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Sample records for newly emerging therapeutic

  1. Current, emerging, and newly available insomnia medications.

    PubMed

    Krystal, Andrew D

    2015-08-01

    Research into the sleep-wake cycle has provided new treatment targets for patients with insomnia as well as a better understanding of how medications affect sleep processes. Current insomnia medications, including benzodiazepines and nonbenzodiazepines, focus on enhancing sleep-promoting systems through broad antagonism of GABA. Other medications that promote sleep by blocking wake-promoting systems include antidepressants, antipsychotics, and antihistamines, but adverse effects and nonspecific therapeutic effects limit their use. New and emerging insomnia medications are focusing on blocking wake-promoting systems via more selective antagonism of orexin, serotonin, and norepinephrine. These medications may offer improved efficacy with fewer adverse effects. © Copyright 2015 Physicians Postgraduate Press, Inc.

  2. Out of the reach of children? Young people's health-seeking practices and agency in Africa's newly-emerging therapeutic landscapes.

    PubMed

    Hampshire, Kate R; Porter, Gina; Owusu, Samuel Asiedu; Tanle, Augustine; Abane, Albert

    2011-09-01

    Despite a dominant view within Western biomedicine that children and medicines should be kept apart, a growing literature suggests that children and adolescents often take active roles in health-seeking. Here, we consider young people's health-seeking practices in Ghana: a country with a rapidly-changing therapeutic landscape, characterised by the recent introduction of a National Health Insurance Scheme, mass advertising of medicines, and increased use of mobile phones. Qualitative and quantitative data are presented from eight field-sites in urban and rural Ghana, including 131 individual interviews, focus groups, plus a questionnaire survey of 1005 8-to-18-year-olds. The data show that many young people in Ghana play a major role in seeking healthcare for themselves and others. Young people's ability to secure effective healthcare is often constrained by their limited access to social, economic and cultural resources and information; however, many interviewees actively generated, developed and consolidated such resources in their quest for healthcare. Health insurance and the growth of telecommunications and advertising present new opportunities and challenges for young people's health-seeking practices. We argue that policy should take young people's medical realities as a starting point for interventions to facilitate safe and effective health-seeking. Copyright © 2011 Elsevier Ltd. All rights reserved.

  3. Emerging therapeutic aspects in oncology

    PubMed Central

    MacEwan, David J

    2013-01-01

    Cancer remains a peculiarly stubborn disease to treat. Some forms of cancer have seen tremendous advances in the effectiveness of their treatments, whereas other forms have remained resistant to pharmacological control. This lack of hope for success is in part due to the types of drugs that are used in the clinic, and the targeted biological system being based purely on cellular growth rates. However, recent drugs designed to affect specific signalling pathways or proteins have been showing much success. Thanks to the ingenuity of pharmacologists in understanding and targeting these processes, there have been real improvements in treatment. Here we are presented with some of the research into such critical systems that have to be understood, so that they can be conquered. We will also look at the challenges facing cancer pharmacologists and what the field may present to us all in the future. Linked Articles This article is part of a themed section on Emerging Therapeutic Aspects in Oncology. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.169.issue-8 PMID:23889318

  4. Emerging therapeutics for Alzheimer's disease.

    PubMed

    Chiang, Karen; Koo, Edward H

    2014-01-01

    Despite decades of intense research, therapeutics for Alzheimer's disease (AD) are still limited to symptomatic treatments that possess only short-term efficacy. Recently, several large-scale Phase III trials targeting amyloid-β production or clearance have failed to show efficacy, leading to a reexamination of the amyloid hypothesis as well as highlighting the need to explore alternatives in both clinical testing strategies and drug discovery targets. In this review, we discuss therapeutics currently being tested in clinical trials and up-and-coming interventions that have shown promise in animal models, devoting attention to the mechanisms that may underlie their ability to influence disease progression and placing particular emphasis on tau therapeutics.

  5. Therapeutic enhancement of newly derived bacteriocins against Giardia lamblia.

    PubMed

    Amer, Eglal I; Mossallam, Shereen F; Mahrous, Hoda

    2014-11-01

    Trials for identifying efficient anti-giardial agents are still ongoing. Nowadays, bacteriocins have attracted the attention as potential antimicrobial compounds. For the first time, the current study evaluated the therapeutic efficacy of bacteriocins derived from newly isolated Egyptian strains of probiotics Lactobacilli; L. acidophilus (P106) and L. plantarum (P164) against Giardia lamblia. Bacteriocins' efficacy was evaluated both in vitro; by growth inhibition and adherence assays, and in vivo; through estimation of parasite density, intestinal histopathological examination and ultrastructural analysis of Giardia trophozoites. In vivo bacteriocins' clinical safety was assessed. In vitro results proved that 50 µg of L. acidophilus bacteriocin induced reduction of the mean Giardia lamblia trophozoites by 58.3 ± 4.04%, while at lower concentrations of 10 and 20 µg of both L. acidophilus and L. plantarum, non significant reduction of the mean parasite density was achieved. In vitro trophozoites adherence was susceptible to the tested bacteriocins at all studied concentrations with variable degrees, while the highest adherence reduction was demonstrated using 50 µg of L acidophilus bacteriocin. In vivo, oral inoculation of 50 µg/mouse L. acidophilus bacteriocin for 5 successive days resulted in a noteworthy decline of the intestinal parasite density, along with amelioration of intestinal pathology of infected mice. Ultrastructural examination proved thatfive doses of L. acidophilus bacteriocin showed marked changes in cellular architecture of the trophozoites with evident disorganization of the cell membrane, adhesive disc and cytoplasmic components. This is the first reported study of the safe anti-giardial efficacy of L. acidophilus (P106) derived bacteriocin, hence highlighting its great promise as a potential therapeutic safe alternative to existing commercial drugs.

  6. Emerging therapeutic options for asthma.

    PubMed

    Colice, Gene L

    2011-04-01

    Asthma is characterized by eosinophilic airway inflammation and elevated serum immunoglobulin E (IgE) levels. Due to these pathologic features, the foundation of asthma treatment has historically been anti-inflammatory therapy with inhaled corticosteroids (ICSs). Numerous factors in addition to IgE and eosinophils, however, likely play important roles in mediating the airway inflammatory response characteristic of asthma. ICSs are effective therapy for some patients with persistent asthma, but clinical trials have shown that even increasing doses of ICSs under carefully controlled situations does not always result in acceptable asthma control. Consequently, other classes of medications, in addition to ICSs, are recommended in those patients with more severe asthma. The class of medication most commonly used in more severe asthma, along with ICSs, is long-acting inhaled beta2-agonists, but leukotriene modifying agents and anti-IgE monoclonal antibodies may also be used. Agents such as tiotropium, a long-acting inhaled anti-muscarinic agent, and those aimed at inhibiting cytokines, such as mepoluzimab, daclizumab, and etanercept, hold promise in the treatment of asthma. Other agents under investigation include phosphodiesterase type 4 inhibitors and oligonucleotides. Bronchial thermoplasty, a nonpharmacologic option, may also be beneficial in patients with poorly controlled asthma. As our understanding of the complex pathophysiology of asthma increases, it will enable the development of novel therapeutic approaches for patients who are not responding well to traditional treatments. Although more studies are necessary to ensure the efficacy and safety of both pharmacologic and nonpharmacologic approaches, there is future promise for therapeutic advances in severe, persistent asthma.

  7. Emerging therapeutic drugs for AML

    PubMed Central

    Tallman, Martin S.

    2016-01-01

    Multiple new drugs are being developed to treat acute myeloid leukemia (AML), including novel formulations of traditional chemotherapy-antibody drug conjugates and agents that target specific mutant enzymes. Next-generation sequencing has allowed us to discover the genetic mutations that lead to the development and clinical progression of AML. Studies of clonal hierarchy suggest which mutations occur early and dominate. This has led to targeted therapy against mutant driver proteins as well as the development of drugs such as CPX-351 and SGN-CD33A whose mechanisms of action and efficacy may not be dependent on mutational complexity. In this brief review, we discuss drugs that may emerge as important for the treatment of AML in the next 10 years. PMID:26660428

  8. [Synthetic Drugs - An Overview of Important and Newly Emerging Substances].

    PubMed

    Betzler, F; Heinz, A; Köhler, S

    2016-11-01

    Background: Synthetic drug use and abuse are on the rise. Governmental institutions report a shift in consumption from natural drugs to synthetic drugs, and show an increase in confiscation, particularly of methamphetamine and newly identified psychoactive substances. In addition, the media report an alarming increase in the rate of consumption and casualties resulting from the use of drugs such as "crystal meth" and warn against a flood of this and other designer drugs from eastern European countries. Objectives: The present article gives an overview of current popular and widely used synthetic drugs, both classical substances (amphetamine, methamphetamine, MDMA) and new psychoactive substances ("designer drugs", "legal highs"). It addresses their pharmacology, effects, side effects, and risks. It furthermore explores newly emerging problems for the health system and clinical practice regarding the treatment of intoxication as well as withdrawal. Methods: The current scientific literature concerning synthetic drugs is summarized and official statistics and reports provided by the government are reviewed. Results: Different derivatives of amphetamine vary in their risk of harm and addictive potential. Methamphetamine, one of the most dangerous derivatives, is increasingly being consumed in certain regions of Germany. New psychoactive substances represent a heterogeneous group of substances. Since the substances are often unknown to the user, they are unpredictable in their effects and side effects.

  9. Radiation grafted adsorbents for newly emerging environmental applications

    NASA Astrophysics Data System (ADS)

    Mahmoud Nasef, Mohamed; Ting, T. M.; Abbasi, Ali; Layeghi-moghaddam, Alireza; Sara Alinezhad, S.; Hashim, Kamaruddin

    2016-01-01

    Radiation induced grafting (RIG) is acquired to prepare a number of adsorbents for newly emerging environmental applications using a single route involving RIG of glycidymethacrylate (GMA) onto polyethylene-polypropylene (PE-PP) non-woven fabric. The grafted fabric was subjected to one of three functionalization reactions to impart desired ionic characters. This included treatment with (1) N-dimethyl-D-glucamine, (2) triethylamine and (3) triethylamine and alkalisation with KOH. Fourier transform infrared spectroscopy (FTIR) and scanning electron microscope (SEM) were used to study the changes in chemical and physical structures of the obtained fibrous adsorbents. The potential applications of the three adsorbents for removal of boron from solutions, capturing CO2 from CO2/N2 mixtures and catalysing transesterification of triacetin/methanol to methyl acetate (biodiesel) were explored. The obtained fibrous adsorbents provide potential alternatives to granular resins for the investigated applications and require further development.

  10. Clobazam: A Safe, Efficacious, and Newly Rediscovered Therapeutic for Epilepsy.

    PubMed

    Gauthier, Angela C; Mattson, Richard H

    2015-07-01

    Clobazam is an oral 1,5-benzodiazepine used worldwide for the treatment of many types of epilepsies, although it is currently only approved for Lennox-Gastaut syndrome in the USA. This anticonvulsant and anxiolytic therapeutic has repeatedly demonstrated great efficacy and a high safety profile in refractory epilepsy as well as in a few monotherapy trials in both children and adults. Clobazam allosterically activates the GABAA receptor, and it binds less to subunits that mediate sedative effects than other benzodiazepines. It acts quickly, maintaining a therapeutic effect for a long duration due to its active metabolite, N-desmethylclobazam. Dosage is between 5 mg and 40 mg a day, depending on patient weight, efficacy, and tolerability. Efficacy tolerance has not been a problem in the best studies. Clobazam has provided many benefits to epileptic patients. It should be used by clinicians early as an adjuvant therapy in the treatment of refractory epilepsy and even considered as monotherapy in a broad spectrum of epilepsy syndromes. © 2015 John Wiley & Sons Ltd.

  11. Emerging Mitochondrial Therapeutic Targets in Optic Neuropathies.

    PubMed

    Lopez Sanchez, M I G; Crowston, J G; Mackey, D A; Trounce, I A

    2016-09-01

    Optic neuropathies are an important cause of blindness worldwide. The study of the most common inherited mitochondrial optic neuropathies, Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (ADOA) has highlighted a fundamental role for mitochondrial function in the survival of the affected neuron-the retinal ganglion cell. A picture is now emerging that links mitochondrial dysfunction to optic nerve disease and other neurodegenerative processes. Insights gained from the peculiar susceptibility of retinal ganglion cells to mitochondrial dysfunction are likely to inform therapeutic development for glaucoma and other common neurodegenerative diseases of aging. Despite it being a fast-evolving field of research, a lack of access to human ocular tissues and limited animal models of mitochondrial disease have prevented direct retinal ganglion cell experimentation and delayed the development of efficient therapeutic strategies to prevent vision loss. Currently, there are no approved treatments for mitochondrial disease, including optic neuropathies caused by primary or secondary mitochondrial dysfunction. Recent advances in eye research have provided important insights into the molecular mechanisms that mediate pathogenesis, and new therapeutic strategies including gene correction approaches are currently being investigated. Here, we review the general principles of mitochondrial biology relevant to retinal ganglion cell function and provide an overview of the major optic neuropathies with mitochondrial involvement, LHON and ADOA, whilst highlighting the emerging link between mitochondrial dysfunction and glaucoma. The pharmacological strategies currently being trialed to improve mitochondrial dysfunction in these optic neuropathies are discussed in addition to emerging therapeutic approaches to preserve retinal ganglion cell function. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Hα Surges Initiated by Newly-emerging Satellite Magnetic Fields

    NASA Astrophysics Data System (ADS)

    Wang, Jun-feng; Zhou, Tuan-hui; Ji, Hai-sheng

    2014-01-01

    On July 22, 2011 and in the active region NOAA 11259 there ap- peared the event of the ejection of solar atmospheric Hα surges. According to the full-disc Hα observations of the Big Bear Solar Observatory in United States, three consecutive surges at one and the same place in the north of the main spot of the active region were discovered. The trajectories of these three surges exhib- ited the figure of straight lines, and their integral configuration is like an inverted Eiffel Tower. The first two surges are quite similar, and in each of them there appeared two bright points in the northern part of the main spot. After several minutes, the surges appeared in the midst of bright points. When the bright- ness of the bright points attained the maximum value, the surges spouted out from the midst of bright points. And after reaching the maximum altitude, they quickly vanished. Before the ejection of the third surge took place, no bright points appeared. Besides, its maximal altitude is merely one half of that of the first two surges. Via a comparison with the SDO/HMI (Solar Dynamics Obser- vatory/Helioseismic and Magnetic Imager) data of radial magnetic fields, it is found that in more than one hour before the appearance of the first surge there emerged bipolar magnetic fields in the region of ejection. Besides, in several min- utes before the ejection of each Hα surge the magnetic fluxes of positive polarity diminished. Via our analysis it is found that there appeared reconnections be- tween the newly emerging satellite magnetic fields and the preexisting magnetic fields in the spot, and this caused the continuous ejections of Hα surges.

  13. Emerging therapeutic agents for cervical cancer.

    PubMed

    Cornelio, Daniela B; Roesler, Rafael; Schwartsmann, Gilberto

    2009-11-01

    Cervical cancer is the second most frequent malignancy affecting women worldwide. The highest incidences occur in the developing world, where, in most countries, cervical cancer is the leading cause of cancer mortality in women. Although surgery and chemoradiotherapy can cure 80-95% of women with early stage cancer and 60% of locoregionally advanced cancer, the recurrent and metastatic disease remains a major cause of cancer death. The current cytotoxic treatment options for advanced and metastatic cancer demonstrate modest results, with response rates of maximum 30% and overall survival of less than 10 months. Given this limited degree of success with conventional therapies, interest has increased in other therapeutic alternatives. In this way, targeted agents are emerging as potential candidates for improving survival in cervical cancer patients. In this review we highlight the main current therapeutic strategies for cervical cancer and summarize the most relevant patents from the latest five years. Special attention was given to patents with potential applications in the clinical practice.

  14. Emerging drugs and therapeutics for systemic sclerosis.

    PubMed

    Lee, Jason J; Pope, Janet E

    2016-12-01

    Treatment of systemic sclerosis (SSc) is challenging despite advances in medical therapeutics for other rheumatologic diseases. Significant disease modifying therapy is lacking for most patients with SSc, due to the heterogeneous multisystem nature of SSc and its complex pathophysiology. The emergence of organ based management strategies has provided guidance in patient care as well as research and drug development. Areas covered: Design and development of new compounds focused on the underlying fibrotic disease processes have been sparse. Therefore, organ based strategies with targeted approaches have been directed towards the most devastating and life threatening features of systemic sclerosis. These include pulmonary arterial hypertension, interstitial lung disease, peripheral vasculopathy and skin thickening. In this context, new treatment regimens using older drugs as well as discovery of novel compounds based on recent insights of the disease pathophysiology are discussed. Expert opinion: Systemic sclerosis is a heterogeneous rare disease that carries a high burden of morbidity and mortality. Organ based management strategies have improved the natural history of systemic sclerosis using targeted interventions or strategies, particularly vascular features. However, more research is required to better understand disease mechanisms, including an ultimate unifying pathway that explains the multisystem nature of systemic sclerosis.

  15. Emergence of chironomidae in a newly impounded cooling reservoir

    SciTech Connect

    Lauritsen, D. . Southeastern Regional Office)

    1990-01-01

    L Lake, a once-through cooling reservoir on the Savannah River Plant in South Carolina, was created in late 1985. Biological sampling, initiated in January 1986, included monthly emergence trap sampling in littoral regions. Chironomids were the most abundant insects emerging from L Lake in the first three years of sampling (1986--1988). Glyptotendipes lobiferus dominated emergence in all three years, although its relative abundance declined substantially after the first year (mean emergence was 6.38/m{sup 2}/day in 1986, and declined to 1.79 /m{sup 2}/day in 1988). The relative importance of other littoral chironomid species changed over the three years--facultative chironomids were most abundant in the first year, while in 1987 and 1988, community composition began to shift towards species that are considered to be less characteristic of enriched habitats. This benthic community succession'' is probably in part due to the shift in the food base from decomposing organic material (after impoundment) to autochthonous production (with increasing reservoir age). 11 refs., 6 figs., 3 tabs.

  16. Del 1p36 syndrome: a newly emerging clinical entity.

    PubMed

    Battaglia, Agatino

    2005-08-01

    Monosomy 1p36 is a recently delineated contiguous gene syndrome, which is now considered to be the most common subtelomeric microdeletion syndrome. From the recent literature it appears as if 1p36 deletions account for 0.5-1.2% of idiopathic mental retardation. The deletions can be detected by high resolution cytogenetic studies in a minority of patients, and fluorescence in situ hybridisation (FISH) is required in most. The deletions' parent of origin seems still unclear, although in one large series it was shown to be maternal. 1p36 deletion syndrome is characterized by distinct craniofacial features, associated with developmental delay/mental retardation, hypotonia, muscle hypotrophy, seizures, brain abnormalities, and heart defects. To help child neurologists and other professionals in the recognition of this emerging and common chromosomal syndrome, we have reviewed published articles on patients with this deletion.

  17. California dreamin' 'bout endothelin: emerging new therapeutics.

    PubMed

    Warner, T D; Elliott, J D; Ohlstein, E H

    1996-05-01

    Progress in our understanding of endothelins has been extremely rapid since their discovery in 1988. A number of pharmaceutical companies have developed potent, orally active, nonpeptide endothelin receptor antagonists with efficacies in a wide variety of animal disease models and potential for treating human disease. However, only time will tell whether or not these compounds are developed into drugs that are perceived as worthy of a place in the therapeutic marketplace. If this is the case, endothelin will have been promoted from the status of striking scientific discovery to therapeutic target in a remarkably short period.

  18. Toll gates: An emerging therapeutic target

    PubMed Central

    Maheaswari, Rajendran; Sivasankar, Kiruthika; Subbarayan, Sathya

    2014-01-01

    Innate immune system forms the first line of defense against microbial infections, as it exerts an immediate response. Innate immunity works through Toll-like receptors (TLRs) which functions as primary sensors of pathogens. TLR activates multiple signaling cascades leading to the induction of genes responsible for the release of inflammatory cytokines and type I interferon. Thus, they induce antimicrobial responses and also have an instructive role in adaptive immunity. However, TLR-mediated inflammation is said to be responsible for many of the destructive host responses in inflammatory diseases like periodontitis. Hence, therapeutics targeting TLRs are being used to treat disease such as HIV, Hepatitis B, asthma etc. Recently, synthetic TLR agonists are tried as novel vaccine adjuvant in treating periodontal diseases. This paper reviews the scope of TLR-based therapeutics in treating periodontitis. PMID:25624622

  19. Emerging therapeutics for targeting Akt in cancer.

    PubMed

    Gdowski, Andrew; Panchoo, Marlyn; Treuren, Timothy Van; Basu, Alakananda

    2016-01-01

    The ultimate goal of cancer therapeutic research is to develop effective, targeted therapeutics that exploit the vulnerabilities of cancer cells. The three isoforms of Akt, also known as protein kinase B (PKB), are important mediators of various pathways that transmit mitogenic signals from the cell's exterior to the effector proteins of the cell's interior. Due to Akt\\\\\\\\\\\\\\'s importance in cell functions such as growth, proliferation and cell survival, many cancer cells rely on this pathway to aid in their survival. This dependence can lead to chemoresistance and selection of more adapted populations of cancer cells. Thus, it is important to understand the functional significance of isoform specificity and its relation to chemoresistance. In this review, we have summarized recent studies on Akt isoform specific regulation as well as each isoform's role in chemoresistance, emphasizing their potential as targets for cancer therapy. We have also condensed ongoing clinical studies involving various types of Akt inhibitors while highlighting the type of study, rationale and co-therapies involved in identifying Akt isoforms as promising therapeutic targets.

  20. Emerging Therapeutic Approaches to Mitochondrial Diseases

    ERIC Educational Resources Information Center

    Wenz, Tina; Williams, Sion L.; Bacman, Sandra R.; Moraes, Carlos T.

    2010-01-01

    Mitochondrial diseases are very heterogeneous and can affect different tissues and organs. Moreover, they can be caused by genetic defects in either nuclear or mitochondrial DNA as well as by environmental factors. All of these factors have made the development of therapies difficult. In this review article, we will discuss emerging approaches to…

  1. Emerging Therapeutic Approaches to Mitochondrial Diseases

    ERIC Educational Resources Information Center

    Wenz, Tina; Williams, Sion L.; Bacman, Sandra R.; Moraes, Carlos T.

    2010-01-01

    Mitochondrial diseases are very heterogeneous and can affect different tissues and organs. Moreover, they can be caused by genetic defects in either nuclear or mitochondrial DNA as well as by environmental factors. All of these factors have made the development of therapies difficult. In this review article, we will discuss emerging approaches to…

  2. Emerging therapeutics for ocular surface disease.

    PubMed

    Bielory, Brett P; Shah, Steven P; O'Brien, Terrence P; Perez, Victor L; Bielory, Leonard

    2016-10-01

    The present review provides an overview on the potential of different systemic and topical treatments in chronic forms of ocular allergy and dry eye disorder (DED). The impact on anterior surface of ocular inflammatory disorder encompasses an array of conditions, which are frequently underreported. This can contribute to underdiagnoses and ineffective management from healthcare providers such as an allergist and/or ophthalmologist who routinely provide care for these common disorders. Owing to the current limited therapeutic options, healthcare providers are routinely seeking alternative treatments that could facilitate effective management of the conditions. Recent advances in immunopathophysiology of ocular surface disorders has provided new potential targets and therapeutic strategies for the treatment of DED and ocular allergy that may include various immunobiological modulators. These modulators have focused on regulating the Th1 and Th2 immune-mediated inflammatory pathways that inhibit various cytokines (e.g. IL-1, IL-4, IL-5, IL-9, IL-13) antibodies (e.g. IgE), and other surface markers of various cell lines (e.g. activated T-lymphocytes, lymphocyte function-associated antigen-1). Recent findings about the pathophysiology of DED and ocular allergy have led to the greater understanding of the molecular and cellular mechanisms of ocular surface diseases leading to the potential novel targets for immunomodulation of anterior surface ocular disorders. New topical glucocorticoids, leukotriene receptor antagonists, IL-1 antagonists, IL-5, IL-4/IL-13 antagonists, integrin antagonists, and quinolone derivatives appear to be encouraging.

  3. Emerging Therapeutics Targeting mRNA Translation

    PubMed Central

    Malina, Abba; Mills, John R.; Pelletier, Jerry

    2012-01-01

    A defining feature of many cancers is deregulated translational control. Typically, this occurs at the level of recruitment of the 40S ribosomes to the 5′-cap of cellular messenger RNAs (mRNAs), the rate-limiting step of protein synthesis, which is controlled by the heterotrimeric eukaryotic initiation complex eIF4F. Thus, eIF4F in particular, and translation initiation in general, represent an exploitable vulnerability and unique opportunity for therapeutic intervention in many transformed cells. In this article, we discuss the development, mode of action and biological activity of a number of small-molecule inhibitors that interrupt PI3K/mTOR signaling control of eIF4F assembly, as well as compounds that more directly block eIF4F activity. PMID:22474009

  4. SLC Transporters as Therapeutic Targets: Emerging Opportunities

    PubMed Central

    Lin, Lawrence; Yee, Sook Wah; Kim, Richard B.; Giacomini, Kathleen M.

    2015-01-01

    Solute carrier (SLC) transporters — a family of more than 300 membrane-bound proteins that facilitate the transport of a wide array of substrates across biological membranes — have important roles in physiological processes ranging from the cellular uptake of nutrients to the absorption of drugs and other xenobiotics. Several classes of marketed drugs target well-known SLC transporters, such as neurotransmitter transporters, and human genetic studies have provided powerful insight into the roles of more-recently characterized SLC transporters in both rare and common diseases, indicating a wealth of new therapeutic opportunities. This Review summarizes knowledge on the roles of SLC transporters in human disease, describes strategies to target such transporters, and highlights current and investigational drugs that modulate SLC transporters, as well as promising drug targets. PMID:26111766

  5. Nanotechnology: emerging tool for diagnostics and therapeutics.

    PubMed

    Chakraborty, Mainak; Jain, Surangna; Rani, Vibha

    2011-11-01

    Nanotechnology is an emerging technology which is an amalgamation of different aspects of science and technology that includes disciplines such as electrical engineering, mechanical engineering, biology, physics, chemistry, and material science. It has potential in the fields of information and communication technology, biotechnology, and medicinal technology. It involves manipulating the dimensions of nanoparticles at an atomic scale to make use of its physical and chemical properties. All these properties are responsible for the wide application of nanoparticles in the field of human health care. Promising new technologies based on nanotechnology are being utilized to improve diverse aspects of medical treatments like diagnostics, imaging, and gene and drug delivery. This review summarizes the most promising nanomaterials and their application in human health.

  6. Emerging Therapeutic Options for Celiac Disease

    PubMed Central

    Bakshi, Anita; Stephen, Sindu; Borum, Marie L.

    2012-01-01

    Celiac disease is an autoimmune disorder of the small intestine that is more common than was previously thought. This disease is caused by an inappropriate immune response to wheat gluten, barley, and rye. Three main pathways cause celiac disease: the environmental trigger (gluten), genetic susceptibility, and unusual gut permeability. The only treatment currently available is a strict gluten-free diet. Unfortunately, a majority of patients have difficulty complying with this diet, and the response to therapy is poor. Therefore, alternative treatments are being developed, and new insights into the pathophysiology of celiac disease have led to research into novel therapies. New treatments include engineering gluten-free grains, decreasing intestinal permeability by blockage of the epithelial zonulin receptor, inducing oral tolerance to gluten with a therapeutic vaccine, and degrading immunodominant gliadin peptides using probiotics with endopeptidases or transglutaminase inhibitors. These nondiet-based therapies provide hope for enhanced, lifelong celiac disease management with improved patient compliance and better quality of life. PMID:23483819

  7. Emerging therapeutic targets in esophageal adenocarcinoma

    PubMed Central

    Gaur, Puja; Hunt, Clayton R.; Pandita, Tej K.

    2016-01-01

    The incidence of gastro-esophageal disease and associated rate of esophageal adenocarcinoma (EAC) is rising at an exponential rate in the United States. However, research targeting EAC is lagging behind, and much research is needed in the field to identify ways to diagnose EAC early as well as to improve the rate of pathologic complete response (pCR) to systemic therapies. Esophagectomy with subsequent reconstruction is known to be a morbid procedure that significantly impacts a patient's quality of life. If indeed the pCR rate of patients can be improved and those patients destined to be pCR can be identified ahead of time, they may be able to avoid this life-altering procedure. While cancer-specific biological pathways have been thoroughly investigated in other solid malignancies, much remains unexplored in EAC. In this review, we will highlight some of the latest research in the field in regards with EAC, along with new therapeutic targets that are currently being explored. After reviewing conventional treatment and current changes in medical therapy for EAC, we will focus on unchartered grounds such as cancer stem cells, genetics and epigenetics, immunotherapy, and chemoradio-resistant pathways as we simultaneously propose some investigational possibilities that could be applicable to EAC. PMID:27102294

  8. Phytotherapy: emerging therapeutic option in urologic disease

    PubMed Central

    2012-01-01

    Phytotherapy belongs to the area of complementary and alternative medicine (CAM) and the definition of phytotherapy is the use of plants or plant extracts for medicinal uses. Interest in phytotherapy is growing in both Asian and western countries for its use in the prevention and management of disease, improvement of general health and anti-aging. And also, there are several studies about the efficacy of phytotherapy in urologic diseases like benign prostatic hyperplasia (BPH), erectile dysfunction (ED), late-onset hypogonadism (LOH) and infertility in males. Phytotherapy for BPH including saw palmetto, pygeum, and nettles, is under vigorous research for the therapeutic effect. No solid evidence showing better effective treatment modality for ED than placebo has been found yet for phytotherapy. Recently, a potent NO donor, L-arginine is under research with promising results. Phytotherapy is used by a number of patients with urological disease, and urologists need to have accurate knowledge about phytotherapy as well as keep a cautious approach. The possible effects and side effects should be defined and related to urologic patients by urologists. PMID:26816707

  9. Polymorphic SSR markers for Plasmopara obducens (Peronosporaceae), the newly emergent downy mildew pathogen of Impatiens (Balsaminaceae)

    USDA-ARS?s Scientific Manuscript database

    Premise of the study: Microsatellite markers were developed for Plasmopara obducens, the causal agent of the newly emergent downy mildew disease of Impatiens walleriana. Methods and Results: A 151.2 Mb draft genome assembly was generated from P. obducens using Illumina technology and mined to identi...

  10. Cholera: pathophysiology and emerging therapeutic targets.

    PubMed

    Muanprasat, Chatchai; Chatsudthipong, Varanuj

    2013-05-01

    Cholera is a diarrheal disease that remains an important global health problem with several hundreds of thousands of reported cases each year. This disease is caused by intestinal infection with Vibrio cholerae, which is a highly motile gram-negative bacterium with a single-sheathed flagellum. In the course of cholera pathogenesis, V. cholerae expresses a transcriptional activator ToxT, which subsequently transactivates expressions of two crucial virulence factors: toxin-coregulated pilus and cholera toxin (CT). These factors are responsible for intestinal colonization of V. cholerae and induction of fluid secretion, respectively. In intestinal epithelial cells, CT binds to GM1 ganglioside receptors on the apical membrane and undergoes retrograde vesicular trafficking to endoplasmic reticulum, where it exploits endoplasmic reticulum-associated protein degradation systems to release a catalytic A1 subunit of CT (CT A1) into cytoplasm. CT A1, in turn, catalyzes ADP ribosylation of α subunits of stimulatory G proteins, leading to a persistent activation of adenylate cyclase and an elevation of intracellular cAMP. Increased intracellular cAMP in human intestinal epithelial cells accounts for pathogenesis of profuse diarrhea and severe fluid loss in cholera. This review provides an overview of the pathophysiology of cholera diarrhea and discusses emerging drug targets for cholera, which include V. cholerae virulence factors, V. cholerae motility, CT binding to GM1 receptor, CT internalization and intoxication, as well as cAMP metabolism and transport proteins involved in cAMP-activated Cl(-) secretion. Future directions and perspectives of research on drug discovery and development for cholera are discussed.

  11. Equity and access: understanding emergency health service use by newly arrived refugees.

    PubMed

    Sheikh, Mohamud; Nugus, Peter I; Gao, Zhanhai; Holdgate, Anna; Short, Alison E; Al Haboub, Ayman; Macintyre, C Raina

    2011-07-18

    To determine issues that affect newly resettled refugees in accessing an emergency department (ED). We conducted a descriptive community survey using a semistructured questionnaire. Newly resettled refugees from the Middle East and Africa were interviewed, statistical analysis was performed, and standard content analysis methods were applied to free-text responses. Emergency health-seeking behaviour, sociocultural barriers and beliefs about Australia's emergency health services. Half the African refugees (53/106) (50%), compared with only 15/49 (31%) of the Middle Eastern refugees, preferred an ED service over other forms of care for an urgent medical condition (P = 0.024). Qualitative data revealed that most newly resettled refugees understand how to use the emergency health services. However, while most indicated that they were able to make a call for emergency medical help, a substantial number of our respondents revealed that they were afraid to make such a call for fear of security implications, on the basis of experiences from their home countries. Reasons for differences in preferences of health care access, and determining how best to educate the community on the use of ED services, warrant further investigation. From a policy perspective, the increasing health care needs of refugees need re-examination when planning health care provision to refugees.

  12. A novel strategy for exploring the reassortment origins of newly emerging influenza virus.

    PubMed

    Tian, Deqiao; Wang, Yumin; Zheng, Tao

    2011-01-01

    In early 2009, new swine-origin influenza A (H1N1) virus emerged in Mexico and the United States. The emerging influenza virus had made global influenza pandemic for nearly one year. To every emerging pathogen, exploring the origin sources is vital for viral control and clearance. Influenza virus is different from other virus in that it has 8 segments, making the segment reassortment a main drive in virus evolution. In exploring reassortment evolution origins of a newly emerging influenza virus, integrated comparing of the origin sources of all the segments is necessary. If some segments have high homologous with one parental strain, lower homologous with another parental strain, while other segments are reverse, can we proposed that this emerging influenza virus may re-assort from the two parental strains. Here we try to explore the multilevel reassortment evolution origins of 2009 H1N1 influenza virus using this method. By further validating the fidelity of this strategy, this method might be useful in judging the reassortment origins of newly emerging influenza virus.

  13. History dependent effects on phenotypic expression of a newly emerged gene.

    PubMed

    Suzuki, Takao; Kashiwagi, Akiko; Mori, Kotaro; Urabe, Itaru; Yomo, Tetsuya

    2004-11-01

    In this study, we investigate the history dependence of the penetrance of a newly emerged gene. Penetrance is defined as the percentage of individuals with a given genotype who exhibit the phenotype associated with that particular genotype. Here, we used the glutamine synthetase gene and its mutants with lower fitness as model genes. They were introduced into host cells of Escherichia coli deprived of the gene, and their penetrance was measured using the host having a different history: either with or without glutamine starvation. Results show that for all genes tested, the value of penetrance was higher when they were introduced into the host cell without starvation than that when introduced into the starved cell, demonstrating the history dependence of the penetrance of a newly emerged gene. In addition, genes with lower fitness showed lower penetrance, and the effect of the difference in fitness on gene penetrance also depended on the history of the host cell.

  14. Emergency contraception for newly arrested women: evidence for an unrecognized public health opportunity.

    PubMed

    Sufrin, Carolyn B; Tulsky, Jacqueline P; Goldenson, Joseph; Winter, Kelly S; Cohan, Deborah L

    2010-03-01

    Incarceration affords an opportunity to provide health care to populations with limited access to care. Women in this population are at high risk for experiencing unintended pregnancies. It is not known what proportion of these women engage in unprotected intercourse in the days prior to incarceration and therefore may benefit from being offered emergency contraception upon their arrest to decrease their risk of unintended pregnancies. We sought to describe the proportion and characteristics of newly arrested women who are eligible for and interested in taking emergency contraception by conducting a cross-sectional study in an urban county jail booking facility. A 63-item survey was administered to women ages 18-44 within 24 h of being arrested in San Francisco. Eighty-four (29%) women were eligible for emergency contraception. Of these, 48% indicated a willingness to take emergency contraception if offered. Half of the women eligible for emergency contraception expressed ambivalent attitudes about pregnancy. Women who had taken emergency contraception in the past were more likely to say they would accept it (45%) than women who had never used it (25%, p = .05). The strongest predictor of willingness to take emergency contraception was not having a misperception about its safety, efficacy, or mechanism of action (RR = 1.9, 95% CI 1.2-3.0). Seventy-one percent of all women indicated that they would accept an advance supply of emergency contraception upon release from jail. Emergency contraception counseling and provision should be offered to newly arrested women as a key reproductive and public health intervention for a traditionally marginalized, high-risk population.

  15. Emerging Therapeutic Targets of Sepsis-Associated Acute Kidney Injury

    PubMed Central

    Swaminathan, Sundararaman; Rosner, Mitchell H.; Okusa, Mark D.

    2015-01-01

    Sepsis-associated acute kidney injury (SA-AKI) is linked to high morbidity and mortality. Thus far singular approaches to target specific pathways known to contribute to the pathogenesis of SA-AKI have failed. Because of the complexity of the pathogenesis of SA-AKI, a reassessment necessitates integrative approaches to therapeutics of SA-AKI that include general supportive therapies such as the use of vasopressors, fluids, antimicrobial and target specific and time dependent therapeutics. There has been recent progress in our understanding of the pathogenesis and treatment of SA-AKI including temporal nature of pro- and anti-inflammatory processes. In this review, we will discuss the clinical and experimental basis of emerging therapeutic approaches that focus on targeting early proinflammatory and late anti-inflammatory processes as well as therapeutics that may enhance cellular survival and recovery. Lastly we include ongoing clinical trials in sepsis. PMID:25795498

  16. Newly approved antibiotics and antibiotics reserved for resistant infections: Implications for emergency medicine.

    PubMed

    Mazer-Amirshahi, Maryann; Pourmand, Ali; May, Larissa

    2017-01-01

    Millions of patients are evaluated every year in the emergency department (ED) for bacterial infections. Emergency physicians often diagnose and prescribe initial antibiotic therapy for a variety of bacterial infections, ranging from simple urinary tract infections to severe sepsis. In life-threatening infections, inappropriate choice of initial antibiotic has been shown to increase morbidity and mortality. As such, initiation of appropriate antibiotic therapy on the part of the emergency physician is critical. Increasing rates of antibiotic resistance, drug allergies, and antibiotic shortages further complicates the choice of antibiotics. Patients may have a history of prior resistant infections or culture data indicating that common first-line antibiotics used in the ED may be ineffective. In recent years, there have been several new antibiotic approvals as well as renewed interest in second and third line antibiotics because of the aforementioned concerns. In addition, several newly approved antibiotics have the advantage of being administered once weekly or even as a single infusion, which has the potential to decrease hospitalizations and healthcare costs. This article reviews newly approved antibiotics and antibiotics used to treat resistant infections with a focus on implications for emergency medicine.

  17. H{α} Surges Aroused by Newly-emerging Satellite Bipolar Magnetic Field

    NASA Astrophysics Data System (ADS)

    Wang, J. F.; Zhou, T. H.; Ji, H. S.

    2013-07-01

    An Hα surge event occurred at AR NOAA 11259 on 2011 July 22. According to the BBSO (Big Bear Solar Observatory) Hα line-center observations, three surges continuously ejected from the same region to the north of the main-sunspot of AR 11259. All of surges ejected along a straight trajectory, and looked like the reversed Eiffel Tower. The first and second surges had the same process. Two bright points firstly appeared to the north of the main-sunspot. After several minutes, a surge appeared between the two bright points, and then rapidly ejected when the two points got most brightness.When the surge reached the maximum height, it disappeared quickly. However, the third surge appeared without bright points, and its height was only half of the others. Compared with SDO/HMI (Solar Dynamics Observatory/Helioseismic and Magnetic Imager) line-of-sight magnetogram, more than one hour before the first surge appeared, a satellite bipolar magnetic field emerged from the surge-ejection region. The newly-emerging positive magnetic flux showed a distinct decrease several minutes earlier than the ejection of the surges. We assumed that the surges was associated with the reconnection between the newly-emerging bipolar magnetic field and the existing (sunspot) magnetic field.

  18. Newly Emerging Feeding Difficulties in a 33-Year-Old Adult With CHARGE Syndrome

    PubMed Central

    Hudson, Alexandra; Blake, Kim

    2016-01-01

    Feeding and swallowing difficulties are common among individuals with CHARGE syndrome. Many children require gastrostomy tube feeding in their early years and often undergo a delay in feeding and oral-motor skill development. There is little information available on adults with CHARGE syndrome, and the feeding difficulties they face. The present case describes newly emerging mouth over-stuffing feeding behaviors and feeding difficulties in a 33-year-old adult with CHARGE syndrome who had not undergone feeding therapy since childhood. PMID:26668685

  19. The role of infections and coinfections with newly identified and emerging respiratory viruses in children

    PubMed Central

    2012-01-01

    Acute respiratory infections are a major cause of morbidity in children both in developed and developing countries. A wide range of respiratory viruses, including respiratory syncytial virus (RSV), influenza A and B viruses, parainfluenza viruses (PIVs), adenovirus, rhinovirus (HRV), have repeatedly been detected in acute lower respiratory tract infections (LRTI) in children in the past decades. However, in the last ten years thanks to progress in molecular technologies, newly discovered viruses have been identified including human Metapneumovirus (hMPV), coronaviruses NL63 (HcoV-NL63) and HKU1 (HcoV-HKU1), human Bocavirus (HBoV), new enterovirus (HEV), parechovirus (HpeV) and rhinovirus (HRV) strains, polyomaviruses WU (WUPyV) and KI (KIPyV) and the pandemic H1N1v influenza A virus. These discoveries have heavily modified previous knowledge on respiratory infections mainly highlighting that pediatric population is exposed to a variety of viruses with similar seasonal patterns. In this context establishing a causal link between a newly identified virus and the disease as well as an association between mixed infections and an increase in disease severity can be challenging. This review will present an overview of newly recognized as well as the main emerging respiratory viruses and seek to focus on the their contribution to infection and co-infection in LRTIs in childhood. PMID:23102237

  20. The role of infections and coinfections with newly identified and emerging respiratory viruses in children.

    PubMed

    Debiaggi, Maurizia; Canducci, Filippo; Ceresola, Elisa Rita; Clementi, Massimo

    2012-10-27

    Acute respiratory infections are a major cause of morbidity in children both in developed and developing countries. A wide range of respiratory viruses, including respiratory syncytial virus (RSV), influenza A and B viruses, parainfluenza viruses (PIVs), adenovirus, rhinovirus (HRV), have repeatedly been detected in acute lower respiratory tract infections (LRTI) in children in the past decades. However, in the last ten years thanks to progress in molecular technologies, newly discovered viruses have been identified including human Metapneumovirus (hMPV), coronaviruses NL63 (HcoV-NL63) and HKU1 (HcoV-HKU1), human Bocavirus (HBoV), new enterovirus (HEV), parechovirus (HpeV) and rhinovirus (HRV) strains, polyomaviruses WU (WUPyV) and KI (KIPyV) and the pandemic H1N1v influenza A virus. These discoveries have heavily modified previous knowledge on respiratory infections mainly highlighting that pediatric population is exposed to a variety of viruses with similar seasonal patterns. In this context establishing a causal link between a newly identified virus and the disease as well as an association between mixed infections and an increase in disease severity can be challenging. This review will present an overview of newly recognized as well as the main emerging respiratory viruses and seek to focus on the their contribution to infection and co-infection in LRTIs in childhood.

  1. Translocation of radiocesium from stems and leaves of plants and the effect on radiocesium concentrations in newly emerged plant tissues.

    PubMed

    Tagami, Keiko; Uchida, Shigeo; Ishii, Nobuyoshi; Kagiya, Shigeo

    2012-09-01

    An accident occurred at the Fukushima Dai-ichi Nuclear Power Plant in March 2011 at which time large amounts of radionuclides were released into the atmosphere and the sea. In early May 2011, it was found that newly emerged tea (Camellia sinensis) leaves contained radiocesium, both (134)Cs and (137)Cs in some areas more than 300 km away from the Fukushima plant. To understand the mechanisms of radiocesium transfer to newly emerged tissues (shoots, leaves and fruits) of other plants in the future, radiocesium concentrations in newly emerged leaves of 14 plant species collected from the sampling areas in and near National Institute of Radiological Sciences in Chiba, Japan. The studied plant types were: (1) herbaceous plants, (2) woody plants with no old leaves at the time of the March accident, and (3) woody plants with old leaves out before the accident. About 40-50 d after the start of the accident, newly emerged leaves from woody plant with old leaves tended to show higher values than other woody or herbaceous plants. Concentrations of radiocesium in newly emerged tissues of trees decreased with time, but they did not decrease to the level of herbaceous plants. The type of the plant and presence of old leaves at the time of the heavy deposition period affected the radiocesium concentrations in newly emerged tissues. Copyright © 2011 Elsevier Ltd. All rights reserved.

  2. Sleeping with the hypothalamus: emerging therapeutic targets for sleep disorders.

    PubMed

    Mignot, Emmanuel; Taheri, Shahrad; Nishino, Seiji

    2002-11-01

    Delineating the basic mechanisms that regulate sleep will likely result in the development of better treatments for sleep disorders. The hypothalamus is now recognized as a key center for sleep regulation, with hypothalamic neurotransmitter systems providing the framework for therapeutic advances. An increased awareness of the close interaction between sleep and homeostatic systems is also emerging. Progress has occurred in the understanding of narcolepsy--molecular techniques have identified the lateral hypothalamic hypocretin (orexin) neuropeptide system as key to the disorder. Other sleep disorders are now being tackled in the same way and are likely to yield to efforts combining basic and clinical research. Here we highlight the role of the hypothalamus in sleep physiology and discuss neurotransmitter systems, such as adenosine, dopamine, GABA, histamine and hypocretin, that may have therapeutic applications for sleep disorders.

  3. Emerging Therapeutic Targets for Male Germ Cell Tumors.

    PubMed

    Fankhauser, Christian Daniel; Honecker, Friedemann; Beyer, Jörg; Bode, Peter Karl

    2015-12-01

    Male germ cell tumors (GCTs) are curable cancers, yet 10-15 % of patients with metastatic disease fail cisplatin-based first-line treatments. While therapeutic options have increased for various other cancers, little progress has been made in the management of GCT in the last decades. A better understanding of the molecular alterations underlying the disease and identification of new therapeutic targets are needed. Several phase I/II studies with promising new agents are ongoing or have been completed, but most of those trials have been small and have not included translational research. Therefore, molecular profiles predictive for response or new agents have not been identified in male GCT so far. The purpose of this review is to highlight emerging targets and therapies with the potential to improve systemic treatment of metastatic male GCT and to develop strategies for future clinical trials.

  4. microRNA Therapeutics in Cancer - An Emerging Concept.

    PubMed

    Shah, Maitri Y; Ferrajoli, Alessandra; Sood, Anil K; Lopez-Berestein, Gabriel; Calin, George A

    2016-10-01

    MicroRNAs (miRNAs) are an evolutionarily conserved class of small, regulatory non-coding RNAs that negatively regulate protein coding gene and other non-coding transcripts expression. miRNAs have been established as master regulators of cellular processes, and they play a vital role in tumor initiation, progression and metastasis. Further, widespread deregulation of microRNAs have been reported in several cancers, with several microRNAs playing oncogenic and tumor suppressive roles. Based on these, miRNAs have emerged as promising therapeutic tools for cancer management. In this review, we have focused on the roles of miRNAs in tumorigenesis, the miRNA-based therapeutic strategies currently being evaluated for use in cancer, and the advantages and current challenges to their use in the clinic.

  5. 'BRICS without straw'? A systematic literature review of newly emerging economies' influence in global health.

    PubMed

    Harmer, Andrew; Xiao, Yina; Missoni, Eduardo; Tediosi, Fabrizio

    2013-04-15

    Since 2010, five newly emerging economies collectively known as 'BRICS' (Brazil, India, Russia, China and South Africa) have caught the imagination, and scholarly attention, of political scientists, economists and development specialists. The prospect of a unified geopolitical bloc, consciously seeking to re-frame international (and global) health development with a new set of ideas and values, has also, if belatedly, begun to attract the attention of the global health community. But what influence, if any, do the BRICS wield in global health, and, if they do wield influence, how has that influence been conceptualized and recorded in the literature? We conducted a systematic literature review in (March-December 2012) of documents retrieved from the databases EMBASE, PubMed/Medline, Global Health, and Google Scholar, and the websites of relevant international organisations, research institutions and philanthropic organisations. The results were synthesised using a framework of influence developed for the review from the political science literature. Our initial search of databases and websites yielded 887 documents. Exclusion criteria narrowed the number of documents to 71 journal articles and 23 reports. Two researchers using an agreed set of inclusion criteria independently screened the 94 documents, leaving just 7 documents. We found just one document that provided sustained analysis of the BRICS' collective influence; the overwhelming tendency was to describe individual BRICS countries influence. Although influence was predominantly framed by BRICS countries' material capability, there were examples of institutional and ideational influence - particularly from Brazil. Individual BRICS countries were primarily 'opportunity seekers' and region mobilisers but with potential to become 'issue leaders' and region organisers. Though small in number, the written output on BRICS influence in global health has increased significantly since a similar review conducted in

  6. Suicide epidemics: the impact of newly emerging methods on overall suicide rates - a time trends study.

    PubMed

    Thomas, Kyla; Chang, Shu-Sen; Gunnell, David

    2011-05-14

    The impact of newly emerging, popular suicide methods on overall rates of suicide has not previously been investigated systematically. Understanding these effects may have important implications for public health surveillance. We examine the emergence of three novel methods of suicide by gassing in the 20th and 21st centuries and determine the impact of emerging methods on overall suicide rates. We studied the epidemic rises in domestic coal gas (1919-1935, England and Wales), motor vehicle exhaust gas (1975-1992, England and Wales) and barbecue charcoal gas (1999-2006, Taiwan) suicide using Poisson and joinpoint regression models. Joinpoint regression uses contiguous linear segments and join points (points at which trends change) to describe trends in incidence. Epidemic increases in the use of new methods of suicide were generally associated with rises in overall suicide rates of between 23% and 71%. The recent epidemic of barbecue charcoal suicides in Taiwan was associated with the largest rise in overall rates (40-50% annual rise), whereas the smallest rise was seen for car exhaust gassing in England and Wales (7% annual rise). Joinpoint analyses were only feasible for car exhaust and charcoal burning suicides; these suggested an impact of the emergence of car exhaust suicides on overall suicide rates in both sexes in England and Wales. However there was no statistical evidence of a change in the already increasing overall suicide trends when charcoal burning suicides emerged in Taiwan, possibly due to the concurrent economic recession. Rapid rises in the use of new sources of gas for suicide were generally associated with increases in overall suicide rates. Suicide prevention strategies should include strengthening local and national surveillance for early detection of novel suicide methods and implementation of effective media guidelines and other appropriate interventions to limit the spread of new methods.

  7. A Novel Botrytis Species Is Associated with a Newly Emergent Foliar Disease in Cultivated Hemerocallis

    PubMed Central

    Grant-Downton, Robert T.; Terhem, Razak B.; Kapralov, Maxim V.; Mehdi, Saher; Rodriguez-Enriquez, M. Josefina; Gurr, Sarah J.; van Kan, Jan A. L.; Dewey, Frances M.

    2014-01-01

    Foliar tissue samples of cultivated daylilies (Hemerocallis hybrids) showing the symptoms of a newly emergent foliar disease known as ‘spring sickness’ were investigated for associated fungi. The cause(s) of this disease remain obscure. We isolated repeatedly a fungal species which proved to be member of the genus Botrytis, based on immunological tests. DNA sequence analysis of these isolates, using several different phyogenetically informative genes, indicated that they represent a new Botrytis species, most closely related to B. elliptica (lily blight, fire blight) which is a major pathogen of cultivated Lilium. The distinction of the isolates was confirmed by morphological analysis of asexual sporulating cultures. Pathogenicity tests on Hemerocallis tissues in vitro demonstrated that this new species was able to induce lesions and rapid tissue necrosis. Based on this data, we infer that this new species, described here as B. deweyae, is likely to be an important contributor to the development of ‘spring sickness’ symptoms. Pathogenesis may be promoted by developmental and environmental factors that favour assault by this necrotrophic pathogen. The emergence of this disease is suggested to have been triggered by breeding-related changes in cultivated hybrids, particularly the erosion of genetic diversity. Our investigation confirms that emergent plant diseases are important and deserve close monitoring, especially in intensively in-bred plants. PMID:24887415

  8. Polymorphic SSR Markers for Plasmopara obducens (Peronosporaceae), the Newly Emergent Downy Mildew Pathogen of Impatiens (Balsaminaceae)

    DOE PAGES

    Salgado-Salazar, Catalina; Rivera, Yazmín; Veltri, Daniel; ...

    2015-11-10

    Premise of the study: Simple sequence repeat (SSR) markers were developed for Plasmopara obducens, the causal agent of the newly emergent downy mildew disease of Impatiens walleriana. Methods and Results: A 202-Mb draft genome assembly was generated from P. obducens using Illumina technology and mined to identify 13,483 SSR motifs. Primers were synthesized for 62 marker candidates, of which 37 generated reliable PCR products. Testing of the 37 markers using 96 P. obducens samples showed 96% of the markers were polymorphic, with 2-6 alleles observed. Observed and expected heterozygosity ranged from 0.000-0.892 and 0.023-0.746, respectively. Just 17 markers were sufficientmore » to identify all multilocus genotypes. Conclusions: These are the first SSR markers available for this pathogen, and one of the first molecular resources. These markers will be useful in assessing variation in pathogen populations and determining the factors contributing to the emergence of destructive impatiens downy mildew disease.« less

  9. [Rapidly progressive glomerulonephritis: a diagnostic and therapeutic emergency].

    PubMed

    Halfon, Matthieu; Teta, Daniel; Rotman, Samuel; Pruijm, Menno; Humbert, Antoine

    2014-02-26

    Rapidly progressive glomerulonephritis (RPG) is a rare clinical syndrome characterized by kidney damage that can lead to irreversible kidney failure. RPG can be caused by primary glomerular disease or can be part of a systemic autoimmune disorder. All RPG have a similar pathophysiology (proliferation of cells in Bowman's capsule and formation of crescents) and clinical evolution (rapidly progressive kidney failure with proteinuria and an active urine sediment). Immunosuppressive therapy and sometimes plasma exchanges are required. Overall- and kidney survival are closely linked to the blood creatinine level at presentation, the percentage of damaged glomeruli, and to the underlying cause. RPG is therefore a diagnostic and therapeutic emergency that needs quick referral to a nephrologist.

  10. Emerging diagnostic and therapeutic molecular imaging applications in vascular disease

    PubMed Central

    Eraso, Luis H; Reilly, Muredach P; Sehgal, Chandra; Mohler, Emile R

    2013-01-01

    Assessment of vascular disease has evolved from mere indirect and direct measurements of luminal stenosis to sophisticated imaging methods to depict millimeter structural changes of the vasculature. In the near future, the emergence of multimodal molecular imaging strategies may enable robust therapeutic and diagnostic (‘theragnostic’) approaches to vascular diseases that comprehensively consider structural, functional, biological and genomic characteristics of the disease in individualized risk assessment, early diagnosis and delivery of targeted interventions. This review presents a summary of recent preclinical and clinical developments in molecular imaging and theragnostic applications covering diverse atherosclerosis events such as endothelial activation, macrophage infammatory activity, plaque neovascularization and arterial thrombosis. The main focus is on molecular targets designed for imaging platforms commonly used in clinical medicine including magnetic resonance, computed tomography and positron emission tomography. A special emphasis is given to vascular ultrasound applications, considering the important role this imaging platform plays in the clinical and research practice of the vascular medicine specialty. PMID:21310769

  11. Sports doping: emerging designer and therapeutic β2-agonists.

    PubMed

    Fragkaki, A G; Georgakopoulos, C; Sterk, S; Nielen, M W F

    2013-10-21

    Beta2-adrenergic agonists, or β2-agonists, are considered essential bronchodilator drugs in the treatment of bronchial asthma, both as symptom-relievers and, in combination with inhaled corticosteroids, as disease-controllers. The use of β2-agonists is prohibited in sports by the World Anti-Doping Agency (WADA) due to claimed anabolic effects, and also, is prohibited as growth promoters in cattle fattening in the European Union. This paper reviews the last seven-year (2006-2012) literature concerning the development of novel β2-agonists molecules either by modifying the molecule of known β2-agonists or by introducing moieties producing indole-, adamantyl- or phenyl urea derivatives. New emerging β2-agonists molecules for future therapeutic use are also presented, intending to emphasize their potential use for doping purposes or as growth promoters in the near future.

  12. Emerging Insights into Barriers to Effective Brain Tumor Therapeutics

    PubMed Central

    Woodworth, Graeme F.; Dunn, Gavin P.; Nance, Elizabeth A.; Hanes, Justin; Brem, Henry

    2014-01-01

    There is great promise that ongoing advances in the delivery of therapeutics to the central nervous system (CNS) combined with rapidly expanding knowledge of brain tumor patho-biology will provide new, more effective therapies. Brain tumors that form from brain cells, as opposed to those that come from other parts of the body, rarely metastasize outside of the CNS. Instead, the tumor cells invade deep into the brain itself, causing disruption in brain circuits, blood vessel and blood flow changes, and tissue swelling. Patients with the most common and deadly form, glioblastoma (GBM) rarely live more than 2 years even with the most aggressive treatments and often with devastating neurological consequences. Current treatments include maximal safe surgical removal or biopsy followed by radiation and chemotherapy to address the residual tumor mass and invading tumor cells. However, delivering effective and sustained treatments to these invading cells without damaging healthy brain tissue is a major challenge and focus of the emerging fields of nanomedicine and viral and cell-based therapies. New treatment strategies, particularly those directed against the invasive component of this devastating CNS disease, are sorely needed. In this review, we (1) discuss the history and evolution of treatments for GBM, (2) define and explore three critical barriers to improving therapeutic delivery to invasive brain tumors, specifically, the neuro-vascular unit as it relates to the blood brain barrier, the extra-cellular space in regard to the brain penetration barrier, and the tumor genetic heterogeneity and instability in association with the treatment efficacy barrier, and (3) identify promising new therapeutic delivery approaches that have the potential to address these barriers and create sustained, meaningful efficacy against GBM. PMID:25101239

  13. Emerging Therapeutics for Advanced Thyroid Malignancies: Rationale and Targeted Approaches

    PubMed Central

    Harris, Pamela; Bible, Keith C.

    2011-01-01

    Introduction Thyroid cancer is an emerging public health concern. In the U.S., its incidence has doubled in the past decade, making it the 8th most commonly diagnosed neoplasm in 2010. Despite this alarming increase, most thyroid cancer patients benefit from conventional approaches (surgery, radioiodine, radiotherapy, TSH suppression with levothyroxine) and are often cured. Nevertheless, a minority have aggressive tumors resistant to cytotoxic and other historical therapies; these patients sorely need new treatment options. Areas covered Herein the biology and molecular characteristics of the common histological types of thyroid cancer are reviewed to provide context for subsequent discussion of recent developments and emerging therapeutics for advanced thyroid cancers. Expert opinion Several kinase inhibitors, especially those targeting VEGFR and/or RET, have already demonstrated promising activity in differentiated and medullary thyroid cancers (DTC, MTC). Although of minimal benefit in DTC and MTC, cytotoxic chemotherapy with anti-microtubule agents and/or anthracyclines in combination with intensity modulated radiation therapy appears to extend survival for patients with locoregionally-confined anaplastic thyroid cancer (ATC), but to have only modest benefit in metastatic ATC. Further discovery and development of novel agents and combinations of agents will be critical to further progress in treating advanced thyroid cancers of all histotypes. PMID:21910667

  14. Cross-protection of newly emerging HPAI H5 viruses by neutralizing human monoclonal antibodies: A viable alternative to oseltamivir

    PubMed Central

    Ren, Huanhuan; Wang, Guiqin; Wang, Shuangshuang; Chen, Honglin; Chen, Zhiwei; Hu, Hongxing; Cheng, Genhong; Zhou, Paul

    2016-01-01

    ABSTRACT Newly emerging highly pathogenic avian influenza (HPAI) H5N2, H5N3, H5N5, H5N6, H5N8 and H5N9 viruses have been spreading in poultry and wild birds. The H5N6 viruses have also caused 10 human infections with 4 fatal cases in China. Here, we assessed the cross-neutralization and cross-protection of human and mouse monoclonal antibodies against 2 viruses: a HPAI H5N8 virus, A/chicken/Netherlands/14015526/2014 (NE14) and a HPAI H5N6 virus, A/Sichuan/26221/2014 (SC14). The former was isolated from an infected chicken in Netherlands in 2014 and the latter was isolated from an infected human patient in Sichuan, China. We show that antibodies FLA5.10, FLD21.140, 100F4 and 65C6, but not AVFluIgG01, AVFluIgG03, S139/1 and the VRC01 control, potently cross-neutralize the H5N8 NE14 and H5N6 SC14 viruses. Furthermore, we show that a single injection of >1 mg/kg of antibody 100F4 at 4 hours before, or 20 mg/kg antibody 100F4 at 72 hours after, a lethal dose of H5N8 NE14 enables mice to withstand the infection. Finally, we show that a single injection of 0.5 or 1 mg/kg antibody 100F4 prophylactically or 10 mg/kg 100F4 therapeutically outperforms a 5-day course of 10 mg/kg/day oseltamivir treatment against lethal H5N8 NE14 or H5N6 SC14 infection in mice. Our results suggest that further preclinical evaluation of human monoclonal antibodies against newly emerging H5 viruses is warranted. PMID:27167234

  15. Emergent properties of neural repair: elemental biology to therapeutic concepts.

    PubMed

    Carmichael, S Thomas

    2016-06-01

    Stroke is the leading cause of adult disability. The past decade has seen advances in basic science research of neural repair in stroke. The brain forms new connections after stroke, which have a causal role in recovery of function. Brain progenitors, including neuronal and glial progenitors, respond to stroke and initiate a partial formation of new neurons and glial cells. The molecular systems that underlie axonal sprouting, neurogenesis, and gliogenesis after stroke have recently been identified. Importantly, tractable drug targets exist within these molecular systems that might stimulate tissue repair. These basic science advances have taken the field to its first scientific milestone; the elemental principles of neural repair in stroke have been identified. The next stages in this field involve understanding how these elemental principles of recovery interact in the dynamic cellular systems of the repairing brain. Emergent principles arise out of the interaction of the fundamental or elemental principles in a system. In neural repair, the elemental principles of brain reorganization after stroke interact to generate higher order and distinct concepts of regenerative brain niches in cellular repair, neuronal networks in synaptic plasticity, and the distinction of molecular systems of neuroregeneration. Many of these emergent principles directly guide the development of new therapies, such as the necessity for spatial and temporal control in neural repair therapy delivery and the overlap of cancer and neural repair mechanisms. This review discusses the emergent principles of neural repair in stroke as they relate to scientific and therapeutic concepts in this field. Ann Neurol 2016;79:895-906. © 2016 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.

  16. Emergent properties of neural repair: elemental biology to therapeutic concepts

    PubMed Central

    2016-01-01

    Stroke is the leading cause of adult disability. The past decade has seen advances in basic science research of neural repair in stroke. The brain forms new connections after stroke, which have a causal role in recovery of function. Brain progenitors, including neuronal and glial progenitors, respond to stroke and initiate a partial formation of new neurons and glial cells. The molecular systems that underlie axonal sprouting, neurogenesis, and gliogenesis after stroke have recently been identified. Importantly, tractable drug targets exist within these molecular systems that might stimulate tissue repair. These basic science advances have taken the field to its first scientific milestone; the elemental principles of neural repair in stroke have been identified. The next stages in this field involve understanding how these elemental principles of recovery interact in the dynamic cellular systems of the repairing brain. Emergent principles arise out of the interaction of the fundamental or elemental principles in a system. In neural repair, the elemental principles of brain reorganization after stroke interact to generate higher order and distinct concepts of regenerative brain niches in cellular repair, neuronal networks in synaptic plasticity, and the distinction of molecular systems of neuroregeneration. Many of these emergent principles directly guide the development of new therapies, such as the necessity for spatial and temporal control in neural repair therapy delivery and the overlap of cancer and neural repair mechanisms. This review discusses the emergent principles of neural repair in stroke as they relate to scientific and therapeutic concepts in this field. Ann Neurol 2016;79:895–906 PMID:27043816

  17. The initiation of coronal mass ejections by newly emerging magnetic flux

    NASA Technical Reports Server (NTRS)

    Feynman, J.; Martin, S. F.

    1995-01-01

    We present observational evidence that eruptions of quiescent filaments and associated coronal mass ejections (CMEs) occur as a consequence of the destabilization of large-scale coronal arcades due to interactions between these structures and new and growing active regions. Both statistical and case studies have been carried out. In a case study of a 'bulge' observed by the High-Altitude Observatory Solar Maximum Mission coronagraph, the high-resolution magnetograms from the Big Bear Solar Observatory show newly emerging and rapidly changing flux in the magnetic fields that apparently underlie the bugle. For other case studies and in the statistical work the eruption of major quiescent filaments was taken as a proxy for CME eruption. We have found that two thirds of the quiescent-filament-associated CMEs occurred after substantial amounts of new magnetic flux emerged in the vicinity of the filament. In addition, in a study of all major quiescent filaments and active regions appearing in a 2-month period we found that 17 of the 22 filaments that were associated with new active regions erupted and 26 of the 31 filaments that were not associated with new flux did not erupt. In all cases in which the new flux was oriented favorably for reconnection with the preexisting large-scale coronal arcades; the filament was observed to erupt. The appearance of the new flux in the form of new active regions begins a few days before the eruption and typically is still occurring at the time of the eruption. A CME initiation scenario taking account of these observational results is proposed.

  18. A guide for clinicians in the evaluation of emerging molecular diagnostics for newly diagnosed prostate cancer.

    PubMed

    Canfield, Steven E; Kibel, Adam S; Kemeter, Michael J; Febbo, Phillip G; Lawrence, H Jeffrey; Moul, Judd W

    2014-01-01

    Prostate-specific antigen (PSA) screening is associated with a decline in prostate cancer-related mortality. However, screening has also led to overdiagnosis and overtreatment of clinically insignificant tumors. Recently, certain national guidelines (eg, US Preventive Services Task Force) have recommended against PSA screening, which may lead to a reverse-stage migration. Although many prostate tumors are indolent at presentation, others are aggressive and are appropriate targets for treatment interventions. Utilization of molecular markers may improve our ability to measure tumor biology and allow better discrimination of indolent and aggressive tumors at diagnosis. Many emerging commercial molecular diagnostic assays have been designed to provide more accurate risk stratification for newly diagnosed prostate cancer. Unfamiliarity with molecular diagnostics may make it challenging for some clinicians to navigate and interpret the medical literature to ascertain whether particular assays are appropriately developed and validated for clinical use. Herein, the authors provide a framework for practitioners to use when assessing new tissue-based molecular assays. This review outlines aspects of assay development, clinical and analytic validation and clinical utility studies, and regulatory issues, which collectively determine whether tests (1) are actionable for specific clinical indications, (2) measurably influence treatment decisions, and (3) are sufficiently validated to warrant incorporation into clinical practice.

  19. Biology and natural enemies of Agrilus fleischeri (Coleoptera: Buprestidae), a newly emerging destructive buprestid pest in Northeast China

    USDA-ARS?s Scientific Manuscript database

    The jewel beetle Agrilus fleischeri Obenberger (Coleoptera: Buprestidae) is a newly emerging major pest of poplar trees (Populus spp.) in northeast China and is responsible for the poplar mortality throughout its distribution range. In order to determine how to manage this pest effectively, we stud...

  20. "Candidatus phytoplasma costaricanum" a new phytoplasma associated with a newly emerging disease in soybean in Costa Rica

    USDA-ARS?s Scientific Manuscript database

    A new phytoplasma associated with a newly emerging disease, soybean stunt (SoyST), in soybean (Glycine max) was found in 2002 in a soybean plantation in Alajuela Province, Costa Rica. The same or very closely related phytoplasma also infected sweet pepper (Capsicum annuum) with purple vein syndrome ...

  1. Sugar administration to newly emerged Aedes albopictus males increases their survival probability and mating performance.

    PubMed

    Bellini, Romeo; Puggioli, Arianna; Balestrino, Fabrizio; Brunelli, Paolo; Medici, Anna; Urbanelli, Sandra; Carrieri, Marco

    2014-04-01

    Aedes albopictus male survival in laboratory cages is no more than 4-5 days when kept without any access to sugar indicating their need to feed on a sugar source soon after emergence. We therefore developed a device to administer energetic substances to newly emerged males when released as pupae as part of a sterile insect technique (SIT) programme, made with a polyurethane sponge 4 cm thick and perforated with holes 2 cm in diameter. The sponge was imbibed with the required sugar solution and due to its high retention capacity the sugar solution was available for males to feed for at least 48 h. When evaluated in lab cages, comparing adults emerged from the device with sugar solution vs the device with water only (as negative control), about half of the males tested positive for fructose using the Van Handel anthrone test, compared to none of males in the control cage. We then tested the tool in semi-field and in field conditions with different sugar concentrations (10%, 15%, and 20%) and compared results to the controls fed with water only. Males were recaptured by a battery operated manual aspirator at 24 and 48 h after pupae release. Rather high share 10-25% of captured males tested positive for fructose in recollections in the vicinity of the control stations, while in the vicinity of the sugar stations around 40-55% of males were positive, though variability between replicates was large. The sugar positive males in the control test may have been released males that had access to natural sugar sources found close to the release station and/or wild males present in the environment. Only a slight increase in the proportion of positive males was obtained by increasing the sugar concentration in the feeding device from 10% to 20%. Surprisingly, modification of the device to add a black plastic inverted funnel above the container reduced rather than increased the proportion of fructose positive males collected around the station. No evidence of difference in the

  2. Iron deficiency: an emerging therapeutic target in heart failure.

    PubMed

    Cohen-Solal, Alain; Leclercq, Christophe; Deray, Gilbert; Lasocki, Sigismond; Zambrowski, Jean-Jacques; Mebazaa, Alexandre; de Groote, Pascal; Damy, Thibaud; Galinier, Michel

    2014-09-15

    In patients with heart failure, iron deficiency is frequent but overlooked, with a prevalence of 30%-50%. Since it contributes to cardiac and peripheral muscle dysfunction, iron deficiency is associated with poorer clinical outcomes and a greater risk of death, independent of haemoglobin level. Therefore, iron deficiency emerges as a new comorbidity and a therapeutic target of chronic heart failure in addition to chronic renal insufficiency, anaemia and diabetes. In a series of placebo-controlled, randomised studies in patients with heart failure and iron deficiency, intravenous iron had a favourable effect on exercise capacity, functional class, LVEF, renal function and quality of life. These clinical studies were performed in the context of a renewed interest in iron metabolism. During the past 10 years, knowledge about the transport, storage and homeostasis of iron has improved dramatically, and new molecules involved in iron metabolism have been described (eg, hepcidin, ferroportin, divalent metal transporter 1). Recent European guidelines recommend the monitoring of iron parameters (ie, serum ferritin, transferrin saturation) for all patients with heart failure. Ongoing clinical trials will explore the benefits of iron deficiency correction on various heart failure parameters.

  3. The inflammasome: an emerging therapeutic oncotarget for cancer prevention

    PubMed Central

    Wang, Qi; Peng, Cheng; Zhang, Jin; Liu, Pengxi; Ou, Aihua; Zhong, Shaowen; Cordero, Mario D.; Lin, Yi

    2016-01-01

    Deregulated inflammation is considered to be one of the hallmarks of cancer initiation and development regulation. Emerging evidence indicates that the inflammasome plays a central role in regulating immune cells and cytokines related to cancer. The inflammasome is a multimeric complex consisting of NOD-like receptors (NLRs) and responds to a variety of endogenous (damage-associated molecular patterns) and exogenous (pathogen-associated molecular patterns) stimuli. Several lines of evidence suggests that in cancer the inflammasome is positively associated with characteristics such as elevated levels of IL-1β and IL-18, activation of NF-κB signaling, enhanced mitochondrial oxidative stress, and activation of autophagic process. A number of NLRs, such as NLRP3 and NLRC4 are also highlighted in carcinogenesis and closely correlate to chemoresponse and prognosis. Although conflicting evidence suggested the duplex role of inflammasome in cancer development, the phenomenon might be attributed to NLRs difference, cell and tissue type, cancer stage, and specific experimental conditions. Given the promising role of inflammasome in mediating cancer development, precise elucidation of its signaling network and pathological significance may lead to novel therapeutic options for malignancy therapy and prevention. PMID:27206676

  4. The inflammasome: an emerging therapeutic oncotarget for cancer prevention.

    PubMed

    Zhiyu, Wang; Wang, Neng; Wang, Qi; Peng, Cheng; Zhang, Jin; Liu, Pengxi; Ou, Aihua; Zhong, Shaowen; Cordero, Mario D; Lin, Yi

    2016-08-02

    Deregulated inflammation is considered to be one of the hallmarks of cancer initiation and development regulation. Emerging evidence indicates that the inflammasome plays a central role in regulating immune cells and cytokines related to cancer. The inflammasome is a multimeric complex consisting of Nod-like receptors (NLRs) and responds to a variety of endogenous (damage-associated molecular patterns) and exogenous (pathogen-associated molecular patterns) stimuli. Several lines of evidence suggests that in cancer the inflammasome is positively associated with characteristics such as elevated levels of IL-1β and IL-18, activation of NF-κB signaling, enhanced mitochondrial oxidative stress, and activation of autophagic process. A number of NLRs, such as NLRP3 and NLRC4 are also highlighted in carcinogenesis and closely correlate to chemoresponse and prognosis. Although conflicting evidence suggested the duplex role of inflammasome in cancer development, the phenomenon might be attributed to NLRs difference, cell and tissue type, cancer stage, and specific experimental conditions. Given the promising role of inflammasome in mediating cancer development, precise elucidation of its signaling network and pathological significance may lead to novel therapeutic options for malignancy therapy and prevention.

  5. CCR5 inhibitors: Emerging promising HIV therapeutic strategy.

    PubMed

    Rao, Padmasri Kutikuppala Surya

    2009-01-01

    safety issues do not emerge, these compounds could be positioned for use from very early stage of HIV infection to salvage strategies that would be an emerging therapeutic novel strategy for HIV/AIDS patients.

  6. Tryptophan Hydroxylase-2: An Emerging Therapeutic Target for Stress Disorders

    PubMed Central

    Chen, Guo-Lin; Miller, Gregory M.

    2013-01-01

    Serotonin (5-HT) has been long recognized to modulate the stress response, and dysfunction of 5-HT has been implicated in numerous stress disorders. Accordingly, the 5-HT system has been targeted for the treatment of stress disorders. Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in 5-HT synthesis, and the recent identification of a second, neuron-specific TPH isoform (TPH2) opened up a new area of research. With a decade of extensive investigation, it is now recognized that: 1) TPH2 exhibits a highly flexible gene expression that is modulated by an increasing number of internal and external environmental factors including the biological clock, stressors, endogenous hormones, and antidepressant therapies; and 2) genetically determined TPH2 activity is linked to a growing body of stress-related neuronal correlates and behavioral traits. These findings reveal an active role of TPH2 in the stress response and provide new insights into the long recognized but not yet fully understood 5-HT-stress interaction. As a major modulator of 5-HT neurotransmission and the stress response, TPH2 is of both pathophysiological and pharmacological significance, and is emerging as a new therapeutic target for the treatment of stress disorders. Given that numerous antidepressant therapies influence TPH2 gene expression, TPH2 is already inadvertently targeted for the treatment of stress disorders. With increased understanding of the regulation of TPH2 activity we can now purposely utilize TPH2 as a target to develop new or optimize current therapies, which are expected to greatly improve the prevention and treatment of a wide variety of stress disorders. PMID:23435356

  7. Newly Emergent Highly Pathogenic H5N9 Subtype Avian Influenza A Virus

    PubMed Central

    Yu, Yang; Wang, Xingbo; Jin, Tao; Wang, Hailong; Si, Weiying; Yang, Hui; Wu, Jiusheng; Yan, Yan; Liu, Guang; Sang, Xiaoyu; Wu, Xiaopeng; Gao, Yuwei; Xia, Xianzhu; Yu, Xinfen; Pan, Jingcao; Gao, George F.

    2015-01-01

    ABSTRACT The novel H7N9 avian influenza virus (AIV) was demonstrated to cause severe human respiratory infections in China. Here, we examined poultry specimens from live bird markets linked to human H7N9 infection in Hangzhou, China. Metagenomic sequencing revealed mixed subtypes (H5, H7, H9, N1, N2, and N9). Subsequently, AIV subtypes H5N9, H7N9, and H9N2 were isolated. Evolutionary analysis showed that the hemagglutinin gene of the novel H5N9 virus originated from A/Muscovy duck/Vietnam/LBM227/2012 (H5N1), which belongs to clade 2.3.2.1. The neuraminidase gene of the novel H5N9 virus originated from human-infective A/Hangzhou/1/2013 (H7N9). The six internal genes were similar to those of other H5N1, H7N9, and H9N2 virus strains. The virus harbored the PQRERRRKR/GL motif characteristic of highly pathogenic AIVs at the HA cleavage site. Receptor-binding experiments demonstrated that the virus binds α-2,3 sialic acid but not α-2,6 sialic acid. Identically, pathogenicity experiments also showed that the virus caused low mortality rates in mice. This newly isolated H5N9 virus is a highly pathogenic reassortant virus originating from H5N1, H7N9, and H9N2 subtypes. Live bird markets represent a potential transmission risk to public health and the poultry industry. IMPORTANCE This investigation confirms that the novel H5N9 subtype avian influenza A virus is a reassortant strain originating from H5N1, H7N9, and H9N2 subtypes and is totally different from the H5N9 viruses reported before. The novel H5N9 virus acquired a highly pathogenic H5 gene and an N9 gene from human-infecting subtype H7N9 but caused low mortality rates in mice. Whether this novel H5N9 virus will cause human infections from its avian host and become a pandemic subtype is not known yet. It is therefore imperative to assess the risk of emergence of this novel reassortant virus with potential transmissibility to public health. PMID:26085150

  8. Therapeutic Hypothermia Protocol in a Community Emergency Department

    PubMed Central

    Kulstad, Christine E.; Holt, Shannon C.; Abrahamsen, Aaron A.; Lovell, Elise O.

    2010-01-01

    Objectives: Therapeutic hypothermia (TH) has been shown to improve survival and neurological outcome in patients resuscitated after out of hospital cardiac arrest (OHCA) from ventricular fibrillation/ventricular tachycardia (VF/VT). We evaluated the effects of using a TH protocol in a large community hospital emergency department (ED) for all patients with neurological impairment after resuscitated OHCA regardless of presenting rhythm. We hypothesized improved mortality and neurological outcomes without increased complication rates. Methods: Our TH protocol entails cooling to 33°C for 24 hours with an endovascular catheter. We studied patients treated with this protocol from November 2006 to November 2008. All non-pregnant, unresponsive adult patients resuscitated from any initial rhythm were included. Exclusion criteria were initial hypotension or temperature less than 30°C, trauma, primary intracranial event, and coagulopathy. Control patients treated during the 12 months before the institution of our TH protocol met the same inclusion and exclusion criteria. We recorded survival to hospital discharge, neurological status at discharge, and rates of bleeding, sepsis, pneumonia, renal failure, and dysrhythmias in the first 72 hours of treatment. Results: Mortality rates were 71.1% (95% CI, 56–86%) for 38 patients treated with TH and 72.3% (95% CI 59–86%) for 47 controls. In the TH group, 8% of patients (95% CI, 0–17%) had a good neurological outcome on discharge, compared to 0 (95% CI 0–8%) in the control group. In 17 patients with VF/VT treated with TH, mortality was 47% (95% CI 21–74%) and 18% (95% CI 0–38%) had good neurological outcome; in 9 control patients with VF/VT, mortality was 67% (95% CI 28–100%), and 0% (95% CI 0–30%) had good neurological outcome. The groups were well-matched with respect to sex and age. Complication rates were similar or favored the TH group. Conclusion: Instituting a TH protocol for OHCA patients with any

  9. Ability of newly emerged adult Culex quinquefasciatus (Diptera: Culicidae) mosquitoes to exit belowground stormwater treatment systems via lateral conveyance pipes.

    PubMed

    Metzger, Marco E; Harbison, Justin E; Burns, Joseph E; Hu, Renjie

    2012-03-01

    Culex quinquefasciatus Say mosquitoes flourish in belowground stormwater systems in the southern United States. Recent evidence suggests that oviposition-site-seeking females may have difficulties locating, entering, and ovipositing inside permanent water chambers when surface entry through pickholes in manhole covers are sealed. It remains unknown, however, if newly emerged adults are able to detect cues necessary to exit these partly sealed systems via lateral conveyance pipes or if they perish belowground. Fourth instar Cx. quinquefasciatus were placed within proprietary belowground stormwater treatment systems to determine the percentage of newly emerged adults able to escape treatment chambers via a single lateral conveyance pipe. Overall, 56% of deployed mosquitoes were captured in adult exit traps with an 1:1 male:female ratio. The percentage of adults captured varied significantly among chambers, but was not associated with structural site characteristics such as the chamber depth or the length and course of conveyance pipe to the exit trap. Empirical observations suggested that longbodied cellar spiders, Pholcus phalangioides (Fuesslin), ubiquitous in these structures, may have reduced adult trap capture. Findings demonstrate that newly emerged Cx. quinquefasciatus can exit subterranean chambers under potentially difficult structural conditions but suggest that a portion may perish in the absence of surface exit points in manhole shafts.

  10. Can the exposure of Apis mellifera (Hymenoptera, Apiadae) larvae to a field concentration of thiamethoxam affect newly emerged bees?

    PubMed

    Friol, Priscila Sepúlveda; Catae, Aline Fernanda; Tavares, Daiana Antonia; Malaspina, Osmar; Roat, Thaisa Cristina

    2017-10-01

    The use of insecticides on crops can affect non-target insects, such as bees. In addition to the adult bees, larvae can be exposed to the insecticide through contaminated floral resources. Therefore, this study aimed to investigate the possible effects of the exposure of A. mellifera larvae to a field concentration of thiamethoxam (0.001 ng/μL thiamethoxam) on larval and pupal survival and on the percentage of adult emergence. Additionally, its cytotoxic effects on the digestive cells of midgut, Malpighian tubules cells and Kenyon cells of the brain of newly emerged A. mellifera bees were analyzed. The results showed that larval exposure to this concentration of thiamethoxam did not influence larval and pupal survival or the percentage of adult bee emergence. However, this exposure caused ultra-structural alterations in the target and non-target organs of newly emerged bees. The digestive cell of bees that were exposed to the insecticide exhibited a basal labyrinth without long and thin channels and compromised mitochondria. In Malpighian tubules cells, disorganized basal labyrinth, dilated mitochondria with a deformed shape and a loss of cristae, and disorganized microvilli were observed. The results showed that the exposed bees presented Kenyon cells with alterations in the nucleus and mitochondria. These alterations indicate possible tissue degeneration, demonstrating the cytotoxicity of thiamethoxam in the target and non-target organs of newly emerged bees. Such results suggest cellular organelle impairment that can compromise cellular function of the midgut cells, Malpighian tubules cells and Kenyon cells, and, consequently, can compromise the longevity of the bees of the whole colony. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. Recent developments in emerging therapeutic targets of osteoarthritis

    PubMed Central

    Sun, Margaret Man-Ger; Beier, Frank; Pest, Michael A.

    2017-01-01

    Purpose of review Despite the tremendous individual suffering and socioeconomic burden caused by osteoarthritis, there are currently no effective disease-modifying treatment options. This is in part because of our incomplete understanding of osteoarthritis disease mechanism. This review summarizes recent developments in therapeutic targets identified from surgical animal models of osteoarthritis that provide novel insight into osteoarthritis pathology and possess potential for progression into preclinical studies. Recent findings Several candidate pathways and processes that have been identified include chondrocyte autophagy, growth factor signaling, inflammation, and nociceptive signaling. Major strategies that possess therapeutic potential at the cellular level include inhibiting autophagy suppression and decreasing reactive oxygen species (ROS) production. Cartilage anabolism and prevention of cartilage degradation has been shown to result from growth factor signaling modulation, such as TGF-β, TGF-α, and FGF; however, the results are context-dependent and require further investigation. Pain assessment studies in rodent surgical models have demonstrated potential in employing anti-NGF strategies for minimizing osteoarthritis-associated pain. Summary Studies of potential therapeutic targets in osteoarthritis using animal surgical models are helping to elucidate osteoarthritis pathology and propel therapeutics development. Further studies should continue to elucidate pathological mechanisms and therapeutic targets in various joint tissues to improve overall joint health. PMID:27906752

  12. Recent developments in emerging therapeutic targets of osteoarthritis.

    PubMed

    Sun, Margaret Man-Ger; Beier, Frank; Pest, Michael A

    2017-01-01

    Despite the tremendous individual suffering and socioeconomic burden caused by osteoarthritis, there are currently no effective disease-modifying treatment options. This is in part because of our incomplete understanding of osteoarthritis disease mechanism. This review summarizes recent developments in therapeutic targets identified from surgical animal models of osteoarthritis that provide novel insight into osteoarthritis pathology and possess potential for progression into preclinical studies. Several candidate pathways and processes that have been identified include chondrocyte autophagy, growth factor signaling, inflammation, and nociceptive signaling. Major strategies that possess therapeutic potential at the cellular level include inhibiting autophagy suppression and decreasing reactive oxygen species (ROS) production. Cartilage anabolism and prevention of cartilage degradation has been shown to result from growth factor signaling modulation, such as TGF-β, TGF-α, and FGF; however, the results are context-dependent and require further investigation. Pain assessment studies in rodent surgical models have demonstrated potential in employing anti-NGF strategies for minimizing osteoarthritis-associated pain. Studies of potential therapeutic targets in osteoarthritis using animal surgical models are helping to elucidate osteoarthritis pathology and propel therapeutics development. Further studies should continue to elucidate pathological mechanisms and therapeutic targets in various joint tissues to improve overall joint health.

  13. Recent discoveries and emerging therapeutics in eosinophilic esophagitis.

    PubMed

    Goyal, Aakash; Cheng, Edaire

    2016-02-06

    Eosinophilic esophagitis (EoE) is an allergy-mediated disease culminating in severe eosinophilic inflammation and dysfunction of the esophagus. This chronic disorder of the esophagus causes significant morbidity, poor quality of life, and complications involving fibrosis and esophageal remodeling. Overlapping features between EoE and gastroesophageal reflux disease (GERD) pose great challenges to differentiating the two conditions, although the two disorders are not mutually exclusive. Recent findings suggest that the confounding condition proton pump inhibitor - responsive esophageal eosinophilia (PPI-REE) is likely a subset of EoE. Since PPIs have therapeutic properties that can benefit EoE, PPIs should be considered as a therapeutic option for EoE rather than a diagnostic screen to differentiate GERD, PPI-REE, and EoE. Other current treatments include dietary therapy, corticosteroids, and dilation. Immunomodulators and biologic agents might have therapeutic value, and larger trials are needed to assess efficacy and safety. Understanding the pathophysiology of EoE is critical to the development of novel therapeutics.

  14. Recent discoveries and emerging therapeutics in eosinophilic esophagitis

    PubMed Central

    Goyal, Aakash; Cheng, Edaire

    2016-01-01

    Eosinophilic esophagitis (EoE) is an allergy-mediated disease culminating in severe eosinophilic inflammation and dysfunction of the esophagus. This chronic disorder of the esophagus causes significant morbidity, poor quality of life, and complications involving fibrosis and esophageal remodeling. Overlapping features between EoE and gastroesophageal reflux disease (GERD) pose great challenges to differentiating the two conditions, although the two disorders are not mutually exclusive. Recent findings suggest that the confounding condition proton pump inhibitor - responsive esophageal eosinophilia (PPI-REE) is likely a subset of EoE. Since PPIs have therapeutic properties that can benefit EoE, PPIs should be considered as a therapeutic option for EoE rather than a diagnostic screen to differentiate GERD, PPI-REE, and EoE. Other current treatments include dietary therapy, corticosteroids, and dilation. Immunomodulators and biologic agents might have therapeutic value, and larger trials are needed to assess efficacy and safety. Understanding the pathophysiology of EoE is critical to the development of novel therapeutics. PMID:26855809

  15. Focused Ultrasound: An Emerging Therapeutic Modality for Neurologic Disease.

    PubMed

    Fishman, Paul S; Frenkel, Victor

    2017-02-27

    Therapeutic ultrasound is only beginning to be applied to neurologic conditions, but the potential of this modality for a wide spectrum of brain applications is high. Engineering advances now allow sound waves to be targeted through the skull to a brain region selected with real time magnetic resonance imaging and thermography, using a commercial array of focused emitters. High intensities of sonic energy can create a coagulation lesion similar to that of older radiofrequency stereotactic methods, but without opening the skull. This has led to the recent Food and Drug Administration approval of focused ultrasound (FUS) thalamotomy for unilateral treatment of essential tremor. Clinical studies of stereotactic FUS for aspects of Parkinson's disease, chronic pain, and refractory psychiatric indications are underway, with promising results. Moderate-intensity FUS has the potential to safely open the blood-brain barrier for localized delivery of therapeutics, while low levels of sonic energy can be used as a form of neuromodulation.

  16. Current and Emerging Therapeutic Options in Adrenocortical Cancer Treatment

    PubMed Central

    Stigliano, Antonio; Cerquetti, Lidia; Sampaoli, Camilla; Bucci, Barbara; Toscano, Vincenzo

    2012-01-01

    Adrenocortical carcinoma (ACC) is a very rare endocrine tumour, with variable prognosis, depending on tumour stage and time of diagnosis. The overall survival is five years from detection. Radical surgery is considered the therapy of choice in the first stages of ACC. However postoperative disease-free survival at 5 years is only around 30% and recurrence rates are frequent. o,p'DDD (ortho-, para'-, dichloro-, diphenyl-, dichloroethane, or mitotane), an adrenolytic drug with significant toxicity and unpredictable therapeutic response, is used in the treatment of ACC. Unfortunately, treatment for this aggressive cancer is still ineffective. Over the past years, the growing interest in ACC has contributed to the development of therapeutic strategies in order to contrast the neoplastic spread. In this paper we discuss the most promising therapies which can be used in this endocrine neoplasia. PMID:22934112

  17. Pro-Tumoral Inflammatory Myeloid Cells as Emerging Therapeutic Targets

    PubMed Central

    Szebeni, Gabor J.; Vizler, Csaba; Nagy, Lajos I.; Kitajka, Klara; Puskas, Laszlo G.

    2016-01-01

    Since the observation of Virchow, it has long been known that the tumor microenvironment constitutes the soil for the infiltration of inflammatory cells and for the release of inflammatory mediators. Under certain circumstances, inflammation remains unresolved and promotes cancer development. Here, we review some of these indisputable experimental and clinical evidences of cancer related smouldering inflammation. The most common myeloid infiltrate in solid tumors is composed of myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). These cells promote tumor growth by several mechanisms, including their inherent immunosuppressive activity, promotion of neoangiogenesis, mediation of epithelial-mesenchymal transition and alteration of cellular metabolism. The pro-tumoral functions of TAMs and MDSCs are further enhanced by their cross-talk offering a myriad of potential anti-cancer therapeutic targets. We highlight these main pro-tumoral mechanisms of myeloid cells and give a general overview of their phenotypical and functional diversity, offering examples of possible therapeutic targets. Pharmacological targeting of inflammatory cells and molecular mediators may result in therapies improving patient condition and prognosis. Here, we review experimental and clinical findings on cancer-related inflammation with a major focus on creating an inventory of current small molecule-based therapeutic interventions targeting cancer-related inflammatory cells: TAMs and MDSCs. PMID:27886105

  18. Cold-adapted proteases as an emerging class of therapeutics.

    PubMed

    Fornbacke, Marcus; Clarsund, Mats

    2013-06-01

    Proteases have been used in medicine for several decades and are an established and well tolerated class of therapeutic agent. These proteases were sourced from mammals or bacteria that exist or have adapted to moderate temperatures (mesophilic organisms); however, proteases derived from organisms from cold environments-cold-adapted or psychrophilic proteases-generally have high specific activity, low substrate affinity, and high catalytic rates at low and moderate temperatures. Made possible by greater flexibility, psychrophilic enzymes interact with and transform the substrate at lower energy costs. Cold-adapted proteases have been used in a wide range of applications, including industrial functions, textiles, cleaning/hygiene products, molecular biology, environmental bioremediations, consumer food products, cosmetics, and pharmaceutical production. In addition to these applications, they have also shown promise as therapeutic modalities for cosmeceutical applications (by reducing glabellar [frown] lines) and a number of disease conditions, including bacterial infections (by disrupting biofilms to prevent bacterial infection), topical wound management (when used as a debridement agent to remove necrotic tissue and fibrin clots), oral/dental health management (by removing plaque and preventing periodontal disease), and in viral infections (by reducing the infectivity of viruses, such as human rhinovirus 16 and herpes simplex virus). Psychrophilic proteases with greater activity and stability (than the original organism-derived variant) have been developed; this coupled with available manufacturing recombinant production techniques suggests that cold-adapted proteases have a promising future as a distinct therapeutic class with diverse clinical applications.

  19. Emergency therapeutic leukapheresis in a case of acute myeloid leukemia M5

    PubMed Central

    Ranganathan, Sudha; Sesikeran, Shyamala; Gupta, Vineet; Vanajakshi

    2008-01-01

    Cell separators in India are routinely used for plateletpheresis, peripheral blood stem cell collections and therapeutic plasma exchange. Therapeutic leukapheresis, particularly as an emergency procedure, has been uncommonly performed and reported. Here, a case of a 53-year-old male, diagnosed with acute myeloid leukemia subtype M5 (AML M5) with hyperleukocytosis, who underwent emergency leukaphereis, is reported. After two procedures, there was a decrease of WBC count by 85%, which enabled cytotoxic therapy to be initiated. PMID:20041073

  20. Emerging Non-Cancer Applications of Therapeutic Ultrasound

    PubMed Central

    O’Reilly, Meaghan A.; Hynynen, Kullervo

    2015-01-01

    Ultrasound therapy has been investigated for over half a century. Ultrasound can act on tissue through a variety of mechanisms, including thermal, shockwave and cavitation mechanisms, and through these can elicit different responses. Ultrasound therapy can provide a non-invasive or minimally invasive treatment option, and ultrasound technology has advanced to the point where devices can be developed to investigate a wide range of applications. This review focuses on non-cancer, clinical applications of therapeutic ultrasound, with an emphasis on treatments that have recently reached clinical investigations, and preclinical research programs that have great potential to impact patient care. PMID:25792225

  1. Biomaterials and Emerging Anticancer Therapeutics: Engineering the Microenvironment

    PubMed Central

    Gu, Luo; Mooney, David J

    2016-01-01

    The microenvironment is increasingly recognized to play key roles in cancer, and biomaterials provide a means to engineer microenvironments both in vitro and in vivo to study and manipulate cancer. In vitro cancer models using 3D matrices recapitulate key elements of the tumor microenvironment and have revealed new aspects of cancer biology. Cancer vaccines based on some of the same biomaterials have, in parallel, allowed for the engineering of durable prophylactic and therapeutic anticancer activity in preclinical studies, and some of these vaccines have moved to clinical trials. The impact of biomaterials engineering on cancer treatment is expected to further increase in importance in the years to come. PMID:26694936

  2. Time in Therapeutic Range and Outcomes After Warfarin Initiation in Newly Diagnosed Atrial Fibrillation Patients With Renal Dysfunction.

    PubMed

    Szummer, Karolina; Gasparini, Alessandro; Eliasson, Staffan; Ärnlöv, Johan; Qureshi, Abdul Rashid; Bárány, Peter; Evans, Marie; Friberg, Leif; Carrero, Juan Jesus

    2017-03-01

    It is unknown whether renal dysfunction conveys poor anticoagulation control in warfarin-treated patients with atrial fibrillation and whether poor anticoagulation control associates with the risk of adverse outcomes in these patients. This was an observational study from the Stockholm CREatinine Measurements (SCREAM) cohort including all newly diagnosed atrial fibrillation patients initiating treatment with warfarin (n=7738) in Stockholm, Sweden, between 2006 and 2011. Estimated glomerular filtration rate (eGFR; mL/min per 1.73 m(2)) was calculated from serum creatinine. Time-in-therapeutic range (TTR) was assessed from international normalized ratio (INR) measurements up to warfarin cessation, adverse event, or end of follow-up (2 years). Adverse events considered a composite of intracranial hemorrhage, ischemic stroke, myocardial infarction, or death. During median 254 days, TTR was 83%, based on median 21 INR measurements per patient. TTR was 70% among patients with eGFR <30, around 10% lower than in those with normal renal function. During observation, adverse events occurred in 4.0% of patients, and those with TTR ≤75% were at higher adverse event risk. This was independent of patient characteristics, comorbidities, number of INR tests, days exposed to warfarin, and, notably, independent of eGFR: adjusted odds ratio (OR) 1.84 (95% CI, 1.41-2.40) for TTR 75% to 60% and adjusted OR 2.09 (1.59-2.74) for TTR <60%. No interaction was observed between eGFR and TTR in association to adverse events (P=0.2). Severe chronic kidney disease (eGFR <30) patients with atrial fibrillation have worse INR control while on warfarin. An optimal TTR (>75%) is associated with lower risk of adverse events, independently of underlying renal function. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

  3. A comparison of the reactivating and therapeutic efficacy of newly developed bispyridinium oximes (K250, K251) with commonly used oximes against tabun in rats and mice.

    PubMed

    Kassa, Jiri; Karasova, Jana; Bajgar, Jiri; Kuca, Kamil; Musilek, Kamil; Kopelikova, Irena

    2009-08-01

    The potency of newly developed bispyridinium compounds (K250, K251) in reactivating tabun-inhibited acetylcholinesterase and reducing tabun-induced lethal toxic effects was compared with currently available oximes (obidoxime, trimedoxime, the oxime HI-6) using in vivo methods. Studies determined percentage of reactivation of tabun-inhibited blood and tissue AChE in poisoned rats and showed that the reactivating efficacy of both newly developed oximes is comparable with the oxime HI-6 but it is significantly lower than the reactivating effects of obidoxime and trimedoxime, especially in diaphragm and brain. Both newly developed oximes were also found to be able to slightly reduce lethal toxic effects in tabun-poisoned mice. Their therapeutic efficacy is higher than the potency of the oxime HI-6 but it is lower than the therapeutic effects of trimedoxime and obidoxime. Thus, the reactivating and therapeutic potency of both newly developed oximes (K250, K251) does not prevail over the effectiveness of currently available oximes and, therefore, they are not suitable for their replacement for the treatment of acute tabun poisoning.

  4. Emergency endoscopy for gastrointestinal bleeding after bariatric surgery. Therapeutic algorithm.

    PubMed

    García-García, María Luisa; Martín-Lorenzo, Juan Gervasio; Torralba-Martínez, José Antonio; Lirón-Ruiz, Ramón; Miguel Perelló, Joana; Flores Pastor, Benito; Pérez Cuadrado, Enrique; Aguayo Albasini, José Luis

    2015-02-01

    Gastrointestinal bleeding (GB) is a potential complication after bariatric surgery and its frequency is around 2-4% according to the literature. The aim of this study is to present our experience with GB after bariatric surgery, its presentation and possible treatment options by means of an algorithm. From January 2004 to December 2012, we performed 300 consecutive laparoscopic bariatric surgeries. A total of 280 patients underwent a laparoscopic Roux en Y gastric bypass with creation of a gastrojejunal anastomosis using a circular stapler type CEAA No 21 in 265 patients and with a linear stapler in 15 patients. Demographics, clinical presentation, diagnostic evaluation and treatment were reviewed. A total of 20 patients underwent a sleeve gastrectomy. Twenty-seven cases (9%) developed GB. Diagnosis and therapeutic endoscopy was required in 13 patients. The onset of bleeding occurred between the 1(st)-6(th) postop days in 10 patients, and the origin was at the gastrojejunostomy staple-lines, and 3 patients had bleeding from an anastomotic ulcer 15-20 days after surgery. All other patients were managed non-operatively. Conservative management of gastrointestinal bleeding is effective in most cases, but endoscopy with therapeutic intent should be considered in patients with severe or recurrent bleeding. Multidisciplinary postoperative follow- up is very important for early detention and treatment of this complication. Copyright © 2014 AEC. Publicado por Elsevier España, S.L.U. All rights reserved.

  5. Modulating the human gut microbiome as an emerging therapeutic paradigm.

    PubMed

    Rajpal, Deepak K; Brown, James R

    2013-01-01

    The human body is actually a vast and changing ecosystem comprised of billions of microbial organisms, known collectively as the microbiome. Within the last few years, the study of the microbiome and its impact on human health has been a rapidly growing area of biomedical science. The gut intestinal tract microbiome has been a particular focus of research given its potential role in many inflammatory and metabolic diseases as well as drug metabolism. Although a nascent field, the potential for modulating the gut microbiome or human host interactions associated with these microbes offers new therapeutic strategies for many chronic diseases, in particular obesity, diabetes and inflammatory bowel diseases. Here we provide an overview of present knowledge about the gut microbiome, its putative role in metabolic diseases and the potential for microbiome focused treatments from the drug development perspective.

  6. Emerging Supramolecular Therapeutic Carriers Based on Host-Guest Interactions.

    PubMed

    Karim, Anis Abdul; Dou, Qingqing; Li, Zibiao; Loh, Xian Jun

    2016-05-06

    Recent advances in host-guest chemistry have significantly influenced the construction of supramolecular soft biomaterials. The highly selective and non-covalent interactions provide vast possibilities of manipulating supramolecular self-assemblies at the molecular level, allowing a rational design to control the sizes and morphologies of the resultant objects as carrier vehicles in a delivery system. In this Focus Review, the most recent developments of supramolecular self-assemblies through host-guest inclusion, including nanoparticles, micelles, vesicles, hydrogels, and various stimuli-responsive morphology transition materials are presented. These sophisticated materials with diverse functions, oriented towards therapeutic agent delivery, are further summarized into several active domains in the areas of drug delivery, gene delivery, co-delivery and site-specific targeting deliveries. Finally, the possible strategies for future design of multifunctional delivery carriers by combining host-guest chemistry with biological interface science are proposed.

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

    PubMed

    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.

  8. Emerging therapeutics for the treatment of diabetic nephropathy.

    PubMed

    Brenneman, Jehrod; Hill, Jon; Pullen, Steve

    2016-09-15

    Diabetic nephropathy (DN) is the most common pathology contributing to the development of chronic kidney disease (CKD). DN caused by hypertension and unmitigated inflammation in diabetics, renders the kidneys unable to perform normally, and leads to renal fibrosis and organ failure. The increasing global prevalence of DN has been directly attributed to rising incidences of Type II diabetes, and is now the largest non-communicable cause of death worldwide. Despite the high morbidity, successful new treatments for DN are lacking. This review seeks to provide new insight on emerging clinical candidates under investigation for the treatment of DN.

  9. The future of osteoarthritis therapeutics: emerging biological therapy.

    PubMed

    Mobasheri, A

    2013-12-01

    Biological therapy is a thriving area of research and development, and is well established for chronic forms of rheumatoid arthritis (RA) and ankylosing spondylitis (AS). However, there is no clinically validated biological therapy for osteoarthritis (OA). Chronic forms of OA are increasingly viewed as an inflammatory disease. OA was largely regarded as a "wear and tear disease". However, the disease is now believed to involve "low grade" inflammation and the growth of blood vessels and nerves from the subchondral bone into articular cartilage. This realization has focused research effort on the development and evaluation of biological therapy that targets proinflammatory mediators, angiogenic factors and cytokines in articular cartilage, subchondral bone and synovium in chronic forms of OA. This review article provides an overview of emerging biological therapy for OA, and discusses recent molecular targets implicated in angiogenesis and neurogenesis and progress with antibody-based therapy, calcitonin, and kartogenin, the small molecule stimulator of chondrogenesis.

  10. The potential for emerging therapeutic options for Clostridium difficile infection.

    PubMed

    Mathur, Harsh; Rea, Mary C; Cotter, Paul D; Ross, R Paul; Hill, Colin

    2014-01-01

    Clostridium difficile is mainly a nosocomial pathogen and is a significant cause of antibiotic-associated diarrhea. It is also implicated in the majority of cases of pseudomembranous colitis. Recently, advancements in next generation sequencing technology (NGS) have highlighted the extent of damage to the gut microbiota caused by broad-spectrum antibiotics, often resulting in C. difficile infection (CDI). Currently the treatment of choice for CDI involves the use of metronidazole and vancomycin. However, recurrence and relapse of CDI, even after rounds of metronidazole/vancomycin administration is a problem that must be addressed. The efficacy of alternative antibiotics such as fidaxomicin, rifaximin, nitazoxanide, ramoplanin and tigecycline, as well as faecal microbiota transplantation has been assessed and some have yielded positive outcomes against C. difficile. Some bacteriocins have also shown promising effects against C. difficile in recent years. In light of this, the potential for emerging treatment options and efficacy of anti-C. difficile vaccines are discussed in this review.

  11. Microtubules (tau) as an emerging therapeutic target: NAP (davunetide).

    PubMed

    Gozes, Illana

    2011-01-01

    This review focuses on the discovery of activity-dependent neuroprotective protein (ADNP) and the ensuing discovery of NAP (davunetide) toward clinical development with emphasis on microtubule protection. ADNP immunoreactivity was shown to occasionally decorate microtubules and ADNP silencing inhibited neurite outgrowth as measured by microtubule associated protein 2 (MAP2) labeling. ADNP knockout is lethal, while 50% reduction in ADNP (ADNP haploinsufficiency) resulted in the microtubule associated protein tau pathology coupled to cognitive dysfunction and neurodegeneration. NAP (davunetide), an eight amino acid peptide derived from ADNP partly ameliorated deficits associated with ADNP deficiency. NAP (davunetide) interacted with microtubules, protected against microtubule toxicity associated with zinc, nocodazole and oxidative stress in vitro and against tau pathology and MAP6 (stable tubuleonly polypeptide - STOP) pathology in vivo. NAP (davunetide) provided neurotrophic functions promoting neurite outgrowth as measured by increases in MAP2 immunoreactivity and synapse formation by increasing synaptophysin expression. NAP (davunetide) protection against neurodegeneration has recently been shown to extend to katanin-related microtubule disruption under conditions of tau deficiencies. In conclusion, NAP (davunetide) provided potent neuroprotection in a broad range of neurodegenerative models, protecting the neuroglial cytoskeleton in vitro and inhibiting tau pathology (tauopathy) in vivo. Based on these extensive preclinical results, davunetide (NAP) is now being evaluated in a Phase II/III study of the tauopathy, progressive supranuclear palsy (PSP); (Allon Therapeutics Inc.).

  12. Intralipid Emulsion Rescue Therapy: Emerging Therapeutic Indications in Medical Practice.

    PubMed

    Muller, Sam H; Diaz, James H; Kaye, Alan David

    2016-01-01

    Intralipid emulsion therapy is well-established for the treatment of local-anesthetic systemic toxicities. In recent years, its role has expanded as an important therapeutic agent in the reversal of other types of drug overdoses, including certain types of antipsychotics, antidepressants, antiarrhythmics, and calcium channel blockers. A literature review identified thirty-one case reports including forty-nine separate drug overdose cases involving ten separate drug classes which were successfully reversed with Intralipid. The present clinical case study describes an elderly unresponsive woman refractory to conventional treatments after ingesting a potentially lethal amount of 5.6 grams of diltiazem in a suicide attempt. After treatment with Intralipid over a twenty-four hour period, the patient's hemodynamic and metabolic derangements were corrected and stabilized completely. Intralipid emulsion rescue therapy provides another potential strategy for the reversal of many drug toxicities, most likely by providing a lipid layer safety net for drug overdose by passive diffusion. Clinicians are urged to embrace an expanded role of Intralipid emulsion rescue therapy, not only for local anesthetic drug toxicities, but also for other lipophilic drug overdoses.

  13. Stress urinary incontinence in women: Current and emerging therapeutic options.

    PubMed

    Shamout, Samer; Campeau, Lysanne

    2017-06-01

    Surgical management of stress urinary incontinence (SUI) is most commonly achieved by midurethral synthetic sling (MUS) insertion as a first-line surgical option. A great deal of research continues to evolve new management strategies to reach an optimal balance of high efficacy and minimal adverse events. This expert opinion review provides a brief and comprehensive discussion of recent advances and ongoing research in the management of SUI, with an emphasis on single-incision mini-slings, vaginal laser treatment, and cell-based therapy. It is based on data obtained from numerous published meta-analyses and original studies identified through literature search. Single-incision mini-slings appear equally effective initially compared with standard MUS (retropubic or transobturator) for the treatment of female SUI; however, this efficacy lacks durability evidence beyond one-year followup. There is a lack of sufficient clinical evidence to currently confirm long-term safety and effectiveness of cell-therapy and non-ablative vaginal laser therapy, besides suggestion of apparent initial safety. There are still significant challenges to overcome before widespread clinical practice of the latter two modalities. Future research should be aimed at identifying groups of patients who might benefit from these minimally invasive therapeutic options.

  14. Voluntary emergence and water detection in a newly recognized amphibious fish.

    PubMed

    Magellan, K

    2015-06-01

    Galaxias 'nebula', a small fish which has adaptations for air-breathing but is not known to be amphibious, voluntarily emerged from water and, in an unfamiliar environment, moved preferentially towards an alternative water source. Nebula may thus be considered one of the few truly amphibious fishes, and their ability to detect water provides a selective advantage which aids their survival in unpredictable natural environments. © 2015 The Fisheries Society of the British Isles.

  15. Emerging Targets for Addiction Neuropharmacology; From Mechanisms to Therapeutics

    PubMed Central

    Ubaldi, Massimo; Cannella, Nazzareno; Ciccocioppo, Roberto

    2016-01-01

    Drug abuse represents a considerable burden of disease and has enormous economic impacts on societies. Over the years, few medications have been developed for clinical use. Their utilization is endowed with several limitations, including partial efficacy or significant side effects. On the other hand, the successful advancement of these compounds provides an important proof-of-concept for the feasibility of drug development programs in addiction. In recent years, a wealth of information has been generated on the psychological mechanisms, genetic or epigenetic predisposing factors, and neurobiological adaptations induced by drug consumption that interact with each other to contribute to disease progression. It is now clear that addiction develops through phases, from initial recreational use to excessive consumption and compulsive drug seeking, with a shift from positive to negative reinforcement driving motivated behaviors. A greater understanding of these mechanisms has opened new vistas in drug development programs. Researchers’ attention has been shifted from investigation of classical targets associated with reward to biological substrates responsible for negative reinforcement, impulse loss of control and maladaptive mechanisms resulting from protracted drug use. From this research, several new biological targets for the development of innovative therapies have started to emerge. The present article offers an overview of targets currently under scrutiny for the development of new medications for addiction. This work is not exhaustive but rather it provides a few examples of how this research has advanced in recent years by virtue of studies carried out in our laboratory. PMID:26822362

  16. Therapeutic options and emerging alternatives for multidrug resistant staphylococcal infections.

    PubMed

    Magana, Maria; Ioannidis, Anastasios; Magiorkinis, Emmanouil; Ursu, Oleg; Bologa, Cristian G; Chatzipanagiotou, Stylianos; Hamblin, Michael R; Tegos, George P

    2015-01-01

    Methicillin-resistant Staphylococcus aureus (MRSA) remains the single biggest challenge in infectious disease in the civilized world. Moreover, vancomycin resistance is also spreading, leading to fears of untreatable infections as were common in ancient times. Molecular microbiology and bioinformatics have revealed many of the mechanisms involved in resistance development. Mobile genetic elements, up-regulated virulence factors and multi-drug efflux pumps have been implicated. A range of approved antibiotics from the glycopeptide, lipopeptide, pleuromutilin, macrolide, oxazolidinone, lincosamide, aminoglycoside, tetracycline, steptogramin, and cephalosporin classes has been employed to treat MRSA infections. The upcoming pipeline of drugs for MRSA includes some new compounds from the above classes, together with fluoroquinolones, antibacterial peptide mimetics, aminomethylciclines, porphyrins, peptide deformylase inhibitors, oxadiazoles, and diaminopyrimidines. A range of non-drug alternative approaches has emerged for MRSA treatment. Bacteriophage-therapy including purified lysins has made a comeback after being discovered in the 1930s. Quorum-sensing inhibitors are under investigation. Small molecule inhibitors of multi-drug efflux pumps may potentiate existing antibiotics. The relative failure of staphylococcal vaccines is being revisited by efforts with multi-valent vaccines and improved adjuvants. Photodynamic therapy uses non-toxic photosensitizers and harmless visible light to produce reactive oxygen species that can nonspecifically destroy bacteria while preserving host cells. Preparation of nanoparticles can kill bacteria themselves, as well as improve the delivery of anti-bacterial drugs. Anti-MRSA drug discovery remains an exciting field with great promise for the future.

  17. Proteins: emerging carrier for delivery of cancer therapeutics.

    PubMed

    Yewale, Chetan; Baradia, Dipesh; Vhora, Imran; Misra, Ambikanandan

    2013-10-01

    Over the past decades, proteins have emerged as versatile carriers for the diagnosis and treatment of cancer, diabetes, rheumatoid arthritis, and many more diseases. Proteins have gained considerable attention in formulation of several delivery systems for anticancer drugs due to their nontoxic, non-immunogenic, biocompatible and biodegradable nature. Proteins are good candidates for conjugation with drugs as they provide good pharmacokinetics as well as better cancer tissue accumulation. Protein nanoparticulate systems are also of advancing importance owing to their modifiable functionalities and potential applications in various biological fields. The customizable nature of proteins also makes them outstanding carriers as target-specific delivery systems. This review emphasizes on protein conjugates (drug-albumin, drug-gelatin, drug-transferrin, and drug-antibody conjugates), protein nanoparticles (prepared using albumin, gelatin, casein, silk proteins, elastin, and lectins), surface modification of protein nanoparticles (using surfactant, polyethylene glycol, cationic/thermosensitive polymers, folic acid, monoclonal antibodies, and peptides/proteins), and their preclinical and clinical status with respect to cancer therapy. The major obstacles for commercial success of protein-based delivery are lack of inexpensive as well as quality methods for their preparation and quality control; and if overcome, proteins will stand out as a superior drug-delivery carrier for cancer therapy.

  18. The potential for emerging therapeutic options for Clostridium difficile infection

    PubMed Central

    Mathur, Harsh; Rea, Mary C; Cotter, Paul D; Ross, R Paul; Hill, Colin

    2014-01-01

    Clostridium difficile is mainly a nosocomial pathogen and is a significant cause of antibiotic-associated diarrhea. It is also implicated in the majority of cases of pseudomembranous colitis. Recently, advancements in next generation sequencing technology (NGS) have highlighted the extent of damage to the gut microbiota caused by broad-spectrum antibiotics, often resulting in C. difficile infection (CDI). Currently the treatment of choice for CDI involves the use of metronidazole and vancomycin. However, recurrence and relapse of CDI, even after rounds of metronidazole/vancomycin administration is a problem that must be addressed. The efficacy of alternative antibiotics such as fidaxomicin, rifaximin, nitazoxanide, ramoplanin and tigecycline, as well as faecal microbiota transplantation has been assessed and some have yielded positive outcomes against C. difficile. Some bacteriocins have also shown promising effects against C. difficile in recent years. In light of this, the potential for emerging treatment options and efficacy of anti-C. difficile vaccines are discussed in this review. PMID:25564777

  19. ‘BRICS without straw’? A systematic literature review of newly emerging economies’ influence in global health

    PubMed Central

    2013-01-01

    Background Since 2010, five newly emerging economies collectively known as ‘BRICS’ (Brazil, India, Russia, China and South Africa) have caught the imagination, and scholarly attention, of political scientists, economists and development specialists. The prospect of a unified geopolitical bloc, consciously seeking to re-frame international (and global) health development with a new set of ideas and values, has also, if belatedly, begun to attract the attention of the global health community. But what influence, if any, do the BRICS wield in global health, and, if they do wield influence, how has that influence been conceptualized and recorded in the literature? Methods We conducted a systematic literature review in (March-December 2012) of documents retrieved from the databases EMBASE, PubMed/Medline, Global Health, and Google Scholar, and the websites of relevant international organisations, research institutions and philanthropic organisations. The results were synthesised using a framework of influence developed for the review from the political science literature. Results Our initial search of databases and websites yielded 887 documents. Exclusion criteria narrowed the number of documents to 71 journal articles and 23 reports. Two researchers using an agreed set of inclusion criteria independently screened the 94 documents, leaving just 7 documents. We found just one document that provided sustained analysis of the BRICS’ collective influence; the overwhelming tendency was to describe individual BRICS countries influence. Although influence was predominantly framed by BRICS countries’ material capability, there were examples of institutional and ideational influence - particularly from Brazil. Individual BRICS countries were primarily ‘opportunity seekers’ and region mobilisers but with potential to become ‘issue leaders’ and region organisers. Conclusion Though small in number, the written output on BRICS influence in global health has

  20. A newly emerging toxic dinoflagellate, Pfiesteria piscicida: natural ecology and toxicosis to fish and other species.

    PubMed

    Faith, S A; Miller, C A

    2000-02-01

    Pfiesteria, a toxic dinoflagellate, recently has emerged as a cause of fish kills near the East Coast. Recent research into one species. Pfiesteria piscicida, has revealed a complex life cycle of at least 24 stages. Metamorphosis of one stage to another often depends on presence or absence of fish. Growth of P piscicida is promoted both directly and indirectly by nutrients such as inorganic phosphate and nitrate, as well as organic phosphate, and may be related to effluent-induced blooms. Sewage and agricultural runoff flowing into estuaries often provide these nutrients and may be correlated with the majority of fish kills in the Atlantic coastal region of the US (5). P piscicida is extremely toxic, with a low density capable of killing fish within 3 minutes (1,3,12). Fish exposed to sublethal doses of the toxin have prominent lesions. The syndrome leads to population level death losses and associated economic losses in local fisheries.

  1. Newly emerged nulliparous Culicoides imicola Kieffer (Diptera: Ceratopogonidae) with pigmented abdomen.

    PubMed

    Braverman, Yehuda; Mumcuoglu, Kosta

    2009-03-23

    The method of segregating nulliparous and parous females of Culicoides spp. based on the presence of burgundy-red pigment inside the abdominal wall of parous Culicoides midges, is used worldwide. Out of 320 females of Culicoides imicola trapped by emergence traps, set over an artificial breeding site for 10 and 24 days, 73 (22.8%) showed a red-pigmentation despite the fact that they were nulliparous. This finding indicated that 23% of the "parous" females that are examined for the presence of arboviruses and other pathogens or for age-grading purposes, are actually old nulliparous females, which had no chance of acquiring pathogens. This bias in parous rate distorts upward the calculation of vectorial capacity.

  2. The effect of experience on the hunting success of newly emerged spiderlings.

    PubMed

    Morse

    2000-12-01

    Initial interactions with prey may affect a predator's subsequent foraging success. With experience, second-instar Misumena vatia spiderlings (Thomisidae) that had recently emerged from their egg sacs oriented faster to fruit flies (Drosophila melanogaster) than näive individuals. Orientation time of these spiderlings decreased rapidly for the first two to three runs (every third day) in a simple laboratory setting, and then remained low and relatively constant. Time to capture a fly also declined initially, but subsequently became extremely variable, increasing prior to moult. Increase in capture time and the failure to capture prey appeared associated with impending moult, rather than satiation. Spiderlings oriented to prey more rapidly at the beginning of the third instar than at the start of the second instar, suggesting that experience still enhanced performance after a moult cycle. Overall capture times at the beginning of the third instar decreased from those at the end of the second instar, but did not differ significantly from the beginning of the second instar, although spiderlings gaining the most biomass had the shortest mean capture times. In a second experiment, time to orient and time to capture prey did not differ in näive, second-instar siblings run 1 and 3 days after emergence from their egg sacs. However, 3-day individuals that had captured prey each day (confiscated before they could feed) oriented faster than näive 3-day-old siblings, but did not differ in the time taken to capture prey. Experience, rather than age or energetic condition, best explains these changes in performance. Copyright 2000 The Association for the Study of Animal Behaviour.

  3. Limited and localized outbreak of newly emergent type 2 vaccine-derived poliovirus in Sichuan, China.

    PubMed

    Yan, Dongmei; Zhang, Yong; Zhu, Shuangli; Chen, Na; Li, Xiaolei; Wang, Dongyan; Ma, Xiaozhen; Zhu, Hui; Tong, Wenbin; Xu, Wenbo

    2014-07-01

    From August 2011 to February 2012, an outbreak caused by type 2 circulating vaccine-derived poliovirus (cVDPV) occurred in Aba County, Sichuan, China. During the outbreak, four type 2 VDPVs (≥0.6% nucleotide divergence in the VP1 region relative to the Sabin 2 strain) were isolated from 3 patients with acute flaccid paralysis (AFP) and one close contact. In addition, a type 2 pre-VDPV (0.3% to 0.5% divergence from Sabin 2) that was genetically related to these type 2 VDPVs was isolated from another AFP patient. These 4 patients were all unimmunized children 0.7 to 1.1 years old. Nucleotide sequencing revealed that the 4 VDPV isolates differed from Sabin 2 by 0.7% to 1.2% in nucleotides in the VP1 region and shared 5 nucleotide substitutions with the pre-VDPV. All 5 isolates were closely related, and all were S2/S3/S2/S3 recombinants sharing common recombination crossover sites. Although the two major determinants of attenuation and temperature sensitivity phenotype of Sabin 2 (A481 in the 5' untranslated region and Ile143 in the VP1 protein) had reverted in all 5 isolates, one VDPV (strain CHN16017) still retained the temperature sensitivity phenotype. Phylogenetic analysis of the third coding position of the complete P1 coding region suggested that the cVDPVs circulated locally for about 7 months following the initiating oral poliovirus vaccine (OPV) dose. Our findings reinforce the point that cVDPVs can emerge and spread in isolated communities with immunity gaps and highlight the emergence risks of type 2 cVDPVs accompanying the trivalent OPV used. To solve this issue, it is recommended that type 2 OPV be removed from the trivalent OPV or that inactivated polio vaccine (IPV) be used instead.

  4. Behavioural type in newly emerged steelhead Oncorhynchus mykiss does not predict growth rate in a conventional hatchery rearing environment.

    PubMed

    Conrad, J L; Sih, A

    2009-10-01

    Behavioural assays were conducted on newly emerged steelhead Oncorhynchus mykiss to investigate the presence of behavioural syndromes and to determine whether behavioural type in young fish predicts growth rate in a conventional hatchery rearing environment. Individual fry were consistent in their position choice and activity behaviours across safe and unsafe contexts, as well as among assays conducted on different days. Position choice and activity behaviours, however, were not necessarily correlated to each other. Both behaviours predicted feeding rates during behavioural assays, but there was no relationship between fry behaviour and subsequent growth rate or survival during the first 3 months of hatchery rearing. These results support the hypothesis that selection in captivity may be relaxed with respect to behavioural type rather than directional, allowing for increased behavioural variance in domesticated populations. Modest magnitudes of correlations among fry behaviours, however, suggest that behavioural type may be unstable at the onset of the juvenile feeding stage.

  5. A simple and rapid identification method for newly emerged porcine Deltacoronavirus with loop-mediated isothermal amplification.

    PubMed

    Zhang, Fanfan; Ye, Yu; Song, Deping; Guo, Nannan; Peng, Qi; Li, Anqi; Zhou, Xingrong; Chen, Yanjun; Zhang, Min; Huang, Dongyan; Tang, Yuxin

    2017-09-21

    Porcine Deltacoronavirus (PDCoV) is a newly emerged enteropathogenic coronavirus that causes diarrhea and mortality in neonatal piglets. PDCoV has spread to many countries around the world, leading to significant economic losses in the pork industry. Therefore, a rapid and sensitive method for detection of PDCoV in clinical samples is urgently needed. In this study, we developed a single-tube one-step reverse transcription loop-mediated isothermal amplification (RT-LAMP) assay specific for nucleocapsid gene to diagnose and monitor PDCoV infections. The detection limit of RT-LAMP assay was 1 × 10(1) copies of PDCoV, which was approximately 100-fold more sensitive than gel-based one-step reverse transcription polymerase chain reaction (RT-PCR). This assay could specifically amplify PDCoV and had no cross amplification with porcine epidemic diarrhea virus (PEDV), transmissible gastroenteritis virus (TGEV), porcine kobuvirus (PKoV), porcine astrovirus (PAstV), porcine reproductive and respiratory syndrome virus (PRRSV), classic swine fever virus (CSFV), and porcine circovirus type 2 (PCV2). By screening a panel of clinical specimens (N = 192), this method presented a similar sensitivity with nested RT-PCR and was 1-2 log more sensitive than conventional RT-PCR in detection of PDCoV. The RT-LAMP assay established in this study is a potentially valuable tool, especially in low-resource laboratories and filed settings, for a rapid diagnosis, surveillance, and molecular epidemiology investigation of PDCoV infections. To the best of our knowledge, this is the first work for detection of newly emerged PDCoV with LAMP technology.

  6. Structural, Antigenic, and Evolutionary Characterizations of the Envelope Protein of Newly Emerging Duck Tembusu Virus

    PubMed Central

    Huang, Bing; Ma, Xiuli; Li, Yufeng; Yuan, Xiaoyuan; Qin, Zhuoming; Wang, Dan; Chakravarty, Suvobrata; Li, Feng; Song, Minxun; Sun, Huaichang

    2013-01-01

    Since the first reported cases of ducks infected with a previously unknown flavivirus in eastern China in April 2010, the virus, provisionally designated Duck Tembusu Virus (DTMUV), has spread widely in domestic ducks in China and caused significant economic losses to poultry industry. In this study, we examined in detail structural, antigenic, and evolutionary properties of envelope (E) proteins of six DTMUV isolates spanning 2010–2012, each being isolated from individual farms with different geographical locations where disease outbreaks were documented. Structural analysis showed that E proteins of DTMUV and its closely related flavivirus (Japanese Encephalitis Virus) shared a conserved array of predicted functional domains and motifs. Among the six DTMUV strains, mutations were observed only at thirteen amino acid positions across three separate domains of the E protein. Interestingly, these genetic polymorphisms resulted in no detectable change in viral neutralization properties as demonstrated in a serum neutralization assay. Furthermore, phylogenetic analysis of the nucleotide sequences of the E proteins showed that viruses evolved into two distinct genotypes, termed as DTMUV.I and DTMUV.II, with II emerging as the dominant genotype. New findings described here shall give insights into the antigenicity and evolution of this new pathogen and provide guidance for further functional studies of the E protein for which no effective vaccine has yet been developed. PMID:23990944

  7. Therapeutic communication part 2: strategies that can enhance the quality of the emergency care consultation.

    PubMed

    O'gara, Paula E; Fairhurst, Wendy

    2004-10-01

    Therapeutic, patient-centred communication as well as being desirable in its own right may also have the potential to improve satisfaction, health outcomes and change health behaviours in Emergency Care. This paper, the second of two, identifies from a substantive literature review five specific communication strategies that, when employed in an Emergency Care consultation, could significantly enhance its therapeutic potential. The five strategies: questioning, listening and noticing, communicating empathy, establishing and incorporating the patient's cares and concerns and concluding the consultation have been derived from the purposeful selection and analysis of communication research between 1990 and 2002.

  8. A comparison of the therapeutic and reactivating efficacy of newly developed bispyridinium compounds (K206, K269) with currently available oximes against tabun in rats and mice.

    PubMed

    Kassa, Jiri; Karasova, Jana; Bajgar, Jiri; Kuca, Kamil; Musilek, Kamil

    2008-12-01

    The potency of newly developed bispyridinium compounds (K206, K269) in reactivating tabun-inhibited acetylcholinesterase and eliminating tabun-induced lethal toxic effects was compared with commonly used oximes (obidoxime, trimedoxime, the oxime HI-6) using in vivo methods. Studies which determined percentage of reactivation of tabun-inhibited blood and tissue AChE in poisoned rats showed that the reactivating efficacy of both newly developed oximes is comparable with obidoxime and trimedoxime in blood but lower than the reactivating potency of trimedoxime and obidoxime in the diaphragm and brain. Nevertheless, the differences in reactivating efficacy of obidoxime, trimedoxime and K206 was not significant while the potency of K269 to reactivate tabun-inhibited acetylcholinesterase was significantly lower. Both newly developed oximes were also found to be relatively efficacious in elimination of the lethal toxic effects in tabun-poisoned mice. Their therapeutic efficacy corresponds to the therapeutic potency of obidoxime. The oxime HI-6, relatively efficacious against soman, did not seem to be an adequately effective oxime in reactivation of tabun-inhibited AChE and to counteract lethal effects of tabun. Both newly developed oximes (K206, K269) are significantly more efficacious in reactivating tabun-inhibited AChE in rats and to eliminate lethal toxic effects of tabun in mice than the oxime HI-6 but their reactivating and therapeutic potency does not prevail over the effectiveness of currently available obidoxime and trimedoxime and, therefore, they are not suitable for their replacement of commonly used oximes for the treatment of acute tabun poisoning.

  9. Role of structured individual patient education in the prevention of vascular complications in newly diagnosed type 2 diabetes: the INdividual Therapeutic Education in Newly Diagnosed type 2 diabetes (INTEND) randomized controlled trial.

    PubMed

    Coppola, Adriana; Luzi, Livio; Montalcini, Tiziana; Giustina, Andrea; Gazzaruso, Carmine

    2017-09-21

    Recent studies showed that a structured patient therapeutic education (PTE) may decrease both mortality and the development of diabetes complications. Nevertheless, no data are available in the literature on the impact of individual PTE on the complications in newly diagnosed type 2 diabetic patients. Aim of the present randomized controlled trial is to evaluate the impact of individual PTE on the occurrence of macrovascular complications in newly diagnosed type 2 diabetic patients when compared to usual care (UC) and group PTE. Six hundred newly diagnosed type 2 diabetic patients will be enrolled. The patients will be randomly assigned to one of these three groups: individual PTE, group PTE and UC. A comprehensive and complete PTE will be delivered to all the patients: PTE will include eleven themes. Primary composite endpoint of the study is occurrence of vascular complications, including cardiovascular death, non fatal coronary disease, non fatal stroke, peripheral artery disease. Secondary endpoints are: foot ulcers, amputations, sexual dysfunction, quality of life, microvascular complications, bone health, intensification of diabetes and hypertension therapy. The present trial can give precious information on the features for the most effective PTE.

  10. Lessons Learned From an Active Shooter Full-Scale Functional Exercise In a Newly Constructed Emergency Department.

    PubMed

    Wexler, Bryan; Flamm, Avram

    2017-03-06

    The primary objective of this exercise was to conduct a full-scale functional exercise utilizing an active-shooter-based scenario to test and evaluate hospital response and coordination with local law enforcement. A multidisciplinary group, including community partners, formulated objectives in accordance with the Homeland Security Exercise and Evaluation Program and defined a scenario. A date to conduct the exercise was chosen on the basis of the expected completion of a large section of the new emergency department but prior to its opening for patient care. The exercise highlighted several strengths, but more importantly, illuminated areas for improvement that might otherwise have been missed in tabletop exercises and smaller-scale drills. Educational opportunities to improve functional skills and protocol were recognized. Conducting a full-scale functional exercise of an active shooter in a newly constructed emergency department prior to opening for patient care provided valuable insight into areas for improvement while minimizing the impact such an exercise can have on daily operations. Should a similar opportunity arise as a result of new facilities being developed or renovations and maintenance requiring temporary closure, we advise hospitals to consider planning an exercise in the area prior to reopening for patient care. (Disaster Med Public Health Preparedness. 2017;page 1 of 4).

  11. Polymorphic SSR markers for Plasmopara obducens (Peronosporaceae), the newly emergent downy mildew pathogen of Impatiens (Balsaminaceae)1

    PubMed Central

    Salgado-Salazar, Catalina; Rivera, Yazmín; Veltri, Daniel; Crouch, Jo Anne

    2015-01-01

    Premise of the study: Simple sequence repeat (SSR) markers were developed for Plasmopara obducens, the causal agent of the newly emergent downy mildew disease of Impatiens walleriana. Methods and Results: A 202-Mb draft genome assembly was generated from P. obducens using Illumina technology and mined to identify 13,483 SSR motifs. Primers were synthesized for 62 marker candidates, of which 37 generated reliable PCR products. Testing of the 37 markers using 96 P. obducens samples showed 96% of the markers were polymorphic, with 2−6 alleles observed. Observed and expected heterozygosity ranged from 0.000−0.892 and 0.023−0.746, respectively. Just 17 markers were sufficient to identify all multilocus genotypes. Conclusions: These are the first SSR markers available for this pathogen, and one of the first molecular resources. These markers will be useful in assessing variation in pathogen populations and determining the factors contributing to the emergence of destructive impatiens downy mildew disease. PMID:26649270

  12. An Empirical Model of Therapeutic Process for Psychiatric Emergency Room Clients with Dual Disorders.

    ERIC Educational Resources Information Center

    Loneck, Barry; Banks, Steven; Way, Bruce; Bonaparte, Ernest

    2002-01-01

    Many individuals with dual disorders of mental illness and substance abuse enter the mental health system through psychiatric emergency rooms, but may resist treatment and not follow through with referrals. This study examines the impact of therapeutic process on referral outcome. Finds that therapist warmth and friendliness had a positive…

  13. Recent patents and emerging therapeutics for HIV infections: a focus on protease inhibitors.

    PubMed

    Patel, Mitesh; Mandava, Nanda K; Vadlapatla, Ramya Krishna; Mitra, Ashim K

    2013-07-01

    The inclusion of protease inhibitors (PIs) in highly active antiretroviral therapy has significantly improved clinical outcomes in HIV-1-infected patients. To date, PIs are considered to be the most important therapeutic agents for the treatment of HIV infections. Despite high anti-HIV-1 potency, poor oral bioavailability of PIs has been a major concern. For achieving therapeutic concentrations, large doses of PIs are administered, which results in unacceptable systemic toxicities. Such severe and long-term toxicities necessitate the development of safer and potentially promising PIs. Recently, considerable attention has been paid to the development of newer compounds capable of inhibiting wild-type and resistant HIV-1 protease. Some of these PIs have displayed potent HIV-1 protease inhibitory activity. In this review, we have made an attempt to provide an overview on clinically approved and newly developing PIs, and related recent patents in the development of novel PIs.

  14. Monitoring of Plasmodium infection in humans and potential vectors of malaria in a newly emerged focus in southern Iran.

    PubMed

    Kalantari, Mohsen; Soltani, Zahra; Ebrahimi, Mostafa; Yousefi, Masoud; Amin, Masoumeh; Shafiei, Ayda; Azizi, Kourosh

    2017-02-01

    Despite control programs, which aim to eliminate malaria from Iran by 2025, transmission of malaria has not been removed from the country. This study aimed to monitor malaria from asymptomatic parasitaemia and clinical cases from about one year of active case surveillance and potential vectors of malaria in the newly emerged focus of Mamasani and Rostam, southern Iran during 2014-2015. Samples were collected and their DNAs were extracted for Polymerase Chain Reaction (PCR) assay using specific primers for detection of Plasmodium species. The Annual Parasite Incidence rate (API) was three cases per 1,000 population from 2,000 individuals in three villages. Parasites species were detected in 9 out of the 4,000 blood smear samples among which, 6 cases were indigenous and had no history of travels to endemic areas of malaria. Also, the prevalence rate of asymptomatic parasites was about 0.3%. Overall, 1073 Anopheles spp. were caught from 9 villages. Totally, 512 female samples were checked by PCR, which indicated that none of them was infected with Plasmodium. Despite new malaria local transmission in humans in Mamasani and Rostam districts, no infection with Plasmodium was observed in Anopheles species. Because of neighboring of the studied area to the re-emerged focus in Fars province (Kazerun) and important endemic foci of malaria in other southern provinces, such as Hormozgan and Kerman, monitoring of the vectors and reservoir hosts of Plasmodium species would be unavoidable. Application of molecular methods, such as PCR, can simplify access to the highest level of accuracy in malaria researches.

  15. Group process research and emergence of therapeutic factors in critical incident stress debriefing.

    PubMed

    Pender, Debra A; Prichard, Karen K

    2008-01-01

    Critical incident stress debriefing is a highly utilized and often debated form of post-trauma exposure intervention. This article presents exploratory group process research that utilized a mixed method approach and group process research techniques. The article's findings, the emergence of therapeutic factors, support that CISD group work does yield indicators consistent with support/ psychoeducation groups with a crisis theme. Further the events that trigger the intervention yield specific therapeutic factors. CISD group work may be better understood through established group research patterns.

  16. Post-traumatic knee osteoarthritis in the young patient: therapeutic dilemmas and emerging technologies.

    PubMed

    Stiebel, Matthew; Miller, Larry E; Block, Jon E

    2014-01-01

    Traumatic knee injury is common in young adults and strongly contributes to premature development of knee osteoarthritis (OA). Post-traumatic knee OA poses a therapeutic dilemma to the physician, since no known therapy has an acceptable safety profile, effectively relieves joint pain, and enjoys reasonable patient acceptance. Consequently, these young patients will ultimately be faced with the decision to either undergo surgical intervention, despite prosthesis durability concerns, or to continue with ineffective nonsurgical treatment. Emerging therapies, such as biologics, disease-modifying drugs, partial joint resurfacings, and minimally invasive joint-unloading implants are currently being studied to fill this therapeutic void in the young patient with post-traumatic knee OA.

  17. Life-threatening endocrine emergencies during pregnancy - management and therapeutic features.

    PubMed

    Harbeck, Birgit; Rahvar, Amir-Hossein; Danneberg, Sven; Schütt, Morten; Sayk, Friedhelm

    2017-03-31

    Endocrine emergencies during pregnancy may be life-threatening events for both mother and fetus. Besides pregnancy-associated endocrine disorders, several pre-existing endocrinopathies such as type-1 diabetes and Grave's disease or adrenal failure may acutely deteriorate during pregnancy. Since "classical" signs are often modified by pregnancy, early diagnosis and management may be hampered. In addition, laboratory tests show altered physiologic ranges and pharmacologic options are limited while therapeutic goals are mostly tighter than in the non-pregnant patient. Though subclinical endocrinopathies are more frequent and worth consideration due to their related adverse sequelae, this article focuses on endocrine emergencies complicating pregnancy.

  18. Recent Patents on Emerging Therapeutics for the Treatment of Glaucoma, Age Related Macular Degeneration and Uveitis

    PubMed Central

    Vadlapudi, Aswani Dutt; Patel, Ashaben; Cholkar, Kishore; Mitra, Ashim K.

    2014-01-01

    Advancements in the field and rising interest among pharmaceutical researchers have led to the development of new molecules with enhanced therapeutic activity. Design of new drugs which can target a particular pathway and/or explore novel targets is of immense interest to ocular pharmacologists worldwide. Delivery of suitable pharmacologically active agents at proper dose (within the therapeutic window) to the target tissues without any toxicity to the healthy ocular tissues still remain an elusive task. Moreover, the presence of static and dynamic barriers to drug absorption including the corneal epithelium (lipophilic), corneal and scleral stroma (hydrophilic), conjunctival lymphatics, choroidal vasculature and the blood-ocular barriers also pose a significant challenge for achieving therapeutic drug concentrations at the target site. Although many agents are currently available, new compounds are being introduced for treating various ocular diseases. Deeper understanding of the etiology and complex mechanisms associated with the disease condition would aid in the development of potential therapeutic candidates. Novel small molecules as well as complex biotechnology derived macromolecules with superior efficacy, safety and tolerability are being developed. Therefore, this review article provides an overview of existing drugs, treatment options, advances in emerging therapeutics and related recent patents for the treatment of ocular disorders such as glaucoma, age related macular degeneration (AMD) and uveitis. PMID:25414810

  19. Experimental and computational studies on newly synthesized resveratrol derivative: a new method for cancer chemoprevention and therapeutics?

    PubMed

    Banaganapalli, Babajan; Mulakayala, Chaitanya; Pulaganti, Madhusudana; Mulakayala, Naveen; Anuradha, C M; Suresh Kumar, Chitta; Shaik, Noor Ahmad; Yousuf Al-Aama, Jumana; Gudla, Dhananjaya

    2013-11-01

    Nature has been a provenance of medicinal agents for thousands of years. Resveratrol (RESL) is a naturally occurring polyphenolic compound in food stuffs such as peanuts, seeds, berries, grapes, and beverages (red wine). RESL has received significant attention due to a plethora of in vitro and in vivo reports on its cancer chemopreventive and therapeutic properties. In the present study, diacetate RESL derivative (RESL43) was synthesized. The RESL43 displayed potent cytotoxicity and triggered apoptosis in U937 cells as evidenced by poly (ADP-ribose) polymerase (PARP) cleavage, DNA fragmentation, morphological changes, and activation of FasR and FasL genes. The electrophoretic mobility shift assay revealed the suppression NFkB activity in U937 cells after treatment with RESL43 in corroboration with the deactivation of NFkB dependent genes such as IL-8, TNFR, and TNFα. Furthermore, molecular docking and dynamics studies have shown that RESL and RESL43 might exert their inhibitory activity on NFkB by altering the intramolecular binding abilities between DNA and NFkB. Taken together, RESL43 can have greater putative activity than parental RESL in a context of cancer chemoprevention and therapeutics. We suggest that the diacetate resveratrol derivative RESL43 warrants further evaluation in preclinical and clinical bridging studies in the near future.

  20. Increased therapeutic efficacy of a newly synthesized tyrosinase inhibitor by solid lipid nanoparticles in the topical treatment of hyperpigmentation

    PubMed Central

    Al-Amin, Md; Cao, Jiafu; Naeem, Muhammad; Banna, Hasanul; Kim, Min-Soo; Jung, Yunjin; Chung, Hae Young; Moon, Hyung Ryong; Yoo, Jin-Wook

    2016-01-01

    Hyperpigmentation caused by melanin overproduction is a major skin disorder in humans. Inhibition of tyrosinase, a key regulator of melanin production, has been used as an effective strategy to treat hyperpigmentation. In this study, we investigated the use of solid lipid nanoparticles (SLNs) as a highly effective and nontoxic means to deliver a newly synthesized potent tyrosinase inhibitor, MHY498, and to target melanocytes through the skin. MHY498-loaded SLNs (MHY-SLNs) were prepared by an oil-in-water emulsion solvent-evaporation method, and their morphological and physicochemical properties were characterized. MHY-SLNs showed a prolonged drug-release profile and higher skin permeation than that of MHY solution. In an in vivo evaluation of antimelanogenic activity, MHY-SLNs showed a prominent inhibitory effect against ultraviolet B-induced melanogenesis, resulting in no change in the skin color of C57BL/6 mouse, compared with that observed in an MHY solution-treated group and an untreated control group. The antimelanogenic effect of MHY-SLNs was further confirmed through Fontana–Masson staining. Importantly, MHY-SLNs did not induce any toxic effects in the L929 cell line. Overall, these data indicate that MHY-SLNs show promise in the topical treatment of hyperpigmentation. PMID:27980392

  1. Increased therapeutic efficacy of a newly synthesized tyrosinase inhibitor by solid lipid nanoparticles in the topical treatment of hyperpigmentation.

    PubMed

    Al-Amin, Md; Cao, Jiafu; Naeem, Muhammad; Banna, Hasanul; Kim, Min-Soo; Jung, Yunjin; Chung, Hae Young; Moon, Hyung Ryong; Yoo, Jin-Wook

    2016-01-01

    Hyperpigmentation caused by melanin overproduction is a major skin disorder in humans. Inhibition of tyrosinase, a key regulator of melanin production, has been used as an effective strategy to treat hyperpigmentation. In this study, we investigated the use of solid lipid nanoparticles (SLNs) as a highly effective and nontoxic means to deliver a newly synthesized potent tyrosinase inhibitor, MHY498, and to target melanocytes through the skin. MHY498-loaded SLNs (MHY-SLNs) were prepared by an oil-in-water emulsion solvent-evaporation method, and their morphological and physicochemical properties were characterized. MHY-SLNs showed a prolonged drug-release profile and higher skin permeation than that of MHY solution. In an in vivo evaluation of antimelanogenic activity, MHY-SLNs showed a prominent inhibitory effect against ultraviolet B-induced melanogenesis, resulting in no change in the skin color of C57BL/6 mouse, compared with that observed in an MHY solution-treated group and an untreated control group. The antimelanogenic effect of MHY-SLNs was further confirmed through Fontana-Masson staining. Importantly, MHY-SLNs did not induce any toxic effects in the L929 cell line. Overall, these data indicate that MHY-SLNs show promise in the topical treatment of hyperpigmentation.

  2. [A newly-discovered deposit of sea-silt sulfide therapeutic muds in Primoskiĭ Kraĭ].

    PubMed

    Chelnokova, B I; Ivanov, E M; Shchetinin, V M

    2009-01-01

    A new rich deposit of sea-silt sulfide muds (Melkovodnenskoye) have recently been found on Island Russky, Primosky krai (territory). A comprehensive survey of bottom sediments in the Melkovodnaya (Voevoda) Bay was undertaken to map out the underwater landscape, calculate mud reserves, investigate physico-chemical, radiological, bacteriological, and microbial composition of the mud. Results of experimental and clinical studies give reason to recommend sea-silt sulfide muds of the Melkovodnenskoye deposit for therapeutic and preventive use not only by the sick but also by healthy subjects. In either group, they may exert beneficial effect by stimulating preventive and compensatory reactions of the organism, activating the immune system, preventing undesirable metabolic changes, and suppressing inflammatory processes.

  3. A Budget Impact Analysis of Newly Available Hepatitis C Therapeutics and the Financial Burden on a State Correctional System.

    PubMed

    Nguyen, John T; Rich, Josiah D; Brockmann, Bradley W; Vohr, Fred; Spaulding, Anne; Montague, Brian T

    2015-08-01

    Hepatitis C virus (HCV) infection continues to disproportionately affect incarcerated populations. New HCV drugs present opportunities and challenges to address HCV in corrections. The goal of this study was to evaluate the impact of the treatment costs for HCV infection in a state correctional population through a budget impact analysis comparing differing treatment strategies. Electronic and paper medical records were reviewed to estimate the prevalence of hepatitis C within the Rhode Island Department of Corrections. Three treatment strategies were evaluated as follows: (1) treating all chronically infected persons, (2) treating only patients with demonstrated fibrosis, and (3) treating only patients with advanced fibrosis. Budget impact was computed as the percentage of pharmacy and overall healthcare expenditures accrued by total drug costs assuming entirely interferon-free therapy. Sensitivity analyses assessed potential variance in costs related to variability in HCV prevalence, genotype, estimated variation in market pricing, length of stay for the sentenced population, and uptake of newly available regimens. Chronic HCV prevalence was estimated at 17% of the total population. Treating all sentenced inmates with at least 6 months remaining of their sentence would cost about $34 million-13 times the pharmacy budget and almost twice the overall healthcare budget. Treating inmates with advanced fibrosis would cost about $15 million. A hypothetical 50% reduction in total drug costs for future therapies could cost $17 million to treat all eligible inmates. With immense costs projected with new treatment, it is unlikely that correctional facilities will have the capacity to treat all those afflicted with HCV. Alternative payment strategies in collaboration with outside programs may be necessary to curb this epidemic. In order to improve care and treatment delivery, drug costs also need to be seriously reevaluated to be more accessible and equitable now that HCV

  4. SU-E-T-571: Newly Emerging Integrated Transmission Detector Systems Provide Online Quality Assurance of External Beam Radiation Therapy

    SciTech Connect

    Hoffman, D; Chung, E; Hess, C; Stern, R; Benedict, S

    2015-06-15

    Purpose: Two newly emerging transmission detectors positioned upstream from the patient have been evaluated for online quality assurance of external beam radiotherapy. The prototype for the Integral Quality Monitor (IQM), developed by iRT Systems GmbH (Koblenz, Germany) is a large-area ion chamber mounted on the linac accessory tray to monitor photon fluence, energy, beam shape, and gantry position during treatment. The ion chamber utilizes a thickness gradient which records variable response dependent on beam position. The prototype of Delta4 Discover™, developed by ScandiDos (Uppsala, Sweden) is a linac accessory tray mounted 4040 diode array that measures photon fluence during patient treatment. Both systems are employable for patient specific QA prior to treatment delivery. Methods: Our institution evaluated the reproducibility of measurements using various beam types, including VMAT treatment plans with both the IQM ion chamber and the Delta4 Discover diode array. Additionally, the IQM’s effect on photon fluence, dose response, simulated beam error detection, and the accuracy of the integrated barometer, thermometer, and inclinometer were characterized. The evaluated photon beam errors are based on the annual tolerances specified in AAPM TG-142. Results: Repeated VMAT treatments were measured with 0.16% reproducibility by the IQM and 0.55% reproducibility by the Delta4 Discover. The IQM attenuated 6, 10, and 15 MV photon beams by 5.43±0.02%, 4.60±0.02%, and 4.21±0.03% respectively. Photon beam profiles were affected <1.5% in the non-penumbra regions. The IQM’s ion chamber’s dose response was linear and the thermometer, barometer, and inclinometer agreed with other calibrated devices. The device detected variations in monitor units delivered (1%), field position (3mm), single MLC leaf positions (13mm), and photon energy. Conclusion: We have characterized two new transmissions detector systems designed to provide in-vivo like measurements upstream

  5. The activity of carbohydrate-degrading enzymes in the development of brood and newly emerged workers and drones of the Carniolan honeybee, Apis mellifera carnica.

    PubMed

    Żółtowska, Krystyna; Lipiński, Zbigniew; Łopieńska-Biernat, Elżbieta; Farjan, Marek; Dmitryjuk, Małgorzata

    2012-01-01

    The activity of glycogen Phosphorylase and carbohydrate hydrolyzing enzymes α-amylase, glucoamylase, trehalase, and sucrase was studied in the development of the Carniolan honey bee, Apis mellifera carnica Pollman (Hymenoptera: Apidae), from newly hatched larva to freshly emerged imago of worker and drone. Phosphorolytic degradation of glycogen was significantly stronger than hydrolytic degradation in all developmental stages. Developmental profiles of hydrolase activity were similar in both sexes of brood; high activity was found in unsealed larvae, the lowest in prepupae followed by an increase in enzymatic activity. Especially intensive increases in activity occurred in the last stage of pupae and newly emerged imago. Besides α-amylase, the activities of other enzymes were higher in drone than in worker broods. Among drones, activity of glucoamylase was particularly high, ranging from around three times higher in the youngest larvae to 13 times higher in the oldest pupae. This confirms earlier suggestions about higher rates of metabolism in drone broods than in worker broods.

  6. RGS17: an emerging therapeutic target for lung and prostate cancers

    PubMed Central

    Bodle, Christopher R; Mackie, Duncan I; Roman, David L

    2013-01-01

    Ligands for G-protein-coupled receptors (GPCRs) represent approximately 50% of currently marketed drugs. RGS proteins modulate heterotrimeric G proteins and, thus, GPCR signaling, by accelerating the intrinsic GTPase activity of the Gα subunit. Given the prevalence of GPCR targeted therapeutics and the role RGS proteins play in G protein signaling, some RGS proteins are emerging as targets in their own right. One such RGS protein is RGS17. Increased RGS17 expression in some prostate and lung cancers has been demonstrated to support cancer progression, while reduced expression of RGS17 can lead to development of chemotherapeutic resistance in ovarian cancer. High-throughput screening is a powerful tool for lead compound identification, and utilization of high-throughput technologies has led to the discovery of several RGS inhibitors, thus far. As screening technologies advance, the identification of novel lead compounds the subsequent development of targeted therapeutics appears promising. PMID:23734683

  7. Emerging therapeutic targets in metastatic progression: a focus on breast cancer

    PubMed Central

    Li, Zhuo; Kang, Yibin

    2016-01-01

    Metastasis is the underlying cause of death for the majority of breast cancer patients. Despite significant advances in recent years in basic research and clinical development, therapies that specifically target metastatic breast cancer remain inadequate, and represents the single greatest obstacle to reducing mortality of late-stage breast cancer. Recent efforts have leveraged genomic analysis of breast cancer and molecular dissection of tumor-stromal cross-talk to uncover a number of promising candidates for targeted treatment of metastatic breast cancer. Rational combinations of therapeutic agents targeting tumor-intrinsic properties and microenvironmental components provide a promising strategy to develop precision treatments with higher specificity and less toxicity. In this review, we discuss the emerging therapeutic targets in breast cancer metastasis, from tumor-intrinsic pathways to those that involve the host tissue components, including the immune system. PMID:27000769

  8. Plant Alkaloids as an Emerging Therapeutic Alternative for the Treatment of Depression

    PubMed Central

    Perviz, Sadia; Khan, Haroon; Pervaiz, Aini

    2016-01-01

    Depression is a heterogeneous mood disorder that has been classified and treated in a variety of ways. Although, a number of synthetic drugs are being used as standard treatment for clinically depressed patients, but they have adverse effects that can compromise the therapeutic treatments and patient's compliance. Unlike, synthetic medications, herbal medicines are widely used across the globe due to their wide applicability and therapeutic efficacy associated with least side effects, which in turn has initiated the scientific research regarding the antidepressant activity. This review is mostly based on the literature of the last decade, aimed at exploring the preclinical profile of plant-based alkaloids (the abundant secondary metabolite) as an emerging therapy for depression. PMID:26913004

  9. Too Fresh Is Unattractive! The Attraction of Newly Emerged Nicrophorus vespilloides Females to Odour Bouquets of Large Cadavers at Various Stages of Decomposition

    PubMed Central

    von Hoermann, Christian; Steiger, Sandra; Müller, Josef K.; Ayasse, Manfred

    2013-01-01

    The necrophagous burying beetle Nicrophorus vespilloides reproduces on small carcasses that are buried underground to serve as food for their offspring. Cadavers that are too large to bury have previously been postulated to be important food sources for newly emerged beetles; however, the attractiveness of distinct successive stages of decomposition were not further specified. Therefore, we investigated the potential preference of newly emerged N. vespilloides females for odour bouquets of piglet cadavers at specific stages of decomposition. Analyses of walking tracks on a Kramer sphere revealed a significantly higher mean walking speed and, consequently, a higher mean total track length when beetles were confronted with odour plumes of the decomposition stages ‘post-bloating’, ‘advanced decay’ or ‘dry remains’ in comparison with the solvent control. Such a change of the walking speed of newly emerged N. vespilloides females indicates a higher motivation to locate such food sources. In contrast to less discriminating individuals this behaviour provides the advantage of not wasting time at unsuitable food sources. Furthermore, in the advanced decay stage, we registered a significantly higher preference of beetles for upwind directions to its specific odour plume when compared with the solvent control. Such a change to upwind walking behaviour increases the likelihood that a large cadaver will be quickly located. Our findings are of general importance for applied forensic entomology: newly emerged N. vespilloides females on large cadavers can and should be regarded as potential indicators of prolonged post mortem intervals as our results clearly show that they prefer emitted odour bouquets of later decomposition stages. PMID:23516497

  10. Enhancers and their dynamics during hematopoietic differentiation and emerging strategies for therapeutic action.

    PubMed

    Cico, Alba; Andrieu-Soler, Charlotte; Soler, Eric

    2016-11-01

    Cellular differentiation requires precisely regulated tissue-specific and developmental stage-specific gene expression patterns. Numerous studies have highlighted the predictive power of enhancers on lineage-specific gene expression programs and have started to unravel their mechanisms of action. We review here the dynamics of the enhancer landscape during hematopoietic differentiation and how enhancers function in the context of the 3D organization of the genome. We further discuss the involvement of aberrant enhancer activity in human diseases and emerging strategies aiming at controlling enhancer activity and chromosome topology for therapeutic purposes.

  11. Current and emerging therapeutic options for the treatment of chronic chagasic cardiomyopathy

    PubMed Central

    Muratore, Claudio A; Baranchuk, Adrian

    2010-01-01

    Chagas’ disease is an endemic disease in Latin America caused by a unicellular parasite (Trypanosoma cruzi) that affects almost 18 million people. This condition involves the heart, causing heart failure, arrhythmias, heart block, thromboembolism, stroke, and sudden death. In this article, we review the current and emerging treatment of Chagas’ cardiomyopathy focusing mostly on management of heart failure and arrhythmias. Heart failure therapeutical options including drugs, stem cells and heart transplantation are revised. Antiarrhythmic drugs, catheter ablation, and intracardiac devices are discussed as well. Finally, the evidence for a potential role of specific antiparasitic treatment for the prevention of cardiovascular disease is reviewed. PMID:20730015

  12. The therapeutic itinerary in urgent/emergency pediatric situations in a Maroon community.

    PubMed

    Siqueira, Samylla Maira Costa; Jesus, Viviane Silva de; Camargo, Climene Laura de

    2016-01-01

    The goal was to understand the therapeutic itinerary of Maroon children in urgent/emergency situation. Is a descriptive research with a qualitative approach that uses the Health Care System model of Arthur Kleinman as its theoretical support. Participants included 12 mothers of children who had experienced any urgent or emergency medical situation. Data collection took place from December 2013 to June 2014 through semi-structured interviews with a thematic analysis of the data. The care of the child started in the "informal" subsystem, and access to a "formal" subsystem was characterized as a pilgrimage for health services. A development of specific strategies is needed to ensure and facilitate full access to the services of the professional subsystem for Maroon communities.

  13. Scabies: molecular perspectives and therapeutic implications in the face of emerging drug resistance.

    PubMed

    Mounsey, Kate E; Holt, Deborah C; McCarthy, James; Currie, Bart J; Walton, Shelley F

    2008-02-01

    Limited effective treatments, coupled with recent observations of emerging drug resistance to oral ivermectin and 5% permethrin, raise concerns regarding the future control of scabies, especially in severe cases and in endemic areas where repeated community treatment programs are in place. There is consequently an urgent need to define molecular mechanisms of drug resistance in scabies mites and to develop and assess alternative therapeutic options, such as tea tree oil, in the event of increasing treatment failure. Molecular studies on scabies mites have, until recently, been restricted; however, recent advances are providing new insights into scabies mite biology and genetic mechanisms underlying drug resistance. These may assist in overcoming many of the current difficulties in monitoring treatment efficacy and allow the development of more sensitive tools for monitoring emerging resistance.

  14. American Society for Therapeutic Radiology and Oncology (ASTRO) Emerging Technology Committee report on electronic brachytherapy.

    PubMed

    Park, Catherine C; Yom, Sue S; Podgorsak, Matthew B; Harris, Eleanor; Price, Robert A; Bevan, Alison; Pouliot, Jean; Konski, Andre A; Wallner, Paul E

    2010-03-15

    The development of novel technologies for the safe and effective delivery of radiation is critical to advancing the field of radiation oncology. The Emerging Technology Committee of the American Society for Therapeutic Radiology and Oncology appointed a Task Group within its Evaluation Subcommittee to evaluate new electronic brachytherapy methods that are being developed for, or are already in, clinical use. The Task Group evaluated two devices, the Axxent Electronic Brachytherapy System by Xoft, Inc. (Fremont, CA), and the Intrabeam Photon Radiosurgery Device by Carl Zeiss Surgical (Oberkochen, Germany). These devices are designed to deliver electronically generated radiation, and because of their relatively low energy output, they do not fall under existing regulatory scrutiny of radioactive sources that are used for conventional radioisotope brachytherapy. This report provides a descriptive overview of the technologies, current and future projected applications, comparison of competing technologies, potential impact, and potential safety issues. The full Emerging Technology Committee report is available on the American Society for Therapeutic Radiology and Oncology Web site.

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

    PubMed

    Islam, Nazrul; Abbas, Muzaffar; Rahman, Shafiqur

    2016-12-12

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

  16. American Society for Therapeutic Radiology and Oncology (ASTRO) Emerging Technology Committee Report on Electronic Brachytherapy

    SciTech Connect

    Park, Catherine C.; Yom, Sue S.; Podgorsak, Matthew B.; Harris, Eleanor; Price, Robert A.; Bevan, Alison; Pouliot, Jean; Konski, Andre A.; Wallner, Paul E.

    2010-03-15

    The development of novel technologies for the safe and effective delivery of radiation is critical to advancing the field of radiation oncology. The Emerging Technology Committee of the American Society for Therapeutic Radiology and Oncology appointed a Task Group within its Evaluation Subcommittee to evaluate new electronic brachytherapy methods that are being developed for, or are already in, clinical use. The Task Group evaluated two devices, the Axxent Electronic Brachytherapy System by Xoft, Inc. (Fremont, CA), and the Intrabeam Photon Radiosurgery Device by Carl Zeiss Surgical (Oberkochen, Germany). These devices are designed to deliver electronically generated radiation, and because of their relatively low energy output, they do not fall under existing regulatory scrutiny of radioactive sources that are used for conventional radioisotope brachytherapy. This report provides a descriptive overview of the technologies, current and future projected applications, comparison of competing technologies, potential impact, and potential safety issues. The full Emerging Technology Committee report is available on the American Society for Therapeutic Radiology and Oncology Web site.

  17. Emergence of FGFR family gene fusions as therapeutic targets in a wide spectrum of solid tumours.

    PubMed

    Parker, Brittany C; Engels, Manon; Annala, Matti; Zhang, Wei

    2014-01-01

    The emergence of fibroblast growth factor receptor (FGFR) family fusions across diverse cancers has brought attention to FGFR-derived cancer therapies. The discovery of the first recurrent FGFR fusion in glioblastoma was followed by discoveries of FGFR fusions in bladder, lung, breast, thyroid, oral, and prostate cancers. Drug targeting of FGFR fusions has shown promising results and should soon be translating into clinical trials. FGFR fusions form as a result of various mechanisms – predominantly deletion for FGFR1, translocation for FGFR2, and tandem duplication for FGFR3. The ability to exploit the unique targetability of FGFR fusions proves that FGFR-derived therapies could have a promising future in cancer therapeutics. Drug targeting of fusion genes has proven to be an extremely effective therapeutic approach for cancers such as the recurrent BCR–ABL1 fusion in chronic myeloid leukaemia. The recent discovery of recurrent FGFR family fusions in several cancer types has brought to attention the unique therapeutic potential for FGFR-positive patients. Understanding the diverse mechanisms of FGFR fusion formation and their oncogenic potential will shed light on the impact of FGFR-derived therapy in the future.

  18. Inhibitory G proteins and their receptors: emerging therapeutic targets for obesity and diabetes.

    PubMed

    Kimple, Michelle E; Neuman, Joshua C; Linnemann, Amelia K; Casey, Patrick J

    2014-06-20

    The worldwide prevalence of obesity is steadily increasing, nearly doubling between 1980 and 2008. Obesity is often associated with insulin resistance, a major risk factor for type 2 diabetes mellitus (T2DM): a costly chronic disease and serious public health problem. The underlying cause of T2DM is a failure of the beta cells of the pancreas to continue to produce enough insulin to counteract insulin resistance. Most current T2DM therapeutics do not prevent continued loss of insulin secretion capacity, and those that do have the potential to preserve beta cell mass and function are not effective in all patients. Therefore, developing new methods for preventing and treating obesity and T2DM is very timely and of great significance. There is now considerable literature demonstrating a link between inhibitory guanine nucleotide-binding protein (G protein) and G protein-coupled receptor (GPCR) signaling in insulin-responsive tissues and the pathogenesis of obesity and T2DM. These studies are suggesting new and emerging therapeutic targets for these conditions. In this review, we will discuss inhibitory G proteins and GPCRs that have primary actions in the beta cell and other peripheral sites as therapeutic targets for obesity and T2DM, improving satiety, insulin resistance and/or beta cell biology.

  19. Pharmacists' adoption into practice of newly reclassified medicines from diverse therapeutic areas in Scotland: a quantitative study of factors associated with decision-making.

    PubMed

    Paudyal, Vibhu; Hansford, Denise; Cunningham, Scott; Stewart, Derek

    2014-01-01

    In the UK, over 90 medicines that were previously available only through prescription have been reclassified to allow over-the-counter (OTC) availability via pharmacies. Pharmacists are personally responsible for undertaking or supervising the sales and supplies of these OTC 'pharmacy only' (P) medicines. Reclassification facilitates pharmacy management of a wide range of conditions. This research aimed to evaluate Scottish community pharmacists' perspectives of newly reclassified 'P' medicines from diverse therapeutic areas and to identify factors associated with their adoption into practice of these medicines. A cross-sectional postal survey of all community pharmacies in Scotland (N = 1138) was undertaken. The questionnaire was mailed to the pharmacist responsible for OTC medicines. Four newly reclassified 'P' medicines: omeprazole, naproxen, simvastatin and chloramphenicol eye drops were evaluated. Outcomes of interests included pharmacist support for the reclassified status, perceived adoption into practice of these medicines (i.e., how often they supplied each of these medicines) and factors associated with decision-making. Analyses included descriptive, bivariate correlation, principal component factor and binary regression. Five hundred sixty-three pharmacists responded (response rate: 49.5%). Newly reclassified medicines studied had been adopted into practice by the respondent pharmacists to varying degrees. A high majority of the respondents expressed support for the reclassified status (82.4%) and perceived that the level of adoption into practice of OTC chloramphenicol was high (92.1%). In contrast, over 80% of respondents had not yet made a supply of OTC simvastatin to patients, mainly owing to pharmacists' perceptions of lack of evidence of efficacy of the OTC dose and patient demand. Decision-making was influenced by factors such as perceived benefits to patients and pharmacy practice; e.g., respondents who agreed that reclassified naproxen was a

  20. Encephalitis due to emerging viruses: CNS innate immunity and potential therapeutic targets.

    PubMed

    Denizot, M; Neal, J W; Gasque, P

    2012-07-01

    The emerging viruses represent a group of pathogens that are intimately connected to a diverse range of animal vectors. The recent escalation of air travel climate change and urbanization has meant humans will have increased risk of contacting these pathogens resulting in serious CNS infections. Many RNA viruses enter the CNS by evading the BBB due to axonal transport from the periphery. The systemic adaptive and CNS innate immune systems express pattern recognition receptors PRR (TLRs, RiG-1 and MDA-5) that detect viral nucleic acids and initiate host antiviral response. However, several emerging viruses (West Nile Fever, Influenza A, Enterovirus 71 Ebola) are recognized and internalized by host cell receptors (TLR, MMR, DC-SIGN, CD162 and Scavenger receptor B) and escape immuno surveillance by the host systemic and innate immune systems. Many RNA viruses express viral proteins WNF (E protein), Influenza A (NS1), EV71 (protein 3C), Rabies (Glycoprotein), Ebola proteins (VP24 and VP 35) that inhibit the host cell anti-virus Interferon type I response promoting virus replication and encephalitis. The therapeutic use of RNA interference methodologies to silence gene expression of viral peptides and treat emerging virus infection of the CNS is discussed.

  1. Targeted therapeutics in SLE: emerging strategies to modulate the interferon pathway

    PubMed Central

    Oon, Shereen; Wilson, Nicholas J; Wicks, Ian

    2016-01-01

    Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by impaired immune tolerance, resulting in the generation of pathogenic autoantibodies and immune complexes. Although autoreactive B lymphocytes have been the first targets for biologic therapies in SLE, the importance of the innate immune system, and in particular, pathways involved in interferon (IFN) signaling, has emerged. There are now data supporting a central role for a plasmacytoid dendritic cell-derived type I IFN pathway in SLE, with a number of biologic therapeutics and small-molecule inhibitors undergoing clinical trials. Monoclonal antibodies targeting IFN-α have completed phase II clinical trials, and an antibody against the type I IFN receptor is entering a phase III trial. However, other IFNs, such as IFN gamma, and the more recently discovered type III IFNs, are also emerging as targets in SLE; and blockade of upstream components of the IFN signaling pathway may enable inhibition of more than one IFN subtype. In this review, we discuss the current understanding of IFNs in SLE, focusing on emerging therapies. PMID:27350879

  2. G protein-coupled receptors as oncogenic signals in glioma: emerging therapeutic avenues.

    PubMed

    Cherry, A E; Stella, N

    2014-10-10

    Gliomas are the most common malignant intracranial tumors. Newly developed targeted therapies for these cancers aim to inhibit oncogenic signals, many of which emanate from receptor tyrosine kinases, including the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor receptor (VEGFR). Unfortunately, the first-generation treatments targeting these oncogenic signals provide little survival benefit in both mouse xenograft models and human patients. The search for new treatment options has uncovered several G protein-coupled receptor (GPCR) candidates and generated a growing interest in this class of proteins as alternative therapeutic targets for the treatment of various cancers, including glioblastoma multiforme (GBM). GPCRs constitute a large family of membrane receptors that influence oncogenic pathways through canonical and non-canonical signaling. Accordingly, evidence indicates that GPCRs display a unique ability to crosstalk with receptor tyrosine kinases, making them important molecular components controlling tumorigenesis. This review summarizes the current research on GPCR functionality in gliomas and explores the potential of modulating these receptors to treat this devastating disease.

  3. G protein-coupled receptors as oncogenic signals in glioma: emerging therapeutic avenues

    PubMed Central

    Cherry, Allison E; Stella, Nephi

    2014-01-01

    Gliomas are the most common malignant intracranial tumors. Newly developed targeted therapies for these cancers aim to inhibit oncogenic signals, many of which emanate from receptor tyrosine kinases, including the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor receptor (VEGFR). Unfortunately, the first generation treatments targeting these oncogenic signals provide little survival benefit in both mouse xenograft models and human patients. The search for new treatment options has uncovered several G protein-coupled receptor (GPCR) candidates and generated a growing interest in this class of proteins as alternative therapeutic targets for the treatment of various cancers, including GBM. GPCRs constitute a large family of membrane receptors that influence oncogenic pathways through canonical and non-canonical signaling. Accordingly, evidence indicates that GPCRs display a unique ability to crosstalk with receptor tyrosine kinases, making them important molecular components controlling tumorigenesis. This review summarizes the current research on GPCR functionality in gliomas and explores the potential of modulating these receptors to treat this devastating disease. PMID:25158675

  4. Emerging therapeutic approaches for the management of diabetes mellitus and macrovascular complications.

    PubMed

    Golden, Sherita Hill

    2011-08-02

    Type 2 diabetes mellitus (DM) affects an estimated 25.8 million people in the United States and is the 7th leading cause of death. While effective therapy can prevent or delay the complications that are associated with diabetes, according to the Center for Disease Control, 35% of Americans with DM are undiagnosed, and another 79 million Americans have blood glucose levels that greatly increase their risk of developing DM in the next several years. One of the Healthy People 2020 goals is to reduce the disease and economic burden of DM and improve the quality of life for all persons who have, or are at risk for, DM. Achieving this goal requires a concentrated focus on improving the management of diabetes and in targeting prevention of macrovascular complications. This article reviews established and emerging therapeutic approaches for managing DM and prevention of macrovascular complications.

  5. Recent Patents and Emerging Therapeutics in the Treatment of Allergic Conjunctivitis

    PubMed Central

    Mishra, Gyan P.; Tamboli, Viral; Jwala, Jwala; Mitra, Ashim K.

    2011-01-01

    Ocular allergy is an inflammatory response of the conjunctival mucosa that also affects the cornea and eyelids. Allergic conjunctivitis includes seasonal allergic conjunctivitis (SAC), perennial allergic conjunctivitis (PAC), vernal keratoconjunctivitis (VKC), atopic keratoconjunctivitis (AKC) and giant papillary conjunctivitis (GPC). In general, allergic conditions involve mast cell degranulation that leads to release of inflammatory mediators and activation of enzymatic cascades generating pro-inflammatory mediators. In chronic ocular inflammatory disorders associated with mast cell activation such as VKC and AKC constant inflammatory response is observed due to predominance of inflammatory mediators such as eosinophils and Th2-generated cytokines. Antihistamines, mast-cell stabilizers, non-steroidal anti-inflammatory agents, corticosteroids and immunomodulatory agents are commonly indicated for the treatment of acute and chronic allergic conjunctivitis. In recent years newer drug molecules have been introduced in the treatment of allergic conjunctivitis. This article reviews recent patents and emerging therapeutics in the treatment of allergic conjunctivitis. PMID:21171952

  6. Emerging role of microRNAs in major depressive disorder: diagnosis and therapeutic implications.

    PubMed

    Dwivedi, Yogesh

    2014-03-01

    Major depressive disorder (MDD) is a major public health concern. Despite tremendous advances, the pathogenic mechanisms associated with MDD are still unclear. Moreover, a significant number of MDD subjects do not respond to the currently available medication. MicroRNAs (miRNAs) are a class of small noncoding RNAs that control gene expression by modulating translation, messenger RNA (mRNA) degradation, or stability of mRNA targets. The role of miRNAs in disease pathophysiology is emerging rapidly. Recent studies demonstrating the involvement of miRNAs in several aspects of neural plasticity, neurogenesis, and stress response, and more direct studies in human postmortem brain provide strong evidence that miRNAs can not only play a critical role in MDD pathogenesis, but can also open up new avenues for the development of therapeutic targets. Circulating miRNAs are now being considered as possible biomarkers in disease pathogenesis and in monitoring therapeutic responses because of the presence and/or release of miRNAs in blood cells as well as in other peripheral tissues. In this review, these aspects are discussed in a comprehensive and critical manner.

  7. F-BOX proteins in cancer cachexia and muscle wasting: Emerging regulators and therapeutic opportunities.

    PubMed

    Sukari, Ammar; Muqbil, Irfana; Mohammad, Ramzi M; Philip, Philip A; Azmi, Asfar S

    2016-02-01

    Cancer cachexia is a debilitating metabolic syndrome accounting for fatigue, an impairment of normal activities, loss of muscle mass associated with body weight loss eventually leading to death in majority of patients with advanced disease. Cachexia patients undergoing skeletal muscle atrophy show consistent activation of the SCF ubiquitin ligase (F-BOX) family member Atrogin-1 (also known as MAFBx/FBXO32) alongside the activation of the muscle ring finger protein1 (MuRF1). Other lesser known F-BOX family members are also emerging as key players supporting muscle wasting pathways. Recent work highlights a spectrum of different cancer signaling mechanisms impacting F-BOX family members that feed forward muscle atrophy related genes during cachexia. These novel players provide unique opportunities to block cachexia induced skeletal muscle atrophy by therapeutically targeting the SCF protein ligases. Conversely, strategies that induce the production of proteins may be helpful to counter the effects of these F-BOX proteins. Through this review, we bring forward some novel targets that promote atrogin-1 signaling in cachexia and muscle wasting and highlight newer therapeutic opportunities that can help in the better management of patients with this devastating and fatal disorder.

  8. Current Treatment, Emerging Translational Therapies, and New Therapeutic Targets for Autoimmune Myasthenia Gravis.

    PubMed

    Guptill, Jeffrey T; Soni, Madhu; Meriggioli, Matthew N

    2016-01-01

    Myasthenia gravis (MG) is an autoimmune disease associated with the production of autoantibodies against 1) the skeletal muscle acetylcholine receptor; 2) muscle-specific kinase, a receptor tyrosine kinase critical for the maintenance of neuromuscular synapses; 3) low-density lipoprotein receptor-related protein 4, an important molecular binding partner for muscle-specific kinase; and 4) other muscle endplate proteins. In addition to the profile of autoantibodies, MG may be classified according the location of the affected muscles (ocular vs generalized), the age of symptom onset, and the nature of thymic pathology. Immunopathologic events leading to the production of autoantibodies differ in the various disease subtypes. Advances in our knowledge of the immunopathogenesis of the subtypes of MG will allow for directed utilization of the ever-growing repertoire of therapeutic agents that target distinct nodes in the immune pathway relevant to the initiation and maintenance of autoimmune disease. In this review, we examine the pathogenesis of MG subtypes, current treatment options, and emerging new treatments and therapeutic targets.

  9. The Emerging Role of HMGB1 in Neuropathic Pain: A Potential Therapeutic Target for Neuroinflammation

    PubMed Central

    Wan, Wenbin; Cao, Lan; Khanabdali, Ramin; Kalionis, Bill; Tai, Xiantao; Xia, Shijin

    2016-01-01

    Neuropathic pain (NPP) is intolerable, persistent, and specific type of long-term pain. It is considered to be a direct consequence of pathological changes affecting the somatosensory system and can be debilitating for affected patients. Despite recent progress and growing interest in understanding the pathogenesis of the disease, NPP still presents a major diagnostic and therapeutic challenge. High mobility group box 1 (HMGB1) mediates inflammatory and immune reactions in nervous system and emerging evidence reveals that HMGB1 plays an essential role in neuroinflammation through receptors such as Toll-like receptors (TLR), receptor for advanced glycation end products (RAGE), C-X-X motif chemokines receptor 4 (CXCR4), and N-methyl-D-aspartate (NMDA) receptor. In this review, we present evidence from studies that address the role of HMGB1 in NPP. First, we review studies aimed at determining the role of HMGB1 in NPP and discuss the possible mechanisms underlying HMGB1-mediated NPP progression where receptors for HMGB1 are involved. Then we review studies that address HMGB1 as a potential therapeutic target for NPP. PMID:27294160

  10. The Emerging Role of HMGB1 in Neuropathic Pain: A Potential Therapeutic Target for Neuroinflammation.

    PubMed

    Wan, Wenbin; Cao, Lan; Khanabdali, Ramin; Kalionis, Bill; Tai, Xiantao; Xia, Shijin

    2016-01-01

    Neuropathic pain (NPP) is intolerable, persistent, and specific type of long-term pain. It is considered to be a direct consequence of pathological changes affecting the somatosensory system and can be debilitating for affected patients. Despite recent progress and growing interest in understanding the pathogenesis of the disease, NPP still presents a major diagnostic and therapeutic challenge. High mobility group box 1 (HMGB1) mediates inflammatory and immune reactions in nervous system and emerging evidence reveals that HMGB1 plays an essential role in neuroinflammation through receptors such as Toll-like receptors (TLR), receptor for advanced glycation end products (RAGE), C-X-X motif chemokines receptor 4 (CXCR4), and N-methyl-D-aspartate (NMDA) receptor. In this review, we present evidence from studies that address the role of HMGB1 in NPP. First, we review studies aimed at determining the role of HMGB1 in NPP and discuss the possible mechanisms underlying HMGB1-mediated NPP progression where receptors for HMGB1 are involved. Then we review studies that address HMGB1 as a potential therapeutic target for NPP.

  11. F-BOX proteins in cancer cachexia and muscle wasting: emerging regulators and therapeutic opportunities

    PubMed Central

    Sukari, Ammar; Muqbil, Irfana; Mohammad, Ramzi M.; Philip, Philip A.; Azmi, Asfar S.

    2016-01-01

    Cancer cachexia is a debilitating metabolic syndrome accounting for fatigue, an impairment of normal activities, loss of muscle mass associated with body weight loss eventually leading to death in majority of patients with advanced disease. Cachexia patients undergoing skeletal muscle atrophy show consistent activation of the SCF ubiquitin ligase (F-BOX) family member Atrogin-1 (also known as MAFBx/FBXO32) alongside the activation of the muscle ring finger protein1 (MuRF1). Other lesser known F-BOX family members are also emerging as key players supporting muscle wasting pathways. Recent work highlights a spectrum of different cancer signaling mechanisms impacting F-BOX family members that feed forward muscle atrophy related genes during cachexia. These novel players provide unique opportunities to block cachexia induced skeletal muscle atrophy by therapeutically targeting the SCF protein ligases. Conversely, strategies that induce the production of proteins may be helpful to counter the effects of these F-BOX proteins. Through this review, we bring forward some novel targets that promote atrogin-1 signaling in cachexia and muscle wasting and highlight newer therapeutic opportunities that can help in the better management of patients with this devastating and fatal disorder. PMID:26804424

  12. Glycoprotein non-metastatic b (GPNMB): A metastatic mediator and emerging therapeutic target in cancer

    PubMed Central

    Maric, Gordana; Rose, April AN; Annis, Matthew G; Siegel, Peter M

    2013-01-01

    Molecularly targeted therapies are rapidly growing with respect to their clinical development and impact on cancer treatment due to their highly selective anti-tumor action. However, many aggressive cancers such as triple-negative breast cancer (TNBC) currently lack well-defined therapeutic targets against which such agents can be developed. The identification of tumor-associated antigens and the generation of antibody drug-conjugates represent an emerging area of intense interest and growth in the field of cancer therapeutics. Glycoprotein non-metastatic b (GPNMB) has recently been identified as a gene that is over-expressed in numerous cancers, including TNBC, and often correlates with the metastatic phenotype. In breast cancer, GPNMB expression in the tumor epithelium is associated with a reduction in disease-free and overall survival. Based on these findings, glembatumumab vedotin (CDX-011), an antibody-drug conjugate that selectively targets GPNMB, is currently being investigated in clinical trials for patients with metastatic breast cancer and unresectable melanoma. This review discusses the physiological and potential pathological roles of GPNMB in normal and cancer tissues, respectively, and details the clinical advances and challenges in targeting GPNMB-expressing malignancies. PMID:23874106

  13. A comparison of the reactivating and therapeutic efficacy of newly developed oximes (K347, K628) with commonly used oximes (obidoxime, HI-6) against tabun in rats and mice.

    PubMed

    Kassa, Jiri; Karasova, Jana Zdarova; Kuca, Kamil; Musilek, Kamil

    2010-07-01

    The potency of newly developed reactivators of nerve agent-inhibited acetylcholinesterase (K347, K628) in reactivating tabun-inhibited acetylcholinesterase and reducing tabun-induced lethal toxic effects was compared with currently available oximes (obidoxime, the oxime HI-6), using in vivo methods. Studies that determined the percentage of reactivation of tabun-inhibited blood and tissue acetycholinesterase in poisoned rats showed that the reactivating efficacy of both newly developed oximes is comparable with the oxime HI-6, but it is significantly lower than the reactivating effects of obidoxime. The monopyridinium oxime, K347, was also found to be able to reduce lethal toxic effects in tabun-poisoned mice, while the therapeutic efficacy of another newly developed bispyridinium oxime, K628, was negligible. The therapeutic efficacy of K347 was higher than the potency of the oxime, HI-6, but it was lower than the therapeutic effects of obidoxime. Thus, the reactivating and therapeutic potency of both newly developed oximes (K347, K628) was not more effective then currently available oximes, and therefore, they are not suitable for the replacement of commonly used oximes (especially obidoxime) for the treatment of acute tabun poisoning.

  14. EPA and USGS scientists conduct study to determine prevalence of newly-emerging contaminants in treated and untreated drinking water

    EPA Pesticide Factsheets

    Scientists from the EPA and USGS are collaborating on a research study to determine the presence of contaminants of emerging concern in treated and untreated drinking water collected from drinking water treatment plants.

  15. Neonatal infections due to multi-resistant strains: Epidemiology, current treatment, emerging therapeutic approaches and prevention.

    PubMed

    Tzialla, Chryssoula; Borghesi, Alessandro; Pozzi, Margherita; Stronati, Mauro

    2015-12-07

    Severe infections represent the main cause of neonatal mortality accounting for more than one million neonatal deaths worldwide every year. Antibiotics are the most commonly prescribed medications in neonatal intensive care units. The benefits of antibiotic therapy when indicated are clearly enormous, but the continued and widespread use of antibiotics has generated over the years a strong selective pressure on microorganisms, favoring the emergence of resistant strains. Health agencies worldwide are galvanizing attention toward antibiotic resistance in gram-positive and gram-negative bacteria. Infections in neonatal units due to multidrug and extensively multidrug resistant bacteria are rising and are already seriously challenging antibiotic treatment options. While there is a growing choice of agents against multi-resistant gram-positive bacteria, new options for multi-resistant gram-negative bacteria in the clinical practice have decreased significantly in the last 20 years making the treatment of infections caused by multidrug-resistant pathogens challenging mostly in neonates. Treatment options are currently limited and will be some years before any new treatment for neonates become available for clinical use, if ever. The aim of the review is to highlight the current knowledge on antibiotic resistance in the neonatal population, the possible therapeutic choices, and the prevention strategies to adopt in order to reduce the emergency and spread of resistant strains.

  16. Impact of Prior Therapeutic Opioid Use by Emergency Department Providers on Opioid Prescribing Decisions

    PubMed Central

    Pomerleau, Adam C.; Perrone, Jeanmarie; Hoppe, Jason A.; Salzman, Matthew; Weiss, Paul S.; Nelson, Lewis S.

    2016-01-01

    Introduction Our study sought to examine the opioid analgesic (OA) prescribing decisions of emergency department (ED) providers who have themselves used OA therapeutically and those who have not. A second objective was to determine if OA prescribing decisions would differ based on the patient’s relationship to the provider. Methods We distributed an electronic survey to a random sample of ED providers at participating centers in a nationwide research consortium. Question topics included provider attitudes about OA prescribing, prior personal therapeutic use of OAs (indications, dosing, and disposal of leftover medication), and hypothetical analgesic-prescribing decisions for their patients, family members, and themselves for different painful conditions. Results The total survey population was 957 individuals; 515 responded to the survey, a 54% response rate. Prior personal therapeutic OA use was reported in 63% (95% CI = [58–68]). A majority of these providers (82%; 95% CI = [77–87]) took fewer than half the number of pills prescribed. Regarding provider attitudes towards OA prescribing, 66% (95% CI = [61–71]) agreed that OA could lead to addiction even with short-term use. When providers were asked if they would prescribe OA to a patient with 10/10 pain from an ankle sprain, 21% (95% CI = [17–25]) would for an adult patient, 13% (95% CI = [10–16]) would for an adult family member, and 6% (95% CI = [4–8]) indicated they themselves would take an opioid for the same pain. When the scenario involved an ankle fracture, 86% (95% CI = [83–89]) would prescribe OA for an adult patient, 75% (95% CI = [71–79]) for an adult family member, and 52% (95% CI = [47–57]) would themselves take OA. Providers who have personally used OA to treat their pain were found to make similar prescribing decisions compared to those who had not. Conclusion No consistent differences in prescribing decisions were found between ED providers based on their prior therapeutic use

  17. Polymorphic SSR Markers for Plasmopara obducens (Peronosporaceae), the Newly Emergent Downy Mildew Pathogen of Impatiens (Balsaminaceae)

    SciTech Connect

    Salgado-Salazar, Catalina; Rivera, Yazmín; Veltri, Daniel; Crouch, Jo Anne

    2015-11-10

    Premise of the study: Simple sequence repeat (SSR) markers were developed for Plasmopara obducens, the causal agent of the newly emergent downy mildew disease of Impatiens walleriana. Methods and Results: A 202-Mb draft genome assembly was generated from P. obducens using Illumina technology and mined to identify 13,483 SSR motifs. Primers were synthesized for 62 marker candidates, of which 37 generated reliable PCR products. Testing of the 37 markers using 96 P. obducens samples showed 96% of the markers were polymorphic, with 2-6 alleles observed. Observed and expected heterozygosity ranged from 0.000-0.892 and 0.023-0.746, respectively. Just 17 markers were sufficient to identify all multilocus genotypes. Conclusions: These are the first SSR markers available for this pathogen, and one of the first molecular resources. These markers will be useful in assessing variation in pathogen populations and determining the factors contributing to the emergence of destructive impatiens downy mildew disease.

  18. The Activity of Carbohydrate-Degrading Enzymes in the Development of Brood and Newly Emerged workers and Drones of the Carniolan Honeybee, Apis mellifera carnica

    PubMed Central

    Żółtowska, Krystyna; Lipiński, Zbigniew; Łopieńska-Biernat, Elżbieta; Farjan, Marek; Dmitryjuk, Małgorzata

    2012-01-01

    The activity of glycogen Phosphorylase and carbohydrate hydrolyzing enzymes α-amylase, glucoamylase, trehalase, and sucrase was studied in the development of the Carniolan honey bee, Apis mellifera carnica Pollman (Hymenoptera: Apidae), from newly hatched larva to freshly emerged imago of worker and drone. Phosphorolytic degradation of glycogen was significantly stronger than hydrolytic degradation in all developmental stages. Developmental profiles of hydrolase activity were similar in both sexes of brood; high activity was found in unsealed larvae, the lowest in prepupae followed by an increase in enzymatic activity. Especially intensive increases in activity occurred in the last stage of pupae and newly emerged imago. Besides α-amylase, the activities of other enzymes were higher in drone than in worker broods. Among drones, activity of glucoamylase was particularly high, ranging from around three times higher in the youngest larvae to 13 times higher in the oldest pupae. This confirms earlier suggestions about higher rates of metabolism in drone broods than in worker broods. PMID:22943407

  19. Newly emerged populations of Plasmopara halstedii infecting rudbeckia exhibit unique genotypic profiles and are distinct from sunflower-infecting strains

    USDA-ARS?s Scientific Manuscript database

    The oomycete Plasmopara halstedii emerged at the onset of the 21st century as a destructive new pathogen causing downy mildew disease of ornamental Rudbeckia fulgida (rudbeckia) in the U.S.A. The pathogen is also a significant global problem of sunflower (Helianthus annuus), and is widely regarded a...

  20. A Cancer Research UK First Time in Human Phase I Trial of IMA950 (Novel Multi-Peptide Therapeutic Vaccine) in Patients with Newly Diagnosed Glioblastoma

    PubMed Central

    Rampling, Roy; Peoples, Sharon; Mulholland, Paul J.; James, Allan; Al-Salihi, Omar; Twelves, Christopher J.; McBain, Catherine; Jefferies, Sarah; Jackson, Alan; Stewart, Willie; Lindner, Juha; Kutscher, Sarah; Hilf, Norbert; McGuigan, Lesley; Peters, Jane; Hill, Karen; Schoor, Oliver; Singh-Jasuja, Harpreet; Halford, Sarah E.; Ritchie, James W.A.

    2016-01-01

    Purpose To perform a two-cohort, phase 1 safety and immunogenicity study of IMA950 in addition to standard chemo-radiotherapy (CRT) and adjuvant temozolomide in patients with newly diagnosed glioblastoma (GBM). IMA950 is a novel GBM specific therapeutic vaccine containing 11 tumor-associated peptides (TUMAPs), identified on human leukocyte antigen (HLA) surface receptors in primary human GBM tissue. Experimental Design Patients were HLA-A*02 positive and had undergone tumor resection. Vaccination comprised 11 intradermal injections with IMA950 plus GM-CSF over a 24 week period, beginning 7-14 days prior to initiation of CRT (Cohort 1) or 7 days post CRT (Cohort 2). Safety was assessed according to NCI CTCAE Version 4.0 and TUMAP specific T-cell immune responses determined. Secondary observations included progression-free survival (PFS), pre-treatment regulatory T-cell (Treg) levels and the effect of steroids on T-cell responses. Results Forty five patients were recruited. Related adverse events included minor injection site reactions, rash, pruritus, fatigue, neutropenia and single cases of allergic reaction, anemia and anaphylaxis. Two patients experienced Grade 3 dose limiting toxicity of fatigue and anaphylaxis. Of 40 evaluable patients, 36 were TUMAP responders and 20 were multi-TUMAP responders, with no important differences between cohorts. No effect of pre-treatment Treg levels on IMA950 immunogenicity was observed and steroids did not affect TUMAP responses. PFS was 74% at 6 months and 31% at 9 months. Conclusion IMA950 plus GM-CSF was well tolerated with the primary immunogenicity endpoint of observing multi-TUMAP responses in at least 30% of patients exceeded. Further development of IMA950 is encouraged. PMID:27225692

  1. A Cancer Research UK First Time in Human Phase I Trial of IMA950 (Novel Multipeptide Therapeutic Vaccine) in Patients with Newly Diagnosed Glioblastoma.

    PubMed

    Rampling, Roy; Peoples, Sharon; Mulholland, Paul J; James, Allan; Al-Salihi, Omar; Twelves, Christopher J; McBain, Catherine; Jefferies, Sarah; Jackson, Alan; Stewart, Willie; Lindner, Juha; Kutscher, Sarah; Hilf, Norbert; McGuigan, Lesley; Peters, Jane; Hill, Karen; Schoor, Oliver; Singh-Jasuja, Harpreet; Halford, Sarah E; Ritchie, James W A

    2016-10-01

    To perform a two-cohort, phase I safety and immunogenicity study of IMA950 in addition to standard chemoradiotherapy and adjuvant temozolomide in patients with newly diagnosed glioblastoma. IMA950 is a novel glioblastoma-specific therapeutic vaccine containing 11 tumor-associated peptides (TUMAP), identified on human leukocyte antigen (HLA) surface receptors in primary human glioblastoma tissue. Patients were HLA-A*02-positive and had undergone tumor resection. Vaccination comprised 11 intradermal injections with IMA950 plus granulocyte macrophage colony-stimulating factor (GM-CSF) over a 24-week period, beginning 7 to 14 days prior to initiation of chemoradiotherapy (Cohort 1) or 7 days after chemoradiotherapy (Cohort 2). Safety was assessed according to NCI CTCAE Version 4.0 and TUMAP-specific T-cell immune responses determined. Secondary observations included progression-free survival (PFS), pretreatment regulatory T cell (Treg) levels, and the effect of steroids on T-cell responses. Forty-five patients were recruited. Related adverse events included minor injection site reactions, rash, pruritus, fatigue, neutropenia and single cases of allergic reaction, anemia and anaphylaxis. Two patients experienced grade 3 dose-limiting toxicity of fatigue and anaphylaxis. Of 40 evaluable patients, 36 were TUMAP responders and 20 were multi-TUMAP responders, with no important differences between cohorts. No effect of pretreatment Treg levels on IMA950 immunogenicity was observed, and steroids did not affect TUMAP responses. PFS rates were 74% at 6 months and 31% at 9 months. IMA950 plus GM-CSF was well-tolerated with the primary immunogenicity endpoint of observing multi-TUMAP responses in at least 30% of patients exceeded. Further development of IMA950 is encouraged. Clin Cancer Res; 22(19); 4776-85. ©2016 AACRSee related commentary by Lowenstein and Castro, p. 4760. ©2016 American Association for Cancer Research.

  2. Dosimetric characteristics of a newly designed grid block for megavoltage photon radiation and its therapeutic advantage using a linear quadratic model

    SciTech Connect

    Meigooni, Ali S.; Dou Kai; Meigooni, Navid J.; Gnaster, Michael; Awan, Shahid; Dini, Sharifeh; Johnson, Ellis L.

    2006-09-15

    Grid radiation therapy with megavoltage x-ray beam has been proven to be an effective technique for management of large, bulky malignant tumors. The clinical advantage of GRID therapy, combined with conventional radiation therapy, has been demonstrated using a prototype GRID block [Mohiuddin, Curtis, Grizos, and Komarnicky, Cancer 66, 114-118 (1990)]. Recently, a new GRID block design with improved dosimetric properties has become commercially available from Radiation Product Design, Inc. (Albertive, MN). This GRID collimator consists of an array of focused apertures in a cerrobend block arranged in a hexagonal pattern having a circular cross-section with a diameter and center-to-center spacing of 14.3 and 21.1 mm, respectively, in the plane of isocenter. In this project, dosimetric characteristics of the newly redesigned GRID block have been investigated for a Varian 21EX linear accelerator (Varian Associates, Palo Alto, CA). These determinations were performed using radiographic films, thermoluminescent dosimeters in Solid Water trade mark sign phantom materials, and an ionization chamber in water. The output factor, percentage depth dose, beam profiles, and isodose distributions of the GRID radiation as a function of field size and beam energy have been measured using both 6 and 18 MV x-ray beams. In addition, the therapeutic advantage obtained from this treatment modality with the new GRID block design for a high, single fraction of dose has been calculated using the linear quadratic model with {alpha}/{beta} ratios for typical tumor and normal cells. These biological characteristics of the new GRID block design will also be presented.

  3. Field assessment of reproduction-related traits of chironomids using a newly developed emergence platform (E-Board).

    PubMed

    Ferrari, Benoît J D; Faburé, Juliette

    2017-03-01

    Further progress in the development of reliable biomonitoring strategies requires to better link effects in aquatic ecological systems to ambient concentrations of chemical contaminants. Among existing tools, in situ bioassays using caging method represent an interesting way to achieve this challenge. However, elaboration of adapted exposure chambers and suitable operating procedures is still required, particularly to assess ecological relevant traits such as those related to the reproduction. In such context, we developed a new device (Emergence board - E-Board) which allows assessing in rivers the development of the Chironomus riparius species from the early fourth instar larvae to the adult stage. The system acts as a suspended matter trap floating in the subsurface of the water equipped of an emergence trap for catching adults. The system was tested in actual field conditions. Its easy handling allowed obtaining data which demonstrated its applicability for assessing the development of the chironomids. Moreover, by adapting energy-based models (DEB) specifically developed in the laboratory for the species C. riparius, we were able to predict the growth pattern and the emergence of chironomids in real environmental conditions. The E-Board represents thus a promising new in situ tool in perspective of evaluation of the quality of the ecosystems.

  4. Application of Emerging Pharmaceutical Technologies for Therapeutic Challenges of Space Exploration Missions

    NASA Technical Reports Server (NTRS)

    Putcha, Lakshmi

    2011-01-01

    An important requirement of therapeutics for extended duration exploration missions beyond low Earth orbit will be the development of pharmaceutical technologies suitable for sustained and preventive health care in remote and adverse environmental conditions. Availability of sustained, stable and targeted delivery pharmaceuticals for preventive health of major organ systems including gastrointestinal, hepato-renal, musculo-skeletal and immune function are essential to offset adverse effects of space environment beyond low Earth orbit. Specifically, medical needs may include multi-drug combinations for hormone replacement, radiation protection, immune enhancement and organ function restoration. Additionally, extended stability of pharmaceuticals dispensed in space must be also considered in future drug development. Emerging technologies that can deliver stable and multi-therapy pharmaceutical preparations and delivery systems include nanotechnology based drug delivery platforms, targeted-delivery systems in non-oral and non-parenteral formulation matrices. Synthetic nanomaterials designed with molecular precision offer defined structures, electronics, and chemistries to be efficient drug carriers with clear advantages over conventional materials of drug delivery matricies. Nano-carrier materials like the bottle brush polymers may be suitable for systemic delivery of drug cocktails while Superparamagnetic Iron Oxide Nanoparticles or (SPIONS) have great potential to serve as carriers for targeted drug delivery to a specific site. These and other emerging concepts of drug delivery and extended shelf-life technologies will be reviewed in light of their application to address health-care challenges of exploration missions. Innovations in alternate treatments for sustained immune enhancement and infection control will be also discussed.

  5. Age-related macular degeneration--emerging pathogenetic and therapeutic concepts.

    PubMed

    Gehrs, Karen M; Anderson, Don H; Johnson, Lincoln V; Hageman, Gregory S

    2006-01-01

    Today, the average life expectancy in developed nations is over 80 years and climbing. And yet, the quality of life during those additional years is often significantly diminished by the effects of age-related, degenerative diseases, including age-related macular degeneration (AMD), the leading cause of blindness in the elderly worldwide. AMD is characterized by a progressive loss of central vision attributable to degenerative and neovascular changes in the macula, a highly specialized region of the ocular retina responsible for fine visual acuity. Estimates gathered from the most recent World Health Organization (WHO) global eye disease survey conservatively indicate that 14 million persons are blind or severely visually impaired because of AMD. The disease has a tremendous impact on the physical and mental health of the geriatric population and their families and is becoming a major public health burden. Currently, there is neither a cure nor a means to prevent AMD. Palliative treatment options for the less prevalent, late-stage 'wet' form of the disease include anti-neovascular agents, photodynamic therapy and thermal laser. There are no current therapies for the more common 'dry' AMD, except for the use of antioxidants that delay progression in 20%-25% of eyes. New discoveries, however, are beginning to provide a much clearer picture of the relevant cellular events, genetic factors, and biochemical processes associated with early AMD. Recently, compelling evidence has emerged that the innate immune system and, more specifically, uncontrolled regulation of the complement alternative pathway plays a central role in the pathobiology of AMD. The complement Factor H gene--which encodes the major inhibitor of the complement alternative pathway--is the first gene identified in multiple independent studies that confers a significant genetic risk for the development of AMD. The emergence of this new paradigm of AMD pathogenesis should hasten the development of novel

  6. Age-related macular degeneration—emerging pathogenetic and therapeutic concepts

    PubMed Central

    GEHRS, KAREN M.; ANDERSON, DON H.; JOHNSON, LINCOLN V.; HAGEMAN, GREGORY S.

    2014-01-01

    Today, the average life expectancy in developed nations is over 80 years and climbing. And yet, the quality of life during those additional years is often significantly diminished by the effects of age-related, degenerative diseases, including age-related macular degeneration (AMD), the leading cause of blindness in the elderly worldwide. AMD is characterized by a progressive loss of central vision attributable to degenerative and neovascular changes in the macula, a highly specialized region of the ocular retina responsible for fine visual acuity. Estimates gathered from the most recent World Health Organization (WHO) global eye disease survey conservatively indicate that 14 million persons are blind or severely visually impaired because of AMD. The disease has a tremendous impact on the physical and mental health of the geriatric population and their families and is becoming a major public health burden. Currently, there is neither a cure nor a means to prevent AMD. Palliative treatment options for the less prevalent, late-stage ‘wet’ form of the disease include anti-neovascular agents, photodynamic therapy and thermal laser. There are no current therapies for the more common ‘dry’ AMD, except for the use of antioxidants that delay progression in 20%–25% of eyes. New discoveries, however, are beginning to provide a much clearer picture of the relevant cellular events, genetic factors, and biochemical processes associated with early AMD. Recently, compelling evidence has emerged that the innate immune system and, more specifically, uncontrolled regulation of the complement alternative pathway plays a central role in the pathobiology of AMD. The complement Factor H gene—which encodes the major inhibitor of the complement alternative pathway—is the first gene identified in multiple independent studies that confers a significant genetic risk for the development of AMD. The emergence of this new paradigm of AMD pathogenesis should hasten the development

  7. Genomic and antigenic characterization of the newly emerging Chinese duck egg-drop syndrome flavivirus: genomic comparison with Tembusu and Sitiawan viruses.

    PubMed

    Liu, Peipei; Lu, Hao; Li, Shuang; Moureau, Gregory; Deng, Yong-Qiang; Wang, Yongyue; Zhang, Lijiao; Jiang, Tao; de Lamballerie, Xavier; Qin, Cheng-Feng; Gould, Ernest A; Su, Jingliang; Gao, George F

    2012-10-01

    Duck egg-drop syndrome virus (DEDSV) is a newly emerging pathogenic flavivirus causing avian diseases in China. The infection occurs in laying ducks characterized by a severe drop in egg production with a fatality rate of 5-15 %. The virus was found to be most closely related to Tembusu virus (TMUV), an isolate from mosquitoes in South-east Asia. Here, we have sequenced and characterized the full-length genomes of seven DEDSV strains, including the 5'- and 3'-non-coding regions (NCRs). We also report for the first time the ORF sequences of TMUV and Sitiawan virus (STWV), another closely related flavivirus isolated from diseased chickens. We analysed the phylogenetic and antigenic relationships of DEDSV in relation to the Asian viruses TMUV and STWV, and other representative flaviviruses. Our results confirm the close relationship between DEDSV and TMUV/STWV and we discuss their probable evolutionary origins. We have also characterized the cleavage sites, potential glycosylation sites and unique motifs/modules of these viruses. Additionally, conserved sequences in both 5'- and 3'-NCRs were identified and the predicted secondary structures of the terminal sequences were studied. Antigenic cross-reactivity comparisons of DEDSV with related pathogenic flaviviruses identified a surprisingly close relationship with dengue virus (DENV) and raised the question of whether or not DEDSV may have a potential infectious threat to man. Importantly, DEDSV can be efficiently recognized by a broadly cross-reactive flavivirus mAb, 2A10G6, derived against DENV. The significance of these studies is discussed in the context of the emergence, evolution, epidemiology, antigenicity and pathogenicity of the newly emergent DEDSV.

  8. Preventing the next 'SARS' - European healthcare workers' attitudes towards monitoring their health for the surveillance of newly emerging infections: qualitative study

    PubMed Central

    2011-01-01

    Background Hospitals are often the epicentres of newly circulating infections. Healthcare workers (HCWs) are at high risk of acquiring infectious diseases and may be among the first to contract emerging infections. This study aims to explore European HCWs' perceptions and attitudes towards monitoring their absence and symptom reports for surveillance of newly circulating infections. Methods A qualitative study with thematic analysis was conducted using focus group methodology. Forty-nine hospital-based HCWs from 12 hospitals were recruited to six focus groups; two each in England and Hungary and one each in Germany and Greece. Results HCWs perceived risk factors for occupationally acquired infectious diseases to be 1.) exposure to patients with undiagnosed infections 2.) break-down in infection control procedures 3.) immuno-naïvety and 4.) symptomatic colleagues. They were concerned that a lack of monitoring and guidelines for infectious HCWs posed a risk to staff and patients and felt employers failed to take a positive interest in their health. Staffing demands and loss of income were noted as pressures to attend work when unwell. In the UK, Hungary and Greece participants felt monitoring staff absence and the routine disclosure of symptoms could be appropriate provided the effectiveness and efficiency of such a system were demonstrable. In Germany, legislation, privacy and confidentiality were identified as barriers. All HCWs highlighted the need for knowledge and structural improvements for timelier recognition of emerging infections. These included increased suspicion and awareness among staff and standardised, homogenous absence reporting systems. Conclusions Monitoring absence and infectious disease symptom reports among HCWs may be a feasible means of surveillance for emerging infections in some settings. A pre-requisite will be tackling the drivers for symptomatic HCWs to attend work. PMID:21740552

  9. Adenosine, Ketogenic Diet and Epilepsy: The Emerging Therapeutic Relationship Between Metabolism and Brain Activity

    PubMed Central

    Masino, S.A; Kawamura, M; Wasser, C.D.; Pomeroy, L.T; Ruskin, D.N

    2009-01-01

    For many years the neuromodulator adenosine has been recognized as an endogenous anticonvulsant molecule and termed a “retaliatory metabolite.” As the core molecule of ATP, adenosine forms a unique link between cell energy and neuronal excitability. In parallel, a ketogenic (high-fat, low-carbohydrate) diet is a metabolic therapy that influences neuronal activity significantly, and ketogenic diets have been used successfully to treat medically-refractory epilepsy, particularly in children, for decades. To date the key neural mechanisms underlying the success of dietary therapy are unclear, hindering development of analogous pharmacological solutions. Similarly, adenosine receptor–based therapies for epilepsy and myriad other disorders remain elusive. In this review we explore the physiological regulation of adenosine as an anticonvulsant strategy and suggest a critical role for adenosine in the success of ketogenic diet therapy for epilepsy. While the current focus is on the regulation of adenosine, ketogenic metabolism and epilepsy, the therapeutic implications extend to acute and chronic neurological disorders as diverse as brain injury, inflammatory and neuropathic pain, autism and hyperdopaminergic disorders. Emerging evidence for broad clinical relevance of the metabolic regulation of adenosine will be discussed. PMID:20190967

  10. Cardiovascular and Hemostatic Disorders: SOCE in Cardiovascular Cells: Emerging Targets for Therapeutic Intervention.

    PubMed

    Groschner, Klaus; Shrestha, Niroj; Fameli, Nicola

    2017-01-01

    The discovery of the store-operated Ca(2+) entry (SOCE) phenomenon is tightly associated with its recognition as a pathway of high (patho)physiological significance in the cardiovascular system. Early on, SOCE has been investigated primarily in non-excitable cell types, and the vascular endothelium received particular attention, while a role of SOCE in excitable cells, specifically cardiac myocytes and pacemakers, was initially ignored and remains largely enigmatic even to date. With the recent gain in knowledge on the molecular components of SOCE as well as their cellular organization within nanodomains, potential tissue/cell type-dependent heterogeneity of the SOCE machinery along with high specificity of linkage to downstream signaling pathways emerged for cardiovascular cells. The basis of precise decoding of cellular Ca(2+) signals was recently uncovered to involve correct spatiotemporal organization of signaling components, and even minor disturbances in these assemblies trigger cardiovascular pathologies. With this chapter, we wish to provide an overview on current concepts of cellular organization of SOCE signaling complexes in cardiovascular cells with particular focus on the spatiotemporal aspects of coupling to downstream signaling and the potential disturbance of these mechanisms by pathogenic factors. The significance of these mechanistic concepts for the development of novel therapeutic strategies will be discussed.

  11. Role of Nitrosative Stress and Peroxynitrite in the Pathogenesis of Diabetic Complications. Emerging New Therapeutical Strategies

    PubMed Central

    Pacher, Pál; Obrosova, Irina G.; Mabley, Jon G.; Szabó, Csaba

    2008-01-01

    Macro- and microvascular disease are the most common causes of morbidity and mortality in patients with diabetes mellitus. Diabetic cardiovascular dysfunction represents a problem of great clinical importance underlying the development of various severe complications including retinopathy, nephropathy, neuropathy and increase the risk of stroke, hypertension and myocardial infarction. Hyperglycemic episodes, which complicate even well-controlled cases of diabetes, are closely associated with increased oxidative and nitrosative stress, which can trigger the development of diabetic complications. Hyperglycemia stimulates the production of advanced glycosylated end products, activates protein kinase C, and enhances the polyol pathway leading to increased superoxide anion formation. Superoxide anion interacts with nitric oxide, forming the potent cytotoxin peroxynitrite, which attacks various biomolecules in the vascular endothelium, vascular smooth muscle and myocardium, leading to cardiovascular dysfunction. The pathogenetic role of nitrosative stress and peroxynitrite, and downstream mechanisms including poly(ADP-ribose) polymerase (PARP) activation, is not limited to the diabetes-induced cardiovascular dysfunction, but also contributes to the development and progression of diabetic nephropathy, retinopathy and neuropathy. Accordingly, neutralization of peroxynitrite or pharmacological inhibition of PARP is a promising new approach in the therapy and prevention of diabetic complications. This review focuses on the role of nitrosative stress and downstream mechanisms including activation of PARP in diabetic complications and on novel emerging therapeutical strategies offered by neutralization of peroxynitrite and inhibition of PARP. PMID:15723618

  12. The ubiquitin-proteasome pathway an emerging anticancer strategy for therapeutics: a patent analysis.

    PubMed

    Jain, Chakresh K; Arora, Shivam; Khanna, Aparna; Gupta, Money; Wadhwa, Gulshan; Sharma, Sanjeev K

    2015-01-01

    The degradation of intracellular proteins is targeted by ubiquitin via non-lysosomal proteolytic pathway in the cell system. These ubiquitin molecules have been found to be conserved from yeast to humans. Ubiquitin proteasome machinery utilises ATP and other mechanisms for degrading proteins of cytosol as well as nucleus. This process of ubiquitination is regulated by activating the E3 enzyme ligase, involved in phosphorylation. In humans, proteins which regulate the cell cycle are controlled by ubiquitin; therefore the ubiquitin-proteasome pathway can be targeted for novel anti-cancer strategies. Dysregulation of the components of the ubiquitin system has been linked to many diseases like cancer and inflammation. The primary triggering mechanism (apoptosis) of these diseases can also be induced when TNF-related apoptosis-inducing ligand (TRAIL) binds to its specific receptor DR4 and DR5. In this review, the emerging prospects and importance of ubiquitin proteasome pathway as an evolving anticancer strategy have been discussed. Current challenges in the field of drug discovery have also been discussed on the basis of recent patents on cancer diagnosis and therapeutics.

  13. Emerging aspects of nanotoxicology in health and disease: From agriculture and food sector to cancer therapeutics.

    PubMed

    Piperigkou, Zoi; Karamanou, Konstantina; Engin, Ayse Basak; Gialeli, Chrysostomi; Docea, Anca Oana; Vynios, Demitrios H; Pavão, Mauro S G; Golokhvast, Kirill S; Shtilman, Mikhail I; Argiris, Athanassios; Shishatskaya, Ekaterina; Tsatsakis, Aristidis M

    2016-05-01

    Nanotechnology is an evolving scientific field that has allowed the manufacturing of materials with novel physicochemical and biological properties, offering a wide spectrum of potential applications. Properties of nanoparticles that contribute to their usefulness include their markedly increased surface area in relation to mass, surface reactivity and insolubility, ability to agglomerate or change size in different media and enhanced endurance over conventional-scale substance. Here, we review nanoparticle classification and their emerging applications in several fields; from active food packaging to drug delivery and cancer research. Nanotechnology has exciting therapeutic applications, including novel drug delivery for the treatment of cancer. Additionally, we discuss that exposure to nanostructures incorporated to polymer composites, may result in potential human health risks. Therefore, the knowledge of processes, including absorption, distribution, metabolism and excretion, as well as careful toxicological assessment is critical in order to determine the effects of nanomaterials in humans and other biological systems. Expanding the knowledge of nanoparticle toxicity will facilitate designing of safer nanocomposites and their application in a beneficial manner. Copyright © 2016 Elsevier Ltd. All rights reserved.

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

    PubMed

    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. [The pulmonary-renal syndrome: a diagnostic and therapeutic emergency for the internist and the intensivist].

    PubMed

    Hié, M; Costedoat-Chalumeau, N; Saadoun, D; Azoulay, E

    2013-11-01

    The pulmonary-renal syndrome is a rare and life-threatening condition. It is defined as the association of a diffuse alveolar hemorrhage and a rapidly progressive glomerulonephritis. The characteristic histological lesion common to all underlying diseases is a necrotizing and crescentic glomerulonephritis. The pulmonary-renal syndrome is a diagnostic and therapeutic emergency: any delay in its management will lead to death or serious functional damage as pulmonary and renal impairment. ANCA-associated vasculitis and Goodpasture's disease are the main disorders associated to pulmonary-renal syndrome. More rarely systemic lupus, cryoglobulinaemia, Henoch-Schonlein purpura or subacute endocarditis may induce a pulmonary-renal syndrome. Differential diagnosis can sometimes be difficult, highlighting some ambiguity in the definition of the syndrome. Initial treatment usually associates systemic corticosteroid, cyclophosphamide and plasma exchange. The role of biotherapy as first line therapy remains to be determined. Copyright © 2013 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.

  16. Current and Emerging Uses of Statins in Clinical Therapeutics: A Review

    PubMed Central

    Davies, Jonathan T.; Delfino, Spencer F.; Feinberg, Chad E.; Johnson, Meghan F.; Nappi, Veronica L.; Olinger, Joshua T.; Schwab, Anthony P.; Swanson, Hollie I.

    2016-01-01

    Statins, a class of cholesterol-lowering medications that inhibit 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, are commonly administered to treat atherosclerotic cardiovascular disease. Statin use may expand considerably given its potential for treating an array of cholesterol-independent diseases. However, the lack of conclusive evidence supporting these emerging therapeutic uses of statins brings to the fore a number of unanswered questions including uncertainties regarding patient-to-patient variability in response to statins, the most appropriate statin to be used for the desired effect, and the efficacy of statins in treating cholesterol-independent diseases. In this review, the adverse effects, costs, and drug–drug and drug–food interactions associated with statin use are presented. Furthermore, we discuss the pleiotropic effects associated with statins with regard to the onset and progression of autoimmune and inflammatory diseases, cancer, neurodegenerative disorders, strokes, bacterial infections, and human immunodeficiency virus. Understanding these issues will improve the prognosis of patients who are administered statins and potentially expand our ability to treat a wide variety of diseases. PMID:27867302

  17. Connexin 43 is an emerging therapeutic target in ischemia/reperfusion injury, cardioprotection and neuroprotection

    PubMed Central

    Schulz, Rainer; Görge, Philipp Maximilian; Görbe, Anikó; Ferdinandy, Péter; Lampe, Paul D.; Leybaert, Luc

    2015-01-01

    Connexins are widely distributed proteins in the body that are crucially important for heart and brain function. Six connexin subunits form a connexon or hemichannel in the plasma membrane. Interactions between two hemichannels in a head-to-head arrangement result in the formation of a gap junction channel. Gap junctions are necessary to coordinate cell function by passing electrical current flow between heart and nerve cells or by allowing exchange of chemical signals and energy substrates. Apart from its localisation at the sarcolemma of cardiomyocytes and brain cells, connexins are also found in mitochondria where they are involved in the regulation of mitochondrial matrix ion fluxes and respiration. Connexin expression is affected by age and gender as well as several pathophysiological alterations such as hypertension, hypertrophy, diabetes, hypercholesterolemia, ischemia, post-myocardial infarction remodelling or heart failure, and post-translationally connexins are modified by phosphorylation/de-phosphorylation and nitros(yl)ation which can modulate channel activity. Using knockout/knockin technology as well as pharmacological approaches, one of the connexins, namely connexin 43, has been identified to be important for cardiac and brain ischemia/reperfusion injury as well as protection from it. Therefore, the current review will focus on the importance of connexin 43 for irreversible injury of heart and brain tissue following ischemia/reperfusion and will highlight the importance of connexin 43 as an emerging therapeutic target in cardio- and neuroprotection. PMID:26073311

  18. Recent and emerging therapeutic medications in type 2 diabetes mellitus: incretin-based, Pramlintide, Colesevelam, SGLT2 Inhibitors, Tagatose, Succinobucol.

    PubMed

    Lo, Margaret C; Lansang, M Cecilia

    2013-01-01

    Nearly 285 million people worldwide, with 10% being Americans, suffer from diabetes mellitus and its associated comorbidities. This is projected to increase by 6.5% per year, with 439 million inflicted by year 2030. Both morbidity and mortality from diabetes stem from the consequences of microvascular and macrovascular complications. Of the 285 million with diabetes, over a quarter of a million die per year from related complications, making diabetes the fifth leading cause of death in high-income countries. These startling statistics illustrate the therapeutic failure of current diabetes drugs to retard the progression of diabetes. These statistics further illustrate the continual need for further research and development of alternative drugs with novel mechanisms to slow disease progression and disease complications. The treatment algorithm updated in 2008 by American Diabetes Association and the European Association for the Study of Diabetes currently recommends the traditional medications of metformin, either as monotherapy or in combination with sulfonylurea or insulin, as the preferred choice in the tier 1 option. The algorithm only suggests addition of alternative medications such as pioglitazone and incretin-based drugs as second-line agents in the tier 2 "less well-validated" option. However, these traditional medications have not proven to delay the progressive course of diabetes as evidence of increasing need over time for multiple drug therapy to maintain sufficient glycemic control. Because current diabetes medications have limited efficacy and untoward side effects, the development of diabetes mellitus drugs with newer mechanisms of action continues. This article will review the clinical data on the newly available incretin-based drugs on the market, including glucagon-like peptide agonists and of dipeptidyl peptidase type-4 inhibitors. It will also discuss 2 unique medications: pramlintide, which is indicated for both type and type-2 diabetes, and

  19. Maintenance of remission in Crohn's disease: current and emerging therapeutic options.

    PubMed

    Brookes, Matthew J; Green, Jonathon R B

    2004-01-01

    cases to treating active disease; however, these data are discussed in this article in order to provide an overview of future potential therapies. The aim of this review is to provide clinicians with an insight into current and emerging therapeutic agents for the maintenance of remission of Crohn's disease.

  20. Summary Report for ASC L2 Milestone #4782: Assess Newly Emerging Programming and Memory Models for Advanced Architectures on Integrated Codes

    SciTech Connect

    Neely, J. R.; Hornung, R.; Black, A.; Robinson, P.

    2014-09-29

    This document serves as a detailed companion to the powerpoint slides presented as part of the ASC L2 milestone review for Integrated Codes milestone #4782 titled “Assess Newly Emerging Programming and Memory Models for Advanced Architectures on Integrated Codes”, due on 9/30/2014, and presented for formal program review on 9/12/2014. The program review committee is represented by Mike Zika (A Program Project Lead for Kull), Brian Pudliner (B Program Project Lead for Ares), Scott Futral (DEG Group Lead in LC), and Mike Glass (Sierra Project Lead at Sandia). This document, along with the presentation materials, and a letter of completion signed by the review committee will act as proof of completion for this milestone.

  1. A comparison of the therapeutic and reactivating efficacy of newly developed oximes (K117, K127) and currently available oximes (obidoxime, trimedoxime, HI-6) in tabun-poisoned rats and mice.

    PubMed

    Kassa, Jiri; Karasova, Jana; Musilek, Kamil; Kuca, Kamil; Jung, Young-Sik

    2008-01-01

    The potency of newly developed bispyridinium compounds (K117, K127) to reactivate tabun-inhibited acetylcholinesterase and reduce tabun-induced lethal toxic effects was compared with currently available oximes (obidoxime, trimedoxime, oxime HI-6) by using in vivo methods. A study that determined the percentage of reactivation of tabun-inhibited blood and tissue acetylcholinesterase in poisoned rats showed that the reactivating efficacy of newly developed oxime K127 is comparable with obidoxime and trimedoxime in blood but lower than the reactivating potency of trimedoxime and obidoxime in the diaphragm and brain. The potency of another newly developed K117 to reactivate tabun-inhibited acetylcholinesterase is comparable with obidoxime or trimedoxime in the diaphragm, but it is significantly lower than the reactivating potency of trimedoxime and obidoxime in the blood and brain. The oxime, K127, was also found to be relatively effective in reducing lethal toxic effects in tabun-poisoned mice. Its therapeutic efficacy is consistent with the therapeutic potency of obidoxime. On the other hand, the potency of the oxime, K117, to reduce acute toxicity of tabun is significantly lower compared to trimedoxime and obidoxime. The therapeutic efficacy of K117 and K127 corresponds to their potency to reactivate tabun-inhibited acetylcholinesterase, especially in the diaphragm and brain. Contrary to obidoxime and trimedoxime, the oxime, HI-6, is not an effective oxime in the reactivation of tabun-inhibited acetycholinesterase and in reducing the lethal effects of tabun. The reactivating and therapeutic potency of both newly developed oximes does not prevail over the effectiveness of currently available obidoxime and trimedoxime and, therefore, they are not suitable for their replacement of commonly used oximes for the treatment of acute tabun poisoning.

  2. Genesis and Spread of Newly Emerged Highly Pathogenic H7N9 Avian Viruses in Mainland China.

    PubMed

    Yang, Lei; Zhu, Wenfei; Li, Xiyan; Chen, Minmei; Wu, Jie; Yu, Pengbo; Qi, Shunxiang; Huang, Yiwei; Shi, Weixian; Dong, Jie; Zhao, Xiang; Huang, Weijuan; Li, Zi; Zeng, Xiaoxu; Bo, Hong; Chen, Tao; Chen, Wenbing; Liu, Jia; Zhang, Ye; Liang, Zhenli; Shi, Wei; Shu, Yuelong; Wang, Dayan

    2017-09-27

    The novel low pathogenic H7N9 avian influenza A viruses (LPAI H7N9) have caused a threat to public health for their high mortality and morbidity since their emergence in 2013. Recently, highly pathogenic variants of these H7N9 viruses (HPAI H7N9) have emerged and caused human infections and poultry outbreaks in Mainland China. However, it is still unclear how the HPAI H7N9 virus was generated and how it evolved and spread in China. Here, we show that the ancestor virus of the HPAI H7N9 viruses originated in the Yangtze Delta Region and spread southward to the Pearl Delta Region, possibly through live poultry trades. After introduction into the Pearl Delta Region, the origin LPAI H7N9 virus acquired four amino acid insertions in the HA protein cleavage site and mutated into the HPAI H7N9 virus in late May 2016. Afterward, the HPAI H7N9 viruses further reassorted with LPAI H7N9 or H9N2 viruses locally and generated multiple different genotypes. As of 14 July 2017, the HAPI H7N9 viruses had spread from Guangdong province to at least 12 provinces. The rapid geographical expansion and genetic evolution of the HPAI H7N9 viruses pose a great challenge, not only to public health, but also to poultry production. Effective control measures, including enhanced surveillance, are therefore urgently needed.IMPORTANCE The LPAI H7N9 virus has caused five outbreak waves in humans and was recently reported to have mutated into highly pathogenic variants. It is unknown how the HPAI H7N9 virus originated, evolved, and disseminated in China. In this study, we comprehensively analyzed the sequences of HPAI H7N9 viruses from 28 human and 21 environmental samples covering eight provinces in China that were taken from November 2016 to June 2017. The results show that the ancestor virus of the HPAI H7N9 viruses originated in the Yangtze Delta Region. However, the insertion event of four amino acids in the HA protein cleavage site of a LPAI H7N9 virus occurred in late May 2016, in the Pearl

  3. Trading Capsule for Increased Cytotoxin Production: Contribution to Virulence of a Newly Emerged Clade of emm89 Streptococcus pyogenes

    PubMed Central

    Zhu, Luchang; Olsen, Randall J.; Nasser, Waleed; de la Riva Morales, Ivan

    2015-01-01

    ABSTRACT Strains of emm89 Streptococcus pyogenes have become one of the major causes of invasive infections worldwide in the last 10 years. We recently sequenced the genome of 1,125 emm89 strains and identified three major phylogenetic groups, designated clade 1, clade 2, and the epidemic clade 3. Epidemic clade 3 strains, which now cause the great majority of infections, have two distinct genetic features compared to clade 1 and clade 2 strains. First, all clade 3 organisms have a variant 3 nga promoter region pattern, which is associated with increased production of secreted cytolytic toxins SPN (S. pyogenes NADase) and SLO (streptolysin O). Second, all clade 3 strains lack the hasABC locus mediating hyaluronic acid capsule synthesis, whereas this locus is intact in clade 1 and clade 2 strains. We constructed isogenic mutant strains that produce different levels of SPN and SLO toxins and capsule (none, low, or high). Here we report that emm89 strains with elevated toxin production are significantly more virulent than low-toxin producers. Importantly, we also show that capsule production is dispensable for virulence in strains that already produce high levels of SPN and SLO. Our results provide new understanding about the molecular mechanisms contributing to the rapid emergence and molecular pathogenesis of epidemic clade 3 emm89 S. pyogenes. PMID:26443457

  4. Identification of Goose-Origin Parvovirus as a Cause of Newly Emerging Beak Atrophy and Dwarfism Syndrome in Ducklings

    PubMed Central

    Yu, Kexiang; Ma, Xiuli; Sheng, Zizhang; Qi, Lihong; Liu, Cunxia; Wang, Dan; Huang, Bing

    2016-01-01

    A recent epizootic outbreak, in China, of duck beak atrophy and dwarfism syndrome (BADS) was investigated using electron microscopic, genetic, and virological studies, which identified a parvovirus with a greater similarity to goose parvovirus (GPV) (97% protein homology) than to Muscovy duck parvovirus (MDPV) (90% protein homology). The new virus, provisionally designated GPV-QH15, was found to be antigenically more closely related to GPV than to MDPV in a virus neutralization assay. These findings were further supported by phylogenetic analysis showing that GPV-QH15 evolved from goose lineage parvoviruses, rather than from Muscovy duck- or other duck species-related parvoviruses. In all, two genetic lineages (GPV I and GPV II) were identified from the GPV samples analyzed, and GPV-QH15 was found to be closely clustered with two known goose-origin parvoviruses (GPVa2006 and GPV1995), together forming a distinctive GPV IIa sublineage. Finally, structural modeling revealed that GPV-QH15 and the closely related viruses GPVa2006 and GPV1995 possessed identical clusters of receptor-interacting amino acid residues in the VP2 protein, a major determinant of viral receptor binding and host specificity. Significantly, these three viruses differed from MDPVs and other GPVs at these positions. Taken together, these results suggest that GPV-QH15 represents a new variant of goose-origin parvovirus that currently circulates in ducklings and causes BADS, a syndrome reported previously in Europe. This new finding highlights the need for future surveillance of GPV-QH15 in poultry in order to gain a better understanding of both the evolution and the biology of this emerging parvovirus. PMID:27194692

  5. Identification of Goose-Origin Parvovirus as a Cause of Newly Emerging Beak Atrophy and Dwarfism Syndrome in Ducklings.

    PubMed

    Yu, Kexiang; Ma, Xiuli; Sheng, Zizhang; Qi, Lihong; Liu, Cunxia; Wang, Dan; Huang, Bing; Li, Feng; Song, Minxun

    2016-08-01

    A recent epizootic outbreak, in China, of duck beak atrophy and dwarfism syndrome (BADS) was investigated using electron microscopic, genetic, and virological studies, which identified a parvovirus with a greater similarity to goose parvovirus (GPV) (97% protein homology) than to Muscovy duck parvovirus (MDPV) (90% protein homology). The new virus, provisionally designated GPV-QH15, was found to be antigenically more closely related to GPV than to MDPV in a virus neutralization assay. These findings were further supported by phylogenetic analysis showing that GPV-QH15 evolved from goose lineage parvoviruses, rather than from Muscovy duck- or other duck species-related parvoviruses. In all, two genetic lineages (GPV I and GPV II) were identified from the GPV samples analyzed, and GPV-QH15 was found to be closely clustered with two known goose-origin parvoviruses (GPVa2006 and GPV1995), together forming a distinctive GPV IIa sublineage. Finally, structural modeling revealed that GPV-QH15 and the closely related viruses GPVa2006 and GPV1995 possessed identical clusters of receptor-interacting amino acid residues in the VP2 protein, a major determinant of viral receptor binding and host specificity. Significantly, these three viruses differed from MDPVs and other GPVs at these positions. Taken together, these results suggest that GPV-QH15 represents a new variant of goose-origin parvovirus that currently circulates in ducklings and causes BADS, a syndrome reported previously in Europe. This new finding highlights the need for future surveillance of GPV-QH15 in poultry in order to gain a better understanding of both the evolution and the biology of this emerging parvovirus. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  6. Cross-Border Sexual Transmission of the Newly Emerging HIV-1 Clade CRF51_01B

    PubMed Central

    Cheong, Hui Ting; Ng, Kim Tien; Ong, Lai Yee; Chook, Jack Bee; Chan, Kok Gan; Takebe, Yutaka; Kamarulzaman, Adeeba; Tee, Kok Keng

    2014-01-01

    A novel HIV-1 recombinant clade (CRF51_01B) was recently identified among men who have sex with men (MSM) in Singapore. As cases of sexually transmitted HIV-1 infection increase concurrently in two socioeconomically intimate countries such as Malaysia and Singapore, cross transmission of HIV-1 between said countries is highly probable. In order to investigate the timeline for the emergence of HIV-1 CRF51_01B in Singapore and its possible introduction into Malaysia, 595 HIV-positive subjects recruited in Kuala Lumpur from 2008 to 2012 were screened. Phylogenetic relationship of 485 amplified polymerase gene sequences was determined through neighbour-joining method. Next, near-full length sequences were amplified for genomic sequences inferred to be CRF51_01B and subjected to further analysis implemented through Bayesian Markov chain Monte Carlo (MCMC) sampling and maximum likelihood methods. Based on the near full length genomes, two isolates formed a phylogenetic cluster with CRF51_01B sequences of Singapore origin, sharing identical recombination structure. Spatial and temporal information from Bayesian MCMC coalescent and maximum likelihood analysis of the protease, gp120 and gp41 genes suggest that Singapore is probably the country of origin of CRF51_01B (as early as in the mid-1990s) and featured a Malaysian who acquired the infection through heterosexual contact as host for its ancestral lineages. CRF51_01B then spread rapidly among the MSM in Singapore and Malaysia. Although the importation of CRF51_01B from Singapore to Malaysia is supported by coalescence analysis, the narrow timeframe of the transmission event indicates a closely linked epidemic. Discrepancies in the estimated divergence times suggest that CRF51_01B may have arisen through multiple recombination events from more than one parental lineage. We report the cross transmission of a novel CRF51_01B lineage between countries that involved different sexual risk groups. Understanding the cross

  7. A Newly Emerging HIV-1 Recombinant Lineage (CRF58_01B) Disseminating among People Who Inject Drugs in Malaysia

    PubMed Central

    Chow, Wei Zhen; Takebe, Yutaka; Syafina, Nur Ezreen; Prakasa, Malarvelli Soorya; Chan, Kok Gan; Al-Darraji, Haider Abdulrazzaq Abed; Koh, Clayton; Kamarulzaman, Adeeba; Tee, Kok Keng

    2014-01-01

    The HIV epidemic is primarily characterised by the circulation of HIV-1 group M (main) comprising of 11 subtypes and sub-subtypes (A1, A2, B–D, F1, F2, G, H, J, and K) and to date 55 circulating recombinant forms (CRFs). In Southeast Asia, active inter-subtype recombination involving three main circulating genotypes—subtype B (including subtype B′, the Thai variant of subtype B), CRF01_AE, and CRF33_01B—have contributed to the emergence of novel unique recombinant forms. In the present study, we conducted the molecular epidemiological surveillance of HIV-1 gag-RT genes among 258 people who inject drugs (PWIDs) in Kuala Lumpur, Malaysia, between 2009 and 2011 whereby a novel CRF candidate was recently identified. The near full-length genome sequences obtained from six epidemiologically unlinked individuals showed identical mosaic structures consisting of subtype B′ and CRF01_AE, with six unique recombination breakpoints in the gag-RT, pol, and env regions. Among the high-risk population of PWIDs in Malaysia, which was predominantly infected by CRF33_01B (>70%), CRF58_01B circulated at a low but significant prevalence (2.3%, 6/258). Interestingly, the CRF58_01B shared two unique recombination breakpoints with other established CRFs in the region: CRF33_01B, CRF48_01B, and CRF53_01B in the gag gene, and CRF15_01B (from Thailand) in the env gene. Extended Bayesian Markov chain Monte Carlo sampling analysis showed that CRF58_01B and other recently discovered CRFs were most likely to have originated in Malaysia, and that the recent spread of recombinant lineages in the country had little influence from neighbouring countries. The isolation, genetic characterization, and evolutionary features of CRF58_01B among PWIDs in Malaysia signify the increasingly complex HIV-1 diversity in Southeast Asia that may hold an implication on disease treatment, control, and prevention. PMID:24465513

  8. A newly emerging HIV-1 recombinant lineage (CRF58_01B) disseminating among people who inject drugs in Malaysia.

    PubMed

    Chow, Wei Zhen; Takebe, Yutaka; Syafina, Nur Ezreen; Prakasa, Malarvelli Soorya; Chan, Kok Gan; Al-Darraji, Haider Abdulrazzaq Abed; Koh, Clayton; Kamarulzaman, Adeeba; Tee, Kok Keng

    2014-01-01

    The HIV epidemic is primarily characterised by the circulation of HIV-1 group M (main) comprising of 11 subtypes and sub-subtypes (A1, A2, B-D, F1, F2, G, H, J, and K) and to date 55 circulating recombinant forms (CRFs). In Southeast Asia, active inter-subtype recombination involving three main circulating genotypes--subtype B (including subtype B', the Thai variant of subtype B), CRF01_AE, and CRF33_01B--have contributed to the emergence of novel unique recombinant forms. In the present study, we conducted the molecular epidemiological surveillance of HIV-1 gag-RT genes among 258 people who inject drugs (PWIDs) in Kuala Lumpur, Malaysia, between 2009 and 2011 whereby a novel CRF candidate was recently identified. The near full-length genome sequences obtained from six epidemiologically unlinked individuals showed identical mosaic structures consisting of subtype B' and CRF01_AE, with six unique recombination breakpoints in the gag-RT, pol, and env regions. Among the high-risk population of PWIDs in Malaysia, which was predominantly infected by CRF33_01B (>70%), CRF58_01B circulated at a low but significant prevalence (2.3%, 6/258). Interestingly, the CRF58_01B shared two unique recombination breakpoints with other established CRFs in the region: CRF33_01B, CRF48_01B, and CRF53_01B in the gag gene, and CRF15_01B (from Thailand) in the env gene. Extended Bayesian Markov chain Monte Carlo sampling analysis showed that CRF58_01B and other recently discovered CRFs were most likely to have originated in Malaysia, and that the recent spread of recombinant lineages in the country had little influence from neighbouring countries. The isolation, genetic characterization, and evolutionary features of CRF58_01B among PWIDs in Malaysia signify the increasingly complex HIV-1 diversity in Southeast Asia that may hold an implication on disease treatment, control, and prevention.

  9. Cross-border sexual transmission of the newly emerging HIV-1 clade CRF51_01B.

    PubMed

    Cheong, Hui Ting; Ng, Kim Tien; Ong, Lai Yee; Chook, Jack Bee; Chan, Kok Gan; Takebe, Yutaka; Kamarulzaman, Adeeba; Tee, Kok Keng

    2014-01-01

    A novel HIV-1 recombinant clade (CRF51_01B) was recently identified among men who have sex with men (MSM) in Singapore. As cases of sexually transmitted HIV-1 infection increase concurrently in two socioeconomically intimate countries such as Malaysia and Singapore, cross transmission of HIV-1 between said countries is highly probable. In order to investigate the timeline for the emergence of HIV-1 CRF51_01B in Singapore and its possible introduction into Malaysia, 595 HIV-positive subjects recruited in Kuala Lumpur from 2008 to 2012 were screened. Phylogenetic relationship of 485 amplified polymerase gene sequences was determined through neighbour-joining method. Next, near-full length sequences were amplified for genomic sequences inferred to be CRF51_01B and subjected to further analysis implemented through Bayesian Markov chain Monte Carlo (MCMC) sampling and maximum likelihood methods. Based on the near full length genomes, two isolates formed a phylogenetic cluster with CRF51_01B sequences of Singapore origin, sharing identical recombination structure. Spatial and temporal information from Bayesian MCMC coalescent and maximum likelihood analysis of the protease, gp120 and gp41 genes suggest that Singapore is probably the country of origin of CRF51_01B (as early as in the mid-1990s) and featured a Malaysian who acquired the infection through heterosexual contact as host for its ancestral lineages. CRF51_01B then spread rapidly among the MSM in Singapore and Malaysia. Although the importation of CRF51_01B from Singapore to Malaysia is supported by coalescence analysis, the narrow timeframe of the transmission event indicates a closely linked epidemic. Discrepancies in the estimated divergence times suggest that CRF51_01B may have arisen through multiple recombination events from more than one parental lineage. We report the cross transmission of a novel CRF51_01B lineage between countries that involved different sexual risk groups. Understanding the cross

  10. Rethinking the Response to Emerging Microbes: Vaccines and Therapeutics in the Ebola Era--a Conference at Harvard Medical School.

    PubMed

    Knipe, David M; Whelan, Sean P

    2015-08-01

    Harvard Medical School convened a meeting of biomedical and clinical experts on 5 March 2015 on the topic of "Rethinking the Response to Emerging Microbes: Vaccines and Therapeutics in the Ebola Era," with the goals of discussing the lessons from the recent Ebola outbreak and using those lessons as a case study to aid preparations for future emerging infections. The speakers and audience discussed the special challenges in combatting an infectious agent that causes sporadic outbreaks in resource-poor countries. The meeting led to a call for improved basic medical care for all and continued support of basic discovery research to provide the foundation for preparedness for future outbreaks in addition to the targeted emergency response to outbreaks and targeted research programs against Ebola virus and other specific emerging pathogens.

  11. An evaluation of therapeutic and reactivating effects of newly developed oximes (K156, K203) and commonly used oximes (obidoxime, trimedoxime, HI-6) in tabun-poisoned rats and mice.

    PubMed

    Kassa, Jiri; Karasova, Jana; Musilek, Kamil; Kuca, Kamil

    2008-01-20

    The potency of newly developed monoxime bispyridinium compounds (K156, K203) in reactivating tabun-inhibited acetylcholinesterase and reducing tabun-induced lethal toxic effects was compared with commonly used oximes (obidoxime, trimedoxime, the oxime HI-6) using in vivo methods. Studies determining percentage of reactivation of tabun-inhibited blood and tissue acetylcholinesterase in poisoned rats showed that the reactivating efficacy of newly developed oxime K203 is comparable with obidoxime and trimedoxime in blood and higher than the reactivating potency of trimedoxime and obidoxime in diaphragm and brain, where the difference in reactivating efficacy of obidoxime, trimedoxime and K203 is significant. On the other hand, the potency of newly developed K156 to reactivate tabun-inhibited acetylcholinesterase is comparable with obidoxime or trimedoxime in diaphragm and brain. It is significantly lower than the reactivating efficacy of trimedoxime and obidoxime in blood. Moreover, both newly developed oximes were found to be relatively efficacious in the reduction of lethal toxic effects in tabun-poisoned mice. Especially, the oxime K203 is able to decrease the acute toxicity of tabun nearly two times. The therapeutic efficacy of K156 and K203 corresponds to their potency to reactivate tabun-inhibited acetylcholinesterase, especially in diaphragm and brain. In contrast to obidoxime and trimedoxime, the oxime HI-6 is not effective in reactivation of tabun-inhibited acetycholinesterase and in reducing tabun lethality. While the oxime K156 does not improve the reactivating and therapeutic effectiveness of currently available obidoxime and trimedoxime, the newly developed oxime K203 is markedly more effective in reactivation of tabun-inhibited acetylcholinesterase in rats, especially in brain, and in reducing lethal toxic effects of tabun in mice and, therefore, it is suitable for the replacement of commonly used oximes for the antidotal treatment of acute tabun

  12. [Knowledge about previous psychiatric care: is it a guaranty for therapeutic investment or a curse in psychiatric emergencies].

    PubMed

    De Clercq, M; Hoyois, P

    1990-04-01

    A sample of 755 psychiatric emergencies taken in charge in the emergency service of the St-Luc Hospital, Brussels, was divided into two groups: patients without psychiatric background (498) and patients having received previous psychiatric care (238). A background of psychiatric follow-up strongly influence the taking on and therapeutic decisions to be made by psychiatrists: its absence protects the patient and is seen as the guaranty of a good investment from the therapist while the existence of previous psychiatric treatment rather leads to hospital in lieu of crisis intervention, even when the crisis mechanisms are not significantly different in both samples.

  13. Emerging antibody-based therapeutic strategies for bladder cancer: A systematic review.

    PubMed

    Azevedo, Rita; Ferreira, José Alexandre; Peixoto, Andreia; Neves, Manuel; Sousa, Nuno; Lima, Aurea; Santos, Lucio Lara

    2015-09-28

    Bladder cancer is the most common malignancy of the urinary tract, presents the highest recurrence rate among solid tumors and is the second leading cause of death in genitourinary cancers. Despite recent advances in understanding of pathophysiology of the disease, the management of bladder cancer patients remains a clinically challenging problem. Particularly, bladder tumors invading the muscularis propria and disseminated disease are often not responsive to currently available therapeutic approaches, which include surgery and conventional chemotherapy. Antibody-based therapeutic strategies have become an established treatment option for over a decade in several types of cancer. However, bladder cancer has remained mostly an "orphan disease" regarding the introduction of these novel therapeutics, which has been translated in few improvements in patients overall survival. In order to shift this paradigm, several clinical studies involving antibody-based therapeutic strategies targeting the most prominent bladder cancer-related biomolecular pathways and immunological mediators are ongoing. This systematic review explores antibody-based therapeutics for bladder cancer undergoing clinical trial and discusses the future perspectives in this field, envisaging the development of more effective guided therapeutics. Copyright © 2015 Elsevier B.V. All rights reserved.

  14. The use of therapeutic plasmapheresis in the treatment of poisoned and snake bite victims: an academic emergency department's experiences.

    PubMed

    Yildirim, Cuma; Bayraktaroğlu, Ziya; Gunay, Nurullah; Bozkurt, Selim; Köse, Ataman; Yilmaz, Mehmet

    2006-12-01

    The objective of this study is to describe the clinical status, procedural interventions, and outcomes of critically ill patients with poisoning and snake bite injuries presenting to a tertiary-care emergency department for treatment with therapeutic plasmapheresis. Records of 20 patients who presented to our academic emergency department over a 2-year period and who underwent plasmapheresis for poisoning or snake bite were retrospectively reviewed. Plasmapheresis was performed using centrifugation technology via an intravenous antecubital venous or subclavian vein catheter access. Human albumin or fresh frozen plasma were used as replacement fluids. Data extracted from the patient record included demographic data, clinical status, and outcome measures. Sixteen patients underwent plasmapheresis because of toxicity from snake bite. Three patients were treated for drug poisoning (phenytoin, theophylline, bipyridene HCl) and one patient for mushroom poisoning. Haematologic parameters such as platelet count, PT, and INR resolved rapidly in victims of snake bite injuries after treatment with plasmapheresis. Loss of limbs did not occur in these cases. Seven patients required admission to the intensive care unit. One patient with mushroom poisoning died. Mean length of hospital stay was 14.3 days (range 3-28 days) for all cases. Plasmapheresis was a clinically effective and safe approach in the treatment of snake bite envenomation and other drug poisoning victims especially in the management of hematologic problems and in limb preservation/salvage strategies. In addition to established conventional therapies, emergency physicians should consider plasmapheresis among the therapeutic options in treatment strategies for selected toxicologic emergencies.

  15. Randomized Controlled Trial of Parent Therapeutic Education on Antibiotics to Improve Parent Satisfaction and Attitudes in a Pediatric Emergency Department

    PubMed Central

    Prot-Labarthe, Sonia; Boizeau, Priscilla; Skurnik, David; Morin, Laurence; Mercier, Jean-Christophe; Alberti, Corinne; Bourdon, Olivier

    2013-01-01

    Objective To evaluate therapeutic education delivered in a pediatric emergency department to improve parents’ satisfaction and attitudes about judicious antibiotic use. Methods In an emergency department of a tertiary pediatric hospital, children aged 1 month to 6 years and discharged with an oral antibiotic prescription for an acute respiratory or urinary tract infection were randomized to a patient therapeutic education on antibiotic use (intervention group) or fever control (control group) delivered to the parents (in the presence of the children) by a pharmacist trained in therapeutic education. Education consisted in a 30-minute face-to-face session with four components: educational diagnosis, educational contract, education, and evaluation. The main outcome measure was parent satisfaction about information on antibiotics received at the hospital, as assessed by a telephone interview on day 14. The secondary outcome was attitudes about antibiotic use evaluated on day 14 and at month 6. Results Of the 300 randomized children, 150 per arm, 259 were evaluated on day 14. Parent satisfaction with information on antibiotics was higher in the intervention group (125/129, 96.9%, versus 108/130, 83.0%; P=0.002, exact Fisher test). Intervention Group parents had higher proportions of correct answers on day 14 to questions on attitudes about judicious antibiotic use than did control-group parents (P=0.017, Mann-Whitney U test). Conclusion Therapeutic education delivered by a clinical pharmacist in the pediatric emergency department holds promise for improving the use of antibiotics prescribed to pediatric outpatients. Trial Registration ClinicalTrials.gov NCT00948779 http://clinicaltrials.gov/show/NCT00948779 PMID:24086581

  16. Molecular characterization and infectivity of a Tomato leaf curl New Delhi virus variant associated with newly emerging yellow mosaic disease of eggplant in India

    PubMed Central

    2011-01-01

    Background Begomoviruses have emerged as serious problem for vegetable and fiber crops in the recent past, frequently in tropical and subtropical region of the world. The association of begomovirus with eggplant yellow mosaic disease is hitherto unknown apart from one report from Thailand. A survey in Nagpur, Central India, in 2009-2010 showed severe incidence of eggplant yellow mosaic disease. Here, we have identified and characterized a begomovirus responsible for the newly emerging yellow mosaic disease of eggplant in India. Results The complete DNA-A and DNA-B genomic components of the causative virus were cloned and sequenced. Nucleotide sequence analysis of DNA-A showed that it shared highest 97.6% identity with Tomato leaf curl New Delhi virus-India[India:Udaipur:Okra:2007] and lowest 87.9% identity with Tomato leaf curl New Delhi virus-India[India:NewDelhi:Papaya:2005], while DNA-B showed highest 94.1% identity with ToLCNDV-IN[IN:UD:Ok:07] and lowest 76.2% identity with ToLCNDV-India[India:Lucknow]. Thus, it appears that this begomovirus is a variant of ubiquitous ToLCNDV and hence, we suggest the name ToLCNDV-India[India:Nagpur:Eggplant:2009] for this variant. The pathogenicity of ToLCNDV-IN[IN:Nag:Egg:09] isolate was confirmed by agroinfiltraion and dimeric clones of DNA-A and DNA-B induced characteristic yellow mosaic symptoms in eggplants and leaf curling in tomato plants. Conclusion This is the first report of a ToLCNDV variant moving to a new agriculturally important host, eggplant and causing yellow mosaic disease. This is also a first experimental demonstration of Koch's postulate for a begomovirus associated with eggplant yellow mosaic disease. PMID:21676270

  17. Plasmodium knowlesi from archival blood films: Further evidence that human infections are widely distributed and not newly emergent in Malaysian Borneo

    PubMed Central

    Lee, Kim-Sung; Cox-Singh, Janet; Brooke, George; Matusop, Asmad; Singh, Balbir

    2009-01-01

    Human infections with Plasmodium knowlesi have been misdiagnosed by microscopy as Plasmodium malariae due to their morphological similarities. Although microscopy-identified P. malariae cases have been reported in the state of Sarawak (Malaysian Borno) as early as 1952, recent epidemiological studies suggest the absence of indigenous P. malariae infections. The present study aimed to determine the past incidence and distribution of P. knowlesi infections in the state of Sarawak based on archival blood films from patients diagnosed by microscopy as having P. malariae infections. Nested PCR assays were used to identify Plasmodium species in DNA extracted from 47 thick blood films collected in 1996 from patients in seven different divisions throughout the state of Sarawak. Plasmodium knowlesi DNA was detected in 35 (97.2%) of 36 blood films that were positive for Plasmodium DNA, with patients originating from all seven divisions. Only one sample was positive for P. malariae DNA. This study provides further evidence of the widespread distribution of human infections with P. knowlesi in Sarawak and its past occurrence. Taken together with data from previous studies, our findings suggest that P. knowlesi malaria is not a newly emergent disease in humans. PMID:19358848

  18. First report of two rapid-onset fatal infections caused by a newly emerging hypervirulent K. Pneumonia ST86 strain of serotype K2 in China.

    PubMed

    Zhang, Yibo; Sun, Jingyong; Mi, Chenrong; Li, Wenhui; Zhao, Shengyuan; Wang, Qun; Shi, Dake; Liu, Luo; Ding, Bingyu; Chang, Yung-Fu; Guo, Hongxiong; Guo, XiaoKui; Li, Qingtian; Zhu, Yongzhang

    2015-01-01

    Here, we present the first report of one suspected dead case and two confirmed rapid-onset fatal infections caused by a newly emerging hypervirulent Klebsiella pneumoniae ST86 strain of serotype K2. The three cases occurred in a surgery ward during 2013 in Shanghai, China. A combination of multilocus sequence typing, pulsed-field gel electrophoresis, phenotypic and PCR tests for detecting virulence factors (VFs) was used to identify the isolates as K2 ST86 strains with common VFs, including Aerobactin and rmpA. Furthermore, the two K2 ST86 strains additionally harbored a distinct VF kfu (responsible for iron uptake system), which commonly existed in invasive K1 strains only. Thus, the unusual presence of both K1 and K2 VFs in the lethal ST86 strain might further enhance its hypervirulence and cause rapid onset of a life-threatening infection. Nevertheless, despite the administration of a combined antibiotic treatment, these three patients all died within 24 h of acute onset, thereby highlighting that the importance of early diagnosis to determine whether the ST86 strains harbor key K2 VF and unusual K1 kfu and whether patients should receive a timely and targeted antibiotic therapy to prevent ST86 induced fatal pneumonia. Finally, even though these patients are clinically improved, keeping on with oral antibiotic treatment for additional 2-3 weeks will be also vital for successfully preventing hvKP reinfection or relapse.

  19. Molecular and Morphological Characterization of Fasciola spp. Isolated from Different Host Species in a Newly Emerging Focus of Human Fascioliasis in Iran.

    PubMed

    Shafiei, Reza; Sarkari, Bahador; Sadjjadi, Seyed Mahmuod; Mowlavi, Gholam Reza; Moshfe, Abdolali

    2014-01-01

    The current study aimed to find out the morphometric and genotypic divergences of the flukes isolated from different hosts in a newly emerging focus of human fascioliasis in Iran. Adult Fasciola spp. were collected from 34 cattle, 13 sheep, and 11 goats from Kohgiluyeh and Boyer-Ahmad province, southwest of Iran. Genomic DNA was extracted from the flukes and PCR-RFLP was used to characterize the isolates. The ITS1, ITS2, and mitochondrial genes (mtDNA) of NDI and COI from individual liver flukes were amplified and the amplicons were sequenced. Genetic variation within and between the species was evaluated by comparing the sequences. Moreover, morphometric characteristics of flukes were measured through a computer image analysis system. Based on RFLP profile, from the total of 58 isolates, 41 isolates (from cattle, sheep, and goat) were identified as Fasciola hepatica, while 17 isolates from cattle were identified as Fasciola gigantica. Comparison of the ITS1 and ITS2 sequences showed six and seven single-base substitutions, resulting in segregation of the specimens into two different genotypes. The sequences of COI markers showed seven DNA polymorphic sites for F. hepatica and 35 DNA polymorphic sites for F. gigantica. Morphological diversity of the two species was observed in linear, ratios, and areas measurements. The findings have implications for studying the population genetics, epidemiology, and control of the disease.

  20. Genetic and antigenic characterization of a newly emerging porcine circovirus type 2b mutant first isolated in cases of vaccine failure in Korea.

    PubMed

    Seo, Hwi Won; Park, Changhoon; Kang, Ikjae; Choi, Kyuhyung; Jeong, Jiwoon; Park, Su-Jin; Chae, Chanhee

    2014-11-01

    This study describes the genetic and antigenic characterization of a newly emerging porcine circovirus type 2b (PCV2b) mutant first isolated in cases of vaccine failure in Korea. The full genome of the PCV2b isolates (SNUVR130689 and SNUVR140004) is 1,767 base pairs (bp) in length. The size of ORF1 is 945 bp, encoding a protein of 314 amino acids (aa), and the size of ORF2 is 705 bp, encoding a protein of 234 aa, which is 1 aa longer than that of the common PCV2 (233 aa). Korean PCV2b mutant strains had higher levels of nucleotide sequence identity to other PCV2b mutant strains (99.7-99.8 %) than to reference PCV2a (94.5-95.0 %) and PCV2b (95.5-96.1 %) strains. There was no difference in antigenic reactivity among PCV2a, PCV2b and PCV2b mutant strains to the polyclonal and monoclonal PCV2a antibodies. PCV2b mutant strains have distinct genetic characteristics but similar antigenic reactivity when compared to common PCV2a and 2b strains.

  1. Emerging therapeutic strategies for Epstein-Barr virus+ post-transplant lymphoproliferative disorder.

    PubMed

    Hatton, Olivia; Martinez, Olivia M; Esquivel, Carlos O

    2012-05-01

    De novo malignancies represent an increasing concern in the transplant population, particularly as long-term graft and patient survival improves. EBV-associated B-cell lymphoma in the setting of PTLD is the leading malignancy in children following solid organ transplantation. Therapeutic strategies can be categorized as pharmacologic, biologic, and cell-based but the variable efficacy of these approaches and the complexity of PTLD suggest that new treatment options are warranted. Here, we review current therapeutic strategies for treatment of PTLD. We also describe the life cycle of EBV, addressing the viral mechanisms that contribute to the genesis and persistence of EBV+ B-cell lymphomas. Specifically, we focus on the oncogenic signaling pathways activated by the EBV LMP1 and LMP2a to understand the underlying mechanisms and mediators of lymphomagenesis with the goal of identifying novel, rational therapeutic targets for the treatment of EBV-associated malignancies.

  2. The Molecular Revolution in Cutaneous Biology: Emerging Landscape in Genomic Dermatology: New Mechanistic Ideas, Gene Editing, and Therapeutic Breakthroughs.

    PubMed

    Titeux, Matthias; Izmiryan, Araksya; Hovnanian, Alain

    2017-05-01

    Stunning technological advances in genomics have led to spectacular breakthroughs in the understanding of the underlying defects, biological pathways and therapeutic targets of skin diseases leading to new therapeutic interventions. Next-generation sequencing has revolutionized the identification of disease-causing genes and has a profound impact in deciphering gene and protein signatures in rare and frequent skin diseases. Gene addition strategies have shown efficacy in junctional EB and in recessive dystrophic EB (RDEB). TALENs and Cripsr/Cas9 have emerged as highly efficient new tools to edit genomic sequences to creat new models and to correct or disrupt mutated genes to treat human diseases. Therapeutic approaches have not been limited to DNA modification and strategies at the mRNA, protein and cellular levels have also emerged, some of which have already proven clinical efficacy in RDEB. Improved understanding of the pathogenesis of skin disorders has led to the development of specific drugs or repurposing of existing medicines as in basal cell nevus syndrome, alopecia areata, melanoma and EB simplex. These discoveries pave the way for improved targeted personalized medicine for rare and frequent diseases. It is likely that a growing number of orphan skin diseases will benefit from combinatory new therapies in a near future. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  3. Far Forward Battlefield Telemedicine: Ultrasonic Guidance in Diagnosis and Emergency Therapeutics

    DTIC Science & Technology

    2006-08-01

    include (1) validation of portable ultrasound to diagnose cardiac tamponade , pneumothorax, intraabdominal hemorrhage, etc.; (2) extension of digital...1. Validation of small portable ultrasound units for the diagnosis of various medical and surgical emergencies, including cardiac tamponade

  4. Far Forward Battlefield Telemedicine: Ultrasonic Guidance in Diagnosis and Emergency Therapeutics

    DTIC Science & Technology

    2005-09-01

    connectivity. Specific aims include (1) validation of portable ultrasound to diagnose cardiac tamponade , pneumothorax, intraabdominal hemorrhage, etc...medical and surgical emergencies, including cardiac tamponade , pneumothorax, and intraabdominal hemorrhage. 2. Extension of our extensive experience in

  5. In the Footsteps of Nature: Nature Therapy as an Emerging Therapeutic-Educational Model.

    ERIC Educational Resources Information Center

    Berger, Ronen

    2003-01-01

    Basic principles of the nature therapy model are described, integrating the author's personal journey and examples from fieldwork and theory. Four aspects are nature as "sacred space"; nature as therapeutic setting; healing potential of nature's physical and aesthetic elements and connections to "universal truths"; and…

  6. The emerging functions of UCP2 in health, disease, and therapeutics.

    PubMed

    Mattiasson, Gustav; Sullivan, Patrick G

    2006-01-01

    The uncoupling proteins (UCPs) are attracting an increased interest as potential therapeutic targets in a number of important diseases. UCP2 is expressed in several tissues, but its physiological functions as well as potential therapeutic applications are still unclear. Unlike UCP1, UCP2 does not seem to be important to thermogenesis or weight control, but appears to have an important role in the regulation of production of reactive oxygen species, inhibition of inflammation, and inhibition of cell death. These are central features in, for example, neurodegenerative and cardiovascular disease, and experimental evidence suggests that an increased expression and activity of UCP2 in models of these diseases has a beneficial effect on disease progression, implicating a potential therapeutic role for UCP2. UCP2 has an important role in the pathogenesis of type 2 diabetes by inhibiting insulin secretion in islet beta cells. At the same time, type 2 diabetes is associated with increased risk of cardiovascular disease and atherosclerosis where an increased expression of UCP2 appears to be beneficial. This illustrates that therapeutic applications involving UCP2 likely will have to regulate expression and activity in a tissue-specific manner.

  7. In the Footsteps of Nature: Nature Therapy as an Emerging Therapeutic-Educational Model.

    ERIC Educational Resources Information Center

    Berger, Ronen

    2003-01-01

    Basic principles of the nature therapy model are described, integrating the author's personal journey and examples from fieldwork and theory. Four aspects are nature as "sacred space"; nature as therapeutic setting; healing potential of nature's physical and aesthetic elements and connections to "universal truths"; and…

  8. Emergency Ultrasound Predicting the Need for Therapeutic Laparotomy among Blunt Abdominal Trauma Patients in a Sub-Saharan African Hospital

    PubMed Central

    Musiitwa, P. C. M.; Galukande, M.; Bugeza, S.; Wanzira, H.; Wangoda, R.

    2014-01-01

    Background. The trauma burden globally accounts for high levels of mortality and morbidity. Blunt abdominal trauma (BAT) contributes significantly to this burden. Patient's evaluation for BAT remains a diagnostic challenge for emergency physicians. SSORTT gives a score that can predict the need for laparotomy. The objective of this study was to assess the accuracy of SSORTT score in predicting the need for a therapeutic laparotomy after BAT. Method. A prospective observational study. Eligible patients were evaluated for shock and the presence of haemoperitoneum using a portable ultrasound machine. Further evaluation of patients following the standard of care (SOC) protocol was done. The accuracy of SSORTT score in predicting therapeutic laparotomy was compared to SOC. Results. In total, 195 patients were evaluated; M : F ratio was 6 : 1. The commonest injuries were to the head 80 (42%) and the abdomen 54 (28%). A SSORTT score of >2 appropriately identified patients that needed a therapeutic laparotomy (with sensitivity 90%, specificity 90%, PPV 53%, and NPV 98%). The overall mortality rate was 17%. Conclusion. Patients with a SSORTT score of 2 and above had a high likelihood of requiring a therapeutic laparotomy. SSORTT scoring should be adopted for routine practice in low technology settings. PMID:24688794

  9. Combined MYC and P53 defects emerge at medulloblastoma relapse and define rapidly progressive, therapeutically targetable disease.

    PubMed

    Hill, Rebecca M; Kuijper, Sanne; Lindsey, Janet C; Petrie, Kevin; Schwalbe, Ed C; Barker, Karen; Boult, Jessica K R; Williamson, Daniel; Ahmad, Zai; Hallsworth, Albert; Ryan, Sarra L; Poon, Evon; Robinson, Simon P; Ruddle, Ruth; Raynaud, Florence I; Howell, Louise; Kwok, Colin; Joshi, Abhijit; Nicholson, Sarah Leigh; Crosier, Stephen; Ellison, David W; Wharton, Stephen B; Robson, Keith; Michalski, Antony; Hargrave, Darren; Jacques, Thomas S; Pizer, Barry; Bailey, Simon; Swartling, Fredrik J; Weiss, William A; Chesler, Louis; Clifford, Steven C

    2015-01-12

    We undertook a comprehensive clinical and biological investigation of serial medulloblastoma biopsies obtained at diagnosis and relapse. Combined MYC family amplifications and P53 pathway defects commonly emerged at relapse, and all patients in this group died of rapidly progressive disease postrelapse. To study this interaction, we investigated a transgenic model of MYCN-driven medulloblastoma and found spontaneous development of Trp53 inactivating mutations. Abrogation of p53 function in this model produced aggressive tumors that mimicked characteristics of relapsed human tumors with combined P53-MYC dysfunction. Restoration of p53 activity and genetic and therapeutic suppression of MYCN all reduced tumor growth and prolonged survival. Our findings identify P53-MYC interactions at medulloblastoma relapse as biomarkers of clinically aggressive disease that may be targeted therapeutically.

  10. Combined MYC and P53 Defects Emerge at Medulloblastoma Relapse and Define Rapidly Progressive, Therapeutically Targetable Disease

    PubMed Central

    Hill, Rebecca M.; Kuijper, Sanne; Lindsey, Janet C.; Petrie, Kevin; Schwalbe, Ed C.; Barker, Karen; Boult, Jessica K.R.; Williamson, Daniel; Ahmad, Zai; Hallsworth, Albert; Ryan, Sarra L.; Poon, Evon; Robinson, Simon P.; Ruddle, Ruth; Raynaud, Florence I.; Howell, Louise; Kwok, Colin; Joshi, Abhijit; Nicholson, Sarah Leigh; Crosier, Stephen; Ellison, David W.; Wharton, Stephen B.; Robson, Keith; Michalski, Antony; Hargrave, Darren; Jacques, Thomas S.; Pizer, Barry; Bailey, Simon; Swartling, Fredrik J.; Weiss, William A.; Chesler, Louis; Clifford, Steven C.

    2015-01-01

    Summary We undertook a comprehensive clinical and biological investigation of serial medulloblastoma biopsies obtained at diagnosis and relapse. Combined MYC family amplifications and P53 pathway defects commonly emerged at relapse, and all patients in this group died of rapidly progressive disease postrelapse. To study this interaction, we investigated a transgenic model of MYCN-driven medulloblastoma and found spontaneous development of Trp53 inactivating mutations. Abrogation of p53 function in this model produced aggressive tumors that mimicked characteristics of relapsed human tumors with combined P53-MYC dysfunction. Restoration of p53 activity and genetic and therapeutic suppression of MYCN all reduced tumor growth and prolonged survival. Our findings identify P53-MYC interactions at medulloblastoma relapse as biomarkers of clinically aggressive disease that may be targeted therapeutically. PMID:25533335

  11. The emergence and popularisation of autologous somatic cellular therapies in Australia: therapeutic innovation or regulatory failure?

    PubMed

    McLean, Alison K; Stewart, Cameron; Kerridge, Ian

    2014-09-01

    Private stem cell clinics throughout Australia are providing autologous stem cell therapies for a range of chronic and debilitating illnesses despite the lack of published literature to support the clinical application of these therapies. The Therapeutic Goods Administration has excluded autologous stem cell therapies from its regulatory domain leaving such therapies to be regulated by the same mechanisms that regulate research, such as the National Health and Medical Research Council Research Ethics Guidelines, and clinical practice, such as the Australian Health Practitioner Regulation Agency. However, the provision of these stem cell therapies does not follow the established pathways for legitimate medical advance--therapeutic innovation or research. The current regulatory framework is failing to achieve its aims of protecting vulnerable patients and ensuring the proper conduct of medical practitioners in the private stem cell industry.

  12. Emerging therapeutic strategies to prevent infection-related microvascular endothelial activation and dysfunction

    PubMed Central

    Darwish, Ilyse; Liles, W Conrad

    2013-01-01

    Recent evidence suggests that loss of endothelial barrier function and resulting microvascular leak play important mechanistic roles in the pathogenesis of infection-related end-organ dysfunction and failure. Several distinct therapeutic strategies, designed to prevent or limit infection-related microvascular endothelial activation and permeability, thereby mitigating end-organ injury/dysfunction, have recently been investigated in pre-clinical models. In this review, these potential therapeutic strategies, namely, VEGFR2/Src antagonists, sphingosine-1-phosphate agonists, fibrinopeptide Bβ15–42, slit2N, secinH3, angiopoietin-1/tie-2 agonists, angiopoietin-2 antagonists, statins, atrial natriuretic peptide, and mesenchymal stromal (stem) cells, are discussed in terms of their translational potential for the management of clinical infectious diseases. PMID:23863603

  13. Human monoclonal antibodies as candidate therapeutics against emerging viruses and HIV-1.

    PubMed

    Zhu, Zhongyu; Prabakaran, Ponraj; Chen, Weizao; Broder, Christopher C; Gong, Rui; Dimitrov, Dimiter S

    2013-04-01

    More than 40 monoclonal antibodies (mAbs) have been approved for a number of disease indications with only one of these (Synagis) - for a viral disease, and not for therapy but for prevention. However, in the last decade novel potent mAbs have been discovered and characterized with potential as therapeutics against viruses of major importance for public health and biosecurity including Hendra virus (HeV), Nipah virus (NiV), severe acute respiratory syndrome coronavirus (SARS-CoV), Ebola virus (EBOV), West Nile virus (WNV), influenza virus (IFV) and human immunodeficiency virus type 1 (HIV-1). Here, we review such mAbs with an emphasis on antibodies of human origin, and highlight recent results as well as technologies and mechanisms related to their potential as therapeutics.

  14. Bone morphogenetic protein-7 and Gremlin: New emerging therapeutic targets for diabetic nephropathy.

    PubMed

    Zhang, Yanling; Zhang, Qingxian

    2009-05-22

    Specific therapies of diabetic nephropathy (DN) are not available, and current treatment strategies are limited to management of blood glucose levels and control of hypertension. The re-activation of developmental programs in DN suggests new potential therapeutic targets. Bone morphogenetic protein-7 (BMP-7) and its antagonist, Gremlin is revealed to be involved in renal development and diabetic nephropathy. This article reviews the changes of BMP-7 and Gremlin in diabetic kidney, the protective effects on diabetic nephropathy when targeting BMP-7 and Gremlin, and the possible mechanism. The reorganization of the re-activation of Gremlin and BMP-7 in diabetic kidney had shed light on the identification of novel therapeutic targets for DN.

  15. The emerging role of molecular imaging and targeted therapeutics in peritoneal carcinomatosis.

    PubMed

    Gunn, Andrew J; Brechbiel, Martin W; Choyke, Peter L

    2007-07-01

    Peritoneal carcinomatosis is a common and often fatal late-stage complication of many gastrointestinal and gynecologic malignancies. This review discusses the ongoing evolution of diagnostic and treatment strategies for peritoneal carcinomatosis and the role that molecular imaging and radioimmunotherapy may play in improving patient survival. An overview of recent developments in targeted imaging and therapeutics for peritoneal carcinomatosis, as well as the authors' opinions as to future developments in this field is also provided.

  16. Emerging Roles of microRNAs in Ischemic Stroke: As Possible Therapeutic Agents.

    PubMed

    Khoshnam, Seyed Esmaeil; Winlow, William; Farbood, Yaghoob; Moghaddam, Hadi Fathi; Farzaneh, Maryam

    2017-05-01

    Stroke is one of the leading causes of death and physical disability worldwide. The consequences of stroke injuries are profound and persistent, causing in considerable burden to both the individual patient and society. Current treatments for ischemic stroke injuries have proved inadequate, partly owing to an incomplete understanding of the cellular and molecular changes that occur following ischemic stroke. MicroRNAs (miRNA) are endogenously expressed RNA molecules that function to inhibit mRNA translation and have key roles in the pathophysiological processes contributing to ischemic stroke injuries. Potential therapeutic areas to compensate these pathogenic processes include promoting angiogenesis, neurogenesis and neuroprotection. Several miRNAs, and their target genes, are recognized to be involved in these recoveries and repair mechanisms. The capacity of miRNAs to simultaneously regulate several target genes underlies their unique importance in ischemic stroke therapeutics. In this Review, we focus on the role of miRNAs as potential diagnostic and prognostic biomarkers, as well as promising therapeutic agents in cerebral ischemic stroke.

  17. Emerging Roles of microRNAs in Ischemic Stroke: As Possible Therapeutic Agents

    PubMed Central

    Khoshnam, Seyed Esmaeil; Winlow, William; Farbood, Yaghoob; Moghaddam, Hadi Fathi; Farzaneh, Maryam

    2017-01-01

    Stroke is one of the leading causes of death and physical disability worldwide. The consequences of stroke injuries are profound and persistent, causing in considerable burden to both the individual patient and society. Current treatments for ischemic stroke injuries have proved inadequate, partly owing to an incomplete understanding of the cellular and molecular changes that occur following ischemic stroke. MicroRNAs (miRNA) are endogenously expressed RNA molecules that function to inhibit mRNA translation and have key roles in the pathophysiological processes contributing to ischemic stroke injuries. Potential therapeutic areas to compensate these pathogenic processes include promoting angiogenesis, neurogenesis and neuroprotection. Several miRNAs, and their target genes, are recognized to be involved in these recoveries and repair mechanisms. The capacity of miRNAs to simultaneously regulate several target genes underlies their unique importance in ischemic stroke therapeutics. In this Review, we focus on the role of miRNAs as potential diagnostic and prognostic biomarkers, as well as promising therapeutic agents in cerebral ischemic stroke. PMID:28480877

  18. MicroRNAs in Leukemias: Emerging Diagnostic Tools and Therapeutic Targets

    PubMed Central

    Mian, Yousaf A.; Zeleznik-Le, Nancy J.

    2010-01-01

    MicroRNAs (miRNA) are small non-coding RNAs of ~22 nucleotides that regulate the translation and stability of mRNA to control different functions of the cell. Misexpression of miRNA has been linked to disruption of normal cellular functions, which results in various disorders including cancers such as leukemias. MicroRNA involvement in disease has been the subject of much attention and is increasing our current understanding of disease biology. Such linkages have been determined by high-throughput studies, which provide a framework for characterizing differential miRNA expression levels correlating to different cytogenetic abnormalities and their corresponding malignancies. In addition, functional studies of particular miRNAs have begun to define the effects of miRNA on predicted mRNA targets. It is clear that miRNAs can serve as molecular markers of leukemias and the hope is that they can also serve as new therapeutic targets. Studies are beginning to elucidate how to deliver therapeutic antagonists to attenuate overexpressed miRNAs and to replace underexpressed miRNAs. In this review, we: i) discuss the current understanding of miRNA function and expression in normal hematopoiesis, ii) provide examples of miRNAs that are misregulated in leukemias, and iii) evaluate the current status and potential future directions for the burgeoning field of antisense oligonucleotides and other therapeutic attempts to intervene in miRNA disregulation in leukemias. PMID:20370647

  19. A Newly Emergent Turkey Arthritis Reovirus Shows Dominant Enteric Tropism and Induces Significantly Elevated Innate Antiviral and T Helper-1 Cytokine Responses.

    PubMed

    Sharafeldin, Tamer A; Mor, Sunil K; Sobhy, Nader M; Xing, Zheng; Reed, Kent M; Goyal, Sagar M; Porter, Robert E

    2015-01-01

    Newly emergent turkey arthritis reoviruses (TARV) were isolated from tendons of lame 15-week-old tom turkeys that occasionally had ruptured leg tendons. Experimentally, these TARVs induced remarkable tenosynovitis in gastrocnemius tendons of turkey poults. The current study aimed to characterize the location and the extent of virus replication as well as the cytokine response induced by TARV during the first two weeks of infection. One-week-old male turkeys were inoculated orally with TARV (O'Neil strain). Copy numbers of viral genes were estimated in intestines, internal organs and tendons at ½, 1, 2, 3, 4, 7, 14 days Post inoculation (dpi). Cytokine profile was measured in intestines, spleen and leg tendons at 0, 4, 7 and 14 dpi. Viral copy number peaked in jejunum, cecum and bursa of Fabricius at 4 dpi. Copy numbers increased dramatically in leg tendons at 7 and 14 dpi while minimal copies were detected in internal organs and blood during the same period. Virus was detected in cloacal swabs at 1-2 dpi, and peaked at 14 dpi indicating enterotropism of the virus and its early shedding in feces. Elevation of IFN-α and IFN-β was observed in intestines at 7 dpi as well as a prominent T helper-1 response (IFN-γ) at 7 and 14 dpi. IFN-γ and IL-6 were elevated in gastrocnemius tendons at 14 dpi. Elevation of antiviral cytokines in intestines occurred at 7dpi when a significant decline of viral replication in intestines was observed. T helper-1 response in intestines and leg tendons was the dominant T-helper response. These results suggest the possible correlation between viral replication and cytokine response in early infection of TARV in turkeys. Our findings provide novel insights which help elucidate viral pathogenesis in turkey tendons infected with TARV.

  20. Human cytotoxic T lymphocytes directed to seasonal influenza A viruses cross-react with the newly emerging H7N9 virus.

    PubMed

    van de Sandt, Carolien E; Kreijtz, Joost H C M; de Mutsert, Gerrie; Geelhoed-Mieras, Martina M; Hillaire, Marine L B; Vogelzang-van Trierum, Stella E; Osterhaus, Albert D M E; Fouchier, Ron A M; Rimmelzwaan, Guus F

    2014-02-01

    In February 2013, zoonotic transmission of a novel influenza A virus of the H7N9 subtype was reported in China. Although at present no sustained human-to-human transmission has been reported, a pandemic outbreak of this H7N9 virus is feared. Since neutralizing antibodies to the hemagglutinin (HA) globular head domain of the virus are virtually absent in the human population, there is interest in identifying other correlates of protection, such as cross-reactive CD8(+) T cells (cytotoxic T lymphocytes [CTLs]) elicited during seasonal influenza A virus infections. These virus-specific CD8(+) T cells are known to recognize conserved internal proteins of influenza A viruses predominantly, but it is unknown to what extent they cross-react with the newly emerging H7N9 virus. Here, we assessed the cross-reactivity of seasonal H3N2 and H1N1 and pandemic H1N1 influenza A virus-specific polyclonal CD8(+) T cells, obtained from HLA-typed study subjects, with the novel H7N9 virus. The cross-reactivity of CD8(+) T cells to H7N9 variants of known influenza A virus epitopes and H7N9 virus-infected cells was determined by their gamma interferon (IFN-γ) response and lytic activity. It was concluded that, apart from recognition of individual H7N9 variant epitopes, CD8(+) T cells to seasonal influenza viruses display considerable cross-reactivity with the novel H7N9 virus. The presence of these cross-reactive CD8(+) T cells may afford some protection against infection with the new virus.

  1. Human Cytotoxic T Lymphocytes Directed to Seasonal Influenza A Viruses Cross-React with the Newly Emerging H7N9 Virus

    PubMed Central

    van de Sandt, Carolien E.; Kreijtz, Joost H. C. M.; de Mutsert, Gerrie; Geelhoed-Mieras, Martina M.; Hillaire, Marine L. B.; Vogelzang-van Trierum, Stella E.; Osterhaus, Albert D. M. E.; Fouchier, Ron A. M.

    2014-01-01

    In February 2013, zoonotic transmission of a novel influenza A virus of the H7N9 subtype was reported in China. Although at present no sustained human-to-human transmission has been reported, a pandemic outbreak of this H7N9 virus is feared. Since neutralizing antibodies to the hemagglutinin (HA) globular head domain of the virus are virtually absent in the human population, there is interest in identifying other correlates of protection, such as cross-reactive CD8+ T cells (cytotoxic T lymphocytes [CTLs]) elicited during seasonal influenza A virus infections. These virus-specific CD8+ T cells are known to recognize conserved internal proteins of influenza A viruses predominantly, but it is unknown to what extent they cross-react with the newly emerging H7N9 virus. Here, we assessed the cross-reactivity of seasonal H3N2 and H1N1 and pandemic H1N1 influenza A virus-specific polyclonal CD8+ T cells, obtained from HLA-typed study subjects, with the novel H7N9 virus. The cross-reactivity of CD8+ T cells to H7N9 variants of known influenza A virus epitopes and H7N9 virus-infected cells was determined by their gamma interferon (IFN-γ) response and lytic activity. It was concluded that, apart from recognition of individual H7N9 variant epitopes, CD8+ T cells to seasonal influenza viruses display considerable cross-reactivity with the novel H7N9 virus. The presence of these cross-reactive CD8+ T cells may afford some protection against infection with the new virus. PMID:24257602

  2. Effect of 1,3-1,6 β-Glucan on Natural and Experimental Deformed Wing Virus Infection in Newly Emerged Honeybees (Apis mellifera ligustica).

    PubMed

    Mazzei, Maurizio; Fronte, Baldassare; Sagona, Simona; Carrozza, Maria Luisa; Forzan, Mario; Pizzurro, Federica; Bibbiani, Carlo; Miragliotta, Vincenzo; Abramo, Francesca; Millanta, Francesca; Bagliacca, Marco; Poli, Alessandro; Felicioli, Antonio

    2016-01-01

    The Western Honeybee is a key pollinator for natural as well as agricultural ecosystems. In the last decade massive honeybee colony losses have been observed worldwide, the result of a complex syndrome triggered by multiple stress factors, with the RNA virus Deformed Wing Virus (DWV) and the mite Varroa destructor playing crucial roles. The mite supports replication of DWV to high titers, which exert an immunosuppressive action and correlate with the onset of the disease. The aim of this study was to investigate the effect of 1,3-1,6 β-glucan, a natural innate immune system modulator, on honeybee response to low-titer natural and high-titer experimental DWV infection. As the effects exerted by ß-glucans can be remarkably different, depending on the target organism and the dose administered, two parallel experiments were performed, where 1,3-1,6 ß-glucan at a concentration of 0.5% and 2% respectively, was added to the diet of three cohorts of newly emerged honeybees, which were sampled from a Varroa-free apiary and harboured a low endogenous DWV viral titer. Each cohort was subjected to one of the following experimental treatments: no injection, injection of a high-copy number DWV suspension into the haemocel (experimental DWV infection) or injection of PBS into the haemocoel (physical injury). Control bees fed a ß-glucan-free diet were subjected to the same treatments. Viral load, survival rate, haemocyte populations and phenoloxidase activity of each experimental group were measured and compared. The results indicated that oral administration of 0.5% ß-glucan to naturally infected honeybees was associated with a significantly decrease of the number of infected bees and viral load they carried, and with a significant increase of the survival rate, suggesting that this natural immune modulator molecule might contribute to increase honeybee resistance to viral infection.

  3. Effect of 1,3-1,6 β-Glucan on Natural and Experimental Deformed Wing Virus Infection in Newly Emerged Honeybees (Apis mellifera ligustica)

    PubMed Central

    Sagona, Simona; Carrozza, Maria Luisa; Forzan, Mario; Pizzurro, Federica; Bibbiani, Carlo; Miragliotta, Vincenzo; Abramo, Francesca; Millanta, Francesca; Bagliacca, Marco; Poli, Alessandro; Felicioli, Antonio

    2016-01-01

    The Western Honeybee is a key pollinator for natural as well as agricultural ecosystems. In the last decade massive honeybee colony losses have been observed worldwide, the result of a complex syndrome triggered by multiple stress factors, with the RNA virus Deformed Wing Virus (DWV) and the mite Varroa destructor playing crucial roles. The mite supports replication of DWV to high titers, which exert an immunosuppressive action and correlate with the onset of the disease. The aim of this study was to investigate the effect of 1,3–1,6 β-glucan, a natural innate immune system modulator, on honeybee response to low-titer natural and high-titer experimental DWV infection. As the effects exerted by ß-glucans can be remarkably different, depending on the target organism and the dose administered, two parallel experiments were performed, where 1,3–1,6 ß-glucan at a concentration of 0.5% and 2% respectively, was added to the diet of three cohorts of newly emerged honeybees, which were sampled from a Varroa-free apiary and harboured a low endogenous DWV viral titer. Each cohort was subjected to one of the following experimental treatments: no injection, injection of a high-copy number DWV suspension into the haemocel (experimental DWV infection) or injection of PBS into the haemocoel (physical injury). Control bees fed a ß-glucan-free diet were subjected to the same treatments. Viral load, survival rate, haemocyte populations and phenoloxidase activity of each experimental group were measured and compared. The results indicated that oral administration of 0.5% ß-glucan to naturally infected honeybees was associated with a significantly decrease of the number of infected bees and viral load they carried, and with a significant increase of the survival rate, suggesting that this natural immune modulator molecule might contribute to increase honeybee resistance to viral infection. PMID:27829027

  4. Identification of the critical therapeutic entity in secreted Hsp90α that promotes wound healing in newly re-standardized healthy and diabetic pig models.

    PubMed

    O'Brien, Kathryn; Bhatia, Ayesha; Tsen, Fred; Chen, Mei; Wong, Alex K; Woodley, David T; Li, Wei

    2014-01-01

    Chronic and non-healing skin wounds represent a significant clinical, economic and social problem worldwide. Currently, there are few effective treatments. Lack of well-defined animal models to investigate wound healing mechanisms and furthermore to identify new and more effective therapeutic agents still remains a major challenge. Pig skin wound healing is close to humans. However, standardized pig wound healing models with demonstrated validity for testing new wound healing candidates are unavailable. Here we report a systematic evaluation and establishment of both acute and diabetic wound healing models in pigs, including wound-creating pattern for drug treatment versus control, measurements of diabetic parameters and the time for detecting delayed wound healing. We find that treatment and control wounds should be on the opposite and corresponding sides of a pig. We demonstrate a strong correlation between duration of diabetic conditions and the length of delay in wound closure. Using these new models, we narrow down the minimum therapeutic entity of secreted Hsp90α to a 27-amino acid peptide, called fragment-8 (F-8). In addition, results of histochemistry and immunohistochemistry analyses reveal more organized epidermis and dermis in Hsp90α-healed wounds than the control. Finally, Hsp90α uses a similar signaling mechanism to promote migration of isolated pig and human keratinocytes and dermal fibroblasts. This is the first report that shows standardized pig models for acute and diabetic wound healing studies and proves its usefulness with both an approved drug and a new therapeutic agent.

  5. Identification of the Critical Therapeutic Entity in Secreted Hsp90α That Promotes Wound Healing in Newly Re-Standardized Healthy and Diabetic Pig Models

    PubMed Central

    Chen, Mei; Wong, Alex K.; Woodley, David T.; Li, Wei

    2014-01-01

    Chronic and non-healing skin wounds represent a significant clinical, economic and social problem worldwide. Currently, there are few effective treatments. Lack of well-defined animal models to investigate wound healing mechanisms and furthermore to identify new and more effective therapeutic agents still remains a major challenge. Pig skin wound healing is close to humans. However, standardized pig wound healing models with demonstrated validity for testing new wound healing candidates are unavailable. Here we report a systematic evaluation and establishment of both acute and diabetic wound healing models in pigs, including wound-creating pattern for drug treatment versus control, measurements of diabetic parameters and the time for detecting delayed wound healing. We find that treatment and control wounds should be on the opposite and corresponding sides of a pig. We demonstrate a strong correlation between duration of diabetic conditions and the length of delay in wound closure. Using these new models, we narrow down the minimum therapeutic entity of secreted Hsp90α to a 27-amino acid peptide, called fragment-8 (F-8). In addition, results of histochemistry and immunohistochemistry analyses reveal more organized epidermis and dermis in Hsp90α-healed wounds than the control. Finally, Hsp90α uses a similar signaling mechanism to promote migration of isolated pig and human keratinocytes and dermal fibroblasts. This is the first report that shows standardized pig models for acute and diabetic wound healing studies and proves its usefulness with both an approved drug and a new therapeutic agent. PMID:25464502

  6. Emerging Therapeutic Enhancement Enabling Health Technologies and Their Discourses: What Is Discussed within the Health Domain?

    PubMed Central

    Wolbring, Gregor; Diep, Lucy; Yumakulov, Sophya; Ball, Natalie; Leopatra, Verlyn; Yergens, Dean

    2013-01-01

    So far, the very meaning of health and therefore, treatment and rehabilitation is benchmarked to the normal or species-typical body. We expect certain abilities in members of a species; we expect humans to walk but not to fly, but a bird we expect to fly. However, increasingly therapeutic interventions have the potential to give recipients beyond species-typical body related abilities (therapeutic enhancements, TE). We believe that the perfect storm of TE, the shift in ability expectations toward beyond species-typical body abilities, and the increasing desire of health consumers to shape the health system will increasingly influence various aspects of health care practice, policy, and scholarship. We employed qualitative and quantitative methods to investigate among others how human enhancement, neuro/cognitive enhancement, brain machine interfaces, and social robot discourses cover (a) healthcare, healthcare policy, and healthcare ethics, (b) disability and (c) health consumers and how visible various assessment fields are within Neuro/Cogno/Human enhancement and within the BMI and social robotics discourse. We found that health care, as such, is little discussed, as are health care policy and ethics; that the term consumers (but not health consumers) is used; that technology, impact and needs assessment is absent; and that the imagery of disabled people is primarily a medical one. We submit that now, at this early stage, is the time to gain a good understanding of what drives the push for the enhancement agenda and enhancement-enabling devices, and the dynamics around acceptance and diffusion of therapeutic enhancements. PMID:27429129

  7. Emerging Therapeutic Enhancement Enabling Health Technologies and Their Discourses: What Is Discussed within the Health Domain?

    PubMed

    Wolbring, Gregor; Diep, Lucy; Yumakulov, Sophya; Ball, Natalie; Leopatra, Verlyn; Yergens, Dean

    2013-07-25

    So far, the very meaning of health and therefore, treatment and rehabilitation is benchmarked to the normal or species-typical body. We expect certain abilities in members of a species; we expect humans to walk but not to fly, but a bird we expect to fly. However, increasingly therapeutic interventions have the potential to give recipients beyond species-typical body related abilities (therapeutic enhancements, TE). We believe that the perfect storm of TE, the shift in ability expectations toward beyond species-typical body abilities, and the increasing desire of health consumers to shape the health system will increasingly influence various aspects of health care practice, policy, and scholarship. We employed qualitative and quantitative methods to investigate among others how human enhancement, neuro/cognitive enhancement, brain machine interfaces, and social robot discourses cover (a) healthcare, healthcare policy, and healthcare ethics, (b) disability and (c) health consumers and how visible various assessment fields are within Neuro/Cogno/ Human enhancement and within the BMI and social robotics discourse. We found that health care, as such, is little discussed, as are health care policy and ethics; that the term consumers (but not health consumers) is used; that technology, impact and needs assessment is absent; and that the imagery of disabled people is primarily a medical one. We submit that now, at this early stage, is the time to gain a good understanding of what drives the push for the enhancement agenda and enhancement-enabling devices, and the dynamics around acceptance and diffusion of therapeutic enhancements.

  8. Therapeutic Targets for Neurodevelopmental Disorders Emerging from Animal Models with Perinatal Immune Activation

    PubMed Central

    Ibi, Daisuke; Yamada, Kiyofumi

    2015-01-01

    Increasing epidemiological evidence indicates that perinatal infection with various viral pathogens enhances the risk for several psychiatric disorders. The pathophysiological significance of astrocyte interactions with neurons and/or gut microbiomes has been reported in neurodevelopmental disorders triggered by pre- and postnatal immune insults. Recent studies with the maternal immune activation or neonatal polyriboinosinic polyribocytidylic acid models of neurodevelopmental disorders have identified various candidate molecules that could be responsible for brain dysfunction. Here, we review the functions of several candidate molecules in neurodevelopment and brain function and discuss their potential as therapeutic targets for psychiatric disorders. PMID:26633355

  9. Heterocyclic N-Oxides – An Emerging Class of Therapeutic Agents

    PubMed Central

    Mfuh, Adelphe M.; Larionov, Oleg V.

    2016-01-01

    Heterocyclic N-oxides have emerged as potent compounds with anticancer, antibacterial, antihypertensive, antiparasitic, anti-HIV, anti-inflammatory, herbicidal, neuroprotective, and procognitive activities. The N-oxide motif has been successfully employed in a number of recent drug development projects. This review surveys the emergence of this scaffold in the mainstream medicinal chemistry with a focus on the discovery of the heterocyclic N-oxide drugs, N-oxide-specific mechanisms of action, drug-receptor interactions and synthetic avenues to these compounds. As the first review on this subject that covers the developments since 1950s to date, it is expected that it will inspire wider implementation of the heterocyclic N-oxide motif in the rational design of new medicinal agents. PMID:26087764

  10. Targeting Bruton's tyrosine kinase signaling as an emerging therapeutic agent of B-cell malignancies.

    PubMed

    Xia, Bing; Qu, Fulian; Yuan, Tian; Zhang, Yizhuo

    2015-12-01

    It is becoming increasingly evident that B-cell receptor (BCR) signaling is central to the development and function of B cells. BCR signaling has emerged as a pivotal pathway and a key driver of numerous B-cell lymphomas. Disruption of BCR signaling can be lethal to malignant B cells. Recently, kinase inhibitors that target BCR signaling have induced notable clinical responses. These inhibitors include spleen tyrosine kinase, mammalian target of rapamycin, phosphoinositide 3'-kinase and Bruton's tyrosine kinase (BTK). Ibrutinib, an oral irreversible BTK inhibitor, has emerged as a promising targeted therapy for patients with B-cell malignancies. The present review discusses the current understanding of BTK-mediated BCR signaling in the biology and pathobiology of normal and malignant B cells, and the cellular interaction with the tumor microenvironment. The data on ibrutinib in the preclinical and clinical settings is also discussed, and perspectives for the future use of ibrutinib are outlined.

  11. Targeting Bruton's tyrosine kinase signaling as an emerging therapeutic agent of B-cell malignancies

    PubMed Central

    XIA, BING; QU, FULIAN; YUAN, TIAN; ZHANG, YIZHUO

    2015-01-01

    It is becoming increasingly evident that B-cell receptor (BCR) signaling is central to the development and function of B cells. BCR signaling has emerged as a pivotal pathway and a key driver of numerous B-cell lymphomas. Disruption of BCR signaling can be lethal to malignant B cells. Recently, kinase inhibitors that target BCR signaling have induced notable clinical responses. These inhibitors include spleen tyrosine kinase, mammalian target of rapamycin, phosphoinositide 3′-kinase and Bruton's tyrosine kinase (BTK). Ibrutinib, an oral irreversible BTK inhibitor, has emerged as a promising targeted therapy for patients with B-cell malignancies. The present review discusses the current understanding of BTK-mediated BCR signaling in the biology and pathobiology of normal and malignant B cells, and the cellular interaction with the tumor microenvironment. The data on ibrutinib in the preclinical and clinical settings is also discussed, and perspectives for the future use of ibrutinib are outlined. PMID:26788133

  12. The therapeutic use of magnesium in anesthesiology, intensive care and emergency medicine: a review.

    PubMed

    Dubé, Laurent; Granry, Jean-Claude

    2003-01-01

    To review current knowledge concerning the use of magnesium in anesthesiology, intensive care and emergency medicine. References were obtained from Medline(R) (1995 to 2002). All categories of articles (clinical trials, reviews, or meta-analyses) on this topic were selected. The key words used were magnesium, anesthesia, analgesia, emergency medicine, intensive care, surgery, physiology, pharmacology, eclampsia, pheochromocytoma, asthma, and acute myocardial infarction. Hypomagnesemia is frequent postoperatively and in the intensive care and needs to be detected and corrected to prevent increased morbidity and mortality. Magnesium reduces catecholamine release and thus allows better control of adrenergic response during intubation or pheochromocytoma surgery. It also decreases the frequency of postoperative rhythm disorders in cardiac surgery as well as convulsive seizures in preeclampsia and their recurrence in eclampsia. The use of adjuvant magnesium during perioperative analgesia may be beneficial for its antagonist effects on N-methyl-D-aspartate receptors. The precise role of magnesium in the treatment of asthmatic attacks and myocardial infarction in emergency conditions needs to be determined. Magnesium has many known indications in anesthesiology and intensive care, and others have been suggested by recent publications. Because of its interactions with drugs used in anesthesia, anesthesiologists and intensive care specialists need to have a clear understanding of the role of this important cation.

  13. Cannabidiol as an emergent therapeutic strategy for lessening the impact of inflammation on oxidative stress.

    PubMed

    Booz, George W

    2011-09-01

    Oxidative stress with reactive oxygen species generation is a key weapon in the arsenal of the immune system for fighting invading pathogens and initiating 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 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 1 and 2 diabetes, atherosclerosis, Alzheimer disease, hypertension, the metabolic syndrome, ischemia-reperfusion injury, depression, and neuropathic pain.

  14. [Therapeutic approach in kidney trauma. Assessments of 49 patients treated at surgical emergencies clinics].

    PubMed

    Velenciuc, I; Luncă, S; Romedea, N; Velenciuc, Natalia; Mihalache, St

    2010-01-01

    The aim of this study is to contribute to efficiency of therapeutical interventions, using an optimal stadialisation followed by a maximum preservation of renal function. A number of 49 cases with polytrauma, included urinary lesions, were studied between January, 2002 and December, 2009. Demographical, clinical, paraclinical data were collected, as well as those regarding therapeutical measures. From a number of 1436 cases with polytrauma, 49 (3.41%) suffered from urinary tract prejudices and 36 (73.46%) with major kidney lesions--11 (30.55%) severe at admission; 5 (13.89%) patients with multiple lesions and hypovolemic shock. The conservative treatment was applied in 24 (66.64%) cases and other types of surgical interventions for the other patients. The urinary apparatus is affected in aproximately 10% of cases of abdominal trauma due to road and falls from heights accidents, especially in patients of 26-50 age groups: 30.5% with severe lesions, 13.89% with hypovolemic shock at admission, and 1 death. The treatment was conservative in 66.64% of cases and various types of surgical interventions for the others patients.

  15. Genomics and the prospects of existing and emerging therapeutics for cardiovascular diseases.

    PubMed

    Zaiou, M; Benachour, H; Marteau, J B; Visvikis-Siest, S; Siest, G

    2009-01-01

    The growing knowledge about genetic influence on cardiovascular diseases (CVD) combined with the recently generated amounts of genomic data hold promise to the identification of new markers for atherosclerotic CVD. Cardiovascular pharmacogenomics and pharmacogenetics have now the potential for leading to identification of genetic contributors and therefore to the development of predictive genetic tests that could optimize drugs efficacy and minimize toxicity. Clinical studies have shown that genetic variations within cytochromes P450 (CYPs), 3-Hydroxyl-3-Methylglutaryl Coenzyme A Reductase (HMGCR) and apolipoprotein E (APOE) genes influence individual's response to lipid lowering statins. Furthermore, development of antagonists or inhibitors of molecules such as peroxisome proliferator-activated receptors (PPARs), lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), angiotensin-converting enzyme (ACE), angiotensin receptors and tumor necrosis factor (TNF)-alpha could be another alternative to prevent atherosclerosis. In addition, novel molecules under the name of biologics including family of peptides such as atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), urocortin, apelin and antimicrobial peptides (AMPs) could be considered as new targets for the prevention and treatment of CVD. In this article, we will focus mainly on recent genomic advances in the development of new markers and therapeutic agents for CVD. We present an array of molecules that could have pharmacological benefit for the treatment of heart disease. We also discuss in details new strategies including biologics, which are actually the focus of companies for clinical development of therapeutic drugs. All these efforts provide optimism and attractive promise to cure CVD.

  16. Emerging Role and Therapeutic Implication of Wnt Signaling Pathways in Autoimmune Diseases

    PubMed Central

    Shi, Juan; Chi, Shuhong; Xue, Jing; Yang, Jiali; Li, Feng; Liu, Xiaoming

    2016-01-01

    The Wnt signaling pathway plays a key role in many biological aspects, such as cellular proliferation, tissue regeneration, embryonic development, and other systemic effects. Under a physiological condition, it is tightly controlled at different layers and arrays, and a dysregulated activation of this signaling has been implicated into the pathogenesis of various human disorders, including autoimmune diseases. Despite the fact that therapeutic interventions are available for ameliorating disease manifestations, there is no curative therapy currently available for autoimmune disorders. Increasing lines of evidence have suggested a crucial role of Wnt signaling during the pathogenesis of many autoimmune diseases; in addition, some of microRNAs (miRNAs), a class of small, noncoding RNA molecules capable of transcriptionally regulating gene expression, have also recently been demonstrated to possess both physiological and pathological roles in autoimmune diseases by regulating the Wnt signaling pathway. This review summarizes currently our understanding of the pathogenic roles of Wnt signaling in several major autoimmune disorders and miRNAs, those targeting Wnt signaling in autoimmune diseases, with a focus on the implication of the Wnt signaling as potential biomarkers and therapeutic targets in immune diseases, as well as miRNA-mediated regulation of Wnt signaling activation in the development of autoimmune diseases. PMID:27110577

  17. Emergence of Laplace therapeutics: declaring an end to end-stage heart failure.

    PubMed

    Mehra, Mandeep R; Uber, Patricia A

    2002-01-01

    A large number of chronic heart failure patients escape from the benefits of neurohormonal blockade only to transit into a discouragingly miserable state of what the physician often refers to as end-stage heart failure. Conceptually, the designation of end-stage as a description of a clinical scenario implies pessimism concerning recourse to a therapeutic avenue. A variety of surgical therapeutic techniques that take advantage of the law of Laplace, designed to effectively restore the cardiac shape from a spherical, mechanically inefficient pump to a more elliptical, structurally sound organ are now being employed. Additionally, the field of mechanical device implantation is surging ahead at a rapid pace. The weight of evidence regarding mechanical unloading using assist devices suggests that hemodynamic restoration is accompanied by regression of cellular hypertrophy, normalization of the neuroendocrine axis, improved expression of contractile proteins, enhanced cellular respiratory control, and decreases in markers of apoptosis and cellular stress. Thus, these lines of data point toward discarding the notion of end-stage heart failure. We are at a new crossroad in our quest to tackle chronic heart failure. It is our contention that the use of antiremodeling strategies, including device approaches, will soon signal the end of end-stage heart failure.

  18. Mitochondrial Neurogastrointestinal Encephalomyopathy Caused by Thymidine Phosphorylase Enzyme Deficiency: From Pathogenesis to Emerging Therapeutic Options

    PubMed Central

    Yadak, Rana; Sillevis Smitt, Peter; van Gisbergen, Marike W.; van Til, Niek P.; de Coo, Irenaeus F. M.

    2017-01-01

    Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a progressive metabolic disorder caused by thymidine phosphorylase (TP) enzyme deficiency. The lack of TP results in systemic accumulation of deoxyribonucleosides thymidine (dThd) and deoxyuridine (dUrd). In these patients, clinical features include mental regression, ophthalmoplegia, and fatal gastrointestinal complications. The accumulation of nucleosides also causes imbalances in mitochondrial DNA (mtDNA) deoxyribonucleoside triphosphates (dNTPs), which may play a direct or indirect role in the mtDNA depletion/deletion abnormalities, although the exact underlying mechanism remains unknown. The available therapeutic approaches include dialysis and enzyme replacement therapy, both can only transiently reverse the biochemical imbalance. Allogeneic hematopoietic stem cell transplantation is shown to be able to restore normal enzyme activity and improve clinical manifestations in MNGIE patients. However, transplant related complications and disease progression result in a high mortality rate. New therapeutic approaches, such as adeno-associated viral vector and hematopoietic stem cell gene therapy have been tested in Tymp-/-Upp1-/- mice, a murine model for MNGIE. This review provides background information on disease manifestations of MNGIE with a focus on current management and treatment options. It also outlines the pre-clinical approaches toward future treatment of the disease. PMID:28261062

  19. Disruptions in autobiographical memory processing in depression and the emergence of memory therapeutics.

    PubMed

    Dalgleish, Tim; Werner-Seidler, Aliza

    2014-11-01

    Depression is characterized by distinct profiles of disturbance in ways autobiographical memories are represented, recalled, and maintained. We review four core domains of difficulty: systematic biases in favor of negative material; impoverished access and responses to positive memories; reduced access to the specific details of the personal past; and dysfunctional processes of rumination and avoidance around personal autobiographical material. These difficulties drive the onset and maintenance of depression; consequently, interventions targeted at these maladaptive processes have clinical potential. Memory therapeutics is the development of novel clinical techniques, translated from basic research, that target memory difficulties in those with emotional disorders. We discuss prototypical examples from this clinical domain including MEmory Specificity Training, positive memory elaboration, memory rescripting, and the method-of-loci (MoL).

  20. Emerging therapeutic options for celiac disease: potential alternatives to a gluten-free diet.

    PubMed

    Bakshi, Anita; Stephen, Sindu; Borum, Marie L; Doman, David B

    2012-09-01

    Celiac disease is an autoimmune disorder of the small intestine that is more common than was previously thought. This disease is caused by an inappropriate immune response to wheat gluten, barley, and rye. Three main pathways cause celiac disease: the environmental trigger (gluten), genetic susceptibility, and unusual gut permeability. The only treatment currently available is a strict gluten-free diet. Unfortunately, a majority of patients have difficulty complying with this diet, and the response to therapy is poor. Therefore, alternative treatments are being developed, and new insights into the pathophysiology of celiac disease have led to research into novel therapies. New treatments include engineering gluten-free grains, decreasing intestinal permeability by blockage of the epithelial zonulin receptor, inducing oral tolerance to gluten with a therapeutic vaccine, and degrading immunodominant gliadin peptides using probiotics with endopeptidases or transglutaminase inhibitors. These nondiet-based therapies provide hope for enhanced, lifelong celiac disease management with improved patient compliance and better quality of life.

  1. Reactive Oxygen-Related Diseases: Therapeutic Targets and Emerging Clinical Indications.

    PubMed

    Casas, Ana I; Dao, V Thao-Vi; Daiber, Andreas; Maghzal, Ghassan J; Di Lisa, Fabio; Kaludercic, Nina; Leach, Sonia; Cuadrado, Antonio; Jaquet, Vincent; Seredenina, Tamara; Krause, Karl H; López, Manuela G; Stocker, Roland; Ghezzi, Pietro; Schmidt, Harald H H W

    2015-11-10

    Enhanced levels of reactive oxygen species (ROS) have been associated with different disease states. Most attempts to validate and exploit these associations by chronic antioxidant therapies have provided disappointing results. Hence, the clinical relevance of ROS is still largely unclear. We are now beginning to understand the reasons for these failures, which reside in the many important physiological roles of ROS in cell signaling. To exploit ROS therapeutically, it would be essential to define and treat the disease-relevant ROS at the right moment and leave physiological ROS formation intact. This breakthrough seems now within reach. Rather than antioxidants, a new generation of protein targets for classical pharmacological agents includes ROS-forming or toxifying enzymes or proteins that are oxidatively damaged and can be functionally repaired. Linking these target proteins in future to specific disease states and providing in each case proof of principle will be essential for translating the oxidative stress concept into the clinic.

  2. Nitric oxide and disorders of the erythrocyte: emerging roles and therapeutic targets.

    PubMed

    Maley, Jason H; Lasker, George F; Kadowitz, Philip J

    2010-12-01

    Nitric oxide (NO) plays an important role in states of erythrocyte dysfunction, including sickle cell disease (SCD), malaria, and banked blood preservation. By understanding the role of nitric oxide in these conditions, which are accompanied by hemolysis, vasoocclusion, and erythrocyte dysfunction, new therapeutic targets may be identified to treat complications of these disease states. Furthermore, the role of the erythrocyte in the controlled release of NO in hypoxic tissues is of particular interest, and two theories are discussed regarding this mechanism. In this article, the role of nitric oxide in erythrocyte function, sickle cell anemia, malaria, and damage to banked blood is reviewed, and the use of NO targeted therapies for erythrocyte disease states is discussed.

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

    PubMed

    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.

  4. Quercetin as an Emerging Anti-Melanoma Agent: A Four-Focus Area Therapeutic Development Strategy

    PubMed Central

    Harris, Zoey; Donovan, Micah G.; Branco, Gisele Morais; Limesand, Kirsten H.; Burd, Randy

    2016-01-01

    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 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 antiproliferative and proapoptotic activity in various cancer cell types. Quercetin is readily metabolized by tyrosinase into various compounds that promote anticancer 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. PMID:27843913

  5. Quercetin as an Emerging Anti-Melanoma Agent: A Four-Focus Area Therapeutic Development Strategy.

    PubMed

    Harris, Zoey; Donovan, Micah G; Branco, Gisele Morais; Limesand, Kirsten H; Burd, Randy

    2016-01-01

    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 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 antiproliferative and proapoptotic activity in various cancer cell types. Quercetin is readily metabolized by tyrosinase into various compounds that promote anticancer 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.

  6. Emerging roles for vasoactive peptides in diagnostic and therapeutic strategies against atherosclerotic cardiovascular diseases.

    PubMed

    Watanabe, Takuya; Sato, Kengo; Itoh, Fumiko; Noguchi, Yuri; Fujimoto, Kazumi; Koyama, Takatoshi; Shichiri, Masayoshi

    2013-09-01

    Coronary artery disease (CAD) arising from atherosclerosis remains the most common cause of death and morbidity worldwide, although its risk factors, such as hypertension, dyslipidemia, and diabetes, have been individually treated with increasingly improved outcomes. Therefore, it is important to develop diagnostic and therapeutic windows for CAD. Many classical vasoactive hormones, inflammatory cytokines, and oxidative products have been implicated as potential biomarkers. Our recent studies have shown that high levels of the pro-atherogenic vasoactive agents, serotonin and urotensin II, which are potent vasoconstrictors, can be used as biomarkers for CAD. In subsequent trials, we unraveled anti- and pro-atherogenic roles for more recently identified peptides. Anti-atherogenic peptides include the adipocytokine adiponectin, the neuronal growth factor heregulin-β₁ (neuregulin-1 type I), the incretin hormone, glucagon-like peptide-1 (GLP-1), and a peptide recently identified by an in silico approach, salusin-α. Atherogenic roles have been demonstrated by cellular, animal, and clinical experiments, which indicate that human adiponectin, heregulin-β₁, GLP-1, and salusin-α attenuate the development of atherosclerotic lesions by suppressing macrophage foam cell formation via down-regulation of acyl-CoA:cholesterol acyltransferase-1. Circulating levels of these peptides in the blood are markedly decreased in CAD patients compared with those in non-CAD patients. Receiver operating characteristic curve analyses have shown that salusin-α is the most useful biomarker for detecting CAD among the four peptides examined. Therefore, salusin-α, alone or in various combinations with heregulin-β₁, adiponectin, and/or GLP-1, is a candidate biomarker for predicting CAD. Further, anti-atherogenic peptides could potentially serve as useful therapeutic targets for atherosclerotic cardiovascular diseases.

  7. Mysteries of α1-antitrypsin deficiency: emerging therapeutic strategies for a challenging disease

    PubMed Central

    Ghouse, Raafe; Chu, Andrew; Wang, Yan; Perlmutter, David H.

    2014-01-01

    The classical form of α1-antitrypsin deficiency (ATD) is an autosomal co-dominant disorder that affects ~1 in 3000 live births and is an important genetic cause of lung and liver disease. The protein affected, α1-antitrypsin (AT), is predominantly derived from the liver and has the function of inhibiting neutrophil elastase and several other destructive neutrophil proteinases. The genetic defect is a point mutation that leads to misfolding of the mutant protein, which is referred to as α1-antitrypsin Z (ATZ). Because of its misfolding, ATZ is unable to efficiently traverse the secretory pathway. Accumulation of ATZ in the endoplasmic reticulum of liver cells has a gain-of-function proteotoxic effect on the liver, resulting in fibrosis, cirrhosis and/or hepatocellular carcinoma in some individuals. Moreover, because of reduced secretion, there is a lack of anti-proteinase activity in the lung, which allows neutrophil proteases to destroy the connective tissue matrix and cause chronic obstructive pulmonary disease (COPD) by loss of function. Wide variation in the incidence and severity of liver and lung disease among individuals with ATD has made this disease one of the most challenging of the rare genetic disorders to diagnose and treat. Other than cigarette smoking, which worsens COPD in ATD, genetic and environmental modifiers that determine this phenotypic variability are unknown. A limited number of therapeutic strategies are currently available, and liver transplantation is the only treatment for severe liver disease. Although replacement therapy with purified AT corrects the loss of anti-proteinase function, COPD progresses in a substantial number of individuals with ATD and some undergo lung transplantation. Nevertheless, advances in understanding the variability in clinical phenotype and in developing novel therapeutic concepts is beginning to address the major clinical challenges of this mysterious disorder. PMID:24719116

  8. Emerging novel and antimicrobial-resistant respiratory tract infections: new drug development and therapeutic options.

    PubMed

    Zumla, Alimuddin; Memish, Ziad A; Maeurer, Markus; Bates, Matthew; Mwaba, Peter; Al-Tawfiq, Jaffar A; Denning, David W; Hayden, Frederick G; Hui, David S

    2014-11-01

    The emergence and spread of antimicrobial-resistant bacterial, viral, and fungal pathogens for which diminishing treatment options are available is of major global concern. New viral respiratory tract infections with epidemic potential, such as severe acute respiratory syndrome, swine-origin influenza A H1N1, and Middle East respiratory syndrome coronavirus infection, require development of new antiviral agents. The substantial rise in the global numbers of patients with respiratory tract infections caused by pan-antibiotic-resistant Gram-positive and Gram-negative bacteria, multidrug-resistant Mycobacterium tuberculosis, and multiazole-resistant fungi has focused attention on investments into development of new drugs and treatment regimens. Successful treatment outcomes for patients with respiratory tract infections across all health-care settings will necessitate rapid, precise diagnosis and more effective and pathogen-specific therapies. This Series paper describes the development and use of new antimicrobial agents and immune-based and host-directed therapies for a range of conventional and emerging viral, bacterial, and fungal causes of respiratory tract infections.

  9. A comparison of the reactivating and therapeutic efficacy of two newly developed oximes (k727 and k733) with oxime k203 and trimedoxime in tabun-poisoned rats and mice.

    PubMed

    Kassa, Jiri; Sepsova, Vendula; Tumova, Martina; Horova, Anna; Musilek, Kamil

    2015-04-01

    The reactivating and therapeutic efficacy of three original bispyridinium oximes (K727, K733 and K203) and one currently available oxime (trimedoxime) was evaluated in tabun-poisoned rats and mice. The oxime-induced reactivation of tabun-inhibited acetylcholinesterase was measured in diaphragm and brain of tabun-poisoned rats. The results showed that the reactivating efficacy of two recently developed oximes (K727 and K733) does not achieve the level of the reactivation of tabun-inhibited acetylcholinesterase induced by oxime K203 and trimedoxime. While all oximes studied were able to increase the activity of tabun-inhibited acetylcholinesterase in diaphragm, oxime K733 was not able to reactivate tabun-inhibited acetylcholinesterase in the brain. The therapeutic efficacy of all oximes studied roughly corresponds to their reactivating efficacy. While both recently developed oximes were able to reduce acute toxicity of tabun less than 1.5-fold, another original oxime K203 and commonly used trimedoxime reduced the acute toxicity of tabun almost two times. In conclusion, the reactivating and therapeutic potency of both newly developed oximes does not prevail the effectiveness of oxime K203 and trimedoxime, and therefore, they are not suitable for their replacement of commonly used oximes for the antidotal treatment of acute tabun poisoning.

  10. Emerging therapeutic paradigms to target the dysregulated JAK/STAT pathways in hematological malignancies

    PubMed Central

    Mughal, Tariq I.; Girnius, Saulius; Rosen, Steven T.; Kumar, Shaji; Wiestner, Adrian; Abdel-Wahab, Omar; Kiladjian, Jean-Jacques; Wilson, Wyndham H.; Van Etten, Richard A.

    2014-01-01

    Over the past decade, there has been increasing biochemical evidence that the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is aberrantly activated in malignant cells from patients with a wide spectrum of cancers of the blood and immune systems. The emerging availability of small molecule inhibitors of JAK kinases and other signaling molecules in the JAK-STAT pathway has allowed preclinical studies validating an important role of this pathway in the pathogenesis of many hematologic malignancies, and provided motivation for new strategies for treatment of these diseases. Here, a roundtable panel of experts reviews the current preclinical and clinical landscape of the JAK-STAT pathway in acute lymphoid and myeloid leukemias, lymphomas and myeloma, and chronic myeloid neoplasms. PMID:24206094

  11. T cell coinhibition in prostate cancer: new immune evasion pathways and emerging therapeutics

    PubMed Central

    Barach, Yael S; Lee, Jun Sik; Zang, Xingxing

    2010-01-01

    T cell-mediated adaptive immune response is controlled by both positive costimulation and negative coinhibition, generated mainly by the interaction between the B7 family and their receptor CD28 family. Coinhibition is exploited by prostate cancer as an immune evasion pathway. Overexpression of coinhibitory B7x and B7-H3 in prostate cancer correlates with poor disease outcome, whereas tumor-infiltrating immune cells have enhanced expression of PD-L1 and its receptor PD-1. New insights into the complex mechanisms governing B7 expression in the tumor microenvironment have been reported and therapies aimed at overcoming T cell coinhibition with antagonistic monoclonal antibodies are emerging as effective tumor immunotherapies. Therapies that block B7x and B7-H3, either as monotherapies or in synergism with traditional therapies, should be pursued. PMID:20971039

  12. Therapeutic Approaches for Renal Colic in the Emergency Department: A Review Article

    PubMed Central

    Golzari, Samad EJ; Soleimanpour, Hassan; Rahmani, Farzad; Zamani Mehr, Nahid; Safari, Saeid; Heshmat, Yaghoub; Ebrahimi Bakhtavar, Hanieh

    2014-01-01

    Context: Renal colic is frequently described as the worst pain ever experienced, and management of this intense pain is necessary. The object of our review was to discuss different approaches of pain control for patients with acute renal colic in the emergency department. Evidence Acquisition: Studies that discussed the treatment of renal colic pain were included in this review. We collected articles from reputable internet databases. Results: Our study showed that some new treatment approaches, such as the use of lidocaine or nerve blocks, can be used to control the severe and persistent pain of renal colic. Conclusions: Some new approaches are discussed and their impact on renal colic pain control was compared with traditional therapies. The effectiveness of the new approaches in this review is similar or even better than in traditional treatments. PMID:24701420

  13. New advances in molecular mechanisms and emerging therapeutic targets in alcoholic liver diseases

    PubMed Central

    Williams, Jessica A; Manley, Sharon; Ding, Wen-Xing

    2014-01-01

    Alcoholic liver disease is a major health problem in the United States and worldwide. Chronic alcohol consumption can cause steatosis, inflammation, fibrosis, cirrhosis and even liver cancer. Significant progress has been made to understand key events and molecular players for the onset and progression of alcoholic liver disease from both experimental and clinical alcohol studies. No successful treatments are currently available for treating alcoholic liver disease; therefore, development of novel pathophysiological-targeted therapies is urgently needed. This review summarizes the recent progress on animal models used to study alcoholic liver disease and the detrimental factors that contribute to alcoholic liver disease pathogenesis including miRNAs, S-adenosylmethionine, Zinc deficiency, cytosolic lipin-1β, IRF3-mediated apoptosis, RIP3-mediated necrosis and hepcidin. In addition, we summarize emerging adaptive protective effects induced by alcohol to attenuate alcohol-induced liver pathogenesis including FoxO3, IL-22, autophagy and nuclear lipin-1α. PMID:25278688

  14. Emergency coronary and peripheral arteries combined with percutaneous intervention in the elderly: success or therapeutic excess?

    PubMed

    Pepe, Martino; Furgieri, Alessandro; Miranda, Marianna; Cafaro, Alessandro; Paradies, Valeria; Iacovelli, Fortunato; Castriota, Fausto; Liso, Armando

    2015-09-01

    Acute lower extremities peripheral artery disease represents a clinical emergency. Peripheral artery disease incidence ranges from 2.5 to 22% and has progressively increased due to the world population aging phenomenon and associates with coronary artery disease with a rate of 40-60%. The authors present the case of an 89-year-old man coming to their attention with acute lower extremities ischemia and unstable angina. Despite the short-to-midterm favorable outcome, doubts remain about the opportunity of treating 'very old' patients. The lack of dedicated randomized trials and of defined guidelines is a problem the scientific community needs to face considering that patients over 85 years represent a raising quote of the whole population of our catheterization laboratories.

  15. Lipid Mediators of Allergic Disease: Pathways, Treatments, and Emerging Therapeutic Targets

    PubMed Central

    Schauberger, Eric; Peinhaupt, Miriam; Cazares, Tareian

    2017-01-01

    Bioactive lipids are critical regulators of inflammation. Over the last 75 years, these diverse compounds have emerged as clinically-relevant mediators of allergic disease pathophysiology. Animal and human studies have demonstrated the importance of lipid mediators in the development of asthma, allergic rhinitis, urticaria, anaphylaxis, atopic dermatitis, and food allergy. Lipids are critical participants in cell signaling events which influence key physiologic (bronchoconstriction) and immune phenomena (degranulation, chemotaxis, sensitization). Lipid-mediated cellular mechanisms including: (1) formation of structural support platforms (lipid rafts) for receptor signaling complexes, (2) activation of a diverse family of G-protein coupled receptors, and (3) mediating intracellular signaling cascades by acting as second messengers. Here, we review four classes of bioactive lipids (platelet activating factor, the leukotrienes, the prostanoids, and the sphingolipids) with special emphasis on lipid synthesis pathways and signaling, atopic disease pathology, and the ongoing development of atopy treatments targeting lipid mediator pathways. PMID:27333777

  16. Contemporary Review of Testicular Torsion: New Concepts, Emerging Technologies and Potential Therapeutics

    PubMed Central

    DaJusta, Daniel; Granberg, Candace F.; Villanueva, Carlos; Baker, Linda A.

    2012-01-01

    Testicular torsion is one of the few emergencies in pediatric urology which requires an accurate and timely diagnosis in order to avoid testis loss. It is not an uncommon event affecting a young male population. In fact, testicular torsion is more common than testicular tumors for this same age group, yet testicular torsion has not been given the public attention it deserves as a male health risk. In this review we highlight the new information published over the past four years regarding testicular torsion. We will discuss a variety of topics associated with torsion including: medical legal issues, etiology and genetics, imaging diagnostics, innovative surgical techniques, management controversies, fertility, and new drug therapies. PMID:23044376

  17. Bioterrorism and emerging infectious disease - antimicrobials, therapeutics and immune-modulators. SARS coronavirus.

    PubMed

    Shurtleff, Amy C

    2004-02-01

    The purpose of this meeting was to provide a forum for expert presentations and discussion about the threats of bioterrorism and emerging infectious diseases, and to address the issues relating to epidemics, prevention of infection and treatment of some of these emerging infectious diseases classified as potential agents of bioterror. Included in the talks were state-of-the-art presentations about infectious clone technology and recombinant viruses, pathogen and receptor interactions at the cellular and molecular level, genomic responses to infection, and new information on antiviral mechanisms of action. Severe acute respiratory syndrome (SARS) and progress toward understanding the epidemic was addressed, and other sessions were presented concerning immune therapy and immunopotentiation of disease, siRNA and gene silencing, host responses to pathogen infections, as well as the use of genetic engineering to circumvent and direct the immune response. Many discussions were held and data were presented about possible compounds and new drugs that may have antiviral properties, yet there were few discussions of any available new drugs. This report addresses reverse genetics of SARS virus, as well as its epidemiology, and a host of different recent approaches to developing antivirals effective against SARS, including some potential vaccine candidates. Also presented are hypotheses about the human immune response to SARS infection, as well as immune therapies against botulinum and anthrax toxins. This report also addresses antiviral approaches exploiting siRNAs, and different aspects of the host immune response to many of the different dangerous pathogens discussed at this meeting. Finally, approaches to circumventing and directing the immune response using genetic engineering will be reported.

  18. 'Doing the writing' and 'working in parallel': how 'distal nursing' affects delegation and supervision in the emerging role of the newly qualified nurse.

    PubMed

    Johnson, Martin; Magnusson, Carin; Allan, Helen; Evans, Karen; Ball, Elaine; Horton, Khim; Curtis, Kathy; Westwood, Sue

    2015-02-01

    The role of the acute hospital nurse has moved away from the direct delivery of patient care and more towards the management of the delivery of bedside care by healthcare assistants. How newly qualified nurses delegate to and supervise healthcare assistants is important as failures can lead to care being missed, duplicated and/or incorrectly performed. The data described here form part of a wider study which explored how newly qualified nurses recontextualise knowledge into practice, and develop and apply effective delegation and supervision skills. This article analyses team working between newly qualified nurses and healthcare assistants, and nurses' balancing of administrative tasks with bedside care. Ethnographic case studies were undertaken in three hospital sites in England, using a mixed methods approach involving: participant observations; interviews with 33 newly qualified nurses, 10 healthcare assistants and 12 ward managers. Data were analysed using thematic analysis, aided by the qualitative software NVivo. Multiple demands upon the newly qualified nurses' time, particularly the pressures to maintain records, can influence how effectively they delegate to, and supervise, healthcare assistants. While some nurses and healthcare assistants work successfully together, others work 'in parallel' rather than as an efficient team. While some ward cultures and individual working styles promote effective team working, others lead to less efficient collaboration between newly qualified nurses and healthcare assistants. In particular the need for qualified nurses to maintain records can create a gap between them, and between nurses and patients. Newly qualified nurses require more assistance in managing their own time and developing successful working relationships with healthcare assistants. Copyright © 2014 Elsevier Ltd. All rights reserved.

  19. Reactive Oxygen-Related Diseases: Therapeutic Targets and Emerging Clinical Indications

    PubMed Central

    Daiber, Andreas; Maghzal, Ghassan J.; Di Lisa, Fabio; Kaludercic, Nina; Leach, Sonia; Cuadrado, Antonio; Jaquet, Vincent; Seredenina, Tamara; Krause, Karl H.; López, Manuela G.; Stocker, Roland

    2015-01-01

    Abstract Significance: Enhanced levels of reactive oxygen species (ROS) have been associated with different disease states. Most attempts to validate and exploit these associations by chronic antioxidant therapies have provided disappointing results. Hence, the clinical relevance of ROS is still largely unclear. Recent Advances: We are now beginning to understand the reasons for these failures, which reside in the many important physiological roles of ROS in cell signaling. To exploit ROS therapeutically, it would be essential to define and treat the disease-relevant ROS at the right moment and leave physiological ROS formation intact. This breakthrough seems now within reach. Critical Issues: Rather than antioxidants, a new generation of protein targets for classical pharmacological agents includes ROS-forming or toxifying enzymes or proteins that are oxidatively damaged and can be functionally repaired. Future Directions: Linking these target proteins in future to specific disease states and providing in each case proof of principle will be essential for translating the oxidative stress concept into the clinic. Antioxid. Redox Signal. 23, 1171–1185. PMID:26583264

  20. Emerging role of orexin antagonists in insomnia therapeutics: An update on SORAs and DORAs.

    PubMed

    Kumar, Anil; Chanana, Priyanka; Choudhary, Supriti

    2016-04-01

    The pharmacological management of insomnia has lately become a challenge for researchers worldwide. As per the third International Classification of Sleep disorders (ICSD-3) insomnia can be defined as a state with repeated difficulty in sleep initiation, duration, consolidation, or quality that occurs despite adequate opportunity and circumstances for sleep, and results in some form of daytime impairment. The conventional treatments approved for management of insomnia were benzodiazepines (BZDs) (estazolam, quazepam, triazolam, flurazepam and temazepam) and non-BZDs, also known as z-drugs (zaleplon, zolpidem, and eszopiclone), tricyclic antidepressant (TCA) doxepin as well as melatonin agonists, e.g. ramelteon. But the potential of these agents to address sleep problems has been limited due to substantial side effects associated with them like hangover, dependence and tolerance, rebound insomnia, muscular atonia, inhibition of respiratory system, cognitive dysfunctions, and increased anxiety. Recently, orexin neuropeptides have been identified as regulators of transition between wakefulness and sleep and documented to aid an initial transitory effect towards wakefulness by activating cholinergic/monoaminergic neural pathways of the ascending arousal system. This has led to the development of orexin peptides and receptors, as possible therapeutic targets for the treatment of sleep disorders with the advantage of having lesser side effects as compared to conventional treatments. The present review focuses on the orexin peptides and receptors signifying their physiological profile as well as the development of orexin receptor antagonists as novel strategies in sleep medicine.

  1. Emergence of ETS transcription factors as diagnostic tools and therapeutic targets in prostate cancer.

    PubMed

    Rahim, Said; Uren, Aykut

    2013-01-01

    The discovery of chromosomal translocations in prostate cancer has greatly enhanced our understanding of prostate cancer biology. Genomic rearrangements involving the ETS family of transcription factors are estimated to be present in 50-70% of prostate cancer cases. These rearrangements fuse the ETS factors with promoters of genes that are androgen regulated. Thus, the expression of ETS factors, such as ERG, ETV1, ETV4 and ETV5, is mediated by androgen. In-vitro and in-vivo studies suggest that overexpression of ETS proteins increase cell proliferation and confer an invasive phenotype to prostate cancer cells. Epidemiological studies demonstrate that ETS-fusion positive patients exhibit tumors corresponding to a more advanced disease. The ability of ETS factors to serve as markers for screening and diagnosing prostate cancer patients is being investigated, and the results have been largely positive to date. Additionally, ETS factors present an excellent opportunity as therapeutic targets and several strategies have been devised to directly target ETS proteins or their binding partners and downstream effectors.

  2. New and emerging developments in extensive-stage small cell lung cancer therapeutics.

    PubMed

    Parikh, Mamta; Riess, Jonathan; Lara, Primo N

    2016-03-01

    Extensive-stage small cell lung cancer (ES-SCLC) remains a disease with a dismal prognosis, with median survival of approximately 8-10 months. Despite many attempts to develop effective systemic therapies, very little progress has been made in the last several decades. Platinum-based combination chemotherapy remains the standard of care in the first-line setting and is associated with high response rates albeit short-lived. However, there have been recent advances in the use of radiation therapy, as well as new insights into the biology of SCLC. Some of the most appreciable advances in the last decade have involved the use of local radiation therapy. With the use of new laboratory techniques such as genomic sequencing, there remains promise of rationally targeted drug development. Circulating tumor cell research may also provide insights to SCLC biology and further refine treatment. Systemic therapy for SCLC has changed little over the past 30 years with the most significant advances in ES-SCLC relating to radiotherapy rather than systemic therapy. The effectiveness of prophylactic cranial irradiation and thoracic radiotherapy has renewed interest in therapeutics focused on the modulation of DNA damage or repair. Recent developments in genomic sequencing and immunotherapy may translate to new treatment paradigms for SCLC.

  3. BRCA1 and microRNAs: emerging networks and potential therapeutic targets.

    PubMed

    Chang, Suhwan; Sharan, Shyam K

    2012-11-01

    BRCA1 is a well-known tumor suppressor implicated in familial breast and ovarian cancer. Since its cloning in 1994, numerous studies have established BRCA1's role in diverse cellular and biochemical processes, such as DNA damage repair, cell cycle control, and transcriptional regulation as well as ubiquitination. In addition, a number of recent studies have functionally linked this tumor suppressor to another important cellular regulator, microRNAs, which are short (19-22 nt) RNAs that were discovered in the nematode in 1993. Soon their presence and function were validated in mammals, and since then, the role of microRNAs has been actively investigated in almost all biological processes, including cancer. In this review, we will describe recent progress in the understanding of the BRCA1 function through microRNAs and the role of microRNAs in regulating BRCA1, with emphasis on the implication of these processes on the development and progression of cancer. We will also discuss the therapeutic potential of microRNA mimics or inhibitors of microRNAs to affect BRCA1 function.

  4. Emerging therapeutic approaches based on nanotechnology for the treatment of diseases associated with telomere dysfunction.

    PubMed

    Egusquiaguirre, Susana Patricia; Pedraz, Jose Luis; Hernandez, Rosa Maria; Igartua, Manuela

    2015-01-01

    Telomeric diseases are a group of rare progeroid genetic syndromes, presenting premature aging phenotypes, characterized for defects on telomere maintenance. In humans, telomeres are heterochromatic structures consisting of long TTAGGG repeats located at the chromosomal ends, which shorten progressively after each DNA replication because of the 'end replication problem'. Critically short telomeres activate a DNA damage response that leads to the arrest of the cell cycle and resulting in cellular senescence or apoptosis. Furthermore, excessively short telomeres are prone to create telomeric fusions, causing genomic instability and malignant transformation. In order to counteract this process, there are two enzymatic complexes, the telomerase complex, with the capacity to elongate telomeres; and the shelterin complex, which protects them from being recognized as DNA breaks. Over the last few decades, several studies have confirmed that critically short telomeres and defects in telomere-associated enzymatic complexes are involved in the development of a group of rare human genetic diseases, with the accumulation of excessive telomere attrition as the underlying cause of these pathologies. Despite the severity of these disorders, there is no curative treatment for any of them. In light of this, this review summarizes the most important defective telomere diseases, their current management, and it presents possible therapeutic strategies based on nanotechnology which may open up new possibilities for their treatment.

  5. Dendritic Cell-Based Vaccination in Cancer: Therapeutic Implications Emerging from Murine Models

    PubMed Central

    Mac Keon, Soledad; Ruiz, María Sol; Gazzaniga, Silvina; Wainstok, Rosa

    2015-01-01

    Dendritic cells (DCs) play a pivotal role in the orchestration of immune responses, and are thus key targets in cancer vaccine design. Since the 2010 FDA approval of the first cancer DC-based vaccine (Sipuleucel-T), there has been a surge of interest in exploiting these cells as a therapeutic option for the treatment of tumors of diverse origin. In spite of the encouraging results obtained in the clinic, many elements of DC-based vaccination strategies need to be optimized. In this context, the use of experimental cancer models can help direct efforts toward an effective vaccine design. This paper reviews recent findings in murine models regarding the antitumoral mechanisms of DC-based vaccination, covering issues related to antigen sources, the use of adjuvants and maturing agents, and the role of DC subsets and their interaction in the initiation of antitumoral immune responses. The summary of such diverse aspects will highlight advantages and drawbacks in the use of murine models, and contribute to the design of successful DC-based translational approaches for cancer treatment. PMID:26042126

  6. Emerging Applications of Therapeutic Ultrasound in Neuro-oncology: Moving Beyond Tumor Ablation.

    PubMed

    Hersh, David S; Kim, Anthony J; Winkles, Jeffrey A; Eisenberg, Howard M; Woodworth, Graeme F; Frenkel, Victor

    2016-11-01

    : Transcranial focused ultrasound (FUS) can noninvasively transmit acoustic energy with a high degree of accuracy and safety to targets and regions within the brain. Technological advances, including phased-array transducers and real-time temperature monitoring with magnetic resonance thermometry, have created new opportunities for FUS research and clinical translation. Neuro-oncology, in particular, has become a major area of interest because FUS offers a multifaceted approach to the treatment of brain tumors. FUS has the potential to generate cytotoxicity within tumor tissue, both directly via thermal ablation and indirectly through radiosensitization and sonodynamic therapy; to enhance the delivery of therapeutic agents to brain tumors by transiently opening the blood-brain barrier or improving distribution through the brain extracellular space; and to modulate the tumor microenvironment to generate an immune response. In this review, we describe each of these applications for FUS, the proposed mechanisms of action, and the preclinical and clinical studies that have set the foundation for using FUS in neuro-oncology.

  7. Low temperature plasmas as emerging cancer therapeutics: the state of play and thoughts for the future.

    PubMed

    Hirst, Adam M; Frame, Fiona M; Arya, Manit; Maitland, Norman J; O'Connell, Deborah

    2016-06-01

    The field of plasma medicine has seen substantial advances over the last decade, with applications developed for bacterial sterilisation, wound healing and cancer treatment. Low temperature plasmas (LTPs) are particularly suited for medical purposes since they are operated in the laboratory at atmospheric pressure and room temperature, providing a rich source of reactive oxygen and nitrogen species (RONS). A great deal of research has been conducted into the role of reactive species in both the growth and treatment of cancer, where long-established radio- and chemo-therapies exploit their ability to induce potent cytopathic effects. In addition to producing a plethora of RONS, LTPs can also create strong electroporative fields. From an application perspective, it has been shown that LTPs can be applied precisely to a small target area. On this basis, LTPs have been proposed as a promising future strategy to accurately and effectively control and eradicate tumours. This review aims to evaluate the current state of the literature in the field of plasma oncology and highlight the potential for the use of LTPs in combination therapy. We also present novel data on the effect of LTPs on cancer stem cells, and speculatively outline how LTPs could circumvent treatment resistance encountered with existing therapeutics.

  8. Emerging Role of Spinal Dynorphin in Chronic Pain, a Therapeutic Perspective

    PubMed Central

    Podvin, Sonia; Yaksh, Tony; Hook, Vivian

    2016-01-01

    Notable findings point to the significance of the dynorphin peptide neurotransmitter in chronic pain. Spinal dynorphin neuropeptide levels are elevated during development of chronic pain. Importantly, knockout of the dynorphin gene prevents development of chronic pain in mice, but acute nociception is unaffected. Intrathecal (IT) administration of opioid and non-opioid dynorphin peptides initiate allodynia through a non-opioid receptor mechanism; furthermore, anti-dynorphin antibodies administered by the IT route attenuate chronic pain. Thus, this review presents the compelling evidence in the field supporting the role of dynorphin in facilitating the development of a persistent pain state. These observations raise the question of the control mechanisms responsible for the upregulation of spinal dynorphin leading to chronic pain development. Also, spinal dynorphin regulation of downstream signaling molecules may be implicated in hyperpathic states. Therapeutic strategies to reduce spinal dynorphin may provide a non-addictive approach to improve the devastating condition of chronic pain that occurs in numerous human diseases. PMID:26738478

  9. Neurotrophic factor small-molecule mimetics mediated neuroregeneration and synaptic repair: emerging therapeutic modality for Alzheimer's disease.

    PubMed

    Kazim, Syed Faraz; Iqbal, Khalid

    2016-07-11

    brain-derived neurotrophic factor (BDNF) expression. It robustly inhibits tau abnormal hyperphosphorylation via increased BDNF mediated decrease in glycogen synthase kinase-3β (GSK-3β, major tau kinase) activity. P021 is a small molecular weight, BBB permeable compound with suitable pharmacokinetics for oral administration, and without adverse effects associated with native CNTF or BDNF molecule. P021 has shown beneficial therapeutic effect in several preclinical studies and has emerged as a highly promising compound for AD drug development.

  10. Novel and emerging drugs for systemic lupus erythematosus: mechanism of action and therapeutic activity.

    PubMed

    Robak, E; Robak, T

    2012-01-01

    Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by B cell hyperactivity and defective T-cell function, and several cytokine aberrations, with high titer production of autoantibodies and clinical involvement in multiple organ systems. It can present with a wide variety of symptoms, most commonly involving the skin, joints, kidneys, and blood vessels. Patients with mild SLE can be treated with non-steroidal antiinflammatory drugs and antimalarials. Corticosteroids, azathioprine and cyclophosphamide, remain important for long term management of most patients with active disease. In recent years, significant progress in molecular and cellular biology of SLE has resulted in a better characterization and understanding of the biology and prognosis of this disease. These achievements have provided new opportunities for the development of innovative, more effective, therapies. Novel agents potentially useful in the treatment of patients with SLE include tolerogens, monoclonal antibodies and other agents. Tolerogens are synthetic molecules that can bind and cross-link autoantibodies on reactive B-cell surface, promoting B-cell depletion or inactivity. An anti-DNA antibody based peptide, pCons, might have also therapeutic efficacy in SLE patients who are positive for anti-DNA antibodies. In addition, prasterone, a proprietary synthetic dehydroepiandrosterone product is under investigation for the treatment of SLE. Blockade of TLR9 with specific G-rich DNAoligonucleotids also suppresses lupus activity. Several newer mAbs have been developed and are being evaluated in phase I/II clinical trials. These include newer anti-CD20 mAbs, anti-cytokine therapies, anti-BLys mAbs and anti-C5 mAbs. Most of the new agents which could be potentially useful in the treatment of patients with SLE need further laboratory investigations and clinical trials. In this review, promising new agents, potentially useful in SLE, are presented.

  11. Reactive oxygen species signalling in the diabetic heart: emerging prospect for therapeutic targeting.

    PubMed

    Wilson, Adam J; Gill, Eleanor K; Abudalo, Rawan A; Edgar, Kevin S; Watson, Chris J; Grieve, David J

    2017-09-27

    Despite being first described 45 years ago, the existence of a distinct diabetic cardiomyopathy remains controversial. Nonetheless, it is widely accepted that the diabetic heart undergoes characteristic structural and functional changes in the absence of ischaemia and hypertension, which are independently linked to heart failure progression and are likely to underlie enhanced susceptibility to stress. A prominent feature is marked collagen accumulation linked with inflammation and extensive extracellular matrix changes, which appears to be the main factor underlying cardiac stiffness and subclinical diastolic dysfunction, estimated to occur in as many as 75% of optimally controlled diabetics. Whether this characteristic remodelling phenotype is primarily driven by microvascular dysfunction or alterations in cardiomyocyte metabolism remains unclear. Although hyperglycaemia regulates multiple pathways in the diabetic heart, increased reactive oxygen species (ROS) generation is thought to represent a central mechanism underlying associated adverse remodelling. Indeed, experimental and clinical diabetes are linked with oxidative stress which plays a key role in cardiomyopathy, while key processes underlying diabetic cardiac remodelling, such as inflammation, angiogenesis, cardiomyocyte hypertrophy and apoptosis, fibrosis and contractile dysfunction, are redox sensitive. This review will explore the relative contributions of the major ROS sources (dysfunctional nitric oxide synthase, mitochondria, xanthine oxidase, nicotinamide adenine dinucleotide phosphate oxidases) in the diabetic heart and the potential for therapeutic targeting of ROS signalling using novel pharmacological and non-pharmacological approaches to modify specific aspects of the remodelling phenotype in order to prevent and/or delay heart failure development and progression. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No

  12. The therapeutic management of gut barrier leaking: the emerging role for mucosal barrier protectors.

    PubMed

    Lopetuso, L R; Scaldaferri, F; Bruno, G; Petito, V; Franceschi, F; Gasbarrini, A

    2015-01-01

    Gut barrier is a functional unit organized as a multi-layer system and its multiple functions are crucial for maintaining gut homeostasis. Numerous scientific evidences showed a significant association between gut barrier leaking and gastro-intestinal/extra-intestinal diseases. In this review we focus on the relationship between gut barrier leaking and human health. At the same time we speculate on the possible new role of gut barrier protectors in enhancing and restoring gut barrier physiology with the final goal of promoting gut health. The alteration of the equilibrium in gut barrier leads to the passage of the luminal contents to the underlying tissues and thus into the bloodstream, resulting in the activation of the immune response and in the induction of gut inflammation. This permeability alteration is the basis for the pathogenesis of many diseases, including infectious enterocolitis, inflammatory bowel diseases, irritable bowel syndrome, small intestinal bacterial overgrowth, celiac disease, hepatic fibrosis, food intolerances and also atopic manifestations. Many drugs or compounds used in the treatment of gastrointestinal disease are able to alter the permeability of the intestinal barrier. Recent data highlighted and introduced the possibility of using gelatin tannate, a mucosal barrier protector, for an innovative approach in the management of intestinal diseases, allowing an original therapeutic orientation with the aim of enhancing mucus barrier activity and restoring gut barrier. These results suggest how the mucus layer recovering, beside the gut microbiota modulation, exerted by gut barrier protectors could be a useful weapon to re-establish the physiological intestinal homeostasis after an acute and chronic injury.

  13. Current and Emerging Therapeutic Strategies for the Treatment of Meibomian Gland Dysfunction (MGD).

    PubMed

    Thode, Adam R; Latkany, Robert A

    2015-07-01

    Meibomian gland (MG) dysfunction (MGD) is a multifactorial, chronic condition of the eyelids, leading to eye irritation, inflammation and ocular surface disease. Initial conservative therapy often includes a combination of warm compresses in addition to baby shampoo or eyelid wipes. The practice of lid hygiene dates back to the 1950s, when selenium sulfide-based shampoo was first used to treat seborrhoeic dermatitis of the eyelids. Today, tear-free baby shampoo has replaced dandruff shampoo for MGD treatment and offers symptom relief in selected patients. However, many will not achieve significant improvement on this therapy alone; some may even develop an allergy to the added dyes and fragrances in these products. Other manual and mechanical techniques to treat MGD include MG expression and massage, MG probing and LipiFlow(®). While potentially effective in patients with moderate MGD, these procedures are more invasive and may be cost prohibitive. Pharmacological treatments are another course of action. Supplements rich in omega-3 fatty acids have been shown to improve both MGD and dry eye symptoms. Tea tree oil, specifically the terpenin-4-ol component, is especially effective in treating MGD associated with Demodex mites. Topical antibiotics, such as azithromycin, or systemic antibiotics, such as doxycycline or azithromycin, can improve MGD symptoms both by altering the ocular flora and through anti-inflammatory mechanisms. Addressing and treating concurrent ocular allergy is integral to symptom management. Topical N-acetylcysteine and topical cyclosporine can both be effective therapeutic adjuncts in patients with concurrent dry eye. A short course of topical steroid may be used in some severe cases, with monitoring for steroid-induced glaucoma and cataracts. While the standard method to treat MGD is simply warm compresses and baby shampoo, a more tailored approach to address the multiple aetiologies of the disease is suggested.

  14. [A nursing experience with a child with rape trauma by using therapeutic play in an emergency room].

    PubMed

    Kao, Ying-Fen; Liu, Shu-Hua

    2005-02-01

    This article conceptualized a therapeutic game theory to discuss the pickings process of a preschool sexually violated victim with respect to nursing care delivery in our department of emergency medicine. In cooperation with the victim, we offered support to prevent her from fearing loss of her capacity for self-defense when facing a similar scenario. The overall exercise included observation time, a return outpatient visit and a follow-up phone interview. By using observation, role-play, leading drawing and interviews, we used Piaget's Cognitive Child Development model and game therapy theory to reduce the victim's sense of fear and shame, inducing the victim to eliminate her confusion by talking and to complete the whole pickings process.

  15. Emerging Roles of the Host Defense Peptide LL-37 in Human Cancer and its Potential Therapeutic Applications

    PubMed Central

    Wu, William K.K.; Wang, Guangshun; Coffelt, Seth B.; Betancourt, Aline M.; Lee, Chung W.; Fan, Daiming; Wu, Kaichun; Yu, Jun; Sung, Joseph J.Y.; Cho, Chi H.

    2010-01-01

    Human cathelicidin LL-37, a host defense peptide derived from leukocytes and epithelial cells, plays a crucial role in innate and adaptive immunity. Not only does it eliminate pathogenic microbes directly, LL-37 also modulates host immune responses. Emerging evidence from tumor biology studies indicates that LL-37 plays a prominent and complex role in carcinogenesis. While overexpression of LL-37 has been implicated in the development or progression of many human malignancies, including breast, ovarian and lung cancers, LL-37 suppresses tumorigenesis in gastric cancer. These data are beginning to unveil the intricate and contradictory functions of LL-37. The reasons for the tissue-specific function of LL-37 in carcinogenesis remain to be elucidated. Here, we review the relationship between LL-37, its fragments and cancer progression as well as discuss the potential therapeutic implications of targeting this peptide. PMID:20521250

  16. Emerging roles of the host defense peptide LL-37 in human cancer and its potential therapeutic applications.

    PubMed

    Wu, William K K; Wang, Guangshun; Coffelt, Seth B; Betancourt, Aline M; Lee, Chung W; Fan, Daiming; Wu, Kaichun; Yu, Jun; Sung, Joseph J Y; Cho, Chi H

    2010-10-15

    Human cathelicidin LL-37, a host defense peptide derived from leukocytes and epithelial cells, plays a crucial role in innate and adaptive immunity. Not only does LL-37 eliminate pathogenic microbes directly but also modulates host immune responses. Emerging evidence from tumor biology studies indicates that LL-37 plays a prominent and complex role in carcinogenesis. Although overexpression of LL-37 has been implicated in the development or progression of many human malignancies, including breast, ovarian and lung cancers, LL-37 suppresses tumorigenesis in gastric cancer. These data are beginning to unveil the intricate and contradictory functions of LL-37. The reasons for the tissue-specific function of LL-37 in carcinogenesis remain to be elucidated. Here, we review the relationship between LL-37, its fragments and cancer progression as well as discuss the potential therapeutic implications of targeting this peptide.

  17. Therapeutic Affordances of Social Media: Emergent Themes From a Global Online Survey of People With Chronic Pain

    PubMed Central

    Gray, Kathleen; Martin-Sanchez, Fernando

    2014-01-01

    Background Research continues to present tenuous suggestions that social media is well suited to enhance management of chronic disease and improve health outcomes. Various studies have presented qualitative reports of health outcomes from social media use and have examined discourse and communication themes occurring through different social media. However, there is an absence of published studies examining and unpacking the underlying therapeutic mechanisms driving social media’s effects. Objective This paper presents a qualitative analysis thoroughly describing what social media therapeutically affords people living with chronic pain who are self-managing their condition. From this therapeutic affordance perspective, we aim to formulate a preliminary conceptual model aimed at better understanding "how" social media can influence patient outcomes. Methods In total, 218 people with chronic pain (PWCP) completed an online survey, investigating patient-reported outcomes (PROs) from social media use. Supplementary to quantitative data collected, participants were also given the opportunity to provide further open commentary regarding their use of social media as part of chronic pain management; 68/218 unique users (31.2%) chose to provide these free-text responses. Through thematic content analysis, 117 free-text responses regarding 10 types of social media were coded. Quotes were extracted and tabulated based on therapeutic affordances that we had previously identified. Inductive analysis was then performed to code defining language and emergent themes central to describing each affordance. Three investigators examined the responses, developed the coding scheme, and applied the coding to the data. Results We extracted 155 quotes from 117 free-text responses. The largest source of quotes came from social network site users (78/155, 50.3%). Analysis of component language used to describe the aforementioned affordances and emergent themes resulted in a final revision

  18. Therapeutic affordances of social media: emergent themes from a global online survey of people with chronic pain.

    PubMed

    Merolli, Mark; Gray, Kathleen; Martin-Sanchez, Fernando

    2014-12-22

    Research continues to present tenuous suggestions that social media is well suited to enhance management of chronic disease and improve health outcomes. Various studies have presented qualitative reports of health outcomes from social media use and have examined discourse and communication themes occurring through different social media. However, there is an absence of published studies examining and unpacking the underlying therapeutic mechanisms driving social media's effects. This paper presents a qualitative analysis thoroughly describing what social media therapeutically affords people living with chronic pain who are self-managing their condition. From this therapeutic affordance perspective, we aim to formulate a preliminary conceptual model aimed at better understanding "how" social media can influence patient outcomes. In total, 218 people with chronic pain (PWCP) completed an online survey, investigating patient-reported outcomes (PROs) from social media use. Supplementary to quantitative data collected, participants were also given the opportunity to provide further open commentary regarding their use of social media as part of chronic pain management; 68/218 unique users (31.2%) chose to provide these free-text responses. Through thematic content analysis, 117 free-text responses regarding 10 types of social media were coded. Quotes were extracted and tabulated based on therapeutic affordances that we had previously identified. Inductive analysis was then performed to code defining language and emergent themes central to describing each affordance. Three investigators examined the responses, developed the coding scheme, and applied the coding to the data. We extracted 155 quotes from 117 free-text responses. The largest source of quotes came from social network site users (78/155, 50.3%). Analysis of component language used to describe the aforementioned affordances and emergent themes resulted in a final revision and renaming of therapeutic affordances

  19. Emerging roles for integrated imaging modalities in cardiovascular cell-based therapeutics: a clinical perspective.

    PubMed

    Psaltis, Peter J; Simari, Robert D; Rodriguez-Porcel, Martin

    2012-01-01

    Despite preclinical promise, the progress of cell-based therapy to clinical cardiovascular practice has been slowed by several challenges and uncertainties that have been highlighted by the conflicting results of human trials. Most telling has been the revelation that current strategies fall short of achieving sufficient retention and engraftment of cells to meet the ambitious objective of myocardial regeneration. This has sparked novel research into the refinement of cell biology and delivery to overcome these shortcomings. Within this context, molecular imaging has emerged as a valuable tool for providing noninvasive surveillance of cell fate in vivo. Direct and indirect labelling of cells can be coupled with clinically relevant imaging modalities, such as radionuclide single photon emission computed tomography and positron emission tomography, and magnetic resonance imaging, to assess their short- and long-term distributions, along with their viability, proliferation and functional interaction with the host myocardium. This review details the strengths and limitations of the different cell labelling and imaging techniques and their potential application to the clinical realm. We also consider the broader, multifaceted utility of imaging throughout the cell therapy process, providing a discussion of its considerable value during cell delivery and its importance during the evaluation of cardiac outcomes in clinical studies.

  20. Emerging roles for integrated imaging modalities in cardiovascular cell-based therapeutics: a clinical perspective

    PubMed Central

    Psaltis, Peter J.; Simari, Robert D.

    2012-01-01

    Despite preclinical promise, the progress of cell-based therapy to clinical cardiovascular practice has been slowed by several challenges and uncertainties that have been highlighted by the conflicting results of human trials. Most telling has been the revelation that current strategies fall short of achieving sufficient retention and engraftment of cells to meet the ambitious objective of myocardial regeneration. This has sparked novel research into the refinement of cell biology and delivery to overcome these shortcomings. Within this context, molecular imaging has emerged as a valuable tool for providing noninvasive surveillance of cell fate in vivo. Direct and indirect labelling of cells can be coupled with clinically relevant imaging modalities, such as radionuclide single photon emission computed tomography and positron emission tomography, and magnetic resonance imaging, to assess their short- and long-term distributions, along with their viability, proliferation and functional interaction with the host myocardium. This review details the strengths and limitations of the different cell labelling and imaging techniques and their potential application to the clinical realm. We also consider the broader, multifaceted utility of imaging throughout the cell therapy process, providing a discussion of its considerable value during cell delivery and its importance during the evaluation of cardiac outcomes in clinical studies. PMID:21901381

  1. Cationic host defense peptides; novel antimicrobial therapeutics against Category A pathogens and emerging infections.

    PubMed

    Findlay, Fern; Proudfoot, Lorna; Stevens, Craig; Barlow, Peter G

    2016-01-01

    Cationic Host Defense Peptides (HDP, also known as antimicrobial peptides) are crucial components of the innate immune system and possess broad-spectrum antibacterial, antiviral, and immunomodulatory activities. They can contribute to the rapid clearance of biological agents through direct killing of the organisms, inhibition of pro-inflammatory mediators such as lipopolysaccharide, and by modulating the inflammatory response to infection. Category A biological agents and materials, as classified by the United States National Institutes for Health, the US Centers for Disease Control and Prevention, and the US Department of Homeland Security, carry the most severe threat in terms of human health, transmissibility, and preparedness. As such, there is a pressing need for novel frontline approaches for prevention and treatment of diseases caused by these organisms, and exploiting the broad antimicrobial activity exhibited by cationic host defense peptides represents an exciting priority area for clinical research. This review will summarize what is known about the antimicrobial and antiviral effects of the two main families of cationic host defense peptides, cathelicidins, and defensins in the context of Category A biological agents which include, but are not limited to; anthrax (Bacillus anthracis), plague (Yersinia pestis), smallpox (Variola major), tularemia (Francisella tularensis). In addition, we highlight priority areas, particularly emerging viral infections, where more extensive research is urgently required.

  2. Boron neutron capture therapy of brain tumors: an emerging therapeutic modality.

    PubMed

    Barth, R F; Soloway, A H; Goodman, J H; Gahbauer, R A; Gupta, N; Blue, T E; Yang, W; Tjarks, W

    1999-03-01

    , as capture agents, and the Japanese trial is a Phase II study. Boron compound and neutron dose escalation studies are planned, and these could lead to Phase II and possibly to randomized Phase III clinical trials that should provide data regarding therapeutic efficacy.

  3. The emerging role of nitrite as an endogenous modulator and therapeutic agent of cardiovascular function.

    PubMed

    Tota, B; Quintieri, A M; Angelone, T

    2010-01-01

    Recently, the circulating anion nitrite (NO2-), the largest physiological reservoir of nitric oxide (NO) in the body, has revealed itself as a signalling molecule mediating numerous biological responses. Since it was estimated that as much as 70% of plasma nitrite originates from nitric oxide synthases (NOSs), mainly in the endothelium by endothelial NOS, nitrite is considered an index of NOSs activity. Exogenous sources, principally environmental pollutants and intake of vegetables, also contribute to this NO reserve. In mammalian blood, nitrite, present at nanomolar concentrations, can be reduced to bioactive NO along a physiological oxygen and pH gradient either non-enzymatically (acidic disproportionation) or by a number of enzymes including xanthine oxidoreductase, NOS, mitochondrial cytochromes and deoxygenated haemoglobin and myoglobin. The various NO-dependent nitrite-induced biological responses include hypoxic vasodilation, inhibition of mitochondrial respiration, cytoprotection following ischemia/reperfusion, and regulation of protein and gene expression. Since NO is a major paracrine-autocrine cardiovascular modulator and nitrite acts mainly as an endocrine store of NO, it is not surprising that NO2 - exerts important cardiovascular actions both under normal and physio-pathological conditions. In the interdisciplinary framework of the NO cycle concept, this review illustrates the actions exerted by nitrite on the cardiovascular system. Since the majority of the NO2 - -oriented studies focused on the systemic and regional control of blood flow both under physiological and ischemia/reperfusion conditions, we will firstly consider this issue. Secondly, the nitrite- induced effects on myocardial contractile and relaxation processes will be discussed, emphasizing the biomedical interest of nitrite as a new therapeutic agent. The importance of cardiac myoglobin as nitrite-reductase able to exert cardioprotection through a novel function, in addition to its

  4. The Nucleoprotein of Newly Emerged H7N9 Influenza A Virus Harbors a Unique Motif Conferring Resistance to Antiviral Human MxA

    PubMed Central

    Riegger, David; Hai, Rong; Dornfeld, Dominik; Mänz, Benjamin; Leyva-Grado, Victor; Sánchez-Aparicio, Maria T; Albrecht, Randy A.; Palese, Peter; Haller, Otto; Schwemmle, Martin; García-Sastre, Adolfo

    2014-01-01

    ABSTRACT Interferon-induced Mx proteins show strong antiviral activity against influenza A viruses (IAVs). We recently demonstrated that the viral nucleoprotein (NP) determines resistance of seasonal and pandemic human influenza viruses to Mx, while avian isolates retain Mx sensitivity. We identified a surface-exposed cluster of amino acids in NP of pandemic A/BM/1/1918 (H1N1), comprising isoleucine-100, proline-283, and tyrosine-313, that is essential for reduced Mx sensitivity in cell culture and in vivo. This cluster has been maintained in all descendant seasonal strains, including A/PR/8/34 (PR/8). Accordingly, two substitutions in the NP of PR/8 [PR/8(mut)] to the Mx-sensitive amino acids (P283L and Y313F) led to attenuation in Mx1-positive mice. Serial lung passages of PR/8(mut) in Mx1 mice resulted in a single exchange of tyrosine to asparagine at position 52 in NP (in close proximity to the amino acid cluster at positions 100, 283, and 313), which partially compensates loss of Mx resistance in PR/8(mut). Intriguingly, the NP of the newly emerged avian-origin H7N9 virus also contains an asparagine at position 52 and shows reduced Mx sensitivity. N52Y substitution in NP results in increased sensitivity of the H7N9 virus to human Mx, indicating that this residue is a determinant of Mx resistance in mammals. Our data strengthen the hypothesis that the human Mx protein represents a potent barrier against zoonotic transmission of avian influenza viruses. However, the H7N9 viruses overcome this restriction by harboring an NP that is less sensitive to Mx-mediated host defense. This might contribute to zoonotic transmission of H7N9 and to the severe to fatal outcome of H7N9 infections in humans. IMPORTANCE The natural host of influenza A viruses (IAVs) are aquatic birds. Occasionally, these viruses cross the species barrier, as in early 2013 when an avian H7N9 virus infected humans in China. Since then, multiple transmissions of H7N9 viruses to humans have occurred

  5. Sequence type 72 community-associated meticillin-resistant Staphylococcus aureus emerged as a predominant clone of nasal colonization in newly admitted patients.

    PubMed

    Park, S Y; Chung, D R; Yoo, J R; Baek, J Y; Kim, S H; Ha, Y E; Kang, C-I; Peck, K R; Lee, N Y; Song, J-H

    2016-08-01

    Current knowledge of community-associated (CA) meticillin-resistant Staphylococcus aureus (MRSA) carriage in hospitalized patients is incomplete. Genotypic characteristics of 637 nasal MRSA isolates from newly admitted patients in South Korea were investigated. Sequence type (ST) 72 accounted for 52.1%, 46.3%, and 52.8% of the isolates during the periods of 2007-2008, 2009-2010, and 2013-2014, respectively. Instead of classic MRSA clones responsible for healthcare-associated infections, including ST5 and ST239, MRSA with community genotype ST72 was the predominant strain in newly admitted patients regardless of age and home province of the patients. Active strategies are needed to prevent healthcare-associated infection by CA-MRSA. Copyright © 2015 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.

  6. Identification and Characterization of Potential Therapeutic Candidates in Emerging Human Pathogen Mycobacterium abscessus: A Novel Hierarchical In Silico Approach

    PubMed Central

    Shanmugham, Buvaneswari; Pan, Archana

    2013-01-01

    Mycobacterium abscessus, a non-tuberculous rapidly growing mycobacterium, is recognized as an emerging human pathogen causing a variety of infections ranging from skin and soft tissue infections to severe pulmonary infections. Lack of an optimal treatment regimen and emergence of multi-drug resistance in clinical isolates necessitate the development of better/new drugs against this pathogen. The present study aims at identification and qualitative characterization of promising drug targets in M. abscessus using a novel hierarchical in silico approach, encompassing three phases of analyses. In phase I, five sets of proteins were mined through chokepoint, plasmid, pathway, virulence factors, and resistance genes and protein network analysis. These were filtered in phase II, in order to find out promising drug target candidates through subtractive channel of analysis. The analysis resulted in 40 therapeutic candidates which are likely to be essential for the survival of the pathogen and non-homologous to host, human anti-targets, and gut flora. Many of the identified targets were found to be involved in different metabolisms (viz., amino acid, energy, carbohydrate, fatty acid, and nucleotide), xenobiotics degradation, and bacterial pathogenicity. Finally, in phase III, the candidate targets were qualitatively characterized through cellular localization, broad spectrum, interactome, functionality, and druggability analysis. The study explained their subcellular location identifying drug/vaccine targets, possibility of being broad spectrum target candidate, functional association with metabolically interacting proteins, cellular function (if hypothetical), and finally, druggable property. Outcome of the present study could facilitate the identification of novel antibacterial agents for better treatment of M. abscesses infections. PMID:23527108

  7. Major depression: emerging therapeutics.

    PubMed

    Sen, Srijan; Sanacora, Gerard

    2008-01-01

    The first effective antidepressants, monoamine oxidase inhibitors and tricyclic antidepressants, were identified 50 years ago, largely through serendipity. These medications were found to improve mood in a little more than half of depressed patients after a few weeks of chronic use. Almost all antidepressants prescribed today were developed through minor modifications of these original antidepressants and, like monoamine oxidase inhibitors and tricyclic antidepressants, act primarily through monoaminergic mechanisms. Although there have been improvements in side-effect profiles and overdose toxicity, these newer medications have not provided substantial advances in the efficacy and speed of the antidepressant effect for patients. Over the last 2 decades, our understanding of the neurobiology underlying depression has expanded exponentially. Given this expansion, we may be nearing an inflection point in antidepressant drug development, at which useful medicines will be designed through a rational understanding of the biological systems. In this review, we discuss the biological basis and preclinical and clinical evidence for a series of promising classes of antidepressants developed primarily out of a pathophysiologically informed approach.

  8. Emerging therapeutic targets in cancer induced bone disease: A focus on the peripheral type 2 cannabinoid receptor.

    PubMed

    Marino, Silvia; Idris, Aymen I

    2017-03-05

    Skeletal complications are a common cause of morbidity in patients with primary bone cancer and bone metastases. The type 2 cannabinoid (Cnr2) receptor is implicated in cancer, bone metabolism and pain perception. Emerging data have uncovered the role of Cnr2 in the regulation of tumour-bone cell interactions and suggest that agents that target Cnr2 in the skeleton have potential efficacy in the reduction of skeletal complications associated with cancer. This review aims to provide an overview of findings relating to the role of Cnr2 receptor in the regulation of skeletal tumour growth, osteolysis and bone pain, and highlights the many unanswered questions and unmet needs. This review argues that development and testing of peripherally-acting, tumour-, Cnr2-selective ligands in preclinical models of metastatic cancer will pave the way for future research that will advance our knowledge about the basic mechanism(s) by which the endocannabinoid system regulate cancer metastasis, stimulate the development of a safer cannabis-based therapy for the treatment of cancer and provide policy makers with powerful tools to assess the science and therapeutic potential of cannabinoid-based therapy. Thus, offering the prospect of identifying selective Cnr2 ligands, as novel, alternative to cannabis herbal extracts for the treatment of advanced cancer patients.

  9. The emerging roles and therapeutic potential of cyclin-dependent kinase 11 (CDK11) in human cancer

    PubMed Central

    Zhou, Yubing; Shen, Jacson K.; Hornicek, Francis J.; Kan, Quancheng; Duan, Zhenfeng

    2016-01-01

    Overexpression and/or hyperactivation of cyclin-dependent kinases (CDKs) are common features of most cancer types. CDKs have been shown to play important roles in tumor cell proliferation and growth by controlling cell cycle, transcription, and RNA splicing. CDK4/6 inhibitor palbociclib has been recently approved by the FDA for the treatment of breast cancer. CDK11 is a serine/threonine protein kinase in the CDK family and recent studies have shown that CDK11 also plays critical roles in cancer cell growth and proliferation. A variety of genetic and epigenetic events may cause universal overexpression of CDK11 in human cancers. Inhibition of CDK11 has been shown to lead to cancer cell death and apoptosis. Significant evidence has suggested that CDK11 may be a novel and promising therapeutic target for the treatment of cancers. This review will focus on the emerging roles of CDK11 in human cancers, and provide a proof-of-principle for continued efforts toward targeting CDK11 for effective cancer treatment. PMID:27049727

  10. Molecular detection of HIV-1 subtype B, CRF01_AE, CRF33_01B, and newly emerging recombinant lineages in Malaysia.

    PubMed

    Chook, Jack Bee; Ong, Lai Yee; Takebe, Yutaka; Chan, Kok Gan; Choo, Martin; Kamarulzaman, Adeeba; Tee, Kok Keng

    2015-03-01

    A molecular genotyping assay for human immunodeficiency virus type 1 (HIV-1) circulating in Southeast Asia is difficult to design because of the high level of genetic diversity. We developed a multiplex real-time polymerase chain reaction (PCR) assay to detect subtype B, CRF01_AE, CRF33_01B, and three newly described circulating recombinant forms, (CRFs) (CRF53_01B, CRF54_01B, and CRF58_01B). A total of 785 reference genomes were used for subtype-specific primers and TaqMan probes design targeting the gag, pol, and env genes. The performance of this assay was compared and evaluated with direct sequencing and phylogenetic analysis. A total of 180 HIV-infected subjects from Kuala Lumpur, Malaysia were screened and 171 samples were successfully genotyped, in agreement with the phylogenetic data. The HIV-1 genotype distribution was as follows: subtype B (16.7%); CRF01_AE (52.8%); CRF33_01B (24.4%); CRF53_01B (1.1%); CRF54_01B (0.6%); and CRF01_AE/B unique recombinant forms (4.4%). The overall accuracy of the genotyping assay was over 95.0%, in which the sensitivities for subtype B, CRF01_AE, and CRF33_01B detection were 100%, 100%, and 97.7%, respectively. The specificity of genotyping was 100%, inter-subtype specificities were > 95% and the limit of detection of 10(3) copies/mL for plasma. The newly developed real-time PCR assay offers a rapid and cost-effective alternative for large-scale molecular epidemiological surveillance for HIV-1. © The American Society of Tropical Medicine and Hygiene.

  11. S100A12 and the S100/Calgranulins - Emerging Biomarkers for Atherosclerosis and Possibly Therapeutic Targets

    PubMed Central

    Oesterle, Adam; Hofmann Bowman, Marion A

    2016-01-01

    Atherosclerosis is mediated by local and systematic inflammation. The multi-ligand receptor for advanced glycation end products (RAGE) has been studied in animals and humans, and is an important mediator of inflammation and atherosclerosis. This review focuses on S100/calgranulin proteins (S100A8, S100A9, and S100A12) and their receptor RAGE in mediating vascular inflammation. Mice lack the gene for S100A12, which in humans is located on chromosome 3 between S100A8 and S100A9. Transgenic mice with smooth muscle cell targeted expression of S100A12 demonstrate increased coronary and aortic calcification as well as increased plaque vulnerability. Serum S100A12 has recently been shown to predict future cardiovascular events in a longitudinal population study, underscoring a role for S100A12 as a potential biomarker for coronary artery disease. Genetic ablation of S100A9 or RAGE in atherosclerosis susceptible Apolipoprotein E (ApoE) null mice results in reduced atherosclerosis. Importantly, S100A12 and the RAGE axis can be modified pharmacologically. For example, soluble RAGE reduces murine atherosclerosis and vascular inflammation. Additionally, a class of compounds currently in phase III clinical trials for multiple sclerosis and rheumatologic conditions, the Quinoline-3-carboxamides, reduce atherosclerotic plaque burden and complexity in transgenic S100A12 ApoE null mice, but have not been tested with regards to human atherosclerosis. The RAGE axis is an important mediator for inflammation-induced atherosclerosis and S100A12 has emerged as biomarker for human atherosclerosis. Decreasing inflammation by inhibiting S100/calgranulin-mediated activation of RAGE attenuates murine atherosclerosis, and future studies in patients with coronary artery disease are warranted to confirm S100/RAGE as therapeutic target for atherosclerosis. PMID:26515415

  12. Voltage-Dependent Anion Channel 1 As an Emerging Drug Target for Novel Anti-Cancer Therapeutics

    PubMed Central

    Shoshan-Barmatz, Varda; Krelin, Yakov; Shteinfer-Kuzmine, Anna; Arif, Tasleem

    2017-01-01

    Cancer cells share several properties, high proliferation potential, reprogramed metabolism, and resistance to apoptotic cues. Acquiring these hallmarks involves changes in key oncogenes and non-oncogenes essential for cancer cell survival and prosperity, and is accompanied by the increased energy requirements of proliferating cells. Mitochondria occupy a central position in cell life and death with mitochondrial bioenergetics, biosynthesis, and signaling are critical for tumorigenesis. Voltage-dependent anion channel 1 (VDAC1) is situated in the outer mitochondrial membrane (OMM) and serving as a mitochondrial gatekeeper. VDAC1 allowing the transfer of metabolites, fatty acid ions, Ca2+, reactive oxygen species, and cholesterol across the OMM and is a key player in mitochondrial-mediate apoptosis. Moreover, VDAC1 serves as a hub protein, interacting with diverse sets of proteins from the cytosol, endoplasmic reticulum, and mitochondria that together regulate metabolic and signaling pathways. The observation that VDAC1 is over-expressed in many cancers suggests that the protein may play a pivotal role in cancer cell survival. However, VDAC1 is also important in mitochondria-mediated apoptosis, mediating release of apoptotic proteins and interacting with anti-apoptotic proteins, such as B-cell lymphoma 2 (Bcl-2), Bcl-xL, and hexokinase (HK), which are also highly expressed in many cancers. Strategically located in a “bottleneck” position, controlling metabolic homeostasis and apoptosis, VDAC1 thus represents an emerging target for anti-cancer drugs. This review presents an overview on the multi-functional mitochondrial protein VDAC1 performing several functions and interacting with distinct sets of partners to regulate both cell life and death, and highlights the importance of the protein for cancer cell survival. We address recent results related to the mechanisms of VDAC1-mediated apoptosis and the potential of associated proteins to modulate of VDAC1 activity

  13. Taking blood cultures from a newly established intravenous catheter in the emergency department does not increase the rate of contaminated blood cultures.

    PubMed

    Kelly, Anne-Maree; Klim, Sharon

    2013-10-01

    It has been suggested that blood cultures drawn from vascular catheters have a higher false positive rate than those drawn by venepuncture. In the face of institutionally imposed practice change prohibiting obtaining blood cultures from intravenous (i.v.) catheters in the ED, our aim of was to compare the rate of contaminated blood cultures between those taken from recently placed i.v. catheters and those taken by direct venepuncture. Prospective, non-randomised, observational study comparing the rate of contaminated blood cultures for specimens taken from recently placed (<1 h) i.v. catheters and direct venepuncture in adult ED patients. Outcome of interest was the rate of false positive cultures. Analysis was by comparison of proportions (χ(2) -test). Four hundred seventy-two blood culture sets were studied. There were 65 positive cultures, of which 49 (75%; 95% confidence interval [CI], 63-85%) were classified as true positive. The overall rate of contaminated blood cultures was 3.4% (95% CI, 2.0-5.6%). There was no difference in false positive rate between blood cultures taken via venepuncture and those taken from a recently placed i.v. cannula (P = 0.52; odds ratio, 0.9; 95% CI, 0.33-2.44). We found no difference in contaminated blood culture rate between recently placed i.v. catheters and direct venepuncture when infection control procedures were followed. © 2013 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine.

  14. Silver nanoparticles: synthesis, properties, and therapeutic applications

    PubMed Central

    Wei, Liuya; Lu, Jingran; Xu, Huizhong; Patel, Atish; Chen, Zhe-Sheng; Chen, Guofang

    2014-01-01

    Silver nanoparticles (AgNPs) have been widely used in biomedical fields because of their intrinsic therapeutic properties. Here, we introduce methods of synthesizing AgNPs and discuss their physicochemical, localized surface plasmon resonance (LSPR) and toxicity properties. We also review the impact of AgNPs on human health and the environment along with the underlying mechanisms. More importantly, we highlight the newly emerging applications of AgNPs as antiviral agents, photosensitizers and/or radiosensitizers, and anticancer therapeutic agents in the treatment of leukemia, breast cancer, hepatocellular carcinoma, lung cancer, and skin and/or oral carcinoma. PMID:25543008

  15. Development and validation of one-step SYBR green real-time RT-PCR for the rapid detection of newly emerged duck Tembusu virus.

    PubMed

    Liu, Zongliang; Fu, Yuguang; Ji, Yanhong; Wei, Jianzhong; Cai, Xuepeng; Zhu, Qiyun

    2013-09-01

    Duck Tembusu virus (DTMUV) is a single-stranded positive-sense RNA virus that causes disease to emerge in duck flocks and results in huge economic losses to the duck industry. However, no vaccines and control measures are available in China to date. Development of reliable and fast detection methods is necessary to prevent and control this disease. Therefore, a one-step SYBR Green real-time reverse transcription polymerase chain reaction (RT-PCR) method is established here for DTMUV detection. The results show that the method can specifically detect DTMUV without cross-reactions with selected avian pathogens. The sensitivity of the assay was 1000 times greater than that of a conventional RT-PCR and able to test as few as 20 copies from RNA standard samples. The coefficients of variations of inter- and intra-assay values ranged from 0.09% to 0.36% and 0.1% to 0.23%, respectively. Testing 168 field samples and 96 experimentally infected samples by conventional RT-PCR and the one-step SYBR Green real-time RT-PCR, the positive rates were 35.1% and 73.8% from field samples and 30.2% and 64.6% from infected samples. The one-step SYBR Green real-time RT-PCR developed in this study was shown to be a sensitive, specific, high-throughput, cost-effective, and simple diagnostic tool for the rapid detection and epidemiological surveillance of the emerging DTMUV infection.

  16. Goose Mx and OASL Play Vital Roles in the Antiviral Effects of Type I, II, and III Interferon against Newly Emerging Avian Flavivirus

    PubMed Central

    Chen, Shun; Zhang, Wei; Wu, Zhen; Zhang, Jinyue; Wang, Mingshu; Jia, Renyong; Zhu, Dekang; Liu, Mafeng; Sun, Kunfeng; Yang, Qiao; Wu, Ying; Chen, Xiaoyue; Cheng, Anchun

    2017-01-01

    Duck Tembusu virus (TMUV), an emerging avian flavivirus, is highly pathogenic to birds and has the potential to become a zoonotic pathogen. Here, the molecular antiviral mechanism of goose type I, II, and III interferon (goIFNα, goIFNγ, and goIFNλ), the key components of the innate immune pathway, against TMUV was studied. We found that the transcription of goIFNs was obviously driven by TMUV infection in vivo and in vitro, and the titers and copies of TMUV were significantly reduced following treatment with goIFNs. The results of RNA sequencing (RNA-seq) revealed that goIFN stimulation triggered a set of differentially expressed genes at different levels and a positive regulatory feedback loop of IFN release against infection. Two important interferon-stimulated genes, goMx and goOASL, were identified as workhorse IFNs in the inhibition of TMUV replication. The antiviral effects of goMx and goOASL were confirmed by transient overexpression and knockdown assay in vitro. Overall, our findings defined that goose Mx and OASL play key roles in the antiviral effects of type I, II, and III interferon against the TMUV. These results extend our understanding of the transcriptional profile of the goose IFN-mediated signaling pathway and provide insight into the antiviral mechanism of goIFNs against flavivirus infection. PMID:28878774

  17. Determinants of decision-to-intervention time in the management and therapeutic outcome of emergency gynecological surgeries in south east Nigeria.

    PubMed

    Onyebuchi, Azubuike Kanario; Lawani, Lucky Osaheni; Nkwo, Peter O; Iyoke, Chukwuemeka Anthony; Onoh, Robinson Chukwudi; Ajah, Leonard O

    2014-01-01

    Prompt and timely response in the management of gynecological surgical cases can significantly affect the therapeutic surgical outcome of patients in emergency situations. The aim of this study was to evaluate the decision-to-intervention time (DIT), its determinants, and the significance in the therapeutic outcome of emergency gynecological surgeries managed at a federal teaching hospital in south east Nigeria over an 18-month period. This was a prospective descriptive study of 105 emergency gynecological cases managed at a federal teaching hospital over an 18-month period. Patients were recruited at the point of admission and followed up until discharge for outcome. Data were abstracted with a data entry pro forma and then analyzed with the Epi Info™ statistical software version 7.0. The incidence of gynecological surgical emergencies was 5.1% of the total gynecological cases managed during the study period. The mean DIT was 4.25 (range 1.45-5.50) hours with delay in intervention, mainly due to delays in securing blood/blood products and other materials for resuscitation (46.7%) and a lack of finance (15.2%). Six maternal deaths were recorded, giving a case fatality ratio of 5.7%, while the commonest maternal complications associated with the delays were hemorrhage (61.9%) and the need for blood transfusion (57.1%), respectively. The risk ratio of losing ≥1,000 mL of blood, anemia, hemorrhagic shock, and wound infection in those with DIT ≥120 minutes was statistically greater and significant at 95% confidence interval. Inadequacies in health care services and policies due to poor infrastructure, organizational framework, and financing were the major determinants of the prolonged DIT and therapeutic outcomes.

  18. Poor performance of laboratories assaying newly developed antiretroviral agents: results for darunavir, etravirine, and raltegravir from the international quality control program for therapeutic drug monitoring of antiretroviral drugs in human plasma/serum.

    PubMed

    Burger, David; Krens, Stefanie; Robijns, Karen; Aarnoutse, Rob; Brüggemann, Roger; Touw, Daan

    2014-12-01

    The International Interlaboratory Quality Control PROGRAM for Therapeutic Drug Monitoring of Antiretroviral Drugs in Human Plasma/Serum was initiated in 1999. We have previously published our experience during the first 10 years of the PROGRAM. Since 2010, 3 newly developed antiretroviral agents have been added to the darunavir, etravirine, and raltegravir. The objective of this analysis is to describe the performance of participating laboratories measuring these newer agents in 2011-2012. Each year, laboratories received 2 blind samples of human plasma/serum spiked with a low (<1.0 mg/L), medium (1.0-5.0 mg/L), or high (>5.0 mg/L) concentration of these drugs. Laboratory results were standardized to percentages with reference to the nominal (true) concentration. Any result that deviated more than 20% of the nominal values was defined as inaccurate. The numbers of laboratories that participated by the end of 2012 were 44 for darunavir, 28 for etravirine, and 30 for raltegravir. A total of 357 results were evaluable for analysis. Of these, 64 (17.9%) results were reported with >20% deviation, so "inaccurate" (7.6% too low, 10.4% too high). The proportion of inaccurate results in 2011 was 21.3% for darunavir, 31.0% for etravirine, and 26.3% for raltegravir; in 2012, these figures improved to 8.1%, 23.2%, and 8.3% for darunavir, etravirine, and raltegravir, respectively. Taking darunavir as the reference, performance for etravirine was significantly lower [odds ratio = 0.462, 95% confidence interval: 0.246-0.866, P = 0.016] and performance for raltegravir was not significantly different. Low concentrations were significantly more frequently reported as inaccurate than medium or high concentrations: 28.6% versus 10.6% versus 8.8%, respectively (P < 0.001). Laboratories that used Liquid Chromatography with tandem Mass Spectrometry did not perform better than those using High Performance Liquid Chromatography/Ultrarapid Performance Liquid Chromatography: 41 inaccurate

  19. Recent insights into the molecular pathogenesis of Crohn’s disease: a review of emerging therapeutic targets

    PubMed Central

    Manuc, Teodora-Ecaterina M; Manuc, Mircea M; Diculescu, Mircea M

    2016-01-01

    Chronic inflammatory bowel diseases (IBDs) are a subject of great interest in gastroenterology, due to a pathological mechanism that is difficult to explain and an optimal therapeutic approach still undiscovered. Crohn’s disease (CD) is one of the main entities in IBD, characterized by clinical polymorphism and great variability in the treatment response. Modern theories on the pathogenesis of CD have proven that gut microbiome and environmental factors lead to an abnormal immune response in a genetically predisposed patient. Genome-wide association studies in patients with CD worldwide revealed several genetic mutations that increase the risk of IBD and that predispose to a more severe course of disease. Gut microbiota is considered a compulsory and an essential part in the pathogenesis of CD. Intestinal dysmicrobism with excessive amounts of different bacterial strains can be found in all patients with IBD. The discovery of Escherichia coli entero-invasive on resection pieces in patients with CD now increases the likelihood of antimicrobial or vaccine-type treatments. Recent studies targeting intestinal immunology and its molecular activation pathways provide new possibilities for therapeutics. In addition to antitumor necrosis factor molecules, which were a breakthrough in IBD, improving mucosal healing and resection-free survival rate, other classes of therapeutic agents come to focus. Leukocyte adhesion inhibitors block the leukocyte homing mechanism and prevent cellular immune response. In addition to anti-integrin antibodies, chemokine receptor antagonists and SMAD7 antisense oligonucleotides have shown encouraging results in clinical trials. Micro-RNAs have demonstrated their role as disease biomarkers but it could also become useful for the treatment of IBD. Moreover, cellular therapy is another therapeutic approach under development, aimed for severe refractory CD. Other experimental treatments include intravenous immunoglobulins, exclusive enteral

  20. HDL cholesterol: all hope is not lost after the torcetrapib setback--emerging therapeutic strategies on the horizon.

    PubMed

    Verma, Nitin; Figueredo, Vincent M

    2014-01-01

    Lowering low-density lipoprotein cholesterol (LDL) has been definitely shown to reduce cardiovascular events and improve clinical outcomes in the literature. As a result, LDL lowering has become the cornerstone of therapeutic approaches to cardiovascular disease prevention. Recently, there has been a focus on targeting other lipid fractions to improve the clinical risk profile of patients. Raising high-density lipoprotein (HDL) has received considerable attention. Low HDL levels are often seen in combination with elevated triglyceride levels. New therapeutic modalities are being developed to increase HDL levels. Recent failure of agents such as cholesteryl ester transferase protein inhibitor torcetrapib has highlighted the importance of measuring functionality of HDL particles and not just focus quantitatively on HDL-C levels. The heterogeneity of HDL within the systemic circulation results from constant remodeling of particles in response to several factors. Established dyslipidemia therapies such as stains, fibrates, and niacin have already been well known in the literature to have a substantial benefit. Lifestyle changes such as smoking cessation and moderate alcohol consumption have also shown to have some benefit. Several novel HDL therapies are currently being developed, but only the cholesteryl ester transferase protein inhibitors have received considerable attention. Although torcetrapib has received some negative attention due to adverse effects, this overall class of therapeutic agents still holds a lot of promise. Newer agents without the concerned toxicities are currently being developed. ApoA-1-related peptides, peroxisome proliferator-activated receptor agonists, endothelial lipase inhibitors, and liver X receptor agonists are some of the other novel agents currently in various stages of development.

  1. Emerging biogeography of the newly discovered Zetaproteobacteria

    NASA Astrophysics Data System (ADS)

    McAllister, S.; Davis, R.; Emerson, D.; Moyer, C. L.

    2009-12-01

    The Zetaproteobacteria represent a novel candidatus class of Proteobacteria found predominantly at sites of microbially mediated iron oxidation in marine environments. The chemoautotrophic, neutrophilic Fe-oxidizing representative isolate for this novel class, Mariprofundus ferrooxydans, was isolated from Fe-oxide encrusted microbial mats at Loihi Seamount, Hawaii. To date, environmental clones from the Zetaproteobacteria have been detected at numerous sites with iron-rich mats, including the Loihi Seamount, Juan de Fuca Ridge, Guaymas Basin, Tonga-Kermadec Arc, East Lau Spreading Center, Vailulu’u Seamount, Southern Mariana Trough, and the Red Sea. More than 50 full-length (>1300bp) small subunit ribosomal gene (SSU rRNA gene) sequences representing more than 100 potential Zetaproteobacteria clones were identified using the Ribosomal Database Project (RDP) Version 10.14 seqmatch algorithm. Nine operational taxonomic units (OTUs) with more than three representative clones per OTU were detected based on a minimum similarity of 97% (DOTUR). Eight OTUs contained clones from more than one geographic region. The representative Zetaproteobacteria isolates (M. ferrooxydans JV-1 and PV-1) did not group in the top four most abundant OTUs. Each of the nine OTUs detected represents a unique, geographically dispersed Zetaproteobacteria phylotype, the most abundant of which still lack isolated representatives. Further attempts at detecting Zetaproteobacteria from more diverse geographic regions are required to characterize and expand the proposed phylogenetic groupings. In addition, more isolates are necessary to characterize the breath of Zetaproteobacteria physiology and metabolic potential.

  2. MicroRNAs as regulators of metabolic disease: pathophysiologic significance and emerging role as biomarkers and therapeutics

    PubMed Central

    Deiuliis, J A

    2016-01-01

    The prevalence of overweight and obesity in developed and developing countries has greatly increased the risk of insulin resistance and type 2 diabetes mellitus. It is evident from human and animal studies that obesity alters microRNA (miRNA) expression in metabolically important organs, and that miRNAs are involved in changes to normal physiology, acting as mediators of disease. miRNAs regulate multiple pathways including insulin signaling, immune-mediated inflammation, adipokine expression, adipogenesis, lipid metabolism, and food intake regulation. Thus, miRNA-based therapeutics represent an innovative and attractive treatment modality, with non-human primate studies showing great promise. In addition, miRNA measures in plasma or bodily fluids may be used as disease biomarkers and predictors of metabolic disease in humans. This review analyzes the role of miRNAs in obesity and insulin resistance, focusing on the miR-17/92, miR-143-145, miR-130, let-7, miR-221/222, miR-200, miR-223, miR-29 and miR-375 families, as well as miRNA changes by relevant tissue (adipose, liver and skeletal muscle). Further, the current and future applications of miRNA-based therapeutics and diagnostics in metabolic disease are discussed. PMID:26311337

  3. MicroRNAs as regulators of metabolic disease: pathophysiologic significance and emerging role as biomarkers and therapeutics.

    PubMed

    Deiuliis, J A

    2016-01-01

    The prevalence of overweight and obesity in developed and developing countries has greatly increased the risk of insulin resistance and type 2 diabetes mellitus. It is evident from human and animal studies that obesity alters microRNA (miRNA) expression in metabolically important organs, and that miRNAs are involved in changes to normal physiology, acting as mediators of disease. miRNAs regulate multiple pathways including insulin signaling, immune-mediated inflammation, adipokine expression, adipogenesis, lipid metabolism, and food intake regulation. Thus, miRNA-based therapeutics represent an innovative and attractive treatment modality, with non-human primate studies showing great promise. In addition, miRNA measures in plasma or bodily fluids may be used as disease biomarkers and predictors of metabolic disease in humans. This review analyzes the role of miRNAs in obesity and insulin resistance, focusing on the miR-17/92, miR-143-145, miR-130, let-7, miR-221/222, miR-200, miR-223, miR-29 and miR-375 families, as well as miRNA changes by relevant tissue (adipose, liver and skeletal muscle). Further, the current and future applications of miRNA-based therapeutics and diagnostics in metabolic disease are discussed.

  4. Concise Review: Emerging Role of CD44 in Cancer Stem Cells: A Promising Biomarker and Therapeutic Target

    PubMed Central

    Yan, Yongmin; Zuo, Xiangsheng

    2015-01-01

    The reception and integration of the plethora of signals a cell receives from its microenvironment determines the cell’s fate. CD44 functions as a receptor for hyaluronan and many other extracellular matrix components, as well as a cofactor for growth factors and cytokines, and thus, CD44 is a signaling platform that integrates cellular microenvironmental cues with growth factor and cytokine signals and transduces signals to membrane-associated cytoskeletal proteins or to the nucleus to regulate a variety of gene expression levels related to cell-matrix adhesion, cell migration, proliferation, differentiation, and survival. Accumulating evidence indicates that CD44, especially CD44v isoforms, are cancer stem cell (CSC) markers and critical players in regulating the properties of CSCs, including self-renewal, tumor initiation, metastasis, and chemoradioresistance. Furthermore, there is ample evidence that CD44, especially CD44v isoforms, are valuable prognostic markers in various types of tumors. Therefore, therapies that target CD44 may destroy the CSC population, and this holds great promise for the cure of life-threatening cancers. However, many challenges remain to determining how best to use CD44 as a biomarker and therapeutic target. Here we summarize the current findings concerning the critical role of CD44/CD44v in the regulation of cancer stemness and the research status of CD44/CD44v as biomarkers and therapeutic targets in cancer. We also discuss the current challenges and future directions that may lead to the best use of CD44/CD44v for clinical applications. Significance Mounting evidence indicates that cancer stem cells (CSCs) are mainly responsible for cancer aggressiveness, drug resistance, and tumor relapse. CD44, especially CD44v isoforms, have been identified as CSC surface markers for isolating and enriching CSCs in different types of cancers. The current findings concerning the critical role of CD44/CD44v in regulation of cancer stemness and

  5. Concise Review: Emerging Role of CD44 in Cancer Stem Cells: A Promising Biomarker and Therapeutic Target.

    PubMed

    Yan, Yongmin; Zuo, Xiangsheng; Wei, Daoyan

    2015-09-01

    The reception and integration of the plethora of signals a cell receives from its microenvironment determines the cell's fate. CD44 functions as a receptor for hyaluronan and many other extracellular matrix components, as well as a cofactor for growth factors and cytokines, and thus, CD44 is a signaling platform that integrates cellular microenvironmental cues with growth factor and cytokine signals and transduces signals to membrane-associated cytoskeletal proteins or to the nucleus to regulate a variety of gene expression levels related to cell-matrix adhesion, cell migration, proliferation, differentiation, and survival. Accumulating evidence indicates that CD44, especially CD44v isoforms, are cancer stem cell (CSC) markers and critical players in regulating the properties of CSCs, including self-renewal, tumor initiation, metastasis, and chemoradioresistance. Furthermore, there is ample evidence that CD44, especially CD44v isoforms, are valuable prognostic markers in various types of tumors. Therefore, therapies that target CD44 may destroy the CSC population, and this holds great promise for the cure of life-threatening cancers. However, many challenges remain to determining how best to use CD44 as a biomarker and therapeutic target. Here we summarize the current findings concerning the critical role of CD44/CD44v in the regulation of cancer stemness and the research status of CD44/CD44v as biomarkers and therapeutic targets in cancer. We also discuss the current challenges and future directions that may lead to the best use of CD44/CD44v for clinical applications. Mounting evidence indicates that cancer stem cells (CSCs) are mainly responsible for cancer aggressiveness, drug resistance, and tumor relapse. CD44, especially CD44v isoforms, have been identified as CSC surface markers for isolating and enriching CSCs in different types of cancers. The current findings concerning the critical role of CD44/CD44v in regulation of cancer stemness and the research

  6. Bench-to-bedside review: Critical illness-associated cognitive dysfunction – mechanisms, markers, and emerging therapeutics

    PubMed Central

    Milbrandt, Eric B; Angus, Derek C

    2006-01-01

    Cognitive dysfunction is common in critically ill patients, not only during the acute illness but also long after its resolution. A large number of pathophysiologic mechanisms are thought to underlie critical illness-associated cognitive dysfunction, including neuro-transmitter abnormalities and occult diffuse brain injury. Markers that could be used to evaluate the influence of specific mechanisms in individual patients include serum anticholinergic activity, certain brain proteins, and tissue sodium concentration determination via high-resolution three-dimensional magnetic resonance imaging. Although recent therapeutic advances in this area are exciting, they are still too immature to influence patient care. Additional research is needed if we are to understand better the relative contributions of specific mechanisms to the development of critical illness-associated cognitive dysfunction and to determine whether these mechanisms might be amenable to treatment or prevention. PMID:17118217

  7. APE1/Ref-1 as an emerging therapeutic target for various human diseases: phytochemical modulation of its functions

    PubMed Central

    Thakur, Shweta; Sarkar, Bibekananda; Cholia, Ravi P; Gautam, Nandini; Dhiman, Monisha; Mantha, Anil K

    2014-01-01

    Apurinic/apyrimidinic endonuclease 1 (APE1) is a multifunctional enzyme involved in the base excision repair (BER) pathway, which repairs oxidative base damage caused by endogenous and exogenous agents. APE1 acts as a reductive activator of many transcription factors (TFs) and has also been named redox effector factor 1, Ref-1. For example, APE1 activates activator protein-1, nuclear factor kappa B, hypoxia-inducible factor 1α, paired box gene 8, signal transducer activator of transcription 3 and p53, which are involved in apoptosis, inflammation, angiogenesis and survival pathways. APE1/Ref-1 maintains cellular homeostasis (redox) via the activation of TFs that regulate various physiological processes and that crosstalk with redox balancing agents (for example, thioredoxin, catalase and superoxide dismutase) by controlling levels of reactive oxygen and nitrogen species. The efficiency of APE1/Ref-1's function(s) depends on pairwise interaction with participant protein(s), the functions regulated by APE1/Ref-1 include the BER pathway, TFs, energy metabolism, cytoskeletal elements and stress-dependent responses. Thus, APE1/Ref-1 acts as a ‘hub-protein' that controls pathways that are important for cell survival. In this review, we will discuss APE1/Ref-1's versatile nature in various human etiologies, including neurodegeneration, cancer, cardiovascular and other diseases that have been linked with alterations in the expression, subcellular localization and activities of APE/Ref-1. APE1/Ref-1 can be targeted for therapeutic intervention using natural plant products that modulate the expression and functions of APE1/Ref-1. In addition, studies focusing on translational applications based on APE1/Ref-1-mediated therapeutic interventions are discussed. PMID:25033834

  8. Biochemistry, molecular biology, and pharmacology of fatty acid synthase, an emerging therapeutic target and diagnosis/prognosis marker

    PubMed Central

    Liu, Hailan; Liu, Jing-Yuan; Wu, Xi; Zhang, Jian-Ting

    2010-01-01

    Human fatty acid synthase (FASN) is a 270-kDa cytosolic dimeric enzyme that is responsible for palmitate synthesis. FASN is slowly emerging and rediscovered as a marker for diagnosis and prognosis of human cancers. Recent studies showed that FASN is an oncogene and inhibition of FASN effectively and selectively kill cancer cells. With recent publications of the FASN crystal structure and the new development of FASN inhibitors, targeting FASN opens a new window of opportunity for metabolically combating cancers. In this article, we will review critically the recent progresses in understanding the structure, function, and the role of FASN in cancers and pharmacologically targeting FASN for human cancer treatment. PMID:20706604

  9. Differential Impact of Cysteine Cathepsins on Genetic Mouse Models of De novo Carcinogenesis: Cathepsin B as Emerging Therapeutic Target

    PubMed Central

    Reinheckel, Thomas; Peters, Christoph; Krüger, Achim; Turk, Boris; Vasiljeva, Olga

    2012-01-01

    Lysosomal cysteine cathepsins belong to a family of 11 human proteolytic enzymes. Some of them correlate with progression in a variety of cancers and therefore are considered as potential therapeutic targets. Until recently, the contribution of individual cathepsins to tumorigenesis and tumor progression remained unknown. By crossing various types of mouse cancer models with mice where specific cathepsins have been ablated, we contributed to this gap of knowledge and will summarize the results in this report. The employed models are the Rip1-Tag2 model for pancreatic neuroendocrine tumors, the K14-HPV16 model for squamous skin and cervical cancers, and the MMTV-PyMT model for metastasizing breast cancer, the KPC model for pancreatic ductal adenocarcinoma, and the APCmin mice developing early stages of intestinal neoplasia. All models harbor mutations in relevant tumor suppressors and/or cell-type specific expression of potent oncogenes, which initiate de novo carcinogenesis in the targeted tissues. In all these models deletion of cathepsin B led to suppression of the aggressiveness of the respective cancer phenotype. Cathepsin B is networking with other proteases as it was shown for cathepsin X/Z. In contrast, deletion of cathepsin L was beneficial in the RiP1-Tag2 model, but enhanced tumorigenesis in the APCmin, and the K14-HPV16 mice. A logical consequence of these results would be to further pursue selective inhibition of cathepsin B. Moreover, it became clear that cathepsins B and S derived from cells of the tumor microenvironment support cancer growth. Strikingly, delivery of broad spectrum cysteine cathepsin inhibitors in the tumor microenvironment disrupts the permissive ecosystem of the cancer and results in impaired growth or even in regression of the tumor. In addition, combination of cysteine cathepsin inhibition and standard chemotherapy improves the therapeutic response of the latter. Taken together, the next preclinical challenges for developing

  10. The emerging process of Top Down mass spectrometry for protein analysis: biomarkers, protein-therapeutics, and achieving high throughput†

    PubMed Central

    Kellie, John F.; Tran, John C.; Lee, Ji Eun; Ahlf, Dorothy R.; Thomas, Haylee M.; Ntai, Ioanna; Catherman, Adam D.; Durbin, Kenneth R.; Zamdborg, Leonid; Vellaichamy, Adaikkalam; Thomas, Paul M.

    2011-01-01

    Top Down mass spectrometry (MS) has emerged as an alternative to common Bottom Up strategies for protein analysis. In the Top Down approach, intact proteins are fragmented directly in the mass spectrometer to achieve both protein identification and characterization, even capturing information on combinatorial post-translational modifications. Just in the past two years, Top Down MS has seen incremental advances in instrumentation and dedicated software, and has also experienced a major boost from refined separations of whole proteins in complex mixtures that have both high recovery and reproducibility. Combined with steadily advancing commercial MS instrumentation and data processing, a high-throughput workflow covering intact proteins and polypeptides up to 70 kDa is directly visible in the near future. PMID:20711533

  11. Ataxin-3 protein and RNA toxicity in spinocerebellar ataxia type 3: current insights and emerging therapeutic strategies.

    PubMed

    Evers, Melvin M; Toonen, Lodewijk J A; van Roon-Mom, Willeke M C

    2014-06-01

    Ataxin-3 is a ubiquitously expressed deubiqutinating enzyme with important functions in the proteasomal protein degradation pathway and regulation of transcription. The C-terminus of the ataxin-3 protein contains a polyglutamine (PolyQ) region that, when mutationally expanded to over 52 glutamines, causes the neurodegenerative disease spinocerebellar ataxia 3 (SCA3). In spite of extensive research, the molecular mechanisms underlying the cellular toxicity resulting from mutant ataxin-3 remain elusive and no preventive treatment is currently available. It has become clear over the last decade that the hallmark intracellular ataxin-3 aggregates are likely not the main toxic entity in SCA3. Instead, the soluble PolyQ containing fragments arising from proteolytic cleavage of ataxin-3 by caspases and calpains are now regarded to be of greater influence in pathogenesis. In addition, recent evidence suggests potential involvement of a RNA toxicity component in SCA3 and other PolyQ expansion disorders, increasing the pathogenic complexity. Herein, we review the functioning of ataxin-3 and the involvement of known protein and RNA toxicity mechanisms of mutant ataxin-3 that have been discovered, as well as future opportunities for therapeutic intervention.

  12. Clinical Implications of 20-Hydroxyeicosatetraenoic Acid in the Kidney, Liver, Lung and Brain: An Emerging Therapeutic Target.

    PubMed

    Elshenawy, Osama H; Shoieb, Sherif M; Mohamed, Anwar; El-Kadi, Ayman O S

    2017-02-20

    Cytochrome P450-mediated metabolism of arachidonic acid (AA) is an important pathway for the formation of eicosanoids. The ω-hydroxylation of AA generates significant levels of 20-hydroxyeicosatetraenoic acid (20-HETE) in various tissues. In the current review, we discussed the role of 20-HETE in the kidney, liver, lung, and brain during physiological and pathophysiological states. Moreover, we discussed the role of 20-HETE in tumor formation, metabolic syndrome and diabetes. In the kidney, 20-HETE is involved in modulation of preglomerular vascular tone and tubular ion transport. Furthermore, 20-HETE is involved in renal 19 ischemia/reperfusion (I/R) injury and polycystic kidney diseases. The role of 20-HETE in the liver is not clearly understood although it represents 50%-75% of liver CYP-dependent AA metabolism, and it is associated with liver cirrhotic ascites. In the respiratory system, 20-HETE plays a role in pulmonary cell survival, pulmonary vascular tone and tone of the airways. As for the brain, 20-HETE is involved in cerebral I/R injury. Moreover, 20-HETE has angiogenic and mitogenic properties and thus helps in tumor promotion. Several inhibitors and inducers of the synthesis of 20-HETE as well as 20-HETE analogues and antagonists are recently available and could be promising therapeutic options for the treatment of many disease states in the future.

  13. Self-assembling, protein-based intracellular bacterial organelles: emerging vehicles for encapsulating, targeting and delivering therapeutical cargoes

    PubMed Central

    2011-01-01

    Many bacterial species contain intracellular nano- and micro-compartments consisting of self-assembling proteins that form protein-only shells. These structures are built up by combinations of a reduced number of repeated elements, from 60 repeated copies of one unique structural element self-assembled in encapsulins of 24 nm to 10,000-20,000 copies of a few protein species assembled in a organelle of around 100-150 nm in cross-section. However, this apparent simplicity does not correspond to the structural and functional sophistication of some of these organelles. They package, by not yet definitely solved mechanisms, one or more enzymes involved in specific metabolic pathways, confining such reactions and sequestering or increasing the inner concentration of unstable, toxics or volatile intermediate metabolites. From a biotechnological point of view, we can use the self assembling properties of these particles for directing shell assembling and enzyme packaging, mimicking nature to design new applications in biotechnology. Upon appropriate engineering of the building blocks, they could act as a new family of self-assembled, protein-based vehicles in Nanomedicine to encapsulate, target and deliver therapeutic cargoes to specific cell types and/or tissues. This would provide a new, intriguing platform of microbial origin for drug delivery. PMID:22046962

  14. Clinical Implications of 20-Hydroxyeicosatetraenoic Acid in the Kidney, Liver, Lung and Brain: An Emerging Therapeutic Target

    PubMed Central

    Elshenawy, Osama H.; Shoieb, Sherif M.; Mohamed, Anwar; El-Kadi, Ayman O.S.

    2017-01-01

    Cytochrome P450-mediated metabolism of arachidonic acid (AA) is an important pathway for the formation of eicosanoids. The ω-hydroxylation of AA generates significant levels of 20-hydroxyeicosatetraenoic acid (20-HETE) in various tissues. In the current review, we discussed the role of 20-HETE in the kidney, liver, lung, and brain during physiological and pathophysiological states. Moreover, we discussed the role of 20-HETE in tumor formation, metabolic syndrome and diabetes. In the kidney, 20-HETE is involved in modulation of preglomerular vascular tone and tubular ion transport. Furthermore, 20-HETE is involved in renal ischemia/reperfusion (I/R) injury and polycystic kidney diseases. The role of 20-HETE in the liver is not clearly understood although it represents 50%–75% of liver CYP-dependent AA metabolism, and it is associated with liver cirrhotic ascites. In the respiratory system, 20-HETE plays a role in pulmonary cell survival, pulmonary vascular tone and tone of the airways. As for the brain, 20-HETE is involved in cerebral I/R injury. Moreover, 20-HETE has angiogenic and mitogenic properties and thus helps in tumor promotion. Several inhibitors and inducers of the synthesis of 20-HETE as well as 20-HETE analogues and antagonists are recently available and could be promising therapeutic options for the treatment of many disease states in the future. PMID:28230738

  15. Analytical approaches for the detection of emerging therapeutics and non-approved drugs in human doping controls.

    PubMed

    Thevis, Mario; Schänzer, Wilhelm

    2014-12-01

    The number and diversity of potentially performance-enhancing substances is continuously growing, fueled by new pharmaceutical developments but also by the inventiveness and, at the same time, unscrupulousness of black-market (designer) drug producers and providers. In terms of sports drug testing, this situation necessitates reactive as well as proactive research and expansion of the analytical armamentarium to ensure timely, adequate, and comprehensive doping controls. This review summarizes literature published over the past 5 years on new drug entities, discontinued therapeutics, and 'tailored' compounds classified as doping agents according to the regulations of the World Anti-Doping Agency, with particular attention to analytical strategies enabling their detection in human blood or urine. Among these compounds, low- and high-molecular mass substances of peptidic (e.g. modified insulin-like growth factor-1, TB-500, hematide/peginesatide, growth hormone releasing peptides, AOD-9604, etc.) and non-peptidic (selective androgen receptor modulators, hypoxia-inducible factor stabilizers, siRNA, S-107 and ARM036/aladorian, etc.) as well as inorganic (cobalt) nature are considered and discussed in terms of specific requirements originating from physicochemical properties, concentration levels, metabolism, and their amenability for chromatographic-mass spectrometric or alternative detection methods.

  16. Manipulating autophagic processes in autoimmune diseases: a special focus on modulating chaperone-mediated autophagy, an emerging therapeutic target.

    PubMed

    Wang, Fengjuan; Muller, Sylviane

    2015-01-01

    Autophagy, a constitutive intracellular degradation pathway, displays essential role in the homeostasis of immune cells, antigen processing and presentation, and many other immune processes. Perturbation of autophagy has been shown to be related to several autoimmune syndromes, including systemic lupus erythematosus. Therefore, modulating autophagy processes appears most promising for therapy of such autoimmune diseases. Autophagy can be said non-selective or selective; it is classified into three main forms, namely macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA), the former process being by far the most intensively investigated. The role of CMA remains largely underappreciated in autoimmune diseases, even though CMA has been claimed to play pivotal functions into major histocompatibility complex class II-mediated antigen processing and presentation. Therefore, hereby, we give a special focus on CMA as a therapeutic target in autoimmune diseases, based in particular on our most recent experimental results where a phosphopeptide modulates lupus disease by interacting with CMA regulators. We propose that specifically targeting lysosomes and lysosomal pathways, which are central in autophagy processes and seem to be altered in certain autoimmune diseases such as lupus, could be an innovative approach of efficient and personalized treatment.

  17. Manipulating Autophagic Processes in Autoimmune Diseases: A Special Focus on Modulating Chaperone-Mediated Autophagy, an Emerging Therapeutic Target

    PubMed Central

    Wang, Fengjuan; Muller, Sylviane

    2015-01-01

    Autophagy, a constitutive intracellular degradation pathway, displays essential role in the homeostasis of immune cells, antigen processing and presentation, and many other immune processes. Perturbation of autophagy has been shown to be related to several autoimmune syndromes, including systemic lupus erythematosus. Therefore, modulating autophagy processes appears most promising for therapy of such autoimmune diseases. Autophagy can be said non-selective or selective; it is classified into three main forms, namely macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA), the former process being by far the most intensively investigated. The role of CMA remains largely underappreciated in autoimmune diseases, even though CMA has been claimed to play pivotal functions into major histocompatibility complex class II-mediated antigen processing and presentation. Therefore, hereby, we give a special focus on CMA as a therapeutic target in autoimmune diseases, based in particular on our most recent experimental results where a phosphopeptide modulates lupus disease by interacting with CMA regulators. We propose that specifically targeting lysosomes and lysosomal pathways, which are central in autophagy processes and seem to be altered in certain autoimmune diseases such as lupus, could be an innovative approach of efficient and personalized treatment. PMID:26042127

  18. Butaclamol hydrochloride in newly admitted schizophrenics.

    PubMed

    Hollister, L E; Davis, K L; Berger, P A

    1975-01-01

    Butaclamol hydrochloride, a new type of antipsychotic drug, was evaluated by an uncontrolled study of 13 newly admitted schizophrenic patients. The drug had antipsychotic effects as well as a strong propensity for evoking extrapyramidal side effects. With the maximal daily doses of 30 mg used in this study, therapeutic results obtained were probably somewhat less than optimal.

  19. Chaperoning to the metabolic party: The emerging therapeutic role of heat-shock proteins in obesity and type 2 diabetes

    PubMed Central

    Henstridge, Darren C.; Whitham, Martin; Febbraio, Mark A.

    2014-01-01

    Background From their initial, accidental discovery 50 years ago, the highly conserved Heat Shock Proteins (HSPs) continue to exhibit fundamental roles in the protection of cell integrity. Meanwhile, in the midst of an obesity epidemic, research demonstrates a key involvement of low grade inflammation, and mitochondrial dysfunction amongst other mechanisms, in the pathology of insulin resistance and type 2 diabetes mellitus (T2DM). In particular, tumor necrosis factor alpha (TNFα), endoplasmic reticulum (ER) and oxidative stress all appear to be associated with obesity and stimulate inflammatory kinases such as c jun amino terminal kinase (JNK), inhibitor of NF-κβ kinase (IKK) and protein kinase C (PKC) which in turn, inhibit insulin signaling. Mitochondrial dysfunction in skeletal muscle has also been proposed to be prominent in the pathogenesis of T2DM either by reducing the ability to oxidize fatty acids, leading to the accumulation of deleterious lipid species in peripheral tissues such as skeletal muscle and liver, or by altering the cellular redox state. Since HSPs act as molecular chaperones and demonstrate crucial protective functions in stressed cells, we and others have postulated that the manipulation of HSP expression in metabolically relevant tissues represents a therapeutic avenue for obesity-induced insulin resistance. Scope of Review This review summarizes the literature from both animal and human studies, that has examined how HSPs, particularly the inducible HSP, Heat Shock Protein 72 (Hsp72) alters glucose homeostasis and the possible approaches to modulating Hsp72 expression. A summation of the role of chemical chaperones in metabolic disorders is also included. Major Conclusions Targeted manipulation of Hsp72 or use of chemical chaperiones may have clinical utility in treating metabolic disorders such as insulin resistance and T2DM. PMID:25379403

  20. Emerging therapeutic targets for the treatment of human acute myeloid leukemia (part 1) - gene transcription, cell cycle regulation, metabolism and intercellular communication.

    PubMed

    Reikvam, Håkon; Hauge, Michelle; Brenner, Annette K; Hatfield, Kimberley Joanne; Bruserud, Øystein

    2015-06-01

    Human acute myeloid leukemia is a heterogeneous disease and the effect of therapeutic targeting of specific molecular mechanisms will probably vary between patient subsets. Cell cycle regulators are among the emerging targets (e.g., aurora and polo-like kinases, cyclin-dependent kinases). Inhibition of communication between acute myeloid leukemia and stromal cells is also considered; among the most promising of these strategies are inhibition of hedgehog-initiated, CXCR4-CXCL12 and Axl-Gas6 signaling. Finally, targeting of energy and protein metabolism is considered, the most promising strategy being inhibition of isocitrate dehydrogenase in patients with IDH mutations. Thus, several strategies are now considered, and a major common challenge for all of them is to clarify how they should be combined with each other or with conventional chemotherapy, and whether their use should be limited to certain subsets of patients.

  1. The melanocortin-4 receptor as target for obesity treatment: a systematic review of emerging pharmacological therapeutic options.

    PubMed

    Fani, L; Bak, S; Delhanty, P; van Rossum, E F C; van den Akker, E L T

    2014-02-01

    Obesity is one of the greatest public health challenges of the 21st century. Obesity is currently responsible for ∼0.7-2.8% of a country's health costs worldwide. Treatment is often not effective because weight regulation is complex. Appetite and energy control are regulated in the brain. Melanocortin-4 receptor (MC4R) has a central role in this regulation. MC4R defects lead to a severe clinical phenotype with lack of satiety and early-onset severe obesity. Preclinical research has been carried out to understand the mechanism of MC4R regulation and possible effectors. The objective of this study is to systematically review the literature for emerging pharmacological obesity treatment options. A systematic literature search was performed in PubMed and Embase for articles published until June 2012. The search resulted in 664 papers matching the search terms, of which 15 papers remained after elimination, based on the specific inclusion and exclusion criteria. In these 15 papers, different MC4R agonists were studied in vivo in animal and human studies. Almost all studies are in the preclinical phase. There are currently no effective clinical treatments for MC4R-deficient obese patients, although MC4R agonists are being developed and are entering phase I and II trials.

  2. Newly emerging mutations in the matrix genes of the human influenza A(H1N1)pdm09 and A(H3N2) viruses reduce the detection sensitivity of real-time reverse transcription-PCR.

    PubMed

    Yang, Ji-Rong; Kuo, Chuan-Yi; Huang, Hsiang-Yi; Wu, Fu-Ting; Huang, Yi-Lung; Cheng, Chieh-Yu; Su, Yu-Ting; Chang, Feng-Yee; Wu, Ho-Sheng; Liu, Ming-Tsan

    2014-01-01

    New variants of the influenza A(H1N1)pdm09 and A(H3N2) viruses were detected in Taiwan between 2012 and 2013. Some of these variants were not detected in clinical specimens using a common real-time reverse transcription-PCR (RT-PCR) assay that targeted the conserved regions of the viral matrix (M) genes. An analysis of the M gene sequences of the new variants revealed that several newly emerging mutations were located in the regions where the primers or probes of the real-time RT-PCR assay bind; these included three mutations (G225A, T228C, and G238A) in the A(H1N1)pdm09 virus, as well as one mutation (C163T) in the A(H3N2) virus. These accumulated mismatch mutations, together with the previously identified C154T mutation of the A(H1N1)pdm09 virus and the C153T and G189T mutations of the A(H3N2) virus, result in a reduced detection sensitivity for the real-time RT-PCR assay. To overcome the loss of assay sensitivity due to mismatch mutations, we established a real-time RT-PCR assay using degenerate nucleotide bases in both the primers and probe and successfully increased the sensitivity of the assay to detect circulating variants of the human influenza A viruses. Our observations highlight the importance of the simultaneous use of different gene-targeting real-time RT-PCR assays for the clinical diagnosis of influenza.

  3. Emergence of trimethoprim-resistant Escherichia coli in healthy persons in the absence of prophylactic or therapeutic antibiotics during travel to Guadalajara, Mexico.

    PubMed

    Huang, D B; Jiang, Z D; Ericsson, C D; Adachi, J; Dupont, H L

    2001-01-01

    Thirty-nine healthy US students without diarrheal disease and who had not received prophylactic or therapeutic antibiotics were monitored for emergence of trimethoprim-resistant gram-negative fecal flora for a 3-week period after arrival in Guadalajara, Mexico. During this time period, most students showed no change in total fecal gram-negative bacteria (p > 0.05) but showed an increasing level of trimethoprim (TMP) resistance (p < 0.01) among fecal coliforms. Escherichia coli was the TMP-resistant organism isolated in 18 of 39 (46%) healthy students. These 18 TMP-resistant E. coli were also resistant to ampicillin (44%), azithromycin (11%), chloramphenicol (39%), ciprofloxacin (11%), doxycycline (89%), erythromycin (100%), furazolidone (72%), levofloxacin (17%), trimethoprim-sulfamethoxazole (89%) and trovafloxacin (17%). In the absence of prophylactic and therapeutic antibiotics, increased acquisition of TMP-resistant gram-negative fecal flora in this developing country is probably due to poor sanitary conditions and the recurrent and heavy exposure to antimicrobial-resistant indigenous flora as a result of contaminated food and drink.

  4. Current Understanding of HSP90 as a Novel Therapeutic Target: An Emerging Approach for the Treatment of Cancer.

    PubMed

    Haque, Absarul; Alam, Qamre; Alam, Mohammad Zubair; Azhar, Esam I; Sait, Khalid Hussain Wali; Anfinan, Nisrin; Mushtaq, Gohar; Kamal, Mohammad Amjad; Rasool, Mahmood

    2016-01-01

    Heat Shock Protein 90 (HSP90) is a ubiquitous molecular chaperone that is considered to be the most abundantly expressed protein in various human cancers such as breast, lung, colon, prostate, leukemia and skin. The master regulator, HSP90 plays a pivotal role in the conformational stabilization, maturation and activity of its various labile oncogenic client proteins such as p53, ErbB2, Bcr-Abl, Akt, Her-2, Cdk4, Cdk6, Raf-1 and v-Src in altered cells. Hence, making a guaranteed attempt to inhibit such a master regulator for cancer therapy appears to be a potential approach for combinatorial inhibition of numerous oncogenic signaling pathways simultaneously. Considerable efforts are being under way to develop novel molecular targets and its inhibitors that may block key signaling pathways involved in the process of tumorigenesis and metastasis. In this regards, HSP90 has acquired immense interest as a potent anticancer drug-target due to its key functional link with multiple signaling pathways involved in the process of cell proliferation and cell survival. Notably, geldanamycin and its derivatives (17-AAG, 17-DMAG) have shown quite encouraging results in inhibiting HSP90 function in several cancers and currently almost 17 drug candidates known to be target HSP90 are being under clinical trials either as single agents or combinatorial therapy. Hence, this review is an attempt to get new insight into novel drug target therapy by focusing on recent advances made in understanding HSP90 chaperone structure-function relationships, identification of new HSP90 client proteins and, more importantly, on the advancements of HSP90 targeted therapy based on various existing and emerging classical inhibitors.

  5. Emergence of quantification in clinical investigation and the quest for certainty in therapeutics: the road from Hammurabi to Kefauver.

    PubMed

    Eknoyan, Garabed

    2005-01-01

    Throughout most of history, medical knowledge was descriptive in nature and derived from the work of individual investigators of independent mind pursuing careful but often chance observations. Using deductive reasoning, these findings were then generalized, authoritatively presented, and dogmatically promulgated. This, coupled with firmly grounded principles of divine determinism, precluded any serious consideration of randomness, even when variations from recorded, but erroneous, statements were actually observed. Although probability remained an integral component of diagnosis and therapy, it was only as an attribute of opinion and not one supported by numbers. The gradual erosion of this edifice began during the scientific revolution of the seventeenth century that led to the burgeoning of the sciences basic to medicine. Although clinicians applauded these contributions, they failed to apply the inductive method of investigation to the study of disease or to therapy. The "numerical method" of Pierre Louis (1787-1872) first introduced systematic quantification into medicine during the first half of the nineteenth century. Analysis of quantifiable data found its principal application in epidemiology, which flourished during the second half of the nineteenth century. The subsequent adoption of probability calculus for the analysis of quantifiable data, during the first half of the twentieth century, refined the process further and led to the gradual emergence of medical statistics, with a distinct role in clinical research. The mathematical precision provided by quantification and statistical analysis established certainty in medicine and ultimately changed the conjectural art of clinical practice into a disciplined science founded on clinical investigation, the very basis of present-day, evidence-based medicine.

  6. Ghost probiotics with a combined regimen: a novel therapeutic approach against the Zika virus, an emerging world threat.

    PubMed

    Bajpai, Vivek K; Chandra, Vishal; Kim, Na-Hyung; Rai, Rajni; Kumar, Pradeep; Kim, Kangmin; Aeron, Abhinav; Kang, Sun Chul; Maheshwari, D K; Na, MinKyun; Rather, Irfan A; Park, Yong-Ha

    2017-09-07

    The Zika virus (ZIKV) used to be an obscure flavivirus closely related to dengue virus (DENV). Transmission of this epidemic pathogen occurs mainly via mosquitoes, but it is also capable of placental and sexual transmission. Although the characteristics of these viruses are well defined, infections are unpredictable in terms of disease severity, unusual clinical manifestations, unexpected methods of transmission, long-term persistence, and the development of new strains. Recently, ZIKV has gained huge medical attention following the large-scale epidemics around the world, and reported cases of congenital abnormalities associated with Zika virus infections which have created a public health emergency of international concern. Despite continuous research on ZIKV, no specific treatment or vaccine has been developed, excepting a preventive strategy for congenital ZIKV infection. Probiotics, known as GRAS, are bacteria that confer various health beneficial effects, and have been shown to be effective at curing a number of viral diseases by modulating the immune system. Furthermore, probiotic preparations consisting of dead cells and cellular metabolites, so-called "Ghost probiotics", can also act as biological response modifiers. Here, we review available information on the epidemiology, transmission, and clinical features of ZIKV, and on treatment and prevention strategies. In addition, we emphasize the use of probiotics and plant-based natural remedies and describe their action mechanisms, and the green technologies for microbial conversion, which could contribute to the development of novel therapies that may reduce the pathogenicity of ZIKV. Accordingly, we draw attention to new findings, unanswered questions, unresolved issues, and controversies regarding ZIKV.

  7. Therapeutic Nanodevices

    NASA Astrophysics Data System (ADS)

    Lee, Stephen C.; Ruegsegger, Mark; Barnes, Philip D.; Smith, Bryan R.; Ferrari, Mauro

    Therapeutic nanotechnology offers minimally invasive therapies with high densities of function concentrated in small volumes, features that may reduce patient morbidity and mortality. Unlike other areas of nanotechnology, novel physical properties associated with nanoscale dimensionality are not the raison d'etre of therapeutic nanotechnology, whereas the aggregation of multiple biochemical (or comparably precise) functions into controlled nanoarchitectures is. Multifunctionality is a hallmark of emerging nanotherapeutic devices, and multifunctionality can allow nanotherapeutic devices to perform multi-step work processes, with each functional component contributing to one or more nanodevice subroutine such that, in aggregate, subroutines sum to a cogent work process. Cannonical nanotherapeutic subroutines include tethering (targeting) to sites of disease, dispensing measured doses of drug (or bioactive compound), detection of residual disease after therapy and communication with an external clinician/operator. Emerging nanotherapeutics thus blur the boundaries between medical devices and traditional pharmaceuticals. Assembly of therapeutic nanodevices generally exploits either (bio)material self assembly properties or chemoselective bioconjugation techniques, or both. Given the complexity, composition, and the necessity for their tight chemical and structural definition inherent in the nature of nanotherapeutics, their cost of goods (COGs) might exceed that of (already expensive) biologics. Early therapeutic nanodevices will likely be applied to disease states which exhibit significant unmet patient need (cancer and cardiovascular disease), while application to other disease states well-served by conventional therapy may await perfection of nanotherapeutic design and assembly protocols.

  8. Therapeutic Nanodevices

    NASA Astrophysics Data System (ADS)

    Lee, Stephen; Ruegsegger, Mark; Barnes, Philip; Smith, Bryan; Ferrari, Mauro

    Therapeutic nanotechnology offers minimally invasive therapies with high densities of function concentrated in small volumes, features that may reduce patient morbidity and mortality. Unlike other areas of nanotechnology, novel physical properties associated with nanoscale dimensionality are not the raison d'être of therapeutic nanotechnology, whereas the aggregation of multiple biochemical (or comparably precise) functions into controlled nanoarchitectures is. Multifunctionality is a hallmark of emerging nanotherapeutic devices, and multifunctionality can allow nanotherapeutic devices to perform multistep work processes, with each functional component contributing to one or more nanodevice subroutine such that, in aggregate, subroutines sum to a cogent work process. Cannonical nanotherapeutic subroutines include tethering (targeting) to sites of disease, dispensing measured doses of drug (or bioactive compound), detection of residual disease after therapy and communication with an external clinician/operator. Emerging nanotherapeutics thus blur the boundaries between medical devices and traditional pharmaceuticals. Assembly of therapeutic nanodevices generally exploits either (bio)material self-assembly properties or chemoselective bioconjugation techniques, or both. Given the complexity, composition, and the necessity for their tight chemical and structural definition inherent in the nature of nanotherapeutics, their cost of goods (COGs) might exceed that of (already expensive) biologics. Early therapeutic nanodevices will likely be applied to disease states which exhibit significant unmet patient need (cancer and cardiovascular disease), while application to other disease states well-served by conventional therapy may await perfection of nanotherapeutic design and assembly protocols.

  9. Genetic characterization of EV71 isolates from 2004 to 2010 reveals predominance and persistent circulation of the newly proposed genotype D and recent emergence of a distinct lineage of subgenotype C2 in Hong Kong.

    PubMed

    Yip, Cyril C Y; Lau, Susanna K P; Lo, Janice Y C; Chan, Kwok-Hung; Woo, Patrick C Y; Yuen, Kwok-Yung

    2013-07-04

    Enterovirus 71 (EV71) is a common etiological agent of hand, foot and mouth disease (HFMD) in children. EV71 epidemics have been reported in Hong Kong in recent years, and yet the genetic information of EV71 strains circulating in our locality is limited. The objective of this study was to investigate the genetic evolution of these EV71 isolates in Hong Kong over a 7-year period. Twenty-two EV71 isolates from Hong Kong during 2004-2010 were included for phylogenetic analysis using partial VP2-VP3, 2C and 3D regions. Eight EV71 strains were selected for complete genome sequencing and recombination analysis. Among the 22 EV71 isolates, 20 belonged to subgenotype C4 and 2 belonged to subgenotype C2 based on the phylogenetic analysis of partial VP2-VP3, 2C and 3D gene regions. Phylogenetic, similarity plot and bootscan analyses using complete genome sequences of seven EV71 isolates of subgenotype C4 supported that the "double-recombinant" strains of subgenotype C4 persistently circulating in Hong Kong should belong to a newly proposed genotype D. Further analysis revealed two clusters, subgenotypes C4b and C4a (proposed genotypes D1a and D1b respectively), with "genotype D1b" strains being predominant in recent years in Hong Kong. A distinct lineage of EV71 subgenotype C2 has emerged in Hong Kong in 2008. The evolutionary rate of EV71 was 3.1 × 10-3 nucleotide substitutions per site per year similar to that of other enterovirus, such as EV68, but was relatively lower than those of echovirus 30 and poliovirus. Molecular clock analysis using VP1 gene dated the time to the most recent common ancestor of all EV71 genotypes to 1900s, while the EV71 "double-recombinant" strains of "genotype D" were detected as early as 1998. This study provides the molecular basis for proposing a new "genotype D" of EV71 and assigning a discrete lineage of subgenotype C2. EV71 strains of "genotype D" have been circulating in Hong Kong for over 7 years, with "genotype D1b" being predominant.

  10. Genetic characterization of EV71 isolates from 2004 to 2010 reveals predominance and persistent circulation of the newly proposed genotype D and recent emergence of a distinct lineage of subgenotype C2 in Hong Kong

    PubMed Central

    2013-01-01

    Background Enterovirus 71 (EV71) is a common etiological agent of hand, foot and mouth disease (HFMD) in children. EV71 epidemics have been reported in Hong Kong in recent years, and yet the genetic information of EV71 strains circulating in our locality is limited. The objective of this study was to investigate the genetic evolution of these EV71 isolates in Hong Kong over a 7-year period. Methods Twenty-two EV71 isolates from Hong Kong during 2004–2010 were included for phylogenetic analysis using partial VP2-VP3, 2C and 3D regions. Eight EV71 strains were selected for complete genome sequencing and recombination analysis. Results Among the 22 EV71 isolates, 20 belonged to subgenotype C4 and 2 belonged to subgenotype C2 based on the phylogenetic analysis of partial VP2-VP3, 2C and 3D gene regions. Phylogenetic, similarity plot and bootscan analyses using complete genome sequences of seven EV71 isolates of subgenotype C4 supported that the “double-recombinant” strains of subgenotype C4 persistently circulating in Hong Kong should belong to a newly proposed genotype D. Further analysis revealed two clusters, subgenotypes C4b and C4a (proposed genotypes D1a and D1b respectively), with “genotype D1b” strains being predominant in recent years in Hong Kong. A distinct lineage of EV71 subgenotype C2 has emerged in Hong Kong in 2008. The evolutionary rate of EV71 was 3.1 × 10-3 nucleotide substitutions per site per year similar to that of other enterovirus, such as EV68, but was relatively lower than those of echovirus 30 and poliovirus. Molecular clock analysis using VP1 gene dated the time to the most recent common ancestor of all EV71 genotypes to 1900s, while the EV71 “double-recombinant” strains of “genotype D” were detected as early as 1998. Conclusions This study provides the molecular basis for proposing a new “genotype D” of EV71 and assigning a discrete lineage of subgenotype C2. EV71 strains of “genotype D” have been circulating in

  11. The pathological cross talk between apolipoprotein E and amyloid-beta peptide in Alzheimer's disease: emerging gene-based therapeutic approaches.

    PubMed

    Iurescia, Sandra; Fioretti, Daniela; Mangialasche, Francesca; Rinaldi, Monica

    2010-01-01

    Apolipoprotein E (ApoE) plays a key role in lipid transport in the plasma and in the central nervous system through its interaction with members of the low-density lipoprotein receptor family. The three common isoforms of ApoE (ApoE2, ApoE3, and ApoE4) differ in their ability to perform neuronal maintenance and repair functions and differentially affect the risk of developing neurodegenerative disorders. The ApoE4 isoform is a strong genetic risk factor for Alzheimer's disease. Up-to-date knowledge about the structural and biophysical features of ApoE4 shed light on the molecular basis underlying the isoform-specific pathogenic role of ApoE4 and its contribution to AD pathology through several different mechanisms. ApoE4 impacts on amyloid-beta (Abeta) production, Abeta clearance, Abeta fibrillation, and tangle formation as well as on mitochondrial functions leading to neuronal toxicity and synaptic damage. This review summarizes the pathological cross talk between ApoE and Abeta peptide in Alzheimer's disease. Lastly, we examine emerging gene-based therapeutic approaches encompassing the use of ApoE and their potential opportunities to preventing or treating Alzheimer's disease.

  12. Inhibition of bromodomain and extra-terminal proteins (BET) as a potential therapeutic approach in haematological malignancies: emerging preclinical and clinical evidence

    PubMed Central

    Chaidos, Aristeidis; Caputo, Valentina

    2015-01-01

    Post-translational modifications of the nucleosomal histone proteins orchestrate chromatin organization and gene expression in normal and cancer cells. Among them, the acetylation of N-terminal histone tails represents the fundamental epigenetic mark of open structure chromatin and active gene transcription. The bromodomain and extra-terminal (BET) proteins are epigenetic readers which utilize tandem bromodomains (BRD) modules to recognize and dock themselves on the acetylated lysine tails. The BET proteins act as scaffolds for the recruitment of transcription factors and chromatin organizers required in transcription initiation and elongation. The recent discovery of small molecules capable of blocking their lysine-binding pocket is the first paradigm of successful pharmacological inhibition of epigenetic readers. JQ1 is a prototype benzodiazepine molecule and a specific BET inhibitor with antineoplastic activity both in solid tumours and haematological malignancies. The quinolone I-BET151 and the suitable for clinical development I-BET762 benzodiazepine were introduced in parallel with JQ1 and have also shown potent antitumour activity in preclinical studies. I-BET762 is currently being tested in early phase clinical trials, along with a rapidly growing list of other BET inhibitors. Unlike older epigenetic therapies, the study of BET inhibitors has offered substantial, context-specific, mechanistic insights of their antitumour activity, which will facilitate optimal therapeutic targeting in future. Here, we review the development of this novel class of epigenetic drugs, the biology of BET protein inhibition, the emerging evidence from preclinical work and early phase clinical studies and we discuss their potential role in the treatment of haematological malignancies. PMID:26137204

  13. Inhibition of bromodomain and extra-terminal proteins (BET) as a potential therapeutic approach in haematological malignancies: emerging preclinical and clinical evidence.

    PubMed

    Chaidos, Aristeidis; Caputo, Valentina; Karadimitris, Anastasios

    2015-06-01

    Post-translational modifications of the nucleosomal histone proteins orchestrate chromatin organization and gene expression in normal and cancer cells. Among them, the acetylation of N-terminal histone tails represents the fundamental epigenetic mark of open structure chromatin and active gene transcription. The bromodomain and extra-terminal (BET) proteins are epigenetic readers which utilize tandem bromodomains (BRD) modules to recognize and dock themselves on the acetylated lysine tails. The BET proteins act as scaffolds for the recruitment of transcription factors and chromatin organizers required in transcription initiation and elongation. The recent discovery of small molecules capable of blocking their lysine-binding pocket is the first paradigm of successful pharmacological inhibition of epigenetic readers. JQ1 is a prototype benzodiazepine molecule and a specific BET inhibitor with antineoplastic activity both in solid tumours and haematological malignancies. The quinolone I-BET151 and the suitable for clinical development I-BET762 benzodiazepine were introduced in parallel with JQ1 and have also shown potent antitumour activity in preclinical studies. I-BET762 is currently being tested in early phase clinical trials, along with a rapidly growing list of other BET inhibitors. Unlike older epigenetic therapies, the study of BET inhibitors has offered substantial, context-specific, mechanistic insights of their antitumour activity, which will facilitate optimal therapeutic targeting in future. Here, we review the development of this novel class of epigenetic drugs, the biology of BET protein inhibition, the emerging evidence from preclinical work and early phase clinical studies and we discuss their potential role in the treatment of haematological malignancies.

  14. Psychiatric Emergencies

    PubMed Central

    Bayrakal, Sadi

    1972-01-01

    Dr. Bayrakal believes that the time has come for the family physician to deal with minor psychiatric disturbances in his office as well as psychiatric emergencies in the emergency department. The newly emerging medico-social philosophy of both the federal and provincial governments, he says, is giving greater responsibility and authority to the family physician in every area of medicine, including psychiatry. The author discusses major psychiatric emergencies (suicide, suicidal attempt, homicide, social scandal, as well as other psychiatric emergencies) on the ward including adolescent psychiatry. (The descriptions and treatment procedures are given on a concrete clinical level without theoretical overload.) In the family physician's work, psychological understanding is of profound importance. Giving him the added scope of psychiatric consideration to see the patient in bio-psycho-social totality will enable him to practice a more humanized form of medicine. PMID:20468779

  15. Clustering of Emerging Flux

    NASA Technical Reports Server (NTRS)

    Ruzmaikin, A.

    1997-01-01

    Observations show that newly emerging flux tends to appear on the Solar surface at sites where there is flux already. This results in clustering of solar activity. Standard dynamo theories do not predict this effect.

  16. Newly Deployed Sojourner Rover

    NASA Technical Reports Server (NTRS)

    1999-01-01

    This 8-image mosaic was acquired during the late afternoon (near 5pm LST, note the long shadows) on Sol 2 as part of the predeploy 'insurance panorama' and shows the newly deployed rover sitting on the Martian surface. This color image was generated from images acquired at 530,600, and 750 nm. The insurance panorama was designed as 'insurance' against camera failure upon deployment. Had the camera failed, the losslessly-compressed, multispectral insurance panorama would have been the main source of image data from the IMP.

    However, the camera deployment was successful, leaving the insurance panorama to be downlinked to Earth several weeks later. Ironically enough, the insurance panorama contains some of the best quality image data because of the lossless data compression and relatively dust-free state of the camera and associated lander/rover hardware on Sol 2.

    Mars Pathfinder is the second in NASA's Discovery program of low-cost spacecraft with highly focused science goals. The Jet Propulsion Laboratory, Pasadena, CA, developed and manages the Mars Pathfinder mission for NASA's Office of Space Science, Washington, D.C. JPL is an operating division of the California Institute of Technology (Caltech). The IMP was developed by the University of Arizona Lunar and Planetary Laboratory under contract to JPL. Peter Smith is the Principal investigator.

  17. Newly Deployed Sojourner Rover

    NASA Technical Reports Server (NTRS)

    1999-01-01

    This 8-image mosaic was acquired during the late afternoon (near 5pm LST, note the long shadows) on Sol 2 as part of the predeploy 'insurance panorama' and shows the newly deployed rover sitting on the Martian surface. This color image was generated from images acquired at 530,600, and 750 nm. The insurance panorama was designed as 'insurance' against camera failure upon deployment. Had the camera failed, the losslessly-compressed, multispectral insurance panorama would have been the main source of image data from the IMP.

    However, the camera deployment was successful, leaving the insurance panorama to be downlinked to Earth several weeks later. Ironically enough, the insurance panorama contains some of the best quality image data because of the lossless data compression and relatively dust-free state of the camera and associated lander/rover hardware on Sol 2.

    Mars Pathfinder is the second in NASA's Discovery program of low-cost spacecraft with highly focused science goals. The Jet Propulsion Laboratory, Pasadena, CA, developed and manages the Mars Pathfinder mission for NASA's Office of Space Science, Washington, D.C. JPL is an operating division of the California Institute of Technology (Caltech). The IMP was developed by the University of Arizona Lunar and Planetary Laboratory under contract to JPL. Peter Smith is the Principal investigator.

  18. Utility and applications of orthotopic models of human non-small cell lung cancer (NSCLC) for the evaluation of novel and emerging cancer therapeutics.

    PubMed

    Justilien, Verline; Fields, Alan P

    2013-10-08

    Lung cancer is a leading cause of cancer deaths worldwide. Despite advances in chemotherapy, radiation therapy, and surgery, lung cancer continues to have a low 5-year survival rate, highlighting a dire need for more effective means of prevention, diagnosis, prognosis, and treatment. Mouse models that recapitulate the clinical features of advanced human lung cancer are critical for testing novel therapeutic approaches. This unit describes a highly reproducible, easy-to-establish orthotopic murine model of lung cancer, provides methods for in vivo imaging and monitoring of tumor growth, and discusses the usefulness of this model for translational lung cancer research and the development of therapeutic strategies.

  19. Lessons Learned: Newly Hired Nurses' Perspectives on Transition Into Practice.

    PubMed

    Ziebert, Carolyn; Klingbeil, Carol; Schmitt, Catherine A; Stonek, Alice V; Totka, Joan P; Stelter, Ashley; Schiffman, Rachel F

    2016-01-01

    This descriptive qualitative study explored data from debriefs of all newly hired nurses at 3, 6, and 12 months posthire during a newly designed transition-to-practice program at a pediatric hospital. Four major themes emerged: preceptors, education process, adaptation to the organization, and role transition. Supportive factors included staged orientation, limited preceptors, mentors, regular communication with leaders, and a culture of teamwork. Stressors included too many preceptors, mentorship needs, floating, communication challenges, and organizational changes.

  20. Newly Diagnosed Acute Promyelocytic Leukemia

    PubMed Central

    Avvisati, Giuseppe

    2011-01-01

    Acute promyelocytic leukemia (APL) represents a medical emergency with a high rate of early mortality. As a consequence, as soon as the diagnosis is suspected based upon cytologic criteria, it is necessary to start all- trans retinoic acid (ATRA) treatment without delay. For patients with newly diagnosed APL, induction therapy with ATRA plus anthracycline based chemotherapy is recommended. At present the combination of arsenic trioxide plus ATRA should be considered for patients who are not candidates for anthracycline-based therapy. For pediatric and adult patients with APL aged < 60 years who achieve a CR with induction, I recommend 3 intensive courses of consolidation chemotherapy associated to ATRA, targeted on the basis of the risk group at diagnosis. In patients treated with a very intensive consolidation chemotherapy maintenance treatment can be omitted. However If a maintenance treatment has to be adopted I suggest the use of intermittent ATRA for 15 days every 3 months for a period of 2 years, rather than ATRA associated to chemotherapy. Moreover, taking into account the medical literature, a reduced dosage of ATRA ( 25 mg/m2) in pediatric patients and a consolidation chemotherapy of reduced intensity in elderly patients is recommended. Furthermore, in order to maximize survival, careful attention should be reserved to the coagulopathy and to the appearance of the differentiation syndrome. Finally, PCR for the PML/RARA fusion gene on a bone marrow specimen every three months for two years, and then every six months for additional three years are needed during the follow-up. PMID:22220261

  1. Newly democratic Mongolia offering exploration contracts

    SciTech Connect

    Penttila, W.C. )

    1992-12-07

    This paper reports that Mongolia, formerly the Mongolian People's Republic, is working to open its exploration prospects to international operators as it emerges as the world's 15th largest independent nation. The country, about the same size as Alaska with a population of 2 million, held its first free election in July 1990. The newly elected government drafted a constitution that took effect Feb. 12, 1992. The document modifies the previous government's structures to eliminate bureaucracy and allows for political pluralism. At the same time, the government is formulating energy policies, state oil company structure, and resource development philosophy.

  2. Reassessment: neuroimaging in the emergency patient presenting with seizure (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology.

    PubMed

    Harden, C L; Huff, J S; Schwartz, T H; Dubinsky, R M; Zimmerman, R D; Weinstein, S; Foltin, J C; Theodore, W H

    2007-10-30

    To reassess the value of neuroimaging of the emergency patient presenting with seizure as a screening procedure for providing information that will change acute management, and to reassess clinical and historical features associated with an abnormal neuroimaging study in these patients. A broad-based panel with topic expertise evaluated the available evidence based on a structured literature review using a Medline search from 1966 until November 2004. The 15 articles meeting criteria were Class II or III evidence since interpretation was not masked to the patient's clinical presentation; most were series including 22 to 875 patients. There is evidence that for adults with first seizure, cranial CT will change acute management in 9 to 17% of patients. CT in the emergency department for children presenting with first seizure will change acute management in approximately 3 to 8%. There is no clear difference between rates of abnormal emergent CT for patients with chronic seizures vs first. Children <6 months presenting with seizures have clinically relevant abnormalities on CT scans 50% of the time. Persons with AIDS and first seizure have high rates of abnormalities, and CNS toxoplasmosis is frequently found. Abnormal neurologic examination, predisposing history, or focal seizure onset are probably predictive of an abnormal CT study in this context. Immediate noncontrast CT is possibly useful for emergency patients presenting with seizure to guide appropriate acute management especially where there is an abnormal neurologic examination, predisposing history, or focal seizure onset.

  3. [Utilization of radionuclide therapy facility and assembly-temporary type therapeutic facility for medical treatment of radioactivity contaminated patients in nuclear emergency].

    PubMed

    Watanabe, Naoyuki; Satro, Hiroyuki; Kawahara, Hiroshi; Sasaki, Yasuhito

    2011-05-01

    Medical management of patients internally contaminated in nuclear emergency needs, in addition to general medical treatment, to evaluate doses due to intakes of radioactive materials, to conduct effective treatment with stable isotopes and chelating agents and to keep public away from radioactive materials in and excreted from patients. The idea of medical treatment for internal contamination is demonstrated in the general principles on medical management of victims in nuclear emergency issued by the Cabinet Office in Japan. However, if impressive number patients with internal contamination are generated, the current medical management scheme in nuclear emergency is not able to admit them. The utilization of radionuclide therapy facilities where patients with thyroid diseases are treated with radioisotope and assembly-temporary housing type treatment facilities dedicated for internal contaminated patients may be expected to complement the medical management scheme in nuclear emergency. The effect or more medical management system for patients internally contaminated may become one of the safety nets in the contemporary society that inclines to use nuclear energy on account of accessibility.

  4. Rosacea: new and emerging treatments.

    PubMed

    Moustafa, Farah A; Sandoval, Laura F; Feldman, Steven R

    2014-09-01

    Rosacea is a chronic inflammatory skin condition that negatively impacts patients' quality of life. We sought to review important aspects of the pathogenesis of rosacea and the role of new treatment options in its management. New, emerging treatments show promise; however, quality randomized controlled trials for many of these drugs are lacking. Brimonidine tartrate is an effective newly approved treatment for erythematotelangiectatic rosacea. Topical oxymetazoline has potential for the treatment of erythematotelangiectatic rosacea, with efficacy described in case reports and randomized controlled trials currently underway. Both oral and topical ivermectin have been studied for the treatment of papulopustular rosacea, both showing benefit; however, only topical ivermectin 1 % cream has been studied in randomized controlled trials. As our understanding of the etiology of rosacea continues to evolve, so will our options for therapeutic interventions. Further studies need to be performed to assess the long-term safety and efficacy of these treatments.

  5. Biomimetic particles as therapeutics.

    PubMed

    Meyer, Randall A; Sunshine, Joel C; Green, Jordan J

    2015-09-01

    In recent years, there have been major advances in the development of novel nanoparticle- and microparticle-based therapeutics. An emerging paradigm is the incorporation of biomimetic features into these synthetic therapeutic constructs to enable them to better interface with biological systems. Through the control of size, shape, and material consistency, particle cores have been generated that better mimic natural cells and viruses. In addition, there have been significant advances in biomimetic surface functionalization of particles through the integration of bio-inspired artificial cell membranes and naturally derived cell membranes. Biomimetic technologies enable therapeutic particles to have increased potency to benefit human health.

  6. Biomimetic Particles as Therapeutics

    PubMed Central

    Green, Jordan J.

    2015-01-01

    In recent years, there have been major advances in the development of novel nanoparticle and microparticle-based therapeutics. An emerging paradigm is the incorporation of biomimetic features into these synthetic therapeutic constructs to enable them to better interface with biological systems. Through the control of size, shape, and material consistency, particle cores have been generated that better mimic natural cells and viruses. In addition, there have been significant advances in biomimetic surface functionalization of particles through the integration of bio-inspired artificial cell membranes and naturally derived cell membranes. Biomimetic technologies enable therapeutic particles to have increased potency to benefit human health. PMID:26277289

  7. Engineering therapeutic antibodies targeting G-protein–coupled receptors

    PubMed Central

    Jo, Migyeong; Jung, Sang Taek

    2016-01-01

    G-protein–coupled receptors (GPCRs) are one of the most attractive therapeutic target classes because of their critical roles in intracellular signaling and their clinical relevance to a variety of diseases, including cancer, infection and inflammation. However, high conformational variability, the small exposed area of extracellular epitopes and difficulty in the preparation of GPCR antigens have delayed both the isolation of therapeutic anti-GPCR antibodies as well as studies on the structure, function and biochemical mechanisms of GPCRs. To overcome the challenges in generating highly specific anti-GPCR antibodies with enhanced efficacy and safety, various forms of antigens have been successfully designed and employed for screening with newly emerged systems based on laboratory animal immunization and high-throughput-directed evolution. PMID:26846450

  8. Engineering therapeutic antibodies targeting G-protein-coupled receptors.

    PubMed

    Jo, Migyeong; Jung, Sang Taek

    2016-02-05

    G-protein-coupled receptors (GPCRs) are one of the most attractive therapeutic target classes because of their critical roles in intracellular signaling and their clinical relevance to a variety of diseases, including cancer, infection and inflammation. However, high conformational variability, the small exposed area of extracellular epitopes and difficulty in the preparation of GPCR antigens have delayed both the isolation of therapeutic anti-GPCR antibodies as well as studies on the structure, function and biochemical mechanisms of GPCRs. To overcome the challenges in generating highly specific anti-GPCR antibodies with enhanced efficacy and safety, various forms of antigens have been successfully designed and employed for screening with newly emerged systems based on laboratory animal immunization and high-throughput-directed evolution.

  9. Synthetic biology and therapeutic strategies for the degenerating brain

    PubMed Central

    Agustín-Pavón, Carmen; Isalan, Mark

    2014-01-01

    Synthetic biology is an emerging engineering discipline that attempts to design and rewire biological components, so as to achieve new functions in a robust and predictable manner. The new tools and strategies provided by synthetic biology have the potential to improve therapeutics for neurodegenerative diseases. In particular, synthetic biology will help design small molecules, proteins, gene networks, and vectors to target disease-related genes. Ultimately, new intelligent delivery systems will provide targeted and sustained therapeutic benefits. New treatments will arise from combining ‘protect and repair’ strategies: the use of drug treatments, the promotion of neurotrophic factor synthesis, and gene targeting. Going beyond RNAi and artificial transcription factors, site-specific genome modification is likely to play an increasing role, especially with newly available gene editing tools such as CRISPR/Cas9 systems. Taken together, these advances will help develop safe and long-term therapies for many brain diseases in human patients. PMID:25100403

  10. Two TIR-like domain containing proteins in a newly emerging zoonotic Staphylococcus aureus strain sequence type 398 are potential virulence factors by impacting on the host innate immune response

    PubMed Central

    Patterson, Nicholas J.; Günther, Juliane; Gibson, Amanda J.; Offord, Victoria; Coffey, Tracey J.; Splitter, Gary; Monk, Ian; Seyfert, Hans-Martin; Werling, Dirk

    2014-01-01

    Staphylococcus aureus, sequence type (ST) 398, is an emerging pathogen and the leading cause of livestock-associated methicillin-resistant S. aureus infections in Europe and North America. This strain is characterized by high promiscuity in terms of host-species and also lacks several traditional S. aureus virulence factors. This does not, however, explain the apparent ease with which it crosses species-barriers. Recently, TIR-domain containing proteins (Tcps) which inhibit the innate immune response were identified in some Gram-negative bacteria. Here we report the presence of two proteins, S. aureus TIR-like Protein 1 (SaTlp1) and S. aureus TIR-like Protein 2 (SaTlp2), expressed by ST398 which contain domain of unknown function 1863 (DUF1863), similar to the Toll/IL-1 receptor (TIR) domain. In contrast to the Tcps in Gram-negative bacteria, our data suggest that SaTlp1 and SaTlp2 increase activation of the transcription factor NF-κB as well as downstream pro-inflammatory cytokines and immune effectors. To assess the role of both proteins as potential virulence factors knock-out mutants were created. These showed a slightly enhanced survival rate in a murine infectious model compared to the wild-type strain at one dose. Our data suggest that both proteins may act as factors contributing to the enhanced ability of ST398 to cross species-barriers. PMID:25538689

  11. Two TIR-like domain containing proteins in a newly emerging zoonotic Staphylococcus aureus strain sequence type 398 are potential virulence factors by impacting on the host innate immune response.

    PubMed

    Patterson, Nicholas J; Günther, Juliane; Gibson, Amanda J; Offord, Victoria; Coffey, Tracey J; Splitter, Gary; Monk, Ian; Seyfert, Hans-Martin; Werling, Dirk

    2014-01-01

    Staphylococcus aureus, sequence type (ST) 398, is an emerging pathogen and the leading cause of livestock-associated methicillin-resistant S. aureus infections in Europe and North America. This strain is characterized by high promiscuity in terms of host-species and also lacks several traditional S. aureus virulence factors. This does not, however, explain the apparent ease with which it crosses species-barriers. Recently, TIR-domain containing proteins (Tcps) which inhibit the innate immune response were identified in some Gram-negative bacteria. Here we report the presence of two proteins, S. aureus TIR-like Protein 1 (SaTlp1) and S. aureus TIR-like Protein 2 (SaTlp2), expressed by ST398 which contain domain of unknown function 1863 (DUF1863), similar to the Toll/IL-1 receptor (TIR) domain. In contrast to the Tcps in Gram-negative bacteria, our data suggest that SaTlp1 and SaTlp2 increase activation of the transcription factor NF-κB as well as downstream pro-inflammatory cytokines and immune effectors. To assess the role of both proteins as potential virulence factors knock-out mutants were created. These showed a slightly enhanced survival rate in a murine infectious model compared to the wild-type strain at one dose. Our data suggest that both proteins may act as factors contributing to the enhanced ability of ST398 to cross species-barriers.

  12. What next for newly diagnosed glioblastoma?

    PubMed Central

    Domingo-Musibay, Evidio; Galanis, Evanthia

    2015-01-01

    Glioblastoma is the most common primary brain tumor in adults. Despite current multimodality treatment including surgical resection and temozolomide-based chemoradiotherapy, median survival is only 14–16 months. Characterization of molecular alterations in glioblastoma has identified prognostic subgroups and therapeutic opportunities for clinical trials across glioblastoma subsets. Following a number of negative Phase III trials testing temozolomide dose intensification and angiogenesis inhibition, recent interim analysis data indicate survival prolongation with use of a device (Optune™) delivering alternating electrical field therapy in newly diagnosed glioblastoma patients. In this review, we present an overview of the data supporting the current standard of care and discuss novel experimental therapies in early and late phase clinical testing including devices, small molecule drugs, angiogenesis inhibitors, oncolytic virotherapy and immunotherapy. PMID:26558493

  13. Towards microRNA-based therapeutics for diabetic nephropathy.

    PubMed

    Alvarez, M L; DiStefano, J K

    2013-03-01

    There is no cure for diabetic nephropathy and the molecular mechanisms underlying disease aetiology remain poorly understood. While current paradigms for clinical management of diabetic nephropathy are useful in delaying disease onset and preventing its progression, they do not do so for a significant proportion of diabetic individuals, who eventually end up developing renal failure. Thus, novel therapeutic targets are needed for the treatment and prevention of the disease. MicroRNAs (miRNAs), a class of non-coding RNAs that negatively regulate gene expression, have recently been identified as attractive targets for therapeutic intervention. It is widely recognised that dysregulation of miRNA expression or action contributes to the development of a number of different human diseases, and evidence of a role for miRNAs in the aetiology of diabetic nephropathy is emerging. The discovery that modulation of miRNA expression in vivo is feasible, combined with recent results from successful clinical trials using this technology, opens the way for future novel therapeutic applications. For instance, inhibition of miRNAs that are commonly upregulated in diabetic nephropathy decreases albuminuria and mesangial matrix accumulation in animal models, suggesting that a therapeutic agent against these molecules may help to prevent the development of diabetic nephropathy. Certain challenges, including the development of safe and reliable delivery systems, remain to be overcome before miRNA-based therapeutics become a reality. However, the findings accumulated to date, in conjunction with newly emerging results, are expected to yield novel insights into the complex pathogenesis of diabetic nephropathy, and may eventually lead to the identification of improved therapeutic targets for treatment of this disease.

  14. The Emerging Role of Complement Lectin Pathway in Trypanosomatids: Molecular Bases in Activation, Genetic Deficiencies, Susceptibility to Infection, and Complement System-Based Therapeutics

    PubMed Central

    Evans-Osses, Ingrid; de Messias-Reason, Iara; Ramirez, Marcel I.

    2013-01-01

    The innate immune system is evolutionary and ancient and is the pivotal line of the host defense system to protect against invading pathogens and abnormal self-derived components. Cellular and molecular components are involved in recognition and effector mechanisms for a successful innate immune response. The complement lectin pathway (CLP) was discovered in 1990. These new components at the complement world are very efficient. Mannan-binding lectin (MBL) and ficolin not only recognize many molecular patterns of pathogens rapidly to activate complement but also display several strategies to evade innate immunity. Many studies have shown a relation between the deficit of complement factors and susceptibility to infection. The recently discovered CLP was shown to be important in host defense against protozoan microbes. Although the recognition of pathogen-associated molecular patterns by MBL and Ficolins reveal efficient complement activations, an increase in deficiency of complement factors and diversity of parasite strategies of immune evasion demonstrate the unsuccessful effort to control the infection. In the present paper, we will discuss basic aspects of complement activation, the structure of the lectin pathway components, genetic deficiency of complement factors, and new therapeutic opportunities to target the complement system to control infection. PMID:23533355

  15. Re-emergence of an orphan therapeutic target for the treatment of resistant prostate cancer - a thorough conformational and binding analysis for ROR-γ protein.

    PubMed

    Ndagi, Umar; Mhlongo, Ndumiso N; Soliman, Mahmoud E

    2017-01-16

    Recent studies have linked a deadly form of prostate cancer known as metastatic castration-resistant prostate cancer to retinoic acid-related orphan-receptor gamma (ROR-γ). Most of these studies continued to place ROR-γ as orphan because of unidentifiable inhibitor. Recently identified inhibitors of ROR-γ and their therapeutic potential were evaluated, among which inhibitor XY018 was the potent. However, molecular understanding of the conformational features of XY018-ROR-γ complex is still elusive. Herein, molecular dynamics simulations were conducted on HC9-ROR-γ and XY018-ROR-γ complexes to understand their conformational features at molecular level and the influence of XY018 binding on the dynamics of ROR-γ with the aid of post-dynamic analytical tools. These include; principal component analysis, radius of gyration, binding free energy calculation (MM/GBSA), per-residue fluctuation and hydrogen bond occupancy. Findings from this study revealed that (1) hydrophobic packing contributes significantly to binding free energy, (2) Ile136 and Leu60 exhibited high hydrogen-bond occupancy in XY018-ROR-γ and HC9-ROR-γ, respectively, (3) XY018-ROR-γ displayed a relatively high loop region residue fluctuation compared to HC9-ROR-γ, (4) electrostatic interactions are a potential binding force in XY018-ROR-γ complex compared to HC9-ROR-γ, (5) XY018-ROR-γ assumes a rigid conformation which is highlighted by a decrease in residual fluctuation, (6) XY018 could potentially induce pseudoporphyria, nephritis and interstitial nephritis but potentially safe in renal failure. This study could serve as a base line for the design of new potential ROR-γ inhibitors.

  16. Comprehensive risk reduction in patients with atrial fibrillation: emerging diagnostic and therapeutic options—a report from the 3rd Atrial Fibrillation Competence NETwork/European Heart Rhythm Association consensus conference

    PubMed Central

    Kirchhof, Paulus; Lip, Gregory Y.H.; Van Gelder, Isabelle C.; Bax, Jeroen; Hylek, Elaine; Kaab, Stefan; Schotten, Ulrich; Wegscheider, Karl; Boriani, Giuseppe; Brandes, Axel; Ezekowitz, Michael; Diener, Hans; Haegeli, Laurent; Heidbuchel, Hein; Lane, Deirdre; Mont, Luis; Willems, Stephan; Dorian, Paul; Aunes-Jansson, Maria; Blomstrom-Lundqvist, Carina; Borentain, Maria; Breitenstein, Stefanie; Brueckmann, Martina; Cater, Nilo; Clemens, Andreas; Dobrev, Dobromir; Dubner, Sergio; Edvardsson, Nils G.; Friberg, Leif; Goette, Andreas; Gulizia, Michele; Hatala, Robert; Horwood, Jenny; Szumowski, Lukas; Kappenberger, Lukas; Kautzner, Josef; Leute, Angelika; Lobban, Trudie; Meyer, Ralf; Millerhagen, Jay; Morgan, John; Muenzel, Felix; Nabauer, Michael; Baertels, Christoph; Oeff, Michael; Paar, Dieter; Polifka, Juergen; Ravens, Ursula; Rosin, Ludger; Stegink, W.; Steinbeck, Gerhard; Vardas, Panos; Vincent, Alphons; Walter, Maureen; Breithardt, Günter; Camm, A. John

    2012-01-01

    While management of atrial fibrillation (AF) patients is improved by guideline-conform application of anticoagulant therapy, rate control, rhythm control, and therapy of accompanying heart disease, the morbidity and mortality associated with AF remain unacceptably high. This paper describes the proceedings of the 3rd Atrial Fibrillation NETwork (AFNET)/European Heart Rhythm Association (EHRA) consensus conference that convened over 60 scientists and representatives from industry to jointly discuss emerging therapeutic and diagnostic improvements to achieve better management of AF patients. The paper covers four chapters: (i) risk factors and risk markers for AF; (ii) pathophysiological classification of AF; (iii) relevance of monitored AF duration for AF-related outcomes; and (iv) perspectives and needs for implementing better antithrombotic therapy. Relevant published literature for each section is covered, and suggestions for the improvement of management in each area are put forward. Combined, the propositions formulate a perspective to implement comprehensive management in AF. PMID:21791573

  17. Development, validation, and application of a fast and simple GC-MS method for determination of some therapeutic drugs relevant in emergency toxicology.

    PubMed

    Meyer, Markus R; Welter, Jessica; Weber, Armin A; Maurer, Hans H

    2011-10-01

    To date, immunoassays are commercially available for quantification of valproic acid, salicylic acid, paracetamol, phenobarbital, phenytoin, and primidone. As they are no longer available, a fast, simple, and cost-effective quantitative gas chromatography-mass spectrometry (GC-MS) method was developed and fully validated for these drugs. After simple and fast liquid-liquid extraction, the samples were analyzed by GC-MS using the selected ion monitoring mode. The method was validated including the parameters selectivity, calibration model, precision, accuracy, and extraction efficiency. The above-mentioned analytes were separated within 8.5 minutes and sensitively detected. No interfering peaks were observed in blank samples from 8 different sources. The linearity ranges were 20-200 mg/L for valproic acid, 100-1200 mg/L for salicylic acid, 10-200 mg/L for paracetamol, 10-200 mg/L for phenobarbital, 4-20 mg/L for primidone, and 2.5-30 mg/L for phenytoin. Generally accepted criteria for accuracy and precision were fulfilled for all analytes using 6-point calibration. Even 1-point calibration was applicable for all analytes. The assay was successfully applied to analysis of real plasma samples and proficiency testing material. The assay described allowed fast and reliable determination of analytes relevant in the diagnosis of poisonings. Furthermore, time- and cost-saving 1-point calibration was shown to be suitable for daily routine work, especially in emergency cases.

  18. Clinical features and therapeutic management of patients admitted to Italian acute hospital psychiatric units: the PERSEO (psychiatric emergency study and epidemiology) survey

    PubMed Central

    Ballerini, Andrea; Boccalon, Roberto M; Boncompagni, Giancarlo; Casacchia, Massimo; Margari, Francesco; Minervini, Lina; Righi, Roberto; Russo, Federico; Salteri, Andrea; Frediani, Sonia; Rossi, Andrea; Scatigna, Marco

    2007-01-01

    Background The PERSEO study (psychiatric emergency study and epidemiology) is a naturalistic, observational clinical survey in Italian acute hospital psychiatric units, called SPDCs (Servizio Psichiatrico Diagnosi e Cura; in English, the psychiatric service for diagnosis and management). The aims of this paper are: (i) to describe the epidemiological and clinical characteristics of patients, including sociodemographic features, risk factors, life habits and psychiatric diagnoses; and (ii) to assess the clinical management, subjective wellbeing and attitudes toward medications. Methods A total of 62 SPDCs distributed throughout Italy participated in the study and 2521 patients were enrolled over the 5-month study period. Results Almost half of patients (46%) showed an aggressive behaviour at admission to ward, but they engaged more commonly in verbal aggression (38%), than in aggression toward other people (20%). A total of 78% of patients had a psychiatric diagnosis at admission, most frequently schizophrenia (36%), followed by depression (16%) and personality disorders (14%), and no relevant changes in the diagnoses pattern were observed during hospital stay. Benzodiazepines were the most commonly prescribed drugs, regardless of diagnosis, at all time points. Overall, up to 83% of patients were treated with neuroleptic drugs and up to 27% received more than one neuroleptic either during hospital stay or at discharge. Atypical and conventional antipsychotics were equally prescribed for schizophrenia (59 vs 65% during stay and 59 vs 60% at discharge), while atypical drugs were preferred in schizoaffective psychoses (72 vs 49% during stay and 70 vs 46% at discharge) and depression (41 vs 32% during stay and 44 vs 25% at discharge). Atypical neuroleptics were slightly preferred to conventional ones at hospital discharge (52 vs 44%). Polypharmacy was in general widely used. Patient attitudes toward medications were on average positive and self-reported compliance

  19. Canine Leishmaniasis in North America: Emerging or Newly Recognized?

    PubMed Central

    Petersen, Christine A.; Barr, Stephen C.

    2009-01-01

    Synopsis Canine Leishmaniasis is a fatal zoonotic visceralizing disease usually associated with tropical areas. The etiologic agent is an obligate intracellular protozoan, Leishmania infantum. In 1999, an outbreak of a canine leishmaniasis was reported in a Foxhound kennel in New York, and since that report, several other outbreaks have occurred across the United States in additional Foxhound kennels. Because of the high mortality and transmissibility associated with these outbreaks, it is essential that clinicians be aware of this disease to permit its rapid recognition and institution of control measures. Cases with a travel history may suggest imported disease, these are mainly observed from Southern Europe (south of France, Spain, Italy). Breeds from these and other endemic areas may be at higher risk of infection with Leishmania due to vertical transmission. The purpose of this report is to discuss the clinical signs, epidemiology, diagnosis, control and treatment of canine leishmaniasis with focus on the aspects of this disease within North America. PMID:19932363

  20. Zika virus: history of a newly emerging arbovirus.

    PubMed

    Wikan, Nitwara; Smith, Duncan R

    2016-07-01

    Zika virus was originally identified in a sentinel rhesus monkey in the Zika Forest of Uganda in 1947. The virus is a member of the family Flaviviridae, genus Flavivirus, and is transmitted to humans by Aedes species mosquitoes. The first report of Zika virus outside Africa and Asia was in 2007 when the virus was associated with a small outbreak in Yap State, part of the Federated States of Micronesia. Since then, Zika virus infections have been reported around the world, including in southeast Asia; French Polynesia and other islands in the Pacific Ocean; and parts of South, Central, and North America. Symptomatic infection in human beings normally results in a mild and self-limiting febrile disease, although recent reports have suggested a possible association with more serious sequelae such as Guillain-Barré syndrome, and microcephaly in newborn infants of mothers infected with Zika virus during pregnancy. In this Review, we summarise the history of Zika virus from its first detection to its current worldwide distribution. Copyright © 2016 Elsevier Ltd. All rights reserved.

  1. Acetic Acid Bacteria, Newly Emerging Symbionts of Insects▿

    PubMed Central

    Crotti, Elena; Rizzi, Aurora; Chouaia, Bessem; Ricci, Irene; Favia, Guido; Alma, Alberto; Sacchi, Luciano; Bourtzis, Kostas; Mandrioli, Mauro; Cherif, Ameur; Bandi, Claudio; Daffonchio, Daniele

    2010-01-01

    Recent research in microbe-insect symbiosis has shown that acetic acid bacteria (AAB) establish symbiotic relationships with several insects of the orders Diptera, Hymenoptera, Hemiptera, and Homoptera, all relying on sugar-based diets, such as nectars, fruit sugars, or phloem sap. To date, the fruit flies Drosophila melanogaster and Bactrocera oleae, mosquitoes of the genera Anopheles and Aedes, the honey bee Apis mellifera, the leafhopper Scaphoideus titanus, and the mealybug Saccharicoccus sacchari have been found to be associated with the bacterial genera Acetobacter, Gluconacetobacter, Gluconobacter, Asaia, and Saccharibacter and the novel genus Commensalibacter. AAB establish symbiotic associations with the insect midgut, a niche characterized by the availability of diet-derived carbohydrates and oxygen and by an acidic pH, selective factors that support AAB growth. AAB have been shown to actively colonize different insect tissues and organs, such as the epithelia of male and female reproductive organs, the Malpighian tubules, and the salivary glands. This complex topology of the symbiosis indicates that AAB possess the keys for passing through body barriers, allowing them to migrate to different organs of the host. Recently, AAB involvement in the regulation of innate immune system homeostasis of Drosophila has been shown, indicating a functional role in host survival. All of these lines of evidence indicate that AAB can play different roles in insect biology, not being restricted to the feeding habit of the host. The close association of AAB and their insect hosts has been confirmed by the demonstration of multiple modes of transmission between individuals and to their progeny that include vertical and horizontal transmission routes, comprising a venereal one. Taken together, the data indicate that AAB represent novel secondary symbionts of insects. PMID:20851977

  2. Education and Technology Accelerate Economic Growth for Newly Emerging Economies.

    ERIC Educational Resources Information Center

    Workforce Economics Trends, 2001

    2001-01-01

    Technology provides a new and effective tool for accelerating economic growth, and developing countries are embracing technology and education as the means toward attaining economic parity with the United States and other developed nations. Evidence suggests that this strategy is paying off. Developing countries are building a technology…

  3. Studies on a newly emerging protozoal pathogen: Cyclospora cayetanensis.

    PubMed

    Abou el Naga, I F

    1999-08-01

    Cyclospora is frequently misdiagnosed with Cryptosporidia. Stool samples were collected from 150 immunocompromised patients and concentrated by the parasep faecal parasite concentration and the discontinuous percoll gradients methods. Wet mount examination was done and the parasite was successfully stained with modified Ziehl Neelsen (ZN) and safranin methylene blue stain. Cyclospora was detected in 4% of cases examined. Cyclospora was easily differentiated from Cryptosporidia by using the modified detergent ZN stain whereby Cyclospora resist staining and Cryptosporidia pick up the pink colouration. Scanning and transmission electron microscopic examination were done to the unsporulated Cyclospora oocysts. They appeared as spherical objects with an outer fibrillar coat, an indentation and sutures. These spherical objects also contained light and dark granules. In studying the possible sources of transmission of this parasite, sporulated and unsporulated oocysts were detected in tap water and lettuce heads which support the theory that water and food could be the sources of transmission of this parasite.

  4. Newly Emerging Needs of Children and Youth. Annual Report, 2005

    ERIC Educational Resources Information Center

    International Child Development Initiatives (NJ1), 2005

    2005-01-01

    In global terms, 2005 was not much different from the years before, as it was again not a happy time for the world's children. The trend of many countries sinking further back into poverty continued, with people living shorter lives, fewer children going to school and more children dying than ever before. Wars keep raging on, taking heavy tolls on…

  5. [Pediatric emergencies in the emergency medical service].

    PubMed

    Silbereisen, C; Hoffmann, F

    2015-01-01

    Out-of-hospital pediatric emergencies occur rarely but are feared among medical personnel. The particular characteristics of pediatric cases, especially the unaccustomed anatomy of the child as well as the necessity to adapt the drug doses to the little patient's body weight, produce high cognitive and emotional pressure. In an emergency standardized algorithms can facilitate a structured diagnostic and therapeutic approach. The aim of this article is to provide standardized procedures for the most common pediatric emergencies. In Germany, respiratory problems, seizures and analgesia due to trauma represent the most common emergency responses. This article provides a practical approach concerning the diagnostics and therapy of emergencies involving children.

  6. Targeted Strategies for Henipavirus Therapeutics

    PubMed Central

    Bossart, Katharine N; Bingham, John; Middleton, Deborah

    2007-01-01

    Hendra and Nipah viruses are related emergent paramyxoviruses that infect and cause disease in animals and humans. Disease manifests as a generalized vasculitis affecting multiple organs, but is the most severe in the respiratory and central nervous systems. The high case fatality and person-to-person transmission associated with the most recent NiV outbreaks, and the recent re-emergence of HeV, emphasize the importance and necessity of effective therapeutics for these novel agents. In recent years henipavirus research has revealed a more complete understanding of pathogenesis and, as a consequence, viable approaches towards vaccines and therapeutics have emerged. All strategies target early steps in viral replication including receptor binding and membrane fusion. Animal models have been developed, some of which may prove more valuable than others for evaluating the efficacy of therapeutic agents and regimes. Assessments of protective host immunity and drug pharmacokinetics will be crucial to the further advancement of therapeutic compounds. PMID:19440455

  7. Career Motivation in Newly Licensed Registered Nurses: What Makes Them Remain

    ERIC Educational Resources Information Center

    Banks, Zarata Mann; Bailey, Jessica H.

    2010-01-01

    Despite vast research on newly licensed registered nurses (RNs), we don't know why some newly licensed registered nurses remain in their current jobs and others leave the nursing profession early in their career. Job satisfaction, the most significant factor emerging from the literature, plays a significant role in nurses' decisions to remain in…

  8. Therapeutic ERCP

    MedlinePlus

    ... the recovery unit. You should not drive a car for the rest of the day although most patients can return to full activity the next day. What are possible complications of therapeutic ERCP? The overall ERCP complication rate requiring hospitalization ...

  9. Therapeutic Recreation

    ERIC Educational Resources Information Center

    Parks and Recreation, 1971

    1971-01-01

    Graphic profiles of (1) the professional membership of the National Therapeutic Recreation Society, (2) state-level employment opportunities in the field, and (3) educational opportunities at U.S. colleges and universities. (MB)

  10. Emergency Mask OBT

    NASA Image and Video Library

    2015-07-28

    ISS044E025035 (07/29/2015) --- NASA astronaut Kjell Lindgren prepares to don protective breathing apparatus that would be used in the unlikely event of a fire or hazardous chemical leak inside the pressurized air volume of the International Space Station. Familiarization of safety and emergency equipment is standard practice for all newly arrived crew members.

  11. Emergency Mask OBT

    NASA Image and Video Library

    2015-07-28

    ISS044E025035 (07/29/2015) --- NASA astronaut Kjell Lindgren wears protective breathing apparatus that would be used in the unlikely event of a fire or hazardous chemical leak inside the pressurized air volume of the International Space Station. Familiarization of safety and emergency equipment is standard practice for all newly arrived crew members.

  12. MACROMOLECULAR THERAPEUTICS

    PubMed Central

    Yang, Jiyuan; Kopeček, Jindřich

    2014-01-01

    This review covers water-soluble polymer-drug conjugates and macromolecules that possess biological activity without attached low molecular weight drugs. The main design principles of traditional and backbone degradable polymer-drug conjugates as well as the development of a new paradigm in nanomedicines – (low molecular weight) drug-free macromolecular therapeutics are discussed. To address the biological features of cancer, macromolecular therapeutics directed to stem/progenitor cells and the tumor microenvironment are deliberated. Finally, the future perspectives of the field are briefly debated. PMID:24747162

  13. Macromolecular therapeutics.

    PubMed

    Yang, Jiyuan; Kopeček, Jindřich

    2014-09-28

    This review covers water-soluble polymer-drug conjugates and macromolecules that possess biological activity without attached low molecular weight drugs. The main design principles of traditional and backbone degradable polymer-drug conjugates as well as the development of a new paradigm in nanomedicines - (low molecular weight) drug-free macromolecular therapeutics are discussed. To address the biological features of cancer, macromolecular therapeutics directed to stem/progenitor cells and the tumor microenvironment are deliberated. Finally, the future perspectives of the field are briefly debated.

  14. The emerging market dynamics of targeted therapeutics.

    PubMed

    Calfee, John E; Dupré, Elizabeth

    2006-01-01

    Targeted biotech drugs that attack specific biological molecules that cause disease are bringing new benefits even as they foment pricing dynamics that are very different from those of traditional drugs. Targeted drugs tend not to compete with each other even when treating closely related diseases, which makes them resistant to price controls. We can expect the supply of expensive new so-called biotech drugs to continue. But the same properties that generate premium prices also facilitate inventing around successful drugs, eventually leading to vigorous competition despite the lack of generic alternatives.

  15. Emerging therapeutics in refractory renal cell carcinoma.

    PubMed

    Koshkin, Vadim S; Rini, Brian I

    2016-06-01

    Metastatic renal cell carcinoma (mRCC) has seen the introduction of numerous new treatments over the past decade. However, the efficacy of these therapies has plateaued, and new treatment options are needed for the majority of patients with mRCC whose disease inevitably progresses through one or more standard therapies ('refractory' mRCC). Recently approved agents in this space have shown great promise. This article reviews the evidence behind current management strategies for mRCC. After reviewing clinical trials that established current first-line therapies and agents used in the refractory setting, we address new ideas for the treatment of refractory disease including combination therapies and novel targeted agents. In particular, we focus on targeted immunotherapy in refractory mRCC. We conclude by considering future directions in combination treatments utilizing these novel agents. Numerous approaches have produced tangible benefits for the treatment of patients with mRCC. These include development of next generation VEGFR/TKIs, targeted immunotherapy agents, and the development of combined regimens. In particular, immunotherapy agents targeting the PD1/PD-L1 pathway have shown great promise with a robust survival advantage seen in patients treated with nivolumab. A tolerable side effect profile of immunotherapy agents makes them amenable for use in combination therapies and ongoing trials are addressing this question.

  16. Discoidin Domains as Emerging Therapeutic Targets.

    PubMed

    Villoutreix, Bruno O; Miteva, Maria A

    2016-08-01

    Discoidin (DS) domains are found in eukaryotic and prokaryotic extracellular and transmembrane multidomain proteins. These small domains play different functional roles and can interact with phospholipids, glycans, and proteins, including collagens. DS domain-containing proteins are often involved in cellular adhesion, migration, proliferation, and matrix-remodeling events, while some play a major role in blood coagulation. Mutations in DS domains have been associated with various disease conditions. This review provides an update on the structure, function, and modulation of the DS domains, with a special emphasis on two circulating blood coagulation cofactors, factor V and factor VIII, and the transmembrane neuropilin receptors that have been targeted for inhibition by biologics and small chemical compounds.

  17. Emerging therapeutic strategies to enhance HDL function.

    PubMed

    Redondo, Santiago; Martínez-González, José; Urraca, Concha; Tejerina, Teresa

    2011-10-10

    Epidemiologic studies indicate a strong inverse correlation between plasma levels of high-density lipoproteins (HDL) and cardiovascular disease (CVD). The most relevant cardioprotective mechanism mediated by HDL is thought to be reverse cholesterol transport (RCT). New insights in HDL biology and RCT have allowed the development of promising agents aimed to increase HDL function and promote atherosclerosis regression. In this regard, apo-AI analogs and CETP inhibitors dalcetrapib and anacetrapib have aroused a great interest and opened new expectations in the treatment of CVD.

  18. Smoldering Multiple Myeloma: Emerging Concepts and Therapeutics.

    PubMed

    Sundararajan, Srinath; Kumar, Abhijeet; Korde, Neha; Agarwal, Amit

    2016-04-01

    Smoldering multiple myeloma (SMM) is a pre-malignant condition with an inherent risk for progression to multiple myeloma (MM). The 2014 IMWG guidelines define smoldering multiple myeloma as a monoclonal gammopathy disorder with serum monoclonal protein (IgG or IgA) ≥30 g/L or urinary monoclonal protein ≥500 mg per 24 h and/or clonal bone marrow plasma cells 10-60 % without any myeloma-defining events or amyloidosis. The risk for progression of SMM to MM vary based on clinical, laboratory, imaging, and molecular characteristics. Observation, with periodic monitoring is the current standard of care for SMM. Over last few years, research advances in SMM have led to the delineation of newer risk factors for progression and identification of a "high-risk" group that would potentially benefit from early treatment. This review focuses on advances in the SMM risk-stratification model and recent clinical trials in this patient population.

  19. Recurrent pericarditis: new and emerging therapeutic options.

    PubMed

    Imazio, Massimo; Lazaros, George; Brucato, Antonio; Gaita, Fiorenzo

    2016-02-01

    Recurrent pericarditis is one of the most common and troublesome complications after an episode of pericarditis, and affects 20-50% of patients treated for pericarditis. In most of these patients, the pericarditis remains idiopathic, although an immune-mediated (either autoimmune or autoinflammatory) pathogenesis is often presumed. The mainstay of therapy for recurrences is aspirin or NSAIDs, with the adjunct of colchicine. Corticosteroids are a second-line option to be considered for specific indications, such as connective tissue disease or pregnancy; contraindications or intolerance to aspirin, NSAIDs, and/or colchicine; or insufficient response to these medications. Furthermore, corticosteroids can be added to NSAIDs and colchicine in patients with persistent symptoms. In patients who do not respond adequately to any of these conventional therapies, alternative treatment options include azathioprine, intravenous human immunoglobulins, and anakinra. An improved understanding of how recurrent pericarditis develops after an initiating event is critical to prevent this complication, and further research is needed into the pathogenesis of recurrences. We discuss the aetiology and diagnosis of recurrent pericarditis, and extensively review the treatment options for this condition.

  20. The injectable neurostimulator: an emerging therapeutic device.

    PubMed

    Li, Xiaolong; Serdijn, Wouter A; Zheng, Wei; Tian, Yubo; Zhang, Bing

    2015-07-01

    Injectable neurostimulators are currently applied in clinical trials to minimize the side effects such as discomfort, risk of infection, and post-surgery trauma, which can be pronounced with conventional, bulky implantable neurostimulators. Owing to its smaller size, wireless-updatable software, and wireless power supply, the injectable neurostimulator is presumably less invasive, 'smarter', and has a longer lifetime. We discuss the concept and development of the injectable neurostimulator, persistent implementation challenges, and obstacles to be overcome in its evolution. We survey the use of new materials, technologies, and design methods for injectable electrodes, batteries, antennas, and packaging to enhance reliability and other features. These advances in the field are accompanied by progress in electrophysiology, neuroscience, neurology, clinical trials, and treatments.

  1. Feedlot therapeutics.

    PubMed

    Apley, M D; Fajt, V R

    1998-07-01

    This article discusses therapeutic approaches to conditions commonly encountered in feedlots. Challenges discussed include bovine respiratory complex, tracheal edema, atypical interstitial pneumonia, footrot, toe abscesses, mycoplasma arthritis, cardiovascular disease, lactic acidosis, bloat, coccidiosis, central nervous system diseases, abscesses and cellulitis, pregnancy management and abortion, and ocular disease.

  2. Therapeutic proteins.

    PubMed

    Dimitrov, Dimiter S

    2012-01-01

    Protein-based therapeutics are highly successful in clinic and currently enjoy unprecedented recognition of their potential. More than 100 genuine and similar number of modified therapeutic proteins are approved for clinical use in the European Union and the USA with 2010 sales of US$108 bln; monoclonal antibodies (mAbs) accounted for almost half (48%) of the sales. Based on their pharmacological activity, they can be divided into five groups: (a) replacing a protein that is deficient or abnormal; (b) augmenting an existing pathway; (c) providing a novel function or activity; (d) interfering with a molecule or organism; and (e) delivering other compounds or proteins, such as a radionuclide, cytotoxic drug, or effector proteins. Therapeutic proteins can also be grouped based on their molecular types that include antibody-based drugs, Fc fusion proteins, anticoagulants, blood factors, bone morphogenetic proteins, engineered protein scaffolds, enzymes, growth factors, hormones, interferons, interleukins, and thrombolytics. They can also be classified based on their molecular mechanism of activity as (a) binding non-covalently to target, e.g., mAbs; (b) affecting covalent bonds, e.g., enzymes; and (c) exerting activity without specific interactions, e.g., serum albumin. Most protein therapeutics currently on the market are recombinant and hundreds of them are in clinical trials for therapy of cancers, immune disorders, infections, and other diseases. New engineered proteins, including bispecific mAbs and multispecific fusion proteins, mAbs conjugated with small molecule drugs, and proteins with optimized pharmacokinetics, are currently under development. However, in the last several decades, there are no conceptually new methodological developments comparable, e.g., to genetic engineering leading to the development of recombinant therapeutic proteins. It appears that a paradigm change in methodologies and understanding of mechanisms is needed to overcome major

  3. The emerging role of the intestine in metabolic diseases.

    PubMed

    Bradley, William D; Zwingelstein, Catherine; Rondinone, Cristina M

    2011-07-01

    The intestine is an important metabolic organ that has gained attention in recent years for the newly identified role that it plays in the pathophysiology of various metabolic diseases including obesity, insulin resistance and diabetes. Recent insights regarding the role of enteroendocrine hormones, such as GIP, GLP-1, and PYY in metabolic diseases, as well as the emerging role of the gut microbial community and gastric bypass bariatric surgeries in modulating metabolic function and dysfunction have sparked a wave of interest in understanding the mechanisms involved, in an effort to identify new therapeutics and novel regulators of metabolism. This review summarizes the current evidence that the gastrointestinal tract has a key role in the development of obesity, inflammation, insulin resistance and diabetes and discusses the possible players that can be targeted for therapeutic intervention.

  4. Lung Emergencies

    MedlinePlus

    ... Emergencies Cardiac Emergencies Eye Emergencies Lung Emergencies Surgeries Lung Emergencies People with Marfan syndrome can be at ... should be considered an emergency. Symptoms of sudden lung collapse (pneumothorax) Symptoms of a sudden lung collapse ...

  5. Characterization of newly isolated lytic bacteriophages active against Acinetobacter baumannii.

    PubMed

    Merabishvili, Maia; Vandenheuvel, Dieter; Kropinski, Andrew M; Mast, Jan; De Vos, Daniel; Verbeken, Gilbert; Noben, Jean-Paul; Lavigne, Rob; Vaneechoutte, Mario; Pirnay, Jean-Paul

    2014-01-01

    Based on genotyping and host range, two newly isolated lytic bacteriophages, myovirus vB_AbaM_Acibel004 and podovirus vB_AbaP_Acibel007, active against Acinetobacter baumannii clinical strains, were selected from a new phage library for further characterization. The complete genomes of the two phages were analyzed. Both phages are characterized by broad host range and essential features of potential therapeutic phages, such as short latent period (27 and 21 min, respectively), high burst size (125 and 145, respectively), stability of activity in liquid culture and low frequency of occurrence of phage-resistant mutant bacterial cells. Genomic analysis showed that while Acibel004 represents a novel bacteriophage with resemblance to some unclassified Pseudomonas aeruginosa phages, Acibel007 belongs to the well-characterized genus of the Phikmvlikevirus. The newly isolated phages can serve as potential candidates for phage cocktails to control A. baumannii infections.

  6. Therapeutic HPV DNA vaccines

    PubMed Central

    Lin, Ken; Roosinovich, Elena; Ma, Barbara; Hung, Chien-Fu

    2010-01-01

    It is now well established that most cervical cancers are causally associated with HPV infection. This realization has led to efforts to control HPV-associated malignancy through prevention or treatment of HPV infection. Currently, commercially available HPV vaccines are not designed to control established HPV infection and associated premalignant and malignant lesions. To treat and eradicate pre-existing HPV infections and associated lesions which remain prevalent in the U.S. and worldwide, effective therapeutic HPV vaccines are needed. DNA vaccination has emerged as a particularly promising form of therapeutic HPV vaccines due to its safety, stability and ability to induce antigen-specific immunity. This review focuses on improving the potency of therapeutic HPV vaccines through modification of dendritic cells (DCs) by [1] increasing the number of antigen-expressing/antigen-loaded DCs, [2] improving HPV antigen expression, processing and presentation in DCs, and [3] enhancing DC and T cell interaction. Continued improvement in therapeutic HPV DNA vaccines may ultimately lead to an effective DNA vaccine for the treatment of HPV-associated malignancies. PMID:20066511

  7. Emerging and re-emerging infections.

    PubMed

    Lim, V K

    1999-06-01

    An emerging infection is defined as an infection which has newly appeared in a population while a re-emerging infection is one which has existed in the past but its incidence is rapidly increasing. The reasons for the emergence and re-emergence of infections are not well understood but appear to be associated with factors that involve the pathogen, the host and the environment. These factors are often inter-related and act together in a complex manner to bring about changes in patterns of infection. Pathogens are extremely resourceful and possess mechanisms to adapt to new hosts and environments as well as to acquire new virulence traits. Host factors include herd immunity, social behaviour and demographics. Environmental factors like the climate, deforestation and new technologies have an impact on the emergence of infections. The challenge is to contain an infection when it emerges but more importantly to prevent its emergence in the first place. As the emergence of an infection is complex and multifactorial, a multidisciplinary approach is required. Health based strategies alone are insufficient. Social, economic and environmental measures and the political will to implement appropriate policies are equally important.

  8. Export of newly formed LSW

    NASA Astrophysics Data System (ADS)

    Müller, Katharina; Klein, Birgit; Karstensen, Johannes; Fischer, Jürgen; Baumann, Till; Kanzow, Torsten

    2015-04-01

    The Atlantic meridional overturning circulation represents the strongest mechanism for oceanic northward heat transport. This is accomplished by moving warm water northward in the upper ocean compensated by a deep return flow of cold and dense North Atlantic Deep Water (NADW). Labrador Sea Water (LSW) constitutes the shallowest component of NADW. Since LSW is also supposed to be the most sensitive NADW component to climate change it is of particular interest. LSW is formed by deep convection not only in the centre of the Labrador Sea but also near its western boundary. Recent studies have suggested that LSW formed in the boundary region enters its export route from the Labrador Sea, the Deep Western Boundary Current, faster than LSW originating from the central Labrador Sea. In this study the spatial and temporal evolution of the export of newly formed LSW is investigated. For this purpose hydrographic mooring data from an array located at the western bounndary at 53°N starting in the late 1990s until 2014 and data from the Argo float network is used. The averaged seasonal salinity cycle at the array, particularly at the moorings further onshore, shows a pronounced freshwater signal in May indicating the arrival of newly formed LSW in the boundary current. In order to learn more about its preceding pathway and the corresponding export timescale the mooring data is complemented by data from Argo floats. Besides the annual cycles of LSW formation and export, their interannual variations are important aspects affecting the large-scale circulation. For instance, in years of relatively strong convection, as in 2008 and 2012, LSW is observed to pass the boundary current array at 53°N earlier, i.e. in February and March, respectively, than in years with weak convection, as in 2007 or 2010. Besides seasonal variations in the boundary current, a possible explanation for the earlier freshwater signal in years of enhanced convection might be a shift in convection sites

  9. Newly Installed S-1 Truss

    NASA Technical Reports Server (NTRS)

    2002-01-01

    Launched October 7, 2002 aboard the Space Shuttle Orbiter Atlantis, the STS-112 mission lasted 11 days and performed three sessions of Extra Vehicular Activity (EVA). Its primary mission was to install the Starboard (S1) Integrated Truss Structure and Equipment Translation Aid (CETA) Cart to the International Space Station (ISS). The S1 truss provides structural support for the orbiting research facility's radiator panels, which use ammonia to cool the Station's complex power system. The S1 truss, attached to the S0 (S Zero) truss installed by the previous STS-110 mission, flows 637 pounds of anhydrous ammonia through three heat rejection radiators. The truss is 45-feet long, 15-feet wide, 10-feet tall, and weighs approximately 32,000 pounds. The CETA is the first of two human-powered carts that will ride along the International Space Station's railway providing a mobile work platform for future extravehicular activities by astronauts. This is a view of the newly installed S1 Truss as photographed during the mission's first scheduled EVA. The Station's Canadarm2 is in the foreground. Visible are astronauts Piers J. Sellers (lower left) and David A. Wolf (upper right), both STS-112 mission specialists.

  10. Newly Installed S-1 Truss

    NASA Technical Reports Server (NTRS)

    2002-01-01

    Launched October 7, 2002 aboard the Space Shuttle Orbiter Atlantis, the STS-112 mission lasted 11 days and performed three sessions of Extra Vehicular Activity (EVA). Its primary mission was to install the Starboard (S1) Integrated Truss Structure and Equipment Translation Aid (CETA) Cart to the International Space Station (ISS). The S1 truss provides structural support for the orbiting research facility's radiator panels, which use ammonia to cool the Station's complex power system. The S1 truss, attached to the S0 (S Zero) truss installed by the previous STS-110 mission, flows 637 pounds of anhydrous ammonia through three heat rejection radiators. The truss is 45-feet long, 15-feet wide, 10-feet tall, and weighs approximately 32,000 pounds. The CETA is the first of two human-powered carts that will ride along the International Space Station's railway providing a mobile work platform for future extravehicular activities by astronauts. This is a view of the newly installed S1 Truss as photographed during the mission's first scheduled EVA. The Station's Canadarm2 is in the foreground. Visible are astronauts Piers J. Sellers (lower left) and David A. Wolf (upper right), both STS-112 mission specialists.

  11. Diabetic Emergencies

    MedlinePlus

    ... Sheet Health & Safety Tips Campaigns SUBSCRIBE Emergencies A-Z Share this! Home » Emergency 101 Diabetic Emergencies It ... seek immediate medical assistance. READ IN EMERGENCIES A-Z Mental Health Emergencies - Waits for Care Grow Dramatically ...

  12. Assessment of metal retention in newly constructed highway embankments.

    PubMed

    Werkenthin, Moritz; Kluge, Björn; Wessolek, Gerd

    2016-12-01

    Newly constructed embankments should provide both a specific bearing capacity to enable trafficability in emergency cases and a sufficient pollutant retention capacity to protect the groundwater. A number of lysimeters were installed along the A115 highway to determine total and dissolved metal concentrations in road runoff and in the soil solution of newly constructed embankments. Dissolved concentrations in soil solution of the embankments did not exceed the trigger values of the German legislation. Depending on the metal, total concentrations in soil solution were more than twice as high as dissolved concentrations. The high infiltration rates lead to increased groundwater recharge beneath the embankments (up to 4100 mm a(-1)). Although metal concentrations were not problematic from the legislators' point of view, the elevated infiltration rates beside the road facilitated the transfer of high metal loads into deeper soil layers and potentially into the groundwater as well.

  13. Proteases as therapeutics

    PubMed Central

    Craik, Charles S.; Page, Michael J.; Madison, Edwin L.

    2015-01-01

    Proteases are an expanding class of drugs that hold great promise. The U.S. FDA (Food and Drug Administration) has approved 12 protease therapies, and a number of next generation or completely new proteases are in clinical development. Although they are a well-recognized class of targets for inhibitors, proteases themselves have not typically been considered as a drug class despite their application in the clinic over the last several decades; initially as plasma fractions and later as purified products. Although the predominant use of proteases has been in treating cardiovascular disease, they are also emerging as useful agents in the treatment of sepsis, digestive disorders, inflammation, cystic fibrosis, retinal disorders, psoriasis and other diseases. In the present review, we outline the history of proteases as therapeutics, provide an overview of their current clinical application, and describe several approaches to improve and expand their clinical application. Undoubtedly, our ability to harness proteolysis for disease treatment will increase with our understanding of protease biology and the molecular mechanisms responsible. New technologies for rationally engineering proteases, as well as improved delivery options, will expand greatly the potential applications of these enzymes. The recognition that proteases are, in fact, an established class of safe and efficacious drugs will stimulate investigation of additional therapeutic applications for these enzymes. Proteases therefore have a bright future as a distinct therapeutic class with diverse clinical applications. PMID:21406063

  14. Emerging strategies for the treatment of pulmonary tuberculosis: promise and limitations?

    PubMed

    Yew, Wing Wai; Koh, Won-Jung

    2016-01-01

    A worsening scenario of drug-resistant tuberculosis has increased the need for new treatment strategies to tackle this worldwide emergency. There is a pressing need to simplify and shorten the current 6-month treatment regimen for drug-susceptible tuberculosis. Rifamycins and fluoroquinolones, as well as several new drugs, are potential candidates under evaluation. At the same time, treatment outcomes of patients with drug-resistant tuberculosis should be improved through optimizing the use of fluoroquinolones, repurposed agents and newly developed drugs. In this context, the safety and tolerance of new therapeutic approaches must be addressed.

  15. Eye Emergencies

    MedlinePlus

    ... The Marfan Foundation Marfan & Related Disorders What is Marfan Syndrome? What are Related Disorders? What are the Signs? ... Emergencies Eye Emergencies Lung Emergencies Surgeries Eye Emergencies Marfan syndrome significantly increases your risk of retinal detachment, a ...

  16. Emergency care of raptors.

    PubMed

    Joseph, V

    1998-09-01

    Emergency care of raptors often requires extensive diagnostics and therapeutic regimens to stabilize and support the ill or injured raptor. Whether falconry birds, educational birds, or raptors from the wild are presented, various medical conditions must be addressed to help guide the practitioner toward a complete recovery for the raptor.

  17. The probability of preservation of a newly arisen gene duplicate.

    PubMed

    Lynch, M; O'Hely, M; Walsh, B; Force, A

    2001-12-01

    Newly emerging data from genome sequencing projects suggest that gene duplication, often accompanied by genetic map changes, is a common and ongoing feature of all genomes. This raises the possibility that differential expansion/contraction of various genomic sequences may be just as important a mechanism of phenotypic evolution as changes at the nucleotide level. However, the population-genetic mechanisms responsible for the success vs. failure of newly arisen gene duplicates are poorly understood. We examine the influence of various aspects of gene structure, mutation rates, degree of linkage, and population size (N) on the joint fate of a newly arisen duplicate gene and its ancestral locus. Unless there is active selection against duplicate genes, the probability of permanent establishment of such genes is usually no less than 1/(4N) (half of the neutral expectation), and it can be orders of magnitude greater if neofunctionalizing mutations are common. The probability of a map change (reassignment of a key function of an ancestral locus to a new chromosomal location) induced by a newly arisen duplicate is also generally >1/(4N) for unlinked duplicates, suggesting that recurrent gene duplication and alternative silencing may be a common mechanism for generating microchromosomal rearrangements responsible for postreproductive isolating barriers among species. Relative to subfunctionalization, neofunctionalization is expected to become a progressively more important mechanism of duplicate-gene preservation in populations with increasing size. However, even in large populations, the probability of neofunctionalization scales only with the square of the selective advantage. Tight linkage also influences the probability of duplicate-gene preservation, increasing the probability of subfunctionalization but decreasing the probability of neofunctionalization.

  18. The probability of preservation of a newly arisen gene duplicate.

    PubMed Central

    Lynch, M; O'Hely, M; Walsh, B; Force, A

    2001-01-01

    Newly emerging data from genome sequencing projects suggest that gene duplication, often accompanied by genetic map changes, is a common and ongoing feature of all genomes. This raises the possibility that differential expansion/contraction of various genomic sequences may be just as important a mechanism of phenotypic evolution as changes at the nucleotide level. However, the population-genetic mechanisms responsible for the success vs. failure of newly arisen gene duplicates are poorly understood. We examine the influence of various aspects of gene structure, mutation rates, degree of linkage, and population size (N) on the joint fate of a newly arisen duplicate gene and its ancestral locus. Unless there is active selection against duplicate genes, the probability of permanent establishment of such genes is usually no less than 1/(4N) (half of the neutral expectation), and it can be orders of magnitude greater if neofunctionalizing mutations are common. The probability of a map change (reassignment of a key function of an ancestral locus to a new chromosomal location) induced by a newly arisen duplicate is also generally >1/(4N) for unlinked duplicates, suggesting that recurrent gene duplication and alternative silencing may be a common mechanism for generating microchromosomal rearrangements responsible for postreproductive isolating barriers among species. Relative to subfunctionalization, neofunctionalization is expected to become a progressively more important mechanism of duplicate-gene preservation in populations with increasing size. However, even in large populations, the probability of neofunctionalization scales only with the square of the selective advantage. Tight linkage also influences the probability of duplicate-gene preservation, increasing the probability of subfunctionalization but decreasing the probability of neofunctionalization. PMID:11779815

  19. [Diabetic emergencies].

    PubMed

    Berger, W

    1997-02-18

    Based on case reports pathogenesis and treatment of the following diabetic emergencies were discussed: 1. The hyperosmolar non-ketotic coma without or with only modest ketosis occurring mainly in type II diabetics and the severe ketoacidosis with or without disturbed consciousness occurring mainly in type I diabetics are the two forms of severe metabolic decompensation of diabetes mellitus. 2. Severe hypoglycaemia may be caused by treatment with sulfonylureas and insulin. 3. The most dangerous life threatening adverse effect of biguanides is lactic acidosis. The incidence of ketoacidosis is about 1-5% in type I diabetics with a mortality of 3-9%. Mortality rates of hyperosmolar non-ketotic comas are much higher, approaching 20-40%, and are explained by severe concomitant complications and older age. The most important triggering factors of diabetic coma are infections, insulin dispensing errors and non-compliance. Carefully instructing patients about the risks of loosing appetite and vomiting as early signs of ketoacidosis is essential. Adequate replacement of fluid, electrolyte and water are the most important therapeutical aspects of ketoacidosis and hyperosmolar non-ketotic coma. Early diagnosis and appropriate treatment of infection by antibiotics are important. Complication of therapy (hypokalemia, hypovolemia and rapid full of oncotic pressure) should be avoided by clinical and laboratory monitoring. Treatment of acidosis with bicarbonate has been found more dangerous than useful. Severe hypoglycaemia is the most important and most dangerous side effect of sulfonylurea and insulin. The incidence of severe hypoglycaemia under glibenclamide ist 3-5 fold higher than under treatment with tolbutamide or glibornurid. Glibenclamide should not be recommended anymore. Longterm experience of the therapeutic security of new sulfonylurea derivates like glimepirid is lacking. Blood-glucose-measurements in the afternoon are important for recognizing disposition to

  20. Emerging causes of canine lameness.

    PubMed

    Rochat, Mark C

    2005-09-01

    Most orthopedic conditions that affect dogs are well described established conditions. Often, the current literature is focused on refinements in diagnosis, treatment, and management of these conditions. Improvement in worldwide reporting of emerging conditions offers veterinarians a greater awareness of new conditions as they occur. This article compiles into a single source what has been reported for five newly described disorders.

  1. Therapeutic approaches for celiac disease

    PubMed Central

    Plugis, Nicholas M.; Khosla, Chaitan

    2015-01-01

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

  2. Potential therapeutic applications of biosurfactants.

    PubMed

    Gudiña, Eduardo J; Rangarajan, Vivek; Sen, Ramkrishna; Rodrigues, Lígia R

    2013-12-01

    Biosurfactants have recently emerged as promising molecules for their structural novelty, versatility, and diverse properties that are potentially useful for many therapeutic applications. Mainly due to their surface activity, these molecules interact with cell membranes of several organisms and/or with the surrounding environments, and thus can be viewed as potential cancer therapeutics or as constituents of drug delivery systems. Some types of microbial surfactants, such as lipopeptides and glycolipids, have been shown to selectively inhibit the proliferation of cancer cells and to disrupt cell membranes causing their lysis through apoptosis pathways. Moreover, biosurfactants as drug delivery vehicles offer commercially attractive and scientifically novel applications. This review covers the current state-of-the-art in biosurfactant research for therapeutic purposes, providing new directions towards the discovery and development of molecules with novel structures and diverse functions for advanced applications.

  3. Targeting caspases in cancer therapeutics

    PubMed Central

    Hensley, Patrick; Mishra, Murli; Kyprianou, Natasha

    2013-01-01

    The identification of the fundamental role of apoptosis in the growth balance and normal homeostasis against cell proliferation led to the recognition of its loss contributing to tumorigenesis. The mechanistic significance of reinstating apoptosis signaling towards selective targeting of malignant cells heavily exploits the caspase family of death-inducing molecules as a powerful therapeutic platform for the development of potent anticancer strategies. Some apoptosis inhibitors induce caspase expression and activity in preclinical models and clinical trials by targeting both the intrinsic and extrinsic apoptotic pathways and restoring the apoptotic capacity in human tumors. Furthermore, up-regulation of caspases emerges as a sensitizing mechanism for tumors exhibiting therapeutic resistance to radiation and adjuvant chemotherapy. This review provides a comprehensive discussion of the functional involvement of caspases in apoptosis control and the current understanding of reactivating caspase-mediated apoptosis signaling towards effective therapeutic modalities in cancer treatment. PMID:23509217

  4. Emerging application of quantum dots for drug delivery and therapy.

    PubMed

    Qi, Lifeng; Gao, Xiaohu

    2008-03-01

    Quantum dots have proven themselves as powerful fluorescent probes, especially for long-term, multiplexed, and quantitative imaging and detection. Newly engineered quantum dots with integrated targeting, imaging and therapeutic functionalities have become excellent material to study drug delivery in cells and small animals. This fluorescent 'prototype' will provide important information in the rational design of biocompatible drug carriers and will serve as a superior alternative to magnetic and radioactive imaging contrast agents in preclinical drug screening, validation and delivery research. This Editorial article is not intended to offer a comprehensive review on drug delivery, but to highlight the breakthroughs in the emerging applications of quantum dots in this field and to provide our perspective on future research.

  5. Emergent geometry, emergent forces

    NASA Astrophysics Data System (ADS)

    Selesnick, S. A.

    2017-10-01

    We give a brief account of some aspects of Finkelstein’s quantum relativity, namely an extension of it that derives elements of macroscopic geometry and the Lagrangians of the standard model including gravity from a presumed quantum version of spacetime. These emerge as collective effects in this quantal substrate. Our treatment, which is largely self-contained, differs mathematically from that originally given by Finkelstein. Dedicated to the memory of David Ritz Finkelstein

  6. [Pediatric emergencies: Knowledge of basic measures for the emergency physician].

    PubMed

    Meyer, S; Grundmann, U; Reinert, J; Gortner, L

    2015-11-01

    Life-threatening pediatric emergencies are relatively rare in the prehospital setting. Thus, the treating emergency physician may not always be familiar with and well trained in these situations. However, pediatric emergencies require early recognition and initiation of specific diagnostic and therapeutic interventions to prevent further damage. The treatment of pediatric emergencies follows current recommendations as detailed in published international guidelines. The aim of this review is to familiarize the emergency physician with general aspects pertinent to this topic-most importantly anatomical and physiological characteristics in this cohort. Also, specific information with regard to analgesia and sedation, which may be warranted in the prehospital setting, will be provided.

  7. Ubiquitination of newly synthesized proteins at the ribosome.

    PubMed

    Wang, Feng; Canadeo, Larissa A; Huibregtse, Jon M

    2015-07-01

    Newly synthesized proteins can be misfolded or damaged because of errors during synthesis or environmental insults (e.g., heat shock), placing a significant burden on protein quality control systems. In addition, numerous human diseases are associated with a deficiency in eliminating aberrant proteins or accumulation of aggregated proteins. Understanding the mechanisms of protein quality control and disposal pathways for misfolded proteins is therefore crucial for therapeutic intervention in these diseases. Quality control processes function at many points in the life cycle of proteins, and a subset act at the actual site of protein synthesis, the ribosome. Here we summarize recent advances in the role of the ubiquitin proteasome system in protein quality control during the process of translation.

  8. Ubiquitination of Newly Synthesized Proteins at the Ribosome

    PubMed Central

    Wang, Feng; Canadeo, Larissa A.; Huibregtse, Jon M.

    2015-01-01

    Newly synthesized proteins can be misfolded or damaged because of errors during synthesis or environmental insults (e.g., heat shock), placing a significant burden on protein quality control systems. In addition, numerous human diseases are associated with a deficiency in eliminating aberrant proteins or accumulation of aggregated proteins. Understanding the mechanisms of protein quality control and disposal pathways for misfolded proteins is therefore crucial for therapeutic intervention in these diseases. Quality control processes function at many points in the life cycle of proteins, and a subset act at the actual site of protein synthesis, the ribosome. Here we summarize recent advances in the role of the ubiquitin proteasome system in protein quality control during the process of translation. PMID:25701549

  9. Semantic Representation of Newly Learned L2 Words and Their Integration in the L2 Lexicon

    ERIC Educational Resources Information Center

    Bordag, Denisa; Kirschenbaum, Amit; Rogahn, Maria; Opitz, Andreas

    2017-01-01

    The present semantic priming study explores the integration of newly learnt L2 German words into the L2 semantic network of German advanced learners. It provides additional evidence in support of earlier findings reporting semantic inhibition effects for emergent representations. An inhibitory mechanism is proposed that temporarily decreases the…

  10. Emergency Contraception

    MedlinePlus

    ... contraception are available: emergency contraceptive pills and the copper-containing intrauterine device (IUD).Emergency contraceptive pills include ... for emergency use, talk to your doctor.The copper-containing IUD (brand name: Paragard) is a small, ...

  11. Chemical Emergency

    MedlinePlus

    ... listen to a local Emergency Alert System (EAS) station for emergency instructions from county or state officials. ... and your family. Listen to your emergency broadcast stations on radio and TV. Use your phone only ...

  12. On the advancement of therapeutic penality: therapeutic authority, personality science and the therapeutic community.

    PubMed

    McBride, Ruari-Santiago

    2017-09-01

    In this article I examine the advancement of therapeutic penality in the UK, a penal philosophy that reimagines prison policy, practices and environments utilising psychological knowledge. Adopting a historical approach, I show how modern therapeutic penality is linked to the emergence of personality science in the nineteenth century and the development of the democratic therapeutic community (DTC) model in the twentieth century. I outline how at the turn of the twenty-first century a catalytic event generated a moral panic that led the British government to mobilise psychological knowledge and technologies in an attempt to manage dangerous people with severe personality disorder. Tracing subsequent developments, I argue psychological ways of talking, thinking and acting have obtained unparalleled salience in domains of penality and, in turn, radically transformed the conditions of imprisonment. © 2017 Foundation for the Sociology of Health & Illness.

  13. Chemotherapy in newly diagnosed primary central nervous system lymphoma

    PubMed Central

    Hashemi-Sadraei, Nooshin; Peereboom, David M.

    2010-01-01

    Primary central nervous system lymphoma (PCNSL) accounts for only 3% of brain tumors. It can involve the brain parenchyma, leptomeninges, eyes and the spinal cord. Unlike systemic lymphoma, durable remissions remain uncommon. Although phase III trials in this rare disease are difficult to perform, many phase II trials have attempted to define standards of care. Treatment modalities for patients with newly diagnosed PCNSL include radiation and/or chemotherapy. While the role of radiation therapy for initial management of PCNSL is controversial, clinical trials will attempt to improve the therapeutic index of this modality. Routes of chemotherapy administration include intravenous, intraocular, intraventricular or intra-arterial. Multiple trials have outlined different methotrexate-based chemotherapy regimens and have used local techniques to improve drug delivery. A major challenge in the management of patients with PCNSL remains the delivery of aggressive treatment with preservation of neurocognitive function. Because PCNSL is rare, it is important to perform multicenter clinical trials and to incorporate detailed measurements of long-term toxicities. In this review we focus on different chemotherapeutic approaches for immunocompetent patients with newly diagnosed PCNSL and discuss the role of local drug delivery in addition to systemic therapy. We also address the neurocognitive toxicity of treatment. PMID:21789140

  14. The threat of emerging infections.

    PubMed

    1996-11-01

    A variety of newly discovered pathogens and new forms of older infectious agents threaten to reemerge. Typical symptoms of acute infection are fever, headache, malaise, vomiting, and diarrhea. Some of the better-known emerging viral infections include dengue, filoviruses (Ebola, Marburg), hantaviruses, hepatitis B, hepatitis C, HIV, influenza, lassa fever, measles, rift valley fever, rotavirus, and yellow fever. Emerging bacterial infections include cholera, Escherichia coli 0157:H7, legionnaires disease (Legionella), lyme disease, streptococcus infections (group A), tuberculosis, and typhoid. Emerging parasitic infections include cryptosporidium and other waterborne pathogens and malaria. The causes of many diseases are still shrouded in mystery; thus, treatments and cures for them are as yet unknown.

  15. Metastasis-associated long noncoding RNAs in gastrointestinal cancer: Implications for novel biomarkers and therapeutic targets

    PubMed Central

    Zhang, Fei-Fei; Luo, Yu-Hao; Wang, Hui; Zhao, Liang

    2016-01-01

    Long non-coding RNAs (lncRNAs), a newly discovered class of ncRNA molecules, have been widely accepted as crucial regulators of various diseases including cancer. Increasing numbers of studies have demonstrated that lncRNAs are involved in diverse physiological and pathophysiological processes, such as cell cycle progression, chromatin remodeling, gene transcription, and posttranscriptional processing. Aberrant expression of lncRNAs frequently occurs in gastrointestinal cancer and plays emerging roles in cancer metastasis. In this review, we focus on and outline the regulatory functions of recently identified metastasis-associated lncRNAs, and evaluate the potential roles of lncRNAs as novel diagnostic biomarkers and therapeutic targets in gastrointestinal cancer. PMID:27818589

  16. Neddylation Pathway as a Novel Anti-cancer Target: Mechanistic Investigation and Therapeutic Implication.

    PubMed

    Jiang, Yanan; Jia, Lijun

    2015-01-01

    Protein neddylation, a newly characterized posttranslational modification that adds the ubiquitin-like molecule NEDD8 to substrates, modulates important biological processes, whereas dysfunction of neddylation may cause several serious diseases, such as cancer. Inhibition of neddylation pathway has emerged as a promising anticancer strategy, as evidenced by development of the NEDD8-activating enzyme (NAE) inhibitor MLN4924. Due to its potent anti-cancer efficacy and well-tolerated toxicity, MLN4924 has been evaluated in multiple Phase I clinical trials for solid tumors and hematologic malignancies. Recently, accumulating evidences indicate that neddylation pathway also plays a pivotal role in the regulation of multiple processes of tumor microenvironment (TME), such as tumor angiogenesis and the function of immune cells. In this review, we briefly summarize the latest progresses in this field and highlight neddylation pathway as an attractive therapeutic target against human cancer.

  17. The Newly Discovered Rembrandt Impact Basin

    NASA Image and Video Library

    2009-05-05

    This NAC mosaic of the newly discovered Rembrandt impact basin was presented last week during a NASA media teleconference. The number per area and size distribution of impact craters superposed on Rembrandt rim indicates that it is one of the younges

  18. Newly planted street tree growth and mortality

    Treesearch

    David J. Nowak; Joe R. McBride; Russell A. Beatty

    1990-01-01

    Two-year growth and mortality rates were analyzed for 254 black locust, 199 southern magnolia and 27 London plane trees planted along a major boulevard extending from southern Berkeley through western inner-city Oakland, California. After the first two years, 34% of these newly planted trees were either dead or removed. The average annual mortality rate was 19% with no...

  19. Anxiety and the Newly Returned Adult Student

    ERIC Educational Resources Information Center

    Cleary, Michelle Navarre

    2012-01-01

    Based on interviews with students who had recently returned to school, this essay demonstrates the need for, challenges of, and ways to respond to the writing anxiety many adults bring with them back to school. Jessica and Sam were two of twenty-five newly returned adult students whom the author spent over sixty hours interviewing in the fall of…

  20. The Florida Survey of Newly Legalized Persons.

    ERIC Educational Resources Information Center

    Schilit, Jeffrey; Nimnicht, Glen

    This study was conducted to gather more definitive information about aliens who were newly legalized under the Immigration Reform and Control Act of 1986. Two groups of eligible legal aliens were interviewed in Florida: those residing in the United States before 1982 (PRE-82s) and special agricultural workers (SAWs). The 1,300 subjects were asked…

  1. Recently emerging signaling landscape of ataxia-telangiectasia mutated (ATM) kinase.

    PubMed

    Farooqi, Ammad Ahmad; Attar, Rukset; Arslan, Belkis Atasever; Romero, Mirna Azalea; ul Haq, Muhammad Fahim; Qadir, Muhammad Imran

    2014-01-01

    Research over the years has progressively and sequentially provided near complete resolution of regulators of the DNA repair pathways which are so important for cancer prevention. Ataxia-telangiectasia mutated kinase (ATM), a high-molecular-weight PI3K-family kinase has emerged as a master regulator of DNA damage signaling and extensive cross-talk between ATM and downstream proteins forms an interlaced signaling network. There is rapidly growing scientific evidence emphasizing newly emerging paradigms in ATM biology. In this review, we provide latest information regarding how oxidative stress induced activation of ATM can be utilized as a therapeutic target in different cancer cell lines and in xenografted mice. Moreover, crosstalk between autophagy and ATM is also discussed with focus on how autophagy inhibition induces apoptosis in cancer cells.

  2. Thyroid emergencies.

    PubMed

    Burger, A G; Philippe, J

    1992-01-01

    Thyroid storm is a rapid decompensation of severe hyperthyroidism which can best be described by the three criteria of hyperthermia, tachycardia and altered mental state with severe agitation. There has to be a precipitating factor such as infection, iodine contamination, surgery or even I-131 treatment. Severe hyperthyroidism not fulfilling the criteria of thyroid storm can also be an indication for emergency treatment, particularly in the elderly with heart disease. Suppressed serum TSH and elevated free T4 levels are essential to confirm the diagnosis. When rapidly available, radioiodine uptake of the thyroid can be useful. Therapy aims at rapidly reducing the active circulating hormone pool, hypermetabolic state, tachycardia, and finally hormone synthesis. Thyroid secretion can be blocked by ioipanoic acid or ipodate while hypermetabolic state can be reduced with beta-blockers or calcium channel-blockers. Treatment of hyperthyroidism in patients with iodine contamination is a real therapeutic challenge. Myxoedema coma, a complication of severe hypothyroidism, is defined by hypothermia (rectal temperature less than 36 degrees C), bradycardia, slow mentation, precipitating factor such as infection or drug overdose, and increased serum creatine phosphokinase levels. Diagnosis of severe hypothyroidism should be confirmed by serum measurements of TSH and free T4. Treatment consists of general supporting measures including rewarming, correction of serum electrolyte disturbances, and adequate alimentation. Thyroid hormone treatment should initially be aggressive using either 300-400 micrograms of T4 or 20-40 micrograms of T3 intravenously. Cortisone therapy may be added. Patients should be under close monitoring as arrhythmias and myocardial infarction are frequent complications of myxoedema coma and/or its treatment with thyroid hormones.

  3. Abdominal emergencies during pregnancy.

    PubMed

    Bouyou, J; Gaujoux, S; Marcellin, L; Leconte, M; Goffinet, F; Chapron, C; Dousset, B

    2015-12-01

    Abdominal emergencies during pregnancy (excluding obstetrical emergencies) occur in one out of 500-700 pregnancies and may involve gastrointestinal, gynecologic, urologic, vascular and traumatic etiologies; surgery is necessary in 0.2-2% of cases. Since these emergencies are relatively rare, patients should be referred to specialized centers where surgical, obstetrical and neonatal cares are available, particularly because surgical intervention increases the risk of premature labor. Clinical presentations may be atypical and misleading because of pregnancy-associated anatomical and physiologic alterations, which often result in diagnostic uncertainty and therapeutic delay with increased risks of maternal and infant morbidity. The most common abdominal emergencies are acute appendicitis (best treated by laparoscopic appendectomy), acute calculous cholecystitis (best treated by laparoscopic cholecystectomy from the first trimester through the early part of the third trimester) and intestinal obstruction (where medical treatment is the first-line approach, just as in the non-pregnant patient). Acute pancreatitis is rare, usually resulting from trans-ampullary passage of gallstones; it usually resolves with medical treatment but an elevated risk of recurrent episodes justifies laparoscopic cholecystectomy in the 2nd trimester and endoscopic sphincterotomy in the 3rd trimester. The aim of the present work is to review pregnancy-induced anatomical and physiological modifications, to describe the main abdominal emergencies during pregnancy, their specific features and their diagnostic and therapeutic management.

  4. Novel HIV-1 Therapeutics through Targeting Altered Host Cell Pathways

    PubMed Central

    Coley, William; Kehn-Hall, Kylene; Van Duyne, Rachel; Kashanchi, Fatah

    2009-01-01

    The emergence of drug-resistant human immunodeficiency virus type I (HIV-1) strains presents a challenge for the design of new drugs. Anti-HIV compounds currently in use are the subject of advanced clinical trials using either HIV-1 reverse-transcriptase, viral protease, or integrase inhibitors. Recent studies show an increase in the number of HIV-1 variants resistant to anti-retroviral agents in newly infected individuals. Targeting host cell factors involved in the regulation of HIV-1 replication might be one way to combat HIV-1 resistance to the currently available anti-viral agents. A specific inhibition of HIV-1 gene expression could be expected from the development of compounds targeting host cell factors that participate in the activation of the HIV-1 LTR promoter. Here we will discuss how targeting the host can be accomplished either by using small molecules to alter the function of the host’s proteins such as p53 or cdk9, or by utilizing new advances in siRNA therapies to knock down essential host factors such as CCR5 and CXCR4. Finally, we will discuss how the viral protein interactomes should be performed to better design therapeutics against HIV-1. PMID:19732026

  5. Past Emergencies

    EPA Pesticide Factsheets

    These activities, some of national significance requiring coordination with other agencies, demonstrate the emergency response program and provide valuable experience so that EPA can better prevent, prepare for, and respond to emergencies in the future.

  6. Emergency contraception

    MedlinePlus

    Morning-after pill; Postcoital contraception; Birth control - emergency; Plan B; Family planning - emergency contraception ... prevents pregnancy in the same way as regular birth control pills: By preventing or delaying the release of ...

  7. Emergency Contraception

    MedlinePlus

    ... against STDs even when using another method of birth control. If a condom breaks (or a couple has ... Emergency contraception is not recommended as a regular birth control method . Instead, it is used for emergencies only. ...

  8. Emergency Contraception

    MedlinePlus

    f AQ FREQUENTLY ASKED QUESTIONS FAQ114 CONTRACEPTION Emergency Contraception • What is emergency contraception (EC)? • How does EC work? • What are the different types of EC? • What is the most ...

  9. The practical skills of newly qualified nurses.

    PubMed

    Danbjørg, Dorthe Boe; Birkelund, Regner

    2011-02-01

    This paper reports the findings from a study of newly qualified nurses and which subjects the nurses regarded as the most important in order to be able to live up to the requirements of clinical practice, and how they experience their potential for developing practical and moral skills, after the decrease in practical training. A qualitative approach guided the research process and the analysis of the data. The data was collected by participant observation and qualitative interviews with four nurses as informants. The conclusions made in this study are based on the statements and the observations of the newly qualified nurses. Our findings are discussed in relation to the Aristotelian concept and other relevant literature. The main message is that the newly qualified nurses did not feel equipped when they finished their training. This could be interpreted as a direct consequence of the decrease in practical training. Our study also underlines that the way nursing theory is perceived and taught is problematic. The interviews revealed that the nurses think that nursing theories should be applied directly in practice. This misunderstanding is probably also applicable to the teachers of the theories.

  10. Emergent Expertise?

    ERIC Educational Resources Information Center

    McGivern, Patrick

    2014-01-01

    The concept of emergence appears in various places within the literature on expertise and expert practice. Here, I examine some of these applications of emergence in the light of two prominent accounts of emergence from the philosophy of science and philosophy of mind. I evaluate these accounts with respect to several specific contexts in which…

  11. Emergent Expertise?

    ERIC Educational Resources Information Center

    McGivern, Patrick

    2014-01-01

    The concept of emergence appears in various places within the literature on expertise and expert practice. Here, I examine some of these applications of emergence in the light of two prominent accounts of emergence from the philosophy of science and philosophy of mind. I evaluate these accounts with respect to several specific contexts in which…

  12. Synthetic biology and therapeutic strategies for the degenerating brain: Synthetic biology approaches can transform classical cell and gene therapies, to provide new cures for neurodegenerative diseases.

    PubMed

    Agustín-Pavón, Carmen; Isalan, Mark

    2014-10-01

    Synthetic biology is an emerging engineering discipline that attempts to design and rewire biological components, so as to achieve new functions in a robust and predictable manner. The new tools and strategies provided by synthetic biology have the potential to improve therapeutics for neurodegenerative diseases. In particular, synthetic biology will help design small molecules, proteins, gene networks, and vectors to target disease-related genes. Ultimately, new intelligent delivery systems will provide targeted and sustained therapeutic benefits. New treatments will arise from combining 'protect and repair' strategies: the use of drug treatments, the promotion of neurotrophic factor synthesis, and gene targeting. Going beyond RNAi and artificial transcription factors, site-specific genome modification is likely to play an increasing role, especially with newly available gene editing tools such as CRISPR/Cas9 systems. Taken together, these advances will help develop safe and long-term therapies for many brain diseases in human patients.

  13. Telomerase reverse transcriptase moonlights: Therapeutic targets beyond telomerase.

    PubMed

    Maida, Yoshiko; Masutomi, Kenkichi

    2015-11-01

    Telomeres, the repetitive sequences at chromosomal ends, protect intact chromosomes. Telomeres progressively shorten through successive rounds of cell divisions, and critically shortened telomeres trigger senescence and apoptosis. The enzyme that elongates telomeres and maintains their structure is known as telomerase. The catalytic subunit of this enzyme (telomerase reverse transcriptase [TERT]) is expressed at a high level in malignant cells, but at a very low level in normal cells. Although telomerase activity was long believed to be the only function of TERT, emerging evidence indicates that TERT plays roles beyond telomeres. For example, TERT contributes to stem cell maintenance and cell reprogramming processes in a manner independent of its canonical function. Even some types of splice variants that lack the telomerase catalytic domains exhibit the functions in a manner that does not depend on telomerase activity. We recently demonstrated that the RNA-dependent RNA polymerase (RdRP) activity of TERT is involved in regulation of gene silencing and heterochromatic transcription. Moreover, TERT RdRP activity is mediated by a newly identified complex, distinct from the authentic telomerase complex, that plays a role in cancer stem cells in a telomere maintenance independent manner. TERT has attracted interest as a molecular target for anticancer treatment, but previous efforts aimed at developing novel therapeutic strategies focused only on the canonical function of TERT. However, accumulating evidence about the non-canonical functions of TERT led us to speculate that the functions other than telomerase might be therapeutic targets as well. In this review, we discuss the non-canonical functions of TERT and their potential applications for anticancer treatment. © 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

  14. Contemporary and Novel Therapeutic Options for Hypertriglyceridemia.

    PubMed

    Bell, Damon A; Watts, Gerald F

    2015-12-01

    The purpose of this review was to outline the current and emerging therapeutic options for the treatment of hypertriglyceridemia, with an emphasis on emerging therapies. A systematic literature search was conducted with the use of PubMed and Embase for articles on hypertriglyceridemia, with a focus on therapeutics, pharmacology, and management. Abstracts from recent international meetings were also reviewed for presentations of Phase I and II data on agents with triglyceride-lowering effects. A further review of the references identified from these articles was also performed. Consistent with the multifactorial cause of hypertriglyceridemia, the therapeutic options are broad and numerous. This review explores the current and potential therapeutic options for treating hypertriglyceridemia and outlines the potential mechanisms of action. However, the mechanism of triglyceride reduction is complex, multifactorial, or not fully elucidated for some of these agents. The magnitude of triglyceride reduction and findings of outcome studies are described. Management of hypertriglyceridemia is about to enter an exciting phase, with multiple emerging therapies in the final stages of development. However, caution is warranted, because studies of therapeutic agents over the previous decade have often not found cardiovascular outcome benefits despite encouraging effects on triglyceride concentrations. Copyright © 2015 Elsevier HS Journals, Inc. All rights reserved.

  15. Digesting dietary miRNA therapeutics

    USDA-ARS?s Scientific Manuscript database

    Hippocrates famously advised, "Let food be thy medicine and thy medicine be thy food." Numerous plant-derived compounds are used as cancer therapeutics including antimitotics, topoisomerase inhibitors, and kinase inhibitors. Here we will review emerging evidence suggesting that diet derived small RN...

  16. International intellectual property strategies for therapeutic antibodies

    PubMed Central

    2011-01-01

    Therapeutic antibodies need international patent protection as their markets expand to include industrialized and emerging countries. Because international intellectual property strategies are frequently complex and costly, applicants require sound information as a basis for decisions regarding the countries in which to pursue patents. While the most important factor is the size of a given market, other factors should also be considered. PMID:22123063

  17. Liberation Therapeutics: Consciousness Raising as a Problem.

    ERIC Educational Resources Information Center

    Lasch-Quinn, Elisabeth

    2002-01-01

    Questions the content and form of consciousness raising as a mode of purveying knowledge or bringing about change by considering its emergence in the civil rights movement. Examines such books as "Black Rage" (William Grierand Price Cobbs), "Triumph of the Therapeutic" (Philip Reiff), "Where Do We Go From Here: Chaos or…

  18. Liberation Therapeutics: Consciousness Raising as a Problem.

    ERIC Educational Resources Information Center

    Lasch-Quinn, Elisabeth

    2002-01-01

    Questions the content and form of consciousness raising as a mode of purveying knowledge or bringing about change by considering its emergence in the civil rights movement. Examines such books as "Black Rage" (William Grierand Price Cobbs), "Triumph of the Therapeutic" (Philip Reiff), "Where Do We Go From Here: Chaos or…

  19. Critical thinking dispositions among newly graduated nurses

    PubMed Central

    Wangensteen, Sigrid; Johansson, Inger S; Björkström, Monica E; Nordström, Gun

    2010-01-01

    wangensteen s., johansson i.s., björkström m.e. & nordström g. (2010) Critical thinking dispositions among newly graduated nurses. Journal of Advanced Nursing66(10), 2170–2181. Aim The aim of the study was to describe critical thinking dispositions among newly graduated nurses in Norway, and to study whether background data had any impact on critical thinking dispositions. Background Competence in critical thinking is one of the expectations of nursing education. Critical thinkers are described as well-informed, inquisitive, open-minded and orderly in complex matters. Critical thinking competence has thus been designated as an outcome for judging the quality of nursing education programmes and for the development of clinical judgement. The ability to think critically is also described as reducing the research–practice gap and fostering evidence-based nursing. Methods A cross-sectional descriptive study was performed. The data were collected between October 2006 and April 2007 using the California Critical Thinking Disposition Inventory. The response rate was 33% (n= 618). Pearson’s chi-square tests were used to analyse the data. Results Nearly 80% of the respondents reported a positive disposition towards critical thinking. The highest mean score was on the Inquisitiveness subscale and the lowest on the Truth-seeking subscale. A statistically significant higher proportion of nurses with high critical thinking scores were found among those older than 30 years, those with university education prior to nursing education, and those working in community health care. Conclusion Nurse leaders and nurse teachers should encourage and nurture critical thinking among newly graduated nurses and nursing students. The low Truth-seeking scores found may be a result of traditional teaching strategies in nursing education and might indicate a need for more student-active learning models. PMID:20384637

  20. Polymer therapeutics as nanomedicines: new perspectives.

    PubMed

    Duncan, Ruth

    2011-08-01

    A growing number of polymer therapeutics have entered routine clinical use as nano-sized medicines. Early products were developed as anticancer agents, but treatments for a range of diseases and different routes of administration have followed--recently the PEGylated-anti-TNF Fab Cimzia® for rheumatoid arthritis and the PEG-aptamer Macugen® for age related macular degeneration. New polymer therapeutic concepts continue to emerge with a growing number of conjugates entering clinical development, for example PEGylated-aptamers and a polymer-based siRNA delivery system. 'Hot' topics of the past 2 years include; emerging issues relating to polymer safety, the increasing use of biodegradable polymers, design of technologies for combination therapy, potential biomarkers for patient individualisation of treatment and Regulatory challenges for 'follow-on/generic' polymer therapeutics.

  1. Epilepsy: Novel therapeutic targets

    PubMed Central

    Anovadiya, Ashish P.; Sanmukhani, Jayesh J.; Tripathi, C. B.

    2012-01-01

    Despite of established and effective therapy for epilepsy, 20–25% patients develop therapeutic failure; this encourages finding newer drugs. Novel approaches target receptors which remain unaffected by conventional therapy or inhibit epileptogenesis. AMPA receptor antagonists have shown faster and complete protection compared to diazepam. Protein kinase (PK) plays an important role in the development of epilepsy. PK inhibitors such as K252a, VID-82925, and Herbimycin A have been found effective in inhibition of spread of epileptiform activity and epileptogenesis. Metabotropic glutamate receptors (mGluRs) are G protein-coupled receptors classified into three groups. Group 1 mGluRs antagonist and Groups 2 and 3 mGluRs agonists inhibited pentylenetetrazole-induced kindled seizures. Combined use of these agents has also shown favorable results. Mammalian target of rapamycin (mTOR) plays a central role in multiple mechanisms of epileptogenesis. mTOR causes transcription, induction of proapoptotic proteins, and autophagy inhibition. Rapamycin was effective in suppression of recurrent seizures as well as in tuberous sclerosis and acute brain injury model. 5% CO2 showed potent effects on cortical epileptiform activity and convulsions in animal epilepsy models and in humans with drug-resistant partial epilepsy. It is found to be rapidly acting, safe and cheap, thus it can be a good option in emergency for suppression of seizure. Neurosteroids are considered as fourth generation neuromessengers, they act as positive allosteric modulators of γ-aminobutyric acid (GABAA) receptors. Clinical trial of ganaxolone, an allopregnanolone analogue, has shown a beneficial role in pharmacoresistant epilepsy. However, most of these drugs are tested in early phases of development and the possible use and safety in epilepsy has to be proven in clinical trials. PMID:22629084

  2. Emerging targets in neurodegeneration: new opportunities for Alzheimer's disease treatment?

    PubMed

    Rampa, Angela; Gobbi, Silvia; Belluti, Federica; Bisi, Alessandra

    2013-01-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder of the brain associated with memory impairment, progressive cognitive decline and changes in personality and behavior, with rising incidence among elderly people. Reflecting the world population ageing, the scenario is expected to worsen in the next decades if novel drugs or mechanisms that help to counteract neurodegeneration will not be identified. The complex neuropathology of AD is characterized by cholinergic loss, extracellular deposition of amyloid-β plaques, formation of intracellular neurofibrillary tangles, chronic brain inflammation and oxidative damage. To date, there are no effective treatments that can slow or halt the disease, and currently approved drugs only seem to act as palliative by temporary ameliorating cognitive impairment. On the other hand, the role played by other biological systems in the pathogenetic process is now clearly growing and, as knowledge on how AD develops and triggers brain damage proceeds, drug discovery attempts to identify new potential therapeutic targets. This review will focus on these emerging strategies, some of which could open new therapeutic perspectives in Alzheimer's disease, adding new elements for the medicinal chemist to handle and combine for the design of novel multi-target-directed ligands able to simultaneously modulate 'old classic' and newly identified targets.

  3. Women among newly hired physics faculty

    NASA Astrophysics Data System (ADS)

    White, Susan C.

    2014-09-01

    In May, we noted that the percentage of women among physics faculty members reached 14% in 2010. The 14% is a new high—the continuation of a trend seen since we began measuring these data in 1998 when it was 8%. This growth in women's representation is seen at all levels of the professoriate—from instructors through full professors. In terms of sheer numbers, though, it is the women hired as assistant professors driving the increase. In the table, we highlight the percentage of newly hired faculty members who are women. The percentage of women among newly hired full professors increased quite a bit in 2010; this is an artifact of the lower number of male full professors hired in 2010 (which was the first year we collected data after the recession of 2008). In October, we will look at the proportion of physics departments with women faculty members. If you have any questions or comments, please contact Susan White at the Statistical Research Center of the American Institute of Physics (swhite@aip.org).

  4. Value of a newly sequenced bacterial genome

    PubMed Central

    Barbosa, Eudes GV; Aburjaile, Flavia F; Ramos, Rommel TJ; Carneiro, Adriana R; Le Loir, Yves; Baumbach, Jan; Miyoshi, Anderson; Silva, Artur; Azevedo, Vasco

    2014-01-01

    Next-generation sequencing (NGS) technologies have made high-throughput sequencing available to medium- and small-size laboratories, culminating in a tidal wave of genomic information. The quantity of sequenced bacterial genomes has not only brought excitement to the field of genomics but also heightened expectations that NGS would boost antibacterial discovery and vaccine development. Although many possible drug and vaccine targets have been discovered, the success rate of genome-based analysis has remained below expectations. Furthermore, NGS has had consequences for genome quality, resulting in an exponential increase in draft (partial data) genome deposits in public databases. If no further interests are expressed for a particular bacterial genome, it is more likely that the sequencing of its genome will be limited to a draft stage, and the painstaking tasks of completing the sequencing of its genome and annotation will not be undertaken. It is important to know what is lost when we settle for a draft genome and to determine the “scientific value” of a newly sequenced genome. This review addresses the expected impact of newly sequenced genomes on antibacterial discovery and vaccinology. Also, it discusses the factors that could be leading to the increase in the number of draft deposits and the consequent loss of relevant biological information. PMID:24921006

  5. Clinical value of ST-segment change after return of spontaneous cardiac arrest and emergent coronary angiography in patients with out-of-hospital cardiac arrest: Diagnostic and therapeutic importance of vasospastic angina.

    PubMed

    Tateishi, Kazuya; Abe, Daisuke; Iwama, Tooru; Hamabe, Yuichi; Aonuma, Kazutaka; Sato, Akira

    2017-07-01

    We investigated the association between initial ST-segment change after return of spontaneous circulation (ROSC) and the incidence of acute coronary lesions in patients with out-of-hospital cardiac arrest (OHCA), and clinical outcomes of patients with OHCA caused by vasospastic angina pectoris (VSA). Among 2779 OHCA patients in our institution, all patients with ROSC underwent emergent coronary angiography (CAG) except for those with an obvious extra-cardiac cause of OHCA. Initial ST-segment changes after ROSC were reviewed, and 30-day survival and neurological outcome (Cerebral Performance Category) were evaluated. Of the 155 patients, 52 (34%) had ST-segment elevation (STE) and 103 (66%) had non-STE. Significant coronary culprit lesions were present in 81% of patients with STE and in 33% of patients with non-STE ( P<.001). Percutaneous coronary intervention (PCI) was successful in 60 patients (93.8%) and failed in 4 patients (6.2%). Among 155 patients, 74 patients (47.7%) had favorable neurological prognosis, and 104 patients (67.1%) were alive at 30 days. ST-segment analysis showed good positive predictive value (81%) but low negative predictive value (68%) in diagnosing the presence of acute coronary lesions. VSA was found in 5 patients (9.6%) in the STE group and in 12 patients (11.7%) in the non-STE group. Of these 17 patients, 9 (52.9%) had favorable neurological outcome and 14 (82.4%) were alive at 30 days. An acute culprit lesion may be the cause of OHCA even in the absence of STE. In survivors of OHCA with normal coronary arteries, spasm provocation testing should be performed to detect VSA as a cause of the arrest.

  6. Emergency contraception.

    PubMed

    2012-12-01

    Despite significant declines over the past 2 decades, the United States continues to have teen birth rates that are significantly higher than other industrialized nations. Use of emergency contraception can reduce the risk of pregnancy if used up to 120 hours after unprotected intercourse or contraceptive failure and is most effective if used in the first 24 hours. Indications for the use of emergency contraception include sexual assault, unprotected intercourse, condom breakage or slippage, and missed or late doses of hormonal contraceptives, including the oral contraceptive pill, contraceptive patch, contraceptive ring (ie, improper placement or loss/expulsion), and injectable contraception. Adolescents younger than 17 years must obtain a prescription from a physician to access emergency contraception in most states. In all states, both males and females 17 years or older can obtain emergency contraception without a prescription. Adolescents are more likely to use emergency contraception if it has been prescribed in advance of need. The aim of this updated policy statement is to (1) educate pediatricians and other physicians on available emergency contraceptive methods; (2) provide current data on safety, efficacy, and use of emergency contraception in teenagers; and (3) encourage routine counseling and advance emergency-contraception prescription as 1 part of a public health strategy to reduce teen pregnancy. This policy focuses on pharmacologic methods of emergency contraception used within 120 hours of unprotected or underprotected coitus for the prevention of unintended pregnancy. Emergency contraceptive medications include products labeled and dedicated for use as emergency contraception by the US Food and Drug Administration (levonorgestrel and ulipristal) and the "off-label" use of combination oral contraceptives.

  7. Therapeutic radionuclides: Making the right choice

    SciTech Connect

    Srivastava, S.C.

    1996-08-01

    Recently, there has been a resurgence of interest in nuclear medicine therapeutic procedures. Using unsealed sources for therapy is not a new concept; it has been around since the beginnings of nuclear medicine. Treatment of thyroid disorders with radioiodine is a classic example. The availability of radionuclides with suitable therapeutic properties for specific applications, as well as methods for their selective targeting to diseased tissue have, however, remained the main obstacles for therapy to assume a more widespread role in nuclear medicine. Nonetheless, a number of new techniques that have recently emerged, (e.g., tumor therapy with radiolabeled monoclonal antibodies, treatment of metastatic bone pain, etc.) appear to have provided a substantial impetus to research on production of new therapeutic radionuclides. Although there are a number of new therapeutic approaches requiring specific radionuclides, only selected broad areas will be used as examples in this article.

  8. Contextual Emergence

    NASA Astrophysics Data System (ADS)

    Atmanspacher, Harald

    The concept of contextual emergence has been proposed as a nonreductive, yet well-defined relation between different levels of description of physical and other systems. It yields a formally sound and empirically applicable procedure to translate between descriptive levels in an overall consistent fashion. This will be discussed for the contextual emergence of mental states from a neural level of description.

  9. Dermatologic emergencies.

    PubMed

    Sica, P A

    1986-03-01

    Being able to recognize and treat a dermatologic emergency is extremely important to the primary care physician. This ability is very rewarding for the patient and gratifying to the physician. In this article, some of the more commonly encountered emergencies are discussed.

  10. Potential Therapeutic Effects of Psilocybin.

    PubMed

    Johnson, Matthew W; Griffiths, Roland R

    2017-07-01

    Psilocybin and other 5-hydroxytryptamine2A agonist classic psychedelics have been used for centuries as sacraments within indigenous cultures. In the mid-twentieth century they were a focus within psychiatry as both probes of brain function and experimental therapeutics. By the late 1960s and early 1970s these scientific inquires fell out of favor because classic psychedelics were being used outside of medical research and in association with the emerging counter culture. However, in the twenty-first century, scientific interest in classic psychedelics has returned and grown as a result of several promising studies, validating earlier research. Here, we review therapeutic research on psilocybin, the classic psychedelic that has been the focus of most recent research. For mood and anxiety disorders, three controlled trials have suggested that psilocybin may decrease symptoms of depression and anxiety in the context of cancer-related psychiatric distress for at least 6 months following a single acute administration. A small, open-label study in patients with treatment-resistant depression showed reductions in depression and anxiety symptoms 3 months after two acute doses. For addiction, small, open-label pilot studies have shown promising success rates for both tobacco and alcohol addiction. Safety data from these various trials, which involve careful screening, preparation, monitoring, and follow-up, indicate the absence of severe drug-related adverse reactions. Modest drug-related adverse effects at the time of medication administration are readily managed. US federal funding has yet to support therapeutic psilocybin research, although such support will be important to thoroughly investigate efficacy, safety, and therapeutic mechanisms.

  11. Antibody Engineering and Therapeutics Conference

    PubMed Central

    Almagro, Juan Carlos; Gilliland, Gary L; Scott, Jamie; Larrick, James W; Plückthun, Andreas; Veldman, Trudi; Adams, Gregory P; Parren, Paul WHI; Chester, Kerry A; Bradbury, Andrew; Reichert, Janice M; Huston, James S

    2013-01-01

    The Antibody Engineering and Therapeutics conference, which serves as the annual meeting of The Antibody Society, will be held in Huntington Beach, CA from Sunday December 8 through Thursday December 12, 2013. The scientific program will cover the full spectrum of challenges in antibody research and development, and provide updates on recent progress in areas from basic science through approval of antibody therapeutics. Keynote presentations will be given by Leroy Hood (Institute of System Biology), who will discuss a systems approach for studying disease that is enabled by emerging technology; Douglas Lauffenburger (Massachusetts Institute of Technology), who will discuss systems analysis of cell communication network dynamics for therapeutic biologics design; David Baker (University of Washington), who will describe computer-based design of smart protein therapeutics; and William Schief (The Scripps Research Institute), who will discuss epitope-focused immunogen design.   In this preview of the conference, the workshop and session chairs share their thoughts on what conference participants may learn in sessions on: (1) three-dimensional structure antibody modeling; (2) identifying clonal lineages from next-generation data sets of expressed VH gene sequences; (3) antibodies in cardiometabolic medicine; (4) the effects of antibody gene variation and usage on the antibody response; (5) directed evolution; (6) antibody pharmacokinetics, distribution and off-target toxicity; (7) use of knowledge-based design to guide development of complementarity-determining regions and epitopes to engineer or elicit the desired antibody; (8) optimizing antibody formats for immunotherapy; (9) antibodies in a complex environment; (10) polyclonal, oligoclonal and bispecific antibodies; (11) antibodies to watch in 2014; and (12) polyreactive antibodies and polyspecificity.

  12. Michael Maier--nine newly discovered letters.

    PubMed

    Lenke, Nils; Roudet, Nicolas; Tilton, Hereward

    2014-02-01

    The authors provide a transcription, translation, and evaluation of nine newly discovered letters from the alchemist Michael Maier (1568-1622) to Gebhardt Johann von Alvensleben (1576-1631), a noble landholder in the vicinity of Magdeburg. Stemming from the final year of his life, this correspondence casts new light on Maier's biography, detailing his efforts to secure patronage amid the financial crisis of the early Thirty Years' War. While his ill-fated quest to perfect potable gold continued to form the central focus of his patronage suits, Maier also offered his services in several arts that he had condemned in his printed works, namely astrology and "supernatural" magic. Remarks concerning his previously unknown acquaintance with Heinrich Khunrath call for a re-evaluation of Maier's negotiation of the discursive boundaries between Lutheran orthodoxy and Paracelsianism. The letters also reveal Maier's substantial contribution to a work previously ascribed solely to the English alchemist Francis Anthony.

  13. Newly discovered insect RNA viruses in China.

    PubMed

    Qiu, Yang; Wang, ZhaoWei; Liu, YongXiang; Qi, Nan; Si, Jie; Xiang, Xue; Xia, XiaoLing; Hu, YuanYang; Zhou, Xi

    2013-08-01

    Insects are a group of arthropods and the largest group of animals on Earth, with over one million species described to date. Like other life forms, insects suffer from viruses that cause disease and death. Viruses that are pathogenic to beneficial insects cause dramatic economic losses on agriculture. In contrast, viruses that are pathogenic to insect pests can be exploited as attractive biological control agents. All of these factors have led to an explosion in the amount of research into insect viruses in recent years, generating impressive quantities of information on the molecular and cellular biology of these viruses. Due to the wide variety of insect viruses, a better understanding of these viruses will expand our overall knowledge of their virology. Here, we review studies of several newly discovered RNA insect viruses in China.

  14. Emergency contraception.

    PubMed

    Van Look, P F; von Hertzen, H

    1993-01-01

    The term 'emergency contraception', as employed in this paper, refers to methods that are used as emergency procedures to prevent pregnancy following unprotected intercourse. Alternative, less appropriate, terms are postcoital and 'morning-after' contraception. References to postcoital preparations can be found as far back as 1500 BC in Egyptian papyri, but it was not until fairly recently that contraceptive research has been able to at least partially fulfill that need. The development of hormonal methods of emergency contraception goes back to the 1960s when the first human trials of postcoitally administered high-dose oestrogens were undertaken. Combined oestrogen- progestogen combination therapy (the so-called Yuzpe regimen) was introduced in the early 1970s, while the postcoital insertion of an intrauterine contraceptive device (IUD) for emergency contraception was first reported in 1976. Other compounds that have been tested more recently include levonorgestrel, the antiprogestogen mifepristone, and danazol. Although there is some debate about the magnitude of the protective effect, few people question the important role that emergency contraception can play in preventing unwanted pregnancy and hence maternal mortality and morbidity resulting from unsafe abortion. Given that the most often used methods of emergency contraception, namely the Yuzpe regimen and postcoital insertion of an IUD, rely on technology that has been available for some 30 years, family planning programmes that claim to be concerned with improving women's reproductive health, cannot really be excused if they do not provide emergency contraception as part of their routine services.

  15. Trends in Therapeutic Recreation.

    ERIC Educational Resources Information Center

    Smith, Ralph W.

    1995-01-01

    Discusses the implications of the rapid, dramatic changes taking place in therapeutic recreation for individuals with physical disabilities. The article notes the impact of changes in managed care, examines programming trends in therapeutic recreation (adventure/outdoor education, competitive sports, handcycling, health enhancement activities, and…

  16. Chicanoizing the Therapeutic Community

    ERIC Educational Resources Information Center

    Aron, William S.; And Others

    1974-01-01

    Focusing on the drug addiction problem and its antecedent conditions in a Chicano population, the article examines several therapeutic interventions suggested by these conditions and indicates how they might be incorporated into a drug addiction Therapeutic Community treatment program designed to meet the needs of Chicano drug addicts. (Author/NQ)

  17. Therapeutic Recreation Practicum Manual.

    ERIC Educational Resources Information Center

    Schneegas, Kay

    This manual provides information on the practicum program offered by Moraine Valley Community College (MVCC) for students in its therapeutic recreation program. Sections I and II outline the rationale and goals for providing practical, on-the-job work experiences for therapeutic recreation students. Section III specifies MVCC's responsibilities…

  18. Chicanoizing the Therapeutic Community

    ERIC Educational Resources Information Center

    Aron, William S.; And Others

    1974-01-01

    Focusing on the drug addiction problem and its antecedent conditions in a Chicano population, the article examines several therapeutic interventions suggested by these conditions and indicates how they might be incorporated into a drug addiction Therapeutic Community treatment program designed to meet the needs of Chicano drug addicts. (Author/NQ)

  19. Impact of Therapeutic Camping

    ERIC Educational Resources Information Center

    Shniderman, Craig M.

    1974-01-01

    There has been little interest in, and only slight illumination of, the impact of therapeutic camping for emotionally disturbed children. This study seeks to validate the belief that camping is therapeutic. Subjects were 52 boys, 5 to 11 1/2 years of age. Results support the hypothesis. (Author/HMV)

  20. Current status and opportunities for therapeutic drug monitoring in the treatment of tuberculosis.

    PubMed

    Zuur, Marlanka A; Bolhuis, Mathieu S; Anthony, Richard; den Hertog, Alice; van der Laan, Tridia; Wilffert, Bob; de Lange, Wiel; van Soolingen, Dick; Alffenaar, Jan-Willem C

    2016-05-01

    Tuberculosis remains a global health problem and pharmacokinetic variability has been postulated as one of the causes of treatment failure and acquired drug resistance. New developments enable implementation of therapeutic drug monitoring, a strategy to evaluate drug exposure in order to tailor the dose to the individual patient, in tuberculosis treatment. Literature on pharmacokinetics and pharmacodynamics of anti-tuberculosis drugs was explored to evaluate the effect of drug exposure in relation to drug susceptibility, toxicity and efficacy. New, down-sized strategies, like dried blood spot analysis and limited sampling strategies are reviewed. In addition, molecular resistance testing of Mycobacteria tuberculosis, combining a short turn-around time with relevant information on drug susceptibility of the causative pathogen was explored. Newly emerging host biomarkers provide information on the response to treatment. Therapeutic drug monitoring can minimize toxicity and increase efficacy of tuberculosis treatment and prevent the development of resistance. Dried blood spot analysis and limited sampling strategies, can be combined to provide us with a more patient friendly approach. Furthermore, rapid information on drug susceptibility by molecular testing, and information from host biomarkers on the bacteriological response, can be used to further optimize tuberculosis treatment.

  1. Swimming Emergencies

    PubMed Central

    Beerman, Stephen B.

    1988-01-01

    Persons who have undergone swimming emergencies are seen in emergency departments everywhere. They are frequently young healthy citizens. In some instances they will receive better care in large specialized referral hospitals. Other problems can be managed well at local facilities. This article attempts to equip all family physicians with some knowledge and management guidelines for dealing with swimming emergencies, submersion injuries including near-drowning, accidental hypothermia, and triathalon hypothermia. The unique problems of hot tub near-drowning, infant water intoxication, and spinal injuries caused by diving are presented. PMID:21253260

  2. Virtually Nursing: Emerging Technologies in Nursing Education.

    PubMed

    Foronda, Cynthia L; Alfes, Celeste M; Dev, Parvati; Kleinheksel, A J; Nelson, Douglas A; OʼDonnell, John M; Samosky, Joseph T

    Augmented reality and virtual simulation technologies in nursing education are burgeoning. Preliminary evidence suggests that these innovative pedagogical approaches are effective. The aim of this article is to present 6 newly emerged products and systems that may improve nursing education. Technologies may present opportunities to improve teaching efforts, better engage students, and transform nursing education.

  3. Trends in emerging and high risk activities

    Treesearch

    Robert C. White; Richard Schreyer; Kent Downing

    1980-01-01

    Newly emerging and high risk activities have increased markedly in the last generation, yet little is known about trends in participation. Factors such as technological innovation and creative experimentation with traditional activities appear to play a major role in the development of new activities. Christy's criteria for mass demand in recreation are used to...

  4. Emerging Issues.

    ERIC Educational Resources Information Center

    Carter, Denise

    1988-01-01

    Youth services programs and cholesterol in children's diets, two topics that may emerge as issues in schools and school districts in the near future, are addressed. Resources for further information are listed. (CB)

  5. Emergency Response

    EPA Pesticide Factsheets

    Information for first responders, industry, federal, state and local governments on EPA's role and available resources for response to oil spills, chemical, biological, radiological releases, and large-scale national emergencies.

  6. Rheumatologic emergencies.

    PubMed

    Gutiérrez-González, Luis Arturo

    2015-12-01

    Rheumatological conditions can sometimes present as emergencies. These can occur due to the disease process or infection; contrary to what many people think, rheumatologic emergencies like a pain, rheumatic crisis, or attack gout do not compromise the patient's life. This article mentioned only true emergencies: catastrophic antiphospholipid syndrome (cAPS), kidney-lung syndrome, central nervous system (CNS) vasculitis, anti-Ro syndrome (neonatal lupus), and macrophage activation syndrome (MAS). The management of above emergencies includes critical care, immunosuppression when indicated, and use of a diagnostic flowchart as well as fast laboratory profile for making decisions. Anticoagulants have to be used in the management of antiphospholipid syndrome. A good understanding of these conditions is of paramount importance for proper management.

  7. ["Emergency measures"].

    PubMed

    Louis, Jean-Jacques

    2012-03-01

    This article deals with the impact of health crisis on governance of public health. It tries to show that, in accordance with the thought of Michel Foucault, emergency measures issued during health crisis are akin to those issued during wartime.

  8. Corneal Emergencies.

    PubMed

    Belknap, Ellen B

    2015-09-01

    Corneal emergencies can be due to a number of different causes and may be vision threatening if left untreated. In an attempt to stabilize the cornea, it is of benefit to place an Elizabethan collar on the patient to prevent further corneal damage. This article discusses the diagnosis, prognosis, and management of corneal emergencies in dogs and cats. Copyright © 2015 Elsevier Inc. All rights reserved.

  9. Ethical erosion in newly qualified doctors: perceptions of empathy decline.

    PubMed

    Stratta, Emily C; Riding, David M; Baker, Paul

    2016-09-06

    This study sought to understand whether UK Foundation doctors perceived the phenomena of ethical erosion and empathy decline during their initial period of clinical practice, and if so, why this occurred. This qualitative study used semi-structured interviews with nine doctors in their first year of clinical practice at Royal Bolton Hospital, UK. Participants were invited to discuss the definition of empathy, how individuals acquire and maintain empathic ability, perceptions of ethical erosion in the self and others, and how clinical experiences have influenced their empathic ability. The interviews were transcribed, and analysed to identify emergent themes. Each participant reported a conscious acknowledgement of empathy decline in their own and their colleagues' early clinical experiences as doctors. Stressful working environments, the prioritisation of patients' physical rather than psychological well-being, and the attitudes of senior colleagues were all suggested as possible causes. Some doctors believed that specialties with reduced patient contact had a culture which precluded empathy, and influenced their own practice. In addition, some described how their value judgements of patients had affected their ability to empathise. However, all doctors perceived that empathy skills were desirable in senior clinicians, and some believed that educational interventions may be useful in arresting ethical erosion. Newly qualified doctors are aware of ethical erosion in themselves and their colleagues as they begin clinical practice. This has serious implications for patient care. Improving working conditions may reverse this trend. Empathy skills training within undergraduate and postgraduate curricula may be a useful intervention.

  10. Anorectal emergencies.

    PubMed

    Lohsiriwat, Varut

    2016-07-14

    Anorectal emergencies refer to anorectal disorders presenting with some alarming symptoms such as acute anal pain and bleeding which might require an immediate management. This article deals with the diagnosis and management of common anorectal emergencies such as acutely thrombosed external hemorrhoid, thrombosed or strangulated internal hemorrhoid, bleeding hemorrhoid, bleeding anorectal varices, anal fissure, irreducible or strangulated rectal prolapse, anorectal abscess, perineal necrotizing fasciitis (Fournier gangrene), retained anorectal foreign bodies and obstructing rectal cancer. Sexually transmitted diseases as anorectal non-surgical emergencies and some anorectal emergencies in neonates are also discussed. The last part of this review dedicates to the management of early complications following common anorectal procedures that may present as an emergency including acute urinary retention, bleeding, fecal impaction and anorectal sepsis. Although many of anorectal disorders presenting in an emergency setting are not life-threatening and may be successfully treated in an outpatient clinic, an accurate diagnosis and proper management remains a challenging problem for clinicians. A detailed history taking and a careful physical examination, including digital rectal examination and anoscopy, is essential for correct diagnosis and plan of treatment. In some cases, some imaging examinations, such as endoanal ultrasonography and computerized tomography scan of whole abdomen, are required. If in doubt, the attending physicians should not hesitate to consult an expert e.g., colorectal surgeon about the diagnosis, proper management and appropriate follow-up.

  11. Emergency contraception.

    PubMed

    Grimes, David A; Raymond, Elizabeth G

    2002-08-06

    Emergency contraception is used to prevent pregnancy after a coital act not adequately protected by a regular method of contraception. In contrast to early medical abortion, emergency contraception prevents a pregnancy from starting and does not disrupt an established pregnancy. The most commonly used approaches consist of two oral doses of contraceptive steroids. The levonorgestrel-only regimen (levonorgestrel, 0.75 mg, repeated in 12 hours) appears to be more effective and better tolerated than the Yuzpe regimen (ethinyl estradiol, 100 microg, and levonorgestrel, 0.5 mg, repeated in 12 hours). In the largest randomized, controlled trial to date, levonorgestrel prevented about 85% of pregnancies that would have occurred without its use. Hormonal emergency contraception has no known medical contraindications, although it is not indicated for suspected or confirmed pregnancy. However, if hormonal emergency contraception is inadvertently taken in early pregnancy, neither the woman nor the fetus will be harmed. Nausea and vomiting associated with the Yuzpe regimen can be reduced by prophylactic use of meclizine. A strong medical and legal case exists for making hormonal emergency contraception available over the counter, as has happened in countries other than the United States. Easier access to and wider use of emergency contraception could dramatically lower the high rates of unintended pregnancy and induced abortion in the United States.

  12. Anorectal emergencies

    PubMed Central

    Lohsiriwat, Varut

    2016-01-01

    Anorectal emergencies refer to anorectal disorders presenting with some alarming symptoms such as acute anal pain and bleeding which might require an immediate management. This article deals with the diagnosis and management of common anorectal emergencies such as acutely thrombosed external hemorrhoid, thrombosed or strangulated internal hemorrhoid, bleeding hemorrhoid, bleeding anorectal varices, anal fissure, irreducible or strangulated rectal prolapse, anorectal abscess, perineal necrotizing fasciitis (Fournier gangrene), retained anorectal foreign bodies and obstructing rectal cancer. Sexually transmitted diseases as anorectal non-surgical emergencies and some anorectal emergencies in neonates are also discussed. The last part of this review dedicates to the management of early complications following common anorectal procedures that may present as an emergency including acute urinary retention, bleeding, fecal impaction and anorectal sepsis. Although many of anorectal disorders presenting in an emergency setting are not life-threatening and may be successfully treated in an outpatient clinic, an accurate diagnosis and proper management remains a challenging problem for clinicians. A detailed history taking and a careful physical examination, including digital rectal examination and anoscopy, is essential for correct diagnosis and plan of treatment. In some cases, some imaging examinations, such as endoanal ultrasonography and computerized tomography scan of whole abdomen, are required. If in doubt, the attending physicians should not hesitate to consult an expert e.g., colorectal surgeon about the diagnosis, proper management and appropriate follow-up. PMID:27468181

  13. Emergency contraception.

    PubMed

    1994-01-01

    Two oral postcoital contraceptive agents are currently available. The first is a 2 x 2 pill; the second is a 5 x 5. Both release a higher dose of hormones than conventional contraceptive pills. Success rates range between 96% and 99%. They must be taken within 72 hours of intercourse. Side effects include nausea and vomiting. Contraindications are the same as for the common oral contraceptives. The contraceptive mode of action can be any of the following: 1) by making the lining of the uterus unreceptive; 2) by slowing the movement of the egg in the fallopian tube; or 3) by affecting the release of the egg. Emergency contraceptive pills have no effect once implantation takes place. The IUD can be used as an emergency postcoital contraceptive method if placed within 10 days of coitus. They are usually placed within 5-7 days because of laws regarding when birth control becomes abortion. One failure has been reported in Great Britain (December, 1993). Side effects are the same as with regular use. RU486/PG may be used in the future as an emergency contraceptive agent. Research is in progress on success rates and side effects. This agent could potentially be used at any time. Currently, emergency contraception can only be obtained by prescription. Limited hours and interrogating staff are obstacles in such emergencies. British women's groups are asking that emergency oral contraceptive pills be made available over the counter with advice from the pharmacist.

  14. BET Bromodomain Proteins as Cancer Therapeutic Targets.

    PubMed

    Shu, Shaokun; Polyak, Kornelia

    2017-01-06

    Epigenetic regulators are emerging therapeutic targets in a wide variety of human cancers. BET bromodomain proteins have been identified as key regulators of oncogenic transcription factors including MYC; therefore, their inhibition might provide a way to block these "undruggable" targets. Several BET bromodomain inhibitors are in clinical development with promising preliminary findings. However, tumors acquire resistance to these agents in several different ways. In this review, we summarize the role that BET bromodomain proteins play in tumorigenesis as well as the molecular mechanisms underlying therapeutic responses and resistance to their inhibition with emphasis on BRD4 and breast cancer.

  15. Arsenic behavior in newly drilled wells

    USGS Publications Warehouse

    Kim, M.-J.; Nriagu, J.; Haack, S.

    2003-01-01

    In the present paper, inorganic arsenic species and chemical parameters in groundwater were determined to investigate the factors related to the distribution of arsenic species and their dissolution from rock into groundwater. For the study, groundwater and core samples were taken at different depths of two newly drilled wells in Huron and Lapeer Counties, Michigan. Results show that total arsenic concentrations in the core samples varied, ranging from 0.8 to 70.7 mg/kg. Iron concentration in rock was about 1800 times higher than that of arsenic, and there was no correlation between arsenic and iron occurrences in the rock samples. Arsenic concentrations in groundwater ranged from <1 to 171 ??g/l. The arsenic concentration in groundwater depended on the amount of arsenic in aquifer rocks, and as well decreased with increasing depth. Over 90% of arsenic existed in the form of As(III), implying that the groundwater systems were in the reduced condition. The results such as high ferrous ion, low redox potential and low dissolved oxygen supported the observed arsenic species distribution. There was no noticeable difference in the total arsenic concentration and arsenic species ratio between unfiltered and filtered (0.45 ??m) waters, indicating that the particulate form of arsenic was negligible in the groundwater samples. There were correlations between water sampling depth and chemical parameters, and between arsenic concentration and chemical parameters, however, the trends were not always consistent in both wells. ?? 2003 Elsevier Science Ltd. All rights reserved.

  16. Changing trends in newly licensed RNs.

    PubMed

    Kovner, Christine T; Brewer, Carol S; Fatehi, Farida; Katigbak, Carina

    2014-02-01

    Recent changes in U.S. health care and economics may influence the demand for nurses and the work choices of newly licensed RNs (NLRNs). We sought to compare the work lives of two cohorts of NLRNs licensed six years apart. Data were collected from two groups of NLRNs in 14 states via mailed surveys. The first group consisted of a subset of NLRNs surveyed for a larger study in 2004-05; the second group was surveyed by similar methods in 2010-11. Responses were weighted to adjust for differences in response rates according to geographic area. Response rates were 58% and 47%, respectively, for the 2004-05 cohort (N = 774) and the 2010-11 cohort (N = 1,613). The NLRNs in the later cohort were less likely to work in hospitals, special-care units, and direct care and more likely to work as managers, be enrolled in formal education programs, and view their work environments positively, resulting in more commitment to the organization. Also, those in the later cohort reported fewer local job opportunities, and a greater number held a second job : These findings indicate a shift from the traditional work patterns of NLRNs, who often began their careers in hospitals. Employers' heightened awareness of such changing trends among NLRNs may help them in planning for RN recruitment and retention.

  17. Therapeutic options for lip augmentation.

    PubMed

    Segall, Lorne; Ellis, David A F

    2007-11-01

    Aesthetic ideals vary with emerging fashion trends and within different cultures. However, over the past few decades, fuller lips have been considered a desirable trait. Many younger patients are presenting for lip augmentation to achieve the sought-after look commonly seen in many fashion magazines. In addition, as individuals age, they lose lip volume, with a thinning of the red lip, some effacement of the vermillion border, and elongation and flattening of the white portion of the lip. Rejuvenation of the lips plays a key role in restoring a more youthful appearance. As a result, lip augmentation appeals to a wide spectrum of patients who present with various different aesthetic goals and expectations. Numerous therapeutic options exist for aesthetic lip augmentation, ranging from temporary and permanent injectable fillers to implants and other surgical techniques.

  18. [Informed consent in emergency medicine].

    PubMed

    Ersoy, Nermin; Ozcan Senses, Müesser; Aydin Er, Rahime

    2010-01-01

    Informed consent is a prerequisite for the ethical and legal validity of the emergency intervention in emergency medicine, since it protects the fiduciary relationship between the physician and patient; the principle of honesty that grounds this relationship; the principle of autonomy that necessitates right of self-determination; and the principle of respect for persons. Informed consent in emergency medicine, which is supposed to include the nature, benefits and risks of emergency medical intervention, differentiates with respect to definite groups of patients: (1) conscious patients, (2) unconscious patients, and (3) children and mature minors. In addition, informed consent differentiates between medical, psychological and even social circumstances of the patients, referred to as valid consent, expressed-explicit consent, blanket consent, presumed consent, tacit consent, proxy consent, and parental consent. There are a few exceptions in which emergency medical intervention is administered without informed consent. In addition to the exceptions of life-saving interventions, when a patient can not decide for herself/himself, intervention of the physician in the best interest of the patient or children is based on the "therapeutic privilege" of the physician. As an ethically defensible right, since therapeutic privilege may open a door to hard paternalistic approaches, in those situations, emergency physicians should be cautious not to violate a patient's autonomy.

  19. Anxiety and therapeutic touch.

    PubMed

    Olson, M; Sneed, N

    1995-01-01

    This four-group, repeated-measures experimental design divided 40 healthy professional caregivers/students into high- and low-anxiety groups and further into "therapeutic touch" and comparison groups. The effectiveness of the use of therapeutic touch in reducing anxiety was evaluated, as were the methodologies used. Three self-report measures of anxiety (Profile of Mood States, Spielberger's State/Trait Anxiety Inventory, and visual analogue scales) were evaluated for equivalence and concurrent validity to determine their potential for use in future studies. The correlations among these instruments were highly significant. The small sample size prevented differences between groups from reaching statistical significance, but the reduction of anxiety in the high-anxiety group was greater for those who had received therapeutic touch than for those who did not. Using variability data, the sample size necessary to find statistically significant differences between those who had therapeutic touch and those who did not was determined.

  20. End-of-life experiential learning for newly licensed nurses.

    PubMed

    Warnke, Joellen; Thirlwell, Sarah

    2014-03-01

    Many newly licensed nurses begin their careers with limited knowledge and experience in end-of-life care. Findings from a literature review and a learning needs assessment of newly licensed nurses at a comprehensive cancer center guided the development of an 8-hour educational program on end-of-life care. An experiential learning approach was used to foster confidence and develop knowledge and skills in delivery of end-of-life care by newly licensed nurses. Copyright 2014, SLACK Incorporated.

  1. Occupation emerges in the process of therapy.

    PubMed

    Price, Pollie; Miner, Stephanie

    2007-01-01

    The current literature offers no cohesive definition of occupation-based practice. Current definitions emphasize intervention forms and contexts, which do not reflect the complexity of practice. This article demonstrates that the therapeutic relationship and the meanings that are created in the therapy process are central aspects of occupation-based practice. Occupation, as an idea that emerges in the therapeutic process, has aspects of both doing and becoming. The authors conducted observation sessions and interviews with an occupational therapist, Nancy, who used multiple therapeutic strategies with one child, Hannah, as they worked toward Hannah's goals of going to preschool and becoming a friend. Strategies include changing therapeutic conditions, using cognitive strategies, bridging the person-task-social context, pushing participation, and engaging in narrative micronegotiations. Occupation emerged in the therapeutic processes as the occupational therapist and client co-created meaning about the client moving toward or away from who she wanted to become.

  2. Saliva: diagnostics and therapeutic perspectives.

    PubMed

    Spielmann, N; Wong, D T

    2011-05-01

    For the past two decades, salivary diagnostic approaches have been developed to monitor oral diseases such as periodontal diseases and to assess caries risk. Recently, the combination of emerging biotechnologies and salivary diagnostics has extended the range of saliva-based diagnostics from the oral cavity to the whole physiologic system as most compounds found in blood are also present in saliva. Accordingly, saliva can reflect the physiologic state of the body, including emotional, endocrinal, nutritional and metabolic variations and acts as a source for the monitoring of oral and also systemic health. This review presents an update on the status of saliva diagnostics and delves into their applications to the discovery of biomarkers for cancer detection and therapeutic applications. Translating scientific findings of nucleic acids, proteins and metabolites in body fluids to clinical applications is a cumbersome and challenging journey. Our research group is pursuing the biology of salivary analytes and the development of technologies for detection of distinct biomarkers with high sensitivity and specificity. The avenue of saliva diagnostics incorporating transcriptomic, proteomic and metabolomic findings will enable us to connect salivary molecular analytes to monitor therapies, therapeutic outcomes, and finally disease progression in cancer. © 2010 John Wiley & Sons A/S.

  3. Newly qualified teachers' visions of science learning and teaching

    NASA Astrophysics Data System (ADS)

    Roberts, Deborah L.

    2011-12-01

    This study investigated newly qualified teachers' visions of science learning and teaching. The study also documented their preparation in an elementary science methods course. The research questions were: What educational and professional experiences influenced the instructor's visions of science learning and teaching? What visions of science learning and teaching were promoted in the participants' science methods course? What visions of science learning and teaching did these newly qualified teachers bring with them as they graduated from their teacher preparation program? How did these visions compare with those advocated by reform documents? Data sources included participants' assignments, weekly reflections, and multi-media portfolio finals. Semi-structured interviews provided the emic voice of participants, after graduation but before they had begun to teach. These data were interpreted via a combination of qualitative methodologies. Vignettes described class activities. Assertions supported by excerpts from participants' writings emerged from repeated review of their assignments. A case study of a typical participant characterized weekly reflections and final multi-media portfolio. Four strands of science proficiency articulated in a national reform document provided a framework for interpreting activities, assignments, and interview responses. Prior experiences that influenced design of the methods course included an inquiry-based undergraduate physics course, participation in a reform-based teacher preparation program, undergraduate and graduate inquiry-based science teaching methods courses, participation in a teacher research group, continued connection to the university as a beginning teacher, teaching in diverse Title 1 schools, service as the county and state elementary science specialist, participation in the Carnegie Academy for the Scholarship of Teaching and Learning, service on a National Research Council committee, and experience teaching a

  4. Health status of newly arrived refugees in Toronto, Ont

    PubMed Central

    Redditt, Vanessa J.; Janakiram, Praseedha; Graziano, Daniela; Rashid, Meb

    2015-01-01

    Abstract Objective To determine the prevalence of selected infectious diseases among newly arrived refugee patients and whether there is variation by key demographic factors. Design Retrospective chart review. Setting Primary care clinic for refugee patients in Toronto, Ont. Participants A total of 1063 refugee patients rostered at the clinic from December 2011 to June 2014. Main outcome measures Demographic information (age, sex, and region of birth); prevalence of HIV, hepatitis B, hepatitis C, Strongyloides, Schistosoma, intestinal parasites, gonorrhea, chlamydia, and syphilis infections; and varicella immune status. Results The median age of patients was 29 years and 56% were female. Refugees were born in 87 different countries. Approximately 33% of patients were from Africa, 28% were from Europe, 14% were from the Eastern Mediterranean Region, 14% were from Asia, and 8% were from the Americas (excluding 4% born in Canada or the United States). The overall rate of HIV infection was 2%. The prevalence of hepatitis B infection was 4%, with a higher rate among refugees from Asia (12%, P < .001). Hepatitis B immunity was 39%, with higher rates among Asian refugees (64%, P < .001) and children younger than 5 years (68%, P < .001). The rate of hepatitis C infection was less than 1%. Strongyloides infection was found in 3% of tested patients, with higher rates among refugees from Africa (6%, P = .003). Schistosoma infection was identified in 15% of patients from Africa. Intestinal parasites were identified in 16% of patients who submitted stool samples. Approximately 8% of patients were varicella nonimmune, with higher rates in patients from the Americas (21%, P < .001). Conclusion This study highlights the importance of screening for infectious diseases among refugee patients to provide timely preventive and curative care. Our data also point to possible policy and clinical implications, such as targeted screening approaches and improved access to vaccinations and

  5. Glycemic Response to Newly Initiated Diabetes Therapies

    PubMed Central

    Karter, Andrew J.; Moffet, Howard H.; Liu, Jennifer; Parker, Melissa M.; Ahmed, Ameena T.; Go, Alan S.; Selby, Joe V.

    2008-01-01

    Objective: The glycemic response to antihyperglycemic therapies for type 2 diabetes has been thoroughly evaluated in randomized controlled trials, but inadequately studied in real-world settings. Study Design: We studied glycemic response among 15 126 type 2 diabetic patients who initiated any single new antihyperglycemic agent (metformin, sulfonylureas, thiazolidinediones, or insulin added to medical nutrition therapy or to existing diabetes therapies) during 1999-2000 within Kaiser Permanente of Northern California, an integrated healthcare delivery system. Methods: Pre–post (3-12 months after initiation) change in glycosylated hemoglobin (A1C) was analyzed using ANCOVA (analysis of covariance) models adjusted for baseline A1C, concurrent (ongoing) antihyperglycemic therapy, demographics, health behaviors, medication adherence, clinical factors, and processes of care. Results: Mean A1C was 9.01% (95% confidence interval [CI] 8.98%-9.04%) before therapy initiation and 7.87% (95% CI 7.85%-7.90%) 3 to 12 months after initiation (mean A1C reduction 1.14 percentage points; 95% CI 1.11-1.17). Overall, 30.2% (95% CI 29.2%-31.1%) of patients achieved glycemic target (A1C < 7%). Although baseline disease severity and concurrent therapies differed greatly across therapeutic classes, after adjustment for these baseline clinical characteristics, no significant differences were noted in glucose-lowering effect across therapeutic classes. Treatment effects did not differ by age, race, diabetes duration, obesity, or level of renal function. Conclusions: Metformin, sulfonylures, thiazolidinediones, and insulin were equally effective in improving glucose control. Nonetheless, most patients failed to achieve the glycemic target. Findings suggest that, to keep up with progressive worsening of glycemic control, patients and providers must commit to earlier, more aggressive therapy intensification, triggered promptly after A1C exceeds the recommended glycemic target. PMID:17988185

  6. Emerging therapies for multiple myeloma

    PubMed Central

    Podar, Klaus; Tai, Yu-Tzu; Hideshima, Teru; Vallet, Sonia; Richardson, Paul G; Anderson, Kenneth C

    2011-01-01

    Multiple myeloma (MM) is a clonal plasma cell malignancy clinically characterized by osteolytic lesions, immunodeficiency, and renal disease. There are an estimated 750,000 people diagnosed with MM worldwide, with a median overall survival of 3 – 5 years. Besides chromosomal aberrations, translocations, and mutations in essential growth and tumor-suppressor genes, accumulating data strongly highlight the pathophysiologic role of the bone marrow (BM) microenvironment in MM pathogenesis. Based on this knowledge, several novel agents have been identified, and treatment options in MM have fundamentally changed during the last decade. Thalidomide, bortezomib, and lenalidomide have been incorporated into conventional cytotoxic and transplantation regimens, first in relapsed and refractory and now also in newly diagnosed MM. Despite these significant advances, there remains an urgent need for more efficacious and tolerable drugs. Indeed, a plethora of preclinical agents awaits translation from the bench to the bedside. This article reviews the scientific rationale of new therapy regimens and newly identified therapeutic agents – small molecules as well as therapeutic antibodies – that hold promise to further improve outcome in MM. PMID:19249983

  7. Newly Identified Pathogens Associated with Periodontitis

    PubMed Central

    Pérez-Chaparro, P.J.; Gonçalves, C.; Figueiredo, L.C.; Faveri, M.; Lobão, E.; Tamashiro, N.; Duarte, P.; Feres, M.

    2014-01-01

    There is substantial evidence supporting the role of certain oral bacteria species in the onset and progression of periodontitis. Nevertheless, results of independent-culture diagnostic methods introduced about a decade ago have pointed to the existence of new periodontal pathogens. However, the data of these studies have not been evaluated together, which may generate some misunderstanding on the actual role of these microorganisms in the etiology of periodontitis. The aim of this systematic review was to determine the current weight of evidence for newly identified periodontal pathogens based on the results of “association” studies. This review was conducted and reported in accordance with the PRISMA statement. The MEDLINE, EMBASE, and Cochrane databases were searched up to September 2013 for studies (1) comparing microbial data of subgingival plaque samples collected from subjects with periodontitis and periodontal health and (2) evaluating at least 1 microorganism other than the already-known periodontal pathogens. From 1,450 papers identified, 41 studies were eligible. The data were extracted and registered in predefined piloted forms. The results suggested that there is moderate evidence in the literature to support the association of 17 species or phylotypes from the phyla Bacteroidetes, Candidatus Saccharibacteria, Firmicutes, Proteobacteria, Spirochaetes, and Synergistetes. The phylum Candidatus Saccharibacteria and the Archaea domain also seem to have an association with disease. These data point out the importance of previously unidentified species in the etiology of periodontitis and might guide future investigations on the actual role of these suspected new pathogens in the onset and progression of this infection. PMID:25074492

  8. Dynamics of newly established elk populations

    USGS Publications Warehouse

    Sargeant, G.A.; Oehler, M.W.

    2007-01-01

    The dynamics of newly established elk (Cervus elaphus) populations can provide insights about maximum sustainable rates of reproduction, survival, and increase. However, data used to estimate rates of increase typically have been limited to counts and rarely have included complementary estimates of vital rates. Complexities of population dynamics cannot be understood without considering population processes as well as population states. We estimated pregnancy rates, survival rates, age ratios, and sex ratios for reintroduced elk at Theodore Roosevelt National Park, North Dakota, USA; combined vital rates in a population projection model; and compared model projections with observed elk numbers and population ratios. Pregnancy rates in January (early in the second trimester of pregnancy) averaged 54.1% (SE = 5.4%) for subadults and 91.0% (SE = 1.7%) for adults, and 91.6% of pregnancies resulted in recruitment at 8 months. Annual survival rates of adult females averaged 0.96 (95% CI = 0.94-0.98) with hunting included and 0.99 (95% CI = 0.97-0.99) with hunting excluded from calculations. Our fitted model explained 99.8% of past variation in population estimates and represents a useful new tool for short-term management planning. Although we found no evidence of temporal variation in vital rates, variation in population composition caused substantial variation in projected rates of increase (??=1.20-1.36). Restoring documented hunter harvests and removals of elk by the National Park Service led to a potential rate of ?? = 1.26. Greater rates of increase substantiated elsewhere were within the expected range of chance variation, given our model and estimates of vital rates. Rates of increase realized by small elk populations are too variable to support inferences about habitat quality or density dependence.

  9. Molecular Outflows from Newly Formed Massive Stars

    NASA Astrophysics Data System (ADS)

    Kim, Kee-Tae; Kim, Won-Ju; Kim, Chang-Hee

    2015-12-01

    We map 6 massive young stellar objects (YSOs) in the CO J=2-1 line and survey 18 massive YSOs, including the six, in the hcopj, sioj, water 6_{16}-5_{23} maser, and methanol 7_{0}-6_{1} A^{+} maser lines. We detect CO bipolar outflows in all the six mapped sources. Four of them are newly discovered (ifive, ieight, inine, iten), while itwo is mapped in the CO J=2-1 line for the first time. The detected outflows are much more massive and energetic than outflows from low-mass YSOs with masses >20 M_⊙ and momenta >300 M_⊙ km/s. They have mass outflow rates (3-6)×10^{-4} M_⊙ yr^{-1}, which are at least one order of magnitude greater than those observed in low-mass YSOs. We detect hcop and SiO line emission in 18 (100%) and 4 (22%) sources, respectively. The hcop spectra show high-velocity wings in 11 (61%) sources. We detect water maser emission in 13 (72%) sources and 44 GHz methanol maser emission in 8 (44%) sources. Of the detected sources, 5 water and 6 methanol maser sources are new discoveries. iseven shows high-velocity (>30 kms) water maser lines. We find good correlations of the bolometric luminosity of the central (proto)star with the mechanical force, mechanical luminosity, and mass outflow rate of molecular outflow %L_{bol} with F_{m}, L_{m}, and dot{M}_{out} in the bolometric luminosity range of 10^{-1}-10^6 lsol, and identified 3 intermediate- or high-mass counterparts of Class O objects.

  10. [Psychiatric Emergencies in Psychiatric Hospitals in Germany].

    PubMed

    Schwerthöffer, Dirk; Beuys, David; Hamann, Johannes; Messer, Thomas; Pajonk, Frank-Gerald

    2016-10-01

    Objective: Psychiatric hospitals are confronted with high rates of psychiatric emergencies. There are, however, only few investigations that focus on psychiatric emergency care in German psychiatric hospitals, their supply structures and diagnostic and treatment standards. The aim of the survey was a systematic acquisition of the diagnostic and therapeutic approach in treating psychiatric emergencies in German psychiatric hospitals. Methods: We conducted a survey in psychiatric hospitals throughout Germany. The questionnaire consisted of questions concerning the structures of supply and diagnostic and therapeutic standards treating psychiatric emergencies. Results: 42 % of all admissions to German psychiatric hospitals were emergency admissions. More than 60 % of the patients in psychiatric emergency ambulances had to receive inpatient treatment. As standard procedures for medical clearing in psychiatric emergencies physical examination, measurement of heart rate and blood pressure and conducting certain laboratory tests and breath alcohol were named. The most common psychopharmacological agents for emergency situations were diazepam, lorazepam, haloperidol and zuclopenthixol. Conclusion: Diagnosing and treating psychiatric emergencies need more standardisation. More specific data is required to generate diagnostic and therapeutic standards. © Georg Thieme Verlag KG Stuttgart · New York.

  11. Therapeutic Angiogenesis in Critical Limb Ischemia

    PubMed Central

    Ouma, Geoffrey O.; Zafrir, Barak; Mohler, Emile R.; Flugelman, Moshe Y.

    2013-01-01

    Critical limb ischemia (CLI) is a severe form of peripheral artery disease associated with high morbidity and mortality. The primary therapeutic goals in treating CLI are to reduce the risk of adverse cardiovascular events, relieve ischemic pain, heal ulcers, prevent major amputation, and improve quality of life (QoL) and survival. These goals may be achieved by medical therapy, endovascular intervention, open surgery, or amputation and require a multidisciplinary approach including pain management, wound care, risk factors reduction, and treatment of comorbidities. No-option patients are potential candidates for the novel angiogenic therapies. The application of genetic, molecular, and cellular-based modalities, the so-called therapeutic angiogenesis, in the treatment of arterial obstructive diseases has not shown consistent efficacy. This article summarizes the current status related to the management of patients with CLI and discusses the current findings of the emerging modalities for therapeutic angiogenesis. PMID:23129733

  12. Recent advances in (therapeutic protein) drug development

    PubMed Central

    Lagassé, H.A. Daniel; Alexaki, Aikaterini; Simhadri, Vijaya L.; Katagiri, Nobuko H.; Jankowski, Wojciech; Sauna, Zuben E.; Kimchi-Sarfaty, Chava

    2017-01-01

    Therapeutic protein drugs are an important class of medicines serving patients most in need of novel therapies. Recently approved recombinant protein therapeutics have been developed to treat a wide variety of clinical indications, including cancers, autoimmunity/inflammation, exposure to infectious agents, and genetic disorders. The latest advances in protein-engineering technologies have allowed drug developers and manufacturers to fine-tune and exploit desirable functional characteristics of proteins of interest while maintaining (and in some cases enhancing) product safety or efficacy or both. In this review, we highlight the emerging trends and approaches in protein drug development by using examples of therapeutic proteins approved by the U.S. Food and Drug Administration over the previous five years (2011–2016, namely January 1, 2011, through August 31, 2016). PMID:28232867

  13. Nanotechnology-novel therapeutics for CNS disorders.

    PubMed

    Srikanth, Maya; Kessler, John A

    2012-04-24

    Research into treatments for diseases of the CNS has made impressive strides in the past few decades, but therapeutic options are limited for many patients with CNS disorders. Nanotechnology has emerged as an exciting and promising new means of treating neurological disease, with the potential to fundamentally change the way we approach CNS-targeted therapeutics. Molecules can be nanoengineered to cross the blood-brain barrier, target specific cell or signalling systems, respond to endogenous stimuli, or act as vehicles for gene delivery, or as a matrix to promote axon elongation and support cell survival. The wide variety of available nanotechnologies allows the selection of a nanoscale material with the characteristics best suited to the therapeutic challenges posed by an individual CNS disorder. In this Review, we describe recent advances in the development of nanotechnology for the treatment of neurological disorders-in particular, neurodegenerative disease and malignant brain tumours-and for the promotion of neuroregeneration.

  14. Nanotechnology—novel therapeutics for CNS disorders

    PubMed Central

    Srikanth, Maya; Kessler, John A.

    2013-01-01

    Research into treatments for diseases of the CNS has made impressive strides in the past few decades, but therapeutic options are limited for many patients with CNS disorders. Nanotechnology has emerged as an exciting and promising new means of treating neurological disease, with the potential to fundamentally change the way we approach CNS-targeted therapeutics. Molecules can be nanoengineered to cross the blood–brain barrier, target specific cell or signalling systems, respond to endogenous stimuli, or act as vehicles for gene delivery, or as a matrix to promote axon elongation and support cell survival. The wide variety of available nanotechnologies allows the selection of a nanoscale material with the characteristics best suited to the therapeutic challenges posed by an individual CNS disorder. In this Review, we describe recent advances in the development of nanotechnology for the treatment of neurological disorders—in particular, neurodegenerative disease and malignant brain tumours—and for the promotion of neuroregeneration. PMID:22526003

  15. Quantifying Therapeutic and Diagnostic Efficacy in 2D Microvascular Images

    NASA Technical Reports Server (NTRS)

    Parsons-Wingerter, Patricia; Vickerman, Mary B.; Keith, Patricia A.

    2009-01-01

    VESGEN is a newly automated, user-interactive program that maps and quantifies the effects of vascular therapeutics and regulators on microvascular form and function. VESGEN analyzes two-dimensional, black and white vascular images by measuring important vessel morphology parameters. This software guides the user through each required step of the analysis process via a concise graphical user interface (GUI). Primary applications of the VESGEN code are 2D vascular images acquired as clinical diagnostic images of the human retina and as experimental studies of the effects of vascular regulators and therapeutics on vessel remodeling.

  16. A therapeutic group for parents of transgender adolescents.

    PubMed

    Menvielle, Edgardo J; Rodnan, Leslie A

    2011-10-01

    Therapy for transgender, transsexual, and gender variant persons has traditionally assisted individuals in the process of adjusting to their newly adopted gender role. Increasingly, younger gender variant patients,teens and preteens, present to the clinical consultation raising the need to develop therapeutic interventions that better address the psychosocial needs of minors. The Gender and Sexuality Development Program at Children's National Medical Center (CNMC) in Washington,DC (http://www.childrensnational.org/gendervariance), provides outpatient psychosocial evaluations and therapeutic services for children,adolescents, and their families.

  17. Therapeutic role of nitric oxide as emerging molecule.

    PubMed

    Kumar, Sahil; Singh, Rajesh K; Bhardwaj, T R

    2017-01-01

    NO has many physiological roles; in inflammation, pain, rheumatoid arthritis, immune system, gastroprotection, as antioxidant and reported to be a free radical scavenger.Intensive research on the biological functions of NO and other reactive nitrogen oxide species demands exogenous sources of NO donors as research tools and pharmaceuticals. Since the mid-1980s, the development of new NO donors has offered several advantages over theprevious NO donors, such as spontaneous release of NO, donation of NO under controlled rates, and even the targeting of NO to certain tissues. Nitric oxide releasing derivatives of conventional NSAIDs have been synthesized not only to avoid gastrotoxicity, but also for making them fit for topical delivery, targeting them to brain and increase their analgesic and anti-inflammatory activity. "Hybrid nitrates" have vital role in different like NSAIDs, Anti-platelet, Antileukemic, Glaucoma, Antihypertensive, Antimalarial etc.

  18. Avian Diagnostic and Therapeutic Antibodies to Viral Emerging Pathogens

    SciTech Connect

    David Bradley

    2011-03-31

    During the current period the following key objectives were achieved: demonstration of high titer antibody production by geese following immunization with inactived H1N1 virus; completion of the epitope mapping of West Nile Virus-specific goose antibodies and initiation of epitope mapping of H1N1 flu-specific goose antibodies; advancement in scalable purification of goose antibodies.

  19. Emerging Therapeutic Strategies and Future Challenges in Clinical Periodontics.

    PubMed

    Shin, Daniel; Hamada, Yusuke; John, Vanchit

    2016-01-01

    Currently, the protocol for treating periodontitis follows a standardized and straightforward algorithm: 1) review and reinforce oral hygiene; 2) perform scaling and root planing; 3) proceed to periodontal surgery if the disease process has not been arrested; then 4) enroll the patient in a customized periodontal maintenance recall program to maintain the health of the reduced periodontium. Multiple longitudinal studies have demonstrated that the aforementioned treatment regimen can arrest the progression of periodontitis and can increase the likelihood of tooth retention and periodontal stability.

  20. [Therapeutic efficiency of cytoflavine solution for infusion in emergency conditions].

    PubMed

    Suslina, Z A; Romantsov, M G; Kovalenko, A L; Klocheva, E G; Rumintseva, S A; Bagnenko, S F; Piradov, M A; Semke, V Ia; Sukhanov, D S

    2010-01-01

    The author reports results of clinical assessment of cytoflavin for injections in the treatment of different pathological condition including critical ones. It was shown that therapy reduces mortality among patients with acute disturbances of cerebral circulation to 4.8-9.6% compared with 11.7-17.1% in controls. Positive dynamic of neurologic status was documented in 79% of the patients with dyscirculatory encephalopathy versus 25% in control. Duration of comatose state decreased 1,7-fold, length of stay in resuscitation and intensive therapy wards 1.8-fold, and frequency of internal complications secondary to the effect of neurotropic poisons 2-fold. Cytoflavin corrected the level of metalloproteides and stabilized antioxidative potential of sera and cerebrospinal liquid in patient with meningitis including that of zoonotic etiology. In the period of post-narcosis rehabilitation cytoflavin restored conscience in 77% of the patients within 20 min. The drug also inhibited pathological alcohol addiction within 5 days after the onset of therapy as apparent from the improvement of intellectual-mnestic status and activization of attention. The frequency of infectious complications in patients with acute surgical abdominal pathology decreased by 5.1% and lethality by 3.6% compared with placebo group. Cytoflavin exhibited cardioprotective action in patients with myocardial infarction, during cardiosurgical intervention, and chronic brucellosis. It had hepatoprotective effect in iatrogenic hepatic conditions as well as ophthalmo- and oto-protective activity.