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Sample records for aggressive therapeutic approach

  1. A Strategic Approach to Aggression.

    ERIC Educational Resources Information Center

    Archer, John

    2001-01-01

    Discusses two issues raised by Underwood et al.: the distinction between indirect and relational forms of aggression, and implications of indirect aggression for definitions of aggression; and the normative view of aggression that indicates that aggressive individuals may be socially skilled. Suggests that both issues lead to the conclusion that…

  2. Novel Therapeutics for Aggressive Non-Hodgkin's Lymphoma

    PubMed Central

    Mahadevan, Daruka; Fisher, Richard I.

    2011-01-01

    Application of advances in genomic and proteomic technologies has provided molecular insights into distinct types of aggressive B- and T-cell non-Hodgkin's lymphomas (NHLs). This has led to the validation of novel biomarkers of classification, risk-stratification, and druggable targets. The promise of novel treatments from genomic research has been slow to materialize because of the lack of a therapeutic signature for the distinct NHL subtypes. Patients with lymphoma with aggressive disease urgently require the development of novel therapies on the basis of investigation of dysregulated intracellular oncogenic processes that arise during lymphomagenesis. Although monoclonal antibodies have made significant contributions to the armamentarium of B-cell NHL therapy (eg, anti-CD20), parallel development of small-molecule inhibitors (SMIs) to intracellular targets has lagged behind. Despite these deficiencies, several promising anti-NHL therapies are in development that target immune kinases of the B-cell receptor signaling pathway, mammalian target of rapamycin complex, proteasome, DNA/histone epigenetic complex, antiapoptosis, neoangiogenesis, and immune modulation. This review focuses on novel SMI therapeutic strategies that target overlapping core oncogenic pathways in the context of the 10 hallmarks of cancer. Furthermore, we have developed the concept of a therapeutic signature using the 10 hallmarks of cancer, which may be incorporated into novel phase I/II drug development programs. PMID:21483007

  3. [Hypercholesterolemia: a therapeutic approach].

    PubMed

    Moráis López, A; Lama More, R A; Dalmau Serra, J

    2009-05-01

    High blood cholesterol levels represent an important cardiovascular risk factor. Hypercholesterolemia is defined as levels of total cholesterol and low-density lipoprotein cholesterol above 95th percentile for age and gender. For the paediatric population, selective screening is recommended in children older than 2 years who are overweight, with a family history of early cardiovascular disease or whose parents have high cholesterol levels. Initial therapeutic approach includes diet therapy, appropriate physical activity and healthy lifestyle changes. Drug treatment should be considered in children from the age of 10 who, after having followed appropriate diet recommendations, still have very high LDL-cholesterol levels or moderately high levels with concomitant risk factors. In case of extremely high LDL-cholesterol levels, drug treatment should be taken into consideration at earlier ages (8 years old). Modest response is usually observed with bile acid-binding resins. Statins can be considered first-choice drugs, once evidence on their efficacy and safety has been shown.

  4. Therapeutic approaches to cellulite.

    PubMed

    Green, Jeremy B; Cohen, Joel L; Kaufman, Joely; Metelitsa, Andrei I; Kaminer, Michael S

    2015-09-01

    Cellulite is a condition that affects the vast majority of women. Although it is of no danger to one's overall health, cellulite can be psychosocially debilitating. Consequently, much research has been devoted to understanding cellulite and its etiopathogenesis. With additional insights into the underlying causes of its clinical presentation, therapeutic modalities have been developed that offer hope to cellulite sufferers. This review examines evidence for topical treatments, noninvasive energy-based devices, and recently developed minimally invasive interventions that may finally provide a solution.

  5. Homocystinuria: Therapeutic approach.

    PubMed

    Kumar, Tarun; Sharma, Gurumayum Suraj; Singh, Laishram Rajendrakumar

    2016-07-01

    Homocystinuria is a disorder of sulfur metabolism pathway caused by deficiency of cystathionine β-synthase (CBS). It is characterized by increased accumulation of homocysteine (Hcy) in the cells and plasma. Increased homocysteine results in various vascular and neurological complications. Present strategies to lower cellular and plasma homocysteine levels include vitamin B6 intake, dietary methionine restriction, betaine supplementation, folate and vitamin B12 administration. However, these strategies are inefficient for treatment of homocystinuria. In recent years, advances have been made towards developing new strategies to treat homocystinuria. These mainly include functional restoration to mutant CBS, enhanced clearance of Hcy from the body, prevention of N-homocysteinylation-induced toxicity and inhibition of homocysteine-induced oxidative stress. In this review, we have exclusively discussed the recent advances that have been achieved towards the treatment of homocystinuria. The review is an attempt to help clinicians in developing effective therapeutic strategies and designing novel drugs against homocystinuria. PMID:27059523

  6. Some Therapeutic Uses of Dramatic Play with the Aggressive Child in the Preschool Classroom.

    ERIC Educational Resources Information Center

    Ginnane, Patrick

    The primary purpose of this master's thesis is to describe some therapeutic uses of dramatic play with the mildly aggressive preschool child. The child for whom the suggested play interventions are considered appropriate is characterized by sociality and attachment to both peers and adults, and is not chronically aggressive. After the first…

  7. Novel therapeutic approaches for haemophilia.

    PubMed

    Shetty, S; Ghosh, K

    2015-03-01

    The major therapy for haemophilia is plasma derived or recombinant clotting factors which are evolving steadily to increase potency, stability and half-life. Research in the area of haemophilia therapeutics, however, is not restricted only to modifications in the recombinant products, but alternate therapeutic strategies are being developed which are in different phases of experimental and clinical trials. This chapter reviews the diverse molecular innovations which are being developed for alternate therapeutic approaches in haemophilia. The data is mainly extracted from the literature and the Conference abstracts. Some of the novel therapeutic approaches include inhibition of anticoagulant pathway factors (activated protein C, antithrombin, tissue factor pathway inhibitor) by monoclonal antibodies, peptide inhibitors, DNA or RNA aptamers, use of variant coagulation factors (factor Xa, factor Va) which are more resistant to inactivation or enzymatically more active and antibody-mediated therapy including a humanized anti-factor IXa/X bispecific antibody mimicking factor VIII. Other approaches include nonsense mutation suppression, induction of prothrombotic microparticles by P-selectin-immunoglobulin chimeras, suppression of fibrinolytic potential either by antifibrinolytics or by the use of mutant molecules of fibrinolytic inhibitors. Few products are proposed as 'stand alone' treatment for haemophilia, while a few can be used as adjuvant therapies to recombinant factors with an aim to reduce the amount of factor intake. All efforts are underway to produce an alternate, novel drug for haemophilia which will have an increased half-life, subcutaneously injectable, non-immunogenic and effective both in the presence and absence of inhibitors.

  8. The CBM signalosome: Potential therapeutic target for aggressive lymphoma?

    PubMed Central

    Yang, Chenghua; David, Liron; Qiao, Qi; Damko, Ermelinda; Wu, Hao

    2014-01-01

    The CBM signalosome plays a pivotal role in mediating antigen-receptor induced NF-κB signaling to regulate lymphocyte functions. The CBM complex forms filamentous structure and recruits downstream signaling components to activate NF-κB. MALT1, the protease component in the CBM complex, cleaves key proteins in the feedback loop of the NF-κB signaling pathway and enhances NF-κB activation. The aberrant activity of the CBM complex has been linked to aggressive lymphoma. Recent years have witnessed dramatic progresses in understanding the assembly mechanism of the CBM complex, and advances in the development of targeted therapy for aggressive lymphoma. Here, we will highlight these progresses and give an outlook on the potential translation of this knowledge from bench to bedside for aggressive lymphoma patients. PMID:24411492

  9. 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

  10. Current therapeutic approaches in inflammatory bowel disease.

    PubMed

    Sohrabpour, Amir Ali; Malekzadeh, Reza; Keshavarzian, Ali

    2010-01-01

    , mode of the disease presentation, disease location, disease-associated complications such as perianal disease/fistula, and serology and genetic markers can all help to individualize disease treatment. These factors can help to determine whether one should start with 5-ASA/antibiotic/steroid [step-up where there is no risk factors for aggressive disease course] or whether one should initiate biologic therapy at diagnosis [top-down approach], and whether it is most advisable to use monotherapy with biologic treatment [e.g. in young, Caucasian male or elderly] or use a combination therapy with a biologic and an immunomodulator. Ongoing research promises, in a near future, development of more robust set of markers to be able to model disease behavior to more accurately predict disease course and thus decide on therapeutic approach with most appropriate efficacy/risk ratio for a given patient. Furthermore, current basic laboratory research has provided a large number of potential therapeutic targets to treat IBD with new promising highly specific and targeted agents. PMID:21128898

  11. Novel Therapeutic Approaches in Diabetes.

    PubMed

    Gallwitz, Baptist

    2016-01-01

    This chapter deals with novel therapeutic approaches, predominantly for type 2 diabetes. Incretin-based therapies utilize the effects of glucagon-like peptide-1 (GLP-1), which stimulates insulin and inhibits glucagon secretion in a glucose-dependent manner. Incretin-based therapies comprise injectable GLP-1 receptor agonists and orally active dipeptidyl peptidase-IV inhibitors. Both have a low hypoglycaemia risk. GLP-1 receptor agonists (exenatide, liraglutide, lixisenatide, dulaglutide, albiglutide) reduce glycated haemoglobin levels more effectively than oral antidiabetic agents do and lead to weight loss as well as a slight decrease in systolic blood pressure. The most common side effects are nausea and fullness, especially during the start of therapy. Dipeptidyl peptidase-IV inhibitors (alogliptin, linagliptin, saxagliptin, sitagliptin, vildagliptin) are not inferior to sulfonylureas, causing significantly less hypoglycaemia and not inducing weight gain. Specific adverse effects have not been discovered yet, and cardiovascular safety has been demonstrated in respective studies. Sodium-glucose transporter-2 inhibitors (dapagliflozin, canagliflozin, empagliflozin) were introduced recently. They block the tubular reabsorption of glucose in the kidney and represent an insulin-independent mode of action, with low hypoglycaemia risk and allowing weight loss. The most common side effects are genital and urinary tract infections. Other novel drugs in development (G-protein-coupled receptor agonists, interleukin-1 antagonists) are also described. PMID:26824365

  12. [Therapeutic education, approaches in psychiatry].

    PubMed

    Jouet, Emmanuelle

    2011-01-01

    Therapeutic patient education offers people suffering from chronic illnesses new therapies as well as an appropriation of knowledge of the disease. It has a special place in psychiatric nursing care provision. However, programmes offered by nursing teams or pharmaceutical laboratories are struggling to define themselves.

  13. Approaches for Therapeutic Temperature Management.

    PubMed

    Olson, DaiWai M; Hoffman, Jo

    2016-01-01

    In concert with an evolution toward an increased awareness of the need to tightly manage temperature, the methods used to monitor and manipulate temperature have evolved from mercury-filled glass thermometers, alcohol baths, and ice packs into a high technology-driven multidisciplinary activity. The purpose of this article is to provide a brief overview of the historical development of temperature management and the primary tenets of each of the 3 phases (induction, maintenance, and rewarming), which are now recognized as crucial steps to ensure the safe practice of therapeutic temperature management. PMID:26714116

  14. Bacterial meningitis: new therapeutic approaches.

    PubMed

    Nau, Roland; Djukic, Marija; Spreer, Annette; Eiffert, Helmut

    2013-10-01

    Bacterial meningitis remains a disease with high mortality and long-term morbidity. Outcome critically depends on the rapid initiation of effective antibiotic therapy. Since a further increase of the incidence of pathogens resistant to antibacterials can be expected both in community-acquired and nosocomial bacterial meningitis, the choice of an optimum initial empirical antibiotic regimen will gain significance. In this context, the use of antibiotics which are bactericidal but do not lyse bacteria, may emerge as a therapeutic option. Conversely, the role of corticosteroids, which decrease the entry of hydrophilic antibacterials into the cerebrospinal fluid, as adjunctive therapy will probably decline as a consequence of the increasing antibiotic resistance of bacteria causing meningitis. Consequent vaccination of all children at present is the most efficient manner to reduce disease burden. PMID:24073921

  15. Toxin-Based Therapeutic Approaches

    PubMed Central

    Shapira, Assaf; Benhar, Itai

    2010-01-01

    Protein toxins confer a defense against predation/grazing or a superior pathogenic competence upon the producing organism. Such toxins have been perfected through evolution in poisonous animals/plants and pathogenic bacteria. Over the past five decades, a lot of effort has been invested in studying their mechanism of action, the way they contribute to pathogenicity and in the development of antidotes that neutralize their action. In parallel, many research groups turned to explore the pharmaceutical potential of such toxins when they are used to efficiently impair essential cellular processes and/or damage the integrity of their target cells. The following review summarizes major advances in the field of toxin based therapeutics and offers a comprehensive description of the mode of action of each applied toxin. PMID:22069564

  16. [Anxiogenic and anxiolytic effects of lithium chloride under preventive and therapeutic treatments of male mice with repeated experience of aggression].

    PubMed

    Smagin, D A; Kudryavtseva, N N

    2014-01-01

    Repeated experience of aggression in daily agonistic interactions is accompanied by development of changes in behaviors and psychoemotional states indicating the development of the psychopathology of aggressive behavior, which are difficult to correct by drugs used for decrease of aggression in the clinics. In this paper the influence of lithium chloride on the behavior of aggressive males in different tests assessing anxiety, communication and exploratory activity (elevated plus maze test, social interaction test, partition test), as well as aggressiveness (agonistic interaction test) were studied. Lithium chloride (Sigma-Aldrich Co, 100 mg/kg/day, i.p.) was administered preventively to male in ranging from the 7th day of agonistic interactions, as well as therapeutically to males with 21 days of aggression experience during the period without agonistic interactions. Also the effects of chronic lithium chloride treatment on behaviors of animals without agonistic interactions (intact mice) were studied. Period of drug and saline (as the controls) treatment--14 days. It has been shown that preventive lithium chloride treatment of male mice with repeated experience of aggression induced pronounced anxiogenic effect, under therapeutic treatment--nxiolytic effects. Anxiolytic effect was also observed in intact males. There is no effect of lithium chloride on aggression. Differences in the effects of lithium chloride under preveitive and therapeutic treatments, as well as the causes of individual sensitivity to the drug in male mice in one group were discussed.

  17. New therapeutic approaches in PV

    PubMed Central

    Falchi, Lorenzo; Newberry, Kate J.; Verstovsek, Srdan

    2015-01-01

    Polycytemia vera (PV) is one of the three Philadelphia-negative myeloproliferative neoplasms. Clinically, PV is an indolent disease but its course can be complicated by arterial and venous vascular accidents, evolution to myelofibrosis or leukemic transformation. Treatment of PV is, therefore, aimed at preventing such acute complications. The cornerstone of therapy of low-risk patients remains strict control of cardiovascular risk factors, the use of phlebotomy and low dose aspirin. Higher risk patients should also receive cytoreductive treatments. Hydroxyurea and interferon-α represent standard first-line options for newly diagnosed high-risk PV patients. Recommendations for patients who fail these therapies are less clearly defined. The discovery of a mutation in the Janus kinase 2 gene (V617F) in almost all cases of PV has prompted the development of molecularly targeted agents for the treatment of these patients. In this review we will discuss key clinical aspects, the current therapeutic armamentarium and data on the use of novel agents in patients with PV. PMID:26297275

  18. [Children's Aggressive Behaviour and Therapeutic Interventions on the Parental Couple Level].

    PubMed

    Lux, Ulrike; Hudecek, Matthias

    2015-01-01

    Parents go to see child guidance counselling services for many different reasons. Behavioural problems or rather enraged or aggressive behaviour of children and adolescents towards their siblings or parents is a frequent issue in counselling practice. The current article takes a closer look at the range of problems around defiance, anger and aggression from a developmental and systemic point of view. The meaning of these negative affects within the family system is elaborated. Empirical studies show a clear connection between children's problem behaviour and frequent and destructive interparental conflict. So called spill-over-effects play a crucial role in explaining this connection. From a systemic perspective thus the child is seen as a symptom carrier, which shifts the focus of counselling on the interaction between parents as well. Consequently, family therapeutic sessions on the couple level are often indicated. Do parents succeed in constructively solving their conflicts, typically the aggressive behaviour of the children is reduced, too. On the basis of a compound single case such a process is illustrated.

  19. Future Therapeutic Approaches for Inflammatory Bowel Diseases

    PubMed Central

    Plevy, Scott E.; Targan, Stephan R.

    2016-01-01

    In this review, we speculate about future therapeutic approaches for inflammatory bowel diseases (IBDs), focusing on the need for better preclinical and clinical models and approaches beyond small molecules and systemically administered biologics. We offer ideas to change clinical trial programs and to use immunologic and genetic biomarkers to personalize medicine. We attempt to reconcile past therapeutic successes and failures to improve future approaches. Some of our ideas might be provocative, but we hope that the examples we provide will stimulate discussion about what will advance the field of IBD therapy. PMID:21530750

  20. Topical and oral therapeutic approach to rosacea.

    PubMed

    Helfrich, Yolanda R; Maier, Lisa M

    2016-06-01

    Rosacea is an inflammatory condition of the skin, primarily affecting the central convexities of the face. Various topical and oral therapeutic approaches exist. Most have been developed to treat the papulopustular subtype of rosacea; however, other approaches can be used to treat the erythematotelangiectatic, ocular, and phymatous subtypes. This review provides a summary of available topical and oral approaches for the treatment of rosacea. PMID:27416312

  1. An aggressive multidisciplinary approach reduces mortality in rhinocerebral mucormycosis

    PubMed Central

    Palejwala, Sheri K.; Zangeneh, Tirdad T.; Goldstein, Stephen A.; Lemole, G. Michael

    2016-01-01

    Background: Rhinocerebral mucormycosis occurs in immunocompromised hosts with uncontrolled diabetes, solid organ transplants, and hematologic malignancies. Primary disease is in the paranasal sinuses but often progresses intracranially, via direct extension or angioinvasion. Rhinocerebral mucormycosis is rapidly fatal with a mortality rate of 85%, even when maximally treated with surgical debridement, antifungal therapy, and correction of underlying processes. Methods: We performed a retrospective chart review of patients with rhinocerebral mucormycosis from 2011 to 2014. These patients were analyzed for symptoms, surgical and medical management, and outcome. We found four patients who were diagnosed with rhinocerebral mucormycosis. All patients underwent rapid aggressive surgical debridement and were started on antifungal therapy on the day of diagnosis. Overall, we observed a mortality rate of 50%. Results: An early aggressive multidisciplinary approach with surgical debridement, antifungal therapy, and correction of underlying disease have been shown to improve survivability in rhinocerebral mucormycosis. Conclusion: A multidisciplinary approach to rhinocerebral mucormycosis with otolaryngology, neurosurgery, and ophthalmology, infectious disease and medical intensivists can help reduce mortality in an otherwise largely fatal disease. Even despite these measures, outcomes remain poor, and a high index of suspicion must be maintained in at-risk populations, in order to rapidly execute a multifaceted approach. PMID:27280057

  2. Disentangling impulsiveness, aggressiveness and impulsive aggression: an empirical approach using self-report measures.

    PubMed

    García-Forero, Carlos; Gallardo-Pujol, David; Maydeu-Olivares, Alberto; Andrés-Pueyo, Antonio

    2009-06-30

    There is confusion in the literature concerning the concept of impulsive aggression. Based on previous research, we hypothesize that impulsivity and aggression may be related, though not as closely as to consider them the same construct. So, our aim was to provide empirical evidence of the relationship between the impulsivity and aggressiveness constructs when considered as traits. Two widely used questionnaires [Barratt's Impulsiveness Scale (BIS) and Aggression Questionnaire-Refined (AQ-R)] were administered to 768 healthy respondents. Product-moment and canonical correlations were then calculated. In addition, a principal components analysis was conducted to explore whether impulsive aggression can be defined phenotypically as the expression of a single trait. The common variance between impulsivity and aggressiveness was never higher than 42%. The principal components analysis reveals that one component is not enough to represent all the variables. In conclusion, our results show that impulsivity and aggressiveness are two separate, although related constructs. This is particularly important in view of the misconceptions in the literature.

  3. [Diagnostic-therapeutic approach for retroperitoneal tumors].

    PubMed

    Cariati, A

    1993-12-01

    After a careful review of the Literature, diagnostic and therapeutic strategies for Primary Retroperitoneal Tumours (PRT) are reported. The Author analyzes the experience of the Institute of Clinica Chirurgica "R" (Chief: Prof. E. Tosatti) as well as that of Anatomia Chirurgica (Chief: Prof. E. Cariati),--University of Genoa--in the management of PRT, stressing the importance of preoperative staging for a correct surgical approach.

  4. Novel delivery approaches for cancer therapeutics.

    PubMed

    Mitra, Ashim K; Agrahari, Vibhuti; Mandal, Abhirup; Cholkar, Kishore; Natarajan, Chandramouli; Shah, Sujay; Joseph, Mary; Trinh, Hoang M; Vaishya, Ravi; Yang, Xiaoyan; Hao, Yi; Khurana, Varun; Pal, Dhananjay

    2015-12-10

    Currently, a majority of cancer treatment strategies are based on the removal of tumor mass mainly by surgery. Chemical and physical treatments such as chemo- and radiotherapies have also made a major contribution in inhibiting rapid growth of malignant cells. Furthermore, these approaches are often combined to enhance therapeutic indices. It is widely known that surgery, chemo- and radiotherapy also inhibit normal cells growth. In addition, these treatment modalities are associated with severe side effects and high toxicity which in turn lead to low quality of life. This review encompasses novel strategies for more effective chemotherapeutic delivery aiming to generate better prognosis. Currently, cancer treatment is a highly dynamic field and significant advances are being made in the development of novel cancer treatment strategies. In contrast to conventional cancer therapeutics, novel approaches such as ligand or receptor based targeting, triggered release, intracellular drug targeting, gene delivery, cancer stem cell therapy, magnetic drug targeting and ultrasound-mediated drug delivery, have added new modalities for cancer treatment. These approaches have led to selective detection of malignant cells leading to their eradication with minimal side effects. Lowering multi-drug resistance and involving influx transportation in targeted drug delivery to cancer cells can also contribute significantly in the therapeutic interventions in cancer.

  5. New therapeutic approaches to resistant hypertension.

    PubMed

    Schlaich, Markus P; Krum, Henry; Esler, Murray D

    2010-08-01

    Resistant hypertension is a common and growing clinical problem characterized by failure to achieve target blood pressure levels despite adequate use of at least three antihypertensive agents. Although numerous safe and effective pharmacologic therapies are available to treat elevated blood pressure, novel therapeutic approaches are warranted to improve the management and prognosis of patients with resistant hypertension. In this context, several lines of research have generated promising results based on both novel pharmacologic and device-based approaches that may more effectively treat resistant hypertension and its adverse consequences in the future.

  6. Attitudes and dating aggression: a cognitive dissonance approach.

    PubMed

    Schumacher, Julie A; Slep, Amy M Smith

    2004-12-01

    This study examined the association between attitudes about dating aggression and select dating aggressive behaviors (verbal aggression and jealous behavior) in high school students. Our hypothesis, derived from cognitive dissonance theory, was that discrepancies between self-reported attitudes and aggressive behavior at Time 1 (i.e., putative cognitive dissonance) would predict decreases in aggression between Time 1 and Time 2 beyond what would be predicted by change in attitudes over the same period. Results indicated that cognitive dissonance (as indexed by the discrepancy between attitudes and behavior) was generally a significant predictor of behavior change, providing significant improvement in prediction of behavior over attitude change alone. We discuss the implications of these findings for prevention efforts and directions for future research in this area.

  7. Therapeutic approaches for spinal cord injury

    PubMed Central

    Cristante, Alexandre Fogaça; de Barros Filho, Tarcísio Eloy Pessoa; Marcon, Raphael Martus; Letaif, Olavo Biraghi; da Rocha, Ivan Dias

    2012-01-01

    This study reviews the literature concerning possible therapeutic approaches for spinal cord injury. Spinal cord injury is a disabling and irreversible condition that has high economic and social costs. There are both primary and secondary mechanisms of damage to the spinal cord. The primary lesion is the mechanical injury itself. The secondary lesion results from one or more biochemical and cellular processes that are triggered by the primary lesion. The frustration of health professionals in treating a severe spinal cord injury was described in 1700 BC in an Egyptian surgical papyrus that was translated by Edwin Smith; the papyrus reported spinal fractures as a “disease that should not be treated.” Over the last two decades, several studies have been performed to obtain more effective treatments for spinal cord injury. Most of these studies approach a patient with acute spinal cord injury in one of four manners: corrective surgery or a physical, biological or pharmacological treatment method. Science is unraveling the mechanisms of cell protection and neuroregeneration, but clinically, we only provide supportive care for patients with spinal cord injuries. By combining these treatments, researchers attempt to enhance the functional recovery of patients with spinal cord injuries. Advances in the last decade have allowed us to encourage the development of experimental studies in the field of spinal cord regeneration. The combination of several therapeutic strategies should, at minimum, allow for partial functional recoveries for these patients, which could improve their quality of life. PMID:23070351

  8. Psychosocial approaches to violence and aggression: contextually anchored and trauma-informed interventions.

    PubMed

    Horowitz, Deborah; Guyer, Margaret; Sanders, Kathy

    2015-06-01

    Psychosocial interventions are part of the complex understanding and treatment of violent behavior in our state mental health hospitals. A comprehensive assessment of violence and aggression includes attention to all 3 domains of prevention and assessment (primary-institutional, secondary-structural, and tertiary-direct). Trauma experiences and their consequences may include behavioral violence and aggression. The authors' premise is that trauma is a universal component in the individual assessment of violent behavior. Therapeutic interventions must include a trauma-informed formulation to be effective. Organizational commitment to trauma-informed, person-centered, recovery-oriented (TPR) care is crucial to the efficacy of any of the interventions discussed. Thus, the dynamic nature of the individual, interpersonal, environmental, and cultural factors associated with the daily operations of the inpatient unit need to be assessed through the lens of primary and secondary violence prevention, building on the recognition that the majority of persons served and staff have significant trauma histories. Once a compassionate, respectful, empathic, and empowering approach is embraced by leadership and staff, the work with individuals can proceed more effectively. Interventions used include a variety of cognitive-behavioral, interpersonal, and somatosensory therapies. These interventions, when effectively applied, result in more self-esteem, self-mastery, self-control for the person served, and diminished behavioral violence.

  9. Nanoparticles: a promising therapeutic approach in atherosclerosis.

    PubMed

    Antoniades, Charalambos; Psarros, Costantinos; Tousoulis, Dimitris; Bakogiannis, Constantinos; Shirodaria, Cheerag; Stefanadis, Christodoulos

    2010-10-01

    Coronary atherosclerosis is the largest cause of mortality and morbidity in industrialised countries. Despite recent advances in medical therapies, the prevention and treatment of atherosclerosis remain suboptimal. Atherosclerosis is considered to be a chronic inflammatory disease of the arterial wall, involving the accumulation of macrophages and excess low density lipoproteins (LDL), the formation of foam cells which create the atheromatous plaque, resulting in stenosis, aneurysm and plaque rupture leading to acute coronary events. Every step in the atherogenesis process is a potential therapeutic target for both the prevention and regression of atherosclerosis. A novel approach is the use of nanoparticles containing drugs, providing new perspectives in targeted modification of these pathways. Nanoparticles are ultrafine particles sized between 1-100 nm. By using specific methods, nanoparticles can be filled with drugs and achieve targeted drug delivery near the diseased area. In this review article we describe the basic actions of nanoparticles, and we discuss their potential applications in atherosclerosis. We also discuss their advantages and we expose the existing toxicity issues, making it clear however, that the use of nanoparticles is one of the most promising therapeutic strategies against atherosclerosis.

  10. Therapeutic approaches for spinal cord injury.

    PubMed

    Cristante, Alexandre Fogaça; Barros Filho, Tarcísio Eloy Pessoa de; Marcon, Raphael Martus; Letaif, Olavo Biraghi; Rocha, Ivan Dias da

    2012-10-01

    This study reviews the literature concerning possible therapeutic approaches for spinal cord injury. Spinal cord injury is a disabling and irreversible condition that has high economic and social costs. There are both primary and secondary mechanisms of damage to the spinal cord. The primary lesion is the mechanical injury itself. The secondary lesion results from one or more biochemical and cellular processes that are triggered by the primary lesion. The frustration of health professionals in treating a severe spinal cord injury was described in 1700 BC in an Egyptian surgical papyrus that was translated by Edwin Smith; the papyrus reported spinal fractures as a "disease that should not be treated." Over the last biological or pharmacological treatment method. Science is unraveling the mechanisms of cell protection and neuroregeneration, but clinically, we only provide supportive care for patients with spinal cord injuries. By combining these treatments, researchers attempt to enhance the functional recovery of patients with spinal cord injuries. Advances in the last decade have allowed us to encourage the development of experimental studies in the field of spinal cord regeneration. The combination of several therapeutic strategies should, at minimum, allow for partial functional recoveries for these patients, which could improve their quality of life. PMID:23070351

  11. Novel unconventional therapeutic approaches to atopic eczema.

    PubMed

    Worm, M; Henz, B M

    2000-01-01

    Atopic eczema is a chronic, recurrent, multifactorial skin disease, and, accordingly, there are numerous therapeutic options for its symptomatic treatment. Conventional medications are however often unsatisfactory for many patients because of adverse effects on long-term use. For this reason, patients often readily welcome unconventional therapeutic approaches. We present here a selected number of such treatment modalities, namely gamma-linolenic acid, Chinese herbal tea, diets eliminating allergens, pseudoallergens, metal salts and sodium, and bioresonance. When stringent scientific criteria are applied in the evaluation of such study results, none of the reviewed alternative treatments provides unequivocal, convincing evidence of its efficacy, even when double-blind, placebo-controlled studies are available. With Chinese herbal tea, potentially serious adverse effects should be considered as well. Any new type of unconventional therapy should thus be thoroughly evaluated and shown to be equal or superior to conventional treatments with regard to both efficacy and tolerability before it is recommended for use in clinical practice. PMID:11096188

  12. Recent advances in cancer stem/progenitor cell research: therapeutic implications for overcoming resistance to the most aggressive cancers.

    PubMed

    Mimeault, M; Hauke, R; Mehta, P P; Batra, S K

    2007-01-01

    Overcoming intrinsic and acquired resistance of cancer stem/progenitor cells to current clinical treatments represents a major challenge in treating and curing the most aggressive and metastatic cancers. This review summarizes recent advances in our understanding of the cellular origin and molecular mechanisms at the basis of cancer initiation and progression as well as the heterogeneity of cancers arising from the malignant transformation of adult stem/progenitor cells. We describe the critical functions provided by several growth factor cascades, including epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), stem cell factor (SCF) receptor (KIT), hedgehog and Wnt/beta-catenin signalling pathways that are frequently activated in cancer progenitor cells and are involved in their sustained growth, survival, invasion and drug resistance. Of therapeutic interest, we also discuss recent progress in the development of new drug combinations to treat the highly aggressive and metastatic cancers including refractory/relapsed leukaemias, melanoma and head and neck, brain, lung, breast, ovary, prostate, pancreas and gastrointestinal cancers which remain incurable in the clinics. The emphasis is on new therapeutic strategies consisting of molecular targeting of distinct oncogenic signalling elements activated in the cancer progenitor cells and their local microenvironment during cancer progression. These new targeted therapies should improve the efficacy of current therapeutic treatments against aggressive cancers, and thereby preventing disease relapse and enhancing patient survival. PMID:17979879

  13. Approaches to preventative and therapeutic HIV vaccines.

    PubMed

    Gray, Glenda E; Laher, Fatima; Lazarus, Erica; Ensoli, Barbara; Corey, Lawrence

    2016-04-01

    Novel strategies are being researched to discover vaccines to prevent and treat HIV-1. Non-efficacious preventative vaccine approaches include bivalent recombinant gp120 alone, HIV gene insertion into an Adenovirus 5 (Ad5) virus vector and the DNA prime/Ad5 boost vaccine regimen. However, the ALVAC-HIV prime/AIDSVAX® B/E gp120 boost regimen showed 31.2% efficacy at 3.5 years, and is being investigated as clade C constructs with an additional boost. Likewise, although multiple therapeutic vaccines have failed in the past, in a non-placebo controlled trial, a Tat vaccine demonstrated immune cell restoration, reduction of immune activation, and reduced HIV-1 DNA viral load. Monoclonal antibodies for passive immunization or treatment show promise, with VRC01 entering advanced clinical trials.

  14. LSCI and Aggression Replacement Training: A Multi-Modal Approach

    ERIC Educational Resources Information Center

    Amendola, A. Mark; Oliver, Robert W.

    2003-01-01

    Life Space Crisis Intervention converts a conflict into a meaningful learning experience for the student by discovering what drives his/her behavior and by defining clear outcome goals. Aggression Replacement Training teaches alternatives to problematic behavior. The collaborative use of ART and LSCI is an effective strategy, specifically in stage…

  15. Solving Adolescent Verbal Aggressions through Transactional Analysis Counseling Approach

    ERIC Educational Resources Information Center

    Netrawati; Furqon; Yusuf, Syamsu; Rusmana, Nandang

    2016-01-01

    This study aimed at helping school counselors in solving issues related to adolescent verbal aggressions through implementing Transactional Analysis (TA) counseling, which was particularly given to the students in public vocational schools (SMKs) in Padang city who were majoring in engineering. Recent phenomena in Padang had revealed that among…

  16. [Therapeutic approaches in autism spectrum disorders].

    PubMed

    Ruggieri, Víctor L; Arberas, Claudia L

    2015-02-25

    Autistic spectrum disorders affect one out of every 68 persons, with a 4:1 dominance in males. Since they are dysfunctions rather than irreversible injuries to the central nervous system, which can be attributed to deficits in the neuronal networks and synaptogenesis and are modifiable thanks to the plasticity of the brain, starting therapy as early as possible is essential for more favourable progress. Very few treatments are backed by solid scientific evidence. We will analyse the therapeutic approaches oriented towards improving autism spectrum disorders which showed a clinical improvement that can be related to neurophysiological or functional changes in the central nervous system. We will classify the behavioural educational treatments and those in the research phase into a hierarchy, highlighting the neurogenetic entities with a high prevalence of autism, in which their pathophysiology and molecular base are known, that attempt to modify the consequences of those alterations by means of pharmacological agents. These entities include fragile X syndrome (GABAergic and metabotropic glutamate receptor inhibitors), tuberous sclerosis (mTOR inhibitors), Phelan-McDermid syndrome and Rett syndrome (insulin-like growth factor 1 inhibitors). Oxytocin, which has been shown to improve social cognition in persons with autism spectrum disorders, is analysed separately.

  17. Childhood sleep disorders: diagnostic and therapeutic approaches.

    PubMed

    Pearl, Phillip L

    2002-03-01

    Pediatric sleep physiology begins with development of the sleep/wake cycle, and the origins of active versus quiet sleep. The 24-hour circadian cycle becomes established at 3 to 6 months. Sleep disorders are rationally approached in pediatrics as age-related. Disorders during infancy commonly include mild, usually self-limited conditions such as sleep-onset association disorder, excessive nighttime feedings, and poor limit-setting. These require behavioral management to avoid long-term deleterious sleep habits. In contrast, other sleep disorders are more ominous, including sudden infant death syndrome (SIDS), central congenital hypoventilation syndrome, and sleep apnea. Childhood is generally the golden age of sleep, with brief latency, high efficiency, and easy awakening. Parasomnias, sometimes stage specific, are manifest here. Adolescents have sleep requirements similar to preteens, posing a challenge for them to adapt to school schedules and lifestyles. Narcolepsy, usually diagnosed in adolescence or early adulthood, is a lifelong sleep disorder that has led to the identification of the hypocretin/orexin neurotransmitter system. This will lead to enhanced understanding of what regulates stage rapid eye movement, and to novel therapeutic advances for hypersomnolence.

  18. Novel Therapeutic Approaches in Multiple System Atrophy

    PubMed Central

    Palma, Jose-Alberto; Kaufmann, Horacio

    2014-01-01

    Multiple system atrophy (MSA) is a sporadic, adult onset, relentlessly, progressive neurodegenerative disease characterized by autonomic abnormalities associated with parkinsonism, cerebellar dysfunction, pyramidal signs, or combinations thereof. Treatments that can halt or reverse the progression of MSA have not yet been identified. MSA is neuropathologically defined by the presence of α-synuclein–containing inclusions, particularly in the cytoplasm of oligodendrocytes (glial cytoplasmic inclusions, GCIs), which are associated with neurodegeneration. The mechanisms by which oligodendrocytic α-synuclein inclusions cause neuronal death in MSA are not completely understood. The MSA neurodegenerative process likely comprise cell-to-cell transmission of α-synuclein in a prion-like manner, α-synuclein aggregation, increased oxidative stress, abnormal expression of tubulin proteins, decreased expression of neurotrophic factors, excitotoxicity and microglial activation, and neuroinflammation. In an attempt to block each of these pathogenic mechanisms, several pharmacologic approaches have been tried and shown to exert neuroprotective effects in transgenic mouse or cellular models of MSA. These include sertraline, paroxetine, and lithium, which hamper arrival of α-synuclein to oligodendroglia; rifampicin, lithium, and non-steroidal anti-inflamatory drugs, which inhibit α-synuclein aggregation in oligodendrocytes; riluzole, rasagiline, fluoxetine and mesenchimal stem cells, which exert neuroprotective actions; and minocycline and intravenous immunoglobulins, which reduce neuroinflammation and microglial activation. These and other potential therapeutic strategies for MSA are summarized in this review. PMID:24928797

  19. Childhood sleep disorders: diagnostic and therapeutic approaches.

    PubMed

    Pearl, Phillip L

    2002-03-01

    Pediatric sleep physiology begins with development of the sleep/wake cycle, and the origins of active versus quiet sleep. The 24-hour circadian cycle becomes established at 3 to 6 months. Sleep disorders are rationally approached in pediatrics as age-related. Disorders during infancy commonly include mild, usually self-limited conditions such as sleep-onset association disorder, excessive nighttime feedings, and poor limit-setting. These require behavioral management to avoid long-term deleterious sleep habits. In contrast, other sleep disorders are more ominous, including sudden infant death syndrome (SIDS), central congenital hypoventilation syndrome, and sleep apnea. Childhood is generally the golden age of sleep, with brief latency, high efficiency, and easy awakening. Parasomnias, sometimes stage specific, are manifest here. Adolescents have sleep requirements similar to preteens, posing a challenge for them to adapt to school schedules and lifestyles. Narcolepsy, usually diagnosed in adolescence or early adulthood, is a lifelong sleep disorder that has led to the identification of the hypocretin/orexin neurotransmitter system. This will lead to enhanced understanding of what regulates stage rapid eye movement, and to novel therapeutic advances for hypersomnolence. PMID:11898482

  20. Epigenetic regulation and therapeutic approaches in cancer.

    PubMed

    Recillas-Targa, Félix

    2008-01-01

    The interdependency between genetic and epigenetic regulatory processes renders cancer therapeutics and translational clinic possible, even though they remain difficult tasks considering all the evidence supporting a central role of progenitor-stem cells as a causative source of cellular transformation. In contrast to genetic alterations, epigenetic processes are potentially reversible allowing a better action of complementary therapeutic compounds. Here I would first describe the plethora of interconnected epigenetic processes and targets to then discuss several therapeutic strategies on the basis of different compounds. I conclude that the advent of new and specific epigenetic target drugs will certainly contribute to better treatments and to the development of predictive protocols in a next future.

  1. A genome-wide approach to children's aggressive behavior: The EAGLE consortium.

    PubMed

    Pappa, Irene; St Pourcain, Beate; Benke, Kelly; Cavadino, Alana; Hakulinen, Christian; Nivard, Michel G; Nolte, Ilja M; Tiesler, Carla M T; Bakermans-Kranenburg, Marian J; Davies, Gareth E; Evans, David M; Geoffroy, Marie-Claude; Grallert, Harald; Groen-Blokhuis, Maria M; Hudziak, James J; Kemp, John P; Keltikangas-Järvinen, Liisa; McMahon, George; Mileva-Seitz, Viara R; Motazedi, Ehsan; Power, Christine; Raitakari, Olli T; Ring, Susan M; Rivadeneira, Fernando; Rodriguez, Alina; Scheet, Paul A; Seppälä, Ilkka; Snieder, Harold; Standl, Marie; Thiering, Elisabeth; Timpson, Nicholas J; Veenstra, René; Velders, Fleur P; Whitehouse, Andrew J O; Smith, George Davey; Heinrich, Joachim; Hypponen, Elina; Lehtimäki, Terho; Middeldorp, Christel M; Oldehinkel, Albertine J; Pennell, Craig E; Boomsma, Dorret I; Tiemeier, Henning

    2016-07-01

    Individual differences in aggressive behavior emerge in early childhood and predict persisting behavioral problems and disorders. Studies of antisocial and severe aggression in adulthood indicate substantial underlying biology. However, little attention has been given to genome-wide approaches of aggressive behavior in children. We analyzed data from nine population-based studies and assessed aggressive behavior using well-validated parent-reported questionnaires. This is the largest sample exploring children's aggressive behavior to date (N = 18,988), with measures in two developmental stages (N = 15,668 early childhood and N = 16,311 middle childhood/early adolescence). First, we estimated the additive genetic variance of children's aggressive behavior based on genome-wide SNP information, using genome-wide complex trait analysis (GCTA). Second, genetic associations within each study were assessed using a quasi-Poisson regression approach, capturing the highly right-skewed distribution of aggressive behavior. Third, we performed meta-analyses of genome-wide associations for both the total age-mixed sample and the two developmental stages. Finally, we performed a gene-based test using the summary statistics of the total sample. GCTA quantified variance tagged by common SNPs (10-54%). The meta-analysis of the total sample identified one region in chromosome 2 (2p12) at near genome-wide significance (top SNP rs11126630, P = 5.30 × 10(-8) ). The separate meta-analyses of the two developmental stages revealed suggestive evidence of association at the same locus. The gene-based analysis indicated association of variation within AVPR1A with aggressive behavior. We conclude that common variants at 2p12 show suggestive evidence for association with childhood aggression. Replication of these initial findings is needed, and further studies should clarify its biological meaning. © 2015 Wiley Periodicals, Inc.

  2. A Positive Approach to the Treatment of Aggressive Brain Injured Clients.

    ERIC Educational Resources Information Center

    Burke, William H.; And Others

    1988-01-01

    A broad spectrum behavior therapy approach was used to treat physical aggression in 5 brain-injured males (ages 18-28). The approach employed high density reinforcement, reinforcer sampling, environmental control, selection of appropriate responses, inconvenience review, self-control training, and self-monitoring. All five subjects showed…

  3. PSYCHOBIOLOGY AND THERAPEUTIC APPROACHES TO ANXIETY STATES

    PubMed Central

    Pradhan, N.

    1986-01-01

    SUMMARY The current psychobiology and the therapeutic principles of anxiety states have been reviewed. The seprohippocampal system probably operates as the organ of match-mismatch comparator. A dysfunction of this internal comparator could possibly be the source of anxiety. There seem to be two distinct psychobiologic models for pain disorder and chronic anxiety state. The therapeutic responses of panic disorder to TCA and MAOI and the response to the chronic anxiety state to benzodiazepines supports the classification ot two distinct syndromes. However different provocative challenge tests have not clearly delineated the role of nor-adrenergic (NF) mechanisms in panic disorder and benzodiazepine receptor theory for chronic anxiety state. Challenge tests with receptor specific pharmacologic agents may reveal the molecular basis of these disorders unlike the tests with non-specific agents like lactate and caffeine. PMID:21927157

  4. Psychobiology and therapeutic approaches to anxiety States.

    PubMed

    Pradhan, N

    1986-04-01

    The current psychobiology and the therapeutic principles of anxiety states have been reviewed. The seprohippocampal system probably operates as the organ of match-mismatch comparator. A dysfunction of this internal comparator could possibly be the source of anxiety. There seem to be two distinct psychobiologic models for pain disorder and chronic anxiety state. The therapeutic responses of panic disorder to TCA and MAOI and the response to the chronic anxiety state to benzodiazepines supports the classification ot two distinct syndromes. However different provocative challenge tests have not clearly delineated the role of nor-adrenergic (NF) mechanisms in panic disorder and benzodiazepine receptor theory for chronic anxiety state. Challenge tests with receptor specific pharmacologic agents may reveal the molecular basis of these disorders unlike the tests with non-specific agents like lactate and caffeine.

  5. Avian cytokines - the natural approach to therapeutics.

    PubMed

    Lowenthal, J W; Lambrecht, B; van den Berg, T P; Andrew, M E; Strom, A D; Bean, A G

    2000-01-01

    While the effective use of antibiotics for the control of human disease has saved countless lives and has increased life expectancy over the past few decades, there are concerns arising from their usage in livestock. The use of antibiotic feed additives in food production animals has been linked to the emergence in the food chain of multiple drug-resistant bacteria that appear impervious to even the most powerful antimicrobial agents. Furthermore, the use of chemical antimicrobials has led to concerns involving environmental contamination and unwanted residues in food products. The imminent banning of antibiotic usage in livestock feed has intensified the search for environmentally-friendly alternative methods to control disease. Cytokines, as natural mediators and regulators of the immune response, offer exciting new alternatives to conventional chemical-based therapeutics. The utilisation of cytokines is becoming more feasible, particularly in poultry, with the recent cloning of a number of avian cytokine genes. Chickens offer an attractive small animal model system with which to study the effectiveness of cytokine therapy in the control of disease in intensive livestock. In this report we will review the status of avian cytokines and focus on our recent studies involving the therapeutic potential of chicken interferon gamma (ChIFN-gamma) as a vaccine adjuvant and a growth promoter. PMID:10717298

  6. Therapeutic approaches for muscle wasting disorders.

    PubMed

    Lynch, Gordon S; Schertzer, Jonathan D; Ryall, James G

    2007-03-01

    Muscle wasting and weakness are common in many disease states and conditions including aging, cancer cachexia, sepsis, denervation, disuse, inactivity, burns, HIV-acquired immunodeficiency syndrome (AIDS), chronic kidney or heart failure, unloading/microgravity, and muscular dystrophies. Although the maintenance of muscle mass is generally regarded as a simple balance between protein synthesis and protein degradation, these mechanisms are not strictly independent, but in fact they are coordinated by a number of different and sometimes complementary signaling pathways. Clearer details are now emerging about these different molecular pathways and the extent to which these pathways contribute to the etiology of various muscle wasting disorders. Therapeutic strategies for attenuating muscle wasting and improving muscle function vary in efficacy. Exercise and nutritional interventions have merit for slowing the rate of muscle atrophy in some muscle wasting conditions, but in most cases they cannot halt or reverse the wasting process. Hormonal and/or other drug strategies that can target key steps in the molecular pathways that regulate protein synthesis and protein degradation are needed. This review describes the signaling pathways that maintain muscle mass and provides an overview of some of the major conditions where muscle wasting and weakness are indicated. The review provides details on some therapeutic strategies that could potentially attenuate muscle atrophy, promote muscle growth, and ultimately improve muscle function. The emphasis is on therapies that can increase muscle mass and improve functional outcomes that will ultimately lead to improvement in the quality of life for affected patients. PMID:17258813

  7. A family therapeutic approach to transgenerational traumatization.

    PubMed

    de Graaf, T K

    1998-01-01

    The phenomenon of transgenerational traumatization has currently become widely recognized and described, although the task of disentangling the underlying interactional mechanisms remains a difficult one. These transgenerational mechanisms were first detected in families of the survivors of the Holocaust, but they may be equally prominent in families of parents who have been traumatized in other ways, for example, as victims of child neglect and abuse, as orphaned children, or during military service. In cases in which parents have themselves been subjected to early parental deprivation, one or more children may become projectively identified with a parent's (posttraumatic) "bad child"-self, whereas the parent him/herself has identified with--enacts the role of--the idealized internal "martyr" parent. A case study is presented describing the individual and family therapeutic treatment of a woman who, as a child, had been traumatically separated from her parents.

  8. Nanotechnology based approaches in cancer therapeutics

    NASA Astrophysics Data System (ADS)

    Kumer Biswas, Amit; Reazul Islam, Md; Sadek Choudhury, Zahid; Mostafa, Asif; Fahim Kadir, Mohammad

    2014-12-01

    The current decades are marked not by the development of new molecules for the cure of various diseases but rather the development of new delivery methods for optimum treatment outcome. Nanomedicine is perhaps playing the biggest role in this concern. Nanomedicine offers numerous advantages over conventional drug delivery approaches and is particularly the hot topic in anticancer research. Nanoparticles (NPs) have many unique criteria that enable them to be incorporated in anticancer therapy. This topical review aims to look at the properties and various forms of NPs and their use in anticancer treatment, recent development of the process of identifying new delivery approaches as well as progress in clinical trials with these newer approaches. Although the outcome of cancer therapy can be increased using nanomedicine there are still many disadvantages of using this approach. We aim to discuss all these issues in this review.

  9. Aggressive cervical neuroblastoma with a rare paraneoplastic syndrome: A therapeutic dilemma

    PubMed Central

    Qureshi, Sajid S.; Bhagat, Monica; Anam, Jay; Vora, Tushar

    2016-01-01

    Neuroblastoma is infrequently associated with paraneoplastic syndromes. Amongst the few, opsomyoclonus (Kinsbourne syndrome) is the most common neurological paraneoplastic syndrome and diarrhea secondary to increased secretion of vasoactive intestinal peptide (Kerner-Morrison syndrome), hormonal paraneoplastic syndrome. Hypothalamic dysfunction (HD) is a rare disorder and its manifestation as a paraneoplastic syndrome of neuroblastoma is uncommonly reported. We present an interesting case of an unrelenting cervical neuroblastoma associated with HD, which posed a therapeutic challenge. PMID:27695211

  10. Aggressive cervical neuroblastoma with a rare paraneoplastic syndrome: A therapeutic dilemma

    PubMed Central

    Qureshi, Sajid S.; Bhagat, Monica; Anam, Jay; Vora, Tushar

    2016-01-01

    Neuroblastoma is infrequently associated with paraneoplastic syndromes. Amongst the few, opsomyoclonus (Kinsbourne syndrome) is the most common neurological paraneoplastic syndrome and diarrhea secondary to increased secretion of vasoactive intestinal peptide (Kerner-Morrison syndrome), hormonal paraneoplastic syndrome. Hypothalamic dysfunction (HD) is a rare disorder and its manifestation as a paraneoplastic syndrome of neuroblastoma is uncommonly reported. We present an interesting case of an unrelenting cervical neuroblastoma associated with HD, which posed a therapeutic challenge.

  11. Therapeutic approaches in patients with inflammatory myopathies.

    PubMed

    Dalakas, Marinos C

    2003-06-01

    Among the group of inflammatory myopathies, dermatomyositis (DM) remains the most treatable subset responding, in the majority of the cases, to steroids, intravenous immunoglobulin (IVIg), or immunosuppressants. Inclusion-body myositis (IBM) remains the most difficult disease to treat; in uncontrolled studies immunosuppressants and steroids have not helped, and controlled trials with IVIg have been disappointing. Polymyositis (PM) is a very uncommon, although still overdiagnosed, disorder and its rarity poses difficulties in performing large-scale therapeutic studies; based on small series, however, PM seems to variably respond to immunotherapeutic interventions. The most consistent problem in the treatment of inflammatory myopathies remains the distinction of true PM from the difficult-to-treat cases of IBM, or from necrotizing myopathies and dystrophic processes where secondary endomysial inflammation may be prominent. The future in the management of PM, DM, and IBM seems promising because of the availability of new agents directed at T-cell activation molecules, cytokines, chemokines, and adhesion receptors. In IBM, the use of such immunomodulatory drugs may be combined with agents that block cytokine-enhancing amyloid or with agents that inhibit the formation and polymerization of amyloid fibrils.

  12. 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…

  13. [CARDIORENAL SYNDROME: DIAGNOSTIC AND THERAPEUTIC APPROACHES].

    PubMed

    Sens, Florence; Pouliquen, Éric; Lemoine, Sandrine; Bonnefoy-Cudraz, Éric; Juillard, Laurent

    2016-06-01

    Kidney dysfunction during congestive heart failure, although frequent, is often neglected. Yet, it represents a life-threatening condition, oven when the kidney dysfunction is moderate. The initial approach involvus strict application of recommendations, cardiologic and nephrologic joined management and close follow-up involving patient's general practitioner. Cases of true diuretics resistance are infrequent and late. Yet, it represents a significant turning point. Mortality is high, with a major individual unpredictability. A multidisciplinary approach is needed, which has to take into account patient's preferences. Several treatments may be discussed and are sometimes joined: cardiac transplantation, water and salt extraction (using ultrafiltration, hemodialysis or peritoneal dialysis), vasoconstrictive drugs, ventricular assistance devices and palliative care. Water and salt extraction techniques seem to space out hospitalizations and to provide symptomatic relief even though no benefit on patient survival has been demonstrated to date. The need for randomized clinical trials is mandatory. PMID:27538313

  14. Synthetic lethal approaches exploiting DNA damage in aggressive myeloma

    PubMed Central

    Cottini, Francesca; Hideshima, Teru; Suzuki, Rikio; Tai, Yu-Tzu; Bianchini, Giampaolo; Richardson, Paul G.; Anderson, Kenneth C.; Tonon, Giovanni

    2015-01-01

    Ongoing DNA damage is a common feature of epithelial cancers. Here we show that tumor cells derived from multiple myeloma (MM), a disease of clonal plasma cells, demonstrate DNA replicative stress leading to DNA damage. We identified a poor prognosis subset of MM with extensive chromosomal instability and replicative stress which rely on ATR to compensate for DNA replicative stress; conversely, silencing of ATR or treatment with a specific ATR inhibitor triggers MM cell apoptosis. We show that oncogenes such as MYC induce DNA damage in MM cells not only by increased replicative stress, but also via increased oxidative stress, and that ROS-inducer piperlongumine triggers further DNA damage and apoptosis. Importantly, ATR inhibition combined with piperlongumine triggers synergistic MM cytotoxicity. This synthetic lethal approach, enhancing oxidative stress while concomitantly blocking replicative stress response, provides a novel combination targeted therapy to address an unmet medical need in this subset of MM. PMID:26080835

  15. [Rare malignant tumors of the ovaries in adolescents--clinical aspects in deciding therapeutic aggressiveness].

    PubMed

    Schröder, W; Bau, O

    1990-01-01

    4 patients below the age of 20 years have been treated for a malignant tumor of the ovary during the period November 1, 1984 until April 30, 1988. Dysgerminoma was the diagnosis in two cases, as the third patient suffered from a bilateral malignant teratoma. Burkitt's Lymphoma involved both ovaries primarily in an 17-year-old girl. Retrospectively we analyzed diagnosis, therapy and clinical course of these young patients. Regarding the different histological types of the tumors that have been found we discuss critically current recommendations in therapeutic managements referring chemotherapy and/or radiotherapy. Defined conditions provided surgical treatment, that preserves fertility in early stages of malignant germ cell tumors of adolescent women, may be justified, especially for dysgerminomas. A real benefit relate to survival and quality of life by using chemotherapeutic agents can only be expected, if all prognostic factors are regarded.

  16. A therapeutic approach for senile dementias: neuroangiogenesis.

    PubMed

    Ambrose, Charles T

    2015-01-01

    Alzheimer's disease (AD) and related senile dementias (SDs) represent a growing medical and economic crisis in this country. Apart from cautioning persons about risk factors, no practical, effective therapy is currently available. Much of the recent research in AD has been based on the amyloid cascade theory. Another approach assumes a vascular basis for SDs. This paper presents evidence from a score of studies that cerebral capillary density (CCD) declines during old age in animals and people as well as in AD. Neuroangiogenic (NAG) factors initiate and maintain capillaries in the brain. Thus a waning level of these factors and the ensuing declining CCD would lead to local areas of reduced oxygen and glucose and result in impaired synaptic and neuronal function. The NAG hypothesis developed here proposes that the age-linked decline in CCD is a terminal condition in SDs, including many cases of AD. This age-linked decline is independent of any other of the various pathologies proposed as causing AD and listed in Table 1. Waning NAG factors would render the SDs a deficiency condition, somewhat like falling androgen levels in aging males. A logical corollary of this hypothesis is that chronic replacement therapy with recombinant forms of NAG factors may arrest the age-linked decline in CCD and prevent further loss of memory and mental deterioration. A transnasal route of therapy seems the most practical one for general use in the large aging populations. PMID:25061056

  17. Chemical approaches to stem cell biology and therapeutics

    PubMed Central

    Li, Wenlin; Li, Ke; Wei, Wanguo; Ding, Sheng

    2013-01-01

    SUMMARY Small molecules that modulate stem cell fate and function offer significant opportunities that will allow the full realization of the therapeutic potential of stem cells. Rational design and screening for small molecules have identified useful compounds to probe fundamental mechanisms of stem cell self-renewal, differentiation, and reprogramming, and have facilitated the development of cell-based therapies and therapeutic drugs targeting endogenous stem and progenitor cells for repair and regeneration. Here, we will discuss recent scientific and therapeutic progress, as well as new perspectives and future challenges for using chemical approaches in stem cell biology and regenerative medicine. PMID:24012368

  18. Recent advances in innovative therapeutic approaches for Duchenne muscular dystrophy: from discovery to clinical trials

    PubMed Central

    Shimizu-Motohashi, Yuko; Miyatake, Shouta; Komaki, Hirofumi; Takeda, Shin’ichi; Aoki, Yoshitsugu

    2016-01-01

    Duchenne muscular dystrophy (DMD) is an X-linked progressive degenerative muscle disorder caused by the absence of dystrophin. There is no curative therapy, although innovative therapeutic approaches have been aggressively investigated over recent years. Currently, the international clinical trial registry platform for this disease has been constructed and clinical trials for innovative therapeutic approaches are underway. Among these, exon skipping and read-through of nonsense mutations are in the most advanced stages, with exon skipping theoretically applicable to a larger number of patients. To date, exon skipping that targets exons 51, 44, 45, and 53 is being globally investigated including in USA, EU, and Japan. The latest announcement from Japan was made, demonstrating successful dystrophin production in muscles of patients with DMD after treating with exon 53 skipping antisense oligonucleotides (ASOs). However, the innovative therapeutic approaches have demonstrated limited efficacy. To address this issue in exon skipping, studies to unveil the mechanism underlying gymnotic delivery of ASO uptake in living cells have been conducted in an effort to improve in vivo delivery. Further, establishing the infrastructures to integrate multi-institutional clinical trials are needed to facilitate the development of successful therapies for DMD, which ultimately is applicable to other myopathies and neurodegenerative diseases, including spinal muscular atrophy and motor neuron diseases. PMID:27398133

  19. Recent advances in innovative therapeutic approaches for Duchenne muscular dystrophy: from discovery to clinical trials.

    PubMed

    Shimizu-Motohashi, Yuko; Miyatake, Shouta; Komaki, Hirofumi; Takeda, Shin'ichi; Aoki, Yoshitsugu

    2016-01-01

    Duchenne muscular dystrophy (DMD) is an X-linked progressive degenerative muscle disorder caused by the absence of dystrophin. There is no curative therapy, although innovative therapeutic approaches have been aggressively investigated over recent years. Currently, the international clinical trial registry platform for this disease has been constructed and clinical trials for innovative therapeutic approaches are underway. Among these, exon skipping and read-through of nonsense mutations are in the most advanced stages, with exon skipping theoretically applicable to a larger number of patients. To date, exon skipping that targets exons 51, 44, 45, and 53 is being globally investigated including in USA, EU, and Japan. The latest announcement from Japan was made, demonstrating successful dystrophin production in muscles of patients with DMD after treating with exon 53 skipping antisense oligonucleotides (ASOs). However, the innovative therapeutic approaches have demonstrated limited efficacy. To address this issue in exon skipping, studies to unveil the mechanism underlying gymnotic delivery of ASO uptake in living cells have been conducted in an effort to improve in vivo delivery. Further, establishing the infrastructures to integrate multi-institutional clinical trials are needed to facilitate the development of successful therapies for DMD, which ultimately is applicable to other myopathies and neurodegenerative diseases, including spinal muscular atrophy and motor neuron diseases.

  20. New trends in breast cancer surgery: a therapeutic approach increasingly efficacy and respectful of the patient

    PubMed Central

    FRANCESCHINI, G.; SANCHEZ, A. MARTIN; DI LEONE, A.; MAGNO, S.; MOSCHELLA, F.; ACCETTA, C.; MASETTI, R.

    2015-01-01

    The surgical management of breast cancer has undergone continuous and profound changes over the last 40 years. The evolution from aggressive and mutilating treatment to conservative approach has been long, but constant, despite the controversies that appeared every time a new procedure came to light. Today, the aesthetic satisfaction of breast cancer patients coupled with the oncological safety is the goal of the modern breast surgeon. Breast-conserving surgery with adjuvant radiotherapy is considered the gold standard approach for patients with early stage breast cancer and the recent introduction of “oncoplastic techniques” has furtherly increased the use of breast-conserving procedures. Mastectomy remains a valid surgical alternative in selected cases and is usually associated with immediate reconstructive procedures. New surgical procedures called “conservative mastectomies” are emerging as techniques that combine oncological safety and cosmesis by entirely removing the breast parenchyma sparing the breast skin and nipple-areola complex. Staging of the axilla has also gradually evolved toward less aggressive approaches with the adoption of sentinel node biopsy and new therapeutic strategies are emerging in patients with a pathological positivity in sentinel lymph node biopsy. The present work will highlight the new surgical treatment options increasingly efficacy and respectful of breast cancer patients. PMID:26712068

  1. Childhood Maltreatment and the Development of Relational and Physical Aggression: The Importance of a Gender-Informed Approach

    ERIC Educational Resources Information Center

    Cullerton-Sen, Crystal; Cassidy, Adam R.; Murray-Close, Dianna; Cicchetti, Dante; Crick, Nicki R.; Rogosch, Fred A.

    2008-01-01

    This investigation examined the associations between maltreatment and aggression using a gender-informed approach. Peer ratings, peer nominations, and counselor reports of aggression were collected on 211 maltreated and 199 nonmaltreated inner-city youth (M age = 9.9 years) during a summer day camp. Maltreatment was associated with aggressive…

  2. Therapeutic Recreation in the Community: An Inclusive Approach. Second Edition

    ERIC Educational Resources Information Center

    Carter, Marcia Jean; LeConey, Stephen P.

    2004-01-01

    The second edition of Therapeutic Recreation in the Community: An Inclusive Approach reflects the changing and evolving nature of recreation and health care services. A number of social, economic, and political directives and technological advancements have fostered recreation in the community for all individuals. Due in part to a rising awareness…

  3. Intracellular defenses against HIV, viral evasion and novel therapeutic approaches.

    PubMed

    Lever, Robert A; Lever, Andrew M L

    2011-06-01

    Human immunodeficiency virus (HIV), the causative agent of AIDS, is a retrovirus. It is estimated that, while in the cell, it interacts with almost 10% of cellular proteins. Several of these have evolved to protect the cell from infection with retroviruses and are known as "restriction factors". Restriction factors tell us much about how the virus functions and open up new paradigms for exploring novel antiviral therapeutics. This article gives an update on the three best studied restriction factors, their putative mechanisms of action and how the virus has overcome their effects, together with an indication of novel therapeutic approaches based on this knowledge.

  4. Gene Therapy and Virotherapy: Novel Therapeutic Approaches for Brain Tumors

    PubMed Central

    Kroeger, Kurt M.; Ghulam Muhammad, A.K.M.; Baker, Gregory J.; Assi, Hikmat; Wibowo, Mia K.; Xiong, Weidong; Yagiz, Kader; Candolfi, Marianela; Lowenstein, Pedro R.; Castro, Maria G.

    2010-01-01

    Glioblastoma multiforme (GBM) is a deadly primary brain tumor in adults, with a median survival of ~12–18 months post-diagnosis. Despite recent advances in conventional therapeutic approaches, only modest improvements in median survival have been achieved; GBM usually recurs within 12 months post-resection, with poor prognosis. Thus, novel therapeutic strategies to target and kill GBM cells are desperately needed. Our group and others are pursuing virotherapy and gene therapy strategies for the treatment of GBM. In this review, we will discuss various virotherapy and gene therapy approaches for GBM currently under preclinical and clinical evaluation including direct or conditional cytotoxic, and/or immunostimulatory approaches. We also discuss cutting-edge technologies for drug/gene delivery and targeting brain tumors, including the use of stem cells as delivery platforms, the use of targeted immunotoxins, and the therapeutic potential of using GBM microvesicles to deliver therapeutic siRNAs or virotherapies. Finally, various animal models available to test novel GBM therapies are discussed. PMID:21034670

  5. Therapeutic opportunities involving cellular oncogenes: novel approaches fostered by biotechnology.

    PubMed

    Huber, B E

    1989-01-01

    Biotechnological processes are having a major impact on many industrial sectors, including the pharmaceutical industry. The contributions of recombinant DNA and hybridoma technologies to modern therapeutics include production of natural and unnatural peptides, subunit vaccines, monoclonal antibodies and nucleic acid hybridization probes for in vitro and in vivo diagnostics and biological imaging, therapeutic monoclonal antibodies as tissue-specific delivery systems or as agents to confer passive immunity, production of therapeutic targets for rational drug design, and the use of cloned enzymes as stereospecific catalysts in large-scale production of small medicinal molecules. Biotechnological advances have led to the identification of a discrete set of genes, oncogenes, which may be essential contributing factors for a great variety and number of human cancers. In addition, biotechnological innovations are fostering the exploitation of oncogenes as novel therapeutic targets for cancer diagnosis, prognosis, and treatment. Because oncogenes are activated in transformation by either qualitative or quantitative mechanisms, however, different biotechnology-based therapeutic approaches are required for each class.

  6. A New Approach that Eliminates Handling for Studying Aggression and the "Loser" Effect in Drosophila melanogaster.

    PubMed

    Trannoy, Severine; Chowdhury, Budhaditya; Kravitz, Edward A

    2015-01-01

    Aggressive behavior in Drosophila melanogaster is composed of the sequential expression of stereotypical behavioral patterns (for analysis see (1)). This complex behavior is influenced by genetic, hormonal and environmental factors. As in many organisms, previous fighting experience influences the fighting strategy of flies and the outcome of later contests: losing a fight increases the probability of losing later contests, revealing "loser" effects that likely involve learning and memory (2-4). The learning and memory that accompanies expression of complex social behaviors like aggression, is sensitive to pre-test handling of animals (5,6). Many experimental procedures are used in different laboratories to study aggression (7-9), however, no routinely used protocol that excludes handling of flies is currently available. Here, we report a new behavioral apparatus that eliminates handling of flies, using instead their innate negative geotactic responses to move animals into or out of fighting chambers. In this protocol, small circular fight arenas containing a food cup are divided into two equal halves by a removable plastic slider prior to introduction of flies. Flies enter chambers from their home isolation vials via sliding chamber doors and geotaxis. Upon removal of plastic sliders, flies are free to interact. After specified time periods, flies are separated again by sliders for subsequent experimentation. All of this is done easily without handling of individual flies. This apparatus offers a novel approach to study aggression and the associated learning and memory, including the formation of "loser" effects in fly fights. In addition, this new general-purpose behavioral apparatus can be employed to study other social behaviors of flies and should, in general, be of interest for investigating experience-related changes in fundamental behavioral processes.

  7. Blastic plasmacytoid dendritic cell neoplasm: diagnostic criteria and therapeutical approaches.

    PubMed

    Pagano, Livio; Valentini, Caterina G; Grammatico, Sara; Pulsoni, Alessandro

    2016-07-01

    Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare haematological malignancy derived from the precursors of plamacytoid dendritic cells, with an aggressive clinical course and high frequency of cutaneous and bone marrow involvement. Neoplastic cells express CD4, CD43 (also termed SPN), CD45RA and CD56 (also termed NCAM1), as well as the plasmacytoid dendritic cell-associated antigens CD123 (also termed IL3RA), BDCA-2 (also termed CD303, CLEC4E) TCL1 and CTLA1 (also termed GZMB). The median survival is only a few months as the tumour exhibits a progressive course despite initial response to chemotherapy. The best modality of treatment remains to be defined. Generally, patients receive acute leukaemia-like induction, according to acute myeloid leukaemia (AML)-type or acute lymphoid leukaemia (ALL)-type regimens. The frequent neuromeningeal involvement indicates systematic pre-emptive intrathecal chemotherapy in addition to intensive chemotherapy. Allogeneic haematopoietic stem cell transplantation (HSCT), particularly when performed in first remission, may improve the survival. Preliminary data suggest a potential role for immunomodulatory agents and novel targeted drugs. Herein epidemiology, clinical manifestations, diagnosis and management of BPDCN will be presented. In detail, this review focuses on the therapeutic aspects of BPDCN, proposing a treatment algorithm for the management of the disease, including induction chemotherapy, allogeneic HSCT and intrathecal prophylaxis at different steps of treatment, according to compliance, biological and clinical characteristics of patients. PMID:27264021

  8. Therapeutic approach to IgG4-related disease

    PubMed Central

    Brito-Zerón, Pilar; Kostov, Belchin; Bosch, Xavier; Acar-Denizli, Nihan; Ramos-Casals, Manuel; Stone, John H.

    2016-01-01

    Abstract To review the reported evidence on the therapeutic management of IgG4-related disease (IgG4-RD) in clinical practice. A systematic search of the literature was conducted. The primary outcome measured was the rate of efficacy of first-line therapeutic approaches. Secondary outcomes measured included the rate of disease relapse, the outcome of untreated patients, the rate of patients without drug therapy at the end of follow-up, the rate of side effects, and mortality. The MOOSE, AHRQ, STROBE, and GRACE recommendations/statements were followed. The results of the systematic search strategy yielded 62 studies that included a total of 3034 patients. Complete information about first-line therapeutic regimens was detailed in 1952 patients, including glucocorticoid-based regimens in 1437 (74%), drug-free regimens in 213 (11%), and other therapies in 38 (2%). No therapy (wait and see management) was reported in 264 (13%) patients. The efficacy of monotherapy with glucocorticoids was specified in 1220 patients, of whom 97% had a therapeutic response. Relapses, however, were reported in 464/1395 (33%) patients despite typically short follow-up periods. Therapeutic efficacy was reported in 219/231 (95%) of relapses treated with glucocorticoids, 56/69 (81%) of those treated with azathioprine, 16/22 (72%) of those treated with other immunosuppressive agents, and in the 9 cases treated with rituximab (100%). In 14 studies, the authors detailed the outcome of 159/246 patients with wait-and-see management; spontaneous improvement or resolution was reported in 68 (43%) cases. Wide heterogeneity was observed with respect to the first-line therapeutic approaches used for the different organ-specific disease subsets, including significant differences in the mean dose of glucocorticoids used. Nearly 70% of reported IgG4-RD patients are treated with oral glucocorticoids in monotherapy. However, the therapeutic management is heavily influenced by geographical, epidemiological

  9. MicroRNA Targeted Therapeutic Approach for Pancreatic Cancer

    PubMed Central

    Li, Yiwei; Sarkar, Fazlul H.

    2016-01-01

    Pancreatic cancer remains the fourth leading cause of cancer-related death in the US and is expected to be the second leading cause of cancer-related death by 2030. Therefore, it is important to better understand the molecular pathogenesis, phenotypes and features of pancreatic cancer in order to design novel molecularly targeted therapies for achieving better therapeutic outcome of patients with pancreatic cancer. Recently, the roles of microRNAs (miRNAs) in the development and progression of pancreatic cancer became a hot topic in the scientific community of pancreatic cancer research. By conducting miRNA expression profiling, the aberrant expression of miRNAs was revealed in the serum and in cancer tissues from patients with pancreatic cancer. These aberrantly expressed miRNAs are critically correlated with the disease stage, drug resistance, and survival of pancreatic cancer patients. Hence, targeting these tiny molecules, the specific miRNAs, could provide an efficient and optimal approach in the therapy of pancreatic cancer. Indeed, the pre-clinical and in vivo experiments showed that nanoparticle delivery of synthetic oligonucleotides or treatment with natural agents could be useful to modulate the expression of miRNAs and thereby inhibit pancreatic cancer growth and progression, suggesting that targeting miRNAs combined with conventional anti-cancer therapeutics could be a novel therapeutic strategy for increasing drug sensitivity and achieving better therapeutic outcome of patients diagnosed with pancreatic cancer. PMID:26929739

  10. ERα-Negative and Triple Negative Breast Cancer: Molecular Features and Potential Therapeutic Approaches

    PubMed Central

    Chen, Jin-Qiang; Russo, Jose

    2010-01-01

    Triple negative breast cancer (TNBC) is a type of aggressive breast cancer lacking the expression of estrogen receptors (ER), progesterone receptors (PR) and human epidermal growth factor receptor-2 (HER-2). TNBC patients account for approximately 15% of total breast cancer patients and are more prevalent among young African, African-American and Latino women patients. The currently available ER-targeted and Her-2-based therapies are not effective for treating TNBC. Recent studies have revealed a number of novel features of TNBC. In the present work, we comprehensively addressed these features and discussed potential therapeutic approaches based on these features for TNBC, with particular focus on: 1) the pathological features of TNBC/basal-like breast cancer; 2) E2/ERβ – mediated signaling pathways; 3) G-protein coupling receptor-30/epithelial growth factor receptor (GPCR-30/EGFR) signaling pathway; 4) interactions of ERβ with breast cancer 1/2 (BRCA1/2); 5) chemokine CXCL8 and related chemokines; 6) altered microRNA signatures and suppression of ERα expression/ERα-signaling by micro-RNAs; 7) altered expression of several pro-oncongenic and tumor suppressor proteins; and 8) genotoxic effects caused by oxidative estrogen metabolites. Gaining better insights into these molecular pathways in TNBC may lead to identification of novel biomarkers and targets for development of diagnostic and therapeutic approaches for prevention and treatment of TNBC. PMID:19527773

  11. Therapeutic approaches to age-associated neurocognitive disorders

    PubMed Central

    O'Hara, Ruth; Derouesné, Christian; Fountoulakis, Konstantinos N.; Yesavage, Jerome A.

    2001-01-01

    The United Nations projects that the number of individuals with dementia in developed countries alone will be approximately 36,7 million by the year 2050. International recognition of the significant emotional and economic burden of Alzheimer's disease has been matched by a dramatic increase in the development of pharmacological and nonpharmacological approaches to this illness in the past decade. Changing demographics have underscored the necessity to develop similar approaches for the remediation of the cognitive impairment associated with more benign syndromes, such as mild cognitive impairment (MCI) and age-associated cognitive decline (AACD). The present article aims to provide an overview of the most current therapeutic approaches to age-associated neurocognitive disorders. Additionally, it discusses the conceptual and methodological issues that surround the design, implementation, and interpretation of such approaches. PMID:22033831

  12. CONCEPT ANALYSIS: AGGRESSION

    PubMed Central

    Liu, Jianghong

    2006-01-01

    The concept of aggression is important to nursing because further knowledge of aggression can help generate a better theoretical model to drive more effective intervention and prevention approaches. This paper outlines a conceptual analysis of aggression. First, the different forms of aggression are reviewed, including the clinical classification and the stimulus-based classification. Then the manifestations and measurement of aggression are described. Finally, the causes and consequences of aggression are outlined. It is argued that a better understanding of aggression and the causal factors underlying it are essential for learning how to prevent negative aggression in the future. PMID:15371137

  13. Therapeutic approaches to preventing cell death in Huntington disease

    PubMed Central

    Kaplan, Anna; Stockwell, Brent R.

    2012-01-01

    Neurodegenerative diseases affect the lives of millions of patients and their families. Due to the complexity of these diseases and our limited understanding of their pathogenesis, the design of therapeutic agents that can effectively treat these diseases has been challenging. Huntington disease (HD) is one of several neurological disorders with few therapeutic options. HD, like numerous other neurodegenerative diseases, involves extensive neuronal cell loss. One potential strategy to combat HD and other neurodegenerative disorders is to intervene in the execution of neuronal cell death. Inhibiting neuronal cell death pathways may slow the development of neurodegeneration. However, discovering small molecule inhibitors of neuronal cell death remains a significant challenge. Here, we review candidate therapeutic targets controlling cell death mechanisms that have been the focus of research in HD, as well as an emerging strategy that has been applied to developing small molecule inhibitors—fragment-based drug discovery (FBDD). FBDD has been successfully used in both industry and academia to identify selective and potent small molecule inhibitors, with a focus on challenging proteins that are not amenable to traditional high-throughput screening approaches. FBDD has been used to generate potent leads, pre-clinical candidates, and has led to the development of an FDA approved drug. This approach can be valuable for identifying modulators of cell-death-regulating proteins; such compounds may prove to be the key to halting the progression of HD and other neurodegenerative disorders. PMID:22967354

  14. Therapeutic approaches to preventing cell death in Huntington disease.

    PubMed

    Kaplan, Anna; Stockwell, Brent R

    2012-12-01

    Neurodegenerative diseases affect the lives of millions of patients and their families. Due to the complexity of these diseases and our limited understanding of their pathogenesis, the design of therapeutic agents that can effectively treat these diseases has been challenging. Huntington disease (HD) is one of several neurological disorders with few therapeutic options. HD, like numerous other neurodegenerative diseases, involves extensive neuronal cell loss. One potential strategy to combat HD and other neurodegenerative disorders is to intervene in the execution of neuronal cell death. Inhibiting neuronal cell death pathways may slow the development of neurodegeneration. However, discovering small molecule inhibitors of neuronal cell death remains a significant challenge. Here, we review candidate therapeutic targets controlling cell death mechanisms that have been the focus of research in HD, as well as an emerging strategy that has been applied to developing small molecule inhibitors-fragment-based drug discovery (FBDD). FBDD has been successfully used in both industry and academia to identify selective and potent small molecule inhibitors, with a focus on challenging proteins that are not amenable to traditional high-throughput screening approaches. FBDD has been used to generate potent leads, pre-clinical candidates, and has led to the development of an FDA approved drug. This approach can be valuable for identifying modulators of cell-death-regulating proteins; such compounds may prove to be the key to halting the progression of HD and other neurodegenerative disorders. PMID:22967354

  15. siRNA Genome Screening Approaches to Therapeutic Drug Repositioning

    PubMed Central

    Perwitasari, Olivia; Bakre, Abhijeet; Tompkins, S. Mark; Tripp, Ralph A.

    2013-01-01

    Bridging high-throughput screening (HTS) with RNA interference (RNAi) has allowed for rapid discovery of the molecular basis of many diseases, and identification of potential pathways for developing safe and effective treatments. These features have identified new host gene targets for existing drugs paving the pathway for therapeutic drug repositioning. Using RNAi to discover and help validate new drug targets has also provided a means to filter and prioritize promising therapeutics. This review summarizes these approaches across a spectrum of methods and targets in the host response to pathogens. Particular attention is given to the utility of drug repurposing utilizing the promiscuous nature of some drugs that affect multiple molecules or pathways, and how these biological pathways can be targeted to regulate disease outcome. PMID:24275945

  16. New therapeutic approaches for treatment of tularaemia: a review

    PubMed Central

    Boisset, Sandrine; Caspar, Yvan; Sutera, Vivien; Maurin, Max

    2014-01-01

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

  17. New therapeutic approaches for treatment of tularaemia: a review.

    PubMed

    Boisset, Sandrine; Caspar, Yvan; Sutera, Vivien; Maurin, Max

    2014-01-01

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

  18. New therapeutical approaches for non muscle invasive bladder cancer.

    PubMed

    Volpe, Andrea; Racioppi, Marco; Sacco, Emilio; Bongiovanni, Luca; D'Agostino, Daniele; Cappa, Emanuele; Pinto, Francesco; Gardi, Mario; Totaro, Angelo; Bassi, PierFrancesco

    2008-12-01

    Non muscle invasive bladder cancer, given its high tendency to recur, coupled with an ever-present possibility to progress to potentially life-threatening muscle-invasive disease, remains a challenging clinical problem. Optimal management begins with early detection and accurate risk assessment through careful attention to clinical and histology features. Prevention of recurrence requires the sequential application of tools to completely remove all visible disease, avert reimplantation during surgical resection, ablate microscopic foci and prevent the emergence of new primary tumors amidst a field of carcinogen-exposed urothelium. Previously standard adjunctive intravesical chemo-immunotherapies are obtaining new vitality as optimization strategies, while new drugs and rational drug combinations provide the potential for improved efficacy with reduced toxicity. Novel therapeutic modalities under investigation include activation of the host immune system and enhancement of the cytotoxic effects of chemotherapeutic agents. New technological advances such as microwave chemothermotherapy offer further hope for better outcomes even for disease previously refractory to conservative measures. While much of this research is in the preclinical phase, the encouraging results of many of the studies discussed here suggest that testing in human trials should follow in the coming years. Yet despite these advances, aggressive surgical management involving bladder removal continues to be an indispensable life-saving maneuver that must be considered in all high-risk cases that fail to promptly respond to other measures. Although great strides continue to be made each year in the diagnosis and management of bladder cancer considerably more work needs to be done in order to improve the lives of our patients with this disease.

  19. Computational systems biology approaches to anti-angiogenic cancer therapeutics.

    PubMed

    Finley, Stacey D; Chu, Liang-Hui; Popel, Aleksander S

    2015-02-01

    Angiogenesis is an exquisitely regulated process that is required for physiological processes and is also important in numerous diseases. Tumors utilize angiogenesis to generate the vascular network needed to supply the cancer cells with nutrients and oxygen, and many cancer drugs aim to inhibit tumor angiogenesis. Anti-angiogenic therapy involves inhibiting multiple cell types, molecular targets, and intracellular signaling pathways. Computational tools are useful in guiding treatment strategies, predicting the response to treatment, and identifying new targets of interest. Here, we describe progress that has been made in applying mathematical modeling and bioinformatics approaches to study anti-angiogenic therapeutics in cancer.

  20. A Systems Genetics Approach Identifies CXCL14, ITGAX, and LPCAT2 as Novel Aggressive Prostate Cancer Susceptibility Genes

    PubMed Central

    Andreas, Jonathan; Patel, Shashank J.; Zhang, Suiyuan; Chines, Peter; Elkahloun, Abdel; Chandrasekharappa, Settara; Gutkind, J. Silvio; Molinolo, Alfredo A.; Crawford, Nigel P. S.

    2014-01-01

    Although prostate cancer typically runs an indolent course, a subset of men develop aggressive, fatal forms of this disease. We hypothesize that germline variation modulates susceptibility to aggressive prostate cancer. The goal of this work is to identify susceptibility genes using the C57BL/6-Tg(TRAMP)8247Ng/J (TRAMP) mouse model of neuroendocrine prostate cancer. Quantitative trait locus (QTL) mapping was performed in transgene-positive (TRAMPxNOD/ShiLtJ) F2 intercross males (n = 228), which facilitated identification of 11 loci associated with aggressive disease development. Microarray data derived from 126 (TRAMPxNOD/ShiLtJ) F2 primary tumors were used to prioritize candidate genes within QTLs, with candidate genes deemed as being high priority when possessing both high levels of expression-trait correlation and a proximal expression QTL. This process enabled the identification of 35 aggressive prostate tumorigenesis candidate genes. The role of these genes in aggressive forms of human prostate cancer was investigated using two concurrent approaches. First, logistic regression analysis in two human prostate gene expression datasets revealed that expression levels of five genes (CXCL14, ITGAX, LPCAT2, RNASEH2A, and ZNF322) were positively correlated with aggressive prostate cancer and two genes (CCL19 and HIST1H1A) were protective for aggressive prostate cancer. Higher than average levels of expression of the five genes that were positively correlated with aggressive disease were consistently associated with patient outcome in both human prostate cancer tumor gene expression datasets. Second, three of these five genes (CXCL14, ITGAX, and LPCAT2) harbored polymorphisms associated with aggressive disease development in a human GWAS cohort consisting of 1,172 prostate cancer patients. This study is the first example of using a systems genetics approach to successfully identify novel susceptibility genes for aggressive prostate cancer. Such approaches will

  1. Understanding Neuropathic Corneal Pain--Gaps and Current Therapeutic Approaches.

    PubMed

    Goyal, Sunali; Hamrah, Pedram

    2016-01-01

    The richly innervated corneal tissue is one of the most powerful pain generators in the body. Corneal neuropathic pain results from dysfunctional nerves causing perceptions such as burning, stinging, eye-ache, and pain. Various inflammatory diseases, neurological diseases, and surgical interventions can be the underlying cause of corneal neuropathic pain. Recent efforts have been made by the scientific community to elucidate the pathophysiology and neurobiology of pain resulting from initially protective physiological reflexes, to a more persistent chronic state. The goal of this clinical review is to briefly summarize the pathophysiology of neuropathic corneal pain, describe how to systematically approach the diagnosis of these patients, and finally summarizing our experience with current therapeutic approaches for the treatment of corneal neuropathic pain.

  2. Cardiac Sarcoidosis: Clinical Manifestations, Imaging Characteristics, and Therapeutic Approach

    PubMed Central

    Houston, Brian A; Mukherjee, Monica

    2014-01-01

    Sarcoidosis is a multi-system disease pathologically characterized by the accumulation of T-lymphocytes and mononuclear phagocytes into the sine qua non pathologic structure of the noncaseating granuloma. Cardiac involvement remains a key source of morbidity and mortality in sarcoidosis. Definitive diagnosis of cardiac sarcoidosis, particularly early enough in the disease course to provide maximal therapeutic impact, has proven a particularly difficult challenge. However, major advancements in imaging techniques have been made in the last decade. Advancements in imaging modalities including echocardiography, nuclear spectroscopy, positron emission tomography, and magnetic resonance imaging all have improved our ability to diagnose cardiac sarcoidosis, and in many cases to provide a more accurate prognosis and thus targeted therapy. Likewise, therapy for cardiac sarcoidosis is beginning to advance past a “steroids-only” approach, as novel immunosuppressant agents provide effective steroid-sparing options. The following focused review will provide a brief discussion of the epidemiology and clinical presentation of cardiac sarcoidosis followed by a discussion of up-to-date imaging modalities employed in its assessment and therapeutic approaches. PMID:25452702

  3. Therapeutic Approaches to the Challenge of Neuronal Ceroid Lipofuscinoses

    PubMed Central

    Kohan, R.; Cismondi, I.A.; Oller-Ramirez, A.M.; Guelbert, N.; Anzolini, V. Tapia; Alonso, G.; Mole, S.E.; de Kremer, R. Dodelson; de Halac, I. Noher

    2013-01-01

    The Neuronal Ceroid Lipofuscinoses (NCLs) are lysosomal storage diseases (LSDs) affecting the central nervous system (CNS), with generally with recessive inheritance. They are characterized by pathological lipofuscin-like material accumulating in cells. The clinical phenotypes at all onset ages show progressive loss of vision, decreasing cognitive and motor skills, epileptic seizures and premature death, with dementia without visual loss prominent in the rarer adult forms. Eight causal genes, CLN10/CTSD, CLN1/PPT1, CLN2/TPP1, CLN3, CLN5, CLN6, CLN7/MFSD8, CLN8, with more than 269 mutations and 49 polymorphisms (http://www.ucl.ac.uk/ncl) have been described. Other NCL genes are hypothesized, including CLN4 and CLN9; CLCN6, CLCN7 and possibly SGSH are under study. Some therapeutic strategies applied to other LSDs with significant systemic involvement would not be effective in NCLs due to the necessity of passing the blood brain barrier to prevent the neurodegeneration, repair or restore the CNS functionality. There are therapies for the NCLs currently at preclinical stages and under phase 1 trials to establish safety in affected children. These approaches involve enzyme replacement, gene therapy, neural stem cell replacement, immune therapy and other pharmacological approaches. In the next decade, progress in the understanding of the natural history and the biochemical and molecular cascade of events relevant to the pathogenesis of these diseases in humans and animal models will be required to achieve significant therapeutic advances. PMID:21235444

  4. Cancer Terminator Viruses and Approaches for Enhancing Therapeutic Outcomes

    PubMed Central

    Das, Swadesh K.; Sarkar, Siddik; Dash, Rupesh; Dent, Paul; Wang, Xiang-Yang; Sarkar, Devanand; Fisher, Paul B.

    2015-01-01

    No single or combinatorial therapeutic approach has proven effective in decreasing morbidity or engendering a cure of metastatic cancer. In principle, conditionally replication-competent adenoviruses that induce tumor oncolysis through cancer-specific replication hold promise for cancer therapy. However, a single-agent approach may not be adequate to completely eradicate cancer in a patient because most cancers arise from abnormalities in multiple genetic and signal transduction pathways and targeting disseminated metastases is difficult to achieve. Based on these considerations, a novel class of cancer destroying adenoviruses have been produced, cancer terminator viruses (CTVs), in which cancer-specific replication is controlled by the progression-elevated gene-3 promoter and replicating viruses produce a second transgene encoding an apoptosis-inducing and immunomodulatory cytokine, either melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) or interferon-γ. This review focuses on these viruses and ways to improve their delivery systemically and enhance their therapeutic efficacy. PMID:23021240

  5. Glioblastoma multiforme: Effect of hypoxia and hypoxia inducible factors on therapeutic approaches

    PubMed Central

    Huang, Wen-Juan; Chen, Wei-Wei; Zhang, Xia

    2016-01-01

    Central nervous system-based cancers have a much higher mortality rate with the 2016 estimates at 6.4 for incidence and 4.3 for deaths per 100,000 individuals. Grade IV astrocytomas, known as glioblastomas are highly aggressive and show a high proliferation index, diffused infiltration, angiogenesis, microvascular proliferation and pleomorphic vessels, resistance to apoptosis, and pseudopalisading necrosis. Extensive hypoxic regions in glioblastomas contribute to the highly malignant phenotype of these tumors. Hypoxic regions of glioblastoma exacerbate the prognosis and clinical outcomes of the patients as hypoxic tumor cells are resistant to chemo- and radiation therapy and are also protected by the malfunctional vasculature that developed due to hypoxia. Predominantly, hypoxia-inducible factor-1α, vascular endothelial growth factor (VEGF)/VEGF receptor, transforming growth factor-β, epidermal growth factor receptor and PI3 kinase/Akt signaling systems are involved in tumor progression and growth. Glioblastomas are predominantly glycolytic and hypoxia-induced factors are useful in the metabolic reprogramming of these tumors. Abnormal vessel formation is crucial in generating pseudopalisading necrosis regions that protect cancer stem cells residing in that region from therapeutic agents and this facilitates the cancer stem cell niche to expand and contribute to cell proliferation and tumor growth. Therapeutic approaches that target hypoxia-induced factors, such as use of the monoclonal antibody against VEGF, bevacizumab, have been useful only in stabilizing the disease but failed to increase overall survival. Hypoxia-activated TH-302, a nitroimidazole prodrug of cytotoxin bromo-isophosphoramide mustard, appears to be more attractive due to its better beneficial effects in glioblastoma patients. A better understanding of the hypoxia-mediated protection of glioblastoma cells is required for developing more effective therapeutics. PMID:27698790

  6. Glioblastoma multiforme: Effect of hypoxia and hypoxia inducible factors on therapeutic approaches

    PubMed Central

    Huang, Wen-Juan; Chen, Wei-Wei; Zhang, Xia

    2016-01-01

    Central nervous system-based cancers have a much higher mortality rate with the 2016 estimates at 6.4 for incidence and 4.3 for deaths per 100,000 individuals. Grade IV astrocytomas, known as glioblastomas are highly aggressive and show a high proliferation index, diffused infiltration, angiogenesis, microvascular proliferation and pleomorphic vessels, resistance to apoptosis, and pseudopalisading necrosis. Extensive hypoxic regions in glioblastomas contribute to the highly malignant phenotype of these tumors. Hypoxic regions of glioblastoma exacerbate the prognosis and clinical outcomes of the patients as hypoxic tumor cells are resistant to chemo- and radiation therapy and are also protected by the malfunctional vasculature that developed due to hypoxia. Predominantly, hypoxia-inducible factor-1α, vascular endothelial growth factor (VEGF)/VEGF receptor, transforming growth factor-β, epidermal growth factor receptor and PI3 kinase/Akt signaling systems are involved in tumor progression and growth. Glioblastomas are predominantly glycolytic and hypoxia-induced factors are useful in the metabolic reprogramming of these tumors. Abnormal vessel formation is crucial in generating pseudopalisading necrosis regions that protect cancer stem cells residing in that region from therapeutic agents and this facilitates the cancer stem cell niche to expand and contribute to cell proliferation and tumor growth. Therapeutic approaches that target hypoxia-induced factors, such as use of the monoclonal antibody against VEGF, bevacizumab, have been useful only in stabilizing the disease but failed to increase overall survival. Hypoxia-activated TH-302, a nitroimidazole prodrug of cytotoxin bromo-isophosphoramide mustard, appears to be more attractive due to its better beneficial effects in glioblastoma patients. A better understanding of the hypoxia-mediated protection of glioblastoma cells is required for developing more effective therapeutics.

  7. Disease Mechanisms and Therapeutic Approaches in Spinal Muscular Atrophy

    PubMed Central

    Tisdale, Sarah

    2015-01-01

    Motor neuron diseases are neurological disorders characterized primarily by the degeneration of spinal motor neurons, skeletal muscle atrophy, and debilitating and often fatal motor dysfunction. Spinal muscular atrophy (SMA) is an autosomal-recessive motor neuron disease of high incidence and severity and the most common genetic cause of infant mortality. SMA is caused by homozygous mutations in the survival motor neuron 1 (SMN1) gene and retention of at least one copy of the hypomorphic gene paralog SMN2. Early studies established a loss-of-function disease mechanism involving ubiquitous SMN deficiency and suggested SMN upregulation as a possible therapeutic approach. In recent years, greater knowledge of the central role of SMN in RNA processing combined with deep characterization of animal models of SMA has significantly advanced our understanding of the cellular and molecular basis of the disease. SMA is emerging as an RNA disease not limited to motor neurons, but one that involves dysfunction of motor circuits that comprise multiple neuronal subpopulations and possibly other cell types. Advances in SMA research have also led to the development of several potential therapeutics shown to be effective in animal models of SMA that are now in clinical trials. These agents offer unprecedented promise for the treatment of this still incurable neurodegenerative disease. PMID:26063904

  8. Therapeutic approaches targeting intestinal microflora in inflammatory bowel disease

    PubMed Central

    Andoh, Akira; Fujiyama, Yoshihide

    2006-01-01

    Inflammatory bowel diseases, ulcerative colitis, and Crohn’s disease, are chronic intestinal disorders of unknown etiology in which in genetically susceptible individuals, the mucosal immune system shows an aberrant response towards commensal bacteria. The gastrointestinal tract has developed ingenious mechanisms to coexist with its autologous microflora, but rapidly responds to invading pathogens and then returns to homeostasis with its commensal bacteria after the pathogenic infection is cleared. In case of disruption of this tightly-regulated homeostasis, chronic intestinal inflammation may be induced. Previous studies showed that some commensal bacteria are detrimental while others have either no influence or have a protective action. In addition, each host has a genetically determined response to detrimental and protective bacterial species. These suggest that therapeutic manipulation of imbalance of microflora can influence health and disease. This review focuses on new insights into the role of commensal bacteria in gut health and disease, and presents recent findings in innate and adaptive immune interactions. Therapeutic approaches to modulate balance of intestinal microflora and their potential mechanisms of action are also discussed. PMID:16874854

  9. Affinity approaches in RNAi-based therapeutics purification.

    PubMed

    Pereira, Patrícia; Queiroz, João A; Figueiras, Ana; Sousa, Fani

    2016-05-15

    The recent investigation on RNA interference (RNAi) related mechanisms and applications led to an increased awareness of the importance of RNA in biology. Nowadays, RNAi-based technology has emerged as a potentially powerful tool for silencing gene expression, being exploited to develop new therapeutics for treating a vast number of human disease conditions, as it is expected that this technology can be translated onto clinical applications in a near future. This approach makes use of a large number of small (namely short interfering RNAs, microRNAs and PIWI-interacting RNAs) and long non-coding RNAs (ncRNAs), which are likely to have a crucial role as the next generation therapeutics. The commercial and biomedical interest in these RNAi-based therapy applications have fostered the need to develop innovative procedures to easily and efficiently purify RNA, aiming to obtain the final product with high purity degree, good quality and biological activity. Recently, affinity chromatography has been applied to ncRNAs purification, in view of the high specificity. Therefore, this article intends to review the biogenesis pathways of regulatory ncRNAs and also to discuss the most significant and recent developments as well as applications of affinity chromatography in the challenging task of purifying ncRNAs. In addition, the importance of affinity chromatography in ncRNAs purification is addressed and prospects for what is forthcoming are presented. PMID:26830537

  10. Affinity approaches in RNAi-based therapeutics purification.

    PubMed

    Pereira, Patrícia; Queiroz, João A; Figueiras, Ana; Sousa, Fani

    2016-05-15

    The recent investigation on RNA interference (RNAi) related mechanisms and applications led to an increased awareness of the importance of RNA in biology. Nowadays, RNAi-based technology has emerged as a potentially powerful tool for silencing gene expression, being exploited to develop new therapeutics for treating a vast number of human disease conditions, as it is expected that this technology can be translated onto clinical applications in a near future. This approach makes use of a large number of small (namely short interfering RNAs, microRNAs and PIWI-interacting RNAs) and long non-coding RNAs (ncRNAs), which are likely to have a crucial role as the next generation therapeutics. The commercial and biomedical interest in these RNAi-based therapy applications have fostered the need to develop innovative procedures to easily and efficiently purify RNA, aiming to obtain the final product with high purity degree, good quality and biological activity. Recently, affinity chromatography has been applied to ncRNAs purification, in view of the high specificity. Therefore, this article intends to review the biogenesis pathways of regulatory ncRNAs and also to discuss the most significant and recent developments as well as applications of affinity chromatography in the challenging task of purifying ncRNAs. In addition, the importance of affinity chromatography in ncRNAs purification is addressed and prospects for what is forthcoming are presented.

  11. Gummy smile: clinical parameters useful for diagnosis and therapeutical approach.

    PubMed

    Monaco, Annalisa; Streni, Oriana; Marci, Maria Chiara; Marzo, Giuseppe; Gatto, Roberto; Giannoni, Mario

    2004-01-01

    In the analysis of the characteristics of a pleasant smile, a gummy smile has negative components, which most affect the esthetics of non-verbal communication. For this purpose a proposed classification based upon etiopathogenetic criteria as useful indications for a therapeutical approach is given. The nature of a high smile line can be: dento-gingival, connected to an abnormal dental eruption, which is revealed by a short clinic crown; muscular, caused by an hyperactivity of the elevator muscle of the upper lip; dento-alveolar (skeletal), due to an excessive protuberance or vertical growth of the jawbone (maxillary); lastly, a mixed nature, in the presence of more than one of the above described factors The diagnosis of gummy smile must be precocious and based, with reference to specific parameters, upon a careful analysis of the etiopathogenetic factors and the degree of seriousness of the alteration. A correct treatment plan must contemplate the possibility of an orthognatodontic, orthopedic and/or surgical therapeutic resolution considering the seriousness and complexity of the gums exposures (high smile line) in connection with the age of the subject.

  12. [The APJ receptor: a new therapeutic approach in diabetic treatment].

    PubMed

    Masri, Bernard; Dray, Cédric; Knauf, Claude; Valet, Philippe; Castan-Laurell, Isabelle

    2015-03-01

    The APJ receptor cloned in 1993 found its ligand in 1998 with the discovery of apelin. The presence of APJ in the central nervous system (more particularly in the hypothalamus) and in various tissues (heart, blood vessels, stomach, etc.) makes it a potential pharmacological target. Interest in APJ has allowed the development of peptidic molecules able to stimulate and/or inhibit the receptor and, more recently, to discover another endogenous ligand: apela. Among the functions regulated by the APJ/apelin system, the control of energy metabolism appears today in the forefront. A better understanding of the pharmacology of APJ receptor should allow innovative therapeutic approaches in the treatment of metabolic diseases. PMID:25855281

  13. Therapeutic approaches of magnetic nanoparticles for the central nervous system.

    PubMed

    Dilnawaz, Fahima; Sahoo, Sanjeeb Kumar

    2015-10-01

    The diseases of the central nervous system (CNS) represent one of the fastest growing areas of concern requiring urgent medical attention. Treatment of CNS ailments is hindered owing to different physiological barriers including the blood-brain barrier (BBB), which limits the accessibility of potential drugs. With the assistance of a nanotechnology-based drug delivery strategy, the problems could be overcome. Recently, magnetic nanoparticles (MNPs) have proven immensely useful as drug carriers for site-specific delivery and as contrast agents owing to their magnetic susceptibility and biocompatibility. By utilizing MNPs, diagnosis and treatment of CNS diseases have progressed by overcoming the hurdles of the BBB. In this review, the therapeutic aspect and the future prospects related to the theranostic approach of MNPs are discussed.

  14. Control of Bovine Mastitis: Old and Recent Therapeutic Approaches.

    PubMed

    Gomes, Fernanda; Henriques, Mariana

    2016-04-01

    Mastitis is defined as the inflammatory response resulting of the infection of the udder tissue and it is reported in numerous species, namely in domestic dairy animals. This pathology is the most frequent disease of dairy cattle and can be potentially fatal. Mastitis is an economically important pathology associated with reduced milk production, changes in milk composition and quality, being considered one of the most costly to dairy industry. Therefore, the majority of research in the field has focused on control of bovine mastitis and many efforts are being made for the development of new and effective anti-mastitis drugs. Antibiotic treatment is an established component of mastitis control programs; however, the continuous search for new therapeutic alternatives, effective in the control and treatment of bovine mastitis, is urgent. This review will provide an overview of some conventional and emerging approaches in the management of bovine mastitis' infections. PMID:26687332

  15. Control of Bovine Mastitis: Old and Recent Therapeutic Approaches.

    PubMed

    Gomes, Fernanda; Henriques, Mariana

    2016-04-01

    Mastitis is defined as the inflammatory response resulting of the infection of the udder tissue and it is reported in numerous species, namely in domestic dairy animals. This pathology is the most frequent disease of dairy cattle and can be potentially fatal. Mastitis is an economically important pathology associated with reduced milk production, changes in milk composition and quality, being considered one of the most costly to dairy industry. Therefore, the majority of research in the field has focused on control of bovine mastitis and many efforts are being made for the development of new and effective anti-mastitis drugs. Antibiotic treatment is an established component of mastitis control programs; however, the continuous search for new therapeutic alternatives, effective in the control and treatment of bovine mastitis, is urgent. This review will provide an overview of some conventional and emerging approaches in the management of bovine mastitis' infections.

  16. Suppression of Premature Termination Codons as a Therapeutic Approach

    PubMed Central

    Keeling, Kim M.; Wang, Dan; Conard, Sara E.; Bedwell, David M.

    2012-01-01

    In this review, we describe our current understanding of translation termination and pharmacological agents that influence the accuracy of this process. A number of drugs have been identified that induce suppression of translation termination at in-frame premature termination codons (PTCs; also known as nonsense mutations) in mammalian cells. We discuss efforts to utilize these drugs to suppress disease-causing PTCs that result in the loss of protein expression and function. In-frame PTCs represent a genotypic subset of mutations that make up ~11% of all known mutations that cause genetic diseases, and millions of patients have diseases attributable to PTCs. Current approaches aimed at reducing the efficiency of translation termination at PTCs (referred to as PTC suppression therapy) have the goal of alleviating the phenotypic consequences of a wide range of genetic diseases. Suppression therapy is currently in clinical trials for treatment of several genetic diseases caused by PTCs, and preliminary results suggest that some patients have shown clinical improvements. While current progress is promising, we discuss various approaches that may further enhance the efficiency of this novel therapeutic approach. PMID:22672057

  17. Genome Editing: A New Approach to Human Therapeutics.

    PubMed

    Porteus, Matthew

    2016-01-01

    The ability to manipulate the genome with precise spatial and nucleotide resolution (genome editing) has been a powerful research tool. In the past decade, the tools and expertise for using genome editing in human somatic cells and pluripotent cells have increased to such an extent that the approach is now being developed widely as a strategy to treat human disease. The fundamental process depends on creating a site-specific DNA double-strand break (DSB) in the genome and then allowing the cell's endogenous DSB repair machinery to fix the break such that precise nucleotide changes are made to the DNA sequence. With the development and discovery of several different nuclease platforms and increasing knowledge of the parameters affecting different genome editing outcomes, genome editing frequencies now reach therapeutic relevance for a wide variety of diseases. Moreover, there is a series of complementary approaches to assessing the safety and toxicity of any genome editing process, irrespective of the underlying nuclease used. Finally, the development of genome editing has raised the issue of whether it should be used to engineer the human germline. Although such an approach could clearly prevent the birth of people with devastating and destructive genetic diseases, questions remain about whether human society is morally responsible enough to use this tool.

  18. Axonopathy in peripheral neuropathies: Mechanisms and therapeutic approaches for regeneration.

    PubMed

    Landowski, Lila M; Dyck, P James B; Engelstad, JaNean; Taylor, Bruce V

    2016-10-01

    Peripheral neuropathies (PNs) are injuries or diseases of the nerves which arise from varied aetiology, including metabolic disease, trauma and drug toxicity. The clinical presentation depends on the type of neuropathy, and may include the loss of motor, sensory and autonomic functions, or development of debilitating neuropathic pain distal to the injury site. It can be challenging to identify the aetiology of PNs, as the clinical syndromes are often indistinct. However, the mechanisms that underlie pathological changes in peripheral neuropathy are fundamentally different, depending on the trigger. This review focuses on the axonopathy observed in two frequently encountered forms of peripheral neuropathy, diabetic neuropathy and chemotherapy-induced neuropathy. A key manifestation of axonopathy in PN is the degeneration of terminal arbors of peripheral nerves, resulting in a loss of epidermal nerve fibres and inappropriate termination of nerve endings. Many symptoms of PN arise from aberrant termination of nerve endings, and the underlying axonopathy may be non-reversible, as nerve regeneration after injury and disease is often poor, absent, or aberrant. Directed guidance of terminal arbors back into the epidermis is therefore a suggested approach to treat peripheral neuropathy. This review will outline potential strategies to enhance and guide axonal regeneration and reinnervation in the skin. Using diabetic neuropathy and chemotherapy-induced neuropathy as specific examples, this review examines the setbacks encountered with the translation of growth factors into therapeutics for human neuropathy, and suggests a number of approaches for topical drug delivery.

  19. Therapeutic Approaches to Delay the Onset of Alzheimer's Disease

    PubMed Central

    Kumar, Raj; Atamna, Hani

    2011-01-01

    The key cytopathologies in the brains of Alzheimer's disease (AD) patients include mitochondrial dysfunction and energy hypometabolism, which are likely caused by the accumulation of small aggregates of amyloid-β (Aβ) peptides. Thus, targeting these two abnormalities of the AD brain may hold promising therapeutic value for delaying the onset of AD. In his paper, we discuss two potential approaches to delay the onset of AD. The first is the use of low dose of diaminophenothiazins (redox active agents) to prevent mitochondrial dysfunction and to attenuate energy hypometabolism. Diaminophenothiazines enhance mitochondrial metabolic activity and heme synthesis, both key factors in intermediary metabolism of the AD brain.The second is to use the naturally occurring osmolytes to prevent the formation of toxic forms of Aβ and prevent oxidative stress. Scientific evidence suggests that both approaches may change course of the basic mechanism of neurodegeneration in AD. Osmolytes are brain metabolites which accumulate in tissues at relatively high concentrations following stress conditions. Osmolytes enhance thermodynamic stability of proteins by stabilizing natively-folded protein conformation, thus preventing aggregation without perturbing other cellular processes. Osmolytes may inhibit the formation of Aβ oligomers in vivo, thus preventing the formation of soluble oligomers. The potential significance of combining diaminophenothiazins and osmolytes to treat AD is discussed. PMID:21423548

  20. Risk Models of Dating Aggression across Different Adolescent Relationships: A Developmental Psychopathology Approach

    ERIC Educational Resources Information Center

    Williams, Tricia S.; Connolly, Jennifer; Pepler, Debra; Craig, Wendy; Laporte, Lise

    2008-01-01

    The present study examined physical dating aggression in different adolescent relationships and assessed linear, threshold, and moderator risk models for recurrent aggressive relationships. The 621 participants (59% girls, 41% boys) were drawn from a 1-year longitudinal survey of Canadian high school youths ranging from Grade 9 through Grade 12.…

  1. Helping Children To Manage Emotions which Trigger Aggressive Acts: An Approach through Drama in School.

    ERIC Educational Resources Information Center

    Johnson, Colleen

    2001-01-01

    Suggests ways in which drama can be used to: explore issues that often give rise to aggression or violence; give space to articulate and respond to emotions; model and practice non-violent response to aggression; consider the consequences of one's actions; empower children to stand up to bullying; and channel energy into performance. (TJQ)

  2. [Molecular pathogenesis and therapeutic approach of GM2 gangliosidosis].

    PubMed

    Tsuji, Daisuke

    2013-01-01

    Tay-Sachs and Sandhoff diseases (GM2 gangliosidoses) are autosomal recessive lysosomal storage diseases caused by gene mutations in HEXA and HEXB, each encoding human lysosomal β-hexosaminidase α-subunits and β-subunits, respectively. In Tay-Sachs disease, excessive accumulation of GM2 ganglioside (GM2), mainly in the central nervous system, is caused by a deficiency of the HexA isozyme (αβ heterodimer), resulting in progressive neurologic disorders. In Sandhoff disease, combined deficiencies of HexA and HexB (ββ homodimer) cause not only the accumulation of GM2 but also of oligosaccharides carrying terminal N-acetylhexosamine residues (GlcNAc-oligosaccharides), resulting in systemic manifestations including hepatosplenomegaly as well as neurologic symptoms. Hence there is little clinically effective treatment for these GM2 gangliosidoses. Recent studies on the molecular pathogenesis in Sandhoff disease patients and disease model mice have shown the involvement of microglial activation and chemokine induction in neuroinflammation and neurodegeneration in this disease. Experimental and therapeutic approaches, including recombinant enzyme replacement, have been performed using Sandhoff disease model mice, suggesting the future application of novel techniques to treat GM2 gangliosidoses (Hex deficiencies), including Sandhoff disease as well as Tay-Sachs disease. In this study, we isolated astrocytes and microglia from the neonatal brain of Sandhoff disease model mice and demonstrated abnormalities of glial cells. Moreover, we demonstrated the therapeutic effect of an intracerebroventricular administration of novel recombinant human HexA carrying a high content of M6P residue in Sandhoff disease model mice.

  3. [Molecular pathogenesis and therapeutic approach of GM2 gangliosidosis].

    PubMed

    Tsuji, Daisuke

    2013-01-01

    Tay-Sachs and Sandhoff diseases (GM2 gangliosidoses) are autosomal recessive lysosomal storage diseases caused by gene mutations in HEXA and HEXB, each encoding human lysosomal β-hexosaminidase α-subunits and β-subunits, respectively. In Tay-Sachs disease, excessive accumulation of GM2 ganglioside (GM2), mainly in the central nervous system, is caused by a deficiency of the HexA isozyme (αβ heterodimer), resulting in progressive neurologic disorders. In Sandhoff disease, combined deficiencies of HexA and HexB (ββ homodimer) cause not only the accumulation of GM2 but also of oligosaccharides carrying terminal N-acetylhexosamine residues (GlcNAc-oligosaccharides), resulting in systemic manifestations including hepatosplenomegaly as well as neurologic symptoms. Hence there is little clinically effective treatment for these GM2 gangliosidoses. Recent studies on the molecular pathogenesis in Sandhoff disease patients and disease model mice have shown the involvement of microglial activation and chemokine induction in neuroinflammation and neurodegeneration in this disease. Experimental and therapeutic approaches, including recombinant enzyme replacement, have been performed using Sandhoff disease model mice, suggesting the future application of novel techniques to treat GM2 gangliosidoses (Hex deficiencies), including Sandhoff disease as well as Tay-Sachs disease. In this study, we isolated astrocytes and microglia from the neonatal brain of Sandhoff disease model mice and demonstrated abnormalities of glial cells. Moreover, we demonstrated the therapeutic effect of an intracerebroventricular administration of novel recombinant human HexA carrying a high content of M6P residue in Sandhoff disease model mice. PMID:23370522

  4. A novel approach for oxidation analysis of therapeutic proteins.

    PubMed

    Turyan, Iva; Khatwani, Nikhil; Sosic, Zoran; Jayawickreme, Shiranthi; Mandler, Daniel

    2016-02-01

    Measuring and monitoring of protein oxidation modifications is important for biopharmaceutical process development and stability assessment during long-term storage. Currently available methods for biomolecules oxidation analysis use time-consuming peptide mapping analysis. Therefore, it is desirable to develop high-throughput methods for advanced process control of protein oxidation. Here, we present a novel approach by which oxidative protein modifications are monitored by an indirect potentiometric method. The method is based on adding an electron mediator, which enhances electron transfer (ET) between all redox species and the electrode surface. Specifically, the procedure involves measuring the sharp change in the open circuit potential (OCP) for the mediator system (redox couple) as a result of its interaction with the oxidized protein species in the solution. Application of Pt and Ag/AgCl microelectrodes allowed for a high-sensitivity protein oxidation analysis. We found that the Ru(NH3)6(2+/3+) redox couple is suitable for measuring the total oxidation of a wide range of therapeutic proteins between 1.1 and 13.6%. Accuracy determined by comparing with the known percentage oxidation of the reference standard showed that percentage oxidation determined for each sample was within ± 20% of the expected percentage oxidation determined by mass spectrometry.

  5. Hyperuricaemia with deposition: latest evidence and therapeutic approach

    PubMed Central

    Perez-Ruiz, Fernando; Marimon, Estibaliz; Chinchilla, Sandra P.

    2015-01-01

    This article reviews recent evidence on urate deposition and the opportunity for a therapeutic approach. We reviewed Pubmed 2013–2015 literature using the search terms ‘deposition’ with ‘hyperuricaemia’, ‘gout’, ‘ultrasonography’, ‘DECT’ (dual-energy computed tomography), ‘radiography’, ‘CT’(computed tomography), ‘MRI’ (magnetic resonance imaging), or ‘cardiovascular’, in addition to a digital bibliographic library compiled by the authors with 2072 papers on hyperuricaemia and gout. Relevant papers on the topic were selected. Recent evidence, mostly based on imaging studies, showed a continuum from hyperuricaemia to deposition and clinical manifestations. Chronic inflammation and structural damage may be present even in asymptomatic patients with crystal-proved deposition. The impact of early intervention in patients with asymptomatic deposition either on vascular outcomes or further structural joint damage has not been demonstrated yet. In conclusion, a worldwide definition of gout is still lacking, stages from hyperuricaemia to clinical gout not being definitively defined. Although there is increasing interest on the impact of early deposits on joint damage and cardiovascular outcomes, robust evidence is still lacking to fully support interventions. PMID:26622324

  6. Silver Nanoparticles: Synthesis, Characterization, Properties, Applications, and Therapeutic Approaches.

    PubMed

    Zhang, Xi-Feng; Liu, Zhi-Guo; Shen, Wei; Gurunathan, Sangiliyandi

    2016-01-01

    Recent advances in nanoscience and nanotechnology radically changed the way we diagnose, treat, and prevent various diseases in all aspects of human life. Silver nanoparticles (AgNPs) are one of the most vital and fascinating nanomaterials among several metallic nanoparticles that are involved in biomedical applications. AgNPs play an important role in nanoscience and nanotechnology, particularly in nanomedicine. Although several noble metals have been used for various purposes, AgNPs have been focused on potential applications in cancer diagnosis and therapy. In this review, we discuss the synthesis of AgNPs using physical, chemical, and biological methods. We also discuss the properties of AgNPs and methods for their characterization. More importantly, we extensively discuss the multifunctional bio-applications of AgNPs; for example, as antibacterial, antifungal, antiviral, anti-inflammatory, anti-angiogenic, and anti-cancer agents, and the mechanism of the anti-cancer activity of AgNPs. In addition, we discuss therapeutic approaches and challenges for cancer therapy using AgNPs. Finally, we conclude by discussing the future perspective of AgNPs. PMID:27649147

  7. Clinical Features of Oxaliplatin Induced Hypersensitivity Reactions and Therapeutic Approaches.

    PubMed

    Bano, Nusrat; Najam, Rahila; Qazi, Faaiza; Mateen, Ahmed

    2016-01-01

    Oxaliplatin, a third generation novel platinum compound is the most effective first line chemotherapeutic agent for colorectal cancer (CRC) in combination with 5FU and leucovorin. It is indicated for pancreatic, gastric and testicular cancers combined with bevacuzimab, capecitabine, irinotecan and other cytotoxic agents. However, moderate to severe hypersensitivity reactions (HSR) during or after oxaliplatin infusion usually require cessation of chemotherapy or substitution of the key therapeutic drug which largely interferes with improved patient prognosis. This mini- review showcases recent and accepted opinions/approaches in oxaliplatin induced HSR management. Physicians and oncologists have varying attitudes regarding the decision to rechallenge the patient after an HSR experience, efficacy of desensitization protocols, effectiveness and selection of drugs for premedication and possibilities of cross sensitivity to other platinum agents (e.g. carboplatin). A brief insight into underlying molecular mechanisms and clinical manifestations of oxaliplatin induced HSR is offered. We have also discussed the management of oxaliplatin induced HSR and risk stratification for a successful and complete chemotherapeutic plan. PMID:27221832

  8. Clinical Features of Oxaliplatin Induced Hypersensitivity Reactions and Therapeutic Approaches.

    PubMed

    Bano, Nusrat; Najam, Rahila; Qazi, Faaiza; Mateen, Ahmed

    2016-01-01

    Oxaliplatin, a third generation novel platinum compound is the most effective first line chemotherapeutic agent for colorectal cancer (CRC) in combination with 5FU and leucovorin. It is indicated for pancreatic, gastric and testicular cancers combined with bevacuzimab, capecitabine, irinotecan and other cytotoxic agents. However, moderate to severe hypersensitivity reactions (HSR) during or after oxaliplatin infusion usually require cessation of chemotherapy or substitution of the key therapeutic drug which largely interferes with improved patient prognosis. This mini- review showcases recent and accepted opinions/approaches in oxaliplatin induced HSR management. Physicians and oncologists have varying attitudes regarding the decision to rechallenge the patient after an HSR experience, efficacy of desensitization protocols, effectiveness and selection of drugs for premedication and possibilities of cross sensitivity to other platinum agents (e.g. carboplatin). A brief insight into underlying molecular mechanisms and clinical manifestations of oxaliplatin induced HSR is offered. We have also discussed the management of oxaliplatin induced HSR and risk stratification for a successful and complete chemotherapeutic plan.

  9. Silver Nanoparticles: Synthesis, Characterization, Properties, Applications, and Therapeutic Approaches

    PubMed Central

    Zhang, Xi-Feng; Liu, Zhi-Guo; Shen, Wei; Gurunathan, Sangiliyandi

    2016-01-01

    Recent advances in nanoscience and nanotechnology radically changed the way we diagnose, treat, and prevent various diseases in all aspects of human life. Silver nanoparticles (AgNPs) are one of the most vital and fascinating nanomaterials among several metallic nanoparticles that are involved in biomedical applications. AgNPs play an important role in nanoscience and nanotechnology, particularly in nanomedicine. Although several noble metals have been used for various purposes, AgNPs have been focused on potential applications in cancer diagnosis and therapy. In this review, we discuss the synthesis of AgNPs using physical, chemical, and biological methods. We also discuss the properties of AgNPs and methods for their characterization. More importantly, we extensively discuss the multifunctional bio-applications of AgNPs; for example, as antibacterial, antifungal, antiviral, anti-inflammatory, anti-angiogenic, and anti-cancer agents, and the mechanism of the anti-cancer activity of AgNPs. In addition, we discuss therapeutic approaches and challenges for cancer therapy using AgNPs. Finally, we conclude by discussing the future perspective of AgNPs. PMID:27649147

  10. Hyperuricaemia with deposition: latest evidence and therapeutic approach.

    PubMed

    Perez-Ruiz, Fernando; Marimon, Estibaliz; Chinchilla, Sandra P

    2015-12-01

    This article reviews recent evidence on urate deposition and the opportunity for a therapeutic approach. We reviewed Pubmed 2013-2015 literature using the search terms 'deposition' with 'hyperuricaemia', 'gout', 'ultrasonography', 'DECT' (dual-energy computed tomography), 'radiography', 'CT'(computed tomography), 'MRI' (magnetic resonance imaging), or 'cardiovascular', in addition to a digital bibliographic library compiled by the authors with 2072 papers on hyperuricaemia and gout. Relevant papers on the topic were selected. Recent evidence, mostly based on imaging studies, showed a continuum from hyperuricaemia to deposition and clinical manifestations. Chronic inflammation and structural damage may be present even in asymptomatic patients with crystal-proved deposition. The impact of early intervention in patients with asymptomatic deposition either on vascular outcomes or further structural joint damage has not been demonstrated yet. In conclusion, a worldwide definition of gout is still lacking, stages from hyperuricaemia to clinical gout not being definitively defined. Although there is increasing interest on the impact of early deposits on joint damage and cardiovascular outcomes, robust evidence is still lacking to fully support interventions. PMID:26622324

  11. Rational approaches to design of therapeutics targeting molecular markers.

    PubMed

    Klasa, R J; List, A F; Cheson, B D

    2001-01-01

    This paper introduces novel therapeutic strategies focusing on a molecular marker relevant to a particular hematologic malignancy. Four different approaches targeting specific molecules in unique pathways will be presented. The common theme will be rational target selection in a strategy that has reached the early phase of human clinical trial in one malignancy, but with a much broader potential applicability to the technology. In Section I Dr. Richard Klasa presents preclinical data on the use of antisense oligonucleotides directed at the bcl-2 gene message to specifically downregulate Bcl-2 protein expression in non-Hodgkin's lymphomas and render the cells more susceptible to the induction of apoptosis. In Section II Dr. Alan List reviews the targeting of vascular endothelial growth factor (VEGF) and its receptor in anti-angiogenesis strategies for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). In Section III Dr. Bruce Cheson describes recent progress in inhibiting cell cycle progression by selectively disrupting cyclin D1 with structurally unique compounds such as flavopiridol in mantle cell lymphoma as well as describing a new class of agents that affect proteasome degradation pathways.

  12. Diagnostic and therapeutic endoscopic approaches to intraductal papillary mucinous neoplasm.

    PubMed

    Turner, Brian G; Brugge, William R

    2010-10-27

    Pancreatic cystic lesions are increasingly identified on routine imaging. One specific lesion, known as intraductal papillary mucinous neoplasm (IPMN), is a mucinous, pancreatic lesion characterized by papillary cells projecting from the pancreatic ductal epithelium. The finding of mucin extruding from the ampulla is essentially pathognomonic for diagnosing these lesions. IPMNs are of particular interest due to their malignant potential. Lesions range from benign, adenomatous growths to high-grade dysplasia and invasive cancer. These mucinous lesions therefore require immediate attention to determine the probability of malignancy and whether observation or resection is the best management choice. Unresected lesions need long-term surveillance monitoring for malignant transformation. The accurate diagnosis of these lesions is particularly challenging due to the substantial similarities in morphology of pancreatic cystic lesions and limitations in current imaging technologies. Endoscopic evaluation of these lesions provides additional imaging, molecular, and histologic data to aid in the identification of IPMN and to determine treatment course. The aim of this article is to focus on the diagnostic and therapeutic endoscopic approaches to IPMN.

  13. Development of Nanoscale Approaches for Ovarian Cancer Therapeutics and Diagnostics

    PubMed Central

    Engelberth, Sarah A.; Hempel, Nadine; Bergkvist, Magnus

    2014-01-01

    Ovarian cancer is the deadliest of all gynecological cancers and the fifth leading cause of death due to cancer in women. This is largely due to late-stage diagnosis, poor prognosis related to advanced-stage disease, and the high recurrence rate associated with development of chemoresistance. Survival statistics have not improved significantly over the last three decades, highlighting the fact that improved therapeutic strategies and early detection require substantial improvements. Here, we review and highlight nanotechnology-based approaches that seek to address this need. The success of Doxil, a PEGylated liposomal nanoencapsulation of doxorubicin, which was approved by the FDA for use on recurrent ovarian cancer, has paved the way for the current wave of nanoparticle formulations in drug discovery and clinical trials. We discuss and summarize new nanoformulations that are currently moving into clinical trials and highlight novel nanotherapeutic strategies that have shown promising results in preclinical in vivo studies. Further, the potential for nanomaterials in diagnostic imaging techniques and the ability to leverage nanotechnology for early detection of ovarian cancer are also discussed. PMID:25271436

  14. Behavioral treatment approaches to pathological unsocialized physical aggression in young children.

    PubMed

    Frankel, F; Simmons, J Q

    1985-07-01

    This paper presents some hypotheses regarding the motivation of pathological unsocialized physical aggression in children and also reviews behavioral treatment. Tentative leads were offered as to extrinsic and intrinsic determinants. Among the most promising of these were parent-child interactive and attributive factors, and deficits in information processing in social situations. It was hypothesized that some of these factors might not be specific to pathological unsocialized physical aggression but are characteristic of children with behavior problems. Under this hypothesis, few studies were found which employed appropriate control groups. It was also hypothesized that the study of extrinsic and intrinsic factors for pathological unsocialized physical aggression may improve the design of treatment programs.

  15. Systems approaches to design of targeted therapeutic delivery

    PubMed Central

    Myerson, Jacob W.; Brenner, Jacob S.; Greineder, Colin F.; Muzykantov, Vladimir R.

    2016-01-01

    Targeted drug delivery aims to improve therapeutic effects and enable mechanisms that are not feasible for untargeted agents (e.g., due to impermeable biological barriers). To achieve targeting, a drug or its carrier should possess properties providing specific accumulation from circulation at the desired site. There are several examples of systems-inspired approaches that have been applied to achieve this goal. First, proteomics analysis of plasma membrane fraction of the vascular endothelium has identified a series of target molecules and their ligands (e.g., antibodies) that deliver conjugated cargoes to well-defined vascular cells and subcellular compartments. Second, selection of ligands binding to cells of interest using phage display libraries in vitro and in vivo has provided peptides and polypeptides that bind to normal and pathologically altered cells. Finally, large-scale high-throughput combinatorial synthesis and selection of lipid- and polymer-based nanocarriers varying their chemical components has yielded a series of carriers accumulating in diverse organs and delivering RNA interference agents to diverse cells. Together, these approaches offer a basis for systems-based design and selection of targets, targeting molecules, and targeting vehicles. Current studies focus on expanding the arsenal of these and alternative targeting strategies, devising drug delivery systems capitalizing on these strategies and evaluation of their benefit/risk ratio in adequate animal models of human diseases. These efforts, combined with better understanding of mechanisms and unintended consequences of these targeted interventions, need to be ultimately translated into industrial development and the clinical domain. PMID:25946066

  16. [Aggressive fibromatoses].

    PubMed

    Döhler, J R; Hamelmann, H; Lasson, U

    1984-03-01

    Benign by nature, aggressive fibromatoses (desmoid fibromas) may represent as difficult therapeutic problems as malignant tumours. When subtotally resected they tend to recur. But spontaneous regression is possible. Expense and limits of their surgical treatment are discussed with reference to seven patients. In five cases primary affliction of bone was evident. There are three reports given in detail: In the first, malignant transformation may be due to radiation therapy and hemipelvectomy could not prevent recurrence. In the second, spontaneous regression of untreated pelvic affection may have occurred. In the third, several resections and amputation of the leg failed to cure congenital infantile fibromatosis.

  17. Behavioral treatment approaches to pathological unsocialized physical aggression in young children.

    PubMed

    Frankel, F; Simmons, J Q

    1985-07-01

    This paper presents some hypotheses regarding the motivation of pathological unsocialized physical aggression in children and also reviews behavioral treatment. Tentative leads were offered as to extrinsic and intrinsic determinants. Among the most promising of these were parent-child interactive and attributive factors, and deficits in information processing in social situations. It was hypothesized that some of these factors might not be specific to pathological unsocialized physical aggression but are characteristic of children with behavior problems. Under this hypothesis, few studies were found which employed appropriate control groups. It was also hypothesized that the study of extrinsic and intrinsic factors for pathological unsocialized physical aggression may improve the design of treatment programs. PMID:3894395

  18. Naturalistic Versus Experimental Approaches to the Study of Human Aggression: Theoretical and Methodological Issues.

    ERIC Educational Resources Information Center

    Gaebelein, Jacquelyn W.

    Research strategies used to study human aggression include laboratory study, experimental simulation, field experiment, field study, judgment task, sample survey, and less empirical strategies such as computer simulations and formal theory. The context of these strategies can be classified as either contrived, natural, or irrelevant. Major issues…

  19. A Computer-Assisted Instructional Approach to Teaching Applied Therapeutics.

    ERIC Educational Resources Information Center

    Jim, Lucia K.; And Others

    1984-01-01

    The effectiveness of computer-assisted instruction to conduct pharmacy therapeutics case analysis exercises was compared with the traditional conference format. Pre- and posttest scores were compared statistically within and between groups to determine knowledge gained and comparative effectivness of teaching. (Author/MLW)

  20. Clinical decision-making and therapeutic approaches in osteopathy - a qualitative grounded theory study.

    PubMed

    Thomson, Oliver P; Petty, Nicola J; Moore, Ann P

    2014-02-01

    There is limited understanding of how osteopaths make decisions in relation to clinical practice. The aim of this research was to construct an explanatory theory of the clinical decision-making and therapeutic approaches of experienced osteopaths in the UK. Twelve UK registered osteopaths participated in this constructivist grounded theory qualitative study. Purposive and theoretical sampling was used to select participants. Data was collected using semi-structured interviews which were audio-recorded and transcribed. As the study approached theoretical sufficiency, participants were observed and video-recorded during a patient appointment, which was followed by a video-prompted interview. Constant comparative analysis was used to analyse and code data. Data analysis resulted in the construction of three qualitatively different therapeutic approaches which characterised participants and their clinical practice, termed; Treater, Communicator and Educator. Participants' therapeutic approach influenced their approach to clinical decision-making, the level of patient involvement, their interaction with patients, and therapeutic goals. Participants' overall conception of practice lay on a continuum ranging from technical rationality to professional artistry, and contributed to their therapeutic approach. A range of factors were identified which influenced participants' conception of practice. The findings indicate that there is variation in osteopaths' therapeutic approaches to practice and clinical decision-making, which are influenced by their overall conception of practice. This study provides the first explanatory theory of the clinical decision-making and therapeutic approaches of osteopaths.

  1. Allergen-specific immunotherapy: from therapeutic vaccines to prophylactic approaches.

    PubMed

    Valenta, R; Campana, R; Marth, K; van Hage, M

    2012-08-01

    Immunoglobulin E-mediated allergies affect more than 25% of the population. Allergen exposure induces a variety of symptoms in allergic patients, which include rhinitis, conjunctivitis, asthma, dermatitis, food allergy and life-threatening systemic anaphylaxis. At present, allergen-specific immunotherapy (SIT), which is based on the administration of the disease-causing allergens, is the only disease-modifying treatment for allergy. Current therapeutic allergy vaccines are still prepared from relatively poorly defined allergen extracts. However, with the availability of the structures of the most common allergen molecules, it has become possible to produce well-defined recombinant and synthetic allergy vaccines that allow specific targeting of the mechanisms of allergic disease. Here we provide a summary of the development and mechanisms of SIT, and then review new forms of therapeutic vaccines that are based on recombinant and synthetic molecules. Finally, we discuss possible allergen-specific strategies for prevention of allergic disease.

  2. Epigenetic modulation as a therapeutic approach for pulmonary arterial hypertension

    PubMed Central

    Kim, Jun-Dae; Lee, Aram; Choi, Jihea; Park, Youngsook; Kang, Hyesoo; Chang, Woochul; Lee, Myeong-Sok; Kim, Jongmin

    2015-01-01

    Pulmonary arterial hypertension (PAH) is a rare but progressive and currently incurable disease, which is characterized by vascular remodeling in association with muscularization of the arterioles, medial thickening and plexiform lesion formation. Despite our advanced understanding of the pathogenesis of PAH and the recent therapeutic advances, PAH still remains a fatal disease. In addition, the susceptibility to PAH has not yet been adequately explained. Much evidence points to the involvement of epigenetic changes in the pathogenesis of a number of human diseases including cancer, peripheral hypertension and asthma. The knowledge gained from the epigenetic study of various human diseases can also be applied to PAH. Thus, the pursuit of novel therapeutic targets via understanding the epigenetic alterations involved in the pathogenesis of PAH, such as DNA methylation, histone modification and microRNA, might be an attractive therapeutic avenue for the development of a novel and more effective treatment. This review provides a general overview of the current advances in epigenetics associated with PAH, and discusses the potential for improved treatment through understanding the role of epigenetics in the development of PAH. PMID:26228095

  3. Epigenetic modulation as a therapeutic approach for pulmonary arterial hypertension.

    PubMed

    Kim, Jun-Dae; Lee, Aram; Choi, Jihea; Park, Youngsook; Kang, Hyesoo; Chang, Woochul; Lee, Myeong-Sok; Kim, Jongmin

    2015-01-01

    Pulmonary arterial hypertension (PAH) is a rare but progressive and currently incurable disease, which is characterized by vascular remodeling in association with muscularization of the arterioles, medial thickening and plexiform lesion formation. Despite our advanced understanding of the pathogenesis of PAH and the recent therapeutic advances, PAH still remains a fatal disease. In addition, the susceptibility to PAH has not yet been adequately explained. Much evidence points to the involvement of epigenetic changes in the pathogenesis of a number of human diseases including cancer, peripheral hypertension and asthma. The knowledge gained from the epigenetic study of various human diseases can also be applied to PAH. Thus, the pursuit of novel therapeutic targets via understanding the epigenetic alterations involved in the pathogenesis of PAH, such as DNA methylation, histone modification and microRNA, might be an attractive therapeutic avenue for the development of a novel and more effective treatment. This review provides a general overview of the current advances in epigenetics associated with PAH, and discusses the potential for improved treatment through understanding the role of epigenetics in the development of PAH. PMID:26228095

  4. Mitochondria targeted therapeutic approaches in Parkinson's and Huntington's diseases.

    PubMed

    Chaturvedi, Rajnish K; Beal, M Flint

    2013-07-01

    Substantial evidence from both genetic and toxin induced animal and cellular models and postmortem human brain tissue indicates that mitochondrial dysfunction plays a central role in pathophysiology of the neurodegenerative disorders including Parkinson's disease (PD), and Huntington's disease (HD). This review discusses the emerging understanding of the role of mitochondrial dysfunction including bioenergetics defects, mitochondrial DNA mutations, familial nuclear DNA mutations, altered mitochondrial fusion/fission and morphology, mitochondrial transport/trafficking, altered transcription and increased interaction of pathogenic proteins with mitochondria in the pathogenesis of PD and HD. This review recapitulates some of the key therapeutic strategies applied to surmount mitochondrial dysfunction in these debilitating disorders. We discuss the therapeutic role of mitochondrial bioenergetic agents such as creatine, Coenzyme-Q10, mitochondrial targeted antioxidants and peptides, the SIRT1 activator resveratrol, and the pan-PPAR agonist bezafibrate in toxin and genetic cellular and animal models of PD and HD. We also summarize the phase II-III clinical trials conducted using some of these agents. Lastly, we discuss PGC-1α, TORC and Sirtuins as potential therapeutic targets for mitochondrial dysfunction in neurodegenerative disorders. This article is part of a Special Issue entitled 'Mitochondrial function and dysfunction in neurodegeneration'.

  5. [A nursing experience using the props-integrated communicative approach to ameliorate aggression in a frontotemporal dementia patient].

    PubMed

    Shih, Ying-Jyun; Wang, Ya-Hui; Yang, Yung-Jen

    2014-12-01

    This report introduces the nursing caring experience with a male patient with frontotemporal dementia (FTD) who was hospitalized in an acute psychiatric ward from March 5th to April 30th, 2012 due to the clinical manifestations of verbally expressive impairment, aggression, and subsequent caregiver burden. The patient was assessed according to the guidelines of clinical competencies for mental health nursing assessments developed by the Psychiatric Mental Health Nurses Association. Three clinical diagnoses were identified after this assessment, including (1) impaired verbal communication, (2) chronic confusion, and (3) caregiver role strain. The current report focuses only on the clinical issue of impaired verbal communication. We adopted a props-integrated communicative approach by integrating props and physical motions with communicative strategies. This approach enabled us to formulate a patient-centered communicating model and prompt for active expression and adequate communication, which ultimately resolved the patient's aggression problem. In addition, we provided psychoeducation to the family members in order to teach them the relevant knowledge, skills, and approaches that caregivers may use to enhance their caring capabilities and reduce the burden of caregiving. This successful experience may be used as a reference in caring for FTD patients with communicative impairments. Our proposed approach integrates props with simple language and develops an appropriate communicating model to provide high quality care for patients.

  6. Exploiting Base Excision Repair to Improve Therapeutic Approaches for Pancreatic Cancer

    PubMed Central

    Sharbeen, George; McCarroll, Joshua; Goldstein, David; Phillips, Phoebe A.

    2015-01-01

    Pancreatic ductal adenocarcinoma (PDA) is a highly chemoresistant and metastatic disease with a dismal 5-year survival rate of 6%. More effective therapeutic targets and approaches are urgently needed to tackle this devastating disease. The base excision repair (BER) pathway has been identified as a predictor of therapeutic response, prognostic factor, and therapeutic target in a variety of cancers. This review will discuss our current understanding of BER in PDA and its potential to improve PDA treatment. PMID:25988138

  7. Ofuji disease: a rare dermatosis and its challenging therapeutic approach*

    PubMed Central

    de Brito, Fernanda Freitas; Martelli, Antonio Carlos Ceribelli; Cavalcante, Maria Lopes Lamenha Lins; Pinto, Ana Cecília Versiani Duarte; Itimura, Gabriela; Soares, Cleverson Teixeira

    2016-01-01

    Eosinophilic pustular folliculitis (EPF) or Ofuji disease is a rare dermatosis, prone to recurrence and chronicity. The peak incidence occurs in the third decade of life and its exact etiology remains unknown. Evidence suggests that the expression of adhesion molecules and the production of cytokines activate the follicular unit, but the stimulus that triggers these changes remains unclear. The three clinical variants reported in the literature include classic EPF, immunosuppression-associated EPF, and infancy-associated EPF. We report a case of eosinophilic pustular folliculitis with peculiar epidemiological characteristics, which represents a challenging therapeutic scenario.

  8. Molecular subtyping of breast cancer: opportunities for new therapeutic approaches.

    PubMed

    Mullan, P B; Millikan, R C

    2007-12-01

    Evidence is accumulating that breast cancer is not one disease but many separate diseases. DNA microarray-based gene expression profiling has demonstrated subtypes with distinct phenotypic features and clinical responses. Prominent among the new subtypes is 'basal-like' breast cancer, one of the 'intrinsic' subtypes defined by negativity for the estrogen, progesterone, and HER2/neu receptors and positivity for cytokeratins-5/6. Focusing on basal-like breast cancer, we discuss how molecular technologies provide new chemotherapy targets, optimising treatment whilst sparing patients from unnecessary toxicity. Clinical trials are needed that incorporate long-term follow-up of patients with well-characterised tumour markers. Whilst the absence of an obvious dominant oncogene driving basal-like breast cancer and the lack of specific therapeutic agents are serious stumbling blocks, this review will highlight several promising therapeutic candidates currently under evaluation. Thus, new molecular technologies should provide a fundamental foundation for better understanding breast and other cancers which may be exploited to save lives. (Part of a Multi-author Review). PMID:17957336

  9. Therapeutic Approaches to Histone Reprogramming in Retinal Degeneration.

    PubMed

    Berner, Andre K; Kleinman, Mark E

    2016-01-01

    Recent data have revealed epigenetic derangements and subsequent chromatin remodeling as a potent biologic switch for chronic inflammation and cell survival which are important therapeutic targets in the pathogenesis of several retinal degenerations. Histone deacetylases (HDACs) are a major component of this system and serve as a unique control of the chromatin remodeling process. With a multitude of targeted HDAC inhibitors now available, their use in both basic science and clinical studies has widened substantially. In the field of ocular biology, there are data to suggest that HDAC inhibition may suppress neovascularization and may be a possible treatment for retinitis pigmentosa and dry age-related macular degeneration (AMD). However, the effects of these inhibitors on cell survival and chemokine expression in the chorioretinal tissues remain very unclear. Here, we review the multifaceted biology of HDAC activity and pharmacologic inhibition while offering further insight into the importance of this epigenetic pathway in retinal degenerations. Our laboratory investigations aim to open translational avenues to advance dry AMD therapeutics while exploring the role of acetylation on inflammatory gene expression in the aging and degenerating retina. PMID:26427391

  10. Lung Regeneration: Endogenous and Exogenous Stem Cell Mediated Therapeutic Approaches.

    PubMed

    Akram, Khondoker M; Patel, Neil; Spiteri, Monica A; Forsyth, Nicholas R

    2016-01-19

    The tissue turnover of unperturbed adult lung is remarkably slow. However, after injury or insult, a specialised group of facultative lung progenitors become activated to replenish damaged tissue through a reparative process called regeneration. Disruption in this process results in healing by fibrosis causing aberrant lung remodelling and organ dysfunction. Post-insult failure of regeneration leads to various incurable lung diseases including chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis. Therefore, identification of true endogenous lung progenitors/stem cells, and their regenerative pathway are crucial for next-generation therapeutic development. Recent studies provide exciting and novel insights into postnatal lung development and post-injury lung regeneration by native lung progenitors. Furthermore, exogenous application of bone marrow stem cells, embryonic stem cells and inducible pluripotent stem cells (iPSC) show evidences of their regenerative capacity in the repair of injured and diseased lungs. With the advent of modern tissue engineering techniques, whole lung regeneration in the lab using de-cellularised tissue scaffold and stem cells is now becoming reality. In this review, we will highlight the advancement of our understanding in lung regeneration and development of stem cell mediated therapeutic strategies in combating incurable lung diseases.

  11. Lung Regeneration: Endogenous and Exogenous Stem Cell Mediated Therapeutic Approaches.

    PubMed

    Akram, Khondoker M; Patel, Neil; Spiteri, Monica A; Forsyth, Nicholas R

    2016-01-01

    The tissue turnover of unperturbed adult lung is remarkably slow. However, after injury or insult, a specialised group of facultative lung progenitors become activated to replenish damaged tissue through a reparative process called regeneration. Disruption in this process results in healing by fibrosis causing aberrant lung remodelling and organ dysfunction. Post-insult failure of regeneration leads to various incurable lung diseases including chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis. Therefore, identification of true endogenous lung progenitors/stem cells, and their regenerative pathway are crucial for next-generation therapeutic development. Recent studies provide exciting and novel insights into postnatal lung development and post-injury lung regeneration by native lung progenitors. Furthermore, exogenous application of bone marrow stem cells, embryonic stem cells and inducible pluripotent stem cells (iPSC) show evidences of their regenerative capacity in the repair of injured and diseased lungs. With the advent of modern tissue engineering techniques, whole lung regeneration in the lab using de-cellularised tissue scaffold and stem cells is now becoming reality. In this review, we will highlight the advancement of our understanding in lung regeneration and development of stem cell mediated therapeutic strategies in combating incurable lung diseases. PMID:26797607

  12. Tourette's syndrome: clinical features, pathophysiology, and therapeutic approaches.

    PubMed

    Müller, Norbert

    2007-01-01

    Tourette's syndrome (TS) is a disorder characterized by simple and complex motor tics, vocal tics, and frequently obsessive-compulsive symptoms. Its onset occurs before the age of 21. Typically, TS shows a waxing and waning course, but a chronification of the tics, even during later life, is often observed. TS mainly occurs in boys, and shows genetic heritability with differing penetrance. The pathological mechanism is still unclear Neuroanatomical and neuroimaging studies, as well as effective treatment using antipsychotics, suggest that a disturbance of the dopaminergic system in the basal ganglia plays an important role in the pathogenesis of TS. Several possibly causative mechanisms of the disturbed dopaminergic neurotransmission are discussed, with the main emphasis on the-infection-triggered-inflammatory immune process. Extrapyramidal movement disorders are known to occur as a symptom of poststreptococcal disease, such as in Sydenham's chorea. Cases of childhood TS are proposed to be caused by such a poststreptococcal mechanism, being part of a spectrum of childhood neurobehavioral disorders termed pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS). The overlap between TS and PANDAS is discussed, and a critical view of the PANDAS concept is presented. The therapeutic implications of the different pathological mechanisms are described, taking into consideration not only the acute or chronic natures of different infections, but also an autoimmune process. Moreover, therapeutic strategies using typical and atypical antipsychotics, and also experimental therapies such as repetitive transcranial magnetic stimulation and deep brain stimulation, are critically discussed.

  13. Lung Regeneration: Endogenous and Exogenous Stem Cell Mediated Therapeutic Approaches

    PubMed Central

    Akram, Khondoker M.; Patel, Neil; Spiteri, Monica A.; Forsyth, Nicholas R.

    2016-01-01

    The tissue turnover of unperturbed adult lung is remarkably slow. However, after injury or insult, a specialised group of facultative lung progenitors become activated to replenish damaged tissue through a reparative process called regeneration. Disruption in this process results in healing by fibrosis causing aberrant lung remodelling and organ dysfunction. Post-insult failure of regeneration leads to various incurable lung diseases including chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis. Therefore, identification of true endogenous lung progenitors/stem cells, and their regenerative pathway are crucial for next-generation therapeutic development. Recent studies provide exciting and novel insights into postnatal lung development and post-injury lung regeneration by native lung progenitors. Furthermore, exogenous application of bone marrow stem cells, embryonic stem cells and inducible pluripotent stem cells (iPSC) show evidences of their regenerative capacity in the repair of injured and diseased lungs. With the advent of modern tissue engineering techniques, whole lung regeneration in the lab using de-cellularised tissue scaffold and stem cells is now becoming reality. In this review, we will highlight the advancement of our understanding in lung regeneration and development of stem cell mediated therapeutic strategies in combating incurable lung diseases. PMID:26797607

  14. Mechanism and novel therapeutic approaches to wasting in chronic disease.

    PubMed

    Ebner, Nicole; Springer, Jochen; Kalantar-Zadeh, Kamyar; Lainscak, Mitja; Doehner, Wolfram; Anker, Stefan D; von Haehling, Stephan

    2013-07-01

    Cachexia is a multifactorial syndrome defined by continuous loss of skeletal muscle mass - with or without loss of fat mass - which cannot be fully reversed by conventional nutritional support and which may lead to progressive functional impairment and increased death risk. Its pathophysiology is characterized by negative protein and energy balance driven by a variable combination of reduced food intake and abnormal metabolism. Muscle wasting is encountered in virtually all chronic disease states in particular during advanced stages of the respective illness. Several pre-clinical and clinical studies are ongoing to ameliorate this clinical problem. The mechanisms of muscle wasting and cachexia in chronic diseases such as cancer, chronic heart failure, chronic obstructive pulmonary disease and chronic kidney disease are described. We discuss therapeutic targets and such potential modulators as appetite stimulants, selective androgen receptor modulators, amino acids and naturally occurring peptide hormones.

  15. Amyotrophic Lateral Sclerosis and Metabolomics: Clinical Implication and Therapeutic Approach

    PubMed Central

    Kumar, Alok; Ghosh, Devlina; Singh, R. L.

    2013-01-01

    Amyotrophic lateral sclerosis (ALS) is one of the most common motor neurodegenerative disorders, primarily affecting upper and lower motor neurons in the brain, brainstem, and spinal cord, resulting in paralysis due to muscle weakness and atrophy. The majority of patients die within 3–5 years of symptom onset as a consequence of respiratory failure. Due to relatively fast progression of the disease, early diagnosis is essential. Metabolomics offer a unique opportunity to understand the spatiotemporal metabolic crosstalks through the assessment of body fluids and tissue. So far, one of the most challenging issues related to ALS is to understand the variation of metabolites in body fluids and CNS with the progression of disease. In this paper we will review the changes in metabolic profile in response to disease progression condition and also see the therapeutic implication of various drugs in ALS patients. PMID:26317018

  16. [Limitation of therapeutic effort: Approach to a combined view].

    PubMed

    Bueno Muñoz, M J

    2013-01-01

    Over the past few decades, we have been witnessing that increasing fewer people pass away at home and increasing more do so within the hospital. More specifically, 20% of deaths now occur in an intensive care unit (ICU). However, death in the ICU has become a highly technical process. This sometimes originates excesses because the resources used are not proportionate related to the purposes pursued (futility). It may create situations that do not respect the person's dignity throughout the death process. It is within this context that the situation of the clinical procedure called "limitation of the therapeutic effort" (LTE) is reviewed. This has become a true bridge between Intensive Care and Palliative Care. Its final goal is to guarantee a dignified and painless death for the terminally ill.

  17. Polymicrobial wound infections: pathophysiology and current therapeutic approaches.

    PubMed

    Bertesteanu, Serban; Triaridis, Stefanos; Stankovic, Milan; Lazar, Veronica; Chifiriuc, Mariana Carmen; Vlad, Mihaela; Grigore, Raluca

    2014-03-25

    Acute and chronic wounds represent a very common health problem in the entire world. The dermal wounds are colonized by aerobic and anaerobic bacterial and fungal strains, most of them belonging to the resident microbiota of the surrounding skin, oral cavity and gut, or from the external environment, forming polymicrobial communities called biofilms, which are prevalent especially in chronic wounds. A better understanding of the precise mechanisms by which microbial biofilms delay repair processes together with optimizing methods for biofilm detection and prevention may enhance opportunities for chronic wounds healing. The purpose of this minireview is to assess the role of polymicrobial biofilms in the occurrence and evolution of wound infections, as well as the current and future preventive and therapeutic strategies used for the management of polymicrobial wound infections.

  18. [THERAPEUTIC APPROACH TO HUMERAL BONE FRACTURES COMPLICATED BY PERIPHERAL NERVE TRAUMA].

    PubMed

    Neverov, V A; Chernyaev, S N; Shinkarenko, D V

    2015-01-01

    On the basis of treatment results of 28 patients, the authors suggested that the clinical method of diagnostics allowed performance of topical diagnostics of injury using bedside test. It would help to choose a therapeutic approach in each clinical case.

  19. Therapeutic approaches for treating hemophilia A using embryonic stem cells.

    PubMed

    Kasuda, Shogo; Tatsumi, Kohei; Sakurai, Yoshihiko; Shima, Midori; Hatake, Katsuhiko

    2016-06-01

    Hemophilia A is an X-linked rescessive bleeding disorder that results from F8 gene aberrations. Previously, we established embryonic stem (ES) cells (tet-226aa/N6-Ainv18) that secrete human factor VIII (hFVIII) by introducing the human F8 gene in mouse Ainv18 ES cells. Here, we explored the potential of cell transplantation therapy for hemophilia A using the ES cells. Transplant tet-226aa/N6-Ainv18 ES cells were injected into the spleens of severe combined immunodeficiency (SCID) mice, carbon tetrachloride (CCl4)-pretreated wild-type mice, and CCl4-pretreated hemophilia A mice. F8 expression was induced by doxycycline in drinking water, and hFVIII-antigen production was assessed in all cell transplantation experiments. Injecting the ES cells into SCID mice resulted in an enhanced expression of the hFVIII antigen; however, teratoma generation was confirmed in the spleen. Transplantation of ES cells into wild-type mice after CCl4-induced liver injury facilitated survival and engraftment of transplanted cells without teratoma formation, resulting in hFVIII production in the plasma. Although CCl4 was lethal to most hemophilia A mice, therapeutic levels of FVIII activity, as well as the hFVIII antigen, were detected in surviving hemophilia A mice after cell transplantation. Immunolocalization results for hFVIII suggested that transplanted ES cells might be engrafted at the periportal area in the liver. Although the development of a safer induction method for liver regeneration is required, our results suggested the potential for developing an effective ES-cell transplantation therapeutic model for treating hemophilia A in the future. PMID:27131224

  20. Osteitis pubis in elite athletes: Diagnostic and therapeutic approach.

    PubMed

    Angoules, Antonios G

    2015-10-18

    Osteitis pubis (OP) is a debilitating overuse syndrome characterizing by pelvic pain and local tenderness over the pubic symphysis commonly encountered in athletes often involved in kicking, twisting and cutting activities in sports such as soccer and rugby and to a lesser degree distance running. It is a common source of groin pain in elite athletes attributable to pubis sympysis instability as the result of microtrauma caused by repetitive muscle strains on pubic bones. Diagnosis is based mainly on detailed sports history and a meticulous clinical examination, although occasionally is difficult to distinguish this nosological entity from other pathologies affecting the involved area which may occur concomitantly in the same patient. Radiologic examinations such as plain radiographs, magnetic resonance imaging and 3 phase bone isotope scanning may be helpful to differentiate from other clinical entities with similar clinical presentation. Most cases respond well to conservative treatment which includes several physical modalities and especially a progressive rehabilitation programmed individualized to each one of patients diagnosed with OP. Local injection therapies have been also been proposed as a non-operative therapeutic option for the efficient management of these patients. In refractory cases, surgical therapeutic strategies are warranted. These include several open or minimally invasive surgical interventions such as arthroscopic or open symphysis curettage, wedge or total resection of pubic sympysis, polypropylene mesh placement and pubic fusion. In this review a critical analysis of OP in elite athletes is performed with special focus on current concepts of diagnosis and management of this source of athletic groin pain. PMID:26495244

  1. Osteitis pubis in elite athletes: Diagnostic and therapeutic approach

    PubMed Central

    Angoules, Antonios G

    2015-01-01

    Osteitis pubis (OP) is a debilitating overuse syndrome characterizing by pelvic pain and local tenderness over the pubic symphysis commonly encountered in athletes often involved in kicking, twisting and cutting activities in sports such as soccer and rugby and to a lesser degree distance running. It is a common source of groin pain in elite athletes attributable to pubis sympysis instability as the result of microtrauma caused by repetitive muscle strains on pubic bones. Diagnosis is based mainly on detailed sports history and a meticulous clinical examination, although occasionally is difficult to distinguish this nosological entity from other pathologies affecting the involved area which may occur concomitantly in the same patient. Radiologic examinations such as plain radiographs, magnetic resonance imaging and 3 phase bone isotope scanning may be helpful to differentiate from other clinical entities with similar clinical presentation. Most cases respond well to conservative treatment which includes several physical modalities and especially a progressive rehabilitation programmed individualized to each one of patients diagnosed with OP. Local injection therapies have been also been proposed as a non-operative therapeutic option for the efficient management of these patients. In refractory cases, surgical therapeutic strategies are warranted. These include several open or minimally invasive surgical interventions such as arthroscopic or open symphysis curettage, wedge or total resection of pubic sympysis, polypropylene mesh placement and pubic fusion. In this review a critical analysis of OP in elite athletes is performed with special focus on current concepts of diagnosis and management of this source of athletic groin pain. PMID:26495244

  2. Therapeutic approaches for treating hemophilia A using embryonic stem cells.

    PubMed

    Kasuda, Shogo; Tatsumi, Kohei; Sakurai, Yoshihiko; Shima, Midori; Hatake, Katsuhiko

    2016-06-01

    Hemophilia A is an X-linked rescessive bleeding disorder that results from F8 gene aberrations. Previously, we established embryonic stem (ES) cells (tet-226aa/N6-Ainv18) that secrete human factor VIII (hFVIII) by introducing the human F8 gene in mouse Ainv18 ES cells. Here, we explored the potential of cell transplantation therapy for hemophilia A using the ES cells. Transplant tet-226aa/N6-Ainv18 ES cells were injected into the spleens of severe combined immunodeficiency (SCID) mice, carbon tetrachloride (CCl4)-pretreated wild-type mice, and CCl4-pretreated hemophilia A mice. F8 expression was induced by doxycycline in drinking water, and hFVIII-antigen production was assessed in all cell transplantation experiments. Injecting the ES cells into SCID mice resulted in an enhanced expression of the hFVIII antigen; however, teratoma generation was confirmed in the spleen. Transplantation of ES cells into wild-type mice after CCl4-induced liver injury facilitated survival and engraftment of transplanted cells without teratoma formation, resulting in hFVIII production in the plasma. Although CCl4 was lethal to most hemophilia A mice, therapeutic levels of FVIII activity, as well as the hFVIII antigen, were detected in surviving hemophilia A mice after cell transplantation. Immunolocalization results for hFVIII suggested that transplanted ES cells might be engrafted at the periportal area in the liver. Although the development of a safer induction method for liver regeneration is required, our results suggested the potential for developing an effective ES-cell transplantation therapeutic model for treating hemophilia A in the future.

  3. Encountering place: a psychoanalytic approach for understanding how therapeutic landscapes benefit health and wellbeing.

    PubMed

    Rose, Emma

    2012-11-01

    This paper applies new thinking in psychoanalytic theory to demonstrate how certain therapeutic landscapes work to enhance health and wellbeing. Over the past two decades health geographers have extended the concept of therapeutic landscapes to analyse place and health as it applies to diverse locations embodying therapeutic qualities for different groups of people. Various approaches to how the process works have been psychoanalytic and psychotherapeutic theories. The concept of 'mentalising' as applied to therapeutic landscapes is offered by this paper as a further, hopefully enriching contribution to this line of enquiry. It examines the significance of prior familiarity with representations of specific landscapes, what the actual landscape offers to imaginative or projective reconstructions, the importance of cultural resources enabling landscape to be apprehended metaphorically, and the contribution of landscapes seen in this way to therapeutic effects. Therapeutic landscapes are shown to improve individual self-understanding and to enhance the capacity to empathise with others.

  4. The interdisciplinary approach of an aggressive giant cell tumor of bone complicated with a fracture of the distal femur.

    PubMed

    Vîlcioiu, Iulian Daniel; Zamfirescu, Dragoş George; Cristescu, Ioan; Ursache, Andrei; Popescu, Şerban Arghir; Creangă, Cosmin Antoniu; Lascăr, Ioan

    2016-01-01

    Giant cell tumor of bone (GCTB) represents one of the commonest bone tumors encountered by an orthopedic surgeon. The giant-cell tumor is generally classified as benign but the fast growing rhythm and the aggressive soft-tissue invasion may in some cases demonstrate a malign potential of the tumor. We present the case of an aggressive giant cell tumor in a young patient that was first diagnosed in our emergency department with a fracture of the distal femur after a low energy trauma. With further examinations, we discovered that the tumor was invading the both femoral condyles and was vascularized by three major arterial pedicles. The onset of his problems was the femoral fracture and the changes on the major vessels, muscles and nerves. After an interdisciplinary approach of the patient and a meticulous preoperative planning, we decided to make an extensive total resection of the tumor followed by a complex reconstruction surgery for the bone. A very stable fixation of a vascularized graft allowed the bone to heal even if the surrounded soft-tissue was almost completely invaded by the tumor and removed during the excision. The follow-up of this case demonstrated that using an interdisciplinary approach of the patient with the Plastic Surgery team, we manage to remove the tumor within oncological limits and achieved bone healing with good stability of the distal femur. PMID:27516036

  5. Endothelial Dysfunction: Clinical Implications in Cardiovascular Disease and Therapeutic Approaches.

    PubMed

    Park, Kyoung-Ha; Park, Woo Jung

    2015-09-01

    Atherosclerosis is a chronic progressive vascular disease. It starts early in life, has a long asymptomatic phase, and a progression accelerated by various cardiovascular risk factors. The endothelium is an active inner layer of the blood vessel. It generates many factors that regulate vascular tone, the adhesion of circulating blood cells, smooth muscle proliferation, and inflammation, which are the key mechanisms of atherosclerosis and can contribute to the development of cardiovascular events. There is growing evidence that functional impairment of the endothelium is one of the first recognizable signs of development of atherosclerosis and is present long before the occurrence of atherosclerotic cardiovascular disease. Therefore, understanding the endothelium's central role provides not only insights into pathophysiology, but also a possible clinical opportunity to detect early disease, stratify cardiovascular risk, and assess response to treatments. In the present review, we will discuss the clinical implications of endothelial function as well as the therapeutic issues for endothelial dysfunction in cardiovascular disease as primary and secondary endothelial therapy.

  6. Therapeutic approaches in myelofibrosis and myelodysplastic/myeloproliferative overlap syndromes

    PubMed Central

    Sochacki, Andrew L; Fischer, Melissa A; Savona, Michael R

    2016-01-01

    The discovery of JAK2V617F a decade ago led to optimism for a rapidly developing treatment revolution in Ph− myeloproliferative neoplasms. Unlike BCR–ABL, however, JAK2 was found to have a more heterogeneous role in carcinogenesis. Therefore, for years, development of new therapies was slow, despite standard treatment options that did not address the overwhelming symptom burden in patients with primary myelofibrosis (MF), post-essential thrombocythemia MF, post-polycythemia vera MF, and myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) syndromes. JAK–STAT inhibitors have changed this, drastically ameliorating symptoms and ultimately beginning to show evidence of impact on survival. Now, the genetic foundations of myelofibrosis and MDS/MPN are rapidly being elucidated and contributing to targeted therapy development. This has been empowered through updated response criteria for MDS/MPN and refined prognostic scoring systems in these diseases. The aim of this article is to summarize concisely the current and rationally designed investigational therapeutics directed at JAK–STAT, hedgehog, PI3K–Akt, bone marrow fibrosis, telomerase, and rogue epigenetic signaling. The revolution in immunotherapy and novel treatments aimed at previously untargeted signaling pathways provides hope for considerable advancement in therapy options for those with chronic myeloid disease. PMID:27143923

  7. [Acquierd entero-cutaneous fistulas--diagnostic and therapeutic approach].

    PubMed

    Draganov, K; Dimitrova, V; Ionkov, A; Rusenov, D; Tosheva, E; Dimitrov, K; Tonev, S

    2005-01-01

    The acquired entero-cutaneous fistulas are a current problem in the field of abdominal surgery. Most of them are postoperative--after an intestinal resection and/or anastomosis. Crohn's disease and coplicated colonic diverticulosis rank second as causal factors. The risk factors for the development of an entero-cutaneous fistula and for the poor prognosis at the same time are the next: (1) Most of the patients suffer of severe main and co-exhisting diseases; (2) The presence of previous laparotomies, radion and chemotherapy, significant disturbances in the base-acid and water-electrolyte balance; (3) The fistula itself worsens these disturbances and may doom to fail the substitutional and nutritional therapy. The diagnostics of a fistula, including its location is comparatively easy. The surgical treatment plays an important role in the therapeutic scheme, especially in cases of high-output fistulas of the small intestin. At the same time the adequate total parenteral nutrition and correction of the base-acid and water-electrolyte disbalance is also very important. Recently there are some new diagnostic methods and alternatives of the basic surgical procedures, some of them quite contraversial.

  8. The Endothelial Glycocalyx: New Diagnostic and Therapeutic Approaches in Sepsis

    PubMed Central

    Koczera, Patrick

    2016-01-01

    Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. The endothelial glycocalyx is one of the earliest sites involved during sepsis. This fragile layer is a complex network of cell-bound proteoglycans, glycosaminoglycan side chains, and sialoproteins lining the luminal side of endothelial cells with a thickness of about 1 to 3 μm. Sepsis-associated alterations of its structure affect endothelial permeability and result in the liberation of endogenous damage-associated molecular patterns (DAMPs). Once liberated in the circulatory system, DAMPs trigger the devastating consequences of the proinflammatory cascades in sepsis and septic shock. In this way, the injury to the glycocalyx with the consecutive release of DAMPs contributes to a number of specific clinical effects of sepsis, including acute kidney injury, respiratory failure, and septic cardiomyopathy. Moreover, the extent of glycocalyx degradation serves as a marker of endothelial dysfunction and sepsis severity. In this review, we highlight the crucial role of the glycocalyx in sepsis as a diagnostic tool and discuss the potential of members of the endothelial glycocalyx serving as hopeful therapeutic targets in sepsis-associated multiple organ failures. PMID:27699168

  9. Novel therapeutic approaches for Leber's hereditary optic neuropathy.

    PubMed

    Iyer, Shilpa

    2013-03-01

    Many human childhood mitochondrial disorders result from abnormal mitochondrial DNA (mtDNA) and altered bioenergetics. These abnormalities span most of the mtDNA, demonstrating that there are no "unique" positions on the mitochondrial genome that when deleted or mutated produce a disease phenotype. This diversity implies that the relationship between mitochondrial genotype and clinical phenotype is very complex. The origins of clinical phenotypes are thus unclear, fundamentally difficult-to-treat, and are usually clinically devastating. Current treatment is largely supportive and the disorders progress relentlessly causing significant morbidity and mortality. Vitamin supplements and pharmacological agents have been used in isolated cases and clinical trials, but the efficacy of these interventions is unclear. In spite of recent advances in the understanding of the pathogenesis of mitochondrial diseases, a cure remains elusive. An optimal cure would be gene therapy, which involves introducing the missing gene(s) into the mitochondria to complement the defect. Our recent research results indicate the feasibility of an innovative protein-transduction ("protofection") technology, consisting of a recombinant mitochondrial transcription factor A (TFAM) that avidly binds mtDNA and permits efficient targeting into mitochondria in situ and in vivo. Thus, the development of gene therapy for treating mitochondrial disease offers promise, because it may circumvent the clinical abnormalities and the current inability to treat individual disorders in affected individuals. This review aims to focus on current treatment options and future therapeutics in mitochondrial disease treatment with a special emphasis on Leber's hereditary optic neuropathy.

  10. The Endothelial Glycocalyx: New Diagnostic and Therapeutic Approaches in Sepsis

    PubMed Central

    Koczera, Patrick

    2016-01-01

    Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. The endothelial glycocalyx is one of the earliest sites involved during sepsis. This fragile layer is a complex network of cell-bound proteoglycans, glycosaminoglycan side chains, and sialoproteins lining the luminal side of endothelial cells with a thickness of about 1 to 3 μm. Sepsis-associated alterations of its structure affect endothelial permeability and result in the liberation of endogenous damage-associated molecular patterns (DAMPs). Once liberated in the circulatory system, DAMPs trigger the devastating consequences of the proinflammatory cascades in sepsis and septic shock. In this way, the injury to the glycocalyx with the consecutive release of DAMPs contributes to a number of specific clinical effects of sepsis, including acute kidney injury, respiratory failure, and septic cardiomyopathy. Moreover, the extent of glycocalyx degradation serves as a marker of endothelial dysfunction and sepsis severity. In this review, we highlight the crucial role of the glycocalyx in sepsis as a diagnostic tool and discuss the potential of members of the endothelial glycocalyx serving as hopeful therapeutic targets in sepsis-associated multiple organ failures.

  11. Targeting CBLB as a potential therapeutic approach for disseminated candidiasis.

    PubMed

    Xiao, Yun; Tang, Juan; Guo, Hui; Zhao, Yixia; Tang, Rong; Ouyang, Song; Zeng, Qiuming; Rappleye, Chad A; Rajaram, Murugesan V S; Schlesinger, Larry S; Tao, Lijian; Brown, Gordon D; Langdon, Wallace Y; Li, Belinda T; Zhang, Jian

    2016-08-01

    Disseminated candidiasis has become one of the leading causes of hospital-acquired blood stream infections with high mobility and mortality. However, the molecular basis of host defense against disseminated candidiasis remains elusive, and treatment options are limited. Here we report that the E3 ubiquitin ligase CBLB directs polyubiquitination of dectin-1 and dectin-2, two key pattern-recognition receptors for sensing Candida albicans, and their downstream kinase SYK, thus inhibiting dectin-1- and dectin-2-mediated innate immune responses. CBLB deficiency or inactivation protects mice from systemic infection with a lethal dose of C. albicans, and deficiency of dectin-1, dectin-2, or both in Cblb(-/-) mice abrogates this protection. Notably, silencing the Cblb gene in vivo protects mice from lethal systemic C. albicans infection. Our data reveal that CBLB is crucial for homeostatic control of innate immune responses mediated by dectin-1 and dectin-2. Our data also indicate that CBLB represents a potential therapeutic target for protection from disseminated candidiasis. PMID:27428899

  12. Counselling Refugee Young People: An Exploration of Therapeutic Approaches

    ERIC Educational Resources Information Center

    Warr, Sally

    2010-01-01

    This paper presents and discusses the key findings from a study that considered significant issues that affect refugees and asylum-seekers, and explored beneficial counselling approaches relevant to this group. In-depth narrative interviews were conducted with three counsellors and three specialist children's support advisors. Data were analysed…

  13. Novel therapeutic approaches to Guillain-Barré syndrome.

    PubMed

    Pritchard, J

    2000-10-01

    Guillain-Barré syndrome is an autoimmune disease which occurs throughout the world. Whilst the majority of patients can expect a reasonable recovery, about 10% die and 10% are left disabled with current therapy. The standard treatment is a five day course of iv. immunoglobulin, given at a dose of 0.4 g/kg/day, with plasma exchange as an equally efficacious alternative. Steroids are ineffective in Guillain-Barré syndrome. All new potential therapeutic agents need to be tested in addition to the standard agents available. Future potential therapies are suggested by the study of the animal model experimental autoimmune neuritis in the Lewis rat. Whilst in theory it is possible to target the different stages of the immune response, in practice not all of the steps at which experimental autoimmune neuritis can be prevented will be translatable to human Guillain-Barré syndrome. This is because Guillain-Barré syndrome probably presents after the immune reaction has been ongoing for some time and therefore early aspects of the immune response cannot be prevented. Many of the possible measures would have widespread immunosuppressive effects which would be unacceptable to patients. Interfering with the immune response by attempting to block antigen binding or inducing tolerance may not be practical, owing to the possibility of exacerbating disease. Once we have a more thorough understanding of the pathogenesis of Guillain-Barré syndrome, then immune-specific therapy for Guillain-Barré syndrome may become a possibility, rather than general immunosuppressive measures. Trials of beta-interferon and of a combination of steroid and i.v. immunoglobulin are underway. A trial of a second course of i.v. immunoglobulin is planned. PMID:11060808

  14. Novel therapeutic delivery approaches in development for pediatric gliomas.

    PubMed

    Warren, Katherine E

    2013-09-01

    Pediatric gliomas are a heterogeneous group of diseases, ranging from relatively benign pilocytic astrocytomas with >90% 5-year survival, to glioblastomas and diffuse intrinsic pontine gliomas with <20% 5-year survival. Chemotherapy plays an important role in the management of these tumors, particularly in low-grade gliomas, but many high-grade tumors are resistant to chemotherapy. A major obstacle and contributor to this resistance is the blood–brain barrier, which protects the CNS by limiting entry of potential toxins, including chemotherapeutic agents. Several novel delivery approaches that circumvent the blood–brain barrier have been developed, including some currently in clinical trials. This review describes several of these novel approaches to improve delivery of chemotherapeutic agents to their site of action at the tumor, in attempts to improve their efficacy and the prognosis of children with this disease.

  15. Integration of therapeutic approaches in working with children

    PubMed Central

    Cordell, Antoinette S.; Allen, Susan F.

    1997-01-01

    Child treatment and family therapy have developed divergent theories and methods, yet each contributes concepts that benefit children and families presenting with clinical problems. The authors discuss the theories and methods for both forms of treatment and review the literature on efforts to combine these approaches. They then describe a model, illustrated with case examples, in which careful assessment and planning throughout the treatment process are used to flexibly combine individual and family therapy techniques. PMID:9058560

  16. Transcatheter and ablative therapeutic approaches for solid malignancies.

    PubMed

    Liapi, Eleni; Geschwind, Jean-Francois H

    2007-03-10

    The purpose of this article is to present in a concise manner an overview of the most widely used locoregional transcatheter and ablative therapies for solid malignancies. An extensive MEDLINE search was performed for this review. Therapies used for liver cancer were emphasized because these therapies are used most commonly in the liver. Applications in pulmonary, renal, and bone tumors were also discussed. These approaches were divided into catheter-based therapies (such as transcatheter arterial chemoembolization, bland embolization, and the most recent transcatheter arterial approach with drug-eluting microspheres), ablative therapies (such as chemical [ethanol or acetic acid injection]), and thermal ablative therapies (such as radiofrequency ablation, laser induced thermotherapy, microwave ablation, cryoablation, and extracorporeal high-intensity focused ultrasound ablation). A brief description of each technique and analysis of available data was reported for all therapies. Locoregional transcatheter and ablative therapies continue to be used mostly for palliation, but have also been used with curative intent. A growing body of evidence suggests clear survival benefit, excellent results regarding local tumor control, and improved quality of life. Clinical trials are underway to validate these results. Image-guided transcatheter and ablative approaches currently play an important role in the management of patients with various types of cancer-a role that is likely to grow even more given the technological advances in imaging, image-guidance systems, catheters, ablative tools, and drug delivery systems. As a result, the outcomes of patients with cancer undoubtedly will improve.

  17. A nonsurgical approach to treating aggressive inflammatory papillary hyperplasia: a clinical report.

    PubMed

    Orenstein, Noah P; Taylor, Thomas

    2014-04-01

    Preprosthetic interventions in patients with aggressive forms of inflammatory papillary hyperplasia have historically involved surgery. These procedures often involve significant postoperative discomfort and morbidity. Additionally, some patients who present with dental phobias, aversions to surgery, or underlying systemic disease may not be amenable to this type of surgical intervention. In this report, a patient with severe inflammatory papillary hyperplasia and phobias regarding the dentist and dental surgery was treated nonsurgically, following strict adherence to a clinical protocol. The methodology involved greater patient comfort during treatment, encouraged positive reinforcement to visiting the dentist for recall appointments, and effectively eliminated the underlying inflammatory papillary hyperplasia, allowing for the successful fabrication of the definitive removable prostheses. PMID:24360006

  18. Therapeutic insemination.

    PubMed

    Alexander, N J; Ackerman, S

    1987-12-01

    Except in special circumstances, therapeutic insemination with a husband's sample has a low success rate. Couples in whom oligozoospermia has been identified as the principal cause of infertility do not benefit from therapeutic insemination by husband. Because of this low success rate, intrauterine insemination to provide sperm in closer proximity to the egg has become popular, but intrauterine insemination also has a low success rate. We suggest that intrauterine insemination should be approached aggressively in cases of male factor infertility. The recipient should be stimulated to enhance egg production and closely monitored for ovulation. A semen specimen of not less than 1 X 10(6) motile sperm with antibiotics added should be placed in the uterus the day after ovulation. If no pregnancies occur within four cycles, alternate approaches should be considered. Therapeutic insemination by donor involves careful donor selection to avoid inheritance of malformations and familial diseases. Because of the possibilities of sexually transmitted diseases, careful and repeated screening should be conducted. A complete sexual history should be obtained, and donors should be excluded if they have had any homosexual contact since 1978, if they have been an intravenous drug user, if they come from a geographic area where the sex ratio of AIDS is close to 1:1, or if they have recently had multiple sexual partners. A permanent record preserving the confidentiality but allowing the tracing of genetic anomalies, even if not present at birth, should be kept. PMID:3328130

  19. Novel therapeutic approaches for recurrent nonmuscle invasive bladder cancer.

    PubMed

    Boehm, Brock E; Svatek, Robert S

    2015-05-01

    This article summarizes strategies being investigated in patients with nonmuscle invasive bladder cancer. Progress has been made toward improving the delivery method of intravesical agents. Intravesical therapy is limited by the amount of time that the agent remains in contact with the bladder. Bladder cancer is considered to be responsive to immune therapy. Thus, many novel approaches are immune-based therapies and include cancer vaccines, use of Bacillus Calmette-Guérin (BCG) subcomponents, and checkpoint inhibitors. Finally, access to bladder mucosa via direct catheterization into the bladder via the urethra has enabled unique strategies for delivery of cancer therapy including viral- or plasmid-based gene therapy.

  20. Late-Developing Supernumerary Premolars: Analysis of Different Therapeutic Approaches

    PubMed Central

    Lucchese, Alessandra; Aiello, Domenico

    2016-01-01

    This case series describes the different potential approaches to late-developing supernumerary premolars (LDSP). LDSP are supernumerary teeth (ST) formed after the eruption of the permanent dentition; usually they develop in the premolar region of the upper and lower jaw. The choice to extract or to monitor the LDSP depends on many factors and has to be carefully planned due to the several risks that either the monitoring or the extraction could provoke. These four cases of LDSP showed different treatment plan alternatives derived from a scrupulous assessment of the clinical and radiographic information. PMID:27761271

  1. [Changing the therapeutic approach to acute otitis media in children].

    PubMed

    Grossman, Zahi; Branski, David

    2004-04-01

    Acute Otitis Media (AOM) is the most common reason for pediatrician's visits and for antibiotic prescription in childhood. A significant rise in bacterial resistance to antibiotic treatment has been detected in recent years. Accordingly, the attitude towards antibiotic treatment for AOM has been re-evaluated. Due to various difficulties in ear examination, physicians overdiagnosis Otitis Media with Effusion (OME) as AOM, leading to unnecessary prescription of antibiotics. The natural history of AOM shows spontaneous improvement without complications. Studies that have examined antibiotic treatment versus placebo in AOM have shown only minimal advantage for the antibiotic therapy in symptom reduction. Critical appraisal of the literature according to Evidence-based Medicine (EBM) criteria has led to several meta-analyses that showed only a minor advantage for antibiotics over placebo in AOM. In the Netherlands, the approach to AOM is that of delayed prescribing: symptomatic therapy is given for the first 24-72 hours and an antibiotic drug is prescribed only if symptoms persist after this initial period. This review examines the difficulties in reaching an accurate diagnosis of AOM and describes the natural history of AOM and evaluates the studies and meta-analyses comparing antibiotics to placebo. The Dutch approach to AOM will be discussed as an option and a recommended basis for reduction in antibiotic prescriptions for AOM.

  2. Tau Based Therapeutic Approaches for Alzheimer’s Disease

    PubMed Central

    Boutajangout, Allal; Wisniewski, Thomas

    2014-01-01

    The accumulation of aggregated, hyperphosphorylated tau as neurofibrillary tangles (NFTs) and neuropil threads (NT) are cardinal features of Alzheimer’s disease (AD). The other lesions found in AD include amyloid plaques and congophilic amyloid angiopathy, both associated with the extracellular accumulation of the amyloid β (Aβ) peptide. AD is the most common cause of dementia globally. Currently there are no effective means to treat AD or even to slow it down. The dominant theory for the causation of AD is the amyloid cascade hypothesis, which suggests that the aggregation of Aβ as oligomers and amyloid plaques is central to the pathogenesis of AD. Numerous therapies have been developed directed to Aβ relate pathology, in particular various immunotherapeutic approaches. So far all of these have failed in clinical trials. Recently there has been more focus on therapy directed to tau related pathology, which correlates better with the cognitive status of patients, compared to the amyloid burden. Immunotherapeutic targeting of tau pathology has showed great potential to treat tau pathologies in mouse models of AD. A number of studies have shown the efficacy of both passive and active immunization. This review summarizes recent advances on therapy targeting pathological tau protein, in particular focusing on immunotherapeutic approaches which are showing great promise. PMID:24732638

  3. A Multi-scale Approach to Designing Therapeutics for Tuberculosis

    PubMed Central

    Linderman, Jennifer J.; Cilfone, Nicholas A.; Pienaar, Elsje; Gong, Chang; Kirschner, Denise E.

    2015-01-01

    Approximately one third of the world’s population is infected with Mycobacterium tuberculosis. Limited information about how the immune system fights M. tuberculosis and what constitutes protection from the bacteria impact our ability to develop effective therapies for tuberculosis. We present an in vivo systems biology approach that integrates data from multiple model systems and over multiple length and time scales into a comprehensive multi-scale and multi-compartment view of the in vivo immune response to M. tuberculosis. We describe computational models that can be used to study (a) immunomodulation with the cytokines tumor necrosis factor and interleukin 10, (b) oral and inhaled antibiotics, and (c) the effect of vaccination. PMID:25924949

  4. Myasthenia gravis: new therapeutic approaches based on pathophysiology.

    PubMed

    Lewis, Richard A

    2013-10-15

    Over the past 40 years Dr. Robert Lisak has made important contributions to our understanding of the pathophysiology and therapy of myasthenia gravis. This review will touch upon some of his work as it discusses current therapies and the potential for new treatments based on the evolving knowledge of the underlying basis of the disease. The recognition of different immune mechanisms that can cause the phenotype that we acknowledge as myasthenia gravis coincides with the introduction of monoclonal antibodies and other new therapies that can target specific aspects of the disease. This has raised our hopes for treatments that will have less side effects and be more effective. In some cases these hopes have been realized. In other instances, the situation remains a "work in progress". Dr. Lisak's work and teachings remain cogent to our modern approach to this classic immunologic disease.

  5. Overview of current therapeutic approaches for pulmonary hypertension

    PubMed Central

    Stamm, Jason A.; Risbano, Michael G.; Mathier, Michael A.

    2011-01-01

    There have been tremendous strides in the management of pulmonary hypertension over the past 20 years with the introduction of targeted medical therapies and overall improvements in surgical treatment options and general supportive care. Furthermore, recent data shows that the survival of those with pulmonary arterial hypertension is improving. While there has been tremendous progress, much work remains to be done in improving the care of those with secondary forms of pulmonary hypertension, who constitute the majority of patients with this disorder, and in the optimal treatment approach in those with pulmonary arterial hypertension. This article will review general and targeted medical treatment, along with surgical interventions, of those with pulmonary hypertension. PMID:22034603

  6. Aggression in Persons with Dementia: Use of Nursing Theory to Guide Clinical Practice

    PubMed Central

    Dettmore, Diane; Kolanowski, Ann; Boustani, Malaz

    2009-01-01

    With approximately four million people in the United States today diagnosed with dementia, one of the most devastating problems faced by caregivers and patients is dealing with aggressive behavior. Aggression occurs in half of persons diagnosed with dementia and is associated with more rapid cognitive decline, increased risk of abuse, and caregiver burden. This paper uses the Need-driven Dementia-compromised Behavior (NDB) model to explain aggression and discusses therapeutic approaches to care that combines non-pharmacological and pharmacological interventions targeting both the management of aggression crisis and preventing its future recurrence. A clinical algorithm guided by the NBD model is provided for practitioners. PMID:19215808

  7. Understanding the pelvic pain mechanism is key to find an adequate therapeutic approach.

    PubMed

    Van Kerrebroeck, Philip

    2016-06-25

    Pain is a natural mechanism to actual or potential tissue damage and involves both a sensory and an emotional experience. In chronic pelvic pain, localisation of pain can be widespread and can cause considerable distress. A multidisciplinary approach is needed in order to fully understand the pelvic pain mechanism and to identify an adequate therapeutic approach.

  8. Proteomic Approaches and Identification of Novel Therapeutic Targets for Alcoholism

    PubMed Central

    Gorini, Giorgio; Adron Harris, R; Dayne Mayfield, R

    2014-01-01

    Recent studies have shown that gene regulation is far more complex than previously believed and does not completely explain changes at the protein level. Therefore, the direct study of the proteome, considerably different in both complexity and dynamicity to the genome/transcriptome, has provided unique insights to an increasing number of researchers. During the past decade, extraordinary advances in proteomic techniques have changed the way we can analyze the composition, regulation, and function of protein complexes and pathways underlying altered neurobiological conditions. When combined with complementary approaches, these advances provide the contextual information for decoding large data sets into meaningful biologically adaptive processes. Neuroproteomics offers potential breakthroughs in the field of alcohol research by leading to a deeper understanding of how alcohol globally affects protein structure, function, interactions, and networks. The wealth of information gained from these advances can help pinpoint relevant biomarkers for early diagnosis and improved prognosis of alcoholism and identify future pharmacological targets for the treatment of this addiction. PMID:23900301

  9. [Cormorbidity in multiple sclerosis and its therapeutic approach].

    PubMed

    Estruch, Bonaventura Casanova

    2014-12-01

    Multiple sclerosis (MS) is a long-term chronic disease, in which intercurrent processes develop three times more frequently in affected individuals than in persons without MS. Knowledge of the comorbidity of MS, its definition and measurement (Charlson index) improves patient management. Acting on comorbid conditions delays the progression of disability, which is intimately linked to the number of concurrent processes and with health states and habits. Moreover, the presence of comorbidities delays the diagnosis of MS, which in turn delays the start of treatment. The main comorbidity found in MS includes other autoimmune diseases (thyroiditis, systemic lupus erythematosus, or pemphigus) but can also include general diseases, such as asthma or osteomuscular alterations, and, in particular, psychiatric disturbances. All these alterations should be evaluated with multidimensional scales (Disability Expectancy Table, DET), which allow more accurate determination of the patient's real clinical course and quality of life. These scales also allow identification of how MS, concurrent and intercurrent processes occurring during the clinical course, and the treatment provided affect patients with MS. An overall approach to patients' health status helps to improve quality of life. PMID:25732944

  10. [Cormorbidity in multiple sclerosis and its therapeutic approach].

    PubMed

    Estruch, Bonaventura Casanova

    2014-12-01

    Multiple sclerosis (MS) is a long-term chronic disease, in which intercurrent processes develop three times more frequently in affected individuals than in persons without MS. Knowledge of the comorbidity of MS, its definition and measurement (Charlson index) improves patient management. Acting on comorbid conditions delays the progression of disability, which is intimately linked to the number of concurrent processes and with health states and habits. Moreover, the presence of comorbidities delays the diagnosis of MS, which in turn delays the start of treatment. The main comorbidity found in MS includes other autoimmune diseases (thyroiditis, systemic lupus erythematosus, or pemphigus) but can also include general diseases, such as asthma or osteomuscular alterations, and, in particular, psychiatric disturbances. All these alterations should be evaluated with multidimensional scales (Disability Expectancy Table, DET), which allow more accurate determination of the patient's real clinical course and quality of life. These scales also allow identification of how MS, concurrent and intercurrent processes occurring during the clinical course, and the treatment provided affect patients with MS. An overall approach to patients' health status helps to improve quality of life.

  11. Psychedelics and Immunomodulation: Novel Approaches and Therapeutic Opportunities.

    PubMed

    Szabo, Attila

    2015-01-01

    Classical psychedelics are psychoactive substances, which, besides their psychopharmacological activity, have also been shown to exert significant modulatory effects on immune responses by altering signaling pathways involved in inflammation, cellular proliferation, and cell survival via activating NF-κB and mitogen-activated protein kinases. Recently, several neurotransmitter receptors involved in the pharmacology of psychedelics, such as serotonin and sigma-1 receptors, have also been shown to play crucial roles in numerous immunological processes. This emerging field also offers promising treatment modalities in the therapy of various diseases including autoimmune and chronic inflammatory conditions, infections, and cancer. However, the scarcity of available review literature renders the topic unclear and obscure, mostly posing psychedelics as illicit drugs of abuse and not as physiologically relevant molecules or as possible agents of future pharmacotherapies. In this paper, the immunomodulatory potential of classical serotonergic psychedelics, including N,N-dimethyltryptamine (DMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), lysergic acid diethylamide (LSD), 2,5-dimethoxy-4-iodoamphetamine, and 3,4-methylenedioxy-methamphetamine will be discussed from a perspective of molecular immunology and pharmacology. Special attention will be given to the functional interaction of serotonin and sigma-1 receptors and their cross-talk with toll-like and RIG-I-like pattern-recognition receptor-mediated signaling. Furthermore, novel approaches will be suggested feasible for the treatment of diseases with chronic inflammatory etiology and pathology, such as atherosclerosis, rheumatoid arthritis, multiple sclerosis, schizophrenia, depression, and Alzheimer's disease. PMID:26236313

  12. Adipobiology for novel therapeutic approaches in metabolic syndrome.

    PubMed

    Malagón, María M; Díaz-Ruiz, Alberto; Guzmán-Ruiz, Rocío; Jiménez-Gómez, Yolanda; Moreno, Natalia R; García-Navarro, Socorro; Vázquez-Martínez, Rafael; Peinado, Juan R

    2013-11-01

    Obesity is dramatically increasing virtually worldwide, which has been linked to the rising prevalence of metabolic syndrome. Excess fat accumulation causes severe alterations in adipose tissue function. Actually, adipose tissue is now recognized as a major endocrine and secretory organ that releases a wide variety of signaling molecules (hormones, growth factors, cytokines, chemokines, etc.), the adipokines, which play central roles in the regulation of energy metabolism and homeostasis, immunity and inflammation. In addition, adipose tissue is no longer regarded as a passive lipid storage site but as a highly dynamic energy depot which stores excess energy during periods of positive energy balance and mobilizes it in periods of nutrient deficiency in a tightly regulated manner. Altered lipid release and adipokine production and signaling, as occurs in obesity, are linked to insulin resistance and the associated comorbidities of metabolic syndrome (dyslipidemia, hypertension), which confer an increased risk for the development of type 2 diabetes and cardiovascular disease. Here we summarize current knowledge on adipose tissue and review the contribution of novel techniques and experimental approaches in adipobiology to the identification of novel biomarkers and potential targets for dietary or pharmacological intervention to prevent and treat adipose tissue-associated diseases. PMID:24168446

  13. Treatment of peri-implantitis: surgical therapeutic approaches based on peri-implantitis defects.

    PubMed

    Parma-Benfenati, Stefano; Roncati, Marisa; Tinti, Carlo

    2013-01-01

    Peri-implantitis is a frequently occurring inflammatory disease mediated by bacterial infection that results in the loss of supporting bone. Peri-implantitis should be treated immediately, but there is a lack of evidence regarding the most effective therapeutic interventions. Nonsurgical periodontics may be the treatment of choice in cases of peri-implant mucositis or if the patient has medical contraindications or refuses to consent to more appropriate treatment. Peri-implantitis defects will dictate the therapeutic approach and present a guideline for relative clinical management. The suggested therapeutic solutions are derived from clinical experience and are meant to be a useful guide.

  14. [FUNCTIONAL ANALYTIC PSYCHOTHERAPY: APPROACHES AND SCOPE OF BEHAVIOR THERAPY BASED ON CHANGES IN THE THERAPEUTIC CONTEXT].

    PubMed

    Muñoz-Martínez, Amanda M; Coletti, Juan Pablo

    2015-01-01

    Abstract Functional Analytic Psychotherapy (FAP) is a therapeutic approach developed in context. FAP is characterized by use therapeutic relationship and the behaviors emit into it to improve clients daily life functioning. This therapeutic model is supported in behavior analysis principles and contextual functionalism philosophy. FAP proposes that clients behavior in session are functional equivalent with those out of session; therefore, when therapists respond to clients behaviors in session contingently, they promote and increase improvements in the natural setting. This article poses main features of FAP, its philosophical roots, achievements and research challenges to establish FAP as an independent treatment based on the evidence.

  15. Psychedelics and Immunomodulation: Novel Approaches and Therapeutic Opportunities

    PubMed Central

    Szabo, Attila

    2015-01-01

    Classical psychedelics are psychoactive substances, which, besides their psychopharmacological activity, have also been shown to exert significant modulatory effects on immune responses by altering signaling pathways involved in inflammation, cellular proliferation, and cell survival via activating NF-κB and mitogen-activated protein kinases. Recently, several neurotransmitter receptors involved in the pharmacology of psychedelics, such as serotonin and sigma-1 receptors, have also been shown to play crucial roles in numerous immunological processes. This emerging field also offers promising treatment modalities in the therapy of various diseases including autoimmune and chronic inflammatory conditions, infections, and cancer. However, the scarcity of available review literature renders the topic unclear and obscure, mostly posing psychedelics as illicit drugs of abuse and not as physiologically relevant molecules or as possible agents of future pharmacotherapies. In this paper, the immunomodulatory potential of classical serotonergic psychedelics, including N,N-dimethyltryptamine (DMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), lysergic acid diethylamide (LSD), 2,5-dimethoxy-4-iodoamphetamine, and 3,4-methylenedioxy-methamphetamine will be discussed from a perspective of molecular immunology and pharmacology. Special attention will be given to the functional interaction of serotonin and sigma-1 receptors and their cross-talk with toll-like and RIG-I-like pattern-recognition receptor-mediated signaling. Furthermore, novel approaches will be suggested feasible for the treatment of diseases with chronic inflammatory etiology and pathology, such as atherosclerosis, rheumatoid arthritis, multiple sclerosis, schizophrenia, depression, and Alzheimer’s disease. PMID:26236313

  16. Recent Advances in Therapeutic Approaches for Adult T-cell Leukemia/Lymphoma

    PubMed Central

    Kato, Koji; Akashi, Koichi

    2015-01-01

    Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell lymphoma caused by human T-cell leukemia/lymphoma virus type 1 (HTLV-1). ATLL occurs in approximately 3%–5% of HTLV-1 carriers during their lifetime and follows a heterogeneous clinical course. The Shimoyama classification has been frequently used for treatment decisions in ATLL patients, and antiviral therapy has been reportedly promising, particularly in patients with indolent type ATLL; however, the prognosis continues to be dismal for patients with aggressive-type ATLL. Recent efforts to improve treatment outcomes have been focused on the development of prognostic stratification and improved dosage, timing, and combination of therapeutic modalities, such as antiviral therapy, chemotherapy, allogeneic hematopoietic stem cell transplantation, and molecular targeted therapy. PMID:26694446

  17. Therapeutic Targeting of Siglecs using Antibody- and Glycan-Based Approaches.

    PubMed

    Angata, Takashi; Nycholat, Corwin M; Macauley, Matthew S

    2015-10-01

    The sialic acid-binding immunoglobulin-like lectins (Siglecs) are a family of immunomodulatory receptors whose functions are regulated by their glycan ligands. Siglecs are attractive therapeutic targets because of their cell type-specific expression pattern, endocytic properties, high expression on certain lymphomas/leukemias, and ability to modulate receptor signaling. Siglec-targeting approaches with therapeutic potential encompass antibody- and glycan-based strategies. Several antibody-based therapies are in clinical trials and continue to be developed for the treatment of lymphoma/leukemia and autoimmune disease, while the therapeutic potential of glycan-based strategies for cargo delivery and immunomodulation is a promising new approach. Here we review these strategies with special emphasis on emerging approaches and disease areas that may benefit from targeting the Siglec family. PMID:26435210

  18. Differential diagnosis and therapeutic approach to periapical cysts in daily dental practice.

    PubMed

    Gallego Romero, David; Torres Lagares, Daniel; GarcIa Calderón, Manuel; Romero Ruiz, Manuel María; Infante Cossio, Pedro; Gutiérrez Pérez, José Luis

    2002-01-01

    The diagnosis and therapeutic approach to periapical cysts is an extremely controversial concern for dentists. Furthermore, as this complaint represents the most frequent cystic lesion of the maxilla, together with the fact that its differential diagnosis with chronic apical periodontitis presents special difficulty, the question takes on even greater importance. The purpose of this article is to assess the validity of the various diagnostic techniques used to differentiate between both pathologies and make a critical analysis of the controversy surrounding the therapeutic approach to suspected periapical cysts through non-surgical and follow-up treatment, or surgical enucleation and histopathological analysis.

  19. Mitochondrial Reactive Oxygen Species at the Heart of the Matter: New Therapeutic Approaches for Cardiovascular Diseases

    PubMed Central

    Kornfeld, Opher S.; Hwang, Sunhee; Disatnik, Marie-Hélène; Chen, Che-Hong; Qvit, Nir; Mochly-Rosen, Daria

    2015-01-01

    Reactive oxygen species (ROS) have been implicated in a variety of age-related diseases including multiple cardiovascular disorders. However, translation of ROS scavengers (anti-oxidants) into the clinic has not been successful. These anti-oxidants grossly reduce total levels of cellular ROS including ROS that participate in physiological signaling. In this review, we challenge the traditional anti-oxidant therapeutic approach that targets ROS directly with novel approaches that improve mitochondrial functions to more effectively treat cardiovascular diseases. PMID:25999419

  20. The usefulness of distinguishing types of aggression by function.

    PubMed

    Ramírez, J Martín

    2010-01-01

    Far from being a universally defined notion, aggression is a changing and multifaceted phenomenon encompassing various concepts. There is no consensus as to how different types of aggression should be classified: multiple ways of doing so using a variety of criteria exist in the scientific literature. Some scientists categorise aggressive acts according to how they are expressed, while others prefer to look at motive, function, purpose and objective. Despite the claim of some authors that distinguishing between different types of aggressive acts is not always productive, categorising these according to different purposes and objectives can be very useful, both for developing theory and because such an approach serves forensic practice as well as preventive and therapeutic interventions, as these focus on the propensities and personality of the individual. Furthermore, given that the main functional classifications analysed show a common tendency to dichotomise, it would seem appropriate for their terminology and some of their measurement instruments to be standardised.

  1. The Moderating Effect of Parental Warmth on the Association between Spanking and Child Aggression: A Longitudinal Approach

    ERIC Educational Resources Information Center

    Stacks, Ann Michele; Oshio, Toko; Gerard, Jean; Roe, Jacqueline

    2009-01-01

    Using data from the Early Head Start Research and Evaluation Study, this study analysed the stability of child aggressive behaviour beginning in infancy and tested whether spanking when the child was 36 months was associated with aggressive child behaviour among three ethnic groups and whether maternal warmth moderated the effect of spanking on…

  2. Challenges of glycosylation analysis and control: an integrated approach to producing optimal and consistent therapeutic drugs.

    PubMed

    Zhang, Peiqing; Woen, Susanto; Wang, Tianhua; Liau, Brian; Zhao, Sophie; Chen, Chen; Yang, Yuansheng; Song, Zhiwei; Wormald, Mark R; Yu, Chuanfei; Rudd, Pauline M

    2016-05-01

    Glycosylation of therapeutic proteins has a profound impact on their safety and efficacy. Many factors shape the glycosylation of biotherapeutics, ranging from expression systems and cell culture processes to downstream purification strategies. Various analytical technologies have been developed to address questions concerning different aspects of glycosylation. Informatics tools are also crucial for a systematic understanding of the glycosylation processes. Hence, an integrated approach is required to harness glycosylation for the production of optimal and consistent glycoprotein-based therapeutic drugs. Here, we review the latest developments and challenges in glycosylation analysis and control in the context of bioprocessing monoclonal antibodies.

  3. Lentiviral-based approach for the validation of cancer therapeutic targets in vivo.

    PubMed

    Ambrogio, Chiara; Stern, Patrick; Scuoppo, Claudio; Kranz, Harald; Barbacid, Mariano; Santamaría, David

    2014-10-01

    Despite the pressing need for novel cancer treatments, our improved understanding of tumor biology is not being successfully translated into better therapies. Here we present a lentiviral vector that enables in vivo validation of cancer therapeutic targets when combined with existing cancer animal models that faithfully reproduce the natural history of human disease. Unlike the conventional genetic approaches with targeted alleles, the outlined experimental strategy could be used to assess the preclinical efficacy of a growing number of putative therapeutic hits in a rapid and cost-effective manner. PMID:25312087

  4. Sustained acoustic medicine: a novel long duration approach to biomodulation utilizing low intensity therapeutic ultrasound

    NASA Astrophysics Data System (ADS)

    Langer, Matthew D.; Lewis, George K.

    2015-05-01

    Therapeutic ultrasound is an established technique for biomodulation used by physical therapists. Typically it is used to deliver energy locally for the purpose of altering tissue plasticity and increasing local circulation. Access to ultrasound therapy has been limited by equipment and logistic requirements, which has reduced the overall efficacy of the therapy. Ultrasound miniaturization allows for development of portable, wearable, self-applied ultrasound devices that sidestep these limitations. Additionally, research has shown that the timescale of acoustic stimulation matters, and directly affects the quality of result. This paper describes a novel, long duration approach to therapeutic ultrasound and reviews the current data available for a variety of musculoskeletal conditions.

  5. Exploring the basis for Tai Chi Chuan as a therapeutic exercise approach.

    PubMed

    Wolf, S L; Coogler, C; Xu, T

    1997-08-01

    For many centuries Tai Chi has been a martial art form, practiced primarily in Oriental cultures. For the past 300 years this movement approach has been used as an exercise form, practiced by millions of Chinese elderly people. To date, virtually no information exists about the therapeutic elements of this intriguing movement sequence. This article provides a historical review of existing documentation of reputed Tai Chi benefits. The 108 "forms" of Tai Chi Chuan are reduced to 10 composite forms for ease of application of these forms to older individuals within a reasonable time frame. An effort is set forth to identify the potential therapeutic elements within these forms.

  6. Therapeutic approaches against common structural features of toxic oligomers shared by multiple amyloidogenic proteins.

    PubMed

    Guerrero-Muñoz, Marcos J; Castillo-Carranza, Diana L; Kayed, Rakez

    2014-04-15

    Impaired proteostasis is one of the main features of all amyloid diseases, which are associated with the formation of insoluble aggregates from amyloidogenic proteins. The aggregation process can be caused by overproduction or poor clearance of these proteins. However, numerous reports suggest that amyloid oligomers are the most toxic species, rather than insoluble fibrillar material, in Alzheimer's, Parkinson's, and Prion diseases, among others. Although the exact protein that aggregates varies between amyloid disorders, they all share common structural features that can be used as therapeutic targets. In this review, we focus on therapeutic approaches against shared features of toxic oligomeric structures and future directions.

  7. Splicing-correcting therapeutic approaches for retinal dystrophies: where endogenous gene regulation and specificity matter.

    PubMed

    Bacchi, Niccolò; Casarosa, Simona; Denti, Michela A

    2014-05-27

    Splicing is an important and highly regulated step in gene expression. The ability to modulate it can offer a therapeutic option for many genetic disorders. Antisense-mediated splicing-correction approaches have recently been successfully exploited for some genetic diseases, and are currently demonstrating safety and efficacy in different clinical trials. Their application for the treatment of retinal dystrophies could potentially solve a vast panel of cases, as illustrated by the abundance of mutations that could be targeted and the versatility of the technique. In this review, we will give an insight of the different therapeutic strategies, focusing on the current status of their application for retinal dystrophies.

  8. Human iPSC for Therapeutic Approaches to the Nervous System: Present and Future Applications

    PubMed Central

    Cefalo, Maria Giuseppina; Carai, Andrea; Po, Agnese; Ferretti, Elisabetta; Mastronuzzi, Angela; Germano, Isabelle M.

    2016-01-01

    Many central nervous system (CNS) diseases including stroke, spinal cord injury (SCI), and brain tumors are a significant cause of worldwide morbidity/mortality and yet do not have satisfying treatments. Cell-based therapy to restore lost function or to carry new therapeutic genes is a promising new therapeutic approach, particularly after human iPSCs became available. However, efficient generation of footprint-free and xeno-free human iPSC is a prerequisite for their clinical use. In this paper, we will first summarize the current methodology to obtain footprint- and xeno-free human iPSC. We will then review the current iPSC applications in therapeutic approaches for CNS regeneration and their use as vectors to carry proapoptotic genes for brain tumors and review their applications for modelling of neurological diseases and formulating new therapeutic approaches. Available results will be summarized and compared. Finally, we will discuss current limitations precluding iPSC from being used on large scale for clinical applications and provide an overview of future areas of improvement. In conclusion, significant progress has occurred in deriving iPSC suitable for clinical use in the field of neurological diseases. Current efforts to overcome technical challenges, including reducing labour and cost, will hopefully expedite the integration of this technology in the clinical setting. PMID:26697076

  9. How to guide therapeutic decisions in a patient-tailored approach to treatment of IBD?

    PubMed

    Rutgeerts, Paul

    2012-01-01

    Therapeutic decisions in the treatment of IBD involve the initial choice of therapy(ies) and designing a long-term strategy for the individual patient. Putting forward clear therapeutic aims is therefore critical in order to assess treatment success and to guide the sequential use of therapies. Although the ultimate goal of therapy is to achieve steroid-free remission and avoid complications and surgeries, the first therapeutic intervention will achieve these aims only in a minority of patients. Depending on the requirements and successes of each stage of therapy, interim goals are pursued which may be small steps towards the total control of the disease. A patient-tailored approach does not necessarily conflict with algorithm-based decision-making; indeed, they are complementary. The former allows the skipping of some steps in the algorithm, based on the individual patient characteristics. The latter supplies a basis for the rational sequential use of drugs. Many physicians use an accelerated step-up approach in the treatment of IBD, although it has not yet been established whether this is associated with a better outcome. Whether or not an endoscopic or (and) CT or MRI assessment is conducted, the therapeutic approach should be based on mucosal activity and the location and extent of the disease. Treatments that do not heal (or at least improve) ulcers are not to be continued if they have been given a reasonable time to work. Biomarkers like C-reactive protein and calprotectin can be useful surrogates in this setting.

  10. Signaling aggression.

    PubMed

    van Staaden, Moira J; Searcy, William A; Hanlon, Roger T

    2011-01-01

    From psychological and sociological standpoints, aggression is regarded as intentional behavior aimed at inflicting pain and manifested by hostility and attacking behaviors. In contrast, biologists define aggression as behavior associated with attack or escalation toward attack, omitting any stipulation about intentions and goals. Certain animal signals are strongly associated with escalation toward attack and have the same function as physical attack in intimidating opponents and winning contests, and ethologists therefore consider them an integral part of aggressive behavior. Aggressive signals have been molded by evolution to make them ever more effective in mediating interactions between the contestants. Early theoretical analyses of aggressive signaling suggested that signals could never be honest about fighting ability or aggressive intentions because weak individuals would exaggerate such signals whenever they were effective in influencing the behavior of opponents. More recent game theory models, however, demonstrate that given the right costs and constraints, aggressive signals are both reliable about strength and intentions and effective in influencing contest outcomes. Here, we review the role of signaling in lieu of physical violence, considering threat displays from an ethological perspective as an adaptive outcome of evolutionary selection pressures. Fighting prowess is conveyed by performance signals whose production is constrained by physical ability and thus limited to just some individuals, whereas aggressive intent is encoded in strategic signals that all signalers are able to produce. We illustrate recent advances in the study of aggressive signaling with case studies of charismatic taxa that employ a range of sensory modalities, viz. visual and chemical signaling in cephalopod behavior, and indicators of aggressive intent in the territorial calls of songbirds.

  11. Innovative Approach to Establish Root Causes for Cracking in Aggressive Reactor Environments

    SciTech Connect

    Bruemmer, Stephen M.; Thomas, Larry E.; Vetrano, John S.; Simonen, Edward P.

    2003-10-31

    The research focuses on the high-resolution characterization of degradation microstructures and microchemistries in specimens tested under controlled conditions for the environment and for the material where in-service complexities can be minimized. Thermodynamic and kinetic modeling of crack-tip processes is employed to analyze corrosion-induced structures and gain insights into degradation mechanisms. Novel mechanistic ''fingerprinting'' of crack-tip structures is used to isolate causes of environmental cracking in tandem with quantitative measurements of crack growth. Sample preparation methods and advanced analytical techniques are used to characterize corrosion/oxidation reactions and crack-tip structures at near atomic dimensions in order to gain insight into fundamental environmental cracking mechanisms. Reactions at buried interfaces, not accessible by conventional approaches, are being systematically interrogated. Crack-growth experiments in high-temperature water environments are evaluating and isolating the effects of material condition (matrix strength, grain boundary composition and precipitation) on stress corrosion cracking (SCC). The fundamental understanding of crack advance mechanisms will establish the basis to design new corrosion-resistant alloys for current light-water reactors and advanced reactor systems.

  12. From substance dependence to addiction: impact of a conceptual shift on therapeutic approaches?

    PubMed

    Reynaud, Michel; Karila, Laurent

    2011-01-01

    Switching from the concept of substance or alcohol dependence to that of addiction has profoundly modified our ways of approaching, treating and organizing the care of this disease. This more complex and subtle approach gives less importance to the substance and its effects and focuses more on the initiation of pathological behavior. It is important to keep in mind that the addictive process associates a substance (more or less addictive), an individual (more or less vulnerable) and an environment (more or less condoning). Today, it is no longer possible to consider that a drug acts on only one receptor or one system. Current understanding of inner regulation mechanisms integrates the interactions between the various stimulated brain pathways. Addiction treatments which should benefit from advances in genetics, neuropsychology and neuroimaging could be increasingly individualized in the years to come. The "addictology" approach has triggered thinking about other therapeutic approaches such as modification of therapeutic objectives toward "risk reductions" or applying this model to behavioral addictions (food, sex, sport, gaming...). This conceptual shift seems to enrich clinical analysis, the therapeutic possibilities and the avenues for research.

  13. Novel activity-dependent approaches to therapeutic hypnosis and psychotherapy: the general waking trance.

    PubMed

    Rossi, Ernest; Erickson-Klein, Roxanna; Rossi, Kathryn

    2008-10-01

    This paper presents a highly edited version of a videotape made in 1980 by Marion Moore, M.D., showing Milton H. Erickson and Moore demonstrating novel, activity-dependent approaches to hand-levitation and therapeutic hypnosis on their subject, Ernest Rossi. Erickson's naturalistic and utilization approach is described in his very direct and surprising induction in a trance challenged patient. These novel, and surprising inductions are examples of how Erickson was prescient in developing activity-dependent approaches to therapeutic hypnosis and psychotherapy several generations before modern neuroscience documented the activity-dependent molecular-genomic mechanisms of memory, learning, and behavior change. Erickson describes a case where he utilized what he called, "The General Waking Trance" when he "dared" not use an obvious hypnotic induction. It is proposed that the states of intense mental absorption and response attentiveness that are facilitated by the general waking trance are functionally related to the three conditions neuroscientists have identified as novelty, enrichment, and exercise (both mental and physical), which can turn on activity-dependent gene expression and activity-dependent brain plasticity, that are the molecular-genomic and neural basis ofmemory, learning, consciousness, and behavior change. We recommend that the next step in investigating the efficacy of therapeutic hypnosis will be in partnering with neuroscientists to explore the possibilities and limitations of utilizing the activity-dependent approaches to hypnotic induction and the general waking trance in facilitating activity-dependent gene expression and brain plasticity.

  14. Role of neuroinflammation in adult neurogenesis and Alzheimer disease: therapeutic approaches.

    PubMed

    Fuster-Matanzo, Almudena; Llorens-Martín, María; Hernández, Félix; Avila, Jesús

    2013-01-01

    Neuroinflammation, a specialized immune response that takes place in the central nervous system, has been linked to neurodegenerative diseases, and specially, it has been considered as a hallmark of Alzheimer disease, the most common cause of dementia in the elderly nowadays. Furthermore, neuroinflammation has been demonstrated to affect important processes in the brain, such as the formation of new neurons, commonly known as adult neurogenesis. For this, many therapeutic approaches have been developed in order to avoid or mitigate the deleterious effects caused by the chronic activation of the immune response. Considering this, in this paper we revise the relationships between neuroinflammation, Alzheimer disease, and adult neurogenesis, as well as the current therapeutic approaches that have been developed in the field.

  15. Folate-conjugated nanoparticles as a potent therapeutic approach in targeted cancer therapy.

    PubMed

    Bahrami, Behdokht; Mohammadnia-Afrouzi, Mousa; Bakhshaei, Peyman; Yazdani, Yaghoub; Ghalamfarsa, Ghasem; Yousefi, Mehdi; Sadreddini, Sanam; Jadidi-Niaragh, Farhad; Hojjat-Farsangi, Mohammad

    2015-08-01

    The selective and efficient drug delivery to tumor cells can remarkably improve different cancer therapeutic approaches. There are several nanoparticles (NPs) which can act as a potent drug carrier for cancer therapy. However, the specific drug delivery to cancer cells is an important issue which should be considered before designing new NPs for in vivo application. It has been shown that cancer cells over-express folate receptor (FR) in order to improve their growth. As normal cells express a significantly lower levels of FR compared to tumor cells, it seems that folate molecules can be used as potent targeting moieties in different nanocarrier-based therapeutic approaches. Moreover, there is evidence which implies folate-conjugated NPs can selectively deliver anti-tumor drugs into cancer cells both in vitro and in vivo. In this review, we will discuss about the efficiency of different folate-conjugated NPs in cancer therapy.

  16. She will give birth easily: therapeutic approaches to childbirth in 1st millennium BCE cuneiform sources.

    PubMed

    Couto-Ferreira M Erica

    2014-01-01

    This article offers, in the first place, an overview on women's healthcare in relation to childbirth in ancient Mesopotamia, as an introduction that helps to evaluate the meaning of the 7th century Assur text BAM 248 within therapeutic cuneiform texts on childbirth. We proceed to analyse the variety of therapeutic approaches to childbirth present in BAM 248, which brings together various healing devices to help a woman give birth quickly and safely. We analyse the text in its entirety as an example of intersection between different medical approaches to childbirth, given the number of differences in the complexity of remedies, in the materia medica employed, in the methods of preparation and application, even in the technical knowledge required and also, most probably, in the social origin and/or use of the remedies in question. PMID:25481964

  17. She will givebirth easily: therapeutic approaches to childbirth in 1st millennium BCE cuneiform sources.

    PubMed

    Couto-Ferreira M Erica

    2014-01-01

    This article offers, in the first place, an overview on women's healthcare in relation to childbirth in ancient Mesopotamia, as an introduction that helps to evaluate the meaning of the 7th century Assur text BAM 248 within therapeutic cuneiform texts on childbirth. We proceed to analyse the variety of therapeutic approaches to childbirth present in BAM 248, which brings together various healing devices to help a woman give birth quickly and safely. We analyse the text in its entirety as an example of intersection between different medical approaches to childbirth, given the number of differences in the complexity of remedies, in the materia medica employed, in the methods of preparation and application, even in the technical knowledge required and also, most probably, in the social origin and/or use of the remedies in question. PMID:25508816

  18. Preference for spirituality and twelve-step-oriented approaches among adolescents in a residential therapeutic community.

    PubMed

    Aromin, Romulo A; Galanter, Marc; Solhkhah, Ramon; Bunt, Gregory; Dermatis, Helen

    2006-01-01

    This study sought to determine which adolescents being treated for substance use in a residential Therapeutic Community (TC) would endorse spirituality and Twelve Step oriented approaches as part of their treatment. By identifying individual difference characteristics associated with preference for spirituality and Twelve Step oriented approaches, integrated substance abuse treatments can be targeted to appropriate subgroups of adolescents. A total of 181 adolescents completed a survey assessing their substance use and attitudes toward spirituality and Twelve Step oriented approaches that was similar to a survey completed by 322 adults in the same residential TC program. In the adolescent sample, three spirituality related characteristics: perceived connectedness to others, frequency of prayer, and spiritual orientation to life were associated with preference for both spirituality and twelve step oriented approaches being featured more in TC treatment. Adolescents were less likely than adults to express a preference that both approaches be featured more in TC treatment.

  19. [Hydrofluoric acid burns of the hands in the home environment: correct therapeutic approach].

    PubMed

    Nicoletti, Giovanni; Pellegatta, Tommaso

    2014-01-01

    The broad market penetration of products with components used primarily in the industrial sector requires the precise knowledge of their mechanism of action in order to perform a correct therapeutic approach. The article reports on three cases of domestic hydrofluoric acid burn that came to our Plastic Surgery Unit over the last three years. The treatment options are discussed in detail with emphasis on the importance of a constant update about such emerging diseases.

  20. [Therapeutical approach in severe exacerbation of COPD associating obstructive sleep apnoea and obesity].

    PubMed

    Dumitrache-Rujinski, Stefan; Croitoru, Alina; Bogdan, Miron Alexandru

    2012-01-01

    COPD exacerbations with respiratory acidosis are difficult to manage, especially when OSA and obesity are associated. The solution is the use of noninvasive ventilation associated with oxygenotherapy in order to correct the hypercapnia, hypoxemia and respiratory acidosis and to prevent the invasive mechanical ventilation. Early respiratory rehabilitation and the use of a domiciliary ventilatory support after the acute episode could be a part of the management for these patients. We present a modality of therapeutical approach through a clinical case.

  1. Neoadjuvant Therapy in Patients with Pancreatic Cancer: A Disappointing Therapeutic Approach?

    PubMed Central

    Zimmermann, Carolin; Folprecht, Gunnar; Zips, Daniel; Pilarsky, Christian; Saeger, Hans Detlev; Grutzmann, Robert

    2011-01-01

    Pancreatic cancer is a devastating disease. It is the fourth leading cause of cancer-related death in Germany. The incidence in 2003/2004 was 16 cases per 100.000 inhabitants. Of all carcinomas, pancreatic cancer has the highest mortality rate, with one- and five-year survival rates of 25% and less than 5%, respectively, regardless of the stage at diagnosis. These low survival rates demonstrate the poor prognosis of this carcinoma. Previous therapeutic approaches including surgical resection combined with adjuvant therapy or palliative chemoradiation have not achieved satisfactory results with respect to overall survival. Therefore, it is necessary to evaluate new therapeutic approaches. Neoadjuvant therapy is an interesting therapeutic option for patients with pancreatic cancer. For selected patients with borderline or unresectable disease, neoadjuvant therapy offers the potential for tumor downstaging, increasing the probability of a margin-negative resection and decreasing the occurrence of lymph node metastasis. Currently, there is no universally accepted approach for treating patients with pancreatic cancer in the neoadjuvant setting. In this review, the most common neoadjuvant strategies will be described, compared and discussed. PMID:24212810

  2. Lipid disorders in chronic kidney disease: reverse epidemiology and therapeutic approach.

    PubMed

    Chmielewski, Michal; Carrero, Juan Jesus; Nordfors, Louise; Lindholm, Bengt; Stenvinkel, Peter

    2008-01-01

    Dyslipidemia is an established cardiovascular risk factor in the general population. However, in patients suffering from chronic kidney disease (CKD) this relationship is less clear, and many studies show that low, rather than high, cholesterol levels predict mortality in this patient population. This review presents an overview of the major disorders of lipid metabolism in the course of CKD and their clinical implications. We also discuss the role of genetic determinants predisposing to dyslipidemia, as well as current therapeutic approaches. Finally, the mendelian randomization approach as a novel tool to elucidate the seemingly paradoxical association between hypercholesterolemia and mortality in CKD will be discussed.

  3. Comparison of a Cognitive Re-Appraisal Approach and a Problem-Solving Approach to Improve Social Cognition in Adults with Intellectual Disabilities Who Exhibit Aggressive Behavior

    ERIC Educational Resources Information Center

    Collado-Castillo, Carmen J.

    2010-01-01

    It has been established in the literature that aggressive behaviors in individuals with intellectual disabilities (ID) represents a high percentage of referrals to mental health services (Davidson, Cain, Sloane-Reeves, Speybroech, Segel, et al., 1994). The results of several studies conducted with children with ID and aggressive behaviors indicate…

  4. Novel therapeutic approaches for hepatitis B virus covalently closed circular DNA.

    PubMed

    Ohno, Motoko; Otsuka, Motoyuki; Kishikawa, Takahiro; Yoshikawa, Takeshi; Takata, Akemi; Koike, Kazuhiko

    2015-06-21

    Hepatitis B virus (HBV) infection is a major global health problem. Although current therapies, such as the use of nucleos(t)ide analogs, inhibit HBV replication efficiently, they do not eliminate covalently closed circular DNA (cccDNA), which persists in hepatocyte nuclei. As HBV cccDNA is a viral transcription template, novel therapeutic approaches to directly target HBV cccDNA are necessary to completely eradicate persistent HBV infections. HBV cccDNA levels in HBV-infected human liver cells are extremely low; thus, more reliable and simple measurement methods are needed to correctly monitor their levels during therapeutic treatment. Although reverse transcription-polymerase chain reaction or Southern blot procedures are currently used in research studies, these methods are not completely reliable and are also time-consuming and labor-intensive. Genome editing technologies, such as zinc finger nucleases, transcription activator-like effector nucleases, and the clustered regularly interspaced short palindromic repeats/Cas9 (CRISPR/Cas9) system, which are designed to target specific DNA sequences, represent highly promising potential therapeutic tools. In particular, the CRISPR/Cas9 system is an easily customizable sequence-specific nuclease with high flexibility and may be the most feasible approach to target HBV cccDNA. Further research to develop easier, safer, and more effective protocols should be pursued.

  5. Making sense of loss: a content analysis of end-of-life practitioners' therapeutic approaches.

    PubMed

    Currier, Joseph M; Holland, Jason M; Neimeyer, Robert A

    2008-01-01

    Clinical professionals working in end-of-life (EOL) contexts are frequently relied upon to address questions of meaning with dying and bereaved persons. Similar to the gulf between researchers and practitioners besetting the larger healthcare community, the voices of EOL practitioners are often underrepresented in the empirical literature. This study aimed to further the dialogue in the field of thanatology by surveying and describing the therapeutic approaches that EOL practitioners most commonly report using to facilitate meaning-making. A total of 119 practitioners from a range of EOL disciplines were surveyed to write about their intervention strategies for helping clients/patients make sense of loss. Overall, participants discussed using 23 different therapeutic approaches that comprised three overarching categories: 1) presence of the helping professional; 2) elements of the process; and 3) therapeutic procedures. Importantly, the results also indicated that practitioners from the different EOL occupations are converging on many of the same strategies for promoting meaning-making. Implications for future research on evaluating the effectiveness of meaning-making interventions are also discussed.

  6. Identification of novel therapeutic targets in acute leukemias with NRAS mutations using a pharmacologic approach.

    PubMed

    Nonami, Atsushi; Sattler, Martin; Weisberg, Ellen; Liu, Qingsong; Zhang, Jianming; Patricelli, Matthew P; Christie, Amanda L; Saur, Amy M; Kohl, Nancy E; Kung, Andrew L; Yoon, Hojong; Sim, Taebo; Gray, Nathanael S; Griffin, James D

    2015-05-14

    Oncogenic forms of NRAS are frequently associated with hematologic malignancies and other cancers, making them important therapeutic targets. Inhibition of individual downstream effector molecules (eg, RAF kinase) have been complicated by the rapid development of resistance or activation of bypass pathways. For the purpose of identifying novel targets in NRAS-transformed cells, we performed a chemical screen using mutant NRAS transformed Ba/F3 cells to identify compounds with selective cytotoxicity. One of the compounds identified, GNF-7, potently and selectively inhibited NRAS-dependent cells in preclinical models of acute myelogenous leukemia and acute lymphoblastic leukemia. Mechanistic analysis revealed that its effects were mediated in part through combined inhibition of ACK1/AKT and of mitogen-activated protein kinase kinase kinase kinase 2 (germinal center kinase). Similar to genetic synthetic lethal approaches, these results suggest that small molecule screens can be used to identity novel therapeutic targets in cells addicted to RAS oncogenes.

  7. Bone Marrow-Derived Cells as a Therapeutic Approach to Optic Nerve Diseases

    PubMed Central

    Mesentier-Louro, Louise A.; Zaverucha-do-Valle, Camila; Rosado-de-Castro, Paulo H.; Silva-Junior, Almir J.; Pimentel-Coelho, Pedro M.; Mendez-Otero, Rosalia; Santiago, Marcelo F.

    2016-01-01

    Following optic nerve injury associated with acute or progressive diseases, retinal ganglion cells (RGCs) of adult mammals degenerate and undergo apoptosis. These diseases have limited therapeutic options, due to the low inherent capacity of RGCs to regenerate and due to the inhibitory milieu of the central nervous system. Among the numerous treatment approaches investigated to stimulate neuronal survival and axonal extension, cell transplantation emerges as a promising option. This review focuses on cell therapies with bone marrow mononuclear cells and bone marrow-derived mesenchymal stem cells, which have shown positive therapeutic effects in animal models of optic neuropathies. Different aspects of available preclinical studies are analyzed, including cell distribution, potential doses, routes of administration, and mechanisms of action. Finally, published and ongoing clinical trials are summarized. PMID:26649049

  8. Teaching communication and therapeutic relationship skills to baccalaureate nursing students: a peer mentorship simulation approach.

    PubMed

    Miles, Leslie W; Mabey, Linda; Leggett, Sarah; Stansfield, Katie

    2014-10-01

    The literature on techniques for improving student competency in therapeutic communication and interpersonal skills is limited. A simulation approach to enhance the learning of communication skills was developed to address these issues. Second-semester and senior nursing students participated in videorecorded standardized patient simulations, with senior students portraying the patient. Following simulated interactions, senior students provided feedback to junior students on their use of communication skills and other therapeutic factors. To integrate the learning experience, junior students completed a written assignment, in which they identified effective and noneffective communication; personal strengths and weaknesses; and use of genuineness, empathy, and positive regard. A videorecording of each student interaction gave faculty the opportunity to provide formative feedback to students. Student evaluations have been positive. Themes identified in student evaluations include the impact of seeing oneself, significance of practicing, getting below the surface in communication, and moving from insight to goal setting.

  9. Teaching communication and therapeutic relationship skills to baccalaureate nursing students: a peer mentorship simulation approach.

    PubMed

    Miles, Leslie W; Mabey, Linda; Leggett, Sarah; Stansfield, Katie

    2014-10-01

    The literature on techniques for improving student competency in therapeutic communication and interpersonal skills is limited. A simulation approach to enhance the learning of communication skills was developed to address these issues. Second-semester and senior nursing students participated in videorecorded standardized patient simulations, with senior students portraying the patient. Following simulated interactions, senior students provided feedback to junior students on their use of communication skills and other therapeutic factors. To integrate the learning experience, junior students completed a written assignment, in which they identified effective and noneffective communication; personal strengths and weaknesses; and use of genuineness, empathy, and positive regard. A videorecording of each student interaction gave faculty the opportunity to provide formative feedback to students. Student evaluations have been positive. Themes identified in student evaluations include the impact of seeing oneself, significance of practicing, getting below the surface in communication, and moving from insight to goal setting. PMID:25207556

  10. [Mindfulness-based therapeutic approaches: benefits for individuals suffering from pain].

    PubMed

    Weber, Béatrice; Jermann, Françoise; Lutz, Antoine; Bizzini, Lucio; Bondolfi, Guido

    2012-06-27

    Chronic diseases and their associated biopsychosocial adjustements tax the limits of modern conventional medicine, with the need then to turn towards new resources. Among these, Mindfulness-Based Stress Reduction (MBSR) is a therapeutic approach developed more than 30 years ago. Designed as an adjuvant to medical care, in particular in the case of chronic pain which is the scope of our article, MBSR is usually provided in group format and based on a meditative practice. Simple, brief and cost-limited, MBSR can potentially be offered to a wide variety of chronic diseases and is part of participatory medicine. After having presented this approach, several results from studies confirming the legitimacy of MBSR as a nonreligious and nonesoteric scientific approach for the treatment of various diseases will be reported.

  11. [Overview on method and strategy of therapeutic material basis in traditional Chinese medicine by multidisciplinary approach].

    PubMed

    Li, Ya-mei; Du, Zhi-min

    2015-05-01

    Traditional Chinese medicine (TCM) has a good reputation for preventing or healing diseases in clinic due to its higher efficacy, minor toxicity and abundant resources. Screening bioactive components in TCMs is not only crucial for clarifying their action mechanisms, but also the basis of their safety and quality control. TCM is characterized by multiple components, multiple targets and multiple mechanisms, however the complex composition of TCM makes it difficult to study the therapeutic material basis which has become the bottleneck in the process of its modernization and internationalization. Recently, with the rapid development of modern technologies and the unceasing progress of various disciplines, multidisciplinary approach, such as analytical chemistry, chemistry of TCM, pharmacology, cell biology, systems biology and bioinformatics has been successfully applied to the study of TCM. Multidisciplinary approach realizes the communication and interaction of multi-discipline, and accelerates the research and development of TCM. This review summarizes the application of multidisciplinary approach which may have certain potential of bringing new thoughts to TCM research and provide references for screening and identification of therapeutic material basis of TCMs. PMID:26323122

  12. A Therapeutic Approach to Teaching Poetry: Individual Development, Psychology, and Social Reparation. Psychoanalysis, Education and Social Transformation

    ERIC Educational Resources Information Center

    Williams, Todd O.

    2012-01-01

    A Therapeutic Approach to Teaching Poetry develops a poetry pedagogy that offers significant benefits to students by helping them to achieve a sense of renewal (a deeper awareness of self and potentials) and reparation (a realistic, but positive and proactive worldview). Todd O. Williams offers a thorough examination of the therapeutic potential…

  13. Similarities between Men and Women in Non-Traditional Aggressive Sexuality: Prevalence, Novel Approaches to Assessment and Treatment Applications

    ERIC Educational Resources Information Center

    Sisco, Melissa M.; Figueredo, Aurelio Jose

    2008-01-01

    Surveys and focus groups were administered to two samples of US university undergraduates to compare sexual aggression prevalence as assessed based on the Power-Assertion model (n = 139) versus the Confluence model (n = 318). Men were more likely to commit all illegal acts, especially conventional rape. Women also committed illegal acts,…

  14. The Singapore approach to human stem cell research, therapeutic and reproductive cloning.

    PubMed

    Kian, Catherine Tay Swee; Leng, Tien Sim

    2005-06-01

    With the controversial ethical issues on the creation of human embryos through cloning for therapeutic research, which holds more promise of medical breakthroughs that the world could ever imagine and the acknowledgement by many scientists that this technology may not lead in the near future to therapies; this country report discusses the approach Singapore takes on human stem cell research, interjected with the authors' own arguments and suggestions especially on research compensation injuries, an often neglected important issue. International comparative viewpoints taken by the major countries in the world are also included in the appendix.

  15. The skin microbiome: potential for novel diagnostic and therapeutic approaches to cutaneous disease

    PubMed Central

    Grice, Elizabeth A.

    2015-01-01

    A vast diversity of microorganisms, including bacteria, fungi, viruses, and arthropods, colonize the human skin. Culture-independent genomic approaches for identifying and characterizing microbial communities have provided glimpses into the topographical, temporal, and interpersonal complexity that defines the skin microbiome. Identification of changes associated with cutaneous disease, including acne, atopic dermatitis, rosacea, and psoriasis, are being established. In this review, our current knowledge of the skin microbiome in health and disease is discussed, with particular attention to potential opportunities to leverage the skin microbiome as a diagnostic, prognostic, and/or therapeutic tool. PMID:25085669

  16. Aptamer-based therapeutics: new approaches to combat human viral diseases.

    PubMed

    Shum, Ka-To; Zhou, Jiehua; Rossi, John J

    2013-11-25

    Viruses replicate inside the cells of an organism and continuously evolve to contend with an ever-changing environment. Many life-threatening diseases, such as AIDS, SARS, hepatitis and some cancers, are caused by viruses. Because viruses have small genome sizes and high mutability, there is currently a lack of and an urgent need for effective treatment for many viral pathogens. One approach that has recently received much attention is aptamer-based therapeutics. Aptamer technology has high target specificity and versatility, i.e., any viral proteins could potentially be targeted. Consequently, new aptamer-based therapeutics have the potential to lead a revolution in the development of anti-infective drugs. Additionally, aptamers can potentially bind any targets and any pathogen that is theoretically amenable to rapid targeting, making aptamers invaluable tools for treating a wide range of diseases. This review will provide a broad, comprehensive overview of viral therapies that use aptamers. The aptamer selection process will be described, followed by an explanation of the potential for treating virus infection by aptamers. Recent progress and prospective use of aptamers against a large variety of human viruses, such as HIV-1, HCV, HBV, SCoV, Rabies virus, HPV, HSV and influenza virus, with particular focus on clinical development of aptamers will also be described. Finally, we will discuss the challenges of advancing antiviral aptamer therapeutics and prospects for future success.

  17. Aptamer-Based Therapeutics: New Approaches to Combat Human Viral Diseases

    PubMed Central

    Shum, Ka-To; Zhou, Jiehua; Rossi, John J.

    2013-01-01

    Viruses replicate inside the cells of an organism and continuously evolve to contend with an ever-changing environment. Many life-threatening diseases, such as AIDS, SARS, hepatitis and some cancers, are caused by viruses. Because viruses have small genome sizes and high mutability, there is currently a lack of and an urgent need for effective treatment for many viral pathogens. One approach that has recently received much attention is aptamer-based therapeutics. Aptamer technology has high target specificity and versatility, i.e., any viral proteins could potentially be targeted. Consequently, new aptamer-based therapeutics have the potential to lead a revolution in the development of anti-infective drugs. Additionally, aptamers can potentially bind any targets and any pathogen that is theoretically amenable to rapid targeting, making aptamers invaluable tools for treating a wide range of diseases. This review will provide a broad, comprehensive overview of viral therapies that use aptamers. The aptamer selection process will be described, followed by an explanation of the potential for treating virus infection by aptamers. Recent progress and prospective use of aptamers against a large variety of human viruses, such as HIV-1, HCV, HBV, SCoV, Rabies virus, HPV, HSV and influenza virus, with particular focus on clinical development of aptamers will also be described. Finally, we will discuss the challenges of advancing antiviral aptamer therapeutics and prospects for future success. PMID:24287493

  18. Treatment for sulfur mustard lung injuries; new therapeutic approaches from acute to chronic phase

    PubMed Central

    2012-01-01

    Objective Sulfur mustard (SM) is one of the major potent chemical warfare and attractive weapons for terrorists. It has caused deaths to hundreds of thousands of victims in World War I and more recently during the Iran-Iraq war (1980–1988). It has ability to develop severe acute and chronic damage to the respiratory tract, eyes and skin. Understanding the acute and chronic biologic consequences of SM exposure may be quite essential for developing efficient prophylactic/therapeutic measures. One of the systems majorly affected by SM is the respiratory tract that numerous clinical studies have detailed processes of injury, diagnosis and treatments of lung. The low mortality rate has been contributed to high prevalence of victims and high lifetime morbidity burden. However, there are no curative modalities available in such patients. In this review, we collected and discussed the related articles on the preventive and therapeutic approaches to SM-induced respiratory injury and summarized what is currently known about the management and therapeutic strategies of acute and long-term consequences of SM lung injuries. Method This review was done by reviewing all papers found by searching following key words sulfur mustard; lung; chronic; acute; COPD; treatment. Results Mustard lung has an ongoing pathological process and is active disorder even years after exposure to SM. Different drug classes have been studied, nevertheless there are no curative modalities for mustard lung. Conclusion Complementary studies on one hand regarding pharmacokinetic of drugs and molecular investigations are mandatory to obtain more effective treatments. PMID:23351279

  19. A Bioequivalence Approach for Generic Narrow Therapeutic Index Drugs: Evaluation of the Reference-Scaled Approach and Variability Comparison Criterion.

    PubMed

    Jiang, Wenlei; Makhlouf, Fairouz; Schuirmann, Donald J; Zhang, Xinyuan; Zheng, Nan; Conner, Dale; Yu, Lawrence X; Lionberger, Robert

    2015-07-01

    Various health communities have expressed concerns regarding whether average bioequivalence (BE) limits (80.00-125.00%) for the 90% confidence interval of the test-to-reference geometric mean ratio are sufficient to ensure therapeutic equivalence between a generic narrow therapeutic index (NTI) drug and its reference listed drug (RLD). Simulations were conducted to investigate the impact of different BE approaches for NTI drugs on study power, including (1) direct tightening of average BE limits and (2) a scaled average BE approach where BE limits are tightened based on the RLD's within-subject variability. Addition of a variability comparison (using a one-tailed F test) increased the difficulty for generic NTIs more variable than their corresponding RLDs to demonstrate bioequivalence. Based on these results, the authors evaluate the fully replicated, 2-sequence, 2-treatment, 4-period crossover study design for NTI drugs where the test product demonstrates BE based on a scaled average bioequivalence criterion and a within-subject variability comparison criterion.

  20. Understanding Aggression.

    ERIC Educational Resources Information Center

    Scott, J. P.

    Research in many fields of the social and biological sciences indicates that there are ecological, cultural, social, psychological, physiological, and genetic causes of aggression. The agonistic behavior system, which adapts to situations of social conflict, includes several patterns of conduct ranging from overt fighting to complete passivity. In…

  1. Clinician perceptions of personal safety and confidence to manage inpatient aggression in a forensic psychiatric setting.

    PubMed

    Martin, T; Daffern, M

    2006-02-01

    Inpatient mental health clinicians need to feel safe in the workplace. They also require confidence in their ability to work with aggressive patients, allowing the provision of therapeutic care while protecting themselves and other patients from psychological and physical harm. The authors initiated this study with the predetermined belief that a comprehensive and integrated organizational approach to inpatient aggression was required to support clinicians and that this approach increased confidence and staff perceptions of personal safety. To assess perceptions of personal safety and confidence, clinicians in a forensic psychiatric hospital were surveyed using an adapted version of the Confidence in Coping With Patient Aggression Instrument. In this study clinicians reported the hospital as safe. They reported confidence in their work with aggressive patients. The factors that most impacted on clinicians' confidence to manage aggression were colleagues' knowledge, experience and skill, management of aggression training, use of prevention and intervention strategies, teamwork and the staff profile. These results are considered with reference to an expanding literature on inpatient aggression. It is concluded that organizational resources, policies and frameworks support clinician perceptions of safety and confidence to manage inpatient aggression. However, how these are valued by clinicians and translated into practice at unit level needs ongoing attention.

  2. Neuroendocrine tumors of the lung: hystological classification, diagnosis, traditional and new therapeutic approaches.

    PubMed

    Cueto, A; Burigana, F; Nicolini, A; Lugnani, F

    2014-01-01

    Lung neuroendocrine tumors are neoplasms originating from bronchopulmonary neuroendocrine cells, usually Kulchitsky cells, loaded with argentaffin granules. They account for 20-25% of all primitive lung tumors, the most common being the small-cell undifferentiated carcinoma. They include different tumors, from tumors of low-grade malignancy, especially the typical carcinoids, with high survival rates after surgical therapy, to the high-grade malignancy tumors, especially small-cell undifferentiated carcinomas. The latter have very few indications for surgical treatment with a low survival rate, even after multimodal therapy. The aim of this review is to describe the present knowledge and discuss possible new developments in the management of pulmonary neuroendocrine tumors. The authors examine and discuss in particular the role that surgical techniques should have in the treatment of small-cell lung cancer in opposition to a nihilism position that has limited therapies to non-surgical approaches. The critical review of this attitude opens the door to a more aggressive approach. In the meantime the review shows that it might be possible to include the new minimally invasive percutaneous ablative techniques as cryosurgery, thermotherapy and irreversible electroporation within a modern and flexible framework. The authors also present the hypothesis that cancer stem cells (CSC) are at the basis of recurrences of small-cell lung cancer (SCLC) and therefore that the issue is of difficult solution with the conventional oncologic approach considering the chemo-resistance of CSC to drugs. For these reasons an epigenetic therapy based on differentiation factors is proposed alongside the usual surgical and chemo-radiation protocols. PMID:24304279

  3. Suppression of nonsense mutations as a therapeutic approach to treat genetic diseases.

    PubMed

    Keeling, Kim M; Bedwell, David M

    2011-01-01

    Suppression therapy is a treatment strategy for genetic diseases caused by nonsense mutations. This therapeutic approach utilizes pharmacological agents that suppress translation termination at in-frame premature termination codons (PTCs) to restore translation of a full-length, functional polypeptide. The efficiency of various classes of compounds to suppress PTCs in mammalian cells is discussed along with the current limitations of this therapy. We also elaborate on approaches to improve the efficiency of suppression that include methods to enhance the effectiveness of current suppression drugs and the design or discovery of new, more effective suppression agents. Finally, we discuss the role of nonsense-mediated mRNA decay (NMD) in limiting the effectiveness of suppression therapy, and describe tactics that may allow the efficiency of NMD to be modulated in order to enhance suppression therapy.

  4. Suppression of Nonsense Mutations As A Therapeutic Approach To Treat Genetic Diseases

    PubMed Central

    Keeling, Kim M.; Bedwell, David M.

    2011-01-01

    Suppression therapy is a treatment strategy for genetic diseases caused by nonsense mutations. This therapeutic approach utilizes pharmacological agents that suppress translation termination at in-frame premature termination codons (PTCs) to restore translation of a full-length, functional polypeptide. The efficiency of various classes of compounds to suppress PTCs in mammalian cells is discussed along with the current limitations of this therapy. We also elaborate on approaches to improve the efficiency of suppression that include methods to enhance the effectiveness of current suppression drugs, and the design or discovery of new, more effective suppression agents. Finally, we discuss the role of nonsense-mediated mRNA decay (NMD) in limiting the effectiveness of suppression therapy, and describe tactics that may allow the efficiency of NMD to be modulated in order to enhance suppression therapy. PMID:21976286

  5. Pathogenesis of cerebral malaria: new diagnostic tools, biomarkers, and therapeutic approaches

    PubMed Central

    Sahu, Praveen K.; Satpathi, Sanghamitra; Behera, Prativa K.; Mishra, Saroj K.; Mohanty, Sanjib; Wassmer, Samuel Crocodile

    2015-01-01

    Cerebral malaria is a severe neuropathological complication of Plasmodium falciparum infection. It results in high mortality and post-recovery neuro-cognitive disorders in children, even after appropriate treatment with effective anti-parasitic drugs. While the complete landscape of the pathogenesis of cerebral malaria still remains to be elucidated, numerous innovative approaches have been developed in recent years in order to improve the early detection of this neurological syndrome and, subsequently, the clinical care of affected patients. In this review, we briefly summarize the current understanding of cerebral malaria pathogenesis, compile the array of new biomarkers and tools available for diagnosis and research, and describe the emerging therapeutic approaches to tackle this pathology effectively. PMID:26579500

  6. Cell- and gene-based therapeutic approaches for neurological deficits in Mucopolysaccharidoses

    PubMed Central

    Pan, Dao

    2014-01-01

    Mucopolysaccharidoses (MPS) are a group of lysosomal storage diseases that are resulted from abnormal accumulation of glycosaminoglycans. Among the progressive multi-organ abnormalities often associated with MPS diseases, the deterioration of central nervous system (CNS) is the most challenging manifestations to be tackled, due to the impermeability of the blood-brain-barrier (BBB). Evolved with recent development in stem cell biotechnology and gene therapy, several novel experimental approaches have been investigated in animal models. In this review, we will address different approaches attempting to bypass the BBB for neuropathic MPS treatment using cell- and gene-based therapies. Several neurological findings in CNS pathophysiology emerged with therapeutic investigation will also be discussed. PMID:21235445

  7. A prodrug approach to the use of coumarins as potential therapeutics for superficial mycoses.

    PubMed

    Mercer, Derry K; Robertson, Jennifer; Wright, Kristine; Miller, Lorna; Smith, Shane; Stewart, Colin S; O Neil, Deborah A

    2013-01-01

    Superficial mycoses are fungal infections of the outer layers of the skin, hair and nails that affect 20-25% of the world's population, with increasing incidence. Treatment of superficial mycoses, predominantly caused by dermatophytes, is by topical and/or oral regimens. New therapeutic options with improved efficacy and/or safety profiles are desirable. There is renewed interest in natural product-based antimicrobials as alternatives to conventional treatments, including the treatment of superficial mycoses. We investigated the potential of coumarins as dermatophyte-specific antifungal agents and describe for the first time their potential utility as topical antifungals for superficial mycoses using a prodrug approach. Here we demonstrate that an inactive coumarin glycone, esculin, is hydrolysed to the antifungal coumarin aglycone, esculetin by dermatophytes. Esculin is hydrolysed to esculetin β-glucosidases. We demonstrate that β-glucosidases are produced by dermatophytes as well as members of the dermal microbiota, and that this activity is sufficient to hydrolyse esculin to esculetin with concomitant antifungal activity. A β-glucosidase inhibitor (conduritol B epoxide), inhibited antifungal activity by preventing esculin hydrolysis. Esculin demonstrates good aqueous solubility (<6 g/l) and could be readily formulated and delivered topically as an inactive prodrug in a water-based gel or cream. This work demonstrates proof-of-principle for a therapeutic application of glycosylated coumarins as inactive prodrugs that could be converted to an active antifungal in situ. It is anticipated that this approach will be applicable to other coumarin glycones.

  8. A Prodrug Approach to the Use of Coumarins as Potential Therapeutics for Superficial Mycoses

    PubMed Central

    Mercer, Derry K.; Robertson, Jennifer; Wright, Kristine; Miller, Lorna; Smith, Shane; Stewart, Colin S.; O′Neil, Deborah A.

    2013-01-01

    Superficial mycoses are fungal infections of the outer layers of the skin, hair and nails that affect 20–25% of the world's population, with increasing incidence. Treatment of superficial mycoses, predominantly caused by dermatophytes, is by topical and/or oral regimens. New therapeutic options with improved efficacy and/or safety profiles are desirable. There is renewed interest in natural product-based antimicrobials as alternatives to conventional treatments, including the treatment of superficial mycoses. We investigated the potential of coumarins as dermatophyte-specific antifungal agents and describe for the first time their potential utility as topical antifungals for superficial mycoses using a prodrug approach. Here we demonstrate that an inactive coumarin glycone, esculin, is hydrolysed to the antifungal coumarin aglycone, esculetin by dermatophytes. Esculin is hydrolysed to esculetin β-glucosidases. We demonstrate that β-glucosidases are produced by dermatophytes as well as members of the dermal microbiota, and that this activity is sufficient to hydrolyse esculin to esculetin with concomitant antifungal activity. A β-glucosidase inhibitor (conduritol B epoxide), inhibited antifungal activity by preventing esculin hydrolysis. Esculin demonstrates good aqueous solubility (<6 g/l) and could be readily formulated and delivered topically as an inactive prodrug in a water-based gel or cream. This work demonstrates proof-of-principle for a therapeutic application of glycosylated coumarins as inactive prodrugs that could be converted to an active antifungal in situ. It is anticipated that this approach will be applicable to other coumarin glycones. PMID:24260474

  9. Huntington's disease: Molecular basis of pathology and status of current therapeutic approaches

    PubMed Central

    Huang, Wen-Juan; Chen, Wei-Wei; Zhang, Xia

    2016-01-01

    Huntington's disease (HD) is a frequent and incurable hereditary neurodegenerative disorder that impairs motor and cognitive functions. Mutations in huntingtin (HTT) protein, which is essential for neuronal development, lead to the development of HD. An increase in the number of CAG repeats within the HTT gene, which lead to an expansion of polyglutamine tract in the resulting mutated HTT protein, which is toxic, is the causative factor of HD. Although the molecular basis of HD is known, there is no known cure for this disease other than symptomatic relief treatment approaches. The toxicity of mutHTT appears to be more detrimental to striatal medium spiny neurons, which degenerate in this disease. Therapeutic strategies addressing a reduction in the mutHTT content at the transcriptional level using zinc finger proteins and at the translational level with RNA interference and antisense oligonucleotides or promoting the proteosomal degradation of mutHTT are being studied extensively in preclinical models and also to a limited extent in clinical trials. The post-translational modification of mutHTT is another possibility that is currently being investigated for drug development. In addition to the pharmacological approaches, several lines of evidence suggested the potential therapeutic use of stem cell therapy, in particular using the patient-derived induced pluripotent stem cells, to replace the lost striatal neurons. The multi-pronged clinical investigations currently underway may identify therapies and potentially improve the quality of life for the HD patients in future. PMID:27698679

  10. Huntington's disease: Molecular basis of pathology and status of current therapeutic approaches

    PubMed Central

    Huang, Wen-Juan; Chen, Wei-Wei; Zhang, Xia

    2016-01-01

    Huntington's disease (HD) is a frequent and incurable hereditary neurodegenerative disorder that impairs motor and cognitive functions. Mutations in huntingtin (HTT) protein, which is essential for neuronal development, lead to the development of HD. An increase in the number of CAG repeats within the HTT gene, which lead to an expansion of polyglutamine tract in the resulting mutated HTT protein, which is toxic, is the causative factor of HD. Although the molecular basis of HD is known, there is no known cure for this disease other than symptomatic relief treatment approaches. The toxicity of mutHTT appears to be more detrimental to striatal medium spiny neurons, which degenerate in this disease. Therapeutic strategies addressing a reduction in the mutHTT content at the transcriptional level using zinc finger proteins and at the translational level with RNA interference and antisense oligonucleotides or promoting the proteosomal degradation of mutHTT are being studied extensively in preclinical models and also to a limited extent in clinical trials. The post-translational modification of mutHTT is another possibility that is currently being investigated for drug development. In addition to the pharmacological approaches, several lines of evidence suggested the potential therapeutic use of stem cell therapy, in particular using the patient-derived induced pluripotent stem cells, to replace the lost striatal neurons. The multi-pronged clinical investigations currently underway may identify therapies and potentially improve the quality of life for the HD patients in future.

  11. New therapeutic approach to corrosive burns of the upper gastrointestinal tract.

    PubMed Central

    Di Costanzo, J; Noirclerc, M; Jouglard, J; Escoffier, J M; Cano, N; Martin, J; Gauthier, A

    1980-01-01

    The therapeutic approach to the management of corrosive burns of the upper gastrointestinal tract leaves a considerable morbidity and a heavy mortality rate. This work evaluates the effectiveness of a new therapeutic approach given to 94 consecutive patients. The management has been based on three major points: (1) the definition of extent of upper gastrointestinal lesions by immediate fibroendoscopy; (2) immediate protection of the upper gastrointestinal tract by total parenteral nutrition in cases with serious burns (41 cases), normal oral nutrition being allowed for minor burns (35 cases); (3) reparative surgical procedures for any of the sequelae of such burns during the fibrosing phase. The results were as follows: (a) healing, depending upon the degree of burn, occurred between eight to 90 days; (b) the frequency of subsequent local complications was small with total parenteral nutrition started a few hours after ingestion of the corrosive product; (c) after reconstructive surgery no serious complications occurred; (d) the overall morbidity stayed at a very low level (four patients). We conclude that the general prognosis of a severe burn of the upper gastrointestinal tract, without other trauma, is appreciably improved by the very early institution of total parenteral nutrition. PMID:6776011

  12. A chemical genetics approach for specific differentiation of stem cells to somatic cells: a new promising therapeutical approach.

    PubMed

    Sachinidis, Agapios; Sotiriadou, Isaia; Seelig, Bianca; Berkessel, Albrecht; Hescheler, Jürgen

    2008-01-01

    Cell replacement therapy of severe degenerative diseases such as diabetes, myocardial infarction and Parkinson's disease through transplantation of somatic cells generated from embryonic stem (ES) cells is currently receiving considerable attention for the therapeutic applications. ES cells harvested from the inner cell mass (ICM) of the early embryo, can proliferate indefinitely in vitro while retaining the ability to differentiate into all somatic cells thereby providing an unlimited renewable source of somatic cells. In this context, identifying soluble factors, in particular chemically synthesized small molecules, and signal cascades involved in specific differentiation processes toward a defined tissue specific cell type are crucial for optimizing the generation of somatic cells in vitro for therapeutic approaches. However, experimental models are required allowing rapid and "easy-to-handle" parallel screening of chemical libraries to achieve this goal. Recently, the forward chemical genetic screening strategy has been postulated to screen small molecules in cellular systems for a specific desired phenotypic effect. The current review is focused on the progress of ES cell research in the context of the chemical genetics to identify small molecules promoting specific differentiation of ES cells to desired cell phenotype. Chemical genetics in the context of the cell ES-based cell replacement therapy remains a challenge for the near future for several scientific fields including chemistry, molecular biology, medicinal physics and robotic technologies.

  13. [Oxidative stress after preterm birth: origins, biomarkers, and possible therapeutic approaches].

    PubMed

    Yzydorczyk, C; Mitanchez, D; Buffat, C; Ligi, I; Grandvuillemin, I; Boubred, F; Simeoni, U

    2015-10-01

    The survival of preterm babies has increased over the last few decades. However, disorders associated with preterm birth, known as oxygen radical diseases of neonatology, such as retinopathy, bronchopulmonary dysplasia, periventricular leukomalacia, and necrotizing enterocolitis are severe complications related to oxidative stress, which can be defined by an imbalance between oxidative reactive species production and antioxidant defenses. Oxidative stress causes lipid, protein, and DNA damage. Preterm infants have decreased antioxidant defenses in response to oxidative challenges, because the physiologic increase of antioxidant capacity occurs at the end of gestation in preparation for the transition to extrauterine life. Therefore, preterm infants are more sensitive to neonatal oxidative stress, notably when supplemental oxygen is being delivered. Furthermore, despite recent advances in the management of neonatal respiratory distress syndrome, controversies persist concerning the oxygenation saturation targets that should be used in caring for preterm babies. Identification of adequate biomarkers of oxidative stress in preterm infants such as 8-iso-prostaglandin F2α, and adduction of malondialdehyde to hemoglobin is important to promote specific therapeutic approaches. At present, no therapeutic strategy has been validated as prevention or treatment against oxidative stress. Breastfeeding should be considered as the main measure to improve the antioxidant status of preterm infants. In the last few years, melatonin has emerged as a protective molecule against oxidative stress, with antioxidant and free-radical scavenger roles, in experimental and preliminary human studies, giving hope that it can be used in preterm infants in the near future.

  14. The current state of stem cell therapeutics: Canadian approaches in the international context.

    PubMed

    Noiseux, Nicolas; Marquis-Gravel, Guillaume; Mansour, Samer; Shahzad, Uswa; Stewart, Duncan J; Yau, Terrence M

    2014-11-01

    After ischemic injury, the endogenous repair mechanisms of the human heart are insufficient for meaningful tissue regeneration, so muscle lost is replaced by noncontractile scar tissue. Current treatments for ischemic cardiomyopathy improve quality of life and increase life expectancy, but cannot cure the underlying disease of cardiomyocyte loss. Cellular transplantation is emerging as a valuable therapeutic approach to heal the ischemic heart. Adult bone marrow stem cells are capable of differentiation, regeneration of infarcted myocardium, and induction of myogenesis and angiogenesis, ultimately leading to improved contractility. Positive results from animal studies have prompted several clinical trials to ascertain the safety and feasibility of cell therapy. However, despite all the excitement in stem cell research resulting from initial experimental data and preliminary clinical trials, the mixed results observed have raised many unanswered questions. A major obstacle to the identification of the optimal cell therapy is that the fate of the implanted cells and the nature of their beneficial effects are ill-defined. A better understanding is fundamental for the development of new therapeutic agents, and to optimize stem cell applications. Well-designed and powered double-blinded randomized studies are clearly needed to confirm promising findings from early studies. With several ongoing randomized trials directed toward evaluation of stem cell therapies in patients with acute or chronic ischemic cardiomyopathy, the Canadian initiative represents a milestone.

  15. Unraveling new therapeutic targets of coronary artery disease by genetic approaches.

    PubMed

    Lee, Sang Eun; Kim, Hyo-Soo

    2015-01-01

    Coronary artery disease (CAD) is the most common cause of death and physical disabilities in developed countries, even though efforts to identify and target causal factors such as hypertension and dyslipidemia have brought tremendous improvements in prevention and treatment. A rapid advance in technology has unraveled new genetic variants associated with CAD and also provided great opportunities to identify novel pathogenic mechanisms and to develop new drugs with higher specificity. Whole-genome sequencing and whole-exome sequencing has made it possible to find rare alleles that are responsible for CAD in small, affected families and case-control studies in a very efficient manner. At present, genome-wide association studies have identified more than 50 loci that explain approximately 10% of the heritability of CAD, most of which is unrelated to traditional risk factors. Mendelian randomization studies enable identification of causal factors among numerous biomarkers and to narrow down promising therapeutic targets. This review highlights new genetic approaches and demonstrates the extent to which the outcome contributes to the finding of new therapeutic targets.

  16. Mechanisms of protein misfolding: Novel therapeutic approaches to protein-misfolding diseases

    NASA Astrophysics Data System (ADS)

    Salahuddin, Parveen; Siddiqi, Mohammad Khursheed; Khan, Sanaullah; Abdelhameed, Ali Saber; Khan, Rizwan Hasan

    2016-11-01

    In protein misfolding, protein molecule acquires wrong tertiary structure, thereby induces protein misfolding diseases. Protein misfolding can occur through various mechanisms. For instance, changes in environmental conditions, oxidative stress, dominant negative mutations, error in post-translational modifications, increase in degradation rate and trafficking error. All of these factors cause protein misfolding thereby leading to diseases conditions. Both in vitro and in vivo observations suggest that partially unfolded or misfolded intermediates are particularly prone to aggregation. These partially misfolded intermediates aggregate via the interaction with the complementary intermediates and consequently enhance oligomers formation that grows into fibrils and proto-fibrils. The amyloid fibrils for example, accumulate in the brain and central nervous system (CNS) as amyloid deposits in the Parkinson's disease (PD), Alzheimer's disease (AD), Prion disease and Amylo lateral Sclerosis (ALS). Furthermore, tau protein shows intrinsically disorder conformation; therefore its interaction with microtubule is impaired and this protein undergoes aggregation. This is also underlying cause of Alzheimers and other neurodegenerative diseases. Treatment of such misfolding maladies is considered as one of the most important challenges of the 21st century. Currently, several treatments strategies have been and are being discovered. These therapeutic interventions partly reversed or prevented the pathological state. More recently, a new approach was discovered, which employs nanobodies that targets multisteps in fibril formation pathway that may possibly completely cure these misfolding diseases. Keeping the above views in mind in the current review, we have comprehensively discussed the different mechanisms underlying protein misfolding thereby leading to diseases conditions and their therapeutic interventions.

  17. Recent Trends in Therapeutic Approaches for Diabetes Management: A Comprehensive Update.

    PubMed

    Tiwari, Pragya

    2015-01-01

    Diabetes highlights a growing epidemic imposing serious social economic crisis to the countries around the globe. Despite scientific breakthroughs, better healthcare facilities, and improved literacy rate, the disease continues to burden several sections, especially middle and low income countries. The present trends indicate the rise in premature death, posing a major threat to global development. Scientific and technological advances have witnessed the development of newer generation of drugs like sulphonylureas, biguanides, alpha glucosidase inhibitors, and thiazolidinediones with significant efficacy in reducing hyperglycemia. Recent approaches in drug discovery have contributed to the development of new class of therapeutics like Incretin mimetics, Amylin analogues, GIP analogs, Peroxisome proliferator activated receptors, and dipeptidyl peptidase-4 inhibitor as targets for potential drugs in diabetes treatment. Subsequently, the identification and clinical investigation of bioactive substances from plants have revolutionized the research on drug discovery and lead identification for diabetes management. With a focus on the emerging trends, the review article explores the current statistical prevalence of the disease, discussing the benefits and limitations of the commercially available drugs. Additionally, the critical areas in clinical diabetology are discussed, with respect to prospects of statins, nanotechnology, and stem cell technology as next generation therapeutics and why the herbal formulations are consistently popular choice for diabetes medication and management.

  18. Recent Trends in Therapeutic Approaches for Diabetes Management: A Comprehensive Update

    PubMed Central

    Tiwari, Pragya

    2015-01-01

    Diabetes highlights a growing epidemic imposing serious social economic crisis to the countries around the globe. Despite scientific breakthroughs, better healthcare facilities, and improved literacy rate, the disease continues to burden several sections, especially middle and low income countries. The present trends indicate the rise in premature death, posing a major threat to global development. Scientific and technological advances have witnessed the development of newer generation of drugs like sulphonylureas, biguanides, alpha glucosidase inhibitors, and thiazolidinediones with significant efficacy in reducing hyperglycemia. Recent approaches in drug discovery have contributed to the development of new class of therapeutics like Incretin mimetics, Amylin analogues, GIP analogs, Peroxisome proliferator activated receptors, and dipeptidyl peptidase-4 inhibitor as targets for potential drugs in diabetes treatment. Subsequently, the identification and clinical investigation of bioactive substances from plants have revolutionized the research on drug discovery and lead identification for diabetes management. With a focus on the emerging trends, the review article explores the current statistical prevalence of the disease, discussing the benefits and limitations of the commercially available drugs. Additionally, the critical areas in clinical diabetology are discussed, with respect to prospects of statins, nanotechnology, and stem cell technology as next generation therapeutics and why the herbal formulations are consistently popular choice for diabetes medication and management. PMID:26273667

  19. Novel therapeutic approaches for the treatment of castration-resistant prostate cancer☆

    PubMed Central

    Heidegger, Isabel; Massoner, Petra; Eder, Iris E.; Pircher, Andreas; Pichler, Renate; Aigner, Friedrich; Bektic, Jasmin; Horninger, Wolfgang; Klocker, Helmut

    2013-01-01

    Prostate cancer is a leading cause of cancer death in men in developed countries. Once the tumor has achieved a castration-refractory metastatic stage, treatment options are limited with the average survival of patients ranging from two to three years only. Recently, new drugs for treatment of castration-resistant prostate cancer (CRPC) have been approved, and others are in an advanced stage of clinical testing. In this review we provide an overview of the new therapeutic agents that arrived in the clinical praxis or are tested in clinical studies and their mode of action including hormone synthesis inhibitors, new androgen receptor blockers, bone targeting and antiangiogenic agents, endothelin receptor antagonists, growth factor inhibitors, novel radiotherapeutics and taxanes, and immunotherapeutic approaches. Results and limitations from clinical studies as well as future needs for improvement of CRPC treatments are critically discussed. PMID:23792785

  20. Brown adipose tissue and novel therapeutic approaches to treat metabolic disorders.

    PubMed

    Roman, Sabiniano; Agil, Ahmad; Peran, Macarena; Alvaro-Galue, Eduardo; Ruiz-Ojeda, Francisco J; Fernández-Vázquez, Gumersindo; Marchal, Juan A

    2015-04-01

    In humans, 2 functionally different types of adipose tissue coexist: white adipose tissue (WAT) and brown adipose tissue (BAT). WAT is involved in energy storage, whereas BAT is involved in energy expenditure. Increased amounts of WAT may contribute to the development of metabolic disorders, such as obesity-associated type 2 diabetes mellitus and cardiovascular diseases. In contrast, the thermogenic function of BAT allows high consumption of fatty acids because of the activity of uncoupling protein 1 in the internal mitochondrial membrane. Interestingly, obesity reduction and insulin sensitization have been achieved by BAT activation-regeneration in animal models. This review describes the origin, function, and differentiation mechanisms of BAT to identify new therapeutic strategies for the treatment of metabolic disorders related to obesity. On the basis of the animal studies, novel approaches for BAT regeneration combining stem cells from the adipose tissue with active components, such as melatonin, may have potential for the treatment of metabolic disorders in humans.

  1. Use of Integrated Computational Approaches in the Search for New Therapeutic Agents.

    PubMed

    Persico, Marco; Di Dato, Antonio; Orteca, Nausicaa; Cimino, Paola; Novellino, Ettore; Fattorusso, Caterina

    2016-09-01

    Computer-aided drug discovery plays a strategic role in the development of new potential therapeutic agents. Nevertheless, the modeling of biological systems still represents a challenge for computational chemists and at present a single computational method able to face such challenge is not available. This prompted us, as computational medicinal chemists, to develop in-house methodologies by mixing various bioinformatics and computational tools. Importantly, thanks to multi-disciplinary collaborations, our computational studies were integrated and validated by experimental data in an iterative process. In this review, we describe some recent applications of such integrated approaches and how they were successfully applied in i) the search of new allosteric inhibitors of protein-protein interactions and ii) the development of new redox-active antimalarials from natural leads. PMID:27546035

  2. Pharmacological targeting of redox regulation systems as new therapeutic approach for psychiatric disorders: A literature overview.

    PubMed

    Schiavone, Stefania; Trabace, Luigia

    2016-05-01

    Redox dysregulation occurs following a disequilibrium between reactive oxygen species (ROS) producing and degrading systems, i.e. mitochondria, nicotinamide adenine dinucleotide phosphate (NADPH) oxidases and nitric oxide synthase (NOS) on one hand and the principal antioxidant system, the glutathione, on the other hand. Increasing recent evidence points towards a pathogenetic role of an altered redox state in the development of several mental disorders, such as anxiety, bipolar disorders, depression, psychosis, autism and post-traumaticstress disorders (PTSD). In this regard, pharmacological targeting of the redox state regulating systems in the brain has been proposed as an innovative and promising therapeutic approach for the treatment of these mental diseases. This review will summarize current knowledge obtained from both pre-clinical and clinical studies in order to descant "lights and shadows" of targeting pharmacologically both the producing and degrading reactive oxygen species (ROS) systems in psychiatric disorders. PMID:26995306

  3. Alcohol liver disease: A review of current therapeutic approaches to achieve long-term abstinence

    PubMed Central

    García, María Luisa Gutiérrez; Blasco-Algora, Sara; Fernández-Rodríguez, Conrado M

    2015-01-01

    Harmful alcohol drinking may lead to significant damage on any organ or system of the body. Alcoholic liver disease (ALD) is the most prevalent cause of advanced liver disease in Europe. In ALD, only alcohol abstinence was associated with a better long-term survival. Therefore, current effective therapeutic strategy should be oriented towards achieving alcohol abstinence or a significant reduction in alcohol consumption. Screening all primary care patients to detect those cases with alcohol abuse has been proposed as population-wide preventive intervention in primary care. It has been suggested that in patients with mild alcohol use disorder the best approach is brief intervention in the primary care setting with the ultimate goal being abstinence, whereas patients with moderate-to-severe alcohol use disorder must be referred to specialized care where detoxification and medical treatment of alcohol dependence must be undertaken. PMID:26229395

  4. New therapeutic approaches for treatment-resistant schizophrenia: a look to the future.

    PubMed

    Miyamoto, Seiya; Jarskog, L Fredrik; Fleischhacker, W Wolfgang

    2014-11-01

    Schizophrenia for many patients is a lifelong mental disorder with significant consequences on most functional domains. One fifth to one third of patients with schizophrenia experience persistent psychotic symptoms despite adequate trials of antipsychotic treatment, and are considered to have treatment-resistant schizophrenia (TRS). Clozapine is the only medication to demonstrate efficacy for psychotic symptoms in such patients. However, clozapine is not effective in 40%-70% of patients with TRS and it has significant limitations in terms of potentially life-threatening side effects and the associated monitoring. Accordingly, a number of pharmacological and non-pharmacological biological approaches for clozapine-resistant TRS have emerged. This article provides a brief updated critical review of recent therapeutic strategies for TRS, particularly for clozapine-resistant TRS, which include pharmacotherapy, electroconvulsive therapy, repetitive transcranial magnetic stimulation, and transcranial direct current stimulation.

  5. Brown adipose tissue and novel therapeutic approaches to treat metabolic disorders.

    PubMed

    Roman, Sabiniano; Agil, Ahmad; Peran, Macarena; Alvaro-Galue, Eduardo; Ruiz-Ojeda, Francisco J; Fernández-Vázquez, Gumersindo; Marchal, Juan A

    2015-04-01

    In humans, 2 functionally different types of adipose tissue coexist: white adipose tissue (WAT) and brown adipose tissue (BAT). WAT is involved in energy storage, whereas BAT is involved in energy expenditure. Increased amounts of WAT may contribute to the development of metabolic disorders, such as obesity-associated type 2 diabetes mellitus and cardiovascular diseases. In contrast, the thermogenic function of BAT allows high consumption of fatty acids because of the activity of uncoupling protein 1 in the internal mitochondrial membrane. Interestingly, obesity reduction and insulin sensitization have been achieved by BAT activation-regeneration in animal models. This review describes the origin, function, and differentiation mechanisms of BAT to identify new therapeutic strategies for the treatment of metabolic disorders related to obesity. On the basis of the animal studies, novel approaches for BAT regeneration combining stem cells from the adipose tissue with active components, such as melatonin, may have potential for the treatment of metabolic disorders in humans. PMID:25433289

  6. Novel therapeutic approaches for the treatment of castration-resistant prostate cancer.

    PubMed

    Heidegger, Isabel; Massoner, Petra; Eder, Iris E; Pircher, Andreas; Pichler, Renate; Aigner, Friedrich; Bektic, Jasmin; Horninger, Wolfgang; Klocker, Helmut

    2013-11-01

    Prostate cancer is a leading cause of cancer death in men in developed countries. Once the tumor has achieved a castration-refractory metastatic stage, treatment options are limited with the average survival of patients ranging from two to three years only. Recently, new drugs for treatment of castration-resistant prostate cancer (CRPC) have been approved, and others are in an advanced stage of clinical testing. In this review we provide an overview of the new therapeutic agents that arrived in the clinical praxis or are tested in clinical studies and their mode of action including hormone synthesis inhibitors, new androgen receptor blockers, bone targeting and antiangiogenic agents, endothelin receptor antagonists, growth factor inhibitors, novel radiotherapeutics and taxanes, and immunotherapeutic approaches. Results and limitations from clinical studies as well as future needs for improvement of CRPC treatments are critically discussed.

  7. Mind-mapping for lung cancer: Towards a personalized therapeutics approach

    PubMed Central

    Mollberg, N; Surati, M; Demchuk, C; Fathi, R; Salama, AK; Husain, AN; Hensing, T; Salgia, R

    2011-01-01

    There will be over 220,000 people diagnosed with lung cancer and over 160,000 dying of lung cancer this year alone in the United States. In order to arrive at better control, prevention, diagnosis, and therapeutics for lung cancer, we must be able to personalize the approach towards lung cancer. Mind-mapping has existed for centuries for physicians to properly think about various “flows” of personalized medicine. We include here the epidemiology, diagnosis, histology, and treatment of lung cancer—specifically, non-small cell lung cancer. As we have new molecular signatures for lung cancer, this is further detailed. This review is not meant to be a comprehensive review, but rather its purpose is to highlight important aspects of lung cancer diagnosis, management, and personalized treatment options. PMID:21337123

  8. Use of Integrated Computational Approaches in the Search for New Therapeutic Agents.

    PubMed

    Persico, Marco; Di Dato, Antonio; Orteca, Nausicaa; Cimino, Paola; Novellino, Ettore; Fattorusso, Caterina

    2016-09-01

    Computer-aided drug discovery plays a strategic role in the development of new potential therapeutic agents. Nevertheless, the modeling of biological systems still represents a challenge for computational chemists and at present a single computational method able to face such challenge is not available. This prompted us, as computational medicinal chemists, to develop in-house methodologies by mixing various bioinformatics and computational tools. Importantly, thanks to multi-disciplinary collaborations, our computational studies were integrated and validated by experimental data in an iterative process. In this review, we describe some recent applications of such integrated approaches and how they were successfully applied in i) the search of new allosteric inhibitors of protein-protein interactions and ii) the development of new redox-active antimalarials from natural leads.

  9. Antihypertensive therapy versus alternative therapeutic options for prehypertension: an evidence-based approach.

    PubMed

    Gaddam, Krishna K; Ventura, Hector; Lavie, Carl J

    2012-01-01

    The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7) defines hypertension as systolic blood pressure (BP) ≥140 mmHg or diastolic BP ≥90 mmHg. The JNC-7 defines 'prehypertension' to include systolic BP values between 120 and 139 mmHg and diastolic BP values between 80 and 89 mmHg. Individuals with blood pressure in the prehypertension range are clearly at increased risk of developing hypertension in the future and have an increased risk of cardiovascular morbidity and mortality, compared with those with normal BP. However, there is paucity of evidence to intervene in these patients. In this article we discuss an evidence-based approach to therapeutic options in patients with prehypertension. PMID:22185450

  10. Amoebic liver abscess: ultrasonographic characteristics and results of different therapeutic approaches.

    PubMed

    Widjaya, P; Bilić, A; Babić, Z; Ljubicić, N; Bakula, B; Pilas, V

    1991-01-01

    This prospective study was carried out on 33 patients with clinically, serologically and ultrasonographically confirmed amoebic liver abscess. All patients were randomly treated with metronidazole and chlorochin or a combination of medicamentous therapy and percutaneous drainage. Ultrasonographic characteristics of amoebic liver abscesses were rotound or oval shape, usually hypoechogenic content with specific dorsal sonic enhancement, and in the majority of cases, location near liver capsule. Shorter duration of amoebic liver abscess resolution time in the group of patients treated with the combined therapy was observed particularly in the first four weeks of the treatment. The authors concluded that percutaneous drainage in combination with medicamentous therapy represents a successful therapeutic approach in the treatment of amoebic liver abscesses. PMID:2035339

  11. Restored glial glutamate transporter EAAT2 function as a potential therapeutic approach for Alzheimer's disease.

    PubMed

    Takahashi, Kou; Kong, Qiongman; Lin, Yuchen; Stouffer, Nathan; Schulte, Delanie A; Lai, Liching; Liu, Qibing; Chang, Ling-Chu; Dominguez, Sky; Xing, Xuechao; Cuny, Gregory D; Hodgetts, Kevin J; Glicksman, Marcie A; Lin, Chien-Liang Glenn

    2015-03-01

    Glutamatergic systems play a critical role in cognitive functions and are known to be defective in Alzheimer's disease (AD) patients. Previous literature has indicated that glial glutamate transporter EAAT2 plays an essential role in cognitive functions and that loss of EAAT2 protein is a common phenomenon observed in AD patients and animal models. In the current study, we investigated whether restored EAAT2 protein and function could benefit cognitive functions and pathology in APPSw,Ind mice, an animal model of AD. A transgenic mouse approach via crossing EAAT2 transgenic mice with APPSw,Ind. mice and a pharmacological approach using a novel EAAT2 translational activator, LDN/OSU-0212320, were conducted. Findings from both approaches demonstrated that restored EAAT2 protein function significantly improved cognitive functions, restored synaptic integrity, and reduced amyloid plaques. Importantly, the observed benefits were sustained one month after compound treatment cessation, suggesting that EAAT2 is a potential disease modifier with therapeutic potential for AD. PMID:25711212

  12. Tendon and ligament engineering in the adult organism: mesenchymal stem cells and gene-therapeutic approaches

    PubMed Central

    Hoffmann, Andrea

    2007-01-01

    Tendons and ligaments are elastic collagenous tissues with similar composition and hierarchical structure, contributing to motion. Their strength is related to the number and size of the collagen fibrils. Collagen fibrils increase in size during development and in response to increased physical demands or training. Tendon disorders are commonly seen in clinical practice and give rise to significant morbidity. Treatment is difficult and patients often suffer from the symptoms for quite a long time. Despite remodelling, the biochemical and mechanical properties of healed tendon tissue never match those of intact tendon. The prerequisite for focussed treatment strategies in the future will be an improved understanding of the molecular events both in the embryo and contributing to regeneration in the adult organism. Novel approaches include the local delivery of growth factors, stem- and tendon-cell-derived therapy, the application of mechanical load and gene-therapeutic approaches based on vehicles encoding selected factors, or combinations of these. Important factors are proteins of the extracellular matrix like the metalloproteinases, growth factors like the bone morphogenetic proteins but also intracellular signalling mediator proteins, such as the Smads and transcription factors from the helix–loop–helix and other families. In this review, we focus specifically on such molecular approaches based on mesenchymal stem cells. PMID:17634943

  13. Mechanistic Evidence in Support of Alpha1-Antitrypsin as a Therapeutic Approach for Type 1 Diabetes

    PubMed Central

    Fleixo-Lima, Gabriella; Ventura, Hilla; Medini, Michal; Bar, Liliana; Strauss, Pnina

    2014-01-01

    Utilizing endogenous molecules as a therapeutic approach is almost unequivocally superior to engineered or synthetic molecules. However, one rarely encounters an anti-inflammatory, cytoprotective, immunomodulatory and wound-healing molecule that has been available for use for decades. α1-antitrypsin (AAT), a circulating protein that rises more than 4-fold during acute-phase responses, has been administered for a rare genetic deficiency at large doses, for life. Aside from advances in insulin therapy, medical research in type 1 diabetes (T1D) has predominantly focused on autoimmunity—controlling the adaptive immune response. However, it is now appreciated that one may need to extend therapeutic targets to incorporate immune responses to cellular injury, as well as promote selective control over excessive inflammation and early tissue repair. Recent data suggest that tissue damage related to lung and renal ischemia-reperfusion injury, stroke, and ischemic heart disease is markedly reduced by AAT. AAT was also shown to protect pancreatic islet β cells at multiple levels. Unlike classic immunosuppressive and anti-inflammatory approaches, AAT exerts some antiviral and antibacterial activities. Based on these and other reports, AAT is under evaluation for treatment of T1D patients in multiple clinical trials. Initial results suggest that AAT therapy could potentially improve insulin production without adverse effects. Up to 50% of individuals displayed improved islet function. It is a rare occurrence in T1D research that a therapy is offered that holds a safety profile equal or superior to that of insulin alone. While placebo-controlled trials are ongoing, the mechanism(s) behind these favorable activities of AAT are still being explored. PMID:25155845

  14. Pediatric minor head trauma: do cranial CT scans change the therapeutic approach?

    PubMed Central

    Andrade, Felipe P; Montoro, Roberto; Oliveira, Renan; Loures, Gabriela; Flessak, Luana; Gross, Roberta; Donnabella, Camille; Puchnick, Andrea; Suzuki, Lisa; Regacini, Rodrigo

    2016-01-01

    OBJECTIVES: 1) To verify clinical signs correlated with appropriate cranial computed tomography scan indications and changes in the therapeutic approach in pediatric minor head trauma scenarios. 2) To estimate the radiation exposure of computed tomography scans with low dose protocols in the context of trauma and the additional associated risk. METHODS: Investigators reviewed the medical records of all children with minor head trauma, which was defined as a Glasgow coma scale ≥13 at the time of admission to the emergency room, who underwent computed tomography scans during the years of 2013 and 2014. A change in the therapeutic approach was defined as a neurosurgical intervention performed within 30 days, hospitalization, >12 hours of observation, or neuro-specialist evaluation. RESULTS: Of the 1006 children evaluated, 101 showed some abnormality on head computed tomography scans, including 49 who were hospitalized, 16 who remained under observation and 36 who were dismissed. No patient underwent neurosurgery. No statistically significant relationship was observed between patient age, time between trauma and admission, or signs/symptoms related to trauma and abnormal imaging results. A statistically significant relationship between abnormal image results and a fall higher than 1.0 meter was observed (p=0.044). The mean effective dose was 2.0 mSv (0.1 to 6.8 mSv), corresponding to an estimated additional cancer risk of 0.05%. CONCLUSION: A computed tomography scan after minor head injury in pediatric patients did not show clinically relevant abnormalities that could lead to neurosurgical indications. Patients who fell more than 1.0 m were more likely to have changes in imaging tests, although these changes did not require neurosurgical intervention; therefore, the use of computed tomography scans may be questioned in this group. The results support the trend of more careful indications for cranial computed tomography scans for children with minor head trauma. PMID

  15. A Person-Centered Counseling Approach as a Primary Therapeutic Support for Women with a History of Childhood Sexual Abuse

    ERIC Educational Resources Information Center

    Edwards, Nivischi N.; Lambie, Glenn W.

    2009-01-01

    Childhood sexual abuse (CSA) is prevalent among women. Person-centered counseling (PCC) is an effective core therapeutic approach to use when treating women with this issue. This article provides (a) an overview of CSA, (b) an orientation to PCC, and (c) a case example illustrating the primary application of this approach.

  16. Systems biology approach to developing S(2)RM-based "systems therapeutics" and naturally induced pluripotent stem cells.

    PubMed

    Maguire, Greg; Friedman, Peter

    2015-05-26

    The degree to, and the mechanisms through, which stem cells are able to build, maintain, and heal the body have only recently begun to be understood. Much of the stem cell's power resides in the release of a multitude of molecules, called stem cell released molecules (SRM). A fundamentally new type of therapeutic, namely "systems therapeutic", can be realized by reverse engineering the mechanisms of the SRM processes. Recent data demonstrates that the composition of the SRM is different for each type of stem cell, as well as for different states of each cell type. Although systems biology has been successfully used to analyze multiple pathways, the approach is often used to develop a small molecule interacting at only one pathway in the system. A new model is emerging in biology where systems biology is used to develop a new technology acting at multiple pathways called "systems therapeutics". A natural set of healing pathways in the human that uses SRM is instructive and of practical use in developing systems therapeutics. Endogenous SRM processes in the human body use a combination of SRM from two or more stem cell types, designated as S(2)RM, doing so under various state dependent conditions for each cell type. Here we describe our approach in using state-dependent SRM from two or more stem cell types, S(2)RM technology, to develop a new class of therapeutics called "systems therapeutics." Given the ubiquitous and powerful nature of innate S(2)RM-based healing in the human body, this "systems therapeutic" approach using S(2)RM technology will be important for the development of anti-cancer therapeutics, antimicrobials, wound care products and procedures, and a number of other therapeutics for many indications.

  17. [Aggressive fibromatoses in orthopedics].

    PubMed

    Adler, C P; Stock, D

    1986-01-01

    Aggressive fibromatoses which may develop either in soft tissue or in the bone present considerable problems for the pathologist trying to establish a diagnosis as well as for the radiologist and surgeon. In radiographs, a destruction of the soft and osseous tissue is seen which suggests a malignant tumor. Histologically a monomorphic connective tissue prevails in the biopsy showing no essential signs of malignancy. Under pathoanatomical aspects often a benign proliferation of the connective tissue is assumed. Surgically the tumor may either be removed in a too radical and mutilating way, or the excision may remain incomplete. Two cases of desmoplastic bone fibroma (aggressive fibromatosis in the ulna and in the sacrum) are described in which the complete tumor removal led to healing, whereas the incomplete excision of the tumor resulted in recurrences. Aggressive fibromatosis represents a semimalignant tumor which has a locally destructive and invasive growth tendency but does not metastasize. The various fibromatoses are defined with regard to their biological growth tendency and the therapeutic consequences are discussed.

  18. A multidisciplinary approach to therapeutic risk management of the suicidal patient

    PubMed Central

    Grant, Cynthia L; Lusk, Jaimie L

    2015-01-01

    As health care trends toward a system of care approach, providers from various disciplines strive to collaborate to provide optimal care for their patients. While a multidisciplinary approach to suicide risk assessment and management has been identified as important for reducing suicidality, standardized clinical guidelines for such an approach do not yet exist. In this article, the authors propose the adoption of the therapeutic risk management of the suicidal patient (TRMSP) to improve suicide risk assessment and management within multidisciplinary systems of care. The TRMSP, which has been fully articulated in previous articles, involves augmenting clinical risk assessment with structured instruments, stratifying risk in terms of both severity and temporality, and developing and documenting a safety plan. Augmenting clinical risk assessments with reliable and valid structured instruments serves several functions, including ensuring important aspects of suicide are addressed, establishing a baseline for suicidal thoughts and behaviors, facilitating interprofessional communication, and mitigating risk. Similarly, a two-dimensional risk stratification qualifying suicide risk in terms of both severity and temporality can enhance communication across providers and settings and improve understanding of acute crises in the context of chronic risk. Finally, safety planning interventions allow providers and patients to collaboratively create a personally meaningful plan for managing a suicidal crisis that can be continually modified across time with multiple providers in different care settings. In a busy care environment, the TRMSP can provide concrete guidance on conducting clinically and medicolegally sound suicide risk assessment and management. This collaborative and comprehensive process would potentially improve care of patients with suicidality, optimize clinical resources, decrease unnecessary and costly admissions, and mitigate medicolegal risk. The TRMSP may

  19. Tick-borne viruses: a review from the perspective of therapeutic approaches.

    PubMed

    Lani, Rafidah; Moghaddam, Ehsan; Haghani, Amin; Chang, Li-Yen; AbuBakar, Sazaly; Zandi, Keivan

    2014-09-01

    Several important human diseases worldwide are caused by tick-borne viruses. These diseases have become important public health concerns in recent years. The tick-borne viruses that cause diseases in humans mainly belong to 3 families: Bunyaviridae, Flaviviridae, and Reoviridae. In this review, we focus on therapeutic approaches for several of the more important tick-borne viruses from these 3 families. These viruses are Crimean-Congo hemorrhagic fever virus (CCHF) and the newly discovered tick-borne phleboviruses, known as thrombocytopenia syndromevirus (SFTSV), Heartland virus and Bhanja virus from the family Bunyaviridae, tick-borne encephalitis virus (TBEV), Powassan virus (POWV), Louping-ill virus (LIV), Omsk hemorrhagic fever virus (OHFV), Kyasanur Forest disease virus (KFDV), and Alkhurma hemorrhagic fever virus (AHFV) from the Flaviviridae family. To date, there is no effective antiviral drug available against most of these tick-borne viruses. Although there is common usage of antiviral drugs such as ribavirin for CCHF treatment in some countries, there are concerns that ribavirin may not be as effective as once thought against CCHF. Herein, we discuss also the availability of vaccines for the control of these viral infections. The lack of treatment and prevention approaches for these viruses is highlighted, and we hope that this review may increase public health awareness with regard to the threat posed by this group of viruses.

  20. Novel therapeutic approaches to lupus glomerulonephritis: translating animal models to clinical practice.

    PubMed

    Bagavant, Harini; Kalantarinia, Kambiz; Scindia, Yogesh; Deshmukh, Umesh

    2011-03-01

    Systemic lupus erythematosus is a chronic autoimmune disease frequently affecting the kidney. Renal involvement is characterized by glomerular immune complex deposits and proliferative glomerulonephritis progressing to glomerulosclerosis and kidney failure. The development of systemic lupus erythematosus is regulated genetically, and lupus susceptibility genes have been linked to immune hyper-responsiveness and loss of immune regulation. In addition to the systemic immune defects, recent studies in animal models show that susceptibility to lupus nephritis is influenced by intrinsic renal factors. Thus, renal cell responses to immune-mediated glomerular injury determine disease outcome. This supports the idea that future treatments for lupus nephritis need to focus on regulating end-organ responses. The feasibility of this approach has been shown in animal models of kidney disease. For more than 50 years, the emphasis in management of lupus nephritis has been suppression of autoimmune responses and systemic control of inflammation. This review describes recently developed targeted drug delivery technologies and potential targets that can regulate glomerular cell responses, offering a novel therapeutic approach for lupus nephritis.

  1. National Heart, Lung, and Blood Institute and the translation of cardiovascular discoveries into therapeutic approaches.

    PubMed

    Galis, Zorina S; Black, Jodi B; Skarlatos, Sonia I

    2013-04-26

    The molecular causes of ≈4000 medical conditions have been described, yet only 5% have associated therapies. For decades, the average time for drug development through approval has taken 10 to 20 years. In recent years, the serious challenges that confront the private sector have made it difficult to capitalize on new opportunities presented by advances in genomics and cellular therapies. Current trends are disturbing. Pharmaceutical companies are reducing their investments in research, and biotechnology companies are struggling to obtain venture funds. To support early-stage translation of the discoveries in basic science, the National Institutes of Health and the National Heart, Lung, and Blood Institute have developed new approaches to facilitating the translation of basic discoveries into clinical applications and will continue to develop a variety of programs that create teams of academic investigators and industry partners. The goal of these programs is to maximize the public benefit of investment of taxpayer dollars in biomedical research and to lessen the risk required for industry partners to make substantial investments. This article highlights several examples of National Heart, Lung, and Blood Institute-initiated translational programs and National Institutes of Health translational resources designed to catalyze and enable the earliest stages of the biomedical product development process. The translation of latest discoveries into therapeutic approaches depends on continued federal funding to enhance the early stages of the product development process and to stimulate and catalyze partnerships between academia, industry, and other sources of capital.

  2. National Heart, Lung, and Blood Institute and the translation of cardiovascular discoveries into therapeutic approaches.

    PubMed

    Galis, Zorina S; Black, Jodi B; Skarlatos, Sonia I

    2013-04-26

    The molecular causes of ≈4000 medical conditions have been described, yet only 5% have associated therapies. For decades, the average time for drug development through approval has taken 10 to 20 years. In recent years, the serious challenges that confront the private sector have made it difficult to capitalize on new opportunities presented by advances in genomics and cellular therapies. Current trends are disturbing. Pharmaceutical companies are reducing their investments in research, and biotechnology companies are struggling to obtain venture funds. To support early-stage translation of the discoveries in basic science, the National Institutes of Health and the National Heart, Lung, and Blood Institute have developed new approaches to facilitating the translation of basic discoveries into clinical applications and will continue to develop a variety of programs that create teams of academic investigators and industry partners. The goal of these programs is to maximize the public benefit of investment of taxpayer dollars in biomedical research and to lessen the risk required for industry partners to make substantial investments. This article highlights several examples of National Heart, Lung, and Blood Institute-initiated translational programs and National Institutes of Health translational resources designed to catalyze and enable the earliest stages of the biomedical product development process. The translation of latest discoveries into therapeutic approaches depends on continued federal funding to enhance the early stages of the product development process and to stimulate and catalyze partnerships between academia, industry, and other sources of capital. PMID:23620235

  3. The recent updates of therapeutic approaches against aβ for the treatment of Alzheimer's disease.

    PubMed

    Ling, Shucai; Zhou, Jing; Rudd, John A; Hu, Zhiying; Fang, Marong

    2011-08-01

    One of the main neuropathological lesions observed in brain autopsy of Alzheimer's disease (AD) patients is the extracellular senile plaques mainly composed of amyloid-beta (Aβ) peptide. Recently, treatment strategies have focused on modifying the formation, clearance, and accumulation of this potentially neurotoxic peptide. β- and γ-secretase are responsible for the cleavage of amyloid precursor protein (APP) and the generation of Aβ peptide. Treatments targeting these two critical secretases may therefore reduce Aβ peptide levels and positive impact on AD. Vaccination is also an advanced approach against Aβ. This review focuses on recent advances of our understanding of this key peptide, with emphasis on Aβ peptide synthesis, accumulation and neurotoxicity, and current therapies including vaccination and two critical secretase inhibitors. MicroRNAs (miRNAs) are a class of conserved endogenous small noncoding RNAs, known to regulate the expression of complementary messenger RNAs, involved in AD development. We therefore address the relationship of miRNAs in the brain and Aβ generation, as a novel therapeutic approach to the treatment of AD while also providing new insights on the etiology of this neurological disorder.

  4. Nutritional and therapeutic approaches to modulate NADPH oxidase-derived ROS signaling in platelets.

    PubMed

    Violi, Francesco; Pastori, Daniele; Carnevale, Roberto; Pignatelli, Pasquale

    2015-01-01

    Experimental and clinical studies provided evidence that formation of intra-platelet reactive oxidant species (ROS) is implicated in the process of thrombosis. Animal models demonstrated that enhanced ROS formation was associated with serious thrombotic complications and death. In recent years, nutritional and therapeutic approaches were tested to modulate ROS mediated thrombus formation. The use of a nutritional approach stems from the observation that foods rich in antioxidant elements, such as polyphenols, were able to modulate ROS formation. Similarly, some drugs used for different diseases (i.e. statins) showed the ability to modulate oxidative stress. Aim of this review is to summarize current evidences supporting the role of nutrients rich in polyphenols, such as olive oil and cocoa, and of some drugs, such as statins as antiplatelet agents interfering with the Nicotinamide Adenine Dinucleotide Phosphate (NADPH) Oxidase signaling. Indeed, for nutrients and statins, the antiplatelet activity seems to be dependent, at least in part, upon the inhibition of platelet NADPH oxidase-derived ROS formation, resulting in down-regulation of isoprostanes, which are pro-aggregating molecules, and up-regulation of nitric oxide, which is a platelet inhibitor. PMID:26510431

  5. Bacteriophage--a common divergent therapeutic approach for Alzheimer's disease and type II diabetes mellitus.

    PubMed

    Sohrab, Sayed S; Karim, Sajjad; Kamal, Mohammad A; Abuzenadah, Adel M; Chaudhary, Adeel G; Al-Qahtani, Mohammed H; Mirza, Zeenat

    2014-04-01

    Alzheimer's disease, the most important neurodegenerative disorder, is an irreversible, age-dependent disease of the brain characterized by problems in progressive impairments in memory, language, reasoning, behavior and visuospatial skills. It is characterized by the deposition of amyloid beta peptide, forming compact fibrillar plaques and neurofibrillary tau tangles. Another major and much more prevalent cause of morbidity and mortality in world is diabetes especially type 2 diabetes mellitus. It is caused by a combination of resistance to insulin action and an inadequate compensatory insulin secretory response. Chronic wounds caused by antibiotic resistant bacterial infections that fail to heal are a common complication of diabetes mellitus and the most frequent reason for nontraumatic lower limb amputation. Holistically, these two diseases are linked at molecular level but the exact mechanism is a topic of debate. Bacteriophages are viruses infecting bacteria and lack ability to infect mammalian cells. They are neither causative agent for Alzheimer's disease or type 2 diabetes mellitus nor involved in their pathogenicity but promises for a novel divergent therapeutic approach. The great versatility of the phage system has led to the development of improved phage delivery vectors, as well as immunomodulation of anti-amyloid beta peptide response. Phages could also constitute valuable prophylaxis against bacterial infections, especially in immunocompromised patients like in the case of diabetes. Patients having diabetes have a high risk of developing foot ulcers which are difficult to be treated by antibiotics alone due to ever increasing antibiotic resistance strains. Combination therapy based on multiple phage and broad spectrum antibiotics holds great promise. The potential therapeutic phage therapy arises from its lack of natural tropism for mammalian cells, resulting in no adverse effects.

  6. Therapeutic Approaches to Genetic Ion Channelopathies and Perspectives in Drug Discovery.

    PubMed

    Imbrici, Paola; Liantonio, Antonella; Camerino, Giulia M; De Bellis, Michela; Camerino, Claudia; Mele, Antonietta; Giustino, Arcangela; Pierno, Sabata; De Luca, Annamaria; Tricarico, Domenico; Desaphy, Jean-Francois; Conte, Diana

    2016-01-01

    In the human genome more than 400 genes encode ion channels, which are transmembrane proteins mediating ion fluxes across membranes. Being expressed in all cell types, they are involved in almost all physiological processes, including sense perception, neurotransmission, muscle contraction, secretion, immune response, cell proliferation, and differentiation. Due to the widespread tissue distribution of ion channels and their physiological functions, mutations in genes encoding ion channel subunits, or their interacting proteins, are responsible for inherited ion channelopathies. These diseases can range from common to very rare disorders and their severity can be mild, disabling, or life-threatening. In spite of this, ion channels are the primary target of only about 5% of the marketed drugs suggesting their potential in drug discovery. The current review summarizes the therapeutic management of the principal ion channelopathies of central and peripheral nervous system, heart, kidney, bone, skeletal muscle and pancreas, resulting from mutations in calcium, sodium, potassium, and chloride ion channels. For most channelopathies the therapy is mainly empirical and symptomatic, often limited by lack of efficacy and tolerability for a significant number of patients. Other channelopathies can exploit ion channel targeted drugs, such as marketed sodium channel blockers. Developing new and more specific therapeutic approaches is therefore required. To this aim, a major advancement in the pharmacotherapy of channelopathies has been the discovery that ion channel mutations lead to change in biophysics that can in turn specifically modify the sensitivity to drugs: this opens the way to a pharmacogenetics strategy, allowing the development of a personalized therapy with increased efficacy and reduced side effects. In addition, the identification of disease modifiers in ion channelopathies appears an alternative strategy to discover novel druggable targets. PMID:27242528

  7. Therapeutic Approaches to Genetic Ion Channelopathies and Perspectives in Drug Discovery

    PubMed Central

    Imbrici, Paola; Liantonio, Antonella; Camerino, Giulia M.; De Bellis, Michela; Camerino, Claudia; Mele, Antonietta; Giustino, Arcangela; Pierno, Sabata; De Luca, Annamaria; Tricarico, Domenico; Desaphy, Jean-Francois; Conte, Diana

    2016-01-01

    In the human genome more than 400 genes encode ion channels, which are transmembrane proteins mediating ion fluxes across membranes. Being expressed in all cell types, they are involved in almost all physiological processes, including sense perception, neurotransmission, muscle contraction, secretion, immune response, cell proliferation, and differentiation. Due to the widespread tissue distribution of ion channels and their physiological functions, mutations in genes encoding ion channel subunits, or their interacting proteins, are responsible for inherited ion channelopathies. These diseases can range from common to very rare disorders and their severity can be mild, disabling, or life-threatening. In spite of this, ion channels are the primary target of only about 5% of the marketed drugs suggesting their potential in drug discovery. The current review summarizes the therapeutic management of the principal ion channelopathies of central and peripheral nervous system, heart, kidney, bone, skeletal muscle and pancreas, resulting from mutations in calcium, sodium, potassium, and chloride ion channels. For most channelopathies the therapy is mainly empirical and symptomatic, often limited by lack of efficacy and tolerability for a significant number of patients. Other channelopathies can exploit ion channel targeted drugs, such as marketed sodium channel blockers. Developing new and more specific therapeutic approaches is therefore required. To this aim, a major advancement in the pharmacotherapy of channelopathies has been the discovery that ion channel mutations lead to change in biophysics that can in turn specifically modify the sensitivity to drugs: this opens the way to a pharmacogenetics strategy, allowing the development of a personalized therapy with increased efficacy and reduced side effects. In addition, the identification of disease modifiers in ion channelopathies appears an alternative strategy to discover novel druggable targets. PMID:27242528

  8. Resolving self-association of a therapeutic antibody by formulation optimization and molecular approaches.

    PubMed

    Casaz, Paul; Boucher, Elisabeth; Wollacott, Rachel; Pierce, Brian G; Rivera, Rachel; Sedic, Maja; Ozturk, Sadettin; Thomas, William D; Wang, Yang

    2014-01-01

    A common challenge encountered during development of high concentration monoclonal antibody formulations is preventing self-association. Depending on the antibody and its formulation, self-association can be seen as aggregation, precipitation, opalescence or phase separation. Here we report on an unusual manifestation of self-association, formation of a semi-solid gel or "gelation." Therapeutic monoclonal antibody C4 was isolated from human B cells based on its strong potency in neutralizing bacterial toxin in animal models. The purified antibody possessed the unusual property of forming a firm, opaque white gel when it was formulated at concentrations >30 mg/mL and the temperature was <6°C. Gel formation was reversible with temperature. Gelation was affected by salt concentration or pH, suggesting an electrostatic interaction between IgG monomers. A comparison of the C4 amino acid sequences to consensus germline sequences revealed differences in framework regions. A C4 variant in which the framework sequence was restored to the consensus germline sequence did not gel at 100 mg/mL at temperatures as low as 1°C. Additional genetic analysis was used to predict the key residue(s) involved in the gelation. Strikingly, a single substitution in the native antibody, replacing heavy chain glutamate 23 with lysine (E23K), was sufficient to prevent gelation. These results indicate that the framework region is involved in intermolecular interactions. The temperature dependence of gelation may be related to conformational changes near glutamate 23 or the regions it interacts with. Molecular engineering of the framework can be an effective approach to resolve the solubility issues of therapeutic antibodies. PMID:25484044

  9. Targeting Neuropilin-1 to Inhibit VEGF Signaling in Cancer: Comparison of Therapeutic Approaches

    PubMed Central

    Gabhann, Feilim Mac; Popel, Aleksander S

    2006-01-01

    Angiogenesis (neovascularization) plays a crucial role in a variety of physiological and pathological conditions including cancer, cardiovascular disease, and wound healing. Vascular endothelial growth factor (VEGF) is a critical regulator of angiogenesis. Multiple VEGF receptors are expressed on endothelial cells, including signaling receptor tyrosine kinases (VEGFR1 and VEGFR2) and the nonsignaling co-receptor Neuropilin-1. Neuropilin-1 binds only the isoform of VEGF responsible for pathological angiogenesis (VEGF165), and is thus a potential target for inhibiting VEGF signaling. Using the first molecularly detailed computational model of VEGF and its receptors, we have shown previously that the VEGFR–Neuropilin interactions explain the observed differential effects of VEGF isoforms on VEGF signaling in vitro, and demonstrated potent VEGF inhibition by an antibody to Neuropilin-1 that does not block ligand binding but blocks subsequent receptor coupling. In the present study, we extend that computational model to simulation of in vivo VEGF transport and binding, and predict the in vivo efficacy of several Neuropilin-targeted therapies in inhibiting VEGF signaling: (a) blocking Neuropilin-1 expression; (b) blocking VEGF binding to Neuropilin-1; (c) blocking Neuropilin–VEGFR coupling. The model predicts that blockade of Neuropilin–VEGFR coupling is significantly more effective than other approaches in decreasing VEGF–VEGFR2 signaling. In addition, tumor types with different receptor expression levels respond differently to each of these treatments. In designing human therapeutics, the mechanism of attacking the target plays a significant role in the outcome: of the strategies tested here, drugs with similar properties to the Neuropilin-1 antibody are predicted to be most effective. The tumor type and the microenvironment of the target tissue are also significant in determining therapeutic efficacy of each of the treatments studied. PMID:17196035

  10. Implications of current therapeutic approaches in colorectal cancer for other gastrointestinal malignancies.

    PubMed

    Lembersky, B C

    1991-02-01

    Novel immunotherapeutic strategies for combating colon cancer are also being explored in pancreatic, hepatic, and esophageal cancers. Preliminary clinical trials in patients with pancreatic cancer suggest a therapeutic role for anti-idiotypic antibodies against tumor-specific monoclonal antibodies (MoAbs)--eg, CO17-1A, BW 494/32--but not for MoAbs when used alone. Adding low doses of interferon gamma to CO17-1A enhances in vitro antibody-dependent cellular cytotoxicity against pancreatic tumor cells; CO17-1A plus a regimen of 5-FU/doxorubicin/mitomycin has resulted in beneficial therapeutic effect. Treatments with immunotoxins, radiolabeled MoAbs, and adoptive immunotherapy are still being tested preclinically. In 105 patients with unresectable hepatocellular cancer, a 7% complete and 41% partial regression rate with 131I-labeled antiferritin has been reported. In several patients, radiolabeled antiferritin caused sufficient shrinkage of lesions to permit curative resection. Pretreatment with low-dose doxorubicin may improve the efficacy of low-dose radiolabeled antiferritin antibody therapy. Chemoembolization of primary hepatocellular carcinoma, based on the concept of regional therapy for metastatic colorectal cancer, has shown considerable palliative and survival benefit in patients with unresectable disease. Although adoptive immunotherapy has been used to treat hepatocellular carcinoma, the results have been disappointing. The development of immunotherapeutic approaches to esophageal cancer is less advanced than that for other gastrointestinal malignancies. Paralleling the successful use of 5-FU/interferon alfa-2a in colon cancer are two phase II studies that have evaluated this combination in patients with locally advanced esophageal cancer. The objective response rate (27%) was encouraging. PMID:1992529

  11. Advances in peripheral nervous system regenerative therapeutic strategies: A biomaterials approach.

    PubMed

    Dalamagkas, Kyriakos; Tsintou, Magdalini; Seifalian, Alexander

    2016-08-01

    Peripheral nerve injury is a very common medical condition with varying clinical severity but always great impact on the patients' productivity and the quality of life. Even the current 1st-choice surgical therapeutic approach or the "gold standard" as frequently called in clinical practice, is not addressing the problem efficiently and cost-effectively, increasing the mortality through the need of a second surgical intervention, while it does not take into account the several different types of nerves involved in peripheral nerve injuries. Neural tissue engineering approaches could potentially offer a very promising and attractive tool for the efficient peripheral nerve injury management, not only by mechanically building the gap, but also by inducing neuroregenerative mechanisms in a well-regulated microenvironment which would mimic the natural environment of the specific nerve type involved in the injury to obtain an optimum clinical outcome. There is still room for a lot of optimizations in regard to the conduits which have been developed with the help of neural engineering since many parameters affect the clinical outcome and the underlying mechanisms are still not well understood. Especially the intraluminal cues controlling the microenvironment of the conduits are in an infantile stage but there is profound potential in the application of the scaffolds. The aim of our review is to provide a quick reference to the recent advances in the field, focusing on the parameters that can significantly affect the clinical potentials of each approach, with suggestions for future improvements that could take the current work from bench to bedside. Thus, further research could shed light to those questions and it might hold the key to discover new more efficient and cost-effective therapies.

  12. Diagnostic and Therapeutic Approaches to Hepatocellular Carcinoma: Understanding the Barcelona Clínic Liver Cancer Protocol

    PubMed Central

    Soldera, Jonathan; Balbinot, Silvana Sartori; Balbinot, Raul Angelo; Cavalcanti, Andreza Gautério

    2016-01-01

    Each year, hepatocellular carcinoma is diagnosed in more than half a million people worldwide and it is the fifth most common cancer in men and the seventh most common cancer in women. This article reviews the Barcelona-Clínic Liver Cancer protocol for the diagnosis, staging, and treatment of this disease, and four cases are presented for the discussion of the therapeutic approach. Understanding the diagnostic and therapeutic approaches to this disease is essential, especially if we keep in mind the quintessential basics of prevention and early detection. PMID:27812296

  13. BK channel agonist represents a potential therapeutic approach for lysosomal storage diseases

    PubMed Central

    Zhong, Xi Zoë; Sun, Xue; Cao, Qi; Dong, Gaofeng; Schiffmann, Raphael; Dong, Xian-Ping

    2016-01-01

    Efficient lysosomal Ca2+ release plays an essential role in lysosomal trafficking. We have recently shown that lysosomal big conductance Ca2+-activated potassium (BK) channel forms a physical and functional coupling with the lysosomal Ca2+ release channel Transient Receptor Potential Mucolipin-1 (TRPML1). BK and TRPML1 forms a positive feedback loop to facilitate lysosomal Ca2+ release and subsequent lysosome membrane trafficking. However, it is unclear whether the positive feedback mechanism is common for other lysosomal storage diseases (LSDs) and whether BK channel agonists rescue abnormal lysosomal storage in LSDs. In this study, we assessed the effect of BK agonist, NS1619 and NS11021 in a number of LSDs including NPC1, mild cases of mucolipidosis type IV (ML4) (TRPML1-F408∆), Niemann-Pick type A (NPA) and Fabry disease. We found that TRPML1-mediated Ca2+ release was compromised in these LSDs. BK activation corrected the impaired Ca2+ release in these LSDs and successfully rescued the abnormal lysosomal storage of these diseases by promoting TRPML1-mediated lysosomal exocytosis. Our study suggests that BK channel activation stimulates the TRPML1-BK positive reinforcing loop to correct abnormal lysosomal storage in LSDs. Drugs targeting BK channel represent a potential therapeutic approach for LSDs. PMID:27670435

  14. Ion channel remodeling in vascular smooth muscle during hypertension: Implications for novel therapeutic approaches

    PubMed Central

    Joseph, Biny K.; Thakali, Keshari M.; Moore, Christopher L.; Rhee, Sung W.

    2013-01-01

    Ion channels are multimeric, transmembrane proteins that selectively mediate ion flux across the plasma membrane in a variety of cells including vascular smooth muscle cells (VSMCs). The dynamic interplay of Ca2+ and K+ channels on the plasma membrane of VSMCs plays a pivotal role in modulating the vascular tone of small arteries and arterioles. The abnormally-elevated arterial tone observed in hypertension thus points to an aberrant expression and function of Ca2+ and K+ channels in the VSMCs. In this short review, we focus on the three well-studied ion channels in VSMCs, namely the L-type Ca2+ (CaV1.2) channels, the voltage-gated K+ (KV) channels, and the large-conductance Ca2+-activated K+ (BK) channels. First, we provide a brief overview on the physiological role of vascular CaV1.2, KV and BK channels in regulating arterial tone. Second, we discuss the current understanding of the expression changes and regulation of CaV1.2, KV and BK channels in the vasculature during hypertension. Third, based on available proof-of-concept studies, we describe the potential therapeutic approaches targeting these vascular ion channels in order to restore blood pressure to normotensive levels. PMID:23376354

  15. The effects of antibiotics on the microbiome throughout development and alternative approaches for therapeutic modulation.

    PubMed

    Langdon, Amy; Crook, Nathan; Dantas, Gautam

    2016-01-01

    The widespread use of antibiotics in the past 80 years has saved millions of human lives, facilitated technological progress and killed incalculable numbers of microbes, both pathogenic and commensal. Human-associated microbes perform an array of important functions, and we are now just beginning to understand the ways in which antibiotics have reshaped their ecology and the functional consequences of these changes. Mounting evidence shows that antibiotics influence the function of the immune system, our ability to resist infection, and our capacity for processing food. Therefore, it is now more important than ever to revisit how we use antibiotics. This review summarizes current research on the short-term and long-term consequences of antibiotic use on the human microbiome, from early life to adulthood, and its effect on diseases such as malnutrition, obesity, diabetes, and Clostridium difficile infection. Motivated by the consequences of inappropriate antibiotic use, we explore recent progress in the development of antivirulence approaches for resisting infection while minimizing resistance to therapy. We close the article by discussing probiotics and fecal microbiota transplants, which promise to restore the microbiota after damage of the microbiome. Together, the results of studies in this field emphasize the importance of developing a mechanistic understanding of gut ecology to enable the development of new therapeutic strategies and to rationally limit the use of antibiotic compounds. PMID:27074706

  16. A Potential New Therapeutic Approach for Friedreich Ataxia: Induction of Frataxin Expression With TALE Proteins.

    PubMed

    Chapdelaine, Pierre; Coulombe, Zoé; Chikh, Amina; Gérard, Catherine; Tremblay, Jacques P

    2013-09-03

    TALEs targeting a promoter sequence and fused with a transcription activation domain (TAD) may be used to specifically induce the expression of a gene as a potential treatment for haploinsufficiency. This potential therapeutic approach was applied to increase the expression of frataxin in fibroblasts of Friedreich ataxia (FRDA) patients. FRDA fibroblast cells were nucleofected with a pCR3.1 expression vector coding for TALEFrat#8 fused with VP64. A twofold increase of the frataxin mRNA (detected by quantitative reverse transcription-PCR (qRT-PCR)) associated with a similar increase of the mature form of the frataxin protein was observed. The frataxin mRNA and protein were also increased by this TALE in the fibroblasts of the YG8R mouse model. The addition of 5-aza-2'-deoxycytidine (5-Aza-dC) or of valproic acid (VPA) to the TALE treatment did not produce significant improvement. Other TADs (i.e., p65, TFAP2α, SRF, SP1, and MyoD) fused with the TALEFrat#8 gene did not produce a significant increase in the frataxin protein. Thus the TALEFrat#8-VP64 recombinant protein targeting the frataxin promoter could eventually be used to increase the frataxin expression and alleviate the FRDA symptoms.Molecular Therapy-Nucleic Acids (2013) 2, e119; doi:10.1038/mtna.2013.41; published online 3 September 2013.

  17. Translational strategies for therapeutic development in nicotine addiction: rethinking the conventional bench to bedside approach.

    PubMed

    Le Foll, Bernard; Pushparaj, Abhiram; Pryslawsky, Yaroslaw; Forget, Benoit; Vemuri, Kiran; Makriyannis, Alexandros; Trigo, Jose M

    2014-07-01

    Tobacco produces an impressive burden of disease resulting in premature death in half of users. Despite effective smoking cessation medications (nicotine replacement therapies, bupropion and varenicline), there is a very high rate of relapse following quit attempts. The use of efficient strategies for the development of novel treatments is a necessity. A 'bench to bedside strategy' was initially used to develop cannabinoid CB1 receptor antagonists for the treatment of nicotine addiction. Unfortunately, after being tested on experimental animals, what seemed to be an interesting approach for the treatment of nicotine addiction resulted in serious unwanted side effects when tested in humans. Current research is focusing again on pre-clinical models in an effort to eliminate unwanted side effects while preserving the initially observed efficacy. A 'bed side to bench strategy' was used to study the role of the insula (part of the frontal cortex) in nicotine addiction. This line of research started based on clinical observations that patients suffering stroke-induced lesions to the insula showed a greater likelihood to report immediate smoking cessation without craving or relapse. Subsequently, animal models of addiction are used to explore the role of insula in addiction. Due to the inherent limitations existing in clinical versus preclinical studies, the possibility of close interaction between both models seems to be critical for the successful development of novel therapeutic strategies for nicotine dependence.

  18. Medication-Related Osteonecrosis of the Jaw: New Insights into Molecular Mechanisms and Cellular Therapeutic Approaches

    PubMed Central

    Lombard, Thomas; Neirinckx, Virginie; Gilon, Yves

    2016-01-01

    In recent years, medication-related osteonecrosis of the jaw (MRONJ) became an arising disease due to the important antiresorptive drug prescriptions to treat oncologic and osteoporotic patients, as well as the use of new antiangiogenic drugs such as VEGF antagonist. So far, MRONJ physiopathogenesis still remains unclear. Aiming to better understand MRONJ physiopathology, the first objective of this review would be to highlight major molecular mechanisms that are known to be involved in bone formation and remodeling. Recent development in MRONJ pharmacological treatments showed good results; however, those treatments are not curative and could have major side effects. In parallel to pharmacological treatments, MSC grafts appeared to be beneficial in the treatment of MRONJ, in multiple aspects: (1) recruitment and stimulation of local or regional endogenous cells to differentiate into osteoblasts and thus bone formation, (2) beneficial impact on bone remodeling, and (3) immune-modulatory properties that decrease inflammation. In this context, the second objective of this manuscript would be to summarize the molecular regulatory events controlling osteogenic differentiation, bone remodeling, and osteoimmunology and potential beneficial effects of MSC related to those aspects, in order to apprehend MRONJ and to develop new therapeutic approaches. PMID:27721837

  19. Acupuncture Points Stimulation for Meniere's Disease/Syndrome: A Promising Therapeutic Approach

    PubMed Central

    He, Jiaojun; Jiang, Liyuan; Peng, Tianqiang; Xia, Meixia

    2016-01-01

    Objective. This study aims to explore evidence for acupuncture points stimulation (APS) in treatment of Meniere's disease (MD). Method. A literature search was conducted in seven databases including EMBASE, Medline, Cochrane Library, Web of Science, CBM, CNKI, and WangFang database and the data analysis was performed by using the RevMan version 5.3. Results. 12 RCTs with 993 participants were acquired after the search. The quality of most eligible studies was very low which limited the value of the meta-analysis. Compared with western medicine comprehensive treatment (WMCT), the APS alone or in combination with WMCT had a significant positive effect in controlling vertigo; however, the result was negative in hearing improvement and DHI. No adverse events were reported in the studies. Conclusion. The APS might be a promising therapeutic approach for MD. However, the currently available evidence is insufficient to make a definitive conclusion for the poor quality of included studies. More high-quality researches with larger sample size are urgently needed to assess the effectiveness and safety. PMID:27547229

  20. The effects of antibiotics on the microbiome throughout development and alternative approaches for therapeutic modulation.

    PubMed

    Langdon, Amy; Crook, Nathan; Dantas, Gautam

    2016-04-13

    The widespread use of antibiotics in the past 80 years has saved millions of human lives, facilitated technological progress and killed incalculable numbers of microbes, both pathogenic and commensal. Human-associated microbes perform an array of important functions, and we are now just beginning to understand the ways in which antibiotics have reshaped their ecology and the functional consequences of these changes. Mounting evidence shows that antibiotics influence the function of the immune system, our ability to resist infection, and our capacity for processing food. Therefore, it is now more important than ever to revisit how we use antibiotics. This review summarizes current research on the short-term and long-term consequences of antibiotic use on the human microbiome, from early life to adulthood, and its effect on diseases such as malnutrition, obesity, diabetes, and Clostridium difficile infection. Motivated by the consequences of inappropriate antibiotic use, we explore recent progress in the development of antivirulence approaches for resisting infection while minimizing resistance to therapy. We close the article by discussing probiotics and fecal microbiota transplants, which promise to restore the microbiota after damage of the microbiome. Together, the results of studies in this field emphasize the importance of developing a mechanistic understanding of gut ecology to enable the development of new therapeutic strategies and to rationally limit the use of antibiotic compounds.

  1. Cellular responses following retinal injuries and therapeutic approaches for neurodegenerative diseases.

    PubMed

    Cuenca, Nicolás; Fernández-Sánchez, Laura; Campello, Laura; Maneu, Victoria; De la Villa, Pedro; Lax, Pedro; Pinilla, Isabel

    2014-11-01

    Retinal neurodegenerative diseases like age-related macular degeneration, glaucoma, diabetic retinopathy and retinitis pigmentosa each have a different etiology and pathogenesis. However, at the cellular and molecular level, the response to retinal injury is similar in all of them, and results in morphological and functional impairment of retinal cells. This retinal degeneration may be triggered by gene defects, increased intraocular pressure, high levels of blood glucose, other types of stress or aging, but they all frequently induce a set of cell signals that lead to well-established and similar morphological and functional changes, including controlled cell death and retinal remodeling. Interestingly, an inflammatory response, oxidative stress and activation of apoptotic pathways are common features in all these diseases. Furthermore, it is important to note the relevant role of glial cells, including astrocytes, Müller cells and microglia, because their response to injury is decisive for maintaining the health of the retina or its degeneration. Several therapeutic approaches have been developed to preserve retinal function or restore eyesight in pathological conditions. In this context, neuroprotective compounds, gene therapy, cell transplantation or artificial devices should be applied at the appropriate stage of retinal degeneration to obtain successful results. This review provides an overview of the common and distinctive features of retinal neurodegenerative diseases, including the molecular, anatomical and functional changes caused by the cellular response to damage, in order to establish appropriate treatments for these pathologies.

  2. The therapeutic approach to complex regional pain syndrome: light and shade.

    PubMed

    Casale, Roberto; Atzeni, Fabiola; Sarzi-Puttini, Piercarlo

    2015-01-01

    Complex regional pain syndrome (CRPS) is a highly painful, limb-confined condition that usually arises after a trauma although its causes remain unknown. It is associated with a particularly poor quality of life, and considerable healthcare and societal costs. Its distinct combination of abnormalities includes limb-confined inflammation and tissue hypoxia, sympathetic dysregulation, small fibre damage, serum autoantibodies, central sensitisation and cortical reorganisation, which place it at the crossroads of disciplines including rheumatology, pain medicine and neurology. The significant scientific and clinical advances made over the past 10 years promise an improved understanding of the causes of CRPS, and for more effective treatments. This review summarises the currently available treatments. The therapeutic approach is multidisciplinary, and involves educating patients about the condition, sustaining or restoring limb function, reducing pain, and providing psychological support. This paper describes the systemic drug treatments, grouped on the basis of their real or presumed antinociceptive mechanisms and reported actions without making any formal distinction between CRPS types I and II.

  3. Therapeutic Approach in the Improvement of Endothelial Dysfunction: The Current State of the Art

    PubMed Central

    Radenković, Miroslav; Stojanović, Marko; Potpara, Tatjana; Prostran, Milica

    2013-01-01

    The endothelium has a central role in the regulation of blood flow through continuous modulation of vascular tone. This is primarily accomplished by balanced release of endothelial relaxing and contractile factors. The healthy endothelial cells are essential for maintenance of vascular homeostasis involving antioxidant, anti-inflammatory, pro-fibrinolytic, anti-adhesive, or anticoagulant effects. Oppositely, endothelial dysfunction is primarily characterized by impaired regulation of vascular tone as a result of reduced endothelial nitric oxide (NO) synthase activity, lack of cofactors for NO synthesis, attenuated NO release, or increased NO degradation. So far, the pharmacological approach in improving/reversal of endothelial dysfunction was shown to be beneficial in clinical trials that have investigated actions of different cardiovascular drugs. The aim of this paper was to summarize some of the latest clinical findings related to therapeutic possibilities for improving endothelial dysfunction in different pathological conditions. In the majority of presented clinical investigations, the assessment of improvement or reversal of endothelial dysfunction was performed through the flow-mediated dilatation measurement, and in some of those endothelial progenitor cells' count was used for the same purpose. Still, given the fast and continuous development of this field, the evidence acquisition included the MEDLINE data base screening and the selection of articles published between 2010 and 2012. PMID:23509696

  4. Xeroderma pigmentosum: diagnostic procedures, interdisciplinary patient care, and novel therapeutic approaches.

    PubMed

    Lehmann, Janin; Schubert, Steffen; Emmert, Steffen

    2014-10-01

    Xeroderma pigmentosum (XP) is an autosomal recessive disease, caused by a gene defect in the nucleotide-excision-repair (NER) pathway or in translesional DNA synthesis. At the age of eight, patients already develop their first skin cancers due to this DNA repair defect. In contrast, in the Caucasian population the first tumor formation in UV exposed skin regions occurs at a mean age of 60. The clinical picture among patients suffering from XP is highly diverse and includes signs of accelerated skin aging, and UV-induced skin cancers, as well as ophthalmologic and neurological symptoms. Patients should therefore receive interdisciplinary care. This includes dermatologists, ophthalmologists, ENT specialists, neurologists, and human geneticists. Patients with XP are clinically diagnosed, but this may be supported by molecular-genetic and functional analyses. These analyses allow pinpointing the exact disease-causing gene defect (complementation group assignment, detection of the type and location of the mutation within the gene). The resulting information is already relevant to predict the course of disease and symptoms and probably will be utilized for individualized therapeutic approaches in the future. Recently, enhanced repair of UV photolesions in xeroderma pigmentosum group C cells induced by translational readthrough of premature termination codons by certain antibiotics could be demonstrated. PMID:25262888

  5. HSP90 and HSP70: Implication in Inflammation Processes and Therapeutic Approaches for Myeloproliferative Neoplasms

    PubMed Central

    Sevin, Margaux; Girodon, François; Garrido, Carmen; de Thonel, Aurélie

    2015-01-01

    Myeloproliferative neoplasms (MPN) are clonal stem cell disorders that lead to the excessive production of one or more blood cell lineages. It has been reported that, in most MPN, inflammatory cytokines are frequently increased, indicating that inflammation plays a crucial role in these disorders. Heat shock proteins (HSP) are induced in response to many stressful conditions from heat shock to hypoxia and inflammation. Besides their chaperone and cytoprotective functions, HSPs are key players during inflammation, hence the term “chaperokine.” Through their chaperone activity, HSP90, a stabilizer of many oncogenes (e.g., JAK2), and HSP70, a powerful antiapoptotic chaperone, tightly regulate Nuclear Factor-kappa B signalling, a critical pathway in mediating inflammatory responses. In light of this potential, several HSP90 inhibitors have been generated as anticancer agents able to degrade oncogenes. As it turns out, however, these drugs are also potent inhibitors of the inflammatory response in various diseases. Given the chaperone potential of HSP70 and the fact that HSP90 inhibitors induce HSP70, interest in HSP70 inhibitors is also increasing. Here, we focus on the implication of HSP90 and HSP70 in inflammatory responses and on the emergence of new therapeutic approaches in MPN based on HSP inhibitors. PMID:26549943

  6. Characterization of novel genomic alterations and therapeutic approaches using acute megakaryoblastic leukemia xenograft models

    PubMed Central

    Thiollier, Clarisse; Lopez, Cécile K.; Gerby, Bastien; Ignacimouttou, Cathy; Poglio, Sandrine; Duffourd, Yannis; Guégan, Justine; Rivera-Munoz, Paola; Bluteau, Olivier; Mabialah, Vinciane; Diop, M’Boyba; Wen, Qiang; Petit, Arnaud; Bauchet, Anne-Laure; Reinhardt, Dirk; Bornhauser, Beat; Gautheret, Daniel; Lecluse, Yann; Landman-Parker, Judith; Radford, Isabelle; Vainchenker, William; Dastugue, Nicole; de Botton, Stéphane; Dessen, Philippe; Bourquin, Jean-Pierre; Crispino, John D.; Ballerini, Paola; Bernard, Olivier A.; Pflumio, Françoise

    2012-01-01

    Acute megakaryoblastic leukemia (AMKL) is a heterogeneous disease generally associated with poor prognosis. Gene expression profiles indicate the existence of distinct molecular subgroups, and several genetic alterations have been characterized in the past years, including the t(1;22)(p13;q13) and the trisomy 21 associated with GATA1 mutations. However, the majority of patients do not present with known mutations, and the limited access to primary patient leukemic cells impedes the efficient development of novel therapeutic strategies. In this study, using a xenotransplantation approach, we have modeled human pediatric AMKL in immunodeficient mice. Analysis of high-throughput RNA sequencing identified recurrent fusion genes defining new molecular subgroups. One subgroup of patients presented with MLL or NUP98 fusion genes leading to up-regulation of the HOX A cluster genes. A novel CBFA2T3-GLIS2 fusion gene resulting from a cryptic inversion of chromosome 16 was identified in another subgroup of 31% of non–Down syndrome AMKL and strongly associated with a gene expression signature of Hedgehog pathway activation. These molecular data provide useful markers for the diagnosis and follow up of patients. Finally, we show that AMKL xenograft models constitute a relevant in vivo preclinical screening platform to validate the efficacy of novel therapies such as Aurora A kinase inhibitors. PMID:23045605

  7. Characterization of novel genomic alterations and therapeutic approaches using acute megakaryoblastic leukemia xenograft models.

    PubMed

    Thiollier, Clarisse; Lopez, Cécile K; Gerby, Bastien; Ignacimouttou, Cathy; Poglio, Sandrine; Duffourd, Yannis; Guégan, Justine; Rivera-Munoz, Paola; Bluteau, Olivier; Mabialah, Vinciane; Diop, M'boyba; Wen, Qiang; Petit, Arnaud; Bauchet, Anne-Laure; Reinhardt, Dirk; Bornhauser, Beat; Gautheret, Daniel; Lecluse, Yann; Landman-Parker, Judith; Radford, Isabelle; Vainchenker, William; Dastugue, Nicole; de Botton, Stéphane; Dessen, Philippe; Bourquin, Jean-Pierre; Crispino, John D; Ballerini, Paola; Bernard, Olivier A; Pflumio, Françoise; Mercher, Thomas

    2012-10-22

    Acute megakaryoblastic leukemia (AMKL) is a heterogeneous disease generally associated with poor prognosis. Gene expression profiles indicate the existence of distinct molecular subgroups, and several genetic alterations have been characterized in the past years, including the t(1;22)(p13;q13) and the trisomy 21 associated with GATA1 mutations. However, the majority of patients do not present with known mutations, and the limited access to primary patient leukemic cells impedes the efficient development of novel therapeutic strategies. In this study, using a xenotransplantation approach, we have modeled human pediatric AMKL in immunodeficient mice. Analysis of high-throughput RNA sequencing identified recurrent fusion genes defining new molecular subgroups. One subgroup of patients presented with MLL or NUP98 fusion genes leading to up-regulation of the HOX A cluster genes. A novel CBFA2T3-GLIS2 fusion gene resulting from a cryptic inversion of chromosome 16 was identified in another subgroup of 31% of non-Down syndrome AMKL and strongly associated with a gene expression signature of Hedgehog pathway activation. These molecular data provide useful markers for the diagnosis and follow up of patients. Finally, we show that AMKL xenograft models constitute a relevant in vivo preclinical screening platform to validate the efficacy of novel therapies such as Aurora A kinase inhibitors. PMID:23045605

  8. Non-viral therapeutic approaches to ocular diseases: An overview and future directions.

    PubMed

    Zulliger, Rahel; Conley, Shannon M; Naash, Muna I

    2015-12-10

    Currently there are no viable treatment options for patients with debilitating inherited retinal degeneration. The vast variability in disease-inducing mutations and resulting phenotypes has hampered the development of therapeutic interventions. Gene therapy is a logical approach, and recent work has focused on ways to optimize vector design and packaging to promote optimized expression and phenotypic rescue after intraocular delivery. In this review, we discuss ongoing ocular clinical trials, which currently use viral gene delivery, but focus primarily on new advancements in optimizing the efficacy of non-viral gene delivery for ocular diseases. Non-viral delivery systems are highly customizable, allowing functionalization to improve cellular and nuclear uptake, bypassing cellular degradative machinery, and improving gene expression in the nucleus. Non-viral vectors often yield transgene expression levels lower than viral counterparts, however their favorable safety/immune profiles and large DNA capacity (critical for the delivery of large ocular disease genes) make their further development a research priority. Recent work on particle coating and vector engineering presents exciting ways to overcome limitations of transient/low gene expression levels, but also highlights the fact that further refinements are needed before use in the clinic.

  9. Acute respiratory distress syndrome following cardiovascular surgery: current concepts and novel therapeutic approaches

    PubMed Central

    Hoegl, Sandra; Zwissler, Bernhard; Eltzschig, Holger K.; Vohwinkel, Christine

    2015-01-01

    Purpose of review This review gives an update on current treatment options and novel concepts on the prevention and treatment of the acute respiratory distress syndrome (ARDS) in cardiovascular surgery patients. Recent findings The only proven beneficial therapeutic options in ARDS are those that help to prevent further ventilator-induced lung injury, such as prone position, use of lung-protective ventilation strategies, and extracorporeal membrane oxygenation. In the future also new approaches like mesenchymal cell therapy, activation of hypoxia-elicited transcription factors or targeting of purinergic signaling may be successful outside the experimental setting. Owing to the so far limited treatment options, it is of great importance to determine patients at risk for developing ARDS already perioperatively. In this context, serum biomarkers and lung injury prediction scores could be useful. Summary Preventing ARDS as a severe complication in the cardiovascular surgery setting may help to reduce morbidity and mortality. As cardiovascular surgery patients are of greater risk to develop ARDS, preventive interventions should be implemented early on. Especially, use of low tidal volumes, avoiding of fluid overload and restrictive blood transfusion regimes may help to prevent ARDS. PMID:26598954

  10. Novel therapeutics for primary biliary cholangitis: Toward a disease-stage-based approach.

    PubMed

    Mousa, Hani S; Carbone, Marco; Malinverno, Federica; Ronca, Vincenzo; Gershwin, M Eric; Invernizzi, Pietro

    2016-09-01

    Primary biliary cholangitis (PBC; previously "primary biliary cirrhosis") is a cholestatic, putatively autoimmune-mediated liver disease with a clear female preponderance affecting the intrahepatic small and medium-size bile ducts and resulting in bile duct destruction, ductopenia and portal fibrosis that progresses slowly to biliary cirrhosis. Despite suboptimal response in one third of patients treated with ursodeoxycholic acid (UDCA), this remains the only FDA-approved agent for this disease. In this review, we cover recent advances in research that have yielded numerous agents currently at different stages of the drug pipeline, some of which are expected to be approved in the near future. We also discuss accumulating evidence supporting the use of older agents (fibrates and glucocorticoids) as an adjunctive therapy to UDCA in non-responsive patients. We suggest that with the imminent expansion of the therapeutic armamentarium for PBC, a more comprehensive approach - ideally taking into account not only biochemical markers of disease stage - is needed to better select patients in whom these strategies might be most useful. Studies are also needed to compare the relative efficacy of different proposed second-line treatments not only against UDCA monotherapy.

  11. Novel therapeutics for primary biliary cholangitis: Toward a disease-stage-based approach.

    PubMed

    Mousa, Hani S; Carbone, Marco; Malinverno, Federica; Ronca, Vincenzo; Gershwin, M Eric; Invernizzi, Pietro

    2016-09-01

    Primary biliary cholangitis (PBC; previously "primary biliary cirrhosis") is a cholestatic, putatively autoimmune-mediated liver disease with a clear female preponderance affecting the intrahepatic small and medium-size bile ducts and resulting in bile duct destruction, ductopenia and portal fibrosis that progresses slowly to biliary cirrhosis. Despite suboptimal response in one third of patients treated with ursodeoxycholic acid (UDCA), this remains the only FDA-approved agent for this disease. In this review, we cover recent advances in research that have yielded numerous agents currently at different stages of the drug pipeline, some of which are expected to be approved in the near future. We also discuss accumulating evidence supporting the use of older agents (fibrates and glucocorticoids) as an adjunctive therapy to UDCA in non-responsive patients. We suggest that with the imminent expansion of the therapeutic armamentarium for PBC, a more comprehensive approach - ideally taking into account not only biochemical markers of disease stage - is needed to better select patients in whom these strategies might be most useful. Studies are also needed to compare the relative efficacy of different proposed second-line treatments not only against UDCA monotherapy. PMID:27393766

  12. Neural stem cell transplantation as a therapeutic approach for treating lysosomal storage diseases.

    PubMed

    Shihabuddin, Lamya S; Cheng, Seng H

    2011-10-01

    Treating the central nervous system manifestations of subjects with neuropathic lysosomal storage diseases remains a major technical challenge. This is because of the low efficiency by which lysosomal enzymes in systemic circulation are able to traverse the blood brain barrier into the central nervous system. Intracranial transplantation of neural stems cells genetically modified to overexpress the respective deficient enzymes represents a potential approach to addressing this group of diseases. The unique properties of neural stem cells and progenitor cells, such as their ability to migrate to distal sites, differentiate into various cell types and integrate within the host brain without disrupting normal function, making them particularly attractive therapeutic agents. In addition, neural stem cells are amenable to ex vivo propagation and modification by gene transfer vectors. In this regard, transplanted cells can serve not only as a source of lysosomal enzymes but also as a means to potentially repair the injured brain by replenishing the organ with healthy cells and effecting the release of neuroprotective factors. This review discusses some of the well-characterized neural stem cell types and their possible use in treating neuropathic lysosomal storage diseases such as the Niemann Pick A disease.

  13. Management of rheumatoid arthritis: Impact and risks of various therapeutic approaches

    PubMed Central

    NEGREI, CAROLINA; BOJINCA, VIOLETA; BALANESCU, ANDRA; BOJINCA, MIHAI; BACONI, DANIELA; SPANDIDOS, DEMETRIOS A.; TSATSAKIS, ARISTIDIS M.; STAN, MIRIANA

    2016-01-01

    Rheumatic diseases are highly prevalent chronic disorders and the leading cause of physical disability worldwide, with a marked socio-economic impact. Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease of unknown etiology with an autoimmune pathogenesis, characterised by arthropathy with chronic, deforming, destructive evolution and multiple systemic manifestations. The management of RA has undergone significant changes as far as objectives and approaches are concerned, ending in the current strategy known as ‘treat to target’. The therapeutic array of RA includes several categories of medicinal products, of varying potential. There are several criteria for the classification of medicinal products used against this disease, one of the most important and modern of which divides such substances according to their effects on the progress of the disease: symptom-modifying antirheumatic drugs (including non-steroidal anti-inflammatory drugs and corticoids), disease-modifying antirheumatic drugs (including various substances, such as gold salts, antimalarials, sulfasalazine, D-penicillamine; non-specific immunosuppressive medication, such as methotrexate, cyclophosphamide, azathioprine and leflunomide) and biological therapy is a recent addition, providing new insight into the treatment of this disease. The selection of the optimal therapy for RA should be based on guidelines and recommendations, but also on clinical particular aspects and patient preferences. PMID:27073419

  14. Inhibition of AAK1 Kinase as a Novel Therapeutic Approach to Treat Neuropathic Pain

    PubMed Central

    Kostich, Walter; Hamman, Brian D.; Li, Yu-Wen; Naidu, Sreenivasulu; Dandapani, Kumaran; Feng, Jianlin; Easton, Amy; Bourin, Clotilde; Baker, Kevin; Allen, Jason; Savelieva, Katerina; Louis, Justin V.; Dokania, Manoj; Elavazhagan, Saravanan; Vattikundala, Pradeep; Sharma, Vivek; Das, Manish Lal; Shankar, Ganesh; Kumar, Anoop; Holenarsipur, Vinay K.; Gulianello, Michael; Molski, Ted; Brown, Jeffrey M.; Lewis, Martin; Huang, Yanling; Lu, Yifeng; Pieschl, Rick; O’Malley, Kevin; Lippy, Jonathan; Nouraldeen, Amr; Lanthorn, Thomas H.; Ye, Guilan; Wilson, Alan; Balakrishnan, Anand; Denton, Rex; Grace, James E.; Lentz, Kimberley A.; Santone, Kenneth S.; Bi, Yingzhi; Main, Alan; Swaffield, Jon; Carson, Ken; Mandlekar, Sandhya; Vikramadithyan, Reeba K.; Nara, Susheel J.; Dzierba, Carolyn; Bronson, Joanne; Macor, John E.; Zaczek, Robert; Westphal, Ryan; Kiss, Laszlo; Bristow, Linda; Conway, Charles M.

    2016-01-01

    To identify novel targets for neuropathic pain, 3097 mouse knockout lines were tested in acute and persistent pain behavior assays. One of the lines from this screen, which contained a null allele of the adapter protein-2 associated kinase 1 (AAK1) gene, had a normal response in acute pain assays (hot plate, phase I formalin), but a markedly reduced response to persistent pain in phase II formalin. AAK1 knockout mice also failed to develop tactile allodynia following the Chung procedure of spinal nerve ligation (SNL). Based on these findings, potent, small-molecule inhibitors of AAK1 were identified. Studies in mice showed that one such inhibitor, LP-935509, caused a reduced pain response in phase II formalin and reversed fully established pain behavior following the SNL procedure. Further studies showed that the inhibitor also reduced evoked pain responses in the rat chronic constriction injury (CCI) model and the rat streptozotocin model of diabetic peripheral neuropathy. Using a nonbrain-penetrant AAK1 inhibitor and local administration of an AAK1 inhibitor, the relevant pool of AAK1 for antineuropathic action was found to be in the spinal cord. Consistent with these results, AAK1 inhibitors dose-dependently reduced the increased spontaneous neural activity in the spinal cord caused by CCI and blocked the development of windup induced by repeated electrical stimulation of the paw. The mechanism of AAK1 antinociception was further investigated with inhibitors of α2 adrenergic and opioid receptors. These studies showed that α2 adrenergic receptor inhibitors, but not opioid receptor inhibitors, not only prevented AAK1 inhibitor antineuropathic action in behavioral assays, but also blocked the AAK1 inhibitor–induced reduction in spinal neural activity in the rat CCI model. Hence, AAK1 inhibitors are a novel therapeutic approach to neuropathic pain with activity in animal models that is mechanistically linked (behaviorally and electrophysiologically) to α2

  15. Biological computational approaches: new hopes to improve (re)programming robustness, regenerative medicine and cancer therapeutics.

    PubMed

    Ebrahimi, Behnam

    2016-01-01

    Hundreds of transcription factors (TFs) are expressed and work in each cell type, but the identity of the cells is defined and maintained through the activity of a small number of core TFs. Existing reprogramming strategies predominantly focus on the ectopic expression of core TFs of an intended fate in a given cell type regardless of the state of native/somatic gene regulatory networks (GRNs) of the starting cells. Interestingly, an important point is that how much products of the reprogramming, transdifferentiation and differentiation (programming) are identical to their in vivo counterparts. There is evidence that shows that direct fate conversions of somatic cells are not complete, with target cell identity not fully achieved. Manipulation of core TFs provides a powerful tool for engineering cell fate in terms of extinguishment of native GRNs, the establishment of a new GRN, and preventing installation of aberrant GRNs. Conventionally, core TFs are selected to convert one cell type into another mostly based on literature and the experimental identification of genes that are differentially expressed in one cell type compared to the specific cell types. Currently, there is not a universal standard strategy for identifying candidate core TFs. Remarkably, several biological computational platforms are developed, which are capable of evaluating the fidelity of reprogramming methods and refining existing protocols. The current review discusses some deficiencies of reprogramming technologies in the production of a pure population of authentic target cells. Furthermore, it reviews the role of computational approaches (e.g. CellNet, KeyGenes, Mogrify, etc.) in improving (re)programming methods and consequently in regenerative medicine and cancer therapeutics.

  16. Calcitriol restores antiestrogen responsiveness in estrogen receptor negative breast cancer cells: A potential new therapeutic approach

    PubMed Central

    2014-01-01

    Background Approximately 30% of breast tumors do not express the estrogen receptor (ER) α, which is necessary for endocrine therapy approaches. Studies are ongoing in order to restore ERα expression in ERα-negative breast cancer. The aim of the present study was to determine if calcitriol induces ERα expression in ER-negative breast cancer cells, thus restoring antiestrogen responses. Methods Cultured cells derived from ERα-negative breast tumors and an ERα-negative breast cancer cell line (SUM-229PE) were treated with calcitriol and ERα expression was assessed by real time PCR and western blots. The ERα functionality was evaluated by prolactin gene expression analysis. In addition, the effects of antiestrogens were assessed by growth assay using the XTT method. Gene expression of cyclin D1 (CCND1), and Ether-à-go-go 1 (EAG1) was also evaluated in cells treated with calcitriol alone or in combination with estradiol or ICI-182,780. Statistical analyses were determined by one-way ANOVA. Results Calcitriol was able to induce the expression of a functional ERα in ER-negative breast cancer cells. This effect was mediated through the vitamin D receptor (VDR), since it was abrogated by a VDR antagonist. Interestingly, the calcitriol-induced ERα restored the response to antiestrogens by inhibiting cell proliferation. In addition, calcitriol-treated cells in the presence of ICI-182,780 resulted in a significant reduction of two important cell proliferation regulators CCND1 and EAG1. Conclusions Calcitriol induced the expression of ERα and restored the response to antiestrogens in ERα-negative breast cancer cells. The combined treatment with calcitriol and antiestrogens could represent a new therapeutic strategy in ERα-negative breast cancer patients. PMID:24678876

  17. Biological computational approaches: new hopes to improve (re)programming robustness, regenerative medicine and cancer therapeutics.

    PubMed

    Ebrahimi, Behnam

    2016-01-01

    Hundreds of transcription factors (TFs) are expressed and work in each cell type, but the identity of the cells is defined and maintained through the activity of a small number of core TFs. Existing reprogramming strategies predominantly focus on the ectopic expression of core TFs of an intended fate in a given cell type regardless of the state of native/somatic gene regulatory networks (GRNs) of the starting cells. Interestingly, an important point is that how much products of the reprogramming, transdifferentiation and differentiation (programming) are identical to their in vivo counterparts. There is evidence that shows that direct fate conversions of somatic cells are not complete, with target cell identity not fully achieved. Manipulation of core TFs provides a powerful tool for engineering cell fate in terms of extinguishment of native GRNs, the establishment of a new GRN, and preventing installation of aberrant GRNs. Conventionally, core TFs are selected to convert one cell type into another mostly based on literature and the experimental identification of genes that are differentially expressed in one cell type compared to the specific cell types. Currently, there is not a universal standard strategy for identifying candidate core TFs. Remarkably, several biological computational platforms are developed, which are capable of evaluating the fidelity of reprogramming methods and refining existing protocols. The current review discusses some deficiencies of reprogramming technologies in the production of a pure population of authentic target cells. Furthermore, it reviews the role of computational approaches (e.g. CellNet, KeyGenes, Mogrify, etc.) in improving (re)programming methods and consequently in regenerative medicine and cancer therapeutics. PMID:27056282

  18. A unique therapeutic approach to emesis and itch with a proanthocyanidin-rich genonutrient

    PubMed Central

    Miller, Mark JS; Reuter, Brian K; Wallace, John L; Sharkey, Keith A

    2008-01-01

    Background We examined the therapeutic potential of a proprietary Croton palanostigma extract (Zangrado®) in the management of emesis and itch. Methods Emesis was induced in ferrets with morphine-6-glucuronide (0.05 mg/kg sc) in the presence of Zangrado (3 mg/kg, ip) and the cannabinoid receptor 1 antagonist, AM 251 (5 mg/kg, ip). Topical Zangrado (1%) was assessed for anti-pruretic actions in the 5-HT-induced scratching model in rats and evaluated in capsaicin-induced gastric hyperemia as measured by laser doppler flow. In the ApcMinmouse model of precancerous adenomatosis polyposis, mice received Zangrado (100 μg/ml in drinking water) from the age of 6 – 16 weeks for effects on polyp number. In RAW 264.7 cells Zangrado was examined for effects on lipopolysaccharide-induced nitrite production. Results Zangrado was a highly effective anti-emetic, reducing morphine-induced vomiting and retching by 77%. These benefits were not associated with sedation or hypothermia and were not reversed by cannabinoid receptor antagonism. Itch responses were blocked in both the morphine and 5-HT models. Zangrado did not exacerbate the ApcMincondition rather health was improved. Capsaicin-induced hyperemia was blocked by Zangrado, which also attenuated the production of nitric oxide by activated macrophages. Conclusion Zangrado is an effective anti-emetic and anti-itch therapy that is devoid of common side-effects, cannabinoid-independent and broadly suppresses sensory afferent nerve activation. This complementary medicine represents a promising new approach to the management of nausea, itch and irritable bowel syndrome. PMID:18205911

  19. Inhibition of AAK1 Kinase as a Novel Therapeutic Approach to Treat Neuropathic Pain.

    PubMed

    Kostich, Walter; Hamman, Brian D; Li, Yu-Wen; Naidu, Sreenivasulu; Dandapani, Kumaran; Feng, Jianlin; Easton, Amy; Bourin, Clotilde; Baker, Kevin; Allen, Jason; Savelieva, Katerina; Louis, Justin V; Dokania, Manoj; Elavazhagan, Saravanan; Vattikundala, Pradeep; Sharma, Vivek; Das, Manish Lal; Shankar, Ganesh; Kumar, Anoop; Holenarsipur, Vinay K; Gulianello, Michael; Molski, Ted; Brown, Jeffrey M; Lewis, Martin; Huang, Yanling; Lu, Yifeng; Pieschl, Rick; O'Malley, Kevin; Lippy, Jonathan; Nouraldeen, Amr; Lanthorn, Thomas H; Ye, Guilan; Wilson, Alan; Balakrishnan, Anand; Denton, Rex; Grace, James E; Lentz, Kimberley A; Santone, Kenneth S; Bi, Yingzhi; Main, Alan; Swaffield, Jon; Carson, Ken; Mandlekar, Sandhya; Vikramadithyan, Reeba K; Nara, Susheel J; Dzierba, Carolyn; Bronson, Joanne; Macor, John E; Zaczek, Robert; Westphal, Ryan; Kiss, Laszlo; Bristow, Linda; Conway, Charles M; Zambrowicz, Brian; Albright, Charles F

    2016-09-01

    To identify novel targets for neuropathic pain, 3097 mouse knockout lines were tested in acute and persistent pain behavior assays. One of the lines from this screen, which contained a null allele of the adapter protein-2 associated kinase 1 (AAK1) gene, had a normal response in acute pain assays (hot plate, phase I formalin), but a markedly reduced response to persistent pain in phase II formalin. AAK1 knockout mice also failed to develop tactile allodynia following the Chung procedure of spinal nerve ligation (SNL). Based on these findings, potent, small-molecule inhibitors of AAK1 were identified. Studies in mice showed that one such inhibitor, LP-935509, caused a reduced pain response in phase II formalin and reversed fully established pain behavior following the SNL procedure. Further studies showed that the inhibitor also reduced evoked pain responses in the rat chronic constriction injury (CCI) model and the rat streptozotocin model of diabetic peripheral neuropathy. Using a nonbrain-penetrant AAK1 inhibitor and local administration of an AAK1 inhibitor, the relevant pool of AAK1 for antineuropathic action was found to be in the spinal cord. Consistent with these results, AAK1 inhibitors dose-dependently reduced the increased spontaneous neural activity in the spinal cord caused by CCI and blocked the development of windup induced by repeated electrical stimulation of the paw. The mechanism of AAK1 antinociception was further investigated with inhibitors of α2 adrenergic and opioid receptors. These studies showed that α2 adrenergic receptor inhibitors, but not opioid receptor inhibitors, not only prevented AAK1 inhibitor antineuropathic action in behavioral assays, but also blocked the AAK1 inhibitor-induced reduction in spinal neural activity in the rat CCI model. Hence, AAK1 inhibitors are a novel therapeutic approach to neuropathic pain with activity in animal models that is mechanistically linked (behaviorally and electrophysiologically) to α2

  20. Inhibition of AAK1 Kinase as a Novel Therapeutic Approach to Treat Neuropathic Pain.

    PubMed

    Kostich, Walter; Hamman, Brian D; Li, Yu-Wen; Naidu, Sreenivasulu; Dandapani, Kumaran; Feng, Jianlin; Easton, Amy; Bourin, Clotilde; Baker, Kevin; Allen, Jason; Savelieva, Katerina; Louis, Justin V; Dokania, Manoj; Elavazhagan, Saravanan; Vattikundala, Pradeep; Sharma, Vivek; Das, Manish Lal; Shankar, Ganesh; Kumar, Anoop; Holenarsipur, Vinay K; Gulianello, Michael; Molski, Ted; Brown, Jeffrey M; Lewis, Martin; Huang, Yanling; Lu, Yifeng; Pieschl, Rick; O'Malley, Kevin; Lippy, Jonathan; Nouraldeen, Amr; Lanthorn, Thomas H; Ye, Guilan; Wilson, Alan; Balakrishnan, Anand; Denton, Rex; Grace, James E; Lentz, Kimberley A; Santone, Kenneth S; Bi, Yingzhi; Main, Alan; Swaffield, Jon; Carson, Ken; Mandlekar, Sandhya; Vikramadithyan, Reeba K; Nara, Susheel J; Dzierba, Carolyn; Bronson, Joanne; Macor, John E; Zaczek, Robert; Westphal, Ryan; Kiss, Laszlo; Bristow, Linda; Conway, Charles M; Zambrowicz, Brian; Albright, Charles F

    2016-09-01

    To identify novel targets for neuropathic pain, 3097 mouse knockout lines were tested in acute and persistent pain behavior assays. One of the lines from this screen, which contained a null allele of the adapter protein-2 associated kinase 1 (AAK1) gene, had a normal response in acute pain assays (hot plate, phase I formalin), but a markedly reduced response to persistent pain in phase II formalin. AAK1 knockout mice also failed to develop tactile allodynia following the Chung procedure of spinal nerve ligation (SNL). Based on these findings, potent, small-molecule inhibitors of AAK1 were identified. Studies in mice showed that one such inhibitor, LP-935509, caused a reduced pain response in phase II formalin and reversed fully established pain behavior following the SNL procedure. Further studies showed that the inhibitor also reduced evoked pain responses in the rat chronic constriction injury (CCI) model and the rat streptozotocin model of diabetic peripheral neuropathy. Using a nonbrain-penetrant AAK1 inhibitor and local administration of an AAK1 inhibitor, the relevant pool of AAK1 for antineuropathic action was found to be in the spinal cord. Consistent with these results, AAK1 inhibitors dose-dependently reduced the increased spontaneous neural activity in the spinal cord caused by CCI and blocked the development of windup induced by repeated electrical stimulation of the paw. The mechanism of AAK1 antinociception was further investigated with inhibitors of α2 adrenergic and opioid receptors. These studies showed that α2 adrenergic receptor inhibitors, but not opioid receptor inhibitors, not only prevented AAK1 inhibitor antineuropathic action in behavioral assays, but also blocked the AAK1 inhibitor-induced reduction in spinal neural activity in the rat CCI model. Hence, AAK1 inhibitors are a novel therapeutic approach to neuropathic pain with activity in animal models that is mechanistically linked (behaviorally and electrophysiologically) to α2

  1. A novel approach to investigate the effect of methionine oxidation on pharmacokinetic properties of therapeutic antibodies

    PubMed Central

    Stracke, Jan; Emrich, Thomas; Rueger, Petra; Schlothauer, Tilman; Kling, Lothar; Knaupp, Alexander; Hertenberger, Hubert; Wolfert, Andreas; Spick, Christian; Lau, Wilma; Drabner, Georg; Reiff, Ulrike; Koll, Hans; Papadimitriou, Apollon

    2014-01-01

    Preserving the chemical and structural integrity of therapeutic antibodies during manufacturing and storage is a major challenge during pharmaceutical development. Oxidation of Fc methionines Met252 and Met428 is frequently observed, which leads to reduced affinity to FcRn and faster plasma clearance if present at high levels. Because oxidation occurs in both positions simultaneously, their individual contribution to the concomitant changes in pharmacokinetic properties has not been clearly established. A novel pH-gradient FcRn affinity chromatography method was applied to isolate three antibody oxidation variants from an oxidized IgG1 preparation based on their FcRn binding properties. Physico-chemical characterization revealed that the three oxidation variants differed predominantly in the number of oxMet252 per IgG (0, 1, or 2), but not significantly in the content of oxMet428. Corresponding to the increase in oxMet252 content, stepwise reduction of FcRn affinity in vitro, as well as faster clearance and shorter terminal half-life, in huFcRn-transgenic mice were observed. A single Met252 oxidation per antibody had no significant effect on pharmacokinetics (PK) compared with unmodified IgG. Importantly, only molecules with both heavy chains oxidized at Met252 exhibited significantly faster clearance. In contrast, Met428 oxidation had no apparent negative effect on PK and even led to somewhat improved FcRn binding and slower clearance. This minor effect, however, seemed to be abrogated by the dominant effect of Met252 oxidation. The novel approach of functional chromatographic separation of IgG oxidation variants followed by physico-chemical and biological characterization has yielded the first experimentally-backed explanation for the unaltered PK properties of antibody preparations containing relatively high Met252 and Met428 oxidation levels. PMID:25517308

  2. Metabolic pathway analysis approach: identification of novel therapeutic target against methicillin resistant Staphylococcus aureus.

    PubMed

    Uddin, Reaz; Saeed, Kiran; Khan, Waqasuddin; Azam, Syed Sikander; Wadood, Abdul

    2015-02-10

    Multiple Drug Resistant (MDR) bacteria are no more inhibited by the front line antibiotics due to extreme resistance. Methicillin Resistant Staphylococcus aureus (MRSA) is one of the MDR pathogens notorious for its widespread infection around the world. The high resistance acquired by MRSA needs a serious concern and efforts should be carried out for the discovery of better therapeutics. With this aim, we designed a comparison of the metabolic pathways of the pathogen, MRSA strain 252 (MRSA252) with the human host (i.e., Homo sapiens) by using well-established in silico methods. We identified several metabolic pathways unique to MRSA (i.e., absent in the human host). Furthermore, a subtractive genomics analysis approach was applied for retrieval of proteins only from the unique metabolic pathways. Subsequently, proteins of unique MRSA pathways were compared with the host proteins. As a result, we have shortlisted few unique and essential proteins that could act as drug targets against MRSA. We further assessed the druggability potential of the shortlisted targets by comparing them with the DrugBank Database (DBD). The identified drug targets could be useful for an effective drug discovery phase. We also searched the sequences of unique as well as essential enzymes from MRSA in Protein Data Bank (PDB). We shortlisted at least 12 enzymes for which there was no corresponding deposition in PDB, reflecting that their crystal structures are yet to be solved! We selected Glutamate synthase out of those 12 enzymes owing to its participation in significant metabolic pathways of the pathogen e.g., Alanine, Aspartate, Glutamate and Nitrogen metabolism and its evident suitability as drug target among other MDR bacteria e.g., Mycobacteria. Due to the unavailability of any crystal structure of Glutamate synthase in PDB, we generated the 3D structure by homology modeling. The modeled structure was validated by multiple analysis tools. The active site of Glutamate synthase was

  3. [Aggressive fibromatoses. Treatment concept and results with special reference to ultrasound diagnosis].

    PubMed

    Sinkwitz, K D; Fischer, R; Geissler, S; Göbel, P

    1986-01-01

    Therapeutic tactics and control regime for aggressive fibromatosis are described in this paper, with reference being made to the authors' own patients. Locally delimited, wide excision without supporting radiotherapy is recommended also for recurrent cases. Anti-oestrogenic treatment has now been adopted to cope with locally delimited inoperability. The polytopic, usually congenital form of aggressive fibromatosis must be interpreted as a particularly unfavourable course with potential malignancy. Sonography so far has proved to be a suitable approach to pre-operative and postoperative screening.

  4. Dynamics of aggregate stability and soil organic C distribution as affected by climatic aggressiveness: a mesocosm approach

    NASA Astrophysics Data System (ADS)

    Pellegrini, Sergio; Elio Agnelli, Alessandro; Costanza Andrenelli, Maria; Barbetti, Roberto; Castelli, Fabio; Costantini, Edoardo A. C.; Lagomarsino, Alessandra; Pasqui, Massimiliano; Tomozeiu, Rodica; Razzaghi, Somayyeh; Vignozzi, Nadia

    2014-05-01

    In the framework of a research project aimed at evaluating the adaptation scenarios of the Italian agriculture to the current climate change, a mesocosm experiment under controlled conditions was set up for studying the dynamics of soil aggregate stability and organic C in different size fractions. Three alluvial loamy soils (BOV - Typic Haplustalfs coarse-loamy; CAS - Typic Haplustalfs fine-loamy; MED - Typic Hapludalfs fine-loamy) along a climatic gradient (from dryer to moister pedoclimatic conditions) in the river Po valley (northern Italy), under crop rotation for animal husbandry from more than 40 years, were selected. The Ap horizons (0-30cm) were taken and placed in 9 climatic chambers under controlled temperature and rainfall. Each soil was subjected to three different climate scenarios in terms of erosivity index obtained by combining Modified Fournier and Bagnouls-Gaussen indexes: i) typical (TYP), the median year of each site related to the 1961-1990 reference period; ii) maximum aggressive year (MAX) observed in the same period, and iii) the simulated climate (SIM), obtained by projections of climate change precipitation and temperature for the period 2021-2050 as provided by the IPCC-A1B emission scenario. In the climatic chambers the year climate was reduced to six months. The soils were analyzed for particle size distribution, aggregate stability by wet and dry sieving, and organic C content at the beginning and at the end of the trial. The soils showed different behaviour in terms of aggregate stability and dynamics of organic C in the diverse size fractions. The soils significantly differed in terms of initial mean weight diameter (MWD) (CAS>MED>BOV). A general reduction of MWD in all sites was observed at the end of the experiment, with the increase of the smallest aggregate fractions (0.250-0.05 mm). In particular, BOV showed the maximum decrease of the aggregate stability and MED the lowest. C distribution in aggregate fractions significantly

  5. Soteria Berne: an innovative milieu therapeutic approach to acute schizophrenia based on the concept of affect-logic

    PubMed Central

    Ciompi, Luc; Hoffmann, Holger

    2004-01-01

    The name "Soteria" stands for an alternative low-drug milieu-therapeutic approach to acute schizophrenia that was first implemented by Mosher and Menn in San Francisco, and since 1984 further developed by Ciompi and co-workers in Berne, on the basis of their concept of affect-logic, that emphasizes the often neglected influence of emotional factors in schizophrenia. In both settings, equal and even partly better therapeutic results, compared with traditional methods, were obtained with much lower doses of antipsychotics and comparable daily costs. Basic concepts, practical proceedings and empirical findings of Soteria Berne are reported, and their theoretical and practical implications for mainstream psychiatry are discussed. They support the hypothesis of a crucial pathogenetic and therapeutic-preventive role played by emotional factors not only in the so-called affective psychoses, but also in schizophrenia. PMID:16633478

  6. Sleep deprivation suppresses aggression in Drosophila

    PubMed Central

    Kayser, Matthew S; Mainwaring, Benjamin; Yue, Zhifeng; Sehgal, Amita

    2015-01-01

    Sleep disturbances negatively impact numerous functions and have been linked to aggression and violence. However, a clear effect of sleep deprivation on aggressive behaviors remains unclear. We find that acute sleep deprivation profoundly suppresses aggressive behaviors in the fruit fly, while other social behaviors are unaffected. This suppression is recovered following post-deprivation sleep rebound, and occurs regardless of the approach to achieve sleep loss. Genetic and pharmacologic approaches suggest octopamine signaling transmits changes in aggression upon sleep deprivation, and reduced aggression places sleep-deprived flies at a competitive disadvantage for obtaining a reproductive partner. These findings demonstrate an interaction between two phylogenetically conserved behaviors, and suggest that previous sleep experiences strongly modulate aggression with consequences for reproductive fitness. DOI: http://dx.doi.org/10.7554/eLife.07643.001 PMID:26216041

  7. Sleep deprivation suppresses aggression in Drosophila.

    PubMed

    Kayser, Matthew S; Mainwaring, Benjamin; Yue, Zhifeng; Sehgal, Amita

    2015-01-01

    Sleep disturbances negatively impact numerous functions and have been linked to aggression and violence. However, a clear effect of sleep deprivation on aggressive behaviors remains unclear. We find that acute sleep deprivation profoundly suppresses aggressive behaviors in the fruit fly, while other social behaviors are unaffected. This suppression is recovered following post-deprivation sleep rebound, and occurs regardless of the approach to achieve sleep loss. Genetic and pharmacologic approaches suggest octopamine signaling transmits changes in aggression upon sleep deprivation, and reduced aggression places sleep-deprived flies at a competitive disadvantage for obtaining a reproductive partner. These findings demonstrate an interaction between two phylogenetically conserved behaviors, and suggest that previous sleep experiences strongly modulate aggression with consequences for reproductive fitness.

  8. Sleep deprivation suppresses aggression in Drosophila.

    PubMed

    Kayser, Matthew S; Mainwaring, Benjamin; Yue, Zhifeng; Sehgal, Amita

    2015-01-01

    Sleep disturbances negatively impact numerous functions and have been linked to aggression and violence. However, a clear effect of sleep deprivation on aggressive behaviors remains unclear. We find that acute sleep deprivation profoundly suppresses aggressive behaviors in the fruit fly, while other social behaviors are unaffected. This suppression is recovered following post-deprivation sleep rebound, and occurs regardless of the approach to achieve sleep loss. Genetic and pharmacologic approaches suggest octopamine signaling transmits changes in aggression upon sleep deprivation, and reduced aggression places sleep-deprived flies at a competitive disadvantage for obtaining a reproductive partner. These findings demonstrate an interaction between two phylogenetically conserved behaviors, and suggest that previous sleep experiences strongly modulate aggression with consequences for reproductive fitness. PMID:26216041

  9. Spinal muscular atrophy phenotype is ameliorated in human motor neurons by SMN increase via different novel RNA therapeutic approaches.

    PubMed

    Nizzardo, Monica; Simone, Chiara; Dametti, Sara; Salani, Sabrina; Ulzi, Gianna; Pagliarani, Serena; Rizzo, Federica; Frattini, Emanuele; Pagani, Franco; Bresolin, Nereo; Comi, Giacomo; Corti, Stefania

    2015-01-01

    Spinal muscular atrophy (SMA) is a primary genetic cause of infant mortality due to mutations in the Survival Motor Neuron (SMN) 1 gene. No cure is available. Antisense oligonucleotides (ASOs) aimed at increasing SMN levels from the paralogous SMN2 gene represent a possible therapeutic strategy. Here, we tested in SMA human induced pluripotent stem cells (iPSCs) and iPSC-differentiated motor neurons, three different RNA approaches based on morpholino antisense targeting of the ISSN-1, exon-specific U1 small nuclear RNA (ExSpeU1), and Transcription Activator-Like Effector-Transcription Factor (TALE-TF). All strategies act modulating SMN2 RNA: ASO affects exon 7 splicing, TALE-TF increase SMN2 RNA acting on the promoter, while ExSpeU1 improves pre-mRNA processing. These approaches induced up-regulation of full-length SMN mRNA and differentially affected the Delta-7 isoform: ASO reduced this isoform, while ExSpeU1 and TALE-TF increased it. All approaches upregulate the SMN protein and significantly improve the in vitro SMA motor neurons survival. Thus, these findings demonstrate that therapeutic tools that act on SMN2 RNA are able to rescue the SMA disease phenotype. Our data confirm the feasibility of SMA iPSCs as in vitro disease models and we propose novel RNA approaches as potential therapeutic strategies for treating SMA and other genetic neurological disorders. PMID:26123042

  10. Aggressive behavior problems.

    PubMed

    Beaver, B V

    1986-12-01

    Accurate diagnosis of the cause of aggression in horses is essential to determining the appropriate course of action. The affective forms of aggression include fear-induced, pain-induced, intermale, dominance, protective, maternal, learned, and redirected aggressions. Non-affective aggression includes play and sex-related forms. Irritable aggression and hypertestosteronism in mares are medical problems, whereas genetic factors, brain dysfunction, and self-mutilation are also concerns. PMID:3492250

  11. Anaphylaxis in referred pediatric patients: demographic and clinical features, triggers, and therapeutic approach.

    PubMed

    De Swert, Liliane F A; Bullens, Dominique; Raes, Marc; Dermaux, Anna-Maria

    2008-11-01

    Anaphylaxis remains under-diagnosed and under-treated. A better knowledge of patterns and triggers of anaphylaxis might contribute to a better management. In this study we evaluated the demographic and clinical features of anaphylaxis in pediatric patients, as well as its triggers and therapeutic approach. From May 1st 2004 until April 30th 2006 we prospectively collected data on all patients referred for investigation of anaphylaxis to the pediatric department of the University Hospital Gasthuisberg Leuven and to two private pediatric practices. Data were stored in a MYSQL database by use of an online encrypted web form. Sixty-four cases of anaphylaxis occurred in 48 children, aged 6 months to 14.8 years. Twenty-seven episodes (42.2%) occurred at home. The symptoms were dermatologic in 62 (96.9%) episodes, respiratory in 57 (89.1%), gastrointestinal in 19 (29.7%), cardiovascular in 14 (21.8%), and neurological or behavioural in 19 (29.7%). Antihistamines were administered in 41/57 (71.9%) cases, corticosteroids in 26/57 (45.6%), beta-2-mimetics in 14/57 (24.6%), and adrenaline in 11/57 (19.3%). Out of nine cases where Epipen was available at the moment of anaphylaxis, it was administered in one case only. Food was the cause of anaphylaxis in 42/55 (76.4%) cases with identified trigger, while medication, insect stings, latex, and birch pollen triggered 5 (9.1%), 4 (7.3%), 3 (5.5%), and 1 (1.8%) case(s), respectively. Allergy to the trigger was known prior to anaphylaxis in 19/55 (34.5%) cases. In conclusion, anaphylaxis in pediatric patients generally presents with dermatologic and respiratory symptoms, while in 1/5 episodes cardiovascular symptoms occur. Food is by far the most frequent trigger. Allergy to the trigger is known in 1/3 cases only. Anaphylaxis is under-treated, even when appropriate medication is available. PMID:18204859

  12. Anaphylaxis in referred pediatric patients: demographic and clinical features, triggers, and therapeutic approach.

    PubMed

    De Swert, Liliane F A; Bullens, Dominique; Raes, Marc; Dermaux, Anna-Maria

    2008-11-01

    Anaphylaxis remains under-diagnosed and under-treated. A better knowledge of patterns and triggers of anaphylaxis might contribute to a better management. In this study we evaluated the demographic and clinical features of anaphylaxis in pediatric patients, as well as its triggers and therapeutic approach. From May 1st 2004 until April 30th 2006 we prospectively collected data on all patients referred for investigation of anaphylaxis to the pediatric department of the University Hospital Gasthuisberg Leuven and to two private pediatric practices. Data were stored in a MYSQL database by use of an online encrypted web form. Sixty-four cases of anaphylaxis occurred in 48 children, aged 6 months to 14.8 years. Twenty-seven episodes (42.2%) occurred at home. The symptoms were dermatologic in 62 (96.9%) episodes, respiratory in 57 (89.1%), gastrointestinal in 19 (29.7%), cardiovascular in 14 (21.8%), and neurological or behavioural in 19 (29.7%). Antihistamines were administered in 41/57 (71.9%) cases, corticosteroids in 26/57 (45.6%), beta-2-mimetics in 14/57 (24.6%), and adrenaline in 11/57 (19.3%). Out of nine cases where Epipen was available at the moment of anaphylaxis, it was administered in one case only. Food was the cause of anaphylaxis in 42/55 (76.4%) cases with identified trigger, while medication, insect stings, latex, and birch pollen triggered 5 (9.1%), 4 (7.3%), 3 (5.5%), and 1 (1.8%) case(s), respectively. Allergy to the trigger was known prior to anaphylaxis in 19/55 (34.5%) cases. In conclusion, anaphylaxis in pediatric patients generally presents with dermatologic and respiratory symptoms, while in 1/5 episodes cardiovascular symptoms occur. Food is by far the most frequent trigger. Allergy to the trigger is known in 1/3 cases only. Anaphylaxis is under-treated, even when appropriate medication is available.

  13. "Am I going crazy, doc?": a self psychology approach to therapeutic assessment.

    PubMed

    Peters, Eric J; Handler, Leonard; White, Kathryn G; Winkel, Justin D

    2008-09-01

    In this case study, we explore the effectiveness of Therapeutic Assessment with a severely disturbed 25-year-old man, referred by his therapist, following Finn's (2007; Finn & Tonsager, 1992, 1997) model. This patient-therapist pair had been working together for approximately 2 months, but the therapy had ceased to progress. The therapist requested a clearer picture of his patient's affective functioning, interpersonal functioning, and self-functioning that might facilitate more effective treatment. Through a collaborative assessment process informed by the principles of Kohutian self psychology, the evaluator and patient slowly formed a working alliance that proved useful for the eventual communication to the patient of his psychologically tenuous reality. This case illustrates the utility of a collaborative, multimethod Therapeutic Assessment with a severely ill patient and the use of Therapeutic Assessment by a less experienced clinician.

  14. "Am I going crazy, doc?": a self psychology approach to therapeutic assessment.

    PubMed

    Peters, Eric J; Handler, Leonard; White, Kathryn G; Winkel, Justin D

    2008-09-01

    In this case study, we explore the effectiveness of Therapeutic Assessment with a severely disturbed 25-year-old man, referred by his therapist, following Finn's (2007; Finn & Tonsager, 1992, 1997) model. This patient-therapist pair had been working together for approximately 2 months, but the therapy had ceased to progress. The therapist requested a clearer picture of his patient's affective functioning, interpersonal functioning, and self-functioning that might facilitate more effective treatment. Through a collaborative assessment process informed by the principles of Kohutian self psychology, the evaluator and patient slowly formed a working alliance that proved useful for the eventual communication to the patient of his psychologically tenuous reality. This case illustrates the utility of a collaborative, multimethod Therapeutic Assessment with a severely ill patient and the use of Therapeutic Assessment by a less experienced clinician. PMID:18704801

  15. Peer Rated Therapeutic Talent and Affective Sensitivity: A Multiple Regression Approach.

    ERIC Educational Resources Information Center

    Jackson, Eugene

    1985-01-01

    Used peer rated measures of Warmth, Understanding and Openness to predict scores on the Kagan Affective Sensitivity Scale-E80 among 66 undergraduates who had participated in interpersonal skills training groups. Results indicated that, as an additively composite index of Therapeutic Talent, they were positively correlated with affective…

  16. Therapeutic landscapes and postcolonial theory: a theoretical approach to medical tourism.

    PubMed

    Buzinde, Christine N; Yarnal, Careen

    2012-03-01

    This paper draws on two conceptual frameworks, therapeutic landscapes and postcolonial theory, to discuss aspects of medical tourism not addressed in extant literature. Building on the intersection between postcolonial and therapeutic landscapes scholarship, it highlights inequalities related to the production of national therapeutic landscapes located in postcolonial regions as well as their discursive (re)positioning as medical tourism destinations. As a framework, therapeutic landscapes can facilitate an understanding of medical tourism sites as curative spaces which combine modern and alternative forms of medicine with travel and leisure. Postcolonial theory critiques the economic, moral and cultural tensions emerging from the intersection between corporations that provide cheaper and more attractive medical services, and the nations on the periphery struggling to offer high medical standards that may not be accessible to their own local populations. In an effort to enhance scholarship on medical tourism, these conceptual frameworks are offered as points of departure, rather than sites of arrival, through which critical dialog on medical tourism can be sustained and broadened.

  17. Novel therapeutic approaches for pulmonary arterial hypertension: Unique molecular targets to site-specific drug delivery.

    PubMed

    Vaidya, Bhuvaneshwar; Gupta, Vivek

    2015-08-10

    Pulmonary arterial hypertension (PAH) is a cardiopulmonary disorder characterized by increased blood pressure in the small arterioles supplying blood to lungs for oxygenation. Advances in understanding of molecular and cellular biology techniques have led to the findings that PAH is indeed a cascade of diseases exploiting multi-faceted complex pathophysiology, with cellular proliferation and vascular remodeling being the key pathogenic events along with several cellular pathways involved. While current therapies for PAH do provide for amelioration of disease symptoms and acute survival benefits, their full therapeutic potential is hindered by patient incompliance and off-target side effects. To overcome the issues related with current therapy and to devise a more selective therapy, various novel pathways are being investigated for PAH treatment. In addition, inability to deliver anti-PAH drugs to the disease site i.e., distal pulmonary arterioles has been one of the major challenges in achieving improved patient outcomes and improved therapeutic efficacy. Several novel carriers have been explored to increase the selectivity of currently approved anti-PAH drugs and to act as suitable carriers for the delivery of investigational drugs. In the present review, we have discussed potential of various novel molecular pathways/targets including RhoA/Rho kinase, tyrosine kinase, endothelial progenitor cells, vasoactive intestinal peptide, and miRNA in PAH therapeutics. We have also discussed various techniques for site-specific drug delivery of anti-PAH therapeutics so as to improve the efficacy of approved and investigational drugs. This review will provide gainful insights into current advances in PAH therapeutics with an emphasis on site-specific drug payload delivery.

  18. Studying aggression in Drosophila (fruit flies).

    PubMed

    Mundiyanapurath, Sibu; Certel, Sarah; Kravitz, Edward A

    2007-01-01

    Aggression is an innate behavior that evolved in the framework of defending or obtaining resources. This complex social behavior is influenced by genetic, hormonal and environmental factors. In many organisms, aggression is critical to survival but controlling and suppressing aggression in distinct contexts also has become increasingly important. In recent years, invertebrates have become increasingly useful as model systems for investigating the genetic and systems biological basis of complex social behavior. This is in part due to the diverse repertoire of behaviors exhibited by these organisms. In the accompanying video, we outline a method for analyzing aggression in Drosophila whose design encompasses important eco-ethological constraints. Details include steps for: making a fighting chamber; isolating and painting flies; adding flies to the fight chamber; and video taping fights. This approach is currently being used to identify candidate genes important in aggression and in elaborating the neuronal circuitry that underlies the output of aggression and other social behaviors.

  19. [Aggressive clients in Dutch veterinary practice].

    PubMed

    Barbonis, T S A E; Endenburg, N

    2007-05-15

    Aggressive clients seem to be becoming more common. This article describes a study in which questionnaires on client behaviour were sent to veterinary assistants and veterinarians in randomly selected practices in the Netherlands. Results showed that 26.4% of the veterinarians and 29.3% of the assistants had experienced aggressive clients in the last year. Age, experience, and sex of the veterinarian or assistant did not influence the frequency with which aggressive clients were encountered. The same was true for the type of veterinary practice (companion animals, farm animals, horses, etc). The risk of encountering aggressive clients was higher among practices in large towns and in practices with a small turnover Of the veterinarians who had encountered aggressive clients at least once in their career, 31% has taken some kind of action after the aggressive encounter Nearly a quarter (24.9%) of veterinary practices have adopted a Risk Inventarization and Evaluation (RI&E) approach to preventing client aggression and 26.6% of practices have adopted another approach. While veterinarians tend not to consider aggression a big problem, they are often open to the suggestion that more attention should be paid to aggression in veterinary practice. PMID:17578228

  20. Plant derived edible nanoparticles as a new therapeutic approach against diseases.

    PubMed

    Zhang, Mingzhen; Viennois, Emilie; Xu, Changlong; Merlin, Didier

    2016-01-01

    In plant cells, nanoparticles containing miRNA, bioactive lipids and proteins serve as extracellular messengers to mediate cell-cell communication in a manner similar to the exosomes secreted by mammalian cells. Notably, such nanoparticles are edible. Moreover, given the proper origin and cargo, plant derived edible nanoparticles could function in interspecies communication and may serve as natural therapeutics against a variety of diseases. In addition, nanoparticles made of plant-derived lipids may be used to efficiently deliver specific drugs. Plant derived edible nanoparticles could be more easily scaled up for mass production, compared to synthetic nanoparticles. In this review, we discuss recent significant developments pertaining to plant derived edible nanoparticles and provide insight into the use of plants as a bio-renewable, sustainable, diversified platform for the production of therapeutic nanoparticles. PMID:27358751

  1. A Novel Therapeutic Approach Using Mesenchymal Stem Cells to Protect Against Mycobacterium abscessus.

    PubMed

    Kim, Jong-Seok; Cha, Sang-Ho; Kim, Woo Sik; Han, Seung Jung; Cha, Seung Bin; Kim, Hong Min; Kwon, Kee Woong; Kim, So Jeong; Choi, Hong-Hee; Lee, Jienny; Cho, Sang-Nae; Koh, Won-Jung; Park, Yeong-Min; Shin, Sung Jae

    2016-07-01

    Recent studies have demonstrated the therapeutic potential of mesenchymal stem cells (MSCs) for the treatment of acute inflammatory injury and bacterial pneumonia, but their therapeutic applications in mycobacterial infections have not been investigated. In this study, we demonstrated the use of MSCs as a novel therapeutic strategy against Mycobacterium abscessus (M. abscessus), which is the most drug-resistant and difficult-to-treat mycobacterial pathogen. The systemic intravenous injection of MSCs not only improved mouse survival but also enhanced bacterial clearance in the lungs and spleen. Additionally, MSCs enhanced IFN-γ, TNF-α, IL-6, MCP-1, nitric oxide (NO) and PGE2 production and facilitated CD4(+) /CD8(+) T cell, CD11b(high) macrophage, and monocyte recruitment in the lungs of M. abscessus-infected mice. To precisely elucidate the functions of MSCs in M. abscessus infection, an in vitro macrophage infection system was used. MSCs caused markedly increased NO production via NF-κB activation in M. abscessus-infected macrophages cultured in the presence of IFN-γ. Inhibiting NO or NF-κB signaling using specific inhibitors reduced the antimycobacterial activity of MSCs. Furthermore, the cellular crosstalk between TNF-α released from IFN-γ-stimulated M. abscessus-infected macrophages and PGE2 produced by MSCs was necessary for the mycobacterial-killing activity of the macrophages. Finally, the importance of increased NO production in response to MSC administration was confirmed in the mouse M. abscessus infection model. Our results suggest that MSCs may offer a novel therapeutic strategy for treating this drug-resistant mycobacterial infection by enhancing the bacterial-killing power of macrophages. Stem Cells 2016;34:1957-1970. PMID:26946350

  2. Combination epigenetic and immunotherapy overcomes resistance to monoclonal antibodies in hematologic malignancies: A new therapeutic approach.

    PubMed

    Epner, Elliot M; Saroya, Bikramajit Singh; Hasanali, Zainul S; Loughran, Thomas P

    2016-03-01

    We recently reported that addition of epigenetic agents could overcome resistance of leukemic cells to monoclonal antibody-mediated anti-tumor effects in T-cell prolymphocytic leukemia. We also reported that epigenetic agents could induce expression of the CD30 gene, thus providing a therapeutic target for the antibody drug conjugate brentuximab vedotin. Here we discuss these findings and their generality to treatment of other hematologic and solid malignancies. PMID:26802532

  3. Combination epigenetic and immunotherapy overcomes resistance to monoclonal antibodies in hematologic malignancies: A new therapeutic approach.

    PubMed

    Epner, Elliot M; Saroya, Bikramajit Singh; Hasanali, Zainul S; Loughran, Thomas P

    2016-03-01

    We recently reported that addition of epigenetic agents could overcome resistance of leukemic cells to monoclonal antibody-mediated anti-tumor effects in T-cell prolymphocytic leukemia. We also reported that epigenetic agents could induce expression of the CD30 gene, thus providing a therapeutic target for the antibody drug conjugate brentuximab vedotin. Here we discuss these findings and their generality to treatment of other hematologic and solid malignancies.

  4. Positive allosteric modulators as an approach to nicotinic acetylcholine receptor-targeted therapeutics: advantages and limitations.

    PubMed

    Williams, Dustin K; Wang, Jingyi; Papke, Roger L

    2011-10-15

    Neuronal nicotinic acetylcholine receptors (nAChR), recognized targets for drug development in cognitive and neuro-degenerative disorders, are allosteric proteins with dynamic interconversions between multiple functional states. Activation of the nAChR ion channel is primarily controlled by the binding of ligands (agonists, partial agonists, competitive antagonists) at conventional agonist binding sites, but is also regulated in either negative or positive ways by the binding of ligands to other modulatory sites. In this review, we discuss models for the activation and desensitization of nAChR, and the discovery of multiple types of ligands that influence those processes in both heteromeric nAChR, such as the high-affinity nicotine receptors of the brain, and homomeric α7-type receptors. In recent years, α7 nAChRs have been identified as a potential target for therapeutic indications leading to the development of α7-selective agonists and partial agonists. However, unique properties of α7 nAChR, including low probability of channel opening and rapid desensitization, may limit the therapeutic usefulness of ligands binding exclusively to conventional agonist binding sites. New enthusiasm for the therapeutic targeting of α7 has come from the identification of α7-selective positive allosteric modulators (PAMs) that work effectively on the intrinsic factors that limit α7 ion channel activation. While these new drugs appear promising for therapeutic development, we also consider potential caveats and possible limitations for their use, including PAM-insensitive forms of desensitization and cytotoxicity issues.

  5. Conducting the G-protein Coupled Receptor (GPCR) Signaling Symphony in Cardiovascular Diseases: New Therapeutic Approaches.

    PubMed

    Belmonte, Stephen L; Blaxall, Burns C

    2012-01-01

    G protein-coupled receptors (GPCRs) are a virtually ubiquitous class of membrane-bound receptors, which functionally couple hormone or neurotransmitter signals to physiological responses. Dysregulation of GPCR signaling contributes to the pathophysiology of a host of cardiovascular disorders. Pharmacological agents targeting GPCRs have been established as therapeutic options for decades. Nevertheless, the persistent burden of cardiovascular diseases necessitates improved treatments. To that end, exciting drug development efforts have begun to focus on novel compounds that discriminately activate particular GPCR signaling pathways.

  6. New therapeutic approaches for Krabbe disease: The potential of pharmacological chaperones

    PubMed Central

    Spratley, Samantha J.

    2016-01-01

    Missense mutations in the lysosomal hydrolase β‐galactocerebrosidase (GALC) account for at least 40% of known cases of Krabbe disease (KD). Most of these missense mutations are predicted to disrupt the fold of the enzyme, preventing GALC in sufficient amounts from reaching its site of action in the lysosome. The predominant central nervous system (CNS) pathology and the absence of accumulated primary substrate within the lysosome mean that strategies used to treat other lysosomal storage disorders (LSDs) are insufficient in KD, highlighting the still unmet clinical requirement for successful KD therapeutics. Pharmacological chaperone therapy (PCT) is one strategy being explored to overcome defects in GALC caused by missense mutations. In recent studies, several small‐molecule inhibitors have been identified as promising chaperone candidates for GALC. This Review discusses new insights gained from these studies and highlights the importance of characterizing both the chaperone interaction and the underlying mutation to define properly a responsive population and to improve the translation of existing lead molecules into successful KD therapeutics. We also highlight the importance of using multiple complementary methods to monitor PCT effectiveness. Finally, we explore the exciting potential of using combination therapy to ameliorate disease through the use of PCT with existing therapies or with more generalized therapeutics, such as proteasomal inhibition, that have been shown to have synergistic effects in other LSDs. This, alongside advances in CNS delivery of recombinant enzyme and targeted rational drug design, provides a promising outlook for the development of KD therapeutics. © 2016 The Authors. Journal of Neuroscience Research Published by Wiley Periodicals, Inc. PMID:27638604

  7. New therapeutic approaches for Krabbe disease: The potential of pharmacological chaperones.

    PubMed

    Spratley, Samantha J; Deane, Janet E

    2016-11-01

    Missense mutations in the lysosomal hydrolase β-galactocerebrosidase (GALC) account for at least 40% of known cases of Krabbe disease (KD). Most of these missense mutations are predicted to disrupt the fold of the enzyme, preventing GALC in sufficient amounts from reaching its site of action in the lysosome. The predominant central nervous system (CNS) pathology and the absence of accumulated primary substrate within the lysosome mean that strategies used to treat other lysosomal storage disorders (LSDs) are insufficient in KD, highlighting the still unmet clinical requirement for successful KD therapeutics. Pharmacological chaperone therapy (PCT) is one strategy being explored to overcome defects in GALC caused by missense mutations. In recent studies, several small-molecule inhibitors have been identified as promising chaperone candidates for GALC. This Review discusses new insights gained from these studies and highlights the importance of characterizing both the chaperone interaction and the underlying mutation to define properly a responsive population and to improve the translation of existing lead molecules into successful KD therapeutics. We also highlight the importance of using multiple complementary methods to monitor PCT effectiveness. Finally, we explore the exciting potential of using combination therapy to ameliorate disease through the use of PCT with existing therapies or with more generalized therapeutics, such as proteasomal inhibition, that have been shown to have synergistic effects in other LSDs. This, alongside advances in CNS delivery of recombinant enzyme and targeted rational drug design, provides a promising outlook for the development of KD therapeutics. © 2016 The Authors. Journal of Neuroscience Research Published by Wiley Periodicals, Inc. PMID:27638604

  8. SY 05-2 PROGRESSION OF HYPERTENSIVE HEART DISEASE: NEW THERAPEUTIC APPROACH.

    PubMed

    Horiuchi, Masatsugu

    2016-09-01

    novel Ang II receptor interacting proteins have been also reported. AT1 receptor-associated protein (ATRAP) was cloned by us as specific binding protein of AT1 receptor C-terminal, and we and others reported that ATRAP could act as a negative regulator in AT1 receptor-mediated effects at least in part by the enhancement of AT1 receptor internalization. We cloned AT2 receptor interacting protein (ATIP) as a protein interacting specifically with the C-terminal tail of the AT2 receptor. We and others demonstrated that ATIP enhanced an important role of AT2 receptor-mediated wide variety of pathophysiological functions. Further elucidation of the functional regulation of these Ang II receptor associated proteins including their transcriptional control, and finding possible ligands could be helpful for new drug developments.I will review and discuss in this symposium "Progression of Hypertensive Heart Disease" focusing on the new therapeutic pharmacological approach with recent clinical evidences. PMID:27642889

  9. Cancer therapeutic approach based on conformational stabilization of mutant p53 protein by small peptides

    PubMed Central

    Tal, Perry; Eizenberger, Shay; Cohen, Elad; Goldfinger, Naomi; Pietrokovski, Shmuel; Oren, Moshe; Rotter, Varda

    2016-01-01

    The p53 tumor suppressor serves as a major barrier against malignant transformation. Over 50% of tumors inactivate p53 by point mutations in its DNA binding domain. Most mutations destabilize p53 protein folding, causing its partial denaturation at physiological temperature. Thus a high proportion of human tumors overexpress a potential potent tumor suppressor in a non-functional, misfolded form. The equilibrium between the properly folded and misfolded states of p53 may be affected by molecules that interact with p53, stabilizing its native folding and restoring wild type p53 activity to cancer cells. To select for mutant p53 (mutp53) reactivating peptides, we adopted the phage display technology, allowing interactions between mutp53 and random peptide libraries presented on phages and enriching for phage that favor the correctly folded p53 conformation. We obtained a large database of potential reactivating peptides. Lead peptides were synthesized and analyzed for their ability to restore proper p53 folding and activity. Remarkably, many enriched peptides corresponded to known p53-binding proteins, including RAD9. Importantly, lead peptides elicited dramatic regression of aggressive tumors in mouse xenograft models. Such peptides might serve as novel agents for human cancer therapy. PMID:26943582

  10. Does a short-term increase in testosterone affect the intensity or persistence of territorial aggression? - An approach using an individual's hormonal reactive scope to study hormonal effects on behavior.

    PubMed

    Goymann, Wolfgang; Villavicencio, Camila P; Apfelbeck, Beate

    2015-10-01

    In this study, we describe an approach based on an individual's hormonal reactive scope to study short-term effects of hormones on behavior. The control of territorial aggression has been traditionally linked to testosterone. Males of some vertebrate species show an increase in testosterone during territorial interactions and implantation studies suggest that such an increase in testosterone enhances the intensity and persistence of aggression. Here, we tested whether a short-term maximum release of testosterone - based on an individual's hormonal reactive scope - affects the intensity or persistence of territorial aggression in male black redstarts, a bird species in which testosterone does not increase during territorial encounters. An injection with gonadotropin-releasing-hormone (GnRH) induced a physiological peak in plasma testosterone that was specific for each individual (=individual reactive scope). However, such short-term surges in an individual's testosterone concentration did not affect the intensity or persistence of aggression. In conclusion, this study demonstrated (1) that a species that naturally does not increase testosterone during male-male encounters would not benefit from such an increase in terms of being more aggressive, (2) that behavioral studies using GnRH-injections represent a promising approach to study species differences in androgen responsiveness, and (3) that injections of releasing or tropic hormones in general may be a suitable approach to study short-term influences of hormones on behavior. These injections effectively mimic the potential short-term changes in hormones that can occur in the real life of individuals and enable us to study the effects of hormonal changes on behavior or other traits within an ecological and evolutionary framework.

  11. Targeting brain microvascular endothelial cells: a therapeutic approach to neuroprotection against stroke

    PubMed Central

    Yu, Qi-jin; Tao, Hong; Wang, Xin; Li, Ming-chang

    2015-01-01

    Brain microvascular endothelial cells form the interface between nervous tissue and circulating blood, and regulate central nervous system homeostasis. Brain microvascular endothelial cells differ from peripheral endothelial cells with regards expression of specific ion transporters and receptors, and contain fewer fenestrations and pinocytotic vesicles. Brain microvascular endothelial cells also synthesize several factors that influence blood vessel function. This review describes the morphological characteristics and functions of brain microvascular endothelial cells, and summarizes current knowledge regarding changes in brain microvascular endothelial cells during stroke progression and therapies. Future studies should focus on identifying mechanisms underlying such changes and developing possible neuroprotective therapeutic interventions. PMID:26807131

  12. Roles of NF-κB in Cancer and Inflammatory Diseases and Their Therapeutic Approaches

    PubMed Central

    Park, Mi Hee; Hong, Jin Tae

    2016-01-01

    Nuclear factor-κB (NF-κB) is a transcription factor that plays a crucial role in various biological processes, including immune response, inflammation, cell growth and survival, and development. NF-κB is critical for human health, and aberrant NF-κB activation contributes to development of various autoimmune, inflammatory and malignant disorders including rheumatoid arthritis, atherosclerosis, inflammatory bowel diseases, multiple sclerosis and malignant tumors. Thus, inhibiting NF-κB signaling has potential therapeutic applications in cancer and inflammatory diseases. PMID:27043634

  13. [Craniopharyngioma in children: importance of a multidisciplinary approach and therapeutic strategies in the treatment of relapsing].

    PubMed

    Fiorito, C M M; Giglione, E; Bellone, S; Peretta, P; Bertin, D; Basso, M E; Bona, G

    2013-12-01

    The craniopharyngioma is a benign intracranial nonglial tumor derived from a malformation of the embryonic tissue. Represents approximately 6-9% of brain tumors in children. It grows close to the optic nerve, hypothalamus and pituitary. The most frequent histological variety in children is adamantinomatous. The initial symptoms of intracranial hypertension is headache and nausea, followed by visual disturbances, impaired hormonal changes such as the secretion of GH, gonadotropins, TSH and ACTH and central diabetes insipidus. We present the clinical case of MD, 5yrs at age, which shows signs of intracranial hypertension syndrome: neuroradiological findings raise the diagnosis of adamantinomatous craniopharyngioma for which the child underwent to sub-total surgical removal of the lesion and radiosurgery treatment. During the disease develops visual impairment, and secondary diabetes insipidus, hypothyroidism hipocotisolism that takes therapy with desmopressin (Minirin), Cortone acetate and L-tiroxine. For the failure of previous therapies, the child has performed chemotherapy with cisplatin (30 mg/sqm/day) and Etoposide (150 mg/mq/day). A year after the end of the last cycle of chemotherapy was detected new progression of the lesion with the appearance of worsening headache and vomiting in the upright position. TC notes the expansion of the third ventricle and the patient undergoes surgery craniotomy. This clinical case underlines the difficulties in treatment of recurrent craniopharyngioma in situations where the anatomical location do not permit aggressive radical surgery. Anyway, new studies are needed to evaluate the effectiveness of systemic chemotherapy as a method of experimental treatment that could reduce the progression of disease. PMID:24217636

  14. Pelvic floor muscle rehabilitation for patients with lifelong premature ejaculation: a novel therapeutic approach

    PubMed Central

    Palleschi, Giovanni; Fuschi, Andrea; Maggioni, Cristina; Rago, Rocco; Zucchi, Alessandro; Costantini, Elisabetta; Carbone, Antonio

    2014-01-01

    Objectives: Premature ejaculation is the most common male sexual disorder. The aim of the study was to evaluate the possible therapeutic role of pelvic floor muscle rehabilitation in patients affected by lifelong premature ejaculation. Methods: We treated 40 men with lifelong premature ejaculation, reporting, a baseline intravaginal ejaculatory latency time (IELT) ≤ 1 min, with 12-week pelvic floor muscle rehabilitation. Results: At the end of the rehabilitation, mean IELTs were calculated to evaluate the effectiveness of the therapy. At the end of the treatment, 33 (82.5%) of the 40 patients gained control of their ejaculatory reflex, with a mean IELT of 146.2 s (range: 123.6–152.4 s). A total of 13 out of 33 (39%) patients were evaluated at 6 months follow up, and they maintained a significant IELT (112.6 s) compared with their initial IELT (mean 39.8 s). Conclusions: The results obtained in our subjects treated with pelvic floor rehabilitation are promising. This therapy represents an important cost reduction compared with the standard treatment (selective serotonin reuptake inhibitors). Based on the present data, we propose pelvic floor muscle rehabilitation as a new, viable therapeutic option for the treatment of premature ejaculation. PMID:24883105

  15. Proteolytic clearance of extracellular α-synuclein as a new therapeutic approach against Parkinson disease.

    PubMed

    Park, Sang Myun; Kim, Kwang Soo

    2013-01-01

    Many neurodegenerative diseases such as Alzheimer disease and Parkinson disease show similar characteristics. They typically show deposits of protein aggregates, the formation of which is considered important in their pathogenesis. Recently, aggregation-prone proteins have been shown to spread between cells and so may contribute to the pathogenesis of diseases like prion disease. Such a pathogenesis pathway is possibly common to many neurodegenerative diseases. If confirmed, it could allow the development of therapeutic interventions against many such diseases. In Parkinson disease, α-synuclein, a major component of cytosolic protein inclusions named Lewy body, has been shown to be released and taken up by cells, which may facilitate its progressive pathological spreading between cells. Accordingly, inhibition of spreading by targeting extracellular α-synuclein may represent a new therapy against Parkinson disease. Research into the intercellular spreading of extracellular protein aggregations of α-synuclein and its clearance pathway are reviewed here with a focus on the proteolytic clearance pathway as a therapeutic target for the treatment of Parkinson disease. Considering the similar characteristics of aggregation-prone proteins, these clearance systems might allow treatment of other neurodegenerative diseases beyond Parkinson disease.

  16. Citric acid as the last therapeutic approach in an acute life-threatening metabolic decompensation of propionic acidaemia.

    PubMed

    Siekmeyer, Manuela; Petzold-Quinque, Stefanie; Terpe, Friederike; Beblo, Skadi; Gebhardt, Rolf; Schlensog-Schuster, Franziska; Kiess, Wieland; Siekmeyer, Werner

    2013-01-01

    The tricarboxylic acid (TCA) cycle represents the key enzymatic steps in cellular energy metabolism. Once the TCA cycle is impaired in case of inherited metabolic disorders, life-threatening episodes of metabolic decompensation and severe organ failure can arise. We present the case of a 6 ½-year-old girl with propionic acidaemia during an episode of acute life-threatening metabolic decompensation and severe lactic acidosis. Citric acid given as an oral formulation showed the potential to sustain the TCA cycle flux. This therapeutic approach may become a treatment option in a situation of acute metabolic crisis, possibly preventing severe disturbance of energy metabolism.

  17. Usefulness of CT-scan in the diagnosis and therapeutic approach of gallstone ileus: report of two surgically treated cases

    PubMed Central

    2013-01-01

    Background Gallstone ileus is a rare cause of gastrointestinal obstruction, more frequent in elderly patients, whose treatment is essentially surgical, although some para-surgical and mini-invasive possibilities exist, allowing the solution of such obstructive condition in a completely non-invasive way. Description In our study, after reporting two cases of biliary ileus managed by our surgical division, we will analyze the most suitable diagnostic procedures and the therapeutic approaches to this pathology. Conclusions Gallstone ileus is a quite rare pathology in population, but affects more frequently elderly people; The treatment of this disease is mainly surgical. PMID:24268073

  18. Approaches targeting the FGF-FGFR system: a review of the recent patent literature and associated advanced therapeutic agents.

    PubMed

    Herbert, Corentin; Lassalle, Gilbert; Alcouffe, Chantal; Bono, Françoise

    2014-01-01

    Fibroblast growth factor receptors (FGFRs) and associated ligands (FGFs) are a family of well-validated targets for therapeutic interventions notably in cancer diseases in relation to their prominent roles in cell growth, survival, differentiation and angiogenesis. This patent review encompasses all different approaches (modulators of FGF or FGFR expression, anti-FGF antibodies, anti-FGFR antibodies, FGF traps, tyrosine-kinase (TK) inhibitors, allosteric modulators) used to block completely or partially the activities of the FGF-FGFR complexes resulting in clinical drug candidates or tool agents. Comparative analysis of biochemical, pharmacological or clinical data will be discussed for each class of molecules together with some perspectives. PMID:25489913

  19. Current tissue engineering and novel therapeutic approaches to axonal regeneration following spinal cord injury using polymer scaffolds☆

    PubMed Central

    Madigan, Nicolas N.; McMahon, Siobhan; O’Brien, Timothy; Yaszemski, Michael J.; Windebank, Anthony J.

    2010-01-01

    This review highlights current tissue engineering and novel therapeutic approaches to axonal regeneration following spinal cord injury. The concept of developing 3-dimensional polymer scaffolds for placement into a spinal cord transection model has recently been more extensively explored as a solution for restoring neurologic function after injury. Given the patient morbidity associated with respiratory compromise, the discrete tracts in the spinal cord conveying innervation for breathing represent an important and achievable therapeutic target. The aim is to derive new neuronal tissue from the surrounding, healthy cord that will be guided by the polymer implant through the injured area to make functional reconnections. A variety of naturally derived and synthetic biomaterial polymers have been developed for placement in the injured spinal cord. Axonal growth is supported by inherent properties of the selected polymer, the architecture of the scaffold, permissive microstructures such as pores, grooves or polymer fibres, and surface modifications to provide improved adherence and growth directionality. Structural support of axonal regeneration is combined with integrated polymeric and cellular delivery systems for therapeutic drugs and for neurotrophic molecules to regionalize growth of specific nerve populations. PMID:19737633

  20. The neurobiology of aggression and violence.

    PubMed

    Rosell, Daniel R; Siever, Larry J

    2015-06-01

    Aggression and violence represent a significant public health concern and a clinical challenge for the mental healthcare provider. A great deal has been revealed regarding the neurobiology of violence and aggression, and an integration of this body of knowledge will ultimately serve to advance clinical diagnostics and therapeutic interventions. We will review here the latest findings regarding the neurobiology of aggression and violence. First, we will introduce the construct of aggression, with a focus on issues related to its heterogeneity, as well as the importance of refining the aggression phenotype in order to reduce pathophysiologic variability. Next we will examine the neuroanatomy of aggression and violence, focusing on regional volumes, functional studies, and interregional connectivity. Significant emphasis will be on the amygdala, as well as amygdala-frontal circuitry. Then we will turn our attention to the neurochemistry and molecular genetics of aggression and violence, examining the extensive findings on the serotonergic system, as well as the growing literature on the dopaminergic and vasopressinergic systems. We will also address the contribution of steroid hormones, namely, cortisol and testosterone. Finally, we will summarize these findings with a focus on reconciling inconsistencies and potential clinical implications; and, then we will suggest areas of focus for future directions in the field.

  1. Relational aggression in marriage.

    PubMed

    Carroll, Jason S; Nelson, David A; Yorgason, Jeremy B; Harper, James M; Ashton, Ruth Hagmann; Jensen, Alexander C

    2010-01-01

    Drawing from developmental theories of relational aggression, this article reports on a study designed to identify if spouses use relationally aggressive tactics when dealing with conflict in their marriage and the association of these behaviors with marital outcomes. Using a sample of 336 married couples (672 spouses), results revealed that the majority of couples reported that relationally aggressive behaviors, such as social sabotage and love withdrawal, were a part of their marital dynamics, at least to some degree. Gender comparisons of partner reports of their spouse's behavior revealed that wives were significantly more likely to be relationally aggressive than husbands. Structural equation modeling demonstrated that relational aggression is associated with lower levels of marital quality and greater marital instability for both husbands and wives. Implications are drawn for the use of relational aggression theory in the future study of couple conflict and marital aggression.

  2. Attenuated Recombinant Influenza A Virus Expressing HPV16 E6 and E7 as a Novel Therapeutic Vaccine Approach

    PubMed Central

    Jindra, Christoph; Huber, Bettina; Shafti-Keramat, Saeed; Wolschek, Markus; Ferko, Boris; Muster, Thomas; Brandt, Sabine; Kirnbauer, Reinhard

    2015-01-01

    Persistent infection with high-risk human papillomavirus (HPV) types, most often HPV16 and HPV18, causes all cervical and most anal cancers, and a subset of vulvar, vaginal, penile and oropharyngeal carcinomas. Two prophylactic virus-like particle (VLPs)-based vaccines, are available that protect against vaccine type-associated persistent infection and associated disease, yet have no therapeutic effect on existing lesions or infections. We have generated recombinant live-attenuated influenza A viruses expressing the HPV16 oncogenes E6 and E7 as experimental immunotherapeutic vaccine candidates. The influenza A virus life cycle lacks DNA intermediates as important safety feature. Different serotypes were generated to ensure efficient prime and boost immunizations. The immune response to vaccination in C57BL/6 mice was characterized by peptide ELISA and IFN-γ ELISpot, demonstrating induction of cell-mediated immunity to HPV16 E6 and E7 oncoproteins. Prophylactic and therapeutic vaccine efficacy was analyzed in the murine HPV16-positive TC-1 tumor challenge model. Subcutaneous (s.c.) prime and boost vaccinations of mice with recombinant influenza A serotypes H1N1 and H3N2, followed by challenge with TC-1 cells resulted in complete protection or significantly reduced tumor growth as compared to control animals. In a therapeutic setting, s.c. vaccination of mice with established TC-1 tumors decelerated tumor growth and significantly prolonged survival. Importantly, intralesional vaccine administration induced complete tumor regression in 25% of animals, and significantly reduced tumor growth in 50% of mice. These results suggest recombinant E6E7 influenza viruses as a promising new approach for the development of a therapeutic vaccine against HPV-induced disease. PMID:26381401

  3. Novel Therapeutic Approaches for Various Cancer Types Using a Modified Sleeping Beauty-Based Gene Delivery System

    PubMed Central

    Kim, Hyun-Pyo

    2014-01-01

    Successful gene therapy largely depends on the selective introduction of therapeutic genes into the appropriate target cancer cells. One of the most effective and promising approaches for targeting tumor tissue during gene delivery is the use of viral vectors, which allow for high efficiency gene delivery. However, the use of viral vectors is not without risks and safety concerns, such as toxicities, a host immune response towards the viral antigens or potential viral recombination into the host's chromosome; these risks limit the clinical application of viral vectors. The Sleeping Beauty (SB) transposon-based system is an attractive, non-viral alternative to viral delivery systems. SB may be less immunogenic than the viral vector system due to its lack of viral sequences. The SB-based gene delivery system can stably integrate into the host cell genome to produce the therapeutic gene product over the lifetime of a cell. However, when compared to viral vectors, the non-viral SB-based gene delivery system still has limited therapeutic efficacy due to the lack of long-lasting gene expression potential and tumor cell specific gene transfer ability. These limitations could be overcome by modifying the SB system through the introduction of the hTERT promoter and the SV40 enhancer. In this study, a modified SB delivery system, under control of the hTERT promoter in conjunction with the SV40 enhancer, was able to successfully transfer the suicide gene (HSV-TK) into multiple types of cancer cells. The modified SB transfected cancer cells exhibited a significantly increased cancer cell specific death rate. These data suggest that our modified SB-based gene delivery system can be used as a safe and efficient tool for cancer cell specific therapeutic gene transfer and stable long-term expression. PMID:24466025

  4. Progress in AQP Research and New Developments in Therapeutic Approaches to Ischemic and Hemorrhagic Stroke

    PubMed Central

    Previch, Lauren E.; Ma, Linlin; Wright, Joshua C.; Singh, Sunpreet; Geng, Xiaokun; Ding, Yuchuan

    2016-01-01

    Cerebral edema often manifests after the development of cerebrovascular disease, particularly in the case of stroke, both ischemic and hemorrhagic. Without clinical intervention, the influx of water into brain tissues leads to increased intracranial pressure, cerebral herniation, and ultimately death. Strategies to manage the development of edema constitute a major unmet therapeutic need. However, despite its major clinical significance, the mechanisms underlying cerebral water transport and edema formation remain elusive. Aquaporins (AQPs) are a class of water channel proteins which have been implicated in the regulation of water homeostasis and cerebral edema formation, and thus represent a promising target for alleviating stroke-induced cerebral edema. This review examines the significance of relevant AQPs in stroke injury and subsequently explores neuroprotective strategies aimed at modulating AQP expression, with a particular focus on AQP4, the most abundant AQP in the central nervous system. PMID:27438832

  5. Implication of Green Tea as a Possible Therapeutic Approach for Parkinson Disease.

    PubMed

    Jurado-Coronel, Juan C; Ávila-Rodriguez, Marco; Echeverria, Valentina; Hidalgo, Oscar Alejandro; Gonzalez, Janneth; Aliev, Gjumrakch; Barreto, George E

    2016-01-01

    Green tea is a beverage consumed around the world that is believed to have substantial health benefits such as reducing the risk of cancer, cardiovascular diseases, diabetes and neurodegeneration. This beverage is prepared from the leaves (steamed and dried) of the Camellia sinesis plant and contains strong antioxidant and neuroprotective phenolic compounds from which the most important is (-)-Epigallocatechin-3-gallate. Parkinson's disease (PD) is the second more common neurodegenerative disorders, after Alzheimer's disease and is characterized by degeneration of dopaminergic neurons in the pars compact of the substantia nigra of the basal ganglia. It has been shown in pre-clinical and clinical studies that green tea may be able to prevent PD, but its optimal dose or a possible mechanism explaining its health benefit in PD has not been properly established. In this review, we discuss the potential role of green tea's phenolic compounds and their therapeutic effectin modulating key signaling pathways in the PD brain. PMID:26831259

  6. New Diagnostic and Therapeutic Approaches for Preventing the Progression of Diabetic Retinopathy

    PubMed Central

    Park, Young Gun; Roh, Young-Jung

    2016-01-01

    Diabetic retinopathy (DR) is a severe sight-threatening complication of diabetes mellitus. Retinal laser photocoagulation, antivascular endothelial growth factors, steroid therapy, and pars plana vitrectomy are now used extensively to treat advanced stages of diabetic retinopathy. Currently, diagnostic devices like ultrawide field fundus fluorescein angiography and the improvement of optical coherence tomography have provided quicker and more precise diagnosis of early diabetic retinopathy. Thus, treatment protocols have been modified accordingly. Various types of lasers, including the subthreshold micropulse laser and RPE-targeting laser, and selective targeted photocoagulation may be future alternatives to conventional retinal photocoagulation, with fewer complications. The new developed intravitreal medications and implants have provided more therapeutic options, with promising results. PMID:26881240

  7. [Therapeutic approach to epilepsy from the nutritional view: current status of dietary treatment].

    PubMed

    Vicente-Hernández, M; Garcia-Garcia, P; Gil-Nagel, A; Lopez-Munoz, F; Alamo, C

    2007-10-01

    Approximately 20%-30% of epilepsy patient do not respond adequately to drug treatment. In this population, a dietary treatment has been posed as a therapeutic alternative or coadjuvant tool. This present work has aimed to carry out a review on the dietary alternatives currently available to treat epilepsy (ketogenic diet, Atkins' diet, etc.). The ketogenic diet has been used and studied the most in this neurological disorder. That is why it is also the one that has undergone the greatest change. Furthermore, this diet has caused the most controversy about its action mechanism, efficacy and adverse effects as well as about what would be the best protocol to carry it out. Many observational studies and reviews on this subject that support the beneficial effect of the ketogenic diet have been conducted. However, controlled, randomized clinical trials with larger population samples are needed to confirm these results in order to achieve an optimum and individualized dietary treatment in refractory epilepsy. PMID:17641989

  8. Low-dose radiation may be a novel approach to enhance the effectiveness of cancer therapeutics.

    PubMed

    Yang, Guozi; Li, Wei; Jiang, Hongyu; Liang, Xinyue; Zhao, Yuguang; Yu, Dehai; Zhou, Lei; Wang, Guanjun; Tian, Huimin; Han, Fujun; Cai, Lu; Cui, Jiuwei

    2016-11-15

    It has been generally accepted that both natural and man-made sources of ionizing radiation contribute to human exposure and consequently pose a possible risk to human health. However, accumulating evidence has shown that the biological effects of low-dose radiation (LDR) are different from those of high-dose radiation. LDR can stimulate proliferation of normal cells and activate their defense systems, while these biological effects are not observed in some cancer cell types. Although there is still no concordance on this matter, the fact that LDR has the potential to enhance the effects of cancer therapeutics and reduce the toxic side effects of anti-cancer therapy has garnered significant interest. Here, we provide an overview of the current knowledge regarding the experimental data detailing the different responses of normal and cancer tissues to LDR, the underlying mechanisms, and its significance in clinical application. PMID:27299986

  9. Tissue barriers and novel approaches to achieve hepatoselectivity of subcutaneously-injected insulin therapeutics.

    PubMed

    Shao, Juntang; Zaro, Jennica L; Shen, Wei-Chiang

    2016-01-01

    Current subcutaneously (s.c.)-injected insulin (INS) products result in a hyperinsulin exposure to peripheral tissues (skeletal muscle and adipose) while INS hardly accesses to liver after injection. This unphysiological distribution raises risks of hypoglycemia episode and causes weight gain after long term treatment. An ideal INS replacement therapy requires the distribution or action of exogenous INS to more closely mimic physiological INS in terms of its preferential hepatic action. However, there are 2 factors that limit the ability of s.c. injected INS to restore the liver: peripheral gradient in INS deficient diabetes patients: (1) the transport of INS in capillary endothelium and peripheral tissues from the injection site; and (2) peripheral INS receptor (IR) mediated INS degradation. In this review, the tissue barriers against efficient liver targeting of s.c. injected INS are discussed and current advances in developing hepatoselective insulin therapeutics are introduced. PMID:27358753

  10. Low-dose radiation may be a novel approach to enhance the effectiveness of cancer therapeutics.

    PubMed

    Yang, Guozi; Li, Wei; Jiang, Hongyu; Liang, Xinyue; Zhao, Yuguang; Yu, Dehai; Zhou, Lei; Wang, Guanjun; Tian, Huimin; Han, Fujun; Cai, Lu; Cui, Jiuwei

    2016-11-15

    It has been generally accepted that both natural and man-made sources of ionizing radiation contribute to human exposure and consequently pose a possible risk to human health. However, accumulating evidence has shown that the biological effects of low-dose radiation (LDR) are different from those of high-dose radiation. LDR can stimulate proliferation of normal cells and activate their defense systems, while these biological effects are not observed in some cancer cell types. Although there is still no concordance on this matter, the fact that LDR has the potential to enhance the effects of cancer therapeutics and reduce the toxic side effects of anti-cancer therapy has garnered significant interest. Here, we provide an overview of the current knowledge regarding the experimental data detailing the different responses of normal and cancer tissues to LDR, the underlying mechanisms, and its significance in clinical application.

  11. Does assessing the value for money of therapeutic medical devices require a flexible approach?

    PubMed

    Iglesias, Cynthia P

    2015-02-01

    Regulation criteria for licensing pharmaceuticals and medical devices (MDs) are asymmetric. This has affected the type, quantity and quality of the evidence produced in support of MDs. This paper has three objectives: to examine the reasons behind the current licensing criteria for MDs; to identify key methodological challenges associated with pre- and post-market evaluation of MDs and to assess the extent to which existing methods for the economic evaluation of pharmaceuticals can be applied to the evaluation of MDs. The belief that MDs cannot be properly evaluated stems from a combination of historical events and complexities in implementing rigorous RCTs in this field. Existing challenges to conduct sound economic evaluation of MDs have begun to be addressed in medical research using mixed research methods. While more challenging to implement, robust evaluations of therapeutic MDs can and need to be carried out to safeguard individual's wellbeing.

  12. Therapeutic approach by Aloe vera in experimental model of multiple sclerosis.

    PubMed

    Mirshafiey, A; Aghily, B; Namaki, S; Razavi, A; Ghazavi, A; Ekhtiari, P; Mosayebi, G

    2010-09-01

    Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that leads to an inflammatory demyelination, axonal damage, and progressive neurologic disability that affects approximately 2.5 million people worldwide. The aim of the present research was to test the therapeutic effect of Aloe vera in experimental model of MS. All experiments were conducted on C57BL/6 male mice aged 6-8 weeks. To induce the experimental autoimmune encephalomyelitis (EAE), 250 microg of the myelin oligodendrocyte glycoprotein 35-55 peptide emulsified in complete freund's adjuvant was injected subcutaneously on day 0 over two flank areas. In addition, 200 ng of pertussis toxin in 100 microL phosphate buffered saline was injected intraperitoneally on days 0 and 2. The therapeutic protocol was carried out intragastrically using 120 mg/kg/day Aloe vera from 7 days before to 21 days after EAE induction. The mice were killed 21 days after EAE induction. The brains of mice were removed for histological analysis and their isolated splenocytes were cultured. The results indicated that treatment with Aloe vera caused a significant reduction in severity of the disease in experimental model of MS. Histological analysis showed 3 +/- 2 plaques in Aloe vera-treated mice compared with 5 +/- 1 plaques in control group. The density of mononuclear infiltration in the CNS of Aloe vera-treated mice (500 +/- 200) was significantly less in comparison to 700 +/- 185 cells in control group. Moreover, the serum level of nitric oxide in treatment group was significantly less than control animals. The level of interferon-gamma in cell culture supernatant of treated mice splenocytes was lower than control group, whereas decrease in serum level of interleukin-10 in treatment group was not significant in comparison with control mice. These data indicate that Aloe vera therapy can attenuate the disease progression in experimental model of MS.

  13. Antisense Modulation of RNA Processing as a Therapeutic Approach in Cancer Therapy

    PubMed Central

    Spraggon, Lee

    2013-01-01

    Next-generation antisense technologies are re-emerging as viable and powerful approaches to the treatment of several genetic diseases. Similar strategies are also being applied to cancer therapy. Re-programming of the expression of endogenous oncogenic products to replace them with functional antagonists, by interfering with alternative splicing or polyadenylation, provides a promising novel approach to address acquired drug resistance and previously undruggable targets. PMID:25589899

  14. Synergy of microRNA and stem cell: a novel therapeutic approach for diabetes mellitus and cardiovascular diseases.

    PubMed

    Tyagi, Aaron C; Sen, Utpal; Mishra, Paras K

    2011-11-01

    MicroRNAs ( miRNAs) are highly conserved, 19-23 nucleotide long, non-coding, endogenous RNA, which are transcribed from either intergenic, intronic or polycistronic regions and modulate gene expression through mRNA degradation or translational repression. They are fine tuners of biological processes and have recently emerged as biomarkers and therapeutic targets of cardiovascular diseases. Several miRNAs regulate stem cell for differentiation, proliferation and degeneration. Stem cells are pluripotent, self-renewing and clonogenic cells having tremendous potential for regenerative therapy. The current therapeutic approach is unable to cope up with rapidly increasing rates of diabetes and cardiovascular diseases. The empirical and clinical evidences revealed that transplantation of exogenous stem cells can regenerate beta cells in diabetic patients and myocardium in patients with myocardial infarction. Nevertheless, the major limitation of stem cell therapy is unpredictable behavior of exogenous stem cells that incur few reports of teratoma and cancer after transplantation. Therefore, understanding the regulation of newly transplanted stem cells into the foreign body is a major challenge to translational research / clinical trail. Since miRNA plays pivotal role in the fine regulation of proliferation and differentiation of stem cells, investigations on the regulation of miRNA in transplanted stem cells in a specific micro-environment that houses the stem cell is indispensable. Additionally, the inhibition or over expression of specific miRNAs in the niche surrounding the stem cell will be crucial for maintaining the specific lineage of exogenous stem cells. This review embodies major advancement in the field of miRNA biogenesis and its regulatory mechanisms, role of different miRNAs and stem cells as a therapeutic target for diabetes and cardiovascular diseases. It also provides insights into the novel future therapy, where synergistic approach for manipulating mi

  15. Return to Competition in a Chronic Low Back Pain Runner: Beyond a Therapeutic Exercise Approach, a Case Report.

    PubMed

    Veneziani, Sergio; Doria, Christian; Falciati, Luca; Castelli, Claudio Carlo; Illic, Giorgio Fanò

    2014-09-23

    Chronic low back pain (CLBP) is a disabling condition affecting both quality of life and performance in athletes. Several approaches have been proposed in the field of physiotherapy, manual therapy, physical exercise and counseling. None apparently is outdoing the other with the exception of trunk stability exercises in specific conditions. The present paper describes a clinical success in managing a CLBP runner affected by MRI documented disk herniation via dietary change. Dietary changes allowed our patient that had failed with previous standard therapeutic approaches, to regain an optimal pain-free condition. We advance the hypothesis that a visceral-autonomic concomitant or primary disturbance possibly generating mild gastrointestinal discomfort in CLBP patients should be ruled out as a possible cause of pain and disability at the somato-motor level. PMID:26913133

  16. Drug utilization and prescribing patterns in a skilled nursing facility: the need for a rational approach to therapeutics.

    PubMed

    Segal, J L; Thompson, J F; Floyd, R A

    1979-03-01

    A study was made of 50 patients drawn at random from a Skilled Nursing Facility (SNF) attended by seven physicians. For 59 percent of these patients, polypharmacy was practiced but no substantiating diagnoses were recorded. Approximately half of the drugs were administered pro re nata. More drugs were prescribed in potentially toxic dosages than in subtherapeutic dosages. The risk of an adverse drug reaction (ADR) was most often associated with anticholinergic agents, sedative-hypnotic drugs, and neuroleptics (thioridazine and chlorpromazine), particularly when prescribed concurrently. Risk of an ADR was highest when a drug was prescribed without recording a definite diagnostic indication. Lack of consistency by individual physicians in their approaches to the therapy of similar disease entities in comparable patients tended to support the concept of peer review in SNFs and also the need for teaching a rational approach to therapeutics in SNFs based on clinical pharmacology as applied to the elderly. PMID:429730

  17. From Mollusks to Medicine: A Venomics Approach for the Discovery and Characterization of Therapeutics from Terebridae Peptide Toxins

    PubMed Central

    Verdes, Aida; Anand, Prachi; Gorson, Juliette; Jannetti, Stephen; Kelly, Patrick; Leffler, Abba; Simpson, Danny; Ramrattan, Girish; Holford, Mandë

    2016-01-01

    Animal venoms comprise a diversity of peptide toxins that manipulate molecular targets such as ion channels and receptors, making venom peptides attractive candidates for the development of therapeutics to benefit human health. However, identifying bioactive venom peptides remains a significant challenge. In this review we describe our particular venomics strategy for the discovery, characterization, and optimization of Terebridae venom peptides, teretoxins. Our strategy reflects the scientific path from mollusks to medicine in an integrative sequential approach with the following steps: (1) delimitation of venomous Terebridae lineages through taxonomic and phylogenetic analyses; (2) identification and classification of putative teretoxins through omics methodologies, including genomics, transcriptomics, and proteomics; (3) chemical and recombinant synthesis of promising peptide toxins; (4) structural characterization through experimental and computational methods; (5) determination of teretoxin bioactivity and molecular function through biological assays and computational modeling; (6) optimization of peptide toxin affinity and selectivity to molecular target; and (7) development of strategies for effective delivery of venom peptide therapeutics. While our research focuses on terebrids, the venomics approach outlined here can be applied to the discovery and characterization of peptide toxins from any venomous taxa. PMID:27104567

  18. From Mollusks to Medicine: A Venomics Approach for the Discovery and Characterization of Therapeutics from Terebridae Peptide Toxins.

    PubMed

    Verdes, Aida; Anand, Prachi; Gorson, Juliette; Jannetti, Stephen; Kelly, Patrick; Leffler, Abba; Simpson, Danny; Ramrattan, Girish; Holford, Mandë

    2016-04-19

    Animal venoms comprise a diversity of peptide toxins that manipulate molecular targets such as ion channels and receptors, making venom peptides attractive candidates for the development of therapeutics to benefit human health. However, identifying bioactive venom peptides remains a significant challenge. In this review we describe our particular venomics strategy for the discovery, characterization, and optimization of Terebridae venom peptides, teretoxins. Our strategy reflects the scientific path from mollusks to medicine in an integrative sequential approach with the following steps: (1) delimitation of venomous Terebridae lineages through taxonomic and phylogenetic analyses; (2) identification and classification of putative teretoxins through omics methodologies, including genomics, transcriptomics, and proteomics; (3) chemical and recombinant synthesis of promising peptide toxins; (4) structural characterization through experimental and computational methods; (5) determination of teretoxin bioactivity and molecular function through biological assays and computational modeling; (6) optimization of peptide toxin affinity and selectivity to molecular target; and (7) development of strategies for effective delivery of venom peptide therapeutics. While our research focuses on terebrids, the venomics approach outlined here can be applied to the discovery and characterization of peptide toxins from any venomous taxa.

  19. Do new therapeutic approaches (autotransplants, thalidomide, dexamethasone) improve the survival of patients with multiple myeloma followed in a rheumatology department?

    PubMed

    El Mahou, S; Attal, M; Jamard, B; Constantin, A; Cantagrel, A; Mazières, B; Arnaud, C; Laroche, M

    2006-03-01

    Survival of patients with multiple myeloma (MM) showed no improvement between the 1960s and 1990s. During the last decade, new therapeutic approaches seemed likely to offer hope of prolonging survival. The aim of this study was to examine if this survival increased with the usage of new treatments. The method involves a retrospective study of 123 patients with MM, diagnosed between 1975 and 1999, all receiving treatment. They were divided into two groups: group 1 included 55 patients given the so-called "old treatments" [melphalan-prednisone, cyclophosphamide-prednisone, polychemotherapy (vincristine, melphalan, cyclophosphamide, prednisone (VMCP), VMCP-VBAP)], and group 2 included 68 patients receiving at least one of the so-called "new treatments" (dexamethasone, thalidomide, high-dose chemotherapy followed by autotransplants, bisphosphonates, interferon). The two groups were similar in terms of age, sex ratio and renal impairment, and the percentage of light-chain MM was identical in both groups. Patients who had been given a "new" treatment (group 2) had longer median survival than the patients in group 1 (54 vs 42 months). Independent analysis of each treatment modality showed increased median survival in MM patients treated using autotransplantation compared with untreated patients (125 vs 45 months). Survival was also longer in MM patients treated with thalidomide than in untreated patients (72 vs 42 months). On the other hand, neither bisphosphonates, interferon-alpha nor dexamethasone result in improved survival. Our findings emphasize the increased survival of the MM patients treated with new therapeutic approaches. PMID:16328086

  20. Pharmacological- and non-pharmacological therapeutic approaches in inflammatory bowel disease in adults.

    PubMed

    Leitner, Gerda C; Vogelsang, Harald

    2016-02-01

    Inflammatory bowel diseases (IBDs) are a group of chronic inflammatory conditions mainly of the colon and small intestine. Crohn's disease (CD) and ulcerative colitis (UC) are the most frequent types of IBD. IBD is a complex disease which arises as a result of the interaction of environmental, genetic and immunological factors. It is increasingly thought that alterations of immunological reactions of the patients to their own enterable bacteria (microfilm) may contribute to inflammation. It is characterized by mucosal and sub mucosal inflammation, perpetuated by infiltration of activated leukocytes. CD may affect the whole gastrointestinal tract while UC only attacks the large intestine. The therapeutic goal is to achieve a steroid-free long lasting remission in both entities. UC has the possibility to be cured by a total colectomy, while CD never can be cured by any operation. A lifelong intake of drugs is mostly necessary and essential. Medical treatment of IBD has to be individualized to each patient and usually starts with anti-inflammatory drugs. The choice what kind of drugs and what route administered (oral, rectal, intravenous) depends on factors including the type, the localization, and severity of the patient's disease. IBD may require immune-suppression to control symptoms such as prednisolone, thiopurines, calcineurin or sometimes folic acid inhibitors or biologics like TNF-α inhibitors or anti-integrin antibodies. For both types of disease (CD, UC) the same drugs are available but they differ in their preference in efficacy between CD and UC as 5-aminosalicylic acid for UC or budesonide for ileocecal CD. As therapeutic alternative the main mediators of the disease, namely the activated pro-inflammatory cytokine producing leukocytes can be selectively removed via two apheresis systems (Adacolumn and Cellsorba) in steroid-refractory or dependent cases. Extracorporeal photopheresis results in an increase of regulatory B cells, regulatory CD8(+) T cells

  1. Pharmacological- and non-pharmacological therapeutic approaches in inflammatory bowel disease in adults

    PubMed Central

    Leitner, Gerda C; Vogelsang, Harald

    2016-01-01

    Inflammatory bowel diseases (IBDs) are a group of chronic inflammatory conditions mainly of the colon and small intestine. Crohn’s disease (CD) and ulcerative colitis (UC) are the most frequent types of IBD. IBD is a complex disease which arises as a result of the interaction of environmental, genetic and immunological factors. It is increasingly thought that alterations of immunological reactions of the patients to their own enterable bacteria (microfilm) may contribute to inflammation. It is characterized by mucosal and sub mucosal inflammation, perpetuated by infiltration of activated leukocytes. CD may affect the whole gastrointestinal tract while UC only attacks the large intestine. The therapeutic goal is to achieve a steroid-free long lasting remission in both entities. UC has the possibility to be cured by a total colectomy, while CD never can be cured by any operation. A lifelong intake of drugs is mostly necessary and essential. Medical treatment of IBD has to be individualized to each patient and usually starts with anti-inflammatory drugs. The choice what kind of drugs and what route administered (oral, rectal, intravenous) depends on factors including the type, the localization, and severity of the patient’s disease. IBD may require immune-suppression to control symptoms such as prednisolone, thiopurines, calcineurin or sometimes folic acid inhibitors or biologics like TNF-α inhibitors or anti-integrin antibodies. For both types of disease (CD, UC) the same drugs are available but they differ in their preference in efficacy between CD and UC as 5-aminosalicylic acid for UC or budesonide for ileocecal CD. As therapeutic alternative the main mediators of the disease, namely the activated pro-inflammatory cytokine producing leukocytes can be selectively removed via two apheresis systems (Adacolumn and Cellsorba) in steroid-refractory or dependent cases. Extracorporeal photopheresis results in an increase of regulatory B cells, regulatory CD8+ T cells

  2. Management of Systemic Sclerosis-Related Skin Disease: A Review of Existing and Experimental Therapeutic Approaches.

    PubMed

    Volkmann, Elizabeth R; Furst, Daniel E

    2015-08-01

    The skin is the most common organ system involved in patients with systemic sclerosis (SSc). Nearly all patients experience cutaneous symptoms, including sclerosis, Raynaud's phenomenon, digital ulcers, telangiectasias, and calcinosis. In addition to posing functional challenges, cutaneous symptoms are often a major cause of pain, psychological distress, and body image dissatisfaction. The present article reviews the main features of SSc-related cutaneous manifestations and highlights an evidence-based treatment approach for treating each manifestation. This article also describes novel treatment approaches and opportunities for further research in managing this important clinical dimension of SSc.

  3. Therapeutic approaches to asthma-chronic obstructive pulmonary disease overlap syndromes.

    PubMed

    Barnes, Peter J

    2015-09-01

    The recognition that there are some patients with features of asthma and chronic obstructive pulmonary disease (COPD) has highlighted the need to develop more specific treatments for these clinical phenotypes. Some patients with COPD have predominantly eosinophilic inflammation and might respond to high doses of inhaled corticosteroids and newly developed specific antieosinophil therapies, including blocking antibodies against IL-5, IL-13, IL-33, and thymic stromal lymphopoietin, as well as oral chemoattractant receptor-homologous molecule expressed on TH2 cells antagonists. Other patients have severe asthma or are asthmatic patients who smoke with features of COPD-induced inflammation and might benefit from treatments targeting neutrophils, including macrolides, CXCR2 antagonists, phosphodiesterase 4 inhibitors, p38 mitogen-activating protein kinase inhibitors, and antibodies against IL-1 and IL-17. Other patients appear to have largely fixed obstruction with little inflammation and might respond to long-acting bronchodilators, including long-acting muscarinic antagonists, to reduce hyperinflation. Highly selected patients with severe asthma might benefit from bronchial thermoplasty. Some patients with overlap syndromes can be conveniently treated with triple fixed-dose combination inhaler therapy with an inhaled corticosteroid, long-acting β2-agonist, and long-acting muscarinic antagonist, several of which are now in development. Corticosteroid resistance is a feature of asthma-COPD overlap syndrome, and understanding the various molecular mechanisms of this resistance has identified novel therapeutic targets and presented the prospect of therapies that can restore corticosteroid responsiveness. PMID:26343937

  4. Microemulgel: an overwhelming approach to improve therapeutic action of drug moiety.

    PubMed

    Ashara, Kalpesh C; Paun, Jalpa S; Soniwala, M M; Chavda, J R; Mendapara, Vishal P; Mori, Nitin M

    2016-07-01

    As compared to gel and other topical preparations microemulgel has been prepared by screening of oils, emulsifier, and co-emulsifier on bases of solubility of an API in it. An API has high solubility and oil may also have more or less pharmacological property, so it may assist the therapeutic action of API. Due to presence of oil portion, it leads to more penetration of API in the skin. Oil Micelle Size was less than 500 nm which provides more area for absorption of API in the skin so more penetration and more effective than macro-emulsion. Microemulgel has an advantage of emulgel that has dual benefits of micro-emulsion and gel and several other desirable properties like good consistency, thyrotrophic, greaseless, easily spreadable as well as removable, emollient, non-staining, water soluble, longer shelf-life, bio-friendly, transparent, pleasant appearance, ability of patients for self-medication, termination of medications will be easy, etc. PMID:27330376

  5. Probiotics as a complementary therapeutic approach in nonalcoholic fatty liver disease

    PubMed Central

    Ferolla, Silvia Marinho; Armiliato, Geyza Nogueira de Almeida; Couto, Cláudia Alves; Ferrari, Teresa Cristina Abreu

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) is currently recognized as one of the most common causes of chronic liver disease. It involves a spectrum of conditions that include pure steatosis without inflammation, steatohepatitis, fibrosis and cirrhosis. The key factor in the pathophysiology of NAFLD is insulin resistance that determines lipid accumulation in the hepatocytes and, thus, oxidative stress, which is followed by inflammatory response. However, NAFLD pathogenesis is still largely unknown and has been extensively investigated. Although life style modification with the aim of losing weight has been advocated to treat this disorder, its effectiveness is limited; additionally, there is no specific pharmacologic treatment until nowadays. Recent evidence suggests that the gut microbiota may play a role in the development of insulin resistance, hepatic steatosis, necroinflammation and fibrosis. Differences in gut microbiota between NAFLD patients and lean individuals as well as presence of small intestinal bacterial overgrowth in NAFLD subjects have been demonstrated. Furthermore, some data indicate that the immunoregulatory effects of probiotics may be beneficial in NAFLD treatment as they modulate the intestinal microbiota; improve epithelial barrier function and strengthen the intestinal wall decreasing its permeability; reduce bacterial translocation and endotoxemia; improve intestinal inflammation; and reduce oxidative and inflammatory liver damage. In this article, we review the clinical trials on the use of probiotics in the treatment of NAFLD and discuss the effects of these agents and their efficacy as an emerging therapeutic resource to treat NAFLD patients. PMID:25848479

  6. Brain aging and Parkinson's disease: New therapeutic approaches using drug delivery systems.

    PubMed

    Rodríguez-Nogales, C; Garbayo, E; Carmona-Abellán, M M; Luquin, M R; Blanco-Prieto, M J

    2016-02-01

    The etiology and pathogenesis of Parkinson's disease (PD) is unknown, aging being the strongest risk factor for brain degeneration. Understanding PD pathogenesis and how aging increases the risk of disease would aid the development of therapies able to slow or prevent the progression of this neurodegenerative disorder. In this review we provide an overview of the most promising therapeutic targets and strategies to delay the loss of dopaminergic neurons observed both in PD and aging. Among them, handling alpha-synuclein toxicity, enhancing proteasome and lysosome clearance, ameliorating mitochondrial disruptions and modifying the glial environment are so far the most promising candidates. These new and conventional drugs may present problems related to their labile nature and to the difficulties in reaching the brain. Thus, we highlight the latest types of drug delivery system (DDS)-based strategies for PD treatment, including DDS for local and systemic drug delivery. Finally, the ongoing challenges for the discovery of new targets and the opportunities for DDS-based therapies to improve and efficacious PD therapy will be discussed.

  7. Nanotechnology-based approaches for the development of diagnostics, therapeutics, and vaccines.

    PubMed

    Srinivasan, Alagarsamy; Rastogi, Anshu; Ayyavoo, Velpandi; Srivastava, Shiv

    2014-06-01

    The architecture of nanoparticles of biological origin, generally also known as bionanoparticles, presents several features that are ideal for their use in developing diagnostics, therapeutics, and vaccines. In this regard, particles formed by viral proteins using recombinant DNA technology resemble authentic virus particles. However, they lack infectivity due to the absence of genetic components such as DNA or RNA. Hence, they are designated as virus-like particles (VLP). VLPs possess the following characteristics: (1) they can be generated by either a single or a few viral proteins; (2) their size, formed by viral proteins, is in the range of 20 to100 nm; (3) the number of protein molecules required for particle assembly is from hundreds to thousands, depending on the VLP; (4) the protein(s) responsible for their assembly are amenable for manipulation; and (5) multiple proteins/peptides can be incorporated into a VLP. The potential advantages of VLPs directed by retroviral proteins are discussed in this review.

  8. Folklore therapeutic indigenous plants in periodontal disorders in India (review, experimental and clinical approach).

    PubMed

    Patel, V K; Venkatakrishna-Bhatt, H

    1988-04-01

    Though a number of plants and their parts are used for dental ailments among population in rural and urban areas of developing countries, in India however, the most common house-hold, road-side plants are mango (Mangifera indica), neem (Azadirachta indica; Melia azadirachta), ocimum (Ocimum basilicum), tea-dust (Camellia sinensis) and uncommonly murayya, i.e., currey leaf (Murayya koenigi) [Chopra et al. 1958, Kirtikar and Basu 1935, Nadakarni 1954, Satyavati 1984]. The leaves of these plants are folded and brushed (massage with teadust) against the teeth. Therefore, the present study is restricted only to the fleshy leaf extracts [Jindal et al. 1975] (except tea) of these plants inspite of certain limitations in the methodology and arbitrations in the microbial identification and isolation in the light of recent advances in folk dentistry. The investigation was carried out in two parts: 1) Experimental study: The efficacy of various dentifrices (commonly available in the market) and the potentiating effect of the leaf extract (LE) of the aforesaid indigenous plants when amalgamated with the tooth-paste against pathogens, were investigated. Further, the protection afforded by the said plant extracts (PE) over the conventional allopathic medicines on the human plaque cultures and gram negative bacteria from patients were studied. 2) Clinical study: The therapeutic effects of the said PE (individually) on clinical application among severely infected patients were examined. PMID:3042642

  9. Bioenergetics and mitochondrial dysfunction in aging: recent insights for a therapeutical approach.

    PubMed

    Romano, Antonino Davide; Greco, Eulalia; Vendemiale, Gianluigi; Serviddio, Gaetano

    2014-01-01

    The present review points out the role of oxidative stress in aging and the potential therapeutic targets of modern antioxidant therapies. Mitochondria are essential for several biological processes including energy production by generating ATP through the electron transport chain (ETC) located on the inner mitochondrial membrane. Due to their relevance in cellular physiology, defects in mitochondria are associated with various human diseases. Moreover, several years of research have demonstrated that mitochondria have a pivotal role in aging. The oxidative stress theory of aging suggests that mitochondria play a key role in aging as they are the main cellular source of reactive oxygen species (ROS), which indiscriminately damage macromolecules leading to an age-dependent decline in biological function. In this review we will discuss the mitochondrial dysfunction occurring in aging. In particular, we will focus on the novel mitochondria targeted therapies and the new selective molecules and nanocarriers technology as potentially effective in targeting mitochondrial dysfunction and diseases involving oxidative stress and metabolic failure. PMID:24079772

  10. Pelvic congestion syndrome and left renal compression syndrome - clinical features and therapeutic approaches.

    PubMed

    Jeanneret, Christina; Beier, Konstantin; von Weymarn, Alexander; Traber, Jürg

    2016-01-01

    Knowledge of the anatomy of the pelvic, gonadal and renal veins is important to understand pelvic congestion syndrome (PCS) and left renal vein compression syndrome (LRCS), which is also known as the nutcracker syndrome. LRCS is related to PCS and to the presence of vulvar, vaginal and pudendal varicose veins. The diagnosis of the two syndromes is difficult, and usually achieved with CT- or phlebography. The gold standard is the intravenous pressure measurement using conventional phlebography. The definition of PCS is described as pelvic pain, aggravated in the standing position and lasting for more than 6 months. Pain in the left flank and microhaematuria is seen in patients with LRCS. Women with multiple pregnancies are at increased risk of developing varicose vein recurrences with pelvic drainage and ovarian vein reflux after crossectomy and stripping of the great saphenous vein. The therapeutic options are: conservative treatment (medroxyprogesteron) or interventional (coiling of the ovarian vein) or operative treatment (clipping of the ovarian vein). Controlled prospective trials are needed to find the best treatment. PMID:27428495

  11. A Review of Therapeutic Aptamer Conjugates with Emphasis on New Approaches

    PubMed Central

    Bruno, John G.

    2013-01-01

    The potential to emulate or enhance antibodies with nucleic acid aptamers while lowering costs has prompted development of new aptamer-protein, siRNA, drug, and nanoparticle conjugates. Specific focal points of this review discuss DNA aptamers covalently bound at their 3' ends to various proteins for enhanced stability and greater pharmacokinetic lifetimes in vivo. The proteins can include Fc tails of IgG for opsonization, and the first component of complement (C1q) to trigger complement-mediated lysis of antibiotic-resistant Gram negative bacteria, cancer cells and possibly some parasites during vulnerable stages. In addition, the 3' protein adduct may be a biotoxin, enzyme, or may simply be human serum albumin (HSA) or a drug known to bind HSA, thereby retarding kidney and other organ clearance and inhibiting serum exonucleases. In this review, the author summarizes existing therapeutic aptamer conjugate categories and describes his patented concept for PCR-based amplification of double-stranded aptamers followed by covalent attachment of proteins or other agents to the chemically vulnerable overhanging 3' adenine added by Taq polymerase. PCR amplification of aptamers could dramatically lower the current $2,000/gram cost of parallel chemical oligonucleotide synthesis, thereby enabling mass production of aptamer-3'-protein or drug conjugates to better compete against expensive humanized monoclonal antibodies. PMID:24276022

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

    PubMed Central

    Bilia, Anna Rita; Guccione, Clizia; Isacchi, Benedetta; Righeschi, Chiara; Firenzuoli, Fabio; Bergonzi, Maria Camilla

    2014-01-01

    Essential oils are complex blends of a variety of volatile molecules such as terpenoids, phenol-derived aromatic components, and aliphatic components having a strong interest in pharmaceutical, sanitary, cosmetic, agricultural, and food industries. Since the middle ages, essential oils have been widely used for bactericidal, virucidal, fungicidal, antiparasitical, insecticidal, and other medicinal properties such as analgesic, sedative, anti-inflammatory, spasmolytic, and locally anaesthetic remedies. In this review their nanoencapsulation in drug delivery systems has been proposed for their capability of decreasing volatility, improving the stability, water solubility, and efficacy of essential oil-based formulations, by maintenance of therapeutic efficacy. Two categories of nanocarriers can be proposed: polymeric nanoparticulate formulations, extensively studied with significant improvement of the essential oil antimicrobial activity, and lipid carriers, including liposomes, solid lipid nanoparticles, nanostructured lipid particles, and nano- and microemulsions. Furthermore, molecular complexes such as cyclodextrin inclusion complexes also represent a valid strategy to increase water solubility and stability and bioavailability and decrease volatility of essential oils. PMID:24971152

  13. Therapeutic Approaches to Acquired Cystic Fibrosis Transmembrane Conductance Regulator Dysfunction in Chronic Bronchitis.

    PubMed

    Solomon, George M; Raju, S Vamsee; Dransfield, Mark T; Rowe, Steven M

    2016-04-01

    Chronic obstructive pulmonary disease is a common cause of morbidity and a rising cause of mortality worldwide. Its rising impact indicates the ongoing unmet need for novel and effective therapies. Previous work has established a pathophysiological link between the chronic bronchitis phenotype of chronic obstructive pulmonary disease and cystic fibrosis as well as phenotypic similarities between these two airways diseases. An extensive body of evidence has established that cigarette smoke and its constituents contribute to acquired dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) protein in the airways, pointing to a mechanistic link with smoking-related and chronic bronchitis. Recent interest surrounding new drugs that target both mutant and wild-type CFTR channels has paved the way for a new treatment opportunity addressing the mucus defect in chronic bronchitis. We review the clinical and pathologic evidence for modulating CFTR to address acquired CFTR dysfunction and pragmatic issues surrounding clinical trials as well as a discussion of other ion channels that may represent alternative therapeutic targets. PMID:27115953

  14. Essential oils loaded in nanosystems: a developing strategy for a successful therapeutic approach.

    PubMed

    Bilia, Anna Rita; Guccione, Clizia; Isacchi, Benedetta; Righeschi, Chiara; Firenzuoli, Fabio; Bergonzi, Maria Camilla

    2014-01-01

    Essential oils are complex blends of a variety of volatile molecules such as terpenoids, phenol-derived aromatic components, and aliphatic components having a strong interest in pharmaceutical, sanitary, cosmetic, agricultural, and food industries. Since the middle ages, essential oils have been widely used for bactericidal, virucidal, fungicidal, antiparasitical, insecticidal, and other medicinal properties such as analgesic, sedative, anti-inflammatory, spasmolytic, and locally anaesthetic remedies. In this review their nanoencapsulation in drug delivery systems has been proposed for their capability of decreasing volatility, improving the stability, water solubility, and efficacy of essential oil-based formulations, by maintenance of therapeutic efficacy. Two categories of nanocarriers can be proposed: polymeric nanoparticulate formulations, extensively studied with significant improvement of the essential oil antimicrobial activity, and lipid carriers, including liposomes, solid lipid nanoparticles, nanostructured lipid particles, and nano- and microemulsions. Furthermore, molecular complexes such as cyclodextrin inclusion complexes also represent a valid strategy to increase water solubility and stability and bioavailability and decrease volatility of essential oils. PMID:24971152

  15. Disease Course and Therapeutic Approach in Dermatomyositis: A Four-Center Retrospective Study of 100 Patients

    PubMed Central

    Johnson, Nicholas E.; Arnold, W. David; Hebert, Donald; Gwathmey, Kelly; Dimachkie, Mazen M.; Barohn, Richard J.; McVey, April L.; Pasnoor, Mamatha; Amato, Anthony A.; McDermott, Michael P.; Kissel, John; Heatwole, Chad R.

    2015-01-01

    Dermatomyositis is a life-altering inflammatory disorder of skin and muscle. Details regarding the natural course of this disorder, the effects of specific therapies on its progression, and the optimal therapeutic dosage and duration of prednisone are limited. We performed a retrospective medical record review of dermatomyositis patients at four medical centers. All patients were over the age of 21 and had a clinical diagnosis of dermatomyositis with pathological confirmation. We reviewed average muscle strength, corticosteroid use, creatine kinase levels, and supplemental immunosuppressant use during the 36-month period following each patient’s initial assessment. 100 patients participated with an average age of 50.1 years. Average muscle strength improved and prednisone requirements lessened six months after initial assessment. There was no difference in the mean change in muscle strength or cumulative corticosteroid use over 36 months among those initially treated with methotrexate, mycophenolate mofetil, pulse IVIG, or azathioprine. There was a 5% mortality rate in dermatomyositis patients due to infections. Treated dermatomyositis patients demonstrate the most significant improvement in strength during the first six-to-twelve months following their initial clinical assessment. Additional prospective studies are needed to determine the relative benefit of select immunosuppressant agents in preserving strength and reducing corticosteroid use in dermatomyositis. PMID:26022999

  16. Disease course and therapeutic approach in dermatomyositis: A four-center retrospective study of 100 patients.

    PubMed

    Johnson, Nicholas E; Arnold, W David; Hebert, Donald; Gwathmey, Kelly; Dimachkie, Mazen M; Barohn, Richard J; McVey, April L; Pasnoor, Mamatha; Amato, Anthony A; McDermott, Michael P; Kissel, John; Heatwole, Chad R

    2015-08-01

    Dermatomyositis is a life-altering inflammatory disorder of skin and muscle. Details regarding the natural course of this disorder, the effects of specific therapies on its progression, and the optimal therapeutic dosage and duration of prednisone are limited. We performed a retrospective medical record review of dermatomyositis patients at four medical centers. All patients were over the age of 21 and had a clinical diagnosis of dermatomyositis with pathological confirmation. We reviewed average muscle strength, corticosteroid use, creatine kinase levels, and supplemental immunosuppressant use during the 36-month period following each patient's initial assessment. One hundred patients participated with an average age of 50.1 years. Average muscle strength improved and prednisone requirements lessened six months after initial assessment. There was no difference in the mean change in muscle strength or cumulative corticosteroid use over 36 months among those initially treated with methotrexate, mycophenolate mofetil, pulse IVIG, or azathioprine. There was a 5% mortality rate in dermatomyositis patients due to infections. Treated dermatomyositis patients demonstrate the most significant improvement in strength during the first six-to-twelve months following their initial clinical assessment. Additional prospective studies are needed to determine the relative benefit of select immunosuppressant agents in preserving strength and reducing corticosteroid use in dermatomyositis.

  17. ACAID as a potential therapeutic approach to modulate inflammation in neurodegenerative diseases.

    PubMed

    Toscano-Tejeida, D; Ibarra, A; Phillips-Farfán, B V; Fuentes-Farías, A L; Meléndez-Herrera, E

    2016-03-01

    The progressive loss of neurons and inflammation characterizes neurodegenerative diseases. Although the etiology, progression and outcome of different neurodegenerative diseases are varied, they share chronic inflammation maintained largely by central nervous system (CNS)-derived antigens recognized by T cells. Inflammation can be beneficial by recruiting immune cells to kill pathogens or to clear cell debris resulting from the primary insult. However, chronic inflammation exacerbates and perpetuates tissue damage. An increasing number of therapies that attempt to modulate neuroinflammation have been developed. However, so far none has succeeded in decreasing the secondary damage associated with chronic inflammation. A potential strategy to modulate the immune system is related to the induction of tolerance to CNS antigens. In this line, it is our hypothesis that this could be accomplished by using anterior chamber associated immune deviation (ACAID) as a strategy. Thus, we review current knowledge regarding some neurodegenerative diseases and the associated immune response that causes inflammation. In addition, we discuss further our hypothesis of the possible usefulness of ACAID as a therapeutic strategy to ameliorate damage to the CNS.

  18. Nanotechnology as a New Therapeutic Approach to Prevent the HIV-Infection of Treg Cells

    PubMed Central

    Jaramillo-Ruiz, Didiana; De La Mata, Francisco Javier; Gómez, Rafael; Correa-Rocha, Rafael; Muñoz-Fernández, Mª Ángeles

    2016-01-01

    Background HIV-1 has proved to infect regulatory T cells (Treg) modifying their phenotype and impairing their suppressive capacity. As Treg cells are a crucial component in the preservation of the immune homeostasis, we researched that the antiviral capacity of carboxilan dendrimers prevents the HIV-1 infection of Treg and their effects. The phenotype and suppressive capacity of Treg treated or non-treated with carbosilane dendrimers were studied by flow cytometry. Treated and non-treated Treg from healthy donors were infected with HIV-1NL4.3. The infection of Treg cells by HIV-1, and protective effect of two dendrimers were determined by measuring antigen p24gag in the supernatant of the culture and intracellular. Results The Treg cells were treated with cationic and anionic carbosilane dendrimers. The results showed that both dendrimers did not modify the phenotype and functionality of Treg cells compared with non- treated Treg cells. Anionic dendrimers showed high biocompatibility with normal activity of the Treg cells and in antiviral assays. These dendrimers were highly active against HIV-1 preventing the infection of Treg, and were able to protect the Treg from the Foxp3 downregulation induced by the HIV-1 infection. Conclusions This is the first work showing that the in vitro use of anionic dendrimers prevent the HIV-1 replication and the infection of expanded Treg cells in culture, which raises the possibility to use Treg cells therapeutically in HIV-1-infected subjects. PMID:26785250

  19. Clinical Features, Genetics and Potential Therapeutic Approaches for Birt-Hogg-Dubé Syndrome

    PubMed Central

    Schmidt, Laura S.; Linehan, W. Marston

    2015-01-01

    Introduction Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant disorder that predisposes to fibrofolliculomas, pulmonary cysts, spontaneous pneumothorax and renal neoplasia. BHD is characterized by germline mutations in tumor suppressor FLCN. Inactivation of the remaining FLCN allele in kidney cells drives tumorigenesis. Novel FLCN-interacting proteins, FNIP1 and FNIP2, were identified. Studies with FLCN-deficient in vitro and in vivo models support a role for FLCN in modulating AKT-mTOR signaling. Emerging evidence suggests that FLCN may interact in a number of pathways/processes. Identification of FLCN’s major functional roles will provide the basis for developing targeted therapies for BHD patients. Areas covered This review covers BHD diagnostic criteria, clinical manifestations and genetics, as well as molecular consequences of FLCN inactivation. Recommended surveillance practices, patient management, and potential therapeutic options are discussed. Expert opinion In the decade since FLCN was identified as causative for BHD, we have gained a greater understanding of the clinical spectrum and genetics of this cancer syndrome. Recent studies have identified interactions between FLCN and a variety of signaling pathways and cellular processes, notably AKT-mTOR. Currently, surgical intervention is the only available therapy for BHD-associated renal tumors. Effective therapies will need to target primary pathways/processes deregulated in FLCN-deficient renal tumors and fibrofolliculomas. PMID:26581862

  20. Quantitative Proteomics Approach to Screening of Potential Diagnostic and Therapeutic Targets for Laryngeal Carcinoma

    PubMed Central

    Wang, Chengyu; Miao, Lei; Zhang, Jianpeng; Wang, Jiasen; Jiao, Binghua; Zhao, Shuwei

    2014-01-01

    To discover candidate biomarkers for diagnosis and detection of human laryngeal carcinoma and explore possible mechanisms of this cancer carcinogenesis, two-dimensional strong cation-exchange/reversed-phase nano-scale liquid chromatography/mass spectrometry analysis was used to identify differentially expressed proteins between the laryngeal carcinoma tissue and the adjacent normal tissue. As a result, 281 proteins with significant difference in expression were identified, and four differential proteins, Profilin-1 (PFN1), Nucleolin (NCL), Cytosolic non-specific dipeptidase (CNDP2) and Mimecan (OGN) with different subcellular localization were selectively validated. Semiquantitative RT-PCR and Western blotting were performed to detect the expression of the four proteins employing a large collection of human laryngeal carcinoma tissues, and the results validated the differentially expressed proteins identified by the proteomics. Furthermore, we knocked down PFN1 in immortalized human laryngeal squamous cell line Hep-2 cells and then the proliferation and metastasis of these transfected cells were measured. The results showed that PFN1 silencing inhibited the proliferation and affected the migration ability of Hep-2 cells, providing some new insights into the pathogenesis of PFN1 in laryngeal carcinoma. Altogether, our present data first time show that PFN1, NCL, CNDP2 and OGN are novel potential biomarkers for diagnosis and therapeutic targets for laryngeal carcinoma, and PFN1 is involved in the metastasis of laryngeal carcinoma. PMID:24587265

  1. [Diagnostic and therapeutic approach to pregnant women suspect on antiphospholipid syndrome].

    PubMed

    Glasnović, Marija; Bosnjak, Ivica; Vcev, Aleksandar; Kosuta, Maja; Lenz, Bahrija; Glasnović-Horvatić, Elizabeta

    2008-01-01

    Antiphospholipid syndrome includes the presence of antiphospholipid antibodies, vascular thrombosis and reproductive function disturbances. The aim was to show our diagnostic and therapeutic experiences. 62 women were included in study, 32 with primary antiphospholipd syndrome (PAPS), and 30 with secondary antiphospholipid syndrome (SAPS). 36 were pregnant and studied prospectively throughout pregnancy and six weeks after the delivery. Lupus-anticoagulant (LA) was positive in 23 patients with PAPS (71.9%), and in 10 patients with SAPS (33.3%). In SAPS group anticardiolipin antibodies (aCL) was positive in 8 patients (26.6%) compared to PAPS group with 3 aCL positive patients (9.4%). Antibeta2glycoprotein1 (antibeta2GP1) was positive in 3 patients with PAPS. Complications in previous pregnancies were in 25 cases (69.4%) spontaneous abortion, in 7 cases (19.4%) preeclampsia with intrauterine growth restriction (IUGR) in 3 patients. In 4 cases the complication was fetal death in utero. Average pregnancy lasted 37.06+/-0.707 weeks. Therapy with low dose aspirin and low-molecular-weight heparin was successful in 97.2%.

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

    PubMed

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

    2015-12-01

    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.

  3. Glycosylation of Glycolipids in Cancer: Basis for Development of Novel Therapeutic Approaches

    PubMed Central

    Daniotti, Jose L.; Vilcaes, Aldo A.; Torres Demichelis, Vanina; Ruggiero, Fernando M.; Rodriguez-Walker, Macarena

    2013-01-01

    Altered networks of gene regulation underlie many pathologies, including cancer. There are several proteins in cancer cells that are turned either on or off, which dramatically alters the metabolism and the overall activity of the cell, with the complex machinery of enzymes involved in the metabolism of glycolipids not being an exception. The aberrant glycosylation of glycolipids on the surface of the majority of cancer cells, associated with increasing evidence about the functional role of these molecules in a number of cellular physiological pathways, has received considerable attention as a convenient immunotherapeutic target for cancer treatment. This has resulted in the development of a substantial number of passive and active immunotherapies, which have shown promising results in clinical trials. More recently, antibodies to glycolipids have also emerged as an attractive tool for the targeted delivery of cytotoxic agents, thereby providing a rationale for future therapeutic interventions in cancer. This review first summarizes the cellular and molecular bases involved in the metabolic pathway and expression of glycolipids, both in normal and tumor cells, paying particular attention to sialosylated glycolipids (gangliosides). The current strategies in the battle against cancer in which glycolipids are key players are then described. PMID:24392350

  4. A natural therapeutic approach for the treatment of periodontitis by MK615.

    PubMed

    Morimoto-Yamashita, Yoko; Kawakami, Yoshiko; Tatsuyama, Syoko; Miyashita, Keiko; Emoto, Makiko; Kikuchi, Kiyoshi; Kawahara, Ko-ichi; Tokuda, Masayuki

    2015-11-01

    Periodontitis is a chronic inflammatory disease that affects the tooth-supporting tissues. Gingival fibroblasts are the most abundant cells in periodontal tissues and they participate actively in the host inflammatory response to periodontal pathogens that is known to mediate local tissue destruction in periodontitis. The Japanese apricot, known as Ume in Japanese, has been a traditional Japanese medicine for centuries and is a familiar and commonly consumed food. The health benefits of Ume are widely recognized and have been confirmed in recent studies showing that MK615, an extract of compounds from Ume, has strong anticancer and anti-inflammatory effects. However, the potential role of MK615 in oral health is unknown. We hypothesized that the anti-inflammatory activities of MK615 could be exploited to inhibit the effects of lipopolysaccharide (LPS) produced by periodontal bacterial pathogens, such as Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis. Here, we show that LPS-induced interleukin (IL)-6 and IL-8 production by gingival fibroblasts was dose-dependently inhibited by MK615. As a potent inhibitor of the inflammatory responses induced by periodontal pathogens, MK615 merits further testing as a therapeutic agent in inflammatory diseases such as periodontitis. PMID:26305447

  5. New approaches to target the mycolic acid biosynthesis pathway for the development of tuberculosis therapeutics.

    PubMed

    North, E Jeffrey; Jackson, Mary; Lee, Richard E

    2014-01-01

    Mycolic acids are the major lipid components of the unique mycobacterial cell wall responsible for the protection of the tuberculosis bacilli from many outside threats. Mycolic acids are synthesized in the cytoplasm and transported to the outer membrane as trehalose- containing glycolipids before being esterified to the arabinogalactan portion of the cell wall and outer membrane glycolipids. The large size of these unique fatty acids is a result of a huge metabolic investment that has been evolutionarily conserved, indicating the importance of these lipids to the mycobacterial cellular survival. There are many key enzymes involved in the mycolic acid biosynthetic pathway, including fatty acid synthesis (KasA, KasB, MabA, InhA, HadABC), mycolic acid modifying enzymes (SAM-dependent methyltransferases, aNAT), fatty acid activating and condensing enzymes (FadD32, Acc, Pks13), transporters (MmpL3) and tranferases (Antigen 85A-C) all of which are excellent potential drug targets. Not surprisingly, in recent years many new compounds have been reported to inhibit specific portions of this pathway, discovered through both phenotypic screening and target enzyme screening. In this review, we analyze the new and emerging inhibitors of this pathway discovered in the post-genomic era of tuberculosis drug discovery, several of which show great promise as selective tuberculosis therapeutics. PMID:24245756

  6. New Approaches to Target the Mycolic Acid Biosynthesis Pathway for the Development of Tuberculosis Therapeutics

    PubMed Central

    North, E. Jeffrey; Jackson, Mary; Lee, Richard E.

    2015-01-01

    Mycolic acids are the major lipid component of the unique mycobacterial cell wall responsible for the protection of the tuberculosis bacilli from many outside threats. Mycolic acids are synthesized in the cytoplasm and transported to the outer membrane as trehalose-containing glycolipids before being esterified to the arabinogalactan portion of the cell wall and outer membrane glycolipids. The large size of these unique fatty acids is a result of a huge metabolic investment that has been evolutionarily conserved, indicating the importance of these lipids to the mycobacterial cellular survival. There are many key enzymes involved in the mycolic acid biosynthetic pathway, including fatty acid synthesis (KasA, KasB, MabA, InhA, HadABC), mycolic acid modifying enzymes (SAM-dependent methyltransferases, aNAT), fatty acid activating and condensing enzymes (FadD32, Acc, Pks13), transporters (MmpL3) and tranferases (Antigen 85A-C) all of which are excellent potential drug targets. Not surprisingly, in recent years many new compounds have been reported to inhibit specific portions of this pathway, discovered through both phenotypic screening and target enzyme screening. In this review, we analyze the new and emerging inhibitors of this pathway discovered in the post-genomic era of tuberculosis drug discovery, several of which show great promise as selective tuberculosis therapeutics. PMID:24245756

  7. Influences on Authoritarian and Educational/Therapeutic Approaches to School Violence Prevention

    ERIC Educational Resources Information Center

    Nickerson, Amanda B.; Spears, William H.

    2007-01-01

    This study examined the use of two philosophical approaches to school violence prevention and the factors that influence the use of specific strategies. School policies, programs, and discipline strategies assessed by the School Survey of Crime and Safety (SSOCS) were categorized as authoritarian (i.e., restrict student autonomy through punitive…

  8. School Violence: Associations with Control, Security/Enforcement, Educational/Therapeutic Approaches, and Demographic Factors

    ERIC Educational Resources Information Center

    Nickerson, Amanda B.; Martens, Matthew P.

    2008-01-01

    This study examined the extent to which three approaches to violence prevention and response were associated with the incidence of school crime and disruption after accounting for the influence of demographic variables. Secondary data analyses were conducted with four subsets of the sample of principals who completed the National Center for…

  9. Neurobiology of aggression and violence.

    PubMed

    Siever, Larry J

    2008-04-01

    Acts of violence account for an estimated 1.43 million deaths worldwide annually. While violence can occur in many contexts, individual acts of aggression account for the majority of instances. In some individuals, repetitive acts of aggression are grounded in an underlying neurobiological susceptibility that is just beginning to be understood. The failure of "top-down" control systems in the prefrontal cortex to modulate aggressive acts that are triggered by anger provoking stimuli appears to play an important role. An imbalance between prefrontal regulatory influences and hyper-responsivity of the amygdala and other limbic regions involved in affective evaluation are implicated. Insufficient serotonergic facilitation of "top-down" control, excessive catecholaminergic stimulation, and subcortical imbalances of glutamatergic/gabaminergic systems as well as pathology in neuropeptide systems involved in the regulation of affiliative behavior may contribute to abnormalities in this circuitry. Thus, pharmacological interventions such as mood stabilizers, which dampen limbic irritability, or selective serotonin reuptake inhibitors (SSRIs), which may enhance "top-down" control, as well as psychosocial interventions to develop alternative coping skills and reinforce reflective delays may be therapeutic.

  10. [A new strategy for preventive and functional therapeutic methods for dementia--approach using natural products].

    PubMed

    Ohizumi, Yasushi

    2015-01-01

    Alzheimer's disease (AD) has become a serious social problem in Japan. However, effective preventive and fundamental therapeutic methods for AD have not yet been developed. Using a new strategy in the course of our survey of numerous natural resouces having neurotrophic activity, we isolated a variety of active constituents and proved their pharmacological properties. As a result, we successfully found nobiletin, a compound with anti-dementia activity that comes from citrus peels. Also, we have demonstrated that nobiletin ameliorates cognitive impairment in several dementia model animals such as chronically amyloid β(Aβ) infused rats, amyloid precursor protein transgenic (APPTg) mice, olfactory-bulbectomized (OBX) mice, N-methyl-D-aspartate (NMDA) receptor antagonist (MK-801)-treated mice, senescence-accelated mice and bilaterial common carotid arteries occlusion mice. In a APPTg mouse of AD, nobiletin greatly improved memory impairment, and this was accompanied by a marked decrease in Aβ deposition. Also, in OBX mice memory impairment was markedly recoverd by nobiletin, accompanied by improvement of a decrease indensity of cholinergic neurons. Interestingly, nobiletin improves age-related congnitive impairment and decreased hyperphosphorylation of tau as well as oxidative stress in senescence-accelerated mice. In cultured cells, nobiletin reversed the Aβ-induced inhibition of glutamate-induced increases in cAMP response element binding protein (CREB) phosphorylation and modulated gen expression of thioredoxin-interacting protein and NMDA resceptor subunits. These results suggest that nobiletin prevents memory impairment and exhibits a protecting action against neurodgeneration in AD model animals. Nobiletin and citrus peels thus have potential as functional foods for prevention of dementia.

  11. Serum 5-LOX: a progressive protein marker for breast cancer and new approach for therapeutic target.

    PubMed

    Kumar, Rahul; Singh, Abhay Kumar; Kumar, Manoj; Shekhar, Shashank; Rai, Nitish; Kaur, Punit; Parshad, Rajinder; Dey, Sharmistha

    2016-09-01

    Lipoxygenase (LOX) pathway has emerged to have a role in carcinogenesis. There is an evidence that both 12-LOX and 5-LOX have procarcinogenic role. We have previously reported the elevated level of serum 12-LOX in breast cancer patients. This study evaluated the serum level of 5-LOX in breast cancer patients and its in vitro inhibition assessment with peptide inhibitor YWCS. The level of 5-LOX was determined by surface plasmon resonance (SPR). The peptide inhibitor of 5-LOX was designed by molecular modeling and kinetic assay was performed by spectrophotometry. The siRNA mediated 5-LOX gene silencing was performed to investigate the effect on proliferation of MDA-MB-231, breast cancer cell line. The serum 5-LOX level in breast cancer (5.69±1.97ng/µl) was almost 2-fold elevated compared to control (3.53±1.0ng/µl) (P < 0.0001). The peptide YWCS had shown competitive inhibitory effects with IC50, 2.2 µM and dissociation constant (K D), 4.92×10(-8) M. The siRNA mediated knockdown of 5-LOX, resulted in the decreased gene expression for 5-LOX and increased cell death in MDA-MB-231 cell line and thereby play a key role in reducing tumor proliferation. Thus, it can be concluded that 5-LOX is one of the potential serum protein marker for breast cancer and a promising therapeutic target for the same. PMID:27432812

  12. The 1985 Walter Hubert lecture. Malignant cell differentiation as a potential therapeutic approach.

    PubMed Central

    Sartorelli, A. C.

    1985-01-01

    Most drugs available for cancer chemotherapy exert their effects through cytodestruction. Although significant advances have been attained with these cytotoxic agents in several malignant diseases, response is often accompanied by significant morbidity and many common malignant tumours respond poorly to existing cytotoxic therapy. Development of chemotherapeutic agents with non-cytodestructive actions appears desirable. Considerable evidence exists which indicates that (a) the malignant state is not irreversible and represents a disease of altered maturation, and (b) some experimental tumour systems can be induced by chemical agents to differentiate to mature end-stage cells with no proliferative potential. Thus, it is conceivable that therapeutic agents can be developed which convert cancer cells to benign forms. To study the phenomenon of blocked maturation, squamous carcinoma SqCC/Y1 cells were employed in culture. Using this system it was possible to demonstrate that physiological levels of retinoic acid and epidermal growth factor were capable of preventing the differentiation of these malignant keratinocytes into a mature tissue-like structure. The terminal differentiation caused by certain antineoplastic agents was investigated in HL-60 promyelocytic leukaemia cells to provide information on the mechanism by which chemotherapeutic agents induce cells to by-pass a maturation block. The anthracyclines aclacinomycin A and marcellomycin were potent inhibitors of N-glycosidically linked glycoprotein biosynthesis and transferrin receptor activity, and active inducers of maturation; temporal studies suggested that the biochemical effects were associated with the differentiation process. 6-Thioguanine produced cytotoxicity in parental cells by forming analog nucleotide. In hypoxanthine-guanine phosphoribosyltransferase negative HL-60 cells the 6-thiopurine initiated maturation; this action was due to the free base (and possibly the deoxyribonucleoside), a finding

  13. [A new strategy for preventive and functional therapeutic methods for dementia--approach using natural products].

    PubMed

    Ohizumi, Yasushi

    2015-01-01

    Alzheimer's disease (AD) has become a serious social problem in Japan. However, effective preventive and fundamental therapeutic methods for AD have not yet been developed. Using a new strategy in the course of our survey of numerous natural resouces having neurotrophic activity, we isolated a variety of active constituents and proved their pharmacological properties. As a result, we successfully found nobiletin, a compound with anti-dementia activity that comes from citrus peels. Also, we have demonstrated that nobiletin ameliorates cognitive impairment in several dementia model animals such as chronically amyloid β(Aβ) infused rats, amyloid precursor protein transgenic (APPTg) mice, olfactory-bulbectomized (OBX) mice, N-methyl-D-aspartate (NMDA) receptor antagonist (MK-801)-treated mice, senescence-accelated mice and bilaterial common carotid arteries occlusion mice. In a APPTg mouse of AD, nobiletin greatly improved memory impairment, and this was accompanied by a marked decrease in Aβ deposition. Also, in OBX mice memory impairment was markedly recoverd by nobiletin, accompanied by improvement of a decrease indensity of cholinergic neurons. Interestingly, nobiletin improves age-related congnitive impairment and decreased hyperphosphorylation of tau as well as oxidative stress in senescence-accelerated mice. In cultured cells, nobiletin reversed the Aβ-induced inhibition of glutamate-induced increases in cAMP response element binding protein (CREB) phosphorylation and modulated gen expression of thioredoxin-interacting protein and NMDA resceptor subunits. These results suggest that nobiletin prevents memory impairment and exhibits a protecting action against neurodgeneration in AD model animals. Nobiletin and citrus peels thus have potential as functional foods for prevention of dementia. PMID:25759053

  14. Targeting the Mevalonate Cascade as a New Therapeutic Approach in Heart Disease, Cancer and Pulmonary Disease

    PubMed Central

    Yeganeh, Behzad; Wiechec, Emmilia; Ande, Sudharsana R; Sharma, Pawan; Moghadam, Adel Rezaei; Post, Martin; Freed, Darren H.; Hashemi, Mohammad; Shojaei, Shahla; Zeki, Amir A.; Ghavami, Saeid

    2014-01-01

    The cholesterol biosynthesis pathway, also known as the mevalonate (MVA) pathway, is an essential cellular pathway that is involved in diverse cell functions. The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMGCR) is the rate-limiting step in cholesterol biosynthesis and catalyzes the conversion of HMG-CoA to MVA. Given its role in cholesterol and isoprenoid biosynthesis, the regulation of HMGCR has been intensely investigated. Because all cells require a steady supply of MVA, both the sterol (i.e. cholesterol) and non-sterol (i.e. isoprenoid) products of MVA metabolism exert coordinated feedback regulation on HMGCR through different mechanisms. The proper functioning of HMGCR as the proximal enzyme in the MVA pathway is essential under both normal physiologic conditions and in many diseases given its role in cell cycle pathways and cell proliferation, cholesterol biosynthesis and metabolism, cell cytoskeletal dynamics and stability, cell membrane structure and fluidity, mitochondrial function, proliferation, and cell fate. The blockbuster statin drugs (‘statins’) directly bind to and inhibit HMGCR, and their use for the past thirty years has revolutionized the treatment of hypercholesterolemia and cardiovascular diseases, in particular coronary heart disease. Initially thought to exert their effects through cholesterol reduction, recent evidence indicates that statins also have pleiotropic immunomodulatory properties independent of cholesterol lowering. In this review we will focus on the therapeutic applications and mechanisms involved in the MVA cascade including Rho GTPase and Rho kinase (ROCK) signaling, statin inhibition of HMGCR, geranylgeranyltransferase (GGTase) inhibition, and farnesyltransferase (FTase) inhibition in cardiovascular disease, pulmonary diseases (e.g. asthma and chronic obstructive pulmonary disease (COPD), and cancer. PMID:24582968

  15. Targeting the mevalonate cascade as a new therapeutic approach in heart disease, cancer and pulmonary disease.

    PubMed

    Yeganeh, Behzad; Wiechec, Emilia; Ande, Sudharsana R; Sharma, Pawan; Moghadam, Adel Rezaei; Post, Martin; Freed, Darren H; Hashemi, Mohammad; Shojaei, Shahla; Zeki, Amir A; Ghavami, Saeid

    2014-07-01

    The cholesterol biosynthesis pathway, also known as the mevalonate (MVA) pathway, is an essential cellular pathway that is involved in diverse cell functions. The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMGCR) is the rate-limiting step in cholesterol biosynthesis and catalyzes the conversion of HMG-CoA to MVA. Given its role in cholesterol and isoprenoid biosynthesis, the regulation of HMGCR has been intensely investigated. Because all cells require a steady supply of MVA, both the sterol (i.e. cholesterol) and non-sterol (i.e. isoprenoid) products of MVA metabolism exert coordinated feedback regulation on HMGCR through different mechanisms. The proper functioning of HMGCR as the proximal enzyme in the MVA pathway is essential under both normal physiologic conditions and in many diseases given its role in cell cycle pathways and cell proliferation, cholesterol biosynthesis and metabolism, cell cytoskeletal dynamics and stability, cell membrane structure and fluidity, mitochondrial function, proliferation, and cell fate. The blockbuster statin drugs ('statins') directly bind to and inhibit HMGCR, and their use for the past thirty years has revolutionized the treatment of hypercholesterolemia and cardiovascular diseases, in particular coronary heart disease. Initially thought to exert their effects through cholesterol reduction, recent evidence indicates that statins also have pleiotropic immunomodulatory properties independent of cholesterol lowering. In this review we will focus on the therapeutic applications and mechanisms involved in the MVA cascade including Rho GTPase and Rho kinase (ROCK) signaling, statin inhibition of HMGCR, geranylgeranyltransferase (GGTase) inhibition, and farnesyltransferase (FTase) inhibition in cardiovascular disease, pulmonary diseases (e.g. asthma and chronic obstructive pulmonary disease (COPD)), and cancer.

  16. Burning mouth syndrome: A review on its diagnostic and therapeutic approach

    PubMed Central

    Aravindhan, R.; Vidyalakshmi, Santhanam; Kumar, Muniapillai Siva; Satheesh, C.; Balasubramanium, A. Murali; Prasad, V. Srinivas

    2014-01-01

    Burning mouth syndrome (BMS), a chronic and intractable orofacial pain syndrome is characterized by the presence of burning sensation of the oral mucosa in the absence of specific oral lesion. This condition affects chiefly of middle aged and elderly woman with hormonal changes or psychological disorders. In addition to burning sensation, patient with BMS also complains of oral mucosal pain, altered taste sensation, and dry mouth. This condition is probably of multifactorial origin, often idiopathic and its exact etiopathogenesis remains unclear. So far, there is no definitive cure for this condition and most of the treatment approaches, medications remains unsatisfactory. An interdisciplinary and systematic approach is required for better patient management. The purpose of this article is to present a review of epidemiology, clinical presentation, classification, etiopathogenesis, diagnosis and management of BMS. PMID:25210377

  17. Understanding Aggressive Behavior Across the Life Span

    PubMed Central

    Liu, Jianghong; Lewis, Gary; Evans, Lois

    2012-01-01

    Aggressive behavior is the observable manifestation of aggression and is often associated with developmental transitions and a range of medical and psychiatric diagnoses across the lifespan. As healthcare professionals involved in the medical and psychosocial care of patients from birth through death, nurses frequently encounter—and may serve as—both victims and perpetrators of aggressive behavior in the workplace. While the nursing literature has continually reported research on prevention and treatment approaches, less emphasis has been given to understanding the etiology, including contextual precipitants of aggressive behavior. This paper provides a brief review of the biological, social, and environmental risk factors that purportedly give rise to aggressive behavior. Further, many researchers have focused specifically on aggressive behavior in adolescence and adulthood. Less attention has been given to understanding the etiology of such behavior in young children and older adults. This paper emphasizes the unique risk factors for aggressive behavior across the developmental spectrum, including childhood, adolescence, adulthood, and late life. Appreciation of the risk factors of aggressive behavior, and, in particular, how they relate to age-specific manifestations, can aid nurses in better design and implementation of prevention and treatment programs. PMID:22471771

  18. Punishment of elicited aggression.

    PubMed

    Azrin, N H

    1970-07-01

    Aversive shocks are known to produce aggression when the shocks are not dependent on behavior and to suppress behavior when the shocks are arranged as a dependent punisher. These two processes were studied by presenting non-dependent shock to monkeys at regular intervals, thereby producing biting attacks on a pneumatic tube. Immediate shock punishment was stimultaneously delivered for each biting attack. The attacks were found to decrease as a function of increasing punishment intensity. These results show that aggression is eliminated by direct punishment of the aggression even when the stimulus that is used as a punisher otherwise causes the aggression. PMID:4988590

  19. Genes and gene networks implicated in aggression related behaviour.

    PubMed

    Malki, Karim; Pain, Oliver; Du Rietz, Ebba; Tosto, Maria Grazia; Paya-Cano, Jose; Sandnabba, Kenneth N; de Boer, Sietse; Schalkwyk, Leonard C; Sluyter, Frans

    2014-10-01

    Aggressive behaviour is a major cause of mortality and morbidity. Despite of moderate heritability estimates, progress in identifying the genetic factors underlying aggressive behaviour has been limited. There are currently three genetic mouse models of high and low aggression created using selective breeding. This is the first study to offer a global transcriptomic characterization of the prefrontal cortex across all three genetic mouse models of aggression. A systems biology approach has been applied to transcriptomic data across the three pairs of selected inbred mouse strains (Turku Aggressive (TA) and Turku Non-Aggressive (TNA), Short Attack Latency (SAL) and Long Attack Latency (LAL) mice and North Carolina Aggressive (NC900) and North Carolina Non-Aggressive (NC100)), providing novel insight into the neurobiological mechanisms and genetics underlying aggression. First, weighted gene co-expression network analysis (WGCNA) was performed to identify modules of highly correlated genes associated with aggression. Probe sets belonging to gene modules uncovered by WGCNA were carried forward for network analysis using ingenuity pathway analysis (IPA). The RankProd non-parametric algorithm was then used to statistically evaluate expression differences across the genes belonging to modules significantly associated with aggression. IPA uncovered two pathways, involving NF-kB and MAPKs. The secondary RankProd analysis yielded 14 differentially expressed genes, some of which have previously been implicated in pathways associated with aggressive behaviour, such as Adrbk2. The results highlighted plausible candidate genes and gene networks implicated in aggression-related behaviour.

  20. Integrated therapeutic approaches in head and neck cancer: the importance of multidisciplinary team management.

    PubMed

    Perri, Francesco; Muto, Paolo; Aversa, Corrado; Daponte, Antonio; Della Vittoria, Giuseppina; Pepe, Stefano; Caponigro, Francesco

    2013-07-01

    Multidisciplinary team (MDT) is of paramount importance in the approach to patients with head and neck cancer. Its aim is to provide the best diagnostic work-up, tumor staging, and treatment. Furthermore, the prognosis of patients who are managed by MDT is usually better. MDT has a great value in all presentation settings. The role of the pathologist in the team is of utmost importance, in particular with regards to information provided on Human Papilloma Virus (HPV) status, which has a well acknowledged independent prognostic value mainly in oropharyngeal carcinoma. In early stage disease, namely in T1-2 N0 M0 patients, the meetings within the MDT mainly involve surgeons and radiation therapists. Surgery represents the mainstay of treatment, while radiation therapy is a suitable alternative, in particular in patients with advanced age, poor performance status and comorbidities. In locally advanced disease, surgeons, medical oncologists and radiotherapists are the key people, since different approaches have been carried out. In operable patients, adjuvant chemoradiation is indicated when resection margins are involved or close, or in presence of extracapsular nodal spread. Concurrent chemoradiotherapy, preceded or not by induction chemotherapy, is the favourite approach in this setting when surgery is strictly not indicated. In recurrent/metastatic disease chemotherapy and best supportive care are the main options, although local treatments, such as reirradiation and salvage surgery, are also worth considering. The standard chemotherapy treatment has finally evolved after about 30 years, and strong efforts are being pursued to further improve the outcome, mainly with the addition of new drugs.

  1. Novel therapeutic strategy in the management of COPD: a systems medicine approach.

    PubMed

    Lococo, Filippo; Cesario, Alfredo; Del Bufalo, Alessandra; Ciarrocchi, Alessia; Prinzi, Giulia; Mina, Marco; Bonassi, Stefano; Russo, Patrizia

    2015-01-01

    Respiratory diseases including chronic-obstructive-pulmonary-disease (COPD) are globally increasing, with COPD predicted to become the third leading cause of global mortality by 2020. COPD is a heterogeneous disease with COPD-patients displaying different phenotypes as a result of a complex interaction between various genetic, environmental and life-style factors. In recent years, several investigations have been performed to better define such interactions, but the identification of the resulting phenotypes is still somewhat difficult, and may lead to inadequate assessment and management of COPD (usually based solely on the severity of airflow limitation parameter FEV1). In this new scenario, the management of COPD has been driven towards an integrative and holistic approach. The degree of complexity requires analyses based on large datasets (also including advanced functional genomic assays) and novel computational biology approaches (essential to extract information relevant for the clinical decision process and for the development of new drugs). Therefore, according to the emerging "systems/network medicine", COPD should be re.-evaluated considering multiple network(s) perturbations such as genetic and environmental changes. Systems Medicine (SM) platforms, in which patients are extensively characterized, offer a basis for a more targeted clinical approach, which is predictive, preventive, personalized and participatory ("P4-medicine"). It clearly emerges that in the next future, new opportunities will become available for clinical research on rare COPD patterns and for the identification of new biomarkers of comorbidity, severity, and progression. Herein, we overview the literature discussing the opportunity coming from the adoption of SMapproaches in COPD management, focusing on proteomics and metabolomics, and emphasizing the identification of disease sub-clusters, to improve the development of more effective therapies.

  2. Experimental Autoimmune Myasthenia Gravis (EAMG): from immunochemical characterization to therapeutic approaches.

    PubMed

    Fuchs, Sara; Aricha, Revital; Reuveni, Debby; Souroujon, Miriam C

    2014-11-01

    Myasthenia Gravis (MG) is an organ-specific autoimmune disease. In high percentage of patients there are autoantibodies to the nicotinic acetylcholine receptor (AChR) that attack AChR on muscle cells at the neuromuscular junction, resulting in muscle weakness. Experimental Autoimmune Myasthenia Gravis (EAMG) is an experimental model disease for MG. EAMG is induced in several animal species by immunization with acetylcholine receptor (AChR), usually isolated from the electric organ of electric fish, which is a rich source for this antigen. Our lab has been involved for several decades in research of AChR and of EAMG. The availability of an experimental autoimmune disease that mimics in many aspects the human disease, provides an excellent model system for elucidating the immunological nature and origin of MG, for studying various existing treatment modalities and for attempting the development of novel treatment approaches. In this review in honor of Michael Sela and Ruth Arnon, we report first on our early pioneering contributions to research on EAMG. These include the induction of EAMG in several animal species, early attempts for antigen-specific treatment for EAMG, elicitation and characterization of monoclonal antibodies and anti-idiotypic antibodies, measuring humoral and cellular AChR-specific immune responses in MG patient and more. In the second part of the review we discuss more recent studies from our lab towards developing and testing novel treatment approaches for myasthenia. These include antigen-dependent treatments aimed at specifically abrogating the humoral and cellular anti-AChR responses, as well as immunomodulatory approaches that could be used either alone, or in conjunction with antigen-specific treatments, or alternatively, serve as steroid-sparing agents.

  3. Geriatric dizziness: evolving diagnostic and therapeutic approaches for the emergency department.

    PubMed

    Lo, Alexander X; Harada, Caroline N

    2013-02-01

    Dizziness affects one in five people over the age of 65 years and is associated with substantial healthcare costs. Serious causes of dizziness are found in 20% of patients over 50 years. The approach to the patient with dizziness is challenging as physical exam and diagnostic tests have suboptimal sensitivities. The risk of vascular events is higher in the first 30 days than after, suggesting some missed diagnoses. Medications and vestibular rehabilitation may serve as treatment options for dizziness, but data on their efficacy in older patients is lacking. PMID:23177607

  4. New Therapeutic Approaches to Modulate and Correct Cystic Fibrosis Transmembrane Conductance Regulator.

    PubMed

    Ong, Thida; Ramsey, Bonnie W

    2016-08-01

    Cystic fibrosis transmembrane conductance regulator (CFTR) modulators are clinically available personalized medicines approved for some individuals with cystic fibrosis (CF) to target the underlying defect of disease. This review summarizes strategies used to develop CFTR modulators as therapies that improve function and availability of CFTR protein. Lessons learned from dissemination of ivacaftor across the CF population responsive to this therapy and future approaches to predict and monitor treatment response of CFTR modulators are discussed. The goal remains to expand patient-centered and personalized therapy to all patients with CF, ultimately improving life expectancy and quality of life for this disease. PMID:27469186

  5. Aggression in autism spectrum disorder: presentation and treatment options

    PubMed Central

    Fitzpatrick, Sarah E; Srivorakiat, Laura; Wink, Logan K; Pedapati, Ernest V; Erickson, Craig A

    2016-01-01

    Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by persistent difficulties in social communication and social interaction, coupled with restricted, repetitive patterns of behavior or interest. Research indicates that aggression rates may be higher in individuals with ASD compared to those with other developmental disabilities. Aggression is associated with negative outcomes for children with ASD and their caregivers, including decreased quality of life, increased stress levels, and reduced availability of educational and social support. Therapeutic strategies including functional behavioral assessment, reinforcement strategies, and functional communication training may have a significant impact in reducing the frequency and intensity of aggressive behavior in individuals with ASD. Pharmacologic treatments, particularly the use of second-generation antipsychotics, may also be of some benefit in reducing aggression in individuals with ASD. With the ever-increasing rate of ASD diagnosis, development of effective therapeutic and pharmacologic methods for preventing and treating aggression are essential to improving outcomes in this disorder. PMID:27382295

  6. Aggression in autism spectrum disorder: presentation and treatment options.

    PubMed

    Fitzpatrick, Sarah E; Srivorakiat, Laura; Wink, Logan K; Pedapati, Ernest V; Erickson, Craig A

    2016-01-01

    Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by persistent difficulties in social communication and social interaction, coupled with restricted, repetitive patterns of behavior or interest. Research indicates that aggression rates may be higher in individuals with ASD compared to those with other developmental disabilities. Aggression is associated with negative outcomes for children with ASD and their caregivers, including decreased quality of life, increased stress levels, and reduced availability of educational and social support. Therapeutic strategies including functional behavioral assessment, reinforcement strategies, and functional communication training may have a significant impact in reducing the frequency and intensity of aggressive behavior in individuals with ASD. Pharmacologic treatments, particularly the use of second-generation antipsychotics, may also be of some benefit in reducing aggression in individuals with ASD. With the ever-increasing rate of ASD diagnosis, development of effective therapeutic and pharmacologic methods for preventing and treating aggression are essential to improving outcomes in this disorder. PMID:27382295

  7. A Novel Strategy to Develop Therapeutic Approaches to Prevent Proliferative Vitreoretinopathy

    PubMed Central

    Pennock, Steven; Rheaume, Marc-Andre; Mukai, Shizuo; Kazlauskas, Andrius

    2011-01-01

    Proliferative vitreoretinopathy (PVR) thwarts the repair of rhegmatogenous retinal detachments. Currently, there is no effective prevention for PVR. Platelet-derived growth factor receptor α (PDGFRα) is associated with PVR in humans and strongly promotes experimental PVR driven by multiple vitreal growth factors outside the PDGF family. We sought to identify vitreal factors required for experimental PVR and to establish a potential approach to prevent PVR. Vitreous was obtained from normal rabbits or those in which PVR was either developing or stabilized. Normal vitreous contained substantial levels of growth factors and cytokines, which changed quantitatively and/or qualitatively as PVR progressed and stabilized. Neutralizing a subset of these agents in rabbit vitreous eliminated their ability to induce PVR-relevant signaling and cellular responses. A single intravitreal injection of neutralizing reagents for this subset prevented experimental PVR. To identify growth factors and cytokines likely driving PVR in humans, we subjected vitreous from patients with or without PVR to a similar series of analyses. This analysis accurately identified those agents required for vitreous-induced contraction of cells from a patient PVR membrane. We conclude that combination therapy encompassing a subset of vitreal growth factors and cytokines is a potential approach to prevent PVR. PMID:22035642

  8. [Induction of myocardial neoangiogenesis by human growth factors. A new therapeutic approach in coronary heart disease].

    PubMed

    Stegmann, T J; Hoppert, T; Schneider, A; Gemeinhardt, S; Köcher, M; Ibing, R; Strupp, G

    2000-09-01

    Currently available approaches for treating human coronary heart disease aim to relieve symptoms and the risk of myocardial infarction either by reducing myocardial oxygen demand, preventing further disease progression, restoring coronary blood flow pharmacologically or mechanically, or bypassing the stenotic lesions and obstructed coronary artery segments. Gene therapy, especially using angiogenic growth factors, has emerged recently as a potential new treatment for cardiovascular disease. Following extensive experimental research on angiogenic growth factors, the first clinical studies on patients with coronary heart disease and peripheral vascular lesions have been performed. The polypeptides fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) appear to be particularly effective in initiating neovascularization (neoangiogenesis) in hypoxic or ischemic tissues. The first clinical study on patients with coronary heart disease treated by local intramyocardial injection of FGF-1 showed a 3-fold increase of capillary density mediated by the growth factor. Also, angiogenic growth factor injection intramyocardially as sole therapy for end-stage coronary disease showed an improvement of myocardial perfusion in the target areas as well as a reduction of symptoms and an increase in working capacity. Angiogenic therapy of the human myocardium introduces a new modality of treatment for coronary heart disease in terms of regulation of blood vessel growth. Beyond drug therapy, angioplasty and bypass surgery, this new approach may evolve into a fourth principle of treatment of atherosclerotic cardiovascular disease. PMID:11076317

  9. Vitamin C: A Concentration-Function Approach Yields Pharmacology and Therapeutic Discoveries12

    PubMed Central

    Levine, Mark; Padayatty, Sebastian J.; Espey, Michael Graham

    2011-01-01

    A concentration-function approach to vitamin C (ascorbate) has yielded new physiology and pharmacology discoveries. To determine the range of vitamin C concentrations possible in humans, pharmacokinetics studies were conducted. They showed that when vitamin C is ingested by mouth, plasma and tissue concentrations are tightly controlled by at least 3 mechanisms in healthy humans: absorption, tissue accumulation, and renal reabsorption. A 4th mechanism, rate of utilization, may be important in disease. With ingested amounts found in foods, vitamin C plasma concentrations do not exceed 100 μmol/L. Even with supplementation approaching maximally tolerated doses, ascorbate plasma concentrations are always <250 μmol/L and frequently <150 μmol/L. By contrast, when ascorbate is i.v. injected, tight control is bypassed until excess ascorbate is eliminated by glomerular filtration and renal excretion. With i.v. infusion, pharmacologic ascorbate concentrations of 25–30 mmol/L are safely achieved. Pharmacologic ascorbate can act as a pro-drug for hydrogen peroxide (H2O2) formation, which can lead to extracellular fluid at concentrations as high as 200 μmol/L. Pharmacologic ascorbate can elicit cytotoxicity toward cancer cells and slow the growth of tumors in experimental murine models. The effects of pharmacologic ascorbate should be further studied in diseases, such as cancer and infections, which may respond to generation of reactive oxygen species via H2O2. PMID:22332036

  10. Tumor-specific HSP90 inhibition as a therapeutic approach in JAK-mutant acute lymphoblastic leukemias.

    PubMed

    Kucine, Nicole; Marubayashi, Sachie; Bhagwat, Neha; Papalexi, Efthymia; Koppikar, Priya; Sanchez Martin, Marta; Dong, Lauren; Tallman, Marty S; Paietta, Elisabeth; Wang, Kai; He, Jie; Lipson, Doron; Stephens, Phil; Miller, Vince; Rowe, Jacob M; Teruya-Feldstein, Julie; Mullighan, Charles G; Ferrando, Adolfo A; Krivtsov, Andrei; Armstrong, Scott; Leung, Laura; Ochiana, Stefan O; Chiosis, Gabriela; Levine, Ross L; Kleppe, Maria

    2015-11-26

    The development of the dual Janus kinase 1/2 (JAK1/2) inhibitor ruxolitinib for the treatment of myeloproliferative neoplasms (MPNs) has led to studies of ruxolitinib in other clinical contexts, including JAK-mutated acute lymphoblastic leukemia (ALL). However, the limited ability of JAK inhibition to induce molecular or clinicopathological responses in MPNs suggests a need for development of better therapies for JAK kinase-dependent malignancies. Here, we demonstrate that heat shock protein 90 (HSP90) inhibition using a purine-scaffold HSP90 inhibitor in early clinical development is an effective therapeutic approach in JAK-dependent ALL and can overcome persistence to JAK-inhibitor therapy in ALL cells. PMID:26443624

  11. Altered joint tribology in osteoarthritis: Reduced lubricin synthesis due to the inflammatory process. New horizons for therapeutic approaches.

    PubMed

    Szychlinska, M A; Leonardi, R; Al-Qahtani, M; Mobasheri, A; Musumeci, G

    2016-06-01

    Osteoarthritis (OA) is the most common form of joint disease. This review aimed to consolidate the current evidence that implicates the inflammatory process in the attenuation of synovial lubrication and joint tissue homeostasis in OA. Moreover, with these findings, we propose some evidence for novel therapeutic strategies for preventing and/or treating this complex disorder. The studies reviewed support that inflammatory mediators participate in the onset and progression of OA after joint injury. The flow of pro-inflammatory cytokines following an acute injury seems to be directly associated with altered lubricating ability in the joint tissue. The latter is associated with reduced level of lubricin, one of the major joint lubricants. Future research should focus on the development of new therapies that attenuate the inflammatory process and restore lubricin synthesis and function. This approach could support joint tribology and synovial lubrication leading to improved joint function and pain relief.

  12. A novel therapeutic approach for the treatment of central sleep apnea: The remedē® system.

    PubMed

    Germany, Robin; Joseph, Susan; James, Kristofer; Kao, Andrew

    2014-06-01

    Central sleep apnea (CSA) occurs primarily in cardiovascular patients and is associated with high morbidity and mortality. The disorder often is unrecognized due to the overlap of symptoms with those of the underlying cardiac disease. CSA can be easily diagnosed with a sleep study. Following optimization of all co-morbidities, the therapeutic approach available currently focuses on mask-based therapies which suffer from poor patient adherence. A new therapy, the remedē® System, has been developed; it utilizes a transvenous, fully implantable system providing phrenic nerve stimulation intended to restore a more normal breathing pattern. The therapy demonstrated promising results based on an initial chronic study and a randomized trial is underway to further evaluate safety and efficacy of this novel system in patients with CSA.

  13. Altered joint tribology in osteoarthritis: Reduced lubricin synthesis due to the inflammatory process. New horizons for therapeutic approaches.

    PubMed

    Szychlinska, M A; Leonardi, R; Al-Qahtani, M; Mobasheri, A; Musumeci, G

    2016-06-01

    Osteoarthritis (OA) is the most common form of joint disease. This review aimed to consolidate the current evidence that implicates the inflammatory process in the attenuation of synovial lubrication and joint tissue homeostasis in OA. Moreover, with these findings, we propose some evidence for novel therapeutic strategies for preventing and/or treating this complex disorder. The studies reviewed support that inflammatory mediators participate in the onset and progression of OA after joint injury. The flow of pro-inflammatory cytokines following an acute injury seems to be directly associated with altered lubricating ability in the joint tissue. The latter is associated with reduced level of lubricin, one of the major joint lubricants. Future research should focus on the development of new therapies that attenuate the inflammatory process and restore lubricin synthesis and function. This approach could support joint tribology and synovial lubrication leading to improved joint function and pain relief. PMID:27118399

  14. Chronic thromboembolic pulmonary arterial hypertension: a review of the literature and novel therapeutic approaches.

    PubMed

    Androulakis, Emmanuel; Lioudaki, Eirini; Christophides, Theodoros; Ahmad, Mahmood; Fayed, Hossam; Laskar, Nabila; Schreiber, Benjamin

    2015-06-01

    Chronic thromboembolic pulmonary hypertension is defined as pulmonary hypertension (PH) caused by single or recurrent pulmonary emboli and is characterized by chronic obstruction of the pulmonary arteries leading to increased vascular resistance and PH. Also, progressive remodeling may occur in occluded and nonoccluded territories. Better understanding of the underlying mechanisms and risk factors could improve diagnosis and allow appropriate interventions. Pulmonary endarterectomy is an established approach and is considered the definitive treatment for chronic PH, resulting from thromboembolic disease. Furthermore, percutaneous transluminal pulmonary angioplasty is technically feasible, especially for those with peripheral-type of the disease. In addition, several agents, including prostanoids, endothelin receptor antagonists and phosphodiesterase type-5 inhibitors, have been tested in selected patients yielding promising results. Several novel agents are under investigation, and extensive research is currently in progress aiming to resolve uncertainties in the understanding and treatment of the disease.

  15. A clinical report of Type III dens invaginatus: relevant aspects of a combined therapeutic approach.

    PubMed

    Silva E Souza, Patricia de Almeida Rodrigues; de Almeida, Bruno Vila Nova; Tartari, Talita; Alves, Ana Claudia Braga Amoras; Tuji, Farbicio Mesquita; Silva E Souza, Mario Honorato

    2013-01-01

    Dens invaginatus is a developmental abnormality that alters dental morphology; as a result, treating this condition is a challenge for endodontic practices. This article describes how a combination of nonsurgical and surgical therapies was utilized to treat a maxillary central incisor with Type III dens invaginatus and vital pulp. The treatment plan included using computed tomography (CT) for a detailed analysis of the dental anatomy and periapical area, endodontic and surgical procedures, and a 4-year follow-up period that included periodic clinical and radiographic examinations. The follow-up examinations revealed a regression of the apical lesion and no other signs or symptoms. Based on the present case report, the authors concluded that this combination of surgical and nonsurgical approaches was effective and that CT is a valuable auxiliary tool for the study of dental anatomy.

  16. A clinical report of Type III dens invaginatus: relevant aspects of a combined therapeutic approach.

    PubMed

    Silva E Souza, Patricia de Almeida Rodrigues; de Almeida, Bruno Vila Nova; Tartari, Talita; Alves, Ana Claudia Braga Amoras; Tuji, Farbicio Mesquita; Silva E Souza, Mario Honorato

    2013-01-01

    Dens invaginatus is a developmental abnormality that alters dental morphology; as a result, treating this condition is a challenge for endodontic practices. This article describes how a combination of nonsurgical and surgical therapies was utilized to treat a maxillary central incisor with Type III dens invaginatus and vital pulp. The treatment plan included using computed tomography (CT) for a detailed analysis of the dental anatomy and periapical area, endodontic and surgical procedures, and a 4-year follow-up period that included periodic clinical and radiographic examinations. The follow-up examinations revealed a regression of the apical lesion and no other signs or symptoms. Based on the present case report, the authors concluded that this combination of surgical and nonsurgical approaches was effective and that CT is a valuable auxiliary tool for the study of dental anatomy. PMID:23302365

  17. Genomic instability in pancreatic adenocarcinoma: a new step towards precision medicine and novel therapeutic approaches.

    PubMed

    Sahin, Ibrahim H; Lowery, Maeve A; Stadler, Zsofia K; Salo-Mullen, Erin; Iacobuzio-Donahue, Christine A; Kelsen, David P; O'Reilly, Eileen M

    2016-08-01

    Pancreatic cancer is one of the most challenging cancers. Whole genome sequencing studies have been conducted to elucidate the underlying fundamentals underscoring disease behavior. Studies have identified a subgroup of pancreatic cancer patients with distinct molecular and clinical features. Genetic fingerprinting of these tumors is consistent with an unstable genome and defective DNA repair pathways, which creates unique susceptibility to agents inducing DNA damage. BRCA1/2 mutations, both germline and somatic, which lead to impaired DNA repair, are found to be important biomarkers of genomic instability as well as of response to DNA damaging agents. Recent studies have elucidated that PARP inhibitors and platinum agents may be effective to induce tumor regression in solid tumors bearing an unstable genome including pancreatic cancer. In this review we discuss the characteristics of genomic instability in pancreatic cancer along with its clinical implications and the utility of DNA targeting agents particularly PARP inhibitors as a novel treatment approach. PMID:26881472

  18. Phase-dependent modulation as a novel approach for therapeutic brain stimulation

    PubMed Central

    Azodi-Avval, Ramin; Gharabaghi, Alireza

    2015-01-01

    Closed-loop paradigms provide us with the opportunity to optimize stimulation protocols for perturbation of pathological oscillatory activity in brain-related disorders. In this vein, spiking activity of motor cortex neurons and beta activity of local field potentials in the subthalamic nucleus have both been used independently of each other as neuronal signals to trigger deep brain stimulation for alleviating Parkinsonism. These approaches were superior to the standard continuous high-frequency stimulation protocols used in daily practice. However, they achieved their effects by bursts of stimulation that were applied at high-frequency as well, i.e., independent of the phase information in the stimulated region. In this context, we propose that, by timing stimulation pulses relative to the ongoing oscillation, an alternative approach, namely the targeted perturbation of pathological rhythms, could be obtained. In this modeling study, we first captured the underlying dynamics of neuronal oscillations in the human subthalamic nucleus by phased coupled neuronal oscillators. We then quantified the nature of the interaction between these coupled oscillators by obtaining a physiologically informed phase response curve from local field potentials. Reconstruction of the phase response curve predicted the sensitivity of the phase oscillator to external stimuli, revealing phase intervals that optimally maximized the degree of perturbation. We conclude that our specifically timed intervention based on the coupled oscillator concept will enable us to identify personalized ways of delivering stimulation pulses in closed-loop paradigms triggered by the phase of pathological oscillations. This will pave the way for novel physiological insights and substantial clinical benefits. In addition, this precisely phased modulation may be capable of modifying the effective interactions between oscillators in an entirely new manner. PMID:25767446

  19. SGLT2 inhibitors – an insulin-independent therapeutic approach for treatment of type 2 diabetes: focus on canagliflozin

    PubMed Central

    Seufert, Jochen

    2015-01-01

    Despite the availability of a great variety of medications, a significant proportion of people with type 2 diabetes mellitus (T2DM) are not able to achieve or maintain adequate glycemic control. Beyond improved glucose control, novel treatments would ideally provide a reduction of cardiovascular risk, with a favorable impact on excess weight, and a low intrinsic hypoglycemia risk, as well as a synergistic mechanism of action for broad combination therapy. With the development of sodium glucose cotransporter 2 (SGLT2) inhibitors, an antidiabetic pharmacologic option has recently become available that comes close to meeting these requirements. For the first time, SGLT2 inhibitors offer a therapeutic approach acting directly on the kidneys without requiring insulin secretion or action. Canagliflozin, dapagliflozin, and empagliflozin are the SGLT2 inhibitors approved to date. Taken once a day, these medications can be combined with all other antidiabetic medications including insulin, due to their insulin-independent mechanism of action, with only a minimal risk of hypoglycemia. SGLT2 inhibitors provide additional reductions in body weight and blood pressure due to the therapeutically induced excretion of glucose and sodium through the kidneys. These “concomitant effects” are particularly interesting with regard to the increased cardiovascular risk in T2DM. In many cases, T2DM treatment requires a multidimensional approach where the treatment goals have to be adapted to the individual patient. While there is a consensus on the use of metformin as a first-line drug therapy, various antidiabetics are used for treatment intensification. New mechanisms of action like that of SGLT2 inhibitors such as canagliflozin, which can be used both in early and late stages of diabetes, are a welcome addition to expand the treatment options for patients at every stage of T2DM. The efficacy and tolerability of canagliflozin have been tested in an extensive clinical trial program

  20. Diagnostic and therapeutic approach to acute pulmonary embolism in an emergency department.

    PubMed

    Tilli, P; Testa, A; Covino, M; Portale, P; Capaldi, L; Carbone, L; Silveri, N Gentiloni

    2006-01-01

    Pulmonary embolism (PE) is the obstruction of the pulmonary arteries by the dislodging and embolization of thrombotic material coming in most cases from the deep veins of the leg. PE is a relatively common disease with an estimated annual incidence up to 37 cases diagnosed per 100,000 persons it is the third cause of death in the United States. Clinical signs and symptoms are non specific and in the 70% of cases there isn't a correct diagnosis. The aim of this review is to summarize the state of the art of the diagnostic and treatment algorithms of PE in the evidence based medicine in order to minimize the "clinician gestalt" by the only guide for the early diagnosis and treatment of the disease. A correct diagnosis based on pre test probability, the use of computed tomographic pulmonary angiography, early anticoagulation/fibrinolysis started in the Emergency Department can change the natural history of the disease. In perspective, a combined approach of localyzed fibrinolysis and mechanical fragmentation could improve the overall outcome of these patients. PMID:16705955

  1. Human microbiomes and their roles in dysbiosis, common diseases, and novel therapeutic approaches

    PubMed Central

    Belizário, José E.; Napolitano, Mauro

    2015-01-01

    The human body is the residence of a large number of commensal (non-pathogenic) and pathogenic microbial species that have co-evolved with the human genome, adaptive immune system, and diet. With recent advances in DNA-based technologies, we initiated the exploration of bacterial gene functions and their role in human health. The main goal of the human microbiome project is to characterize the abundance, diversity and functionality of the genes present in all microorganisms that permanently live in different sites of the human body. The gut microbiota expresses over 3.3 million bacterial genes, while the human genome expresses only 20 thousand genes. Microbe gene-products exert pivotal functions via the regulation of food digestion and immune system development. Studies are confirming that manipulation of non-pathogenic bacterial strains in the host can stimulate the recovery of the immune response to pathogenic bacteria causing diseases. Different approaches, including the use of nutraceutics (prebiotics and probiotics) as well as phages engineered with CRISPR/Cas systems and quorum sensing systems have been developed as new therapies for controlling dysbiosis (alterations in microbial community) and common diseases (e.g., diabetes and obesity). The designing and production of pharmaceuticals based on our own body’s microbiome is an emerging field and is rapidly growing to be fully explored in the near future. This review provides an outlook on recent findings on the human microbiomes, their impact on health and diseases, and on the development of targeted therapies. PMID:26500616

  2. Doxycycline hinders phenylalanine fibril assemblies revealing a potential novel therapeutic approach in phenylketonuria

    PubMed Central

    De Luigi, Ada; Mariani, Alessandro; De Paola, Massimiliano; Re Depaolini, Andrea; Colombo, Laura; Russo, Luca; Rondelli, Valeria; Brocca, Paola; Adler-Abramovich, Lihi; Gazit, Ehud; Del Favero, Elena; Cantù, Laura; Salmona, Mario

    2015-01-01

    A new paradigm for the aetiopathology of phenylketonuria suggests the presence of amyloid-like assemblies in the brains of transgenic mouse models and patients with phenylketonuria, possibly shedding light on the selective cognitive deficit associated with this disease. Paralleling the amyloidogenic route that identifies different stages of peptide aggregation, corresponding to different levels of toxicity, we experimentally address for the first time, the physico-chemical properties of phenylalanine aggregates via Small Angle, Wide Angle X-ray Scattering and Atomic Force Microscopy. Results are consistent with the presence of well-structured, aligned fibres generated by milliMolar concentrations of phenylalanine. Moreover, the amyloid-modulating doxycycline agent affects the local structure of phenylalanine aggregates, preventing the formation of well-ordered crystalline structures. Phenylalanine assemblies prove toxic in vitro to immortalized cell lines and primary neuronal cells. Furthermore, these assemblies also cause dendritic sprouting alterations and synaptic protein impairment in neurons. Doxycycline counteracts these toxic effects, suggesting an approach for the development of future innovative non-dietary preventive therapies. PMID:26510963

  3. Multi-omics approach to infer cancer therapeutic targets on chromosome 20q across tumor types

    PubMed Central

    Snijders, Antoine M; Mao, Jian-Hua

    2016-01-01

    The identification of good targets is a critical step for the development of targeted therapies for cancer treatment. Here, we used a multi-omics approach to delineate potential targets on chromosome 20q, which frequently shows a complex pattern of DNA copy number amplification in many human cancers suggesting the presence of multiple driver genes. By comparing the amounts of individual mRNAs in cancer from 11 different human tissues with those in their corresponding normal tissues, we identified 18 genes that were robustly elevated across human cancers. Moreover, we found that higher expression levels of a majority of these genes were associated with poor prognosis in many human cancer types. Using DNA copy number and expression data for all 18 genes obtained from The Cancer Genome Atlas project, we discovered that amplification is a major mechanism driving overexpression of these 18 genes in the majority of human cancers. Our integrated analysis suggests that 18 genes on chromosome 20q might serve as novel potential molecular targets for targeted cancer therapy. PMID:27642640

  4. Pharmacological approaches to manage persistent symptoms of major depressive disorder: rationale and therapeutic strategies.

    PubMed

    Epstein, Irvin; Szpindel, Isaac; Katzman, Martin A

    2014-12-01

    Major depressive disorder (MDD) is a highly prevalent chronic psychiatric illness associated with significant morbidity, mortality, loss of productivity, and diminished quality of life. Typically, only a minority of patients responds to treatment and meet criteria for remission as residual symptoms may persist, the result of an inadequate course of treatment and/or the presence of persistent side effects. The foremost goal of treatment should be to restore patients to full functioning and eliminate or relieve all MDD symptoms, while being virtually free of troublesome side effects. The current available pharmacological options to manage persistent depressive symptoms include augmentation or adjunctive combination strategies, both of which target selected psychobiological systems and specific mood and somatic symptoms experienced by the patient. As well, non-pharmacological interventions including psychotherapies may be used in either first-line or adjunctive approaches. However, the evidence to date with respect to available adjunct therapies is limited by few studies and those published have utilized only a small number of subjects and lack enough data to allow for a consensus of expert opinion. This underlines the need for further longer term, large population-based studies and those that include comorbid populations, all of which are seen in real world community psychiatry.

  5. Human microbiomes and their roles in dysbiosis, common diseases, and novel therapeutic approaches.

    PubMed

    Belizário, José E; Napolitano, Mauro

    2015-01-01

    The human body is the residence of a large number of commensal (non-pathogenic) and pathogenic microbial species that have co-evolved with the human genome, adaptive immune system, and diet. With recent advances in DNA-based technologies, we initiated the exploration of bacterial gene functions and their role in human health. The main goal of the human microbiome project is to characterize the abundance, diversity and functionality of the genes present in all microorganisms that permanently live in different sites of the human body. The gut microbiota expresses over 3.3 million bacterial genes, while the human genome expresses only 20 thousand genes. Microbe gene-products exert pivotal functions via the regulation of food digestion and immune system development. Studies are confirming that manipulation of non-pathogenic bacterial strains in the host can stimulate the recovery of the immune response to pathogenic bacteria causing diseases. Different approaches, including the use of nutraceutics (prebiotics and probiotics) as well as phages engineered with CRISPR/Cas systems and quorum sensing systems have been developed as new therapies for controlling dysbiosis (alterations in microbial community) and common diseases (e.g., diabetes and obesity). The designing and production of pharmaceuticals based on our own body's microbiome is an emerging field and is rapidly growing to be fully explored in the near future. This review provides an outlook on recent findings on the human microbiomes, their impact on health and diseases, and on the development of targeted therapies. PMID:26500616

  6. Multi-omics approach to infer cancer therapeutic targets on chromosome 20q across tumor types

    PubMed Central

    Snijders, Antoine M; Mao, Jian-Hua

    2016-01-01

    The identification of good targets is a critical step for the development of targeted therapies for cancer treatment. Here, we used a multi-omics approach to delineate potential targets on chromosome 20q, which frequently shows a complex pattern of DNA copy number amplification in many human cancers suggesting the presence of multiple driver genes. By comparing the amounts of individual mRNAs in cancer from 11 different human tissues with those in their corresponding normal tissues, we identified 18 genes that were robustly elevated across human cancers. Moreover, we found that higher expression levels of a majority of these genes were associated with poor prognosis in many human cancer types. Using DNA copy number and expression data for all 18 genes obtained from The Cancer Genome Atlas project, we discovered that amplification is a major mechanism driving overexpression of these 18 genes in the majority of human cancers. Our integrated analysis suggests that 18 genes on chromosome 20q might serve as novel potential molecular targets for targeted cancer therapy.

  7. Human microbiomes and their roles in dysbiosis, common diseases, and novel therapeutic approaches.

    PubMed

    Belizário, José E; Napolitano, Mauro

    2015-01-01

    The human body is the residence of a large number of commensal (non-pathogenic) and pathogenic microbial species that have co-evolved with the human genome, adaptive immune system, and diet. With recent advances in DNA-based technologies, we initiated the exploration of bacterial gene functions and their role in human health. The main goal of the human microbiome project is to characterize the abundance, diversity and functionality of the genes present in all microorganisms that permanently live in different sites of the human body. The gut microbiota expresses over 3.3 million bacterial genes, while the human genome expresses only 20 thousand genes. Microbe gene-products exert pivotal functions via the regulation of food digestion and immune system development. Studies are confirming that manipulation of non-pathogenic bacterial strains in the host can stimulate the recovery of the immune response to pathogenic bacteria causing diseases. Different approaches, including the use of nutraceutics (prebiotics and probiotics) as well as phages engineered with CRISPR/Cas systems and quorum sensing systems have been developed as new therapies for controlling dysbiosis (alterations in microbial community) and common diseases (e.g., diabetes and obesity). The designing and production of pharmaceuticals based on our own body's microbiome is an emerging field and is rapidly growing to be fully explored in the near future. This review provides an outlook on recent findings on the human microbiomes, their impact on health and diseases, and on the development of targeted therapies.

  8. Cystathionine β-Synthase Inhibition Is a Potential Therapeutic Approach to Treatment of Ischemic Injury

    PubMed Central

    Chan, Su Jing; Chai, Chou; Lim, Tze Wei; Yamamoto, Mie; Lo, Eng H; Lai, Mitchell Kim Peng

    2015-01-01

    Hydrogen sulfide (H2S) has been reported to exacerbate stroke outcome in experimental models. Cystathionine β-synthase (CBS) has been implicated as the predominant H2S-producing enzyme in central nervous system. When SH-SY5Y cells were transfected to overexpress CBS, these cells were able to synthesize H2S when exposed to high levels of enzyme substrates but not substrate concentrations that may reflect normal physiological conditions. At the same time, these cells demonstrated exacerbated cell death when subjected to oxygen and glucose deprivation (OGD) together with high substrate concentrations, indicating that H2S production has a detrimental effect on cell survival. This effect could be abolished by CBS inhibition. The same effect was observed with primary astrocytes exposed to OGD and high substrates or sodium hydrosulfide. In addition, CBS was upregulated and activated by truncation in primary astrocytes subjected to OGD. When rats were subjected to permanent middle cerebral artery occlusion, CBS activation was also observed. These results imply that in acute ischemic conditions, CBS is upregulated and activated by truncation causing an increased production of H2S, which exacerbate the ischemic injuries. Therefore, CBS inhibition may be a viable approach to stroke treatment. PMID:25873304

  9. Doxycycline hinders phenylalanine fibril assemblies revealing a potential novel therapeutic approach in phenylketonuria.

    PubMed

    De Luigi, Ada; Mariani, Alessandro; De Paola, Massimiliano; Re Depaolini, Andrea; Colombo, Laura; Russo, Luca; Rondelli, Valeria; Brocca, Paola; Adler-Abramovich, Lihi; Gazit, Ehud; Del Favero, Elena; Cantù, Laura; Salmona, Mario

    2015-10-29

    A new paradigm for the aetiopathology of phenylketonuria suggests the presence of amyloid-like assemblies in the brains of transgenic mouse models and patients with phenylketonuria, possibly shedding light on the selective cognitive deficit associated with this disease. Paralleling the amyloidogenic route that identifies different stages of peptide aggregation, corresponding to different levels of toxicity, we experimentally address for the first time, the physico-chemical properties of phenylalanine aggregates via Small Angle, Wide Angle X-ray Scattering and Atomic Force Microscopy. Results are consistent with the presence of well-structured, aligned fibres generated by milliMolar concentrations of phenylalanine. Moreover, the amyloid-modulating doxycycline agent affects the local structure of phenylalanine aggregates, preventing the formation of well-ordered crystalline structures. Phenylalanine assemblies prove toxic in vitro to immortalized cell lines and primary neuronal cells. Furthermore, these assemblies also cause dendritic sprouting alterations and synaptic protein impairment in neurons. Doxycycline counteracts these toxic effects, suggesting an approach for the development of future innovative non-dietary preventive therapies.

  10. Identification of Ecdysone Hormone Receptor Agonists as a Therapeutic Approach for Treating Filarial Infections

    PubMed Central

    Mhashilkar, Amruta S.; Vankayala, Sai L.; Liu, Canhui; Kearns, Fiona; Mehrotra, Priyanka; Tzertzinis, George; Palli, Subba R.; Woodcock, H. Lee; Unnasch, Thomas R.

    2016-01-01

    Background A homologue of the ecdysone receptor has previously been identified in human filarial parasites. As the ecdysone receptor is not found in vertebrates, it and the regulatory pathways it controls represent attractive potential chemotherapeutic targets. Methodology/ Principal Findings Administration of 20-hydroxyecdysone to gerbils infected with B. malayi infective larvae disrupted their development to adult stage parasites. A stable mammalian cell line was created incorporating the B. malayi ecdysone receptor ligand-binding domain, its heterodimer partner and a secreted luciferase reporter in HEK293 cells. This was employed to screen a series of ecdysone agonist, identifying seven agonists active at sub-micromolar concentrations. A B. malayi ecdysone receptor ligand-binding domain was developed and used to study the ligand-receptor interactions of these agonists. An excellent correlation between the virtual screening results and the screening assay was observed. Based on both of these approaches, steroidal ecdysone agonists and the diacylhydrazine family of compounds were identified as a fruitful source of potential receptor agonists. In further confirmation of the modeling and screening results, Ponasterone A and Muristerone A, two compounds predicted to be strong ecdysone agonists stimulated expulsion of microfilaria and immature stages from adult parasites. Conclusions The studies validate the potential of the B. malayi ecdysone receptor as a drug target and provide a means to rapidly evaluate compounds for development of a new class of drugs against the human filarial parasites. PMID:27300294

  11. Lipoprotein Subfractions in Metabolic Syndrome and Obesity: Clinical Significance and Therapeutic Approaches

    PubMed Central

    Nikolic, Dragana; Katsiki, Niki; Montalto, Giuseppe; Isenovic, Esma R.; Mikhailidis, Dimitri P.; Rizzo, Manfredi

    2013-01-01

    Small, dense low density lipoprotein (sdLDL) represents an emerging cardiovascular risk factor, since these particles can be associated with cardiovascular disease (CVD) independently of established risk factors, including plasma lipids. Obese subjects frequently have atherogenic dyslipidaemia, including elevated sdLDL levels, in addition to elevated triglycerides (TG), very low density lipoprotein (VLDL) and apolipoprotein-B, as well as decreased high density lipoprotein cholesterol (HDL-C) levels. Obesity-related co-morbidities, such as metabolic syndrome (MetS) are also characterized by dyslipidaemia. Therefore, agents that favourably modulate LDL subclasses may be of clinical value in these subjects. Statins are the lipid-lowering drug of choice. Also, anti-obesity and lipid lowering drugs other than statins could be useful in these patients. However, the effects of anti-obesity drugs on CVD risk factors remain unclear. We review the clinical significance of sdLDL in being overweight and obesity, as well as the efficacy of anti-obesity drugs on LDL subfractions in these individuals; a short comment on HDL subclasses is also included. Our literature search was based on PubMed and Scopus listings. Further research is required to fully explore both the significance of sdLDL and the efficacy of anti-obesity drugs on LDL subfractions in being overweight, obesity and MetS. Improving the lipoprotein profile in these patients may represent an efficient approach for reducing cardiovascular risk. PMID:23507795

  12. A therapeutic approach for diabetic wound healing using biotinylated GHK incorporated collagen matrices.

    PubMed

    Arul, Vadivel; Kartha, Reena; Jayakumar, Rajadas

    2007-01-01

    Chronically elevated blood glucose levels result in reduced leukocyte function and cell malnutrition, which contribute to a high rate of wound infection and associated healing problems in diabetic patients. In the present study, the role of biotinylated GHK peptide (BioGHK) incorporated collagen biomaterial was tested for wound healing in diabetic rats. The rate of wound contraction and the levels of collagen, uronic acid, protein and DNA in the granulation tissue were determined. Further, the concentration of nitric oxide and other skin antioxidants was also monitored during the study. In diabetic rats treated with BioGHK incorporated collagen (Peptide Incorporated Collagen--PIC), the healing process was hastened with an increased rate of wound contraction. Glutathione (GSH) and ascorbic acid levels in the skin of streptozotocin-induced diabetic rats were higher in the PIC group as compared to control (Untreated) and collagen (Collagen Film--CF) treated groups. Superoxide dismutase (SOD) and catalase (CAT) activity was altered in all the groups. In vitro fibroblast cell culture studies suggest that PIC promotes fibroblast growth. Histological evaluation by haematoxylin-eosin and Masson's trichrome method revealed epithelialization, increased synthesis of collagen and activation of fibroblasts and mast cells in the PIC group. This study provides a rationale for the topical application of BioGHK incorporated collagen as a feasible and productive approach to support diabetic wound healing. PMID:17049946

  13. Girls' Aggressive Behavior

    ERIC Educational Resources Information Center

    Owens, Larry; Shute, Rosalyn; Slee, Phillip

    2004-01-01

    In contrast to boys' bullying behavior which is often overt and easily visible, girls' aggression is usually indirect and covert. Less research has been conducted on the types of bullying that girls usually engage in. Using focus groups composed of teenaged girls, Dr. Owens and colleagues examine the nature of teenage girls' indirect aggression.

  14. Third Person Instigated Aggression.

    ERIC Educational Resources Information Center

    Gaebelein, Jacquelyn

    Since many acts of aggression in society are more than simply an aggressor-victim encounter, the role played by third person instigated aggression also needs examination. The purpose of this study was to develop a laboratory procedure to systematically investigate instigation. In a competitive reaction time task, high and low Machiavellian Males…

  15. Social Aggression among Girls.

    ERIC Educational Resources Information Center

    Underwood, Marion K.

    Noting recent interest in girls' social or "relational" aggression, this volume offers a balanced, scholarly analysis of scientific knowledge in this area. The book integrates current research on emotion regulation, gender, and peer relations, to examine how girls are socialized to experience and express anger and aggression from infancy through…

  16. Laminin Receptor-Avid Nanotherapeutic EGCg-AuNPs as a Potential Alternative Therapeutic Approach to Prevent Restenosis

    PubMed Central

    Khoobchandani, Menka; Katti, Kavita; Maxwell, Adam; Fay, William P.; Katti, Kattesh V.

    2016-01-01

    In our efforts to develop new approaches to treat and prevent human vascular diseases, we report herein our results on the proliferation and migration of human smooth muscles cells (SMCs) and endothelial cells (ECs) using epigallocatechin-3-gallate conjugated gold nanoparticles (EGCg-AuNPs) as possible alternatives to drug coated stents. Detailed in vitro stability studies of EGCg-AuNPs in various biological fluids, affinity and selectivity towards SMCs and ECs have been investigated. The EGCg-AuNPs showed selective inhibitory efficacy toward the migration of SMCs. However, the endothelial cells remained unaffected under similar experimental conditions. The cellular internalization studies have indicated that EGCg-AuNPs internalize into the SMCs and ECs within short periods of time through laminin receptor mediated endocytosis mode. Favorable toxicity profiles and selective affinity toward SMCs and ECs suggest that EGCg-AuNPs may provide attractive alternatives to drug coated stents and therefore offer new therapeutic approaches in treating cardiovascular diseases. PMID:26938531

  17. Mapping Brain Development and Aggression

    PubMed Central

    Paus, Tomás

    2005-01-01

    Introduction This article provides an overview of the basic principles guiding research on brain-behaviour relationships in general, and as applied to studies of aggression during human development in particular. Method Key literature on magnetic resonance imaging of the structure and function of a developing brain was reviewed. Results The article begins with a brief introduction to the methodology of techniques used to map the developing brain, with a special emphasis on magnetic resonance imaging (MRI). It then reviews briefly the current knowledge of structural maturation, assessed by MRI, of the human brain during childhood and adolescence. The last part describes some of the results of neuroimaging studies aimed at identifying neural circuits involved in various aspects of aggression and social cognition. Conclusion The article concludes by discussing the potential and limitations of the neuroimaging approach in this field. PMID:19030495

  18. Homeostatic disturbances and human aggression.

    PubMed

    Naisberg, Y

    1997-04-01

    A new model on the nature of human aggression is presented. It rests on the assumption that a pre-established organismic homeostatic modification, based on a decrease in neuronal membrane electric threshold, causes neural facilitation. In turn, this influences the cut-off phenomenon, in particular, neuronal network and therefore either inherited schemata representation, or acquired engram linkage programs run inadequately. These programs adjust the response to working loads of the eight normal serial stages in the body's operational regime activity. The effect of facilitation on these programs is: (1) loss of discrimination when approaching involuntary multi-stimuli; (2) the corruption of acquired engram linkage portions used in neural networks; (3) significant reduction of the voluntary degrees of freedom of response, thus narrowing the body's operational regime activity. This results in damage to certain cognitive links from some acquired engram linkages, enhancing impulse-like program mismatches and causing a unilateral 'fight' response of an aggressive nature.

  19. Ultrasound-Guided Laser Ablation of Incidental Papillary Thyroid Microcarcinoma: A Potential Therapeutic Approach in Patients at Surgical Risk

    PubMed Central

    Papini, Enrico; Guglielmi, Rinaldo; Hosseim, Gharib; Graziano, Filomena; Chianelli, Marco; Crescenzi, Anna; Bianchini, Antonio; Valle, Dario; Bizzarri, Giancarlo

    2011-01-01

    Background Incidental papillary thyroid microcarcinoma (PTMC), a frequent clinical problem, is usually associated with a favorable outcome. During long-term follow-up, only a minority of cases show aggressive behavior with either lymph node or distant metastases. Recently, we had an opportunity to evaluate the efficacy of nonsurgical, ultrasound (US)-guided percutaneous laser ablation (PLA) for local treatment of PTMC in an otherwise inoperable patient. Patient and Methods Neck US examination revealed an incidental, solitary, 8 × 7 × 7 mm hypoechoic nodule with microcalcifications of the right thyroid lobe. The patient suffered from decompensated liver cirrhosis, renal failure, and recent surgery followed by external beam radiation therapy for breast cancer. Cytologic diagnosis showed papillary thyroid carcinoma, but the patient declined surgery because of high risk of thyroid surgery. After local anesthesia with 2% xylocaine, PLA was performed according to the previously reported procedure with an Nd:YAG laser. Summary The procedure was well tolerated, without side effects, and the patient required no analgesics. US-guided fine-needle aspiration biopsy and core-needle biopsy were performed at 1 and 12 months after PLA, which demonstrated necrotic material and inflammatory cells with no viable neoplastic cell. At the 24 months US follow-up examination, the area of necrosis further decreased, demonstrating a 4 × 4 mm hypoechoic zone and a small hyperechoic area due to fibrotic changes. A fine-needle aspiration biopsy confirmed the absence of malignant cells. Conclusions Laser-induced thermal ablation was a safe and effective ablative treatment for a patient with PTMC confined to the thyroid gland who was at high surgical risk. This approach should be considered only in elderly patients and/or in those with comorbidities that might expose the patients to an undue high surgical risk and only after the evaluation by neck US, computed tomography

  20. Yoga: a therapeutic approach.

    PubMed

    Nayak, Nirmala N; Shankar, Kamala

    2004-11-01

    Yoga, practiced widely in the East, is now popular in the West as part of a healthy lifestyle. This article brings a medical perspective to the practice of yoga. Selected yoga postures that are believed to benefit certain medical conditions are highlighted. In addition, the philosophy, general guidelines, and medical benefits of yoga practice are described.

  1. Methotrexate: new therapeutic approaches.

    PubMed

    Puig, L

    2014-01-01

    Although the first study on the efficacy of methotrexate in the treatment of psoriasis was reported in 1958, scientific evidence for this indication has been scant until quite recently. We now have new data on the pharmacokinetics and mechanism of action of methotrexate and new subcutaneous formulations that have improved the bioavailability, efficacy, and ease of administration of the drug. The results of recent clinical trials comparing methotrexate with several biologic agents have shown it to be the first-line therapy among the classic systemic treatments for psoriasis. Moreover, the incremental cost-effectiveness ratio for subcutaneous methotrexate has been shown to be superior to that of ciclosporin, adalimumab, and infliximab.

  2. [Therapeutic approaches to gonarthrosis].

    PubMed

    Argenson, Jean-Noël; Parratte, Sébastien; Ollivier, Matthieu

    2016-01-01

    Often linked to sequelae of a knee injury or knee deformities, gonarthrosis is the most frequent form of osteoarthritis of the limbs. A variety of methods and therapies can be used to treat it. For advanced conditions, treatment may involve partial or total replacement. PMID:27633693

  3. Aggression in Pretend Play and Aggressive Behavior in the Classroom

    ERIC Educational Resources Information Center

    Fehr, Karla K.; Russ, Sandra W.

    2013-01-01

    Research Findings: Pretend play is an essential part of child development and adjustment. However, parents, teachers, and researchers debate the function of aggression in pretend play. Different models of aggression predict that the expression of aggression in play could either increase or decrease actual aggressive behavior. The current study…

  4. Neurogenetics of Aggressive Behavior – Studies in Rodents

    PubMed Central

    Takahashi, Aki; Miczek, Klaus A.

    2014-01-01

    individual differences in aggression, using the so-called forward genetics approach. PMID:24318936

  5. Abnormal Neural Connectivity in Schizophrenia and fMRI-Brain-Computer Interface as a Potential Therapeutic Approach

    PubMed Central

    Ruiz, Sergio; Birbaumer, Niels; Sitaram, Ranganatha

    2012-01-01

    Considering that single locations of structural and functional abnormalities are insufficient to explain the diverse psychopathology of schizophrenia, new models have postulated that the impairments associated with the disease arise from a failure to integrate the activity of local and distributed neural circuits: the “abnormal neural connectivity hypothesis.” In the last years, new evidence coming from neuroimaging have supported and expanded this theory. However, despite the increasing evidence that schizophrenia is a disorder of neural connectivity, so far there are no treatments that have shown to produce a significant change in brain connectivity, or that have been specifically designed to alleviate this problem. Brain-Computer Interfaces based on real-time functional Magnetic Resonance Imaging (fMRI-BCI) are novel techniques that have allowed subjects to achieve self-regulation of circumscribed brain regions. In recent studies, experiments with this technology have resulted in new findings suggesting that this methodology could be used to train subjects to enhance brain connectivity, and therefore could potentially be used as a therapeutic tool in mental disorders including schizophrenia. The present article summarizes the findings coming from hemodynamics-based neuroimaging that support the abnormal connectivity hypothesis in schizophrenia, and discusses a new approach that could address this problem. PMID:23525496

  6. Roles of Triolein and Lipolytic Protein in the Pathogenesis and Survival of Mycobacterium tuberculosis: a Novel Therapeutic Approach.

    PubMed

    Monu; Meena, Laxman S

    2016-04-01

    Discovery of novel secreted enzymes and proteins in Mycobacterium tuberculosis (M. tuberculosis) are imperative to understanding the pathogenic system for pathogenesis requires attention. Till date, the groups of these secreted enzymes are not meaningfully characterized in terms of M. tuberculosis. In this way, cutinase, a small lipolytic protein, exists in both bacteria and fungi as well which have a potential catalytic activity. During our search, we have found a few genes of M. tuberculosis demonstrating a same significant lipase action as fungi Fusarium solani cutinase contain. Genome sequencing of M. tuberculosis uncover a lot of proteins, wherein (Rv1758, Rv1984c, Rv2301, Rv3451, Rv3452, Rv3724A, Rv3724B, and Rv3802c) genes have been noted which are exhibiting a cutinase-like activity and closely homologous to that of F. solani cutinase and having the ability to hydrolyze model substrates including p-nitrophenyl butyrate (p-PNB), cutin, triacylglycerols (TAGs), and triolein (TO), yet their biological significance in pathogenesis stays subtle and uncharacterized. In a basic perspective, the measure of cutinase expressed by M. tuberculosis and part of these small lipolytic enzymes in the pathologic discipline require thorough characterization. So, through focusing on cutinase-encoding genes in M. tuberculosis and their active catalytic motif could help to build up a novel therapeutic approach. PMID:26679705

  7. Surface engineered and ligand anchored nanobioconjugate: an effective therapeutic approach for oral insulin delivery in experimental diabetic rats.

    PubMed

    Sharma, Rajeev; Gupta, Umesh; Garg, Neeraj K; Tyagi, Rajeev K; Jain, N K

    2015-03-01

    The present study was designed to enhance intestinal absorption of insulin by nanobioconjugate formulated with PEGylation and Concanavalin A based targeted synergistic approach. The attempts were aimed at maximizing bioavailability and therapeutic efficacy of insulin by incorporating it in Concanavalin A anchored PEGylated nanoconstructs. The Con A anchored PEGylated PLGA diblock copolymer was synthesized by modified surface functionalization method, and was then characterized by FTIR and 1H NMR spectrum analysis. The nanoparticles from synthesized polymers were prepared and characterized for mean size and distribution by laser diffraction spectroscopy. The physicochemically characterized (by SEM and TEM) formulations were evaluated for optimum particle size, polydispersity index, zeta potential and entrapment efficiency 196.3±4.5 nm, 0.15±0.04, -25.6±1.68 and 44.6±3.5% respectively. The insulin encapsulation efficiency and in vitro release were assessed by bicinchoninic protein assay (BCA). The in vitro results corroborated in vivo studies carried out in experimentally created diabetic albino rats. The nano-encapsulated insulin was discovered to meet the requirements by achieving better stability, improved absorption and enhanced oral bioavailability elucidated by in vivo and in vitro bioassays. PMID:25679489

  8. Integrating the molecular and the population approaches to dementia research to help guide the future development of appropriate therapeutics.

    PubMed

    Hunter, Sally; Brayne, Carol

    2014-04-15

    Dementia research over the last 50 years has expanded enormously and has greater international interest now than at any time in history. A variety of scientific approaches have been brought to bear on this complex disorder in which the syndrome of clinical features is its defining importance in societal terms. Little has emerged in terms of tangible benefits for people with dementia to date other than a hugely increased awareness at societal and governmental levels. One of the drivers for the increase in focus has been epidemiological evidence, which has provided background numbers for the justification of resources for dementia research. However it can be argued that this justification did not take into account the true meaning of the population evidence, drawing instead on preconceptions which were, at the time, the widely accepted interpretations of earlier evidence. Current evidence, along with the lack of single therapeutic successes, suggests that a clearer analysis is required which not only examines the value and applicability of existing knowledge, most particularly its generation and generalizability, but also where future investment should go for most likely benefit of populations. This includes a hard look at the pre-occupation of societies with single therapies, their place in the context of prevention more generally, particularly within aging populations, and how evidence is generated on likely impacts and their timeframes. PMID:24389044

  9. Prospective therapeutic agents for obesity: molecular modification approaches of centrally and peripherally acting selective cannabinoid 1 receptor antagonists.

    PubMed

    Sharma, Mayank Kumar; Murumkar, Prashant R; Kanhed, Ashish M; Giridhar, Rajani; Yadav, Mange Ram

    2014-05-22

    Presently, obesity is one of the major health problems in the developed as well as developing countries due to lack of physical work and increasing sedentary life style. Endocannabinoid system (ECS) and especially cannabinoid 1 (CB1) receptor play a key role in energy homeostasis. Food intake and energy storage is enhanced due to the stimulation of ECS hence, inhibition of ECS by blocking CB1 receptors could be a promising approach in the treatment of obesity. Rimonabant, a diaryl pyrazole was the first potent and selective CB1 receptor antagonist that was introduced into the market in 2006 but was withdrawn in 2008 due to its psychiatric side effects. Researchers all over the world are interested to develop peripherally acting potent and selective CB1 receptor antagonists having a better pharmacokinetic profile and therapeutic index. In this development process, pyrazole ring of rimonabant has been replaced by different bioisosteric scaffolds like pyrrole, imidazole, triazole, pyrazoline, pyridine etc. Variations in substituents around the pyrazole ring have also been done. New strategies were also employed for minimizing the psychiatric side effects by making more polar and less lipophilic antagonists/inverse agonists along with neutral antagonists acting peripherally. It has been observed that some of the peripherally acting compounds do not show adverse effects and could be used as potential leads for the further design of selective CB1 receptor antagonists. Chemical modification strategies used for the development of selective CB1 receptor antagonists are discussed here in this review.

  10. Attentional processes and their remediation in children treated for cancer: a literature review and the development of a therapeutic approach.

    PubMed

    Butler, Robert W; Copeland, Donna R

    2002-01-01

    It is now generally accepted that central nervous system treatments for childhood cancer can result in significant cognitive impairment, most commonly in the areas of attention/concentration. We review the literature on attentional and neurocognitive deficits in this population, and also efforts to remediate attentional deficits in other brain injured populations. It was our goal to develop an innovative, psychologically based outpatient rehabilitation program that would improve dysfunctional attentional processes and associated neuropsychological deficits. The characteristics of this program and a pilot study of its effectiveness are described. Participants were 31 off-therapy cancer survivors with documented attention deficits. Twenty-one completed the cognitive remediation program (CRP) and 10 served as comparisons. All participants completed a test of vigilance attention, 2 tests with an attentional component, and an arithmetic academic achievement measure. When the scores of the 2 groups were compared, the CRP group exhibited statistically significant improvement on all attentional measures. In contrast, the comparison group did not manifest any significant changes. Neither group demonstrated statistically significant changes on the arithmetic achievement test. We believe that the CRP has potential for improving attention/concentration, but generalization to academic achievement remains unproven. Phase 3 clinical trials and the documentation of long-term treatment gains are needed. Furthermore, it will be necessary to demonstrate the ecological validity of the CRP. With these caveats, this therapeutic approach may be helpful in other populations of cognitively impaired children and young adults, such as patients who have suffered traumatic brain injury.

  11. Biologics and other novel approaches as new therapeutic options in myasthenia gravis: a view to the future.

    PubMed

    Dalakas, Marinos C

    2012-12-01

    Myasthenia gravis (MG) is caused by complement-fixing antibodies against the acetylcholine receptors (AChR). Regulatory T cells (T(reg) cells), Th17 cells, and recognition of AChR epitopes by CD4(+) T cells are fundamental. Novel biological agents now in the offing, offer the potential for specific treatment options in MG by targeting the following: (1) T cell intracellular signaling pathways, costimulation, and transduction molecules; (2) B cells, against CD20 molecules, or the B cell trophic factors BAFF and APRIL; (3) complement, against C5 that intercepts the formation of MAC; (4) cytokines and cytokine receptors targeting interleukin (IL)-6, IL-17, and the Janus tyrosine kinases (JAK)1 and JAK3; and (5) cellular adhesion and T cell migration molecules. Reengineering of pathogenic antibodies (i.e., molecular decoys) by constructing recombinant antibodies that block the complement binding of the pathogenic AChR antibodies is an additional approach. The promising therapeutic profile of these agents should be weighted against excessive cost and rare complications necessitating the need for controlled trials to secure efficacy and balance benefit against risks. PMID:23252891

  12. Biologics and other novel approaches as new therapeutic options in myasthenia gravis: a view to the future.

    PubMed

    Dalakas, Marinos C

    2012-12-01

    Myasthenia gravis (MG) is caused by complement-fixing antibodies against the acetylcholine receptors (AChR). Regulatory T cells (T(reg) cells), Th17 cells, and recognition of AChR epitopes by CD4(+) T cells are fundamental. Novel biological agents now in the offing, offer the potential for specific treatment options in MG by targeting the following: (1) T cell intracellular signaling pathways, costimulation, and transduction molecules; (2) B cells, against CD20 molecules, or the B cell trophic factors BAFF and APRIL; (3) complement, against C5 that intercepts the formation of MAC; (4) cytokines and cytokine receptors targeting interleukin (IL)-6, IL-17, and the Janus tyrosine kinases (JAK)1 and JAK3; and (5) cellular adhesion and T cell migration molecules. Reengineering of pathogenic antibodies (i.e., molecular decoys) by constructing recombinant antibodies that block the complement binding of the pathogenic AChR antibodies is an additional approach. The promising therapeutic profile of these agents should be weighted against excessive cost and rare complications necessitating the need for controlled trials to secure efficacy and balance benefit against risks.

  13. Insights into the role of components of the tumor microenvironment in oral carcinoma call for new therapeutic approaches

    SciTech Connect

    Salo, Tuula; Vered, Marilena; Bello, Ibrahim O.; Nyberg, Pia; Bitu, Carolina Cavalcante; Zlotogorski Hurvitz, Ayelet; Dayan, Dan

    2014-07-15

    The research on oral cancer has focused mainly on the cancer cells, their genetic changes and consequent phenotypic modifications. However, it is increasingly clear that the tumor microenvironment (TME) has been shown to be in a dynamic state of inter-relations with the cancer cells. The TME contains a variety of components including the non-cancerous cells (i.e., immune cells, resident fibroblasts and angiogenic vascular cells) and the ECM milieu [including fibers (mainly collagen and fibronectin) and soluble factors (i.e., enzymes, growth factors, cytokines and chemokines)]. Thus, it is currently assumed that TME is considered a part of the cancerous tissue and the functionality of its key components constitutes the setting on which the hallmarks of the cancer cells can evolve. Therefore, in terms of controlling a malignancy, one should control the growth, invasion and spread of the cancer cells through modifications in the TME components. This mini review focuses on the TME as a diagnostic approach and reports the recent insights into the role of different TME key components [such as carcinoma-associated fibroblasts (CAFs) and inflammation (CAI) cells, angiogenesis, stromal matrix molecules and proteases] in the molecular biology of oral carcinoma. Furthermore, the impact of TME components on clinical outcomes and the concomitant need for development of new therapeutic approaches will be discussed. - Highlights: • Tumor depth and budding, hypoxia and TME cells associate with worse prognosis. • Pro-tumoral CAFs and CAI cells aid proliferation, invasion and spread hypoxia. • Some ECM-bound factors exert pro-angiogenic or pro-tumor activities. • Tumor spread is greatly dependent on ECM proteolysis, mediated by TME cells. • Direct targeting of TME components for treatment is still experimental.

  14. Substance use, aggression perpetration, and victimization: temporal co-occurrence in college males and females.

    PubMed

    Margolin, Gayla; Ramos, Michelle C; Baucom, Brian R; Bennett, Diana C; Guran, Elyse L

    2013-09-01

    Many studies have documented associations of substance use with aggression perpetration and aggression victimization; however, little is known about the co-occurrence of these problem behaviors within the same day in college students. The present study investigated whether substance use and aggression increase the likelihood of each other and whether attitudes justifying aggression strengthen those associations. College student participants (N = 378, 32% males) self-selected into an online study in which they reported on 2 days of alcohol/drug use and on aggression perpetration and victimization (including physical, psychological and electronic aggression, and sexual coercion) with friends and dating partners. Using regression to test for nonequivalence of predictor and outcome variables, we found bidirectional effects for males only. Males' substance use was associated with an increased likelihood on the same day of aggression perpetration and of aggression victimization; males' aggression perpetration and aggression victimization were associated with an increased likelihood of substance use on the same day. Females did not show significant contingencies between substance use and aggression in either direction. Males' attitudes justifying male-to-female aggression were associated with their aggression perpetration and victimization and their justification of female-to-male aggression strengthened the link between substance use and aggression perpetration. With interpersonal aggression and substance use being significant problems on college campuses, many colleges offer separate preventive intervention programs aimed at these public health challenges; this study suggests possible benefits of an integrated approach that addresses connections between alcohol/drug use and aggression.

  15. Effects of oxytocin on aggressive responding in healthy adult men.

    PubMed

    Alcorn, Joseph L; Green, Charles E; Schmitz, Joy; Lane, Scott D

    2015-12-01

    This study investigated the acute effects of oxytocin (OT) on human aggression using a well-established laboratory measure of state (reactive) aggression to test the hypothesis that OT would decrease the frequency of aggressive responding. In a within-subject design, 17 healthy male volunteers received placebo or 24 IU of intranasal OT. Aggression was measured using the Point Subtraction Aggression Paradigm at 30 min before and 30, 60, and 90 min after dose. Acute OT did not produce a significant main effect on aggressive behavior. OT attenuated the expected rise in diastolic blood pressure from morning to early afternoon observed under placebo, providing a possible indication of biological activity. Examination of individual differences showed that aggressive responding following OT dosing (but not placebo) was positively correlated with psychometric measures of interpersonal manipulation and anger (Pearson's r=0.57), indicating that higher scores on these antisocial personality traits were related to increased aggressive behavior following OT administration. These preliminary results stand in contrast to previous work on the prosocial effects of OT and highlight the need for further understanding of individual differences in aggression following OT administration. Such individual differences may have implications for the therapeutic use of OT in individuals with psychiatric disorders and dysfunctional social behavior. PMID:26241153

  16. Preclinical Development of Novel Rac1-GEF Signaling Inhibitors using a Rational Design Approach in Highly Aggressive Breast Cancer Cell Lines

    PubMed Central

    Cardama, Georgina A; Comin, Maria J; Hornos, Leandro; Gonzalez, Nazareno; Defelipe, Lucas; Turjanski, Adrian G; Alonso, Daniel F; Gomez, Daniel E; Menna, Pablo Lorenzano

    2014-01-01

    Rho GTPases play a key role in the regulation of multiple essential cellular processes, including actin dynamics, gene transcription and cell cycle progression. Aberrant activation of Rac1, a member of Rho family of small GTPases, is associated with tumorigenesis, cancer progression, invasion and metastasis. Particularly, Rac1 is overexpressed and hyperactivated in highly aggressive breast cancer. Thus, Rac1 appears to be a promising and relevant target for the development of novel anticancer drugs. We identified the novel Rac1 inhibitor ZINC69391 through a docking-based virtual library screening targeting Rac1 activation by GEFs. This compound was able to block Rac1 interaction with its GEF Tiam1, prevented EGF-induced Rac1 activation and inhibited cell proliferation, cell migration and cell cycle progression in highly aggressive breast cancer cell lines. Moreover, ZINC69391 showed an in vivo antimetastatic effect in a syngeneic animal model. We further developed the novel analog 1A-116 by rational design and showed to be specific and more potent than the parental compound in vitro and interfered Rac1-P-Rex1 interaction. We also showed an enhanced in vivo potency of 1A-116 analog. These results show that we have developed novel Rac1 inhibitors that may be used as a novel anticancer therapy. PMID:24066799

  17. Overview of Alzheimer's Disease and Some Therapeutic Approaches Targeting Aβ by Using Several Synthetic and Herbal Compounds

    PubMed Central

    Singh, Sandeep Kumar; Srivastav, Saurabh; Yadav, Amarish Kumar; Srikrishna, Saripella; Perry, George

    2016-01-01

    Alzheimer's disease (AD) is a complex age-related neurodegenerative disease. In this review, we carefully detail amyloid-β metabolism and its role in AD. We also consider the various genetic animal models used to evaluate therapeutics. Finally, we consider the role of synthetic and plant-based compounds in therapeutics. PMID:27034741

  18. "Of Mind, Body, and Spirit": Therapeutic Foster Care - An Innovative Approach to Healing from an NTU Perspective.

    ERIC Educational Resources Information Center

    Gregory, Shawan D. P.; Phillips, Frederick B.

    1997-01-01

    Examines Progressive Life Center's (PLC) Therapeutic Foster Care program and its incorporation of NTU psychotherapy into its program model. Describes how PLC strives to improve the delivery of mental health services through culturally competent therapeutic techniques for African Americans, including seriously emotionally disturbed children. (MOK)

  19. Use of haloperidol and risperidone in highly aggressive Swiss Webster mice by applying the model of spontaneous aggression (MSA).

    PubMed

    Fragoso, Viviane Muniz da Silva; Hoppe, Luanda Yanaan; de Araújo-Jorge, Tânia Cremonini; de Azevedo, Marcos José; Campos, Jerônimo Diego de Souza; Cortez, Célia Martins; de Oliveira, Gabriel Melo

    2016-03-15

    Aggression is defined as the act in which an individual intentionally harms or injures another of their own species. Antipsychotics are a form of treatment used in psychiatric routine. They have been used for decades in treatment of patients with aggressive behavior. Haloperidol and risperidone promote the control of psychiatric symptoms, through their respective mechanisms of action. Experimental models are obtained by behavioral, genetic, and pharmacological manipulations, and use a reduced number of animals. In this context, we applied the model of spontaneous aggression (MSA), originating the presence of highly aggressive mice (AgR) when reassembled in adulthood. We administered haloperidol and risperidone in escalating doses, for ten consecutive days. Using positive and negative control groups, we evaluated the effectiveness of these drugs and the reversal of the aggressive behavior, performing the tail suspension test (TST) and open field test (OFT) on 10th day of treatment and 10 days after its discontinuation. The results showed that both antipsychotic drugs were effective in AgR and reversed the aggressive phenotype, reducing the number of attacks by AgR and the extent of lesions in the subordinate mice (AgD) exposed to the pattern of aggressive behavior (PAB) of the aggressors. This conclusion is based on the reduction in the animals' motor and exploratory activity, and on the reversal of patterns of aggressive behavior. The association between the MSA and experiments with other therapeutic protocols and different antipsychotics can be an important methodology in the study of aggressive behavior in psychiatric patients.

  20. The Third International Meeting on Genetic Disorders in the RAS/MAPK Pathway: Toward a Therapeutic Approach

    PubMed Central

    Korf, Bruce; Ahmadian, Reza; Allanson, Judith; Aoki, Yoko; Bakker, Annette; Wright, Emma Burkitt; Denger, Brian; Elgersma, Ype; Gelb, Bruce D.; Gripp, Karen W.; Kerr, Bronwyn; Kontaridis, Maria; Lazaro, Conxi; Linardic, Corinne; Lozano, Reymundo; MacRae, Calum A.; Messiaen, Ludwine; Mulero-Navarro, Sonia; Neel, Benjamin; Plotkin, Scott; Rauen, Katherine A.; Roberts, Amy; Silva, Alcino J.; Sittampalam, Sitta G.; Zhang, Chao; Schoyer, Lisa

    2015-01-01

    “The Third International Meeting on Genetic Disorders in the RAS/MAPK Pathway: Towards a Therapeutic Approach” was held at the Renaissance Orlando at SeaWorld Hotel (August 2–4, 2013). Seventy-one physicians and scientists attended the meeting, and parallel meetings were held by patient advocacy groups (CFC International, Costello Syndrome Family Network, NF Network and Noonan Syndrome Foundation). Parent and patient advocates opened the meeting with a panel discussion to set the stage regarding their hopes and expectations for therapeutic advances. In keeping with the theme on therapeutic development, the sessions followed a progression from description of the phenotype and definition of therapeutic endpoints, to definition of genomic changes, to identification of therapeutic targets in the RAS/MAPK pathway, to preclinical drug development and testing, to clinical trials. These proceedings will review the major points of discussion. PMID:25900621

  1. Aggression in Drosophila.

    PubMed

    Kravitz, Edward A; Fernandez, Maria de la Paz

    2015-10-01

    Aggression is used by essentially all species of animals to gain access to desired resources, including territory, food, and potential mates: Fruit flies are no exception. In Drosophila, both males and females compete in same sex fights for resources, but only males establish hierarchical relationships. Many investigators now study aggression using the fruit fly model, mainly because (a) aggression in fruit flies is a quantifiable well-defined and easily evoked behavior; (b) powerful genetic methods allow investigators to manipulate genes of interest at any place or time during embryonic, larval, pupal or adult life, and while flies are behaving; (c) the growth of the relatively new field of optogenetics makes physiological studies possible at single neuron levels despite the small sizes of neurons and other types of cells in fly brains; and (d) the rearing of fly stocks with their short generation times and limited growth space requirements can easily be performed at relatively low cost in most laboratories. This review begins with an examination of the behavior, both from a historical perspective and then from the birth of the "modern" era of studies of aggression in fruit flies including its quantitative analysis. The review continues with examinations of the roles of genes, neurotransmitters and neurohormones, peptides, nutritional and metabolic status, and surface cuticular hydrocarbons in the initiation and maintenance of aggression. It concludes with suggestions for future studies with this important model system.

  2. 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

  3. Lessons from the Past: Opportunities to Improve Childhood Cancer Survivor Care through Outcomes Investigations of Historical Therapeutic Approaches for Pediatric Hematological Malignancies

    PubMed Central

    Hudson, Melissa M.; Neglia, Joseph P.; Woods, William G.; Sandlund, John T.; Ching-Hon, Pui; Kun, Larry E.; Robison, Leslie L.; Green, Daniel M.

    2011-01-01

    Investigations of long-term outcomes have been instrumental in designing safer and more effective contemporary therapies for pediatric hematological malignancies. Despite the significant therapeutic changes that have occurred over the last five decades, therapy modifications largely represent refinements of treatment protocols using agents and modalities that have been available for more than 30 years. This review summarizes major trends in the evolution of treatment of pediatric hematological malignancies since 1960 to support the relevance of the study of late effects of historical therapeutic approaches to the design and evaluation of contemporary treatment protocols and the follow-up of present-day survivors. PMID:22038641

  4. Management Strategies for Aggressive Cushing's Syndrome: From Macroadenomas to Ectopics

    PubMed Central

    Pozza, Carlotta; Graziadio, Chiara; Giannetta, Elisa; Lenzi, Andrea; Isidori, Andrea M.

    2012-01-01

    Cushing's syndrome (CS) is a rare but severe clinical condition represented by an excessive endogenous cortisol secretion and hence excess circulating free cortisol, characterized by loss of the normal feedback regulation and circadian rhythm of the hypothalamic-pituitary axis due to inappropriate secretion of ACTH from a pituitary tumor (Cushing's disease, CD) or an ectopic source (ectopic ACTH secretion, EAS). The remaining causes (20%) are ACTH independent. As soon as the diagnosis is established, the therapeutic goal is the removal of the tumor. Whenever surgery is not curative, management of patients with CS requires a major effort to control hypercortisolemia and associated symptoms. A multidisciplinary approach that includes endocrinologists, neurosurgeons, oncologists, and radiotherapists should be adopted. This paper will focus on traditional and novel medical therapy for aggressive ACTH-dependent CS. Several drugs are able to reduce cortisol levels. Their mechanism of action involves blocking adrenal steroidogenesis (ketoconazole, metyrapone, aminoglutethimide, mitotane, etomidate) or inhibiting the peripheral action of cortisol through blocking its receptors (mifepristone “RU-486”). Other drugs include centrally acting agents (dopamine agonists, somatostatin receptor agonists, retinoic acid, peroxisome proliferator-activated receptor γ “PPAR-γ” ligands) and novel chemotherapeutic agents (temozolomide and tyrosine kinase inhibitors) which have a significant activity against aggressive pituitary or ectopic tumors. PMID:22934113

  5. Anti-inflammatory/antioxidant use in long-term maintenance cancer therapy: a new therapeutic approach to disease progression and recurrence

    PubMed Central

    2014-01-01

    The chronic, progressive clinical characteristics of many adult solid tumor malignancies suggest that a more effective therapeutic approach to cancer management may require long-term intervention using nontoxic systemic agents that block critical components of abnormal tumor physiology. Two highly promising systemic targets common to the development, progression and recurrence of many common cancers are dysregulated inflammatory and oxidation/reduction (redox) pathways. Compelling clinical data support the use of anti-inflammatory and antioxidant agents as a therapeutic modality for long-term use in patients diagnosed with several common cancers, including colon cancer and breast cancer. The therapeutic paradigm presented in this paper is the product of a synthesis of what is currently understood about the biological effects of inflammation and oxidative stress that contribute to tumorigenesis, disease progression and recurrence as well as results obtained from research on the use of prophylactics with anti-inflammatory or antioxidant properties in cancer prevention and treatment. PMID:24587831

  6. The influence of dysfunctional impulsivity and alexithymia on aggressive behavior of psychiatric patients.

    PubMed

    de Schutter, Marja A M; Kramer, Hein J M Th; Franken, Ernest J F; Lodewijkx, Hein F M; Kleinepier, Tom

    2016-09-30

    Current approaches in Dutch mental health care institutions towards inpatients' aggression have focused predominantly on environmental factors, such as training the staff in aggression management. However, personality traits might be an important factor in patients' aggression - as shown by incidents in the wards. This study explores the influence of dysfunctional impulsivity and alexithymia on psychiatric patients' aggressive behavior, through self-reports and through involvement in aggressive incidents. Personality traits influencing patients' aggression emphasize the importance of a more direct approach to their aggression. Clinical patients at Dutch mental health care institution Emergis (n=84) filled out questionnaires about their aggressiveness (using Buss and Perry's Aggression Questionnaire Short Form), dysfunctional impulsivity and alexithymia. Multiple regression analyses indicated that dysfunctional impulsivity positively related to self-reported aggressive behavior. The relationship, however, could not be confirmed for inpatients' aggression as reported by the staff on the wards. Unexpectedly affective alexithymia negatively related to hostility. Gender differences in self-reported aggression were found. Female patients showed higher levels of hostility. Regression analyses indicated that the male gender positively related to physical aggression. Findings emphasize the importance of a new approach in Dutch mental health care, in which patients may engage in aggression-regulation training programs. PMID:27387554

  7. The influence of dysfunctional impulsivity and alexithymia on aggressive behavior of psychiatric patients.

    PubMed

    de Schutter, Marja A M; Kramer, Hein J M Th; Franken, Ernest J F; Lodewijkx, Hein F M; Kleinepier, Tom

    2016-09-30

    Current approaches in Dutch mental health care institutions towards inpatients' aggression have focused predominantly on environmental factors, such as training the staff in aggression management. However, personality traits might be an important factor in patients' aggression - as shown by incidents in the wards. This study explores the influence of dysfunctional impulsivity and alexithymia on psychiatric patients' aggressive behavior, through self-reports and through involvement in aggressive incidents. Personality traits influencing patients' aggression emphasize the importance of a more direct approach to their aggression. Clinical patients at Dutch mental health care institution Emergis (n=84) filled out questionnaires about their aggressiveness (using Buss and Perry's Aggression Questionnaire Short Form), dysfunctional impulsivity and alexithymia. Multiple regression analyses indicated that dysfunctional impulsivity positively related to self-reported aggressive behavior. The relationship, however, could not be confirmed for inpatients' aggression as reported by the staff on the wards. Unexpectedly affective alexithymia negatively related to hostility. Gender differences in self-reported aggression were found. Female patients showed higher levels of hostility. Regression analyses indicated that the male gender positively related to physical aggression. Findings emphasize the importance of a new approach in Dutch mental health care, in which patients may engage in aggression-regulation training programs.

  8. [Molecular psychogenetics of deviant aggressive behavior in humans].

    PubMed

    Vasil'ev, V A

    2011-09-01

    The review considers the known candidate gene loci that are involved in the dopamine, serotonin, and androgen systems and are associated with human deviant aggressive behavior. Both positive and negative correlations with deviant aggressive behavior have been observed for almost all of the candidate gene loci. Many genes of the neurotransmitter and androgen system and intricate interactions among them may influence the propensity to aggression. Further studies should focus not only on individual gene polymorphisms, but also on complex interactions among the alleles of all candidate genes that have functionally important polymorphisms affecting their expression and function. A complex analysis should be performed to study the association of the homozygous genotypes at all candidate gene markers with various forms of human deviant aggressive behavior. The approach will make it possible to assess the individual reactivity to various environmental stimuli that provoke aggression and to develop a means of predicting and preventing deviant aggressive behavior in humans.

  9. Controlling Aggressive Students. Fastback Series, No. 387.

    ERIC Educational Resources Information Center

    Blendinger, Jack; And Others

    Coping with aggressive student behavior is crucial to providing a safe and orderly classroom and school environment. Approaches for improving student behavior, ranging from enhancing a student's interpersonal skills to restraint techniques (such as the prudent use of physical force) are covered in this booklet. The material blends information in…

  10. Aggressiveness and Disobedience

    ERIC Educational Resources Information Center

    Vaaland, Grete Sorensen; Idsoe, Thormod; Roland, Erling

    2011-01-01

    This study aims to conceptualize disobedient pupil behavior within the more general framework of antisocial behavior and to reveal how two forms of aggressiveness are related to disobedience. Disobedience, in the context of this article, covers disruptive pupil behavior or discipline problems when the pupil is aware of breaking a standard set by…

  11. Neuroimaging and Aggression.

    ERIC Educational Resources Information Center

    Mills, Shari; Raine, Adrian

    1994-01-01

    Brain imaging research allows direct assessment of structural and functional brain abnormalities, and thereby provides an improved methodology for studying neurobiological factors predisposing to violent and aggressive behavior. This paper reviews 20 brain imaging studies using four different types of neuroimaging techniques that were conducted in…

  12. Intellectual Competence and Aggression.

    ERIC Educational Resources Information Center

    Huesmann, L. Rowell; Yarmel, Patty Warnick

    Using data from a broader longitudinal study, this investigation explores within-subject and cross-generational stability of intellectual competence and the relationship of such stability to aggressive behavior. Data were gathered three times (when subjects' modal age was 8, 19, and 30 years). Initially, subjects included the entire population…

  13. Stability of Aggressive Behavior.

    ERIC Educational Resources Information Center

    Eron, Leonard D.; Huesmann, L. Rowell

    As indicated by multiple measures (including overt criminal behavior), stability of aggressive behavior was investigated across 22 years for males and females in a variety of situations. Originally, subjects included the entire population enrolled in the third grade in a semi-rural county in New York State. The sample included approximately 870…

  14. Relational Aggression among Students

    ERIC Educational Resources Information Center

    Young, Ellie L.; Nelson, David A.; Hottle, America B.; Warburton, Brittney; Young, Bryan K.

    2011-01-01

    "Relational aggression" refers to harm within relationships caused by covert bullying or manipulative behavior. Examples include isolating a youth from his or her group of friends (social exclusion), threatening to stop talking to a friend (the silent treatment), or spreading gossip and rumors by email. This type of bullying tends to be…

  15. Human Aggression and Suicide

    ERIC Educational Resources Information Center

    Brown, Gerald L.; Goodwin, Frederick K

    1986-01-01

    The central nervous system transmitter serontonin may be altered in aggressive/impulsive and suicidal behaviors in humans. These reports are largely consistent with animal data, and constitute one of the most highly replicated set of findings in biological psychiatry. Suggests that some suicidal behavior may be a special kind of aggressive…

  16. Aggressive and acute periodontal diseases.

    PubMed

    Albandar, Jasim M

    2014-06-01

    genetic profile, currently do not exist. Genetic markers have the potential to be implemented as screening tools to identify subjects at risk. This approach may significantly enhance treatment outcome through the early detection and treatment of affected subjects, as well as using future approaches based on gene therapy. At present, the treatment of this disease is directed toward elimination of the subgingival bacterial load and other local risk factors. Adjunctive use of appropriate systemic antibiotics is recommended and may contribute to a longer suppression of the microbial infection. Other aggressive forms of periodontal diseases occur in patients who are affected with certain systemic diseases, including the leukocyte adhesion deficiency syndrome, Papillon-Lefèvre syndrome, Chediak-Higashi syndrome and Down syndrome. Management of the periodontal component of these diseases is very challenging. Acute gingival and periodontal lesions include a group of disorders that range from nondestructive to destructive forms, and these lesions are usually associated with pain and are a common reason for emergency dental consultations. Some of these lesions may cause a rapid and severe destruction of the periodontal tissues and loss of teeth. Oral infections, particularly acute infections, can spread to extra-oral sites and cause serious medical complications, and even death. Hence, prompt diagnosis and treatment are paramount.

  17. [The role of biological sciences in understanding the genesis and a new therapeutic approach to Alzheimer's disease].

    PubMed

    Tęgowska, Eugenia; Wosińska, Adrianna

    2011-01-01

    The paper contrasts the historical view on causal factors in Alzheimer's disease (AD) with the modern concept of the symptoms' origin. Biological sciences dealing with cell structure and physiology enabled comprehension of the role of mitochondrial defects in the processes of formation of neurofibrillary tangles and β-amyloid, which in turn gives hope for developing a new, more effective therapeutic strategy for AD. It has been established that although mitochondria constantly generate free radicals, from which they are protected by their own defensive systems, in some situations these systems become deregulated, which leads to free radical-based mitochondrial defects. This causes an energetic deficit in neurons and a further increase in the free radical pool. As a result, due to compensation processes, formation of tangles and/or acceleration of β-amyloid production takes place. The nature of these processes is initially a protective one, due to their anti-oxidative action, but as the amount of the formations increases, their beneficial effect wanes. They become a storage place for substances enhancing free radical processes, which makes them toxic themselves. It is such an approach to the primary causal factor for AD which lies at the roots of the new view on AD therapy, suggesting the use of methylene blue-based drugs, laser or intranasally applied insulin. A necessary condition, however, for these methods' effectiveness is definitely an earlier diagnosis of the disease. Although there are numerous diagnostic methods for AD, their low specificity and high price, often accompanied by a considerable level of patient discomfort, make them unsuitable for early, prodromal screening. In this matter a promising method may be provided using an olfactory test, which is an inexpensive and non-invasive method and thus suitable for screening, although as a test of low specificity, it should be combined with other methods. Introducing new methods of AD treatment does not

  18. Parents' Aggressive Influences and Children's Aggressive Problem Solutions with Peers

    ERIC Educational Resources Information Center

    Duman, Sarah; Margolin, Gayla

    2007-01-01

    This study examined children's aggressive and assertive solutions to hypothetical peer scenarios in relation to parents' responses to similar hypothetical social scenarios and parents' actual marital aggression. The study included 118 children ages 9 to 10 years old and their mothers and fathers. Children's aggressive solutions correlated with…

  19. Relational Aggression and Physical Aggression among Adolescent Cook Islands Students

    ERIC Educational Resources Information Center

    Page, Angela; Smith, Lisa F.

    2016-01-01

    Both physical and relational aggression are characterised by the intent to harm another. Physical aggression includes direct behaviours such as hitting or kicking; relational aggression involves behaviours designed to damage relationships, such as excluding others, spreading rumours, and delivering threats and verbal abuse. This study extended…

  20. A first approach for the production of human adipose tissue-derived stromal cells for therapeutic use.

    PubMed

    Bourin, Philippe; Peyrafitte, Julie-Anne; Fleury-Cappellesso, Sandrine

    2011-01-01

    Adipose tissue-derived stromal cells (ASCs) are promising tools for the new therapeutic field of regenerative medicine. Many research teams are intent on producing these cells for therapeutic purposes. The cell production must follow strict rules for safety and for constant quality of the cell product to ensure a reliable effect in patients. These rules are grouped under the generic term Good Manufacturing Practices. In this chapter, we describe the general concepts of ASC production for therapeutic use, explaining new terms such as traceability and qualification. We also introduce general requirements for the installation, equipment, material, and staff for the cell production. Then, we outline a general strategy for building a cell culture process. Finally, as an example, we describe the use of CellStack™ chambers and specific tube sets that allow for producing cells beginning with the stromal vascular fraction under near-closed conditions.

  1. Reverse Discrimination and Aggressive Behavior.

    ERIC Educational Resources Information Center

    Johnson, Stephen D.

    1980-01-01

    White subjects were aggressive toward Black opponents when contest results appeared to reflect elements of reverse discrimination; but they showed less aggressive behavior toward Black opponents when they thought their loss was due to their opponents' superior ability. (RL)

  2. Autologous hematopoietic stem cell transplantation (AHSCT) for aggressive multiple sclerosis - whom, when and how.

    PubMed

    Szczechowski, Lech; Śmiłowski, Marek; Helbig, Grzegorz; Krawczyk-Kuliś, Małgorzata; Kyrcz-Krzemień, Sławomira

    2016-10-01

    Multiple sclerosis (MS) is an autoimmune disease of the central nervous system that leads to an inflammatory process resulting in demyelination and axonal degeneration. The most common form of MS is the relapsing-remitting MS (RRMS) characterized by the presence of numerous relapses. After few years of disease course, 90% of those patients eventually develop a secondary progressive form. About 10% of patients may suffer from a slowly progressive MS form - the primary progressive. The current treatment of RRMS includes immunomodulatory and immunosuppressive agents, which are effective, but usually in earlier and more benign forms. The immunomodulatory treatment has limited efficacy in aggressive forms of RRMS, and relapses occur despite treatment continuation. AHSCT should be considered as a therapeutic approach for patients with aggressive relapsing-remitting and aggressive progressive MS who failed conventional therapy. The mechanism of action of AHSCT for MS results from resetting the aberrant patient's immune system and eliminating the autoreactive T-lymphocytes. AHSCT can serve as an effective and safe procedure only when strict neurological eligibility criteria are adhered. The procedure should be performed in highly specialized hematological centers. The aim of our paper is to summarize the current eligibility criteria for AHSCT in MS patients as well as to present data on efficacy and safety of this approach.

  3. Effects of aggressive approach to the multiple risk factors for diabetic nephro-pathy on proteinuria reduction in diabetes type 2 patients.

    PubMed

    Ascić-Buturović, Belma; Kacila, Mirsad; Kulić, Mehmed

    2009-02-01

    Dietary interventions with protein and salt restriction, good glucose control, smoking cessation, aggressive blood pressure control, good control of cholesterol and triglycerides, use of ACE inhibitors and ARBs can delay the progression of diabetic nephropathy. The aim of this study was to present the effects of aggressive treatment of the multiple risk factors for diabetic nephropathy on proteinuria in patients with type 2 diabetes. In this study we included 15 patients with diabetes type 2 and insufficient regulation of glycaemia. The patients were followed for three months period. Glycated haemoglobin (HbA1c), fasting plasma glucose (FPG), postprandial plasma glucose (PPG), blood pressure, cholesterol and triglycerides and proteinuria were followed prior and after the study. Prior the study patients were treated with premix insulin divided in two daily doses + metformin after the lunch and they had insufficient regulation of glycaemia. During the study patients were treated with one daily dose of basal insulin, three doses of metformin (2550 mg), one daily dose of atorvastatin (20 mg) and one daily dose of ramipril (5 to 10 mg). Doses of insulin were titrated separately for each patients (0,7-1,0 IU/kg). Patients were advised to start with lifestyle modification, increased physical activity and dietary interventions with protein and salt restriction, energy restricted diet and smoking cessation. A total of 20 patients (male 12 and female 8) with diabetes type 2 were studied. The mean age of the subjects was 53+/-5,25 years. The mean diabetes duration was 4,05+/-1,96 years. The mean body mass index decreased from 28,1+/-1,67 kg/m2 to 25,9 +/-1,22 kg/m2 after the study. Mean HbA1c decreased from 8,82 +/- 0,53 % to 7,15 +/- 0,23 % (p<0,05). Mean fasting glycemia decreased from 8,79+/-0,58 mmol/dm3 to 7,03+/-0,18 mmol/dm3 (p < 0,05). Mean postmeal glycemia decreased from 9,93 +/- 0,77 mmol/dm3 to 7,62 +/- 0,42 mmol/dm3 (p<0,05). The mean cholesterol level decreased

  4. Predicting hospital aggression in secure psychiatric care

    PubMed Central

    Priday, Lee J.; Ireland, Carol A.; Chu, Simon; Kilcoyne, Jennifer; Mulligan, Caroline

    2016-01-01

    Background Risk assessment instruments have become a preferred means for predicting future aggression, claiming to predict long-term aggression risk. Aims To investigate the predictive value over 12 months and 4 years of two commonly applied instruments (Historical, Clinical and Risk Management - 20 (HCR-20) and Violence Risk Appraisal Guide (VRAG)). Method Participants were adult male psychiatric patients detained in a high secure hospital. All had a diagnosis of personality disorder. The focus was on aggression in hospital. Results The actuarial risk assessment (VRAG) was generally performing better than the structured risk assessment (HCR-20), although neither approach performed particularly well overall. Any value in their predictive potential appeared focused on the longer time period under study (4 years) and was specific to certain types of aggression. Conclusions The value of these instruments for assessing aggression in hospital among patients with personality disorder in a high secure psychiatric setting is considered. Declaration of interest J.L.I., C.A.M. and J.K. are employed by the trust where the data were collected. Copyright and usage © The Royal College of Psychiatrists 2016. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) licence. PMID:27703760

  5. "Ladettes," Social Representations, and Aggression.

    ERIC Educational Resources Information Center

    Muncer, Steven; Campbell, Anne; Jervis, Victoria; Lewis, Rachel

    2001-01-01

    Examined the relationship among "laddishness" (traditionally working-class, youthful, male social behavior by young women), social representations, and self-reported aggression among English college students. Measures of aggression correlated with holding more instrumental representations of aggression. Females indicated no relationship between…

  6. Children's normative beliefs about aggression and aggressive behavior.

    PubMed

    Huesmann, L R; Guerra, N G

    1997-02-01

    Normative beliefs have been defined as self-regulating beliefs about the appropriateness of social behaviors. In 2 studies the authors revised their scale for assessing normative beliefs about aggression, found that it is reliable and valid for use with elementary school children, and investigated the longitudinal relation between normative beliefs about aggression and aggressive behavior in a large sample of elementary school children living in poor urban neighborhoods. Using data obtained in 2 waves of observations 1 year apart, the authors found that children tended to approve more of aggression as they grew older and that this increase appeared to be correlated with increases in aggressive behavior. More important, although individual differences in aggressive behavior predicted subsequent differences in normative beliefs in younger children, individual differences in aggressive behavior were predicted by preceding differences in normative beliefs in older children. PMID:9107008

  7. Single serotonergic neurons that modulate aggression in Drosophila.

    PubMed

    Alekseyenko, Olga V; Chan, Yick-Bun; Fernandez, Maria de la Paz; Bülow, Torsten; Pankratz, Michael J; Kravitz, Edward A

    2014-11-17

    Monoamine serotonin (5HT) has been linked to aggression for many years across species. However, elaboration of the neurochemical pathways that govern aggression has proven difficult because monoaminergic neurons also regulate other behaviors. There are approximately 100 serotonergic neurons in the Drosophila nervous system, and they influence sleep, circadian rhythms, memory, and courtship. In the Drosophila model of aggression, the acute shut down of the entire serotonergic system yields flies that fight less, whereas induced activation of 5HT neurons promotes aggression. Using intersectional genetics, we restricted the population of 5HT neurons that can be reproducibly manipulated to identify those that modulate aggression. Although similar approaches were used recently to find aggression-modulating dopaminergic and Fru(M)-positive peptidergic neurons, the downstream anatomical targets of the neurons that make up aggression-controlling circuits remain poorly understood. Here, we identified a symmetrical pair of serotonergic PLP neurons that are necessary for the proper escalation of aggression. Silencing these neurons reduced aggression in male flies, and activating them increased aggression in male flies. GFP reconstitution across synaptic partners (GRASP) analyses suggest that 5HT-PLP neurons form contacts with 5HT1A receptor-expressing neurons in two distinct anatomical regions of the brain. Activation of these 5HT1A receptor-expressing neurons, in turn, caused reductions in aggression. Our studies, therefore, suggest that aggression may be held in check, at least in part, by inhibitory input from 5HT1A receptor-bearing neurons, which can be released by activation of the 5HT-PLP neurons.

  8. Aggressive drowsy cache cells

    NASA Astrophysics Data System (ADS)

    Shawkey, H. A.; El-Dib, D. A.; Abid, Z.

    2010-01-01

    An aggressive drowsy cache block management, where the cache block is forced into drowsy mode all the time except during write and read operations, is proposed. The word line (WL) is used to enable the normal supply voltage (V DD_high) to the cache line only when it is accessed for read or write whereas the drowsy supply voltage (V DD_low) is enabled to the cache cell otherwise. The proposed block management neither needs extra cycles nor extra control signals to wake the drowsy cache cell, thereby reducing the performance penalty associated with traditional drowsy caches. In fact, the proposed aggressive drowsy mode can reduce the total power consumption of the traditional drowsy mode by 13% or even more, depending on the cache access rate, access frequency and the CMOS technology used.

  9. Unravelling the neurophysiological basis of aggression in a fish model

    PubMed Central

    2010-01-01

    Background Aggression is a near-universal behaviour with substantial influence on and implications for human and animal social systems. The neurophysiological basis of aggression is, however, poorly understood in all species and approaches adopted to study this complex behaviour have often been oversimplified. We applied targeted expression profiling on 40 genes, spanning eight neurological pathways and in four distinct regions of the brain, in combination with behavioural observations and pharmacological manipulations, to screen for regulatory pathways of aggression in the zebrafish (Danio rerio), an animal model in which social rank and aggressiveness tightly correlate. Results Substantial differences occurred in gene expression profiles between dominant and subordinate males associated with phenotypic differences in aggressiveness and, for the chosen gene set, they occurred mainly in the hypothalamus and telencephalon. The patterns of differentially-expressed genes implied multifactorial control of aggression in zebrafish, including the hypothalamo-neurohypophysial-system, serotonin, somatostatin, dopamine, hypothalamo-pituitary-interrenal, hypothalamo-pituitary-gonadal and histamine pathways, and the latter is a novel finding outside mammals. Pharmacological manipulations of various nodes within the hypothalamo-neurohypophysial-system and serotonin pathways supported their functional involvement. We also observed differences in expression profiles in the brains of dominant versus subordinate females that suggested sex-conserved control of aggression. For example, in the HNS pathway, the gene encoding arginine vasotocin (AVT), previously believed specific to male behaviours, was amongst those genes most associated with aggression, and AVT inhibited dominant female aggression, as in males. However, sex-specific differences in the expression profiles also occurred, including differences in aggression-associated tryptophan hydroxylases and estrogen receptors

  10. Effect of prepubertal versus postpubertal castration on sexual and aggressive behavior in male horses.

    PubMed

    Line, S W; Hart, B L; Sanders, L

    1985-02-01

    Males horses castrated prepubertally occasionally display stallion-like sexual and aggressive behavior as adults. A retrospective survey of 140 horse owners was undertaken to compare the effectiveness of prepubertal versus postpubertal castration on objectionable sexual and aggressive behavior. Of 94 geldings that had been castrated prepubertally (before 2 years of age), 20% to 30% displayed stallion-like sexual behavior and aggression toward horses, and 5% were aggressive toward people in a stallion-like manner. This occurrence of problem behavior was not significantly different from the occurrence of these behavioral patterns in 46 geldings that had been castrated as stallions (over 3 years of age). When castration was examined as a therapeutic measure to eliminate sexual and aggressive behavior in stallions in which the behavior had become objectionable, it was found that the operation was effective on sexual behavior and aggression toward people in 60% to 70% of horses and on aggression toward horses in 40% of horses. PMID:4038698

  11. Capoeira as a Clinical Intervention: Addressing Adolescent Aggression with Brazilian Martial Arts

    ERIC Educational Resources Information Center

    Burt, Isaac; Butler, S. Kent

    2011-01-01

    Aggression in adolescents is harmful and emotionally devastating to youth and surrounding communities. This article integrates martial arts and therapeutic principles into a culturally sensitive model that cultivates change in the aggressive behaviors of disenfranchised adolescents. The art form of Capoeira is proposed for promoting positive…

  12. Tryptophan via serotonin/kynurenine pathways abnormalities in a large cohort of aggressive inmates: markers for aggression.

    PubMed

    Comai, Stefano; Bertazzo, Antonella; Vachon, Jeanne; Daigle, Marc; Toupin, Jean; Côté, Gilles; Turecki, Gustavo; Gobbi, Gabriella

    2016-10-01

    Aggressive behavior is one of the most challenging symptoms in psychiatry, and biological markers for aggression lack of large sample validations. Serotonin (5-HT) and other neuroactive compounds deriving from Tryptophan (Trp), including kynurenine (Kyn), have not yet been investigated in large cohorts of aggressive individuals to validate their potential as biomarkers of aggression. In 361 male inmates we measured serum levels of Trp, 5-hydroxytryptophan, 5-HT, Kyn, the ratios 5-HT/Trp∗1000 and Kyn/Trp∗1000, and performed Structured Clinical Interview for DSM-IV Axis-I and -II Disorders (SCID-I and -II), global assessment of functioning (GAF), and scales for aggressive behavior, impulsivity, adult attention-deficit/hyperactivity disorder (ADHD), and intelligent quotient (IQ). Aggressive compared to non-aggressive inmates exhibited lower Trp and Kyn serum levels but higher levels of 5-HT and 5-HT/Trp∗1000, higher levels of impulsivity and ADHD indices, lower IQ and GAF, higher prevalence of mood disorders, drug abuse/dependence, and borderline, conduct and antisocial behaviors. Interestingly, Kyn/Trp∗1000 was positively correlated to the number of severe aggressive acts (r=0.593, P<0.001). After adjusting for confounding factors, logistic regression analysis indicated that 5-HT/Trp∗1000, antisocial behavior, and GAF were predictors of aggressive behavior. The model combining these three predictors had an area under the ROC curve of 0.851 (95% CI 0.806-0.895). This study indicates that while circulating Trp is reduced in aggressive individuals, the combination of biological (5-HT/Trp ratio) and psychopathological (antisocial behavior and GAF) markers discriminates between aggressive and non-aggressive behavior suggesting the potential of a multi-marker approach in psychiatry given the heterogenic nature of mental diseases.

  13. Alzheimer's disease: An overview of amyloid beta dependent pathogenesis and its therapeutic implications along with in silico approaches emphasizing the role of natural products.

    PubMed

    Awasthi, Manika; Singh, Swati; Pandey, Veda P; Dwivedi, Upendra N

    2016-02-15

    Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder characterized by amyloid beta (Aβ) deposition in brain with subsequent formation of neuritic plaques leading to dementia. A number of therapeutic strategies targeted against Aβ depositions have been rigorously explored which provided successful results corresponding to the existing symptomatic treatments. However, at the same time, several failures corresponding to the disease altering therapies and drugs have also been observed due to potential drawbacks in understanding of the pathogenesis of the disease, development of drug candidates and subsequent designing of clinical trials. Preclinical research, along with experimental and clinical studies, is continuously providing novel information which may reveal multi-target directed ligands and combination therapies for targeting Aβ. Thus, in view of the estimated increase in the number of AD patients globally, the present review attempts to summarize the available evidence dealing with various therapeutic approaches targeting Aβ, focusing specifically on pharmaceutical compounds under various stages of clinical trials. Furthermore, in view of a number of computational advances having significant impact in the field of computer aided drug design, we have also presented results of analysis of natural compounds as potential therapeutic molecules in preventing Aβ plaque formation using in silico approaches.

  14. Alzheimer's disease: An overview of amyloid beta dependent pathogenesis and its therapeutic implications along with in silico approaches emphasizing the role of natural products.

    PubMed

    Awasthi, Manika; Singh, Swati; Pandey, Veda P; Dwivedi, Upendra N

    2016-02-15

    Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder characterized by amyloid beta (Aβ) deposition in brain with subsequent formation of neuritic plaques leading to dementia. A number of therapeutic strategies targeted against Aβ depositions have been rigorously explored which provided successful results corresponding to the existing symptomatic treatments. However, at the same time, several failures corresponding to the disease altering therapies and drugs have also been observed due to potential drawbacks in understanding of the pathogenesis of the disease, development of drug candidates and subsequent designing of clinical trials. Preclinical research, along with experimental and clinical studies, is continuously providing novel information which may reveal multi-target directed ligands and combination therapies for targeting Aβ. Thus, in view of the estimated increase in the number of AD patients globally, the present review attempts to summarize the available evidence dealing with various therapeutic approaches targeting Aβ, focusing specifically on pharmaceutical compounds under various stages of clinical trials. Furthermore, in view of a number of computational advances having significant impact in the field of computer aided drug design, we have also presented results of analysis of natural compounds as potential therapeutic molecules in preventing Aβ plaque formation using in silico approaches. PMID:26810552

  15. Herbal therapeutics that block the oncogenic kinase PAK1: a practical approach towards PAK1-dependent diseases and longevity.

    PubMed

    Maruta, Hiroshi

    2014-05-01

    Over 35 years research on PAKs, RAC/CDC42(p21)-activated kinases, comes of age, and in particular PAK1 has been well known to be responsible for a variety of diseases such as cancer (mainly solid tumors), Alzheimer's disease, acquired immune deficiency syndrome and other viral/bacterial infections, inflammatory diseases (asthma and arthritis), diabetes (type 2), neurofibromatosis, tuberous sclerosis, epilepsy, depression, schizophrenia, learning disability, autism, etc. Although several distinct synthetic PAK1-blockers have been recently developed, no FDA-approved PAK1 blockers are available on the market as yet. Thus, patients suffering from these PAK1-dependent diseases have to rely on solely a variety of herbal therapeutics such as propolis and curcumin that block PAK1 without affecting normal cell growth. Furthermore, several recent studies revealed that some of these herbal therapeutics significantly extend the lifespan of nematodes (C. elegans) and fruit flies (Drosophila), and PAK1-deficient worm lives longer than the wild type. Here, I outline mainly pathological phenotypes of hyper-activated PAK1 and a list of herbal therapeutics that block PAK1, but cause no side (harmful) effect on healthy people or animals.

  16. Herbal therapeutics that block the oncogenic kinase PAK1: a practical approach towards PAK1-dependent diseases and longevity.

    PubMed

    Maruta, Hiroshi

    2014-05-01

    Over 35 years research on PAKs, RAC/CDC42(p21)-activated kinases, comes of age, and in particular PAK1 has been well known to be responsible for a variety of diseases such as cancer (mainly solid tumors), Alzheimer's disease, acquired immune deficiency syndrome and other viral/bacterial infections, inflammatory diseases (asthma and arthritis), diabetes (type 2), neurofibromatosis, tuberous sclerosis, epilepsy, depression, schizophrenia, learning disability, autism, etc. Although several distinct synthetic PAK1-blockers have been recently developed, no FDA-approved PAK1 blockers are available on the market as yet. Thus, patients suffering from these PAK1-dependent diseases have to rely on solely a variety of herbal therapeutics such as propolis and curcumin that block PAK1 without affecting normal cell growth. Furthermore, several recent studies revealed that some of these herbal therapeutics significantly extend the lifespan of nematodes (C. elegans) and fruit flies (Drosophila), and PAK1-deficient worm lives longer than the wild type. Here, I outline mainly pathological phenotypes of hyper-activated PAK1 and a list of herbal therapeutics that block PAK1, but cause no side (harmful) effect on healthy people or animals. PMID:23943274

  17. Therapeutic approach beyond conventional temozolomide for newly diagnosed glioblastoma: Review of the present evidence and future direction

    PubMed Central

    Mallick, Supriya; Gandhi, Ajeet Kumar; Rath, Goura Kishor

    2015-01-01

    Glioblastoma multiforme (GBM) is the most aggressive form of primary brain tumor. Maximal safe surgical resection followed by adjuvant partial brain radiation with concurrent and adjuvant temozolomide (TMZ) (oral alkylating agent) is the standard of care. Five years survival in TMZ treated patient reaches 9.8%. We aimed to summarize the changes in the management of GBM beyond conventional temozolomide based adjuvant treatment. We searched the PUBMED with the following key words: Glioblastoma, phase III trial, Phase II trial, adjuvant treatment in GBM. Clinical research has found a wide range of molecular aberrations in GBM and attempts are being made to further improve survival with the addition of different classes of drugs. Angiogenesis inhibitors, oncolytic vaccines, dose dense TMZ, and anti-epidermal growth factor receptor monoclonal antibody in phase III trials have failed to improve survival. Recent studies have also shown that the management strategies might be different and needs to be customized as per the age of patients such as pediatric and elderly patients. In addition, treatments should be personalized depending on the molecular aberrations. We reviewed all published phase III trials for newly diagnosed GBM as well as also looked into possible future directions in this review. Limited progress has happed beyond conventional TMZ in the adjuvant treatment of GBM. Newer insights are emerging about treatment intensification and introduction of newer molecular targeted drugs with more information about molecular aberrations. PMID:26811592

  18. Interrogating Tumor Metabolism and Tumor Microenvironments Using Molecular Positron Emission Tomography Imaging. Theranostic Approaches to Improve Therapeutics

    PubMed Central

    Jacobson, Orit

    2013-01-01

    Positron emission tomography (PET) is a noninvasive molecular imaging technology that is becoming increasingly important for the measurement of physiologic, biochemical, and pharmacological functions at cellular and molecular levels in patients with cancer. Formation, development, and aggressiveness of tumor involve a number of molecular pathways, including intrinsic tumor cell mutations and extrinsic interaction between tumor cells and the microenvironment. Currently, evaluation of these processes is mainly through biopsy, which is invasive and limited to the site of biopsy. Ongoing research on specific target molecules of the tumor and its microenvironment for PET imaging is showing great potential. To date, the use of PET for diagnosing local recurrence and metastatic sites of various cancers and evaluation of treatment response is mainly based on [18F]fluorodeoxyglucose ([18F]FDG), which measures glucose metabolism. However, [18F]FDG is not a target-specific PET tracer and does not give enough insight into tumor biology and/or its vulnerability to potential treatments. Hence, there is an increasing need for the development of selective biologic radiotracers that will yield specific biochemical information and allow for noninvasive molecular imaging. The possibility of cancer-associated targets for imaging will provide the opportunity to use PET for diagnosis and therapy response monitoring (theranostics) and thus personalized medicine. This article will focus on the review of non-[18F]FDG PET tracers for specific tumor biology processes and their preclinical and clinical applications. PMID:24064460

  19. Modelling verbal aggression, physical aggression and inappropriate sexual behaviour after acquired brain injury

    PubMed Central

    James, Andrew I. W.; Böhnke, Jan R.; Young, Andrew W.; Lewis, Gary J.

    2015-01-01

    Understanding the underpinnings of behavioural disturbances following brain injury is of considerable importance, but little at present is known about the relationships between different types of behavioural disturbances. Here, we take a novel approach to this issue by using confirmatory factor analysis to elucidate the architecture of verbal aggression, physical aggression and inappropriate sexual behaviour using systematic records made across an eight-week observation period for a large sample (n = 301) of individuals with a range of brain injuries. This approach offers a powerful test of the architecture of these behavioural disturbances by testing the fit between observed behaviours and different theoretical models. We chose models that reflected alternative theoretical perspectives based on generalized disinhibition (Model 1), a difference between aggression and inappropriate sexual behaviour (Model 2), or on the idea that verbal aggression, physical aggression and inappropriate sexual behaviour reflect broadly distinct but correlated clinical phenomena (Model 3). Model 3 provided the best fit to the data indicating that these behaviours can be viewed as distinct, but with substantial overlap. These data are important both for developing models concerning the architecture of behaviour as well as for clinical management in individuals with brain injury. PMID:26136449

  20. Modelling verbal aggression, physical aggression and inappropriate sexual behaviour after acquired brain injury.

    PubMed

    James, Andrew I W; Böhnke, Jan R; Young, Andrew W; Lewis, Gary J

    2015-07-22

    Understanding the underpinnings of behavioural disturbances following brain injury is of considerable importance, but little at present is known about the relationships between different types of behavioural disturbances. Here, we take a novel approach to this issue by using confirmatory factor analysis to elucidate the architecture of verbal aggression, physical aggression and inappropriate sexual behaviour using systematic records made across an eight-week observation period for a large sample (n = 301) of individuals with a range of brain injuries. This approach offers a powerful test of the architecture of these behavioural disturbances by testing the fit between observed behaviours and different theoretical models. We chose models that reflected alternative theoretical perspectives based on generalized disinhibition (Model 1), a difference between aggression and inappropriate sexual behaviour (Model 2), or on the idea that verbal aggression, physical aggression and inappropriate sexual behaviour reflect broadly distinct but correlated clinical phenomena (Model 3). Model 3 provided the best fit to the data indicating that these behaviours can be viewed as distinct, but with substantial overlap. These data are important both for developing models concerning the architecture of behaviour as well as for clinical management in individuals with brain injury.