from the perspective of drug delivery. The expertised design of a suitable delivery form will undoubtedly provide valuable insight into their clinical application in the regenerative medicine. Copyright © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  16. Coping with hallucinated voices in schizophrenia: a review of self-initiated strategies and therapeutic interventions.

    Science.gov (United States)

    Farhall, John; Greenwood, Kenneth Mark; Jackson, Henry J

    2007-05-01

    This article reviews the state of knowledge about strategies used by people with a diagnosis of schizophrenia to cope with hallucinated voices, and considers the role of coping in psychological treatments for persisting symptoms. The use of self-initiated ('natural') coping strategies appears almost universal amongst voice-hearers. These strategies are similar across cultures, and include diverse behaviours, only a minority of which is specific to hallucinations. Most strategies are reported by at least some users to be effective, but more sophisticated outcome studies are lacking. Some evidence for the efficacy of certain behavioural techniques of coping, for the manipulation of auditory input, and for strategies involving subvocalisation, is available from experimental studies. Therapeutic enhancement of natural coping strategies for persisting symptoms has demonstrated some efficacy, but its benefit for voices is unknown. Despite this, it has become an established part of some CBT interventions for psychosis. Further advances in knowledge and practice may come from utilisation of coping models in research, longitudinal and ideographic methods of study and a movement away from descriptive coping lists to investigations of coping styles, mechanisms of action, and the process of coping.

  17. Promising Therapeutic Strategies for Mesenchymal Stem Cell-Based Cardiovascular Regeneration: From Cell Priming to Tissue Engineering

    Directory of Open Access Journals (Sweden)

    Seung Taek Ji

    2017-01-01

    Full Text Available The primary cause of death among chronic diseases worldwide is ischemic cardiovascular diseases, such as stroke and myocardial infarction. Recent evidence indicates that adult stem cell therapies involving cardiovascular regeneration represent promising strategies to treat cardiovascular diseases. Owing to their immunomodulatory properties and vascular repair capabilities, mesenchymal stem cells (MSCs are strong candidate therapeutic stem cells for use in cardiovascular regeneration. However, major limitations must be overcome, including their very low survival rate in ischemic lesion. Various attempts have been made to improve the poor survival and longevity of engrafted MSCs. In order to develop novel therapeutic strategies, it is necessary to first identify stem cell modulators for intracellular signal triggering or niche activation. One promising therapeutic strategy is the priming of therapeutic MSCs with stem cell modulators before transplantation. Another is a tissue engineering-based therapeutic strategy involving a cell scaffold, a cell-protein-scaffold architecture made of biomaterials such as ECM or hydrogel, and cell patch- and 3D printing-based tissue engineering. This review focuses on the current clinical applications of MSCs for treating cardiovascular diseases and highlights several therapeutic strategies for promoting the therapeutic efficacy of MSCs in vitro or in vivo from cell priming to tissue engineering strategies, for use in cardiovascular regeneration.

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

    Science.gov (United States)

    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.

  19. [Preliminary discussion of therapeutic strategies in persistent inflammation immunosuppression catabolism syndrome].

    Science.gov (United States)

    Su, Heyi; Guo, Zhenhui

    2017-12-25

    So far, there is still lack of effective treatment to control persistent inflammation immunosuppression catabolism syndrome (PICS) appeared generally in those chronic critical illnesses (CCI) patients, restricted by the development of medicine and scientific research nowadays. Because the uncontrolled PICS aggravates continuously, ICU stay of the CCI patients has been obviously prolonging and the late mortality elevates greatly. So exploring effective therapeutic strategies is obviously pressing. With the characteristics in PICS such as that elderly with sepsis or severe trauma tops the list of morbidity, progressing illness is difficult to intervent and various pathology changes occur simultaneously, the fundamental principle of treatment, "Focal screening, early control, joint intervention" must be followed. As for the specific intervention, lessoning from some diseases with immune and metabolic disorders to take "anabolic nutrition support", is a research focus presently as well as a considerably potential breakthrough at the treatment research in the future. This review retrospects a series of therapeutic strategies of PICS, such as immunity, metabolism regulation, nutrition support, glucose control and physiotherapy, in the purpose of laying the foundation of the development of joint intervention strategy for PICS.

  20. Towards Therapeutic Delivery of Extracellular Vesicles: Strategies for In Vivo Tracking and Biodistribution Analysis

    Science.gov (United States)

    Di Rocco, Giuliana; Baldari, Silvia

    2016-01-01

    Extracellular vesicles (EVs), such as microvesicles and exosomes, are membranous structures containing bioactive material released by several cells types, including mesenchymal stem/stromal cells (MSCs). Increasing lines of evidences point to EVs as paracrine mediators of the beneficial effects on tissue remodeling associated with cell therapy. Administration of MSCs-derived EVs has therefore the potential to open new and safer therapeutic avenues, alternative to cell-based approaches, for degenerative diseases. However, an enhanced knowledge about in vivo EVs trafficking upon delivery is required before effective clinical translation. Only a few studies have focused on the biodistribution analysis of exogenously administered MSCs-derived EVs. Nevertheless, current strategies for in vivo tracking in animal models have provided valuable insights on the biodistribution upon systemic delivery of EVs isolated from several cellular sources, indicating in liver, spleen, and lungs the preferential target organs. Different strategies for targeting EVs to specific tissues to enhance their therapeutic efficacy and reduce possible off-target effects have been investigated. Here, in the context of a possible clinical application of MSC-derived EVs for tissue regeneration, we review the existing strategies for in vivo tracking and targeting of EVs isolated from different cellular sources and the studies elucidating the biodistribution of exogenously administered EVs. PMID:27994623

  1. 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.

  2. Central Pain Mechanisms and Novel Therapeutic Strategies in a Model of Closed Head Injury

    Science.gov (United States)

    2016-10-01

    de nt ifi ed a t le as t th re e un iq ue p ar am et er s th at i de nt ify r C H I an im al s, a nd th at w ill se rv e as e xc el le...system reverses amyloid‐induced memory deficiency. Neurobiol  Aging , 2013. 34(3): p. 791‐804. Central pain mechanisms and novel therapeutic strategies in

  3. 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.

  4. The Conceptual Oligometastatic Non-small Cell Lung Cancer and Therapeutic Strategies

    Directory of Open Access Journals (Sweden)

    Xiaozheng KANG

    2012-04-01

    Full Text Available Non-small cell lung cancer (NSCLC ranks among the most prevalent malignancies and is the major cause of cancer-related deaths worldwide. Nearly 20%-50% will accompany by metastatic disease and the most common extrapulmonary sites of distant metastases are the brain, bone, liver and adrenal gland. The oligometastatic state is a biologically mild tumor stage and a intermediate state in which spread may be limited to specific organs and metastases might be present in limited numbers. Oligometastases are thought to arise from micrometastases, which have been dormant for a period of time. Local control may be an crucial component of a curative therapeutic strategy in the following four clinical schemes: to prohibit metastases; to cure occult metastatic disease; to remedy oligometastases; and to deracinate any residual lesion after systemic therapy. This review aims to outline the concept of the oligometastatic NSCLC and its strategies of treatment.

  5. Cell death-based treatments of melanoma:conventional treatments and new therapeutic strategies.

    Science.gov (United States)

    Mattia, Gianfranco; Puglisi, Rossella; Ascione, Barbara; Malorni, Walter; Carè, Alessandra; Matarrese, Paola

    2018-01-25

    The incidence of malignant melanoma has continued to rise during the past decades. However, in the last few years, treatment protocols have significantly been improved thanks to a better understanding of the key oncogenes and signaling pathways involved in its pathogenesis and progression. Anticancer therapy would either kill tumor cells by triggering apoptosis or permanently arrest them in the G1 phase of the cell cycle. Unfortunately, melanoma is often refractory to commonly used anticancer drugs. More recently, however, some new anticancer strategies have been developed that are "external" to cancer cells, for example stimulating the immune system's response or inhibiting angiogenesis. In fact, the increasing knowledge of melanoma pathogenetic mechanisms, in particular the discovery of genetic mutations activating specific oncogenes, stimulated the development of molecularly targeted therapies, a form of treatment in which a drug (chemical or biological) is developed with the goal of exclusively destroying cancer cells by interfering with specific molecules that drive growth and spreading of the tumor. Again, after the initial exciting results associated with targeted therapy, tumor resistance and/or relapse of the melanoma lesion have been observed. Hence, very recently, new therapeutic strategies based on the modulation of the immune system function have been developed. Since cancer cells are known to be capable of evading immune-mediated surveillance, i.e., to block the immune system cell activity, a series of molecular strategies, including monoclonal antibodies, have been developed in order to "release the brakes" on the immune system igniting immune reactivation and hindering metastatic melanoma cell growth. In this review we analyze the various biological strategies underlying conventional chemotherapy as well as the most recently developed targeted therapies and immunotherapies, pointing at the molecular mechanisms of cell injury and death engaged by

  6. Therapeutic strategies in severe neuropsychiatric systemic lupus erythematosus: experience from a tertiary referral centre

    Directory of Open Access Journals (Sweden)

    F. De Leonardis

    2012-12-01

    Full Text Available The management of neuropsychiatric systemic lupus erythematosus (NPSLE still remains empirical and based on clinical experience due to the lack of randomized controlled trials. Objective: to report the experience accumulated in a single tertiary referral centre about treatment of severe cases of NPSLE patients and to discuss therapeutic strategies on the background of EULAR recommendations. Methods: retrospective analysis of all consecutive cases of severe NPSLE treated in our centre since 1990 to 2010, satisfying the 1999 ACR criteria. Results: among 633 SLE patients who consecutively attended our centre, 231 (36% displayed at least one neuropsychiatric (NP manifestation for a total of 408 events attributable to SLE. Thirty-one patients (4.8%, 27 females and 4 males, experienced 35 major NP events requiring immunosuppressive therapy (including 3 relapses and 1 new event. An aggressive immunosuppressive strategy was applied to those patients with an immune mediated inflammatory NP event and to those patients with an increased disease activity as judged by ECLAM and SLEDAI scores. Overall at the end of the therapy 74% of the patients reached clinical remission or significant improvement of their symptoms measured by mean SLEDAI (from 10.09±1.09 to 2.04±0.52, PConclusions: the prevalence of NP involvement, described in our case series, is similar to those reported in literature as well as the treatment strategies applied. Nowadays, it is not possible to establish a standardized approach for each single NPSLE manifestation, and different therapeutic strategies must be tailored taking into account the most probable pathogenic mechanism involved, the general disease activity background, the co-morbidities, the type and the stage of the systemic involvement.

  7. Neutral endopeptidase inhibition and the natriuretic peptide system: an evolving strategy in cardiovascular therapeutics

    Science.gov (United States)

    Mangiafico, Sarah; Costello-Boerrigter, Lisa C.; Andersen, Ingrid A.; Cataliotti, Alessandro; Burnett, John C.

    2013-01-01

    Hypertension and heart failure (HF) are common diseases that, despite advances in medical therapy, continue to be associated with high morbidity and mortality. Therefore, innovative therapeutic strategies are needed. Inhibition of the neutral endopeptidase (NEPinh) had been investigated as a potential novel therapeutic approach because of its ability to increase the plasma concentrations of the natriuretic peptides (NPs). Indeed, the NPs have potent natriuretic and vasodilator properties, inhibit the activity of the renin–angiotensin–aldosterone system, lower sympathetic drive, and have antiproliferative and antihypertrophic effects. Such potentially beneficial effects can be theoretically achieved by the use of NEPinh. However, studies have shown that NEPinh alone does not result in clinically meaningful blood pressure-lowering actions. More recently, NEPinh has been used in combination with other cardiovascular agents, such as angiotensin-converting enzyme inhibitors, and antagonists of the angiotensin receptor. Another future possible combination would be the use of NEPinh with NPs or their newly developed chimeric peptides. This review summarizes the current knowledge of the use and effects of NEPinh alone or in combination with other therapeutic agents for the treatment of human cardiovascular disease such as HF and hypertension. PMID:22942338

  8. 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

  9. The arsenal of pathogens and antivirulence therapeutic strategies for disarming them

    Directory of Open Access Journals (Sweden)

    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

  10. Therapeutic strategies for the treatment of accidental radiation-induced hematopoietic syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Bertho, J.M.; Frick, J.; Demarquay, C.; Prat, M.; Dudoignon, N.; Thierry, D.; Gourmelon, P. [Institut de Radioprotection et de Surete Nucleaire (IRSN) DRPH/SRBE, LTCRA, 92 - Fontenay aux Roses (France)

    2006-07-01

    The hematopoietic syndrome induced by large field high dose accidental irradiation remains difficult to treat, mainly due to the heterogeneity of irradiation. As a result, there always remains an area of active hematopoiesis that was partly protected from irradiation. The choice of a therapeutic strategy thus must be based upon the estimate of radiation damage to the bone marrow. This can be achieved by the use of biological indicators of damage to specific organs. With this respect, we recently showed that the follow up of Flt3 ligand concentration in the blood allowed a direct evaluation of residual hematopoiesis soon after irradiation in animal models as well as in humans. Nevertheless, the possible therapeutic strategies available for the treatment of radiation-induced hematopoietic syndrome are limited to the choice between either stem cell transplantation or supportive care. Recently, the use of autologous cell therapy was proposed. The principle is to harvest the hematopoietic cells surviving to irradiation, to expand these cells in vitro and to re inject these cells to the patient. This is based upon the existence of a residual hematopoiesis and on the possibility to expand in vitro irradiated hematopoietic cells. Experimental work in a non human primate model of high-dose, heterogeneous irradiation showed that it was possible to harvest surviving hematopoietic cells after irradiation and to amplify these cells in vitro. However, the therapeutic efficiency of the reinjected cells was limited by the occurrence of a combined disease, implicating the lungs, the kidney and the liver, but also a severe vascular damage. Such a multiple organ disease syndrome induced by ionizing radiations was already observed in two radiation accidents, the Tokai MURA accident and the Neshvish accident. In an attempt to accelerate the hematopoietic recovery, we combined autologous cell therapy with G-CSF injections in the same model of heterogeneous irradiation with non human

  11. 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

  12. 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.

  13. 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.

  14. Polyphenols as Modulator of Oxidative Stress in Cancer Disease: New Therapeutic Strategies

    Science.gov (United States)

    Mileo, Anna Maria; Miccadei, Stefania

    2016-01-01

    Cancer onset and progression have been linked to oxidative stress by increasing DNA mutations or inducing DNA damage, genome instability, and cell proliferation and therefore antioxidant agents could interfere with carcinogenesis. It is well known that conventional radio-/chemotherapies influence tumour outcome through ROS modulation. Since these antitumour treatments have important side effects, the challenge is to develop new anticancer therapeutic strategies more effective and less toxic for patients. To this purpose, many natural polyphenols have emerged as very promising anticancer bioactive compounds. Beside their well-known antioxidant activities, several polyphenols target epigenetic processes involved in cancer development through the modulation of oxidative stress. An alternative strategy to the cytotoxic treatment is an approach leading to cytostasis through the induction of therapy-induced senescence. Many anticancer polyphenols cause cellular growth arrest through the induction of a ROS-dependent premature senescence and are considered promising antitumour therapeutic tools. Furthermore, one of the most innovative and interesting topics is the evaluation of efficacy of prooxidant therapies on cancer stem cells (CSCs). Several ROS inducers-polyphenols can impact CSCs metabolisms and self-renewal related pathways. Natural polyphenol roles, mainly in chemoprevention and cancer therapies, are described and discussed in the light of the current literature data. PMID:26649142

  15. 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

  16. Improving Cerebral Blood Flow after Arterial Recanalization: A Novel Therapeutic Strategy in Stroke.

    Science.gov (United States)

    El Amki, Mohamad; Wegener, Susanne

    2017-12-09

    Ischemic stroke is caused by a disruption in blood supply to a region of the brain. It induces dysfunction of brain cells and networks, resulting in sudden neurological deficits. The cause of stroke is vascular, but the consequences are neurological. Decades of research have focused on finding new strategies to reduce the neural damage after cerebral ischemia. However, despite the incredibly huge investment, all strategies targeting neuroprotection have failed to demonstrate clinical efficacy. Today, treatment for stroke consists of dealing with the cause, attempting to remove the occluding blood clot and recanalize the vessel. However, clinical evidence suggests that the beneficial effect of post-stroke recanalization may be hampered by the occurrence of microvascular reperfusion failure. In short: recanalization is not synonymous with reperfusion. Today, clinicians are confronted with several challenges in acute stroke therapy, even after successful recanalization: (1) induce reperfusion, (2) avoid hemorrhagic transformation (HT), and (3) avoid early or late vascular reocclusion. All these parameters impact the restoration of cerebral blood flow after stroke. Recent advances in understanding the molecular consequences of recanalization and reperfusion may lead to innovative therapeutic strategies for improving reperfusion after stroke. In this review, we will highlight the importance of restoring normal cerebral blood flow after stroke and outline molecular mechanisms involved in blood flow regulation.

  17. Improving Cerebral Blood Flow after Arterial Recanalization: A Novel Therapeutic Strategy in Stroke

    Directory of Open Access Journals (Sweden)

    Mohamad El Amki

    2017-12-01

    Full Text Available Ischemic stroke is caused by a disruption in blood supply to a region of the brain. It induces dysfunction of brain cells and networks, resulting in sudden neurological deficits. The cause of stroke is vascular, but the consequences are neurological. Decades of research have focused on finding new strategies to reduce the neural damage after cerebral ischemia. However, despite the incredibly huge investment, all strategies targeting neuroprotection have failed to demonstrate clinical efficacy. Today, treatment for stroke consists of dealing with the cause, attempting to remove the occluding blood clot and recanalize the vessel. However, clinical evidence suggests that the beneficial effect of post-stroke recanalization may be hampered by the occurrence of microvascular reperfusion failure. In short: recanalization is not synonymous with reperfusion. Today, clinicians are confronted with several challenges in acute stroke therapy, even after successful recanalization: (1 induce reperfusion, (2 avoid hemorrhagic transformation (HT, and (3 avoid early or late vascular reocclusion. All these parameters impact the restoration of cerebral blood flow after stroke. Recent advances in understanding the molecular consequences of recanalization and reperfusion may lead to innovative therapeutic strategies for improving reperfusion after stroke. In this review, we will highlight the importance of restoring normal cerebral blood flow after stroke and outline molecular mechanisms involved in blood flow regulation.

  18. 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.

  19. Therapeutic Strategies to Enhance the Anticancer Efficacy of Histone Deacetylase Inhibitors

    Directory of Open Access Journals (Sweden)

    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.

  20. 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.

  1. A novel therapeutic strategy for experimental stroke using docosahexaenoic acid complexed to human albumin

    Directory of Open Access Journals (Sweden)

    Belayev Ludmila

    2016-01-01

    Full Text Available Despite tremendous efforts in ischemic stroke research and significant improvements in patient care within the last decade, therapy is still insufficient. There is a compelling, urgent need for safe and effective neuroprotective strategies to limit brain injury, facilitate brain repair, and improve functional outcome. Recently, we reported that docosahexaenoic acid (DHA; 22:6, n-3 complexed to human albumin (DHA-Alb is highly neuroprotective after temporary middle cerebral artery occlusion (MCAo in young rats. This review highlights the potency of DHA-Alb therapy in permanent MCAo and aged rats and whether protection persists with chronic survival. We discovered that a novel therapy with DHA-Alb improved behavioral outcomes accompanied by attenuation of lesion volumes even when animals were allowed to survive three weeks after experimental stroke. This treatment might provide the basis for future therapeutics for patients suffering from ischemic stroke.

  2. 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.

  3. Dystrophins, Utrophins, and Associated Scaffolding Complexes: Role in Mammalian Brain and Implications for Therapeutic Strategies

    Directory of Open Access Journals (Sweden)

    Caroline Perronnet

    2010-01-01

    Full Text Available Two decades of molecular, cellular, and functional studies considerably increased our understanding of dystrophins function and unveiled the complex etiology of the cognitive deficits in Duchenne muscular dystrophy (DMD, which involves altered expression of several dystrophin-gene products in brain. Dystrophins are normally part of critical cytoskeleton-associated membrane-bound molecular scaffolds involved in the clustering of receptors, ion channels, and signaling proteins that contribute to synapse physiology and blood-brain barrier function. The utrophin gene also drives brain expression of several paralogs proteins, which cellular expression and biological roles remain to be elucidated. Here we review the structural and functional properties of dystrophins and utrophins in brain, the consequences of dystrophins loss-of-function as revealed by numerous studies in mouse models of DMD, and we discuss future challenges and putative therapeutic strategies that may compensate for the cognitive impairment in DMD based on experimental manipulation of dystrophins and/or utrophins brain expression.

  4. Potential Therapeutic Strategies to Overcome Acquired Resistance to BRAF or MEK Inhibitors in BRAF Mutant Cancers

    Science.gov (United States)

    Corcoran, Ryan B.; Settleman, Jeffrey; Engelman, Jeffrey A.

    2011-01-01

    Recent clinical trials with selective inhibitors of the BRAF and MEK kinases have shown promising results in patients with tumors harboring BRAF V600 mutations. However, as has been observed previously with similarly successful targeted therapies, acquired resistance to these agents is an emerging problem that limits their clinical benefit. Several recent studies from our laboratory and others have investigated the causes of acquired resistance to BRAF and MEK inhibitors, and multiple resistance mechanisms have been identified. Here, we review these mechanisms and suggest that they can be broadly grouped into two main classes: ERK-dependent and ERK-independent. We also propose distinct therapeutic strategies that might be employed to overcome each class of acquired resistance. PMID:21505228

  5. Immunologic Regulation in Pregnancy: From Mechanism to Therapeutic Strategy for Immunomodulation

    Directory of Open Access Journals (Sweden)

    Shyi-Jou Chen

    2012-01-01

    Full Text Available The immunologic interaction between the fetus and the mother is a paradoxical communication that is regulated by fetal antigen presentation and/or by recognition of and reaction to these antigens by the maternal immune system. There have been significant advances in understanding of abnormalities in the maternal-fetal immunologic relationship in the placental bed that can lead to pregnancy disorders. Moreover, immunologic recognition of pregnancy is vital for the maintenance of gestation, and inadequate recognition of fetal antigens may cause abortion. In this paper, we illustrate the complex immunologic aspects of human reproduction in terms of the role of human leukocyte antigen (HLA, immune cells, cytokines and chemokines, and the balance of immunity in pregnancy. In addition, we review the immunologic processes of human reproduction and the current immunologic therapeutic strategies for pathological disorders of pregnancy.

  6. 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

  7. 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.

  8. 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

  9. [Medico-economic evaluation of therapeutic strategies at hospital: A systematic review of French studies].

    Science.gov (United States)

    Baudouin, A; Armoiry, X; Dussart, C

    2017-05-01

    Therapeutic innovation contributes to the increase of health care expenditures in France. Medico-economic evaluation has still a minor role in the decision-making for the registration of drugs and medical devices in hospitals. This study aimed to systematically review published works on medico-economic studies conducted within French hospitals. A literature review was carried out to search for medico-economic studies conducted by hospital teams on therapeutic or diagnostic strategies employed within French hospitals and published from 2010 to 2014. Quality assessment of selected studies was performed according to Drummond et al.'s checklist, which is also used within French guidelines. Of the 44 analyzed articles, methods for identification and measure of costs and results complied with guidelines in 95 % of cases. For results interpretation, compliance was 91 %. Costs discounting (29 %) and the use of sensitivity analysis to account for results uncertainty (70 %) were the parameters with the lowest compliance to guidelines. A good training of health professionals in using economic and statistic tools, and the transferability of results of medico-economic studies are essential and should be optimized to enable a broader use of medico-economic evaluation within the scope of decision-making in French hospitals. Copyright © 2016 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.

  10. Delivery strategies of the CRISPR-Cas9 gene-editing system for therapeutic applications.

    Science.gov (United States)

    Liu, Chang; Zhang, Li; Liu, Hao; Cheng, Kun

    2017-11-28

    The CRISPR-Cas9 genome-editing system is a part of the adaptive immune system in archaea and bacteria to defend against invasive nucleic acids from phages and plasmids. The single guide RNA (sgRNA) of the system recognizes its target sequence in the genome, and the Cas9 nuclease of the system acts as a pair of scissors to cleave the double strands of DNA. Since its discovery, CRISPR-Cas9 has become the most robust platform for genome engineering in eukaryotic cells. Recently, the CRISPR-Cas9 system has triggered enormous interest in therapeutic applications. CRISPR-Cas9 can be applied to correct disease-causing gene mutations or engineer T cells for cancer immunotherapy. The first clinical trial using the CRISPR-Cas9 technology was conducted in 2016. Despite the great promise of the CRISPR-Cas9 technology, several challenges remain to be tackled before its successful applications for human patients. The greatest challenge is the safe and efficient delivery of the CRISPR-Cas9 genome-editing system to target cells in human body. In this review, we will introduce the molecular mechanism and different strategies to edit genes using the CRISPR-Cas9 system. We will then highlight the current systems that have been developed to deliver CRISPR-Cas9 in vitro and in vivo for various therapeutic purposes. Copyright © 2017 Elsevier B.V. All rights reserved.

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

    Science.gov (United States)

    Zhen, Shuai; Li, Xu

    2017-01-01

    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. © 2017 The Author(s). Published by S. Karger AG, Basel.

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

    Science.gov (United States)

    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.

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

    Directory of Open Access Journals (Sweden)

    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.

  14. Initiating therapeutic relaxation in Britain: a twentieth-century strategy for health and wellbeing

    Science.gov (United States)

    Nathoo, Ayesha

    2016-01-01

    In 1972, a British charity, Relaxation for Living, was established “to promote the teaching of physical relaxation, to combat stress, strain, anxiety and the tension of modern life, and to reduce fatigue”. This article explores the origins and development of “physical relaxation” techniques and ideologies, starting in the interwar period, and the development of practical, therapeutic, social and cultural frameworks necessary for such an organization to come into being in 1970s Britain. It traces how relaxation was reconstituted as a scientifically-based skill that could be learnt and taught, imbued with therapeutic value for combating and preventing specific physical ailments and enhancing individual health and wellbeing. The article explores how relaxation techniques gained currency among particular demographic and clinical groups, ranging from middle-class, child-bearing women to middle-aged, “coronary-prone” men. This analysis highlights the role that relaxation practitioners played in both creating and responding to demand for individualistic health-management strategies, many of which have shaped contemporary health and wellbeing agendas. This article is published as part of a collection entitled “On balance: lifestyle, mental health and wellbeing”. PMID:27563437

  15. 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.

  16. Optimized nonclinical safety assessment strategies supporting clinical development of therapeutic monoclonal antibodies targeting inflammatory diseases.

    Science.gov (United States)

    Brennan, Frank R; Cauvin, Annick; Tibbitts, Jay; Wolfreys, Alison

    2014-05-01

    An increasing number of immunomodulatory monoclonal antibodies (mAbs) and IgG Fc fusion proteins are either approved or in early-to-late stage clinical trials for the treatment of chronic inflammatory conditions, autoimmune diseases and organ transplant rejection. The exquisite specificity of mAbs, in combination with their multi-functional properties, high potency, long half-life (permitting intermittent dosing and prolonged pharamcological effects), and general lack of off-target toxicity makes them ideal therapeutics. Dosing with mAbs for these severe and debilitating but often non life-threatening diseases is usually prolonged, for several months or years, and not only affects adults, including sensitive populations such as woman of child-bearing potential (WoCBP) and the elderly, but also children. Immunosuppression is usually a therapeutic goal of these mAbs and when administered to patients whose treatment program often involves other immunosuppressive therapies, there is an inherent risk for frank immunosuppression and reduced host defence which when prolonged increases the risk of infection and cancer. In addition when mAbs interact with the immune system they can induce other adverse immune-mediated drug reactions such as infusion reactions, cytokine release syndrome, anaphylaxis, immune-complex-mediated pathology and autoimmunity. An overview of the nonclinical safety assessment and risk mitigation strategies utilized to characterize these immunomodulatory mAbs and Fc fusion proteins to support first-in human (FIH) studies and futher clinical development in inflammatory disease indications is provided. Specific emphasis is placed on the design of studies to qualify animal species for toxicology studies, early studies to investigate safety and define PK/PD relationships, FIH-enabling and chronic toxicology studies, immunotoxicity, developmental, reproductive and juvenile toxicity studies and studies to determine the potential for immunosuppression and

  17. 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.

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

    Science.gov (United States)

    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.

  19. Novel therapeutic strategy for neurodegeneration by blocking Aβ seeding mediated aggregation in models of Alzheimer's disease.

    Science.gov (United States)

    Eleuteri, Simona; Di Giovanni, Saviana; Rockenstein, Edward; Mante, Mike; Adame, Antony; Trejo, Margarita; Wrasidlo, Wolf; Wu, Fang; Fraering, Patrick C; Masliah, Eliezer; Lashuel, Hilal A

    2015-02-01

    Aβ accumulation plays a central role in the pathogenesis of Alzheimer's disease (AD). Recent studies suggest that the process of Aβ nucleated polymerization is essential for Aβ fibril formation, pathology spreading and toxicity. Therefore, targeting this process represents an effective therapeutic strategy to slow or block disease progression. To discover compounds that might interfere with the Aβ seeding capacity, toxicity and pathology spreading, we screened a focused library of FDA-approved drugs in vitro using a seeding polymerization assay and identified small molecule inhibitors that specifically interfered with Aβ seeding-mediated fibril growth and toxicity. Mitoxantrone, bithionol and hexachlorophene were found to be the strongest inhibitors of fibril growth and protected primary cortical neuronal cultures against Aβ-induced toxicity. Next, we assessed the effects of these three inhibitors in vivo in the mThy1-APPtg mouse model of AD (8-month-old mice). We found that mitoxantrone and bithionol, but not hexachlorophene, stabilized diffuse amyloid plaques, reduced the levels of Aβ42 oligomers and ameliorated synapse loss, neuronal damage and astrogliosis. Together, our findings suggest that targeting fibril growth and Aβ seeding capacity constitutes a viable and effective strategy for protecting against neurodegeneration and disease progression in AD. Copyright © 2014 Elsevier Inc. All rights reserved.

  20. 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

  1. 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.

  2. 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.

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

    Science.gov (United States)

    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.

  4. Therapeutic Strategies for Oxidative Stress-Related Cardiovascular Diseases: Removal of Excess Reactive Oxygen Species in Adult Stem Cells

    Directory of Open Access Journals (Sweden)

    Hyunyun Kim

    2016-01-01

    Full Text Available Accumulating evidence indicates that acute and chronic uncontrolled overproduction of oxidative stress-related factors including reactive oxygen species (ROS causes cardiovascular diseases (CVDs, atherosclerosis, and diabetes. Moreover ROS mediate various signaling pathways underlying vascular inflammation in ischemic tissues. With respect to stem cell-based therapy, several studies clearly indicate that modulating antioxidant production at cellular levels enhances stem/progenitor cell functionalities, including proliferation, long-term survival in ischemic tissues, and complete differentiation of transplanted cells into mature vascular cells. Recently emerging therapeutic strategies involving adult stem cells, including endothelial progenitor cells (EPCs, for treating ischemic CVDs have highlighted the need to control intracellular ROS production, because it critically affects the replicative senescence of ex vivo expanded therapeutic cells. Better understanding of the complexity of cellular ROS in stem cell biology might improve cell survival in ischemic tissues and enhance the regenerative potentials of transplanted stem/progenitor cells. In this review, we will discuss the nature and sources of ROS, drug-based therapeutic strategies for scavenging ROS, and EPC based therapeutic strategies for treating oxidative stress-related CVDs. Furthermore, we will discuss whether primed EPCs pretreated with natural ROS-scavenging compounds are crucial and promising therapeutic strategies for vascular repair.

  5. New Strategies for the Next Generation of Matrix-Metalloproteinase Inhibitors: Selectively Targeting Membrane-Anchored MMPs with Therapeutic Antibodies

    Directory of Open Access Journals (Sweden)

    Laetitia Devy

    2011-01-01

    Full Text Available MMP intervention strategies have met with limited clinical success due to severe toxicities. In particular, treatment with broad-spectrum MMP-inhibitors (MMPIs caused musculoskeletal pain and inflammation. Selectivity may be essential for realizing the clinical potential of MMPIs. Here we review discoveries pinpointing membrane-bound MMPs as mediators of mechanisms underlying cancer and inflammation and as possible therapeutic targets for prevention/treatment of these diseases. We discuss strategies to target these therapeutic proteases using highly selective inhibitory agents (i.e., human blocking antibodies against individual membrane-bound MMPs.

  6. Photochemical internalization of therapeutic macromolecular agents: a novel strategy to kill multidrug-resistant cancer cells.

    Science.gov (United States)

    Selbo, Pål K; Weyergang, Anette; Bonsted, Anette; Bown, Stephen G; Berg, Kristian

    2006-11-01

    Drug resistance is a major problem for chemotherapy. Entrapment of anticancer drugs in endolysosomal compartments or active extrusions by plasma membrane proteins of the ATP-binding cassette (ABC) superfamily are important resistance mechanisms. This study evaluated photochemical internalization (PCI) of membrane-impermeable macromolecules that are not the target of ABC drug pumps for treating multidrug-resistant (MDR) cancer cells. We used the drug-sensitive uterine fibrosarcoma cell line MES-SA and its MDR, P-glycoprotein (P-gp)-overexpressing derivative MES-SA/Dx5 with the photosensitizer disulfonated meso-tetraphenylporphine (TPPS(2a)) and broad spectrum illumination. The PCI of doxorubicin, the ribosome-inactivating protein gelonin and adenoviral transduction were assessed in both cell lines, together with the uptake and excretion of TPPS(2a) and of two fluid phase markers easily detectable by fluorescence [lucifer yellow (LY) and fluorescein isothiocyanate (FITC)-dextran], as a model of gelonin uptake. Both cell lines were resistant to PCI of doxorubicin, but equally sensitive to PCI of gelonin, even though the endocytosis rates of LY and FITC-dextran were significantly lower in the MDR cells. In control studies, MES-SA/Dx5 cells were more resistant to photodynamic therapy (TPPS(2a) + light only). This was not mediated by P-gp, as there were no differences in the uptake and efflux of TPPS(2a) between the cell lines. After adenoviral infection, PCI enhanced gene delivery in both cell lines. In conclusion, PCI of macromolecular therapeutic agents that are not targets of P-gp is a novel therapeutic strategy to kill MDR cancer cells.

  7. 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.

  8. Eosinophilic Esophagitis: Impact of Latest Insights Into Pathophysiology on Therapeutic Strategies.

    Science.gov (United States)

    Schoepfer, Alain; Safroneeva, Ekaterina; Straumann, Alex

    underlying inflammation. This review highlights the latest insights regarding pathophysiology and its impact regarding current and future therapeutic strategies. © 2016 S. Karger AG, Basel.

  9. New therapeutic strategies for the treatment of male lower urinary tract symptoms

    Directory of Open Access Journals (Sweden)

    Dimitropoulos K

    2016-04-01

    Full Text Available Konstantinos Dimitropoulos, Stavros Gravas Department of Urology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece Abstract: Male lower urinary tract symptoms (LUTS are prevalent in the general population, especially in those of advanced age, and are characterized by notable diversity in etiology and presentation, and have been proven to cause various degrees of impairment on quality of life. The prostate has traditionally been regarded as the core cause of male LUTS. As a result, medical treatment aims to provide symptomatic relief and effective management of progression of male LUTS due to benign prostatic enlargement. In this context, α1-blockers, phosphodiesterase-5 inhibitors, and 5α-reductase inhibitors have long been used as monotherapies or in combination treatment to control voiding LUTS. There is accumulating evidence, however, that highlights the role of the bladder in the pathogenesis of male LUTS. Current research interests have shifted to bladder disorders, and medical management is aimed at the bladder. Muscarinic receptor antagonists and the newly approved β3-adrenergic agonist mirabegron aim to alleviate the most bothersome storage LUTS and thus improve quality of life. As voiding and storage LUTS frequently coexist, combination therapeutic strategies with α1-blockers and antimuscarinics or β3-agonists have been introduced to manage symptoms effectively. Anti-inflammatory agents, vitamin D3-receptor analogs, and cannabinoids represent treatment modalities currently under investigation for use in LUTS patients. Furthermore, luteinizing hormone-releasing hormone antagonists, transient receptor-potential channel blockers, purinergic neurotransmission antagonists, Rho-kinase inhibitors, and inhibitors of endothelin-converting enzymes could have therapeutic potential in LUTS management, but still remain in the experimental setting. This article reviews new strategies for the medical

  10. 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.

  11. [Congenital toxoplasmosis: randomised comparison of strategies for retinochoroiditis prevention].

    Science.gov (United States)

    Wallon, Martine; Kieffer, François; Binquet, Christine; Thulliez, Philippe; Garcia-Méric, Patricia; Dureau, Pascal; Franck, Jacqueline; Peyron, François; Bonnin, Alain; Villena, Isabelle; Bonithon-Kopp, Claire; Gouyon, Jean-Bernard; Masson, Sandrine; Félin, Alexandrin; Cornu, Catherine

    2011-01-01

    In France, children with confirmed congenital toxoplasmosis receive a treatment for a period of 12 to 24 months. Such prolonged treatment may generate potentially severe risks, in particular hematologic and cutaneous. Our objective is to compare the effectiveness of two therapeutic strategies on the prevention of retinochoroiditis by a randomized, non-inferiority, open-label, parallel study including 486 children, 3 to 6 months of age with a non-severe form of congenital toxoplasmosis. Following randomization, pyrimethamine-sulphonamide treatment is initiated for a period of three months, followed by a treatment with Fansidar(®) for 9 months, or therapeutic abstention. Follow-up visits during a two-year period will include an examination of the eye, a blood test, and questionnaires to evaluate the children's quality of life and their parents' anxiety. Confirming the non-inferiority of the effectiveness of a short-term treatment will improve the quality of life of parents and children. © 2011 Société Française de Pharmacologie et de Thérapeutique.

  12. 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.

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

    Science.gov (United States)

    Pey, Angel L.; Albert, Armando; Salido, Eduardo

    2013-01-01

    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. PMID:23956997

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

    Directory of Open Access Journals (Sweden)

    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.

  15. Neurogenesis in Huntington's disease: can studying adult neurogenesis lead to the development of new therapeutic strategies?

    Science.gov (United States)

    Gil-Mohapel, Joana; Simpson, Jessica M; Ghilan, Mohamed; Christie, Brian R

    2011-08-11

    Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by an unstable expansion of CAG repeats in the HD gene. The symptoms include cognitive dysfunction and severe motor impairments. The neuropathology is characterized by neuronal loss mainly in the striatum and cortex, although other regions including the hippocampus are also affected. In this review we discuss the different mouse models of HD, and how the process of neurogenesis in the dentate gyrus (DG) of the hippocampus and the subventricular zone (SVZ) is affected in each. Deficits in adult hippocampal neurogenesis have been repeatedly shown in different genetic models of HD, raising the possibility that an impairment of the neurogenic process might underlie some of the cognitive deficits associated with this neurodegenerative disorder. On the other hand, an increase in SVZ neurogenesis has been observed in human HD brains while no differences in SVZ cell proliferation have been detected in the mouse models. In this review we will discuss the discrepancies between these findings as well as the several mechanisms that might contribute to a dysregulation of adult neurogenesis in HD. Finally, we will provide an overview of the various therapeutic strategies aimed at stimulating the endogenous neurogenic capacity that have been tested in HD genetic models. Ultimately, the insights obtained from these and future studies will greatly improve our understanding of the cognitive impairment characteristic of HD. Copyright © 2011 Elsevier B.V. All rights reserved.

  16. Proteasome inhibitors: possible novel therapeutic strategy for ischemia-reperfusion injury?

    Science.gov (United States)

    Kandilis, Apostolos N; Karidis, Nikolaos P; Kouraklis, Gregory; Patsouris, Efstratios; Vasileiou, Ioanna; Theocharis, Stamatios

    2014-01-01

    The ubiquitin-proteasome system (UPS) is responsible for the degradation of misfolded or damaged proteins, regulating inflammatory processes and cell cycle progression. The aim of this article is to summarize the currently available data regarding the possible utility of proteasome inhibitors (PIs) in the treatment of ischemia-reperfusion injury (IRI). Data were reviewed from the published literature using the Medline database. The effect of PIs on IRI is dependent on the dosage, time of administration (prior to or post IRI induction), the affected organ, and the experimental model used. Undoubtedly, in most cases PIs' application resulted in attenuated IRI, although it was uniformly shown that inhibition of the UPS prior to ischemic preconditioning (IPC) abolished the protective effect of IPC in IRI. Mechanism of action involves several pathways, including nuclear factor kappa-B (NF-κB) inactivation, antineutrophil action, decreased intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expression, and the cytoprotective proteins eNOS, heme oxigenase 1 and hsp70 up-regulation. Current data are limited, but appear promising with regard to PI consideration as an effective future therapeutic strategy for IRI. Nevertheless, further investigation is required in terms of safety and validation of the appropriate for each agent dosage, in order to establish their possible contribution in human IRI.

  17. HDAC4 reduction: a novel therapeutic strategy to target cytoplasmic huntingtin and ameliorate neurodegeneration.

    Directory of Open Access Journals (Sweden)

    Michal Mielcarek

    2013-11-01

    Full Text Available Histone deacetylase (HDAC 4 is a transcriptional repressor that contains a glutamine-rich domain. We hypothesised that it may be involved in the molecular pathogenesis of Huntington's disease (HD, a protein-folding neurodegenerative disorder caused by an aggregation-prone polyglutamine expansion in the huntingtin protein. We found that HDAC4 associates with huntingtin in a polyglutamine-length-dependent manner and co-localises with cytoplasmic inclusions. We show that HDAC4 reduction delayed cytoplasmic aggregate formation, restored Bdnf transcript levels, and rescued neuronal and cortico-striatal synaptic function in HD mouse models. This was accompanied by an improvement in motor coordination, neurological phenotypes, and increased lifespan. Surprisingly, HDAC4 reduction had no effect on global transcriptional dysfunction and did not modulate nuclear huntingtin aggregation. Our results define a crucial role for the cytoplasmic aggregation process in the molecular pathology of HD. HDAC4 reduction presents a novel strategy for targeting huntingtin aggregation, which may be amenable to small-molecule therapeutics.

  18. Essential Oils Loaded in Nanosystems: A Developing Strategy for a Successful Therapeutic Approach

    Directory of Open Access Journals (Sweden)

    Anna Rita Bilia

    2014-01-01

    Full Text Available Essential oils are complex blends of a variety of volatile molecules such as terpenoids, phenol-derived aromatic components, and aliphatic components having a strong interest in pharmaceutical, sanitary, cosmetic, agricultural, and food industries. Since the middle ages, essential oils have been widely used for bactericidal, virucidal, fungicidal, antiparasitical, insecticidal, and other medicinal properties such as analgesic, sedative, anti-inflammatory, spasmolytic, and locally anaesthetic remedies. In this review their nanoencapsulation in drug delivery systems has been proposed for their capability of decreasing volatility, improving the stability, water solubility, and efficacy of essential oil-based formulations, by maintenance of therapeutic efficacy. Two categories of nanocarriers can be proposed: polymeric nanoparticulate formulations, extensively studied with significant improvement of the essential oil antimicrobial activity, and lipid carriers, including liposomes, solid lipid nanoparticles, nanostructured lipid particles, and nano- and microemulsions. Furthermore, molecular complexes such as cyclodextrin inclusion complexes also represent a valid strategy to increase water solubility and stability and bioavailability and decrease volatility of essential oils.

  19. Targeting the Central Pocket in Human Transcription Factor TEAD as a Potential Cancer Therapeutic Strategy.

    Science.gov (United States)

    Pobbati, Ajaybabu V; Han, Xiao; Hung, Alvin W; Weiguang, Seetoh; Huda, Nur; Chen, Guo-Ying; Kang, CongBao; Chia, Cheng San Brian; Luo, Xuelian; Hong, Wanjin; Poulsen, Anders

    2015-11-03

    The human TEAD family of transcription factors (TEAD1-4) is required for YAP-mediated transcription in the Hippo pathway. Hyperactivation of TEAD's co-activator YAP contributes to tissue overgrowth and human cancers, suggesting that pharmacological interference of TEAD-YAP activity may be an effective strategy for anticancer therapy. Here we report the discovery of a central pocket in the YAP-binding domain (YBD) of TEAD that is targetable by small-molecule inhibitors. Our X-ray crystallography studies reveal that flufenamic acid, a non-steroidal anti-inflammatory drug (NSAID), binds to the central pocket of TEAD2 YBD. Our biochemical and functional analyses further demonstrate that binding of NSAIDs to TEAD inhibits TEAD-YAP-dependent transcription, cell migration, and proliferation, indicating that the central pocket is important for TEAD function. Therefore, our studies discover a novel way of targeting TEAD transcription factors and set the stage for therapeutic development of specific TEAD-YAP inhibitors against human cancers. Copyright © 2015 Elsevier Ltd. All rights reserved.

  20. Inhibition of c-Met as a Therapeutic Strategy for Esophageal Adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Gregory A. Watson

    2006-11-01

    Full Text Available The hepatocyte growth factor (HGF receptor c-Met is a tyrosine kinase receptor with established oncogenic properties. We have previously shown that c-Met is usually overexpressed in esophageal adenocarcinoma (EA, yet the implications of c-Met inhibition in EA remain unknown. Three c-Met-overexpressiog EA cell lines (Seg-1, Bic-1, Flo-1 were used to examine the effects of a c-Met-specific small molecule inhibitor (PHA665752 on cell viability, apoptosis, motility, invasion, downstream signaling pathways. PHA665752 demonstrated dose-dependent inhibition of constitutive and/or HGF-induced phosphorylation of c-Met, which correlated with reduced cell viability and inhibition of extracellular regulated kinase 1/2 phosphorylation in all three EA cell lines. In contrast, PHA665752 induced apoptosis and reduced motility and invasion in only one EA cell line, Flo-1. Interestingly, Flo-1 was the only cell line in which phosphatidylinositol 3-kinase (PI3K/Akt was induced following HGF stimulation. The PI3K inhibitor LY294002 produced effects equivalent to those of PHA665752 in these cells. We conclude that inhibition of c-Met may be a useful therapeutic strategy for EA. Factors other than receptor overexpression, such as c-Met-dependent PI3K/Akt signaling, may be predictive of an individual tumor's response to c-Met inhibition.

  1. Chronic Subdural Hematoma Associated with Spontaneous Intracranial Hypotension: Therapeutic Strategies and Outcomes of 55 Cases.

    Science.gov (United States)

    Takahashi, Koichi; Mima, Tatsuo; Akiba, Yoichi

    2016-01-01

    Spontaneous intracranial hypotension (SIH) has increasingly been recognized, and it is well known that SIH is sometimes complicated by chronic subdural hematoma (SDH). In this study, 55 cases of SIH with SDH were retrospectively analyzed, focusing on therapeutic strategies and outcomes. Of 169 SIH cases (75 males, 84 females), 55 (36 males, 19 females) were complicated by SDH. SIH was diagnosed based on clinical symptoms, neuroimaging, and/or low cerebrospinal fluid pressure. Presence of orthostatic headache and diffuse meningeal enhancement on magnetic resonance imaging were regarded as the most important criteria. Among 55 SIH with SDH cases, 13 improved with conservative treatment, 25 initially received an epidural blood patch (EBP), and 17 initially underwent irrigation of the hematomas. Of the 25 initially treated with EBP, 7 (28.0%) needed SDH surgery and 18 (72.0%) recovered fully without surgery. Of 17 SDH cases initially treated with surgery, 6 (35.7%) required no EBP therapy and the other 11 (64.3%) needed EBP and/or additional SDH operations. In the latter group, 2 cases had transient severe complications during and after the procedures. One of these 2 cases developed a hoarse voice complication. Despite this single, non-severe complication, all enrolled in this study achieved good outcomes. The present study suggests that patients initially receiving SDH surgery may need additional treatments and may occasionally have complications. If conservative treatment is insufficient, EBP should be performed prior to hematoma irrigation.

  2. 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.

  3. 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...

  4. Geroprotectors as a novel therapeutic strategy for COPD, an accelerating aging disease

    Directory of Open Access Journals (Sweden)

    Ito K

    2012-09-01

    Full Text Available Kazuhiro Ito, Thomas Colley, Nicolas MercadoAirways Disease Section, National Heart and Lung Institute, Imperial College London, London, United KingdomAbstract: Chronic obstructive pulmonary disease (COPD progresses very slowly and the majority of patients are therefore elderly. COPD is characterized by an abnormal persistent inflammatory response to noxious environmental stimuli and there are increasing evidences for a close relationship between premature aging and chronic inflammatory diseases. Thus, COPD is considered to be a disease of an accelerating aging. In this review, we collected the evidence for roles of aging on pathogenesis of COPD and considered future therapeutic strategy for COPD based on this senescence hypothesis. Since calorie restriction has been proved to extend lifespan, many efforts were made to clarify the molecular mechanism of aging. Aging is defined as the progressive decline of homeostasis that occurs after the reproductive phase of life is complete, leading to an increasing risk of disease or death due to impaired DNA repair after damage by oxidative stress or telomere shortening as a result of repeated cell division. During aging, pulmonary function progressively deteriorates; innate immunity is impaired and pulmonary inflammation increases, accompanied by structural changes, such as an enlargement of airspaces. Noxious environmental gases, such as cigarette smoke, may worsen these aging-related events in the lung or accelerate aging of the lung due to reduction in anti-aging molecules and/or stimulation of aging molecules. Aging signaling are complex but conserved in divert species, such as worm, fruit fry, rodent and humans. Especially the insulin like growth factor (IGF-1 signaling was well documented. Geroprotectors are therapeutics that affect the root cause of aging and age-related diseases, and thus prolong the life-span of animals. Most of geroprotectors such as melatonin, metformin, rapamycin and

  5. Comparisons of Particulate Size Distributions from Multiple Combustion Strategies

    Science.gov (United States)

    Zhang, Yizhou

    In this study, a comparison of particle size distribution (PSD) measurements from eight different combustion strategies was conducted at four different load-speed points. The PSDs were measured using a scanning mobility particle sizer (SMPS) together with a condensation particle counter (CPC). To study the influence of volatile particles, PSD measurements were performed with and without a volatile particle remover (thermodenuder, TD) at both low and high dilution ratios. The common engine platform utilized in the experiment helps to eliminate the influence of background particulate and ensures similarity in dilution conditions. The results show a large number of volatile particles were present under LDR sample conditions for most of the operating conditions. The use of a TD, especially when coupled with HDR, was demonstrated to be effective at removing volatile particles and provided consistent measurements across all combustion strategies. The PSD comparison showed that gasoline premixed combustion strategies such as HCCI and GCI generally have low PSD magnitudes for particle sizes greater than the Particle Measurement Programme (PMP) cutoff diameter (23 nm), and the PSDs were highly nuclei-mode particle dominated. The strategies using diesel as the only fuel (DLTC and CDC) generally showed the highest particle number emissions for particles larger than 23 nm and had accumulation-mode particle dominated PSDs. A consistent correlation between the increase of the direct-injection of diesel fuel and a higher fraction of accumulation-mode particles was observed over all combustion strategies. A DI fuel substitution study and injector nozzle geometry study were conducted to better understand the correlation between PSD shape and DI fueling. It was found that DI fuel properties has a clear impact on PSD behavior for CDC and NG DPI. Fuel with lower density and lower sooting tendency led to a nuclei-mode particle dominated PSD shape. For NG RCCI, accumulation

  6. Targeting HER2 signaling pathway for radiosensitization: alternative strategy for therapeutic resistance.

    Science.gov (United States)

    No, Mina; Choi, Eun Jung; Kim, In Ah

    2009-12-01

    Several studies have indicated the potential value of targeting HER-2 signaling to enhance the anti-tumor activity of ionizing radiation. However, therapeutic resistance resulting from several factors, including activation of the downstream pathway, represents a major obstacle to treatment. Here, we investigated whether inhibitors targeting downstream of HER-2 signaling would radiosensitize SKBR3 breast cancer cells that exhibit overamplification of HER2. Selective inhibition of MEK-ERK signaling using pharmacologic inhibitors (PD98059, UO126) did not increase the radiosensitivity of SKBR3 cells. Selective inhibition of the PI3K-AKT-mTOR pathway using pharmacologic inhibitors (LY294002, AKT inhibitor VIII, Rapamycin) significantly attenuated expression of p-AKT and p-70S6K, respectively and radiosensitized SKBR3 cells. MCF-7 cells those did not overexpress HER-2, showed less radiosensitization compared to SKBR3 cells by inhibition of this pathway. Pre-treatment with these inhibitors also caused significant abrogation of typical G(2) arrest following ionizing radiation and induced marked prolongation of gammaH2AX foci indicating impairment of DNA damage repair. A dual inhibitor of Class I PI3K and mTOR, PI103 effectively radiosensitized SKBR3 cells and showed significant prolongation of gammaH2AX foci. Inhibition of PI3K-AKT signaling was associated with downregulation of DNA-PKs, respectively. While apoptosis was the major mode of cell death when the cells were pretreated with LY294002 or AKT inhibitor VIII, the cells were pretreated by rapamycin or PI103 showed mixed mode of cell death including autophagy. Our results suggest possible mechanisms to counteract the HER-2 prosurvival signaling implicated in radioresistance, and offer an alternative strategy to overcome resistance to HER-2 inhibitors combined with radiation.

  7. N-Palmitoylethanolamine and Neuroinflammation: a Novel Therapeutic Strategy of Resolution.

    Science.gov (United States)

    Skaper, Stephen D; Facci, Laura; Barbierato, Massimo; Zusso, Morena; Bruschetta, Giuseppe; Impellizzeri, Daniela; Cuzzocrea, Salvatore; Giusti, Pietro

    2015-10-01

    Inflammation is fundamentally a protective cellular response aimed at removing injurious stimuli and initiating the healing process. However, when prolonged, it can override the bounds of physiological control and becomes destructive. Inflammation is a key element in the pathobiology of chronic pain, neurodegenerative diseases, stroke, spinal cord injury, and neuropsychiatric disorders. Glia, key players in such nervous system disorders, are not only capable of expressing a pro-inflammatory phenotype but respond also to inflammatory signals released from cells of immune origin such as mast cells. Chronic inflammatory processes may be counteracted by a program of resolution that includes the production of lipid mediators endowed with the capacity to switch off inflammation. These naturally occurring lipid signaling molecules include the N-acylethanolamines, N-arachidonoylethanolamine (an endocannabinoid), and its congener N-palmitoylethanolamine (palmitoylethanolamide or PEA). PEA may play a role in maintaining cellular homeostasis when faced with external stressors provoking, for example, inflammation. PEA is efficacious in mast cell-mediated models of neurogenic inflammation and neuropathic pain and is neuroprotective in models of stroke, spinal cord injury, traumatic brain injury, and Parkinson disease. PEA in micronized/ultramicronized form shows superior oral efficacy in inflammatory pain models when compared to naïve PEA. Intriguingly, while PEA has no antioxidant effects per se, its co-ultramicronization with the flavonoid luteolin is more efficacious than either molecule alone. Inhibiting or modulating the enzymatic breakdown of PEA represents a complementary therapeutic approach to treat neuroinflammation. This review is intended to discuss the role of mast cells and glia in neuroinflammation and strategies to modulate their activation based on leveraging natural mechanisms with the capacity for self-defense against inflammation.

  8. Computationally derived points of fragility of a human cascade are consistent with current therapeutic strategies.

    Directory of Open Access Journals (Sweden)

    Deyan Luan

    2007-07-01

    Full Text Available The role that mechanistic mathematical modeling and systems biology will play in molecular medicine and clinical development remains uncertain. In this study, mathematical modeling and sensitivity analysis were used to explore the working hypothesis that mechanistic models of human cascades, despite model uncertainty, can be computationally screened for points of fragility, and that these sensitive mechanisms could serve as therapeutic targets. We tested our working hypothesis by screening a model of the well-studied coagulation cascade, developed and validated from literature. The predicted sensitive mechanisms were then compared with the treatment literature. The model, composed of 92 proteins and 148 protein-protein interactions, was validated using 21 published datasets generated from two different quiescent in vitro coagulation models. Simulated platelet activation and thrombin generation profiles in the presence and absence of natural anticoagulants were consistent with measured values, with a mean correlation of 0.87 across all trials. Overall state sensitivity coefficients, which measure the robustness or fragility of a given mechanism, were calculated using a Monte Carlo strategy. In the absence of anticoagulants, fluid and surface phase factor X/activated factor X (fX/FXa activity and thrombin-mediated platelet activation were found to be fragile, while fIX/FIXa and fVIII/FVIIIa activation and activity were robust. Both anti-fX/FXa and direct thrombin inhibitors are important classes of anticoagulants; for example, anti-fX/FXa inhibitors have FDA approval for the prevention of venous thromboembolism following surgical intervention and as an initial treatment for deep venous thrombosis and pulmonary embolism. Both in vitro and in vivo experimental evidence is reviewed supporting the prediction that fIX/FIXa activity is robust. When taken together, these results support our working hypothesis that computationally derived points of

  9. Pneumonia in nursing home patients: is it time for a specific therapeutic strategy?

    Directory of Open Access Journals (Sweden)

    Gualberto Gussoni

    2013-04-01

    Full Text Available Background: Nursing home-acquired pneumonia (NHAP was described in 1978, but only in 2005 it has been proposed as part of a new category (health care-associated pneumonia distinct from community- or hospital-acquired infections. However, limited clinical data exist to validate this proposal. Aim of the study: To compare characteristics and outcome of patients hospitalised for pneumonia and coming from private residence or nursing home. Methods: Post-hoc analysis of the prospective phase of the FASTCAP study, performed to evaluate the impact of the Recommendations issued by the Italian Federation of Internal Medicine (FADOI in 2002 on the management of hospitalised community-acquired pneumonia (CAP. Results: The study examined 1,219 patients coming from private residence, and 179 with NHAP. Failures of therapy were significantly more frequent in patients with NHAP (35.8% vs 24.9%; Odds Ratio 1.48; 95% confidence interval 1.05-2.09. Mortality was higher in patients coming from nursing home (24.0% vs 9.8%; OR 2.59; 95% CI 1.72-3.90. Antibiotic treatment was more frequently performed as monotherapy in case of NHAP. Conclusions: At the time of FASTCAP, NHAP was included in the category of CAP, and coherently, treatment of NHAP was not more aggressive if compared to community-acquired infections. However, our results confirm that NHAP is at increased risk for worst outcome, and probably worth considering for specific therapeutic strategies. Future studies are needed to better assess the microbiology of NHAP, and to evaluate if specific treatments, as those recommended by recent guidelines, may improve the outcome for these high-risk patients.

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

    Directory of Open Access Journals (Sweden)

    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.

  11. 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

  12. 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

  13. The Therapeutic Potential of PTEN Modulation: Targeting Strategies from Gene to Protein

    NARCIS (Netherlands)

    McLoughlin, N.M.; Mueller, C.; Grossmann, T.N.

    2018-01-01

    Two decades have passed since the discovery of the tumor suppressor, PTEN. A multitude of biological functions have since been revealed, suggesting potential therapeutic applications for both PTEN activation (e.g., cancer) and inhibition (e.g., neuroregeneration). Nevertheless, PTEN's therapeutic

  14. STUDY OF THERAPEUTIC COMPARISON OF TACROLIMUS 0.1% AND MINOXIDIL 2% IN ALOPECIA AREATA

    Directory of Open Access Journals (Sweden)

    Kallappa C. Herkal

    2013-07-01

    Full Text Available Introduction: Alopecia areata is a unique, idiopathic disease in which there is patchy hair loss. The variable and uncertain natural history of alopecia areata is accounting for the multiplicity of uncritical claims for a large variety of therapeutic procedures. Aim: to find the therapeutic comparison between tacrolimus 0.1% ointment and minoxidil 2% solution. Material and Methods: Patients attending skin out patient department in Navodaya medical college hospital and research centre, Raichur were screened and the consenting consecutive cases of Aopecia Areata (AA from December 2010 to November 2011 were chosen for study. There were 75 patients in the study. It is a randomized, single blind, intension to treat study. The eligible patients for the study were randomly allocated into two groups-Group A and Group B (38 in Group A and 37 in Group B. Patients in Group A were treated with 2% Minoxidi solution to be applied twice daily over the alopecia patch, where as Patients in Group B were treated with Tacrolimus 0.1% ointment applied twice daily. Patients were followed up at 2, 4, 6, 8, 10 and 12 weeks. Alopecia Grading Score (AGS was calculated at baseline and 12 weeks. Regrowth Score (RGS was calculated at 12 weeks. Results: Total 69 patients completed the study (35 in Group A and 34 in Group B. In our study RGS ≥ 3 was observed in 65.71% of patients treated with Tinoxidil 2% solution and 44.12% of patients treated with Tacrolimus 0.1% ointment. Conclusion: In our study Minoxidil 2% solution had better stimulatory effect on hair growth compared to Tacrolimus 0.1% ointment in the treatment of mild to moderate patchy alopecia areata. The combination treatment may yield a better clinical response than either of the agents used singly.

  15. A New Therapeutic Strategy for Autosomal Dominant Polycystic Kidney Disease: Activation of AMP Kinase by Metformin. Addendum

    Science.gov (United States)

    2014-07-01

    KS, Abrahamson DR, De Lisle RC, Wallace DP, Maser RL, Grantham JJ, and Calvet JP. Early embryonic renal tubules of wild-type and polycystic kidney ...embryonic renal tubules of wild-type and polycystic kidney disease kidneys respond to cAMP stimulation with cystic fibrosis transmembrane conductance...AD_________________ Award Number: W81XWH-10-1-0504 TITLE: A New Therapeutic Strategy for Autosomal Dominant Polycystic Kidney Disease: Activation

  16. [Modulating the survival and maturation system of B lymphocytes: Current and future new therapeutic strategies in systemic lupus erythematosus].

    Science.gov (United States)

    Valor, Lara; López-Longo, Francisco Javier

    2015-09-07

    Systemic lupus erythematosus is an autoimmune disease associated with an aberrant production of autoantibodies by self-reactive B lymphocytes. The study of the phenotypic characteristics of B lymphocytes and the identification of their surface receptors such as BAFF-R, TACI and BCMA, which are responsible of their survival and maturation, have contributed to the development of new therapeutic strategies in recent years. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

  17. 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.

  18. Human organ-on-a-chip BioMEMS devices for testing new diagnostic and therapeutic strategies

    Science.gov (United States)

    Leary, James F.; Key, Jaehong; Vidi, Pierre-Alexandre; Cooper, Christy L.; Kole, Ayeeshik; Reece, Lisa M.; Lelièvre, Sophie A.

    2013-03-01

    MEMS human "organs-on-a-chip" can be used to create model human organ systems for developing new diagnostic and therapeutic strategies. They represent a promising new strategy for rapid testing of new diagnostic and therapeutic approaches without the need for involving risks to human subjects. We are developing multicomponent, superparamagnetic and fluorescent nanoparticles as X-ray and MRI contrast agents for noninvasive multimodal imaging and for antibody- or peptide-targeted drug delivery to tumor and precancerous cells inside these artificial organ MEMS devices. Magnetic fields can be used to move the nanoparticles "upstream" to find their target cells in an organs-on-achip model of human ductal breast cancer. Theoretically, unbound nanoparticles can then be removed by reversing the magnetic field to give a greatly enhanced image of tumor cells within these artificial organ structures. Using branched PDMS microchannels and 3D tissue engineering of normal and malignant human breast cancer cells inside those MEMS channels, we can mimic the early stages of human ductal breast cancer with the goal to improve the sensitivity and resolution of mammography and MRI of very small tumors and test new strategies for treatments. Nanomedical systems can easily be imaged by multicolor confocal microscopy inside the artificial organs to test targeting and therapeutic responses including the differential viability of normal and tumor cells during treatments. Currently we are using 2-dimensional MEMS structures, but these studies can be extended to more complex 3D structures using new 3D printing technologies.

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

    Science.gov (United States)

    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.

  20. Adenosine can thwart antitumor immune responses elicited by radiotherapy. Therapeutic strategies alleviating protumor ADO activities

    Energy Technology Data Exchange (ETDEWEB)

    Vaupel, Peter [Klinikum rechts der Isar, Technische Universitaet Muenchen (TUM), Department of Radiation Oncology, Munich (Germany); Multhoff, Gabriele [Klinikum rechts der Isar, Technische Universitaet Muenchen (TUM), Department of Radiation Oncology, Munich (Germany); Helmholtz Zentrum Muenchen, Institute for innovative Radiotherapy (iRT), Experimental Immune Biology, Neuherberg (Germany)

    2016-05-15

    By studying the bioenergetic status we could show that the development of tumor hypoxia is accompanied, apart from myriad other biologically relevant effects, by a substantial accumulation of adenosine (ADO). ADO has been shown to act as a strong immunosuppressive agent in tumors by modulating the innate and adaptive immune system. In contrast to ADO, standard radiotherapy (RT) can either stimulate or abrogate antitumor immune responses. Herein, we present ADO-mediated mechanisms that may thwart antitumor immune responses elicited by RT. An overview of the generation, accumulation, and ADO-related multifaceted inhibition of immune functions, contrasted with the antitumor immune effects of RT, is provided. Upon hypoxic stress, cancer cells release ATP into the extracellular space where nucleotides are converted into ADO by hypoxia-sensitive, membrane-bound ectoenzymes (CD39/CD73). ADO actions are mediated upon binding to surface receptors, mainly A2A receptors on tumor and immune cells. Receptor activation leads to a broad spectrum of strong immunosuppressive properties facilitating tumor escape from immune control. Mechanisms include (1) impaired activity of CD4 + T and CD8 + T, NK cells and dendritic cells (DC), decreased production of immuno-stimulatory lymphokines, and (2) activation of Treg cells, expansion of MDSCs, promotion of M2 macrophages, and increased activity of major immunosuppressive cytokines. In addition, ADO can directly stimulate tumor proliferation and angiogenesis. ADO mechanisms described can thwart antitumor immune responses elicited by RT. Therapeutic strategies alleviating tumor-promoting activities of ADO include respiratory hyperoxia or mild hyperthermia, inhibition of CD39/CD73 ectoenzymes or blockade of A2A receptors, and inhibition of ATP-release channels or ADO transporters. (orig.) [German] Untersuchungen des bioenergetischen Status ergaben, dass Tumorhypoxie neben vielen anderen bedeutsamen biologischen Effekten zu einem starken

  1. Trajectory optimization on multiprocessors - A comparison of three implementation strategies

    Science.gov (United States)

    Summerset, Twain K.; Chowkwanyun, Raymond M.

    The optimization of atmospheric flight vehicle trajectories can require the simulation of several thousand individual trajectories. Such a task can be extremely time consuming if simulating each trajectory requires numerically integrating a set of nonlinear differential equations. This traditional approach, which may require many hours' worth of analysis on a time-shared computer facility, is a bottleneck in space mission planning and limits the number of trajectory design options a mission planner can evaluate. To achieve marked reductions in trajectory design solution times, parallel optimization techniques are proposed. In this paper, three strategies for implementing trajectory optimization methods on multiprocessors will be compared. The comparisons will be illustrated through four trajectory design examples. In the first two examples, maximum reentry downrange and crossrange optimal control problems are posed for a generic maneuvering aerodynamic space vehicle. The third example is Troesch's problem, while the fourth example is the classic Brachistochrone problem. Each of the examples are posed as two-point boundary value problems whose solutions can be expressed as the solutions to a set of nonlinear equations.

  2. Multiple sclerosis in children: an update on clinical diagnosis, therapeutic strategies, and research

    OpenAIRE

    Waldman, Amy; Ghezzi, Angelo; Bar-Or, Amit; Mikaeloff, Yann; Tardieu, Marc; Banwell, Brenda

    2014-01-01

    The clinical features, diagnostic challenges, neuroimaging appearance, therapeutic options, and pathobiological research progress in childhood—and adolescent—onset multiple sclerosis have been informed by many new insights in the past 7 years. National programmes in several countries, collaborative research efforts, and an established international paediatric multiple sclerosis study group have contributed to revised clinical diagnostic definitions, identified clinical features of multiple sc...

  3. In Vitro Evaluation of Biofilm Dispersal as a Therapeutic Strategy To Restore Antimicrobial Efficacy

    DEFF Research Database (Denmark)

    Roizman, Dan; Vidaillac, Celine; Givskov, Michael

    2017-01-01

    engineered strain PAO1/pBAD-yhjH resulted in increased antimicrobial efficacy and synergy of the imipenem-tobramycin combination. These results support the use of biofilm dispersal to enhance antimicrobial efficacy in the treatment of biofilm-associated infections, representing a promising therapeutic...

  4. RGD-based strategies for selective delivery of therapeutics and imaging agents to the tumour vasculature

    NARCIS (Netherlands)

    Temming, K; Molema, G; Kok, RJ

    2005-01-01

    During the past decade, RGD-peptides have become a popular tool for the targeting of drugs and imaging agents to a(v)beta(3)-integrin expressing tumour vasculature. RGD-peptides have been introduced by recombinant means into therapeutic proteins and viruses. Chemical means have been applied to

  5. 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.

  6. Myocardial Bridging: Contemporary Understanding of Pathophysiology with Implications for Diagnostic and Therapeutic Strategies

    Science.gov (United States)

    Eshtehardi, Parham; Rasoul-Arzrumly, Emad; McDaniel, Michael; Mekonnen, Girum; Timmins, Lucas H.; Lutz, Jerre; Guyton, Robert A; Samady, Habib

    2014-01-01

    Patients with myocardial bridges are often asymptomatic but this anomaly may be associated with exertional angina, acute coronary syndromes, cardiac arrhythmias, syncope or even sudden cardiac death. This review presents our understanding of the pathophysiology of myocardial bridging and describes prevailing diagnostic modalities and therapeutic options for this challenging clinical entity. PMID:24583304

  7. 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.

  8. 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.

  9. 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

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

    Science.gov (United States)

    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.

  11. 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

  12. Advanced new strategies for metastatic cancer treatment by therapeutic stem cells and oncolytic virotherapy

    OpenAIRE

    Park, Geon-Tae; Choi, Kyung-Chul

    2016-01-01

    The field of therapeutic stem cell and oncolytic virotherapy for cancer treatment has rapidly expanded over the past decade. Oncolytic viruses constitute a promising new class of anticancer agent because of their ability to selectively infect and destroy tumor cells. Engineering of viruses to express anticancer genes and specific cancer targeting molecules has led to the use of these systems as a novel platform of metastatic cancer therapy. In addition, stem cells have a cancer specific migra...

  13. Developing a Novel Therapeutic Strategy Targeting Kallikrein-4 to Inhibit Prostate Cancer Growth and Metastasis

    Science.gov (United States)

    2015-08-01

    Kallikrein-related peptidase 4 (KLK4) is a rational therapeutic target for prostate cancer (PCa) as it is up-regulated in both localised and bone...both localised and bone metastatic cancerous tissue, and is an independent biomarker discriminating between benign and malignant prostate tissue [1,2...cellular function . siKLK4(A), siKLK4(B) and siControl are currently being conjugated onto HBP-peptide by collaborators from AIBN. siRNA sequences are

  14. Vatuximab(Trademark): Optimizing Therapeutic Strategies for Prostate Cancer Based on Dynamic MR Tumor Oximetry

    Science.gov (United States)

    2010-01-01

    therapeutic efficacy in experimental diabetic retinopathy . Invest Ophthalmol Vis Sci, 42, 2964-9 (2001) 141. Berkowitz, B. A., C. McDonald, Y. Ito, P...tumors measured over a period of 11 weeks of thrice weekly treatment with bavituximab (2.5 mg/kg IP). A predicted mean growth rate for untreated... predicted control tumor in Figure 18. However, R1L1 and R0L0 both show growth rates considerably slower than control and greatly increased DCE

  15. Therapeutic step-up strategy for management of hereditary pancreatitis in children.

    Science.gov (United States)

    Kargl, S; Kienbauer, M; Duba, H C; Schöfl, R; Pumberger, W

    2015-04-01

    Various different regimes exist for the treatment of hereditary pancreatitis in childhood. Here, we propose a therapeutic pathway with emphasis on endoscopic and surgical procedures. From 2006 to 2013, 12 patients with a diagnosis of hereditary pancreatitis were prospectively included in a therapeutic step-up schema. The treatment outcome was evaluated and correlated to aetiological factors and pathoanatomic findings. After diagnostic work-up (laboratory data, ultrasound examination, magnetic resonance cholangiopancreatography and genetic testing), all 12 patients underwent early endoscopic retrograde cholangiopancreatography (ERCP), which was successfully performed in ten children. Obstructive pancreatitis was found in eight children, and required sphincterotomy, dilation and stenting for 12 months. In two children with unsuccessful ERCP, open surgical drainage procedures were performed. After a mean follow-up of 32 months all children are free of recurrence of pancreatitis without any impairment of everyday activities. For children with hereditary pancreatitis, a therapeutic step plan with early ERCP and open surgical drainage procedures in case of impossible or insufficient endoscopic treatment prevents recurring pancreatitis and offers a normal quality of life without any major complications. Copyright © 2015 Elsevier Inc. All rights reserved.

  16. GABAB receptors as a therapeutic strategy in substance use disorders: focus on positive allosteric modulators.

    Science.gov (United States)

    Filip, Małgorzata; Frankowska, Małgorzata; Sadakierska-Chudy, Anna; Suder, Agata; Szumiec, Lukasz; Mierzejewski, Paweł; Bienkowski, Przemyslaw; Przegaliński, Edmund; Cryan, John F

    2015-01-01

    γ-Aminobutyric acid B (GABAB) receptors and their ligands are postulated as potential therapeutic targets for the treatment of several brain disorders, including drug dependence. Over the past fifteen years positive allosteric modulators (PAMs) have emerged that enhance the effects of GABA at GABAB receptors and which may have therapeutic effects similar to those of agonists but with superior side-effect profiles. This review summarizes current preclinical evidence supporting a role of GABAB receptor PAMs in drug addiction in several paradigms with relevance to reward processes and drug abuse liability. Extensive behavioral research in recent years has indicated that PAMs of GABAB receptors may have a therapeutic efficacy in cocaine, nicotine, amphetamine and alcohol dependence. The magnitude of the effects observed are similar to that of the clinically approved drug baclofen, an agonist at GABAB receptors. Moreover, given that anxiolytic effects are also reported with such ligands they may also benefit in mitigating the withdrawal from drugs of abuse. In summary, a wealth of data now supports the benefits of GABAB receptor PAMs and clinical validation is now warranted. Copyright © 2014. Published by Elsevier Ltd.

  17. Comparison of the mechanical properties of therapeutic elastic tapes used in sports and clinical practice

    NARCIS (Netherlands)

    Matheus, Joao Paulo Chieregato; Zille, Rafael Ribeiro; Gomide Matheus, Liana Barbaresco; Lemos, Thiago Vilela; Carregaro, Rodrigo Luiz; Shimano, Antônio Carlos

    2016-01-01

    Study design Cross-sectional laboratory study. Objective The aim of the present study was to evaluate and compare the mechanical properties of different therapeutic elastic tapes used in sports and clinical practice. Background Therapeutic tapes have been used since around the 1800s. They are

  18. Comparison of the mechanical properties of therapeutic elastic tapes used in sports and clinical practice

    NARCIS (Netherlands)

    Matheus, Joao Paulo Chieregato; Zille, Rafael Ribeiro; Gomide Matheus, Liana Barbaresco; Lemos, Thiago Vilela; Carregaro, Rodrigo Luiz; Shimano, Antônio Carlos

    2017-01-01

    Study design Cross-sectional laboratory study. Objective The aim of the present study was to evaluate and compare the mechanical properties of different therapeutic elastic tapes used in sports and clinical practice. Background Therapeutic tapes have been used since around the 1800s. They are

  19. 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.

  20. New drugs, therapeutic strategies, and future direction for the treatment of Pulmonary Arterial Hypertension.

    Science.gov (United States)

    Mercurio, Valentina; Bianco, Anna; Campi, Giacomo; Cuomo, Alessandra; Diab, Nermin; Mancini, Angela; Parrella, Paolo; Petretta, Mario; Hassoun, Paul; Bonaduce, Domenico

    2018-01-31

    Despite recent advances in pulmonary arterial hypertension (PAH) treatment, this condition is still characterized by an extremely poor prognosis. In this review, we discuss the use of newly-approved drugs for PAH treatment with already known mechanisms of action (macitentan), innovative targets (riociguat and selexipag), and novel therapeutic approaches with initial up-front combination therapy. Secondly, we describe new potential signalling pathways and investigational drugs with promising role in the treatment of PAH. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  1. Comparison of Value Generation Strategies Between Planned and Emerging Strategies: A Study Based on Games of Companies

    Directory of Open Access Journals (Sweden)

    Marcos Paixão Garcez

    2012-06-01

    Full Text Available This study aims to analyze the economic results of the planned strategies compared to the emergent strategies in decision-making. The theoretical background emphasizes some aspects, like the strategy concept evolution throughout the time, the typology of strategies proposed by Mintzberg, the comparison between competition and cooperation, and the use of a business simulator as a tool for business research purposes. As a controlled experiment, the EGS simulator (Management Exercise Simulated allowed comparison of the economic results of the two decision-making situations. The findings show that when planned strategies were implemented without corrections, the value generated (expressed by the internal rate of return IRR = 1.51% was greater than in the case of adjusted emerging strategies in three periods (IRR= 1.40%. Comparing the two situations, it is possible to find a value added advantage of 7.86% in favor of the planned strategies, indicating the competition might be responsible for the value decreasing in real environment. Analyzing the performance degrees reached by the competitors, the ranking results show that there is no association between planned strategy and emerging strategies. Although the business simulators can be considered weak approximations for the business environment, the experiment contributed new evidence of the competition rise in oligopoly industries and a new methodological approach for studying this phenomenon.

  2. 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.

  3. Cell- and gene-based therapeutic strategies for periodontal regenerative medicine.

    Science.gov (United States)

    Rios, Hector F; Lin, Zhao; Oh, Bina; Park, Chan Ho; Giannobile, William V

    2011-09-01

    Inflammatory periodontal diseases are a leading cause of tooth loss and are linked to multiple systemic conditions, such as cardiovascular disease and stroke. Reconstruction of the support and function of affected tooth-supporting tissues represents an important therapeutic endpoint for periodontal regenerative medicine. An improved understanding of periodontal biology coupled with current advances in scaffolding matrices has introduced novel treatments that use cell and gene therapy to enhance periodontal tissue reconstruction and its biomechanical integration. Cell and gene delivery technologies have the potential to overcome limitations associated with existing periodontal therapies, and may provide a new direction in sustainable inflammation control and more predictable tissue regeneration of supporting alveolar bone, periodontal ligament, and cementum. This review provides clinicians with the current status of these early-stage and emerging cell- and gene-based therapeutics in periodontal regenerative medicine, and introduces their future application in clinical periodontal treatment. The paper concludes with prospects on the application of cell and gene tissue engineering technologies for reconstructive periodontology.

  4. Targeting Nicotinamide Phosphoribosyltransferase as a Potential Therapeutic Strategy to Restore Adult Neurogenesis.

    Science.gov (United States)

    Wang, Shu-Na; Xu, Tian-Ying; Li, Wen-Lin; Miao, Chao-Yu

    2016-06-01

    Adult neurogenesis is the process of generating new neurons throughout life in the olfactory bulb and hippocampus of most mammalian species, which is closely related to aging and disease. Nicotinamide phosphoribosyltransferase (NAMPT), also an adipokine known as visfatin, is the rate-limiting enzyme for mammalian nicotinamide adenine dinucleotide (NAD) salvage synthesis by generating nicotinamide mononucleotide (NMN) from nicotinamide. Recent findings from our laboratory and other laboratories have provided much evidence that NAMPT might serve as a therapeutic target to restore adult neurogenesis. NAMPT-mediated NAD biosynthesis in neural stem/progenitor cells is important for their proliferation, self-renewal, and formation of oligodendrocytes in vivo and in vitro. Therapeutic interventions by the administration of NMN, NAD, or recombinant NAMPT are effective for restoring adult neurogenesis in several neurological diseases. We summarize adult neurogenesis in aging, ischemic stroke, traumatic brain injury, and neurodegenerative disease and review the advances of targeting NAMPT in restoring neurogenesis. Specifically, we provide emphasis on the P7C3 family, a class of proneurogenic compounds that are potential NAMPT activators, which might shed light on future drug development in neurogenesis restoration. © 2016 John Wiley & Sons Ltd.

  5. Mesenchymal Stem Cells-Derived Exosomes: A Possible Therapeutic Strategy for Osteoporosis.

    Science.gov (United States)

    Li, Yue; Jin, Daxiang; Xie, Weixing; Wen, Longfei; Chen, Weijian; Xu, Jixi; Ding, Jinyong; Ren, Dongcheng; Xiao, Zenglin

    2018-04-03

    Osteoporosis is a common age-related disorder characterized by low bone mass and deterioration in bone microarchitecture, leading to increased skeletal fragility and fracture risk. The pathophysiology of osteoporosis is multifactorial. It is related to the imbalance between osteoblasts and osteoclasts; reduced bone mass and increased adipogenesis in the bone marrow. Moreover, angiogenesis, inflammatory process and miRNAs have shown effects in the formation of osteoporosis. In the recent years, mesenchymal stem cells (MSCs) have been regarded as an excellent choice for cell-based tissue engineering therapy of osteoporosis. Growing evidence showed that, paracrine effect have been considered as the predominant mechanism for the role of MSCs in tissue repair. Recently, many studies have proposed that MSCs-derived exosomes are effective for a variety of diseases like cancer, cardiovascular diseases, etc. However, whether the MSCs-derived exosomes could serve as a novel therapeutic tool for osteoporosis has not clearly described. In this review, we summarize the MSCs-derived exosomes and the relationship with osteogenesis, osteoclast differentiation, angiogenesis, immune processes and miRNAs. Finally, we suggest that MSCs-derived exosomes might be a promising therapeutic method for osteoporosis in the future. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  6. Cannabidiol as an Emergent Therapeutic Strategy for Lessening the Impact of Inflammation on Oxidative Stress

    Science.gov (United States)

    Booz, George W.

    2011-01-01

    Oxidative stress with reactive oxygen species generation is a key weapon in the arsenal of the immune system for fighting invading pathogens and to initiate tissue repair. If excessive or unresolved, however, immune-related oxidative stress can initiate further increasing levels of oxidative stress that cause organ damage and dysfunction. Targeting oxidative stress in these various diseases therapeutically has proven more problematic than first anticipated given the complexities and perversity of both the underlying disease and the immune response. However, growing evidence suggests that the endocannabinoid system, which includes the CB1 and CB2 G protein-coupled receptors and their endogenous lipid ligands, may be an area that is ripe for therapeutic exploitation. In this context, the related nonpsychotropic cannabinoid cannabidiol, which may interact with the endocannabinoid system, but has actions that are distinct, offers promise as a prototype for anti-inflammatory drug development. This review discusses recent studies suggesting that cannabidiol may have utility in treating a number of human diseases and disorders now known to involve activation of the immune system and associated oxidative stress, as a contributor to their etiology and progression. These include rheumatoid arthritis, types I and II diabetes, atherosclerosis, Alzheimer’s disease, hypertension, the metabolic syndrome, ischemia-reperfusion injury, depression, and neuropathic pain. PMID:21238581

  7. 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.

  8. Insights into the molecular pathogenesis of atherosclerosis and therapeutic strategies using gene transfer.

    Science.gov (United States)

    Hiltunen, M O; Turunen, M P; Laitinen, M; Ylä-Herttuala, S

    2000-01-01

    Gene therapy for the treatment of atherosclerosis and related diseases has shown its potential in animal models and in the first human trials. Gene transfer to the vascular system can be performed both via intravascular and extravascular periadventitial routes. Intravascular gene transfer can be done with several types of catheters under fluoroscopic control. Extravascular gene transfer, on the other hand, provides a well-targeted gene delivery route available during vascular surgery. It can be done with direct injection or by using perivascular cuffs or surgical collagen sheets. Ex vivo gene delivery via transfected smooth muscle cells or endothelial cells might be useful for the production of secreted therapeutic compounds. Gene transfer to the liver has been used for the treatment of hyperlipidemia. The first clinical trials for the induction of therapeutic angiogenesis in ischemic myocardium or peripheral muscles with VEGF or FGF gene transfer are under way and preliminary results are promising. VEGF has also been used for the prevention of postangioplasty restenosis because of its capability to induce endothelial repair and production of NO and prostacyclin. However, further basic research is needed to fully understand the pathophysiological mechanisms involved in conditions related to atherosclerosis. Also, further development of gene transfer vectors and gene delivery techniques will improve the efficacy and safety of human gene therapy.

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

    Directory of Open Access Journals (Sweden)

    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 

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

    Directory of Open Access Journals (Sweden)

    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.

  11. Therapeutic strategy for hair regeneration: Hair cycle activation, niche environment modulation, wound-induced follicle neogenesis and stem cell engineering

    Science.gov (United States)

    Chueh, Shan-Chang; Lin, Sung-Jan; Chen, Chih-Chiang; Lei, Mingxing; Wang, Ling Mei; Widelitz, Randall B.; Hughes, Michael W.; Jiang, Ting-Xing; Chuong, Cheng Ming

    2013-01-01

    Introduction There are major new advancements in the fields of stem cell biology, developmental biology, regenerative hair cycling, and tissue engineering. The time is ripe to integrate, translate and apply these findings to tissue engineering and regenerative medicine. Readers will learn about new progress in cellular and molecular aspects of hair follicle development, regeneration and potential therapeutic opportunities these advances may offer. Areas covered Here we use hair follicle formation to illustrate this progress and to identify targets for potential strategies in therapeutics. Hair regeneration is discussed in four different categories. (1) Intra-follicle regeneration (or renewal) is the basic production of hair fibers from hair stem cells and dermal papillae in existing follicles. (2) Chimeric follicles via epithelial-mesenchymal recombination to identify stem cells and signaling centers. (3) Extra-follicular factors including local dermal and systemic factors can modulate the regenerative behavior of hair follicles, and may be relatively easy therapeutic targets. (4) Follicular neogenesis means the de novo formation of new follicles. In addition, scientists are working to engineer hair follicles, which require hair forming competent epidermal cells and hair inducing dermal cells. Expert opinion Ideally self-organizing processes similar to those occurring during embryonic development should be elicited with some help from biomaterials. PMID:23289545

  12. Utilizing TH9 cells as a novel therapeutic strategy for malignancies

    OpenAIRE

    Lu, Yong; Yi, Qing

    2013-01-01

    TH9 cells join the ever-growing list of CD4+ T helper subsets and primarily mediate anti-parasite immune responses. We have recently demonstrated that tumor-specific TH9 cells induce a CCL20-CCR6-dependent regulation of DCs while stimulating CD8+ T cell-mediated antitumor immunity. These findings offer a novel immunotherapeutic strategy against cancer.

  13. 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.

  14. MEK inhibition is a promising therapeutic strategy for MLL-rearranged infant acute lymphoblastic leukemia patients carrying RAS mutations.

    Science.gov (United States)

    Kerstjens, Mark; Driessen, Emma M C; Willekes, Merel; Pinhanços, Sandra S; Schneider, Pauline; Pieters, Rob; Stam, Ronald W

    2017-02-28

    Acute lymphoblastic leukemia (ALL) in infants is an aggressive malignancy with a poor clinical outcome, and is characterized by translocations of the Mixed Lineage Leukemia (MLL) gene. Previously, we identified RAS mutations in 14-24% of infant ALL patients, and showed that the presence of a RAS mutation decreased the survival chances even further. We hypothesized that targeting the RAS signaling pathway could be a therapeutic strategy for RAS-mutant infant ALL patients. Here we show that the MEK inhibitors Trametinib, Selumetinib and MEK162 severely impair primary RAS-mutant MLL-rearranged infant ALL cells in vitro. While all RAS-mutant samples were sensitive to MEK inhibitors, we found both sensitive and resistant samples among RAS-wildtype cases. We confirmed enhanced RAS pathway signaling in RAS-mutant samples, but found no apparent downstream over-activation in the wildtype samples. However, we did confirm that MEK inhibitors reduced p-ERK levels, and induced apoptosis in the RAS-mutant MLL-rearranged ALL cells. Finally, we show that MEK inhibition synergistically enhances prednisolone sensitivity, both in RAS-mutant and RAS-wildtype cells. In conclusion, MEK inhibition represents a promising therapeutic strategy for MLL-rearranged ALL patients harboring RAS mutations, while patients without RAS mutations may benefit through prednisolone sensitization.

  15. Gut Microbiota Dysbiosis Drives and Implies Novel Therapeutic Strategies for Diabetes Mellitus and Related Metabolic Diseases

    Directory of Open Access Journals (Sweden)

    Xuan Li

    2017-12-01

    Full Text Available Accumulating evidence over the past decade has linked the development of metabolic syndrome related to diabetes to variations in gut microbiota, an emerging, critical homeostatic regulator of host energy metabolism and immune responses. Mechanistic studies in rodent models have revealed an ever-increasing multitude of molecular mechanisms whereby the gut microbiota interacts with various host sensing and signaling pathways, leading to modulation of endocrine system, immune responses, nervous system activity, and hence, the predisposition to metabolic diseases. Remarkably, the microbiota-driven immune responses in metabolic tissues and the host nutrient-sensing mechanisms of gut microbial metabolites, in particular short-chain fatty acids, have been significantly associated with the proneness to diabetes and related disorders. This review will synthesize the recent efforts on unraveling the mediating role of gut microbiota in the pathogenesis of metabolic diseases, aiming to reveal new therapeutic opportunities.

  16. Next-generation mTOR inhibitors in clinical oncology: how pathway complexity informs therapeutic strategy.

    LENUS (Irish Health Repository)

    Wander, Seth A

    2011-04-01

    Mammalian target of rapamycin (mTOR) is a PI3K-related kinase that regulates cell growth, proliferation, and survival via mTOR complex 1 (mTORC1) and mTORC2. The mTOR pathway is often aberrantly activated in cancers. While hypoxia, nutrient deprivation, and DNA damage restrain mTORC1 activity, multiple genetic events constitutively activate mTOR in cancers. Here we provide a brief overview of the signaling pathways up- and downstream of mTORC1 and -2, and discuss the insights into therapeutic anticancer targets - both those that have been tried in the clinic with limited success and those currently under clinical development - that knowledge of these pathways gives us.

  17. Novel strategies and therapeutic options for the management of primary biliary cholangitis.

    Science.gov (United States)

    Khanna, Amardeep; Jones, David E

    2017-10-01

    Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease. It has a varied course of progression ranging from being completely asymptomatic to aggressive disease leading to cirrhosis and resulting in liver transplantation. In addition, symptoms can be debilitating and can have a major impact on quality of life. For decades, there was only one anti-cholestatic agent available to target this disease and that was only effective in around half of patients, with little or no effect on symptoms. With increasing understanding of the pathogenic mechanisms of PBC and potential targets for drug treatment, pharmaceutical companies have shown a greater interest in this rare disease. A large number of novel therapeutic molecules have been developed and are currently being evaluated. In this review article all the novel molecules in use and in trials targeting cholestasis and symptoms in PBC are discussed.

  18. The Capsular Polysaccharide of Acinetobacter baumannii Is an Obstacle for Therapeutic Passive Immunization Strategies.

    Science.gov (United States)

    Wang-Lin, Shun Xin; Olson, Ruth; Beanan, Janet M; MacDonald, Ulrike; Balthasar, Joseph P; Russo, Thomas A

    2017-12-01

    Acinetobacter baumannii has become an important concern for human health due to rapid development and wide spread of antimicrobial-resistant strains and high mortality associated with the infection. Passive immunizations with antisera targeting outer membrane proteins (OMPs) have shown encouraging results in protecting mice from A. baumannii infection, but monoclonal anti-OMP antibodies have not been developed, and their potential therapeutic properties have not been explored. The goal of this report is to evaluate the antibacterial activity of monoclonal antibodies (MAbs) targeting outer membrane protein A (OmpA) of A. baumannii Five anti-OmpA MAbs were developed using hybridoma technology and showed strong binding to strain ATCC 19606. However, low antibody binding was observed when they were tested against six clinical isolates, which included extensively drug-resistant strains. In contrast, high binding to an isogenic K1 capsule-negative mutant (AB307.30) was shown, suggesting that capsular polysaccharide mediated the inhibition of MAb binding to OmpA. Anti-OmpA MAbs increased the macrophage-mediated bactericidal activity of AB307.30 but failed to increase phagocytic killing of capsule-positive strains. Capsular polysaccharide was also protective against complement-mediated bactericidal activity in human ascites in the presence and absence of opsonization. Lastly, passive immunization with anti-OmpA MAbs did not confer protection against challenge with AB307-0294, the encapsulated parent strain of AB307.30, in a mouse sepsis infection model. These results reveal the important role of capsule polysaccharide in shielding OmpA and thereby inhibiting anti-OmpA MAb binding to clinical isolates. This property of capsule hindered the therapeutic utility of anti-OmpA MAbs, and it may apply to other conserved epitopes in A. baumannii . Copyright © 2017 American Society for Microbiology.

  19. Utilizing TH9 cells as a novel therapeutic strategy for malignancies.

    Science.gov (United States)

    Lu, Yong; Yi, Qing

    2013-03-01

    T H 9 cells join the ever-growing list of CD4 + T helper subsets and primarily mediate anti-parasite immune responses. We have recently demonstrated that tumor-specific T H 9 cells induce a CCL20-CCR6-dependent regulation of DCs while stimulating CD8 + T cell-mediated antitumor immunity. These findings offer a novel immunotherapeutic strategy against cancer.

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

    Science.gov (United States)

    Natsume, Osamu; Ohya, Yukihiro

    2018-01-01

    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. Copyright © 2017 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.

  1. A Comparison of First and Second Language Reading Strategies.

    Science.gov (United States)

    Hauptman, Philip C.

    1981-01-01

    Briefly discusses theories on second language reading strategies and describes pilot study conducted at University of Ottawa using cloze procedure to help determine roles of syntactic versus semantic cues and similarities and/or differences between L1 and L2 reading strategies. (Author/BK)

  2. Comparison of manual and automated size measurements of lung metastases on MDCT images: Potential influence on therapeutic decisions

    International Nuclear Information System (INIS)

    Pauls, Sandra; Kuerschner, Christian; Dharaiya, Ekta; Muche, Rainer; Schmidt, Stefan A.; Krueger, Stefan; Brambs, Hans-Juergen; Aschoff, Andrik J.

    2008-01-01

    Purpose: The goal of this study was to evaluate the influence of automated measurement of diameter, area, and volume from chest CT scans on therapeutic decisions of lung nodules as compared to manual 2-D measurements. Patients and method: The retrospective study involved 25 patients with 75 lung metastases. Contrast enhanced CT scans (16 row) of the lung were performed three times during chemotherapy with a mean time interval of 67.9 days between scans. In each patient, three metastases were evaluated (n = 225). Automatic measurements were compared to manual assessment for the following parameters: diameter, area, and density. The influence on the therapeutic decisions was evaluated using the RECIST criteria. Results: The maximum diameter measured by the automatic application was on an average 27% (S.D. 39; CI: 0.22-0.32; p < 0.0001) higher than the maximum diameter with manual assessment, and the differences depended on metastases size. Based on diameter calculation, manual and automated assessment disagreed in up to 32% of therapeutic decisions. Volumetric assessment tended towards more changes in therapy as compared to diameter calculation. The calculation of mean transversal area of metastases was 36% (S.D. 0.305; CI: -0.40 to -0.32; p < 0.0001) less with automated measurement. Therapeutic strategy would be changed in up to 25.7% of nodules using automated area calculation. Automated assessment of nodules' area and volume could influence the therapeutic decisions in up to 51.4% of all nodules. Density of the nodules was not validated to determine the influence on therapeutic decisions. Conclusion: There is a discrepancy between the manual and automated size measurement of lung metastases which could be significant

  3. Surgical and therapeutic strategy of recurrent malignant gliomas in intractable location

    Directory of Open Access Journals (Sweden)

    LU Yun-tao

    2012-12-01

    Full Text Available Objective Recurrent malignant gliomas often violate important neurological function parts or deep brain structures due to tumor invasion, further increasing the difficulty of reoperation and treatment. Therefore, how to develop a reasonable treatment strategy, maximize the removal of the tumor, and ensure a basic quality of life of the patient, is nowadays hotly debated by scholars from various countries. This article aims to explore the reasonable treatment and optimal surgical strategy of recurrent malignant gliomas. Methods Four cases of recurrent malignant glioma were collceted. A comprehensive assessment on preoperative imaging, intraoperative operation, postoperative complications and long-term follow-up was made, and treatment strategy was elaborated. Results Postoperative MRI in 2 cases showed the recurrent tumors located in remnant edema parts, which were revealed by T2WI after first resections. One case underwent expanded resection of edema parts according to T2WI. This patient suffered short-sensory aphasia and weakness of right limbs, but recovered by improving cerebral circulation, hyperbaric oxygen, auxiliary acupuncture and physical rehabilitation trainings. One case with brainstem glioma underwent precise resection by laser knife, without postoperative neurological disorders. All the 4 cases received postoperative chemotherapy with TMZ (200 mg/kg, 5 d/28 d. The average follow-up period was (14.00 ± 12.50 months. Conclusion For obvious recurrence of malignant glioma, reoperation is still the key factor to lengthen the survival of patients, and expanded resection of the edema area supplemented by T2WI can reduce recurrence. Under the precondition of maintaining the basic postoperative quality of life of patients (KPS > 70, expanded resection should be used. As for tumors adjacent to the eloquent areas, precise engraving resection should be used to minimize residual tumor cells.

  4. New Therapeutic Strategies for Systemic Sclerosis—a Critical Analysis of the Literature

    Directory of Open Access Journals (Sweden)

    Gisele Zandman-Goddard

    2005-01-01

    Full Text Available Systemic sclerosis (SSc is a multi-system disease characterized by skin fibrosis and visceral disease. Therapy is organ and pathogenesis targeted. In this review, we describe novel strategies in the treatment of SSc. Utilizing the MEDLINE and the COCHRANE REGISTRY, we identified open trials, controlled trials, for treatment of SSc from 1999 to April 2005. We used the terms scleroderma, systemic sclerosis, Raynaud's phenomenon, pulmonary hypertension, methotrexate, cyclosporin, tacrolimus, relaxin, low-dose penicillamine, IVIg, calcium channel blockers, losartan, prazocin, iloprost, N-acetylcysteine, bosentan, cyclophosphamide, lung transplantation, ACE inhibitors, anti-thymocyte globulin, and stem cell transplantation. Anecdotal reports were omitted.

  5. Targeting the Central Pocket in Human Transcription Factor TEAD as a Potential Cancer Therapeutic Strategy

    OpenAIRE

    Pobbati, Ajaybabu V.; Han, Xiao; Hung, Alvin W.; Weiguang, Seetoh; Huda, Nur; Chen, Guo-Ying; Kang, CongBao; Chia, Cheng San Brian; Luo, Xuelian; Hong, Wanjin; Poulsen, Anders

    2015-01-01

    The human TEAD family of transcription factors (TEAD1-4) is required for YAP-mediated transcription in the Hippo pathway. Hyperactivation of TEAD’s co-activator YAP contributes to tissue overgrowth and human cancers, suggesting that pharmacological interference of TEAD-YAP activity may be an effective strategy for anticancer therapy. Here we report the discovery of a central pocket in the YAP-binding domain (YBD) of TEAD that is targetable by small molecule inhibitors. Our X-ray crystallograp...

  6. Surgical strategies and modern therapeutic options in the treatment of craniopharyngiomas.

    Science.gov (United States)

    Mortini, Pietro; Gagliardi, Filippo; Boari, Nicola; Losa, Marco

    2013-12-01

    The optimal treatment of patients with craniopharyngioma remains controversial. In particular, the role of aggressive treatment compared to less aggressive therapeutic options is poorly understood. Radical resection is the therapy of choice at any age, because it is associated with the best outcome in terms of survival. Nevertheless, aggressive behaviour, location, involvement of critical structures, tumour size, calcifications, and patient age may limit the extent of resection. Surgery can also carry significant morbidity in terms of visual, hypothalamic, and endocrinological disturbances. Long term sequelae reduce the quality of life in 50% of long-term survivors, notably obesity and neurobehavioral impairment due to hypthalamic involvement and iatrogenic induced lesions. The quality of life should be considered as a clinically important endpoint in patients, who currently experience good overall survival rates, regardless of the degree of surgical resection. Tendency to recur despite negative postoperative imaging led many authors to advocate a less aggressive surgical treatment followed by radiation therapy. We review the data reported in the literature, especially early outcome after surgical treatment and factors affecting the risk of tumour recurrence, to elucidate the role of attempted radical resection in the treatment of craniopharyngioma and to identify the clinical and morphological characteristics predictive for the best surgical prognosis. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  7. Geroprotectors as a therapeutic strategy for COPD – where are we now?

    Directory of Open Access Journals (Sweden)

    Miłkowska-Dymanowska J

    2017-10-01

    Full Text Available Joanna Miłkowska-Dymanowska,1,2 Adam J Białas,1,2 Joanna Makowska,2,3 Aleksandra Wardzynska,2,4 Paweł Górski,1,2 Wojciech J Piotrowski1,2 1Department of Pneumology and Allergy, 1st Chair of Internal Medicine, 2Healthy Aging Research Centre, 3Department of Rheumatology, 4Department of Immunology, Rheumatology, and Allergy, Medical University of Lodz, Lodz, Poland Abstract: Although current therapies in chronic obstructive pulmonary disease (COPD improve the quality of life, they do not satisfactorily reduce disease progression or mortality. There are still many gaps in knowledge about the cellular, molecular, and genetic mechanisms contributing to pathobiology of this disease. However, increasing evidence suggests that accelerated aging, chronic systemic inflammation, and oxidative stress play major roles in pathogenesis in COPD, thus opening new opportunities in therapy. Therefore, the aim of our review was to describe and discuss some of the most widely used therapeutics that affect the root cause of aging and oxidative stress (metformin, melatonin, sirolimus, statins, vitamin D, and testosterone in context of COPD therapy. Keywords: COPD, metformin, melatonin, statins, vitamin D, testosterone

  8. [Therapeutics strategies for the management of urinary tract infection in children].

    Science.gov (United States)

    Launay, E; Bingen, E; Cohen, R

    2012-11-01

    Urinary tract infections is one of the most common bacterial infections in pediatrics The increasing involvement of multiresistant bacteria including E. coli producing extended spectrum ß-lactamase (ESBL) makes its management difficult. The purpose of this article is to evaluate the state of the art and to propose ways of thinking about the management of E. coli urinary tract infection in children. The current percentage (less than 10%) of E. coli strains resistant to third generation cephalosporins and the relative efficiency of the latter, should not led to an immediate change of our protocols. Nevertheless, we should verify as soon as possible susceptibility of E. coli responsible for urinary tract infections and consider other therapeutic options for initial therapy and adaptation after obtaining antibiogram. The use of an aminoglycosid as initial treatment seems very interesting. Aminoglycosides have a very good distribution in the renal parenchyma and are still working on the majority of ESBL-producing bacteria. A rapid oral relay after 48 to 72 hours may be proposed according to the results of the susceptibility with either cotrimoxazole, cefixime, ciprofloxacin or an association cefixime-amoxicilline/clavulanate. The treatment of cystitis due to ESBL E. coli is much less problematic given the good urinary beta-lactam antibiotics diffusion. If clinical improvement occurs, even if antibiogram shows that the strain is resistant to the antibiotic prescribed, it is usually unnecessary to change treatment. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

  9. Multiple sclerosis in children: an update on clinical diagnosis, therapeutic strategies, and research.

    Science.gov (United States)

    Waldman, Amy; Ghezzi, Angelo; Bar-Or, Amit; Mikaeloff, Yann; Tardieu, Marc; Banwell, Brenda

    2014-09-01

    The clinical features, diagnostic challenges, neuroimaging appearance, therapeutic options, and pathobiological research progress in childhood-and adolescent-onset multiple sclerosis have been informed by many new insights in the past 7 years. National programmes in several countries, collaborative research efforts, and an established international paediatric multiple sclerosis study group have contributed to revised clinical diagnostic definitions, identified clinical features of multiple sclerosis that differ by age of onset, and made recommendations regarding the treatment of paediatric multiple sclerosis. The relative risks conveyed by genetic and environmental factors to paediatric multiple sclerosis have been the subject of several large cohort studies. MRI features have been characterised in terms of qualitative descriptions of lesion distribution and applicability of MRI aspects to multiple sclerosis diagnostic criteria, and quantitative studies have assessed total lesion burden and the effect of the disease on global and regional brain volume. Humoral-based and cell-based assays have identified antibodies against myelin, potassium-channel proteins, and T-cell profiles that support an adult-like T-cell repertoire and cellular reactivity against myelin in paediatric patients with multiple sclerosis. Finally, the safety and efficacy of standard first-line therapies in paediatric multiple sclerosis populations are now appreciated in more detail, and consensus views on the future conduct and feasibility of phase 3 trials for new drugs have been proposed. Copyright © 2014 Elsevier Ltd. All rights reserved.

  10. Gene Editing and CRISPR Therapeutics: Strategies Taught by Cell and Gene Therapy.

    Science.gov (United States)

    Ramirez, Juan C

    2017-01-01

    A few years ago, we assisted in the demonstration for the first time of the revolutionary idea of a type of adaptive-immune system in the bacteria kingdom. This system, named CRISPR, and variants engineered in the lab, have been demonstrated as functional with extremely high frequency and fidelity in almost all eukaryotic cells studied to date. The capabilities of this RNA-guided nuclease have added to the interest that was announced with the advent of previous technologies for genome editing tools, such as ZFN and TALEN. The capabilities exhibited by these gene editors, opens up a novel scenario that indicates the promise of a next-generation medicine based on precision and personalized objectives, mostly due to the change in the paradigm regarding gene-surgery. This has certainly attracted, like never before, the attention of the biotech business and investor community. This chapter offers a brief overview of some of the factors that have contributed to a rapid entry into the biotech and pharmaceutical company's pipeline, focusing on how cell and gene therapies (CGT), collectively known as advanced therapies, have become the driving forces toward the therapeutic uses of gene editing technology. The sum of all those efforts for more than 30years has contributed to the new paradigm of considering genes as medicines. Copyright © 2017. Published by Elsevier Inc.

  11. The third therapeutic system: faith healing strategies in the context of a generalized AIDS epidemic.

    Science.gov (United States)

    Manglos, Nicolette D; Trinitapoli, Jenny

    2011-03-01

    Faith healing in sub-Saharan Africa has primarily been studied qualitatively among Pentecostal-Charismatic groups, and considered as its own phenomenon with little attention to its relationship to other modes of healing. Using data from Malawi, a religiously diverse African country with high HIV prevalence, we find that faith healing is pervasive across multiple religious traditions. For individuals, attending a faith healing congregation is associated with lower levels of generalized worry about AIDS, and this association is driven by those who switched churches before AIDS became widespread in rural areas. Use of condoms and traditional medicine are, on the other hand, positively associated with worry about AIDS. We argue that faith healing can be understood as a third therapeutic system that coexists with the well-documented biomedical and traditional systems. The success of faith healing approaches lies in their unique ability to combine individual-pragmatic and communal-ritualized aspects of healing to inform interpretations of the AIDS epidemic and its consequences.

  12. Therapeutics for Graft-versus-Host Disease: From Conventional Therapies to Novel Virotherapeutic Strategies

    Directory of Open Access Journals (Sweden)

    Nancy Y. Villa

    2016-03-01

    Full Text Available Allogeneic hematopoietic stem cell transplantation (allo-HSCT has a curative potential for many hematologic malignancies and blood diseases. However, the success of allo-HSCT is limited by graft-versus-host disease (GVHD, an immunological syndrome that involves inflammation and tissue damage mediated by donor lymphocytes. Despite immune suppression, GVHD is highly incident even after allo-HSCT using human leukocyte antigen (HLA-matched donors. Therefore, alternative and more effective therapies are needed to prevent or control GVHD while preserving the beneficial graft-versus-cancer (GVC effects against residual disease. Among novel therapeutics for GVHD, oncolytic viruses such as myxoma virus (MYXV are receiving increased attention due to their dual role in controlling GVHD while preserving or augmenting GVC. This review focuses on the molecular basis of GVHD, as well as state-of-the-art advances in developing novel therapies to prevent or control GVHD while minimizing impact on GVC. Recent literature regarding conventional and the emerging therapies are summarized, with special emphasis on virotherapy to prevent GVHD. Recent advances using preclinical models with oncolytic viruses such as MYXV to ameliorate the deleterious consequences of GVHD, while maintaining or improving the anti-cancer benefits of GVC will be reviewed.

  13. Mini-Review: Novel Therapeutic Strategies to Blunt Actions of Pneumolysin in the Lungs

    Directory of Open Access Journals (Sweden)

    Martin Leustik

    2013-07-01

    Full Text Available Severe pneumonia is the main single cause of death worldwide in children under five years of age. The main etiological agent of pneumonia is the G+ bacterium Streptococcus pneumoniae, which accounts for up to 45% of all cases. Intriguingly, patients can still die days after commencing antibiotic treatment due to the development of permeability edema, although the pathogen was successfully cleared from their lungs. This condition is characterized by a dramatically impaired alveolar epithelial-capillary barrier function and a dysfunction of the sodium transporters required for edema reabsorption, including the apically expressed epithelial sodium channel (ENaC and the basolaterally expressed sodium potassium pump (Na+-K+-ATPase. The main agent inducing this edema formation is the virulence factor pneumolysin, a cholesterol-binding pore-forming toxin, released in the alveolar compartment of the lungs when pneumococci are being lysed by antibiotic treatment or upon autolysis. Sub-lytic concentrations of pneumolysin can cause endothelial barrier dysfunction and can impair ENaC-mediated sodium uptake in type II alveolar epithelial cells. These events significantly contribute to the formation of permeability edema, for which currently no standard therapy is available. This review focuses on discussing some recent developments in the search for the novel therapeutic agents able to improve lung function despite the presence of pore-forming toxins. Such treatments could reduce the potentially lethal complications occurring after antibiotic treatment of patients with severe pneumonia.

  14. Bariatric Surgery for Adolescents with Type 2 Diabetes: an Emerging Therapeutic Strategy.

    Science.gov (United States)

    Stefater, M A; Inge, T H

    2017-08-01

    Type 2 diabetes (T2D) is a growing public health problem in youth, but conventional treatments are often insufficient to treat this disease and its comorbidities. We review evidence supporting an emerging role for bariatric surgery as a treatment for adolescent T2D. Paralleling what has been seen in adult patients, bariatric surgery dramatically improves glycemic control in patients with T2D. In fact, remission of T2D has been observed in as many as 95-100% of adolescents with diabetes after bariatric surgery, particularly vertical sleeve gastrectomy (VSG) and Roux-en-Y gastric bypass (RYGB) surgery. This striking outcome may be due to both weight-dependent- and weight-independent factors, and recent studies suggest that T2D-related comorbidities may also improve after surgery. Bariatric surgery including RYGB and VSG is a powerful therapeutic option for obese adolescents with T2D. Benefits must be weighed against risk for postoperative complications such as nutritional deficiencies, but earlier surgical intervention might lead to more complete metabolic remission in obese patients with T2D.

  15. Targeting protein neddylation: a novel therapeutic strategy for the treatment of cancer.

    Science.gov (United States)

    Wang, Meng; Medeiros, Bruno C; Erba, Harry P; DeAngelo, Daniel J; Giles, Francis J; Swords, Ronan T

    2011-03-01

    The NEDD8 (neural precursor cell-expressed developmentally downregulated 8) conjugation pathway regulates the post-translational modification of oncogenic proteins. This pathway has important potential for cancer therapeutics. Several proteins vital in cancer biology are regulated by protein neddylation. These observations led to the development of a small molecule inhibitor that disrupts protein neddylation and leads to cancer cell death and important activity in early phase clinical trials. This review provides an extensive coverage of cellular protein homeostasis with particular emphasis on the NEDD8 conjugation pathway. Insights into a new investigational drug that specifically disrupts the NEDD8 pathway are discussed. The clinical data for this agent are also updated. Neddylation controls key cellular pathways found to be dysregulated in many cancers. Protein neddylation is a relatively under-explored pathway for pharmacologic inhibition in cancer. Selective disruption of this pathway has demonstrated clinical activity in patients with myeloid neoplasms and is worth exploring further in combination with other anti-leukemia agents.

  16. Exploring RNAi as a therapeutic strategy for controlling disease in aquaculture.

    Science.gov (United States)

    Lima, Paula C; Harris, James O; Cook, Mathew

    2013-03-01

    Aquatic animal diseases are one of the most significant constraints to the development and management of aquaculture worldwide. As a result, measures to combat diseases of fish and shellfish have assumed a high priority in many aquaculture-producing countries. RNA interference (RNAi), a natural mechanism for post-transcriptional silencing of homologous genes by double-stranded RNA (dsRNA), has emerged as a powerful tool not only to investigate the function of specific genes, but also to suppress infection or replication of many pathogens that cause severe economic losses in aquaculture. However, despite the enormous potential as a novel therapeutical approach, many obstacles must still be overcome before RNAi therapy finds practical application in aquaculture, largely due to the potential for off-target effects and the difficulties in providing safe and effective delivery of RNAi molecules in vivo. In the present review, we discuss the current knowledge of RNAi as an experimental tool, as well as the concerns and challenges ahead for the application of such technology to combat infectious disease of farmed aquatic animals. Crown Copyright © 2012. Published by Elsevier Ltd. All rights reserved.

  17. Rendering factor Xa zymogen-like as a therapeutic strategy to treat bleeding.

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    Thalji, Nabil K; Camire, Rodney M

    2017-09-01

    New therapies are needed to control bleeding in a range of clinical conditions. This review will discuss the biochemical properties of zymogen-like factor Xa, its preclinical assessment in different model systems, and future development prospects. Underlying many procoagulant therapeutic approaches is the rapid generation of thrombin to promote robust clot formation. Clinically tested prohemostatic agents (e.g., factor VIIa) can provide effective hemostasis to mitigate bleeding in hemophilia and other clinical situations. Over the past decade, we explored the possibility of using zymogen-like factor Xa variants to rapidly improve clot formation for the treatment of bleeding conditions. Compared to the wild-type enzyme, these variants adopt an altered, low activity, conformation which enables them to resist plasma protease inhibitors. However, zymogen-like factor Xa variants are conformationally dynamic and ligands such as its cofactor, factor Va, stabilize the molecule rescuing procoagulant activity. At the site of vascular injury, the variants in the presence of factor Va serve as effective prohemostatic agents. Preclinical data support their use to stop bleeding in a variety of clinical settings. Phase 1 studies suggest that zymogen-like factor Xa is safe and well tolerated, and a phase 1b is ongoing to assess safety in patients with intracerebral hemorrhage. Zymogen-like factor Xa is a unique prohemostatic agent for the treatment of a range of bleeding conditions.

  18. The impact of cellular senescence in skin ageing: A notion of mosaic and therapeutic strategies.

    Science.gov (United States)

    Toutfaire, Marie; Bauwens, Emilie; Debacq-Chainiaux, Florence

    2017-10-15

    Cellular senescence is now recognized as one of the nine hallmarks of ageing. Recent data show the involvement of senescent cells in tissue ageing and some age-related diseases. Skin represents an ideal model for the study of ageing. Indeed, skin ageing varies between individuals depending on their chronological age but also on their exposure to various exogenous factors (mainly ultraviolet rays). If senescence traits can be detected with ageing in the skin, the senescent phenotype varies among the various skin cell types. Moreover, the origin of cellular senescence in the skin is still unknown, and multiple origins are possible. This reflects the mosaic of skin ageing. Senescent cells can interfere with their microenvironment, either via the direct secretion of factors (the senescence-associated secretory phenotype) or via other methods of communication, such as extracellular vesicles. Knowledge regarding the impact of cellular senescence on skin ageing could be integrated into dermatology research, especially to limit the appearance of senescent cells after photo(chemo)therapy or in age-related skin diseases. Therapeutic approaches include the clearance of senescent cells via the use of senolytics or via the cooperation with the immune system. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Multiple sclerosis in children: an update on clinical diagnosis, therapeutic strategies, and research

    Science.gov (United States)

    Waldman, Amy; Ghezzi, Angelo; Bar-Or, Amit; Mikaeloff, Yann; Tardieu, Marc; Banwell, Brenda

    2015-01-01

    The clinical features, diagnostic challenges, neuroimaging appearance, therapeutic options, and pathobiological research progress in childhood—and adolescent—onset multiple sclerosis have been informed by many new insights in the past 7 years. National programmes in several countries, collaborative research efforts, and an established international paediatric multiple sclerosis study group have contributed to revised clinical diagnostic definitions, identified clinical features of multiple sclerosis that differ by age of onset, and made recommendations regarding the treatment of paediatric multiple sclerosis. The relative risks conveyed by genetic and environmental factors to paediatric multiple sclerosis have been the subject of several large cohort studies. MRI features have been characterised in terms of qualitative descriptions of lesion distribution and applicability of MRI aspects to multiple sclerosis diagnostic criteria, and quantitative studies have assessed total lesion burden and the effect of the disease on global and regional brain volume. Humoral-based and cell-based assays have identified antibodies against myelin, potassium-channel proteins, and T-cell profiles that support an adult-like T-cell repertoire and cellular reactivity against myelin in paediatric patients with multiple sclerosis. Finally, the safety and efficacy of standard first-line therapies in paediatric multiple sclerosis populations are now appreciated in more detail, and consensus views on the future conduct and feasibility of phase 3 trials for new drugs have been proposed. PMID:25142460

  20. The Incremental Induction of Neuroprotective Properties by Multiple Therapeutic Strategies for Primary and Secondary Neural Injury

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    Seunghoon Lee

    2015-08-01

    Full Text Available Neural diseases including injury by endogenous factors, traumatic brain injury, and degenerative neural injury are eventually due to reactive oxygen species (ROS. Thus ROS generation in neural tissues is a hallmark feature of numerous forms of neural diseases. Neural degeneration and the neural damage process is complex, involving a vast array of tissue structure, transcriptional/translational, electrochemical, metabolic, and functional events within the intact neighbors surrounding injured neural tissues. During aging, multiple changes involving physical, chemical, and biochemical processes occur from the molecular to the morphological levels in neural tissues. Among many recommended therapeutic candidates, melatonin also plays a role in protecting the nervous system from anti-inflammation and efficiently safeguards neuronal cells via antioxidants and other endogenous/exogenous beneficial factors. Therefore, given the wide range of mechanisms responsible for neuronal damage, multi-action drugs or therapies for the treatment of neural injury that make use of two or more agents and target several pathways may have greater efficacy in promoting functional recovery than a single therapy alone.

  1. The Incremental Induction of Neuroprotective Properties by Multiple Therapeutic Strategies for Primary and Secondary Neural Injury.

    Science.gov (United States)

    Lee, Seunghoon; Park, Sookyoung; Won, Jinyoung; Lee, Sang-Rae; Chang, Kyu-Tae; Hong, Yonggeun

    2015-08-19

    Neural diseases including injury by endogenous factors, traumatic brain injury, and degenerative neural injury are eventually due to reactive oxygen species (ROS). Thus ROS generation in neural tissues is a hallmark feature of numerous forms of neural diseases. Neural degeneration and the neural damage process is complex, involving a vast array of tissue structure, transcriptional/translational, electrochemical, metabolic, and functional events within the intact neighbors surrounding injured neural tissues. During aging, multiple changes involving physical, chemical, and biochemical processes occur from the molecular to the morphological levels in neural tissues. Among many recommended therapeutic candidates, melatonin also plays a role in protecting the nervous system from anti-inflammation and efficiently safeguards neuronal cells via antioxidants and other endogenous/exogenous beneficial factors. Therefore, given the wide range of mechanisms responsible for neuronal damage, multi-action drugs or therapies for the treatment of neural injury that make use of two or more agents and target several pathways may have greater efficacy in promoting functional recovery than a single therapy alone.

  2. Overcoming ABC transporter-mediated multidrug resistance: Molecular mechanisms and novel therapeutic drug strategies.

    Science.gov (United States)

    Li, Wen; Zhang, Han; Assaraf, Yehuda G; Zhao, Kun; Xu, Xiaojun; Xie, Jinbing; Yang, Dong-Hua; Chen, Zhe-Sheng

    2016-07-01

    Multidrug resistance is a key determinant of cancer chemotherapy failure. One of the major causes of multidrug resistance is the enhanced efflux of drugs by membrane ABC transporters. Targeting ABC transporters projects a promising approach to eliminating or suppressing drug resistance in cancer treatment. To reveal the functional mechanisms of ABC transporters in drug resistance, extensive studies have been conducted from identifying drug binding sites to elucidating structural dynamics. In this review article, we examined the recent crystal structures of ABC proteins to depict the functionally important structural elements, such as domains, conserved motifs, and critical amino acids that are involved in ATP-binding and drug efflux. We inspected the drug-binding sites on ABC proteins and the molecular mechanisms of various substrate interactions with the drug binding pocket. While our continuous battle against drug resistance is far from over, new approaches and technologies have emerged to push forward our frontier. Most recent developments in anti-MDR strategies include P-gp inhibitors, RNA-interference, nano-medicines, and delivering combination strategies. With the advent of the 'Omics' era - genomics, epigenomics, transcriptomics, proteomics, and metabolomics - these disciplines play an important role in fighting the battle against chemoresistance by further unraveling the molecular mechanisms of drug resistance and shed light on medical therapies that specifically target MDR. Copyright © 2016 Elsevier Ltd. All rights reserved.

  3. CRISPR-Cas9 systems: versatile cancer modelling platforms and promising therapeutic strategies.

    Science.gov (United States)

    Wen, Wan-Shun; Yuan, Zhi-Min; Ma, Shi-Jie; Xu, Jiang; Yuan, Dong-Tang

    2016-03-15

    The RNA-guided nuclease CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats-CRISPR associated nuclease 9) and its variants such as nickase Cas9, dead Cas9, guide RNA scaffolds and RNA-targeting Cas9 are convenient and versatile platforms for site-specific genome editing and epigenome modulation. They are easy-to-use, simple-to-design and capable of targeting multiple loci simultaneously. Given that cancer develops from cumulative genetic and epigenetic alterations, CRISPR-Cas9 and its variants (hereafter referred to as CRISPR-Cas9 systems) hold extensive application potentials in cancer modeling and therapy. To date, they have already been applied to model oncogenic mutations in cell lines (e.g., Choi and Meyerson, Nat Commun 2014;5:3728) and in adult animals (e.g., Xue et al., Nature 2014;514:380-4), as well as to combat cancer by disabling oncogenic viruses (e.g., Hu et al., Biomed Res Int 2014;2014:612823) or by manipulating cancer genome (e.g., Liu et al., Nat Commun 2014;5:5393). Given the importance of epigenome and transcriptome in tumourigenesis, manipulation of cancer epigenome and transcriptome for cancer modeling and therapy is a promising area in the future. Whereas (epi)genetic modifications of cancer microenvironment with CRISPR-Cas9 systems for therapeutic purposes represent another promising area in cancer research. Herein, we introduce the functions and mechanisms of CRISPR-Cas9 systems in genome editing and epigenome modulation, retrospect their applications in cancer modelling and therapy, discuss limitations and possible solutions and propose future directions, in hope of providing concise and enlightening information for readers interested in this area. © 2015 UICC.

  4. Metabolic profiling of follistatin overexpression: a novel therapeutic strategy for metabolic diseases

    Directory of Open Access Journals (Sweden)

    Singh R

    2018-03-01

    Full Text Available Rajan Singh,1,2 Shehla Pervin,1,2 Se-Jin Lee,3,4 Alan Kuo,5 Victor Grijalva,6 John David,7 Laurent Vergnes,8 Srinivasa T Reddy1,6 1Department of Obstetrics and Gynecology, UCLA School of Medicine, Los Angeles, CA, USA; 2Division of Endocrinology and Metabolism, Charles R. Drew University of Medicine and Science, Los Angeles, CA, USA; 3The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA; 4Department of Genetics and Genome Sciences, University of Connecticut School of Medicine, CT, USA; 5Department of Biology, California State University Dominguez Hills, CA, USA; 6Department of Molecular and Medical Pharmacology, UCLA School of Medicine, Los Angeles, CA, USA; 7Department of Comparative Medicine, Pfizer Inc, San Diego, CA, USA; 8Department of Human Genetics, UCLA School of Medicine, Los Angeles, CA, USA Background: Follistatin (Fst promotes brown adipocyte characteristics in adipose tissues.Methods: Abdominal fat volume (CT scan, glucose clearance (GTT test, and metabolomics analysis (mass spectrometry of adipose tissues from Fst transgenic (Fst-Tg and wild type (WT control mice were analyzed. Oxygen consumption (Seahorse Analyzer and lipidomics (gas chromatography was analyzed in 3T3-L1 cells.Results: Fst-Tg mice show significant decrease in abdominal fat content, increased glucose clearance, improved plasma lipid profiles and significant changes in several conventional metabolites compared to the WT mice. Furthermore, overexpression of Fst in 3T3-L1 cells resulted in up regulation of key brown/beige markers and changes in lipidomics profiles. Conclusion: Fst modulates key factors involved in promoting metabolic syndrome and could be used for therapeutic intervention. Keywords: follistatin, transgenic, adipocyte, fibroblast growth factor 21, AdipoQ

  5. Skeletal muscle homeostasis in Duchenne muscular dystrophy: modulating autophagy as a promising therapeutic strategy

    Directory of Open Access Journals (Sweden)

    Clara eDe Palma

    2014-07-01

    Full Text Available Muscular dystrophies are a group of genetic and heterogeneous neuromuscular disorders characterised by the primary wasting of skeletal muscle. In Duchenne muscular dystrophy (DMD, the most severe form of these diseases, the mutations in the dystrophin gene lead to muscle weakness and wasting, exhaustion of muscular regenerative capacity and chronic local inflammation leading to substitution of myofibres by connective and adipose tissue. DMD patients suffer of continuous and progressive skeletal muscle damage followed by complete paralysis and death, usually by respiratory and/or cardiac failure. No cure is yet available, but several therapeutic approaches aiming at reversing the ongoing degeneration have been investigated in preclinical and clinical settings. The autophagy is an important proteolytic system of the cell and has a crucial role in the removal of proteins, aggregates and organelles. Autophagy is constantly active in skeletal muscle and its role in tissue homeostasis is complex: at high levels it can be detrimental and contribute to muscle wasting; at low levels it can cause weakness and muscle degeneration, due to the unchecked accumulation of damaged proteins and organelles. The causal relationship between DMD pathogenesis and dysfunctional autophagy has been recently investigated. At molecular levels, the Akt axis is one of the key disregulated pathways, although the molecular events are not completely understood.The aim of this review is to describe and discuss the clinical relevance of the recent advances dissecting autophagy and its signalling pathway in DMD. The picture might pave the way for the development of interventions that are able to boost muscle growth and/or prevent muscle wasting.

  6. Targeting the TLR4 signaling pathway by polyphenols: A novel therapeutic strategy for neuroinflammation.

    Science.gov (United States)

    Rahimifard, Mahban; Maqbool, Faheem; Moeini-Nodeh, Shermineh; Niaz, Kamal; Abdollahi, Mohammad; Braidy, Nady; Nabavi, Seyed Mohammad; Nabavi, Seyed Fazel

    2017-07-01

    A wide array of cell signaling mediators and their interactions play vital roles in neuroinflammation associated with ischemia, brain trauma, developmental disorders and age-related neurodegeneration. Along with neurons, microglia and astrocytes are also affected by the inflammatory cascade by releasing pro-inflammatory cytokines, chemokines and reactive oxygen species. The release of pro-inflammatory mediators in response to neural dysfunction may be helpful, neutral or even deleterious to normal cellular survival. Moreover, the important role of NF-κB factors in the central nervous system (CNS) through toll-like receptor (TLR) activation has been well established. This review demonstrates recent findings regarding therapeutic aspects of polyphenolic compounds for the treatment of neuroinflammation, with the aim of regulating TLR4. Polyphenols including flavonoids, phenolic acids, phenolic alcohols, stilbenes and lignans, can target TLR4 signaling pathways in multiple ways. Toll interacting protein expression could be modulated by epigallocatechin-3-gallate. Resveratrol may also exert neuroprotective effects via the TLR4/NF-κB/STAT signaling cascade. Its role in activation of cascade via interfering with TLR4 oligomerization upon receptor stimulation has also been reported. Curcumin, another polyphenol, can suppress overexpression of inflammatory mediators via inhibiting the TLR4-MAPK/NF-κB pathway. It can also reduce neuronal apoptosis via a mechanism concerning the TLR4/MyD88/NF-κB signaling pathway in microglia/macrophages. Despite a symphony of in vivo and in vitro studies, many molecular and pharmacological aspects of neuroinflammation remain unclear. It is proposed that natural compounds targeting TLR4 may serve as important pharmacophores for the development of potent drugs for the treatment of neurological disorders. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Comparison of Mathematics and Humanitarian Sciences Students’ Metacognitive Strategies

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    Gholam Hossein Javanmard

    2014-09-01

    Full Text Available Abstract The purpose of this study was to compare the differences of using meta-cognitive strategies in high school students who study in the fields of mathematics and humanities. For do this, 140 high school students were selected randomly. The Swanson’s Meta-cognition Strategies Test was administrated for sample groups. The acquired means for two regroups were compared with t-test for two independent groups’ method. Results indicated that two groups were meaningfully differed from each other (sig=0.01 in using meta-cognitive strategies, and mean of students in mathematics field were high. Also there was a meaningful difference in task component between two groups (sig=0.002, and the mean of students in mathematics field was higher than from students in humanities field in this component. The high school students in mathematics field use more metacognitive strategies, especially task component, than the students in humanities field.

  8. Study Strategies Comparison and Self-Regulationin University Students

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    Irma Rosa Alvarado Guerrero

    2014-04-01

    Full Text Available The main factors associated with academic performance are study strategies and self-regulation in university students, thus the objective of this paper is to compare two sample groups: those in a regular status and others under certain academic lag. The Study Strategies Inventory and Self-Regulation (IEEA BY Castaneda was applied to 41 learners. It was observed that both groups need support to develop strategies for the four scales of the instrument: Information acquisition, memory resource management, information processing and self-regulation in all three dimensions: people, tasks and materials. In conclusion there is a need to develop programs to help the consolidation of study strategies and self-regulation and highlights the importance of analyzing the factors in teacher’s education and development of programs and curricula, to improve academic performance in higher educationinstitutions.

  9. Breakthrough candidemia in children: clinical and microbiological characteristics, therapeutic strategies and impact on outcomes.

    Science.gov (United States)

    Lai, Mei-Yin; Hsu, Jen-Fu; Chu, Shih-Ming; Wu, I-Hsyuan; Huang, Hsuan-Rong; Lin, Chun-Chih; Lee, I-Ta; Chiang, Ming-Chou; Fu, Ren-Huei; Tsai, Ming-Horng

    2017-06-01

    To assess the characteristics, treatments, risk factors and outcomes of breakthrough candidemia in children. Episodes of breakthrough candidemia in children were compared with the remaining episodes in a 13-year cohort study. Out of 319 episodes, 45 (14.1%) were breakthrough candidemia. Breakthrough candidemia occurred in patients with more acutely ill conditions, and the majority was caused by non-albicans Candida species (73.3%; 33 episodes). A total of 79.1% of breakthrough candidemia were caused by antifungal-susceptible Candida isolates and emergence of resistance was the mechanism in five cases of patients receiving fluconazole. Episodes of breakthrough candidemia had significantly higher illness severity and higher rates of fungemia-attributable mortality. Breakthrough candidemia independently contributed to unfavorable outcomes, and more aggressive treatment strategies are warranted when breakthrough candidemia is encountered.

  10. Therapeutic Strategies against Epstein-Barr Virus-Associated Cancers Using Proteasome Inhibitors.

    Science.gov (United States)

    Hui, Kwai Fung; Tam, Kam Pui; Chiang, Alan Kwok Shing

    2017-11-21

    Epstein-Barr virus (EBV) is closely associated with several lymphomas (endemic Burkitt lymphoma, Hodgkin lymphoma and nasal NK/T-cell lymphoma) and epithelial cancers (nasopharyngeal carcinoma and gastric carcinoma). To maintain its persistence in the host cells, the virus manipulates the ubiquitin-proteasome system to regulate viral lytic reactivation, modify cell cycle checkpoints, prevent apoptosis and evade immune surveillance. In this review, we aim to provide an overview of the mechanisms by which the virus manipulates the ubiquitin-proteasome system in EBV-associated lymphoid and epithelial malignancies, to evaluate the efficacy of proteasome inhibitors on the treatment of these cancers and discuss potential novel viral-targeted treatment strategies against the EBV-associated cancers.

  11. [Resistances to targeted therapies and strategy for following therapeutic lines in metastatic NSCLC].

    Science.gov (United States)

    Brosseau, Solenn; Oulkhouir, Youssef; Naltet, Charles; Zalcman, Gérard

    2015-06-01

    EGFR, ALK, ROS1 Tyrosine Kinase Inhibitors (TKis) have changed natural history of 12 to 15% of patients with metastatic Non-Small Cell Lung Cancer (NSCLC) and molecular alterations (mutations or translocations) in these genes. Median Progression Free Survival (PFS) of these patients has increased from 12 months with a platinum-based chemotherapy associated with bevacizumab, to 18 months with TKIs, overall survival reaching several years in these patients. However, rare primary resistance have been described in less than 10% of patients with EGFR or ALK-mutated cancer, whereas secondary resistance occur systematically. New generations TKIs are currently in clinical development, which are active on tumor clones harboring a resistance mutation, and some of them diffuse perfectly well into brain, a classical sanctuary for metastasis. Strategies are developed to delay secondary resistance apparition, to prolong PFS, and then overall survival. These strategies use combinations, as soon as first linesetting, of TKIs with either an anti-angiogenic drug (bevacizumab), or with an immunological checkpoint inhibitors, or with Heat-Shock Protein (Hsp) inhibitors. In order to delay acquired resistance to EGFR TKIs, the French Intergroup (IFCT) has launched a combination trial of EGFR TKIs with an anti-estrogen (fulvestrant) in postmenopausal women, whereas other trials associate EGFR TKIs with EFGR monoclonal antibody cetuximab, or with a monoclonal antibody targeting c-met. Copyright © 2015 Société Françise du Cancer. Publié par Elsevier Masson SAS. Tous droits réservés. Published by Elsevier Masson SAS. All rights reserved.

  12. Obesity, Oxidative Stress, Adipose Tissue Dysfunction, and the Associated Health Risks: Causes and Therapeutic Strategies

    Science.gov (United States)

    Manna, Prasenjit

    2015-01-01

    Abstract Obesity is gaining acceptance as a serious primary health burden that impairs the quality of life because of its associated complications, including diabetes, cardiovascular diseases, cancer, asthma, sleep disorders, hepatic dysfunction, renal dysfunction, and infertility. It is a complex metabolic disorder with a multifactorial origin. Growing evidence suggests that oxidative stress plays a role as the critical factor linking obesity with its associated complications. Obesity per se can induce systemic oxidative stress through various biochemical mechanisms, such as superoxide generation from NADPH oxidases, oxidative phosphorylation, glyceraldehyde auto-oxidation, protein kinase C activation, and polyol and hexosamine pathways. Other factors that also contribute to oxidative stress in obesity include hyperleptinemia, low antioxidant defense, chronic inflammation, and postprandial reactive oxygen species generation. In addition, recent studies suggest that adipose tissue plays a critical role in regulating the pathophysiological mechanisms of obesity and its related co-morbidities. To establish an adequate platform for the prevention of obesity and its associated health risks, understanding the factors that contribute to the cause of obesity is necessary. The most current list of obesity determinants includes genetic factors, dietary intake, physical activity, environmental and socioeconomic factors, eating disorders, and societal influences. On the basis of the currently identified predominant determinants of obesity, a broad range of strategies have been recommended to reduce the prevalence of obesity, such as regular physical activity, ad libitum food intake limiting to certain micronutrients, increased dietary intake of fruits and vegetables, and meal replacements. This review aims to highlight recent findings regarding the role of oxidative stress in the pathogenesis of obesity and its associated risk factors, the role of dysfunctional adipose tissue

  13. Obesity, Oxidative Stress, Adipose Tissue Dysfunction, and the Associated Health Risks: Causes and Therapeutic Strategies.

    Science.gov (United States)

    Manna, Prasenjit; Jain, Sushil K

    2015-12-01

    Obesity is gaining acceptance as a serious primary health burden that impairs the quality of life because of its associated complications, including diabetes, cardiovascular diseases, cancer, asthma, sleep disorders, hepatic dysfunction, renal dysfunction, and infertility. It is a complex metabolic disorder with a multifactorial origin. Growing evidence suggests that oxidative stress plays a role as the critical factor linking obesity with its associated complications. Obesity per se can induce systemic oxidative stress through various biochemical mechanisms, such as superoxide generation from NADPH oxidases, oxidative phosphorylation, glyceraldehyde auto-oxidation, protein kinase C activation, and polyol and hexosamine pathways. Other factors that also contribute to oxidative stress in obesity include hyperleptinemia, low antioxidant defense, chronic inflammation, and postprandial reactive oxygen species generation. In addition, recent studies suggest that adipose tissue plays a critical role in regulating the pathophysiological mechanisms of obesity and its related co-morbidities. To establish an adequate platform for the prevention of obesity and its associated health risks, understanding the factors that contribute to the cause of obesity is necessary. The most current list of obesity determinants includes genetic factors, dietary intake, physical activity, environmental and socioeconomic factors, eating disorders, and societal influences. On the basis of the currently identified predominant determinants of obesity, a broad range of strategies have been recommended to reduce the prevalence of obesity, such as regular physical activity, ad libitum food intake limiting to certain micronutrients, increased dietary intake of fruits and vegetables, and meal replacements. This review aims to highlight recent findings regarding the role of oxidative stress in the pathogenesis of obesity and its associated risk factors, the role of dysfunctional adipose tissue in

  14. Amyloid Beta and Tau Proteins as Therapeutic Targets for Alzheimer’s Disease Treatment: Rethinking the Current Strategy

    Directory of Open Access Journals (Sweden)

    Siddhartha Mondragón-Rodríguez

    2012-01-01

    Full Text Available Alzheimer’s disease (AD is defined by the concurrence of accumulation of abnormal aggregates composed of two proteins: Amyloid beta (Aβ and tau, and of cellular changes including neurite degeneration and loss of neurons and cognitive functions. Based on their strong association with disease, genetically and pathologically, it is not surprising that there has been a focus towards developing therapies against the aggregated structures. Unfortunately, current therapies have but mild benefit. With this in mind we will focus on the relationship of synaptic plasticity with Aβ and tau protein and their role as potential targets for the development of therapeutic drugs. Finally, we will provide perspectives in developing a multifactorial strategy for AD treatment.

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

    Science.gov (United States)

    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.

  16. Activation of the Tumor Suppressor PP2A Emerges as a Potential Therapeutic Strategy for Treating Prostate Cancer

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    Ion Cristóbal

    2015-05-01

    Full Text Available Protein phosphatase 2A (PP2A is a tumor suppressor complex that has recently been reported as a novel and highly relevant molecular target in prostate cancer (PCa. However, its potential therapeutic value remains to be fully clarified. We treated PC-3 and LNCaP cell lines with the PP2A activators forskolin and FTY720 alone or combined with the PP2A inhibitor okadaic acid. We examined PP2A activity, cell growth, prostasphere formation, levels of PP2A phosphorylation, CIP2A and SET expression, and AKT and ERK activation. Interestingly, both forskolin and FTY720 dephosphorylated and activated PP2A, impairing proliferation and prostasphere formation and inducing changes in AKT and ERK phosphorylation. Moreover, FTY720 led to reduced CIP2A levels. Treatment with okadaic acid impaired PP2A activation thus demonstrating the antitumoral PP2A-dependent mechanism of action of both forskolin and FTY720. Levels of PP2A phosphorylation together with SET and CIP2A protein expression were studied in 24 PCa patients and both were associated with high Gleason scores and presence of metastatic disease. Altogether, our results suggest that PP2A inhibition could be involved in PCa progression, and the use of PP2A-activating drugs might represent a novel alternative therapeutic strategy for treating PCa patients.

  17. Quality-guided phase unwrapping technique: comparison of quality maps and guiding strategies.

    Science.gov (United States)

    Zhao, Ming; Huang, Lei; Zhang, Qican; Su, Xianyu; Asundi, Anand; Kemao, Qian

    2011-11-20

    Quality-guided phase unwrapping is a widely used technique with different quality definitions and guiding strategies reported. It is thus necessary to do a detailed comparison of these approaches to choose the optimal quality map and guiding strategy. For quality maps, in the presence of noise, transform-based methods are found to be the best choice. However in the presence of discontinuities, phase unwrapping is itself unresolved and hence quality-guided phase unwrapping is not sufficient. For guiding strategies, classical, two-section, and stack-chain guiding strategies are chosen for comparison. If accuracy is the foremost criterion then the classical guiding strategy with a data structure of indexed interwoven linked list is best. If speed is of essence then the stack-chain guiding strategy is the one to use.

  18. Comparison of large networks with sub-sampling strategies

    Science.gov (United States)

    Ali, Waqar; Wegner, Anatol E.; Gaunt, Robert E.; Deane, Charlotte M.; Reinert, Gesine

    2016-07-01

    Networks are routinely used to represent large data sets, making the comparison of networks a tantalizing research question in many areas. Techniques for such analysis vary from simply comparing network summary statistics to sophisticated but computationally expensive alignment-based approaches. Most existing methods either do not generalize well to different types of networks or do not provide a quantitative similarity score between networks. In contrast, alignment-free topology based network similarity scores empower us to analyse large sets of networks containing different types and sizes of data. Netdis is such a score that defines network similarity through the counts of small sub-graphs in the local neighbourhood of all nodes. Here, we introduce a sub-sampling procedure based on neighbourhoods which links naturally with the framework of network comparisons through local neighbourhood comparisons. Our theoretical arguments justify basing the Netdis statistic on a sample of similar-sized neighbourhoods. Our tests on empirical and synthetic datasets indicate that often only 10% of the neighbourhoods of a network suffice for optimal performance, leading to a drastic reduction in computational requirements. The sampling procedure is applicable even when only a small sample of the network is known, and thus provides a novel tool for network comparison of very large and potentially incomplete datasets.

  19. Functional Role of Adult Hippocampal Neurogenesis as a Therapeutic Strategy for Mental Disorders

    Directory of Open Access Journals (Sweden)

    Heechul Jun

    2012-01-01

    Full Text Available Adult neurogenesis, the process of generating new neurons from neural stem cells, plays significant roles in synaptic plasticity, memory, and mood regulation. In the mammalian brain, it continues to occur well into adulthood in discrete regions, namely, the hippocampus and olfactory bulb. During the past decade, significant progress has been made in understanding the mechanisms regulating adult hippocampal neurogenesis and its role in the etiology of mental disorders. In addition, adult hippocampal neurogenesis is highly correlated with the remission of the antidepressant effect. In this paper, we discuss three major psychiatric disorders, depression, schizophrenia, and drug addiction, in light of preclinical evidence used in establishing the neurobiological significance of adult neurogenesis. We interpret the significance of these results and pose questions that remain unanswered. Potential treatments which include electroconvulsive therapy, deep brain stimulation, chemical antidepressants, and exercise therapy are discussed. While consensus lacks on specific mechanisms, we highlight evidence which indicates that these treatments may function via an increase in neural progenitor proliferation and changes to the hippocampal circuitry. Establishing a significant role of adult neurogenesis in the pathogenicity of psychiatric disorders may hold the key to potential strategies toward effective treatment.

  20. Nanomedicine targeting the tumor microenvironment: Therapeutic strategies to inhibit angiogenesis, remodel matrix, and modulate immune responses

    Directory of Open Access Journals (Sweden)

    Elizabeth L. Siegler

    2016-11-01

    Full Text Available Increasing attention has been given to the tumor microenvironment (TME, which includes cellular and structural components such as fibroblasts, immune cells, vasculature, and extracellular matrix (ECM that surround tumor sites. These components contribute to tumor growth and metastasis and are one reason why traditional chemotherapy often is insufficient to eradicate the tumor completely. Newer treatments that target aspects of the TME, such as antiangiogenic and immunostimulatory therapies, have seen limited clinical success despite promising preclinical results. This can be attributed to a number of reasons, including a lack of drug penetration deeper into the necrotic tumor core, nonspecific delivery, rapid clearance from serum, or toxic side effects at high doses. Nanoparticles offer a potential solution to all of these obstacles, and many recent studies have shown encouraging results using nanomedicine to target TME vasculature, ECM, and immune response. While few of these platforms have made it to clinical trials to date, these strategies are relatively new and may offer a way to improve the effects of anticancer therapies.

  1. The oxytocin system in drug discovery for autism: Animal models and novel therapeutic strategies

    Science.gov (United States)

    Modi, Meera E.; Young, Larry J.

    2012-01-01

    Animal models and behavioral paradigms are critical for elucidating the neural mechanism involved in complex behaviors, including social cognition. Both genotype and phenotype based models have implicated the neuropeptide oxytocin (OT) in the regulation of social behavior. Based on the findings in animal models, alteration of the OT system has been hypothesized to play a role in the social deficits associated with autism and other neuropsychiatric disorders. While the evidence linking the peptide to the etiology of the disorder is not yet conclusive, evidence from multiple animal models suggest modulation of the OT system may be a viable strategy for the pharmacological treatment of social deficits. In this review, we will discuss how animal models have been utilized to understand the role of OT in social cognition and how those findings can be applied to the conceptualization and treatment of the social impairments in ASD. Animal models with genetic alterations of the OT system, like the OT, OT receptor and CD38 knock-out mice, and those with phenotypic variation in social behavior, like BTBR inbred mice and prairie voles, coupled with behavioral paradigms with face and construct validity may prove to have predictive validity for identifying the most efficacious methods of stimulating the OT system to enhance social cognition in humans. The widespread use of strong animal models of social cognition has the potential yield pharmacological, interventions for the treatment social impairments psychiatric disorders. This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior. PMID:22206823

  2. Transcutaneous spinal stimulation as a therapeutic strategy for spinal cord injury: state of the art

    Directory of Open Access Journals (Sweden)

    Grecco LH

    2015-03-01

    Full Text Available Leandro H Grecco,1,3,4,* Shasha Li,1,5,* Sarah Michel,1,6,* Laura Castillo-Saavedra,1 Andoni Mourdoukoutas,7 Marom Bikson,7 Felipe Fregni1,21Spaulding Neuromodulation Center, Spaulding Rehabilitation Hospital, Harvard Medical School, Boston, MA, 2Spaulding-Harvard Spinal Cord Injury Model System, Spaulding Rehabilitation Hospital, Harvard Medical School, Charlestown, MA, USA; 3Special Laboratory of Pain and Signaling, Butantan Institute, 4Department of Pharmacology, Institute of Biomedical Science, University of São Paulo, São Paulo, Brazil; 5Department of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China; 6Department of Pharmacy and Biomedical Sciences, University of Namur, Belgium; 7Department of Biomedical Engineering, The City College of New York, New York, NY, USA*These authors contributed equally to this workAbstract: Treatments for spinal cord injury (SCI still have limited effects. Electrical stimulation might facilitate plastic changes in affected spinal circuitries that may be beneficial in improving motor function and spasticity or SCI-related neuropathic pain. Based on available animal and clinical evidence, we critically reviewed the physiological basis and therapeutic action of transcutaneous spinal cord stimulation in SCI. We analyzed the literature published on PubMed to date, looking for the role of three main noninvasive stimulation techniques in the recovery process of SCI and focusing mainly on transcutaneous spinal stimulation. This review discusses the main clinical applications, latest advances, and limitations of noninvasive electrical stimulation of the spinal cord. Although most recent research in this topic has focused on transcutaneous spinal direct current stimulation (tsDCS, we also reviewed the technique of transcutaneous electric nerve stimulation (TENS and neuromuscular electrical stimulation (NMES as potential methods to modulate spinal cord

  3. Comparison of Power Control Strategies for DFIG Wind Turbines

    DEFF Research Database (Denmark)

    Teodorescu, Remus; Luna, A.; Rodríguez, P.

    2008-01-01

    The classical control techniques for regulating the active and reactive power delivery in doubly fed induction generators (DFIG), for wind power applications, are normally based on voltage oriented control (VOC) strategies. Among these algorithms, those that work in a synchronous reference frame...... VOC strategy able to control the operation of a DFIG in the αβ reference frame, with no need of flux position estimation, something that conducts to a more simple and robust algorithm. In order to evaluate the advantages of this new control proposal, namely VOC-RRF, their performance will be compared...

  4. Shifting social identities as a strategy for deflecting threatening social comparisons.

    Science.gov (United States)

    Mussweiler, T; Gabriel, S; Bodenhausen, G V

    2000-09-01

    Results of three studies suggest that the multifaceted nature of identity provides a strategic basis for reducing the threat involved in upward social comparisons. After performing worse than a comparison standard, people may strategically emphasize aspects of their identity that differentiate them from the standard, thereby making the standard less relevant for self-evaluation. On the basis of previous research showing that persons low in self-esteem are less likely to make effective use of self-protection strategies, we hypothesized that this strategy of deflecting the threat involved in upward comparison (i.e., decreasing perceived comparability by emphasizing an unshared social identity) would be used primarily by persons who are characteristically high in self-esteem. This pattern was confirmed in three studies. Moreover, use of the strategy was associated with relatively more positive affect following threatening upward comparisons.

  5. Novel nervous and multi-system regenerative therapeutic strategies for diabetes mellitus with mTOR

    Directory of Open Access Journals (Sweden)

    Kenneth Maiese

    2016-01-01

    Full Text Available Throughout the globe, diabetes mellitus (DM is increasing in incidence with limited therapies presently available to prevent or resolve the significant complications of this disorder. DM impacts multiple organs and affects all components of the central and peripheral nervous systems that can range from dementia to diabetic neuropathy. The mechanistic target of rapamycin (mTOR is a promising agent for the development of novel regenerative strategies for the treatment of DM. mTOR and its related signaling pathways impact multiple metabolic parameters that include cellular metabolic homeostasis, insulin resistance, insulin secretion, stem cell proliferation and differentiation, pancreatic β-cell function, and programmed cell death with apoptosis and autophagy. mTOR is central element for the protein complexes mTOR Complex 1 (mTORC1 and mTOR Complex 2 (mTORC2 and is a critical component for a number of signaling pathways that involve phosphoinositide 3-kinase (PI 3-K, protein kinase B (Akt, AMP activated protein kinase (AMPK, silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae (SIRT1, Wnt1 inducible signaling pathway protein 1 (WISP1, and growth factors. As a result, mTOR represents an exciting target to offer new clinical avenues for the treatment of DM and the complications of this disease. Future studies directed to elucidate the delicate balance mTOR holds over cellular metabolism and the impact of its broad signaling pathways should foster the translation of these targets into effective clinical regimens for DM.

  6. Deciphering the therapeutic stem cell strategies of large and midsize pharmaceutical firms.

    Science.gov (United States)

    Vertès, Alain A

    2014-01-01

    The slow adoption of cytotherapeutics remains a vexing hurdle given clinical progress achieved to date with a variety of stem cell lineages. Big and midsize pharmaceutical companies as an asset class still delay large-scale investments in this arena until technological and market risks will have been further reduced. Nonetheless, a handful of stem cell strategic alliance and licensing transactions have already been implemented, indicating that progress is actively monitored, although most of these involve midsize firms. The greatest difficulty is, perhaps, that the regenerative medicine industry is currently only approaching the point of inflexion of the technology development S-curve, as many more clinical trials read out. A path to accelerating technology adoption is to focus on innovation outliers among healthcare actors. These can be identified by analyzing systemic factors (e.g., national science policies and industry fragmentation) and intrinsic factors (corporate culture, e.g., nimble decision-making structures; corporate finance, e.g., opportunity costs and ownership structure; and operations, e.g., portfolio management strategies, threats on existing businesses and patent expirations). Another path is to accelerate the full clinical translation and commercialization of an allogeneic cytotherapeutic product in any indication to demonstrate the disease-modifying potential of the new products for treatment and prophylaxis, ideally for a large unmet medical need such as dry age-related macular degeneration, or for an orphan disease such as biologics-refractory acute graft-versus-host disease. In times of decreased industry average research productivities, regenerative medicine products provide important prospects for creating new franchises with a market potential that could very well mirror that achieved with the technology of monoclonal antibodies.

  7. Treatment strategies for combining immunostimulatory oncolytic virus therapeutics with dendritic cell injections.

    Science.gov (United States)

    Wares, Joanna R; Crivelli, Joseph J; Yun, Chae-Ok; Choi, Il-Kyu; Gevertz, Jana L; Kim, Peter S

    2015-12-01

    Oncolytic viruses (OVs) are used to treat cancer, as they selectively replicate inside of and lyse tumor cells. The efficacy of this process is limited and new OVs are being designed to mediate tumor cell release of cytokines and co-stimulatory molecules, which attract cytotoxic T cells to target tumor cells, thus increasing the tumor-killing effects of OVs. To further promote treatment efficacy, OVs can be combined with other treatments, such as was done by Huang et al., who showed that combining OV injections with dendritic cell (DC) injections was a more effective treatment than either treatment alone. To further investigate this combination, we built a mathematical model consisting of a system of ordinary differential equations and fit the model to the hierarchical data provided from Huang et al. We used the model to determine the effect of varying doses of OV and DC injections and to test alternative treatment strategies. We found that the DC dose given in Huang et al. was near a bifurcation point and that a slightly larger dose could cause complete eradication of the tumor. Further, the model results suggest that it is more effective to treat a tumor with immunostimulatory oncolytic viruses first and then follow-up with a sequence of DCs than to alternate OV and DC injections. This protocol, which was not considered in the experiments of Huang et al., allows the infection to initially thrive before the immune response is enhanced. Taken together, our work shows how the ordering, temporal spacing, and dosage of OV and DC can be chosen to maximize efficacy and to potentially eliminate tumors altogether.

  8. Comparison of three school feeding strategies for primary school ...

    African Journals Online (AJOL)

    The aim of this study was to compare the impact of three school feeding strategies on the nutritional status of primary school children aged six to 13 in an informal settlement in Gauteng. The methods included dietary surveys and anthropometric and biochemical measurements of a sample of 160 primary school children ...

  9. Comparison of Power Control Strategies for DFIG Wind Turbines

    DEFF Research Database (Denmark)

    Teodorescu, Remus; Luna, A.; Rodríguez, P.

    2008-01-01

    The classical control techniques for regulating the active and reactive power delivery in doubly fed induction generators (DFIG), for wind power applications, are normally based on voltage oriented control (VOC) strategies. Among these algorithms, those that work in a synchronous reference frame,...

  10. Comparison of different strategies for decommissioning a tritium laboratory

    International Nuclear Information System (INIS)

    Kris Dylst

    2009-01-01

    Full text: Between 2003 and 2009 two rooms that served as tritium laboratory at SCK-CEN and its ventilation system were decommissioned. Initially, the decommissioning strategy was to free release as much materials as possible. The low free release limit imposed by the Belgian authorities made decommissioning of the first laboratory room very labor intensive. Timing restrictions forced us to use a different strategy for the ventilation system. Steel that could not be easily decontaminated was disposed to a nuclear melting facility. Compared to similar work done on steel in the lab, the new strategy took less than 80% of the man hours in only 40% of the calendar days. For the second laboratory a similar strategy was used: contaminated steel was disposed to a nuclear melting facility, other materials that could not be easily decontaminated were disposed as nuclear waste. Compared to the first laboratory the decommissioning was done in less than 40% of the time using merely one third of the man hours, although at the expense of extra waste generation. Economically, as far as not easily decontaminated materials are concerned, steel is best disposed to a nuclear melting and it is worth to invest in the decontamination of other materials. (author)

  11. Multiple function benefit - cost comparison of conservation buffer placement strategies

    Science.gov (United States)

    Z. Qiu; M.G. Dosskey

    2012-01-01

    Conservation buffers are considered to be effective practices for repairing impaired streams and restoring multiple ecosystem functions in degraded agricultural watersheds. Six different planning strategies for targeting their placement within watersheds were compared in terms of cost-effectiveness for environmental improvement in the 144 km² Neshanic River...

  12. Comparison of Two Educational Strategies in Teaching Preventive Cardiology.

    Science.gov (United States)

    Stroup-Benham, Christine A.; And Others

    This study assessed the impact of two educational strategies: text only versus text plus small group discussion, among two groups of third-year internal medicine clerkship students in a preventive cardiology course. The course was a required, 12-week Internal Medical clerkship at the University of Texas Medical Branch. The first group reviewed…

  13. Modulation of valosin-containing protein by Kyoto University Substances (KUS as a novel therapeutic strategy for ischemic neuronal diseases

    Directory of Open Access Journals (Sweden)

    Masayuki Hata

    2017-01-01

    Full Text Available Retinal ischemia causes several vision-threatening diseases, including diabetic retinopathy, retinal artery occlusion, and retinal vein occlusion. Intracellular adenosine triphosphate (ATP depletion and subsequent induced endoplasmic reticulum (ER stress are proposed to be the underlying mechanisms of ischemic retinal cell death. Recently, we found that a naphthalene derivative can inhibit ATPase activity of valosin-containing protein, universally expressed within various types of cells, including retinal neural cells, with strong cytoprotective activity. Based on the chemical structure, we developed novel valosin-containing protein modulators, Kyoto University Substances (KUSs, that not only inhibit intracellular ATP depletion, but also ameliorate ER stress. Suppressing ER stress by KUSs is associated with neural cell survival in animal models of several neurodegenerative diseases, such as glaucoma and retinal degeneration. Given that a major pathology of ischemic retinal diseases, other than intracellular ATP depletion, is ER stress-induced cell death, KUSs may provide a novel strategy for cell protection in ischemic conditions. Hence, we investigated the efficacy of KUS121 in a rat model of retinal ischemic injury. Intravitreal injections of KUS121, which is clinically preferable route of drug administration in retinal diseases, significantly suppressed inner retinal thinning and retinal cell death, and maintained visual functions. Valosin-containing protein modulation by KUS is a promising novel therapeutic strategy for ischemic retinal diseases.

  14. Comparison of equalisation strategies for multi-carrier CDMA

    OpenAIRE

    Cooper, MA; Armour, SMD; Bian, YQ; McGeehan, JP

    2003-01-01

    This paper focuses on the bit error rate (BER) performance of equalisation strategies for a downlink MC-CDMA based system. Simulation results utilising maximal ratio combining (MRC), orthogonal restoring combining (ORC), equal gain combining (EGC) and minimum mean square error combining (MMSEC) for a multiuser scenario are presented. In addition, we analyse the relative complexities of each scheme and discuss their suitability for implementation in future consumer products

  15. Comparison of the toxic and radiosensitizing effects of five therapeutic drugs on the mouse jejunum

    International Nuclear Information System (INIS)

    Veena, K.; Uma Devi, P.

    1990-01-01

    Tissue toxicity and radiosensitizing effects of five different therapeutic drugs, bleomycin (BLM), chlorpromazine (CPZ), misonidazole (MISO), metronidazole (Metro) and Cis-diamminedichloro platinum (II) (c-DDP) on the jejunal crypts of Swiss albino mice were compared. All the drugs except Metro, when used alone, showed comparable toxicity. When combined with radiation, BLM produced a pronounced enhancement in the radiation damage (DMF=1.5) while Metro did not have any effect; the other drugs lay between BLM and Metro in their radiosensitizing effect. (orig.) [de

  16. Comparison of therapeutic effects of liposomal Tranexamic Acid and conventional Hydroquinone on melasma.

    Science.gov (United States)

    Banihashemi, Mahnaz; Zabolinejad, Naghmeh; Jaafari, Mahmoud Reza; Salehi, Maryam; Jabari, Asma

    2015-09-01

    Melasma is one of the most common cosmetic disorders with skin darkening. Although several treatment modalities are available, none is satisfactorily used in management of this condition. Tranexamic acid (TA), a plasmin inhibitor, is reported to improve melasma when injected locally or used as oral and topical forms. The aim of this study was to compare therapeutic effects of liposomal tranexamic acid and conventional hydroquinone on melasma. Thirty women with bilateral melasma were enrolled in a split-face trial lasting 12 weeks. Patients blindly applied 5% topical liposomal TA and 4% hydroquinone cream, to the designated sides of the face twice daily in addition to the assigned sunscreen in the morning. Skin pigmentation was measured using MASI (Melasma Area and Severity Index) at each visit separately for each side at the base line and every month until one month after treatment course. Data were obtained from patients file and were analyzed statistically using SPSS software, paired samples t-test, and repeated measured ANOVA. Twenty-three patients completed the study. The mean MASI scores significantly reduced in both treated sides (P < P = 0.001) after 12 week. A greater decrease was observed with 5% liposomal TA, although this difference was not statistically significant. Irritation occurred in three patients with hydroquinone, while no serious adverse events occurred with TA. On the basis of these results, topical liposomal TA can be used as a new, effective, safe, and promising therapeutic agent in melasma. © 2015 Wiley Periodicals, Inc.

  17. Therapeutic drug monitoring and use of an adjusted body weight strategy for high-dose voriconazole therapy.

    Science.gov (United States)

    Richards, Patrick G; Dang, Kimberlyn M; Kauffman, Carol A; Stalker, Kay Lyn; Sudekum, David; Kerr, Lisa; Brinker-Bodley, Michelle; Cheriyan, Beena; West, Nina; Collins, Curtis D; Polega, Shikha; Malani, Anurag N

    2017-04-01

    A high-dose 12 mg/kg/day (6 mg/kg twice daily) voriconazole regimen was recommended by the CDC to treat patients injected with contaminated methylprednisolone acetate that caused a multi-state fungal outbreak in 2012-13. Therapeutic drug monitoring results of this unique regimen are unknown, as is the most appropriate dosing weight for obese patients. We evaluated voriconazole trough measurements for this dosing scheme, as well as the use of adjusted body weight dosing for obese patients. Voriconazole trough levels were analysed in obese (BMI ≥35 kg/m 2 ) and non-obese (BMI voriconazole troughs were supratherapeutic (>5 mg/L) in 65 (47%) patients, therapeutic (2-5 mg/L) in 57 (41%) patients and subtherapeutic (Voriconazole doses >11 and >8 mg/kg/day produced mainly first steady-state supratherapeutic troughs in 44 obese and 94 non-obese patients, respectively. An initial 12 mg/kg/day was progressively lowered to a median maintenance dose of 8.5 mg/kg/day in the obese and 8.6 mg/kg/day in the non-obese. A high-dose voriconazole regimen produced initial supratherapeutic troughs that required dose adjustment downward by nearly 30%. Adjusted body weight dosing in obese patients resulted in a similar maintenance dose to total body weight dosing in the non-obese, and appears to be a sensible dosing strategy for these patients.

  18. 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

  19. A comparison of three CT voltage optimization strategies

    Science.gov (United States)

    Ogden, Kent M.; Huda, Walter; Khorasani, Mohammad R.; Scalzetti, Ernest M.

    2008-03-01

    We evaluated three strategies for optimizing the x-ray tube voltage in chest CT examinations: (1) keeping patient dose constant and maximizing contrast to noise ratios (CNR); (2) keeping CNR constant and minimizing patient effective dose (E); (3) maximizing CNR2/E. Lung and soft tissue Hounsfield unit values, together with the corresponding image noise, were measured in a Rando phantom at x-ray tube voltages between 80 and 140 kV. A CT dosimetry software package (ImPACT) was used to compute effective doses as a function of CT x-ray tube voltage for adult patients undergoing chest CT examinations. CNR and patient dose in chest CT examinations both increase with increasing x-ray tube voltage at a fixed mAs. All optimization strategies provided similar qualitative results, which showed the best imaging performance was achieved at the lowest x-ray tube voltage (80 kV). Optimization using constant CNR or effective dose is preferred since these methods provide explicit choices of optimal kV/mAs combinations, as well as quantitative data on how changing kV would modify CNR and/or patient dose. The CNR2/Dose figure of merit does not offer explicit choices of kV/mAs for performing CT examinations, and changes in FOM value are more difficult to relate to changes in imaging performance or patient dose.

  20. Comparison of FEV1reference equations for evaluating a cystic fibrosis therapeutic intervention.

    Science.gov (United States)

    Konstan, Michael W; Wagener, Jeffrey S; VanDevanter, Donald R; Pasta, David J; Millar, Stefanie J; Morgan, Wayne J

    2017-08-01

    The Global Lung Function Initiative (GLI, 2012) developed reference equations for forced expiratory volume in 1 s (FEV 1 ). Previous equations were developed by groups led by Knudson (1983), Wang (1993), Hankinson (1999), and Stanojevic (2008). 1,2,4,6 We assessed how different prediction equations affect the conclusions from a therapeutic intervention study that evaluated the rate of percent predicted FEV 1 (ppFEV 1 ) decline. Using data from the Epidemiologic Study of cystic fibrosis (CF), we re-analyzed our previous study evaluating the relationship of dornase alfa (DA) use with ppFEV 1 using the Knudson, Wang & Hankinson, Stanojevic, and GLI equations. The change in intercept and change in slope of ppFEV 1 from a 2-year pre-index period and 2-year post-index period were compared between the treated (N = 2483) and comparator groups (N = 6992, from 4110 unique patients). Change in intercept for the comparator group was similar across equations except that Wang & Hankinson values were more negative. The difference in change in intercept between the DA and comparator groups ranged from 3.38 to 4.02% predicted. The change in slope for the comparator group ranged from -0.58 to +0.30 ppFEV 1 /year, but the difference in change in slope between the DA and comparator groups was in a narrower range from +0.53 to +0.89 ppFEV 1 /year. Although individual patient results are impacted by the choice of reference equations, the study conclusions from this evaluation of a therapeutic intervention were minimally affected. GLI equations are recommended for future studies, but prior results based on other equations should be accepted as reliable. © 2017 Wiley Periodicals, Inc.

  1. A systematic analysis and comparison of warfarin initiation strategies

    Science.gov (United States)

    French, Benjamin; Wang, Le; Gage, Brian F.; Horenstein, Richard B.; Limdi, Nita A.; Kimmel, Stephen E.

    2016-01-01

    Objective Randomized trials have reported inconsistent evidence regarding the effectiveness of algorithms that use genotypes to initiate warfarin therapy. The Clarification of Optimal Anticoagulation through Genetics (COAG) trial initiated therapy based on predicted maintenance doses, with a pharmacogenetic-guided algorithm in one study group and a clinically guided algorithm in the other. The European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) consortium initiated therapy based on loading doses, with an algorithm-based prediction in one study group and a fixed-dose regimen in the other. To understand the differences between these trials, we compared the initial doses between alternative dosing algorithms (the pharmacogenetic-guided and clinically guided algorithms developed by Gage and colleagues and those developed by the International Warfarin Pharmacogenetics Consortium), and between the COAG and EU-PACT dose-initiation strategies. Methods Secondary analysis of the COAG trial—a double-blind, randomized controlled trial (2009–2013)—conducted at 18 clinical centers in the United States, which included 1,010 adults initiating warfarin therapy, of whom 719 achieved maintenance dose. Results Among COAG participants, the distribution of initial doses differed between algorithms, but exhibited similar prediction accuracy for maintenance dose. However, had the COAG trial implemented the EU-PACT strategy, the 3-day initial dose would have been 4.8 mg greater among participants randomized to pharmacogenetic-guided dosing, but only 2.5 mg greater among participants randomized to clinically guided dosing (P<0.001). Conclusions Compared to the COAG trial, the EU-PACT trial used systematically larger loading doses in the pharmacogenetic-guided group and might have inadequately adjusted for clinical variability in warfarin dose requirements in the fixed-dose group. PMID:27383664

  2. [Randomized Comparison of Two Approaches to Initial Warfarin Dosing: Time in Therapeutic Range of International Normalized Ratio During Hospitalization].

    Science.gov (United States)

    Gordeev, I G; Averkov, O V; Mishchenko, L N; Levchuk, N N; Vechorko, V I

    2017-09-01

    To perform a randomized, open-label comparison of average time in therapeutic range (TTR) of international normalized ratio (INR) using two approaches to initial warfarin dosing during hospitalization: the standard method and the one using individual patient characteristics (clinical algorithm - the studied approach). We randomly assigned 60 patients with different indications for vitamin K antagonist therapy to the studied approach (n=31, intervention group) or to the standard method (n=29, control group). А target INR range for all patients was 2.0 to 3.0. The average TTR and portions of INR values within target range during the whole time of drug dosing turned out to be small. TTR was 22.4% with standard method and 21.4% with clinical algorithm, which was well below desired 60%. The opportunities for achieving target INR in inpatient settings, regardless of warfarin dosing regimen, are limited.

  3. Comparison among nonlinear excitation control strategies used for damping power system oscillations

    International Nuclear Information System (INIS)

    Leon, A.E.; Solsona, J.A.; Valla, M.I.

    2012-01-01

    Highlights: ► A description and comparison of nonlinear control strategies for synchronous generators are presented. ► Advantages of using nonlinear controllers are emphasized against the use of classical PSSs. ► We find that a particular selection of IDA gains achieve the same performance that FL controllers. - Abstract: This work is focused on the problem of power system stability. A thorough description of nonlinear control strategies for synchronous generator excitation, which are designed for damping oscillations and improving transient stability on power systems, is presented along with a detailed comparison among these modern strategies and current solutions based on power system stabilizers. The performance related to damping injection in each controller, critical time enhancement, robustness against parametric uncertainties, and control signal energy consumption is analyzed. Several tests are presented to validate discussions on various advantages and disadvantages of each control strategy.

  4. 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.

  5. Comparison of Teaching Strategies for Cultural Humility in Physical Therapy.

    Science.gov (United States)

    Paparella-Pitzel, Susan; Eubanks, Robin; Kaplan, Sandra L

    2016-01-01

    Cultural competence and cultural humility are ongoing processes that healthcare professionals should continually strive for in order to provide effective and comprehensive plans of care for patients. This 2-year, longitudinal, educational pilot study describes the levels of competency in second-year entry-level physical therapy students and compares the outcomes of three teaching strategies for cultural competence and cultural humility. All students received a standard 2-hour lecture; study volunteers were randomly assigned to one of two enriched educational groups, involving a standardized patient or a paper case enrichment. Students shifted from initial levels of "culturally incompetent" and/or "culturally aware" to "culturally competent" as measured by the Inventory for Assessing the Process of Cultural Competence Among Healthcare Professionals-Revised. This shift was maintained after 1.5 yrs following the exposure. Because the enriched educational groups were underpowered, preliminary quantitative data are inconclusive, but qualitative feedback from students is strongly positive. A minimal dose of a structured 2-hr lecture with a skilled instructor, who creates a safe environment for cultural learning, produced positive shifts toward greater cultural competence. Five processes emerged for teaching cultural humility that may assist in designing comprehensive educational experiences on this topic. A framework for organizing course content is presented.

  6. Performance Comparison of Geobroadcast Strategies for Winding Roads

    Directory of Open Access Journals (Sweden)

    Edgar Talavera

    2018-03-01

    Full Text Available Vehicle-to-X (V2X communications allow real-time information sharing between vehicles and Roadside Units (RSUs. These kinds of technologies allow for the improvement of road safety and can be used in combination with other systems. Advanced Driver Assistance Systems (ADAS are an example and can be used along with V2X communications to improve performance and enable Cooperative Systems. A key element of vehicular communications is that the information transmitted through the network is always linked to a GPS position related to origin and destination (GeoNetworking protocol in order to adjust the data broadcast to the dynamic road environment needs. In this paper, we present the implementation and development of Institute for Automobile Research (INSIA V2X communication modules that follow the European vehicular networking standards in a close curve in a winding road where poor visibility causes a risk to the safety of road users. The technology chosen to support these communications is ETSI ITS-G5, which has the capability to enable specific services that support GeoNetworking protocols, specifically the Geobroadcast (GBC algorithm. These functionalities have been implemented and validated in a real environment in order to demonstrate the performance of the communication devices in real V2V (Vehicle-to-Vehicle and V2I (Vehicle-to-Infrastructure situations. GBC messages are also compared with two different configurations of emission area. A comparison with/without RSU modules in critical areas of the road with previous knowledge of the road cartography has also been made.

  7. Comparison on therapeutic effect of plasma exchange and intravenous immunoglobulin for Guillian-Barre syndrome.

    Science.gov (United States)

    Ye, Y; Li, S-L; Li, Y-J

    2015-04-01

    To observe and compare the clinical curative effect of the plasma exchange (PE) and intravenous immunoglobulin (IVIg) for Guillian-Barre Syndrome (GBS). Overall, 64 adult patients with GBS for PE and IVIg treatment, respectively, and nerve function were observed pre-treatment and at 1 week/2 weeks after completion of treatment; the blood immunoglobulin, complement, fibrinogen (Fib) and monocyte percentage (MON%) were detected simultaneously. After PE treatment, nerve function defect appeared to improve better than the IVIg group and clinical effect was better than the IVIg group. Treatment effective rates of the two groups after 2 weeks, respectively, are 96 and 79%. PE and IVIg can significantly reduce the GBS patients' blood immunoglobulin IgG, IgA, IgM, C3 and C4, but these were significantly lower in the PE group than in the IVIg group. Fib and MON% were significantly lower in the PE group than in the IVIg group. Both PE and IVIg have a high response as therapy and are reasonable therapeutic options for GBS. However, PE treatment has a more significantly curative effect, as it can effectively improve symptoms and be helpful in the early rehabilitation of patients. © 2014 British Blood Transfusion Society.

  8. Comparison of treatment strategies for Space Motion Sickness

    Science.gov (United States)

    Davis, J. R.; Jennings, R. T.; Beck, B. G.

    1992-01-01

    Treatment strategies for Space Motion Sickness were compared using the results of postflight oral debriefings. Standardized questionnaires were administered to all crewmembers immediately following Space Shuttle flights by NASA flight surgeons. Cases of Space Motion Sickness were graded as mild, moderate or severe based on published criteria, and medication effectiveness was judged based on subjective reports of symptom relief. Since October 1989, medication effectiveness is reported inflight through Private Medical Conferences with the crew. A symptom matrix was analyzed for 19 crewmembers treated with an oral combination of scopolamine and dextroamphetamine (scopdex) and 15 crewmembers treated with promethazine delivered by intramuscular (IM) or suppository routes. Scopdex has been given preflight as prophaxis for Space Motion Sickness but analysis showed delayed symptom presentation in 9 crewmembers or failed to prevent symptoms in 7. Only three crewmembers who took scopdex had no symptoms inflight. Fourteen out of 15 crewmembers treated with IM promethazine and 6 of 8 treated with promethazine suppositories after symptom development had immediate (within 12 h) symptom relief and required no additional medication. There were no cases of delayed symptom presentation in the crewmembers treated with promethazine. This response is in contrast to untreated crewmembers who typically have slow symptom resolution over 72-96 h. We conclude that promethazine is an effective treatment of Space Motion Sickness symptoms inflight. NASA policy currently recommends treating crewmembers with Space Motion Sickness after symptom development, and no longer recommends prophylaxis with scopdex due to delayed symptom development and apparent variable absorption of oral medications during early flight days.

  9. Comparison of Ultrasound-Guided to Fluoroscopy-Guided Biceps Tendon Sheath Therapeutic Injection.

    Science.gov (United States)

    Petscavage-Thomas, Jonelle; Gustas, Cristy

    2016-10-01

    Biceps tendinitis is a source of anterior shoulder pain and is amenable to therapeutic injection. Studies have shown greater accuracy with image-guided compared to unguided injection of the biceps tendon sheath. There is no literature comparing ultrasound-guided to fluoroscopy-guided biceps tendon sheath injection. The purpose of this study was to compare clinical outcomes, complication rates, procedure success rates, and financial costs of the two imaging-guided methods. A 10-year retrospective review of the picture archiving and communication system was performed to identify patients who underwent image-guided proximal biceps tendon sheath injection. Two radiologists reviewed the picture archiving and communication system and clinical notes to record pain relief, complications, fluoroscopy time, first-pass success rate (defined as injection into the sheath on the first needle pass), final success rate (needle placement in the tendon sheath on the final needle pass), and average costs. Fifty fluoroscopy-guided and 53 ultrasound-guided cases were identified. There was no statistically significant difference in pain relief or complications. The first-pass success rate was 90.6% for ultrasound compared to 74.0% for fluoroscopy. The final-pass success rate was 98.2% for ultrasound versus 92.0% for fluoroscopy. The mean fluoroscopy time was 57.6 seconds. Ultrasound showed preinjection abnormalities of the biceps tendon in 47.5% of cases. Compared to fluoroscopy-guided biceps tendon sheath injection, ultrasound had higher initial- and final-pass success rates, visualized abnormalities before injection, and had similar pain relief and complication rates. Ultrasound is more accurate and has greater diagnostic benefits than unguided or fluoroscopy-guided biceps tendon sheath injection.

  10. [Ascariasis: comparison of the therapeutic efficacy between paico and albendazole in children from Huaraz].

    Science.gov (United States)

    López De Guimaraes, D; Neyra Llanos, R S; Romero Acevedo, J H

    2001-01-01

    A therapeutical clinical trial was designed to study the effectiveness of Paico and Albendazole, for the treatment of ascariasis in a group of 60 children, between 3 and 14 years old, from a rural community in Huaraz. It was carried out between May and August, 2000. The sample was randomly divided into 30 cases for Paico and 30 for Albendazole, the criteria for entering the trial being a positive examination for Ascaris lumbricoides in feces. The treatment consisted in Paico juice: 1 ml/Kg for less than 10 Kg, and 2 ml/Kg in larger children, one dose before breakfast, for three consecutive days. The Albendazole was administered in a single dose of 400 mg in those over five years of age, and 200 mg in younger children. The effectiveness was evaluated qualitatively (the disappearance of the ascaris eggs from the feces) and quantitatively (decrease in the parasitic burden); in the stool examinations carried out in all cases on entering the study and 15 days after the treatment. All the stool samples were processed in the Referential Laboratory of the Regional Health Authority in Ancash. The qualitative effectiveness between Paico and Albendazole for the eradication of ascariasis was similar at 86.7%. The quantitative effectiveness was 59.5% for Paico and 58.3% for Albendazole. However, it was observed that, unlike Albedazole, Paico is 100% effective in the treatment of Hymenolepsis nana. Adverse effects were presented in 23.3% of the cases for both drugs. It is concluded that, although Paico and Albendazole have a similar effectiveness against Ascaris lumbricoides, Paico has the additional benefit of being effective against Hymenolepsis nana.

  11. Outcomes and cost comparison of three therapeutic approaches to allergic rhinitis.

    Science.gov (United States)

    Fairchild, Carol J; Durden, Emily; Cao, Zhun; Smale, Patrick

    2011-01-01

    Allergic rhinitis (AR) is a global health problem because of its increasing impact on economics, society, and the individual's quality of life. This study compares the outcomes and cost of three intranasal therapeutic approaches to the treatment of AR. This was a retrospective cohort study using propensity scores to achieve balanced cohorts. The study population included patients ≥16 years of age with at least one intranasal prescription claim, without concurrent nasal polyps or sinusitis. Health care use and costs, airway infections, pharmacy costs, and indicators of unsatisfactory treatment (i.e., treatment augmentation or switching) were evaluated in the 1-year follow-up period using a claims database. Data from 141,190 patients in intranasal antihistamines (INA) therapy, intranasal steroids (INS) therapy, and intranasal combination therapy (ICT) cohorts were analyzed. The INA cohort showed the lowest rate of change in treatment (switching or augmentation). Switching rates were lowest in the INS therapy cohort, whereas augmentation was lowest in the INA cohort. AR- and asthma-related medication costs were significantly lower in the INA cohort. No differences were observed in airway infections and overall health care costs. Concurrent chronic obstructive pulmonary disorder and asthma were the strongest predictors of health care cost and respiratory infection in the follow-up period. A change in treatment was noted in ∼⅓ of the entire study population. None of the treatments had a remarkable effect on health care costs or the occurrence of airway infections. The INA treatment cohort had lower AR- and asthma-related medication costs.

  12. A comparison of cooling methods used in therapeutic hypothermia for perinatal asphyxia.

    Science.gov (United States)

    Hoque, Nicholas; Chakkarapani, Ela; Liu, Xun; Thoresen, Marianne

    2010-07-01

    The objective of this study was to compare cooling methods during therapeutic hypothermia (TH) for moderate or severe perinatal asphyxia with regard to temperature and hemodynamic stability. A total of 73 newborns received TH in our center between 1999 and 2009 by 4 methods: (1) selective head cooling with mild systemic hypothermia by using cap (SHC; n = 20); (2) whole-body cooling with mattress manually controlled (WBCmc; n = 23); (3) whole-body cooling with body wrap servo-controlled (WBCsc; n = 28); and (4) whole-body cooling with water-filled gloves (n = 2). Target rectal temperatures (Trec) were 34.5 +/- 0.5 degrees C (SHC) and 33.5 +/- 0.5 degrees C (WBC). Trec, mean arterial blood pressure, and heart rate were collected from retrospective chart review. Groups had similar baseline characteristics and condition at birth. Trec was within target temperature +/-0.5 degree C for 97% of the time in infants with WBCsc, 81% in infants with WBCmc, 76% in infants with SHC, and 74% in infants who were cooled with gloves. Mean overshoot was 0.3 degree C for WBCsc, 1.3 degrees C for WBCmc, and 0.8 degree C for SHC groups. There was no difference in mean arterial blood pressure or mean heart between groups during the maintenance of cooling. In infants who were rewarmed at similar speed, there was greater variation in Trec in the SHC compared with the WBCsc group. Manually controlled cooling systems are associated with greater variability in Trec compared with servo-controlled systems. A manual mattress often causes initial overcooling. It is unknown whether large variation in temperature adversely affects the neuroprotection of TH.

  13. Comparison of therapeutic effect of topical Nigella with Betamethasone and Eucerin in hand eczema.

    Science.gov (United States)

    Yousefi, M; Barikbin, B; Kamalinejad, M; Abolhasani, E; Ebadi, A; Younespour, S; Manouchehrian, M; Hejazi, S

    2013-12-01

    Nigella sativa has been used in traditional medicine. Although it was investigated in different studies, its effect on hand eczema has not been studied yet. To compare the effects of Nigella, Betamethasone and Eucerin on severity of hand eczema and patients' life quality. In this randomized, controlled, double-blinded clinical trial, we allocated new cases of hand eczema with 18-60 years of age in three therapeutic groups (Nigella, Betamethasone and Eucerin) by using permuted blocks for randomization. Patients applied medications twice a day and followed in a 4-week period. The primary outcome of the study was changes in severity and life quality, which were assessed at the beginning, 14th and 28th days of the study by Hand Eczema Severity index (HECSI) and Dermatology Life Quality Index (DLQI) respectively. Sixty patients recruited in the study with 20 patients allocated in each study arm. Eighteen, 19 and 15 patients in Eucerin, Nigella and Betamethasone groups, respectively, attended at least one of the therapy sessions. Nigella and Betamethasone showed significantly more rapid improvement in hand eczema compared with Eucerin (P = 0.003 and P = 0.012 respectively); Nigella and Betamethasone ointments caused significant decreases in DLQI scores compared with Eucerin (P Nigella and Betamethasone groups over time (P = 0.38 and P = 0.99 respectively). It seems that Nigella might have the same efficacy as Betamethasone in improvement of life quality and decreasing severity of hand eczema. © 2012 The Authors. Journal of the European Academy of Dermatology and Venereology © 2012 European Academy of Dermatology and Venereology.

  14. Alternative end points to evaluate a therapeutic strategy in advanced colorectal cancer: evaluation of progression-free survival, duration of disease control, and time to failure of strategy--an Aide et Recherche en Cancerologie Digestive Group Study.

    Science.gov (United States)

    Chibaudel, Benoist; Bonnetain, Franck; Shi, Qian; Buyse, Marc; Tournigand, Christophe; Sargent, Daniel J; Allegra, Carmen J; Goldberg, Richard M; de Gramont, Aimery

    2011-11-01

    Progression-free survival (PFS) is not an optimal end point to evaluate therapeutic strategies in advanced colorectal cancer (ACRC). Therefore, composite end points have been proposed to evaluate a chemotherapy strategy when sequential treatments are available: duration of disease control (DDC) and time to failure of strategy (TFS). The goal of this study was to evaluate these alternative end points and their potential surrogacy for overall survival (OS). We pooled individual patient data from three randomized trials evaluating chemotherapy strategy, which accrued 1,042 patients with previously untreated ACRC. In these trials, first-line treatment was either oxaliplatin- or irinotecan-based chemotherapy. Compared with TFS, DDC included neither time interval between progression and next sequence of treatment nor time to progression if the best result of the next sequence of treatment was progression. There was good correlation between DDC and OS (correlation of median: r, 0.62; correlation of hazard ratio [HR]: adjusted copula R(2), 0.72) and between TFS and OS (correlation of median: r, 0.59; correlation of HR: adjusted copula R(2), 0.67). There was no correlation between PFS and OS (correlation of median: r, 0.45; correlation of HR: adjusted copula R(2), 0.47). DDC and TFS roughly achieved the same results. Both are acceptable new end points to evaluate a therapeutic strategy in ACRC. Although TFS achieved a pragmatic evaluation of a multiline strategy, DDC captured the effect of a specific sequence in a therapeutic strategy.

  15. Overview: clinical and physiological comparison of meditation with other self-control strategies.

    Science.gov (United States)

    Shapiro, D H

    1982-03-01

    In 1977 the American Psychiatric Association called for a critical examination of the clinical effectiveness of meditation. The author provides a review of the literature bearing on clinical and physiological comparisons of meditation with other self-control strategies. He begins by providing a definition of mediation and then cites the literature comparing mediation with such self-regulation strategies as biofeedback, hypnosis, and progressive relaxation. He pays particular attention to the "uniqueness" of mediation as a clinical intervention strategy a well as the adverse effects of meditation. Finally, he offers suggestions and guidelines for future research.

  16. An Optimized Voriconazole Dosing Strategy to Achieve Therapeutic Serum Concentrations in Children Younger than 2 Years Old.

    Science.gov (United States)

    Zembles, Tracy N; Thompson, Nathan E; Havens, Peter L; Kaufman, Bruce A; Huppler, Anna R

    2016-10-01

    To describe our experience with voriconazole in three patients younger than 2 years using an optimized dosing strategy for voriconazole that incorporates intensive therapeutic drug monitoring (TDM). Case series. Large pediatric hospital. Three patients younger than 2 years who received voriconazole therapy and had serum trough concentrations measured between January 1, 2010, and October 31, 2015. A clinical practice guideline developed at our institution was used to standardize initial dosing, appropriate use and timing of TDM, and dosage modifications based on TDM. TDM was used to guide dosing to achieve a target voriconazole serum trough concentration of 2-6 μg/ml. Voriconazole samples were assayed by using a high-performance liquid chromatography analytical method with solid-phase extraction. Initial dosages for the three patients were 9 mg/kg intravenously every 12 hours (one patient) and 9 mg/kg enterally twice/day (two patients). Multiple dose escalations and a more frequent dosing interval were required to achieve trough concentrations within the target range. The final dosages were 12 mg/kg intravenously every 8 hours, 17.7 mg/kg enterally 3 times/day, and 8.5 mg/kg enterally 3 times/day, respectively. In addition to voriconazole trough concentrations, TDM included evaluations for drug toxicities. Visual, neurologic, or hepatic adverse effects were not encountered in the three patients. Our data support higher initial doses and perhaps a 3 times/day dosing schedule to achieve voriconazole serum concentrations in the target range for children younger than 2 years. Implementation of a clinical practice guideline with the participation of pharmacists specializing in pharmacokinetics allows for effective use of voriconazole in young children. © 2016 Pharmacotherapy Publications, Inc.

  17. Mathematical modeling of tumor-induced immunosuppression by myeloid-derived suppressor cells: Implications for therapeutic targeting strategies.

    Science.gov (United States)

    Shariatpanahi, Seyed Peyman; Shariatpanahi, Seyed Pooya; Madjidzadeh, Keivan; Hassan, Moustapha; Abedi-Valugerdi, Manuchehr

    2018-04-07

    Myeloid-derived suppressor cells (MDSCs) belong to immature myeloid cells that are generated and accumulated during the tumor development. MDSCs strongly suppress the anti-tumor immunity and provide conditions for tumor progression and metastasis. In this study, we present a mathematical model based on ordinary differential equations (ODE) to describe tumor-induced immunosuppression caused by MDSCs. The model consists of four equations and incorporates tumor cells, cytotoxic T cells (CTLs), natural killer (NK) cells and MDSCs. We also provide simulation models that evaluate or predict the effects of anti-MDSC drugs (e.g., l-arginine and 5-Fluorouracil (5-FU)) on the tumor growth and the restoration of anti-tumor immunity. The simulated results obtained using our model were in good agreement with the corresponding experimental findings on the expansion of splenic MDSCs, immunosuppressive effects of these cells at the tumor site and effectiveness of l-arginine and 5-FU on the re-establishment of antitumor immunity. Regarding this latter issue, our predictive simulation results demonstrated that intermittent therapy with low-dose 5-FU alone could eradicate the tumors irrespective of their origins and types. Furthermore, at the time of tumor eradication, the number of CTLs prevailed over that of cancer cells and the number of splenic MDSCs returned to the normal levels. Finally, our predictive simulation results also showed that the addition of l-arginine supplementation to the intermittent 5-FU therapy reduced the time of the tumor eradication and the number of iterations for 5-FU treatment. Thus, the present mathematical model provides important implications for designing new therapeutic strategies that aim to restore antitumor immunity by targeting MDSCs. Copyright © 2018 Elsevier Ltd. All rights reserved.

  18. Beyond Brooding on Oncometabolic Havoc in IDH-Mutant Gliomas and AML: Current and Future Therapeutic Strategies

    Directory of Open Access Journals (Sweden)

    Hanumantha Rao Madala

    2018-02-01

    Full Text Available Isocitrate dehydrogenases 1 and 2 (IDH1,2, the key Krebs cycle enzymes that generate NADPH reducing equivalents, undergo heterozygous mutations in >70% of low- to mid-grade gliomas and ~20% of acute myeloid leukemias (AMLs and gain an unusual new activity of reducing the α-ketoglutarate (α-KG to D-2 hydroxyglutarate (D-2HG in a NADPH-consuming reaction. The oncometabolite D-2HG, which accumulates >35 mM, is widely accepted to drive a progressive oncogenesis besides exacerbating the already increased oxidative stress in these cancers. More importantly, D-2HG competes with α-KG and inhibits a large number of α-KG-dependent dioxygenases such as TET (Ten-eleven translocation, JmjC domain-containing KDMs (histone lysine demethylases, and the ALKBH DNA repair proteins that ultimately lead to hypermethylation of the CpG islands in the genome. The resulting CpG Island Methylator Phenotype (CIMP accounts for major gene expression changes including the silencing of the MGMT (O6-methylguanine DNA methyltransferase repair protein in gliomas. Glioma patients with IDH1 mutations also show better therapeutic responses and longer survival, the reasons for which are yet unclear. There has been a great surge in drug discovery for curtailing the mutant IDH activities, and arresting tumor proliferation; however, given the unique and chronic metabolic effects of D-2HG, the promise of these compounds for glioma treatment is uncertain. This comprehensive review discusses the biology, current drug design and opportunities for improved therapies through exploitable synthetic lethality pathways, and an intriguing oncometabolite-inspired strategy for primary glioblastoma.

  19. Comparison of the therapeutic effect between sodium bicarbonate and insulin on acute propafenone toxicity.

    Science.gov (United States)

    Yi, Hwa Yeon; Lee, Jang Young; Lee, Won Suk; Sung, Won Young; Seo, Sang Won

    2014-10-01

    Unlike other sodium-channel-blocking antiarrhythmic agents, propafenone has β-blocking effects and calcium-channel-blocking effects. Yi et al recently studied insulin's treatment effect on acute propafenone toxicity in rats. However, because the degree of effectiveness of insulin compared to the previously known antidote sodium bicarbonate (NaHCO3) was not studied, the 2 treatment methods were compared for propafenone intoxication in rats. Rats received intravenous propafenone (36 mg/[kg h]) for 12 minutes. After the induction of toxicity, rats (n = 10 per group) received normal saline solution (NSS), NaHCO3, or insulin with glucose as treatment. Animals in the NSS, NaHCO3, and Insulin groups received an intravenous infusion of 36 mg/(kg h) propafenone until death occurred. For each animal, the mean arterial pressure (MAP, heart rate, PR interval, QRS duration, total hemoglobin, sodium, potassium, potential of hydrogen, bicarbonate, glucose, lactate, and central venous oxygen saturation (Scvo2) were measured and compared among the groups. Survival of the Insulin group was greater than that of the NSS group by log-rank test (P = .021). Sodium bicarbonate prevented the decline of MAP for 55 minutes. In comparison, insulin prevented the decline of MAP and heart rate, and the elongation of the PR interval and QRS duration for 55 minutes (P < .05). Propafenone toxicity led to decreased Ca(2+), potential of hydrogen, and Scvo2 and increased lactate levels. Insulin prevented the decrease of Ca(2+) and Scvo2, whereas NaHCO3 prevented the increase in lactate. Insulin treatment was more effective than NaHCO3 on acute propafenone toxicity in rat. Therefore, when propafenone-induced cardiotoxicity occurs, which is unresponsive to current treatment methods, glucose-insulin infusion may be considered. Copyright © 2014 Elsevier Inc. All rights reserved.

  20. Effects Comparison of Different Resilience Enhancing Strategies for Municipal Water Distribution Network: A Multidimensional Approach

    Directory of Open Access Journals (Sweden)

    Xudong Zhao

    2015-01-01

    Full Text Available Water distribution network (WDN is critical to the city service, economic rehabilitation, public health, and safety. Reconstructing the WDN to improve its resilience in seismic disaster is an important and ongoing issue. Although a considerable body of research has examined the effects of different reconstruction strategies on seismic resistance, it is still hard for decision-makers to choose optimal resilience enhancing strategy. Taking the pipeline ductile retrofitting and network meshed expansion as demonstration, we proposed a feasible framework to contrast the resilience enhancing effects of two reconstruction strategies—units retrofitting strategy and network optimization strategy—in technical and organizational dimension. We also developed a new performance response function (PRF which is based on network equilibrium theory to conduct the effects comparison in integrated technical and organizational dimension. Through the case study of municipal WDN in Lianyungang, China, the comparison results were thoroughly shown and the holistic decision-making support was provided.

  1. COMPARISON OF SUBLINGUAL THERAPEUTIC VACCINE WITH ANTIBIOTICS FOR THE PROPHYLAXIS OF RECURRENT URINARY TRACT INFECTIONS

    Directory of Open Access Journals (Sweden)

    María Fernanda Lorenzo-Gómez

    2015-06-01

    Full Text Available Objective: To evaluate the clinical impact of the prophylactic treatment with sublingual immunostimulation in the prevention of recurrent urinary tract infections (rUTIs compared with the use of antibiotics.Material and Methods: Retrospective cohort study evaluating the clinical records of 669 women with rUTIs; 339 had a 6-month prophylaxis with antibiotics and 360 had a 3-month prophylaxis with a sublingual bacterial preparation (MV 140-Uromune®. The time after the prophylaxis-period until the appearance of a new infection (assessed by uroculture was scored during one year. Absolute risk reduction (ARR and number needed to treat (NNT were also calculated.Results: All patients (100% treated with antibiotics experienced a new UTI during the scoring period of 12 months, being the mean time free of UTI 29 (±38 days. In the group treated with the bacterial preparation, only 35 (9.7% patients experienced UTI in the same period. Kaplan-Meier curves comparing the accumulated survival (disease-free time between both groups were significant (P < 0.0001. ARR was 90.28 % (87.18-93.38 and NNT 1.1 (1.1-1.1.Conclusions: These results suggest that the treatment with the bacterial preparation reduces rUTIs very effectively, arising as an effective strategy to reduce the frequency of rUTIs. It reduces antibiotic consumption, matching the current recommendations due to the raise of antimicrobial resistance. Randomized, double-blind and placebo-controlled, clinical trials are needed to establish more accurately the clinical impact of this bacterial preparation in patients with rUTIs.

  2. Comparison of therapeutic dosimetric data from passively scattered proton and photon craniospinal irradiations for medulloblastoma

    Directory of Open Access Journals (Sweden)

    Howell Rebecca M

    2012-07-01

    Full Text Available Abstract Background For many decades, the standard of care radiotherapy regimen for medulloblastoma has been photon (megavoltage x-rays craniospinal irradiation (CSI. The late effects associated with CSI are well-documented in the literature and are in-part attributed to unwanted dose to healthy tissue. Recently, there is growing interest in using proton therapy for CSI in pediatric and adolescent patients to reduce this undesirable dose. Previous comparisons of dose to target and non-target organs from conventional photon CSI and passively scattered proton CSI have been limited to small populations (n ≤ 3 and have not considered the use of age-dependent target volumes in proton CSI. Methods Standard of care treatment plans were developed for both photon and proton CSI for 18 patients. This cohort included both male and female medulloblastoma patients whose ages, heights, and weights spanned a clinically relevant and representative spectrum (age 2–16, BMI 16.4–37.9 kg/m2. Differences in plans were evaluated using Wilcoxon signed rank tests for various dosimetric parameters for the target volumes and normal tissue. Results Proton CSI improved normal tissue sparing while also providing more homogeneous target coverage than photon CSI for patients across a wide age and BMI spectrum. Of the 24 parameters (V5, V10, V15, and V20 in the esophagus, heart, liver, thyroid, kidneys, and lungs Wilcoxon signed rank test results indicated 20 were significantly higher for photon CSI compared to proton CSI (p ≤ 0.05 . Specifically, V15 and V20 in all six organs and V5, V10 in the esophagus, heart, liver, and thyroid were significantly higher with photon CSI. Conclusions Our patient cohort is the largest, to date, in which CSI with proton and photon therapies have been compared. This work adds to the body of literature that proton CSI reduces dose to normal tissue compared to photon CSI for pediatric patients who are at substantial risk for

  3. Therapeutic substitution and therapeutic conservatism as cost-containment strategies in primary care: a study of fundholders and non-fundholders.

    OpenAIRE

    Wilson, R P; Hatcher, J; Barton, S; Walley, T

    1999-01-01

    BACKGROUND: General practice (GP) fundholders contained prescribing costs by restricting the rise in volume of prescribing and by increasing generic prescribing. It is uncertain whether they used more sophisticated approaches to medicine choice in attempts to contain costs. AIM: To examine whether fundholding practices have adopted medicine-specific strategies to contain prescribing costs--i.e. switching to less expensive but equally effective medicines or resisting the uptake of newer more e...

  4. Plasma extraction rate and collection efficiency during therapeutic plasma exchange with Spectra Optia in comparison with Haemonetics MCS+.

    Science.gov (United States)

    Lambert, Catherine; Gericke, Marion; Smith, Richard; Hermans, Cedric

    2011-01-01

    For therapeutic plasma exchange (TPE), continuous and intermittent flow separators are known to be efficient. This study was undertaken to compare the performances of the Spectra Optia, a continuous flow centrifugal apheresis system recently developed by CaridianBCT, with the Haemonetics Multicomponents System (MCS)+ apheresis system based on intermittent flow centrifugation. The primary objective of the study was to compare the time required to exchange one total plasma volume with both separators. The secondary objectives were to determine the plasma exchange efficiency, the plasma extraction rate, the percentage of target exchange volume achieved, and the loss of cellular components. The study involved prospectively paired comparison of 16 TPE on each device performed in patients with chronic diseases treated with TPE. The time required to exchange 1 total plasma volume was 182 ± 36 minutes for MCS+ procedures and 100 ± 20 minutes for the Spectra Optia procedures (P higher plasma extraction rate was achieved (30.2 ± 4.3 vs 16.8 ± 3.4 mL/min, respectively, P exchange efficiency was slightly better with the Spectra Optia compared with the MCS+ procedures (83.4 ± 7.0 vs 80.0 ± 8.5%, P higher extraction rate and exchange efficiency than the MCS+ allowing to remove the same amount of plasma in less time, by processing less blood. It also removes significantly less platelets than the MCS+ separator. Copyright © 2010 Wiley-Liss, Inc.

  5. [The role of selective monoamine oxidase B inhibitors in the therapeutic strategy of Parkinson's disease in the neurology clinics of Tirgu Mures County Emergency Clinical Hospital].

    Science.gov (United States)

    Szász, József Attila; Constantin, Viorelia; Fazakas, Péter Alpár; Blényesi, Eszter; Grieb, Levente Gábor; Balla, Antal; Sárig, Mónika; Szegedi, Kinga; Bartha, Eszter Noémi; Szatmári, Szabolcs

    2017-12-01

    Selective monoamine oxidase B inhibitors have an accurate place in therapeutical strategy of Parkinsons's disease. In the early stages of the disease, especially in younger patients with milder symptoms, the introduction of levodopa substitution could be efficacious in delaying; in advanced stages they are mainly used to treat motor complications, as an adjunct to levodopa. The evaluation of therapeutical strategies used in the neurology clinics of Tirgu Mures County Emergency Clinical Hospital in order to define the role of monoamine oxidase B inhibitors. This retrospective study includes all records of patients with Parkinson's disease hospitalized between 1 January 2003 and 31 December 2016. From the 2194 reports we used data focusing on the therapeutic recommendations. Regarding disease duration, we divided the patients in two groups: less than or equal to 5 years and more than 5 years. From the 1183 patients in first group, 243 received monoamine oxidase inhibitors: 12 as monotherapy, 52 together with dopamine agonists, in 61 cases combined with levodopa. In 118 cases monoamine oxidase inhibitors were combined with levodopa and dopamine agonists. From 582 cases whith Parkinson's disease for more than 5 years, 195 received monoamine oxidase B inhibitors (selegiline: 10 cases, rasagiline: 185 cases). In 429 cases we did not find accurate data regarding disease duration (selegiline: 5 cases, rasagiline: 93 cases). The use of monoamine oxidase B inhibitors was similar to those found in literature. The treating physicians should utilise more confidently the available therapeutical combinations. Orv Hetil. 2017; 158(51): 2023-2028.

  6. A comparison of general health and coping strategies in fertile and infertile women in Yazd

    OpenAIRE

    Bakhshayesh, Ali Reza; Kazeraninejad, Mahsa; Dehghan Mongabadi, Mahsa; Raghebian, Malihe

    2012-01-01

    Background: Infertility affects various aspects of personality and psychology, familial and career performances, and relationships. Studies show that stress, anxiety, life dissatisfaction, and other psychological problems follow infertility .Infertility issue, its tests and remedy are stressful and may lead to anxiety and depression and have destructive effects on couple relationships. Objective: The present study was done in order to comparison general health and coping strategies in fertile...

  7. Succinic semialdehyde dehydrogenase deficiency, a disorder of GABA metabolism: an update on pharmacological and enzyme-replacement therapeutic strategies.

    Science.gov (United States)

    Vogel, Kara R; Ainslie, Garrett R; Walters, Dana C; McConnell, Alice; Dhamne, Sameer C; Rotenberg, Alexander; Roullet, Jean-Baptiste; Gibson, K Michael

    2018-02-19

    We present an update to the status of research on succinic semialdehyde dehydrogenase (SSADH) deficiency (SSADHD), a rare disorder of GABA metabolism. This is an unusual disorder featuring the accumulation of both GABA and its neuromodulatory analog, gamma-hydroxybutyric acid (GHB), and recent studies have advanced the potential clinical application of NCS-382, a putative GHB receptor antagonist. Animal studies have provided proof-of-concept that enzyme replacement therapy could represent a long-term therapeutic option. The characterization of neuronal stem cells (NSCs) derived from aldehyde dehydrogenase 5a1 -/- (aldh5a1 -/- ) mice, the murine model of SSADHD, has highlighted NSC utility as an in vitro system in which to study therapeutics and associated toxicological properties. Gene expression analyses have revealed that transcripts encoding GABA A receptors are down-regulated and may remain largely immature in aldh5a1 -/- brain, characterized by excitatory as opposed to inhibitory outputs, the latter being the expected action in the mature central nervous system. This indicates that agents altering chloride channel activity may be therapeutically relevant in SSADHD. The most recent therapeutic prospects include mTOR (mechanistic target of rapamycin) inhibitors, drugs that have received attention with the elucidation of the effects of elevated GABA on autophagy. The outlook for novel therapeutic trials in SSADHD continues to improve.

  8. Cross-gender Comparison of Metacognitive Strategies Utilized by Omani Students in Reading Comprehension Classes

    Directory of Open Access Journals (Sweden)

    Manizheh Alami

    2016-07-01

    Full Text Available Given the fact that English is the language of the latest technological and scientific developments, comprehending English texts has priority for students to gain the knowledge and skills they will need in the future. However, most Omani students are not efficient L2 readers and do not have sufficient competence in reading authentic English texts. There is a variety of factors that might affect Omani students’ ability to read and comprehend English texts effectively. To find out what factors are involved in Omani students’ reading comprehension, in the first place, it is necessary to know what strategies they employ in reading. To this end, the current study attempts  to explore Omani students reported use of reading strategies using ‘Metacognitive Awareness of Reading Strategies Inventory’ (MARSI developed by Mokhtari and Reichard (2002. The self-reported survey completed by 200 students (90 female and110 male who enrolled for Advanced Foundation program (level 4 at Salalah College of Technology (SCT. The results show that SCT students’ awareness of metacognitive strategies is at medium level (3.46. Furthermore, the comparison between two gender groups (Males Vs. Females shows that male students use metacognitive reading strategies moderately (3.28 while female students use them more frequently (3.64. The outcomes of the study contribute to the improvement of SCT students reading ability and can be used by teachers to teach students different strategies to build meaning of the reading material which is among the goals of any educational system.

  9. Analysis and Comparison of Shading Strategies to Increase Human Thermal Comfort in Urban Areas

    Directory of Open Access Journals (Sweden)

    Ivan Lee

    2018-03-01

    Full Text Available With the expected increase in warmer conditions caused by climate change, heat-related illnesses are becoming a more pressing issue. One way that humans can protect themselves from this is to seek shade. The design of urban spaces can provide individuals with a variety of ways to obtain this shade. The objective of this study was to perform a detailed evaluation and comparison of three shading strategies that could be used in an urban environment: shade from a building, from a tree, and from an umbrella. This was done through using field measurements to calculate the impact of each strategy on a thermal comfort index (Comfort Formula (COMFA in two urban settings during sunny days of the summer of 2013 and 2014 in London, Canada. Building shade was found to be the most effective cooling strategy, followed by the tree strategy and the umbrella strategy. As expected, the main determinant of this ranking was a strategy’s ability to block incoming shortwave radiation. Further analysis indicated that changes in the convective loss of energy and in longwave radiation absorption had a smaller impact that caused variations in the strategy effectiveness between settings. This suggests that under non-sunny days, these rankings could change.

  10. The Comparison Among Antibacterial Activity of Mespilus germanica Extracts and Number of Common Therapeutic Antibiotics “In Vitro”

    Directory of Open Access Journals (Sweden)

    Farideh Tabatabaei-Yazdi

    2015-12-01

    Full Text Available Background: Antibiotic resistance is a serious and growing phenomenon in contemporary medicine and has emerged as one of the pre-eminent public health concerns of the 21st century. Objectives: In this study, antibacterial activity of Mespilus germanica extract against some pathogenic bacterial strains (Streptococcus pyogene, Listeria innocua, Enterobacter aerogenes and Klebsiella pneumoniae was evaluated. Materials and Methods: In this experimental study, maceration extraction method was used for M. germanica extract. Disk diffusion method was used to evaluate the antimicrobial effect and broth microdilution method was used to determine the minimum inhibitory concentration and minimum bactericidal concentration. Then, the data were entered into the SPSS-18 statistical software and analyzed using one-way ANOVA and Tukey test. Results: Antimicrobial activity was assessed by inhibition diameters which were found to range from 8 to 21.5 mm for the two extracts against all the bacterial strains tested. The minimum inhibitory concentrations (MIC for the extracts were later determined by three fold serial dilutions method and they ranged 2 - 64 mg/mL against all the strains and minimum bactericidal concentrations (MBC for the extracts were later determined by three fold serial dilutions method and they ranged 4 - 128 mg/mL against all the strains. Conclusions: The M. germanica extract showed the more effective impact on the growth S. pyogene and L. innocua than E. aerogenes and K. pneumoniae (P < 0.05. M. germanica in comparison with common therapeutic antibiotics had more inhibitory effect on some of the studied strains in vitro.

  11. A Comparison of Pharmacologic Therapeutic Agents Used for the Reduction of Intracranial Pressure After Traumatic Brain Injury.

    Science.gov (United States)

    Alnemari, Ahmed M; Krafcik, Brianna M; Mansour, Tarek R; Gaudin, Daniel

    2017-10-01

    In neurotrauma care, a better understanding of treatments after traumatic brain injury (TBI) has led to a significant decrease in morbidity and mortality in this population. TBI represents a significant medical problem, and complications after TBI are associated with the initial injury and postevent intracranial processes such as increased intracranial pressure and brain edema. Consequently, appropriate therapeutic interventions are required to reduce brain tissue damage and improve cerebral perfusion. We present a contemporary review of literature on the use of pharmacologic therapies to reduce intracranial pressure after TBI and a comparison of their efficacy. This review was conducted by PubMed query. Only studies discussing pharmacologic management of patients after TBI were included. This review includes prospective and retrospective studies and includes randomized controlled trials as well as cohort, case-control, observational, and database studies. Systematic literature reviews, meta-analyses, and studies that considered conditions other than TBI or pediatric populations were not included. Review of the literature describing the current pharmacologic treatment for intracranial hypertension after TBI most often discussed the use of hyperosmolar agents such as hypertonic saline and mannitol, sedatives such as fentanyl and propofol, benzodiazepines, and barbiturates. Hypertonic saline is associated with faster resolution of intracranial hypertension and restoration of optimal cerebral hemodynamics, although these advantages did not translate into long-term benefits in morbidity or mortality. In patients refractory to treatment with hyperosmolar therapy, induction of a barbiturate coma can reduce intracranial pressure, although requires close monitoring to prevent adverse events. Current research suggests that the use of hypertonic saline after TBI is the best option for immediate decrease in intracranial pressure. A better understanding of the efficacy of

  12. Comparison of the Effects of Seated, Supine, and Walking Interset Rest Strategies on Work Rate.

    Science.gov (United States)

    Ouellette, Kristen A; Brusseau, Timothy A; Davidson, Lance E; Ford, Candus N; Hatfield, Disa L; Shaw, Janet M; Eisenman, Patricia A

    2016-12-01

    Ouellette, KA, Brusseau, TA, Davidson, LE, Ford, CN, Hatfield, DL, Shaw, JM, and Eisenman, PA. Comparison of the effects of seated, supine, and walking interset rest strategies on work rate. J Strength Cond Res 30(12): 3396-3404, 2016-The idea that an upright posture should be maintained during the interset rest periods of training sessions is pervasive. The primary aim of this study was to determine differences in work rate associated with 3 interset rest strategies. Male and female members of the CrossFit community (male n = 5, female n = 10) were recruited to perform a strenuous training session designed to enhance work capacity that involved both cardiovascular and muscular endurance exercises. The training session was repeated on 3 separate occasions to evaluate 3 interset rest strategies, which included lying supine on the floor, sitting on a flat bench, and walking on a treadmill (0.67 m·s). Work rate was calculated for each training session by summing session joules of work and dividing by the time to complete the training session (joules of work per second). Data were also collected during the interset rest periods (heart rate [HR], respiratory rate [RR], and volume of oxygen consumed) and were used to explain why one rest strategy may positively impact work rate compared with another. Statistical analyses revealed significant differences (p ≤ 0.05) between the passive and active rest strategies, with the passive strategies allowing for improved work rate (supine = 62.77 ± 7.32, seated = 63.66 ± 8.37, and walking = 60.61 ± 6.42 average joules of work per second). Results also suggest that the passive strategies resulted in superior HR, RR, and oxygen consumption recovery. In conclusion, work rate and physiological recovery were enhanced when supine and seated interset rest strategies were used compared with walking interset rest.

  13. Molecular mechanisms of action of anti-TNF-α agents - Comparison among therapeutic TNF-α antagonists.

    Science.gov (United States)

    Mitoma, Hiroki; Horiuchi, Takahiko; Tsukamoto, Hiroshi; Ueda, Naoyasu

    2018-01-01

    Tumor necrosis factor (TNF)-α is a potent pro-inflammatory and pathological cytokines in inflammatory diseases such as rheumatoid arthritis and inflammatory bowel diseases. Anti-TNF-α therapy has been established as an efficacious therapeutic strategy in these diseases. In clinical settings, three monoclonal anti-TNF-α full IgG1 antibodies infliximab, adalimumab, and golimumab, PEGylated Fab' fragment of anti-TNF-α antibody certolizumab pegol, extracellular domain of TNF receptor 2/IgG1-Fc fusion protein etanercept, are almost equally effective for rheumatoid arthritis. Although monoclonal full IgG1 antibodies are able to induce clinical and endoscopic remission in inflammatory bowel diseases, certolizumab pegol without Fc portion has been shown to be less effective for inflammatory bowel diseases compared to full IgG1 antibodies. In addition, there are no evidences that etanercept leads clinical remission in inflammatory bowel diseases. Besides the common effect of anti-TNF-α agents on neutralization of soluble TNF-α, each anti-TNF-α agent has its own distinctive pharmacological properties which cause the difference in clinical efficacies. Here we focus on the distinctions of action of anti-TNF-α agents especially in following points; (1) blocking ability against ligands, transmembrane TNF-α and lymphotoxin, (2) effects toward transmembrane TNF-α-expressing cells, (3) effects toward Fcγ receptor-expressing cells, (4) degradation and distribution in inflamed tissue. Accumulating evidence will give us the idea how to modify anti-TNF-α agents to enhance the clinical efficacy in inflammatory diseases. Copyright © 2016 Elsevier Ltd. All rights reserved.

  14. The Comparison of Emotion Regulation Strategies in Adolescents with Oppositional Defiant Disorder and Normal

    Directory of Open Access Journals (Sweden)

    A. Ghasempour

    2014-08-01

    Full Text Available Introduction: Emotion regulation strategies were of affection factors in disruptive behavior disorders. The aim of the study was to comparison emotion regulation strategies in boy adolescents with oppositional defiant disorder and normal in Amol town. Materials and Methods: A causative- comparative design and the study statistical population was all boy student of Amol town high school. The study sample comprised 36 people (18 people with oppositional defiant and 18 people normal who were selected by single- stage cluster sampling. Data was collected using Achenbach Youth Self-Report Scale (YSR and Garnefski & Kraaij emotional regulation questionnaire. To analyze the data, multi-vitiate analyze of variance (MANOVA was used. Results: The mean age of the adolescents with oppositional defiant disorder was 15/16±0/51and normal 15/11±0/67 years. The results of this study showed that adolescents with oppositional defiant disorder have negative emotion regulation strategies and adolescents normal have positive emotion regulation strategies. Conclusion: These findings highlighted the importance of positive and negative emotion regulation strategies in given oppositional defiant disorder in adolescents.

  15. Feeding strategies of primates in temperate and alpine forests: comparison of Asian macaques and colobines.

    Science.gov (United States)

    Tsuji, Yamato; Hanya, Goro; Grueter, Cyril C

    2013-07-01

    We analyzed regional variation in the diets of two primate clades, Asian macaques and colobines, whose distributions include temperate-alpine forests. We addressed feeding strategies that enabled them to adapt to harsh environments characterized by relatively low mean temperatures and strong seasonality in both temperature and food availability. Macaques in tropical-lowland forests feed mainly on fruit and animal matter whereas populations in temperate-alpine forests feed more on foliage and on such items as bark and fungi. In comparison, colobines in tropical-lowland forests feed more on fruit and foliage whereas populations in temperate-alpine forests feed less on flowers and more on lichens. Annual precipitation and mean temperature, both of which reflect primary production, had the most significant effects on the feeding behavior of the macaques, whereas only mean temperature had a significant effect on that of colobines. We found two behavioral strategies used by both clades to cope with severe environmental conditions in temperate-alpine forests--shifting to other food items and adjusting feeding plasticity for fruit and foliage. Macaques responded to latitudinal changes by use of both strategies whereas the colobines adapted by using the latter only. By contrast, changes in altitude resulted in the macaques' using the latter strategy and colobines' using both. The different current distributions of Asian macaques and colobines could be attributed to differences in their feeding strategies originating in their digestive systems.

  16. Managing radioactive waste issues and misunderstandings (radiation realities, energy comparison, waste strategies)

    International Nuclear Information System (INIS)

    Rosen, M.

    2001-01-01

    The technical specialist is confident that radioactive waste can be safely managed, but many in the public remain totally unconvinced. There are issues and deep-seated misunderstandings that drive public doubts. Currently, a growing concern with pollution from other industrial waste is enabling radioactive waste issues to be debated in a wider context that allows comparisons with other potentially hazardous waste, particularly from energy generation sources. Health effects and time period issues are not unique to radioactive waste. This paper concentrates on 3 topics. The first concerns radiation health effects where the real realities of radiation are covered. The large misunderstandings that exist about radiation and its health effects have led to an almost zero health impact regulatory policy. A policy which must be more fully understood and dealt with. The second topic deals with a few revealing comparisons about the various energy generation systems. Nuclear power's 10 thousand fold lower fuel requirements, compared with a comparable fossil fuelled plant, is a dominating factor decisively minimising environmental impacts. The third topic examines waste disposal strategies. Extraordinarily small radioactive waste quantities permit a confinement strategy for disposal as opposed to the more common dispersion strategy for most toxic waste. The small quantities coupled with radioactive decay, contrary to the public perception, make any potential hazard from both low and high level radioactive waste exceedingly small. (author)

  17. Optimizing therapeutic efficacy of chemopreventive agents: A critical review of delivery strategies in oral cancer chemoprevention clinical trials

    Directory of Open Access Journals (Sweden)

    Andrew S Holpuch

    2011-01-01

    Full Text Available Due to its characterized progression from recognized premalignant oral epithelial changes (i.e., oral epithelial dysplasia to invasive cancer, oral squamous cell carcinoma represents an optimal disease for chemopreventive intervention prior to malignant transformation. The primary goal of oral cancer chemoprevention is to reverse, suppress, or inhibit the progression of premalignant lesions to cancer. Over the last several decades, numerous oral cancer chemoprevention clinical trials have assessed the therapeutic efficacy of diverse chemopreventive agents. The standard of care for more advanced oral dysplastic lesions entails surgical excision and close clinical follow-up due to the potential (~33% for local recurrence at a similar or more advanced histological stage. The purpose of this review was to identify prominent oral cancer chemoprevention clinical trials, assess their overall therapeutic efficacy, and delineate effects of local versus systemic drug administration. In addition, these compiled clinical trial data present concepts for consideration in the design and conduction of future clinical trials.

  18. Recent Perspectives on Genome, Transmission, Clinical Manifestation, Diagnosis, Therapeutic Strategies, Vaccine Developments, and Challenges of Zika Virus Research

    Directory of Open Access Journals (Sweden)

    Apoorva Shankar

    2017-09-01

    Full Text Available One of the potential threats to public health microbiology in 21st century is the increased mortality rate caused by Zika virus (ZIKV, a mosquito-borne flavivirus. The severity of ZIKV infection urged World Health Organization (WHO to declare this virus as a global concern. The limited knowledge on the structure, virulent factors, and replication mechanism of the virus posed as hindrance for vaccine development. Several vector and non-vector-borne mode of transmission are observed for spreading the disease. The similarities of the virus with other flaviviruses such as dengue and West Nile virus are worrisome; hence, there is high scope to undertake ZIKV research that probably provide insight for novel therapeutic intervention. Thus, this review focuses on the recent aspect of ZIKV research which includes the outbreak, genome structure, multiplication and propagation of the virus, current animal models, clinical manifestations, available treatment options (probable vaccines and therapeutics, and the recent advancements in computational drug discovery pipelines, challenges and limitation to undertake ZIKV research. The review suggests that the infection due to ZIKV became one of the universal concerns and an interdisciplinary environment of in vitro cellular assays, genomics, proteomics, and computational biology approaches probably contribute insights for screening of novel molecular targets for drug design. The review tried to provide cutting edge knowledge in ZIKV research with future insights required for the development of novel therapeutic remedies to curtail ZIKV infection.

  19. Accelerating Multiple Compound Comparison Using LINGO-Based Load-Balancing Strategies on Multi-GPUs

    Directory of Open Access Journals (Sweden)

    Chun-Yuan Lin

    2015-01-01

    Full Text Available Compound comparison is an important task for the computational chemistry. By the comparison results, potential inhibitors can be found and then used for the pharmacy experiments. The time complexity of a pairwise compound comparison is O(n2, where n is the maximal length of compounds. In general, the length of compounds is tens to hundreds, and the computation time is small. However, more and more compounds have been synthesized and extracted now, even more than tens of millions. Therefore, it still will be time-consuming when comparing with a large amount of compounds (seen as a multiple compound comparison problem, abbreviated to MCC. The intrinsic time complexity of MCC problem is O(k2n2 with k compounds of maximal length n. In this paper, we propose a GPU-based algorithm for MCC problem, called CUDA-MCC, on single- and multi-GPUs. Four LINGO-based load-balancing strategies are considered in CUDA-MCC in order to accelerate the computation speed among thread blocks on GPUs. CUDA-MCC was implemented by C+OpenMP+CUDA. CUDA-MCC achieved 45 times and 391 times faster than its CPU version on a single NVIDIA Tesla K20m GPU card and a dual-NVIDIA Tesla K20m GPU card, respectively, under the experimental results.

  20. 3p22.1p21.31 microdeletion identifies CCK as Asperger syndrome candidate gene and shows the way for therapeutic strategies in chromosome imbalances.

    Science.gov (United States)

    Iourov, Ivan Y; Vorsanova, Svetlana G; Voinova, Victoria Y; Yurov, Yuri B

    2015-01-01

    In contrast to other autism spectrum disorders, chromosome abnormalities are rare in Asperger syndrome (AS) or high-functioning autism. Consequently, AS was occasionally subjected to classical positional cloning. Here, we report on a case of AS associated with a deletion of the short arm of chromosome 3. Further in silico analysis has identified a candidate gene for AS and has suggested a therapeutic strategy for manifestations of the chromosome rearrangement. Using array comparative genomic hybridization, an interstitial deletion of 3p22.1p21.31 (~2.5 Mb in size) in a child with Asperger's syndrome, seborrheic dermatitis and chronic pancreatitis was detected. Original bioinformatic approach to the prioritization of candidate genes/processes identified CCK (cholecystokinin) as a candidate gene for AS. In addition to processes associated with deleted genes, bioinformatic analysis of CCK gene interactome indicated that zinc deficiency might be a pathogenic mechanism in this case. This suggestion was supported by plasma zinc concentration measurements. The increase of zinc intake produced a rise in zinc plasma concentration and the improvement in the patient's condition. Our study supported previous linkage findings and had suggested a new candidate gene in AS. Moreover, bioinformatic analysis identified the pathogenic mechanism, which was used to propose a therapeutic strategy for manifestations of the deletion. The relative success of this strategy allows speculating that therapeutic or dietary normalization of metabolic processes altered by a chromosome imbalance or genomic copy number variations may be a way for treating at least a small proportion of cases of these presumably incurable genetic conditions.

  1. The Impact of Price Comparison Service on Pricing Strategy in a Dual-Channel Supply Chain

    Directory of Open Access Journals (Sweden)

    Qi Xu

    2013-01-01

    Full Text Available Recently, price comparison service (PCS websites are more and more popular due to its features in facilitating transparent price and promoting rational purchase decision. Motivated by the industrial practices, in this study, we examine the pricing strategies of retailers and supplier in a dual-channel supply chain influenced by the signals of PCS. We categorize and discuss three situations according to the signal availability of PCS, under which the optimal pricing strategies are derived. Finally, we conduct a numerical study and find that in fact the retailers and supplier are all more willing to avoid the existence of PCS with the objective of profit maximization. When both of retailers are affected by the PCS, the supplier is more willing to reduce the availability of price information. Important managerial insights are discussed.

  2. The National Strategy of Ecological Transition towards Sustainable Development - International comparisons

    International Nuclear Information System (INIS)

    Kleiber, Florence; Vey, Frederic; Moreau, Sylvain; Bottin, Anne; Baudu-Baret, Claude

    2017-05-01

    The National Strategy of Ecological Transition towards Sustainable Development (SNTEDD) 2015-2020 follows on from the 2010-2013 National Strategy for Sustainable Development. Adopted at the Council of Ministers meeting of 4 February 2015, the SNTEDD identifies four major ecological challenges and nine strategic areas of action. The SNTEDD is monitored by 72 indicators developed via a collaborative process of selection implemented by a special commission of the National Council for Ecological Transition (CNTE) responsible for the indicators. This 'indicators' commission has sought to obtain a perspective on outcomes by means of international comparisons. This study presents initial elements of an analysis of France's situation compared with that of other countries (mostly EU or OECD members) with regard to each of the challenges and areas of action identified in the SNTEDD

  3. The Use of Humor and Storytelling with African American Men: Innovative Therapeutic Strategies for Success in Counseling

    Science.gov (United States)

    Vereen, Linwood G.; Hill, Nicole R.; Butler, S. Kent

    2013-01-01

    In recent years, the use of culturally appropriate humor as a tool for change within the parameters of counseling has grown within the literature. In comparison, the art of storytelling has had little attention within the literature as a tool for strategic change. This article outlines a framework for the use of humor and storytelling as…

  4. Dynamic probabilistic simulation of dairy herd management practices 2. Comparison of strategies in order to change a herd's calving pattern.

    NARCIS (Netherlands)

    Jalvingh, A.W.; Arendonk, van J.A.M.; Dijkhuizen, A.A.; Renkema, J.A.

    1993-01-01

    A dynamic probabilistic simulation model is further extended and used for a comparison of different strategies in order to change the calving pattern of a herd. The Markov chain approach is used to simulate herd dynamics. Strategies to change the calving pattern focusing on the farm's intake of

  5. Research strategy of the therapeutic quality of mud and salty water from Ursu(Bear Lake, Sovata, 

    Directory of Open Access Journals (Sweden)

    Munteanu Constantin

    2012-05-01

    Full Text Available Infertility (sterility is a health problem affecting 15% of couples of reproductive age. Today only a few are known about causes and treatment options involved in the pathology of infertility, while a number of issues remain unknown. Currently natural therapeutic factors from Sovata are used, based on experience over the years, for the following causes of infertility: tubal obstruction, laparoscopic postneosalpingostomiei recovery treatment (prevention of restenozations, sequelae after pelvic inflammatory disease, peritonitis, post-inflammatory adhesions; secretory ovarian dysfunction (estrogen, progesterone, polycystic ovarian syndrome, endometriosis, infertility induced by stress.

  6. The network model of depression as a basis for new therapeutic strategies for treating major depressive disorder in Parkinson’s disease

    Directory of Open Access Journals (Sweden)

    Kevin eD'Ostilio

    2016-04-01

    Full Text Available The high prevalence of major depressive disorder in people with Parkinson's disease, 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 Parkinson's disease within the framework of the network model of depression. According to this model, major depressive disorder reflects maladaptive neuronal plasticity. Non-invasive brain stimulation using high frequency repetitive transcranial magnetic stimulation 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 non-invasive brain stimulation together with cognitive and behavioral interventions.

  7. 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

  8. Assessment of refractive astigmatism and simulated therapeutic refractive surgery strategies in coma-like-aberrations-dominant corneal optics.

    Science.gov (United States)

    Zhou, Wen; Stojanovic, Aleksandar; Utheim, Tor Paaske

    2016-01-01

    The aim of the study is to raise the awareness of the influence of coma-like higher-order aberrations (HOAs) on power and orientation of refractive astigmatism (RA) and to explore how to account for that influence in the planning of topography-guided refractive surgery in eyes with coma-like-aberrations-dominant corneal optics. Eleven eyes with coma-like-aberrations-dominant corneal optics and with low lenticular astigmatism (LA) were selected for astigmatism analysis and for treatment simulations with topography-guided custom ablation. Vector analysis was used to evaluate the contribution of coma-like corneal HOAs to RA. Two different strategies were used for simulated treatments aiming to regularize irregular corneal optics: With both strategies correction of anterior corneal surface irregularities (corneal HOAs) were intended. Correction of total corneal astigmatism (TCA) and RA was intended as well with strategies 1 and 2, respectively. Axis of discrepant astigmatism (RA minus TCA minus LA) correlated strongly with axis of coma. Vertical coma influenced RA by canceling the effect of the with-the-rule astigmatism and increasing the effect of the against-the-rule astigmatism. After simulated correction of anterior corneal HOAs along with TCA and RA (strategies 1 and 2), only a small amount of anterior corneal astigmatism (ACA) and no TCA remained after strategy 1, while considerable amount of ACA and TCA remained after strategy 2. Coma-like corneal aberrations seem to contribute a considerable astigmatic component to RA in eyes with coma-like-aberrations dominant corneal optics. If topography-guided ablation is programmed to correct the corneal HOAs and RA, the astigmatic component caused by the coma-like corneal HOAs will be treated twice and will result in induced astigmatism. Disregarding RA and treating TCA along with the corneal HOAs is recommended instead.

  9. Comparison of various online IGRT strategies: The benefits of online treatment plan re-optimization

    International Nuclear Information System (INIS)

    Schulze, Derek; Liang, Jian; Yan, Di; Zhang Tiezhi

    2009-01-01

    Purpose: To compare the dosimetric differences of various online IGRT strategies and to predict potential benefits of online re-optimization techniques in prostate cancer radiation treatments. Materials and methods: Nine prostate patients were recruited in this study. Each patient has one treatment planning CT images and 10-treatment day CT images. Five different online IGRT strategies were evaluated which include 3D conformal with bone alignment, 3D conformal re-planning via aperture changes, intensity modulated radiation treatment (IMRT) with bone alignment, IMRT with target alignment and IMRT daily re-optimization. Treatment planning and virtual treatment delivery were performed. The delivered doses were obtained using in-house deformable dose mapping software. The results were analyzed using equivalent uniform dose (EUD). Results: With the same margin, rectum and bladder doses in IMRT plans were about 10% and 5% less than those in CRT plans, respectively. Rectum and bladder doses were reduced as much as 20% if motion margin is reduced by 1 cm. IMRT is more sensitive to organ motion. Large discrepancies of bladder and rectum doses were observed compared to the actual delivered dose with treatment plan predication. The therapeutic ratio can be improved by 14% and 25% for rectum and bladder, respectively, if IMRT online re-planning is employed compared to the IMRT bone alignment approach. The improvement of target alignment approach is similar with 11% and 21% dose reduction to rectum and bladder, respectively. However, underdosing in seminal vesicles was observed on certain patients. Conclusions: Online treatment plan re-optimization may significantly improve therapeutic ratio in prostate cancer treatments mostly due to the reduction of PTV margin. However, for low risk patient with only prostate involved, online target alignment IMRT treatment would achieve similar results as online re-planning. For all IGRT approaches, the delivered organ-at-risk doses may be

  10. Significance of Glucose Transporter Type 1 (GLUT-1) Expression in the Therapeutic Strategy for Pancreatic Ductal Adenocarcinoma.

    Science.gov (United States)

    Kurahara, Hiroshi; Maemura, Kosei; Mataki, Yuko; Sakoda, Masahiko; Iino, Satoshi; Kawasaki, Yota; Arigami, Takaaki; Mori, Shinichiro; Kijima, Yuko; Ueno, Shinichi; Shinchi, Hiroyuki; Natsugoe, Shoji

    2018-02-05

    This study aimed to examine the prognostic relevance of glucose transporter type 1 (GLUT-1), which is a key regulator of the glucose metabolism. In particular, the study aimed to examine the association between GLUT-1 expression and the therapeutic effect of chemoradiotherapy (CRT) in pancreatic ductal adenocarcinoma (PDAC). Patients with PDAC were enrolled in the study. Patients with distant metastases and those who received only chemotherapy as treatment were excluded from the study. Specimens for immunohistochemical evaluations were obtained through surgical resection and endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) of the primary tumor before any treatment. This study included 197 patients. Of these 197 patients, 100 underwent upfront surgery, and 97 received neoadjuvant CRT (NACRT), which was performed mainly for patients with locally advanced tumors. Of the 97 patients who received NACRT, 21 later underwent surgical resection. For the patients who underwent upfront surgery, low GLUT-1 expression was an independent factor for a better prognosis. For the patients who underwent NACRT, low GLUT-1 expression was significantly associated with greater tumor size reduction, a higher resection rate, and a better prognosis. Additionally, GLUT-1 expression was significantly increased after NACRT treatment. Among the patients with PDAC, those with low GLUT-1 expression in the primary tumor had a better prognosis those with high GLUT-1 expression. Moreover, the patients with low GLUT-1 expression displayed a better therapeutic response to NACRT.

  11. The modulation of metal bio-availability as a therapeutic strategy for the treatment of Alzheimer's disease.

    Science.gov (United States)

    Crouch, Peter J; White, Anthony R; Bush, Ashley I

    2007-08-01

    The postmortem Alzheimer's disease brain is characterized histochemically by the presence of extracellular amyloid plaques and neurofibrillary tangles. Also consistent with the disease is evidence for chronic oxidative damage within the brain. Considerable research data indicates that these three critical aspects of Alzheimer's disease are interdependent, raising the possibility that they share some commonality with respect to the ever elusive initial factor(s) that triggers the development of Alzheimer's disease. Here, we discuss reports that show a loss of metal homeostasis is also an important event in Alzheimer's disease, and we identify how metal dyshomeostasis may contribute to development of the amyloid-beta, tau and oxidative stress biology of Alzheimer's disease. We propose that therapeutic agents designed to modulate metal bio-availability have the potential to ameliorate several of the dysfunctional events characteristic of Alzheimer's disease. Metal-based therapeutics have already provided promising results for the treatment of Alzheimer's disease, and new generations of pharmaceuticals are being developed. In this review, we focus on copper dyshomeostasis in Alzheimer's disease, but we also discuss zinc and iron.

  12. Place of the brachytherapy in the therapeutic strategy of rhabdomyosarcomas of the nasogenian groove of children; Place de la curietherapie dans la strategie therapeutique des rhabdomyosarcomes du sillon nasogenien de l'enfant

    Energy Technology Data Exchange (ETDEWEB)

    Breton-Callu, C.; Haie-Meder, C.; Oberlin, O.; Delapierre, M.; Gerbaulet, A. [Institut Gustave Roussy, 94 - Villejuif (France)

    2000-12-01

    The brachytherapy in the treatment of rhabdomyosarcomas of the nasogenian groove has to be discussed when it exists a residual tumor after an initial chemotherapy and leads to good results, in term of local control. An advantage of the brachytherapy in comparison with external irradiation, in the treatment of children tumors, is the small size of the treated volume, that allows to decrease the aftereffects incidence. The brachytherapy comes in the frame of a therapeutic needing a multidisciplinary approach and a cooperation between surgeons, brachy-therapists and onco-pediatricians. (N.C.)

  13. Conclusion: imaging in strategy of endocrine diagnosis and therapeutics; Place de l`imagerie dans la strategie d`exploration et de suivi therapeutique des pathologies endocriniennes

    Energy Technology Data Exchange (ETDEWEB)

    Mornex, R. [Hopital Edouard-Herriot, 69 - Lyon (France)

    1995-12-31

    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.

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

    Science.gov (United States)

    Wilson, Joanna B; Manet, Evelyne; Gruffat, Henri; Busson, Pierre; Blondel, Marc; Fahraeus, Robin

    2018-04-06

    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 means to cripple

  15. Therapeutic strategies to address neuronal nitric oxide synthase deficiency and the loss of nitric oxide bioavailability in Duchenne Muscular Dystrophy.

    Science.gov (United States)

    Timpani, Cara A; Hayes, Alan; Rybalka, Emma

    2017-05-25

    Duchenne Muscular Dystrophy is a rare and fatal neuromuscular disease in which the absence of dystrophin from the muscle membrane induces a secondary loss of neuronal nitric oxide synthase and the muscles capacity for endogenous nitric oxide synthesis. Since nitric oxide is a potent regulator of skeletal muscle metabolism, mass, function and regeneration, the loss of nitric oxide bioavailability is likely a key contributor to the chronic pathological wasting evident in Duchenne Muscular Dystrophy. As such, various therapeutic interventions to re-establish either the neuronal nitric oxide synthase protein deficit or the consequential loss of nitric oxide synthesis and bioavailability have been investigated in both animal models of Duchenne Muscular Dystrophy and in human clinical trials. Notably, the efficacy of these interventions are varied and not always translatable from animal model to human patients, highlighting a complex interplay of factors which determine the downstream modulatory effects of nitric oxide. We review these studies herein.

  16. Color-flow duplex screening for upper extremity proximity injuries: a low-yield strategy for therapeutic intervention.

    Science.gov (United States)

    Mollberg, Nathan M; Wise, Stephen R; Banipal, Simpledeep; Sullivan, Ryan; Holevar, Michelle; Vafa, Amir; Clark, Elizabeth; Merlotti, Gary J

    2013-07-01

    Although the incidence of injury to the upper extremity screened with angiography as a result of proximity penetrating trauma is similar to that of the lower extremity, intervention rates seem to be higher. However, studies evaluating the incidence of injury as a result of proximity penetrating trauma have primarily focused on the lower extremity. This study shows the incidence and clinical significance of vascular injury as a result of proximity trauma to the upper extremity in a large cohort of patients screened with color-flow duplex. A retrospective study was conducted from January 1, 2005 to January 1, 2012 on all patients undergoing color-flow duplex as a result of proximity penetrating trauma to the upper extremity. Data on injury location, mechanism, associated extremity and nonextremity injuries, and use and results of color-flow duplex were recorded and analyzed. A total of 341 patients were identified who underwent color-flow duplex because of proximity penetrating trauma to the upper extremity. Injuries occurred in 370 extremities, with 253 located in the upper arm and 117 in the forearm. Overall, 18 (4.9%) injuries were identified on screening duplex ultrasound, of which 12 (3.2%) were arterial and 5 (1.4%) were venous. The therapeutic intervention rate for detected injuries to the upper arm was 1.6% (4/253), whereas no injuries of the forearm were identified that necessitated intervention. Although color-flow duplex is an inexpensive and noninvasive means of detecting injuries as a result of proximity penetrating trauma, screening upper extremity wounds is unlikely to detect clinically significant arterial injuries in need of therapeutic intervention. Venous injuries in the form of deep venous thromboses were detected in only 1.4% of patients. These findings suggest that screening for proximity penetrating trauma of the upper extremity is unlikely to detect injuries at a rate that would prove cost-effective on formal decision analysis. Copyright

  17. Comparison of therapeutic response of keloids and hypertrophic scars to cryotherapy plus intralesional steroid and bleomycin tattoo

    Directory of Open Access Journals (Sweden)

    Farahnaz Fatemi

    2005-01-01

    Full Text Available Keloids and hypertrophic scars are abnormal responses of body to skin injuries. Overproduction of compacted fibrous tissue is the basic cause of these lesions. In this study the result of treatment of these skin conditions with bleomycin tattoo are compared with cryotherapy and triamcinolone injection. This study involved 45 patients with hypertrophic scar or keloid. Patients were divided into two groups consecutively. Group A (23 patients was treated with bleomycin tattoo and the group B with cryotherapy and triamcinolone injection. There were four therapeutic sessions one month apart. All patients were followedup for three month after the end of treatment .The therapeutic response was determined as reduction of lesion size or flattening relative to initial size. Therapeutic response was 88.3±14% in group A and 67.4 ±22.5% in group B (p<0.001. In group A 69%, but in group B only 49% of patients were asymptomatic after the end of treatment. In group A there was no relation between therapeutic response and lesion size (p=0.58 but in group B lesions those were smaller (<100mm2 had better therapeutic response than larger ones (p=0.007. It was concluded that bleomycin tattoo is more effective in treatment of hypertrophic scar and keloid than traditional treatment, cryotherapy plus triamcinolone injection especially in larger ones.

  18. Effectiveness comparison of partially executed t-way test suite based generated by existing strategies

    Science.gov (United States)

    Othman, Rozmie R.; Ahmad, Mohd Zamri Zahir; Ali, Mohd Shaiful Aziz Rashid; Zakaria, Hasneeza Liza; Rahman, Md. Mostafijur

    2015-05-01

    Consuming 40 to 50 percent of software development cost, software testing is one of the most resource consuming activities in software development lifecycle. To ensure an acceptable level of quality and reliability of a typical software product, it is desirable to test every possible combination of input data under various configurations. Due to combinatorial explosion problem, considering all exhaustive testing is practically impossible. Resource constraints, costing factors as well as strict time-to-market deadlines are amongst the main factors that inhibit such consideration. Earlier work suggests that sampling strategy (i.e. based on t-way parameter interaction or called as t-way testing) can be effective to reduce number of test cases without effecting the fault detection capability. However, for a very large system, even t-way strategy will produce a large test suite that need to be executed. In the end, only part of the planned test suite can be executed in order to meet the aforementioned constraints. Here, there is a need for test engineers to measure the effectiveness of partially executed test suite in order for them to assess the risk they have to take. Motivated by the abovementioned problem, this paper presents the effectiveness comparison of partially executed t-way test suite generated by existing strategies using tuples coverage method. Here, test engineers can predict the effectiveness of the testing process if only part of the original test cases is executed.

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

    Science.gov (United States)

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

    2015-01-01

    expected by The Cochrane Collaboration. Main results We identified seven RCTs that compared therapeutic platelet transfusions to prophylactic platelet transfusions in haematology patients undergoing myelosuppressive chemotherapy or HSCT. One trial is still ongoing, leaving six trials eligible with a total of 1195 participants. These trials were conducted between 1978 and 2013 and enrolled participants from fairly comparable patient populations. We were able to critically appraise five of these studies, which contained separate data for each arm, and were unable to perform quantitative analysis on one study that did not report the numbers of participants in each treatment arm. Overall the quality of evidence per outcome was low to moderate according to the GRADE approach. None of the included studies were at low risk of bias in every domain, and all the studies identified had some threats to validity. We deemed only one study to be at low risk of bias in all domains other than blinding. Two RCTs (801 participants) reported at least one bleeding episode within 30 days of the start of the study. We were unable to perform a meta-analysis due to considerable statistical heterogeneity between studies. The statistical heterogeneity seen may relate to the different methods used in studies for the assessment and grading of bleeding. The underlying patient diagnostic and treatment categories also appeared to have some effect on bleeding risk. Individually these studies showed a similar effect, that a therapeutic-only platelet transfusion strategy was associated with an increased risk of clinically significant bleeding compared with a prophylactic platelet transfusion policy. Number of days with a clinically significant bleeding event per participant was higher in the therapeutic-only group than in the prophylactic group (one RCT; 600 participants; mean difference 0.50, 95% confidence interval (CI) 0.10 to 0.90; moderate-quality evidence). There was insufficient evidence to determine

  20. Haemophilia at various stages of life: design of new therapeutic strategies through an interactive course--the Kogeniale project.

    Science.gov (United States)

    Santagostino, Elena; Messina, Maria; Tagliaferri, Annarita; Iorio, Alfonso; Morfini, Massimo

    2013-04-01

    High-quality evidence is lacking in several areas of haemophilia treatment, in part because little time is allocated to the treatment and care of haemophilia in university education in Italy. Physicians caring for patients with haemophilia must, therefore, rely on their information on background pathophysiology and more experienced colleagues. This makes diagnostic and therapeutic choices difficult, especially when the patient has concomitant disorders or psychological issues. This article describes a course to educate young physicians who were already engaged in the management of haemophilia on the emerging and unmet issues of haemophilia care and to implement existing guidelines. Physicians (n=53) already caring for patients with haemophilia in their haematology, internal medicine, or paediatric practices in Italy attended the course. Problem-solving group activity and open discussion were the methods chosen to formulate consensus statements. During the specifically designed interactive course, three clinical cases were simulated: a young child with congenital dislocation of the hip, an adolescent refusing prophylactic treatment, and an elderly man with cardiovascular disorders. The physicians were asked questions during the course and, through a Wi-Fi console, were able to answer and discuss each case interactively. Following discussion of each case, agreement was reached regarding general statements on the management of patients with severe haemophilia A in the three different age ranges considered. This project helped to outline useful decision-making tools for handling diagnostic and treatment issues in the field of haemophilia.

  1. Comparison of competitive ligand-binding assay and bioassay formats for the measurement of neutralizing antibodies to protein therapeutics.

    Science.gov (United States)

    Finco, Deborah; Baltrukonis, Daniel; Clements-Egan, Adrienne; Delaria, Kathy; Gunn, George R; Lowe, John; Maia, Mauricio; Wong, Teresa

    2011-01-25

    Administration of biological therapeutic proteins can lead to unwanted immunogenicity in recipients of these products. The assessment and characterization of such immune reactions can be helpful to better understand their clinical relevance and how they relate to patient safety and therefore, have become an integral part of a product development program for biological therapeutics. Testing for anti-drug antibodies (ADA) to biological/biotechnology-derived therapeutic proteins generally follows a tiered approach. Samples are initially screened for binding antibodies; presumptive positives are then confirmed in a confirmatory assay; subsequently, confirmed-positive samples may be further characterized by titration and with a neutralizing antibody (NAb) assay. Regulatory guidances on immunogenicity state that assessing the neutralizing capacity of antibodies should preferably be done using functional bioassays, while recognizing that competitive ligand-binding (CLB) assays may be substituted when neutralizing bioassays are inadequate or not feasible. This manuscript describes case studies from four companies in which CLB assays and functional bioassays were compared for their ability to detect neutralizing ADA against a variety of biotechnology-derived therapeutic proteins. Our findings indicate that CLB assays are comparable to bioassays for the detection of NAbs, in some cases offering better detection sensitivity, lower variability, and less matrix interference. Copyright © 2010 Elsevier B.V. All rights reserved.

  2. The Role of the Tumor Vasculature in the Host Immune Response: Implications for Therapeutic Strategies Targeting the Tumor Microenvironment.

    Science.gov (United States)

    Hendry, Shona A; Farnsworth, Rae H; Solomon, Benjamin; Achen, Marc G; Stacker, Steven A; Fox, Stephen B

    2016-01-01

    Recently developed cancer immunotherapy approaches including immune checkpoint inhibitors and chimeric antigen receptor T cell transfer are showing promising results both in trials and in clinical practice. These approaches reflect increasing recognition of the crucial role of the tumor microenvironment in cancer development and progression. Cancer cells do not act alone, but develop a complex relationship with the environment in which they reside. The host immune response to tumors is critical to the success of immunotherapy; however, the determinants of this response are incompletely understood. The immune cell infiltrate in tumors varies widely in density, composition, and clinical significance. The tumor vasculature is a key component of the microenvironment that can influence tumor behavior and treatment response and can be targeted through the use of antiangiogenic drugs. Blood vascular and lymphatic endothelial cells have important roles in the trafficking of immune cells, controlling the microenvironment, and modulating the immune response. Improving access to the tumor through vascular alteration with antiangiogenic drugs may prove an effective combinatorial strategy with immunotherapy approaches and might be applicable to many tumor types. In this review, we briefly discuss the host's immune response to cancer and the treatment strategies utilizing this response, before focusing on the pathological features of tumor blood and lymphatic vessels and the contribution these might make to tumor immune evasion.

  3. A comparison of fuzzy logic-PID control strategies for PWR pressurizer control

    International Nuclear Information System (INIS)

    Kavaklioglu, K.; Ikonomopoulos, A.

    1993-01-01

    This paper describes the results obtained from a comparison performed between classical proportional-integral-derivative (PID) and fuzzy logic (FL) controlling the pressure in a pressurized water reactor (PWR). The two methodologies have been tested under various transient scenarios, and their performances are evaluated with respect to robustness and on-time response to external stimuli. One of the main concerns in the safe operation of PWR is the pressure control in the primary side of the system. In order to maintain the pressure in a PWR at the desired level, the pressurizer component equipped with sprayers, heaters, and safety relief valves is used. The control strategy in a Westinghouse PWR is implemented with a PID controller that initiates either the electric heaters or the sprayers, depending on the direction of the coolant pressure deviation from the setpoint

  4. Comparison of Taiwanese and Canadian Students' Metacognitive Awareness of Science Reading, Text, and Strategies

    Science.gov (United States)

    Wang, Jing-Ru; Chen, Shin-Feng; Fang, I.; Chou, Ching-Ting

    2014-03-01

    This study used a Chinese-language version of the Index of Science Reading Awareness to explore the science reading metacognition and comprehension of Taiwanese students. Structural equation modelling results confirmed the underlying model comprised three clusters of metacognitive knowledge: beliefs and confidence in science reading, knowledge of structure of science text, and knowledge of science reading strategies. The main contribution of the current research was to provide evidence about the relationship between metacognitive awareness and comprehension of science text. In addition, data comparisons to Canadian (British Columbia) benchmarks from the original development revealed that metacognitive awareness of science reading deteriorated from elementary to middle school in both countries, and there were no significant differences of metacognitive awareness of science reading between Canadian and Taiwanese students. Instructional suggestions for raising students' metacognitive awareness on science reading were discussed.

  5. The Wound Healing and Antibacterial Activity of Five Ethnomedical Calophyllum inophyllum Oils: An Alternative Therapeutic Strategy to Treat Infected Wounds

    Science.gov (United States)

    Léguillier, Teddy; Lecsö-Bornet, Marylin; Lémus, Christelle; Rousseau-Ralliard, Delphine; Lebouvier, Nicolas; Hnawia, Edouard; Nour, Mohammed; Aalbersberg, William; Ghazi, Kamelia; Raharivelomanana, Phila; Rat, Patrice

    2015-01-01

    Background Calophyllum inophyllum L. (Calophyllaceae) is an evergreen tree ethno-medically used along the seashores and islands of the Indian and Pacific Oceans, especially in Polynesia. Oil extracted from the seeds is traditionally used topically to treat a wide range of skin injuries from burn, scar and infected wounds to skin diseases such as dermatosis, urticaria and eczema. However, very few scientific studies reported and quantified the therapeutic properties of Calophyllum inophyllum oil (CIO). In this work, five CIO from Indonesia (CIO1), Tahiti (CIO2, 3), Fiji islands (CIO4) and New Caledonia (CIO5) were studied and their cytotoxic, wound healing, and antibacterial properties were presented in order to provide a scientific support to their traditional use and verify their safety. Methods The safety of the five CIO was ascertained using the Alamar blue assay on human keratinocyte cells. CIO wound healing properties were determined using the scratch test assay on human keratinocyte cells. CIO-stimulated antibacterial innate immune response was evaluated using ELISA by measuring β defensin-2 release in human derivative macrophage cells. CIO antibacterial activity was tested using oilogramme against twenty aerobic Gram- bacteria species, twenty aerobic Gram+ bacteria species, including a multi-drug resistant Staphylococcus aureus strain and two anaerobic Gram+ bacteria species e.g. Propionibacterium acnes and Propionibacterium granulosum. To detect polarity profile of the components responsible of the antibacterial activity, we performed bioautography against a Staphylococcus aureus strain. Results Based on Alamar Blue assay, we showed that CIO can be safely used on keratinocyte cells between 2.7% and 11.2% depending on CIO origin. Concerning the healing activity, all the CIO tested accelerated in vitro wound closure, the healing factor being 1.3 to 2.1 higher compared to control when keratinocytes were incubated after scratch with CIO at 0.1%. Furthermore

  6. The Wound Healing and Antibacterial Activity of Five Ethnomedical Calophyllum inophyllum Oils: An Alternative Therapeutic Strategy to Treat Infected Wounds.

    Science.gov (United States)

    Léguillier, Teddy; Lecsö-Bornet, Marylin; Lémus, Christelle; Rousseau-Ralliard, Delphine; Lebouvier, Nicolas; Hnawia, Edouard; Nour, Mohammed; Aalbersberg, William; Ghazi, Kamelia; Raharivelomanana, Phila; Rat, Patrice

    2015-01-01

    Calophyllum inophyllum L. (Calophyllaceae) is an evergreen tree ethno-medically used along the seashores and islands of the Indian and Pacific Oceans, especially in Polynesia. Oil extracted from the seeds is traditionally used topically to treat a wide range of skin injuries from burn, scar and infected wounds to skin diseases such as dermatosis, urticaria and eczema. However, very few scientific studies reported and quantified the therapeutic properties of Calophyllum inophyllum oil (CIO). In this work, five CIO from Indonesia (CIO1), Tahiti (CIO2, 3), Fiji islands (CIO4) and New Caledonia (CIO5) were studied and their cytotoxic, wound healing, and antibacterial properties were presented in order to provide a scientific support to their traditional use and verify their safety. The safety of the five CIO was ascertained using the Alamar blue assay on human keratinocyte cells. CIO wound healing properties were determined using the scratch test assay on human keratinocyte cells. CIO-stimulated antibacterial innate immune response was evaluated using ELISA by measuring β defensin-2 release in human derivative macrophage cells. CIO antibacterial activity was tested using oilogramme against twenty aerobic Gram- bacteria species, twenty aerobic Gram+ bacteria species, including a multi-drug resistant Staphylococcus aureus strain and two anaerobic Gram+ bacteria species e.g. Propionibacterium acnes and Propionibacterium granulosum. To detect polarity profile of the components responsible of the antibacterial activity, we performed bioautography against a Staphylococcus aureus strain. Based on Alamar Blue assay, we showed that CIO can be safely used on keratinocyte cells between 2.7% and 11.2% depending on CIO origin. Concerning the healing activity, all the CIO tested accelerated in vitro wound closure, the healing factor being 1.3 to 2.1 higher compared to control when keratinocytes were incubated after scratch with CIO at 0.1%. Furthermore, our results showed that CIO

  7. Regulation of sclerostin expression in multiple myeloma by Dkk-1; a potential therapeutic strategy for myeloma bone disease

    Science.gov (United States)

    Eda, Homare; Santo, Loredana; Wein, Marc N.; Hu, Dorothy Z.; Cirstea, Diana D.; Nemani, Neeharika; Tai, Yu-Tzu; Raines, Sarah E.; Kuhstoss, Stuart Allen; Munshi, Nikhil C.; Kronenberg, Henry M.; Raje, Noopur S.

    2016-01-01

    Sclerostin is a potent inhibitor of osteoblastogenesis. Interestingly, newly diagnosed multiple myeloma (MM) patients have high levels of circulating sclerostin that correlate with disease stage and fractures. However, the source and impact of sclerostin in MM remains to be defined. Our goal was to determine the role of sclerostin in the biology of MM and its bone microenvironment as well as investigate the effect of targeting sclerostin with a neutralizing antibody (scl-Ab) in MM bone disease. Here we confirm increased sclerostin levels in MM compared to precursor disease states like Monoclonal Gammopathy of Undetermined Significance (MGUS) and smoldering MM. Furthermore, we found that a humanized MM xenograft mouse model bearing human MM cells (NOD-SCID.CB17 male mice injected intravenously with 2.5 million of MM1.S-Luc-GFP cells) demonstrated significantly higher concentrations of mouse-derived sclerostin, suggesting a microenvironmental source of sclerostin. Associated with the increased sclerostin levels, activated β-catenin expression levels were lower than normal in MM mouse bone marrow. Importantly, a high affinity grade scl-Ab reversed osteolytic bone disease in this animal model. Because scl-Ab did not demonstrate significant in vitro anti-MM activity, we combined it with the proteasome inhibitor, carfilzomib. Our data demonstrated that this combination therapy significantly inhibited tumor burden and improved bone disease in our in vivo MM mouse model. In agreement with our in vivo data, sclerostin expression was noted in marrow stromal cells and osteoblasts of MM patient BM samples. Moreover, MM cells stimulated sclerostin expression in immature osteoblasts while inhibiting osteoblast differentiation in vitro. This was in part regulated by Dkk-1 secreted by MM cells and is a potential mechanism contributing to the osteoblast dysfunction noted in MM. Our data confirms the role of sclerostin as a potential therapeutic target in MM bone disease, and

  8. Phenylbutyrate counteracts Shigella mediated downregulation of cathelicidin in rabbit lung and intestinal epithelia: a potential therapeutic strategy.

    Directory of Open Access Journals (Sweden)

    Protim Sarker

    Full Text Available BACKGROUND: Cathelicidins and defensins are endogenous antimicrobial peptides (AMPs that are downregulated in the mucosal epithelia of the large intestine in shigellosis. Oral treatment of Shigella infected rabbits with sodium butyrate (NaB reduces clinical severity and counteracts the downregulation of cathelicidin (CAP-18 in the large intestinal epithelia. AIMS: To develop novel regimen for treating infectious diseases by inducing innate immunity, we selected sodium 4-phenylbutyrate (PB, a registered drug for a metabolic disorder as a potential therapeutic candidate in a rabbit model of shigellosis. Since acute respiratory infections often cause secondary complications during shigellosis, the systemic effect of PB and NaB on CAP-18 expression in respiratory epithelia was also evaluated. METHODS: The readouts were clinical outcomes, CAP-18 expression in mucosa of colon, rectum, lung and trachea (immunohistochemistry and real-time PCR and release of the CAP-18 peptide/protein in stool (Western blot. PRINCIPAL FINDINGS: Significant downregulation of CAP-18 expression in the epithelia of rectum and colon, the site of Shigella infection was confirmed. Interestingly, reduced expression of CAP-18 was also noticed in the epithelia of lung and trachea, indicating a systemic effect of the infection. This suggests a causative link to acute respiratory infections during shigellosis. Oral treatment with PB resulted in reduced clinical illness and upregulation of CAP-18 in the epithelium of rectum. Both PB and NaB counteracted the downregulation of CAP-18 in lung epithelium. The drug effect is suggested to be systemic as intravenous administration of NaB could also upregulate CAP-18 in the epithelia of lung, rectum and colon. CONCLUSION: Our results suggest that PB has treatment potential in human shigellosis. Enhancement of CAP-18 in the mucosal epithelia of the respiratory tract by PB or NaB is a novel discovery. This could mediate protection from

  9. The Use of Comprehensive Molecular Profiling with Network and Control Theory to Better Understand GWI and Model Therapeutic Strategies

    Science.gov (United States)

    2012-07-01

    Fosså o Levels of circulating interleukin-1 receptor antagonist and C-reactive protein in long-term survivors of testicular cancer with chronic...Importantly, these models serve to simulate strategies for re‐directing immune and  endocrine processes using well‐chosen sequence of  interventions .   15...computational model of illness and relapse, with the hopes to use this modeling method to propose  virtual clinical trials and  intervention  modeling that could

  10. Combined effect of therapeutic strategies for bleeding injury on early survival, transfusion needs and correction of coagulopathy

    DEFF Research Database (Denmark)

    Balvers, K.; van Dieren, S.; Baksaas-Aasen, K.

    2017-01-01

    fibrinogen on the outcome of injured patients with bleeding. Methods: A prospective multicentre observational study was performed in six level 1 trauma centres. Injured patients who received at least 4 units of red blood cells (RBCs) were analysed and divided into groups receiving a low (less than 1 : 1......Background: The combined effects of balanced transfusion ratios and use of procoagulant and antifibrinolytic therapies on trauma-induced exsanguination are not known. The aim of this study was to investigate the combined effect of transfusion ratios, tranexamic acid and products containing......) or high (1 or more : 1) ratio of plasma or platelets to RBCs, and in receipt or not of tranexamic acid or fibrinogen products (fibrinogen concentrates or cryoprecipitate). Logistic regression models were used to assess the effect of transfusion strategies on the outcomes ‘alive and free from massive...

  11. Tacrolimus concentration/dose ratio as a therapeutic drug monitoring strategy: The influence of gender and comedication

    Directory of Open Access Journals (Sweden)

    Rančić Nemanja

    2015-01-01

    Full Text Available Background/Aim. A combination of tacrolimus and other drugs such as corticosteroids has been commonly used immunosuppresive regimens. On the other hand, there is a growing body of evidence that male and female may differ in their response to the equal drug treatment. The aim of the study was to estimated the use of tacrolimus concentration/dose (C/D ratio for the assessment of the influence of gender differences and comedication on tacrolimus exposure in renal transplant recipients. Methods. This prospective case series study included 54 patients, in which the unit of monitoring was outpatient examination (1,872 of the renal transplant patients. The patients were monitored in the period 2010-2014, starting one month after the transplantation. Tacrolimus trough concentrations (TTC were measured by chemiluminescence microparticles immunoassay. Results. TTC and the tacrolimus C/D ratio were significantly lower in the females comparing with the males. Contrary to the males, in the females a significant increase of the tacrolimus daily dose (TDD per body weight and TTC, along with the corticosteroid dose increase, was not accompanied by any significant changes in the tacrolimus C/D ratio; in different corticosteroid doses faster elimination of tacrolimus was found with the exception of the doses > 0.25 mg/kg. In the patients treated with proton pump inhibitors, mainly with pantoprazole TDD per body weight and TTC were significantly higher, while the tacrolimus C/D ratio was significantly lower compared to the patients without this treatment. In the patients treated with calcium channel blockers, TDD per body weight was significantly lower (particularly with amlodipine while the tacrolimus C/D ratio was higher compared to the patients who were not treated by them. Conclusion. A lower tacrolimus exposure was detected in females in comparison to males. When gender differences were considered in the context of different corticosteroid doses, faster

  12. Therapeutic strategy for hepatocellular carcinoma with tumor thrombi in the major portal branches by using 3 dimensional-conformal radiation therapies

    International Nuclear Information System (INIS)

    Yamada, Terumasa; Sasaki, Yo; Nishiyama, Kinji; Eguchi, Hidetoshi; Ohigashi, Hiroaki; Ishikawa, Osamu; Kasugai, Hiroshi; Inoue, Atsuo; Imaoka, Shingi

    2004-01-01

    The prognosis of hepatocellular carcinoma with tumor thrombus in the major portal branches (Vp-HCC) is extremely poor. Twenty-six inoperable patients and 5 operable patients with Vp-HCC were treated with 3-dimensional conformal radiation therapy (3D-CRT). All patients except for one could receive full-dose 3D-CRT without severe side effects. Six of 21 inoperable patients could receive additional treatments and showed better prognosis than the other patients. Five patients who had received curative hepatectomy after 3D-CRT, showed better prognosis than the patients with Vp-HCC who received hepatectomies without 3D-CRT. These results indicated the usefulness of 3D-CRT as a new therapeutic strategy for Vp-HCCs. (author)

  13. Identification of new tumor associated antigens and their usage for new therapeutic strategies based on the combination of chemotherapy and immunotherapy for colorectal cancer patients

    International Nuclear Information System (INIS)

    Proietti, E.; Maccalli, C.; Rosenberg, S.A.; Robbins, P.F.

    2009-01-01

    The main general objective of this project was to characterize a new colorectal carcinoma (CRC) tumor-associated antigen (TAA) and validate a new therapeutic strategy combining chemotherapy and tumor vaccination for the treatment of cancer patients. To this purpose a strategic interaction between Drs. Proietti/Maccali at the ISS and the group of Drs. Rosenberg/Robbins at the NIH was established. A stage of Dr. Maccalli at the NIH allowed to carry out the first steps for the identification and the initial characterization of the CRC TAA named COA-1. A laboratory meeting with Dr. Robbins has been planned on May 24-25 2006 at the ISS, during the International Meeting on Immunotherapy of Cancer: Challenges and Needs, for discussing results and perspectives of this research project

  14. Regulation of Sclerostin Expression in Multiple Myeloma by Dkk-1: A Potential Therapeutic Strategy for Myeloma Bone Disease.

    Science.gov (United States)

    Eda, Homare; Santo, Loredana; Wein, Marc N; Hu, Dorothy Z; Cirstea, Diana D; Nemani, Neeharika; Tai, Yu-Tzu; Raines, Sarah E; Kuhstoss, Stuart Allen; Munshi, Nikhil C; Kronenberg, Henry M; Raje, Noopur S

    2016-06-01

    Sclerostin is a potent inhibitor of osteoblastogenesis. Interestingly, newly diagnosed multiple myeloma (MM) patients have high levels of circulating sclerostin that correlate with disease stage and fractures. However, the source and impact of sclerostin in MM remains to be defined. Our goal was to determine the role of sclerostin in the biology of MM and its bone microenvironment as well as investigate the effect of targeting sclerostin with a neutralizing antibody (scl-Ab) in MM bone disease. Here we confirm increased sclerostin levels in MM compared with precursor disease states like monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM. Furthermore, we found that a humanized MM xenograft mouse model bearing human MM cells (NOD-SCID.CB17 male mice injected intravenously with 2.5 million of MM1.S-Luc-GFP cells) demonstrated significantly higher concentrations of mouse-derived sclerostin, suggesting a microenvironmental source of sclerostin. Associated with the increased sclerostin levels, activated β-catenin expression levels were lower than normal in MM mouse bone marrow. Importantly, a high-affinity grade scl-Ab reversed osteolytic bone disease in this animal model. Because scl-Ab did not demonstrate significant in vitro anti-MM activity, we combined it with the proteasome inhibitor carfilzomib. Our data demonstrated that this combination therapy significantly inhibited tumor burden and improved bone disease in our in vivo MM mouse model. In agreement with our in vivo data, sclerostin expression was noted in marrow stromal cells and osteoblasts of MM patient bone marrow samples. Moreover, MM cells stimulated sclerostin expression in immature osteoblasts while inhibiting osteoblast differentiation in vitro. This was in part regulated by Dkk-1 secreted by MM cells and is a potential mechanism contributing to the osteoblast dysfunction noted in MM. Our data confirm the role of sclerostin as a potential therapeutic target in MM bone disease

  15. A Comparison of the Thompson Encephalopathy Score and Amplitude-Integrated Electroencephalography in Infants with Perinatal Asphyxia and Therapeutic Hypothermia.

    Science.gov (United States)

    Weeke, Lauren C; Vilan, Ana; Toet, Mona C; van Haastert, Ingrid C; de Vries, Linda S; Groenendaal, Floris

    2017-01-01

    In previous studies clinical signs or amplitude-integrated electroencephalography (aEEG)-based signs of encephalopathy were used to select infants with perinatal asphyxia for treatment with hypothermia. The objective of this study was to compare Thompson encephalopathy scores and aEEG, and relate both to outcome. Thompson scores, aEEG, and outcome were compared in 122 infants with perinatal asphyxia and therapeutic hypothermia. Of these 122 infants, 41 died and 7 had an adverse neurodevelopmental outcome. A receiver operating characteristics (ROC) analysis was also performed. Thompson scores were higher in infants with more abnormal aEEG background patterns (ANOVA, p Thompson score of 11 or higher or an aEEG background pattern of continuous low voltage or worse was associated with an adverse outcome (AUC 0.84 for both). High Thompson scores and a suppressed aEEG background pattern are associated with an adverse outcome after perinatal asphyxia and therapeutic hypothermia. Further studies are needed to identify the best technique with which to select patients for therapeutic hypothermia. © 2017 The Author(s) Published by S. Karger AG, Basel.

  16. Therapeutic collaboration and the assimilation of problematic experiences in emotion-focused therapy for depression: Comparison of two cases.

    Science.gov (United States)

    Ribeiro, Eugénia; Cunha, Carla; Teixeira, Ana Sofia; Stiles, William B; Pires, Nuno; Santos, Beatriz; Basto, Isabel; Salgado, João

    2016-11-01

    The Assimilation model argues that therapists should work responsively within the client's therapeutic zone of proximal development (TZPD). This study analyzed the association between the collaborative processes assessed by the Therapeutic Collaboration Coding System (TCCS) and advances in assimilation, as assessed by the Assimilation of Problematic Experiences Scale (APES). Sessions 1, 4, 8, 12, and 16 of two contrasting cases, Julia and Afonso (pseudonyms), drawn from a clinical trial of 16-sessions emotion-focused therapy (EFT) for depression, were coded according to the APES and the TCCS. Julia met criteria for reliable and clinically significant improvement, whereas Afonso did not. As expected, Julia advanced farther along the APES than did Afonso. Both therapists worked mainly within their client's TZPD. However, Julia's therapist used a balance of supporting and challenging interventions, whereas Afonso's therapist used mainly supporting interventions. Setbacks were common in both cases. This study supports the theoretical expectation that EFT therapists work mainly within their client's TZPD. Therapeutic exchanges involving challenging interventions may foster client change if they occur in an overall climate of safety.

  17. Comparison between double-balloon and single-balloon enteroscopy in therapeutic ERC after Roux-en-Y entero-enteric anastomosis.

    Science.gov (United States)

    Moreels, Tom G; Pelckmans, Paul A

    2010-09-16

    To compare the efficacy of double-balloon enteroscopy (DBE) and single-balloon enteroscopy (SBE) in therapeutic endoscopic retrograde cholangiography (ERC) in patients with Roux-en-Y entero-enteric anastomosis. Retrospective analysis of our patient cohort revealed 4 patients with enterobiliary anastomosis and Roux-en-Y entero-enteric anastomosis who underwent repeated ERC with DBE and SBE because of recurrent cholangitis. A total of 38 endoscopic retrograde cholangiopancreatography procedures were performed in 25 patients with Roux-en-Y entero-enteric anastomosis. DBE was used in 29 procedures and SBE in 9. The 4 patients who underwent repeated ERC with DBE and SBE suffered from recurrent cholangitis due to stenosis of the enterobiliary anastomosis. ERC was performed repeatedly to achieve balloon dilation with/without biliary stone extraction and multiple stent placement at the level of the enterobiliary anastomosis. In all 4 patients DBE and SBE were equally successful. Compared to DBE, SBE was equally effective in passing the Roux-en-Y entero-enteric anastomosis, reaching the enterobiliary anastomosis and performing therapeutic ERC. This retrospective comparison shows that DBE and SBE are equally successful in the performance of therapeutic ERC at the level of the enterobiliary anastomosis after Roux-en-Y entero-enteric anastomosis.

  18. Comparison of Quality of Life and Coping Strategies in Diabetic and Non Diabetic People

    Directory of Open Access Journals (Sweden)

    J Babapour Kheirodin

    2013-01-01

    Full Text Available Introduction: Diabetic patients face with different physical and psychological challenging factors which impress their quality of life. The major problem of these patients, which has made their life circumstances more complicated, is coping and adapting styles with the illness. So, this study aimed to determine quality of life and also different kinds of coping strategies in patients with type 2 diabetes and also to compare it with those of healthy people. Methods: In this study, sixty diabetic patients (30 male, 30 female, were chosen by available sampling method from the people who referred to Sina Diabetes center in Tabriz and were compared with sixty non diabetic people (30 male, 30 female. Data were collected by two questionnaires including the short form health survey (SF-36 and coping style Inventories. MANOVA method was used to analyze the research data. Results: The study results showed that non diabetics were significantly higher than diabetic patients in regard to quality of life and its dimensions (p<0.001. Also results revealed that non diabetic people used the problem–oriented styles (p<0.001, however diabetic patients used emotional-oriented coping and avoidance strategies more (p<0.05. In this study (in both groups, females in comparison with males had lower score in quality of life and used more emotion-oriented coping styles and less problem-oriented styles. Conclusion: The results indicated that individuals’ quality of life was affected by their coping style with different affairs. Emotional-oriented coping and avoidance strategies were related with decrease of quality of life in diabetic patients whereas problem-oriented styles enhanced it. Therefore, it is necessary to perform interventions for teaching problem solving coping in order to improve these patients' quality of life.

  19. Targeting Sentinel Proteins and Extrasynaptic Glutamate Receptors: a Therapeutic Strategy for Preventing the Effects Elicited by Perinatal Asphyxia?

    Science.gov (United States)

    Herrera-Marschitz, Mario; Perez-Lobos, Ronald; Lespay-Rebolledo, Carolyne; Tapia-Bustos, Andrea; Casanova-Ortiz, Emmanuel; Morales, Paola; Valdes, Jose-Luis; Bustamante, Diego; Cassels, Bruce K

    2018-02-01

    Perinatal asphyxia (PA) is a relevant cause of death at the time of labour, and when survival is stabilised, associated with short- and long-term developmental disabilities, requiring inordinate care by health systems and families. Its prevalence is high (1 to 10/1000 live births) worldwide. At present, there are few therapeutic options, apart from hypothermia, that regrettably provides only limited protection if applied shortly after the insult.PA implies a primary and a secondary insult. The primary insult relates to the lack of oxygen, and the secondary one to the oxidative stress triggered by re-oxygenation, formation of reactive oxygen (ROS) and reactive nitrogen (RNS) species, and overactivation of glutamate receptors and mitochondrial deficiencies. PA induces overactivation of a number of sentinel proteins, including hypoxia-induced factor-1α (HIF-1α) and the genome-protecting poly(ADP-ribose) polymerase-1 (PARP-1). Upon activation, PARP-1 consumes high amounts of ATP at a time when this metabolite is scarce, worsening in turn the energy crisis elicited by asphyxia. The energy crisis also impairs ATP-dependent transport, including glutamate re-uptake by astroglia. Nicotinamide, a PARP-1 inhibitor, protects against the metabolic cascade elicited by the primary stage, avoiding NAD + exhaustion and the energetic crisis. Upon re-oxygenation, however, oxidative stress leads to nuclear translocation of the NF-κB subunit p65, overexpression of the pro-inflammatory cytokines IL-1β and TNF-α, and glutamate-excitotoxicity, due to impairment of glial-glutamate transport, extracellular glutamate overflow, and overactivation of NMDA receptors, mainly of the extrasynaptic type. This leads to calcium influx, mitochondrial impairment, and inactivation of antioxidant enzymes, increasing further the activity of pro-oxidant enzymes, thereby making the surviving neonate vulnerable to recurrent metabolic insults whenever oxidative stress is involved. Here, we discuss

  20. Therapeutic strategies for adenoid cystic carcinoma of the nasal and paranasal sinus from the long-term treatment results

    International Nuclear Information System (INIS)

    Terada, Nobuhisa; Numata, Tsutomu; Mutoh, Hiroyuki; Ueki, Yuji; Gorai, Shigeki; Konno, Akiyoshi

    2001-01-01

    This article presents long-term treatment results by analyzing 24 cases with adenoid cystic carcinoma (ACC) of the nasal and paranasal sinus treated from 1975 to 1995 at Akita University Hospital and Chiba University Hospital. The basic strategies for treatment for ACC of the nasal and paranasal sinuses are en bloc tumor resection, followed by primary reconstruction of the maxilla. Preoperative and postoperative radiation were combined. Cumulative 5-year and 10-year survival rates were 70.6% and 47.1% for maxillary sinus tumors, respectively. Cumulative 5-year and 10-year survival rates for nasal tumors were 100% and 75.0%, and those for sphenoid sinus tumors were 50.0% and 0%, respectively. The patient with ethomoid sinus who needed skull base surgery is alive at 8.1 years after therapy. Treatment results closely correlated with tumor extension. Cumulative 5-year survival rates for T2, T3 and, T4 patients with maxillary sinus tumors were 85.7%, 71.4%, and 33.3%, respectively. And cumulative 10-year survival rates for T2, T3, and T4 were 71.4%, 42.9%, and 0%, respectively. The histopathological effects of preoperative radiation were Shimosato II a in 6 out of 10 patients, II b in 2, and III in 2, respectively. Only fast neutron therapy reached Shimosato III. Two of the patients with Shimosato II a died of distant metastasis. The above data suggests that, although radiation therapy alone cannot cure tumors, preoperative full-dose radiation may prevent the development of distant metastasis if it can achieve histopathological effects of a higher classification than Shimosato II b. Because chemotherapy and radiation is not very effective on ACC, the role of skull base surgeries for nasal-paranasal sinus malignancies that invade the skull base is valuable, particularly in cases having a relatively small mass in the ethmoid sinus. (author)

  1. Adverse events and therapeutic efficacy associated with TACE for hepatocellular carcinoma with a miriplatin-lipiodol suspension in comparison with a cisplatin-lipiodol suspension

    International Nuclear Information System (INIS)

    Araki, Takuji; Okada, Taiki; Kimura, Kazufumi; Sawada, Eiichi; Sano, Katushiro; Araki, Tsutomu

    2012-01-01

    The aim of this study was to evaluate the short-term adverse events and therapeutic efficacy of transcatheter arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) with a miriplatin-lipiodol suspension in comparison with a cisplatin-lipiodol suspension. Of patients who underwent TACE for unresectable HCCs in 2009 and 2010, twenty-nine and twenty-seven patients underwent TACE using cisplatin-lipiodol suspension (C-LS) and miriplatin-lipiodol suspension (M-LS), respectively. Adverse events of fever, pain, nausea, anorexia, elevation of aspartate aminotransferase (AST), total bilirubin, creatinine and a decrease in platelet count were evaluated by the National Cancer Institute Common Toxicity Criteria Ver.4. to compare the C-LS and M-LS groups. The short-term therapeutic efficacy of both groups was evaluated by the treatment effect (TE) on the CT images three months after TACE according to the General Rules for the Clinical and Pathological Study of Primary Liver Cancer (the 5th edition, Revised Version). With regard to the adverse events, the M-LS group had significantly less fever and anorexia than the C-LS group. No critical adverse events were observed in either group. The therapeutic efficacy was not significantly different between the groups. TACE with M-LS had fewer adverse events than TACE with C-LS, but neither TACE led to any critical adverse events. The short-term therapeutic efficacy of TACE with M-LS was equivalent to that of TACE with C-LS. (author)

  2. Blocking Aβ seeding-mediated aggregation and toxicity in an animal model of Alzheimer's Disease: A novel therapeutic strategy for neurodegeneration

    Science.gov (United States)

    Eleuteri, Simona; Di Giovanni, Saviana; Rockenstein, Edward; Mante, Mike; Adame, Antony; Trejo, Margarita; Wrasidlo, Wolf; Wu, Fang; Fraering, Patrick C.; Masliah, Eliezer; Lashuel, Hilal A.

    2014-01-01

    Aβ accumulation plays a central role in the pathogenesis of Alzheimer's disease (AD). Recent studies suggest that process of Aβ nucleated polymerization is essential for Aβ fibril formation, pathology spreading and toxicity. Therefore, targeting this process represent an effective therapeutic strategy to slow or block disease progression. To discover compounds that might interfere with the Aβ seeding capacity, toxicity and pathology spreading, we screened a focused library of FDA-approved drugs in vitro using a seeding polymerization assay and identified small molecule inhibitors that specifically interfered with Aβ seeding-mediated fibril growth and toxicity. Mitoxantrone, bithionol and hexachlorophene were found to be the strongest inhibitors of fibril growth and protected primary cortical neuronal cultures against Aβ-induced toxicity. Next, we assessed the effects of these three inhibitors in vivo in the mThy1-APPtg mouse model of AD (8-month-old mice). We found that mitoxantrone and bithionol, but not hexachlorophene, stabilized diffuse amyloid plaques, reduced the levels of Aβ42 oligomers and ameliorated synapse loss, neuronal damage and astrogliosis. Together, our findings suggest that targeting fibril growth and Aβ seeding capacity constitutes a viable and effective strategy for protecting against neurodegeneration and disease progression in AD. PMID:25173807

  3. 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.

  4. Operation and maintenance of waste incinerators - A comparison of two techniques and strategies; Drift och underhaall av avfallsfoerbraenningsanlaeggningar - En jaemfoerelse av tvaa tekniker och strategier

    Energy Technology Data Exchange (ETDEWEB)

    Johansson, Andreas [SP Technical Research Inst. of Sweden, Boraas (Sweden); Hoegskolan i Boraas, Boraas (Sweden); Niklasson, Fredrik [SP Technical Research Inst. of Sweden, Boraas (Sweden); Johnsson, Anders [Boraas Energi och Miljoe, Boraas (Sweden); Fredaeng, Julia [Dalkia, Stockholm (Sweden); Wettergren, Hans [Renova AB, Goeteborg (Sweden)

    2009-06-15

    This work has developed and demonstrated a simple method for comparison of operation and maintenance cost for various waste combustion techniques and plants. The principal of the method is to coarsely and initially divide cost into comparable posts. Post of specific interest is thereafter compared on a more detailed level. This procedure allows comparison with a modest consumption of time and effort. There is a lack of such comparison because of the effort needed to in detail compare the, often for each plant unique, selection of techniques and strategies. A consequence of the lack of comparisons is that success stories become invisible. The same can be said about common research needs. The demonstrated method visualizes the effects of various selections of techniques and strategies. It also points out bottlenecks for further improvement of the investigated units. The method has been simple to use and it is therefore considered as suitable to use in a larger investigation covering several waste combustion units. Thus, the project has accomplished its aims.

  5. Response prediction to neoadjuvant chemotherapy: comparison between pre-therapeutic gene expression profiles and in vitro chemosensitivity assay.

    Directory of Open Access Journals (Sweden)

    Christian F Singer

    Full Text Available Although the use of (neo-adjuvant chemotherapy in breast cancer patients has resulted in improved outcome, not all patients benefit equally. We have evaluated the utility of an in vitro chemosensitivity assay in predicting response to neoadjuvant chemotherapy. Pre-therapeutic biopsies were obtained from 30 breast cancer patients assigned to neoadjuvant epirubicin 75 mg/m2 and docetaxel 75 mg/m2 (Epi/Doc in a prospectively randomized clinical trial. Biopsies were subjected to a standardized ATP-based Epi/Doc chemosensitivity assay, and to gene expression profiling. Patients then received 3 cycles of chemotherapy, and response was evaluated by changes in tumor diameter and Ki67 expression. The efficacy of Epi/Doc in vitro was correlated with differential changes in tumor cell proliferation in response to Epi/Doc in vivo (p = 0.0011; r = 0.73670, Spearmańs rho, but did not predict for changes in tumor size. While a pre-therapeutic gene expression signature identified tumors with a clinical response to Epi/Doc, no such signature could be found for tumors that responded to Epi/Doc in vitro, or tumors in which Epi/Doc exerted an antiproliferative effect in vivo. This is the first prospective clinical trial to demonstrate the utility of a standardized in vitro chemosensitivity assay in predicting the individual biological response to chemotherapy in breast cancer.

  6. A comparison of the effects of deep tissue massage and therapeutic massage on chronic low back pain.

    Science.gov (United States)

    Romanowski, Mateusz; Romanowska, Joanna; Grześkowiak, Marcin

    2012-01-01

    This study compared the effectiveness of two different kind of massage: therapeutic and deep tissue on chronic low back pain. The research was made on 26 patient aged from 60 to 75 years who were separated into 2 groups: I [n=13] and II [n=13]. Group I had therapeutic massage [TM] which uses effleurage, petrissage, tapping and friction. Group II had deep tissue massage [DTM] which uses oblique pressure, a combination of lengthening and cross-fiber strokes, anchor and stretch, freeing muscle from entrapment. TM and DTM lasted for 10 days, each 30 min and were made by qualify massage therapist. Both groups did not have other treatment. Outcome measures obtained at baseline and after treatment consisted of Modified Oswestry Low Back Pain Disability Index [ODI], Quebec Back Pain Disability Scale[QBPD] and Visual Analog Scale [VAS]. There was not statistically significant differences between groups according to age and BMI. Statistically significant differences were noted after TM in every test [ODI p=0.010; QBPD p<0.001; VAS p<0.001] and after DTM in every test [ODI p<0.001; QBPD p<0.001; VAS p<0.001]. DTM was statistically significant better therapy than TM in ODI [p=0.038] and VAS [p=0.015]. Further research is needed to verify the results.

  7. Comparison of Electromyographic Activity of the Superior and Inferior Portions of the Gluteus Maximus Muscle During Common Therapeutic Exercises.

    Science.gov (United States)

    Selkowitz, David M; Beneck, George J; Powers, Christopher M

    2016-09-01

    Study Design Controlled laboratory study, repeated-measures design. Background Previous studies have reported that the superior and inferior portions of the gluteus maximus have different functional roles. Knowledge of how the different portions of the gluteus maximus are activated during therapeutic exercise may lead to more specific exercise prescription. Objective To compare muscle activation of the superior and inferior portions of the gluteus maximus during commonly used therapeutic exercises. Methods Twenty healthy persons participated. Electromyographic (EMG) signals were obtained from the superior and inferior portions of the gluteus maximus using fine-wire electrodes. Normalized EMG signal amplitudes were compared between the superior and inferior gluteus maximus across 11 exercises using a 2-way repeated-measures analysis of variance. Results The superior portion of the gluteus maximus had significantly greater relative EMG activity than the inferior portion of the gluteus maximus during exercises that incorporated elements of hip abduction and/or external rotation (5 of 11 exercises evaluated). There was no significant difference in activation between the superior and inferior portions of the gluteus maximus during the remaining 6 exercises. Conclusion The results of the present study demonstrate preferential activation of the superior portion of the gluteus maximus during exercises that incorporate elements of hip abduction and/or external rotation. In contrast, exercises that primarily involve hip extension target both portions of the gluteus maximus to a similar extent. J Orthop Sports Phys Ther 2016;46(9):794-799. Epub 5 Aug 2016. doi:10.2519/jospt.2016.6493.

  8. DNA familial binding profiles made easy: comparison of various motif alignment and clustering strategies.

    Science.gov (United States)

    Mahony, Shaun; Auron, Philip E; Benos, Panayiotis V

    2007-03-30

    Transcription factor (TF) proteins recognize a small number of DNA sequences with high specificity and control the expression of neighbouring genes. The evolution of TF binding preference has been the subject of a number of recent studies, in which generalized binding profiles have been introduced and used to improve the prediction of new target sites. Generalized profiles are generated by aligning and merging the individual profiles of related TFs. However, the distance metrics and alignment algorithms used to compare the binding profiles have not yet been fully explored or optimized. As a result, binding profiles depend on TF structural information and sometimes may ignore important distinctions between subfamilies. Prediction of the identity or the structural class of a protein that binds to a given DNA pattern will enhance the analysis of microarray and ChIP-chip data where frequently multiple putative targets of usually unknown TFs are predicted. Various comparison metrics and alignment algorithms are evaluated (a total of 105 combinations). We find that local alignments are generally better than global alignments at detecting eukaryotic DNA motif similarities, especially when combined with the sum of squared distances or Pearson's correlation coefficient comparison metrics. In addition, multiple-alignment strategies for binding profiles and tree-building methods are tested for their efficiency in constructing generalized binding models. A new method for automatic determination of the optimal number of clusters is developed and applied in the construction of a new set of familial binding profiles which improves upon TF classification accuracy. A software tool, STAMP, is developed to host all tested methods and make them publicly available. This work provides a high quality reference set of familial binding profiles and the first comprehensive platform for analysis of DNA profiles. Detecting similarities between DNA motifs is a key step in the comparative study

  9. DNA familial binding profiles made easy: comparison of various motif alignment and clustering strategies.

    Directory of Open Access Journals (Sweden)

    Shaun Mahony

    2007-03-01

    Full Text Available Transcription factor (TF proteins recognize a small number of DNA sequences with high specificity and control the expression of neighbouring genes. The evolution of TF binding preference has been the subject of a number of recent studies, in which generalized binding profiles have been introduced and used to improve the prediction of new target sites. Generalized profiles are generated by aligning and merging the individual profiles of related TFs. However, the distance metrics and alignment algorithms used to compare the binding profiles have not yet been fully explored or optimized. As a result, binding profiles depend on TF structural information and sometimes may ignore important distinctions between subfamilies. Prediction of the identity or the structural class of a protein that binds to a given DNA pattern will enhance the analysis of microarray and ChIP-chip data where frequently multiple putative targets of usually unknown TFs are predicted. Various comparison metrics and alignment algorithms are evaluated (a total of 105 combinations. We find that local alignments are generally better than global alignments at detecting eukaryotic DNA motif similarities, especially when combined with the sum of squared distances or Pearson's correlation coefficient comparison metrics. In addition, multiple-alignment strategies for binding profiles and tree-building methods are tested for their efficiency in constructing generalized binding models. A new method for automatic determination of the optimal number of clusters is developed and applied in the construction of a new set of familial binding profiles which improves upon TF classification accuracy. A software tool, STAMP, is developed to host all tested methods and make them publicly available. This work provides a high quality reference set of familial binding profiles and the first comprehensive platform for analysis of DNA profiles. Detecting similarities between DNA motifs is a key step in the

  10. REFLECTIONS ON BLUE OCEAN STRATEGY: A COMPARISON WITH ANSOFF’S, PORTER’S, AND HAX AND WILDE’S STRATEGIES

    Directory of Open Access Journals (Sweden)

    Ailton Conde Jussani

    2010-11-01

    Full Text Available Within the context of the globalized environment, competitiveness has become a critical issue for business. The use of research to inform strategic decisions is thus important for firms on the path to competitiveness, regardless of their market of operation. This paper provides an overview of four strategies—Kim and Mauborgne’s Blue Ocean Strategy, Ansoff’s Matrix, Porter’s Generic Strategies, and Hax and Wilde’s Delta model—in order to find the similarities and approximations among them. Applying the scientific reading method, we conducted a comprehensive review of the literature on strategy to draw up a comparative matrix among the four strategies analyzed so as to discuss the typologies for strategy formation modes. This matrix is intended to be used in future field studies. The comparison led to the observation that several possible approaches exist, each suited for distinctive businesses and business environments. This article aims to contribute to a better knowledge of administrative techniques that can help firms - and their executives - improve strategic decision making by choosing the strategy that best fits the competitive environment in which their business operates. Key-words: Strategic decisions. Strategic approaches. Comparative matrix. 

  11. Comparison of minimalist footwear strategies for simulating barefoot running: a randomized crossover study.

    Directory of Open Access Journals (Sweden)

    Karsten Hollander

    Full Text Available Possible benefits of barefoot running have been widely discussed in recent years. Uncertainty exists about which footwear strategy adequately simulates barefoot running kinematics. The objective of this study was to investigate the effects of athletic footwear with different minimalist strategies on running kinematics. Thirty-five distance runners (22 males, 13 females, 27.9 ± 6.2 years, 179.2 ± 8.4 cm, 73.4 ± 12.1 kg, 24.9 ± 10.9 km x week(-1 performed a treadmill protocol at three running velocities (2.22, 2.78 and 3.33 m x s(-1 using four footwear conditions: barefoot, uncushioned minimalist shoes, cushioned minimalist shoes, and standard running shoes. 3D kinematic analysis was performed to determine ankle and knee angles at initial foot-ground contact, rate of rear-foot strikes, stride frequency and step length. Ankle angle at foot strike, step length and stride frequency were significantly influenced by footwear conditions (p<0.001 at all running velocities. Posthoc pairwise comparisons showed significant differences (p<0.001 between running barefoot and all shod situations as well as between the uncushioned minimalistic shoe and both cushioned shoe conditions. The rate of rear-foot strikes was lowest during barefoot running (58.6% at 3.33 m x s(-1, followed by running with uncushioned minimalist shoes (62.9%, cushioned minimalist (88.6% and standard shoes (94.3%. Aside from showing the influence of shod conditions on running kinematics, this study helps to elucidate differences between footwear marked as minimalist shoes and their ability to mimic barefoot running adequately. These findings have implications on the use of footwear applied in future research debating the topic of barefoot or minimalist shoe running.

  12. Adeno-associated virus-mediated neuroglobin overexpression ameliorates the N-methyl-N-nitrosourea-induced retinal impairments: a novel therapeutic strategy against photoreceptor degeneration

    Directory of Open Access Journals (Sweden)

    Tao Y

    2017-10-01

    Full Text Available Ye Tao,1,* Zhen Yang,2,* Wei Fang,2 Zhao Ma,3 Yi Fei Huang,1 Zhengwei Li4 1Department of Ophthalmology, Key Lab of Ophthalmology and Visual Science, Chinese PLA General Hospital, Beijing, 2Department of Neurosurgery, Institute for Functional Brain Disorders, Tangdu Hospital, Fourth Military Medical University, Xi’an, 3Department of Neurosurgery, Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, 4Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, People’s Republic of China *These authors contributed equally to this work Abstract: Retinal degeneration (RD is a heterogeneous group of inherited dystrophies leading to blindness. The N-methyl-N-nitrosourea (MNU-administered mouse is used as a pharmacologically induced RD animal model in various therapeutic investigations. The present study found the retinal neuroglobin (NGB expression in the MNU-administered mice was significantly lower than in normal controls, suggesting NGB was correlated with RD. Subsequently, an adeno-associated virus (AAV-2-mCMV-NGB vector was delivered into the subretinal space of the MNU-administered mice. The retinal NGB expression of the treated eye was upregulated significantly in both protein and mRNA levels. Further, we found NGB overexpression could alleviate visual impairments and morphological devastations in MNU-administered mice. NGB overexpression could rectify apoptotic abnormalities and ameliorate oxidative stress in MNU-administered mice, thereby promoting photoreceptor survival. The cone photoreceptors in MNU-administered mice were also sensitive to AAV-mediated NGB overexpression. Taken together, our findings suggest that manipulating NGB bioactivity via gene therapy may represent a novel therapeutic strategy against RD. Future elucidation of the exact role of NGB would advance our knowledge about the pathological mechanisms underlying RD. Keywords: neuroglobin, retinal degeneration

  13. The accuracy of PiCCO® in measuring cardiac output in patients under therapeutic hypothermia: Comparison with transthoracic echocardiography.

    Science.gov (United States)

    Souto Moura, T; Aguiar Rosa, S; Germano, N; Cavaco, R; Sequeira, T; Alves, M; Papoila, A L; Bento, L

    2018-03-01

    Invasive cardiac monitoring using thermodilution methods such as PiCCO® is widely used in critically ill patients and provides a wide range of hemodynamic variables, including cardiac output (CO). However, in post-cardiac arrest patients subjected to therapeutic hypothermia, the low body temperature possibly could interfere with the technique. Transthoracic Doppler echocardiography (ECHO) has long proved its accuracy in estimating CO, and is not influenced by temperature changes. To assess the accuracy of PiCCO® in measuring CO in patients under therapeutic hypothermia, compared with ECHO. Thirty paired COECHO/COPiCCO measurements were analyzed in 15 patients subjected to hypothermia after cardiac arrest. Eighteen paired measurements were obtained at under 36°C and 12 at ≥36°C. A value of 0.5l/min was considered the maximum accepted difference between the COECHO and COPiCCO values. Under conditions of normothermia (≥36°C), the mean difference between COECHO and COPiCCO was 0.030 l/min, with limits of agreement (-0.22, 0.28) - all of the measurements differing by less than 0.5 l/min. In situations of hypothermia (<36°C), the mean difference in CO measurements was -0.426 l/min, with limits of agreement (-1.60, 0.75), and only 44% (8/18) of the paired measurements fell within the interval (-0.5, 0.5). The calculated temperature cut-off point maximizing specificity was 35.95°C: above this temperature, specificity was 100%, with a false-positive rate of 0%. The results clearly show clinically relevant discordance between COECHO and COPiCCO at temperatures of <36°C, demonstrating the inaccuracy of PiCCO® for cardiac output measurements in hypothermic patients. Copyright © 2017 Elsevier España, S.L.U. y SEMNIM. All rights reserved.

  14. A comparison of Reactivity Controlled Compression Ignition (RCCI) and Gasoline Compression Ignition (GCI) strategies at high load, low speed conditions

    International Nuclear Information System (INIS)

    Kavuri, Chaitanya; Paz, Jordan; Kokjohn, Sage L.

    2016-01-01

    Highlights: • Targeting high load-low speed, optimizations of RCCI and GCI strategies were performed. • The two strategies were compared in terms of performance, controllability and stability. • The optimum cases had high gross indicated efficiency (∼47%) and low NOx emissions. • RCCI strategy showed better combustion control but had higher soot emissions. • GCI strategy was relatively more sensitive to fluctuations in charge conditions. - Abstract: Past research has shown that Reactivity Controlled Compression Ignition (RCCI) and Gasoline Compression Ignition (GCI) combustion are promising approaches to improve efficiency and reduce pollutant emissions. However, the benefits have generally been confined to mid-load operating conditions. To enable practical application, these approaches must be able to operate over the entire engine map. A particularly challenging area is high load, low speed operation. Accordingly, the present work uses detailed CFD modeling and engine experiments to compare RCCI and GCI combustion strategies at a high load, low speed condition. Computational optimizations of RCCI and GCI combustion were performed at 20 bar gross indicated mean effective pressure (IMEP) and 1300 rev/min. The optimum points from the two combustion strategies were verified using engine experiments and were used to make the comparisons between RCCI and GCI combustion. The comparison showed that both the strategies had very similar combustion characteristics with a near top dead center injection initiating combustion. A parametric study was performed to identify the key input parameters that control combustion for the RCCI and GCI strategies. For both strategies, the combustion phasing could be controlled by the start of injection (SOI) timing of the near TDC injection. The short ignition delay of diesel fuel gave the RCCI strategy better control over combustion than the GCI strategy, but also had a simultaneous tradeoff with soot emissions. With the GCI

  15. Press Communication Strategies in Twitter. A Comparison between Spain and Portugal

    Directory of Open Access Journals (Sweden)

    Belén Puebla Martínez

    2015-05-01

    Full Text Available The development of the Web 2.0 has caused the appearance of several Social Media, whose dynamics leads to a continuous exchange of content by users. The consolidation of the current communication model, characterized by the horizontality, bidirectionality, and decentralization, is one of the most prominent effcts of the interactivity in the process of building the information scene. Thereby, traditional media must face the challenges involved in adapting the traditional journalism to the audience participation in content production and new ways of broadcasting. This study proposes an analysis of the communication strategies used by cybermedia on Twitter microblogging, emphasizing the adequacy of journalistic messages to the typical narrative of this digital environment. In order to make a comparison between Spain and Portugal, we have analyzed the profiles of the newspapers with the largest circulation in their countries of origin: El País (Spain and Jornal de Notícias Portugal. The study reveals both the underutilization of Twitter’s conversational potential by both newspapers and the imminent need to set out style rules about the use of resources such as mentions or hashtags.

  16. Randomized Comparison of the Therapeutic Effect of Acupuncture, Massage, and Tachibana-Style-Method on Stiff Shoulders by Measuring Muscle Firmness, VAS, Pulse, and Blood Pressure

    Directory of Open Access Journals (Sweden)

    Kazuhiro Tachibana

    2012-01-01

    Full Text Available To compare the therapeutic efficacy of acupuncture, massage, and Tachibana-Ryojutsu (one of Japanese traditional body balance therapy techniques (SEITAI, on stiff shoulders, the subjects’ muscle firmness, blood pressure, pulse, VAS, and body temperature were measured before and after the treatment. Forty-seven volunteer subjects gave written informed consent to participate in this study. The subjects were randomly divided into three groups to receive acupuncture, massage, or Tachibana-Ryojutsu. Each therapy lasted for 90 seconds. The acupuncture treatment was applied by a retaining-needle at GB-21, massage was conducted softly on the shoulders, and Tachibana-Ryojutsu treated only the muscles and joints from the legs to buttocks without touching the shoulders or backs. The study indicated that the muscle firmness and VAS of the Tachibana-Ryojutsu group decreased significantly in comparison with the acupuncture and massage groups after treatment.

  17. Role of Pre-therapeutic 18F-FDG PET/CT in Guiding the Treatment Strategy and Predicting Prognosis in Patients with Esophageal Carcinoma

    Directory of Open Access Journals (Sweden)

    Teik Hin Tan

    2016-07-01

    Full Text Available Objective(s: The present study aimed to evaluate the role of pretherapeutic 18fluorine-fluorodeoxyglucose positron emission tomographycomputed tomography (18F-FDG PET-CT and maximum standardized uptake value (SUVmax in guiding the treatment strategy and predicting the prognosis of esophageal carcinoma, using the survival data of thepatients.Methods: The present retrospective, cohort study was performed on 40 consecutive patients with esophageal carcinoma (confirmed by endoscopic biopsy, who underwent pre-operative 18F-FDG PET-CTstaging between January 2009 and June 2014. All the patients underwent contrast-enhanced CT and non-contrasted 18F-FDG PET-CT evaluations.The patients were followed-up over 12 months to assess the changes in therapeutic strategies. Survival analysis was done considering the primary tumor SUVmax, using the Kaplan–Meier product-limit method.Results: In a total of 40 patients, 18F-FDG PET-CT scan led to changes in disease stage in 26n (65.0% cases, with upstaging and downstaging reported in 10n (25.0% and 16n (40.0% patients, respectively. The management strategy changed from palliative to curative in 10 out of 24 patients and from curative to palliative in 7 out of 16 cases. Based on the18F-FDG PET-CT scan alone, the median survival of patients in the palliative group was 4.0n (95 % CI 3.0-5.0 months, whereas the median survival in the curative group has not been reached, based on the 12-month followup.Selection of treatment strategy on the basis of 18F-FDG PET/CT alone was significantly associated with the survival outcomes at nine months (P=0.03 and marginally significant at 12 months (P=0.05. On the basisof SUVmax, the relation between survival and SUVmax was not statistically significant.Conclusion: 18F-FDG PET/CT scan had a significant impact on stage stratification and subsequently, selection of a stage-specific treatment approach and the overall survival outcome in patients with esophageal carcinoma. However, pre

  18. The Comparison of Attention Biases to Opiates in Substance Dependent and Treated Clients of Therapeutic Clinics and Narcotics Anonymous Memberships

    Directory of Open Access Journals (Sweden)

    Javad Enayat

    2012-11-01

    Full Text Available Aim: The purpose of this study was to compare the attention bias about tempting incentives related to opium materials in treated, addicted and normal people. Duration of consumption and treating were also considered. Method: In this causal-comparative study population was all addicted people who were referred to the rehabilitation offices, addiction treatment clinic, rebirthing centers and Narcotics Anonymous of East Azerbaijan. This study consisted of five groups of men, including addicted to opium materials which are divided into two groups namely: long consumption period and people with short consumption period, also, treated people including long term treated and short term treated, and a normal control group. Altogether, 103 selected people were studied. Sample groups were similar in terms of age, education, and sex. For measuring attention bias towards tempting stimuli related opiates, a words recognition test was used. This test included three subtests and one recognition test. The recognition scores for the three categories of words were measured. Results: The findings indicated that there was a difference in attention against opium material incentives between control group and the mild and severe consumers groups. Also there were significant differences between treated people with the short time distance and control group, and control group had less temptation and biases in comparison to the other groups. Finally, those who have mild consumption are threatened more in comparison with the control group. Conclusion: The findings have applied implications.

  19. Evaluation of the effect of transcytolemmal water exchange analysis for therapeutic response assessment using DCE-MRI: a comparison study.

    Science.gov (United States)

    Wang, Chunhao; Subashi, Ergys; Liang, Xiao; Yin, Fang-Fang; Chang, Zheng

    2016-07-07

    This study compares the shutter-speed (SS) and the Tofts models as used in assessing therapeutic response in a longitudinal DCE-MRI experiment. Sixteen nu/nu mice with implanted colorectal adenocarcinoma cell line (LS-174T) were randomly assigned into treatment/control groups (n  =  8/group) and received bevacizumab/saline twice weekly (Day1/Day4/Day8). All mice were scanned at one pre- (Day0) and two post-treatment (Day2/Day9) time points using a high spatiotemporal resolution DCE-MRI pulse sequence. The CA extravasation rate constant [Formula: see text] from the Tofts/SS model and the mean intracellular water residence time [Formula: see text] from the SS model were analyzed. A biological subvolume (BV) within the tumor was identified based on the [Formula: see text] intensity distribution, and the SS model parameters within the BV ([Formula: see text] and [Formula: see text]) were analyzed. It is found that [Formula: see text] and [Formula: see text] have a similar spatial distribution in the tumor volume. The Bayesian information criterion results show that the SS model was a better fit for all scans. At Day9, the treatment group had significantly higher tumor mean [Formula: see text] (p  =  0.021), [Formula: see text] (p  =  0.021) and [Formula: see text] (p  = 0.045). When BV from transcytolemmal water exchange analysis was adopted, the treatment group had higher mean [Formula: see text] at both Day2 (p  =  0.038) and Day9 (p  =  0.007). Additionally, at Day9, the treatment group had higher mean [Formula: see text] (p  =  0.045) and higher [Formula: see text] spatial heterogeneity indices (Rényi dimensions) d 1 (p  = 0.010) and d 2 (p  = 0.021). When mean [Formula: see text] and its coefficient of variation (CV) were used to separate treatment/control group samples using supporting vector machine, the accuracy of treatment/control classification was 68.8% at Day2 and 87.5% at Day9; in contrast, the

  20. Reproducibility of R-fMRI metrics on the impact of different strategies for multiple comparison correction and sample sizes.

    Science.gov (United States)

    Chen, Xiao; Lu, Bin; Yan, Chao-Gan

    2018-01-01

    Concerns regarding reproducibility of resting-state functional magnetic resonance imaging (R-fMRI) findings have been raised. Little is known about how to operationally define R-fMRI reproducibility and to what extent it is affected by multiple comparison correction strategies and sample size. We comprehensively assessed two aspects of reproducibility, test-retest reliability and replicability, on widely used R-fMRI metrics in both between-subject contrasts of sex differences and within-subject comparisons of eyes-open and eyes-closed (EOEC) conditions. We noted permutation test with Threshold-Free Cluster Enhancement (TFCE), a strict multiple comparison correction strategy, reached the best balance between family-wise error rate (under 5%) and test-retest reliability/replicability (e.g., 0.68 for test-retest reliability and 0.25 for replicability of amplitude of low-frequency fluctuations (ALFF) for between-subject sex differences, 0.49 for replicability of ALFF for within-subject EOEC differences). Although R-fMRI indices attained moderate reliabilities, they replicated poorly in distinct datasets (replicability comparison correction strategies and highlight the importance of sufficiently large sample sizes in R-fMRI studies to enhance reproducibility. Hum Brain Mapp 39:300-318, 2018. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  1. [Alzheimer's disease: New therapeutic strategies].

    Science.gov (United States)

    Villegas, Sandra

    2015-07-20

    The rapid increase in prevalence rates of Alzheimer's disease means that treatments to prevent, stop or reverse this devastating disease are urgently needed. Despite advances in understanding its molecular pathology, there are no drugs that can halt its progression. This review takes a tour through phase 2, or higher studies, probing receptor agonist agents interfering with aggregation, inhibitors/modulators of secretases, lipid-lowering agents, and, finally and most extensively, immunotherapy. The fact that phase 3 studies with bapineuzumab and solaneuzumab have recently failed does not invalidate the potential of immunotherapy, as more information is available and new clinical trials are being initiated. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

  2. Online learning applied to a course on rational therapeutics: an international comparison between final year students of two medical schools.

    Science.gov (United States)

    Likic, Robert; White, Casey; Cinti, Sandro; Purkiss, Joel; Fantone, Joseph; Chapman, Chris; Bielen, Luka; Francetic, Igor; Engleberg, Cary

    2013-02-01

    Poor prescribing is probably the most common cause of preventable medication errors and many of these events involve junior doctors. In 2009, an electronic problem-based therapeutics course developed at the University of Michigan Medical School (UMMS) was translated and adapted for use at the University of Zagreb Medical School (UZMS). After students from both schools took the course in 2010, we compared their responses with an online questionnaire addressing the course quality and its effectiveness. There were no statistically significant differences in the overall average grades awarded for the course (UZMS 4.11 ± 0.86 vs. UMMS 3.96 ± 0.93; 95% CI mean difference (MD) -0.36, 0.07; P = 0.175) with both student groups expressing high satisfaction rates with its quality, accessibility and overall design. UZMS students reported spending less time working through the course than their American colleagues (2.14 ± 1.01 vs. 2.89 ± 1.02 on a five point Likert scale; 95% CI MD 0.51, 0.99; P internationally in different countries and health care systems, achieving similar, high student satisfaction rates while decreasing administrative and cost burdens. Web based learning may have great potential to offer a cost effective and safe environment in which prescribing skills can be improved. © 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

  3. The comparison of the effectiveness of conventional therapeutic exercises and Pilates on pain and function in patients with knee osteoarthritis.

    Science.gov (United States)

    Mazloum, Vahid; Rabiei, Pouya; Rahnama, Nader; Sabzehparvar, Elnaz

    2017-10-22

    The aim of this study was to investigate the effectiveness of two different interventions on pain and disability in patients with knee osteoarthritis (KOA). Forty-one individuals (Mean ± SD: Age 52.1 ± 8.9 years, Height 172.8 ± 6.6 cm, Weight 80.2 ± 6.9 kg) with KOA were randomly allocated into Pilates (N = 14), conventional therapeutic exercise (CTE) (N = 14), and control (N = 13) groups. Joint position sense (JPS), functional performance, pain, and disability were examined using Biodex system, aggregate time of four daily activities, and Lequesne Index. One-Way ANOVA, and Post Hoc Scheffe test were administrated to analyze the data (P Pilates training compared to CTE. It seemed that Pilates training was more effective than the CTE to improve pain and disability in individuals with KOA. Copyright © 2017 Elsevier Ltd. All rights reserved.

  4. Comparison of Ready-to-Use Therapeutic Food with cereal legume-based khichri among malnourished children.

    Science.gov (United States)

    Dube, Brinda; Rongsen, Temsunaro; Mazumder, Sarmila; Taneja, Sunita; Rafiqui, Farhana; Bhandari, Nita; Bhan, M K

    2009-05-01

    To compare the acceptability and energy intake of Ready-to-Use Therapeutic Food (RUTF) with cereal legume based khichri among malnourished children. An acceptability trial with cross-over design. Urban low to middle socioeconomic neighbor-hoods in Delhi. 31 children aged > or =6 to or = -3 SD, with no clinical signs of infection or edema. Children were offered weighed amounts of RUTF and khichri in unlimited amounts for 2 days, one meal of each on both days. Water was fed on demand. Caregivers interviews and observations were conducted on the second day. Acceptability of RUTF compared to khichri based on direct observation and energy intake for test and control meals. The proportion of children who accepted RUTF eagerly was 58% as against 77% for khichri. 42% children on RUTF and 23% on khichri accepted the meal but not eagerly. The median (IQR) energy intake over the two day period in children aged 6 to 36 months from RUTF was 305 (153, 534) kcal, and from khichri was 242 (150, 320) kcal (P=0.02). RUTF and khichri were both well accepted by study children. The energy intake from RUTF was higher due to its extra energy density.

  5. A comparison of HK-CONWIP and BK-CONWIP control strategies in a multi-product manufacturing system

    Directory of Open Access Journals (Sweden)

    Chukwunonyelum Emmanuel Onyeocha

    2015-12-01

    Full Text Available This paper evaluates the performance of the Hybrid Kanban Constant Work-In-Process control strategy and Basestock Kanban Constant Work-In-Process control strategy operating Shared Kanban Allocation Policy (S-KAP and Dedicated Kanban Allocation Policy (D-KAP in a multi-product serial flow line. We explored the effect of an increase of product types on the WIP inventory in the system. A simulation-based optimisation technique was used in determining the optimal settings for the strategies. The strategies were compared via pairwise comparison technique and Nelson’s ranking and selection procedure. S-KAP responds quicker to demand than D-KAP. BK-CONWIP outperforms HK-CONWIP in a serial manufacturing system. It was shown that an increase in the number of product-type increases the number of PAC and WIP inventory.

  6. Comparison of INSURE method with conventional mechanical ventilation after surfactant administration in preterm infants with respiratory distress syndrome: therapeutic challenge.

    Science.gov (United States)

    Nayeri, Fatemeh Sadat; Esmaeilnia Shirvani, Tahereh; Aminnezhad, Majid; Amini, Elaheh; Dalili, Hossein; Moghimpour Bijani, Faezeh

    2014-01-01

    Administration of endotracheal surfactant is potentially the main treatment for neonates suffering from RDS (Respiratory Distress Syndrome), which is followed by mechanical ventilation. Late and severe complications may develop as a consequence of using mechanical ventilation. In this study, conventional methods for treatment of RDS are compared with surfactant administration, use of mechanical ventilation for a brief period and NCPAP (Nasal Continuous Positive Airway Pressure), (INSURE method ((Intubation, Surfactant administration and extubation)). A randomized clinical trial study was performed, including all newborn infants with diagnosed RDS and a gestational age of 35 weeks or less, who were admitted in NICU of Valiasr hospital. The patients were then divided randomly into two CMV (Conventional Mechanical Ventilation) and INSURE groups. Surfactant administration and consequent long-term mechanical ventilation were done in the first group (CMV group). In the second group (INSURE group), surfactant was administered followed by a short-term period of mechanical ventilation. The infants were then extubated, and NCPAP was embedded. The comparison included crucial duration of mechanical ventilation and oxygen therapy, IVH (Intraventricular Hemorrhage), PDA (Patent Ductus Arteriosus), air-leak syndromes, BPD (Broncho-Pulmonary Dysplasia) and mortality rate. The need for mechanical ventilation in 5th day of admission was 43% decreased (P=0.005) in INSURE group in comparison to CMV group. A decline (P=0.01) in the incidence of IVH and PDA was also achieved. Pneumothorax, chronic pulmonary disease and mortality rates, were not significantly different among two groups. (P=0.25, P=0.14, P=0.25, respectively). This study indicated that INSURE method in the treatment of RDS decreases the need for mechanical ventilation and oxygen-therapy in preterm neonates. Moreover, relevant complications as IVH and PDA were observed to be reduced. Thus, it seems rationale to perform

  7. Comparison of INSURE method with conventional mechanical ventilation after surfactant administration in preterm infants with respiratory distress syndrome: therapeutic challenge.

    Directory of Open Access Journals (Sweden)

    Fatemeh Sadat Nayeri

    2014-08-01

    Full Text Available Administration of endotracheal surfactant is potentially the main treatment for neonates suffering from RDS (Respiratory Distress Syndrome, which is followed by mechanical ventilation. Late and severe complications may develop as a consequence of using mechanical ventilation. In this study, conventional methods for treatment of RDS are compared with surfactant administration, use of mechanical ventilation for a brief period and NCPAP (Nasal Continuous Positive Airway Pressure, (INSURE method ((Intubation, Surfactant administration and extubation. A randomized clinical trial study was performed, including all newborn infants with diagnosed RDS and a gestational age of 35 weeks or less, who were admitted in NICU of Valiasr hospital. The patients were then divided randomly into two CMV (Conventional Mechanical Ventilation and INSURE groups. Surfactant administration and consequent long-term mechanical ventilation were done in the first group (CMV group. In the second group (INSURE group, surfactant was administered followed by a short-term period of mechanical ventilation. The infants were then extubated, and NCPAP was embedded. The comparison included crucial duration of mechanical ventilation and oxygen therapy, IVH (Intraventricular Hemorrhage, PDA (Patent Ductus Arteriosus, air-leak syndromes, BPD (Broncho-Pulmonary Dysplasia and mortality rate. The need for mechanical ventilation in 5th day of admission was 43% decreased (P=0.005 in INSURE group in comparison to CMV group. A decline (P=0.01 in the incidence of IVH and PDA was also achieved. Pneumothorax, chronic pulmonary disease and mortality rates, were not significantly different among two groups. (P=0.25, P=0.14, P=0.25, respectively. This study indicated that INSURE method in the treatment of RDS decreases the need for mechanical ventilation and oxygen-therapy in preterm neonates. Moreover, relevant complications as IVH and PDA were observed to be reduced. Thus, it seems rationale to

  8. Comparison of therapeutic effects of omega-3 and methylphenidate (ritalin(®)) in treating children with attention deficit hyperactivity disorder.

    Science.gov (United States)

    Dashti, Naser; Hekmat, Hoda; Soltani, Hamid Reza; Rahimdel, Abolghasem; Javaherchian, Mohammad

    2014-01-01

    Attention deficit hyperactivity disorder (ADHD) is a fixed pattern of disregard and hyperactivity that is much more severe than what is normal in children of the same age. Multiple drugs are used for the treatment of children with ADHD; however, their side effects and efficacy are not clearly known. This study was designed to evaluate and compare the therapeutic effects of two drugs, that is, omega-3 and methylphenidate hydrochloride (Ritalin(®)), used to treat patients with ADHD. In a randomized, placebo control clinical trial in Yazd, Iran, 85 ADHD children were divided into two experimental and one control groups. Thus, 29 subjects were treated with Ritalin(®), 28 subjects received omega-3, and the remaining 28 received placebo. The data collection tools used in this study consisted of the Conners' Parent Rating Scale and Teacher Rating Scale. The scores obtained from these questionnaires were analyzed using chi-square test and paired t-test in PASW Statistics. The average age of the population was 8.22 (± 1.65) years. Significant associations were observed between Ritalin(®) therapy and the changes before and after the treatment, and the omega-3 treatment and the changes before and after treatment (p 0.050). Omega-3 had considerable efficacy as well as Ritalin(®) (P = 0.001). More attention should be given to screening, prevention, and treatment with omega-3 and its effective role in the development of the brain and mental health, and increasing children's attention span and thinking ability.

  9. SU-F-T-212: A Comparison of Treatment Strategies for Intracranial Stereotactic Radiosurgery

    International Nuclear Information System (INIS)

    Lamberton, T; Slater, J; Wroe, A

    2016-01-01

    Purpose: Stereotactic radiosurgery is an effective and noninvasive treatment for intracranial lesions that uses highly focused radiation beams in a single treatment fraction. The purpose of this study is to investigate the dosimetric differences between the treatment brain metastasis with a proton beam vs. intensity modulated radiation therapy (IMRT). Methods: Ten separate brain metastasis targets where chosen and treatment plans were created for each, using three different strategies: custom proton beam shaping devices, standardized proton beam shaping devices, and IMRT. Each plan was required to satisfy set parameters for providing adequate coverage and minimizing risk to adjacent tissues. The effectiveness of each plan was calculated by comparing the homogeneity index, conformity index, and V12 for each target using a paired one tailed T-test (α=0.05). Specific comparison of the conformity indices was also made using a subcategory containing targets with volume>1cc. Results: There was no significant difference between the homogeneity indices of the three plans (p>0.05), showing that each plan has the capability of adequately covering the targets. There was a statistically significant difference (p<0.01) between the conformity indices of the custom and the standard proton plan, as with the custom proton and IMRT (p<0.01), with custom proton showing stronger conformity to the target in both cases. There was also a statistical difference between the V12 of all three plans (Custom v. Standardized: p=0.02, Custom v. IMRT: p<0.01, Standardized v. IMRT: p<0.01) with custom proton supplying the lowest dose to surrounding tissues. For large targets (volume>1cc) there was no statistical difference between the proton plans and the IMRT treatment for the conformity index. Conclusion: A custom proton plan is the recommended treatment explored in this study as it is the most reliable way of effectively treating the target while sparing the maximum amount of normal tissue.

  10. Comparison of the therapeutic efficacy of intravenous dimenhydrinate and intravenous piracetam in patients with vertigo: a randomised clinical trial.

    Science.gov (United States)

    Doğan, Nurettin Özgür; Avcu, Nazire; Yaka, Elif; Yılmaz, Serkan; Pekdemir, Murat

    2015-07-01

    The present study aimed to compare the therapeutic efficacy of dimenhydrinate and piracetam in patients with vertigo. A blinded, parallel group, superiority, randomised clinical trial was carried out on patients who presented to the emergency department (ED) with vertigo. Healthy adult patients presenting to the ED with undifferentiated vertigo were included in the study. The efficacy of intravenous dimenhydrinate (100 mg) and intravenous piracetam (2000 mg) for reducing the intensity of vertigo was compared in two randomised treatment groups using a 10-point numeric rating scale (NRS). The determination of NRS scores was performed at presentation and at the 30th minute of presentation, after the study drug was implemented, both in immobile and ambulatory positions. The primary outcome variable was reduction in vertigo intensity documented on the NRS at the 30th minute after medication administration, analysed by intention to treat. A total of 94 patients were included in the randomisation (n=47 in both groups). The baseline NRS scores were 7.55±2.00 in the dimenhydrinate group and 8.19±1.79 in the piracetam group. The changes from baseline for dimenhydrinate and piracetam were 2.92±3.11 and 3.75±3.40 (difference -0.83 (95% CI -2.23 to 0.57)) in the immobile position and were 2.04±3.07 and 2.72±2.91 (difference -0.68 (95% CI -2.03 to 0.67)) in the ambulatory position. Rescue medication need was similar in both treatment groups (p=0.330), and only one adverse reaction was reported. We found no evidence of a difference between dimenhydrinate and piracetam in relieving the symptoms of vertigo. Clinical Trials Registration ID: NCT01890538. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  11. Comparison of Water Allocation Strategies for Wheat Production in the Texas Panhandle

    OpenAIRE

    Colette, W. Arden; Almas, Lal K.

    2007-01-01

    The declining availability of irrigation water from the Ogallala aquifer combined with increasing energy costs make irrigation strategies much more critical. Irrigation strategies that maximize returns to irrigation require less water and achieve higher returns than strategies aimed at satisfying 100% of the crops evapotranspiration (ET) requirements.

  12. Comparison of control strategies for DFIG under symmetrical grid voltage dips

    DEFF Research Database (Denmark)

    Chen, Wenjie; Xu, Dehong; Chen, Min

    2013-01-01

    This paper presents a series of current control strategies for the DFIG under symmetrical grid voltage dips. The controllable range, the damping time constant of the stator natural flux and the torque fluctuations of six control strategies are analyzed and compared. The control strategies which...

  13. Oncological strategies for locally advanced rectal cancer with synchronous liver metastases, interval strategy versus rectum first strategy: a comparison of short-term outcomes.

    Science.gov (United States)

    Salvador-Rosés, H; López-Ben, S; Casellas-Robert, M; Planellas, P; Gómez-Romeu, N; Farrés, R; Ramos, E; Codina-Cazador, A; Figueras, J

    2017-12-22

    The goal of treatment for patients with synchronous liver metastases (SLM) from rectal cancer is to achieve a complete resection of both tumor locations. For patients with symptomatic locally advanced rectal cancer with resectable SLM at diagnosis, our usual strategy has been the rectum first approach (RF). However, since 2014, we advocate for the interval approach (IS) that involves the administration of chemo-radiotherapy followed by the resection of the SLM in the interval of time between rectal cancer radiation and rectal surgery. From 2010 to 2016, 16 patients were treated according to this new strategy and 19 were treated according RF strategy. Data were collected prospectively and analyzed with an intention-to-treat perspective. Complete resection rate, duration of the treatment and morbi-mortality were the main outcomes. The complete resection rate in the IS was higher (100%, n = 16) compared to the RF (74%, n = 14, p = 0.049) and the duration of the strategy was shorter (6 vs. 9 months, respectively, p = 0.006). The incidence of severe complications after liver surgery was 14% (n = 2) in the RF and 0% in the IS (p = 1.000), and after rectal surgery was 24% (n = 4) and 12% (n = 2), respectively (p = 1.000). The IS is a feasible and safe strategy that procures higher level of complete resection rate in a shorter period of time compared to RF strategy.

  14. Involvement of pro-inflammatory cytokines and growth factors in the pathogenesis of Dupuytren's contracture: a novel target for a possible future therapeutic strategy?

    Science.gov (United States)

    Bianchi, Enrica; Taurone, Samanta; Bardella, Lia; Signore, Alberto; Pompili, Elena; Sessa, Vincenzo; Chiappetta, Caterina; Fumagalli, Lorenzo; Di Gioia, Cira; Pastore, Francesco S; Scarpa, Susanna; Artico, Marco

    2015-10-01

    Dupuytren's contracture (DC) is a benign fibro-proliferative disease of the hand causing fibrotic nodules and fascial cords which determine debilitating contracture and deformities of fingers and hands. The present study was designed to characterize pro-inflammatory cytokines and growth factors involved in the pathogenesis, progression and recurrence of this disease, in order to find novel targets for alternative therapies and strategies in controlling DC. The expression of pro-inflammatory cytokines and of growth factors was detected by immunohistochemistry in fibrotic nodules and normal palmar fascia resected respectively from patients affected by DC and carpal tunnel syndrome (CTS; as negative controls). Reverse transcription (RT)-PCR analysis and immunofluorescence were performed to quantify the expression of transforming growth factor (TGF)-β1, interleukin (IL)-1β and vascular endothelial growth factor (VEGF) by primary cultures of myofibroblasts and fibroblasts isolated from Dupuytren's nodules. Histological analysis showed high cellularity and high proliferation rate in Dupuytren's tissue, together with the presence of myofibroblastic isotypes; immunohistochemical staining for macrophages was completely negative. In addition, a strong expression of TGF-β1, IL-1β and VEGF was evident in the extracellular matrix and in the cytoplasm of fibroblasts and myofibroblasts in Dupuytren's nodular tissues, as compared with control tissues. These results were confirmed by RT-PCR and by immunofluorescence in pathological and normal primary cell cultures. These preliminary observations suggest that TGF-β1, IL-1β and VEGF may be considered potential therapeutic targets in the treatment of Dupuytren's disease (DD). © 2015 Authors; published by Portland Press Limited.

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

    Directory of Open Access Journals (Sweden)

    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.

  16. Therapeutic potential of inhibiting ABCE1 and eRF3 genes via siRNA strategy using chitosan nanoparticles in breast cancer cells

    Science.gov (United States)

    Cengiz, Bagdat Burcu; Asik, Mehmet Dogan; Kara, Goknur; Turk, Mustafa; Denkbas, Emir Baki

    2015-04-01

    In recent years, targeted cancer therapy strategies have begun to take the place of the conventional treatments. Inhibition of the specific genes, involved in cancer progress, via small interfering RNA (siRNA) has become one of the promising therapeutic approaches for cancer therapy. However, due to rapid nuclease degradation and poor cellular uptake of siRNA, a suitable carrier for siRNA penetration inside the cells is required. We used chitosan nanoparticles (CS-NPs) to efficiently deliver ATP-binding casette E1 (ABCE1) and eukaryotic release factor 3 (eRF3)-targeting siRNAs, individually and together, to reduce the proliferation and induce the apoptosis of breast cancer cells. The CS-NPs were generated by ionic gelation method using tripolyphosphate (TPP) as a crosslinker. Nanoparticles (NPs) were obtained with diameters ranging between 110 and 230 nm and the zeta potential of approximately 27 mV optimizing the solution pH to 4.5 and CS/TPP mass ratio to 3:1. Loading efficiencies of 98.69 % ± 0.051 and 98.83 % ± 0.047 were achieved when ABCE1 siRNA and eRF3 siRNA were entrapped into the NPs, respectively. Cell proliferation assay demonstrated that siRNA-loaded CS-NPs were more effective on cancer cells when compared to siRNAs without CS-NPs. Parallel results were also obtained by apoptosis/necrosis, double-staining analysis. Within our study, the potency of ABCE1 and eRF3 siRNAs were shown for the first time with this kind of polymeric delivery system. The results also indicated that ABCE1 and eRF3, important molecules in protein synthesis, could serve as effective targets to inhibit the cancer cells.

  17. Therapeutic potential of inhibiting ABCE1 and eRF3 genes via siRNA strategy using chitosan nanoparticles in breast cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Cengiz, Bagdat Burcu; Asik, Mehmet Dogan [Hacettepe University, Nanotechnology and Nanomedicine Division (Turkey); Kara, Goknur [Hacettepe University, Biochemistry Division, Chemistry Department (Turkey); Turk, Mustafa [Kirikkale University, Bioengineering Department (Turkey); Denkbas, Emir Baki, E-mail: denkbas@hacettepe.edu.tr [Hacettepe University, Biochemistry Division, Chemistry Department (Turkey)

    2015-04-15

    In recent years, targeted cancer therapy strategies have begun to take the place of the conventional treatments. Inhibition of the specific genes, involved in cancer progress, via small interfering RNA (siRNA) has become one of the promising therapeutic approaches for cancer therapy. However, due to rapid nuclease degradation and poor cellular uptake of siRNA, a suitable carrier for siRNA penetration inside the cells is required. We used chitosan nanoparticles (CS-NPs) to efficiently deliver ATP-binding casette E1 (ABCE1) and eukaryotic release factor 3 (eRF3)-targeting siRNAs, individually and together, to reduce the proliferation and induce the apoptosis of breast cancer cells. The CS-NPs were generated by ionic gelation method using tripolyphosphate (TPP) as a crosslinker. Nanoparticles (NPs) were obtained with diameters ranging between 110 and 230 nm and the zeta potential of approximately 27 mV optimizing the solution pH to 4.5 and CS/TPP mass ratio to 3:1. Loading efficiencies of 98.69 % ± 0.051 and 98.83 % ± 0.047 were achieved when ABCE1 siRNA and eRF3 siRNA were entrapped into the NPs, respectively. Cell proliferation assay demonstrated that siRNA-loaded CS-NPs were more effective on cancer cells when compared to siRNAs without CS-NPs. Parallel results were also obtained by apoptosis/necrosis, double-staining analysis. Within our study, the potency of ABCE1 and eRF3 siRNAs were shown for the first time with this kind of polymeric delivery system. The results also indicated that ABCE1 and eRF3, important molecules in protein synthesis, could serve as effective targets to inhibit the cancer cells.

  18. Characteristics of mouse adipose tissue-derived stem cells and therapeutic comparisons between syngeneic and allogeneic adipose tissue-derived stem cell transplantation in experimental autoimmune thyroiditis.

    Science.gov (United States)

    Choi, Eun Wha; Shin, Il Seob; Park, So Young; Yoon, Eun Ji; Kang, Sung Keun; Ra, Jeong Chan; Hong, Sung Hwa

    2014-01-01

    Previously, we found that the intravenous administration of human adipose tissue-derived mesenchymal stem cells was a promising therapeutic option for autoimmune thyroiditis even when the cells were transplanted into a xenogeneic model without an immunosuppressant. Therefore, we explored the comparison between the therapeutic effects of syngeneic and allogeneic adipose tissue-derived stem cells on an experimental autoimmune thyroiditis mouse model. Experimental autoimmune thyroiditis was induced in C57BL/6 mice by immunization with porcine thyroglobulin. Adipose tissue-derived stem cells derived from C57BL/6 mice (syngeneic) or BALB/c mice (allogeneic) or saline as a vehicle control were administered intravenously four times weekly. Blood and tissue samples were collected 1 week after the last transplantation. Adipose tissue-derived stem cells from mice were able to differentiate into multiple lineages in vitro; however, mouse adipose tissue-derived stem cells did not have immunophenotypes identical to those from humans. Syngeneic and allogeneic administrations of adipose tissue-derived stem cells reduced thyroglobulin autoantibodies and the inflammatory immune response, protected against lymphocyte infiltration into the thyroid, and restored the Th1/Th2 balance without any adverse effects. However, different humoral immune responses were observed for infused cells from different stem cell sources. The strongest humoral immune response was induced by xenogeneic transplantation, followed by allogeneic and syngeneic administration, in that order. The stem cells were mostly found in the spleen, not the thyroid. This migration might be because the stem cells primarily function in systemic immune modulation, due to being given prior to disease induction. In this study, we confirmed that there were equal effects of adipose tissue-derived stem cells in treating autoimmune thyroiditis between syngeneic and allogeneic transplantations.

  19. Malignant hepatic tumors treated with percutaneous radio-frequency ablation: Comparison between contrast-enhanced color Doppler ultrasound and spiral CT in evaluating the therapeutic efficacy

    International Nuclear Information System (INIS)

    Yoon, Jung Hee; Han, Sang Suk; Cha, Sung Sook

    2002-01-01

    To compare contrast-enhanced color Doppler ultrasound (CECDUS) with spiral CT in the evaluation of the therapeutic efficacy of malignant hepatic tumors after radio-frequency ablation (RFA). During a recent 2 year period (April 1999 to March 2001). One hundred fifteen hepatic tumors (95 hepatocellular carcinomas and 20 metastases; mean diameter, 2.7 cm) from 83 consecutive patients (60 men and 23 women; mean age, 57 years) that were treated with RFA were included in this study. Both CECDUS and two-or three phase spiral CT were performed a day after RFA as the immediate follow-up study in most cases. Afterward, both imaging studies were alternatively performed on monthly basis, but when incomplete ablation was suspected on one follow-up imaging study, the other imaging study was performed within a week for comparison. For ultrasound contrast agent, a suspension of 2.5 g or 4.0 g Levovist (Schering AG, Berlin, Germany) with a concentration of 300 mg/mL was used. For evaluating the therapeutic efficacy, the presence of viable portion, either residual or recurrent, within the ablated tumor was determined on each imaging study. The criteria for viable portion were defined as focal or irregular enhancement at the periphery of the ablated tumor on the arterial or portal phase spiral CT images and intratumoral vascularities on CECDUS. The correspondence rate between both imaging studies was assessed to compare the diagnostic accuracy of both studies in evaluating a residual or recurrent tumor. In addition, their imaging findings were analyzed. Analyzing both imaging findings of 116 malignant hepatic tumors, the correspondence rate between CECDUS and CT obtained after 116 times of imaging studies was 91.4% (106/116). For the diagnosis of residual or recurrent tumors, the sensitivity, specificity and diagnostic accuracy of spiral CT were 71%, 99%, and 94%, respectively, while those of CECDUS were 87%, 99%, and 97%, respectively. As the immediate follow-up study, CECDUS seemed

  20. Head-to-head comparison of aggressive conventional therapy and three biological treatments and comparison of two de-escalation strategies in patients who respond to treatment

    DEFF Research Database (Denmark)

    Glinatsi, Daniel; Heiberg, Marte S; Rudin, Anna

    2017-01-01

    -to-head comparison between csDMARD plus glucocorticoid therapy and three different biological DMARD (bDMARD) therapies with different modes of action and (2) two de-escalation strategies in patients who respond to first-line therapy. METHODS/DESIGN: In a pragmatic, 80-160-week, multicenter, randomized, open......-label, assessor-blinded, phase 4 study, 800 patients with early RA (symptom duration less than 24 months) are randomized 1:1:1:1 to one of four different treatment arms: (1) aggressive csDMARD therapy with methotrexate + sulphasalazine + hydroxychloroquine + i.a. glucocorticoids (arm 1A) or methotrexate...

  1. COMPARISON OF FAST PERIMETRIC STRATEGIES USING G2 PROGRAM ON OCTOPUS 101 PERIMETER

    Directory of Open Access Journals (Sweden)

    Jernej Pajek

    2002-12-01

    Full Text Available Background. The duration of the perimetric examination was significantly shortened by development of fast perimetric strategies. By analyzing the results of normal, dynamic and TOP strategy we studied the differences in determination of MD, LV, in determination of number of all points with a deficit and number of points with a significant deficit of p < 0.5%.Methods. 22 normal visual fields of 17 subjects (mean age 33 ± 15 years and 22 visual fields with defects of 17 patients (47 ± 16 years having different types and degrees of visual lesions were examined. All visual fields were examined once with each strategy in alternating order using Octopus 101 perimeter with the G2 program.Results. No statistically significant differences were measured in MD values. In abnormal visual fields group, TOP strategy showed 11 ± 14 dB2 lower LV values compared to dynamic strategy (p < 0.01 and 9.8 ± 16 dB2 lower LV values compared to normal strategy (p = 0.02. In the abnormal visual fields group the dynamic strategy measured in average 3 points with the deficit less compared to the other two strategies (p < 0.05. There were no significant differences between strategies in the number of points with a deficit of p < 0.5%.Conclusions. With the exception of lower LV values measured with TOP strategy, the differences between TOP, dynamic strategy results are small and the time sparing benefits are substantial. Therefore the usage of fast perimetric strategies is clinically justified.

  2. Structure, coercive control, and autonomy promotion: A comparison of fathers' and mothers' food parenting strategies.

    Science.gov (United States)

    Pratt, Mercedes; Hoffmann, Debra; Taylor, Maija; Musher-Eizenman, Dara

    2017-05-01

    This study explored differences in mothers' and fathers' food parenting strategies, specifically coercive control, structure, and autonomy promotion, and whether parenting style and parental responsibility for food parenting related to the use of these strategies. Parents of children aged 2.5-7.5 years ( N = 497) reported about their parenting practices and food parenting strategies. Parenting style accounted for the majority of the variance in food parenting. Fathers were more authoritarian than mothers. Authoritarian and permissive parenting practices were related to more coercive strategies. Mothers reported more food parenting responsibility. Responsibility was related to less coercive practices and more autonomy promotion and structure.

  3. Comparison of methods for the analysis of therapeutic immunoglobulin G Fc-glycosylation profiles--part 1: separation-based methods.

    Science.gov (United States)

    Reusch, Dietmar; Haberger, Markus; Maier, Bernd; Maier, Maria; Kloseck, Ronny; Zimmermann, Boris; Hook, Michaela; Szabo, Zoltan; Tep, Samnang; Wegstein, Jo; Alt, Nadja; Bulau, Patrick; Wuhrer, Manfred

    2015-01-01

    Immunoglobulin G (IgG) crystallizable fragment (Fc) glycosylation is crucial for antibody effector functions, such as antibody-dependent cell-mediated cytotoxicity, and for their pharmacokinetic and pharmacodynamics behavior. To monitor the Fc-glycosylation in bioprocess development, as well as product characterization and release analytics, reliable techniques for glycosylation analysis are needed. A wide range of analytical methods has found its way into these applications. In this study, a comprehensive comparison was performed of separation-based methods for Fc-glycosylation profiling of an IgG biopharmaceutical. A therapeutic antibody reference material was analyzed 6-fold on 2 different days, and the methods were compared for precision, accuracy, throughput and other features; special emphasis was placed on the detection of sialic acid-containing glycans. Seven, non-mass spectrometric methods were compared; the methods utilized liquid chromatography-based separation of fluorescent-labeled glycans, capillary electrophoresis-based separation of fluorescent-labeled glycans, or high-performance anion exchange chromatography with pulsed amperometric detection. Hydrophilic interaction liquid chromatography-ultra high performance liquid chromatography of 2-aminobenzamide (2-AB)-labeled glycans was used as a reference method. All of the methods showed excellent precision and accuracy; some differences were observed, particularly with regard to the detection and quantitation of minor glycan species, such as sialylated glycans.

  4. Experimental study and nuclear model calculations on the $^{192}Os (p, n)^{192}$Ir reaction Comparison of reactor and cyclotron production of the therapeutic radionuclide $^{192}$Ir

    CERN Document Server

    Hilgers, K; Sudar, S; 10.1016/j.apradiso.2004.12.010

    2005-01-01

    In a search for an alternative route of production of the important therapeutic radionuclide /sup 192/Ir (T/sub 1/2/=78.83 d), the excitation function of the reaction /sup 192/Os(p, n)/sup 192/Ir was investigated from its threshold up to 20MeV. Thin samples of enriched /sup 192/Os were obtained by electrodeposition on Ni, and the conventional stacked-foil technique was used for cross section measurements. The experimental data were compared with the results of theoretical calculations using the codes EMPIRE-II and ALICE-IPPE. Good agreement was found with EMPIRE-II, but slightly less with the ALICE-IPPE calculations. The theoretical thick target yield of /sup 192/Ir over the energy range E/sub p/=16 to 8MeV amounts to only 0.16MBq/ mu A.h. A comparison of the reactor and cyclotron production methods is given. In terms of yield and radionuclidic purity of /sup 192/Ir the reactor method appears to be superior; the only advantage of the cyclotron method could be the higher specific activity of the product.

  5. Enhanced neuro-therapeutic potential of Wharton's Jelly-derived mesenchymal stem cells in comparison with bone marrow mesenchymal stem cells culture.

    Science.gov (United States)

    Drela, Katarzyna; Lech, Wioletta; Figiel-Dabrowska, Anna; Zychowicz, Marzena; Mikula, Michał; Sarnowska, Anna; Domanska-Janik, Krystyna

    2016-04-01

    Substantial inconsistencies in mesenchymal stem (stromal) cell (MSC) therapy reported in early translational and clinical studies may indicate need for selection of the proper cell population for any particular therapeutic purpose. In the present study we have examined stromal stem cells derived either from umbilical cord Wharton's Jelly (WJ-MSC) or bone marrow (BM-MSC) of adult, healthy donors. The cells characterized in accordance with the International Society for Cellular Therapy (ISCT) indications as well as other phenotypic and functional parameters have been compared under strictly controlled culture conditions. WJ-MSC, in comparison with BM-MSC, exhibited a higher proliferation rate, a greater expansion capability being additionally stimulated under low-oxygen atmosphere, enhanced neurotrophic factors gene expression and spontaneous tendency toward a neural lineage differentiation commitment confirmed by protein and gene marker induction. Our data suggest that WJ-MSC may represent an example of immature-type "pre-MSC," where a substantial cellular component is embryonic-like, pluripotent derivatives with the default neural-like differentiation. These cells may contribute in different extents to nearly all classical MSC populations adversely correlated with the age of cell donors. Our data suggest that neuro-epithelial markers, like nestin, stage specific embryonic antigens-4 or α-smooth muscle actin expressions, may serve as useful indicators of MSC culture neuro-regeneration-associated potency. Copyright © 2016 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  6. Comparison of the Efficiency of Reading Comprehension Strategies on Iranian University Students' Comprehension

    Science.gov (United States)

    Fotovatian, Sepideh; Shokrpour, Nasrin

    2007-01-01

    Knowledge of the strategies used by English as a foreign language (EFL) or second language (ESL) readers can help instructors teach these techniques and thereby enhance their students' reading comprehension. The present study compared three categories of reading comprehension strategies (metacognitive, cognitive, and socio-affective) to determine…

  7. The comparison of the performance of two screening strategies identifying newly-diagnosed HIV during pregnancy

    NARCIS (Netherlands)

    Boer, K.; Smit, C.; Flier, M. van der; Wolf, F. de; Koopmans †, P.P.; Crevel, R. van; Eggink, A.J.; Groot, R. de; Keuter, M.; Post, F.; Ven, A.J.A.M. van der; Warris, A.; et al.,

    2011-01-01

    BACKGROUND: In the Netherlands, a non-selective opt-out instead of a selective opt-in antenatal HIV screening strategy was implemented in 2004. In case of infection, screening was followed by prevention of mother-to-child-transmission (PMTCT). We compared the performance of the two strategies in

  8. Comparison of Coping Strategies of Student Teachers Based on Their Subject of Specialisation

    Science.gov (United States)

    P. M., Majitha; Sajan, K. S.

    2015-01-01

    The purpose of the study was to find out the difference in the mean scores of coping strategies of student teachers based on their subject of specialisation. A total of 558 student teachers were selected for the study. Results indicate that there exists a significant difference in the mean scores of Coping Strategies of student teachers of Arts…

  9. A Comparison of Two Strategies for Teaching Third Graders to Summarize Information Text

    Science.gov (United States)

    Dromsky, Ann Marie

    2011-01-01

    Summarizing text is one of the most effective comprehension strategies (National Institute of Child Health and Human Development, 2000) and an effective way to learn from information text (Dole, Duffy, Roehler, & Pearson, 1991; Pressley & Woloshyn, 1995). In addition, much research supports the explicit instruction of such strategies as…

  10. Magnetic resonance colonography with limited bowel preparation: a comparison of three strategies

    NARCIS (Netherlands)

    Florie, Jasper; van Gelder, Rogier E.; Haberkorn, Brigitte; Birnie, Erwin; Lavini, Cristina; Reitsma, Johannes B.; Stoker, Jaap

    2007-01-01

    PURPOSE: To prospectively compare three strategies of magnetic resonance colonography (MRC) with fecal tagging. MATERIALS AND METHODS: Three strategies were compared: (S1) gadolinium as oral tagging agent and a gadolinium-water mixture for rectal filling (bright lumen), (S2) oral barium and water

  11. A Comparison of L2 and L3 Learners' Strategy Use in School Settings

    Science.gov (United States)

    Haukås, Åsta

    2015-01-01

    Research on third-language learning (L3) has documented that plurilingualism is an asset in many respects. Particularly relevant for this study is research showing that L3 learners use more strategies more frequently and efficiently than L2 learners. However, previous studies have mainly concentrated on L3 learners' strategy use at the university…

  12. The Effects of Computer-Assisted Feedback Strategies in Technology Education: A Comparison of Learning Outcomes

    Science.gov (United States)

    Adams, Ruifang Hope; Strickland, Jane

    2012-01-01

    This study investigated the effects of computer-assisted feedback strategies that have been utilized by university students in a technology education curriculum. Specifically, the study examined the effectiveness of the computer-assisted feedback strategy "Knowledge of Response feedback" (KOR), and the "Knowledge of Correct Responses feedback"…

  13. Study and Comparison Between Personality Traits and Coping Strategies Among Opium Addicts (within the age of 30-36

    Directory of Open Access Journals (Sweden)

    Alireza Jazayeri

    2003-05-01

    Full Text Available The research is looking into the study and comparison between personality traits and coping strategies and their relationship with one another among opium addicts within the age of 30-36. For this purpose, a research group comprising 50 opium addicts was selected with respect to control variables. In order to compare the results, 50 other individuals were selected as a observation group and with regard to control variables both groups were matched together. The five-factor personality trait inventory (NEO-FFI and the coping strategy inventory of Carver and Shearer were used. Moreover, in order to control the effects of depression and anxiety on personality traits, Beck’s test for anxiety and depression was used. The results indicated that without taking the effects of depression and anxiety into account, the addicts showed higher neuroticism trait but lower extraversion, agreeableness and conscientious traits. But when the effects of depression and anxiety were taken into account, the two groups showed a meaningful difference in the conscientious trait. Furthermore, addicts rarely use concentrated coping strategies and usually use non-effective strategies. Non-effective strategies had direct relationship with neuroticism and opposite relationship with conscientiousness.

  14. Lurking: a challenge or a fruitful strategy? A comparison between lurkers and active participants in an online corporate community of practice

    NARCIS (Netherlands)

    Mirjam, Neelen; Sibren, Fetter

    2011-01-01

    Neelen, M., & Fetter, S. (2010). Lurking: a challenge or a fruitful strategy? A comparison between lurkers and active participants in an online corporate community of practice. International Journal of Knowledge and Learning, 6(4), 269-284.

  15. Comparison of two vaccination strategies against hepatitis A and B in patients with chronic hepatitis C.

    Science.gov (United States)

    Díez Redondo, M P; Almaraz, A; Jiménez Rodríguez-Vila, M; Santamaría, A; de Castro, J; Torrego, J C; Caro-Patón, A

    2009-04-01

    although the vaccination against hepatitis A (VAH) and hepatitis B (VBH) is recommended in patients with HCV, the most cost-effective strategy has not been established. Our objective was to compare the cost-effectiveness of universal strategy (vaccination all patients) with selective strategy (vaccination only patients against virus they lack immunity to) in patients with HCV. we compared the direct medical costs of the two vaccination strategies against both viruses in 313 patients with HC. Serological markers for HAV (anti-HAV) and HBV (HbsAg, anti HBs, anti HBc) were determined in the 313 patients and the costs of the vaccines and the blood tests necessary to determinate the immunity state in our care system were considered. the prevalence of anti-HAV was 81,2% and of anti-HBc was 24,6%. The prevalence of anti-HAV increases with age. HAV vaccination with universal strategy has a cost of 19.806,64 euro and with selective one of 9.899,62 euro. HBV vaccination with universal strategy rose to 18.780 euro and to 20.385,57 euro with selective one (employing anti-HBc). Costs were analysed in different groups of age and several hepatitis HBV risk factors. the selective vaccination strategy against HAV was most cost-effective in our patients with HCV. However, when the prevalence of the anti-HAV decreased to less than 20% universal strategy will be the best option. Difference of cost-effective between the two vaccination strategies against HBV was small, on behalf of universal one, so in groups with higher anti-HBc prevalence, like parenteral drugs users and tattoos, the selective strategy could be the best option.

  16. Treatment with Rutin - A Therapeutic Strategy for Neutrophil-Mediated Inflammatory and Autoimmune Diseases - Anti-inflammatory Effects of Rutin on Neutrophils -

    Directory of Open Access Journals (Sweden)

    Bahareh Abd Nikfarjam

    2017-03-01

    due to its inhibiting NO and TNF-α productions, as well as MPO activity, in activated human neutrophils. Treatment with rutin may be considered as a therapeutic strategy for neutrophil-mediated inflammatory/ autoimmune diseases.

  17. Radiation-Induced Esophagitis In Vivo and In Vitro Reveals That Epidermal Growth Factor Is a Potential Candidate for Therapeutic Intervention Strategy

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Kyung Su [Department of Radiation Oncology, Seoul National University College of Medicine, Seoul (Korea, Republic of); Jeon, Seong-Uk; Lee, Chan-Ju; Kim, Young-Eun; Bok, Seoyeon; Hong, Beom-Ju; Park, Dong-Young [Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, Gyeongbuk (Korea, Republic of); Ahn, G-One, E-mail: goneahn@postech.ac.kr [Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, Gyeongbuk (Korea, Republic of); Kim, Hak Jae, E-mail: khjae@snu.ac.kr [Department of Radiation Oncology, Seoul National University College of Medicine, Seoul (Korea, Republic of)

    2016-07-01

    in the irradiated esophagus suggests that EGF may be a potential therapeutic intervention strategy to treat RIE.

  18. Targeting immune co-stimulatory effects of PD-L1 and PD-L2 might represent an effective therapeutic strategy in stroke.

    Science.gov (United States)

    Bodhankar, Sheetal; Chen, Yingxin; Lapato, Andrew; Vandenbark, Arthur A; Murphy, Stephanie J; Offner, Halina

    2014-01-01

    -L1 and PD-L2 might represent a valuable therapeutic strategy in stroke.

  19. A new era of therapeutic strategies for chronic thromboembolic pulmonary hypertension by two different interventional therapies; pulmonary endarterectomy and percutaneous transluminal pulmonary angioplasty.

    Directory of Open Access Journals (Sweden)

    Takumi Inami

    and catheter-based interventional therapies leads us to expect the dawn of a new era of therapeutic strategies for CTEPH.

  20. Spinocellular carcinoma from warts in a HPV infection natural history lasting 49 years. Virus strategy or host choice? Implications for researches and therapeutic vaccines.

    Science.gov (United States)

    Criscione, S M

    2011-11-01

    There is a very strong evidence that progression (also to cancer) in variable percentages of cases infected by HPV, HBV, HCV, and HIV depends on host immune response. A large number of observations demonstrate that virus set up a postulated "active strategy" to modify host reactions or to avoid it. But in all those infections it also seems that antigen load (viral RNA or DNA), chronic activation of immune response and time elapsing from the primary infection play a pivotal role in determining clearing or persisting outcomes. My wife's HPV and cancer natural history, lasting 49 years, started at the age of 10 years with facial warts and progressed to CIN 2/3, cervical in situ carcinoma, perineal warts, perianal carcinoma, inguinal lymph nodes, and invasion of bones and muscular structures, until death is paradigmatic: a progressive immune failure was detected in her scaling up all those clinical features, ending in a massive apoptosis of her lymphocytes collected by leukapheresis and cultured with HPV antigens E6/E7, with the aim of obtaining antigen presenting cells and CD8+ specific T lymphocytes. From this experience, a concept of "host choice to reach a tolerance (mainly by a Tregs mediated anergy) or symbiotic-like state" arises, underlining all the affected host's immune-responses to virus persistence (and to consequent tumors). It might be then postulated as the hallmark of a long-term host/parasites co-evolution, and considered a "normal" reaction when the host faces overwhelming numbers of non-self cancer cells (high antigen loads) preceded by persistent virus infections (chronic activation). This happens in patients who do not clear HPV or other viruses soon enough after infection. These observations may lead to a better understanding of many phenomena that are actually difficult to explain or still are open questions. The auto-limiting host's immune-responses are likely to be aimed to avoid risks arising mainly in the protection of "self" (autoimmunity

  1. A Comparison of Two Strategies for Building an Exposure Prediction Model.

    Science.gov (United States)

    Heiden, Marina; Mathiassen, Svend Erik; Garza, Jennifer; Liv, Per; Wahlström, Jens

    2016-01-01

    Cost-efficient assessments of job exposures in large populations may be obtained from models in which 'true' exposures assessed by expensive measurement methods are estimated from easily accessible and cheap predictors. Typically, the models are built on the basis of a validation study comprising 'true' exposure data as well as an extensive collection of candidate predictors from questionnaires or company data, which cannot all be included in the models due to restrictions in the degrees of freedom available for modeling. In these situations, predictors need to be selected using procedures that can identify the best possible subset of predictors among the candidates. The present study compares two strategies for selecting a set of predictor variables. One strategy relies on stepwise hypothesis testing of associations between predictors and exposure, while the other uses cluster analysis to reduce the number of predictors without relying on empirical information about the measured exposure. Both strategies were applied to the same dataset on biomechanical exposure and candidate predictors among computer users, and they were compared in terms of identified predictors of exposure as well as the resulting model fit using bootstrapped resamples of the original data. The identified predictors were, to a large part, different between the two strategies, and the initial model fit was better for the stepwise testing strategy than for the clustering approach. Internal validation of the models using bootstrap resampling with fixed predictors revealed an equally reduced model fit in resampled datasets for both strategies. However, when predictor selection was incorporated in the validation procedure for the stepwise testing strategy, the model fit was reduced to the extent that both strategies showed similar model fit. Thus, the two strategies would both be expected to perform poorly with respect to predicting biomechanical exposure in other samples of computer users. © The

  2. Optimum allocation of test resources and comparison of breeding strategies for hybrid wheat.

    Science.gov (United States)

    Longin, C Friedrich H; Mi, Xuefei; Melchinger, Albrecht E; Reif, Jochen C; Würschum, Tobias

    2014-10-01

    The use of a breeding strategy combining the evaluation of line per se with testcross performance maximizes annual selection gain for hybrid wheat breeding. Recent experimental studies confirmed a high commercial potential for hybrid wheat requiring the design of optimum breeding strategies. Our objectives were to (1) determine the optimum allocation of the type and number of testers, the number of test locations and the number of doubled haploid lines for different breeding strategies, (2) identify the best breeding strategy and (3) elaborate key parameters for an efficient hybrid wheat breeding program. We performed model calculations using the selection gain for grain yield as target variable to optimize the number of lines, testers and test locations in four different breeding strategies. A breeding strategy (BS2) combining the evaluation of line per se performance and general combining ability (GCA) had a far larger annual selection gain across all considered scenarios than a breeding strategy (BS1) focusing only on GCA. In the combined strategy, the production of testcross seed conducted in parallel with the first yield trial for line per se performance (BS2rapid) resulted in a further increase of the annual selection gain. For the current situation in hybrid wheat, this relative superiority of the strategy BS2rapid amounted to 67 % in annual selection gain compared to BS1. Varying a large number of parameters, we identified the high costs for hybrid seed production and the low variance of GCA in hybrid wheat breeding as key parameters limiting selection gain in BS2rapid.

  3. Comparison of mixotrophic to cyclic autotrophic/heterotrophic growth strategies to optimize productivity of Chlorella sorokiniana

    DEFF Research Database (Denmark)

    van Wagenen, Jonathan Myerson; De Francisci, Davide; Angelidaki, Irini

    2015-01-01

    to autotrophic growth. Chlorella sorokiniana was cultivated in medium supplemented with sodium acetate in concentrations equivalent to the volatile fatty acid concentration found in anaerobic digester effluent. Flat-panel photobioreactors were operated using 16:8 light:dark cycles, with different strategies...... for acetate addition. Acetate was added during the light period for the mixotrophic strategy and during the dark one for the cyclic autotrophic/heterotrophic strategy. Autotrophic productivity of up to 0.99 g L−1 day−1 was obtained using the optimal tested dilution rate of 0.031 h−1. The highest mixotrophic...

  4. Model-based comparison of strategies for reduction of stormwater micropollutant emissions

    DEFF Research Database (Denmark)

    Vezzaro, Luca; Sharma, Anitha Kumari; Mikkelsen, Peter Steen

    to improve the recipient quality by reducing the fluxes of heavy metals (copper, zinc) and organic compounds (fluoranthene) to natural waters. MP sources were identified by using GIS land usage data. When comparing the different control strategies, the integrated model showed the greater benefits...... of the source-control strategy in terms of MP loads discharged in the environment and sediment accumulated in the pond. None of the simulated pollution control strategies managed to fulfil water quality criteria based on Emission Limit Values. This study highlights the great contribution that integrated models...

  5. Comparison of control strategies for Doubly fed induction generator under recurring grid faults

    DEFF Research Database (Denmark)

    Chen, Wenjie; Blaabjerg, Frede; Zhu, Nan

    2014-01-01

    The new grid codes demand the wind turbine systems to ride through recurring grid faults. Many control strategies have been proposed for the Doubly Fed Induction Generator under single grid fault, but their performance under recurring grid faults have not been studied yet. In this paper, five...... different control strategies for DFIG to ride through single grid faults are presented, and their performance under recurring grid faults are analyzed. The controllable range, stator time constant and torque fluctuations of the DFIG with different control strategies are compared. The results are verified...

  6. Locating the difference: A comparison of pedagogic strategies in high and low performing schools

    Directory of Open Access Journals (Sweden)

    Kaylianne Rialda Aploon-Zokufa

    2013-12-01

    Full Text Available A number of research studies have suggested that specific pedagogic strategies can have a positive impact on learning, and in turn, have a positive impact on school performance, in particular for children being schooled in disadvantaged contexts. This analysis describes and measures how four of these pedagogic strategies identified in research – the pacing of a lesson, the sequence and coherence of a lesson, cognitive demand and the nature of feedback within a lesson – are displayed in higher and lower performing schools located in lower-income communities in the Western Cape. The analysis forms part of a broader research project, SPADE (Schools Performing Above Demographic Expectation, and is based on fifteen video-recorded Grade 3 numeracy lessons. The analysis suggests a relationship between specific pedagogic strategies and higher performance for individual learners and for schools. The analysis also identifies further effective pedagogic strategies in higher performing schools in lower-income communities.

  7. A Comparison of Emotion Regulation Strategies of Blind Students With Sighted Students

    Directory of Open Access Journals (Sweden)

    Samaneh Salimi

    2016-06-01

    Discussion: Emotion regulation is a possible influential factor in many problems that blind people suffer from, more than sighted ones, and using interventions that target emotion regulation strategies would be useful.

  8. Organize First or Write First? A Comparison of Alternative Writing Strategies

    Science.gov (United States)

    1991-02-01

    Baddeley, A.D. (1976). The psychology of memory . New York: Basic Books. Becker, H.S. (1986). Writing for social scientists. Chicago: University of...Writing Without Teachers (1973), to anyone who would like to read more about the write-first strategy. Social scientists who describe similar...strategies are Howard Becker (1986), a sociologist, in a book called Writing for Social Scientists, and P. C. Wason (1980), a cognitive psychologist. Upon

  9. Social Media Strategies of The European Union Bodies: A Comparison With Turkey's Experience

    OpenAIRE

    Çömlekçi, Fatih; Güney, Serhat

    2016-01-01

    The aim of this research is to explain andbring forward social media strategies of the European Union bodies and compare withthe Turkish experience in terms of Turkey’s accession process to the EU.Social media is critical for governments and institutions regarding informingcitizens and allowing youth involvement in politics. In this context,strengths and weaknesses of social media strategies (perspectives) of EU andTurkish government will be brought into qu...

  10. Economic analysis of HPAI control in the Netherlands II: comparison of control strategies.

    Science.gov (United States)

    Longworth, N; Mourits, M C M; Saatkamp, H W

    2014-06-01

    A combined epidemiological-economic modelling approach was used to analyse strategies for highly pathogenic avian influenza (HPAI) control for the Netherlands. The modelling framework used was InterSpread Plus (ISP), a spatially based, stochastic and dynamic simulation model. A total of eight control strategies were analysed, including pre-emptive depopulation and vaccination strategies. The analysis was carried out for three different regions in the Netherlands: high-, medium- and low-density areas (HDA, MDA and LDA, respectively). The analysis included the veterinary impact (e.g. number of infected premises and duration), but was particularly focused on the impact on direct costs (DC) and direct consequential costs. The efficient set of control strategies for HDA and MDA included strategies based on either pre-emptive depopulation only or combined vaccination and pre-emptive depopulation: D2 (pre-emptive depopulation within a radius of 2 km), RV3 + D1 (ring vaccination within a radius of 3 km and additional pre-emptive depopulation within a radius of 1 km) and PV + D1 (preventive vaccination in non-affected HDAs and pre-emptive depopulation within a radius of 1 km in the affected HDA). Although control solely based on depopulation in most cases showed to be effective for LDA, pre-emptive depopulation showed to have an additional advantage in these areas, that is, prevention of 'virus jumps' to other areas. The pros and cons of the efficient control strategies were discussed, for example, public perception and risk of export restrictions. It was concluded that for the Netherlands control of HPAI preferably should be carried out using strategies including pre-emptive depopulation with or without vaccination. Particularly, the short- and long-term implications on export, that is, indirect consequential costs (ICC) and aftermath costs of these strategies, should be analysed further. © 2012 Blackwell Verlag GmbH.

  11. The “meta” reflection: a comparison between ironic strategies in Golden Age comedy and Don Quixote

    Directory of Open Access Journals (Sweden)

    Federica Zoppi

    2017-11-01

    Full Text Available The study examines the ironic and critical function that the “meta” reflection plays in dramatic and narrative works. In particular, a comparison is made between the metatheatrical strategies used in Golden Age comedies and the metaliterary discourse proposed by Cervantes in Don Quixote. These self-reflexive elements form part of a ludic structure of detachment and complicity that creates a dynamic and interactive relationship among author, characters and receiver. The main vehicle of this communication is the meta-character, which is projected outside the conventional confines of the work to dialogue with the spectator or the reader and to question the author’s control.

  12. A comparison of information functions and search strategies for sensor planning in target classification.

    Science.gov (United States)

    Zhang, Guoxian; Ferrari, Silvia; Cai, Chenghui

    2012-02-01

    This paper investigates the comparative performance of several information-driven search strategies and decision rules using a canonical target classification problem. Five sensor models are considered: one obtained from classical estimation theory and four obtained from Bernoulli, Poisson, binomial, and mixture-of-binomial distributions. A systematic approach is presented for deriving information functions that represent the expected utility of future sensor measurements from mutual information, Rènyi divergence, Kullback-Leibler divergence, information potential, quadratic entropy, and the Cauchy-Schwarz distance. The resulting information-driven strategies are compared to direct-search, alert-confirm, task-driven (TS), and log-likelihood-ratio (LLR) search strategies. Extensive numerical simulations show that quadratic entropy typically leads to the most effective search strategy with respect to correct-classification rates. In the presence of prior information, the quadratic-entropy-driven strategy also displays the lowest rate of false alarms. However, when prior information is absent or very noisy, TS and LLR strategies achieve the lowest false-alarm rates for the Bernoulli, mixture-of-binomial, and classical sensor models.

  13. A comparison of traditional food and health strategies among Taiwanese and Chinese immigrants in Atlanta, Georgia, USA.

    Science.gov (United States)

    Jiang, Sandy; Quave, Cassandra L

    2013-08-27

    Ethnobotanical studies on the use of plants amongst migrant populations are of great relevance to public health. Traditional health strategies, which incorporate plants as medicines, foods, or both - can play an important role in individual well-being. However, at the same time, migrant populations' traditional knowledge of such practices may be under a state of greater threat of decline due to factors such as limited access to the plant materials and physical isolation from the homeland, which serves as the primary living reservoir for this knowledge. In this study, we conducted a medical ethnobotanical survey focusing on a comparison of local medicinal food and health strategies with members of two Asian immigrant populations in metro-Atlanta: Chinese and Taiwanese. Snowball sampling techniques were employed to recruit 83 study participants, 57 of which were included in the final analysis. Semi-structured interview techniques were used to question participants about their beliefs and usage of the yin yang system, usage of Chinese herbs and medicinal foods, preference and usage of Eastern and Western medicines, and gardening for medicinal foods. Comparison of the two groups demonstrated a remarkable difference in health strategies concerning medicinal plant use, including statistically significant differences in beliefs concerning yin and yang, uses of Eastern versus Western medicine, and gardening for medicinal foods. Domestic health strategies in the form of medicinal foods play an important role in local health practices, especially among the Taiwanese participants. The collective desire for the use of both Eastern and Western medicine by both groups highlights the important role that cultural competency training will play in preparing allopathic health practitioners to serve increasingly diverse patient populations in the US.

  14. Men who were sexually abused in childhood: coping strategies and comparisons in psychological functioning.

    Science.gov (United States)

    O'Leary, Patrick J

    2009-07-01

    Coping strategies of men who were sexually abused in childhood were examined to ascertain their relationship to clinical diagnoses. Time elapsed since the abuse occurred was examined for its relationship to psychological functioning. Clinical psychopathology of this primary sample of sexually abused men was compared to a community sample of men. A primary sample of 147 Australian men was recruited from agencies and self-help groups who support adults who were sexually abused in childhood. For comparative purposes a secondary data set that consisted of 1,231 men recruited randomly in an Australian community survey was utilized. Both samples were administered the 28-item General Health Questionnaire (GHQ28). The primary sample was administered the 60-item coping style inventory instrument (COPE). Coping strategies influenced the possibility of being classified as clinical or nonclinical. The most important strategies associated with better functioning were positive reinterpretation and growth and seeking instrumental social support. Whereas strategies that were more associated with a clinical outcome were themed around internalization, acceptance and disengagement. The sample of men who were sexually abused in childhood was up to 10 times more likely to be classified as "clinical" then the sample of community men. Time elapsed since the abuse occurred did not have a moderating effect on men's psychological functioning. Men who have been sexually abused in childhood are more likely to have clinical diagnoses but coping strategies may play an important part in this outcome. Seeking active assistance appears to be important coping strategy in reframing the experience, however, the timing of this help seeking is not critical. The findings reinforce the importance of professionals being aware that men's psychiatric symptoms might be the sequel to past child sexual abuse. Coping strategies that focus on internalization or disengagement are potentially damaging to the men

  15. Comparison of De Novo Transcriptome Assemblers and k-mer Strategies Using the Killifish, Fundulus heteroclitus.

    Science.gov (United States)

    Rana, Satshil B; Zadlock, Frank J; Zhang, Ziping; Murphy, Wyatt R; Bentivegna, Carolyn S

    2016-01-01

    De novo assembly of non-model organism's transcriptomes has recently been on the rise in concert with the number of de novo transcriptome assembly software programs. There is a knowledge gap as to what assembler software or k-mer strategy is best for construction of an optimal de novo assembly. Additionally, there is a lack of consensus on which evaluation metrics should be used to assess the quality of de novo transcriptome assemblies. Six different assembly strategies were evaluated from four different assemblers. The Trinity assembly was used in its default 25 single k-mer value while Bridger, Oases, and SOAPdenovo-Trans were performed with multiple k-mer strategies. Bridger, Oases, and SOAPdenovo-Trans used a small multiple k-mer (SMK) strategy consisting of the k-mer lengths of 21, 25, 27, 29, 31, and 33. Additionally, Oases and SOAPdenovo-Trans were performed using a large multiple k-mer (LMK) strategy consisting of k-mer lengths of 25, 35, 45, 55, 65, 75, and 85. Eleven metrics were used to evaluate each assembly strategy including three genome related evaluation metrics (contig number, N50 length, Contigs >1 kb, reads) and eight transcriptome evaluation metrics (mapped back to transcripts (RMBT), number of full length transcripts, number of open reading frames, Detonate RSEM-EVAL score, and percent alignment to the southern platyfish, Amazon molly, BUSCO and CEGMA databases). The assembly strategy that performed the best, that is it was within the top three of each evaluation metric, was the Bridger assembly (10 of 11) followed by the Oases SMK assembly (8 of 11), the Oases LMK assembly (6 of 11), the Trinity assembly (4 of 11), the SOAP LMK assembly (4 of 11), and the SOAP SMK assembly (3 of 11). This study provides an in-depth multi k-mer strategy investigation concluding that the assembler itself had a greater impact than k-mer size regardless of the strategy employed. Additionally, the comprehensive performance transcriptome evaluation metrics utilized

  16. Comparison of selective genotyping strategies for prediction of breeding values in a population undergoing selection.

    Science.gov (United States)

    Boligon, A A; Long, N; Albuquerque, L G; Weigel, K A; Gianola, D; Rosa, G J M

    2012-12-01

    Genomewide marker information can improve the reliability of breeding value predictions for young selection candidates in genomic selection. However, the cost of genotyping limits its use to elite animals, and how such selective genotyping affects predictive ability of genomic selection models is an open question. We performed a simulation study to evaluate the quality of breeding value predictions for selection candidates based on different selective genotyping strategies in a population undergoing selection. The genome consisted of 10 chromosomes of 100 cM each. After 5,000 generations of random mating with a population size of 100 (50 males and 50 females), generation G(0) (reference population) was produced via a full factorial mating between the 50 males and 50 females from generation 5,000. Different levels of selection intensities (animals with the largest yield deviation value) in G(0) or random sampling (no selection) were used to produce offspring of G(0) generation (G(1)). Five genotyping strategies were used to choose 500 animals in G(0) to be genotyped: 1) Random: randomly selected animals, 2) Top: animals with largest yield deviation values, 3) Bottom: animals with lowest yield deviations values, 4) Extreme: animals with the 250 largest and the 250 lowest yield deviations values, and 5) Less Related: less genetically related animals. The number of individuals in G(0) and G(1) was fixed at 2,500 each, and different levels of heritability were considered (0.10, 0.25, and 0.50). Additionally, all 5 selective genotyping strategies (Random, Top, Bottom, Extreme, and Less Related) were applied to an indicator trait in generation G(0,) and the results were evaluated for the target trait in generation G(1), with the genetic correlation between the 2 traits set to 0.50. The 5 genotyping strategies applied to individuals in G(0) (reference population) were compared in terms of their ability to predict the genetic values of the animals in G(1) (selection

  17. Comparison of advertising strategies between the indoor tanning and tobacco industries.

    Science.gov (United States)

    Greenman, Jennifer; Jones, David A

    2010-04-01

    The indoor tanning industry is large and continues to grow, with 2007 domestic sales in excess of $5 billion. Advertising is central to shaping the consumer's perception of indoor tanning as well as driving industry demand. This article aims to identify key drivers of consumer appeal by comparing tanning advertising strategies to those used by tobacco marketers. Tobacco advertising was selected as a reference framework because it is both well documented and designed to promote a product with known health hazards. Two thousand advertisements from 4 large tobacco advertisement databases were analyzed for type of advertisement strategy used, and 4 advertising method categories were devised to incorporate the maximum number of advertisements reviewed. Subsequently, contemporary tanning advertisements were collected from industry magazines and salon websites and evaluated relative to the identified strategy profiles. Both industries have relied on similar advertising strategies, including mitigating health concerns, appealing to a sense of social acceptance, emphasizing psychotropic effects, and targeting specific population segments. This examination is a small observational study, which was conducted without rigorous statistical analysis, and which is limited both by the number of advertisements and by advertising strategies examined. Given the strong parallels between tobacco and tanning advertising methodologies, further consumer education and investigation into the public health risks of indoor tanning is needed. Copyright 2009 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

  18. Steady-State Analysis and Comparison of Control Strategies for PMSM

    Directory of Open Access Journals (Sweden)

    Jyoti Agrawal

    2015-01-01

    Full Text Available Permanent Magnet Synchronous Motor (PMSM has been considered as the best choice for numerous applications. To make PMSM a high performance drive, effective control system is required. Vector control is accepted widely due to its decoupling effect but it is not the only performance requirement. Additional control methods such as constant torque angle control (CTAC, optimum torque per ampere control (OTPAC, unity power factor control (UPFC, constant mutual flux linkages control (CMFLC, and angle control of air gap flux and current phasor (ACAGF can also be implemented. This paper therefore presents some important control strategies for PMSM along with merits and limitations which provide a wide variety of control choices in many applications. The performance characteristics for each strategy under steady state are modelled and simulated in MATLAB environment. Based on the simulation results, a conclusion is drawn that OTPAC is superior in normalized torque per unit normalized stator current (Ten/isn ratio whereas UPFC yields very low Ten/isn ratio. In addition, performances of these control strategies are compared, which is a key to select optimum strategy depending on requirements. Based on the comparative study, it can be concluded that CMFLC is superior to CTAC, ACAGF, OTPAC, and UPFC. Hence, it can be a good control strategy to consider.

  19. The roles of the central executive and visuospatial storage in mental arithmetic: a comparison across strategies.

    Science.gov (United States)

    Hubber, Paula J; Gilmore, Camilla; Cragg, Lucy

    2014-05-01

    Previous research has demonstrated that working memory plays an important role in arithmetic. Different arithmetical strategies rely on working memory to different extents-for example, verbal working memory has been found to be more important for procedural strategies, such as counting and decomposition, than for retrieval strategies. Surprisingly, given the close connection between spatial and mathematical skills, the role of visuospatial working memory has received less attention and is poorly understood. This study used a dual-task methodology to investigate the impact of a dynamic spatial n-back task (Experiment 1) and tasks loading the visuospatial sketchpad and central executive (Experiment 2) on adults' use of counting, decomposition, and direct retrieval strategies for addition. While Experiment 1 suggested that visuospatial working memory plays an important role in arithmetic, especially when counting, the results of Experiment 2 suggested this was primarily due to the domain-general executive demands of the n-back task. Taken together, these results suggest that maintaining visuospatial information in mind is required when adults solve addition arithmetic problems by any strategy but the role of domain-general executive resources is much greater than that of the visuospatial sketchpad.

  20. Comparison among different retrofitting strategies for the vulnerability reduction of masonry bell towers

    Science.gov (United States)

    Milani, Gabriele; Shehu, Rafael; Valente, Marco

    2017-11-01

    This paper investigates the effectiveness of reducing the seismic vulnerability of masonry towers by means of innovative and traditional strengthening techniques. The followed strategy for providing the optimal retrofitting for masonry towers subjected to seismic risk relies on preventing active failure mechanisms. These vulnerable mechanisms are pre-assigned failure patterns based on the crack patterns experienced during the past seismic events. An upper bound limit analysis strategy is found suitable to be applied for simplified tower models in their present state and the proposed retrofitted ones. Taking into consideration the variability of geometrical features and the uncertainty of the strengthening techniques, Monte Carlo simulations are implemented into the limit analysis. In this framework a wide range of idealized cases are covered by the conducted analyses. The retrofitting strategies aim to increase the shear strength and the overturning load carrying capacity in order to reduce vulnerability. This methodology gives the possibility to use different materials which can fulfill the structural implementability requirements.

  1. SMEs Going Global: A Comparison of the Internationalization Strategies of Publishers and Online Social Networks

    Directory of Open Access Journals (Sweden)

    Bettina Lis

    2012-01-01

    Full Text Available Up to now, most research has been conducted on the internationalization strategies of large media companies and groups. But tapping new foreign markets is also relevant to small- and medium-sized enterprises (SMEs of all media sectors. This paper therefore focuses on the internationalization strategies of different types of media SMEs. It aims at describing and comparing the motives for becoming an international player as well as the specific market selection, market entry, and market development strategies. Furthermore, it focuses on the main organizational implications. On the basis of a multiple-case design we compare two German regional newspaper publishers with two German special interest publishers and two online social business networks. Results show similarities and differences between these media sectors according to the nature of the media businesses. The cases also highlight the importance of international management skills also in the context of SMEs.

  2. [Curriculum analysis and comparison between strategies or programs for early child development in Mexico].

    Science.gov (United States)

    Vargas-López, Guillermo; Guadarrama-Orozco, Jessica Haydee; Rizzoli-Córdoba, Antonio; Narcizo-Cenobio, Francisco Javier; Medrano-Loera, Gerónimo; Villagrán, Daniel Aceves; O'Shea Cuevas, Gabriel; Muñoz Hernández, Onofre

    Most of the strategies or programs that support early child development in Mexico are independent efforts that vary in scale, services offered and means of providing them. For the evaluation of the quality of these programs, an important aspect is the curriculum content. The aim of this study was to analyze and compare the curriculum content of the different strategies or programs focused on the promotion and intervention of early child development, which are offered by the Federal Government in Health and Education sectors in Mexico. We conducted a review of the curriculum content of the strategies and programs. The qualitative phase consisted of a comparative analysis where 75 indicators proposed by the Inter-American Development Bank were identified. The quantitative phase consisted of a descriptive analysis of the indicators. Finally, the analyses were compared to establish the performance of each one. Six strategies or programs were identified. In the analysis of the presence of indicators, the Oportunidades de Aprendizaje (Learning Opportunities, LO) strategy showed a larger number of indicators. In the amplitude analysis, both PEI-CONAFE and LO were the best balanced. Finally, in-depth analysis of the indicators LO and Skills for life were the best balanced while PEI-CONAFE was the best balanced in the social-emotional area, CeNSIA program for language and LO for cognitive development area. LO strategy showed the closest level of contents established by the Inter-American Development Bank. Copyright © 2016 Hospital Infantil de México Federico Gómez. Publicado por Masson Doyma México S.A. All rights reserved.

  3. Comparison of Various Online Strategies to Account for Interfractional Variations for Pancreatic Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Ahunbay, Ergun E., E-mail: eahunbay@mcw.edu [Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin (United States); Kimura, Brad; Liu, Feng; Erickson, Beth A.; Li, X. Allen [Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin (United States)

    2013-08-01

    Purpose: To identify practical techniques to address the large interfractional variations for pancreas irradiation by comparing various used/proposed online strategies. Methods and Materials: The daily computed tomography (CT) images acquired using a respiration-gated in-room CT (CTVision; Siemens) for 10 pancreatic cancer patients treated with image guided radiation therapy (IGRT) were analyzed. The contours of the pancreas and organs at risk on each daily CT set were generated by populating from the planning CT using a deformable registration tool (ABAS; Elekta) with manual editing. Nine online strategies were considered: (1) standard IGRT (ie, IGRT with 0-mm additional margin [AM]); (2) IGRT with 2-mm AM; (3) IGRT with 5-mm AM; (4) IGRT with plan renormalized to maintain 95% planning target volume (PTV) coverage; (5) full-scale reoptimization; (6) reoptimization starting from the original plan; (7) segment aperture morphing (SAM) from the original plan, based on PTV shape change; (8) SAM plus segment weight optimization; and (9) reoptimization starting from the SAM plan. One-way analysis of variance was applied to plan qualities for the 9 strategies to assess statistical significance in difference. Results: The 3 IGRT strategies (1-3) lead to either inadequate PTV coverage or higher doses to critical structures, indicating that the additional margins alone are not adequate to account for the changes. The full-scale reoptimization results in the best plan but requires the delineation of several structures, which is time consuming. The SAM strategy (7) was the fastest one, because it requires delineating only 1 structure (target), and its plan quality was comparable to that for the full-scale reoptimization. Conclusion: Online replanning strategies can lead to either reduced organs-at-risk dose and/or improved target coverage as compared with the current practice of IGRT. The SAM-based online replanning is comparable to full-scale reoptimization and is efficient

  4. Comparison of Various Online Strategies to Account for Interfractional Variations for Pancreatic Cancer

    International Nuclear Information System (INIS)

    Ahunbay, Ergun E.; Kimura, Brad; Liu, Feng; Erickson, Beth A.; Li, X. Allen

    2013-01-01

    Purpose: To identify practical techniques to address the large interfractional variations for pancreas irradiation by comparing various used/proposed online strategies. Methods and Materials: The daily computed tomography (CT) images acquired using a respiration-gated in-room CT (CTVision; Siemens) for 10 pancreatic cancer patients treated with image guided radiation therapy (IGRT) were analyzed. The contours of the pancreas and organs at risk on each daily CT set were generated by populating from the planning CT using a deformable registration tool (ABAS; Elekta) with manual editing. Nine online strategies were considered: (1) standard IGRT (ie, IGRT with 0-mm additional margin [AM]); (2) IGRT with 2-mm AM; (3) IGRT with 5-mm AM; (4) IGRT with plan renormalized to maintain 95% planning target volume (PTV) coverage; (5) full-scale reoptimization; (6) reoptimization starting from the original plan; (7) segment aperture morphing (SAM) from the original plan, based on PTV shape change; (8) SAM plus segment weight optimization; and (9) reoptimization starting from the SAM plan. One-way analysis of variance was applied to plan qualities for the 9 strategies to assess statistical significance in difference. Results: The 3 IGRT strategies (1-3) lead to either inadequate PTV coverage or higher doses to critical structures, indicating that the additional margins alone are not adequate to account for the changes. The full-scale reoptimization results in the best plan but requires the delineation of several structures, which is time consuming. The SAM strategy (7) was the fastest one, because it requires delineating only 1 structure (target), and its plan quality was comparable to that for the full-scale reoptimization. Conclusion: Online replanning strategies can lead to either reduced organs-at-risk dose and/or improved target coverage as compared with the current practice of IGRT. The SAM-based online replanning is comparable to full-scale reoptimization and is efficient

  5. Investigation and Comparison of Separate Meter-In Separate Meter-Out Control Strategies

    DEFF Research Database (Denmark)

    Pedersen, Henrik C.; Andersen, Torben Ole; Skoubo, Tobias

    2014-01-01

    multivariable control strategies for SMISMO control of a single axis hydraulic system with a differential cylinder, when not taking other measures to improve performance. The paper first presents an experimentally verified model of the system considered, from which a linear model is derived. Based on the model......, the control strategies are discussed and severalH¥ controllers are designed, for which both simulation and experimental results are presented. The controllers are evaluated with regard to performance and robustness and compared to a simple SISO control. Based on the findings, the possibilities and limitations...

  6. A Comparison of the Metacognitive Reading Strategies Used by EFL and ESL Readers

    Science.gov (United States)

    Karbalaei, Alireza

    2010-01-01

    This study investigated whether there are any significant differences between EFL and ESL readers in metacognitive reading strategies when they are reading academic texts in English. One hundred and ninety undergraduate students (96 Iranians and 93 Indians) completed an instrument designed to measure the students' metacognitive awareness of…

  7. A Comparison of General and Content-Specific Literacy Strategies for Learning Science Content

    Science.gov (United States)

    Reed, Deborah K.; Whalon, Kelly; Lynn, Devon; Miller, Nicole; Smith, Keely

    2017-01-01

    This study employed an adapted alternating treatments single-case design to explore students' learning of biology content when using a general note-taking (GNT) strategy and a content-specific graphic organizer (CGO) to support reading high school biology texts. The 4 focal participants were 15-18-year-olds committed to a moderate risk juvenile…

  8. Comparison of between-training-sessions recovery strategies for world-class BMX pilots.

    Science.gov (United States)

    Marquet, Laurie-Anne; Hausswirth, Christophe; Hays, Arnaud; Vettoretti, Fabrice; Brisswalter, Jeanick

    2015-03-01

    To assess the impact of between-training-sessions recovery strategies (passive [PAS], active [ACT], cold-water immersion [CWI], and ingestion of a recovery drink [NUTR]) on maximal cycling performance, perceptions of delayed-onset muscle soreness (DOMS), and fatigue in world-class BMX riders. Eleven elite BMX athletes, members of the French national team (top country in the 2011 international ranking, 4 medals at the 2012 World Championships, top European country), participated in the study, which involved standardized training periods. Athletes performed 3 maximal-sprint power tests: the first day of the week before the training session and before and after training on the third day of the week (D3). The recovery strategy was randomly assigned to each participant on day 2 immediately after the last training period of the day. Perceptions of DOMS and general fatigue were recorded on D3. After training on D3, the decrease in maximal-sprint power (Pmax) was significantly greater for PAS than with CWI (P=.02) and NUTR (P=.018). Similar results were found with ACT (vs CWI P=.044, and vs NUTR P=.042). Self-reported DOMS and fatigue were significantly greater after PAS than after other strategies. For elite BMX riders, between training days, nutritional and/or CWI recovery strategies appear to be best for reducing muscle fatigue and increasing the capacity to withstand the training schedule.

  9. Improving prediction models with new markers: A comparison of updating strategies

    NARCIS (Netherlands)

    D. Nieboer (Daan); Y. Vergouwe (Yvonne); D. Ankerst (Donna); M.J. Roobol-Bouts (Monique); E.W. Steyerberg (Ewout)

    2016-01-01

    textabstractBackground: New markers hold the promise of improving risk prediction for individual patients. We aimed to compare the performance of different strategies to extend a previously developed prediction model with a new marker. Methods: Our motivating example was the extension of a risk

  10. Multiple imputation of missing data in multilevel designs: A comparison of different strategies.

    Science.gov (United States)

    Lüdtke, Oliver; Robitzsch, Alexander; Grund, Simon

    2017-03-01

    Multiple imputation is a widely recommended means of addressing the problem of missing data in psychological research. An often-neglected requirement of this approach is that the imputation model used to generate the imputed values must be at least as general as the analysis model. For multilevel designs in which lower level units (e.g., students) are nested within higher level units (e.g., classrooms), this means that the multilevel structure must be taken into account in the imputation model. In the present article, we compare different strategies for multiply imputing incomplete multilevel data using mathematical derivations and computer simulations. We show that ignoring the multilevel structure in the imputation may lead to substantial negative bias in estimates of intraclass correlations as well as biased estimates of regression coefficients in multilevel models. We also demonstrate that an ad hoc strategy that includes dummy indicators in the imputation model to represent the multilevel structure may be problematic under certain conditions (e.g., small groups, low intraclass correlations). Imputation based on a multivariate linear mixed effects model was the only strategy to produce valid inferences under most of the conditions investigated in the simulation study. Data from an educational psychology research project are also used to illustrate the impact of the various multiple imputation strategies. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  11. Performance and strategy comparisons of human listeners and logistic regression in discriminating underwater targets.

    Science.gov (United States)

    Yang, Lixue; Chen, Kean

    2015-11-01

    To improve the design of underwater target recognition systems based on auditory perception, this study compared human listeners with automatic classifiers. Performances measures and strategies in three discrimination experiments, including discriminations between man-made and natural targets, between ships and submarines, and among three types of ships, were used. In the experiments, the subjects were asked to assign a score to each sound based on how confident they were about the category to which it belonged, and logistic regression, which represents linear discriminative models, also completed three similar tasks by utilizing many auditory features. The results indicated that the performances of logistic regression improved as the ratio between inter- and intra-class differences became larger, whereas the performances of the human subjects were limited by their unfamiliarity with the targets. Logistic regression performed better than the human subjects in all tasks but the discrimination between man-made and natural targets, and the strategies employed by excellent human subjects were similar to that of logistic regression. Logistic regression and several human subjects demonstrated similar performances when discriminating man-made and natural targets, but in this case, their strategies were not similar. An appropriate fusion of their strategies led to further improvement in recognition accuracy.

  12. Comparison of strategies for model predictive control for home heating in future energy systems

    DEFF Research Database (Denmark)

    Vogler-Finck, Pierre Jacques Camille; Popovski, Petar; Wisniewski, Rafal

    2017-01-01

    using historical weather and power system data from Denmark. Trade-offs between energy consumption, comfort and incurred CO2 emissions depending on the chosen objective function are quantified, highlighting the need to carefully select the strategy used in future design and implementation, rather than...... simply operating energy or SPOT price optimisation....

  13. A Comparison of Alternative Strategies for Cost-Effective Water Quality Management in Lakes

    Science.gov (United States)

    Daniel Boyd Kramer; Stephen Polasky; Anthony Starfield; Brian Palik; Lynn Westphal; Stephanie Snyder; Pamela Jakes; Rachel Hudson; Eric Gustafson

    2006-01-01

    Roughly 45% of the assessed lakes in the United States are impaired for one or more reasons. Eutrophication due to excess phosphorus loading is common in many impaired lakes. Various strategies are available to lake residents for addressing declining lake water quality, including septic system upgrades and establishing riparian buffers. This study examines 25 lakes to...

  14. Early Child Care Teachers' Socialization Goals and Preferred Behavioral Strategies: A Cross-Cultural Comparison

    Science.gov (United States)

    Gernhardt, Ariane; Lamm, Bettina; Keller, Heidi; Döge, Paula

    2014-01-01

    This study investigated early child care teachers' culturally shaped socialization goals and preferred behavioral strategies. The participants were 183 female teachers and trainees, 93 from Osnabrück, Germany, representing an urban Western context, which can be characterized by a primary cultural orientation toward psychological autonomy and a…

  15. American and Chinese Students' Profiles Based on Spanish-Learning Strategies: A Transcultural Comparison

    Science.gov (United States)

    Bernardo, Aránzazu; Amérigo, María; García, Juan A.

    2017-01-01

    This paper presents a study on the use of learning strategies in foreign languages, and more specifically Spanish. The study was conducted with 376 Chinese and American students who were studying Spanish in their countries of origin. The results obtained from a latent class cluster analysis identified five groups of participants based on the…

  16. Comparison of different modelling strategies for simulating gas exchange of Douglas-fir forest

    NARCIS (Netherlands)

    Wijk, van M.T.; Bouten, W.; Verstraten, J.M.

    2002-01-01

    Carbon and latent heat fluxes can be simulated with different model strategies to fulfil different research purposes. In this study we compared four different model concepts: artificial neural networks (ANN), fuzzy logic (FL), an index model (IM, using light use efficiency and water use efficiency)

  17. Increasing Intervention Implementation in General Education Following Consultation: A Comparison of Two Follow-Up Strategies.

    Science.gov (United States)

    Noell, George H.; Witt, Joseph C.; LaFleur, Lynn H.; Mortenson, Bruce P.; Ranier, Deborah D.; LeVelle, James

    2000-01-01

    A study examined two strategies for increasing the accuracy with which five elementary teachers implemented a peer tutoring intervention for students with reading difficulties. Four teachers implemented the intervention at levels substantially above baseline during the performance feedback condition. Student reading comprehension scores improved…

  18. A New Comparison of Active Learning Strategies to Traditional Lectures for Teaching College Astronomy

    Science.gov (United States)

    LoPresto, Michael C.; Slater, Timothy F.

    2016-01-01

    Although traditional lectures are still the dominant form of undergraduate instruction, there have been relatively few studies comparing various learner-centered and active learning teaching strategies to one another in order to guide professors in making informed instructional decisions. To study the impact of different active learning…

  19. A Comparison of Low Performing Students' Achievements in Factoring Cubic Polynomials Using Three Different Strategies

    Science.gov (United States)

    Ogbonnaya, Ugorji I.; Mogari, David L.; Machisi, Eric

    2013-01-01

    In this study, repeated measures design was employed to compare low performing students' achievements in factoring cubic polynomials using three strategies. Twenty-five low-performing Grade 12 students from a secondary school in Limpopo province took part in the study. Data was collected using achievement test and was analysed using repeated…

  20. Comparison of acceptance and distraction strategies in coping with experimentally induced pain

    Directory of Open Access Journals (Sweden)

    Moore H

    2015-03-01

    Full Text Available Hazel Moore,1 Ian Stewart,1 Dermot Barnes-Holmes,2 Yvonne Barnes-Holmes,2 Brian E McGuire1,31School of Psychology, National University of Ireland, Galway, 2Department of Psychology, National University of Ireland, Maynooth, 3Centre for Pain Research, National University of Ireland, Galway, IrelandBackground: This study compared an acceptance-based strategy with a control-based strategy (distraction in terms of the ability of participants to tolerate a painful stimulus, across two experiments. In addition, participants were either actively encouraged, or not, to link pain tolerance with pursuit of valued goals to examine the impact of pursuing a personally meaningful goal or value on the extent to which pain will be tolerated.Methods: Participants in experiment 1 (n=41 and experiment 2 (n=52 were equally assigned to acceptance or distraction protocols. Further, half the participants in each group generated examples from their own lives in which they had pursued a valued objective, while the other half did not. In experiment 2, the values focus was enhanced to examine the impact on pain tolerance.Results: There were no significant differences overall between the acceptance and distraction groups on pain tolerance in either experiment. However, in experiment 2, individuals classified as accepting in terms of general coping style and who were assigned to the acceptance strategy showed significantly better pain tolerance than accepting individuals who were in the distraction condition. Across both experiments, those with strong goal-driven values in both protocols were more tolerant of pain. Participants appeared to have more difficulty adhering to acceptance than to distraction as a strategy.Conclusion: Acceptance may be associated with better tolerance of pain, but may also be more difficult to operationalize than distraction in experimental studies. Matching coping style and coping strategy may be most effective, and enhancement of goal

  1. Too Much Fun for Therapy: Therapeutic Recreation as an Intervention Tool with At-Risk Youth. A Series of Solutions and Strategies.

    Science.gov (United States)

    Brooks, Katherine Walker

    This publication introduces the concept of therapeutic recreation (TR), illustrating its natural fit into the educational process and its use with at-risk students, and providing resources for further use. Section 1 examines what places a child at risk, focusing on educational goals, student behaviors, and home life. Section 2 defines TR as a…

  2. Strategy for communicating benefit-risk decisions: a comparison of regulatory agencies' publicly available documents.

    Science.gov (United States)

    Leong Wai Yeen, James; Salek, Sam; Walker, Stuart

    2014-01-01

    The assessment report formats of four major regulatory reference agencies, US Food and Drug Administration, European Medicines Agency, Health Canada, and Australia's Therapeutic Goods Administration were compared to a benefit-risk (BR) documentation template developed by the Centre for Innovation in Regulatory Science and a four-member Consortium on Benefit-Risk Assessment. A case study was also conducted using a US FDA Medical Review, the European Public Assessment Report and Australia's Public Assessment Report for the same product. Compared with the BR Template, existing regulatory report formats are inadequate regarding the listing of benefits and risks, the assigning of relative importance and values, visualization and the utilization of a detailed, systematic, standardized structure. The BR Template is based on the principles of BR assessment common to major regulatory agencies. Given that there are minimal differences among the existing regulatory report formats, it is timely to consider the feasibility of a universal template.

  3. Identifying quality improvement intervention publications - A comparison of electronic search strategies

    Directory of Open Access Journals (Sweden)

    Rubenstein Lisa V

    2011-08-01

    Full Text Available Abstract Background The evidence base for quality improvement (QI interventions is expanding rapidly. The diversity of the initiatives and the inconsistency in labeling these as QI interventions makes it challenging for researchers, policymakers, and QI practitioners to access the literature systematically and to identify relevant publications. Methods We evaluated search strategies developed for MEDLINE (Ovid and PubMed based on free text words, Medical subject headings (MeSH, QI intervention components, continuous quality improvement (CQI methods, and combinations of the strategies. Three sets of pertinent QI intervention publications were used for validation. Two independent expert reviewers screened publications for relevance. We compared the yield, recall rate, and precision of the search strategies for the identification of QI publications and for a subset of empirical studies on effects of QI interventions. Results The search yields ranged from 2,221 to 216,167 publications. Mean recall rates for reference publications ranged from 5% to 53% for strategies with yields of 50,000 publications or fewer. The 'best case' strategy, a simple text word search with high face validity ('quality' AND 'improv*' AND 'intervention*' identified 44%, 24%, and 62% of influential intervention articles selected by Agency for Healthcare Research and Quality (AHRQ experts, a set of exemplar articles provided by members of the Standards for Quality Improvement Reporting Excellence (SQUIRE group, and a sample from the Cochrane Effective Practice and Organization of Care Group (EPOC register of studies, respectively. We applied the search strategy to a PubMed search for articles published in 10 pertinent journals in a three-year period which retrieved 183 publications. Among these, 67% were deemed relevant to QI by at least one of two independent raters. Forty percent were classified as empirical studies reporting on a QI intervention. Conclusions The presented

  4. Effectiveness of a telemonitoring intensive strategy in early rheumatoid arthritis: comparison with the conventional management approach.

    Science.gov (United States)

    Salaffi, Fausto; Carotti, Marina; Ciapetti, Alessandro; Di Carlo, Marco; Gasparini, Stefania; Farah, Sonia; Gutierrez, Marwin

    2016-04-02

    The advent of Internet and World Wide Web has created new perspectives toward interaction between patients and healthcare professionals. Telemonitoring patients with rheumatoid arthritis (RA) is an emerging concept to guide the collaborative management treatment and improve outcomes in patients. The objective of this study was to investigate whether an intensive treatment strategy, according to a telemonitoring protocol, is more effective than conventional management strategy in reaching remission and comprehensive disease control (CDC) after 1 year in early rheumatoid arthritis (ERA) patients. Forty-four ERA patients were randomly allocated into two groups: the telemonitoring intensive strategy (TIS) group (group 1) or the conventional strategy (CS) group (group 2). Three patients refused to participate. In group 1 (n = 21), a remote monitoring system of disease activity, in combination with protocolised treatment adjustments aiming for remission was applied. In group 2 (n = 20), patients were treated according to daily clinical practice, with regular evaluation of disease activity, but without protocolised treatment adjustments. A telemedical care called "REmote TElemonitoring for MAnaging Rheumatologic Condition and HEaltcare programmes" (RETE-MARCHE), was developed to perform the remote monitoring. A higher percentage of patients in the TIS group achieved CDAI remission vs patients in the CS group (38.1 % vs 25 % at year 1, p <0.01). Time to achieve remission was significantly shorter in the group 1 than in the group 2, with a median of 20 weeks vs a median over 36-weeks (p <0.001). Concordantly, the patients in group 1 showed a greater improvement (p <0.001), compared with group 2 in terms of functional impairment (71.4 % vs 35 %) and radiological damage progression (23.8 % vs 10 %), resulting in a greater rate of CDC (19.4 % vs 5 %). According to our results, an intensive treatment strategy by telemonitoring leads to more effective disease

  5. Comparison of Coping Strategies, Perfectionism and Self-Efficacy in Individuals with Substance Use Disorder and Normal Individuals

    Directory of Open Access Journals (Sweden)

    Farzeneh Ranjbar, N

    2013-05-01

    Full Text Available Aim: The aim of the present study was to compare the coping strategies, perfectionism (positive and negative and self-efficacy in individuals with substance use disorder and normal individuals. Method: In this casual-comparative study, 200 persons (100 individuals with substance use disorder and 100 normal individuals were selected by cluster random sampling. The groups were matched with consideration of demographic characteristics (age, gender, marital status and education and they completed the Lazarus and Folkman coping strategies inventory (1984, Terry-Short perfectionism scale (1995 and Schwartz and Jerusalem general self-efficacy questionnaire (1981. Results: Findings of the study showed that the two groups had significant differences on subscales of coping strategies namely: avoidance, self-control, responsibility, avoidance-escape and problem solving. In addition, substance abuse group had also lower scores on the positive perfectionism in comparison of normal group. A significant difference on the level of self-efficacy was observed between the two groups, in this regard, self-efficacy in normal group was more than substance abuse group. Conclusion: The selection of improper coping style, unrealistic and excessive expectations about the abilities and low levels of self-efficacy are factors that can lead to more substance abuse and finally addiction.

  6. Therapeutic radionuclides

    International Nuclear Information System (INIS)

    Choi, Sun Ju; Hong, Young Don; Lee, So Young

    2006-01-01

    Since the development of sophisticated molecular carriers such as octereotides for peptide receptor targeting and monoclonal antibodies against various associated with specific tumor types, radionuclide therapy (RNT) employing open sources of therapeutic agents is promising modality for treatment of tumors. Furthermore, the emerging of new therapeutic regimes and new approaches for tumor treatment using radionuclide are anticipated in near future. In targeted radiotherapy using peptides and other receptor based carrier molecules, the use of radionuclide with high specific activity in formulating the radiopharmaceutical is essential in order to deliver sufficient number of radionuclides to the target site without saturating the target. In order to develop effective radiopharmaceuticals for therapeutic applications, it is crucial to carefully consider the choice of appropriate radionuclides as well as the carrier moiety with suitable pharmacokinetic properties that could result in good in vivo localization and desired excretion. Up to date, only a limited number of radionuclides have been applied in radiopharmaceutical development due to the constraints in compliance with their physical half-life, decay characteristics, cost and availability in therapeutic applications. In this review article, we intend to provide with the improved understanding of the factors of importance of appropriate radionuclide for therapy with respect to their physical properties and therapeutic applications

  7. COMPARISON OF CLASSICAL AND INTERACTIVE MULTI-ROBOT EXPLORATION STRATEGIES IN POPULATED ENVIRONMENTS

    Directory of Open Access Journals (Sweden)

    Nassim Kalde

    2015-06-01

    Full Text Available Multi-robot exploration consists in coordinating robots for mapping an unknown environment. It raises several issues concerning task allocation, robot control, path planning and communication. We study exploration in populated environments, in which pedestrian flows can severely impact performances. However, humans have adaptive skills for taking advantage of these flows while moving. Therefore, in order to exploit these human abilities, we propose a novel exploration strategy that explicitly allows for human-robot interactions. Our model for exploration in populated environments combines the classical frontier-based strategy with our interactive approach. We implement interactions where robots can locally choose a human guide to follow and define a parametric heuristic to balance interaction and frontier assignments. Finally, we evaluate to which extent human presence impacts our exploration model in terms of coverage ratio, travelled distance and elapsed time to completion.

  8. Comparison of global versus Asian clinical trial strategies supportive of registration of drugs in Japan.

    Science.gov (United States)

    Shirotani, Mari; Kurokawa, Tatsuo; Chiba, Koji

    2014-07-01

    The number of worldwide and Asian multiregional clinical trials (MRCTs) submitted for Japanese New Drug Applications increased markedly between 2009 and 2013, with an increasing number performed for simultaneously submission in the USA, EU, and Japan. Asian studies accounted for 32% of MRCTs (14/44 studies) and had comparatively small sample sizes (phase 3 clinical trials were not be planned in the USA/EU, when there was insufficient knowledge of ethnic differences in drug efficacy and safety, or when Caucasian data could not be extrapolated to the Japanese population. New strategies with Asian studies including the Japanese population could be conducted instead of Japanese domestic development strategy. © 2014, The American College of Clinical Pharmacology.

  9. Methodological notes on model comparisons and strategy classification: A falsificationist proposition

    OpenAIRE

    Morten Moshagen; Benjamin E. Hilbig

    2011-01-01

    Taking a falsificationist perspective, the present paper identifies two major shortcomings of existing approaches to comparative model evaluations in general and strategy classifications in particular. These are (1) failure to consider systematic error and (2) neglect of global model fit. Using adherence measures to evaluate competing models implicitly makes the unrealistic assumption that the error associated with the model predictions is entirely random. By means of simple schematic example...

  10. Look-ahead strategies for controlling batch operations in industry: Overview, comparison and exploration

    OpenAIRE

    van der Zee, D.J.

    2000-01-01

    Batching jobs in a manufacturing system is a very common policy in most industries. Main reasons for batching are avoidance of set ups and/or facilitation of material handling. Good examples of batch wise production systems are ovens found in aircraft industry and in semi-conductor manufacturing. Starting from the early nineties much research efforts have been put in constructing strategies for the dynamic control of these systems in order to reduce cycle times. Typically, these so-called "lo...

  11. Comparison in Measuring Effectiveness of Momentum and Contrarian Trading Strategy in Indonesian Stock Exchange

    Directory of Open Access Journals (Sweden)

    Rizky Luxianto

    2014-08-01

    Full Text Available This  paper  wants  to  explore  the  effectiveness  of  momentum  or  contrarian  strategy  in Indonesian  Stock  Exchange  using  different  methods  in  measuring  the  performance.  The point of momentum or contrarian strategy is selecting winner (stocks with highest gain or loser stocks (stocks with highest loss and then buy or sell it based on the research result. This research employed three methods in measuring performance to select winner and loser stocks.  The  irst  method  used  cross  section  relative  return,  while  the  second  method  used cross section relative return plus risk component (return divided by standard deviation, and the  third  method  employed  historical  relative  return  instead  of  cross  section.  The  result  is that,  all  of  those  three  methods  prove  that  momentum  strategy  is  effectively applicable  for winner stock, so in the next period winner stock will continue to make profit, while for loser stock, it is more effective to use contrarian strategy because in the next period, loser stock will rebound and make proit after suffering from high loss. ";} // -->activate javascript

  12. Caregiver burden and coping strategies for patients with schizophrenia: comparison between Japan and Korea.

    Science.gov (United States)

    Hanzawa, Setsuko; Bae, Jeong-Kyu; Tanaka, Hideki; Bae, Yong Jun; Tanaka, Goro; Inadomi, Hiroyuki; Nakane, Yoshibumi; Ohta, Yasuyuki

    2010-08-01

    With the current shift to community-centered mental health services, considerable research on the family burden of caring for patients with schizophrenia has been conducted in developed countries. However, there has been no investigation of families with Japanese or Korean sociocultural backgrounds. Therefore, the present study compared the caregiver burden and coping strategies of families of patients with schizophrenia in Japan and Korea in order to elucidate similarities and differences in the sociocultural factors that affect the care experience of families in Northeast Asia. A total of 99 Japanese (Nagasaki) and 92 Korean (Seoul, Daegu) family members of patients with schizophrenia were surveyed in regards to caregiver burden, coping strategies, and nursing awareness of the caregiver role regarding the patient with schizophrenia. Analysis revealed the following: (i) although no difference in caregiver burden and coping strategy was observed between the countries, the nursing awareness of families' caregiver role was significantly higher in Japan than in Korea; (ii) caregiver burden was significantly associated with the patient's social functioning and care needs in both countries; and (iii) caregiver burden was significantly associated with reduction of social interests, coercion, avoidance, resignation, and nursing awareness of caregiver role in both countries. Although the nursing awareness of families' roles in caring for patients with schizophrenia differed between Japan and Korea, similar trends were observed for the causes of caregiver burden. These findings suggest that in order to provide effective support for reducing caregiver burden, the necessity of such support must be emphasized in both countries.

  13. Comparison of magnetic island stabilization strategies from magneto-hydrodynamic simulations

    Science.gov (United States)

    Février, O.; Maget, P.; Lütjens, H.; Beyer, P.

    2017-04-01

    The degradation of plasma confinement in tokamaks caused by magnetic islands motivates to better understand their possible suppression using electron cyclotron current drive (ECCD) and to investigate the various strategies relevant for this purpose. In this work, we evaluate the efficiency of several control methods through nonlinear simulations of this process with the toroidal magneto-hydro-dynamic (MHD) code XTOR-2F (Lütjens and Luciani 2010 J. Comput. Phys. 229 8130-43), which has been extended to incorporate in Ohm’s law a source term modeling the driven current resulting from the interaction of the EC waves with the plasma. A basic control system has been implemented in the code, allowing testing of advanced strategies that require feedback on island position or phase. We focus in particular on the robustness of the control strategies towards uncertainties that apply to the control and ECCD systems, such as the risk of misalignment of the current deposition or the possible inability to generate narrow current deposition.

  14. Increasing College Students' Interest and Engagement in STEM: A Comparison of Strategies for Challenging STEM Stereotypes

    Science.gov (United States)

    Shin, Jiyun Elizabeth L.

    Increasing science, technology, engineering, and mathematics (STEM) graduates has become an important part of the education agenda in the U.S. in recent years. Stereotypes about STEM (i.e., belief that STEM abilities are innate, and that European American men are best suited for STEM) have been identified as one of the critical factors that may contribute to low recruitment and retention of STEM students. Drawing from the literatures on biological essentialism and role models, this study compared different strategies for challenging STEM stereotypes among undergraduate students in STEM and non-STEM fields. STEM stereotypes were challenged directly with research articles that provided non-biological explanations for STEM success and interest (a strategy used in the essentialism research) and indirectly with biographies of successful STEM role models who are underrepresented in their field and who succeeded through hard work (a strategy used in the role model research). Contrary to the predictions, exposure to the role model biographies, research articles, or combination of both did not have statistically significant effects on participants' reported STEM interest and academic intentions. Possible explanations for the lack of significant findings as well as suggestions for developing effective interventions to promote STEM engagement among students are discussed.

  15. HIV prevention where it is needed most: comparison of strategies for the geographical allocation of interventions.

    Science.gov (United States)

    Anderson, Sarah-Jane; Ghys, Peter D; Ombam, Regina; Hallett, Timothy B

    2017-12-01

    A strategic approach to the application of HIV prevention interventions is a core component of the UNAIDS Fast Track strategy to end the HIV epidemic by 2030. Central to these plans is a focus on high-prevalence geographies, in a bid to target resources to those in greatest need and maximize the reduction in new infections. Whilst this idea of geographical prioritization has the potential to improve efficiency, it is unclear how it should be implemented in practice. There are a range of prevention interventions which can be applied differentially across risk groups and locations, making allocation decisions complex. Here, we use mathematical modelling to compare the impact (infections averted) of a number of different approaches to the implementation of geographical prioritization of prevention interventions, similar to those emerging in policy and practice, across a range of prevention budgets. We use geographically specific mathematical models of the epidemic and response in 48 counties and major cities of Kenya to project the impact of the different geographical prioritization approaches. We compare the geographical allocation strategies with a nationally uniform approach under which the same interventions must be applied across all modelled locations. We find that the most extreme geographical prioritization strategy, which focuses resources exclusively to high-prevalence locations, may substantially restrict impact (41% fewer infections averted) compared to a nationally uniform approach, as opportunities for highly effective interventions for high-risk populations in lower-prevalence areas are missed. Other geographical allocation approaches, which intensify efforts in higher-prevalence areas whilst maintaining a minimum package of cost-effective interventions everywhere, consistently improve impact at all budget levels. Such strategies balance the need for greater investment in locations with the largest epidemics whilst ensuring higher-risk groups in lower

  16. Improving prediction models with new markers: a comparison of updating strategies

    Directory of Open Access Journals (Sweden)

    D. Nieboer

    2016-09-01

    Full Text Available Abstract Background New markers hold the promise of improving risk prediction for individual patients. We aimed to compare the performance of different strategies to extend a previously developed prediction model with a new marker. Methods Our motivating example was the extension of a risk calculator for prostate cancer with a new marker that was available in a relatively small dataset. Performance of the strategies was also investigated in simulations. Development, marker and test sets with different sample sizes originating from the same underlying population were generated. A prediction model was fitted using logistic regression in the development set, extended using the marker set and validated in the test set. Extension strategies considered were re-estimating individual regression coefficients, updating of predictions using conditional likelihood ratios (LR and imputation of marker values in the development set and subsequently fitting a model in the combined development and marker sets. Sample sizes considered for the development and marker set were 500 and 100, 500 and 500, and 100 and 500 patients. Discriminative ability of the extended models was quantified using the concordance statistic (c-statistic and calibration was quantified using the calibration slope. Results All strategies led to extended models with increased discrimination (c-statistic increase from 0.75 to 0.80 in test sets. Strategies estimating a large number of parameters (re-estimation of all coefficients and updating using conditional LR led to overfitting (calibration slope below 1. Parsimonious methods, limiting the number of coefficients to be re-estimated, or applying shrinkage after model revision, limited the amount of overfitting. Combining the development and marker set using imputation of missing marker values approach led to consistently good performing models in all scenarios. Similar results were observed in the motivating example. Conclusion When the

  17. Avidin-conjugated polymers with monobiotinylated antibody fragments: a new strategy for the noncovalent attachment of recombinant proteins for polymer therapeutics

    Czech Academy of Sciences Publication Activity Database

    Laga, Richard; Pola, Robert; Ulbrich, Karel; Hořejší, Magdalena; Sieglová, Irena; Král, Vlastimil; Fábry, Milan; Pechar, Michal

    2013-01-01

    Roč. 28, č. 3 (2013), s. 289-299 ISSN 0883-9115 R&D Projects: GA ČR GCP207/12/J030; GA AV ČR IAAX00500803 Institutional research plan: CEZ:AV0Z50520514 Institutional support: RVO:61389013 ; RVO:68378050 Keywords : avidin- biotin complex * polymer therapeutics * drug targeting Subject RIV: CD - Macromolecular Chemistry Impact factor: 2.500, year: 2013

  18. Logical network of genotoxic stress-induced NF-kappaB signal transduction predicts putative target structures for therapeutic intervention strategies

    Directory of Open Access Journals (Sweden)

    Rainer Poltz

    2009-12-01

    Full Text Available Rainer Poltz1, Raimo Franke1,#, Katrin Schweitzer1, Steffen Klamt2, Ernst-Dieter Gilles2, Michael Naumann11Institute of Experimental Internal Medicine, Otto von Guericke University, Magdeburg, Germany; 2Max Planck Institute for Dynamics of Complex Technical Systems, Magdeburg, Germany; #Present address: Department of Chemical Biology, Helmholtz Centre for Infection Research, Braunschweig, GermanyAbstract: Genotoxic stress is induced by a broad range of DNA-damaging agents and could lead to a variety of human diseases including cancer. DNA damage is also therapeutically induced for cancer treatment with the aim to eliminate tumor cells. However, the effectiveness of radio- and chemotherapy is strongly hampered by tumor cell resistance. A major reason for radio- and chemotherapeutic resistances is the simultaneous activation of cell survival pathways resulting in the activation of the transcription factor nuclear factor-kappa B (NF-κB. Here, we present a Boolean network model of the NF-κB signal transduction induced by genotoxic stress in epithelial cells. For the representation and analysis of the model, we used the formalism of logical interaction hypergraphs. Model reconstruction was based on a careful meta-analysis of published data. By calculating minimal intervention sets, we identified p53-induced protein with a death domain (PIDD, receptor-interacting protein 1 (RIP1, and protein inhibitor of activated STAT y (PIASy as putative therapeutic targets to abrogate NF-κB activation resulting in apoptosis. Targeting these structures therapeutically may potentiate the effectiveness of radio- and chemotherapy. Thus, the presented model allows a better understanding of the signal transduction in tumor cells and provides candidates as new therapeutic target structures.Keywords: apoptosis, Boolean network, cancer therapy, DNA-damage response, NF-κB

  19. A comparison of stable caesium uptake by six grass species of contrasting growth strategy

    International Nuclear Information System (INIS)

    Willey, N.J.; Martin, M.H.

    1997-01-01

    Six plants in the family Gramineae were used to investigate the relationship between Cs uptake, nutrient regime and plant growth strategy sensu Grime (1979: Plant Growth Strategies and Vegetation Processes, John Wiley). The roots of 66 day old Elymus repens (L.) Gould., Bromus sterilis L., Agrostis stolonifera L., Anthoxanthum odoratum L., Festuca ovina L. and Nardus stricta L. plants grown in acid-washed sand at high and low nutrient levels were exposed to a 96 h pulse of stable Cs at 0.05 mM, 0.15 mM, 0.3 mM, 1.0 mM and 3.0 mM concentrations. Different nutrient regimes induced large differences in dry wt in E. repens, B. sterilis and A. stolonifera plants but only small differences in N. stricta and F. ovina plants. At high nutrient concentrations, A. stolonifera, A. odoratum, F. ovina and N. stricta shoots showed significantly greater increases in internal Cs concentration with rising external Cs concentrations than did E. repens and B. sterilis shoots. The relationship between increases in shoot and external Cs concentrations was statistically indistinguishable between species in plants grown at the low nutrient concentration. These patterns of Cs uptake ensured that with long-term high K concentrations the more competitive plants (E. repens and B. sterilis) accumulated higher concentrations of Cs from low external concentrations than did non-competitive plants or competitive plants grown at low nutrient levels. It is suggested that the relationship between plant growth strategy sensu Grime (1979) and Cs accumulation patterns may help to explain the different concentrations to which species accumulate radiocaesium from the soil. (author)

  20. Comparison of Outcomes of Transfemoral Transcatheter Aortic Valve Implantation Using a Minimally Invasive Versus Conventional Strategy.

    Science.gov (United States)

    Attizzani, Guilherme F; Alkhalil, Ahmad; Padaliya, Bimal; Tam, Chor-Cheung; Lopes, Joao Pedro; Fares, Anas; Bezerra, Hiram G; Medallion, Benjamin; Park, Soon; Deo, Salil; Sareyyupoglu, Basar; Parikh, Sahil; Zidar, David; Elgudin, Yakov; Popovich, Kehllee; Davis, Angela; Staunton, Elizabeth; Tomic, Ana; Mazzurco, Stacey; Avery, Edward; Markowitz, Alan; Simon, Daniel I; Costa, Marco A

    2015-12-01

    Some centers, mostly in Europe, have demonstrated the feasibility of a minimally invasive strategy (MIS; i.e., local anesthesia and conscious sedation, performed in the cath laboratory without transesophageal echocardiography guidance). Nonetheless, the experience of MIS for TAVI using both commercially available valves is lacking in the United States. We, therefore, retrospectively studied all transfemoral TAVI cases performed at our institution between March 2011 and November 2014 to assess the safety and efficacy of MIS. Patients were dichotomized according to the strategy (MIS vs conventional strategy [CS]) used for the procedure. One hundred sixteen patients were included in the MIS group and 91 patients were included in the CS group. Baseline characteristics were similar, and procedural success was comparable (99.1% in MIS and 98.9% in CS, p = 1). One intraprocedural death occurred in each group, whereas conversion rates to general anesthesia were low (3.4%). Comparable device success was obtained. Rates of complications and >mild paravalvular leak before discharge were low and comparable. Length of hospital stay was significantly reduced in the MIS (median, 3.0 [2.0 to 5.0] days) compared with than that in CS group (median 6.0 days [3.5, 8.0]). At a median follow-up of 230 days, no significant difference in survival rate was detected (89% vs 88%, p = 0.9). On average, MIS was associated with remarkable cost saving compared with CS ($16,000/case). In conclusion, TAVI through MIS was associated with a shorter postprocedural hospital stay, lower costs, and similar safety profile while keeping procedural efficacy compared with CS. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. A comparison of three strategies for reducing the public stigma associated with stuttering.

    Science.gov (United States)

    Boyle, Michael P; Dioguardi, Lauren; Pate, Julie E

    2016-12-01

    The effects of three anti-stigma strategies for stuttering-contact (hearing personal stories from an individual who stutters), education (replacing myths about stuttering with facts), and protest (condemning negative attitudes toward people who stutter)-were examined on attitudes, emotions, and behavioral intentions toward people who stutter. Two hundred and twelve adults recruited from a nationwide survey in the United States were randomly assigned to one of the three anti-stigma conditions or a control condition. Participants completed questionnaires about stereotypes, negative emotional reactions, social distance, discriminatory intentions, and empowerment regarding people who stutter prior to and after watching a video for the assigned condition, and reported their attitude changes about people who stutter. Some participants completed follow-up questionnaires on the same measures one week later. All three anti-stigma strategies were more effective than the control condition for reducing stereotypes, negative emotions, and discriminatory intentions from pretest to posttest. Education and protest effects for reducing negative stereotypes were maintained at one-week follow-up. Contact had the most positive effect for increasing affirming attitudes about people who stutter from pretest to posttest and pretest to follow-up. Participants in the contact and education groups, but not protest, self-reported significantly more positive attitude change about people who stutter as a result of watching the video compared to the control group. Advocates in the field of stuttering can use education and protest strategies to reduce negative attitudes about people who stutter, and people who stutter can increase affirming attitudes through interpersonal contact with others. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. A comparison of two strategies for generating sound zones in a room

    DEFF Research Database (Denmark)

    Jacobsen, Finn; Olsen, Martin; Møller, Martin

    2011-01-01

    For some purposes it may be of interest to generate sound zones with different acoustic prop-erties in a room. This paper compares two strategies for generating such zones. One method is based on ‘contrast optimisation’: the idea is to maximise the ratio of the potential energy in a ‘bright......’ (ensonified) zone to the potential energy in a ‘dark’ (quiet) zone with a given source configuration. An alternative method based on ‘sound field synthesis’ has the more ambitious goal to control the sound field in the bright zone in detail, for example, to generate a plane wave that propagates in a certain...

  3. A comparison of strategies for Markov chain Monte Carlo computation in quantitative genetics

    DEFF Research Database (Denmark)

    Waagepetersen, Rasmus; Ibanez-Escriche, Noelia; Sorensen, Daniel

    2008-01-01

    In quantitative genetics, Markov chain Monte Carlo (MCMC) methods are indispensable for statistical inference in non-standard models like generalized linear models with genetic random effects or models with genetically structured variance heterogeneity. A particular challenge for MCMC applications...... in quantitative genetics is to obtain efficient updates of the high-dimensional vectors of genetic random effects and the associated covariance parameters. We discuss various