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  1. [Single ventricle and related anomalies. Anatomic findings in 30 cases. Diagnostic and therapeutic implications (author's transl)].

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    Quero Jiménez, M; González Diéguez, M C; Herráiz Sarachaga, I

    1976-01-01

    Anatomic characteristics are studied in 30 cases of single ventricle and related anomalies. Cases are distributed into 6 groups according to: a) the derangement in the expansión of the atrioventricular canal towards the "bulbus cordis", which may be either defective (groups I, II and III) or excessive (groups IV and V), and b) the hypoplastic nature of the ventricular septum (group VI). The most important conclusions are: 1) An L-bulboventricular loop was found in 43.47% of the entire material; all of them pertained to groups I, II and III. 2) A normal position of the great arteries was uncommon, being encountered in 13.4% of the cases. An aorta situated anteriorly and to the left was present in 30.43% of the cases included in groups IV and V. 3) Obstructive anomalies of either outflow tract were discovered in 66.6% of the entire material, regardless of the type of bulboventricular loop. 4) The left atrioventricular orifice was found to be abnormally small in 56.66% of the total case material and in 88.23% of the cases pertaining to groups I, II and III. 5) A mitral atresia was encountered in two cases pertaining to groups I and II. The criteria which have been used to admit cases with this association of anomalies have been established in previous publications by one of the authors of the present study. 6) The changes in the spacial orientation of the leaflets of the right atrioventricular orifice in cases with an L-bulboventricular loop are attributed to the rotation of the heart around its longitudinal axis which takes place in cases with levocardia and mesocardia. 7) A preoperative study as accurate as possible is necessary in order to establish a rational approach to the surgical management of these patients.

  2. Therapeutic implications of coexisting severe pulmonary hemorrhage and pulmonary emboli in a case of Wegener granulomatosis.

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    Dreyer, Gavin; Fan, Stanley

    2009-05-01

    Wegener granulomatosis classically involves the renal, respiratory, and ear, nose, and throat systems. Pulmonary hemorrhage is recognized as a severe respiratory complication. Untreated, the mortality rate approaches 90% at 2 years. We describe a case of Wegener granulomatosis with coexistent severe lung hemorrhage and pulmonary and deep vein thromboses. A 31-year-old man presented with features of vasculitis, including epistaxis, fever, and acute kidney injury with an increased serum creatinine level (3.27 mg/dL). Kidney biopsy confirmed pauci-immune crescentic glomerulonephritis, and antineutrophil cytoplasmic antibody showing a cytoplasmic staining pattern was strongly positive. Standard immunosuppression therapy (prednisolone and cyclophosphamide) was started. Eleven days later, the patient developed sudden dyspnea. A computed tomographic pulmonary angiogram showed pulmonary emboli, and ultrasound of the limbs showed ileofemoral thrombi bilaterally. Subcutaneous enoxaparin and warfarin therapy was started, but 8 days later, the patient had a massive pulmonary hemorrhage. Anticoagulation therapy was stopped, and plasma exchange was started to prevent further life-threatening hemorrhage. An inferior vena cava filter was inserted to prevent further pulmonary emboli during the period when anticoagulation was withheld. Kidney function improved, and pulmonary hemorrhage resolved after 5 plasma exchanges. Reintroduction of intravenous heparin and subsequently warfarin caused no further bleeding. We discuss the difficult management dilemma this combination of disease manifestations presents and review the current literature.

  3. Therapeutic implications of the modular headache theory.

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    Young, William B; Piovesan, Elcio J

    2003-11-01

    A theoretical approach to understanding the primary headaches not yet classified by the International Headache Society classification system has been developed by the authors. It is proposed that groups of neurons, called modules, become activated to produce each symptom of a primary headache disorder and these modules are linked together to produce a headache. Headaches develop phenotypic stability through the process of learned stereotypy. This theory explains the huge diversity of headache phenomenology. It has implications for the classification, research and treatment of headache patients. The modular headache theory has therapeutic implications by directing us to focus on treatable modules and avoiding unnecessary treatment for less treatable symptoms. This allows for rational approaches to CNS hyperexcitability and incorporates the temporal patterns of modular activation into the patient's treatment plan.

  4. The endocannabinoid system and cancer: therapeutic implication.

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    Guindon, Josée; Hohmann, Andrea G

    2011-08-01

    The endocannabinoid system is implicated in a variety of physiological and pathological conditions (inflammation, immunomodulation, analgesia, cancer and others). The main active ingredient of cannabis, Δ(9) -tetrahydrocannabinol (Δ(9) -THC), produces its effects through activation of CB(1) and CB(2) receptors. CB(1) receptors are expressed at high levels in the central nervous system (CNS), whereas CB(2) receptors are concentrated predominantly, although not exclusively, in cells of the immune system. Endocannabinoids are endogenous lipid-signalling molecules that are generated in the cell membrane from phospholipid precursors. The two best characterized endocannabinoids identified to date are anandamide (AEA) and 2-arachidonoylglycerol (2-AG). Here we review the relationship between the endocannabinoid system and anti-tumour actions (inhibition of cell proliferation and migration, induction of apoptosis, reduction of tumour growth) of the cannabinoids in different types of cancer. This review will focus on examining how activation of the endocannabinoid system impacts breast, prostate and bone cancers in both in vitro and in vivo systems. The therapeutic potential of cannabinoids for cancer, as identified in clinical trials, is also discussed. Identification of safe and effective treatments to manage and improve cancer therapy is critical to improve quality of life and reduce unnecessary suffering in cancer patients. In this regard, cannabis-like compounds offer therapeutic potential for the treatment of breast, prostate and bone cancer in patients. Further basic research on anti-cancer properties of cannabinoids as well as clinical trials of cannabinoid therapeutic efficacy in breast, prostate and bone cancer is therefore warranted. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

  5. Host manipulation by cancer cells: Expectations, facts, and therapeutic implications.

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    Tissot, Tazzio; Arnal, Audrey; Jacqueline, Camille; Poulin, Robert; Lefèvre, Thierry; Mery, Frédéric; Renaud, François; Roche, Benjamin; Massol, François; Salzet, Michel; Ewald, Paul; Tasiemski, Aurélie; Ujvari, Beata; Thomas, Frédéric

    2016-03-01

    Similar to parasites, cancer cells depend on their hosts for sustenance, proliferation and reproduction, exploiting the hosts for energy and resources, and thereby impairing their health and fitness. Because of this lifestyle similarity, it is predicted that cancer cells could, like numerous parasitic organisms, evolve the capacity to manipulate the phenotype of their hosts to increase their own fitness. We claim that the extent of this phenomenon and its therapeutic implications are, however, underappreciated. Here, we review and discuss what can be regarded as cases of host manipulation in the context of cancer development and progression. We elaborate on how acknowledging the applicability of these principles can offer novel therapeutic and preventive strategies. The manipulation of host phenotype by cancer cells is one more reason to adopt a Darwinian approach in cancer research. © 2016 WILEY Periodicals, Inc.

  6. Dermatomyositis and myastenia gravis: An uncommon association with therapeutic implications.

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    Sangüesa Gómez, Clara; Flores Robles, Bryan Josué; Méndez Perles, Clara; Barbadillo, Carmen; Godoy, Hildegarda; Andréu, José Luis

    2015-01-01

    The association of dermatomyositis with myasthenia gravis (MG) is uncommon, having been reported so far in only 26 cases. We report the case of a 69 year-old man diagnosed with MG two years ago and currently treated with piridostigmyne. The patient developed acute proximal weakness, shoulder pain and elevated creatine-kinase (CK). He also developed generalized facial erythema and Gottron's papules. Laboratory tests showed positive antinuclear and anti-Mi2 antibodies. Further analysis confirmed CK levels above 1000 U/l. The clinical management of the patient and the therapeutic implications derived from the coexistence of both entities are discusssed. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

  7. [New inflammation modulator interleukins . Therapeutic implications].

    Science.gov (United States)

    Lupuşoru, Catălina Elena; Tarţău, Liliana; Ghiciuc, Cristina

    2002-01-01

    A lot of different leukocyte recruit soluble factors are implicated in both acute and chronic inflammatory processes with a higher expression of the cellular adhesion and chemoattraction molecules. Soluble factors implicated in these processes include: lipid inflammatory metabolites, arachydonic acid derivatives (prostaglandines, leucotrienes, lipoxines, PAF), the three soluble proteases waterfall events/substrates (coagulation, complement, kinines), nitric oxide, as well as cytokines implicated in acute or chronic inflammatory and cellular immune reactions. Recently, new inflammation modulator cytokines were described: IL-20, IL-21, IL-22 and IL-23. The aim of this work was to present some theoretical aspects regarding the biological effects of these new cytokines implicated in inflammation and the pharmacological influence of the processes mediated by them. Particularly IL-20 is implicated in psoriasis pathology. IL-21 and IL-15 are important in NK cells differentiation. IL-22 regulates the IL-4 production from Th2T cells. IL-23 stimulates IFN gamma production and proliferation in PHA blast T cells, as well as in CD45RO (memory) T cells.

  8. Hydrogen Sulfide in Preeclampsia : Potential Therapeutic Implications

    NARCIS (Netherlands)

    Holwerda, Kim

    2015-01-01

    The thesis provide insights into the production and possible therapeutic effect of the gaseous molecule hydrogen sulfide (H2S) in preeclampsia (PE). H2S is an important molecule in the (human) body. It is among others involved in blood pressure regulation, stimulation of vascular growth and

  9. Tumor dedifferentiation: diagnostic and therapeutic implications

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    Abhimanyu Jha

    2017-09-01

    Full Text Available Some of the neoplasm especially malignant tumors are notorious in masquerading their cell of origin because of additional mutations which drives them to differentiate into unusual phenotype. This is implicated to a phenomenon of tumor dedifferentiation which can mislead into inappropriate categorization and therapy. Dedifferentiation is well recognized in sarcomas such as liposarcoma, chondrosarcoma and MPNST. However, it can also develop in carcinomas, melanomas and lymphomas at initial diagnosis, following therapy or at recurrence.  The phenomenon has been reported in both primary tumors as well as at metastatic foci. A correct and early pathological identification of this phenomenon might profoundly help in guiding appropriate therapy. Clinical and radiological findings, immunohistochemistry and genetic analysis are often required for correct lineage identification of these tumors.

  10. Therapeutic Implications of PPARγ in Cardiovascular Diseases

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    Hiroshi Hasegawa

    2010-01-01

    Full Text Available Peroxisome proliferator-activated receptor-γ (PPARγ is the members of the nuclear receptor superfamily as a master transcriptional factor that promotes differentiation of preadipocytes by activating adipose-specific gene expression. Although PPARγ is expressed predominantly in adipose tissue and associated with adipocyte differentiation and glucose homeostasis, PPARγ is also present in a variety of cell types including vascular cells and cardiomyocytes. Activation of PPARγ suppresses production of inflammatory cytokines, and there is accumulating data that PPARγ ligands exert antihypertrophy of cardiomyocytes and anti-inflammatory, antioxidative, and antiproliferative effects on vascular wall cells and cardiomyocytes. In addition, activation of PPARγ is implicated in the regulation of endothelial function, proliferation and migration of vascular smooth muscle cells, and activation of macrophages. Many studies suggest that PPARγ ligands not only ameliorate insulin sensitivity, but also have pleiotropic effects on the pathophysiology of atherosclerosis, cardiac hypertrophy, ischemic heart, and myocarditis.

  11. Alexithymia in eating disorders: therapeutic implications

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    Pinna F

    2014-12-01

    Full Text Available Federica Pinna, Lucia Sanna, Bernardo Carpiniello Department of Public Health, Clinical and Molecular Medicine - Unit of Psychiatry, University of Cagliari, Cagliari, Italy Abstract: A high percentage of individuals affected by eating disorders (ED achieve incomplete recovery following treatment. In an attempt to improve treatment outcome, it is crucial that predictors of outcome are identified, and personalized care approaches established in line with new treatment targets, thus facilitating patient access to evidence-based treatments. Among the psychological factors proposed as predictors of outcome in ED, alexithymia is of outstanding interest. The objective of this paper is to undertake a systematic review of the literature relating to alexithymia, specifically in terms of the implications for treatment of ED. In particular, issues concerning the role of alexithymia as a predictor of outcome and as a factor to be taken into account in the choice of treatment will be addressed. The effect of treatments on alexithymia will also be considered. A search of all relevant literature published in English using PubMed, PsycINFO, and Scopus databases was carried out on the basis of the following keywords: alexithymia, anorexia nervosa, bulimia nervosa, eating disorders, and treatment; no time limits were imposed. Despite the clinical relevance of alexithymia, the number of studies published on the above cited aspects is somewhat limited, and these studies are largely heterogeneous and feature significant methodological weaknesses. Overall, data currently available mostly correlate higher levels of alexithymia with a less favorable outcome in ED. Accordingly, alexithymia is seen as a relevant treatment target with the aim of achieving recovery of these patients. Treatments focusing on improving alexithymic traits, and specifically those targeting emotions, seem to show greater efficacy, although alexithymia levels often remain high even after specific

  12. RNA editing in cancer: Mechanistic, prognostic, and therapeutic implications.

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    Han, Leng; Liang, Han

    2016-03-01

    We have recently provided a comprehensive analysis of A-to-I RNA editing events in various cancer types, revealing many clinically relevant RNA editing sites and demonstrating that RNA editing can selectively affect cancer drug sensitivity. Our results unveil mechanistic, prognostic, and therapeutic implications for RNA editing in cancer.

  13. Arterioportal fistulas: introduction of a novel classification with therapeutic implications.

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    Guzman, Eduardo A; McCahill, Laurence E; Rogers, Frederick B

    2006-04-01

    Arterioportal fistulas (APFs) are arteriovenous communications between the splanchnic arteries and the portal vein that represent an infrequent cause of presinusoidal portal hypertension. They can be acquired or congenital. Penetrating hepatic trauma, including liver biopsies, represent the most common etiology. They can be asymptomatic or manifest with portal hypertension. An abdominal bruit is a valuable physical finding. Persistence of an APF can cause hepatoportal sclerosis and possibly portal fibrosis. A detailed radiologic evaluation is mandatory. One must differentiate between small peripheral intrahepatic APFs (type 1) and large central APFs (type 2). The former usually resolve spontaneously, whereas the latter can cause portal hypertension and hepatic parenchymal changes. Type 1 APFs caused by needle injury can be followed by Doppler ultrasound. All other fistulas need treatment. Arterioportal fistulas are first treated by transcatheter embolization. Surgical approaches are reserved for complex cases. Congenital APFs (type 3) are diffuse and intrahepatic and can be difficult to manage. Overall, the prognosis is good. Herein, we propose a novel classification for arterioportal fistulas with therapeutic implications.

  14. A glycobiology review: carbohydrates, lectins, and implications in cancer therapeutics

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    Ghazarian, Haike; Idoni, Brian; Oppenheimer, Steven B.

    2010-01-01

    This review is intended for general readers who would like a basic foundation in carbohydrate structure and function, lectin biology and the implications of glycobiology in human health and disease, particularly in cancer therapeutics. These topics are among the hundreds included in the field of glycobiology and are treated here because they form the cornerstone of glycobiology or the focus of many advances in this rapidly expanding field. PMID:20199800

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

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    Roszkowski Jeffrey J

    2005-09-01

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

  16. Understanding music’s therapeutic efficacy: Implications for music education

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    Diane Thram

    2014-11-01

    Full Text Available In the current era of electronic domination of human experience, be it via cell phone and/or computer addiction, or the ubiquitous television, actual participation in music- making is less and less common for the average person, child or adult. Passive participation through listening is most often cited by people as their major experience with music in their lives. When asked if listening has therapeutic effects, it is rare for anyone to respond in the negative. Likewise, for performers/active participants in music- making, be it solitary or as part of a group, invariably an enhanced sense of well-being from the act of making music is reported. This paper addresses therapeutic aspects of musical participation (singing, clapping, playing an instrument, dancing, listening by providing a historical overview (12th c to present of attitudes toward music’s therapeutic effects. It argues that music exists through the interaction of our biological capacity to make music with our cultural circumstances. How individuals benefit in all aspects their being – physical, mental and emotional – from engaging in the act of making music is illustrated with examples from field research in southern Africa. Finally implications for Music Education are explored which emphasize how more comprehensive integration of music into the curriculum can serve as an antidote to the increasing isolation and alienation of modern life.

  17. Emerging implications of nanotechnology on cancer diagnostics and therapeutics.

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    Cuenca, Alex G; Jiang, Huabei; Hochwald, Steven N; Delano, Matthew; Cance, William G; Grobmyer, Stephen R

    2006-08-01

    Nanotechnology is multidisciplinary field that involves the design and engineering of objects Cancer Institute has recognized that nanotechnology offers an extraordinary, paradigm-changing opportunity to make significant advances in cancer diagnosis and treatment. In the last several decades, nanotechnology has been studied and developed primarily for use in novel drug-delivery systems (e.g. liposomes, gelatin nanoparticles, micelles). A recent explosion in engineering and technology has led to 1) the development of many new nanoscale platforms, including quantum dots, nanoshells, gold nanoparticles, paramagnetic nanoparticles, and carbon nanotubes, and 2) improvements in traditional, lipid-based nanoscale platforms. The emerging implications of these platforms for advances in cancer diagnostics and therapeutics form the basis of this review. A widespread understanding of these new technologies is important, because they currently are being integrated into the clinical practice of oncology. Copyright 2006 American Cancer Society.

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

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    Alok Kumar

    2013-01-01

    Full Text Available 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.

  19. Fibromyalgia and bipolar disorder: extent of comorbidity and therapeutic implications.

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    Di Tommaso Morrison, M C; Carinci, F; Lessiani, G; Spinas, E; Kritas, S K; Ronconi, G; Caraffa, Al; Conti, P

    2017-01-01

    Fibromyalgia (FM) is a syndrome that affects muscles and soft tissues. Presenting symptoms include chronic muscle pain, fatigue, sleep problems and psychological symptoms, including depression and anxiety. There exists strong evidence of a comorbidity between FM and Bipolar Disorder (BD). In this study, papers from 2006 to February 2016 that examined the comorbidity and etiological similarities of FM and BD were reviewed, as well as the therapeutic implications of these findings. The reviewed articles showed that an adequate psychiatric screening for BD is recommended in FM patients with depressive symptoms, in order to decrease administration of antidepressants for BD, due to the lack of proven efficacy, and to limit antidepressant-induced mania. Alternative therapies, such as agomelatine, memantine and psychotherapic treatment should be considered.

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

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    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

  1. THERAPEUTIC IMPLICATIONS OF GENETIC RISK VARIANTS FOR CORONARY ARTERY DISEASE

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    Rajiv Kumar Srivastava

    2017-02-01

    Full Text Available BACKGROUND This review covers therapeutic implication of genetic risk variant responsible for coronary artery disease by utilising the highdensity single-nucleotide microarrays to screen the entire human genome. The sequence of the human genome provides the blueprint for life. Approximately, 99.5% of the human genome Deoxyribonucleic Acid (DNA sequence is identical among humans with 0.5% of the genome sequence (15 million bps accounting for all individual differences. MATERIALS AND METHODS The new technology of the computerised chip array of millions of Single-Nucleotide Polymorphisms (SNPs as Deoxyribonucleic Acid (DNA markers makes it possible to study and detect genetic predisposition to common polygenic disorders such as Coronary Artery Disease (CAD. The sample sizes required for these studies are massive and large; worldwide consortiums such as Coronary Artery Disease Genome-wide Replication and Meta-Analysis (CARDIoGRAM study have been formed to accommodate this requirement. After the identification of 9p21 progress to detect genetic predisposition has been remarkable. RESULTS There are currently a total of 50 genetic risk variants predisposing to CAD of genome-wide significance with confirmation in independent populations. Rare variants (Minor Allele Frequency, MAF <5% will require direct sequencing to detect genetic predisposition. CONCLUSION We can develop new biomarkers for detecting early CAD as well as unique targets for novel therapy. The challenge for the future will be to identify the molecular mechanisms mediating the risk of those genetic risk variants that act through nonconventional risk factors. The ultimate objective for the future is the sequencing and functional analysis of the causative polymorphisms for its therapeutic implications.

  2. Therapeutic Implications for Overcoming Radiation Resistance in Cancer Therapy

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    Kim, Byeong Mo; Hong, Yunkyung; Lee, Seunghoon; Liu, Pengda; Lim, Ji Hong; Lee, Yong Heon; Lee, Tae Ho; Chang, Kyu Tae; Hong, Yonggeun

    2015-01-01

    Ionizing radiation (IR), such as X-rays and gamma (γ)-rays, mediates various forms of cancer cell death such as apoptosis, necrosis, autophagy, mitotic catastrophe, and senescence. Among them, apoptosis and mitotic catastrophe are the main mechanisms of IR action. DNA damage and genomic instability contribute to IR-induced cancer cell death. Although IR therapy may be curative in a number of cancer types, the resistance of cancer cells to radiation remains a major therapeutic problem. In this review, we describe the morphological and molecular aspects of various IR-induced types of cell death. We also discuss cytogenetic variations representative of IR-induced DNA damage and genomic instability. Most importantly, we focus on several pathways and their associated marker proteins responsible for cancer resistance and its therapeutic implications in terms of cancer cell death of various types and characteristics. Finally, we propose radiation-sensitization strategies, such as the modification of fractionation, inflammation, and hypoxia and the combined treatment, that can counteract the resistance of tumors to IR. PMID:26569225

  3. Therapeutic Implications for Overcoming Radiation Resistance in Cancer Therapy

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    Byeong Mo Kim

    2015-11-01

    Full Text Available Ionizing radiation (IR, such as X-rays and gamma (γ-rays, mediates various forms of cancer cell death such as apoptosis, necrosis, autophagy, mitotic catastrophe, and senescence. Among them, apoptosis and mitotic catastrophe are the main mechanisms of IR action. DNA damage and genomic instability contribute to IR-induced cancer cell death. Although IR therapy may be curative in a number of cancer types, the resistance of cancer cells to radiation remains a major therapeutic problem. In this review, we describe the morphological and molecular aspects of various IR-induced types of cell death. We also discuss cytogenetic variations representative of IR-induced DNA damage and genomic instability. Most importantly, we focus on several pathways and their associated marker proteins responsible for cancer resistance and its therapeutic implications in terms of cancer cell death of various types and characteristics. Finally, we propose radiation-sensitization strategies, such as the modification of fractionation, inflammation, and hypoxia and the combined treatment, that can counteract the resistance of tumors to IR.

  4. Molecular Strategies for Targeting Antioxidants to Mitochondria: Therapeutic Implications

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    2015-01-01

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

  5. Mutation profiling in cholangiocarcinoma: prognostic and therapeutic implications.

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    Chaitanya R Churi

    Full Text Available Cholangiocarcinoma (CCA is clinically heterogeneous; intra and extrahepatic CCA have diverse clinical presentations. Next generation sequencing (NGS technology may identify the genetic differences between these entities and identify molecular subgroups for targeted therapeutics.We describe successful NGS-based testing of 75 CCA patients along with the prognostic and therapeutic implications of findings. Mutation profiling was performed using either a NGS panel of hotspot regions in 46 cancer-related genes using a 318-chip on Ion PGM Sequencer or b Illumina HiSeq 2000 sequencing platform for 3,769 exons of 236 cancer-related genes plus 47 introns from 19 genes to an average depth of 1000X. Clinical data was abstracted and correlated with clinical outcome. Patients with targetable mutations were referred to appropriate clinical trials.There were significant differences between intrahepatic (n = 55 and extrahepatic CCA (n = 20 in regard to the nature and frequency of the genetic aberrations (GAs. IDH1 and DNA repair gene alterations occurred more frequently in intrahepatic CCA, while ERBB2 GAs occurred in the extrahepatic group. Commonly occurring GAs in intrahepatic CCA were TP53 (35%, KRAS (24%, ARID1A (20%, IDH1 (18%, MCL1 (16% and PBRM1 (11%. Most frequent GAs in extrahepatic CCA (n = 20 were TP53 (45%, KRAS (40%, ERBB2 (25%, SMAD4 (25%, FBXW7 (15% and CDKN2A (15%. In intrahepatic CCA, KRAS, TP53 or MAPK/mTOR GAs were significantly associated with a worse prognosis while FGFR GAs correlated with a relatively indolent disease course. IDH1 GAs did not have any prognostic significance. GAs in the chromatin modulating genes, BAP1 and PBRM1 were associated with bone metastases and worse survival in extrahepatic CCA. Radiologic responses and clinical benefit was noted with EGFR, FGFR, C-met, B-RAF and MEK inhibitors.There are significant genetic differences between intra and extrahepatic CCA. NGS can potentially identify disease subsets with distinct

  6. [Histological and molecular classification of endometrial carcinoma and therapeutical implications].

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    Genestie, Catherine; Leary, Alexandra; Devouassoux, Mojgan; Auguste, Aurélie

    2017-12-01

    Endometrial cancer is the fourth cause of cancer in women in France and is the second most common cancer of the gynecologic cancer after breast cancer with 7275 new cases in 2012. The incidence of this neoplasm tends to increase with population aging, diabetes and obesity's augmentation. In rare cases, a hereditary factor has been described: Lynch's syndrome. The therapeutic management of the patient depends on the endometrial biopsy which specifies the histological type and the histo-prognostic grade as well as the MRI which allow the tumor staging. Within the last decade, improvement in technologies such as genomic, transcriptomic and histological analyses, allowed the establishment of new and finer classifications of endometrial carcinomas. The latest classification proposed by The Cancer Genomic Atlas (TCGA), has been made routinely applicable through the international consortium TransPORTEC. It consists of 4 groups listed from good to poor prognosis: (1) ultra-mutated "POLE"; (2) hyper-mutated "MSI"; (3) low copy number "NSMP" and (4) high number of copies "TP53 mutated" (serous-like). This integrated characterization combined with mutational data opens new opportunities for therapeutic strategies. Copyright © 2017 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

  7. The therapeutic collaboration in life design counselling: The case of ...

    African Journals Online (AJOL)

    This study examined the therapeutic collaboration in a case of Life Design Counseling (LDC) with narrative change and positive career outcomes. The therapeutic collaboration-change model and correspondent coding system were used to in-tensively study the helping relationship throughout three sessions of LDC.

  8. Tyrosine Kinase Receptor Landscape in Lung Cancer: Therapeutical Implications

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    A. Quintanal-Villalonga

    2016-01-01

    Full Text Available Lung cancer is a heterogeneous disease responsible for the most cases of cancer-related deaths. The majority of patients are clinically diagnosed at advanced stages, with a poor survival rate. For this reason, the identification of oncodrivers and novel biomarkers is decisive for the future clinical management of this pathology. The rise of high throughput technologies popularly referred to as “omics” has accelerated the discovery of new biomarkers and drivers for this pathology. Within them, tyrosine kinase receptors (TKRs have proven to be of importance as diagnostic, prognostic, and predictive tools and, due to their molecular nature, as therapeutic targets. Along this review, the role of TKRs in the different lung cancer histologies, research on improvement of anti-TKR therapy, and the current approaches to manage anti-TKR resistance will be discussed.

  9. Implications of the tumor immune microenvironment for staging and therapeutics.

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    Taube, Janis M; Galon, Jérôme; Sholl, Lynette M; Rodig, Scott J; Cottrell, Tricia R; Giraldo, Nicolas A; Baras, Alexander S; Patel, Sanjay S; Anders, Robert A; Rimm, David L; Cimino-Mathews, Ashley

    2017-12-01

    Characterizing the tumor immune microenvironment enables the identification of new prognostic and predictive biomarkers, the development of novel therapeutic targets and strategies, and the possibility to guide first-line treatment algorithms. Although the driving elements within the tumor microenvironment of individual primary organ sites differ, many of the salient features remain the same. The presence of a robust antitumor milieu characterized by an abundance of CD8+ cytotoxic T-cells, Th1 helper cells, and associated cytokines often indicates a degree of tumor containment by the immune system and can even lead to tumor elimination. Some of these features have been combined into an 'Immunoscore', which has been shown to complement the prognostic ability of the current TNM staging for early stage colorectal carcinomas. Features of the immune microenvironment are also potential therapeutic targets, and immune checkpoint inhibitors targeting the PD-1/PD-L1 axis are especially promising. FDA-approved indications for anti-PD-1/PD-L1 are rapidly expanding across numerous tumor types and, in certain cases, are accompanied by companion or complimentary PD-L1 immunohistochemical diagnostics. Pathologists have direct visual access to tumor tissue and in-depth knowledge of the histological variations between and within tumor types and thus are poised to drive forward our understanding of the tumor microenvironment. This review summarizes the key components of the tumor microenvironment, presents an overview of and the challenges with PD-L1 antibodies and assays, and addresses newer candidate biomarkers, such as CD8+ cell density and mutational load. Characteristics of the local immune contexture and current pathology-related practices for specific tumor types are also addressed. In the future, characterization of the host antitumor immune response using multiplexed and multimodality biomarkers may help predict which patients will respond to immune-based therapies

  10. Multiple roles and therapeutic implications of Akt signaling in cancer

    Directory of Open Access Journals (Sweden)

    Emiliano Calvo

    2009-06-01

    Full Text Available Emiliano Calvo1, Victoria Bolós2, Enrique Grande21Centro Integral Oncológico Clara Campal (CiOCC, Madrid. Spain; 2Pfizer Oncology, Alcobendas-Madrid, SpainAbstract: The prominence of the PI3K-Akt signaling pathway in several tumors indicates a relationship with tumor grade and proliferation. Critical cellular processes are driven through this pathway. More detailed knowledge of the pathogenesis of tumors would enable us to design targeted drugs to block both membrane tyrosine kinase receptors and the intracellular kinases involved in the transmission of the signal. The newly approved molecular inhibitors sunitinib (an inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and other tyrosine kinase receptors, sorafenib (a serine–threonine kinase inhibitor that acts against B-Raf and temsirolimus (an mTOR inhibitor shown clinical activity in advanced kidney cancer. Chronic myeloid leukemia has changed its natural history thanks to imatinib and dasatinib, both of which inhibit the intracellular bcr/abl protein derived from the alteration in the Philadelphia chromosome. Intracellular pathways are still important in cancer development and their blockade directly affects outcome. Cross-talk has been observed but is not well understood. Vertical and horizontal pathway blockade are promising anticancer strategies. Indeed, preclinical and early clinical data suggest that combining superficial and intracellular blocking agents can synergize and leverage single-agent activity. The implication of the Akt signaling pathway in cancer is well established and has led to the development of new anticancer agents that block its activation.Keywords: Akt, cancer, therapeutic target, Akt inhibitors

  11. Elaborating the assimilation model: Introduction to a special section on case studies of setbacks within sessions and therapeutic collaboration.

    Science.gov (United States)

    Caro Gabalda, Isabel; Stiles, William B

    2016-11-01

    This article introduces a Special Section of case studies that focus on therapeutic collaboration and setbacks in the process of assimilation with the aim of contributing to the evolution of the assimilation model of therapeutic change. The first study examined setbacks in two depression cases (a good vs. a poor outcome) treated with emotion-focused therapy. The second article traced how therapist activities and positions toward internal voices were associated with setbacks in a case treated with linguistic therapy of evaluation. The third article studied contributions of therapeutic collaboration for both advances and setbacks in assimilation in two contrasting cases treated with emotion-focused therapy. The fourth and final article analyzed the therapeutic collaboration in episodes of ambivalence in two cases of narrative therapy (one good outcome, one poor outcome) reflecting on the implications for the assimilation model's perspective on the therapeutic relationship. This Introduction concludes by offering some suggestions for theory-building within the assimilation model.

  12. Caloric intake and Alzheimer's disease. Experimental approaches and therapeutic implications.

    Science.gov (United States)

    Pasinetti, Giulio Maria; Zhao, Zhong; Qin, Weiping; Ho, Lap; Shrishailam, Yemul; Macgrogan, Donal; Ressmann, Wendy; Humala, Nelson; Liu, Xunxian; Romero, Carmen; Stetka, Breton; Chen, Linghong; Ksiezak-Reding, Hanna; Wang, Jun

    2007-01-01

    Alzheimer's disease (AD) is a rapidly growing public health concern with potentially devastating effects. Presently, there are no known cures or effective preventive strategies. While genetic factors are relevant in early-onset cases, they appear to play less of a role in late-onset sporadic AD cases, the most common form of AD. Due to the fact that the disease typically strikes very late in life, delaying symptoms could be as good as a cure for many people. For example, it is now widely accepted that if the onset of the disease could be delayed by even 5 years, the incidence could be cut in half. Both clinical and epidemiological evidence suggests that modification of lifestyle factors such as nutrition may prove crucial to AD management given the mounting experimental evidence suggesting that brain cells are remarkably responsive to "what somebody is doing". Among other nongenetic factors influencing AD, recent studies strongly support the evidence that caloric intake may play a role in the relative risk for AD clinical dementia. Indeed, the effect of diet in AD has been an area of research that has produced promising results, at least experimentally. Most importantly, as mechanistic pathways are defined and their biochemical functions scrutinized, the evidence supporting a direct link between nutrition and AD neuropathology continues to grow. Our work, as well as that of others, has recently resulted in the development of experimental dietary regimens that might promote, attenuate or even reverse features of AD. Most remarkably, while we found that high caloric intake based on saturated fat promotes AD type Beta-amyloidosis, conversely we found that dietary restriction based on reduced carbohydrate intake is able to prevent it. This evidence is very exciting and is, in part, consistent with current epidemiological studies suggesting that obesity and diabetes are associated with a >4-fold increased risk of developing AD. The clarification of the mechanisms

  13. Cancer Stem Cells and Their Microenvironment: Biology and Therapeutic Implications

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    Eunice Yuen-Ting Lau

    2017-01-01

    Full Text Available Tumor consists of heterogeneous cancer cells including cancer stem cells (CSCs that can terminally differentiate into tumor bulk. Normal stem cells in normal organs regulate self-renewal within a stem cell niche. Likewise, accumulating evidence has also suggested that CSCs are maintained extrinsically within the tumor microenvironment, which includes both cellular and physical factors. Here, we review the significance of stromal cells, immune cells, extracellular matrix, tumor stiffness, and hypoxia in regulation of CSC plasticity and therapeutic resistance. With a better understanding of how CSC interacts with its niche, we are able to identify potential therapeutic targets for the development of more effective treatments against cancer.

  14. Cardiac GPCR-Mediated EGFR Transactivation: Impact and Therapeutic Implications.

    Science.gov (United States)

    Grisanti, Laurel A; Guo, Shuchi; Tilley, Douglas G

    2017-07-01

    G protein-coupled receptors (GPCRs) remain primary therapeutic targets for numerous cardiovascular disorders, including heart failure (HF), because of their influence on cardiac remodeling in response to elevated neurohormone signaling. GPCR blockers have proven to be beneficial in the treatment of HF by reducing chronic G protein activation and cardiac remodeling, thereby extending the lifespan of patients with HF. Unfortunately, this effect does not persist indefinitely, thus next-generation therapeutics aim to selectively block harmful GPCR-mediated pathways while simultaneously promoting beneficial signaling. Transactivation of epidermal growth factor receptor (EGFR) has been shown to be mediated by an expanding repertoire of GPCRs in the heart, and promotes cardiomyocyte survival, thus may offer a new avenue of HF therapeutics. However, GPCR-dependent EGFR transactivation has also been shown to regulate cardiac hypertrophy and fibrosis by different GPCRs and through distinct molecular mechanisms. Here, we discuss the mechanisms and impact of GPCR-mediated EGFR transactivation in the heart, focusing on angiotensin II, urotensin II, and β-adrenergic receptor systems, and highlight areas of research that will help us to determine whether this pathway can be engaged as future therapeutic strategy.

  15. Understanding Music's Therapeutic Efficacy with Implications for Why Music Matters

    Science.gov (United States)

    Thram, Diane

    2015-01-01

    In this essay, I focus on how attention to music's therapeutic efficacy is important to the praxial music education philosophy espoused by Elliott and Silverman. I note, despite the use of the term praxis from Aristotle's philosophy dating back to antiquity, there is no mention in Music Matters 2 of what historical evidence tells us about how…

  16. Internet addiction neuroscientific approaches and therapeutical implications including smartphone addiction

    CERN Document Server

    Reuter, Martin

    2017-01-01

    The second edition of this successful book provides further and in-depth insight into theoretical models dealing with Internet addiction, as well as includes new therapeutical approaches. The editors also broach the emerging topic of smartphone addiction. This book combines a scholarly introduction with state-of-the-art research in the characterization of Internet addiction. It is intended for a broad audience including scientists, students and practitioners. The first part of the book contains an introduction to Internet addiction and their pathogenesis. The second part of the book is dedicated to an in-depth review of neuroscientific findings which cover studies using a variety of biological techniques including brain imaging and molecular genetics. The third part of the book focuses on therapeutic interventions for Internet addiction. The fourth part of the present book is an extension to the first edition and deals with a new emerging potential disorder related to Internet addiction – smartphone addicti...

  17. Implication of fractionated dose exposures in therapeutic gain

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Hye-Jin; Lee, Min-Ho; Kim, Eun-Hee [Seoul National University, Seoul (Korea, Republic of)

    2016-10-15

    Radiation therapy pursues killing tumor cells while sparing normal cells from the radiation exposure. Stereotactic radiosurgery (SRS) is a cancer treatment modality that delivers a high dose in a single operation. This high-dose single operation shortens the treatment course, but can increase the risk of normal cell damage. Normal cell damage can be reduced by employing multi-directional exposures for an increasing number of isocenters. In this study, we investigated whether therapeutic benefits would be expected by employing new dose fractionation patterns at a high-dose single operation. The conventional single-dose operation in brain tumor radiosurgery is performed by delivering fractionated uniform doses. According to Figs. 2 and 3, the conventional radiosurgery might have obtained some therapeutic benefit by employing the fractionated uniform-dose exposures instead of a single-dose exposure. We suggest that further therapeutic gain be expected by employing the fractionated radiation exposures in an increasing dose pattern. Until ensuring our suggestion, the significance in gain of cell surviving should be verified for all three dose patterns with both normal and tumor cells. The investigation whether normal and tumor cells show the same responses to the fractionated dose exposures at lower and higher than 15 Gy of total dose is also reserved for future work.

  18. Therapeutic and reproductive cloning--implications and recommendations.

    Science.gov (United States)

    Ng, S C; Ng, Y; Liow, S L; Chen, N

    2003-03-01

    The announcement of Dolly's birth took the world by storm, mainly because what was thought impossible has become possible. Optimism that new approaches in agriculture and medicine abound, as much as fear and imagination leading to Frankenstein-like scenarios. Scientifically, cloning refers to replicating an animal with the same nuclear genetic material; whilst it may refer to embryos as the source material, the current storm refers to differentiated ("somatic") cells. Cloning technology is useful in the following areas: agriculture, to produce animals of superior or specific qualities; endangered animals, to increase genetic diversity through widening the gene pool; understanding fundamental questions in developmental embryology, through the use of laboratory animals; and in human therapy, to produce cells and possibly tissues for repair and regeneration. In the first 2 instances, it is reproductive cloning. In the last instance, it is therapeutic cloning, as no individuals are "produced". Human reproductive cloning is not allowed by all governments that have deliberated on it, and therapeutic cloning is allowed by some under certain circumstances. As therapeutic cloning has great potential in cures of many diseases, it should be allowed but with safeguards to prevent abuse and reproductive cloning in the human.

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

    Science.gov (United States)

    Kraehenmann, Rainer

    2017-01-01

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

  20. Cardiovascular calcifications in chronic kidney disease: Potential therapeutic implications.

    Science.gov (United States)

    Bover, Jordi; Ureña-Torres, Pablo; Górriz, José Luis; Lloret, María Jesús; da Silva, Iara; Ruiz-García, César; Chang, Pamela; Rodríguez, Mariano; Ballarín, José

    Cardiovascular (CV) calcification is a highly prevalent condition at all stages of chronic kidney disease (CKD) and is directly associated with increased CV and global morbidity and mortality. In the first part of this review, we have shown that CV calcifications represent an important part of the CKD-MBD complex and are a superior predictor of clinical outcomes in our patients. However, it is also necessary to demonstrate that CV calcification is a modifiable risk factor including the possibility of decreasing (or at least not aggravating) its progression with iatrogenic manoeuvres. Although, strictly speaking, only circumstantial evidence is available, it is known that certain drugs may modify the progression of CV calcifications, even though a direct causal link with improved survival has not been demonstrated. For example, non-calcium-based phosphate binders demonstrated the ability to attenuate the progression of CV calcification compared with the liberal use of calcium-based phosphate binders in several randomised clinical trials. Moreover, although only in experimental conditions, selective activators of the vitamin D receptor seem to have a wider therapeutic margin against CV calcification. Finally, calcimimetics seem to attenuate the progression of CV calcification in dialysis patients. While new therapeutic strategies are being developed (i.e. vitamin K, SNF472, etc.), we suggest that the evaluation of CV calcifications could be a diagnostic tool used by nephrologists to personalise their therapeutic decisions. Copyright © 2016 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.

  1. BRAF V600E mutations are common in pleomorphic xanthoastrocytoma: diagnostic and therapeutic implications.

    Directory of Open Access Journals (Sweden)

    Dora Dias-Santagata

    2011-03-01

    Full Text Available Pleomorphic xanthoastrocytoma (PXA is low-grade glial neoplasm principally affecting children and young adults. Approximately 40% of PXA are reported to recur within 10 years of primary resection. Upon recurrence, patients receive radiation therapy and conventional chemotherapeutics designed for high-grade gliomas. Genetic changes that can be targeted by selective therapeutics have not been extensively evaluated in PXA and ancillary diagnostic tests to help discriminate PXA from other pleomorphic and often more aggressive astrocytic malignancies are limited. In this study, we apply the SNaPshot multiplexed targeted sequencing platform in the analysis of brain tumors to interrogate 60 genetic loci that are frequently mutated in 15 cancer genes. In our analysis we detect BRAF V600E mutations in 12 of 20 (60% WHO grade II PXA, in 1 of 6 (17% PXA with anaplasia and in 1 glioblastoma arising in a PXA. Phospho-ERK was detected in all tumors independent of the BRAF mutation status. BRAF duplication was not detected in any of the PXA cases. BRAF V600E mutations were identified in only 2 of 71 (2.8% glioblastoma (GBM analyzed, including 1 of 9 (11.1% giant cell GBM (gcGBM. The finding that BRAF V600E mutations are common in the majority of PXA has important therapeutic implications and may help in differentiating less aggressive PXAs from lethal gcGBMs and GBMs.

  2. Glioblastoma Stem-Like Cells—Biology and Therapeutic Implications

    Energy Technology Data Exchange (ETDEWEB)

    Gürsel, Demirkan B., E-mail: jab2029@nyp.org; Shin, Benjamin J.; Burkhardt, Jan-Karl; Kesavabhotla, Kartik; Schlaff, Cody D.; Boockvar, John A., E-mail: jab2029@nyp.org [Laboratory for Translational Brain Tumor and Stem Cell Research, Department of Neurological Surgery, Weill Cornell Brain Tumor Center, Weill Cornell Medical College, New York, NY 10021 (United States)

    2011-06-10

    The cancer stem-cell hypothesis proposes that malignant tumors are likely to encompass a cellular hierarchy that parallels normal tissue and may be responsible for the maintenance and recurrence of glioblastoma multiforme (GBM) in patients. The purpose of this manuscript is to review methods for optimizing the derivation and culturing of stem-like cells also known as tumor stem cells (TSCs) from patient-derived GBM tissue samples. The hallmarks of TSCs are that they must be able to self-renew and retain tumorigenicity. The isolation, optimization and derivation of TSCs as outlined in this review, will be important in understanding biology and therapeutic applications related to these cells.

  3. Microvascular responsiveness in obesity: implications for therapeutic intervention

    Science.gov (United States)

    Bagi, Zsolt; Feher, Attila; Cassuto, James

    2012-01-01

    Obesity has detrimental effects on the microcirculation. Functional changes in microvascular responsiveness may increase the risk of developing cardiovascular complications in obese patients. Emerging evidence indicates that selective therapeutic targeting of the microvessels may prevent life-threatening obesity-related vascular complications, such as ischaemic heart disease, heart failure and hypertension. It is also plausible that alterations in adipose tissue microcirculation contribute to the development of obesity. Therefore, targeting adipose tissue arterioles could represent a novel approach to reducing obesity. This review aims to examine recent studies that have been focused on vasomotor dysfunction of resistance arteries in obese humans and animal models of obesity. Particularly, findings in coronary resistance arteries are contrasted to those obtained in other vascular beds. We provide examples of therapeutic attempts, such as use of statins, ACE inhibitors and insulin sensitizers to prevent obesity-related microvascular complications. We further identify some of the important challenges and opportunities going forward. LINKED ARTICLES This article is part of a themed section on Fat and Vascular Responsiveness. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-3 PMID:21797844

  4. Pancreatic Cancer Genomes: Implications for Clinical Management and Therapeutic Development.

    Science.gov (United States)

    Dreyer, Stephan B; Chang, David K; Bailey, Peter; Biankin, Andrew V

    2017-04-01

    Pancreatic cancer has become the third leading cause of cancer-related death, with little improvement in outcomes despite decades of research. Surgery remains the only chance of cure, yet only 20% of patients will be alive at 5 years after pancreatic resection. Few chemotherapeutics provide any improvement in outcome, and even then, for approved therapies, the survival benefits are marginal. Genomic sequencing studies of pancreatic cancer have revealed a small set of consistent mutations found in most pancreatic cancers and beyond that, a low prevalence for targetable mutations. This may explain the failure of conventional clinical trial designs to show any meaningful survival benefit, except in small and undefined patient subgroups. With the development of next-generation sequencing technology, genomic sequencing and analysis can be performed in a clinically meaningful turnaround time. This can identify therapeutic targets in individual patients and personalize treatment selection. Incorporating preclinical discovery and molecularly guided therapy into clinical trial design has the potential to significantly improve outcomes in this lethal malignancy. In this review, we discuss the findings of recent large-scale genomic sequencing projects in pancreatic cancer and the potential relevance of these data to therapeutic development. Clin Cancer Res; 23(7); 1638-46. ©2017 AACRSee all articles in this CCR Focus section, "Pancreatic Cancer: Challenge and Inspiration." ©2017 American Association for Cancer Research.

  5. [Infectious gastroenteritis in relapses of inflammatory bowel disease. Therapeutic implications].

    Science.gov (United States)

    Baliellas, C; Xiol, X; Barenys, M; Saavedra, J; Casanovas, T; Iborra, M; Sesé, E

    1996-06-01

    The incidence and clinical importance of infectious gastroenteritis was studied in 67 consecutive relapses of inflammatory bowel disease (IBD). A stool culture was done in every case before starting treatment. Stool culture was positive in 6 relapses (8.9%): Four were exacerbations of ulcerative colitis and two of Crohn's disease (8.8% in ulcerative colitis vs 9% in Crohn's disease; NS). The microorganisms isolated were Campylobacter jejuni in three cases, Salmonella enteritidis in two and Staphylococcus aureus in one case. There were not clinical differences between patients with positive and negative stool culture. Treated with antibiotics, stool cultures became negative in all of them but only in three the disease was controlled. The other three had to be treated with corticosteroids to achieve remission. We conclude that stool culture should be practised in all relapses of IBD and in case of positivity, antibiotic therapy should be started. With this approach the use of corticosteroids can be avoided in some patients.

  6. The human gut microbiota and virome: Potential therapeutic implications.

    Science.gov (United States)

    Scarpellini, Emidio; Ianiro, Gianluca; Attili, Fabia; Bassanelli, Chiara; De Santis, Adriano; Gasbarrini, Antonio

    2015-12-01

    Human gut microbiota is a complex ecosystem with several functions integrated in the host organism (metabolic, immune, nutrients absorption, etc.). Human microbiota is composed by bacteria, yeasts, fungi and, last but not least, viruses, whose composition has not been completely described. According to previous evidence on pathogenic viruses, the human gut harbours plant-derived viruses, giant viruses and, only recently, abundant bacteriophages. New metagenomic methods have allowed to reconstitute entire viral genomes from the genetic material spread in the human gut, opening new perspectives on the understanding of the gut virome composition, the importance of gut microbiome, and potential clinical applications. This review reports the latest evidence on human gut "virome" composition and its function, possible future therapeutic applications in human health in the context of the gut microbiota, and attempts to clarify the role of the gut "virome" in the larger microbial ecosystem. Copyright © 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

  7. Therapeutic Implications of Mesenchymal Stem Cells in Liver Injury

    Directory of Open Access Journals (Sweden)

    Maria Ausiliatrice Puglisi

    2011-01-01

    Full Text Available Mesenchymal stem cells (MSCs, represent an attractive tool for the establishment of a successful stem-cell-based therapy of liver diseases. A number of different mechanisms contribute to the therapeutic effects exerted by MSCs, since these cells can differentiate into functional hepatic cells and can also produce a series of growth factors and cytokines able to suppress inflammatory responses, reduce hepatocyte apoptosis, regress liver fibrosis, and enhance hepatocyte functionality. To date, the infusion of MSCs or MSC-conditioned medium has shown encouraging results in the treatment of fulminant hepatic failure and in end-stage liver disease in experimental settings. However, some issues under debate hamper the use of MSCs in clinical trials. This paper summarizes the biological relevance of MSCs and the potential benefits and risks that can result from translating the MSC research to the treatment of liver diseases.

  8. Iron Deprivation in Cancer––Potential Therapeutic Implications

    Directory of Open Access Journals (Sweden)

    Daniel S. Wechsler

    2013-07-01

    Full Text Available Iron is essential for normal cellular function. It participates in a wide variety of cellular processes, including cellular respiration, DNA synthesis, and macromolecule biosynthesis. Iron is required for cell growth and proliferation, and changes in intracellular iron availability can have significant effects on cell cycle regulation, cellular metabolism, and cell division. Perhaps not surprisingly then, neoplastic cells have been found to have higher iron requirements than normal, non-malignant cells. Iron depletion through chelation has been explored as a possible therapeutic intervention in a variety of cancers. Here, we will review iron homeostasis in non-malignant and malignant cells, the widespread effects of iron depletion on the cell, the various iron chelators that have been explored in the treatment of cancer, and the tumor types that have been most commonly studied in the context of iron chelation.

  9. Therapeutic implications of manipulating and mining the microbiota.

    LENUS (Irish Health Repository)

    Shanahan, Fergus

    2009-09-01

    The gut microbiota is increasingly recognized as a health asset but occasionally is a contributor to the pathogenesis of both gastrointestinal and certain extra-intestinal disorders. This is driving research interest, the pace of which has been greatly facilitated by new molecular technologies for studying mixed microbial populations, including the non-cultivable sector. In addition, it appears that elements of a modern lifestyle such as diet, domestic hygiene, urbanization, antibiotic usage and family size, may represent proxy markers of environmental influence on the composition of the microbiota colonizing the host in early life. While manipulation of the microbiota has become a therapeutic strategy in certain clinical disorders, the prospect of mining host-microbe-dietary interactions for novel drug discovery may become an even more intriguing reality.

  10. Endoscopic ultrasound in gastroenterology: from diagnosis to therapeutic implications.

    Science.gov (United States)

    Mekky, Mohamed A; Abbas, Wael A

    2014-06-28

    Since its advent in 1980, the scope of endoscopic ultrasound (EUS) has grown to include a wide range of indications, and it is now being incorporated as an integral part of everyday practice in the field of gastroenterology. Its use is extending from an adjuvant imaging aid to utilization as a therapeutic tool for various gastrointestinal disorders. EUS was first used to visualize remote organs, such as the pancreas and abdominal lymph nodes. When fine needle aspiration was introduced, the indications for EUS expanded to include tissue sampling for diagnostic purposes. At the same time, the needle can be used to convey a potential therapy to the internal organs, allowing access to remote sites. In this review, we aim to highlight the expanding spectrum of EUS indications and uses in the field of gastroenterology.

  11. [Stage models of homosexual identity formation. Implications for therapeutic practice].

    Science.gov (United States)

    Mijas, Magdalena; Iniewicz, Grzegorz; Grabski, Bartosz

    2012-01-01

    The authors discuss stage models of gay and lesbian identity formation first proposed during the 1970s within affirmative approaches to homosexuality. The process of developing homosexual identity is characterized here with linearly ordered stages distinguished around major developmental events leading to new self-definition. Among many stage proposals the authors have chosen and presented two: by Vivienne Cass and Susan McCarn with Ruth Fassinger. The presented models were analysed in terms of their usefulness in therapeutic practice aimed at promoting the formation of gay identity, for which they have been originally designed. An important part of this discussion is evaluation of the accuracy of developmental process descriptions contained in stage models.

  12. Immunogenomic Classification of Colorectal Cancer and Therapeutic Implications

    Directory of Open Access Journals (Sweden)

    Jessica Roelands

    2017-10-01

    Full Text Available The immune system has a substantial effect on colorectal cancer (CRC progression. Additionally, the response to immunotherapeutics and conventional treatment options (e.g., chemotherapy, radiotherapy and targeted therapies is influenced by the immune system. The molecular characterization of colorectal cancer (CRC has led to the identification of favorable and unfavorable immunological attributes linked to clinical outcome. With the definition of consensus molecular subtypes (CMSs based on transcriptomic profiles, multiple characteristics have been proposed to be responsible for the development of the tumor immune microenvironment and corresponding mechanisms of immune escape. In this review, a detailed description of proposed immune phenotypes as well as their interaction with different therapeutic modalities will be provided. Finally, possible strategies to shift the CRC immune phenotype towards a reactive, anti-tumor orientation are proposed per CMS.

  13. Therapeutic Implications of Targeting Energy Metabolism in Breast Cancer

    Directory of Open Access Journals (Sweden)

    Meena K. Sakharkar

    2013-01-01

    Full Text Available PPARs are ligand activated transcription factors. PPARγ agonists have been reported as a new and potentially efficacious treatment of inflammation, diabetes, obesity, cancer, AD, and schizophrenia. Since cancer cells show dysregulation of glycolysis they are potentially manageable through changes in metabolic environment. Interestingly, several of the genes involved in maintaining the metabolic environment and the central energy generation pathway are regulated or predicted to be regulated by PPARγ. The use of synthetic PPARγ ligands as drugs and their recent withdrawal/restricted usage highlight the lack of understanding of the molecular basis of these drugs, their off-target effects, and their network. These data further underscores the complexity of nuclear receptor signalling mechanisms. This paper will discuss the function and role of PPARγ in energy metabolism and cancer biology in general and its emergence as a promising therapeutic target in breast cancer.

  14. Therapeutic abortion and its psychological implications: the Canadian experience.

    Science.gov (United States)

    Greenglass, E. R.

    1975-01-01

    Approximately 9 months after a legal therapeutic abortion, 188 Canadian women were interviewed. One half were single and the rest were married, separated or divorced. They were matched closely for a number of demographic variables with control women who had not had abortions. Neurotic disturbance in several areas of personality functioning was assessed from questionnaire responses. Out of 27 psychological scales, differences between the abortion and control groups were found on only 3: in general, women who had had abortions were more rebellious than control women, abortion tended to be associated with somewhat greater depression in married women, and single women who had had abortions scored higher on the shallow-affect scale. However, all the personality scores were well within the normal range. Perceived social support was strongly associated with favourable psychological reactions after abortion. Use of contraceptives improved greatly after the abortion, when over 90% of women reported using contraceptives regularly. PMID:803127

  15. Cancer stem cell theory: therapeutic implications for nanomedicine.

    Science.gov (United States)

    Wang, Ke; Wu, Xianguo; Wang, Jianwei; Huang, Jian

    2013-01-01

    Evidence continues to accumulate showing that tumors contain a minority population of cells responsible for tumor initiation, growth, and recurrence. These are termed "cancer stem cells" (CSCs). Functional assays have identified the self-renewal and tumor-initiation capabilities of CSCs. Moreover, recent studies have revealed that these CSCs is responsible for chemotherapy resistance within a tumor. Several mechanisms of chemoresistance have been proposed, including increased Wnt/β-catenin and Notch signaling, as well as high expression levels of adenosine triphosphate-binding cassette transporters, an active DNA repair capacity, and slow rate of self-renewal. Nanoscale drug-delivery systems, which transport therapeutically active molecules, prolong circulation, and improve biodistribution in the body, may allow more effective and specific therapies to address the challenges posed by CSCs. In particular, some nanovehicles are being exploited for selective drug delivery to CSCs and show promising results. In this review, we highlight the mechanisms of drug resistance and the novel strategies using nanoscale drugs to eliminate CSCs.

  16. Ethnic and genetic causes of neutropenia: clinical and therapeutic implications.

    Science.gov (United States)

    D'Angelo, Guido

    2009-01-01

    The white blood cell count represents clinical data linked with different pathologic conditions, as well as with lifestyle. Another very important condition that affects the number of leukocytes is race and ethnic group-the geographic zone of origin. Genetic studies have identified the gene that controls the expression of the Duffy antigen receptor for chemokine (DARC), which is associated with the ethnic group to which individuals belong. The single-nucleotide polymorphism strongly associated with race is DARC rs2814778. Currently, it is the only condition that can explain the difference in white blood cell count between different ethnic groups. In a society increasingly characterized by multiracial issues, the leukopenia and/or neutropenia in ethnic groups must be known and accurately assessed clinically. Improved knowledge of this association may help in optimizing therapeutic approaches, mainly for African patients with severe diseases, cancer in particular. Recently, preclinical data have also suggested a link between the Duffy antigen and coagulation. This review also discusses the main causes of genetic neutropenia.

  17. Angiotensin receptor blockers & endothelial dysfunction: Possible correlation & therapeutic implications

    Directory of Open Access Journals (Sweden)

    Miroslav Radenkovic

    2016-01-01

    Full Text Available The endothelium is one of the most important constituents of vascular homeostasis, which is achieved through continual and balanced production of different relaxing and contractile factors. When there is a pathological disturbance in release of these products, endothelial dysfunction (ED will probably occur. ED is considered to be the initial step in the development of atherosclerosis. This pathological activation and inadequate functioning of endothelial cells was shown to be to some extent a reversible process, which all together resulted in increased interest in investigation of different beneficial treatment options. To this point, the pharmacological approach, including for example, the use of angiotensin-converting enzyme inhibitors or statins, was clearly shown to be effective in the improvement of ED. One of many critical issues underlying ED represents instability in the balance between nitric oxide and angiotensin II (Ang II production. Considering that Ang II was confirmed to be important for the development of ED, the aim of this review article was to summarize the findings of up to date clinical studies associated with therapeutic application of angiotensin receptor blockers and improvement in ED. In addition, it was of interest to review the pleiotropic actions of angiotensin receptor blockers linked to the improvement of ED. The prospective, randomized, double-blind, placebo or active-controlled clinical trials were identified and selected for the final evaluation.

  18. Metabolic actions of FGF21: molecular mechanisms and therapeutic implications

    Directory of Open Access Journals (Sweden)

    Xuan Ge

    2012-08-01

    Full Text Available Fibroblast growth factor 21 (FGF21 is an atypical member of the FGF family that functions as an endocrine factor. In obese animals, elevation of plasma FGF21 levels by either pharmacological or genetic approaches reduces body weight, decreases hyperglycemia and hyperlipidemia, alleviates fatty liver and increases insulin sensitivity. FGF21 exerts its pleiotropic metabolic effects through its actions on multiple targets, including adipose tissue, liver, brain and pancreas. The expression of FGF21 is under the control of both peroxisome proliferator-activated receptor gamma (PPARγ and peroxisome proliferator-activated receptor alpha (PPARα. A growing body of evidence suggests that the metabolic benefits of these two nuclear receptors are mediated in part by induction of FGF21. In humans, plasma levels of FGF21 are elevated in obese subjects and patients with type 2 diabetes, but are reduced in patients with autoimmune diabetes. This review summarizes recent advances in understanding the physiological roles of FGF21 and the molecular pathways underlying its actions, and also discusses the future prospective of developing FGF21 or its agonists as therapeutic agents for obesity-related medical complications.

  19. Obesity and inflammatory bowel disease: diagnostic and therapeutic implications.

    Science.gov (United States)

    Swanson, Sophia M; Harper, Jason; Zisman, Timothy L

    2018-03-01

    The review summarizes our current understanding of how obesity impacts diagnostic studies and therapies used in inflammatory bowel disease (IBD) as well as the safety and efficacy of medical and surgical weight loss therapies in the obese IBD patient. Many of the diagnostic tools we rely on in the identification and monitoring of IBD can be altered by obesity. Obesity is associated with increased acute phase proteins and fecal calprotectin. It can be more difficult to obtain and interpret cross sectional imaging of obese patients. Recent studies have also shown that common therapies used to treat IBD may be less effective in the obese population and may impact comorbid disease. Our understanding of how best to measure obesity is evolving. In addition to BMI, studies now include measures of visceral adiposity and subcutaneous to visceral adiposity ratios. An emerging area of interest is the safety and efficacy of obesity treatment including bariatric surgery in patients with IBD. A remaining question is how weight loss may alter the course of IBD. The proportion of obese IBD patients is on the rise. Caring for this population requires a better understanding of how obesity impacts diagnostic testing and therapeutic strategies. The approach to weight loss in this population is complex and future studies are needed to determine the safety of medical or surgical weight loss and its impact on the course of disease.

  20. Inflammatory Cytokines in Depression: Neurobiological Mechanisms and Therapeutic Implications

    Science.gov (United States)

    Felger, Jennifer C.; Lotrich, Francis E.

    2013-01-01

    Mounting evidence indicates that inflammatory cytokines contribute to the development of depression in both medically ill and medically healthy individuals. Cytokines are important for development and normal brain function, and have the ability to influence neurocircuitry and neurotransmitter systems to produce behavioral alterations. Acutely, inflammatory cytokine administration or activation of the innate immune system produces adaptive behavioral responses that promote conservation of energy to combat infection or recovery from injury. However, chronic exposure to elevated inflammatory cytokines and persistent alterations in neurotransmitter systems can lead to neuropsychiatric disorders and depression. Mechanisms of cytokine behavioral effects involve activation of inflammatory signaling pathways in the brain that results in changes in monoamine, glutamate, and neuropeptide systems, and decreases in growth factors, e.g. brain derived neurotrophic factor. Furthermore, inflammatory cytokines may serve as mediators of both environmental (e.g. childhood trauma, obesity, stress, and poor sleep) and genetic (functional gene polymorphisms) factors that contribute to depression’s development. This review explores the idea that specific gene polymorphisms and neurotransmitter systems can confer protection from or vulnerability to specific symptom dimensions of cytokine-related depression. Additionally, potential therapeutic strategies that target inflammatory cytokine signaling or the consequences of cytokines on neurotransmitter systems in the brain to prevent or reverse cytokine effects on behavior are discussed. PMID:23644052

  1. [Abnormalities of synaptogenesis in autism. Pathogenic and therapeutic implications].

    Science.gov (United States)

    García-Peñas, Juan José; Domínguez-Carral, Jana; Pereira-Bezanilla, Elena

    2012-02-29

    The social, language, and behavioural problems that occur with autism suggest that this syndrome affects a functionally diverse and widely distributed set of neural systems. To review the molecular pathways involved in synaptic growth, development, and stability of human synapses. We also examine the genes implicated in synaptogenesis which have been associated with autism. In particular, we highlight the role of these genes in synaptic cell adhesion, organization of presynaptic and postsynaptic specializations, growth signaling pathways, and endosomal function. Proper brain function requires stringent balance of excitatory and inhibitory synapse formation during neural circuit assembly. Mutation of genes that normally sculpt and maintain this balance results in severe dysfunction, causing neurodevelopmental disorders including autism, epilepsy, Angelman syndrome, fragile X syndrome, and Rett syndrome. Such mutations may result in defective architectural structuring of synaptic connections, molecular assembly of synapses and/or functional synaptogenesis. Increased knowledge of abnormal mechanisms of human synaptogenesis may lead to define different etio-pathogenic models of autism and to understand how far abnormal cell/synaptic growth and synaptic function could be reversed.

  2. Respiratory manifestations of panic disorder: causes, consequences and therapeutic implications.

    Science.gov (United States)

    Sardinha, Aline; Freire, Rafael Christophe da Rocha; Zin, Walter Araújo; Nardi, Antonio Egidio

    2009-07-01

    Multiple respiratory abnormalities can be found in anxiety disorders, especially in panic disorder (PD). Individuals with PD experience unexpected panic attacks, characterized by anxiety and fear, resulting in a number of autonomic and respiratory symptoms. Respiratory stimulation is a common event during panic attacks. The respiratory abnormality most often reported in PD patients is increased CO2 sensitivity, which has given rise to the hypothesis of fundamental abnormalities in the physiological mechanisms that control breathing in PD. There is evidence that PD patients with dominant respiratory symptoms are more sensitive to respiratory tests than are those who do not manifest such symptoms, and that the former group constitutes a distinct subtype. Patients with PD tend to hyperventilate and to panic in response to respiratory stimulants such as CO2, triggering the activation of a hypersensitive fear network. Although respiratory physiology seems to remain normal in these subjects, recent evidence supports the idea that they present subclinical abnormalities in respiration and in other functions related to body homeostasis. The fear network, composed of the hippocampus, the medial prefrontal cortex, the amygdala and its brain stem projections, might be oversensitive in PD patients. This theory might explain why medication and cognitive-behavioral therapy are both clearly effective. Our aim was to review the relationship between respiration and PD, addressing the respiratory subtype of PD and the hyperventilation syndrome, with a focus on respiratory challenge tests, as well as on the current mechanistic concepts and the pharmacological implications of this relationship.

  3. Therapeutic implications of mediastinal involvement in advanced Hodgkin's disease

    DEFF Research Database (Denmark)

    Specht, L; Nissen, N I; Walbom-Jørgensen, S

    1985-01-01

    47 patients with advanced Hodgkin's disease (stage IIIB or IV) and mediastinal involvement, treated during the period 1969-78 and followed till death or from 36 to 126 months after initiation of therapy, were analysed. All 47 patients had received combination chemotherapy (MOPP or equivalent...... regimens). 20 had also received additional radiotherapy to mediastinum (and in some cases to other involved areas as well). The 2 treatment groups did not differ significantly with regard to the more important prognostic factors. Both in the case of stages IV and IIIB patients in the group treated......'s disease and crude survival including all causes of death were significantly better for patients treated with combination chemotherapy plus mediastinal irradiation. Consequently, for patients with advanced Hodgkin's disease and mediastinal involvement a combined approach including radiotherapy as well...

  4. Implication of Heat Shock Factors in Tumorigenesis: Therapeutical Potential

    Energy Technology Data Exchange (ETDEWEB)

    Thonel, Aurelie de [INSERM U866, Dijon (France); Faculty of Medicine and Pharmacy, University of Burgundy, 21033 Dijon (France); Mezger, Valerie, E-mail: valerie.mezger@univ-paris-diderot.fr [CNRS, UMR7216 Epigenetics and Cell Fate, Paris (France); University Paris Diderot, 75013 Paris (France); Garrido, Carmen, E-mail: valerie.mezger@univ-paris-diderot.fr [INSERM U866, Dijon (France); Faculty of Medicine and Pharmacy, University of Burgundy, 21033 Dijon (France); CHU, Dijon BP1542, Dijon (France)

    2011-03-07

    Heat Shock Factors (HSF) form a family of transcription factors (four in mammals) which were named according to the discovery of their activation by a heat shock. HSFs trigger the expression of genes encoding Heat Shock Proteins (HSPs) that function as molecular chaperones, contributing to establish a cytoprotective state to various proteotoxic stresses and in pathological conditions. Increasing evidence indicates that this ancient transcriptional protective program acts genome-widely and performs unexpected functions in the absence of experimentally defined stress. Indeed, HSFs are able to re-shape cellular pathways controlling longevity, growth, metabolism and development. The most well studied HSF, HSF1, has been found at elevated levels in tumors with high metastatic potential and is associated with poor prognosis. This is partly explained by the above-mentioned cytoprotective (HSP-dependent) function that may enable cancer cells to adapt to the initial oncogenic stress and to support malignant transformation. Nevertheless, HSF1 operates as major multifaceted enhancers of tumorigenesis through, not only the induction of classical heat shock genes, but also of “non-classical” targets. Indeed, in cancer cells, HSF1 regulates genes involved in core cellular functions including proliferation, survival, migration, protein synthesis, signal transduction, and glucose metabolism, making HSF1 a very attractive target in cancer therapy. In this review, we describe the different physiological roles of HSFs as well as the recent discoveries in term of non-cogenic potential of these HSFs, more specifically associated to the activation of “non-classical” HSF target genes. We also present an update on the compounds with potent HSF1-modulating activity of potential interest as anti-cancer therapeutic agents.

  5. Implication of Heat Shock Factors in Tumorigenesis: Therapeutical Potential

    Directory of Open Access Journals (Sweden)

    Aurelie de Thonel

    2011-03-01

    Full Text Available Heat Shock Factors (HSF form a family of transcription factors (four in mammals which were named according to the discovery of their activation by a heat shock. HSFs trigger the expression of genes encoding Heat Shock Proteins (HSPs that function as molecular chaperones, contributing to establish a cytoprotective state to various proteotoxic stresses and in pathological conditions. Increasing evidence indicates that this ancient transcriptional protective program acts genome-widely and performs unexpected functions in the absence of experimentally defined stress. Indeed, HSFs are able to re-shape cellular pathways controlling longevity, growth, metabolism and development. The most well studied HSF, HSF1, has been found at elevated levels in tumors with high metastatic potential and is associated with poor prognosis. This is partly explained by the above-mentioned cytoprotective (HSP-dependent function that may enable cancer cells to adapt to the initial oncogenic stress and to support malignant transformation. Nevertheless, HSF1 operates as major multifaceted enhancers of tumorigenesis through, not only the induction of classical heat shock genes, but also of “non-classical” targets. Indeed, in cancer cells, HSF1 regulates genes involved in core cellular functions including proliferation, survival, migration, protein synthesis, signal transduction, and glucose metabolism, making HSF1 a very attractive target in cancer therapy. In this review, we describe the different physiological roles of HSFs as well as the recent discoveries in term of non-cogenic potential of these HSFs, more specifically associated to the activation of “non-classical” HSF target genes. We also present an update on the compounds with potent HSF1-modulating activity of potential interest as anti-cancer therapeutic agents.

  6. Interactions between Hsp90 and oncogenic viruses: implications for viral cancer therapeutics.

    Science.gov (United States)

    Defee, Michael R; Qin, Zhiqiang; Dai, Lu; Isaacs, Jennifer S; Parsons, Chris H

    2011-01-01

    Oncogenic viruses are the etiologic agents for a significant proportion of human cancers, but effective therapies and preventative strategies are lacking for the majority of virus-associated cancers. Targeting of virus-induced signal transduction or virus-host protein interactions may offer novel therapeutic strategies for viral cancers. Heat shock protein 90 (Hsp90) is a well-characterized, multifunctional molecular chaperone involved in regulation of signal transduction, transcriptional activation, oncogenic protein stabilization, and neovascularization-pathogenic elements relevant to viral cancer pathogenesis. This review will summarize mechanistic concepts involving regulation of viral oncogenesis by both intracellular and extracellular Hsp90, as well as current therapeutic implications of these data.

  7. A new therapeutic proposal for writer's cramp: a case report

    Directory of Open Access Journals (Sweden)

    Flavia Quadros Boisson Waissman

    Full Text Available CONTEXT: Writer's cramp is a kind of focal hand dystonia that appears when individuals are writing. Since pharmacological treatment has not shown the desired therapeutic response, a study on immobilization of the damaged musculature was performed on two individuals with writer's cramp, using splints with the objective of reducing the handwriting abnormalities. CASE REPORT: Two patients presenting writer's cramp who had previously undergone different therapies, including botulinum toxin, without an adequate response, participated in a body awareness program, followed by immobilization of the hand musculature damaged by dystonia, by means of splints, with handwriting training. At the end of the procedure, objective and subjective improvements in the motor pattern of writing could be observed. The immobilization of the dystonic musculature of the hand by means of splints and the motor training of handwriting helped to improve and consequently to reduce the dystonic component observed in the writer's cramp.

  8. The immunoregulatory properties of oncolytic myxoma virus and their implications in therapeutics.

    Science.gov (United States)

    Liu, Jia; Wennier, Sonia; McFadden, Grant

    2010-12-01

    Myxoma virus (MYXV) is a poxvirus with a strict rabbit-specific host-tropism for pathogenesis. The immunoregulatory factors encoded by MYXV can suppress some functions of immune effectors from other species. We review their mechanisms of action, implications in therapeutics and the potential to improve MYXV as an oncolytic agent in humans. Copyright © 2010 Institut Pasteur. Published by Elsevier SAS. All rights reserved.

  9. A token economy in the framework of a hospital therapeutic community -- practice and psychosocial implications.

    Science.gov (United States)

    Last, U; Ginor, M; Lowental, U; Klein, H

    1979-01-01

    A token economy (TE) aimed at enhancing self care, work habits, and social participation was initiated in conjunction with the restructuring of a chronic ward into a therapeutic community. Recorded data over a year revealed a differential impact of the TE on various patients. An attempt is made to characterize differential response modes to the TE and to delineate their correlates. Both participants in the program and therapeutic agents were interviewed as to their attitudes towards the TE. Beneficial effects were demonstrated mainly in patients with a relatively late onset of psychiatric illness, but a favorable attitude towards the TE was displayed by both patients and staff members. Implications for psychosocial readaptation are discussed taking into account humanistic and psychodynamic points of view. The reconsideration of possible merging of different therapeutic techniques seems to be desirable.

  10. P-selectin, carcinoma metastasis and heparin: novel mechanistic connections with therapeutic implications

    Directory of Open Access Journals (Sweden)

    Varki A.

    2001-01-01

    Full Text Available Metastasis is a multistep cascade initiated when malignant cells penetrate the tissue surrounding the primary tumor and enter the bloodstream. Classic studies indicated that blood platelets form complexes around tumor cells in the circulation and facilitate metastases. In other work, the anticoagulant drug heparin diminished metastasis in murine models, as well is in preliminary human studies. However, attempts to follow up the latter observation using vitamin K antagonists failed, indicating that the primary mechanism of heparin action was unrelated to its anticoagulant properties. Other studies showed that the overexpression of sialylated fucosylated glycans in human carcinomas is associated with a poor prognosis. We have now brought all these observations together into one mechanistic explanation, which has therapeutic implications. Carcinoma cells expressing sialylated fucosylated mucins can interact with platelets, leukocytes and endothelium via the selectin family of cell adhesion molecules. The initial organ colonization of intravenously injected carcinoma cells is attenuated in P-selectin-deficient mice, in mice receiving tumor cells pretreated with O-sialoglycoprotease (to selectively remove mucins from cell surfaces, or in mice receiving a single dose of heparin prior to tumor cell injection. In each case, we found that formation of a platelet coating on cancer cells was impeded, allowing increased access of leukocytes to the tumor cells. Several weeks later, all animals showed a decrease in the extent of established metastasis, indicating a long-lasting effect of the short-term intervention. The absence of obvious synergism amongst the three treatments suggests that they all act via a common pathway. Thus, a major mechanism of heparin action in cancer may be inhibition of P-selectin-mediated platelet coating of tumor cells during the initial phase of the metastatic process. We therefore suggest that heparin use in cancer be re

  11. Turning the gene tap off; implications of regulating gene expression for cancer therapeutics.

    Science.gov (United States)

    Curtin, James F; Candolfi, Marianela; Xiong, Weidong; Lowenstein, Pedro R; Castro, Maria G

    2008-03-01

    Cancer poses a tremendous therapeutic challenge worldwide, highlighting the critical need for developing novel therapeutics. A promising cancer treatment modality is gene therapy, which is a form of molecular medicine designed to introduce into target cells genetic material with therapeutic intent. Anticancer gene therapy strategies currently used in preclinical models, and in some cases in the clinic, include proapoptotic genes, oncolytic/replicative vectors, conditional cytotoxic approaches, inhibition of angiogenesis, inhibition of growth factor signaling, inactivation of oncogenes, inhibition of tumor invasion and stimulation of the immune system. The translation of these novel therapeutic modalities from the preclinical setting to the clinic has been driven by encouraging preclinical efficacy data and advances in gene delivery technologies. One area of intense research involves the ability to accurately regulate the levels of therapeutic gene expression to achieve enhanced efficacy and provide the capability to switch gene expression off completely if adverse side effects should arise. This feature could also be implemented to switch gene expression off when a successful therapeutic outcome ensues. Here, we will review recent developments related to the engineering of transcriptional switches within gene delivery systems, which could be implemented in clinical gene therapy applications directed at the treatment of cancer.

  12. Cell and molecular biology of intervertebral disc degeneration: current understanding and implications for potential therapeutic strategies.

    Science.gov (United States)

    Wang, S Z; Rui, Y F; Lu, J; Wang, C

    2014-10-01

    Intervertebral disc degeneration (IDD) is a chronic, complex process associated with low back pain; mechanisms of its occurrence have not yet been fully elucidated. Its process is not only accompanied by morphological changes, but also by systematic changes in its histological and biochemical properties. Many cellular and molecular mechanisms have been reported to be related with IDD and to reverse degenerative trends, abnormal conditions of the living cells and altered cell phenotypes would need to be restored. Promising biological therapeutic strategies still rely on injection of active substances, gene therapy and cell transplantation. With advanced study of tissue engineering protocols based on cell therapy, combined use of seeding cells, bio-active substances and bio-compatible materials, are promising for IDD regeneration. Recently reported progenitor cells within discs themselves also hold prospects for future IDD studies. This article describes the background of IDD, current understanding and implications of potential therapeutic strategies. © 2014 John Wiley & Sons Ltd.

  13. Differences between invasive lobular and invasive ductal carcinoma of the breast: results and therapeutic implications.

    Science.gov (United States)

    Barroso-Sousa, Romualdo; Metzger-Filho, Otto

    2016-07-01

    Invasive lobular carcinoma (ILC) is the second most common histologic subtype of breast cancer (BC): ILC differs from invasive ductal carcinoma (IDC) in its clinicopathological characteristics and responsiveness to systemic therapy. From the clinical standpoint, data suggest that ILC derives a distinct benefit from systemic therapy compared to IDC. In addition, comprehensive molecular analyses have been reported for ILCs, confirming that these tumors have specific genomic profiles compared to IDC. Despite these differences, clinical trials and practical clinical guidelines tend to treat BC as a single entity. Here we discuss these clinical and molecular data and their therapeutic implications.

  14. Mechanisms and Consequences of Oxidative Stress in Lung Disease: Therapeutic Implications for an Aging Populace.

    Science.gov (United States)

    Hecker, Louise

    2017-12-14

    The rapid expansion of the elderly population has led to the recent epidemic of age-related diseases, including increased incidence and mortality of chronic and acute lung diseases. Numerous studies have implicated aging and oxidative stress in the pathogenesis of various pulmonary diseases; however, despite recent advances in these fields, the specific contributions of aging and oxidative stress remain elusive. This review will discuss the consequences of aging on lung morphology and physiology, and how redox imbalance with aging contributes to lung disease susceptibility. Here, we focus on three lung diseases for which aging is a significant risk factor: acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF). Pre-clinical and clinical development for redox- and senescence-altering therapeutic strategies are discussed, as well as scientific advancements that may direct current and future therapeutic development. A deeper understanding of how aging impacts normal lung function, redox balance, and injury-repair processes will inspire the development of new therapies to prevent and/or reverse age-associated pulmonary diseases, and ultimately increase healthspan and longevity. This review is intended to encourage basic, clinical, and translational research that will bridge knowledge gaps at the intersection of aging, oxidative stress, and lung disease to fuel the development of more effective therapeutic strategies for lung diseases that disproportionately afflict the elderly.

  15. The role of glial cells in Alzheimer disease: potential therapeutic implications.

    Science.gov (United States)

    Lopategui Cabezas, I; Herrera Batista, A; Pentón Rol, G

    2014-06-01

    Alzheimer (AD) disease is a complex neurodegenerative disease characterised by inflammation, neurotoxicity, oxidative stress, and reactive gliosis. Microglia and astrocytes not only act as antigen-presenting cells, but also function as effector cells releasing pro-inflammatory molecules that promote excitotoxicity and neurodegeneration. In the present review we discuss the role of glia, specifically microglia and astrocytes, in the pathophysiology of AD and possible therapeutic implications. The growing body of evidence suggesting that microglia and astrocytes play a pathogenic role and activate inflammation pathways, the neurotoxic factors released by these cells when activated, and the way these factors may disrupt the homeostasis of the central nervous system all support the hypothesis that glia-induced inflammation exacerbates AD. Inhibiting inflammation by deactivating glial cells may reduce the production of factors which contribute to neurotoxicity, and therefore result in clinical improvement. Microglia and astrocytes are therapeutic targets for the development of new drugs to combat this disease. Therapeutic strategies designed to counter the detrimental effects of overactivation of these cell populations should be investigated. Copyright © 2012 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.

  16. The public library as therapeutic landscape: a qualitative case study.

    Science.gov (United States)

    Brewster, Liz

    2014-03-01

    The idea of the therapeutic landscape has been widely used to describe the relationship between place and improvements in mental health. This paper uses data from a qualitative study conducted with people with mental health problems to outline the role of the public library as a therapeutic landscape. It situates the public library as a space that is simultaneously familiar and welcoming, comforting and calming, and empowering. Further, the paper reflects on the impact of proposed library closures in light of these previously hidden benefits, thinking about the library's role as an environment and not as a service provider. Copyright © 2014 Elsevier Ltd. All rights reserved.

  17. Telepsychotherapy and the Therapeutic Relationship: Principles, Advantages, and Case Examples.

    Science.gov (United States)

    Kocsis, Barbara J; Yellowlees, Peter

    2017-08-24

    As the use of technology continues to expand within our mental healthcare system, there has been an increasing interest in conducting psychotherapy online using videoconferencing. Literature pertaining to telepsychotherapy has explored possible drawbacks of this modality on the therapeutic relationship, although several studies have shown that the efficacy of online psychotherapy is equivalent to in-person approaches. Little is written about the potential advantages to the psychotherapeutic relationship when psychotherapy is carried out over videoconferencing. The available literature was reviewed, as were the general principles of telepsychotherapy and the therapeutic relationship, followed by a more in-depth consideration of patient populations for whom telepsychotherapy may offer distinct advantages. The current literature, as well as our own clinical experience, suggests that telepsychotherapy may be effective for a broad range of patients, and it may offer distinct advantages in the building of a trusting psychotherapeutic relationship. Telepsychotherapy offers a novel way to reach and form strong psychotherapeutic relationships with many different types of patients, and it may foster therapeutic intimacy in ways that in-person psychotherapy cannot. More research is needed to further explore this unique modality.

  18. Biology of anti-TNF agents in immune-mediated inflammatory diseases: therapeutic implications.

    Science.gov (United States)

    Levy, Roger A; Guzman, Renato; Castañeda-Hernández, Gilberto; Martinez-Vazquez, Manuel; Damian, Guilherme; Cara, Carlos

    2016-12-01

    Biologics are increasingly being used to modify the course of immune-mediated inflammatory diseases. Some main agents are monoclonal antibodies and a fusion-protein that target TNF. This group includes adalimumab, infliximab, certolizumab pegol, golimumab and etanercept. Although the efficacy of anti-TNFs is supported by numerous randomized clinical trials, their pharmacokinetics depend on many factors, in particular immunogenicity, which can cause marked and rapid clearance and a consequent decrease in efficacy. Kinetics involve receptors that recognize the Fc fragment of the antibody and are responsible for various processes. Pharmacological advances permit optimizing the pharmacokinetics of anti-TNFs. In this review, we examine the kinetics of anti-TNF biologics, and consequent therapeutic implications, and overview some latest developments in the field. First draftsubmitted: 17 May 2016; Accepted for publication: 15 September2016; Published online: 14 October 2016.

  19. Therapeutic implications of viewing sexual identity in terms of essentialist and constructionist theories.

    Science.gov (United States)

    Hart, J

    1984-01-01

    One of the most challenging developments in recent historical studies and in empirical research in sociology has been constructionist theories relating to "sexual personalities." The "constructionist" view is that sexual identity is labile and can be therapeutically modified. In clinical work, this has presented an alternative view of the development of social sex-role and sexual orientation. Previously, views of sexual identity as a fixed personal characteristic (the "essentialist" view) provided clinicians with ways of treating psychologically distressed people either by transsexual conversion or aversion therapy. This article reviews some implications of "constructionist" and "essentialist" theory. It describes the author's clinical attempts to present constructionist views to clients who are in conflict about their sexual orientation and social sex-role. The article concludes that constructionist therapy has not taken into account clinical evidence that clients may adhere to "essentialist" beliefs.

  20. Recent Advances in Developing Inhibitors for Hypoxia-Inducible Factor Prolyl Hydroxylases and Their Therapeutic Implications

    Directory of Open Access Journals (Sweden)

    So Yeon Kim

    2015-11-01

    Full Text Available Hypoxia-inducible factor (HIF prolyl hydroxylases (PHDs are members of the 2-oxoglutarate dependent non-heme iron dioxygenases. Due to their physiological roles in regulation of HIF-1α stability, many efforts have been focused on searching for selective PHD inhibitors to control HIF-1α levels for therapeutic applications. In this review, we first describe the structure of PHD2 as a molecular basis for structure-based drug design (SBDD and various experimental methods developed for measuring PHD activity. We further discuss the current status of the development of PHD inhibitors enabled by combining SBDD approaches with high-throughput screening. Finally, we highlight the clinical implications of small molecule PHD inhibitors.

  1. Heterotypic Cellular Interactions in the Ovarian Tumor Microenvironment: Biological Significance and Therapeutic Implications

    Directory of Open Access Journals (Sweden)

    Honami eNaora

    2014-02-01

    Full Text Available The majority of women who are diagnosed with epithelial ovarian cancer present with extensive peritoneal carcinomatosis and are rarely cured by conventional chemotherapy. Ovarian cancer cells typically disseminate by shedding into the peritoneal fluid and implant on the mesothelium-lined peritoneal surfaces that overlie connective and white adipose tissues. Emerging evidence indicates that ovarian tumor progression is orchestrated by dynamic interplay between tumor cells and a variety of stromal cells such as adipocytes, endothelial cells, fibroblasts, mesenchymal stem cells, macrophages and other immune cells. This mini-review discusses the biological significance of the heterotypic cellular interactions in the ovarian tumor microenvironment and the therapeutic implications of targeting these interactions.

  2. Current and novel insights into the neurophysiology of migraine and its implications for therapeutics.

    Science.gov (United States)

    Akerman, Simon; Romero-Reyes, Marcela; Holland, Philip R

    2017-04-01

    Migraine headache and its associated symptoms have plagued humans for two millennia. It is manifest throughout the world, and affects more than 1/6 of the global population. It is the most common brain disorder, and is characterized by moderate to severe unilateral headache that is accompanied by vomiting, nausea, photophobia, phonophobia, and other hypersensitive symptoms of the senses. While there is still a clear lack of understanding of its neurophysiology, it is beginning to be understood, and it seems to suggest migraine is a disorder of brain sensory processing, characterized by a generalized neuronal hyperexcitability. The complex symptomatology of migraine indicates that multiple neuronal systems are involved, including brainstem and diencephalic systems, which function abnormally, resulting in premonitory symptoms, ultimately evolving to affect the dural trigeminovascular system, and the pain phase of migraine. The migraineur also seems to be particularly sensitive to fluctuations in homeostasis, such as sleep, feeding and stress, reflecting the abnormality of functioning in these brainstem and diencephalic systems. Implications for therapeutic development have grown out of our understanding of migraine neurophysiology, leading to major drug classes, such as triptans, calcitonin gene-related peptide receptor antagonists, and 5-HT1F receptor agonists, as well as neuromodulatory approaches, with the promise of more to come. The present review will discuss the current understanding of the neurophysiology of migraine, particularly migraine headache, and novel insights into the complex neural networks responsible for associated neurological symptoms, and how interaction of these networks with migraine pain pathways has implications for the development of novel therapeutics. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Vitamin D receptor signaling and its therapeutic implications: Genome-wide and structural view.

    Science.gov (United States)

    Carlberg, Carsten; Molnár, Ferdinand

    2015-05-01

    Vitamin D3 is one of the few natural compounds that has, via its metabolite 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) and the transcription factor vitamin D receptor (VDR), a direct effect on gene regulation. For efficiently applying the therapeutic and disease-preventing potential of 1,25(OH)2D3 and its synthetic analogs, the key steps in vitamin D signaling need to be understood. These are the different types of molecular interactions with the VDR, such as (i) the complex formation of VDR with genomic DNA, (ii) the interaction of VDR with its partner transcription factors, (iii) the binding of 1,25(OH)2D3 or its synthetic analogs within the ligand-binding pocket of the VDR, and (iv) the resulting conformational change on the surface of the VDR leading to a change of the protein-protein interaction profile of the receptor with other proteins. This review will present the latest genome-wide insight into vitamin D signaling, and will discuss its therapeutic implications.

  4. Involvement of the mitochondrial benzodiazepine receptor in traumatic brain injury: therapeutic implications.

    Science.gov (United States)

    Vlodavsky, Eugene; Palzur, Eilam; Soustiel, Jean F

    2014-01-01

    Traumatic brain injuries represent the leading cause of death and morbidity in young adults in western countries, and are responsible for a major social and economical burden. For decades, the mainstay of neurotrauma management has been represented by control of post-traumatic edema. With the emergence of a better understanding of the underlying cellular mechanisms responsible for the generation of secondary brain damage, the hope for the "magic bullet" has prompted the development of novel drugs that have repeatedly failed to significantly improve outcome of head-injured patients. During the past decade, mitochondrial functional and structural impairment has emerged as a pivotal event in the pathway of cell to secondary death. Extensive research has identified a vast range of deleterious signals that are generated and integrated at the mitochondrial level resulting in impairment of major mitochondrial functions such as calcium homeostasis, free radicals generation and detoxification, energy production and neurosteroidogenesis. Mitochondria have therefore emerged as a potential therapeutic target. Within the spectrum of major mitochondrial structural components, the 18 kDa translocator protein (TSPO) has shown important and relevant functions such as steroid synthesis and modulation of the mitochondrial permeability transition that may substantially affect the fate of injured cells. This review summarizes the potential therapeutic implications of TSPO modulation in traumatic brain injury in the view of the current knowledge on this intriguing mitochondrial complex.

  5. Mature aggressive B-cell lymphoma across age groups - molecular advances and therapeutic implications.

    Science.gov (United States)

    Lange, Jonas; Lenz, Georg; Burkhardt, Birgit

    2017-02-01

    Mature B-cell lymphoma represents the most common type of Non-Hodgkin lymphoma, and different subtypes prevail at different patient ages. Areas covered: We review recent data on differences and commonalities in mature B-cell lymphoma occurring in adult and pediatric patients, with a special emphasis on molecular advances and therapeutic implications. To this end, we will discuss knowledge on diffuse large B-cell lymphoma and Burkitt lymphoma/leukemia, which are the most frequent subtypes in adult and pediatric patients, respectively, and on primary mediastinal B-cell lymphoma, which is a subtype of mature B-cell lymphoma occurring mainly in adolescents and young adults with a female predominance. Expert commentary: Molecular profiling has revealed molecular alterations that can be used to further classify the subtypes of mature B-cell lymphoma. These new subgroups frequently respond differentially to targeted therapeutic strategies. Future clinical trials utilizing new drugs will address this issue by combining clinical data and response assessment with a molecular workup of the corresponding lymphomas.

  6. Calcium Regulation of Hemorrhagic Fever Virus Budding: Mechanistic Implications for Host-Oriented Therapeutic Intervention.

    Directory of Open Access Journals (Sweden)

    Ziying Han

    2015-10-01

    Full Text Available Hemorrhagic fever viruses, including the filoviruses (Ebola and Marburg and arenaviruses (Lassa and Junín viruses, are serious human pathogens for which there are currently no FDA approved therapeutics or vaccines. Importantly, transmission of these viruses, and specifically late steps of budding, critically depend upon host cell machinery. Consequently, strategies which target these mechanisms represent potential targets for broad spectrum host oriented therapeutics. An important cellular signal implicated previously in EBOV budding is calcium. Indeed, host cell calcium signals are increasingly being recognized to play a role in steps of entry, replication, and transmission for a range of viruses, but if and how filoviruses and arenaviruses mobilize calcium and the precise stage of virus transmission regulated by calcium have not been defined. Here we demonstrate that expression of matrix proteins from both filoviruses and arenaviruses triggers an increase in host cytoplasmic Ca2+ concentration by a mechanism that requires host Orai1 channels. Furthermore, we demonstrate that Orai1 regulates both VLP and infectious filovirus and arenavirus production and spread. Notably, suppression of the protein that triggers Orai activation (Stromal Interaction Molecule 1, STIM1 and genetic inactivation or pharmacological blockade of Orai1 channels inhibits VLP and infectious virus egress. These findings are highly significant as they expand our understanding of host mechanisms that may broadly control enveloped RNA virus budding, and they establish Orai and STIM1 as novel targets for broad-spectrum host-oriented therapeutics to combat these emerging BSL-4 pathogens and potentially other enveloped RNA viruses that bud via similar mechanisms.

  7. Serotonin 5-HT2 receptor interactions with dopamine function: implications for therapeutics in cocaine use disorder.

    Science.gov (United States)

    Howell, Leonard L; Cunningham, Kathryn A

    2015-01-01

    Cocaine exhibits prominent abuse liability, and chronic abuse can result in cocaine use disorder with significant morbidity. Major advances have been made in delineating neurobiological mechanisms of cocaine abuse; however, effective medications to treat cocaine use disorder remain to be discovered. The present review will focus on the role of serotonin (5-HT; 5-hydroxytryptamine) neurotransmission in the neuropharmacology of cocaine and related abused stimulants. Extensive research suggests that the primary contribution of 5-HT to cocaine addiction is a consequence of interactions with dopamine (DA) neurotransmission. The literature on the neurobiological and behavioral effects of cocaine is well developed, so the focus of the review will be on cocaine with inferences made about other monoamine uptake inhibitors and releasers based on mechanistic considerations. 5-HT receptors are widely expressed throughout the brain, and several different 5-HT receptor subtypes have been implicated in mediating the effects of endogenous 5-HT on DA. However, the 5-HT2A and 5-HT2C receptors in particular have been implicated as likely candidates for mediating the influence of 5-HT in cocaine abuse as well as to traits (e.g., impulsivity) that contribute to the development of cocaine use disorder and relapse in humans. Lastly, new approaches are proposed to guide targeted development of serotonergic ligands for the treatment of cocaine use disorder. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

  8. Ameloblastoma: a clinical and therapeutic analysis on six cases,

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    Frederico Barra de Moraes

    2014-06-01

    Full Text Available Ameloblastomas are odontogenic tumors that are locally invasive and slow-growing. Their etiology is still not well defined, but the forms of treatment have been widely discussed because of the possibility of tumor recurrence and postoperative complications. In this study, six patients who were diagnosed with ameloblastoma in the mandibular region and were treated in the Department of Orthopedics and Traumatology of Hospital das Clínicas, Federal University of Goiás, between 1958 and 1963, were evaluated. The radiological, clinical and therapeutic characteristics were evaluated. There was no predominance regarding gender in the sample studied. The symptoms most often presented by the patients were pain and tumor formation. The radiological characteristics with greatest incidence were multilocular lesions and the treatment used for all the patients was radical surgery. There was no recurrence over the minimum follow-up period of one year and six months.

  9. A Phenomenological Case Study of the Therapeutic Impact of ...

    African Journals Online (AJOL)

    Christopher R Stones

    rescripting (IR) of memories of childhood trauma within a schema therapy approach. The study documents how her ... them to be transformed through a healing process that is organic and displays what Bohart and. Tallman (2010) call ..... these served as a basis for writing a case formulation and treatment plan. At step 3, the ...

  10. Prognostic significance and therapeutic implications of centromere protein F expression in human nasopharyngeal carcinoma

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    Cao Jing-Yan

    2010-09-01

    Full Text Available Abstract Background Our recent cDNA microarray data showed that centromere protein F (CENP-F is significantly upregulated in primary cultured nasopharyngeal carcinoma (NPC tumor cells compared with normal nasopharyngeal epithelial cells. The goal of this study was to further investigate the levels of CENP-F expression in NPC cell lines and tissues to clarify the clinical significance of CENP-F expression in NPC as well as the potential therapeutic implications of CENP-F expression. Methods Real-time RT-PCR and western blotting were used to examine CENP-F expression levels in normal primary nasopharyngeal epithelial cells (NPEC, immortalized nasopharyngeal epithelial cells and NPC cell lines. Levels of CENP-F mRNA were determined by real-time RT-PCR in 23 freshly frozen nasopharyngeal biopsy tissues, and CENP-F protein levels were detected by immunohistochemistry in paraffin sections of 202 archival NPC tissues. Statistical analyses were applied to test for prognostic associations. The cytotoxicities of CENP-F potential target chemicals, zoledronic acid (ZOL and FTI-277 alone, or in combination with cisplatin, in NPC cells were determined by the MTT assay. Results The levels of CENP-F mRNA and protein were higher in NPC cell lines than in normal and immortalized NPECs. CENP-F mRNA level was upregulated in nasopharyngeal carcinoma biopsy tissues compared with noncancerous tissues. By immunohistochemical analysis, CENP-F was highly expressed in 98 (48.5% of 202 NPC tissues. Statistical analysis showed that high expression of CENP-F was positively correlated with T classification (P P P P = 0.012 inversely correlated with the overall survival time in NPC patients. Multivariate analysis showed that CENP-F expression was an independent prognostic indicator for the survival of the patient. Moreover, we found that ZOL or FTI-277 could significantly enhance the chemotherapeutic sensitivity of NPC cell lines (HONE1 and 6-10B with high CENP-F expression to

  11. Therapeutic challenges in a case of psoriasis with nail onset

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    Mădălina I. Mitran

    2017-10-01

    Full Text Available Nail psoriasis affects a large number of patients with psoriasis and has a major psychosocial impact. Furthermore, it may be regarded as a predictor of more severe forms of psoriasis and early sign of psoriatic arthritis. The clinical presentations vary depending on the structure affected (nail matrix or nail bed, the nail lesions may range from minor to severe, but they are not specific. Treatment is a challenge, in most cases the lesions being resistant to therapy. We present a rare case of psoriasis with nail onset in a 59-year-old woman. The nail involvement confined to the fingernails was severe, with significant impairment of the patient’s quality of life. Conventional therapies failed to improve the nail lesions, but a marked improvement was achieved under etanercept therapy

  12. The case for therapeutic positivism in head and neck malignancy.

    Science.gov (United States)

    Woods, J E

    1980-10-01

    A negative attitude toward the treatment of advanced malignancy of the head and neck is frequently encountered. Aggressive therapy, at least for certain patients, is reasonable, and the assessment of certain factors in choosing candidates for such therapy is important. Illustrative case presentations demonstrate that a meaningful number of patients receive palliation or even cure with radical therapy. In view of the grim choices, it seems appropriate to take a positive, if radical, approach when the patient is highly motivated.

  13. Therapeutic neuroscience education via e-mail: a case report.

    Science.gov (United States)

    Louw, Adriaan

    2014-11-01

    Therapeutic neuroscience education (TNE) aims to alter a patient's thoughts and beliefs about pain and has shown efficacy in treating chronic pain. To date, TNE sessions mainly consist of one-on-one verbal communication. This approach limits availability of TNE to pain patients in remote areas. A 32-year-old patient with chronic low back pain (CLBP) who underwent surgery for thoracic outlet syndrome (TOS) attended a single clinic one-on-one TNE session followed by TNE via electronic mail (e-mail), pacing and graded exposure over a 4-month period. A physical examination, Numeric Rating Scale (NRS), Oswestry Disability Index (ODI), the Disabilities of Arm, Shoulder and Hand (DASH), and Fear-Avoidance Beliefs Questionnaire (FABQ) were assessed during her initial physical therapy visit as well as 1 and 4 months later. Pre-TNE, the patient reported: NPRS (arm) = 7/10; NPRS (leg) = 4/10; ODI = 10.0%; DASH = 36.7%; FABQ-W = 24; and FABQ-PA = 17. After 5 e-mail sessions all outcome measures improved, most noticeably NRS (arm) = 2/10; NRS (leg) = 0/10; DASH = 16.7%; FABQ-W = 8; and FABQ-PA = 7. TNE can potentially be delivered to suffering pain patients in remote areas or to individuals who have time and financial constraints, and likely at a significant reduced cost via e-mail.

  14. Sub-therapeutic nevirapine concentration during antiretroviral treatment initiation among children living with HIV: Implications for therapeutic drug monitoring.

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    Bindu Parachalil Gopalan

    Full Text Available Nevirapine, a component of antiretroviral therapy (ART in resource-limited settings, known for auto-induction of metabolism, is initiated at half therapeutic dose until day 14 ('lead-in period', and subsequently escalated to full dose. However, studies have shown that this dosing strategy based on adult studies may not be appropriate in children, given that younger children have higher drug clearance rates. In this prospective cohort study, we studied trough plasma nevirapine levels by high performance liquid chromatography (HPLC at days 7, 14 (lead-in period and 28 (full dose period after ART initiation amongst HIV-1 infected children initiating nevirapine-based ART in southern India. Among the 20 children (50% male, median age 9 years included in the study, sub-therapeutic trough plasma nevirapine concentration (<4μg/ml was seen in 65% (13/20 of children during the lead-in period within two weeks of ART initiation and among 10% of children at 4 weeks during full-dose nevirapine. Adherence was documented as ≥95% in all children by both caregiver self-report and pill count. Median nevirapine concentrations achieved at week 1 was 4.8 μg/ml, significantly lower than 8 μg/ml, the concentration achieved at week 4 (p = 0.034. Virological failure at one year of ART was observed in six children, and was not associated with median nevirapine concentration achieved during week 1, 2 or 4. We conclude that the dose escalation strategy currently practiced among young children living with HIV-1 resulted in significant subtherapeutic nevirapine concentration (≤4μg/ml during the lead-in period. We call for a closer look at pediatric-focused dosing strategies for nevirapine initiation in young children. Further studies to establish age-appropriate threshold nevirapine concentration are warranted in young children to corroborate the role of therapeutic drug monitoring in predicting virological outcome.

  15. Biological and therapeutic implications of multisector sequencing in newly diagnosed glioblastomas.

    Science.gov (United States)

    Mahlokozera, Tatenda; Vellimana, Ananth K; Li, Tiandao; Mao, Diane D; Zohny, Zohny S; Kim, David H; Tran, David D; Marcus, Daniel S; Fouke, Sarah J; Campian, Jian L; Dunn, Gavin P; Miller, Christopher A; Kim, Albert H

    2017-12-13

    Diagnostic workflows for glioblastoma (GBM) patients increasingly include DNA sequencing-based analysis of a single tumor site following biopsy or resection. We hypothesized that sequencing of multiple sectors within a given tumor would provide a more comprehensive representation of the molecular landscape and potentially inform therapeutic strategies. 10 newly diagnosed, IDH1 wildtype GBM tumor samples were obtained from two (n = 9) or four (n = 1) spatially distinct tumor regions. Tumor and matched blood DNA samples underwent whole-exome sequencing. Across all 10 tumors, 51% of mutations were clonal and 3% were subclonal and shared in different sectors, whereas 46% of mutations were subclonal and private. Two of the 10 tumors exhibited a regional hypermutator state despite being treatment naive, and remarkably, the high mutational load was predominantly limited to one sector in each tumor. Among the canonical cancer-associated genes, only TERT promoter mutations were observed in the founding clone in all tumors. Reconstruction of the clonal architecture in different sectors revealed regionally divergent evolution, and integration of data from two sectors increased the resolution of inferred clonal architecture in a given tumor. Predicted therapeutic mutations differed in presence and frequency between tumor regions. Similarly, different sectors exhibited significant divergence in the predicted neoantigen landscape. The substantial spatial heterogeneity observed in different glioblastoma tumor sectors, especially in spatially-restricted hypermutator cases, raise important caveats to our current dependence on single-sector molecular information to guide either targeted or immune-based treatments.

  16. Review: NF-κB pathways in the pathogenesis of Multiple Sclerosis and the therapeutic implications

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    Saskia Michaela Leibowitz

    2016-09-01

    Full Text Available Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB signalling pathways are involved in cell immune responses, apoptosis and infections. In Multiple Sclerosis (MS, NF-κB pathways are changed, leading to increased levels of NF-κB activation in cells. This may indicate a key role for NF-κB in MS pathogenesis. NF-κB signalling is complex, with many elements involved in its activation and regulation. Interestingly, current MS treatments are found to be directly or indirectly linked to NF-κB pathways and act to adjust the innate and adaptive immune system in patients. In this review, we will first focus on the intricacies of NF-κB signalling, including the activating pathways and regulatory elements. Next, we will theorise about the role of NF-κB in MS pathogenesis, based on current research findings, and discuss some of the associated therapeutic implications. Lastly, we will review four new MS treatments which interrupt NF-κB pathways - fingolimod, teriflunomide, dimethyl fumarate and laquinimod - and explain their mechanisms, and the possible strategy for MS treatments in the future.

  17. The therapeutic implications of plasticity of the cancer stem cell phenotype.

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    Kevin Leder

    2010-12-01

    Full Text Available The cancer stem cell hypothesis suggests that tumors contain a small population of cancer cells that have the ability to undergo symmetric self-renewing cell division. In tumors that follow this model, cancer stem cells produce various kinds of specified precursors that divide a limited number of times before terminally differentiating or undergoing apoptosis. As cells within the tumor mature, they become progressively more restricted in the cell types to which they can give rise. However, in some tumor types, the presence of certain extra- or intracellular signals can induce committed cancer progenitors to revert to a multipotential cancer stem cell state. In this paper, we design a novel mathematical model to investigate the dynamics of tumor progression in such situations, and study the implications of a reversible cancer stem cell phenotype for therapeutic interventions. We find that higher levels of dedifferentiation substantially reduce the effectiveness of therapy directed at cancer stem cells by leading to higher rates of resistance. We conclude that plasticity of the cancer stem cell phenotype is an important determinant of the prognosis of tumors. This model represents the first mathematical investigation of this tumor trait and contributes to a quantitative understanding of cancer.

  18. Pancreatic Exocrine Insufficiency in Type 1 and 2 Diabetes: Therapeutic Implications.

    Science.gov (United States)

    Talukdar, Rupjyoti; Reddy, D Nageshwar

    2017-09-01

    The objective of the present review is to focus on pancreatic exocrine insufficiency that is associated with Type 1 and 2 diabetes, its clinical and therapeutic implications, including the utility and efficacy of pancreatin supplementation. A literature search was conducted on Pubmed / Medline to identify relevant articles using terms pancreatic exocrine insufficiency in diabetes mellitus patients, pathophysiology, prevalence, treatment and management published between 2006-2016 in English language. Meta-analysis has revealed the prevalence of PEI in patients with type-1 and type-2 diabetes mellitus to be 37.7% (CI 27.2-49.5) and 26.2% (CI 19.4-34.3) respectively. Very scanty data are available that evaluates the efficacy of pancreatin in patients with diabetes. In the available studies, pancreatin was found to reduce hypoglycemia in insulin treated patients. Pancreatic exocrine insufficiency in type 1 and 2 diabetes mellitus is not uncommon and correct use of pancreatin may have a positive effect on the glycemic status of the diabetic patients. © Journal of the Association of Physicians of India 2011.

  19. Pharmacological properties of angiotensin II antagonists: Examining all the therapeutic implications

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    Thomas Unger

    2001-06-01

    Full Text Available Angiotensin II (Ang II, the effector peptide of the renin-angiotensin system (RAS, exerts a variety of actions in physiological blood pressure and body fluid regulation, and is implicated as a major pathogenic factor in the development of cardiovascular disease. Inhibition of the RAS, via treatment with the angiotensin-converting enzyme inhibitors (ACE-I, or more recently the Ang II AT1-receptor blockers (ARBs, has been used as a therapeutic approach to the treatment of hypertension and other cardiovascular dysfunction. Evidence from animal and clinical studies shows that the antihypertensive and overall organ-protective actions of the ARBs are similar to those of ACE-I. However, as the ARBs selectively block the AT1-receptor, which is responsible for the known cardiovascular actions of Ang II, leave the AT2-receptor unopposed and do not interfere with the breakdown of bradykinin, there is the potential for beneficial effects in hypertensive patients with cardiovascular diseases such as left ventricular hypertrophy. Furthermore, there may be additional benefits when the ARBs are combined with ACE-I in such patients. Animal studies contribute to the elucidation and understanding of the role of AT1- and AT2-receptors in the cardiovascular system, and may help in the design of clinical studies aimed at investigating the effects of ACE-I, ARBs, and their combination, on cardiovascular outcomes in hypertensive patients.

  20. Neurovascular cross talk in diabetic retinopathy: Pathophysiological roles and therapeutic implications

    Science.gov (United States)

    Moran, Elizabeth P.; Wang, Zhongxiao; Chen, Jing; Sapieha, Przemyslaw; Smith, Lois E. H.

    2016-01-01

    Diabetic retinopathy (DR) is the leading cause of blindness in the working-age population in developed countries, and its prevalence will increase as the global incidence of diabetes grows exponentially. DR begins with an early nonproliferative stage in which retinal blood vessels and neurons degenerate as a consequence of chronic hyperglycemia, resulting in vasoregression and persistent retinal ischemia, metabolic disequilibrium, and inflammation. This is conducive to overcompensatory pathological neovascularization associated with advanced proliferative DR. Although DR is considered a microvascular complication, the retinal microvasculature is intimately associated with and governed by neurons and glia; neurodegeneration, neuroinflammation, and dysregulation of neurovascular cross talk are responsible in part for vascular abnormalities in both early nonproliferative DR and advanced proliferative DR. Neuronal activity directly regulates microvascular dilation and blood flow in the process of neurovascular coupling. Retinal neurons also secrete guidance cues in response to injury, ischemia, or metabolic stress that may either promote or suppress vascular outgrowth, either alleviating or exacerbating DR, contingent on the stage of disease and retinal microenvironment. Neurodegeneration, impaired neurovascular coupling, and dysregulation of neuronal guidance cues are key events in the pathogenesis of DR, and correcting these events may prevent or delay development of advanced DR. The review discusses the mechanisms of neurovascular cross talk and its dysregulation in DR, and their potential therapeutic implications. PMID:27473938

  1. [Difficult and unusual diagnostic and therapeutic gastric Schwannoma case].

    Science.gov (United States)

    Frejlich, Ewelina; Rudno-Rudzińska, Julia; Hałoń, Agnieszka; Kielan, Wojciech; Grzebianiak, Zygmunt

    2013-01-01

    Schwannoma is a rare, usually benign, generally slow growing, asymptomatic mesenchymal neoplasm derived from nerve cells. In the gastrointestinal tract the most common localization is stomach and the gastric schwannomas represent about 0.2% of all gastric neoplasms. We present a case of 44-years-old male admitted to 2nd Department of General Surgery and Oncological Surgery Medical University for treatment of a submucosal gastric tumor detected in upper gastrointestinal endoscopy, endoscopic ultrasonography and computed tomography (CT). Patient presented with no gastrointestinal disorders and the random endoscopy revealed a gastric tumor, but the biopsy of the lesion showed no carcinomas' cells and the suspicion of GIST. CT confirms the presence of the 5 cm large gastric tumor and intraabdominal lymphadenopathy. The patient was directed to surgery because of the malignant risk. The subtotal gastrectomy with BII anastomosis was performed and no perioperative complications were observed. The postoperative histopathological examination revealed a typical morphology and immunophenotype of tumor. The neoplastic cells were immunoreactive with S-100 protein, but lacked immunoreactivity with CD 117, CD 34 and smooth-muscle actin (SMA). The histopathologic features and immunohistochemical staining pattern were consistent with a gastric schwannoma. The lymph nodes resected, during the operation revealed reactive inflammatory changes without evidence of neoplastic cells and any malignancy. 10-month after the surgery patient has no complains but the follow up will be continued. This case underscores the importance of including gastric schwannomas in the differential diagnosis when preoperative imaging studies reveal a submucosal, exophytic gastric mass.

  2. Case management implications of celiac disease.

    Science.gov (United States)

    Greenberg, Liza

    2008-01-01

    The purpose of this article is to educate case managers on an autoimmune disorder, celiac disease, that is seen with increased frequency due to recent improvements in diagnostic testing. After reading this article, case managers will Outpatient case management, although patients with celiac disease may be encountered in any setting. Celiac disease is a genetic autoimmune disease affecting up to 1% of the population. The majority of people with celiac disease do not know they have it. With new diagnostic tests available on the marketplace, increasing numbers of people are being diagnosed with celiac disease. Case managers are likely to encounter patients with celiac disease as either a primary or secondary diagnosis. Celiac disease may cause gastrointestinal symptoms such as gas, diarrhea, or bloating, and is also associated with osteoporosis, other autoimmune disorders, and certain types of cancer. For children, it is a common disorder underlying growth delays. Celiac disease is present in 3%-8% of persons with diabetes and may affect glycemic control in these patients. The only known treatment of celiac disease is a lifelong gluten-free diet. The increased number of individuals diagnosed with celiac disease has led to an increase in products available, as well as in research on treatment alternatives. People with celiac disease report challenges in adhering to the gluten-free diet. Case managers can assist patients in accessing appropriate therapy, including nutrition counseling and monitoring services. They may also advocate for testing of patients in high-risk groups such as persons with diabetes, and those with unexplained gastrointestinal symptoms. In working with celiac patients, case managers should address psychosocial issues as well as knowledge deficits. Patients may need particular support integrating the gluten-free diet with other requirements, including heart healthy or diabetic diets. Case managers can help patients identify reliable sources of

  3. The neuropeptide Y system: pathophysiological and therapeutic implications in obesity and cancer.

    Science.gov (United States)

    Zhang, Lei; Bijker, Martijn S; Herzog, Herbert

    2011-07-01

    The neuropeptide Y (NPY) system--comprising of neuropeptide Y, peptide YY, pancreatic polypeptide and the corresponding Y receptors through which they act (Y1, Y2, Y4, Y5 and y6)--is well known for its role in the regulation of energy homeostasis and associated processes. Dysfunctions of the system have been implicated in human diseases such as obesity and cancer, raising the possibility that correction of the system may provide therapeutic benefits for these diseases. In addition to the regulation of appetite and satiety that has attracted most attention during the past years, insight has also been gained into the critical role of NPY in the control of energy expenditure, oxidative fuel selection and bone metabolism. Studies using conditional knockout models further shed light on the central versus peripheral, and hypothalamic versus extra-hypothalamic mechanisms of these regulatory effects of NPY. Moreover, a role of NPY family peptides and Y receptors in modulating the growth of tumours has emerged. These findings provide the basis for novel NPY system-targeted strategies to treat obesity as well as cancer. Such strategies include modifying both sides of the energy balance equation--energy intake versus energy expenditure--to achieve a greater weight/fat loss by particularly modulating peripheral Y receptor(s) to ameliorate metabolic conditions without interfering with central functions of Y receptors. In addition, targeting multiple Y receptors and/or multiple systems involved in the regulation of energy balance will have greater beneficial effects. However, long-term interference with the NPY system to target obesity or cancer related aspects needs to consider potential side effects on bone health. Copyright © 2011 Elsevier Inc. All rights reserved.

  4. RAF265, a dual BRAF and VEGFR2 inhibitor, prevents osteoclast formation and resorption. Therapeutic implications.

    Science.gov (United States)

    Garcia-Gomez, Antonio; Ocio, Enrique M; Pandiella, Atanasio; San Miguel, Jesús F; Garayoa, Mercedes

    2013-02-01

    The RAS/RAF/MEK/ERK signaling pathway plays an important role in osteoclast (OC) differentiation and survival mediated by macrophage-colony stimulating factor (M-CSF). Also, vascular endothelial growth factor (VEGF) may greatly influence OC formation and resorption through VEGFR1 and VEGFR2. RAF265 is a novel, orally bioavailable dual inhibitor of RAF kinase and VEGFR2. Effect of RAF265 on osteoclastogenesis from peripheral blood mononuclear cells (PBMCs) and OC resorption on calcium-coated wells was assessed by appropriate in vitro assays. Immunoblotting, real-time RT-PCR and flow cytometry were used to evaluate RAF265 mechanism of action. RAF265 significantly impaired in vitro differentiation of PBMCs to OCs induced by receptor activator of NF-kB ligand (RANKL) and M-CSF (IC(50) ≅ 160 nM). In parallel, RAF265 exerted a potent inhibition of OC resorptive capacity (IC(50) ≅ 20 nM). RAF265 treatment led to ERK inhibition and diminished expression of c-fos and NFATc1 (nuclear factor of activated T cells, calcineurin-dependent 1), which would likely account for inhibition of osteoclastogenesis. The reduced gene expression of aVb3 integrin, CCR1, cathepsin K, carbonic anhydrase II, matrix metalloproteinase 9, urokinase and tissue-type plasminogen activators, vacuolar H(+)-ATPase subunit (ATP6V1A) and Rab7 GTPase would probably mediate RAF265 hindered resorption. RAF265 inhibitory effect on VEGFR2 (noticeable at 10-50 nM) was also found to be implicated in the potent inhibition of this agent on OC function. We have found a new therapeutic application for RAF265 as an inhibitory agent of osteoclastogenesis and OC function, which might be useful for the treatment of skeletal disorders associated with increased bone resorption.

  5. Therapeutic implications of Epstein–Barr virus infection for the treatment of nasopharyngeal carcinoma

    Science.gov (United States)

    Hutajulu, Susanna Hilda; Kurnianda, Johan; Tan, I Bing; Middeldorp, Jaap M

    2014-01-01

    Nasopharyngeal carcinoma (NPC) is highly endemic in certain regions including the People’s Republic of China and Southeast Asia. Its etiology is unique and multifactorial, involving genetic background, epigenetic, and environment factors, including Epstein–Barr virus (EBV) infection. The presence of EBV in all tumor cells, aberrant pattern of antibodies against EBV antigens in patient sera, and elevated viral DNA in patient circulation as well as nasopharyngeal site underline the role of EBV during NPC development. In NPC tumors, EBV expresses latency type II, where three EBV-encoded proteins, Epstein–Barr nuclear antigen 1, latent membrane protein 1 and 2 (LMP1, 2), are expressed along with BamH1-A rightward reading frame 1, Epstein–Barr virus-encoded small nuclear RNAs, and BamH1-A rightward transcripts. Among all encoded proteins, LMP1 plays a central role in the propagation of NPC. Standard treatment of NPC consists of radiotherapy with or without chemotherapy for early stage, concurrent chemoradiotherapy in locally advanced tumors, and palliative systemic chemotherapy in metastatic disease. However, this standard care has limitations, allowing recurrences and disease progression in a certain proportion of cases. Although the pathophysiological link and molecular process of EBV-induced oncogenesis are not fully understood, therapeutic approaches targeting the virus may increase the cure rate and add clinical benefit. The promising results of early phase clinical trials on EBV-specific immunotherapy, epigenetic therapy, and treatment with viral lytic induction offer new options for treating NPC. PMID:25228810

  6. Ebola Virus Altered Innate and Adaptive Immune Response Signalling Pathways: Implications for Novel Therapeutic Approaches.

    Science.gov (United States)

    Kumar, Anoop

    2016-01-01

    Ebola virus (EBOV) arise attention for their impressive lethality by the poor immune response and high inflammatory reaction in the patients. It causes a severe hemorrhagic fever with case fatality rates of up to 90%. The mechanism underlying this lethal outcome is poorly understood. In 2014, a major outbreak of Ebola virus spread amongst several African countries, including Leone, Sierra, and Guinea. Although infections only occur frequently in Central Africa, but the virus has the potential to spread globally. Presently, there is no vaccine or treatment is available to counteract Ebola virus infections due to poor understanding of its interaction with the immune system. Accumulating evidence indicates that the virus actively alters both innate and adaptive immune responses and triggers harmful inflammatory responses. In the literature, some reports have shown that alteration of immune signaling pathways could be due to the ability of EBOV to interfere with dendritic cells (DCs), which link innate and adaptive immune responses. On the other hand, some reports have demonstrated that EBOV, VP35 proteins act as interferon antagonists. So, how the Ebola virus altered the innate and adaptive immune response signaling pathways is still an open question for the researcher to be explored. Thus, in this review, I try to summarize the mechanisms of the alteration of innate and adaptive immune response signaling pathways by Ebola virus which will be helpful for designing effective drugs or vaccines against this lethal infection. Further, potential targets, current treatment and novel therapeutic approaches have also been discussed.

  7. K-12 Implications Seen in Some Cases before High Court

    Science.gov (United States)

    Walsh, Mark

    2010-01-01

    Arizona's variation on government vouchers for religious schools and California's prohibition on the sale of violent video games to minors present the top two cases with implications for education in the U.S. Supreme Court term that formally begins Oct. 4. New Justice Elena Kagan brings to the court extensive education policy experience as a…

  8. [Diagnostic and therapeutic advantages of rigid ureteroscopy: retrospective study of 304 cases].

    Science.gov (United States)

    Hajri, M; Ben Amna, M; Achich, A; Ben Mouelli, S; Bacha, K; Ben Hassine, L; Chebil, M; Ayed, M

    2000-12-01

    Uretroscopy has become a common tool for the diagnosis and management of the upper urinary tract. Between April 1994 and Decembre 1999, 304 ureteroscopy procedures were performed. The most common therapeutic procedure was stone manipulation in 299 cases (distal ureter 259 cases, mid-ureter 23 cases, lumber ureter eight cases and staged in nine cases). Procedure was made by a rigid ureteroscope 8.5 Ch or 11.5 Ch. Dorinia was used in 175 cases (57.5%) with or without fragmentation by ultrasound. Therapeutic ureteroscopy was also used to remove a double-J stent that had migrated into the pelvic ureter in one case and in three cases of ureteral tumor. It was used in one case to confine the extrinsic compression of a ureteral stenosis. Median follow up was 12 months (6-36 months). The overall success rate was 87.6%. Results are comparable in men and women (P = 0.8). Success rate was 90% in single lithiasis and 76.2% in case of numerous stones (P = 0.0094). There was a statistically significant difference in success rate between stones 15 mm or under in size (89% stone-free) and those 15 mm (66% stone-free) or larger. In conclusion, rigid ureteroscopy is a minimally invasive and reliable technique for the management of ureteric calculi and for the diagnosis and treatment of other ureteric lesion.

  9. EATING DISORDERS: DENTAL IMPLICATIONSCASE REPORT

    Directory of Open Access Journals (Sweden)

    Matjaž Rode

    2003-10-01

    Full Text Available Background. Obesity, anorexia and bulimia are typical civilisation diseases or diseases of unhealthy living. They affect mainly white women in their childhood and adolescence. Occurrence of these diseases is getting higher also in Slovenia. Changes inside the oral cavity of a bulimic patient may be detected during a routine clinical examination. This places dental professionals in a position to be among the first to detect bulimia which is usually characterized by episodes of purging behaviors such as self-induced vomiting. Such vomiting brings stomach acids in contact with the mouth and teeth, causing erosion of tooth enamel which often leads to severely decayed teeth.Methods. This study presents a case of successful treatment of oral symptoms and dental rehabilitation in female patient with bulimia.Conclusions. Dental rehabilitation for bulimic patients is more than just a substituting of their bad and lost teeth. It is actually the first step toward their regained self-respect. Therefore it is important for the dentist to be familiar with the clinical symptoms of these diseases that can be revealed in oral cavity to efficiently contribute to a patient rehabilitation.

  10. Treatment Preferences Affect the Therapeutic Alliance: Implications for Randomized Controlled Trials

    Science.gov (United States)

    Iacoviello, Brian M.; McCarthy, Kevin Scott; Barrett, Marna S.; Rynn, Moira; Gallop, Robert; Barber, Jacques P.

    2007-01-01

    The influence of treatment preferences on the development of the therapeutic alliance was investigated. Seventy-five patients were followed while participating in a randomized controlled trial comparing supportive-expressive psychotherapy with sertraline or pill placebo in the treatment of major depressive disorder. Therapeutic alliance was…

  11. [Therapeutic options for portal hypertensive biliopathy: case series and literature review].

    Science.gov (United States)

    Aguilar-Olivos, Nancy Edith; de León-Monterroso, José Luis; Avila-Escobedo, Lourdes; López-Méndez, Eric

    2014-01-01

    Portal hypertensive biliopathy is an underdiagnosed condition because only some patients have symptoms. The major clinical manifestations include cholestasis and cholangitis. The aim of this study is to present a series of cases evaluated, treated and followed at a tertiary-care public institution. Four patients with portal hypertensive biliopathy were exposed to different therapeutic approaches focused on the management of portal hypertension and biliary decompression. They were followed for ~5 years. Three cases achieved a favorable outcome with symptom remission, but one patient died while attempting dilatation of the bile duct. Finally, we carried out a literature review about actual portal hypertensive biliopathy therapeutics. There is currently no consensus on the optimal treatment for this condition. The goal is to decompress the biliary tree. Each case should be individually evaluated to choose the best treatment option.

  12. Immediate Effect of Therapeutic Massage on Pain Sensation and Unpleasantness: A Consecutive Case Series.

    Science.gov (United States)

    Menard, Martha Brown

    2015-09-01

    Musculoskeletal pain is a common condition that poses a significant burden to its sufferers and costs the US economy billions of dollars each year in lost productivity. Individuals complaining of musculoskeletal pain make up a large proportion of clients treated by massage therapists in community practices, yet few studies have examined the immediate effect of therapeutic massage on this type of pain in the practice setting. To assess the immediate effect of therapeutic massage on musculoskeletal pain sensation and unpleasantness in a community setting. Solo private practice in central Virginia, United States. One hundred sixteen first-time clients who complained of musculoskeletal pain as a presenting symptom. Prospective, consecutive practice-based case series. A single 60-minute session of individualized therapeutic massage; techniques used included Swedish massage employing effleurage, petrissage, and friction,;deep tissue; myofascial; positional release; passive and resisted joint mobilization; and biofield modalities. Visual Analog Scales for pain sensation and unpleasantness. Both pain sensation and unpleasantness were significantly reduced by a single session of therapeutic massage. Mean pain sensation decreased from 3.76 (SD=1.87) prior to massage to .89 (SD=1.35) following massage, with t=18.87, P<.001. Mean pain unpleasantness decreased from 5.21 (SD=2.48) prior to massage to .64 (SD=1.23) following massage, with t =20.45, P<.001. Effect sizes were 1.76 and 1.90, respectively. In this case series, therapeutic massage appeared to be an effective intervention for common musculoskeletal pain that influenced both the physical and affective dimension of the pain experience. Although care was taken to reduce potential bias through limiting eligibility to first time clients and use of a standardized script, practice-based case series have inherent limitations. Issues in conducting practice-based research by massage therapists and recommendations for future

  13. Therapeutic implications of Epstein–Barr virus infection for the treatment of nasopharyngeal carcinoma

    Directory of Open Access Journals (Sweden)

    Hutajulu SH

    2014-09-01

    Full Text Available Susanna Hilda Hutajulu,1 Johan Kurnianda,1 I Bing Tan,2,3 Jaap M Middeldorp4 1Department of Internal Medicine, Faculty of Medicine Universitas Gadjah Mada/Dr Sardjito General Hospital, Yogyakarta, Indonesia; 2Department of Ear, Nose and Throat, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands; 3Department of Ear, Nose and Throat, Faculty of Medicine Universitas Gadjah Mada/Dr Sardjito General Hospital, Yogyakarta, Indonesia; 4Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands Abstract: Nasopharyngeal carcinoma (NPC is highly endemic in certain regions including the People's Republic of China and Southeast Asia. Its etiology is unique and multifactorial, involving genetic background, epigenetic, and environment factors, including Epstein–Barr virus (EBV infection. The presence of EBV in all tumor cells, aberrant pattern of antibodies against EBV antigens in patient sera, and elevated viral DNA in patient circulation as well as nasopharyngeal site underline the role of EBV during NPC development. In NPC tumors, EBV expresses latency type II, where three EBV-encoded proteins, Epstein–Barr nuclear antigen 1, latent membrane protein 1 and 2 (LMP1, 2, are expressed along with BamH1-A rightward reading frame 1, Epstein–Barr virus-encoded small nuclear RNAs, and BamH1-A rightward transcripts. Among all encoded proteins, LMP1 plays a central role in the propagation of NPC. Standard treatment of NPC consists of radiotherapy with or without chemotherapy for early stage, concurrent chemoradiotherapy in locally advanced tumors, and palliative systemic chemotherapy in metastatic disease. However, this standard care has limitations, allowing recurrences and disease progression in a certain proportion of cases. Although the pathophysiological link and molecular process of EBV-induced oncogenesis are not fully understood, therapeutic approaches targeting the virus may increase the

  14. [Applicability of the Therapeutic Nursing Theory in Neurological (Early-) Rehabilitation into Nursing Practice - A Case Study].

    Science.gov (United States)

    Lautenschläger, Sindy; Muser, Jürgen; Müller, Elisabeth

    2017-05-30

    Purpose The objective of the study is to describe how the theory of therapeutic nursing in neurological (early) rehabilitation can be transferred into nursing practice. Materials and Methods The theory was developed using the method of grounded theory by Glaser and Strauss. Open participatory observations (n=92) and episodic interviews (n=10) with nursing professionals and nursing auxiliaries were conducted in 5 inpatient rehabilitation clinics. Data analysis was performed using the constant comparative method by Glaser and Strauss. Results By means of a case study, the applicability of the theory into nursing practice with regard to the following care situations is described: (1) training for personal care, (2) therapeutic positioning, (3) oral hygiene, (4) training of sensory-motor perception and (5) counseling relatives. Consequently, the categories of the theory: (1) nursing care, (2) observation/perception, (3) communication, (4) autonomy and individual needs of patients and their relatives, (5) multi-professional team and (6) prerequisites are transferred into the case scenario. Conclusions The case study demonstrates how the therapeutic nursing theory in neurological (early-) rehabilitation can be transferred into nursing practice and reveals the complexity of nursing interventions. © Georg Thieme Verlag KG Stuttgart · New York.

  15. Variability in the pharmacokinetics of mycophenolic acid: Implications for therapeutic drug monitoring

    NARCIS (Netherlands)

    B.C.M. de Winter (Brenda)

    2010-01-01

    textabstractMycophenolate mofetil (MMF) is an immunosuppressive drug used to prevent rejection following solid organ transplantation. MMF was introduced in 1995 with a recommended fixed-dose regimen of 1 g twice daily. Nowadays, dose individualization using therapeutic drug monitoring (TDM) of the

  16. Aberrant mesenchymal differentiation of glioma stem-like cells : Implications for therapeutic targeting

    NARCIS (Netherlands)

    Balasubramaniyan, Veerakumar; Vaillant, Brian; Wang, Shuzhen; Gumin, Joy; Butalid, M. Elena; Sai, Ke; Mukheef, Farah; Kim, Se Hoon; Boddeke, H. W. G. M.; Lang, Frederick; Aldape, Kenneth; Sulman, Erik P.; Bhat, Krishna P.; Colman, Howard

    2015-01-01

    Differentiation has been proposed as a therapeutic strategy for glioblastoma (GBM) in part due to observations of stem-like cells in GBM that have been shown to undergo terminal differentiation in response to growth factor withdrawal and BMP activation. However, the effects of long term exposure to

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

    Science.gov (United States)

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

    2014-01-01

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

  18. Germline genetic variants with implications for disease risk and therapeutic outcomes.

    Science.gov (United States)

    Pasternak, Amy L; Ward, Kristen M; Luzum, Jasmine A; Ellingrod, Vicki L; Hertz, Daniel L

    2017-10-01

    Genetic testing has multiple clinical applications including disease risk assessment, diagnosis, and pharmacogenomics. Pharmacogenomics can be utilized to predict whether a pharmacologic therapy will be effective or to identify patients at risk for treatment-related toxicity. Although genetic tests are typically ordered for a distinct clinical purpose, the genetic variants that are found may have additional implications for either disease or pharmacology. This review will address multiple examples of germline genetic variants that are informative for both disease and pharmacogenomics. The discussed relationships are diverse. Some of the agents are targeted for the disease-causing genetic variant, while others, although not targeted therapies, have implications for the disease they are used to treat. It is also possible that the disease implications of a genetic variant are unrelated to the pharmacogenomic implications. Some of these examples are considered clinically actionable pharmacogenes, with evidence-based, pharmacologic treatment recommendations, while others are still investigative as areas for additional research. It is important that clinicians are aware of both the disease and pharmacogenomic associations of these germline genetic variants to ensure patients are receiving comprehensive personalized care. Copyright © 2017 the American Physiological Society.

  19. Acute pancreatitis related to therapeutic dosing with colchicine: a case report

    Directory of Open Access Journals (Sweden)

    Ting Joseph

    2007-08-01

    Full Text Available Abstract Background Colchicine is used in the treatment and prophylaxis of gout. It possesses a narrow therapeutic window, frequently resulting in dose-limiting gastrointestinal side-effects such as diarrhoea and emesis. As colchicine is a cellular anti-mitotic agent, the most serious effects include myelosuppression, myoneuropathy and multiple organ failure. This occurs with intentional overdose or with therapeutic dosing in patients with reduced clearance of colchicine due to pre-existing renal or hepatic impairment. Acute pancreatitis has rarely been reported, and only in association with severe colchicine overdose accompanied by multi-organ failure. Case presentation We report a case of acute pancreatitis without other organ toxicity related to recent commencement of colchicine for acute gout, occurring in an elderly male with pre-existing renal impairment. Conclusion 1 Colchicine should be used with care in elderly patients or patients with impaired renal function. 2 Aside from myelosuppression, myoneuropathy and multiple organ failure, colchicine may now be associated with acute pancreatitis even with therapeutic dosing; this has not previously being reported.

  20. Immunomodulation in Plasmodium falciparum malaria: experiments in nature and their conflicting implications for potential therapeutic agents

    Science.gov (United States)

    Frosch, Anne EP; John, Chandy C

    2013-01-01

    Effective Plasmodium falciparum immunity requires a precisely timed and balanced response of inflammatory and anti-inflammatory immune regulators. These responses begin with innate immune effectors and are modulated over the course of an infection and between episodes to limit inflammation. To date, there are no effective immunomodulatory therapies for severe malaria. Some of the most potent immunomodulators are naturally occurring infections, including helminthic and chronic viral infections. This review examines malaria coinfection with these organisms, and their impact on malaria morbidity and immune responses. Overall, there is compelling evidence to suggest that chronic coinfections can modulate deleterious malaria-specific immune responses, suggesting that therapeutic agents may be effective if utilized early in infection. Examination of the mechanisms of these effects may serve as a platform to identify more targeted and effective malaria immunomodulatory therapeutics. PMID:23241191

  1. ErbB polymorphisms: Insights and implications for response to targeted cancer therapeutics

    Directory of Open Access Journals (Sweden)

    Moulay A Alaoui-Jamali

    2015-02-01

    Full Text Available Advances in high-throughput genomic-scanning have expanded the repertory of genetic variations in DNA sequences encoding ErbB tyrosine kinase receptors in humans, including single nucleotide polymorphisms (SNPs, polymorphic repetitive elements, microsatellite variations, small-scale insertions and deletions. The ErbB family members: EGFR, ErbB2, ErbB3 and ErbB4 receptors are established as drivers of many aspects of tumor initiation and progression to metastasis. This knowledge has provided rationales for the development of an arsenal of anti-ErbB therapeutics, ranging from small molecule kinase inhibitors to monoclonal antibodies. Anti-ErbB agents are becoming the cornerstone therapeutics for the management of cancers that overexpress hyperactive variants of ErbB receptors, in particular ErbB2-positive breast cancer and non-small cell lung carcinomas. However, their clinical benefit has been limited to a subset of patients due to a wide heterogeneity in drug response despite the expression of the ErbB targets, attributed to intrinsic (primary and to acquired (secondary resistance. Somatic mutations in ErbB tyrosine kinase domains have been extensively investigated in preclinical and clinical setting as determinants for either high sensitivity or resistance to anti-ErbB therapeutics. In contrast, only scant information is available on the impact of SNPs, which are widespread in genes encoding ErbB receptors, on receptor structure and activity, and their predictive values for drug susceptibility. This review aims to briefly update polymorphic variations in genes encoding ErbB receptors based on recent advances in deep sequencing technologies, and to address challenging issues for a better understanding of the functional impact of single versus combined SNPs in ErbB genes to receptor topology, receptor-drug interaction, and drug susceptibility. The potential of exploiting SNPs in the era of stratified targeted therapeutics is discussed.

  2. Mitochondrial Oxidative Damage in Aging and Alzheimer's Disease: Implications for Mitochondrially Targeted Antioxidant Therapeutics

    OpenAIRE

    P. Hemachandra Reddy

    2006-01-01

    The overall aim of this article is to review current therapeutic strategies for treating AD, with a focus on mitochondrially targeted antioxidant treatments. Recent advances in molecular, cellular, and animal model studies of AD have revealed that amyloid precursor protein derivatives, including amyloid beta (Aβ) monomers and oligomers, are likely key factors in tau hyperphosphorylation, mitochondrial oxidative damage, inflammatory changes, and synaptic failure in the brain ...

  3. MAPK/ERK Signaling in Osteosarcomas, Ewing Sarcomas and Chondrosarcomas: Therapeutic Implications and Future Directions

    Directory of Open Access Journals (Sweden)

    Chandhanarat Chandhanayingyong

    2012-01-01

    Full Text Available The introduction of cytotoxic chemotherapeutic drugs in the 1970’s improved the survival rate of patients with bone sarcomas and allowed limb salvage surgeries. However, since the turn of the century, survival data has plateaued for a subset of metastatic, nonresponding osteo, and/or Ewing sarcomas. In addition, most high-grade chondrosarcoma does not respond to current chemotherapy. With an increased understanding of molecular pathways governing oncogenesis, modern targeted therapy regimens may enhance the efficacy of current therapeutic modalities. Mitogen-Activated Protein Kinases (MAPK/Extracellular-Signal-Regulated Kinases (ERK are key regulators of oncogenic phenotypes such as proliferation, invasion, angiogenesis, and inflammatory responses; which are the hallmarks of cancer. Consequently, MAPK/ERK inhibitors have emerged as promising therapeutic targets for certain types of cancers, but there have been sparse reports in bone sarcomas. Scattered papers suggest that MAPK targeting inhibits proliferation, local invasiveness, metastasis, and drug resistance in bone sarcomas. A recent clinical trial showed some clinical benefits in patients with unresectable or metastatic osteosarcomas following MAPK/ERK targeting therapy. Despite in vitro proof of therapeutic concept, there are no sufficient in vivo or clinical data available for Ewing sarcomas or chondrosarcomas. Further experimental and clinical trials are awaited in order to bring MAPK targeting into a clinical arena.

  4. Psychomotor Retardation in Depression: A Systematic Review of Diagnostic, Pathophysiologic, and Therapeutic Implications

    Directory of Open Access Journals (Sweden)

    Djamila Bennabi

    2013-01-01

    Full Text Available Psychomotor retardation is a central feature of depression which includes motor and cognitive impairments. Effective management may be useful to improve the classification of depressive subtypes and treatment selection, as well as prediction of outcome in patients with depression. The aim of this paper was to review the current status of knowledge regarding psychomotor retardation in depression, in order to clarify its role in the diagnostic management of mood disorders. Retardation modifies all the actions of the individual, including motility, mental activity, and speech. Objective assessments can highlight the diagnostic importance of psychomotor retardation, especially in melancholic and bipolar depression. Psychomotor retardation is also related to depression severity and therapeutic change and could be considered a good criterion for the prediction of therapeutic effect. The neurobiological process underlying the inhibition of activity includes functional deficits in the prefrontal cortex and abnormalities in dopamine neurotransmission. Future investigations of psychomotor retardation should help improve the understanding of the pathophysiological mechanisms underlying mood disorders and contribute to improving their therapeutic management.

  5. Cancer stem cells in hepatocellular carcinoma: Therapeutic implications based on stem cell biology.

    Science.gov (United States)

    Chiba, Tetsuhiro; Iwama, Atsushi; Yokosuka, Osamu

    2016-01-01

    Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third most frequent cause of cancer-related death worldwide. Despite advances in its diagnosis and treatment, the prognosis of patients with advanced HCC remains unfavorable. Recent advances in stem cell biology and associated technologies have enabled the identification of minor components of tumorigenic cells, termed cancer stem cells (CSC) or tumor-initiating cells, in cancers such as HCC. Furthermore, because CSC play a central role in tumor development, metastasis and recurrence, they are considered to be a therapeutic target in cancer treatment. Hepatic CSC have been successfully identified using functional and cell surface markers. The analysis of purified hepatic CSC has revealed the molecular machinery and signaling pathways involved in their maintenance. In addition, epigenetic transcriptional regulation has been shown to be important in the development and maintenance of CSC. Although inhibitors of CSC show promise as CSC-targeting drugs, novel therapeutic approaches for the eradication of CSC are yet to be established. In this review, we describe recent progress in hepatic CSC research and provide a perspective on the available therapeutic approaches based on stem cell biology. © 2015 The Japan Society of Hepatology.

  6. Treatment of hyperuricemia in gout: current therapeutic options, latest developments and clinical implications.

    Science.gov (United States)

    Sattui, Sebastian E; Gaffo, Angelo L

    2016-08-01

    Despite being the most common type of inflammatory arthritis, gout is often poorly managed. Except for febuxostat and pegloticase, research in new therapeutic agents for the management of hyperuricemia in gout remained insufficient for several decades. With emerging evidence of possible roles of hyperuricemia in cardiometabolic comorbidities, as well as more convincing evidence regarding poor outcomes (e.g. disability, recurrent hospital admissions) in patients with uncontrolled gout, several agents are current under development. Increasing knowledge regarding renal urate transporters has resulted in the development of new generation uricosurics such as lesinurad and arhalofenate. This review aims at discussing current therapeutic strategies for gout, as well as their limitations and the possible role of emerging agents in the chronic management of hyperuricemia in gout. Drugs in phases I and II of development will be discussed, along with new agents and therapeutic classes, such as purine nucleoside phosphorylase inhibitors and dual-action drugs. These new developments are encouraging, and will hopefully contribute to a more adequate management of hyperuricemia in gout.

  7. Therapeutic High-Density Barium Enema in a Case of Presumed Diverticular Hemorrhage

    Directory of Open Access Journals (Sweden)

    Nonthalee Pausawasdi

    2011-02-01

    Full Text Available Many patients with lower gastrointestinal bleeding do not have an identifiable source of bleeding at colonoscopy. A significant percentage of these patients will have recurrent bleeding. In many patients, the presence of multiple diverticula leads to a diagnosis of presumed diverticular bleeding. Current treatment options include therapeutic endoscopy, angiography, or surgical resection, all of which depend on the identification of the diverticular source of bleeding. This report describes a case of recurrent bleeding in an elderly patient with diverticula but no identifiable source treated successfully with barium impaction therapy. This therapeutic modality does not depend on the identification of the bleeding diverticular lesion and was well tolerated by our 86-year-old patient.

  8. Feed-forward transcriptional programming by nuclear receptors: regulatory principles and therapeutic implications.

    Science.gov (United States)

    Sasse, Sarah K; Gerber, Anthony N

    2015-01-01

    Nuclear receptors (NRs) are widely targeted to treat a range of human diseases. Feed-forward loops are an ancient mechanism through which single cell organisms organize transcriptional programming and modulate gene expression dynamics, but they have not been systematically studied as a regulatory paradigm for NR-mediated transcriptional responses. Here, we provide an overview of the basic properties of feed-forward loops as predicted by mathematical models and validated experimentally in single cell organisms. We review existing evidence implicating feed-forward loops as important in controlling clinically relevant transcriptional responses to estrogens, progestins, and glucocorticoids, among other NR ligands. We propose that feed-forward transcriptional circuits are a major mechanism through which NRs integrate signals, exert temporal control over gene regulation, and compartmentalize client transcriptomes into discrete subunits. Implications for the design and function of novel selective NR ligands are discussed. Copyright © 2014 Elsevier Inc. All rights reserved.

  9. Obesity and psoriasis: inflammatory nature of obesity, relationship between psoriasis and obesity, and therapeutic implications.

    Science.gov (United States)

    Carrascosa, J M; Rocamora, V; Fernandez-Torres, R M; Jimenez-Puya, R; Moreno, J C; Coll-Puigserver, N; Fonseca, E

    2014-01-01

    Obesity, particularly abdominal obesity, is currently considered a chronic low-grade inflammatory condition that plays an active role in the development of the pathophysiologic phenomena responsible for metabolic syndrome and cardiovascular disease through the secretion of proinflammatory adipokines and cytokines. In recent years clear genetic, pathogenic, and epidemiologic links have been established between psoriasis and obesity, with important implications for health. The relationship between the 2 conditions is probably bidirectional, with obesity predisposing to psoriasis and psoriasis favoring obesity. Obesity also has important implications in the treatment of psoriasis, such as a greater risk of adverse effects with conventional systemic drugs and reduced efficacy and/or increased cost with biologic agents, for which dosage should be adjusted to the patient's weight. Copyright © 2012 Elsevier España, S.L. and AEDV. All rights reserved.

  10. Examining the therapeutic relationship and confronting resistances in psychodynamic psychotherapy: a certified public accountant case.

    Science.gov (United States)

    Manetta, Christopher T; Gentile, Julie P; Gillig, Paulette Marie

    2011-05-01

    Psychodynamic psychotherapy is effective for a variety of mental health symptoms. This form of psychotherapy uses patient self reflection and self examination, as well as the therapeutic relationship between the patient and psychiatrist, to explore maladaptive coping strategies and relationship patterns of the patient. A thorough understanding of resistance and the core conflictual relationship theme afford the psychiatrist the ability to facilitate this work. In this article, the composite case illustrates some of the psychodynamic psychotherapy techniques that can be employed in a psychotherapy case. In this example, the case is about a certified public accountant that came to treatment because of an acute stressor that put her career goals at risk. An acute episode or event can bring to light chronic and ongoing symptoms, which have had a remitting and relapsing course, and leave the patient unable to compensate on his or her own.

  11. Consequences of HIV infection on malaria and therapeutic implications: a systematic review.

    Science.gov (United States)

    Flateau, Clara; Le Loup, Guillaume; Pialoux, Gilles

    2011-07-01

    Despite recent changes in the epidemiology of HIV infection and malaria and major improvements in their control, these diseases remain two of the most important infectious diseases and global health priorities. As they have overlapping distribution in tropical areas, particularly sub-Saharan Africa, any of their clinical, diagnostic, and therapeutic interactions might have important effects on patient care and public health policy. The biological basis of these interactions is well established. HIV infection induces cellular depletion and early abnormalities of CD4+ T cells, decreases CD8+ T-cell counts and function (cellular immunity), causes deterioration of specific antigen responses (humoral immunity), and leads to alteration of innate immunity through impairment of cytolytic activity and cytokine production by natural killer cells. Therefore, HIV infection affects the immune response to malaria, particularly premunition in adolescents and adults, and pregnancy-specific immunity, leading to different patterns of disease in HIV-infected patients compared with HIV-uninfected patients. In this systematic review, we collate data on the effects of HIV on malaria and discuss their therapeutic consequences. HIV infection is associated with increased prevalence and severity of clinical malaria and impaired response to antimalarial treatment, depending on age, immunodepression, and previous immunity to malaria. HIV also affects pregnancy-specific immunity to malaria and response to intermittent preventive treatment. Co-trimoxazole (trimethoprim-sulfamethoxazole) prophylaxis and antiretroviral treatment reduce occurrence of clinical malaria; however, these therapies interact with antimalarial drugs, and new therapeutic guidelines are needed for concomitant use. Copyright © 2011 Elsevier Ltd. All rights reserved.

  12. Monoclonal Antibodies against Zika Virus: Therapeutics and Their Implications for Vaccine Design.

    Science.gov (United States)

    Wang, Qihui; Yan, Jinghua; Gao, George Fu

    2017-10-15

    Zika virus (ZIKV) has caused global concern due to its association with neurological complications in newborns and adults. Although no vaccines or antivirals against ZIKV infection have been approved to date, hundreds of monoclonal antibodies (MAbs) have been developed in a short period. Here, we first present a complete picture of the ZIKV MAbs and then focus on the neutralizing mechanisms and immune hot spots uncovered through structural studies, which provide insight for therapeutics and vaccine design. Copyright © 2017 American Society for Microbiology.

  13. Psychosis with paranoid delusions after a therapeutic dose of mefloquine: a case report

    Directory of Open Access Journals (Sweden)

    Browning Joseph

    2006-08-01

    Full Text Available Abstract Background Convenient once-a-week dosing has made mefloquine a popular choice as malaria prophylaxis for travel to countries with chloroquine-resistant malaria. However, the increased use of mefloquine over the past decade has resulted in reports of rare, but severe, neuropsychiatric adverse reactions, such as anxiety, depression, hallucinations and psychosis. A direct causality between mefloquine and severe reactions among travelers has been partly confounded by factors associated with foreign travel and, in the case of therapeutic doses of mefloquine, the central nervous system manifestations of Plasmodium infection itself. The present case provides a unique natural history of mefloquine-induced neuropsychiatric toxicity and revisits its dose-dependent nature. Case presentation This report describes an acute exacerbation of neuropsychiatric symptoms after an unwarranted therapeutic dose (1250 mg of mefloquine in a 37-year-old male previously on a once-a-week prophylactic regimen. Neuropsychiatric symptoms began as dizziness and insomnia of several days duration, which was followed by one week of escalating anxiety and subtle alterations in behaviour. The patient's anxiety culminated into a panic episode with profound sympathetic activation. One week later, he was hospitalized after developing frank psychosis with psychomotor agitation and paranoid delusions. His psychosis remitted with low-dose quetiapine. Conclusion This report suggests that an overt mefloquine-induced psychosis can be preceded by a prodromal phase of moderate symptoms such as dizziness, insomnia, and generalized anxiety. It is important that physicians advise patients taking mefloquine prophylaxis and their relatives to recognize such symptoms, especially when they are accompanied by abrupt, but subtle, changes in behaviour. Patients with a history of psychiatric illness, however minor, may be at increased risk for a mefloquine-induced neuropsychiatric toxicity

  14. RNA sequencing atopic dermatitis transcriptome profiling provides insights into novel disease mechanisms with potential therapeutic implications

    DEFF Research Database (Denmark)

    Suárez-Fariñas, Mayte; Ungar, Benjamin; Correa da Rosa, Joel

    2015-01-01

    Background: Genomic profiling of lesional and nonlesional skin of patients with atopic dermatitis (AD) using microarrays has led to increased understanding of AD and identification of novel therapeutic targets. However, the limitations of microarrays might decrease detection of AD genes. These li......Background: Genomic profiling of lesional and nonlesional skin of patients with atopic dermatitis (AD) using microarrays has led to increased understanding of AD and identification of novel therapeutic targets. However, the limitations of microarrays might decrease detection of AD genes...... (criteria: fold change, ≥2.0; false discovery rate ≤0.05) in lesional versus nonlesional skin from 18 patients with moderate-to-severe AD, with real-time PCR (RT-PCR) and immunohistochemistry used for validation. Results: Both platforms showed robust disease transcriptomes and correlated well with RT-PCR...... RNA-seq showed somewhat better agreement with RT-PCR (intraclass correlation coefficient, 0.57 and 0.70 for microarrays and RNA-seq vs RT-PCR, respectively), bias was not eliminated. Among genes uniquely identified by using RNA-seq were triggering receptor expressed on myeloid cells 1 (TREM-1...

  15. Specific RSK kinase inhibition by dibenzyl trisulfide and implication for therapeutic treatment of cancer.

    Science.gov (United States)

    Lowe, Henry I C; Facey, Caroline O B; Toyang, Ngeh J; Bryant, Joseph L

    2014-04-01

    The Jamaican "Guinea Hen Weed" (Petiveria alliacea L.) plant has been traditionally used in folklore medicine to treat a variety of diseases including cancer. In the present study we investigated on the therapeutic feasibility of dibenzyl trisulfide (DTS) (isolated from the Jamaican Guinea Hen Weed) as a potent small-molecule kinase inhibitor to treat cancer. We investigated the inhibitory effects of DTS against a large panel of kinases using a well-established competitive binding assay. Cell proliferation data were obtained using the WST-1 colorimetric assay. DTS inhibited the activity of the C-terminal kinase domain of RSK1 (80% compared to control) with a Kd of 1.3 μM. Anti-proliferative effects of DTS were observed in small lung, pancreatic, breast, and prostate cancer cells with IC50 values ranging from 0.34-0.84 μM. We have identified DTS as a highly selective and isoform-specific RSK1 kinase inhibitor with broad cancer therapeutic potential.

  16. Ion channel expression patterns in glioblastoma stem cells with functional and therapeutic implications for malignancy.

    Science.gov (United States)

    Pollak, Julia; Rai, Karan G; Funk, Cory C; Arora, Sonali; Lee, Eunjee; Zhu, Jun; Price, Nathan D; Paddison, Patrick J; Ramirez, Jan-Marino; Rostomily, Robert C

    2017-01-01

    Ion channels and transporters have increasingly recognized roles in cancer progression through the regulation of cell proliferation, migration, and death. Glioblastoma stem-like cells (GSCs) are a source of tumor formation and recurrence in glioblastoma multiforme, a highly aggressive brain cancer, suggesting that ion channel expression may be perturbed in this population. However, little is known about the expression and functional relevance of ion channels that may contribute to GSC malignancy. Using RNA sequencing, we assessed the enrichment of ion channels in GSC isolates and non-tumor neural cell types. We identified a unique set of GSC-enriched ion channels using differential expression analysis that is also associated with distinct gene mutation signatures. In support of potential clinical relevance, expression of selected GSC-enriched ion channels evaluated in human glioblastoma databases of The Cancer Genome Atlas and Ivy Glioblastoma Atlas Project correlated with patient survival times. Finally, genetic knockdown as well as pharmacological inhibition of individual or classes of GSC-enriched ion channels constrained growth of GSCs compared to normal neural stem cells. This first-in-kind global examination characterizes ion channels enriched in GSCs and explores their potential clinical relevance to glioblastoma molecular subtypes, gene mutations, survival outcomes, regional tumor expression, and experimental responses to loss-of-function. Together, the data support the potential biological and therapeutic impact of ion channels on GSC malignancy and provide strong rationale for further examination of their mechanistic and therapeutic importance.

  17. Ion channel expression patterns in glioblastoma stem cells with functional and therapeutic implications for malignancy.

    Directory of Open Access Journals (Sweden)

    Julia Pollak

    Full Text Available Ion channels and transporters have increasingly recognized roles in cancer progression through the regulation of cell proliferation, migration, and death. Glioblastoma stem-like cells (GSCs are a source of tumor formation and recurrence in glioblastoma multiforme, a highly aggressive brain cancer, suggesting that ion channel expression may be perturbed in this population. However, little is known about the expression and functional relevance of ion channels that may contribute to GSC malignancy. Using RNA sequencing, we assessed the enrichment of ion channels in GSC isolates and non-tumor neural cell types. We identified a unique set of GSC-enriched ion channels using differential expression analysis that is also associated with distinct gene mutation signatures. In support of potential clinical relevance, expression of selected GSC-enriched ion channels evaluated in human glioblastoma databases of The Cancer Genome Atlas and Ivy Glioblastoma Atlas Project correlated with patient survival times. Finally, genetic knockdown as well as pharmacological inhibition of individual or classes of GSC-enriched ion channels constrained growth of GSCs compared to normal neural stem cells. This first-in-kind global examination characterizes ion channels enriched in GSCs and explores their potential clinical relevance to glioblastoma molecular subtypes, gene mutations, survival outcomes, regional tumor expression, and experimental responses to loss-of-function. Together, the data support the potential biological and therapeutic impact of ion channels on GSC malignancy and provide strong rationale for further examination of their mechanistic and therapeutic importance.

  18. Correlations between edema and the immediate and prolonged painful consequences of inflammation: therapeutic implications?

    Energy Technology Data Exchange (ETDEWEB)

    Chesler, Elissa J [ORNL; Lariviere, William R [University of Pittsburgh; Zhen, Li [Institute for Biomedical Sciences of Pain, Beijing, China; Shang, G [Institute for Biomedical Sciences of Pain, Beijing, China; Chen, Ya [Institute for Biomedical Sciences of Pain, Beijing, China; Yu, Yao [Institute for Biomedical Sciences of Pain, Beijing, China; Lu, Zhuo [Institute for Biomedical Sciences of Pain, Beijing, China; Chang, Ying [Institute for Biomedical Sciences of Pain, Beijing, China; Luo, Ceng [Institute for Biomedical Sciences of Pain, Beijing, China; Li, KaiCheng [Institute for Biomedical Sciences of Pain, Beijing, China; Chen, Jun [Institute for Biomedical Sciences of Pain, Beijing, China

    2005-06-01

    The precise relationship between the degree of pan and the degree of inflammation in the individual remains debated. A quantitative analysis simultaneously applied to the immediate and prolonged painful consequences of inflammation has not yet been done. Thus, the correlations between edema, nociception and hypersensitivity following an inflammatory insult were assessed in rodents. To better understand the therapeutic value of modifying specific aspects of inflammation, the effects of anti-inflammatory drug were compared to the results. Inbred strains of mice and outbred rats received an intraplantar injection of honeybee venom and the between group and within-group correlations were calculated for spontaneous nociceptive measures, thermal and mechanical hypersensitivity, and edema and temperature. The effect of indomethacin on the pain and the inflammation measures was examined. Edema correlated with spontaneous flinching, licking and lifting of the inject paw, and not with thermal or mechanical hypersensitivity. Indomethacin affected edema and spontaneous nociception dose-dependently, and affected hypersensitivity only at the highest dose test (P <0.005). These results suggest that edema may contribute only to immediate spontaneous nociceptive responses to an inflammatory insult, and not to the more clinically relevant prolonged hypersensitivity. This analysis represents a method for determine which inflammatory processes are the most promising therapeutic targets against the multiple painful consequences of inflammation.

  19. Noncoding RNAs and immune checkpoints-clinical implications as cancer therapeutics.

    Science.gov (United States)

    Smolle, Maria A; Calin, Horatiu N; Pichler, Martin; Calin, George A

    2017-07-01

    A major mechanism of tumor development and progression is silencing of the patient's immune response to cancer-specific antigens. Defects in the so-called cancer immunity cycle may occur at any stage of tumor development. Within the tumor microenvironment, aberrant expression of immune checkpoint molecules with activating or inhibitory effects on T lymphocytes induces immune tolerance and cellular immune escape. Targeting immune checkpoint molecules such as programmed cell death protein 1 (PD-1) and its ligand PD-L1 with specific antibodies has proven to be a major advance in the treatment of several types of cancer. Another way to therapeutically influence the tumor microenvironment is by modulating the levels of microRNAs (miRNAs), small noncoding RNAs that shuttle bidirectionally between malignant and tumor microenvironmental cells. These small RNA transcripts have two features: (a) their expression is quite specific to distinct tumors, and (b) they are involved in early regulation of immune responses. Consequently, miRNAs may be ideal molecules for use in cancer therapy. Many miRNAs are aberrantly expressed in human cancer cells, opening new opportunities for cancer therapy, but the exact functions of these miRNAs and their interactions with immune checkpoint molecules have yet to be investigated. This review summarizes recently reported findings about miRNAs as modulators of immune checkpoint molecules and their potential application as cancer therapeutics in clinical practice. © 2017 Federation of European Biochemical Societies.

  20. Visual and Motor Recovery After "Cognitive Therapeutic Exercises" in Cortical Blindness: A Case Study.

    Science.gov (United States)

    De Patre, Daniele; Van de Winckel, Ann; Panté, Franca; Rizzello, Carla; Zernitz, Marina; Mansour, Mariam; Zordan, Lara; Zeffiro, Thomas A; OʼConnor, Erin E; Bisson, Teresa; Lupi, Andrea; Perfetti, Carlo

    2017-07-01

    Spontaneous visual recovery is rare after cortical blindness. While visual rehabilitation may improve performance, no visual therapy has been widely adopted, as clinical outcomes are variable and rarely translate into improvements in activities of daily living (ADLs). We explored the potential value of a novel rehabilitation approach "cognitive therapeutic exercises" for cortical blindness. The subject of this case study was 48-year-old woman with cortical blindness and tetraplegia after cardiac arrest. Prior to the intervention, she was dependent in ADLs and poorly distinguished shapes and colors after 19 months of standard visual and motor rehabilitation. Computed tomographic images soon after symptom onset demonstrated acute infarcts in both occipital cortices. The subject underwent 8 months of intensive rehabilitation with "cognitive therapeutic exercises" consisting of discrimination exercises correlating sensory and visual information. Visual fields increased; object recognition improved; it became possible to watch television; voluntary arm movements improved in accuracy and smoothness; walking improved; and ADL independence and self-reliance increased. Subtraction of neuroimaging acquired before and after rehabilitation showed that focal glucose metabolism increases bilaterally in the occipital poles. This study demonstrates feasibility of "cognitive therapeutic exercises" in an individual with cortical blindness, who experienced impressive visual and sensorimotor recovery, with marked ADL improvement, more than 2 years after ischemic cortical damage.Video Abstract available for additional insights from the authors (see Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A173).

  1. Personal identity narratives of therapeutic songwriting participants following Spinal Cord Injury: a case series analysis.

    Science.gov (United States)

    Roddy, Chantal; Rickard, Nikki; Tamplin, Jeanette; Baker, Felicity Anne

    2017-08-24

    Spinal Cord Injury (SCI) patients face unique identity challenges associated with physical limitations, higher comorbid depression, increased suicidality and reduced subjective well-being. Post-injury identity is often unaddressed in subacute rehabilitation environments where critical physical and functional rehabilitation goals are prioritized. Therapeutic songwriting has demonstrated prior efficacy in promoting healthy adjustment and as a means of expression for post-injury narratives. The current study sought to examine the identity narratives of therapeutic songwriting participants. Case-series analysis of the individual identity trajectories of eight individuals. Subacute rehabilitation facility, Victoria, Australia. Eight individuals with an SCI; 7 males and 1 female. Six-week therapeutic songwriting intervention facilitated by a music therapist to promote identity rehabilitation. Identity, subjective well-being and distress, emotional state. Three participants demonstrated positive trajectories and a further three showed negative trajectories; remaining participants were ambiguous in their response. Injury severity differentiated those with positive trajectories from those with negative trajectories, with greater injury severity apparent for those showing negative trends. Self-concept also improved more in those with positive trajectories. Core demographic variables did not however meaningfully predict the direction of change in core identity or wellbeing indices. Identity-focused songwriting holds promise as a means of promoting healthy identity reintegration. Further research on benefits for those with less severe spinal injuries is warranted.

  2. Neuroendocrine circuits governing energy balance and stress regulation: functional overlap and therapeutic implications.

    Science.gov (United States)

    Ulrich-Lai, Yvonne M; Ryan, Karen K

    2014-06-03

    Significant comorbidities between obesity-related metabolic disease and stress-related psychological disorders suggest important functional interactions between energy balance and brain stress integration. Largely overlapping neural circuits control these systems, and this anatomical arrangement optimizes opportunities for mutual influence. Here we first review the current literature identifying effects of metabolic neuroendocrine signals on stress regulation, and vice versa. Next, the contributions of reward-driven food intake to these metabolic and stress interactions are discussed. Lastly, we consider the interrelationships between metabolism, stress, and reward in light of their important implications in the development of therapies for metabolism- or stress-related disease. Copyright © 2014 Elsevier Inc. All rights reserved.

  3. Human myelopoiesis in culture of liquid medium lacking colony stimulating factors: therapeutic implications for cancer patients with leukopenia.

    Science.gov (United States)

    Diamandopoulos, G T

    1994-01-01

    Patients with cancer often develop leukopenia caused by chemotherapy. Since their treatment with human colony stimulating factors (CSFs) has limitations, it is imperative to determine if CSFs are essential in regulating human myelopoiesis. For this purpose, human primary precursor myeloid cells were cultured in media lacking exogenous human CSFs and stem cell factor (SCF), and supplemented with human sera, or with fetal bovine or other types of animal sera. Cells cultured in human sera survive well, proliferate actively, and differentiate toward granulocytes. Most cells cultured in fetal bovine serum die, few differentiate toward monocytes-macrophages. Cells cultured in other types of animal sera die rapidly. Antibodies neutralizing human serum's CSFs and SCF do not abolish its myeloregulatory activity. It is concluded that cell growth factors other than CSFs and SCF present in human serum regulate human myelopoiesis in vitro. These findings bear important therapeutic implication for patients with cancer having leukopenia.

  4. An integrative view of mechanisms underlying generalized spike-and-wave epileptic seizures and its implication on optimal therapeutic treatments.

    Directory of Open Access Journals (Sweden)

    Boyuan Yan

    Full Text Available Many types of epileptic seizures are characterized by generalized spike-and-wave discharges. In the past, notable effort has been devoted to understanding seizure dynamics and various hypotheses have been proposed to explain the underlying mechanisms. In this paper, by taking an integrative view of the underlying mechanisms, we demonstrate that epileptic seizures can be generated by many different combinations of synaptic strengths and intrinsic membrane properties. This integrative view has important medical implications: the specific state of a patient characterized by a set of biophysical characteristics ultimately determines the optimal therapeutic treatment. Through the same view, we further demonstrate the potentiation effect of rational polypharmacy in the treatment of epilepsy and provide a new angle to resolve the debate on polypharmacy. Our results underscore the need for personalized medicine and demonstrate that computer modeling and simulation may play an important role in assisting the clinicians in selecting the optimal treatment on an individual basis.

  5. The safety of therapeutic monoclonal antibodies: implications for cancer therapy including immuno-checkpoint inhibitors.

    Science.gov (United States)

    Demlova, R; Valík, D; Obermannova, R; ZdraŽilová-Dubská, L

    2016-12-21

    Monoclonal antibody-based treatment of cancer has been established as one of the most successful therapeutic strategies for both hematologic malignancies and solid tumors. In addition to targeting cancer antigens antibodies can also modulate immunological pathways that are critical to immune surveillance. Antibody therapy directed against several negative immunologic regulators (checkpoints) is demonstrating significant success in the past few years. Immune checkpoint inhibitors, ipilimumab, pembrolizumab and nivolumab, have shown significant clinical benefit in several malignancies and are already approved for advanced melanoma and squamous NSCLC. Based on their mechanism of action, these agents can exert toxicities that are unlike conventional cytotoxic chemotherapy, whose nature is close to autoimmune diseases - immune related adverse events (irAEs). In this review we focus on the spectrum of irAEs associated with immune checkpoint antibodies, discussing the pharmacological treatment strategy and possible clinical impact.

  6. The role of PSMD9 in human disease: future clinical and therapeutic implications

    Directory of Open Access Journals (Sweden)

    Joanne L. Hopper

    2015-11-01

    Full Text Available PSMD9 was first characterized as a component of the PA700 proteasomal regulator, and was found to stimulate association of PA700 with the catalytic 20S proteasomal core to form the active 26S proteasome. It was also independently identified under the name “bridge-1” as a transcriptional co-activator that modulates function of the transcription factors PDX-1, E12, and E47, and interacts with the co-activator histone acetyltransferase p300. Here, we discuss the molecular and genetic data linking PSMD9 to a diverse range of conditions including diabetes, cancer, mental health problems, polycystic ovary syndrome and neurodegenerative diseases, and thereby highlight its potential as a therapeutic target in these multiple settings.

  7. Cannabinoids as therapeutic agents in cancer: current status and future implications

    Science.gov (United States)

    Ganju, Ramesh K.

    2014-01-01

    The pharmacological importance of cannabinoids has been in study for several years. Cannabinoids comprise of (a) the active compounds of the Cannabis sativa plant, (b) endogenous as well as (c) synthetic cannabinoids. Though cannabinoids are clinically used for anti-palliative effects, recent studies open a promising possibility as anti-cancer agents. They have been shown to possess anti-proliferative and anti-angiogenic effects in vitro as well as in vivo in different cancer models. Cannabinoids regulate key cell signaling pathways that are involved in cell survival, invasion, angiogenesis, metastasis, etc. There is more focus on CB1 and CB2, the two cannabinoid receptors which are activated by most of the cannabinoids. In this review article, we will focus on a broad range of cannabinoids, their receptor dependent and receptor independent functional roles against various cancer types with respect to growth, metastasis, energy metabolism, immune environment, stemness and future perspectives in exploring new possible therapeutic opportunities. PMID:25115386

  8. Cannabinoids as therapeutic agents in cancer: current status and future implications.

    Science.gov (United States)

    Chakravarti, Bandana; Ravi, Janani; Ganju, Ramesh K

    2014-08-15

    The pharmacological importance of cannabinoids has been in study for several years. Cannabinoids comprise of (a) the active compounds of the Cannabis sativa plant, (b) endogenous as well as (c) synthetic cannabinoids. Though cannabinoids are clinically used for anti-palliative effects, recent studies open a promising possibility as anti-cancer agents. They have been shown to possess anti-proliferative and anti-angiogenic effects in vitro as well as in vivo in different cancer models. Cannabinoids regulate key cell signaling pathways that are involved in cell survival, invasion, angiogenesis, metastasis, etc. There is more focus on CB1 and CB2, the two cannabinoid receptors which are activated by most of the cannabinoids. In this review article, we will focus on a broad range of cannabinoids, their receptor dependent and receptor independent functional roles against various cancer types with respect to growth, metastasis, energy metabolism, immune environment, stemness and future perspectives in exploring new possible therapeutic opportunities.

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

    Directory of Open Access Journals (Sweden)

    Caroline Perronnet

    2010-01-01

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

  10. Implications of microRNAs in Colorectal Cancer Development, Diagnosis, Prognosis and Therapeutics

    Directory of Open Access Journals (Sweden)

    Haiyan eZhai

    2011-11-01

    Full Text Available MicroRNAs (miRNAs are a class of non-coding small RNAs with critical regulatory functions as post-transcriptional regulators. Due to the fundamental importance and broad impact of miRNAs on multiple genes and pathways, dysregulated miRNAs have been associated with human diseases, including cancer. Colorectal cancer (CRC is among the most deadly diseases, and miRNAs offer a new frontier for target discovery and novel biomarkers for both diagnosis and prognosis. In this review, we summarize the recent advancement of miRNA research in CRC, in particular, the roles of miRNAs in colorectal cancer stem cells, EMT, chemoresistance, therapeutics, diagnosis and prognosis.

  11. G protein-coupled receptor signaling complexity in neuronal tissue: implications for novel therapeutics.

    Science.gov (United States)

    Maudsley, Stuart; Martin, Bronwen; Luttrell, Louis M

    2007-02-01

    The manipulation of transmembrane signaling by G protein-coupled receptors (GPCRs) constitutes perhaps the single most important therapeutic target in medicine. Therapeutics acting on GPCRs have traditionally been classified as agonists, partial agonists, or antagonists based on a two state model of receptor function embodied in the ternary complex model. Over the past decade, however, many lines of investigation have shown that GPCR signaling exhibits greater diversity and 'texture' than previously appreciated. Signal diversity arises from numerous factors, among them the ability of receptors to adopt multiple 'active' states with different effector coupling profiles, the formation of receptor dimers that exhibit unique pharmacology, signaling, and trafficking, the dissociation of receptor 'activation' from desensitization and internalization, and the discovery that non-G protein effectors mediate some aspects of GPCR signaling. At the same time, clustering of GPCRs with their downstream effectors in membrane microdomains, and interactions between receptors and a plethora of multidomain scaffolding proteins and accessory/chaperone molecules confers signal preorganization, efficiency, and specificity. More importantly it is likely that alteration in the interactions of these proteins with GPCRs may occur in aging or neurodegenerative disorders, thus defining a distinct 'pharmacology' from that seen in young organisms or normal physiology. In this context, the concept of agonist selective trafficking of receptor signaling, which recognizes that a bound ligand may select between a menu of 'active' receptor conformations and induce only a subset of the possible response profile, presents the opportunity to develop drugs that change the quality as well as the quantity of efficacy and enhance these qualities for specific disorders or other paradigms. As a more comprehensive understanding of the complexity of GPCR signaling is developed, the rational design of ligands

  12. Refractory Celiac Disease Type II: A Case Report that Demonstrates the Diagnostic and Therapeutic Challenges

    Directory of Open Access Journals (Sweden)

    Alexandra Fernandes

    2016-03-01

    Full Text Available Refractory celiac disease is an uncommon but serious complication of celiac disease. We describe a case of a severe refractory celiac disease type II, complicated with ulcerative jejunoileitis, in a 68 years old female, unresponsive to consecutive treatments with budesonide, prednisolone, cladribine and autologous stem cell transplantation. The patient maintained severe malnutrition, advanced osteoporosis, anaemia, vitamin deficiencies and hydro-electrolytic imbalances, necessitating consecutive hospitalizations for total parenteral nutrition. The patient also developed life-threatening complications, namely respiratory and urinary septic shock and also episodes of haemorrhagic shock secondary to ulcerative jejunoileitis. The progression to enteropathy associated T-cell lymphoma was never demonstrated, but the patient died 7 years after the diagnosis due to a septic shock secondary to a nosocomial pneumonia and osteomyelitis related to a spontaneous hip fracture. This case highlights the difficulties in the diagnostic process, therapeutic management and surveillance of this rare condition associated with very poor prognosis.

  13. Therapeutic implications of continuing bonds expressions following the death of a pet.

    Science.gov (United States)

    Packman, Wendy; Carmack, Betty J; Ronen, Rama

    Through the exploration of 12 continuing bonds expressions (CBE), this current study investigated the grief reaction and continuing impact of the death of a pet. Thirty-three individuals were interviewed to determine the degree of connection maintained with the deceased pet and how that affects their coping. Findings emphasize that the majority of respondents frequently maintain ongoing meaningful ties with their deceased pet through the use of CBE such as fond memories, rituals, dreams. The findings suggest that it is not the number of CBE but the degree of adaptability that is significant. The importance of recognizing the unique, total experience of those grieving the death of a pet is addressed. Implications for those working with and supporting those in grief are included. Future directions for research are described.

  14. Peripheral muscle abnormalities in cystic fibrosis: Etiology, clinical implications and response to therapeutic interventions.

    Science.gov (United States)

    Gruet, Mathieu; Troosters, Thierry; Verges, Samuel

    2017-09-01

    Peripheral muscle dysfunction is an important systemic consequence of cystic fibrosis (CF) with major clinical implications, such as exercise intolerance and reduced quality of life. Evidence is now accumulating that lack of physical activity is unlikely to be the sole explanation for peripheral muscle dysfunction of patients with CF. Particularly, the demonstration of CFTR expression in both murine and human skeletal muscle suggests the potential implication of intrinsic CF-related factors. By combining data from both human and animal models, this review describes CF peripheral muscle abnormalities and critically reviews the advances in understanding the impact of the underlying mechanisms. We also describe how peripheral muscles respond to intervention in this population. Methodological concerns and directions for future research are also considered. Peripheral muscle atrophy and weakness is prevalent in patients with CF and associated with reduced aerobic and anaerobic performances. Further investigations are however needed to confirm alterations in peripheral muscle endurance and fatigability. Physical inactivity is probably the major contributor of peripheral muscle abnormalities in patients with CF with mild-to-moderate phenotypes. However, the relative influence of additional factors (e.g. inflammation, metabolic abnormalities) probably increases with disease severity making specific and individualized interventions necessary in severe patients. Exercise training is the most effective intervention to address peripheral muscle dysfunction but other strategies, such as neuromuscular electrical stimulation and nutritional or hormonal supplementation may be of interest in some patients. Investigations are needed to determine whether pharmacological interventions such as CFTR modulators are effective to address this condition. To better elucidate the etiology of peripheral muscle dysfunction in CF, future studies should combine measurements at the cellular level

  15. The role of diet on intestinal microbiota metabolism: downstream impacts on host immune function and health, and therapeutic implications.

    Science.gov (United States)

    Goldsmith, Jason R; Sartor, R Balfour

    2014-05-01

    Dietary impacts on health may be one of the oldest concepts in medicine; however, only in recent years have technical advances in mass spectroscopy, gnotobiology, and bacterial sequencing enabled our understanding of human physiology to progress to the point where we can begin to understand how individual dietary components can affect specific illnesses. This review explores the current understanding of the complex interplay between dietary factors and the host microbiome, concentrating on the downstream implications on host immune function and the pathogenesis of disease. We discuss the influence of the gut microbiome on body habitus and explore the primary and secondary effects of diet on enteric microbial community structure. We address the impact of consumption of non-digestible polysaccharides (prebiotics and fiber), choline, carnitine, iron, and fats on host health as mediated by the enteric microbiome. Disease processes emphasized include non-alcoholic fatty liver disease/non-alcoholic steatohepatitis, IBD, and cardiovascular disease/atherosclerosis. The concepts presented in this review have important clinical implications, although more work needs to be done to develop fully and validate potential therapeutic approaches. Specific dietary interventions offer exciting potential for nontoxic, physiologic ways to alter enteric microbial structure and metabolism to benefit the natural history of many intestinal and systemic disorders.

  16. Differential solubility of curcuminoids in serum and albumin solutions: implications for analytical and therapeutic applications

    Directory of Open Access Journals (Sweden)

    Quitschke Wolfgang W

    2008-11-01

    Full Text Available Abstract Background Commercially available curcumin preparations contain a mixture of related polyphenols, collectively referred to as curcuminoids. These encompass the primary component curcumin along with its co-purified derivatives demethoxycurcumin and bisdemethoxycurcumin. Curcuminoids have numerous biological activities, including inhibition of cancer related cell proliferation and reduction of amyloid plaque formation associated with Alzheimer disease. Unfortunately, the solubility of curcuminoids in aqueous solutions is exceedingly low. This restricts their systemic availability in orally administered formulations and limits their therapeutic potential. Results Methods are described that achieve high concentrations of soluble curcuminoids in serum. Solid curcuminoids were either mixed directly with serum, or they were predissolved in dimethyl sulfoxide and added as aliquots to serum. Both methods resulted in high levels of curcuminoid-solubility in mammalian sera from different species. However, adding aliquots of dimethyl sulfoxide-dissolved curcuminoids to serum proved to be more efficient, producing soluble curcuminoid concentrations of at least 3 mM in human serum. The methods also resulted in the differential solubility of individual curcuminoids in serum. The addition of dimethyl sulfoxide-dissolved curcuminoids to serum preferentially solubilized curcumin, whereas adding solid curcuminoids predominantly solubilized bisdemethoxycurcumin. Either method of solubilization was equally effective in inhibiting dose-dependent HeLa cell proliferation in culture. The maximum concentration of curcuminoids achieved in serum was at least 100-fold higher than that required for inhibiting cell proliferation in culture and 1000-fold higher than the concentration that has been reported to prevent amyloid plaque formation associated with Alzheimer disease. Curcuminoids were also highly soluble in solutions of purified albumin, a major component of

  17. Biochemical regulation of airway smooth muscle tone: current knowledge and therapeutic implications.

    Science.gov (United States)

    Torphy, T J

    1987-01-01

    Evidence collected during the last decade indicates that the molecular processes responsible for smooth muscle contraction are fundamentally different from those responsible for skeletal muscle contraction. Furthermore, because of the diverse functional roles of various smooth muscles, it would not be surprising if significant differences in regulatory processes also exist among different smooth muscles. Such diversity may already be exemplified by differences in cross-bridge kinetics and sources of activator Ca2+. Additional unique regulatory features of various smooth muscle types will undoubtedly be uncovered by further research. A convincing body of data suggests that activation of the adenylate cyclase/protein kinase cascade is responsible for the bronchodilation produced by beta-adrenoceptor agonists. Although the exact mechanism by which the activation of cAMP-dependent protein kinase induces relaxation is not clear, the phosphorylation of multiple substrates may be involved. Phosphorylation of these substrates can promote relaxation by decreasing the myoplasmic Ca2+ concentration, decreasing the Ca2+ sensitivity of the contractile apparatus, or both. Thus, because beta-adrenoceptor agonists act as physiologic antagonists of broncho-constriction, they should relax airway smooth muscle regardless of the mediator(s) responsible for the bronchospasm. Perhaps this is the major reason that the beta-adrenoceptor agonists have become the premier class of drugs used in the treatment of bronchial asthma. As useful as the sympathomimetic bronchodilators have been, they are not without liabilities. These liabilities include: cardiovascular and skeletal muscle side effects, an inherent subsensitivity of the asthmatic patient population to beta-adrenoceptor agonists, the development of tolerance and a loss of efficacy during severe asthmatic episodes. The fact that these drawbacks are probably shared by all sympathomimetic bronchodilators suggests that little therapeutic

  18. Abnormal barrier function in the pathogenesis of ichthyosis: therapeutic implications for lipid metabolic disorders.

    Science.gov (United States)

    Elias, Peter M; Williams, Mary L; Feingold, Kenneth R

    2012-01-01

    Ichthyoses, including inherited disorders of lipid metabolism, display a permeability barrier abnormality in which the severity of the clinical phenotype parallels the prominence of the barrier defect. The pathogenesis of the cutaneous phenotype represents the consequences of the mutation for epidermal function, coupled with a "best attempt" by affected epidermis to generate a competent barrier in a terrestrial environment. A compromised barrier in normal epidermis triggers a vigorous set of metabolic responses that rapidly normalizes function, but ichthyotic epidermis, which is inherently compromised, only partially succeeds in this effort. Unraveling mechanisms that account for barrier dysfunction in the ichthyoses has identified multiple, subcellular, and biochemical processes that contribute to the clinical phenotype. Current treatment of the ichthyoses remains largely symptomatic: directed toward reducing scale or corrective gene therapy. Reducing scale is often minimally effective. Gene therapy is impeded by multiple pitfalls, including difficulties in transcutaneous drug delivery, high costs, and discomfort of injections. We have begun to use information about disease pathogenesis to identify novel, pathogenesis-based therapeutic strategies for the ichthyoses. The clinical phenotype often reflects not only a deficiency of pathway end product due to reduced-function mutations in key synthetic enzymes but often also accumulation of proximal, potentially toxic metabolites. As a result, depending upon the identified pathomechanism(s) for each disorder, the accompanying ichthyosis can be treated by topical provision of pathway product (eg, cholesterol), with or without a proximal enzyme inhibitor (eg, simvastatin), to block metabolite production. Among the disorders of distal cholesterol metabolism, the cutaneous phenotype in Congenital Hemidysplasia with Ichthyosiform Erythroderma and Limb Defects (CHILD syndrome) and X-linked ichthyosis reflect metabolite

  19. Abnormal barrier function in the pathogenesis of ichthyosis: Therapeutic implications for lipid metabolic disorders☆

    Science.gov (United States)

    Elias, Peter M.; Williams, Mary L.; Feingold, Kenneth R.

    2013-01-01

    Ichthyoses, including inherited disorders of lipid metabolism, display a permeability barrier abnormality in which the severity of the clinical phenotype parallels the prominence of the barrier defect. The pathogenesis of the cutaneous phenotype represents the consequences of the mutation for epidermal function, coupled with a “best attempt” by affected epidermis to generate a competent barrier in a terrestrial environment. A compromised barrier in normal epidermis triggers a vigorous set of metabolic responses that rapidly normalizes function, but ichthyotic epidermis, which is inherently compromised, only partially succeeds in this effort. Unraveling mechanisms that account for barrier dysfunction in the ichthyoses has identified multiple, subcellular, and biochemical processes that contribute to the clinical phenotype. Current treatment of the ichthyoses remains largely symptomatic: directed toward reducing scale or corrective gene therapy. Reducing scale is often minimally effective. Gene therapy is impeded by multiple pitfalls, including difficulties in transcutaneous drug delivery, high costs, and discomfort of injections. We have begun to use information about disease pathogenesis to identify novel, pathogenesis-based therapeutic strategies for the ichthyoses. The clinical phenotype often reflects not only a deficiency of pathway end product due to reduced-function mutations in key synthetic enzymes but often also accumulation of proximal, potentially toxic metabolites. As a result, depending upon the identified pathomechanism(s) for each disorder, the accompanying ichthyosis can be treated by topical provision of pathway product (eg, cholesterol), with or without a proximal enzyme inhibitor (eg, simvastatin), to block metabolite production. Among the disorders of distal cholesterol metabolism, the cutaneous phenotype in Congenital Hemidysplasia with Ichthyosiform Erythroderma and Limb Defects (CHILD syndrome) and X-linked ichthyosis reflect metabolite

  20. Influence of sympathetic autonomic arousal on tics: implications for a therapeutic behavioral intervention for Tourette syndrome.

    Science.gov (United States)

    Nagai, Yoko; Cavanna, Andrea; Critchley, Hugo D

    2009-12-01

    The pharmacological treatment of Tourette syndrome (TS) has improved due to the application of new medications and combinations of medications, coupled to greater phenomenological and neurobiological understanding of the condition. Nevertheless, for many individuals with TS, potentially troublesome tics persist despite optimized drug treatment. Anecdotally, a relationship is frequently described between tic frequency and states of bodily arousal and/or focused attention. The galvanic skin response (GSR) is an accessible and sensitive index of sympathetic nervous activity, reflecting centrally induced changes in peripheral autonomic arousal. Sympathetic nervous arousal, measured using GSR, has been shown to have an inverse relationship with an electroencephalographic index of cortical excitability (slow cortical potential), and GSR arousal biofeedback shows promise as an adjunctive therapy in management of treatment-resistant epilepsy. We examined how changes in sympathetic arousal, induced using GSR biofeedback, impact on tic frequency in individuals with TS. Two different physiological states (sympathetic arousal and relaxation) were induced using GSR biofeedback in 15 individuals with a diagnosis of TS. During both biofeedback sessions, participants were videotaped to monitor the occurrence of tics. We observed significantly lower tics during relaxation biofeedback compared to arousal biofeedback, with tic frequency positively correlating with sympathetic arousal during the arousal session. These findings indicate that the conjunction of focused attention to task and reduced peripheral sympathetic tone inhibits tic expression and suggests a potential therapeutic role of biofeedback relaxation training for tic management in patients with TS.

  1. Structural insights into the molecular mechanisms of myasthenia gravis and their therapeutic implications

    Energy Technology Data Exchange (ETDEWEB)

    Noridomi, Kaori; Watanabe, Go; Hansen, Melissa N.; Han, Gye Won; Chen, Lin (USC)

    2017-04-25

    The nicotinic acetylcholine receptor (nAChR) is a major target of autoantibodies in myasthenia gravis (MG), an autoimmune disease that causes neuromuscular transmission dysfunction. Despite decades of research, the molecular mechanisms underlying MG have not been fully elucidated. Here, we present the crystal structure of the nAChR α1 subunit bound by the Fab fragment of mAb35, a reference monoclonal antibody that causes experimental MG and competes with ~65% of antibodies from MG patients. Our structures reveal for the first time the detailed molecular interactions between MG antibodies and a core region on nAChR α1. These structures suggest a major nAChR-binding mechanism shared by a large number of MG antibodies and the possibility to treat MG by blocking this binding mechanism. Structure-based modeling also provides insights into antibody-mediated nAChR cross-linking known to cause receptor degradation. Our studies establish a structural basis for further mechanistic studies and therapeutic development of MG.

  2. Autophagy and Alzheimer’s Disease: From Molecular Mechanisms to Therapeutic Implications

    Directory of Open Access Journals (Sweden)

    Md. Sahab Uddin

    2018-01-01

    Full Text Available Alzheimer’s disease (AD is the most common cause of progressive dementia in the elderly. It is characterized by a progressive and irreversible loss of cognitive abilities and formation of senile plaques, composed mainly of amyloid β (Aβ, and neurofibrillary tangles (NFTs, composed of tau protein, in the hippocampus and cortex of afflicted humans. In brains of AD patients the metabolism of Aβ is dysregulated, which leads to the accumulation and aggregation of Aβ. Metabolism of Aβ and tau proteins is crucially influenced by autophagy. Autophagy is a lysosome-dependent, homeostatic process, in which organelles and proteins are degraded and recycled into energy. Thus, dysfunction of autophagy is suggested to lead to the accretion of noxious proteins in the AD brain. In the present review, we describe the process of autophagy and its importance in AD. Additionally, we discuss mechanisms and genes linking autophagy and AD, i.e., the mTOR pathway, neuroinflammation, endocannabinoid system, ATG7, BCL2, BECN1, CDK5, CLU, CTSD, FOXO1, GFAP, ITPR1, MAPT, PSEN1, SNCA, UBQLN1, and UCHL1. We also present pharmacological agents acting via modulation of autophagy that may show promise in AD therapy. This review updates our knowledge on autophagy mechanisms proposing novel therapeutic targets for the treatment of AD.

  3. Pathophysiological and therapeutic implications in patients with atrial fibrillation and heart failure.

    Science.gov (United States)

    Hohendanner, Felix; Heinzel, F R; Blaschke, F; Pieske, B M; Haverkamp, W; Boldt, H L; Parwani, A S

    2017-10-16

    Heart failure and atrial fibrillation are common and responsible for significant mortality of patients. Both share the same risk factors like hypertension, ischemic heart disease, diabetes, obesity, arteriosclerosis, and age. A variety of microscopic and macroscopic changes favor the genesis of atrial fibrillation in patients with preexisting heart failure, altered subcellular Ca(2+) homeostasis leading to increased cellular automaticity as well as concomitant fibrosis that are induced by pressure/volume overload and altered neurohumoral states. Atrial fibrillation itself promotes clinical deterioration of patients with preexisting heart failure as atrial contraction significantly contributes to ventricular filling. In addition, atrial fibrillation induced tachycardia can even further compromise ventricular function by inducing tachycardiomyopathy. Even though evidence has been provided that atrial functions significantly and independently of confounding ventricular pathologies, correlate with mortality of heart failure patients, rate and rhythm controls have been shown to be of equal effectiveness in improving mortality. Yet, it also has been shown that cohorts of patients with heart failure benefit from a rhythm control concept regarding symptom control and hospitalization. To date, amiodarone is the most feasible approach to restore sinus rhythm, yet its use is limited by its extensive side-effect profile. In addition, other therapies like catheter-based pulmonary vein isolation are of increasing importance. A wide range of heart failure-specific therapies are available with mixed impact on new onset or perpetuation of atrial fibrillation. This review highlights pathophysiological concepts and possible therapeutic approaches to treat patients with heart failure at risk for or with atrial fibrillation.

  4. Dendritic cell-based vaccination in cancer: therapeutic implications emerging from murine models

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    Soledad eMac Keon

    2015-05-01

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

  5. Molecular mechanism and therapeutic implications of selinexor (KPT-330) in liposarcoma.

    Science.gov (United States)

    Garg, Manoj; Kanojia, Deepika; Mayakonda, Anand; Said, Jonathan W; Doan, Ngan B; Chien, Wenwen; Ganesan, Trivadi S; Chuang, Linda Shyue Huey; Venkatachalam, Nachiyappan; Baloglu, Erkan; Shacham, Sharon; Kauffman, Michael; Koeffler, H Phillip

    2017-01-31

    Exportin-1 mediates nuclear export of multiple tumor suppressor and growth regulatory proteins. Aberrant expression of exportin-1 is noted in human malignancies, resulting in cytoplasmic mislocalization of its target proteins. We investigated the efficacy of selinexor against liposarcoma cells both in vitro and in vivo. Exportin-1 was highly expressed in liposarcoma samples and cell lines as determined by immunohistochemistry, western blot, and immunofluorescence assay. Knockdown of endogenous exportin-1 inhibited proliferation of liposarcoma cells. Selinexor also significantly decreased cell proliferation as well as induced cell cycle arrest and apoptosis of liposarcoma cells. The drug also significantly decreased tumor volumes and weights of liposarcoma xenografts. Importantly, selinexor inhibited insulin-like growth factor 1 (IGF1) activation of IGF-1R/AKT pathway through upregulation of insulin-like growth factor binding protein 5 (IGFBP5). Further, overexpression and knockdown experiments showed that IGFBP5 acts as a tumor suppressor and its expression was restored upon selinexor treatment of liposarcoma cells. Selinexor decreased aurora kinase A and B levels in these cells and inhibitors of these kinases suppressed the growth of the liposarcoma cells. Overall, our study showed that selinexor treatment restored tumor suppressive function of IGFBP5 and inhibited aurora kinase A and B in liposarcoma cells supporting the usefulness of selinexor as a potential therapeutic strategy for the treatment of this cancer.

  6. Mitochondrial Dysfunction and Oxidative Stress in Asthma: Implications for Mitochondria-Targeted Antioxidant Therapeutics

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    P. Hemachandra Reddy

    2011-02-01

    Full Text Available Asthma is a complex, inflammatory disorder characterized by airflow obstruction of variable degrees, bronchial hyper-responsiveness, and airway inflammation. Asthma is caused by environmental factors and a combination of genetic and environmental stimuli. Genetic studies have revealed that multiple loci are involved in the etiology of asthma. Recent cellular, molecular, and animal-model studies have revealed several cellular events that are involved in the progression of asthma, including: increased Th2 cytokines leading to the recruitment of inflammatory cells to the airway, and an increase in the production of reactive oxygen species and mitochondrial dysfunction in the activated inflammatory cells, leading to tissue injury in the bronchial epithelium. Further, aging and animal model studies have revealed that mitochondrial dysfunction and oxidative stress are involved and play a large role in asthma. Recent studies using experimental allergic asthmatic mouse models and peripheral cells and tissues from asthmatic humans have revealed antioxidants as promising treatments for people with asthma. This article summarizes the latest research findings on the involvement of inflammatory changes, and mitochondrial dysfunction/oxidative stress in the development and progression of asthma. This article also addresses the relationship between aging and age-related immunity in triggering asthma, the antioxidant therapeutic strategies in treating people with asthma.

  7. Phenotype/genotype correlations in Gaucher disease type 1: Clinical and therapeutic implications

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    Sibille, A.; Eng, C.M.; Kim, S.J.; Pastores, G. (Mount Sinai School of Medicine, New York, NY (United States)); Grabowski, G.A. (Mount Sinai School of Medicine, New York, NY (United States) Univ. of Cincinnati, OH (United States))

    1993-06-01

    Gaucher disease is the most frequent lysosomal storage disease and the most prevalent genetic disease among Ashkenazi Jews. Gaucher disease type 1 is characterized by marked variability of the phenotype and by the absence of neuronopathic involvement. To test the hypothesis that this phenotypic variability was due to genetic compounds of several different mutant alleles, 161 symptomatic patients with Gaucher disease type 1 (> 90% Ashkenazi Jewish) were analyzed for clinical involvement, and their genotypes were determined. Qualitative and quantitative measures of disease involvement included age at onset of the disease manifestations, hepatic and splenic volumes, age at splenectomy, and severity of bony disease. High statistically significant differences (P < .005) were found in each clinical parameter in patients with the N370S/N370S genotype compared with those patients with the N370S/84GG, N370S/L444P, and N370/ genotypes. The symptomatic N370S homozygotes had onset of their disease two to three decades later than patients with the other genotypes. In addition, patients with the latter genotypes have much more severely involved livers, spleens, and bones and had a higher incidence of splenectomy at an earlier age. These predictive genotype analyses provide the basis for genetic care delivery and therapeutic recommendations in patients affected with Gaucher disease type 1. 38 refs., 1 fig., 4 tabs.

  8. Bone morphogenetic protein signalling in pulmonary hypertension: advances and therapeutic implications.

    Science.gov (United States)

    Yang, Kai; Wang, Jian; Lu, Wenju

    2017-09-01

    What is the topic of this review? This review covers recent evidence highlighting the crucial pathophysiological roles and molecular mechanisms of the bone morphogenetic protein (BMP) signalling pathway during the progression of pulmonary hypertension (PH) and discusses targeting of BMP signalling as a new treatment option against PH. What advances does it highlight? A series of breakthrough findings have greatly enriched our understanding about the mechanism of action of BMP signalling in PH and proved the feasibility of BMP targeting strategies in experimental PH models. This review collects these ideas and discusses the frontiers of BMP signalling-targeted PH therapy at different steps of the signal transduction. The bone morphogenetic protein (BMP)-mediated signalling pathway plays crucial roles in the development and progression of pulmonary hypertension (PH). Typical BMP signalling involves BMP ligands, specific transmembrane serine/threonine kinase receptors, cellular responsive kinases and secreted antagonists. As more and more studies have been conducted, the specific protective or pathogenic roles of these molecules within all these subgroups of BMP signalling have been continuously uncovered. Based on this evidence, specific strategies have been designed by targeting these factors as a new treatment approach to PH. In this review, we have collected recent advances in the exciting findings that link BMP signalling with the pathogenesis of PH and we discuss the potential future frontiers in therapeutic design. © 2017 The Authors. Experimental Physiology © 2017 The Physiological Society.

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

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    Van Lint Carine

    2009-12-01

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

  10. [Type I Gaucher's disease: clinical, evolutive and therapeutic features in 8 cases].

    Science.gov (United States)

    Giraldo, P; Pérez-Calvo, J; Cortés, T; Civeira, F; Rubio-Félix, D

    1994-02-01

    complications in most cases. Better long-term prognosis can presently be expected in view of the good response to substitutive therapy. In order to establish an adjusted evaluation of the disease and its economic implications, a national registry would be desirable, thus allowing us to know the actual incidence and to make plans for successful Alglucerase treatment, taking into account the high costs of this last.

  11. Epidemiological, clinical, diagnostic and therapeutic survey in 505 cases with Brucellosis

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    Haj Abdolbaghi M

    2001-09-01

    Full Text Available Brucellosis is an endemic disease in Iran with variety of clinical manifestation. Special characteristics of clinical diagnosis and treatment issues may cause some problems in manegement of patients. In this descriptive study 505 patients with Brucellosis retrospectively were evaluated from clinical point of view, Lab exams and therapeutic issues for 10 years (1990 to 1999. From 505 patients, 321 cases were male and 184 were female. 42.7 percent of cases were in age group of 10 to 30 years. Ingestion of un-pasteurized dairy products was detected in (66.7 percent and 31.86 percent of cases were sheep herders. The most common symptoms and signs were fever (65 percent, sweating (61 percent, arthritis (30.09 percent, sacroilitis (21.5 percent, orchitis (8.2 percent, spondylitis (2-3 percent and endocarditis (1.18. In this survery blood culture for Brucella melitensis became positive in 48.5 percent and bone marrow in 61 percent. Standard tube agglutination was positive in 96 percent (?1.80. Doxycyclin plus Rifampin was the most common regimen we used (37.8 percent. 4 patients died, but just one of those was directly because of Brucella Endocarditis. In this article we have discussed about some interesting cases as well.

  12. Copper dyshomoeostasis in Parkinson's disease: implications for pathogenesis and indications for novel therapeutics.

    Science.gov (United States)

    Davies, Katherine M; Mercer, Julian F B; Chen, Nicholas; Double, Kay L

    2016-04-01

    Copper is a biometal essential for normal brain development and function, thus copper deficiency or excess results in central nervous system disease. Well-characterized disorders of disrupted copper homoeostasis with neuronal degeneration include Menkes disease and Wilson's disease but a large body of evidence also implicates disrupted copper pathways in other neurodegenerative disorders, including Parkinson's disease, Alzheimer's disease, Amyotrophic lateral sclerosis, Huntington's disease and prion diseases. In this short review we critically evaluate the data regarding changes in systemic and brain copper levels in Parkinson's disease, where alterations in brain copper are associated with regional neuronal cell death and disease pathology. We review copper regulating mechanisms in the human brain and the effects of dysfunction within these systems. We then examine the evidence for a role for copper in pathogenic processes in Parkinson's disease and consider reports of diverse copper-modulating strategies in in vitro and in vivo models of this disorder. Copper-modulating therapies are currently advancing through clinical trials for Alzheimer's and Huntington's disease and may also hold promise as disease modifying agents in Parkinson's disease. © 2016 Authors; published by Portland Press Limited.

  13. Presynaptic Mechanisms of l-DOPA-Induced Dyskinesia: The Findings, the Debate, and the Therapeutic Implications.

    Science.gov (United States)

    Cenci, M Angela

    2014-01-01

    The dopamine (DA) precursor l-DOPA has been the most effective treatment for Parkinson's disease (PD) for over 40 years. However, the response to this treatment changes with disease progression, and most patients develop dyskinesias (abnormal involuntary movements) and motor fluctuations within a few years of l-DOPA therapy. There is wide consensus that these motor complications depend on both pre- and post-synaptic disturbances of nigrostriatal DA transmission. Several presynaptic mechanisms converge to generate large DA swings in the brain concomitant with the peaks-and-troughs of plasma l-DOPA levels, while post-synaptic changes engender abnormal functional responses in dopaminoceptive neurons. While this general picture is well-accepted, the relative contribution of different factors remains a matter of debate. A particularly animated debate has been growing around putative players on the presynaptic side of the cascade. To what extent do presynaptic disturbances in DA transmission depend on deficiency/dysfunction of the DA transporter, aberrant release of DA from serotonin neurons, or gliovascular mechanisms? And does noradrenaline (which is synthetized from DA) play a role? This review article will summarize key findings, controversies, and pending questions regarding the presynaptic mechanisms of l-DOPA-induced dyskinesia. Intriguingly, the debate around these mechanisms has spurred research into previously unexplored facets of brain plasticity that have far-reaching implications to the treatment of neuropsychiatric disease.

  14. The shared neuroanatomy and neurobiology of comorbid chronic pain and PTSD: therapeutic implications.

    Science.gov (United States)

    Scioli-Salter, Erica R; Forman, Daniel E; Otis, John D; Gregor, Kristin; Valovski, Ivan; Rasmusson, Ann M

    2015-04-01

    Chronic pain and posttraumatic stress disorder (PTSD) are disabling conditions that affect biological, psychological, and social domains of functioning. Clinical research demonstrates that patients who are affected by chronic pain and PTSD in combination experience greater pain, affective distress, and disability than patients with either condition alone. Additional research is needed to delineate the interrelated pathophysiology of chronic pain and PTSD, with the goal of facilitating more effective therapies to treat both conditions more effectively; current treatment strategies for chronic pain associated with PTSD have limited efficacy and place a heavy burden on patients, who must visit various specialists to manage these conditions separately. This article focuses on neurobiological factors that may contribute to the coprevalence and synergistic interactions of chronic pain and PTSD. First, we outline how circuits that mediate emotional distress and physiological threat, including pain, converge. Secondly, we discuss specific neurobiological mediators and modulators of these circuits that may contribute to chronic pain and PTSD symptoms. For example, neuropeptide Y, and the neuroactive steroids allopregnanolone and pregnanolone (together termed ALLO) have antistress and antinociceptive properties. Reduced levels of neuropeptide Y and ALLO have been implicated in the pathophysiology of both chronic pain and PTSD. The potential contribution of opioid and cannabinoid system factors also will be discussed. Finally, we address potential novel methods to restore the normal function of these systems. Such novel perspectives regarding disease and disease management are vital to the pursuit of relief for the many individuals who struggle with these disabling conditions.

  15. Amyloid-modifying therapies for Alzheimer's disease: therapeutic progress and its implications.

    Science.gov (United States)

    Creed, Meaghan C; Milgram, Norton W

    2010-09-01

    Alzheimer's disease (AD) is the most prevalent form of dementia, affecting an estimated 4.8 million people in North America. For the past decade, the amyloid cascade hypothesis has dominated the field of AD research. This theory posits that the deposition of amyloid-beta protein (Abeta) in the brain is the key pathologic event in AD, which induces a series of neuropathological changes that manifest as cognitive decline and eventual dementia. Based on this theory, interventions that reduce Abeta burden in the brain would be expected to alleviate both the neuropathological changes and dementia, which characterize AD. Several diverse pharmacological strategies have been developed to accomplish this. These include inhibiting the formation of Abeta, preventing the aggregation of Abeta into insoluble aggregates, preventing the entry of Abeta into the brain from the periphery and enhancing the clearance of Abeta from the central nervous system. To date, no amyloid-modifying therapy has yet been successful in phase 3 clinical trials; however, several trials are currently underway. This article provides a review of the status of amyloid-modifying therapies and the implications for the amyloid cascade hypothesis.

  16. Induction of Neuroendocrine Differentiation in Prostate Cancer Cells by Dovitinib (TKI-258 and its Therapeutic Implications

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    Shalini S. Yadav

    2017-06-01

    Full Text Available Prostate cancer (PCa remains the second-leading cause of cancer-related deaths in American men with an estimated mortality of more than 26,000 in 2016 alone. Aggressive and metastatic tumors are treated with androgen deprivation therapies (ADT; however, the tumors acquire resistance and develop into lethal castration resistant prostate cancer (CRPC. With the advent of better therapeutics, the incidences of a more aggressive neuroendocrine prostate cancer (NEPC variant continue to emerge. Although de novo occurrences of NEPC are rare, more than 25% of the therapy-resistant patients on highly potent new-generation anti-androgen therapies end up with NEPC. This, along with previous observations of an increase in the number of such NE cells in aggressive tumors, has been suggested as a mechanism of resistance development during prostate cancer progression. Dovitinib (TKI-258/CHIR-258 is a pan receptor tyrosine kinase (RTK inhibitor that targets VEGFR, FGFR, PDGFR, and KIT. It has shown efficacy in mouse-model of PCa bone metastasis, and is presently in clinical trials for several cancers. We observed that both androgen receptor (AR positive and AR-negative PCa cells differentiate into a NE phenotype upon treatment with Dovitinib. The NE differentiation was also observed when mice harboring PC3-xenografted tumors were systemically treated with Dovitinib. The mechanistic underpinnings of this differentiation are unclear, but seem to be supported through MAPK-, PI3K-, and Wnt-signaling pathways. Further elucidation of the differentiation process will enable the identification of alternative salvage or combination therapies to overcome the potential resistance development.

  17. Anti‐inflammatory properties of the vagus nerve: potential therapeutic implications of vagus nerve stimulation

    Science.gov (United States)

    Sinniger, Valérie; Pellissier, Sonia

    2016-01-01

    Abstract Brain and viscera interplay within the autonomic nervous system where the vagus nerve (VN), containing approximately 80% afferent and 20% efferent fibres, plays multiple key roles in the homeostatic regulations of visceral functions. Recent data have suggested the anti‐inflammatory role of the VN. This vagal function is mediated through several pathways, some of them still debated. The first one is the anti‐inflammatory hypothalamic–pituitary–adrenal axis which is stimulated by vagal afferent fibres and leads to the release of cortisol by the adrenal glands. The second one, called the cholinergic anti‐inflammatory pathway, is mediated through vagal efferent fibres that synapse onto enteric neurons which release acetylcholine (ACh) at the synaptic junction with macrophages. ACh binds to α‐7‐nicotinic ACh receptors of those macrophages to inhibit the release of tumour necrosis (TNF)α, a pro‐inflammatory cytokine. The last pathway is the splenic sympathetic anti‐inflammatory pathway, where the VN stimulates the splenic sympathetic nerve. Norepinephrine (noradrenaline) released at the distal end of the splenic nerve links to the β2 adrenergic receptor of splenic lymphocytes that release ACh. Finally, ACh inhibits the release of TNFα by spleen macrophages through α‐7‐nicotinic ACh receptors. Understanding of these pathways is interesting from a therapeutic point of view, since they could be targeted in various ways to stimulate anti‐inflammatory regulation in TNFα‐related diseases such as inflammatory bowel disease and rheumatoid arthritis. Among others, VN stimulation, either as an invasive or non‐invasive procedure, is becoming increasingly frequent and several clinical trials are ongoing to evaluate the potential effectiveness of this therapy to alleviate chronic inflammation. PMID:27059884

  18. Anti-inflammatory properties of the vagus nerve: potential therapeutic implications of vagus nerve stimulation.

    Science.gov (United States)

    Bonaz, Bruno; Sinniger, Valérie; Pellissier, Sonia

    2016-10-15

    Brain and viscera interplay within the autonomic nervous system where the vagus nerve (VN), containing approximately 80% afferent and 20% efferent fibres, plays multiple key roles in the homeostatic regulations of visceral functions. Recent data have suggested the anti-inflammatory role of the VN. This vagal function is mediated through several pathways, some of them still debated. The first one is the anti-inflammatory hypothalamic-pituitary-adrenal axis which is stimulated by vagal afferent fibres and leads to the release of cortisol by the adrenal glands. The second one, called the cholinergic anti-inflammatory pathway, is mediated through vagal efferent fibres that synapse onto enteric neurons which release acetylcholine (ACh) at the synaptic junction with macrophages. ACh binds to α-7-nicotinic ACh receptors of those macrophages to inhibit the release of tumour necrosis (TNF)α, a pro-inflammatory cytokine. The last pathway is the splenic sympathetic anti-inflammatory pathway, where the VN stimulates the splenic sympathetic nerve. Norepinephrine (noradrenaline) released at the distal end of the splenic nerve links to the β2 adrenergic receptor of splenic lymphocytes that release ACh. Finally, ACh inhibits the release of TNFα by spleen macrophages through α-7-nicotinic ACh receptors. Understanding of these pathways is interesting from a therapeutic point of view, since they could be targeted in various ways to stimulate anti-inflammatory regulation in TNFα-related diseases such as inflammatory bowel disease and rheumatoid arthritis. Among others, VN stimulation, either as an invasive or non-invasive procedure, is becoming increasingly frequent and several clinical trials are ongoing to evaluate the potential effectiveness of this therapy to alleviate chronic inflammation. © 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.

  19. Uterine leiomyosarcoma diffusely express disialoganglioside GD2 and bind the therapeutic immunocytokine 14.18-IL2: implications for immunotherapy.

    Science.gov (United States)

    Ziebarth, Angela J; Felder, Mildred A; Harter, Josephine; Connor, Joseph P

    2012-07-01

    Uterine leiomyosarcoma comprises IL2 generated from the 14G2A sequence. Immunoreactivity was detected by avidin-biotin complex with DAB substrate. Specimens were reviewed by a pathologist with light microscopy and classified as negative, 1+, 2+ or 3+, compared to human melanoma cells as positive control and tissue incubated in the absence of primary antibody as negative control. GD2 was diffusely present in all evaluable samples. 10 tumors (67 %) demonstrated 3+ IHC intensity for GD2, two tumors (13 %) demonstrated 2+ intensity, and 3 (20 %) tumors demonstrated 1+ intensity. Eleven cases had sufficient tissue to assess 14.18-IL2 binding. All 11 cases bound 14.18-IL2 in a pattern identical to the parent antibody. Uterine leiomyosarcoma diffusely express GD2 and bind the therapeutic immunocytokine 14.18-IL2. This warrants further exploration to determine whether immunocytokine therapy may have a clinical role in the management of these aggressive tumors.

  20. Urothelial cancer stem cells and epithelial plasticity: current concepts and therapeutic implications in bladder cancer.

    Science.gov (United States)

    Garg, Minal

    2015-12-01

    Urothelial carcinoma is a highly heterogeneous disease that develops along two distinct biological tracks as evident by candidate gene analysis and genome-wide screening and therefore, offers different challenges for clinical management. Tumors representing the truly distinct molecular entities express molecular markers characteristic of a developmental process and a major mechanism of cancer metastasis, known as epithelial-to-mesenchymal transition (EMT). Recently identified subset of cells known as urothelial cancer stem cells (UroCSCs) in urothelial cell carcinoma (UCC) have self-renewal properties, ability to generate cellular tumor heterogeneity via differentiation and are ultimately responsible for tumor growth and viability. In this review paper, PubMed and Google Scholar electronic databases were searched for original research papers and review articles to extract relevant information on the molecular mechanisms delineating the relationship between EMT and cancer stemness and their clinical implications for different subsets of urothelial cell carcinomas. Experimental and clinical studies over the past few years in bladder cancer cell lines and tumor tissues of different cancer subtypes provide evidences and new insights for mechanistic complexity for induction of EMT, tumorigenicity, and cancer stemness in malignant transformation of urothelial cell carcinomas. Differentiation and elimination therapies targeting EMT-cancer stemness pathway have been proposed as cynosure in the molecular biology of urothelial cell carcinomas and could prove to be clinically beneficial in an ability to reverse the EMT phenotype of tumor cells, suppress the properties of UroCSCs, inhibit bladder cancer progression and tumor relapse, and provide rationale in the treatment and clinical management of urothelial cancer.

  1. Diagnostic and therapeutic implications of genetic heterogeneity in myeloid neoplasms uncovered by comprehensive mutational analysis

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    Sarah M. Choi

    2017-01-01

    Full Text Available While growing use of comprehensive mutational analysis has led to the discovery of innumerable genetic alterations associated with various myeloid neoplasms, the under-recognized phenomenon of genetic heterogeneity within such neoplasms creates a potential for diagnostic confusion. Here, we describe two cases where expanded mutational testing led to amendment of an initial diagnosis of chronic myelogenous leukemia with subsequent altered treatment of each patient. We demonstrate the power of comprehensive testing in ensuring appropriate classification of genetically heterogeneous neoplasms, and emphasize thoughtful analysis of molecular and genetic data as an essential component of diagnosis and management.

  2. Diagnostic and therapeutic implications of genetic heterogeneity in myeloid neoplasms uncovered by comprehensive mutational analysis.

    Science.gov (United States)

    Choi, Sarah M; Goldenson, Ben; Peterson, Lo Ann; Dinner, Shira; Stein, Brady L; Behdad, Amir

    2017-01-01

    While growing use of comprehensive mutational analysis has led to the discovery of innumerable genetic alterations associated with various myeloid neoplasms, the under-recognized phenomenon of genetic heterogeneity within such neoplasms creates a potential for diagnostic confusion. Here, we describe two cases where expanded mutational testing led to amendment of an initial diagnosis of chronic myelogenous leukemia with subsequent altered treatment of each patient. We demonstrate the power of comprehensive testing in ensuring appropriate classification of genetically heterogeneous neoplasms, and emphasize thoughtful analysis of molecular and genetic data as an essential component of diagnosis and management.

  3. Evaluation of possible vertical fractures and therapeutic possibilities: A case report.

    Directory of Open Access Journals (Sweden)

    Luis Espinoza

    2012-12-01

    Full Text Available Restorative treatment of endontic teeth supossed certain complications, especially when the restoration is not adequate. Indications for treatment vary according to the remaining tooth . In cases of which this one is moderated, it is chosen to rehabilitate by a type of indirect obturation, this can be in resin, ceramics or metal. A bad indication of restoration will lead to certain complications due to the fact that the rehabilitation of a treated tooth endodónticamente supposes in the majority of the cases an important challenge for the odontologist since it must solve the loss of structure dentaria, the minor resistance to the fracture before the forces oclusales and the need to provide sufficient retention to the material restorer who will replace the dental lost matter.Dental cracks corresponds to one of the recurring problems, the clinical diagnosis of accounting for it, usually cannot be verified radiographically and clinical examination is necessary.In some cases it opt prematurely for the exodoncy, the implications of this option for the stomatognathic balance should guide the clinician to ensure proper diagnosis and more conservative treatment plan, using the wide variety of new materials and adhesive systems, which allow patient's and clinician's satisfaction.We report the case of a patient presenting a dental crack in the tooth 2.4, which was treated conservatively, obtaining optimal results in terms of aesthetics and functionality.

  4. Symptom combinations associated with outcome and therapeutic effects in a cohort of cases with SARS.

    Science.gov (United States)

    Li, Shao; Wang, Ruiqin; Zhang, Yulong; Zhang, Xuegong; Layon, A Joseph; Li, Yanda; Chen, Mingzhe

    2006-01-01

    Severe acute respiratory syndrome (SARS) is an infectious disease and some of its symptoms were clinically indistinguishable of those from similar diseases. This study aimed to find the symptom combinations associated with adverse outcome and the therapeutic effects in a cohort of patients with probable SARS retrospectively. In 2003, 123 SARS cases in Beijing were subjected to a strictly western medicine (WM) treatment, or a combined treatment (WM plus Herba houttuyniae injection, addition of individualized herbal treatments when necessary), of which 115 were followed till death or discharge; 8 were transferred and lost to follow-up. In both treatment groups, clinical manifestations were evaluated daily; development of signs and symptoms, and their possible relationship with outcome, were assessed. The relationships between these sign/symptom complexes and outcome under two treatment protocols were evaluated and differences were noted. Dynamic symptom combinations, dividing into the early, the medium-term and the durational symptom clusters, were identified as likely being related to the adverse outcomes of SARS (p arterial oxyhemoglobin saturation significantly at day 22 (p < 0.05). In conclusion, the progress and outcome of SARS may be associated with specific temporal patterns of development in combination of several non-specific signs and symptom complexes, which are also helpful for evaluating the therapeutic effects on SARS patients.

  5. "Why am I so stuck?": A Collaborative/Therapeutic Assessment Case Discussion.

    Science.gov (United States)

    Engelman, Diane H; Allyn, J B; Crisi, Alessandro; Finn, Stephen E; Fischer, Constance T; Nakamura, Noriko

    2016-01-01

    Assessors from 3 continents worked together on a single multimethod case study. Their goal was to hold the client at the center and forefront of their attitudes and thinking as each assessor focused on a specific measure or group of measures. The adult client requested a neuropsychological assessment and completed a full battery of cognitive measures as well as the MMPI-2, the Rorschach, and the Wartegg. A basic tenet of collaborative/therapeutic assessment holds that the client is a full partner in the assessment process; he or she is also seen as the final arbiter of the usefulness of the ideas derived. With that in mind, the client worked with the lead assessor to create 6 questions she wished answered by the assessment. Feedback and discussion occurred in a number of ways: through discussion sessions with the lead assessor that included extended inquiry; individualized letters from the other assessors, each addressing her 6 questions; a summary letter from the lead assessor; and a metaphorical, therapeutic story that stressed key findings from the assessment. Results converged powerfully, with similar findings from each assessor. The client stated that she felt heard and understood in the process, even by individuals who she had never met personally.

  6. [Dentascan computed tomography of the mandibular incisive canal. Its radiologic anatomy and the therapeutic implications].

    Science.gov (United States)

    Calgaro, A; Bison, L; Bellis, G B; Pozzi Mucelli, R

    1999-11-01

    To stress the importance of CT depiction of the mandibular incisive canal. This anatomical structure contains a major neurovascular bundle and is thus very important in the planning of mandibular implants in the canine-incisive area. January through December 1998, sixty patients unselected by age and gender were submitted to mandibular CT. Axial slices were acquired with 1-1.5 mm thickness and 1 mm table feed, and the images were then reformatted with a dedicated dental software. Both the conventional and the Helical techniques were used. The incisive canal appears on Dentascan transverse reconstructions as a round low-density area within mandibular trabecular bone, which is surrounded by a higher-density rim representing the canal walls. This anatomical structure originates from the mental foramen and continues mesially to the mental symphysis. The mandibular canal was visualized in 95% of cases bilaterally (57/60); the incisive canal was depicted on the left side in 41.6% of cases (25/60) and on the right side in 51.6% (31/60). The importance of careful assessment of the mandibular canal course before implantology is now widely recognized. The same holds true for the canine-incisive region in the jaw, to detect the incisive canal if present and prevent any complications from its accidental damage. CT with a dedicated software showed the incisive canal in a large number of patients, which calls for precise reporting of its presence, course, and relationships with teeth.

  7. [Food addiction: Definition, measurement and limits of the concept, associated factors, therapeutic and clinical implications].

    Science.gov (United States)

    Cathelain, Sarah; Brunault, Paul; Ballon, Nicolas; Réveillère, Christian; Courtois, Robert

    2016-12-01

    and multidimensional concept which requires integrated care with psychotherapy, pharmacological and social lines of approach. This concept has also practical implications in terms of prevention and public health (e.g., prevention, brief interventions, possible law enforcement regarding some kinds of food which could present some addictive properties). Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  8. Histopathological study of ocular erythema nodosum leprosum and post-therapeutic scleral perforation: a case report.

    Science.gov (United States)

    Rathinam, S R; Khazaei, Hadi M; Job, C K

    2008-01-01

    Leprosy is a chronic granulomatous disease caused by Mycobacterium leprae , clinically present either as tuberculoid, borderline or lepromatous type. Erythema nodosum leprosum (ENL) is an acute humoral response in the chronic course of lepromatous leprosy. Although very severe ENL reactions are known in systemic leprosy, such severity is rare in ocular tissues. A leprosy uveitis patient suffered from a severe form of post-therapeutic ENL reaction which resulted in perforation of the globe at the site of preexisting subconjunctival leproma. Painful blind eye was enucleated. Histopathological study revealed infiltration of numerous polymorphs and macrophages packed with acid-fast bacilli in the conjunctiva, cornea, ciliary body, ora serrata and sclera. A profuse influx of neutrophils on a background of macrophages packed with M. leprae confirmed the ocular ENL reaction. This case is reported to alert the ophthalmologists to a rare ocular complication of ENL.

  9. The Drosophila melanogaster model for Cornelia de Lange syndrome: Implications for etiology and therapeutics.

    Science.gov (United States)

    Dorsett, Dale

    2016-06-01

    Discovery of genetic alterations that cause human birth defects provide key opportunities to improve the diagnosis, treatment, and family counseling. Frequently, however, these opportunities are limited by the lack of knowledge about the normal functions of the affected genes. In many cases, there is more information about the gene's orthologs in model organisms, including Drosophila melanogaster. Despite almost a billion years of evolutionary divergence, over three-quarters of genes linked to human diseases have Drosophila homologs. With a short generation time, a twenty-fold smaller genome, and unique genetic tools, the conserved functions of genes are often more easily elucidated in Drosophila than in other organisms. Here we present how this applies to Cornelia de Lange syndrome, as a model for how Drosophila can be used to increase understanding of genetic syndromes caused by mutations with broad effects on gene transcription and exploited to develop novel therapies. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  10. Markers of Oxidative Stress in Generalized Anxiety Psychiatric Disorder: Therapeutic Implications

    Directory of Open Access Journals (Sweden)

    Khanna Ranjana S.

    2012-05-01

    Full Text Available There is growing evidence that oxidative stress contributes to the pathogenesis of anxiety disorders. Our aim was to measure oxidative stress in anxiety disorders subjects, and assesses the potential confounding influences of anti anxiety therapy. Serum malondialdehyde and antioxidant levels were estimated in patients at the time of presentation and also after anti- anxiety therapy for 3 months. During the period of study no antioxidant/s was given to the patients and control subjects. Serum malondialdehyde levels were significantly higher in the anxiety disorders patients in comparison to control cases. Also, the antioxidant activity of enzymes super oxide dismutase, glutathione and non enzymatic antioxidant levels of vitamins E and C were significantly lower in patients compared to controls at the initial presentation. After 3 months of anti anxiety treatment all the above parameters showed reversal in the respective levels of serum malondialdehyde and antioxidant activity. Anti anxiety medications results in reduced oxidative stress which indicates that oxidative stress is not the cause, but rather a consequence, of anxiety disorders.

  11. Genomic portfolio of Merkel cell carcinoma as determined by comprehensive genomic profiling: implications for targeted therapeutics.

    Science.gov (United States)

    Cohen, Philip R; Tomson, Brett N; Elkin, Sheryl K; Marchlik, Erica; Carter, Jennifer L; Kurzrock, Razelle

    2016-04-26

    Merkel cell carcinoma is an ultra-rare cutaneous neuroendocrine cancer for which approved treatment options are lacking. To better understand potential actionability, the genomic landscape of Merkel cell cancers was assessed. The molecular aberrations in 17 patients with Merkel cell carcinoma were, on physician request, tested in a Clinical Laboratory Improvement Amendments (CLIA) laboratory (Foundation Medicine, Cambridge, MA) using next-generation sequencing (182 or 236 genes) and analyzed by N-of-One, Inc. (Lexington, MA). There were 30 genes harboring aberrations and 60 distinct molecular alterations identified in this patient population. The most common abnormalities involved the TP53 gene (12/17 [71% of patients]) and the cell cycle pathway (CDKN2A/B, CDKN2C or RB1) (12/17 [71%]). Abnormalities also were observed in the PI3K/AKT/mTOR pathway (AKT2, FBXW7, NF1, PIK3CA, PIK3R1, PTEN or RICTOR) (9/17 [53%]) and DNA repair genes (ATM, BAP1, BRCA1/2, CHEK2, FANCA or MLH1) (5/17 [29%]). Possible cognate targeted therapies, including FDA-approved drugs, could be identified in most of the patients (16/17 [94%]). In summary, Merkel cell carcinomas were characterized by multiple distinct aberrations that were unique in the majority of analyzed cases. Most patients had theoretically actionable alterations. These results provide a framework for investigating tailored combinations of matched therapies in Merkel cell carcinoma patients.

  12. Structural Analysis of Monomeric RNA-Dependent Polymerases: Evolutionary and Therapeutic Implications.

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    Rodrigo Jácome

    Full Text Available The crystal structures of monomeric RNA-dependent RNA polymerases and reverse transcriptases of more than 20 different viruses are available in the Protein Data Bank. They all share the characteristic right-hand shape of DNA- and RNA polymerases formed by the fingers, palm and thumb subdomains, and, in many cases, "fingertips" that extend from the fingers towards the thumb subdomain, giving the viral enzyme a closed right-hand appearance. Six conserved structural motifs that contain key residues for the proper functioning of the enzyme have been identified in all these RNA-dependent polymerases. These enzymes share a two divalent metal-ion mechanism of polymerization in which two conserved aspartate residues coordinate the interactions with the metal ions to catalyze the nucleotidyl transfer reaction. The recent availability of crystal structures of polymerases of the Orthomyxoviridae and Bunyaviridae families allowed us to make pairwise comparisons of the tertiary structures of polymerases belonging to the four main RNA viral groups, which has led to a phylogenetic tree in which single-stranded negative RNA viral polymerases have been included for the first time. This has also allowed us to use a homology-based structural prediction approach to develop a general three-dimensional model of the Ebola virus RNA-dependent RNA polymerase. Our model includes several of the conserved structural motifs and residues described in other viral RNA-dependent RNA polymerases that define the catalytic and highly conserved palm subdomain, as well as portions of the fingers and thumb subdomains. The results presented here help to understand the current use and apparent success of antivirals, i.e. Brincidofovir, Lamivudine and Favipiravir, originally aimed at other types of polymerases, to counteract the Ebola virus infection.

  13. Narcolepsy Type 1 and Idiopathic Generalized Epilepsy: Diagnostic and Therapeutic Challenges in Dual Cases.

    Science.gov (United States)

    Baiardi, Simone; Vandi, Stefano; Pizza, Fabio; Alvisi, Lara; Toscani, Lucia; Zambrelli, Elena; Tinuper, Paolo; Mayer, Geert; Plazzi, Giuseppe

    2015-11-15

    The aim of this study is to describe the possible co-occurrence of narcolepsy type 1 and generalized epilepsy, focusing on diagnostic challenge and safety of dual treatments. Four patients with comorbidity for narcolepsy type 1 and idiopathic generalized epilepsy are reported: in three cases the onset of epilepsy preceded narcolepsy type 1 appearance, whereas in one case epileptic spells onset was subsequent. Patients presented with absences, myoclonic and tonic-clonic seizure type: in the patient with tonic-clonic seizures the dual pathology was easily recognized, in the other cases the first diagnosis caused the comorbid disease to be overlooked, independent of the time-course sequence. All four patients underwent neurological examination, video-electroencephalogram during which ictal and interictal epileptic discharges were recorded, and sleep polysomnographic studies. Repeated sleep onset rapid eye movement periods (SOREMPs) were documented with the multiple sleep latency test (MLST) in all the four cases. All patients had unremarkable brain magnetic resonance imaging studies and cerebrospinal hypocretin-1 was assessed in two patients, revealing undetectable levels. The association of antiepileptic drugs and substances currently used to treat narcolepsy type 1, including sodium oxybate, was effective in improving seizures, sleep disturbance, and cataplexy. Narcolepsy type 1 may occur in association with idiopathic generalized epilepsy, leading to remarkable diagnostic and therapeutic challenges. Electrophysiological studies as well as a comprehensive somnologic interview can help confirm the diagnosis in patients with ambiguous neurological history. Sodium oxybate in combination with antiepileptic drugs is safe and effective in treating cataplexy and excessive daytime sleepiness. © 2015 American Academy of Sleep Medicine.

  14. Comprehensive discovery of subsample gene expression components by information explanation: therapeutic implications in cancer.

    Science.gov (United States)

    Pepke, Shirley; Ver Steeg, Greg

    2017-03-15

    De novo inference of clinically relevant gene function relationships from tumor RNA-seq remains a challenging task. Current methods typically either partition patient samples into a few subtypes or rely upon analysis of pairwise gene correlations that will miss some groups in noisy data. Leveraging higher dimensional information can be expected to increase the power to discern targetable pathways, but this is commonly thought to be an intractable computational problem. In this work we adapt a recently developed machine learning algorithm for sensitive detection of complex gene relationships. The algorithm, CorEx, efficiently optimizes over multivariate mutual information and can be iteratively applied to generate a hierarchy of relatively independent latent factors. The learned latent factors are used to stratify patients for survival analysis with respect to both single factors and combinations. These analyses are performed and interpreted in the context of biological function annotations and protein network interactions that might be utilized to match patients to multiple therapies. Analysis of ovarian tumor RNA-seq samples demonstrates the algorithm's power to infer well over one hundred biologically interpretable gene cohorts, several times more than standard methods such as hierarchical clustering and k-means. The CorEx factor hierarchy is also informative, with related but distinct gene clusters grouped by upper nodes. Some latent factors correlate with patient survival, including one for a pathway connected with the epithelial-mesenchymal transition in breast cancer that is regulated by a microRNA that modulates epigenetics. Further, combinations of factors lead to a synergistic survival advantage in some cases. In contrast to studies that attempt to partition patients into a small number of subtypes (typically 4 or fewer) for treatment purposes, our approach utilizes subgroup information for combinatoric transcriptional phenotyping. Considering only the 66

  15. ABCC9/SUR2 in the brain: implications for hippocampal sclerosis of aging and a potential therapeutic target

    Science.gov (United States)

    Nelson, Peter T.; Jicha, Gregory A.; Wang, Wang-Xia; Ighodaro, Eseosa; Artiushin, Sergey; Nichols, Colin G.; Fardo, David W.

    2015-01-01

    The ABCC9 gene and its polypeptide product, SUR2, are increasingly implicated in human neurologic disease, including prevalent diseases of the aged brain. SUR2 proteins are a component of the ATP-sensitive potassium (“KATP”) channel, a metabolic sensor for stress and/or hypoxia that has been shown to change in aging. The KATP channel also helps regulate the neurovascular unit. Most brain cell types express SUR2, including neurons, astrocytes, oligodendrocytes, microglia, vascular smooth muscle, pericytes, and endothelial cells. Thus it is not surprising that ABCC9 gene variants are associated with risk for human brain diseases. For example, Cantu syndrome is a result of ABCC9 mutations; we discuss neurologic manifestations of this genetic syndrome. More common brain disorders linked to ABCC9 gene variants include hippocampal sclerosis of aging (HS-Aging), sleep disorders, and depression. HS-Aging is a prevalent neurological disease with pathologic features of both neurodegenerative (aberrant TDP-43) and cerebrovascular (arteriolosclerosis) disease. As to potential therapeutic intervention, the human pharmacopeia features both SUR2 agonists and antagonists, so ABCC9/SUR2 may provide a “druggable target”, relevant perhaps to both HS-Aging and Alzheimer’s disease. We conclude that more work is required to better understand the roles of ABCC9/SUR2 in the human brain during health and disease conditions. PMID:26226329

  16. The tipping point: The critical role of therapeutic apheresis in a case of refractory acquired hemophilia.

    Science.gov (United States)

    Losos, Michael; Scrape, Scott; Joshi, Sarita; Shmookler, Aaron; Chen, Jian

    2017-12-01

    Acquired hemophilia A (AHA) is a rare autoimmune disorder that leads to factor VIII (FVIII) deficiency via autoantibody formation. Standard treatment options include FVIII bypassing factors and immunosuppression. However, the role of therapeutic plasma exchange (TPE) is not clear in the treatment of AHA. We present a case of idiopathic AHA in a 66 year old female with severe bleeding and a FVIII inhibitor of 17.6 Bethesda units (BU). She failed to respond to standard treatment including maximum dose of recombinant FVIIa (rFVIIa), rituximab, and other immunosuppressive agents. Her FVIII inhibitor rapidly increased to 140 BU and FVIII was below 5%. TPE was initiated 3 weeks after admission and her bleeding stabilized after the first treatment and completely stopped after three treatments. Repeat testing revealed increased FVIII to 15% and FVIII inhibitor decreased to 2.0 BU. After an additional TPE treatment, her FVIII increased to 27% and FVIII inhibitor decreased to 0.6 BU and she was discharged without bleeding 40 days after admission. In this case, TPE played a critical role in reducing FVIII inhibitor, which resulted in a recovery of FVIII activity and hemostasis. Therefore, TPE should be initiated early in AHA patients with bleeding and high titer of FVIII inhibitor. © 2016 Wiley Periodicals, Inc.

  17. Crackpots and basket-cases: a history of therapeutic work and occupation.

    Science.gov (United States)

    Laws, Jennifer

    2011-01-01

    Despite the long history of beliefs about the therapeutic properties of work for people with mental ill health, rarely has therapeutic work itself been a focus for historical analysis. In this article, the development of a therapeutic work ethic (1813-1979) is presented, drawing particular attention to the changing character and quality of beliefs about therapeutic work throughout time. From hospital factories to radical "anti-psychiatric" communities, the article reveals the myriad forms of activities that have variously been considered fit work for people with mental health problems. While popular stereotypes of basket-weaving paint a hapless portrait of institutional work, a more nuanced reading of therapeutic work and its political and philosophical commitments is advanced. The article concludes by arguing that the non-linear and inherently contested development of therapeutic work is less the effect of paradigmatic shifts within the therapeutic professions, but rather evidence of a broader human struggle with work.

  18. Implications for Therapeutic Intervention

    Directory of Open Access Journals (Sweden)

    A. L. Hof

    2001-01-01

    Full Text Available Patients with an upper motor neurone syndrome (CP suffer from many disabling primary symptoms: spasms, weakness, and loss of dexterity. These primary ‘neurogenic’ symptoms often lead to secondary disabilities, muscle contractures, and tertiary effects, bone deformations. A common symptom of CP is hypertonia, with. the consequence that the involved muscles remain in an excessively shortened length for most of the time. As a normal reaction of the muscle tissue, the number of sarcomeres is reduced and the muscle fibers shorten permanently: a contracture develops. A possible second type of contracture is that normal muscle lengthening along with bone growth is affected. Current treatments for the secondary effects include (1 reduction of muscle force, (2lengthening of the muscle fibers by serial plaster casts, and (3surgical lengthening of tendons or aponeurosis. The choice of treatment depends on the cause of the functional deficit. Bone tissue also adapts itself to abnormal forces, especially in the growth period. The hypertonias or contractures of CP so may give rise to bone malformations that interfere with function (e.g. femur endorotation or may reduce the action of muscles by changing the lever arm (e.g. ankle varus. Although prevention should always be preferred, a timely surgical intervention cannot always be avoided. The differences in treatment for the various groups require and justify an extensive laboratory investigation, including EMG recordings in gait, measurement of passive elastic properties, and long-term observation of the hypertonia.

  19. Preoperative therapeutic neuroscience education for lumbar radiculopathy: a single-case fMRI report.

    Science.gov (United States)

    Louw, Adriaan; Puentedura, Emilio J; Diener, Ina; Peoples, Randal R

    2015-01-01

    Therapeutic neuroscience education (TNE) has been shown to be effective in the treatment of mainly chronic musculoskeletal pain conditions. This case study aims to describe the changes in brain activation on functional magnetic resonance imaging (fMRI) scanning, before and after the application of a newly-designed preoperative TNE program. A 30-year-old female with a current acute episode of low back pain (LBP) and radiculopathy participated in a single preoperative TNE session. She completed pre- and post-education measures including visual analog scale (VAS) for LBP and leg pain; Oswestry Disability Index (ODI); Fear Avoidance Beliefs Questionnaire (FABQ); Pain Catastrophizing Scale (PCS) and a series of Likert-scale questions regarding beliefs and attitudes to lumbar surgery (LS). After a 30-minute TNE session, ODI decreased by 10%, PCS decreased by 10 points and her beliefs and attitudes shifted positively regarding LS. Immediately following TNE straight leg raise increased by 7° and forward flexion by 8 cm. fMRI testing following TNE revealed 3 marked differences compared to pre-education scanning: (1) deactivation of the periaqueductal gray area; (2) deactivation of the cerebellum; and (3) increased activation of the motor cortex. The immediate positive fMRI, psychometric and physical movement changes may indicate a cortical mechanism of TNE for patients scheduled for LS.

  20. A Case Report of Clonazepam Dependence: Utilization of Therapeutic Drug Monitoring During Withdrawal Period.

    Science.gov (United States)

    Kacirova, Ivana; Grundmann, Milan; Silhan, Petr; Brozmanova, Hana

    2016-03-01

    Clonazepam is long-acting benzodiazepine agonist used in short-acting benzodiazepine withdrawal; however, recent observations suggest the existence of its abuse. We demonstrate a 40-year-old man with a 20-year history of psychiatric care with recently benzodiazepine dependence (daily intake of ∼60 mg of clonazepam and 10 mg of alprazolam). High serum levels of both drugs were analyzed 3 weeks before admission to hospitalization (clonazepam 543.9 ng/mL, alprazolam 110 ng/mL) and at the time of admission (clonazepam 286.2 ng/mL, alprazolam 140 ng/mL) without any signs of benzodiazepine intoxication. Gradual withdrawal of clonazepam with monitoring of its serum levels and increase of gabapentin dose were used to minimize physical signs and symptoms of clonazepam withdrawal. Alprazolam was discontinued promptly. Clinical consequences of the treatment were controllable tension, intermittent headache, and rarely insomia. It is the first case report showing utilization of therapeutic drug monitoring during withdrawal period in the patient with extreme toleration to severe benzodiazepine dependence.

  1. Immunohistochemical investigations and introduction of new therapeutic strategies in scleromyxoedema: Case report

    Directory of Open Access Journals (Sweden)

    Altmeyer Peter

    2004-09-01

    Full Text Available Abstract Background Scleromyxoedema is a rare chronic skin disease of obscure origin, which may often be associated with severe internal co-morbidity. Even though different casuistic treatment modalities have been described, to date, curing still seems to be impossible. Case presentation We report a 44-year-old Caucasian female presenting with remarkable circumscribed, erythematous to skin-coloured, indurated skin eruptions at the forehead, arms, shoulders, legs and the gluteal region. Routine histology and Alcian blue labelling confirmed a massive deposition of acid mucopolysaccharides. Immunohistochemical investigations revealed proliferating fibroblasts and a discrete lymphocytic infiltration as well as increased dermal expression of MIB-1+ and anti-mastcell-tryptase+ cells. Bone marrow biopsies confirmed a monoclonal gammopathy of undetermined significance without morphological characteristics of plasmocytoma; immunofixation unveiled the presence of IgG-kappa paraproteins. Conclusions Taking all data into account, our patient exhibited a complex form of lichen mxyoedematosus, which could most likely be linked a variant of scleromyxoedema. Experimental treatment with methotrexate resulted in a stabilisation of clinical symptoms but no improvement after five months of therapy. A subsequent therapeutic attempt by the use of medium-dose ultraviolet A1 cold-light photomonotherapy led to a further stabilisation of clinical symptoms, but could not induce a sustained amelioration of skin condition.

  2. Immunoglobulin M 'Flare' Seen in a Case of Waldenstrom's Macroglobulinemia: Successfully Managed by Therapeutic Plasma Exchange.

    Science.gov (United States)

    Datta, Suvro Sankha; Mukherjee, Somnath; Talukder, Biplabendu; Bhattacharya, Prasun

    2016-06-01

    Therapeutic plasma exchange (TPE) is a conjunctive modality of treatment along with rituximab to decrease paraproteinemia associated with hyperviscosity. Here we narrate our experience in treating a diagnosed case of Waldenstrom's macroglobulinemia in 70 years old male patient with moderate anemia and severe features of hyperviscosity syndrome by serial TPE and rituximab combined with bortezomib. The patient was relieved of his symptoms after initial two TPE procedures performed on alternative day. However he again developed signs and symptoms of the disease within 6 weeks following second TPE and starting of rituximab (375 mg/m(2) weekly for 4 weeks) therapy with bortezomib. His serum IgM level became as high as 9.901 g/dl suggesting immunoglobulin M 'Flare' due to rituximab therapy. At the end of third TPE he was relieved symptomatically with low IgM level (3.13 g/dl) and discharged in hemodynamically stable condition. Therefore we concluded that careful monitoring of serum viscosity and IgM level are necessary during treatment with rituximab based chemotherapy and TPE should be promptly initiated to control the treatment related hyperviscosity syndrome.

  3. Therapeutic Plasma Exchange in a rare case myasthenic crisis after Botox injection.

    Science.gov (United States)

    Chegini, Azita

    2017-11-01

    Botulinum toxin (Botox) injections are used as a cosmetic treatment to decrease wrinkles in face and chin. Being a neurotoxic agent it minimizes muscle activity, while side effects are usually rare. This article subsequently presents one case of these rare effects. A 30-year-old woman presenting with ptosis, diplopia, dysarthria, dysphagia and muscle weakness was admitted to our hospital. She had no history of disease. For cosmetic reasons, she had three Botox injections during the preceding months. On physical examination, muscle weakness 4/5 (cervical extensor, ocular and pharynx) was detected and a diagnosis of myasthenia gravis was made. Protective artificial ventilation was necessary. As a consequence, eight sessions of 2.5 L volume Therapeutic Plasma Exchange (TPE) were applied using normal saline/albumin as substitute. Due to TPE, her muscle force and clinical condition improved. Artificial ventilation could be stopped. Clinical symptoms of myasthenia gravis and systemic Botox effects are very similar. This should be taken into consideration during medical history taking. The injection of high doses of Botox (more than 200 units in every injection) or boostering within less than one month is dangerous. (Botox BCC2024). Systemic side effects can be treated using TPE to lower the circulating dose of Botox. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Atelectasis and mucus plugging in spinal cord injury: case report and therapeutic approaches.

    Science.gov (United States)

    Slonimski, M; Aguilera, E J

    2001-01-01

    The leading causes of morbidity and mortality in the spinal cord injury (SCI) population are airway mucus plugging and atelectasis. To illustrate the risks of pulmonary disease in individuals with SCI, and present effective therapeutic interventions. Case study of a 60-year-old veteran with T7 ASIA A spinal cord injury, who presented with a complete collapse of the left lung. This patient developed fever, sepsis, and acute renal failure following colonoscopy. Following nephrostomy to remove a calculus, chest x-ray revealed complete collapse of the left lung. Despite the severe degree of atelectasis, he exhibited only mild respiratory distress. Aggressive treatment including chest physiotherapy techniques and pharmacologic intervention (acetylcysteine; bronchodilators) resulted in significant radiographic and clinical improvement. After his return to the SCI unit, his respiratory function was monitored, and assisted cough techniques were continued. Individuals with SCI have high risk of pulmonary complications. Because of neurological deficits, the usual signs and symptoms may not be apparent. Optimal management depends upon awareness of the risks, and a thorough understanding of the pathophysiology of mucus plugging and atelectasis and the alterations in pulmonary mechanics (dependent on level of injury).

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

    Science.gov (United States)

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

    2018-04-07

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

  6. Supporting Affect Regulation in Children With Multiple Disabilities During Psychotherapy: A Multiple Case Design Study of Therapeutic Attachment. [Miscellaneous Article

    NARCIS (Netherlands)

    Schuengel, C; Sterkenburg, P S; Jeczynski, P; Janssen, C G C; Jongbloed, G

    2009-01-01

    : In a controlled multiple case design study, the development of a therapeutic relationship and its role in affect regulation were studied in 6 children with visual disabilities, severe intellectual disabilities, severe challenging behavior, and prolonged social deprivation. In the 1st phase,

  7. Supporting affect regulation in children with multiple disabilities during psychotherapy: A multiple case design study of therapeutic attachment

    NARCIS (Netherlands)

    Schuengel, C.; Sterkenburg, P.S.; Jeczynski, P.; Janssen, C.G.C.; Jongbloed, G.

    2009-01-01

    In a controlled multiple case design study, the development of a therapeutic relationship and its role in affect regulation were studied in 6 children with visual disabilities, severe intellectual disabilities, severe challenging behavior, and prolonged social deprivation. In the 1st phase, children

  8. [Clinical and therapeutic aspects of early childhood caries and severe early childhood caries--clinical cases].

    Science.gov (United States)

    Maxim, Dana; Danilă, I; Balcoş, Carina

    2011-01-01

    ECC (early childhood caries) and SECC(severe early childhood caries), as a particularization of the dental caries during the early childhood (0-3 years) and the middle childhood (3-6 years), generate important oro-dental problems, with long-term impact, psycho-somatic, psycho-aesthetic, and social-behaviour, in little children as in adults. 35 subjects (20 girls and 15 boys), were evaluated, aged between 3-6 years old, diagnosticated with ECC and SECC. The children were evaluated clinical, paraclinical and psycho-sociological in the Clinic of Paediatric Dentistry, Iasi, Romania. In this article, we present 3 clinical cases that show the implication of the socio-emotional factors that produce the early childhood caries, pacient C.L., 6 years old, pacient C.F., 5, 6 years old, and pacient A.D., 6 years old. In this study we have evaluated a heterogen structure with major impact on caries risk, clinical variability of the carioactivity in decidual dentition. It is known that more than 64% non-cavitary lesions that appear in a 2 year-old child develop to cavitary lesions in less than a year.

  9. Universal design of workplaces through the use of Poka-Yokes: Case study and implications

    Directory of Open Access Journals (Sweden)

    Cristóbal Miralles

    2011-10-01

    Full Text Available Purpose: Employment plays an important part in many people’s lives beyond merely providing income, since continued participation in work can have many therapeutic benefits for workers defined as disabled. However, disabled workers face a range of barriers to employment, despite legislation intended to improve workplace accessibility emphasizing adaptations to the workplace, which many employers often find difficult and expensive. The Poka-Yoke approach was developed in the manufacturing industry as a way of improving productivity by reducing errors using often very simple adaptations. This paper argues that, as Poka-Yokes are designed to make life easier and improve the performance of workers without impairments, they are closer to the philosophy of Universal Design than to Accessible Design, and offer an easy and inclusive way of making work more accessible for all kind of workers. Design/methodology/approach: This paper provides a case study demonstrating the use of the Poka-Yoke approach in a sheltered work centre for disabled; highlighting how they served to improve accessibility to work by fulfilling Universal Design principles. Findings: Our research allows us to demonstrate the great potential of Poka-yokes for gaining accessibility to the workplace. The real application of this approach, both in sheltered work centres and ordinary companies, can contribute to improve the high unemployment rates of disabled people. Research limitations/implications: The proposal is innovative and was applied in one specific company. Thus, a range of customized Poka-yokes would be desirable for different industrial sectors. Practical implications: Managers of sheltered work centres, and also of ordinary companies, can realize about the great potential of Poka-Yokes as an easy means of gaining flexibility and accessibility. Originality/value: There are very few papers relating lean manufacturing tools and disability. Our approach analyzes the benefits of

  10. Structure and activities of pharmacy and therapeutics committees among public hospitals in South Africa; findings and implications.

    Science.gov (United States)

    Matlala, Moliehi; Gous, Andries Gs; Godman, Brian; Meyer, Johanna C

    2017-11-01

    The WHO identified Pharmacy and Therapeutics Committees (PTCs) as a pivotal model to promote rational medicine use in hospitals. This matches a key South African (SA) government objective to establish PTCs in all hospitals to ensure rational, efficient and cost-effective use of medicines. However, documentation on the functionality of PTCs in public hospitals in SA is limited. Areas covered: This study aimed to address this. A 3-phased mixed methods approach involving questionnaires, observations of PTC meetings and semi-structured interviews was used. The findings were converged during the interpretation phase. Expert commentary: Most professionals were represented in the PTCs, with variations across hospitals. Membership of PTCs included a pharmacist, who in the majority of cases was the secretary. PTC activities included dissemination of decisions (100%) and formulary management (89.5%). However, reporting of adverse drug reactions (ADRs) and medication errors was typically poor at all hospital levels. Lack of expertise of pharmacoeconomic analysis and evidence-based decision-making in formulary management was identified as a key challenge in formulary management. In conclusion, future programmes should strengthen PTCs in specialised aspects of formulary management. Further training in the principles of pharmacovigilance is needed to enhance ADR reporting, as well as to ensure compliance with both WHO and provincial guidelines.

  11. Aplasia cutis congenita: review of 29 cases and proposal of a therapeutic strategy.

    Science.gov (United States)

    Maillet-Declerck, Marie; Vinchon, Matthieu; Guerreschi, Pierre; Pasquesoone, Louise; Dhellemmes, Patrick; Duquennoy-Martinot, Véronique; Pellerin, Philippe

    2013-04-01

    Aplasia cutis congenita (ACC) is a rare congenital disorder, which most commonly involves the scalp, and can affect the galea, the pericranium, the bone, and the dura mater. ACC thus is at risk of infection and hemorrhage. There is no consensus over the ideal management and the role for plastic surgery. We reviewed retrospectively our experience with 29 patients treated between 1976 and 2011. The patients were 17 male and 12 female, 25 being referred immediately at birth. The size of the defect ranged from 1 to 192 cm2. Thirteen patients had bone aplasia. Initial conservative treatment was decided in five cases; 15 patients underwent excision-sutures with or without local plasty, 8 underwent pedicled scalp flap, and 1 had skin graft followed by further reconstruction by a free flap. Four patients died in neonatal period because of infection or associated ailments. All others patients achieved complete healing. The mortality rate of ACC remains high and increases with the size of bone defect. We propose a therapeutic strategy based on the size of the skin defect and the nature of underlying exposed structures. Cranioplasty is exceptionally necessary because of good spontaneous bone regeneration within few months or years. Cosmetic appearance can be improved later by skin expansion. Aplasia cutis congenita is a rare malformation with sometimes a rapid fatal issue. A precise evaluation of surface and depth of the lesion is essential to decide if and how to operate, in order to provide rapid and efficient coverage. Georg Thieme Verlag KG Stuttgart · New York.

  12. Inoculation site from a cutaneous melanoma patient treated with an allogeneic therapeutic vaccine: a case report

    Directory of Open Access Journals (Sweden)

    Mariana eAris

    2015-03-01

    Full Text Available We have developed a therapeutic vaccine consisting of a mixture of lethally-irradiated allogeneic cutaneous melanoma cell lines with BCG and GM-CSF as adjuvants. The CSF-470 vaccine is currently being assayed in a Phase II-III trial against medium-dose IFN-a2b. All vaccinated patients immunized intradermally developed large edematous erythema reactions, which then transformed into subcutaneous nodules active for several months. However, vaccine injection sites were not routinely biopsied. We describe the case of a female patient, previously classified as stage III, but who, due to the simultaneous discovery of bone metastases, only received one vaccination, was withdrawn from the study and continued her treatment elsewhere. Patient #1 developed a post-vaccination nodule which was surgically removed 7 weeks later, and allowed to analyze the reactivity and immune profiling of the inoculation site. An inflammatory reaction with zones of fibrosis, high irrigation and brisk lymphoid infiltration, primarily composed of CD8+ and CD20+ lymphocytes, was observed. There were no remaining BCG bacilli, and scarce CD4+ and Foxp3+ T cells were observed. MART-1 Ag was found throughout the vaccination site. CD11c+ Ag presenting cells were either dispersed or forming dense nests. Some CD11c+ cells proliferated; most of them contained intracellular MART-1 Ag, and some interacted with CD8+ lymphocytes. These observations suggest a potent, long-lasting local inflammatory response with recruitment of Ag-presenting cells that incorporate melanoma Ags, probably leading to Ag presentation to naïve T cells.

  13. Umbilical melanoma: case report and review of anatomical and therapeutic aspects

    Energy Technology Data Exchange (ETDEWEB)

    Brandao, Eduardo Miranda; Gomes, Alexandre Santos de Almeida; Ribeiro, Edilana Sa; Vilaca, Thiago Guimaraes; Macedo, Francisco Igor Bulcao de; Santos, Rogerio Luiz dos [Pernambuco Univ., Recife, PE (Brazil). Unidade de Cirurgia e Oncologia (UNIONCO); Pernambuco Univ., Recife, PE (Brazil). Faculdade de Ciencias Medicas

    2005-08-15

    Full text of publication follows: Background: Malignant melanoma corresponds to 5% of cutaneous neoplasias. However, umbilical melanoma is a rare occurrence, with only 13 cases reported on the literature. The purpose of this article is to present a case of umbilical primary melanoma, discuss the anatomy and lymphatic drainage of this region, and the therapeutic aspects. Clinical description: Three years ago, a 65 years-old white woman from Recife-PE, presented an umbilical pigmented nevus. It grew in size and one year ago the pigmentation increased. Examination showed depressed umbilical scarring completely filled by pigmented lesion with 1.5 cm, irregular borders and a depigmented area; no enlarged inguinal and axillary lymph nodes. Chest X-Ray, CT scan of abdomen and pelvis, and ultrasonography of groin and axillary lymphatic chains were normal. The pathological diagnosis after incisional biopsy was ulcerated malignant melanoma, without defining Breslow classification. Subsequently a complete excision of the lesion was performed; slide showed Breslow 8 mm and 1 mm of margin. Lymphoscintillography showed three left axillary lymph nodes. During surgical widening, the peritoneum seemed disease-free. Lymphatic mapping identified three lymph nodes, one of them not coloured by vital blue. All the lymph nodes were free of metastasis on histopathological and immunohistochemical examination. Discussion: Among the umbilical tumors, 80% are metastatic, the most common branch of which is the gastrointestinal tract. Melanoma is included in the other 20% corresponding to primary neoplasias of the umbilicus, which also include sarcomas, basal cell carcinomas and squamous cell carcinomas. From the embryological point of view, the umbilical scar can contain residues of several types of epithelial tissue of the gastrointestinal duct remaining from the omphalomesenteric duct. Anatomical aspects remain to be studied, such as the cylindrical form and the content within its thickness

  14. Rivaroxaban - a safe therapeutic option in patients with antiphospholipid syndrome? Our experience in 23 cases.

    Science.gov (United States)

    Haładyj, Ewa; Olesińska, Marzena

    2016-01-01

    In the therapeutic approach to patients with antiphospholipid syndrome (APS) with thrombotic manifestations, oral vitamin K antagonists (VKA) remain the standard of care. However, the use of VKA is very often associated with inability to achieve a therapeutic dose even in patients maintaining nutritional and therapeutic restrictions. The non-vitamin-K oral anticoagulants (NOAC) have a lot of advantages, but their efficacy and safety in APS have not been proven. We present 23 patients with APS treated with rivaroxaban in our department. Recurrence of thrombosis was observed only in 1 patient. No major or minor bleeding occurred. It proves the efficacy of treatment with rivaroxaban, but our observations require further prospective, randomized studies.

  15. Tax Revenue Implications of Devaluations : A Case Study of Bangladesh

    OpenAIRE

    Nitai C. Nag

    1999-01-01

    A small macroeconomics model is used to estimate empirically the real tax revenue implications of devaluation. Overall effect of devaluation on tax revenue id found to be negative, which contrasts with the theoretical presumption that devaluation improves the government revenue position. According to our estimation a 10 percent devaluation lowers equilibrium output by 1.04 percent and overall tax revenue by 4.2 percent. Import is dependent on output in the model. Contractionary output effect,...

  16. Spinocellular carcinoma from warts in a HPV infection natural history lasting 49 years. Virus strategy or host choice? Implications for researches and therapeutic vaccines.

    Science.gov (United States)

    Criscione, S M

    2011-11-01

    ), to prolong its own survival (balance with the virus), to avoid the risk of producing uncontrolled cells (dangerous outcomes). Finally, the postulated negative implications for therapeutic vaccines in cervical cancer, as they really seem to not work till now might be ascribed just to the cited host immune-specific state itself, through an activation induced cell death, elicited by recall antigens (E6/E7 in the case of my wife). Also this latter hypothesis, as well as the previous ones may be of some value to better account for clinical behaviors and researches. Copyright © 2011 Elsevier Ltd. All rights reserved.

  17. Therapeutic Riding for a Student with Multiple Disabilities and Visual Impairment: A Case Study.

    Science.gov (United States)

    Lehrman, Jennifer; Ross, David B.

    2001-01-01

    A 9-year-old with multiple disabilities and visual impairments was the focus of a 10-week developmental therapeutic riding program incorporating hippotherapy. The program has led to increased mobility, an increase in visual attention span and fixation time, signs of greater verbal communication, and the acquisition of new functional signs.…

  18. The determinants of nurses' therapeutic attitude to patients who use illicit drugs and implications for workforce development.

    Science.gov (United States)

    Ford, Rosemary; Bammer, Gabriele; Becker, Niels

    2008-09-01

    To examine the determinants of generalist nurses' therapeutic attitude to patients who use illicit drugs, and to model workforce development initiatives. Individuals who use illicit drugs rely heavily on healthcare in emergency departments and inpatient hospital wards. Little is known about the determinants of generalist nurses' therapeutic attitude to provide care, therefore limiting our understanding of the important issues for workforce development. The study was a cross-sectional survey of registrants on the Australian Capital Territory Nurses Registration Roll 2002 (N = 3241, 50% response rate). The associations between variables and nurses' therapeutic attitude were examined by multi-variable linear regression analysis. Nurses' therapeutic attitude was assessed using a modified version of the Alcohol and Alcohol Problems Perception Questionnaire. Personal characteristics, attitudes to illicit drugs and professional practice variables such as drug and alcohol education, experience with the patient group and role support were examined using a mix of standardised and new questions. Professional practice variables explained 53% of the variation of nurses' therapeutic attitude, the most important being role support. Although a negative attitude to illicit drugs had a statistically significant association with therapeutic attitude, it added less than 1% to the variation explained. Personal characteristics showed no association. Generalist nurses struggle to provide care to this patient group. Role support was found to be the strongest driver of nurses' therapeutic attitude, and workplace illicit drug education was only useful in combination with high role support. Nurses' caring role with patients who use illicit drugs is complex and demanding. Nursing workforce development must focus on increasing nurses' role support, in terms of appropriately skilled staff readily available for consultation and advice. Support for nurses, in the form of evidence-based practice

  19. Everolimus Implicated in Case of Severe Gastrointestinal Hemorrhage

    Directory of Open Access Journals (Sweden)

    Paul Gonzales

    2017-01-01

    Full Text Available Breast cancer remains the leading cause of cancer and the third leading cause of cancer related deaths among our population with an estimated number of 246,660 new cases and 40,450 deaths in 2016. With treatment advancements, including targeted agents such as Everolimus, a mammalian target of rapamycin (mTOR inhibitor, survivability and quality of life continue to improve. However, with the use of these agents come adverse effects, some of which are still being characterized. Our case demonstrates recurrent episodes of gastrointestinal bleeding in a 60-year-old woman being treated with Everolimus for progressive metastatic breast cancer. On endoscopy, bleeding was secondary to erosive gastritis. Previous case reports have described bleeding due to gastric antral vascular ectasia (GAVE, which was described in two prior reported cases. In our case, bleeding also occurred on a reduced dose of Everolimus compared to what is previously reported (5 mg versus 10 mg. As a result of her gastrointestinal bleeding, she required multiple endoscopic interventions including argon plasma coagulation and multipolar heater probe to achieve hemostasis. This is the first case reported of gastrointestinal bleeding not consistent with GAVE and occurring while being on a reduced dose of Everolimus. It is important to document our case so that the Gastroenterology and Hematology communities can be educated and made aware for their patient populations on Everolimus.

  20. Therapeutic Intervention in a Case of Ataxic Dysarthria Associated with a History of Amateur Boxing

    Science.gov (United States)

    McMicken, Betty L.; Ostergren, Jennifer A.; Vento-Wilson, Margaret

    2011-01-01

    The goals of this study were to (a) describe the presenting features of ataxic dysarthria present in a participant with a long history of amateur boxing, (b) describe a novel application of behavioral principles in the treatment of this participant, and (c) discuss implications in the treatment of ataxic dysarthria secondary to boxing. The…

  1. Six cases of silicosis: implications for health surveillance of stonemasons.

    Science.gov (United States)

    Nicol, L M; McFarlane, P A; Hirani, N; Reid, P T

    2015-04-01

    Silicosis is one of the oldest occupational lung diseases, but it continues to cause significant morbidity and mortality worldwide. To report cases of silicosis presenting to two specialist respiratory clinics. A retrospective analysis of prospectively collected data of cases of silicosis in workers referred to specialist respiratory clinics. Over the course of 6 years, six cases were identified. The patients were all male with an age range between 24 and 39 years. The duration of silica exposure ranged between 7 and 20 years (mean 13 years). Four cases were entirely asymptomatic at presentation, and two cases described minimal shortness of breath on exertion. Pulmonary function tests were normal in three cases, and a mild restrictive ventilatory defect was documented in the other cases. All had a low apparent predicted probability of pneumoconiosis based on health questionnaires, spirometry and duration of silica exposure. The initial chest X-ray was abnormal in all six cases with radiological evidence of silicosis (International Labour Office profusion category ≥1/1) on imaging, and all had evidence of silicosis on high-resolution computed tomography (HRCT). Three patients had already progressed to progressive massive fibrosis on HRCT scanning at the time of referral to specialist respiratory services. The appearances of these six cases of silicosis in young, asymptomatic construction workers emphasizes the importance of enforcing effective exposure control and comprehensive surveillance programmes. Our observations highlight the importance of having a low threshold for early radiological screening to promote early and effective detection of this disease. © The Author 2015. Published by Oxford University Press on behalf of the Society of Occupational Medicine. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  2. 8. Therapeutic and Educational Potential of Combining Cognitive Behavioural Therapy and Art – Qualitative Analysis of a Case Study

    Directory of Open Access Journals (Sweden)

    Růžička Michal

    2016-03-01

    Full Text Available Cognitive behavioural psychotherapy is, just like other psychotherapeutic systems, of an eclectic nature. Should a therapist be successful across a wide range of issues, he/she needs to be adaptable, flexible and eclectic in terms of the techniques applied. Eclectically oriented therapists use a wide range of interventions; however, they adhere to individual theoretical structures. The aim of the paper is to point out the application of a combination of artistic activities within the system of the Cognitive behavioural therapy. For this purpose the paper presents a qualitative analysis of two case studies. We formulated the following research questions. Can the methods of combining the cognitive behavioural therapy and art accelerate the course of therapy? Can the methods of combining the cognitive behavioural therapy and art be perceived by the client as effective? The phenomenon investigated in the case study is a functional analysis of a client’s case and subsequent application of therapeutic and educational techniques of the Cognitive behavioural therapy and art. In both case studies it was demonstrated that the involvement of therapeutic elements accelerated the course of therapy. The clients in the research sample assessed the therapy as beneficial.

  3. The Relation between Spiritual Intelligence and Hospital Performance (Case Study: Therapeutic Personnel of Shahid Fayazbakhsh Hospital)

    OpenAIRE

    Mojgan Asghari; Alireza Shirvani

    2015-01-01

    In the current era, human society strongly needs to spirituality, religiosity and morality. Hospital personnel can treat their job as a spiritual mission through combining spirituality with their profession. The researcher addressed spiritual intelligence since, according to conducted researches; this mechanism has a fundamental role in recovering patients’ health and in improving therapeutic personnel performance. The present research aims to investigate the relationship between spiritual in...

  4. [Observation on therapeutic effect of scalp-acupoint catgut embedding for 33 cases of insomnia patients].

    Science.gov (United States)

    Yao, Hong-Fang; Zhang, Hai-Feng; Chen, Xiao-Li

    2012-10-01

    To observe the therapeutic effect of scalp-acupoint catgut embedding in the treatment of insomnia. Sixty-four insomniacs were randomly divided into catgut embedding group (n = 33) and routine acupuncture group (n = 31). Baihui (GV 20), Shenting (GV 24) and bilateral Fengchi (GB 20) were selected for subcutaneous embedding of catgut, once a week for 4 weeks. GV 20, GV 24, bilateral GB 20, bilateral Shenmen (HT 7), bilateral Neiguan (PC 6) and bilateral Sanyinjiao (SP 6) were punctured with filiform needles for patients of the acupuncture group. The treatment was performed once every other day, 3 times a week for 4 weeks. The therapeutic effect was evaluated by using International Unified Sleep Efficiency Value and Pittsburgh Sleep Quality Index (PSQI). After the treatment, the falling asleep latency and PSQI scores of both catgut embedding and routine acupuncture groups were decreased significantly (P efficiency increased considerably (P acupuncture in prolonging sleep duration and improving sleep efficiency (P 0.05). Both routine acupuncture and scalp-acupoint catgut embedding interventions can effectively reduce falling asleep latency and prolong sleep duration. The therapeutic effect of scalp-acupoint catgut embedding is relatively better in improving sleep duration and sleep efficiency.

  5. Intensive Care Unit-Acquired Weakness: Implications for Case Management.

    Science.gov (United States)

    Harvey, Nina R; Stanton, Marietta P

    The purpose of this case study is to provide a specific example of the disease trajectory for one patient's experience with intensive care unit-acquired weakness (ICUAW). This case study provides those in case management with an overview of some of the common signs and symptoms of ICUAW, as well as the possible prognosis and recovery from ICUAW. The events in this case study take place in the acute care setting including the intensive care unit of a mid-sized health center, a general medical-surgical (med-surg) unit, and a long-term acute care facility. ICUAW affects the clinical, functional, and financial outcomes of patients. If the patient survives, their quality of life and the quality of life of their family members could be severely impacted. Case management practice has a significant role in coordinating care for those diagnosed with ICUAW. Case managers can use knowledge about ICUAW to improve the patient's transition throughout the hospital stay, improve discharge recommendations, and improve the patient's short-term and long-term outcomes. This may reduce unnecessary utilization of health care resources.

  6. Therapeutic effect of transcranial direct current stimulation on neuropsychological symptoms of an elderly patient: A case report

    Directory of Open Access Journals (Sweden)

    Aline Iannone

    Full Text Available ABSTRACT Although growing evidence points to the potential therapeutic effects of transcranial Direct Current Stimulation (tDCS, there is still no consensus on the most appropriate protocol to be used in specific neurological and neuropsychological symptoms. This case report evaluated the neuromodulatory therapeutic effects of two 15-day courses of tDCS on an elderly female patient, aged 78 years with mild neurocognitive disorder, chronic pain and depression-related symptoms. Results indicated an overall significant improvement of cognitive and executive functions, as well as reduction in both depression and chronic pain symptoms. These results highlight the potential of tDCS as a safe and useful neuromodulatory clinical tool in the rehabilitation of elderly patients.

  7. Management of familial hypertriglyceridemia-induced pancreatitis during pregnancy with therapeutic plasma exchange: a case report and review of literature.

    Science.gov (United States)

    Safi, Fadi; Toumeh, Anis; Abuissa Qadan, Mahmoud A; Karaz, Rana; AlAkdar, Bassam; Assaly, Ragheb

    2014-01-01

    Familial severe hypertriglyceridemia (levels greater than 1000 mg/dL) is a known cause of acute pancreatitis. Pregnancy can dysregulate controlled lipid levels in women with familial hypertriglyceridemia and lead to acute pancreatitis and significant morbidity in both mother and fetus. We report a case of hypertriglyceridemia-induced pancreatitis during pregnancy that was successfully treated using therapeutic plasma exchange, resulting in delivery of a healthy preterm infant. Therapeutic plasma exchange is an effective approach to treat gestational hypertriglyceridemia-induced pancreatitis. Other treatment options include combined heparin and insulin infusion. Moreover, particular caution should be applied when interpreting the results of prothrombin time in the setting of severe hypertriglyceridemia as false elevation with testing methods could happen.

  8. An improved interim therapeutic restoration technique for management of anterior early childhood caries: report of two cases.

    Science.gov (United States)

    Nelson, Travis

    2013-01-01

    Early childhood caries presents unique treatment challenges that often require advanced behavior management techniques, such as general anesthesia or procedural sedation. In some cases, use of these pharmacologic adjuncts is undesirable or not possible. The interim therapeutic restoration is a treatment method that, while sometimes employed in such cases, can often produce unsatisfactory results in primary anterior teeth. This is often due to insufficient bulk of material and lack of retention. The purpose of this report was to describe a simple alternative technique (resin modified glass ionomer strip crowns) that may be employed to deliver esthetic anterior restorations to marginally cooperative children in the dental clinic setting and to report on two cases in which it was successfully used. \\\\\\Department of Pediatric Dentistry, University of Washington, Seattle, Wash., USA. tmnelson@uw.edu

  9. Integrating between-session interventions (homework) in therapy: the importance of the therapeutic relationship and cognitive case conceptualization.

    Science.gov (United States)

    Cronin, Timothy J; Lawrence, Katherine A; Taylor, Kate; Norton, Peter J; Kazantzis, Nikolaos

    2015-05-01

    Between-session interventions, or homework, are crucial to a range of psychological therapies, including cognitive behavior therapy (CBT). Therapeutic interventions often involve experiencing emotions and situations, or examining strongly held views about their problems, that clients can find distressing. Hence, the clinician faces a particular challenge in collaborating with the client to carry out these interventions between sessions. In this article, we convey how this process in CBT requires not only a consideration of the theoretically meaningful determinants of adherence behavior but also a sophisticated cognitive case conceptualization. Using case material, we illustrate the interplay between in-session design, planning, and review of between-session interventions and the conceptualization. We also include a distinction between generic elements of the therapeutic relationship and CBT-specific elements. The case material also attends to the person of the therapist, and his or her own cognitive and emotional reactions occurring throughout the process of discussing between-session interventions. © 2015 Wiley Periodicals, Inc.

  10. Alagille syndrome case report: implications for forensic pathology and anthropology.

    Science.gov (United States)

    Petaros, Anja; Miletic, Damir; Stifter, Sanja; Slaus, Mario; Stemberga, Valter

    2015-05-01

    This case report offers a multidisciplinary interpretation of the violent death of a 4-year-old girl suffering from Alagille syndrome who died after a low-height fall that resulted in temporal bone fracture and a large epidural hematoma. The article evidences the macroscopical and microscopical characteristics of the syndrome, focusing especially on the skeletal findings that emerged during autopsy. In the case report, distinction is made between a possible accidental or non-accidental nature of the injuries and the characteristics of the injury have been interpreted in the light of the existing data on Alagille syndrome. In conclusion, the death was documented as accidental since abnormalities in the skeletal system evidenced during autopsy have predisposed the death of the child albeit through a very mild head trauma. The case report evidences the importance of studying features of skull macro- and microstructure in patients with Alagille syndrome, which have been, until now, underreported in literature and which might contribute to fracture vulnerability in these patients. Although rare, Alagille syndrome is a condition that should be known to forensic medicine practitioners and whose features and peculiarities must be taken into consideration in pediatric autopsy and suspected child abuse cases.

  11. Savant Syndrome: Case Studies, Hypotheses, and Implications for Special Education.

    Science.gov (United States)

    Cheatham, Susan Klug; And Others

    1995-01-01

    The concept of savant syndrome, encompassing those individuals historically known as "idiot savants," is reviewed. Case studies demonstrating special abilities in the areas of calendar calculating, musical ability, artistic talent, memorization, mathematical skills, mechanical achievement, and fine sensory discrimination are discussed,…

  12. Implications of the Google’s US 8,996,429 B1 Patent in Cloud Robotics Based Therapeutic Researches

    NARCIS (Netherlands)

    Fosch Villaronga, Eduard; Albo-Canals, Jordi; Neves, Antonio J.R.

    2017-01-01

    Intended for being informative to both legal and engineer communities, this chapter raises awareness on the implications of recent patents in the field of human-robot interaction (HRI) studies. Google patented the use of cloud robotics to create robot personality(-ies). The broad claims of the

  13. Ocular complications due to therapeutic beta-irradiation after pterygum excision. 2 cases of scleromalacia perforans

    Energy Technology Data Exchange (ETDEWEB)

    Kumashiro, O.; Matsuo, N.; Ojima, M. (Okayama Univ. (Japan). School of Medicine); Katayama, N.

    1981-09-01

    Two cases of scleromalacia perforans were seen. The disease occurred 15 years and 4 years after postoperative beta-irradiation, for pterygium excision. In the former, transplantation of the sclera which had been preserved after keratoplasty was performed, and the result was favourable. In the latter, case with mild symptoms, only drug instillation was made.

  14. A rare complication of colonic diverticulosis: giant diverticulum. Case report and overview of pathophysiology, diagnosis and therapeutic options.

    Science.gov (United States)

    Vanderstappen, J H H; Hoofwijk, A G M; Sikkink, C J J M

    2014-01-01

    A rare complication of diverticulosis of the colon is giant colonic diverticulum, an entity first described by Bonvin in 1946. The experience of any surgeon with this problem is at the most still small and reported management in the literature has been varied. We present the case of a 84-year-old woman presenting with a painless abdominal mass and constipation. A 30 x 10 cm gas-filled cyst was discovered on abdominal X-ray and CT examination. Furthermore, we provide an overview of pathophysiology, diagnosis and therapeutic options.

  15. Testing the margin of appreciation: therapeutic abortion, reproductive 'rights' and the intriguing case of Tysiqc v. Poland.

    Science.gov (United States)

    Priaulx, Nicolette

    2008-12-01

    In Tysiac v. Poland (2007) the Strasbourg Court ruled in favour of the applicant (who had been denied access to a lawful therapeutic abortion), finding that Poland had failed to comply with its positive obligations to safeguard the applicant's right to effective respect for her private life under Article 8. Exploring this controversial judgment, the author assesses the claim that Tysiac marks a 'radical shift' on the part of the Court in creating a 'right to abortion'. The author argues that while Tysiac makes an important addition to abortion jurisprudence, the notion it founds such a 'right' greatly overstates the legal significance of this case.

  16. PIM kinases as potential therapeutic targets in a subset of peripheral T cell lymphoma cases.

    Directory of Open Access Journals (Sweden)

    Esperanza Martín-Sánchez

    Full Text Available Currently, there is no efficient therapy for patients with peripheral T cell lymphoma (PTCL. The Proviral Integration site of Moloney murine leukemia virus (PIM kinases are important mediators of cell survival. We aimed to determine the therapeutic value of PIM kinases because they are overexpressed in PTCL patients, T cell lines and primary tumoral T cells. PIM kinases were inhibited genetically (using small interfering and short hairpin RNAs and pharmacologically (mainly with the pan-PIM inhibitor (PIMi ETP-39010 in a panel of 8 PTCL cell lines. Effects on cell viability, apoptosis, cell cycle, key proteins and gene expression were evaluated. Individual inhibition of each of the PIM genes did not affect PTCL cell survival, partially because of a compensatory mechanism among the three PIM genes. In contrast, pharmacological inhibition of all PIM kinases strongly induced apoptosis in all PTCL cell lines, without cell cycle arrest, in part through the induction of DNA damage. Therefore, pan-PIMi synergized with Cisplatin. Importantly, pharmacological inhibition of PIM reduced primary tumoral T cell viability without affecting normal T cells ex vivo. Since anaplastic large cell lymphoma (ALK+ ALCL cell lines were the most sensitive to the pan-PIMi, we tested the simultaneous inhibition of ALK and PIM kinases and found a strong synergistic effect in ALK+ ALCL cell lines. Our findings suggest that PIM kinase inhibition could be of therapeutic value in a subset of PTCL, especially when combined with ALK inhibitors, and might be clinically beneficial in ALK+ ALCL.

  17. Impact on Bacterial Resistance of Therapeutically Nonequivalent Generics: The Case of Piperacillin-Tazobactam.

    Directory of Open Access Journals (Sweden)

    Carlos A Rodriguez

    Full Text Available Previous studies have demonstrated that pharmaceutical equivalence and pharmacokinetic equivalence of generic antibiotics are necessary but not sufficient conditions to guarantee therapeutic equivalence (better called pharmacodynamic equivalence. In addition, there is scientific evidence suggesting a direct link between pharmacodynamic nonequivalence of generic vancomycin and promotion of resistance in Staphylococcus aureus. To find out if even subtle deviations from the expected pharmacodynamic behavior with respect to the innovator could favor resistance, we studied a generic product of piperacillin-tazobactam characterized by pharmaceutical and pharmacokinetic equivalence but a faulty fit of Hill's Emax sigmoid model that could be interpreted as pharmacodynamic nonequivalence. We determined the impact in vivo of this generic product on the resistance of a mixed Escherichia coli population composed of ∼99% susceptible cells (ATCC 35218 strain and a ∼1% isogenic resistant subpopulation that overproduces TEM-1 β-lactamase. After only 24 hours of treatment in the neutropenic murine thigh infection model, the generic amplified the resistant subpopulation up to 20-times compared with the innovator, following an inverted-U dose-response relationship. These findings highlight the critical role of therapeutic nonequivalence of generic antibiotics as a key factor contributing to the global problem of bacterial resistance.

  18. Impact on Bacterial Resistance of Therapeutically Nonequivalent Generics: The Case of Piperacillin-Tazobactam.

    Science.gov (United States)

    Rodriguez, Carlos A; Agudelo, Maria; Aguilar, Yudy A; Zuluaga, Andres F; Vesga, Omar

    2016-01-01

    Previous studies have demonstrated that pharmaceutical equivalence and pharmacokinetic equivalence of generic antibiotics are necessary but not sufficient conditions to guarantee therapeutic equivalence (better called pharmacodynamic equivalence). In addition, there is scientific evidence suggesting a direct link between pharmacodynamic nonequivalence of generic vancomycin and promotion of resistance in Staphylococcus aureus. To find out if even subtle deviations from the expected pharmacodynamic behavior with respect to the innovator could favor resistance, we studied a generic product of piperacillin-tazobactam characterized by pharmaceutical and pharmacokinetic equivalence but a faulty fit of Hill's Emax sigmoid model that could be interpreted as pharmacodynamic nonequivalence. We determined the impact in vivo of this generic product on the resistance of a mixed Escherichia coli population composed of ∼99% susceptible cells (ATCC 35218 strain) and a ∼1% isogenic resistant subpopulation that overproduces TEM-1 β-lactamase. After only 24 hours of treatment in the neutropenic murine thigh infection model, the generic amplified the resistant subpopulation up to 20-times compared with the innovator, following an inverted-U dose-response relationship. These findings highlight the critical role of therapeutic nonequivalence of generic antibiotics as a key factor contributing to the global problem of bacterial resistance.

  19. Pemphigus in North-Western Yemen: A therapeutic study of 75 cases.

    Science.gov (United States)

    Khatri, Mishri Lal

    2016-01-01

    The incidence of pemphigus, though not documented, seems to be quite high in Yemen. There is no universal consensus on the treatment of this disease. The aim was to evaluate the efficacy and side effects of different therapeutic regimens used in patients of pemphigus in North-Western Yemen. Seventy-five Yemeni patients (39 males and 36 females) were included. Diagnosis was based on clinical features, histopathology and the Tzanck test. Results of treatment with these different therapeutic regimens were compared: (1) dexamethasone-cyclophosphamide pulse (DCP), (2) dexamethasone pulse with oral azathioprine, (3) oral prednisolone with azathioprine, (4) oral prednisolone with oral cyclophosphamide, and (5) prednisolone monotherapy. Pemphigus vulgaris (PV) was diagnosed in 46 patients, pemphigus foliaceus (PF) in 23, pemphigus vegetans (PVEG) in 5 and pemphigus herpetiformis (PH) in one. Among the 16 patients who received regular DCP therapy, 13 were in remission for 6 months to 11 years without medications (phase 4). Remission without pharmacotherapy could not be achieved with the other regimens and steroid-induced side-effects appeared to be more than with DCP. Immunofluorescence was not available to confirm the diagnosis of pemphigus. Randomization was not done. The DCP regimen seemed to be superior to the other regimens used.

  20. Expeditionary Air Base Defense: Historical Cases and Modern Implications

    Science.gov (United States)

    2017-06-01

    the 2010s follows, highlighting the increase in training quality and competence , and the decrease in organic weapons capability. A series of case...pervasive problem of standoff indirect fire attacks; the criticality of a competent and dedicated ground intelligence function, and its conspicuous absence...on the ground lines of communication , the “Pavie Track” and Route 41, that passed through the valley. Unlike at Na San, where the strong points were

  1. Risk of stroke after transcatheter prosthetic aortic valve implant with aortic bioprosthesis: subclinical thrombosis and possible therapeutic implications.

    Science.gov (United States)

    Di Pasquale, Giuseppe; Coutsoumbas, Gloria V; Zagnoni, Silvia

    2017-10-16

    : Many factors could increase the risk of stroke after transcatheter prosthetic aortic valve implant, mainly related to the procedure itself, or to the type of valvular prosthesis, or to the presence of atrial fibrillation. There is a wide variability in the antithrombotic treatment utilized in clinical practice, as far as the choice of drugs (anticoagulant, single or dual antiplatelet treatment), and its optimal duration. The most popular therapeutic strategy, also recommended by the Scientific Societies, is dual antiplatelet (aspirin and clopidogrel) for the first 3-6 months then switching to single antiplatelet (usually aspirin), limiting oral anticoagulant therapy only to those patients with other primary indication to the treatment. Recently, it has been outlined that subclinical thrombosis could be responsible for bioprosthetic valve malfunction, whereas some studies suggest the efficacy of a single antiplatelet drug after transcatheter prosthetic aortic valve implant. Therefore, it is possible to personalize the therapeutic regimen balancing the ischemic and hemorrhagic risk. Several studies are ongoing to overcome these therapeutic uncertainties, including the use of new oral anticoagulants.

  2. A rare case of hidebound disease with dental implications

    Directory of Open Access Journals (Sweden)

    Vikram Bali

    2013-01-01

    Full Text Available Systemic sclerosis (also called as Scleroderma or hidebound disease is a chronic sclerotic disease of unknown etiology which causes diffuse, increased deposition of extra cellular matrix in connective tissue with vascular abnormalities, resulting in tissue hypoxia. The disease is characterized by diffuse fibrosis; degenerative changes; and vascular abnormalities in the skin (scleroderma, articular structures, and internal organs. Aesthetic and facial dysfunctions are followed by important oral and facial manifestations. Most oral manifestations begin with tongue rigidity and facial skin changes. Bone resorption of mandibular angle and widening of periodontal ligament space on periapical radiographs are important radiological findings. Other systemic changes include the involvement of internal organs, which lead to serious complications as well as disorders in the cardiac muscle and Raynaud΄s phenomenon. This is a case report of 30-year-old female patient with the classical features of this disease. This case is reported for its rarity and variable expressivity. The main aim of this article is to describe thorough presentation of the case report, various forms of scleroderma, pathogenesis, oral, extraoral, periodontal manifestations of scleroderma, and its treatment options. A brief review of the literature, focusing on dental alterations is also presented.

  3. Therapeutic Hypothermia for Asphyxial Out-of-Hospital Cardiac Arrest Due to Drowning: A Systematic Review of Case Series and Case Reports.

    Science.gov (United States)

    Suen, K-F; Leung, Reynold; Leung, Ling-Pong

    2017-12-01

    The objective of this review was to summarize published evidence of the effectiveness of therapeutic hypothermia in patients with drowning-associated asphyxial out-of-hospital cardiac arrest (OHCA) and to explore any preliminary favorable factors in the management of therapeutic hypothermia to improve survival and neurological outcome. Drowning may result in asphyxial OHCA or hypothermic OHCA, but the former does not provide any potential neuroprotective effect as the latter may do. Electronic literature searches of Ovid Medline, Embase, Cochrane Library, and Scopus were performed for all years from inception to July 2016. Primary studies in the form of case reports, letters to the editor, and others with higher quality are included, but guidelines, reviews, editorials, textbook chapters, conference abstracts, and nonhuman studies are excluded. Non-English articles are excluded. Relevant studies are then deemed eligible if the drowning OHCA patient's initial temperature was above 28°C, which implies asphyxial cardiac arrest, and intentional therapeutic hypothermia was instituted. Because of the narrow scope of interest and strict definition of the condition, limited studies addressed it, and no randomized controlled trials (RCT) could be selected. Thirteen studies covering 35 patients are included. No quantitative synthesis, assessment of study quality, or assessment of bias was performed. It is conjectured that extended therapeutic hypothermia of 48-72 hours might help prevent reperfusion injury during the intermediate phase of postcardiac arrest care to benefit patients of drowning-associated asphyxial OHCA, but this finding only serves as preliminary observation for future research. No conclusive recommendation could be made regarding the duration of and the time of onset of therapeutic hypothermia. Future research should put effort on RCT, particularly the effect of extended duration of 48-72 hours. Important parameters should be reported in detail. Asphyxial

  4. Dopa-Responsive Dystonia and gait analysis: A case study of levodopa therapeutic effects.

    Science.gov (United States)

    Rebour, Rémi; Delporte, Ludovic; Revol, Patrice; Arsenault, Lisette; Mizuno, Katsuhiro; Broussolle, Emmanuel; Luauté, Jacques; Rossetti, Yves

    2015-06-01

    Patients suffering Dopa-Responsive Dystonia present dystonia, abnormal postural balance and gait impairment. Treatment with levodopa typically improves these three symptoms. The present study provides an extensive analysis of gait and posture in a patient with Dopa-Responsive Dystonia, prior to and during levodopa therapy. The patient was assessed with the Unified Dystonia Rating Scale, underwent motion analysis with an optoelectronic system and postural analysis with force plates. This study provides a detailed quantification of gait parameters in a Dopa-Responsive Dystonia patient. Prior to treatment, mean walking speed was severely reduced, gait cadence and step length were decreased and stride width was increased. Right lower limb and pelvis showed kinematic defects, trunk and Centre of Mass were backwards. During levodopa therapy, the walking speed was doubled, gait cadence and step length were increased and stride width was reduced. Nearly all kinematic parameters of lower limbs were significantly improved. The patient's Centre of Mass during gait and Centre of pressure in static position both shifted forward. Levodopa dramatically decreased dystonia and improved spatio-temporal, kinematic and posture parameters. Our main pathophysiological hypothesis is that trunk tilt and its consequences on the Centre of Mass position have a pivotal influence on gait and balance, explaining both the initial impairments and the therapeutic effects. Gait analysis proves to be an effective tool to understand the pathophysiology of this patient, the therapeutic effects and mild residual gait defects in order to plan further rehabilitation strategy for this DRD patient. We propose that it will also prove to be useful for the exploration of other dystonic patients. Copyright © 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

  5. Positive results of serological tests for syphilis in pregnancy – diagnostic and therapeutic problems, report of two cases

    Directory of Open Access Journals (Sweden)

    Marta Koper

    2015-06-01

    Full Text Available Introduction. Undiagnosed and untreated syphilis in pregnancy may result in subsequent complications: early fetal loss, stillbirth, low birth weight of infants and newborns with congenital syphilis. Objective. To analyze diagnostic and therapeutic dilemmas of positive results of serological tests for syphilis (STS in pregnancy. Case reports. We present two cases of pregnant women, hospitalized in our department due to positive results of serological tests for syphilis, performed during the antenatal visit. On the basis of patients' history, physical examination and STS results, early latent syphilis was diagnosed in the first patient; biological false positive reactions were considered in the second one. Both patients received procaine penicillin treatment. Conclusions. Screening for syphilis in pregnancy as a part of antenatal care and appropriate treatment with penicillin are the most effective interventions to prevent complications of syphilis in pregnancy. It is also important to adapt modern European Guidelines for management of syphilis to Polish conditions.

  6. Performance Implications of Business Model Change: A Case Study

    Directory of Open Access Journals (Sweden)

    Jana Poláková

    2015-01-01

    Full Text Available The paper deals with changes in performance level introduced by the change of business model. The selected case is a small family business undergoing through substantial changes in reflection of structural changes of its markets. The authors used the concept of business model to describe value creation processes within the selected family business and by contrasting the differences between value creation processes before and after the change introduced they prove the role of business model as the performance differentiator. This is illustrated with the use of business model canvas constructed on the basis interviews, observations and document analysis. The two business model canvases allow for explanation of cause-and-effect relationships within the business leading to change in performance. The change in the performance is assessed by financial analysis of the business conducted over the period of 2006–2012 demonstrates changes in performance (comparing development of ROA, ROE and ROS having their lowest levels before the change of business model was introduced, growing after the introduction of the change, as well as the activity indicators with similar developments of the family business. The described case study contributes to the concept of business modeling with the arguments supporting its value as strategic tool facilitating decisions related to value creation within the business.

  7. Modelling hemoglobin and hemoglobin:haptoglobin complex clearance in a non-rodent species– pharmacokinetic and therapeutic implications

    Directory of Open Access Journals (Sweden)

    Felicitas S Boretti

    2014-10-01

    Full Text Available Preclinical studies suggest that haptoglobin (Hp supplementation could be an effective therapeutic modality during acute or chronic hemolytic diseases. Hp prevents Hb extravasation and neutralizes Hb’s oxidative and NO scavenging activity in the vasculature. Small animal models such as mouse, rat and guinea pig appear to be valuable to provide proof-of-concept for Hb neutralization by Hp in diverse pre-clinical conditions. However, these species differ significantly from human in the clearance of Hb:Hp complexes, which leads to long persistence of circulating Hb:Hp complexes after administration of human plasma derived Hp. Alternative animal models must therefore be explored to guide pre-clinical development of these potential therapeutics. In contrast to rodents, dogs have high Hp plasma concentrations comparable to human. In this study we show that like human macrophages, dog peripheral blood monocyte derived macrophages express a glucocorticoid inducible endocytic clearance pathways with a high specificity for the Hb:Hp complex. Evaluating the Beagle dog as a non-rodent model species we provide the first pharmacokinetic parameter estimates of free Hb and Hb:Hp phenotype complexes. The data reflect a drastically reduced volume of distribution (Vc of the complex compared to free Hb, increased exposures (Cmax and AUC and significantly reduced total body clearance (CL with a terminal half-life (t1/2 of approximately 12 hours. Distribution and clearance was identical for dog and human Hb (± glucocorticoid stimulation and for dimeric and multimeric Hp preparations bound to Hb. Collectively, our study supports the dog as a non-rodent animal model to study pharmacological and pharmacokinetic aspects of Hb clearance systems and apply the model to studying Hp therapeutics.

  8. Multi-target screening mines hesperidin as a multi-potent inhibitor: Implication in Alzheimer's disease therapeutics.

    Science.gov (United States)

    Chakraborty, Sandipan; Bandyopadhyay, Jaya; Chakraborty, Sourav; Basu, Soumalee

    2016-10-04

    Alzheimer's disease (AD) is the most frequent form of neurodegenerative disorder in elderly people. Involvement of several pathogenic events and their interconnections make this disease a complex disorder. Therefore, designing compounds that can inhibit multiple toxic pathways is the most attractive therapeutic strategy in complex disorders like AD. Here, we have designed a multi-tier screening protocol combining ensemble docking to mine BACE1 inhibitor, as well as 2-D QSAR models for anti-amyloidogenic and antioxidant activities. An in house developed phytochemical library of 200 phytochemicals has been screened through this multi-target procedure which mine hesperidin, a flavanone glycoside commonly found in citrus food items, as a multi-potent phytochemical in AD therapeutics. Steady-state and time-resolved fluorescence spectroscopy reveal that binding of hesperidin to the active site of BACE1 induces a conformational transition of the protein from open to closed form. Hesperidin docks close to the catalytic aspartate residues and orients itself in a way that blocks the cavity opening thereby precluding substrate binding. Hesperidin is a high affinity BACE1 inhibitor and only 500 nM of the compound shows complete inhibition of the enzyme activity. Furthermore, ANS and Thioflavin-T binding assay show that hesperidin completely inhibits the amyloid fibril formation which is further supported by atomic force microscopy. Hesperidin exhibits moderate ABTS(+) radical scavenging assay but strong hydroxyl radical scavenging ability, as evident from DNA nicking assay. Present study demonstrates the applicability of a novel multi-target screening procedure to mine multi-potent agents from natural origin for AD therapeutics. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  9. Theoretical and Policy Implications of Case Study Findings About Federal Efforts to Improve Public Schools

    Science.gov (United States)

    Gross, Neal

    1977-01-01

    Impediments to educational change were identified in six case studies of major innovative efforts in school systems. Their theoretical and policy implications are examined. The findings suggest the need for a reformulation of the theoretical scheme most frequently used to account for the fate of organizational innovations: overcoming resistance to…

  10. Too little? Too late? The implications of the Grootboom case for state ...

    African Journals Online (AJOL)

    Too little? Too late? The implications of the Grootboom case for state responses to child-headed households. Julia Sloth-Nielsen. Abstract. No Abstract. Full Text: EMAIL FREE FULL TEXT EMAIL FREE FULL TEXT · DOWNLOAD FULL TEXT DOWNLOAD FULL TEXT · AJOL African Journals Online. HOW TO USE AJOL.

  11. Evolving Insights into the Pathophysiology of Diabetic Neuropathy: Implications of Malfunctioning Glia and Discovery of Novel Therapeutic Targets.

    Science.gov (United States)

    Rahman, Md Habibur; Jha, Mithilesh Kumar; Suk, Kyoungho

    2016-01-01

    Diabetic neuropathy subsequent to chronic high blood glucose-induced nerve damage is one of the most frustrating and debilitating complications of diabetes, which affects the quality of life in patients with diabetes. Approximately 60-70% of patients with diabetes suffer from a distal symmetrical form of mild to severe neuropathy that progresses in a fiber-length-dependent pattern, with sensory and autonomic manifestations predominating. High glucose and oxidative stress-mediated damage in neurons and glial cells, as well as neuroinflammation and crosstalk between these disease processes, have garnered immense attention as the essential mechanisms underlying the development and progression of diabetic neuropathy. Although the metabolic causes of diabetic neuropathy are well understood and documented, treatment options for this disorder are still limited, highlighting the need for further studies to identify new molecular and therapeutic targets. This review covers recent advances in our knowledge of the pathophysiology of diabetic neuropathy, discusses how persistent hyperglycemic conditions and malfunctioning glia drive disease progression, and finally explores the possibilities and challenges offered by several potential novel therapeutic targets for both preventing and reversing diabetic neuropathy.

  12. Targeted Disruption of Orchestration between Stroma and Tumor Cells in Pancreatic Cancer: Molecular Basis and Therapeutic Implications

    Science.gov (United States)

    Kong, Xiangyu; Li, Lei; Li, Zhaoshen; Xie, Keping

    2012-01-01

    Pancreatic cancer is one of the most lethal malignancies, with a prominent desmoplastic reaction as the defining hallmark of the disease. The past several decades have seen dramatic progress in understanding of pancreatic cancer pathogenesis, including the identification of precursor lesions, sequential transformation from normal pancreas to invasive pancreatic cancer and corresponding signature genetic events, and the biological impact of those alterations on malignant behaviors. However, the current therapeutic strategies for epithelial tumor cells, which have exhibited potent antitumor activity in cell culture and animal models, have failed to have significant effects in the clinic. The desmoplastic stroma surrounding pancreatic cancer cells, which accounts for about 90% of a tumor’s mass, clearly is not a passive scaffold for cancer cells but an active contributor to carcinogenesis. Improved understanding of the dynamic interaction between cancer cells and their stroma will be important to designing new, effective therapeutic strategies for pancreatic cancer. This review focuses on the origination of stromal molecular and cellular components in pancreatic tumors, their biological effects on pancreatic cancer cells, and the orchestration between these two components. PMID:22749856

  13. Rational diagnostic and therapeutic management of deep neck infections: analysis of 233 consecutive cases.

    Science.gov (United States)

    Marioni, Gino; Staffieri, Alberto; Parisi, Saverio; Marchese-Ragona, Rosario; Zuccon, Andrea; Staffieri, Claudia; Sari, Marianna; Speranzoni, Chiara; de Filippis, Cosimo; Rinaldi, Roberto

    2010-03-01

    Although deep neck infections are less common nowadays because of the widespread use of antibiotics, they continue to carry significant morbidity and mortality rates. Between 2000 and 2008, deep neck infections were treated in 233 patients at the University of Padova. Cases of peritonsillar abscess, superficial infections, infections due to external neck injuries, and infections in head and neck tumors were excluded. Clinical, radiologic, laboratory, and microbiological assessments were analyzed. The site of origin was identified in 189 of the 233 cases (81.1%), and the most common cause of deep neck infection was dental infection (39.5%). Intravenous antibiotic therapy was given to 78 patients, and 155 required both medical and surgical procedures. The bacteria most often isolated were gram-positive anaerobic cocci. None of our patients died of the deep neck infection or its complications. It is worth emphasizing that airway support is the priority in patients with deep neck infections. Empirical antibiotic treatments must cover gram-positive and gram-negative aerobic and anaerobic pathogens. Surgical exploration and drainage may be mandatory in selected cases at presentation or in cases that fail to respond to parenteral antibiotics within the first 24 to 48 hours. It is important to perform cultures during operation to establish the pathogen(s) involved and to obtain an antibiogram to tailor the antibiotic treatment.

  14. A rare case of orbital hodgkin lymphoma demonstrating therapeutic response to a novel systemic medication.

    Science.gov (United States)

    Wajda, Brynn N; Rabinowitz, Michael P

    2017-02-01

    Orbital Hodgkin lymphoma is infrequent, representing less than 1% of adult orbital malignancies. It is typically seen in the setting of terminally advanced systemic disease. This case highlights orbital, head, and neck disease in a systemically stable individual treated with the novel anti-CD30 monoclonal antibody brentuximab vedotin.

  15. [Hypertensive crisis. Clinical and therapeutic study of 130 cases (author's transl)].

    Science.gov (United States)

    Jarillo, M D; Alcázar, J M; Pérez Díaz, V; Gutiérrez Millet, V; Morales, J M; Barrientos, A; Rodicio, J L; Ruilope, L M

    1981-05-10

    The clinical aspects and response to therapy of 130 hypertensive emergencies are reviewed in this report. According to the main features of the clinical picture, the patients were divided into neurologic, cardiac or mixed emergencies. The patients were evaluated with clinical examination, fundoscopy, routine biochemistry, ECG, and chest radiograms. According to the response of the blood pressure to the administration of hypotensive drugs, the patients were divided into two groups: group I, with good response to a single drug associated to frusemide, and group II, with good response to two or more drugs associated to frusemide. Neurologic emergencies appeared in 55 patients (42% of total), and cardiac emergencies in 45 (34%), the initial blood pressure beeing higher in the first group (p less than 0.005). The fundus showed hypertensive retinopathy degrees III-IV in 55% of the patients. Patients in group I had less elevation of the initial blood pressure, showed a better response to therapy, and had only mild side effects from the administered drugs. Group II had a mortality of 11% and, as expected, showed more complications due to side effects. The frequency of appearance of toxic side effects from the drugs given is reviewed, and a therapeutic schedule is proposed.

  16. Macromolecular confinement of therapeutic protein in polymeric particles for controlled release: insulin as a case study

    Directory of Open Access Journals (Sweden)

    Luiz Henrique Guerreiro

    2017-06-01

    Full Text Available ABSTRACT Sustained release systems for therapeutic proteins have been widely studied targeting to improve the action of these drugs. Molecular entrapping of proteins is particularly challenging due to their conformational instability. We have developed a micro-structured poly-epsilon-caprolactone (PCL particle system loaded with human insulin using a simple double-emulsion w/o/w method followed by solvent evaporation method. This formulation is comprised by spheric-shaped microparticles with average size of 10 micrometers. In vitro release showed a biphasic behavior such as a rapid release with about 50% of drug delivered within 2 hours and a sustained phase for up to 48 h. The subcutaneous administration of microencapsulated insulin showed a biphasic effect on glycemia in streptozotocin-induced diabetic mice, compatible with short and intermediate-acting behaviors, with first transition peak at about 2 h and the second phase exerting effect for up to 48h after s.c. administration. This study reveals that a simplified double-emulsion system results in biocompatible human-insulin-loaded PCL microparticles that might be used for further development of optimized sustained release formulations of insulin to be used in the restoration of hormonal levels.

  17. Insights Into the Therapeutic Effect of Responsive Neurostimulation Assessed With Scalp EEG Recording: A Case Report.

    Science.gov (United States)

    Bruzzone, Maria Jose; Issa, Naoum; Rose, Sandra; Warnke, Peter; Towle, Vernon L; Tao, James X; Wu, Shasha

    2017-10-10

    The responsive neurostimulation system (RNS) is the first closed-loop neurostimulator approved as an adjunctive treatment for adults with medically refractory focal epilepsy from no more than two seizure foci. In addition to its therapeutic effect, it provides chronic intracranial EEG recordings, with limited storage capacity. Long-term monitoring with scalp EEG recordings can provide additional information regarding seizure patterns, the efficacy of RNS stimulation in aborting individual seizures, and the net effect of RNS on seizure control. We present a 34-year-old woman with medically intractable right temporoparietal lobe epilepsy who failed two resective epilepsy surgeries and MR-guided laser interstitial thermal therapy (MRgLITT), after which RNS was implanted. Long-term scalp EEG performed 16 months after implantation showed continuous right hemisphere slowing and right temporal sharp waves. In addition, RNS stimulation produced bursts of high-voltage, broad-field, surface-negative activity, which allowed correlation of RNS stimulation with scalp EEG patterns. Twenty-seven seizures were captured. Responsive neurostimulation system stimulation did not abort any of the seizures recorded on the scalp EEG. However, the frequency of seizures doubled after RNS stimulation was discontinued and returned to baseline once it was turned back on. This observation supports the neuromodulation effect of RNS.

  18. Combination of a Flipped Classroom Format and a Virtual Patient Case to Enhance Active Learning in a Required Therapeutics Course.

    Science.gov (United States)

    Lichvar, Alicia Beth; Hedges, Ashley; Benedict, Neal J; Donihi, Amy C

    2016-12-25

    Objective. To design and evaluate the integration of a virtual patient activity in a required therapeutics course already using a flipped-classroom teaching format. Design. A narrative-branched, dynamic virtual-patient case was designed to replace the static written cases that students worked through during the class, which was dedicated to teaching the complications of liver disease. Students completed pre- and posttests before and after completing the virtual patient case. Examination scores were compared to those in the previous year. Assessment. Students' posttest scores were higher compared to pretest scores (33% vs 50%). Overall median examination scores were higher compared to the historical control group (70% vs 80%), as well as scores on questions assessing higher-level learning (67% vs 83%). A majority of students (68%) felt the virtual patient helped them apply knowledge gained in the pre-class video lecture. Students preferred this strategy to usual in-class activities (33%) or indicated it was of equal value (37%). Conclusion. The combination of a pre-class video lecture with an in-class virtual patient case is an effective active-learning strategy.

  19. NEW THERAPEUTIC OPTIONS IN THE TREATMENT OF METASTATIC LIMB SARCOMAS: A CASE SERIES

    Directory of Open Access Journals (Sweden)

    Nicola Ratto

    2013-04-01

    Full Text Available Palliative procedures are those usually used in the treatment of metastatic limb sarcoma. However given the impressive results obtained with hyperthermic isolated limb perfusion (ILP, we tested the feasibility of isolated lung perfusion (ILuP, using the same regimen. Three patients with multiple metastases from limb sarcoma were included in this study. ILP was applied in one patient resulting in limb preservation. Patients underwent 90- minute ILuP, and subsequent metastasectomy. In all cases the procedure was completed without complications. No systemic toxicity developed. The only postoperative complication was one case of reversible interstitial and alveolar lung edema. The three patients are still alive and two of them were disease-free at a mean follow-up of 19 months. ILuP, with TNF and Melphaln, proved to be feasible and safe. This technique, in association with ILP, might improve long-term survival and quality of life in patients with multiple metastases from limb sarcoma.

  20. Ovarian fibrosarcoma: case report and latest trends in diagnostic and therapeutic management.

    Science.gov (United States)

    Grauso, F; Messalli, E M; Salzillo, M E; Di Martino, L; Falcone, F; Orabona, P; Caiola, A; Balbi, G

    2015-01-01

    The authors describe a rare case of primary ovarian fibrosarcoma and the latest trends in diagnosis and therapy. The rarity of this dis-ease and the scarce number of reported cases pose serious problems in differentiating it from other fibrous forms. A 58-year-old woman presented intermittent pelvic pain and a demarcated, mobile, and solid lump in the right adnexa. Diagnostic imaging revealed a solid- cystic inhomogeneous mass occupying the right adnexa and the CA125 level was elevated. The patient underwent total hysterectomy with bilateral salpingo-oophorectomy and infracolic omentectomy. Histological findings with immunomarkers led to the final diagnosis of low-grade malignant mesenchymal neoplasm derived from the ovarian stroma compatible with fibrosarcoma. Twenty-four months follow-up showed no recurrence of disease. Ovarian fibrosarcoma is very uncommon neoplasm with a poor prognosis. Despite the efforts of several authors in reporting morphological, histological, and immunohistochemical features of this neoplasm, nowadays, the diagnosis, treatment, and prognosis are unresolved issues. The present case highlights the important role of immunohistochemistry to define histological type and differential diagnosis. As demonstrated by the authors' experience, they believe that surgery is curative in the early stages with low immunohistochemical positivity for ki67 and that chemotherapy should be reserved in advanced stages with regimens in use for the treatment of sarcomas.

  1. Pyoderma gangrenosum, diagnostic and therapeutic difficulties – two cases imitating breast cancer

    Directory of Open Access Journals (Sweden)

    Małgorzata Tupikowska

    2016-02-01

    Full Text Available Introduction . Pyoderma gangrenosum is a rare dermatosis with unknown etiology. Painful and quickly spreading ulcerations with necrotic bottom and heaped wound edges are typical. Objective . The aim of this study is to present patients with pyoderma gangrenosum which imitated breast cancer and their treatment. Case report . Two women suspected of having breast cancer developed painful and non-healing ulceration after surgical excision of nodules. Although in histopathology mastopathic changes were described, the diagnosis was verified and subsequent biopsies showed no cancerous changes. Ulcerations were treated as an infectious surgery complication. The diagnosis of pyoderma gangrenosum was made on the basis of characteristic anamnesis, clinical features and histopathological examination. In the treatment cyclosporine with dapsone and cyclosporine with glucocorticosteroids were used and a very quick local response and pain relief were obtained. Conclusions . The presented cases illustrate diagnostic difficulties and the role of the pathergy phenomenon in the development of pyoderma gangrenosum lesions. The course and treatment of the disease in both cases also reveal the ineffectiveness of monotherapy with glucocorticosteroids.

  2. Therapeutic plasmapheresis for hypertriglyceridemia-associated acute pancreatitis: case series and review of the literature.

    Science.gov (United States)

    Joglekar, Kiran; Brannick, Ben; Kadaria, Dipen; Sodhi, Amik

    2017-04-01

    Severe hypertriglyceridemia (HTG) is the third leading cause of acute pancreatitis (AP) in the United States. The current standard of care includes management of HTG using pharmacological therapy. More recently, plasmapheresis has been proposed as a therapeutic tool for decreasing triglyceride (TG) levels, especially in critically ill patients. Few studies are available to ascertain overall benefits of plasmapheresis over traditional management. To analyze the outcomes of patients treated with plasmapheresis for severe HTG-associated pancreatitis. We conducted a retrospective chart review of three patients with severe HTG- associated (TGs greater than 1000 mg/dl; 11.29 mmol/l) AP at the Methodist University Hospital. All the patients underwent plasmapheresis as part of their treatment. The average TG level before plasmapheresis was 3532 mg/dl (range: 2524-4562 mg/dl; 39.9 mmol/l; range: 28.5-51.6 mmol/l). All patients made a full recovery, with a significant improvement in TG levels after plasmapheresis. The mean number of sessions was 1.3 (range 1-2), and mean TG level after plasmapheresis was 1051 mg/dl (range: 509-1771 mg/dl; 11.9 mmol/l; range: 5.8-20 mmol/l). After the first session, the average reduction of TG level was 2481 mg/dl (range 753-3750 mg/dl; 28 mmol/l; range: 8.5-42.4 mmol/l) or approximately 70%. None of the patients developed complications related to plasmapheresis. Plasmapheresis can be an effective and rapid treatment option in patients with severe HTG and complications. However, further research, including randomized controlled studies, is necessary.

  3. Dextrose-mediated aggregation of therapeutic monoclonal antibodies in human plasma: Implication of isoelectric precipitation of complement proteins

    Science.gov (United States)

    Luo, Shen; Zhang, Baolin

    2015-01-01

    Many therapeutic monoclonal antibodies (mAbs) are clinically administered through intravenous infusion after mixing with a diluent, e.g., saline, 5% dextrose. Such a clinical setting increases the likelihood of interactions among mAb molecules, diluent, and plasma components, which may adversely affect product safety and efficacy. Avastin® (bevacizumab) and Herceptin® (trastuzumab), but not Remicade® (infliximab), were shown to undergo rapid aggregation upon dilution into 5% dextrose when mixed with human plasma in vitro; however, the biochemical pathways leading to the aggregation were not clearly defined. Here, we show that dextrose-mediated aggregation of Avastin or Herceptin in plasma involves isoelectric precipitation of complement proteins. Using mass spectrometry, we found that dextrose-induced insoluble aggregates were composed of mAb itself and multiple abundant plasma proteins, namely complement proteins C3, C4, factor H, fibronectin, and apolipoprotein. These plasma proteins, which are characterized by an isoelectronic point of 5.5–6.7, lost solubility at the resulting pH in the mixture with formulated Avastin (pH 6.2) and Herceptin (pH 6.0). Notably, switching formulation buffers for Avastin (pH 6.2) and Remicade (pH 7.2) reversed their aggregation profiles. Avastin formed little, if any, insoluble aggregates in dextrose-plasma upon raising the buffer pH to 7.2 or above. Furthermore, dextrose induced pH-dependent precipitation of plasma proteins, with massive insoluble aggregates being detected at pH 6.5–6.8. These data show that isoelectric precipitation of complement proteins is a prerequisite of dextrose-induced aggregation of mAb in human plasma. This finding highlights the importance of assessing the compatibility of a therapeutic mAb with diluent and human plasma during product development. PMID:26338058

  4. Dextrose-mediated aggregation of therapeutic monoclonal antibodies in human plasma: Implication of isoelectric precipitation of complement proteins.

    Science.gov (United States)

    Luo, Shen; Zhang, Baolin

    2015-01-01

    Many therapeutic monoclonal antibodies (mAbs) are clinically administered through intravenous infusion after mixing with a diluent, e.g., saline, 5% dextrose. Such a clinical setting increases the likelihood of interactions among mAb molecules, diluent, and plasma components, which may adversely affect product safety and efficacy. Avastin® (bevacizumab) and Herceptin® (trastuzumab), but not Remicade® (infliximab), were shown to undergo rapid aggregation upon dilution into 5% dextrose when mixed with human plasma in vitro; however, the biochemical pathways leading to the aggregation were not clearly defined. Here, we show that dextrose-mediated aggregation of Avastin or Herceptin in plasma involves isoelectric precipitation of complement proteins. Using mass spectrometry, we found that dextrose-induced insoluble aggregates were composed of mAb itself and multiple abundant plasma proteins, namely complement proteins C3, C4, factor H, fibronectin, and apolipoprotein. These plasma proteins, which are characterized by an isoelectronic point of 5.5-6.7, lost solubility at the resulting pH in the mixture with formulated Avastin (pH 6.2) and Herceptin (pH 6.0). Notably, switching formulation buffers for Avastin (pH 6.2) and Remicade (pH 7.2) reversed their aggregation profiles. Avastin formed little, if any, insoluble aggregates in dextrose-plasma upon raising the buffer pH to 7.2 or above. Furthermore, dextrose induced pH-dependent precipitation of plasma proteins, with massive insoluble aggregates being detected at pH 6.5-6.8. These data show that isoelectric precipitation of complement proteins is a prerequisite of dextrose-induced aggregation of mAb in human plasma. This finding highlights the importance of assessing the compatibility of a therapeutic mAb with diluent and human plasma during product development.

  5. [Common physiological basis for post-traumatic stress disorder and dependence to drugs of abuse: Implications for new therapeutic approaches].

    Science.gov (United States)

    Gisquet-Verrier, Pascale; Tolédano, Daniel; Le Dorze, Claire

    2017-06-01

    Post-traumatic stress disorder (PTSD) and addiction to drugs of abuse are two common diseases, showing high comorbidity rates. This review presents a number of evidence showing similarities between these two pathologies, especially the hyper-responsiveness to environmental cues inducing a reactivation of the target memory leading either to re-experiencing (PTSD), or drug craving. Accordingly, PTSD and addiction to drug of abuse might by considered as memory pathologies, underlined by the same physiological process. We propose that these two pathologies rely on an uncoupling of the monoaminergic systems. According to this hypothesis, exposure to extreme conditions, either negative (trauma) or positive (drugs) induced a loss of the reciprocal control that one system usually exerts on the other monoaminergic system, resulting to an uncoupling between the noradrenergic and the serotonergic systems. Results obtained in our laboratory, using animal models of these pathologies, demonstrate that after a trauma, such as after repeated drug injections, rats developed both a behavioral sensitization (increases of the locomotion in response to a stimulation of the monoaminergic systems) and a pharmacological sensitization (increases of noradrenergic release within the prefrontal cortex). These results support our hypothesis and led us to propose new and innovative therapeutic approaches consisting either to induce a re-coupling of the monoaminergic systems, or to modify the pathological memories by using an emotional memory remodeling. Extremely encouraging results have already been obtained in rats and in humans, opening new and promising therapeutic avenues. Copyright © 2016 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.

  6. Swallowing the scroll: legal implications of the recent Supreme Court peyote cases.

    Science.gov (United States)

    Bullis, R K

    1990-01-01

    Two cases decided by the United States Supreme Court in the past two years, with the same factual bases and involving the religious use of peyote by Native American Church members, are described and analyzed. In 1990 the Supreme Court ruled that states may prohibit the use of peyote for religious purposes. These cases are examined by applying traditional equal-protection and First Amendment religious liberty analyses as well as by traditional Western interpretations of sacrament. The Supreme Court now has established a legal precendent running contrary to previous lower court cases that has implications for the religious use of peyote, specifically, and for nontraditional use of sacramental drugs, generally.

  7. Glutamatergic postsynaptic density protein dysfunctions in synaptic plasticity and dendritic spines morphology: relevance to schizophrenia and other behavioral disorders pathophysiology, and implications for novel therapeutic approaches.

    Science.gov (United States)

    de Bartolomeis, Andrea; Latte, Gianmarco; Tomasetti, Carmine; Iasevoli, Felice

    2014-02-01

    Emerging researches point to a relevant role of postsynaptic density (PSD) proteins, such as PSD-95, Homer, Shank, and DISC-1, in the pathophysiology of schizophrenia and autism spectrum disorders. The PSD is a thickness, detectable at electronic microscopy, localized at the postsynaptic membrane of glutamatergic synapses, and made by scaffolding proteins, receptors, and effector proteins; it is considered a structural and functional crossroad where multiple neurotransmitter systems converge, including the dopaminergic, serotonergic, and glutamatergic ones, which are all implicated in the pathophysiology of psychosis. Decreased PSD-95 protein levels have been reported in postmortem brains of schizophrenia patients. Variants of Homer1, a key PSD protein for glutamate signaling, have been associated with schizophrenia symptoms severity and therapeutic response. Mutations in Shank gene have been recognized in autism spectrum disorder patients, as well as reported to be associated to behaviors reminiscent of schizophrenia symptoms when expressed in genetically engineered mice. Here, we provide a critical appraisal of PSD proteins role in the pathophysiology of schizophrenia and autism spectrum disorders. Then, we discuss how antipsychotics may affect PSD proteins in brain regions relevant to psychosis pathophysiology, possibly by controlling synaptic plasticity and dendritic spine rearrangements through the modulation of glutamate-related targets. We finally provide a framework that may explain how PSD proteins might be useful candidates to develop new therapeutic approaches for schizophrenia and related disorders in which there is a need for new biological treatments, especially against some symptom domains, such as negative symptoms, that are poorly affected by current antipsychotics.

  8. Surviving Naegleria fowleri infections: A successful case report and novel therapeutic approach.

    Science.gov (United States)

    Heggie, Travis W; Küpper, Thomas

    Naegleria fowleri is a deadly human pathogen recognized as the causative agent of Primary Amoebic Meningitis (PAM). N. fowleri is commonly found in warm freshwater environments such as natural or man-made lakes, hot springs, and resort spas frequented by tourists. PAM infections have a mortality rate between 95 and 99% with minimal progress being made toward a successful treatment therapy. We report the case of a 12-year old American female who survived a PAM infection and propose a new drug therapy which includes the antimicrobial drug Miltefosine. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. Trends in Therapeutic Recreation.

    Science.gov (United States)

    Smith, Ralph W.

    1995-01-01

    Discusses the implications of the rapid, dramatic changes taking place in therapeutic recreation for individuals with physical disabilities. The article notes the impact of changes in managed care, examines programming trends in therapeutic recreation (adventure/outdoor education, competitive sports, handcycling, health enhancement activities, and…

  10. Cerebral Amyloid Angiopathy-Related Inflammation: Report of a Case with Very Difficult Therapeutic Management

    Directory of Open Access Journals (Sweden)

    Francesca Crosta

    2015-01-01

    Full Text Available Background. Cerebral amyloid angiopathy-related inflammation (CAA-ri results from autoimmune response to beta-amyloid deposits in cerebral vessels. Its clinical course and complications have seldom been described in literature. Case Report. In a patient presenting with delirium and left hemiparesis the diagnosis of CAA-ri was supported by the finding of elevated anti-amyloid autoantibodies in the cerebrospinal fluid (CSF. Steroid therapy produced significant improvements in clinical and investigational assessments, but after two months, it caused Acute Respiratory Distress Syndrome. After steroid therapy discontinuation the patient presented a rapidly progressive dementia, Guillain-Barré syndrome, new cerebral ischemic lesions, and thrombosis of the right cephalic and subclavian veins that were treated with subcutaneous heparin. After a week the patient died because of brain hemorrhage. Conclusion. This case suggests caution in steroid therapy discontinuation and antithrombotic therapy administration in patients with CAA-ri. The CSF search of anti-amyloid autoantibodies could be helpful to support the diagnosis.

  11. Diagnostic and Therapeutic Approach in a Case of Severe Post-Traumatic Hyphema with Subtotal Iridodialysis

    Directory of Open Access Journals (Sweden)

    Filippo Romanazzi

    2017-10-01

    Full Text Available Purpose: To report our diagnostic ultrasound-based approach and surgical strategy in a case of severe blunt trauma with complete hyphema, 270° iris disinsertion, and traumatic subluxated cataract. Case Report: A 70-year-old male was referred to our hospital for a blunt trauma in his right eye. A complete examination revealed visual acuity consisting in light perception, a complete hyphema, and an intraocular pressure of 45 mm Hg with moderate pain. Our diagnostic approached was ultrasound based with B-scan examination showing some vitreous hemorrhage and ultrasound biomicroscopy showing a large iris disinsertion of 270° with the iris entirely dislocated in the inferior sector of the anterior chamber. The patient was hospitalized and a systemic and topical treatment was started to lower intraocular pressure. Our surgery consisted in a single-step approach with removal of traumatic cataract with scleral fixation of an intraocular lens and iridoplasty. Conclusion: In our patient, the single-step surgery, supported by anterior and posterior ultrasound imaging, achieved a satisfactory anatomical and functional outcome.

  12. An Integrative Therapeutic Concept for Surgical Treatment of Severe Cases of Lymphedema of the Lower Extremity.

    Science.gov (United States)

    Kiefer, Jurij; Koulaxouzidis, Georgios; Stark, G Björn; Foeldi, Etelka; Torio-Padron, Nestor; Penna, Vincenzo

    2016-07-01

    Lymphedema results from insufficient lymphatic drainage and typically affects the extremities. Recent studies revealed obesity as another cause of extremity lymphedema. Conservative treatment of patients with elephantiastic lymphedema of the lower extremity is limited and often inadequate. Resecting surgery plays an important role in these cases. Here, we investigated the effects of an integrated therapy concept on outcome and complication rates. We retrospectively analyzed the clinical outcome of 26 patients with elephantiastic lymphedema of the lower limb who underwent a complex decongestive physical therapy (CDP) perioperatively and reduction surgery in our clinic between 1998 and 2011. We subsequently compared these patients (group A) with a control group of 30 patients (group B) who received medial thigh lift due to post-bariatric or aesthetic issues between 2011 and 2013. The incidence of complications, reoperations, blood transfusion, and duration of hospital stay was analyzed. All patients in group A received CDP perioperatively in a specialized lymphological clinic. Both groups are comparable in terms of age and sex. Patients significantly differ in terms of BMI (p treatment of severe cases of lymphedema in appropriate candidates. Furthermore, an adequate perioperative conservative setting helps to minimize possible complications.

  13. [Therapeutic local anesthesia for the management of atypical odontalgia. A clinical case series].

    Science.gov (United States)

    Türp, Jens Christoph

    2005-01-01

    The management of patients diagnosed with atypical odontalgia (AO) is a challenging task. The aim of this longitudinal clinical case series was to document the effect of a 4% carticaine solution without epinephrine among ten patients with AO. Once or on two successive days, 1.7 ml of the local anesthetics was injected buccally in the area of the perceived pain. Pain intensity was recorded four times daily by each participant, beginning at least two weeks prior to the treatment and ending at least four weeks thereafter. The main outcome parameter was pain reduction (in percent) four weeks after treatment compared to the average pain intensity before the injection(s). In addition, study participants were asked to rate their satisfaction with the treatment. Four weeks after treatment, seven of the ten patients experienced significantly less pain than before. Among five individuals, there was a significant pain decrease (about 30% or more). Patient satisfaction was not significantly associated with the amount of pain reduction. Considering the limited treatment options and their side effects, injections with epinephrine-free carticaine seem to be a measure worth to be taken into consideration. Although results gained from uncontrolled case series have to be interpreted with caution, the findings of this observational study sound promising.

  14. Therapeutic approach to "downhill" esophageal varices bleeding due to superior vena cava syndrome in Behcet's disease: a case report

    Directory of Open Access Journals (Sweden)

    Haghighi Mahshid

    2006-12-01

    Full Text Available Abstract Background One of the rare presentations of superior vena cava syndrome is bleeding of "downhill" esophageal varices (DEV and different approaches have been used to control it. This is a case report whose DEV was eradicated by band ligation for the first time. Case presentation We report a 42-year-old man who is a known case of Behcet's disease. The patient's first presentation was superior vena cava syndrome due to thrombosis followed by bipolar ulcers and arthralgia. He received warfarin, prednisolone and azathioprine. The clinical course of the patient was complicated by one episode of hematemesis without abdominal pain when the patient's PT was in therapeutic range. After resuscitation and correction of PT with fresh frozen plasma transfusion, upper gastrointestinal endoscopy was done. Prominent varices were seen in the upper third of the esophagus, tapering to the middle part without acute bleeding. Stomach and duodenum were normal. Color ultrasonography evaluation of the portal, hepatic and splenic veins was negative for thrombosis. Band ligation was done and the patient's bleeding did not recur. Conclusion Band ligation is a safe and effective method for controlling DEV bleeding in patients with uncorrectable underlying disorders.

  15. PARALLEL MODELS OF ASSESSMENT: INFANT MENTAL HEALTH AND THERAPEUTIC ASSESSMENT MODELS INTERSECT THROUGH EARLY CHILDHOOD CASE STUDIES.

    Science.gov (United States)

    Gart, Natalie; Zamora, Irina; Williams, Marian E

    2016-07-01

    Therapeutic Assessment (TA; S.E. Finn & M.E. Tonsager, 1997; J.D. Smith, 2010) is a collaborative, semistructured model that encourages self-discovery and meaning-making through the use of assessment as an intervention approach. This model shares core strategies with infant mental health assessment, including close collaboration with parents and caregivers, active participation of the family, a focus on developing new family stories and increasing parents' understanding of their child, and reducing isolation and increasing hope through the assessment process. The intersection of these two theoretical approaches is explored, using case studies of three infants/young children and their families to illustrate the application of TA to infant mental health. The case of an 18-month-old girl whose parents fear that she has bipolar disorder illustrates the core principles of the TA model, highlighting the use of assessment intervention sessions and the clinical approach to preparing assessment feedback. The second case follows an infant with a rare genetic syndrome from ages 2 to 24 months, focusing on the assessor-parent relationship and the importance of a developmental perspective. Finally, assessment of a 3-year-old boy illustrates the development and use of a fable as a tool to provide feedback to a young child about assessment findings and recommendations. © 2016 Michigan Association for Infant Mental Health.

  16. Cryosurgery with refrigerant gas as a therapeutic option for the treatment of leukoplakia: a case report.

    Science.gov (United States)

    Carvalho Nogueira, Pedro Thalles Bernardo de; Brasil, Ozawa; Albuquerque Neto, Antonio Dionízio de; Nogueira Filho, Luciano Leocádio Teixeira; Souza, Bruna Lopes; Laureano Filho, José Rodrigues

    2016-01-01

    Leukoplakia is a nondetachable, potentially malignant, white lesion that is commonly found in smokers of advanced age. Leukoplakia occurs more frequently in men; however, there is a higher index of dysplastic changes and malignant transformation in women. The proposed treatments for this disease range from monitoring to surgical excision. Cryosurgery has been reported as an alternative to conventional surgery. Cryosurgery destroys the tissues of a potentially malignant lesion through the application of low temperatures. This technique offers a low rate of postsurgical infection, absence of hemorrhage, and ease of application, and it is widely accepted by patients. The most commonly used cryogenic agent, liquid nitrogen, is costly and difficult to use. The objective of this article is to suggest the use of a combination of refrigerant gases (propane and butane), commonly employed in pulp sensitivity tests, for cryosurgery of potentially malignant lesions of the oral cavity and to report a case of leukoplakia treated with this approach.

  17. [Clinical case--voluminous diaphragmatic hernia--surgically acute abdomen: diagnostic and therapeutical challenges].

    Science.gov (United States)

    Dumitrescu, D; Savlovschi, C; Borcan, R; Pantu, H; Serban, D; Gradinaru, S; Smarandache, G; Trotea, T; Branescu, C; Musat, L; Comandasu, M; Priboi, M; Baldir, M; Sandolache, B; Oprescu, S

    2011-01-01

    We present the case of a 58-year old male patient admitted in the surgery section of the University Emergency Hospital of Bucharest and diagnosed with acute abdomen. The minimal clinical-paraclinical investigation (i.e., thorax-pulmonary Xray, biological probes) raises questions as to the differentiated diagnosis and other associated diseases, also suggesting the existence of voluminous diaphragmatic hernia. The CT thorax-abdomen examination confirms the diaphragmatic hernia suspicion, with intra-thorax ascent of the colon up to the anterior C4 level, but does not explain the abdominal suffering; thus we suspected a biliary ileus or acute appendicitis. Medial laparotomy was imperative. Intrasurgically peritonitis was noticed located by gangrenous acute apendicitis, perforated, with coprolite, for which apendictomy and lavage-drainage pf the peritoneal cavity was performed. Post-surgical status: favourable to recovery.

  18. [Therapeutic strategies of atrial fibrillation in patients aged 65 and over. Report of 86 cases].

    Science.gov (United States)

    Jaafari, Aïcha; Zakhama, Lilia; Boussabah, Ehlem; Thameur, Moez; Boukhriss, Bessma; Amara, Yosser; Masmoudi, Mourad; Bencheikh, Mamoun; Benyoussef, Soraya

    2004-01-01

    Auricular fibrillation is the most common sustained cardiac arrhythmia, yet the optimal strategy for its management remains unclear. Since the study AFFIRM from which resulted them final were deferred in December 2002, the assumption of responsibility of the fibrillation of the old subject tends to become clarified. 86 patients at least 65 years or more were enrolled in our retrospective study from January 1997 to June 2003. The mean age is 70 years (65 to 82 years) and sex ratio to 0.79. 34% had a history of hypertension and 12% had a coronary artery disease. 2 groups were individualized, according to the year of admission before or after 2002. It comes out from these work 2 points: the restoration of the sinusal rhythm was the first choice. In the event of failure, the option was to maintain fibrillation and this, in the 2 groups. The AVK were founded in the large majority of the cases only after year 2002.

  19. Therapeutic substitution post-patent expiry: the cases of ACE inhibitors and proton pump inhibitors.

    Science.gov (United States)

    Vandoros, Sotiris

    2014-05-01

    This paper examines whether there is a switch in total (originator and generic) consumption after generic entry from molecules that face generic competition towards other molecules of the same class, which are still in-patent. Data from six European countries for the time period 1991 to 2006 are used to study the cases of angiotensin-converting enzyme inhibitors and proton pump inhibitors. Empirical evidence shows that patent expiry of captopril and enalapril led to a switch in total (off-patent originator and generic) consumption towards other in-patent angiotensin-converting enzyme inhibitors, whereas patent expiry of omeprazole led to a switch in consumption towards other proton pump inhibitors. This phenomenon makes generic policies ineffective and results in an increase in pharmaceutical expenditure due to the absence of generic alternatives in the market of in-patent molecules. Copyright © 2013 John Wiley & Sons, Ltd.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2011-01-24

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

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

    Directory of Open Access Journals (Sweden)

    Osama H. Elshenawy

    2017-02-01

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

  2. A pilot study for robot appearance preferences among high-functioning individuals with autism spectrum disorder: Implications for therapeutic use

    Science.gov (United States)

    Warren, Zachary; Muramatsu, Taro; Yoshikawa, Yuichiro; Matsumoto, Yoshio; Miyao, Masutomo; Nakano, Mitsuko; Mizushima, Sakae; Wakita, Yujin; Ishiguro, Hiroshi; Mimura, Masaru; Minabe, Yoshio; Kikuchi, Mitsuru

    2017-01-01

    Recent rapid technological advances have enabled robots to fulfill a variety of human-like functions, leading researchers to propose the use of such technology for the development and subsequent validation of interventions for individuals with autism spectrum disorder (ASD). Although a variety of robots have been proposed as possible therapeutic tools, the physical appearances of humanoid robots currently used in therapy with these patients are highly varied. Very little is known about how these varied designs are experienced by individuals with ASD. In this study, we systematically evaluated preferences regarding robot appearance in a group of 16 individuals with ASD (ages 10–17). Our data suggest that there may be important differences in preference for different types of robots that vary according to interaction type for individuals with ASD. Specifically, within our pilot sample, children with higher-levels of reported ASD symptomatology reported a preference for specific humanoid robots to those perceived as more mechanical or mascot-like. The findings of this pilot study suggest that preferences and reactions to robotic interactions may vary tremendously across individuals with ASD. Future work should evaluate how such differences may be systematically measured and potentially harnessed to facilitate meaningful interactive and intervention paradigms. PMID:29028837

  3. The Role of Ovarian Sex Steroids in Metabolic Homeostasis, Obesity, and Postmenopausal Breast Cancer: Molecular Mechanisms and Therapeutic Implications

    Directory of Open Access Journals (Sweden)

    Viroj Boonyaratanakornkit

    2015-01-01

    Full Text Available Obese postmenopausal women have an increased risk of breast cancer and are likely to have a worse prognosis than nonobese postmenopausal women. The cessation of ovarian function after menopause results in withdrawal of ovarian sex steroid hormones, estrogen, and progesterone. Accumulating evidence suggests that the withdrawal of estrogen and progesterone causes homeostasis imbalances, including decreases in insulin sensitivity and leptin secretion and changes in glucose and lipid metabolism, resulting in a total reduction in energy expenditure. Together with a decrease in physical activity and consumption of a high fat diet, these factors significantly contribute to obesity in postmenopausal women. Obesity may contribute to breast cancer development through several mechanisms. Obesity causes localized inflammation, an increase in local estrogen production, and changes in cellular metabolism. In addition, obese women have a higher risk of insulin insensitivity, and an increase in insulin and other growth factor secretion. In this review, we describe our current understanding of the molecular actions of estrogen and progesterone and their contributions to cellular metabolism, obesity, inflammation, and postmenopausal breast cancer. We also discuss how modifications of estrogen and progesterone actions might be used as a therapeutic approach for obesity and postmenopausal breast cancer.

  4. A pilot study for robot appearance preferences among high-functioning individuals with autism spectrum disorder: Implications for therapeutic use.

    Directory of Open Access Journals (Sweden)

    Hirokazu Kumazaki

    Full Text Available Recent rapid technological advances have enabled robots to fulfill a variety of human-like functions, leading researchers to propose the use of such technology for the development and subsequent validation of interventions for individuals with autism spectrum disorder (ASD. Although a variety of robots have been proposed as possible therapeutic tools, the physical appearances of humanoid robots currently used in therapy with these patients are highly varied. Very little is known about how these varied designs are experienced by individuals with ASD. In this study, we systematically evaluated preferences regarding robot appearance in a group of 16 individuals with ASD (ages 10-17. Our data suggest that there may be important differences in preference for different types of robots that vary according to interaction type for individuals with ASD. Specifically, within our pilot sample, children with higher-levels of reported ASD symptomatology reported a preference for specific humanoid robots to those perceived as more mechanical or mascot-like. The findings of this pilot study suggest that preferences and reactions to robotic interactions may vary tremendously across individuals with ASD. Future work should evaluate how such differences may be systematically measured and potentially harnessed to facilitate meaningful interactive and intervention paradigms.

  5. Capsid-binding retrovirus restriction factors: discovery, restriction specificity and implications for the development of novel therapeutics.

    Science.gov (United States)

    Sanz-Ramos, Marta; Stoye, Jonathan P

    2013-12-01

    The development of drugs against human immunodeficiency virus type 1 infection has been highly successful, and numerous combinational treatments are currently available. However, the risk of the emergence of resistance and the toxic effects associated with prolonged use of antiretroviral therapies have emphasized the need to consider alternative approaches. One possible area of investigation is provided by the properties of restriction factors, cellular proteins that protect organisms against retroviral infection. Many show potent viral inhibition. Here, we describe the discovery, properties and possible therapeutic uses of the group of restriction factors known to interact with the capsid core of incoming retroviruses. This group comprises Fv1, TRIM5α and TRIMCypA: proteins that all act shortly after virus entry into the target cell and block virus replication at different stages prior to integration of viral DNA into the host chromosome. They have different origins and specificities, but share general structural features required for restriction, with an N-terminal multimerization domain and a C-terminal capsid-binding domain. Their overall efficacy makes it reasonable to ask whether they might provide a framework for developing novel antiretroviral strategies.

  6. Co-receptor tropism prediction among 1045 Indian HIV-1 subtype C sequences: Therapeutic implications for India

    Directory of Open Access Journals (Sweden)

    Kuttiatt Vijesh S

    2010-07-01

    Full Text Available Abstract Background Understanding co-receptor tropism of HIV-1 strains circulating in India will provide key analytical leverage for assessing the potential usefulness of newer antiretroviral drugs such as chemokine co-receptor antagonists among Indian HIV-infected populations. The objective of this study was to determine using in silico methods, HIV-1 tropism among a large number of Indian isolates both from primary clinical isolates as well as from database-derived sequences. Results R5-tropism was seen in 96.8% of a total of 1045 HIV-1 subtype C Indian sequences. Co-receptor prediction of 15 primary clinical isolates detected two X4-tropic strains using the C-PSSM matrix. R5-tropic HIV-1 subtype C V3 sequences were conserved to a greater extent than X4-tropic strains. X4-tropic strains were obtained from subjects who had a significantly longer time since HIV diagnosis (96.5 months compared to R5-tropic strains (20.5 months. Conclusions High prevalence of R5 tropism and greater homogeneity of the V3 sequence among HIV-1 subtype C strains in India suggests the potential benefit of CCR5 antagonists as a therapeutic option in India.

  7. MEK/ERK activation plays a decisive role in yellow fever virus replication: implication as an antiviral therapeutic target.

    Science.gov (United States)

    Albarnaz, Jonas D; De Oliveira, Leonardo C; Torres, Alice A; Palhares, Rafael M; Casteluber, Marisa C; Rodrigues, Claudiney M; Cardozo, Pablo L; De Souza, Aryádina M R; Pacca, Carolina C; Ferreira, Paulo C P; Kroon, Erna G; Nogueira, Maurício L; Bonjardim, Cláudio A

    2014-11-01

    Exploiting the inhibition of host signaling pathways aiming for discovery of potential antiflaviviral compounds is clearly a beneficial strategy for the control of life-threatening diseases caused by flaviviruses. Here we describe the antiviral activity of the MEK1/2 inhibitor U0126 against Yellow fever virus 17D vaccine strain (YFV-17D). Infection of VERO cells with YFV-17D stimulates ERK1/2 phosphorylation early during infection. Pharmacological inhibition of MEK1/2 through U0126 treatment of VERO cells blockades not only the YFV-stimulated ERK1/2 phosphorylation, but also inhibits YFV replication by ∼99%. U0126 was also effective against dengue virus (DENV-2 and -3) and Saint-Louis encephalitis virus (SLEV). Levels of NS4AB, as detected by immunofluorescence, are diminished upon treatment with the inhibitor, as well as the characteristic endoplasmic reticulum membrane invagination stimulated during the infection. Though not protective, treatment of YFV-infected, adult BALB/c mice with U0126 resulted in significant reduction of virus titers in brains. Collectively, our data suggest the potential targeting of the MEK1/2 kinase as a therapeutic tool against diseases caused by flaviviruses such as yellow fever, adverse events associated with yellow fever vaccination and dengue. Copyright © 2014 Elsevier B.V. All rights reserved.

  8. Different adaptations of IgG effector function in human and nonhuman primates and implications for therapeutic antibody treatment.

    Science.gov (United States)

    Warncke, Max; Calzascia, Thomas; Coulot, Michele; Balke, Nicole; Touil, Ratiba; Kolbinger, Frank; Heusser, Christoph

    2012-05-01

    Safety of human therapeutic Abs is generally assessed in nonhuman primates. Whereas IgG1 shows identical FcγR interaction and effector function profile in both species, fundamental differences in the IgG2 and IgG4 Ab subclasses were found between the two species. Granulocytes, the main effector cells against IgG2- and IgG4-opsonized bacteria and parasites, do not express FcγRIIIb, but show higher levels of FcγRII in cynomolgus monkey. In humans, IgG2 and IgG4 adapted a silent Fc region with weak binding to FcγR and effector functions, whereas, in contrast, cynomolgus monkey IgG2 and IgG4 display strong effector function as well as differences in IgG4 Fab arm exchange. To balance this shift toward activation, the cynomolgus inhibitory FcγRIIb shows strongly increased affinity for IgG2. In view of these findings, in vitro and in vivo results for human IgG2 and IgG4 obtained in the cynomolgus monkey have to be cautiously interpreted, whereas effector function-related effects of human IgG1 Abs are expected to be predictable for humans.

  9. The Role of Ovarian Sex Steroids in Metabolic Homeostasis, Obesity, and Postmenopausal Breast Cancer: Molecular Mechanisms and Therapeutic Implications

    Science.gov (United States)

    2015-01-01

    Obese postmenopausal women have an increased risk of breast cancer and are likely to have a worse prognosis than nonobese postmenopausal women. The cessation of ovarian function after menopause results in withdrawal of ovarian sex steroid hormones, estrogen, and progesterone. Accumulating evidence suggests that the withdrawal of estrogen and progesterone causes homeostasis imbalances, including decreases in insulin sensitivity and leptin secretion and changes in glucose and lipid metabolism, resulting in a total reduction in energy expenditure. Together with a decrease in physical activity and consumption of a high fat diet, these factors significantly contribute to obesity in postmenopausal women. Obesity may contribute to breast cancer development through several mechanisms. Obesity causes localized inflammation, an increase in local estrogen production, and changes in cellular metabolism. In addition, obese women have a higher risk of insulin insensitivity, and an increase in insulin and other growth factor secretion. In this review, we describe our current understanding of the molecular actions of estrogen and progesterone and their contributions to cellular metabolism, obesity, inflammation, and postmenopausal breast cancer. We also discuss how modifications of estrogen and progesterone actions might be used as a therapeutic approach for obesity and postmenopausal breast cancer. PMID:25866757

  10. Notch signaling change in pulmonary vascular remodeling in rats with pulmonary hypertension and its implication for therapeutic intervention.

    Science.gov (United States)

    Qiao, Lina; Xie, Liang; Shi, Kun; Zhou, Tongfu; Hua, Yimin; Liu, Hanmin

    2012-01-01

    Pulmonary hypertension (PH) is a fatal disease that lacks an effective therapy. Notch signaling pathway plays a crucial role in the angiogenesis and vascular remodeling. However, its roles in vascular remodeling in PH have not been well studied. In the current study, using hypoxia-induced PH model in rat, we examined the expression of Notch and its downstream factors. Then, we used vessel strip culture system and γ-secretase inhibitor DAPT, a Notch signaling inhibitor to determine the effect of Notch signaling in vascular remodeling and its potential therapeutic value. Our results indicated that Notch 1-4 were detected in the lung tissue with variable levels in different cell types such as smooth muscle cells and endothelial cells of pulmonary artery, bronchia, and alveoli. In addition, following the PH induction, all of Notch1, Notch3, Notch4 receptor, and downstream factor, HERP1 in pulmonary arteries, mRNA expressions were increased with a peak at 1-2 weeks. Furthermore, the vessel wall thickness from rats with hypoxia treatment increased after cultured for 8 days, which could be decreased approximately 30% by DAPT, accompanied with significant increase of expression level of apoptotic factors (caspase-3 and Bax) and transformation of vascular smooth muscle cell (VSMC) phenotype from synthetic towards contractile. In conclusion, the current study suggested Notch pathway plays an important role in pulmonary vascular remodeling in PH and targeting Notch signaling pathway could be a valuable approach to design new therapy for PH.

  11. Notch signaling change in pulmonary vascular remodeling in rats with pulmonary hypertension and its implication for therapeutic intervention.

    Directory of Open Access Journals (Sweden)

    Lina Qiao

    Full Text Available Pulmonary hypertension (PH is a fatal disease that lacks an effective therapy. Notch signaling pathway plays a crucial role in the angiogenesis and vascular remodeling. However, its roles in vascular remodeling in PH have not been well studied. In the current study, using hypoxia-induced PH model in rat, we examined the expression of Notch and its downstream factors. Then, we used vessel strip culture system and γ-secretase inhibitor DAPT, a Notch signaling inhibitor to determine the effect of Notch signaling in vascular remodeling and its potential therapeutic value. Our results indicated that Notch 1-4 were detected in the lung tissue with variable levels in different cell types such as smooth muscle cells and endothelial cells of pulmonary artery, bronchia, and alveoli. In addition, following the PH induction, all of Notch1, Notch3, Notch4 receptor, and downstream factor, HERP1 in pulmonary arteries, mRNA expressions were increased with a peak at 1-2 weeks. Furthermore, the vessel wall thickness from rats with hypoxia treatment increased after cultured for 8 days, which could be decreased approximately 30% by DAPT, accompanied with significant increase of expression level of apoptotic factors (caspase-3 and Bax and transformation of vascular smooth muscle cell (VSMC phenotype from synthetic towards contractile. In conclusion, the current study suggested Notch pathway plays an important role in pulmonary vascular remodeling in PH and targeting Notch signaling pathway could be a valuable approach to design new therapy for PH.

  12. Cribriform carcinoma mimicking breast abscess - case report. Diagnostic and therapeutic management.

    Science.gov (United States)

    Dobruch-Sobczak, Katarzyna; Roszkowska-Purska, Katarzyna; Chrapowicki, Eryk

    2013-06-01

    The authors presents a case of cribriform breast carcinoma in a cyst that clinically imitated an abscess. The case concerns a 71-year-old female patient treated for ankylosing spondylitis, with a positive family history of breast cancer. The patient presented at the surgical clinic for incision of an abscess of the mammary gland localized in the lower inner quadrant that was a consequence of previous trauma to the right breast. The abscess was incised and the serosanguineous contents were evacuated. The wound was drained and antibiotics (Dalacin with Metronidazol) were administered for the period of 10 days. During the treatment, a cutaneous fistula was formed. At the incision site, a hard thickening was palpable (tumor). Core needle biopsy of the clinically palpable tumor was performed and the purulent material from the fistula was collected for a culture test. Complete blood count did not reveal leucocytosis. In accordance with the obtained sensitivity report, the patient was started on antibiotics again. Breast ultrasound performed upon the completion of the antibiotic therapy, in the right breast, revealed two solidcystic oval lesions with thick echogenic walls and blurred margins. Both masses contained dense levels of fluid material and solid polycyclic structures. On sonoelastography, the lesions were heterogeneous with a high Young's modulus. In the right axillary fossa, ultrasound examination revealed three abnormal lymph nodes enlarged to 31 mm length, which were rounded, hypoechoic and without visible sinuses. Histopathology of the core needle biopsy performed at admittance and after the antibiotic therapy indicated a breast abscess (presence of fibrinous and partly fibrinopurulent material). The mass was finally resected to confirm histopathology. The resected material revealed the presence of an invasive, moderately differentiated cribriform carcinoma, which developed within a cyst, with a 40% necrotic component. Eighteen months after the commencement

  13. Emerging evidence on the crystalline water-light interface in ophthalmology and therapeutic implications in photobiomodulation: first communication.

    Science.gov (United States)

    Rodríguez-Santana, Elizabeth; Santana-Blank, Luis

    2014-04-01

    The purpose of this study was to present preliminary evidence of the exclusion zone (EZ) and photobiomodulation (PBM) phenomena relating to ophthalmology. Water is the main media and fluid found in ocular tissues. Water is also an important photoacceptor and energy storage medium. Eyes are abundantly exposed to environmental radiant energy. Therefore, multiple light-energy-absorption mechanisms may exist, including those associated with the recently discovered fourth phase of water, known as EZ. Retrospective analysis of published data indicative of EZ phenomena related, in this first communication, to the retina and optic nerve (ON), using surgical microscopy and diffusion-weighted magnetic resonance imaging (MRI). Images showing removal of the internal limiting membrane (ILM) aided by preservative-free triamcinolone acetonide (TA) during macular hole surgery show continuous whitish lines indicative of water-layer ordering at the interface between collagen matrices and TA crystals. Apparent diffusion coefficient (ADC) results further exhibit an axis parallel to the ON, which may be an ocular expression of the EZ linked to the steady potential of the eye. Although existing results are still being decoded and analyzed in light of the state of the art studies of light-water interactions, they suggest a new understanding of the eye's bioenergetic environment, which may have deep implications in ocular physiology as well as in the pathophysiology, diagnosis, and treatment of blinding diseases using light-based therapies such as photobiomodulation. Research is needed to confirm the interpretation of these findings and validate potential ophthalmic applications.

  14. Hypermethylation of BRCA1 gene: implication for prognostic biomarker and therapeutic target in sporadic primary triple-negative breast cancer.

    Science.gov (United States)

    Zhu, X; Shan, L; Wang, F; Wang, J; Wang, F; Shen, G; Liu, X; Wang, B; Yuan, Y; Ying, J; Yang, H

    2015-04-01

    Paraffin sections from 239 cases of surgical resected mammary gland carcinomas were assessed to determine the role of BRCA1 gene methylation in sporadic triple-negative breast cancer and to evaluate the relationship between BRCA1 gene methylation and clinicopathologic features of triple-negative breast cancer in the National Cancer Center, China. Diagnostic tissues collected from patients received mastectomy in the National Cancer Center from January 1, 1999 to December 31, 2008 were reviewed. Tissue microarrays were constructed using 239 triple-negative breast cancer cases and stained with estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, cytokeratin 5/6, and epidermal growth factor receptor. Methylation status of the BRCA1 promoter was measured by methylation-specific PCR and analyzed against clinicopathologic characteristics, subtypes, and prognosis using standard statistical methods. Among the 239 triple-negative breast cancer cases, 137 (57.3 %) showed methylation of the BRCA1. According to the immunohistochemistry results, triple-negative breast cancer cases were classified into basal-like breast cancer (60.7 %) and non-basal-like breast cancer (39.3 %). The frequency of BRCA1 methylation was significantly higher in basal-like breast cancer subtype (71.7 %) than the non-basal subtype (35.1 %). Thus, BRCA1 methylation is statistically significantly correlated with basal-like breast cancer subtype (p breast cancer. Here we demonstrated that epigenetic alteration of key tumor suppressor gene can be a promising biomarker for the prognosis of triple-negative breast cancer/basal-like breast cancer. Specifically our finding revealed that BRCA1 methylation is closely associated with a significant decrease in overall survival and disease-free survival, highlighting BRCA1 promoter methylation as promising and powerful biomarkers for effect and better prognosis of DNA damaging agents for triple-negative breast cancer/basal-like breast

  15. Therapeutic effect of Mercurius solubilis on immune status of a borderline leprosy case

    Directory of Open Access Journals (Sweden)

    Dhruba Chakraborty

    2014-01-01

    Full Text Available A Borderline Lepromatous (BL leprosy case was treated with Mercurius solubilis, a homoeopathic medicine for two years. The clinical, immunological and histological assessment of the patient before and after treatment was recorded. The patient showed appreciable improvement in clinical signs and symptoms. Lesions on the skin almost disappeared; no swelling of hand and feet was noted along with disappearance of infiltration on eye brows. Nodular lesions on both the ear lobes diminished remarkably. Regain of sensation to touch, pain and pressure were noted and their test responses were normal. Slit skin smears were negative from all sites with 0 Bacteriological Index [BI] which was positive for acid fast bacilli [AFB] with an average of 4+ BI before treatment. Histologic study revealed absence of granuloma in dermis except the presence of occasional clusters of lymphocytes. Lepromin reaction which was negative before treatment was positive with 14 mm after 2 years of treatment. Estimation of different cytokines after completion of treatment showed appreciable changes with remarkable reduction in the levels of proinflammatory cytokines (IFN and TNF.

  16. Manufacturing Economics of Plant-Made Biologics: Case Studies in Therapeutic and Industrial Enzymes

    Science.gov (United States)

    Tusé, Daniel; McDonald, Karen A.

    2014-01-01

    Production of recombinant biologics in plants has received considerable attention as an alternative platform to traditional microbial and animal cell culture. Industrially relevant features of plant systems include proper eukaryotic protein processing, inherent safety due to lack of adventitious agents, more facile scalability, faster production (transient systems), and potentially lower costs. Lower manufacturing cost has been widely claimed as an intuitive feature of the platform by the plant-made biologics community, even though cost information resides within a few private companies and studies accurately documenting such an advantage have been lacking. We present two technoeconomic case studies representing plant-made enzymes for diverse applications: human butyrylcholinesterase produced indoors for use as a medical countermeasure and cellulases produced in the field for the conversion of cellulosic biomass into ethanol as a fuel extender. Production economics were modeled based on results reported with the latest-generation expression technologies on Nicotiana host plants. We evaluated process unit operations and calculated bulk active and per-dose or per-unit costs using SuperPro Designer modeling software. Our analyses indicate that substantial cost advantages over alternative platforms can be achieved with plant systems, but these advantages are molecule/product-specific and depend on the relative cost-efficiencies of alternative sources of the same product. PMID:24977145

  17. Intrathecal baclofen pump, useful and safe therapeutic intervention in spasticity? Report of four cases

    Directory of Open Access Journals (Sweden)

    Cáceres-Jerez, Luz Elena

    2016-10-01

    Full Text Available Spasticity may cause immobility, prostration, chronic pain, bedsores, infections, thrombosis and pneumonia; the purposes of its treatment are to control pain, improve mobility and quality of life, and reincorporate the patient to its daily activities by means of oral anti-spastic drugs; however, patients suffering from severe spasticity may require high oral doses of these medications, which may lead to adverse effects. In such cases, intrathecal baclofen has been proposed as a solution. This procedure has not been widely used in Colombia, so that protocols to perform it have not been established. We report the results obtained with the intrathecal administration of baclofen in four severely spastic patients, who had not previously responded to oral anti-spastic drugs, including high doses of baclofen. Pain, spasticity and quality of life significantly improved in three of them. The remaining one presented tolerance to the medication. Intrathecal baclofen pump is a useful and safe procedure for patients with severe spasticity and poor response to oral treatment.

  18. Manufacturing Economics of Plant-Made Biologics: Case Studies in Therapeutic and Industrial Enzymes

    Directory of Open Access Journals (Sweden)

    Daniel Tusé

    2014-01-01

    Full Text Available Production of recombinant biologics in plants has received considerable attention as an alternative platform to traditional microbial and animal cell culture. Industrially relevant features of plant systems include proper eukaryotic protein processing, inherent safety due to lack of adventitious agents, more facile scalability, faster production (transient systems, and potentially lower costs. Lower manufacturing cost has been widely claimed as an intuitive feature of the platform by the plant-made biologics community, even though cost information resides within a few private companies and studies accurately documenting such an advantage have been lacking. We present two technoeconomic case studies representing plant-made enzymes for diverse applications: human butyrylcholinesterase produced indoors for use as a medical countermeasure and cellulases produced in the field for the conversion of cellulosic biomass into ethanol as a fuel extender. Production economics were modeled based on results reported with the latest-generation expression technologies on Nicotiana host plants. We evaluated process unit operations and calculated bulk active and per-dose or per-unit costs using SuperPro Designer modeling software. Our analyses indicate that substantial cost advantages over alternative platforms can be achieved with plant systems, but these advantages are molecule/product-specific and depend on the relative cost-efficiencies of alternative sources of the same product.

  19. Avermectins differentially affect ethanol intake and receptor function: implications for developing new therapeutics for alcohol use disorders.

    Science.gov (United States)

    Asatryan, Liana; Yardley, Megan M; Khoja, Sheraz; Trudell, James R; Hyunh, Nhat; Louie, Stan G; Petasis, Nicos A; Alkana, Ronald L; Davies, Daryl L

    2014-06-01

    Our laboratory is investigating ivermectin (IVM) and other members of the avermectin family as new pharmaco-therapeutics to prevent and/or treat alcohol use disorders (AUDs). Earlier work found that IVM significantly reduced ethanol intake in mice and that this effect likely reflects IVM's ability to modulate ligand-gated ion channels. We hypothesized that structural modifications that enhance IVM's effects on key receptors and/or increase its brain concentration should improve its anti-alcohol efficacy. We tested this hypothesis by comparing the abilities of IVM and two other avermectins, abamectin (ABM) and selamectin (SEL), to reduce ethanol intake in mice, to alter modulation of GABAARs and P2X4Rs expressed in Xenopus oocytes and to increase their ability to penetrate the brain. IVM and ABM significantly reduced ethanol intake and antagonized the inhibitory effects of ethanol on P2X4R function. In contrast, SEL did not affect either measure, despite achieving higher brain concentrations than IVM and ABM. All three potentiated GABAAR function. These findings suggest that chemical structure and effects on receptor function play key roles in the ability of avermectins to reduce ethanol intake and that these factors are more important than brain penetration alone. The direct relationship between the effect of these avermectins on P2X4R function and ethanol intake suggest that the ability to antagonize ethanol-mediated inhibition of P2X4R function may be a good predictor of the potential of an avermectin to reduce ethanol intake and support the use of avermectins as a platform for developing novel drugs to prevent and/or treat AUDs.

  20. Evaluation of the activated partial thromboplastin time (APTT) sensitivity to heparin using five commercial reagents: implications for therapeutic monitoring.

    Science.gov (United States)

    Manzato, F; Mengoni, A; Grilenzoni, A; Lippi, G

    1998-12-01

    Heparin is an effective drug for prevention and treatment of thromboembolic conditions. Although several biological assays have been proposed for monitoring unfractionated heparin therapy, the measurement of the activated partial thromboplastin time (APTT) is the most widely employed test, and the overall risk of thromboembolic episodes was markedly reduced by maintaining APTT ratios above 1.5. However, the adjustment of the heparin therapy on the basis of APTT presents several questions which are still unresolved. Major discrepancies were found in APTTs performed using different reagents in both ex vivo and in vitro heparinized samples and occasionally with different lots of the same reagents; poor correlation was observed between APTT values and plasma heparin concentrations. In order to gain further insights into this phenomenon, we analysed the sensitivity to heparin of five commercial reagents for APTT measurement in 19 ex vivo heparinized samples. Differences were observed; correlation coefficients ranged from 0.820 to 0.985 and slopes of linear regressions from 0.26 to 1.14. Moreover, unsatisfactory correlations were obtained when APTT ratios were compared with heparin plasma concentrations in the same patients' samples. In the heparin therapeutic range of 0.35 - 0.70 U/ml, reagent-dependent differences were observed in the corresponding APTT values. These results point out a critical role of the assay methodology in monitoring heparin therapy by APTT. We suggest that reference materials and methods should be urgently identified, a universally agreed scale for reporting results should be established and reference ranges for the unfractionated heparin therapy should be reconsidered taking on account the reagent employed.

  1. Human transporters, PEPT1/2, facilitate melatonin transportation into mitochondria of cancer cells: An implication of the therapeutic potential.

    Science.gov (United States)

    Huo, Xiaokui; Wang, Chao; Yu, Zhenlong; Peng, Yulin; Wang, Shumei; Feng, Shengnan; Zhang, Shouji; Tian, Xiangge; Sun, Chengpeng; Liu, Kexin; Deng, Sa; Ma, Xiaochi

    2017-05-01

    Melatonin is present in virtually all organisms from bacteria to mammals, and it exhibits a broad spectrum of biological functions, including synchronization of circadian rhythms and oncostatic activity. Several functions of melatonin are mediated by its membrane receptors, but others are receptor-independent. For the latter, melatonin is required to penetrate membrane and enters intracellular compartments. However, the mechanism by which melatonin enters cells remains debatable. In this study, it was identified that melatonin and its sulfation metabolites were the substrates of oligopeptide transporter (PEPT) 1/2 and organic anion transporter (OAT) 3, respectively. The docking analysis showed that the binding of melatonin to PEPT1/2 was attributed to their low binding energy and suitable binding conformation in which melatonin was embedded in the active site of PEPT1/2 and fitted well with the cavity in three-dimensional space. PEPT1/2 transporters play a pivotal role in melatonin uptake in cells. Melatonin's membrane transportation via PEPT1/2 renders its oncostatic effect in malignant cells. For the first time, PEPT1/2 were identified to localize in the mitochondrial membrane of human cancer cell lines of PC3 and U118. PEPT1/2 facilitated the transportation of melatonin into mitochondria. Melatonin accumulation in mitochondria induced apoptosis of PC3 and U118 cells. Thus, PEPT1/2 can potentially be used as a cancer cell-targeted melatonin delivery system to improve the therapeutic effects of melatonin in cancer treatment. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  2. Effect of enoxaparin and onion extract on human skin fibroblast cell line - therapeutic implications for the treatment of keloids.

    Science.gov (United States)

    Pikuła, Michał; Żebrowska, Maria E; Pobłocka-Olech, Loretta; Krauze-Baranowska, Mirosława; Sznitowska, Małgorzata; Trzonkowski, Piotr

    2014-02-01

    Keloids and hypertrophic scars are hyperproliferative skin disorders resulting in abnormal wound healing. In the prevention and treatment of keloids and hypertrophic scars, ointments containing heparin and onion extract are very popular. Their therapeutic effects, however, are still controversial and the mechanism of action is not fully understood. The aim of this study was to assess the effect of enoxaparin and dry onion extract on proliferation, apoptosis and β1 integrin expression in human fibroblasts. Fibroblast human cell lines (46 BR.1 N) were treated for 48 h with various concentrations of enoxaparin sodium (20, 100, 500 µg/mL) and/or onion [Allium cepa L. (Alliaceae)] extract (50, 250, 1000 µg/mL). The cell proliferation was evaluated by [(3)H]-thymidine incorporation assay. Furthermore, the expression of β1 integrin and apoptosis was determined by flow cytometry. The results demonstrate that enoxaparin and onion extract inhibited the proliferation of human fibroblasts. Almost complete inhibition of cell proliferation was achieved by enoxaparin in 500 µg/mL concentration (91.5% reduction). The onion extract at a concentration of 250 µg/mL also strongly inhibited the proliferation of cells (50.8% reduction). Depending on concentration, enoxaparin and onion extract induced apoptosis (500 and 1000 µg/mL, respectively) and, depending on concentration, downregulated the expression of β1 integrin on human fibroblasts. This work points at possible mechanism of action of enoxaparin and onion extract, when administered in the treatment of patients with keloids and hypertrophic scars.

  3. Avermectins differentially affect ethanol intake and receptor function: Implications for developing new therapeutics for alcohol use disorders

    Science.gov (United States)

    Asatryan, Liana; Yardley, Megan M.; Khoja, Sheraz; Trudell, James R.; Hyunh, Nhat; Louie, Stan G.; Petasis, Nicos A.; Alkana, Ronald L.; Davies, Daryl L.

    2014-01-01

    Our laboratory is investigating ivermectin (IVM) and other members of the avermectin family as new pharmaco-therapeutics to prevent and/or treat alcohol use disorders (AUDs). Prior work found that IVM significantly reduced ethanol intake in mice and that this effect likely reflects IVM’s ability to modulate ligand-gated ion channels. We hypothesized that structural modifications that enhance IVM’s effects on key receptors and/or increase its brain concentration should improve its anti-alcohol efficacy. We tested this hypothesis by comparing the abilities of IVM and two other avermectins, abamectin (ABM) and selamectin (SEL), to reduce ethanol intake in mice, to alter modulation of GABA ARs and P2X4Rs expressed in Xenopus oocytes and to increase their ability to penetrate the brain. IVM and ABM significantly reduced ethanol intake and antagonized the inhibitory effects of ethanol on P2X4R function. In contrast, SEL did not affect either measure, despite achieving higher brain concentrations than IVM and ABM. All three potentiated GABAA receptor function. These findings suggest that chemical structure and effects on receptor function play key roles in the ability of avermectins to reduce ethanol intake and that these factors are more important than brain penetration alone. The direct relationship between the effect of these avermectins on P2X4R function and ethanol intake suggest that the ability to antagonize ethanol-mediated inhibition of P2X4R function may be a good predictor of the potential of an avermectin to reduce ethanol intake and support the use of avermectins as a platform for developing novel drugs to prevent and/or treat AUDs. PMID:24451653

  4. The Role and Potential Therapeutic Implications of the Fibroblast Growth Factors in Energy Balance and Type 2 Diabetes.

    Science.gov (United States)

    Izaguirre, Maitane; Gil, María J; Monreal, Ignacio; Montecucco, Fabrizio; Frühbeck, Gema; Catalán, Victoria

    2017-06-01

    Obesity and its associated metabolic diseases have reached epidemic proportions worldwide, reducing life expectancy and quality of life. Several drugs have been tested to treat these diseases but many of them have damaging side effects. Consequently, there is an urgent need to develop more effective therapies. Recently, endocrine fibroblast growth factors (FGFs) have become attractive targets in the treatment of metabolic diseases. This review summarizes their most important functions as well as FGF-based therapies for the treatment of obesity and type 2 diabetes (T2D). Recent studies demonstrate that circulating levels of FGF19 are reduced in obesity. In fact, exogenous FGF19 administration is associated with a reduction in food intake as well as with improvements in glycaemia. In contrast, FGF21 levels are elevated in subjects with abdominal obesity, insulin resistance and T2D, probably representing a compensatory response. Additionally, elevated levels of circulating FGF23 in individuals with obesity and T2D are reported in most clinical studies. Finally, increased FGF1 levels in obese patients associated with adipogenesis have been described. FGFs constitute important molecules in the treatment of metabolic diseases due to their beneficial effects on glucose and lipid metabolism. Among all members, FGF19 and FGF21 have demonstrated the ability to improve glucose, lipid and energy homeostasis, along with FGF1, which was recently discovered to have beneficial effects on metabolic homeostasis. Additionally, FGF23 may also play a role in insulin resistance or energy homeostasis beyond mineral metabolism control. These results highlight the relevant use of FGFs as potential biomarkers for the early diagnosis of metabolic diseases. In this regard, notable progress has been made in the development of FGF-based therapies and different approaches are being tested in different clinical trials. However, further studies are needed to determine their potential therapeutic

  5. Triple-negative breast cancer risk in women is defined by the defect of estrogen signaling: preventive and therapeutic implications

    Directory of Open Access Journals (Sweden)

    Suba Z

    2014-01-01

    Full Text Available Zsuzsanna Suba National Institute of Oncology, Surgical and Molecular Tumor Pathology Centre, Budapest, Hungary Abstract: Epidemiologic studies strongly support that triple-negative breast cancers (TNBCs may be distinct entities as compared with estrogen receptor (ER+ tumors, suggesting that the etiologic factors, clinical characteristics, and therapeutic possibilities may vary by molecular subtypes. Many investigations propose that reproductive factors and exogenous hormone use differently or even quite inversely affect the risk of TNBCs and ER+ cancers. Controversies concerning the exact role of even the same risk factor in TNBC development justify that the biological mechanisms behind the initiation of both TNBCs and non-TNBCs are completely obscure. To arrive at a comprehensive understanding of the etiology of different breast cancer subtypes, we should also reconsider our traditional concepts and beliefs regarding cancer risk factors. Malignancies are multicausal, but the disturbance of proper estrogen signaling seems to be a crucial risk factor for the development of mammary cancers. The grade of defect in metabolic and hormonal equilibrium is directly associated with TNBC risk for women during their whole life. Inverse impact of menopausal status or parity on the development of ER+ and ER- breast cancers may not be possible; these controversial results derive from the misinterpretation of percentage-based statistical evaluations. Exogenous or parity-associated excessive estrogen supply is suppressive against breast cancer, though the lower the ER expression of tumors, the weaker the anticancer capacity. In women, the most important preventive strategy against breast cancers – included TNBCs – is the strict control and maintenance of hormonal equilibrium from early adolescence through the whole lifetime, particularly during the periods of great hormonal changes. Keywords: cancer prevention, infertility, insulin resistance, menopause

  6. Triple-negative breast cancer risk in women is defined by the defect of estrogen signaling: preventive and therapeutic implications

    Science.gov (United States)

    Suba, Zsuzsanna

    2014-01-01

    Epidemiologic studies strongly support that triple-negative breast cancers (TNBCs) may be distinct entities as compared with estrogen receptor (ER)+ tumors, suggesting that the etiologic factors, clinical characteristics, and therapeutic possibilities may vary by molecular subtypes. Many investigations propose that reproductive factors and exogenous hormone use differently or even quite inversely affect the risk of TNBCs and ER+ cancers. Controversies concerning the exact role of even the same risk factor in TNBC development justify that the biological mechanisms behind the initiation of both TNBCs and non-TNBCs are completely obscure. To arrive at a comprehensive understanding of the etiology of different breast cancer subtypes, we should also reconsider our traditional concepts and beliefs regarding cancer risk factors. Malignancies are multicausal, but the disturbance of proper estrogen signaling seems to be a crucial risk factor for the development of mammary cancers. The grade of defect in metabolic and hormonal equilibrium is directly associated with TNBC risk for women during their whole life. Inverse impact of menopausal status or parity on the development of ER+ and ER− breast cancers may not be possible; these controversial results derive from the misinterpretation of percentage-based statistical evaluations. Exogenous or parity-associated excessive estrogen supply is suppressive against breast cancer, though the lower the ER expression of tumors, the weaker the anticancer capacity. In women, the most important preventive strategy against breast cancers – included TNBCs – is the strict control and maintenance of hormonal equilibrium from early adolescence through the whole lifetime, particularly during the periods of great hormonal changes. PMID:24482576

  7. Mechanisms for food polyphenols to ameliorate insulin resistance and endothelial dysfunction: therapeutic implications for diabetes and its cardiovascular complications.

    Science.gov (United States)

    Munir, Kashif M; Chandrasekaran, Sruti; Gao, Feng; Quon, Michael J

    2013-09-15

    The rising epidemic of diabetes is a pressing issue in clinical medicine worldwide from both healthcare and economic perspectives. This is fueled by overwhelming increases in the incidence and prevalence of obesity. Obesity and diabetes are characterized by both insulin resistance and endothelial dysfunction that lead to substantial increases in cardiovascular morbidity and mortality. Reciprocal relationships between insulin resistance and endothelial dysfunction tightly link metabolic diseases including obesity and diabetes with their cardiovascular complications. Therefore, therapeutic approaches that target either insulin resistance or endothelial dysfunction alone are likely to simultaneously improve both metabolic and cardiovascular pathophysiology and disease outcomes. Moreover, combination therapies with agents targeting distinct mechanisms are likely to have additive or synergistic benefits. Conventional therapies for diabetes and its cardiovascular complications that are both safe and effective are insufficient to meet rising demand. Large, robust, epidemiologic studies demonstrate beneficial metabolic and cardiovascular health effects for many functional foods containing various polyphenols. However, precise molecular mechanisms of action for food polyphenols are largely unknown. Moreover, translation of these insights into effective clinical therapies has not been fully realized. Nevertheless, some functional foods are likely sources for safe and effective therapies and preventative strategies for metabolic diseases and their cardiovascular complications. In this review, we emphasize recent progress in elucidating molecular, cellular, and physiological actions of polyphenols from green tea (EGCG), cocoa (ECG), and citrus fruits (hesperedin) that are related to improving metabolic and cardiovascular pathophysiology. We also discuss a rigorous comprehensive approach to studying functional foods that is essential for developing novel, effective, and safe

  8. Therapeutic implication of 'Iturin A' for targeting MD-2/TLR4 complex to overcome angiogenesis and invasion.

    Science.gov (United States)

    Dey, Goutam; Bharti, Rashmi; Ojha, Probir Kumar; Pal, Ipsita; Rajesh, Y; Banerjee, Indranil; Banik, Payel; Parida, Sheetal; Parekh, Aditya; Sen, Ramkrishna; Mandal, Mahitosh

    2017-07-01

    Tumor angiogenesis and invasion are deregulated biological processes that drive multistage transformation of tumors from a benign to a life-threatening malignant state activating multiple signaling pathways including MD-2/TLR4/NF-κB. Development of potential inhibitors of this signaling is emerging area for discovery of novel cancer therapeutics. In the current investigation, we identified Iturin A (A lipopeptide molecule from Bacillus megaterium) as a potent inhibitor of angiogenesis and cancer invasion by various in vitro and in vivo methods. Iturin A was found to suppress VEGF, a powerful inducer of angiogenesis and key player in tumor invasion, as confirmed by ELISA, western blot and real time PCR. Iturin A inhibited endothelial tube arrangement, blood capillary formation, endothelial sprouting and vascular growth inside the matrigel. In addition, Iturin A inhibited MMP-2/9 expression in MDA-MB-231 and HUVEC cells. Cancer invasion, migration and colony forming ability were significantly hampered by Iturin A. Expressions of MD-2/TLR4 and its downstream MyD88, IKK-α and NF-κB were also reduced in treated MDA-MB-231 and HUVEC cells. Western blot and immunofluorescence study showed that nuclear accumulation of NF-κB was hampered by Iturin A. MD-2 siRNA or plasmid further confirmed the efficacy of Iturin A by suppressing MD-2/TLR4 signaling pathway. The in silico docking study showed that the Iturin A interacted well with the MD-2 in MD-2/TLR4 receptor complex. Conclusively, inhibition of MD-2/TLR4 complex with Iturin A offered strategic advancement in cancer therapy. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Cribriform carcinoma mimicking breast abscess – case report. Diagnostic and therapeutic management

    Directory of Open Access Journals (Sweden)

    Katarzyna Dobruch‑Sobczak

    2013-06-01

    Full Text Available The authors presents a case of cribriform breast carcinoma in a cyst that clinically imitated an abscess. The case concerns a 71-year-old female patient treated for ankylosing spondylitis, with a positive family history of breast cancer. The patient presented at the surgical clinic for incision of an abscess of the mammary gland localized in the lower inner quadrant that was a consequence of previous trauma to the right breast. The abscess was incised and the serosanguineous contents were evacuated. The wound was drained and antibiotics (Dalacin with Metronidazol were administered for the period of 10 days. During the treatment, a cutaneous fistula was formed. At the incision site, a hard thickening was palpable (tumor. Core needle biopsy of the clinically palpable tumor was performed and the purulent material from the fistula was collected for a culture test. Complete blood count did not reveal leucocytosis. In accordance with the obtained sensitivity report, the patient was started on antibiotics again. Breast ultrasound performed upon the completion of the antibiotic therapy, in the right breast, revealed two solidcystic oval lesions with thick echogenic walls and blurred margins. Both masses contained dense levels of fluid material and solid polycyclic structures. On sonoelastography, the lesions were heterogeneous with a high Young’s modulus. In the right axillary fossa, ultrasound examination revealed three abnormal lymph nodes enlarged to 31 mm length, which were rounded, hypoechoic and without visible sinuses. Histopathology of the core needle biopsy performed at admittance and after the antibiotic therapy indicated a breast abscess (presence of fibrinous and partly fibrinopurulent material. The mass was finally resected to confirm histopathology. The resected material revealed the presence of an invasive, moderately differentiated cribriform carcinoma, which developed within a cyst, with a

  10. Rapid Treatment of Leukostasis in Leukemic Mantle Cell Lymphoma Using Therapeutic Leukapheresis: A Case Report

    Directory of Open Access Journals (Sweden)

    Xuan Duc Nguyen

    2011-01-01

    Full Text Available We describe a case of severe leukocytosis caused by leukemic mantle cell lymphoma (MCL, complicated by leukostasis with myocardial infarction in which leukapheresis was used in the initial management. A 73-year-old male presented to the emergency department because of fatigue and thoracic pain. Blood count revealed 630 × 109/L WBC (white blood cells. The electrocardiogram showed ST-elevation with an increase of troponin and creatinine kinase. The diagnosis was ST-elevation myocardial infarction (STEMI induced and complicated by leukostasis. Immunophenotyping, morphology, cytogenetic and fluorescence-in-situ-hybridization analysis revealed the diagnosis of a blastoid variant of MCL. To remove leukocytes rapidly, leukapheresis was performed in the intensive care unit. Based on the differential blood count with 95% blasts, which were assigned to the lymphocyte population by the automatic hematology analyzer, leukapheresis procedures were then performed with the mononuclear cell standard program on the Spectra cell separator. The patient was treated with daily leukapheresis for 3 days. The WBC count decreased to 174 × 109/L after the third leukapheresis, with a 72% reduction. After the second apheresis, treatment with vincristine, cyclophosphamide, and prednisolone was started. The patient fully recovered in the further course of the treatment. To the best of our knowledge, this is the first report on blastoid MCL with leukostasis associated with a STEMI that was successfully treated by leukapheresis. Effective harvest of circulating lymphoma cells by leukapheresis requires adaptation of instrument settings based on the results of the differential blood count prior to apheresis.

  11. Transcriptomic analysis in a Drosophila model identifies previously implicated and novel pathways in the therapeutic mechanism in neuropsychiatric disorders

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    Priyanka eSingh

    2011-03-01

    Full Text Available We have taken advantage of a newly described Drosophila model to gain insights into the potential mechanism of antiepileptic drugs (AEDs, a group of drugs that are widely used in the treatment of several neurological and psychiatric conditions besides epilepsy. In the recently described Drosophila model that is inspired by pentylenetetrazole (PTZ induced kindling epileptogenesis in rodents, chronic PTZ treatment for seven days causes a decreased climbing speed and an altered CNS transcriptome, with the latter mimicking gene expression alterations reported in epileptogenesis. In the model, an increased climbing speed is further observed seven days after withdrawal from chronic PTZ. We used this post-PTZ withdrawal regime to identify potential AED mechanism. In this regime, treatment with each of the five AEDs tested, namely, ethosuximide (ETH, gabapentin (GBP, vigabatrin (VGB, sodium valproate (NaVP and levetiracetam (LEV, resulted in rescuing of the altered climbing behavior. The AEDs also normalized PTZ withdrawal induced transcriptomic perturbation in fly heads; whereas AED untreated flies showed a large number of up- and down-regulated genes which were enriched in several processes including gene expression and cell communication, the AED treated flies showed differential expression of only a small number of genes that did not enrich gene expression and cell communication processes. Gene expression and cell communication related upregulated genes in AED untreated flies overrepresented several pathways - spliceosome, RNA degradation, and ribosome in the former category, and inositol phosphate metabolism, phosphatidylinositol signaling, endocytosis and hedgehog signaling in the latter. Transcriptome remodeling effect of AEDs was overall confirmed by microarray clustering that clearly separated the profiles of AED treated and untreated flies. Besides being consistent with previously implicated pathways, our results provide evidence for a role of

  12. Immunophenotyping of Waldenstroms macroglobulinemia cell lines reveals distinct patterns of surface antigen expression: potential biological and therapeutic implications.

    Directory of Open Access Journals (Sweden)

    Aneel Paulus

    therapeutic exploit.

  13. A Case Study with an Identified Bully: Policy and Practice Implications

    OpenAIRE

    Huddleston, Lillie; Varjas, Kris; Meyers, Joel; Cadenhead, Catherine

    2011-01-01

    Objective: Bullying is a serious public health problem that may include verbal or physical injury as well as social isolation or exclusion. As a result, research is needed to establish a database for policies and interventions designed to prevent bullying and its negative effects. This paper presented a case study that contributed to the literature by describing an intervention for bullies that has implications for research, practice and related policies regarding bullying.Methods: An individ...

  14. Concise Review: Reprogramming, Behind the Scenes: Noncanonical Neural Stem Cell Signaling Pathways Reveal New, Unseen Regulators of Tissue Plasticity With Therapeutic Implications.

    Science.gov (United States)

    Poser, Steven W; Chenoweth, Josh G; Colantuoni, Carlo; Masjkur, Jimmy; Chrousos, George; Bornstein, Stefan R; McKay, Ronald D; Androutsellis-Theotokis, Andreas

    2015-11-01

    Interest is great in the new molecular concepts that explain, at the level of signal transduction, the process of reprogramming. Usually, transcription factors with developmental importance are used, but these approaches give limited information on the signaling networks involved, which could reveal new therapeutic opportunities. Recent findings involving reprogramming by genetic means and soluble factors with well-studied downstream signaling mechanisms, including signal transducer and activator of transcription 3 (STAT3) and hairy and enhancer of split 3 (Hes3), shed new light into the molecular mechanisms that might be involved. We examine the appropriateness of common culture systems and their ability to reveal unusual (noncanonical) signal transduction pathways that actually operate in vivo. We then discuss such novel pathways and their importance in various plastic cell types, culminating in their emerging roles in reprogramming mechanisms. We also discuss a number of reprogramming paradigms (mouse induced pluripotent stem cells, direct conversion to neural stem cells, and in vivo conversion of acinar cells to β-like cells). Specifically for acinar-to-β-cell reprogramming paradigms, we discuss the common view of the underlying mechanism (involving the Janus kinase-STAT pathway that leads to STAT3-tyrosine phosphorylation) and present alternative interpretations that implicate STAT3-serine phosphorylation alone or serine and tyrosine phosphorylation occurring in sequential order. The implications for drug design and therapy are important given that different phosphorylation sites on STAT3 intercept different signaling pathways. We introduce a new molecular perspective in the field of reprogramming with broad implications in basic, biotechnological, and translational research. Reprogramming is a powerful approach to change cell identity, with implications in both basic and applied biology. Most efforts involve the forced expression of key transcription

  15. Esophageal involvement is frequent in lichen planus: study in 32 patients with suggestion of clinicopathologic diagnostic criteria and therapeutic implications.

    Science.gov (United States)

    Kern, Johannes S; Technau-Hafsi, Kristin; Schwacha, Henning; Kuhlmann, Jan; Hirsch, Gunther; Brass, Volker; Deibert, Peter; Schmitt-Graeff, Anette; Kreisel, Wolfgang

    2016-12-01

    Lichen planus (LP) is a classic skin disease that can involve the skin, hair, and nails, as well as the oral and genital mucosa. Histopathology is characterized by a T-lymphocytic, lichenoid, and interface dermatitis. Multiple case reports and small case series have shown that LP can involve the esophagus. However, the diagnostic criteria, incidence, and best treatment options remain uncertain. This study aimed to refine the diagnostic criteria, estimate prevalence, and present an outlook on treatment options to prevent long-term sequelae. Thirty-two consecutive patients with LP of the skin, hair, nails, oral mucosa, and/or genital mucosa underwent a comprehensive clinicopathologic assessment. Esophagogastroduodenoscopy was performed, and biopsies were evaluated histologically, immunohistochemically, and by direct immunofluorescence. Patients diagnosed with esophageal lichen planus (ELP) were followed up prospectively where possible. In total, 20 of 32 patients had ELP. Ten of these 20 patients were classified as having proven ELP, with clear-cut endoscopically visible lesions; the other 10 were classified as having probable ELP. Eight of 10 patients with proven ELP were started on new or additional therapy because of esophageal findings. Treatment with a topical budesonide formulation or systemic corticosteroids was successful in most patients with proven ELP and reversed functional esophageal stenosis. ELP can be found in more than 50% of patients with proven mucocutaneous LP when clinical and pathologic findings are correlated carefully. Topical or systemic corticosteroids are the first-line therapy for ELP. Timely medical therapy seems to prevent scarring stenosis of the esophagus.

  16. Topical ALA-PDT as alternative therapeutic option in treatment-recalcitrant dermatosis: Report of 4 cases.

    Science.gov (United States)

    Theresia, Calvina; Zheng, Jie; Chen, Xiao-Ying

    2017-12-01

    Topical Photodynamic therapy (PDT) is widely acknowledged for its safety and effectiveness in treating oncologic skin diseases such as basal cell carcinoma, actinic keratosis and squamous cell carcinoma in situ. Despite its broad applications in dermatology, this method is a relatively new therapeutic option for treating inflammatory/infectious skin diseases. To determine whether topical PDT is a safe and effective treatment option in treating treatment-recalcitrant dermatosis. We presented one of each case of Acne Vulgaris, facial flat warts, urethral meatus Condyloma Acuminatum and extramammary Paget's disease, where other treatment options were either ineffective or not feasible, then those patients underwent topical PDT and showed significant improvement with minimal side effects. Topical PDT therapy may be applied in cases of Acne Vulgaris, facial flat warts, urethral meatus Condyloma Acuminatum and extramammary Paget's disease, where other treatment has shown no or minimal improvement, or in whom ablative or invasive procedure is to be avoided or not well tolerated. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. [The diagnostic and therapeutic challenges of bilateral renal oncocytosis : Illustrative case presentations and a review of the literature].

    Science.gov (United States)

    Janssen, M; Eckerl, M; Moersler, J; Rotter, M; May, M; Gilfrich, C

    2016-07-01

    Bilateral oncocytosis along with multiple tumours in both kidneys represents a very rare pathology that is accompanied by diagnostic and therapeutic challenges. We report the case of a 60-year old male patient who underwent computer tomography with incidental detection of multiple bilateral and contrast enhancing renal tumours of different size. Subsequently the patient underwent nephron-sparing tumor resection, first on the right side and 4 weeks later on the left side. The histology of all removed tumors showed evidence of pure oncocytoma. There were no postoperative complications and renal function reached a stable state within 6 months follow-up. The major challenge regarding diagnostic process and therapy of this pathology is to distinguish benign oncocytoma from chromophobe renal cell carcinoma and hybrid tumours, which can all be associated with renal oncocytosis. Because of limitations concerning imaging processes and biopsy, all patients should undergo nephron-sparing surgery as far as possible. On the other hand alternative therapies should - regarding to therapy-associated morbidity and the basically benign prognosis of oncocytoma - be well discussed to obtain informed consent. In this case report different therapy options and the international literature concerning renal oncocytosis will be discussed.

  18. Therapeutic hypothermia with the use of intracranial pressure monitoring for acute disseminated encephalomyelitis with brainstem lesion: a case report.

    Science.gov (United States)

    Miyamoto, Kenji; Kozu, Seiki; Arakawa, Akiko; Tsuboi, Tatsuo; Hirao, Jun-Ichi; Ono, Kazuyuki; Arisaka, Osamu

    2014-09-01

    Acute disseminated encephalomyelitis confined to the brainstem is associated with poor prognosis. We describe a case of a 10-year-old boy with acute disseminated encephalomyelitis in the brainstem that developed after influenza A infection. A 10-year-old boy presented with fever and prolonged disturbance of consciousness and was admitted to our hospital. Magnetic resonance imaging (MRI) of the midbrain, with T2-weighted and fluid-attenuated inversion recovery images, suggested acute disseminated encephalomyelitis accompanied by a brainstem lesion. Lumbar puncture showed pleocytosis and increased protein content, including myelin basic protein, interleukin-6, and immunoglobulin G, all suggestive of acute disseminated encephalomyelitis. Treatments such as methylprednisolone pulse therapy, intravenous immunoglobulin, and therapeutic hypothermia were performed. Although the patient presented with anisocoria with increased intracranial pressure monitoring during hypothermia, prompt therapy with d-mannitol and dopamine was effective. Our case results suggest that hypothermia could be included in the choice of therapy for acute disseminated encephalomyelitis with brainstem lesions. © The Author(s) 2013.

  19. [Medico-legal assessment of selected cases of perinatal complications resulting in death of the woman during childbirth. Medical error or therapeutic failure?].

    Science.gov (United States)

    Chowaniec, Małgorzata; Chowaniec, Czesław; Jabłoński, Christian; Nowak, Agnieszka

    2005-01-01

    Medico-legal estimation of therapeutic management in cases of perinatal complications, especially those resulting in death of the women during childbirth is usually very difficult. The authors have investigated medical documentation supported by the results of autopsies of cases chosen from the casuistry of the Forensic Medicine Department, Medical University of Silesia, Katowice. Considering the limits of professional liability and legal responsibility of physicians, close attention was paid to standard therapeutic management and increased risk in treatment with regard to that relating to typical salubrious complications. The presented cases of deaths of women during childbirth can be the succeeding opinion in broad discussion on medical errors as well as an attempt to standardise and differentiate the medical error from therapeutic failure which occurred within the reach of risk in the undertaken treatment.

  20. Nutrition, psychoneuroimmunology and depression: the therapeutic implications of omega-3 fatty acids in interferon-α-induced depression.

    Science.gov (United States)

    Su, Kuan-Pin

    2015-12-01

    The unmet need of current pharmacotherapy and the high occurrence of somatic symptoms and physical illness in depression imply that the 'monoamine hypothesis' is insufficient in approaching the aetiology of depression. Clinically, depressed patients manifest higher levels of inflammatory biomarkers, while proinflammatory cytokines induce neuropsychiatric symptoms (sickness behaviour) as well as major depressive episodes. Indeed, accumulating evidence suggests that inflammation dysregulation plays an important role in the pathophysiology of depression. Biological mechanisms that link inflammation to neuropsychiatric symptoms are vital in the understanding of the "mind-body" interface. IFN-α-induced depression is the most powerful support for the inflammation theory of depression. This clinical observation provides an excellent model for depression research. By comparing subjects with and without major depression induced by the cytokine treatment, statistical powers could be largely increased by reducing phenotypic variation (homogeneity in aetiological factors). In addition, the anti-inflammatory pathway has recently become an important topic in looking for new antidepressant therapies. For example, anti-inflammatory compounds, omega-3 polyunsaturated fatty acids (omega-3 PUFAs or n-3 PUFAs), have been found to be associated with the development and treatment for depression in human and animal models. Here I review recent epidemiological studies, cross-sectional and longitudinal case-controlled studies, interventional clinical trials, as well as basic animal and cellular studies to prove the linkage among omega-3 PUFAs, inflammation, and depression.

  1. Trauma y trastornos de la alimentación: Implicaciones teóricas y terapéuticas Trauma and eating disorders: Theoretical and therapeutical implications

    Directory of Open Access Journals (Sweden)

    Luisa Castaldi

    2008-12-01

    Full Text Available Los trastornos de alimentación representan un fenómeno complejo, cuya aproximación implica miradas que integren múltiples niveles de análisis. El presente documento pretende analizar el concepto de trauma relacional aplicado a contextos relacionales en los cuales un miembro presenta tal sintomatología. Se presentan y articulan las implicancias ligadas a la hipótesis planteada, con el objetivo de evidenciar como el tomar en consideración la existencia de un trauma relacional puede ser útil para profundizar aspectos de la dinámica familiar y del posicionamiento individual del miembro sintomático, integrando los aportes psicoanalíticos y sistémicos. Se articulará dicho concepto con la visión trigeneracional clásica y se explicitarán las implicancias posibles en relación al trabajo terapéutico. Eating disorders represent a complex phenomenon that requires a multiple-level analysis approach. The present document analyzes the concept of relational trauma applied to relational contexts where a member presents the symptomatology. The implications linked to the hypothesis proposed are presented and articulated, with the purpose of providing evidence of how considering the existence of a relational trauma can be useful for analyzing elements of family dynamics and of the individual positioning of the symptomatic member, integrating both psychoanalytic and systemic contributions. The concept of relational trauma is articulated with the traditional third-generation view, and the possible implications concerning therapeutic work are stated.

  2. Aerosol exposure to Rift Valley fever virus causes earlier and more severe neuropathology in the murine model, which has important implications for therapeutic development.

    Directory of Open Access Journals (Sweden)

    Christopher Reed

    Full Text Available Rift Valley fever virus (RVFV is an important mosquito-borne veterinary and human pathogen that can cause severe disease including acute-onset hepatitis, delayed-onset encephalitis, retinitis and blindness, or a hemorrhagic syndrome. Currently, no licensed vaccine or therapeutics exist to treat this potentially deadly disease. Detailed studies describing the pathogenesis of RVFV following aerosol exposure have not been completed and candidate therapeutics have not been evaluated following an aerosol exposure. These studies are important because while mosquito transmission is the primary means for human infection, it can also be transmitted by aerosol or through mucosal contact. Therefore, we directly compared the pathogenesis of RVFV following aerosol exposure to a subcutaneous (SC exposure in the murine model by analyzing survival, clinical observations, blood chemistry, hematology, immunohistochemistry, and virus titration of tissues. Additionally, we evaluated the effectiveness of the nucleoside analog ribavirin administered prophylactically to treat mice exposed by aerosol and SC. The route of exposure did not significantly affect the survival, chemistry or hematology results of the mice. Acute hepatitis occurred despite the route of exposure. However, the development of neuropathology occurred much earlier and was more severe in mice exposed by aerosol compared to SC exposed mice. Mice treated with ribavirin and exposed SC were partially protected, whereas treated mice exposed by aerosol were not protected. Early and aggressive viral invasion of brain tissues following aerosol exposure likely played an important role in ribavirin's failure to prevent mortality among these animals. Our results highlight the need for more candidate antivirals to treat RVFV infection, especially in the case of a potential aerosol exposure. Additionally, our study provides an account of the key pathogenetic differences in RVF disease following two potential

  3. Therapeutic indications and other use-case-driven updates in the drug ontology: anti-malarials, anti-hypertensives, opioid analgesics, and a large term request.

    Science.gov (United States)

    Hogan, William R; Hanna, Josh; Hicks, Amanda; Amirova, Samira; Bramblett, Baxter; Diller, Matthew; Enderez, Rodel; Modzelewski, Timothy; Vasconcelos, Mirela; Delcher, Chris

    2017-03-03

    The Drug Ontology (DrOn) is an OWL2-based representation of drug products and their ingredients, mechanisms of action, strengths, and dose forms. We originally created DrOn for use cases in comparative effectiveness research, primarily to identify historically complete sets of United States National Drug Codes (NDCs) that represent packaged drug products, by the ingredient(s), mechanism(s) of action, and so on contained in those products. Although we had designed DrOn from the outset to carefully distinguish those entities that have a therapeutic indication from those entities that have a molecular mechanism of action, we had not previously represented in DrOn any particular therapeutic indication. In this work, we add therapeutic indications for three research use cases: resistant hypertension, malaria, and opioid abuse research. We also added mechanisms of action for opioid analgesics and added 108 classes representing drug products in response to a large term request from the Program for Resistance, Immunology, Surveillance and Modeling of Malaria in Uganda (PRISM) project. The net result is a new version of DrOn, current to May 2016, that represents three major therapeutic classes of drugs and six new mechanisms of action. A therapeutic indication of a drug product is represented as a therapeutic function in DrOn. Adverse effects of drug products, as well as other therapeutic uses for which the drug product was not designed are dispositions. Our work provides a framework for representing additional therapeutic indications, adverse effects, and uses of drug products beyond their design. Our work also validated our past modeling decisions for specific types of mechanisms of action, namely effects mediated via receptor and/or enzyme binding. DrOn is available at: http://purl.obolibrary.org/obo/dron.owl . A smaller version without NDCs is available at: http://purl.obolibrary.org/obo/dron/dron-lite.owl.

  4. Transcriptional Control of Vascular Smooth Muscle Cell Proliferation by Peroxisome Proliferator-Activated Receptor-γ: Therapeutic Implications for Cardiovascular Diseases

    Directory of Open Access Journals (Sweden)

    Florence Gizard

    2008-01-01

    Full Text Available Proliferation of vascular smooth muscle cells (SMCs is a critical process for the development of atherosclerosis and complications of procedures used to treat atherosclerotic diseases, including postangioplasty restenosis, vein graft failure, and transplant vasculopathy. Peroxisome proliferator-activated receptor (PPAR γ is a member of the nuclear hormone receptor superfamily and the molecular target for the thiazolidinediones (TZD, used clinically to treat insulin resistance in patients with type 2 diabetes. In addition to their efficacy to improve insulin sensitivity, TZD exert a broad spectrum of pleiotropic beneficial effects on vascular gene expression programs. In SMCs, PPARγ is prominently upregulated during neointima formation and suppresses the proliferative response to injury of the arterial wall. Among the molecular target genes regulated by PPARγ in SMCs are genes encoding proteins involved in the regulation of cell-cycle progression, cellular senescence, and apoptosis. This inhibition of SMC proliferation is likely to contribute to the prevention of atherosclerosis and postangioplasty restenosis observed in animal models and proof-of-concept clinical studies. This review will summarize the transcriptional target genes regulated by PPARγ in SMCs and outline the therapeutic implications of PPARγ activation for the treatment and prevention of atherosclerosis and its complications.

  5. Implications of central immune signaling caused by drugs of abuse: mechanisms, mediators and new therapeutic approaches for prediction and treatment of drug dependence.

    Science.gov (United States)

    Coller, Janet K; Hutchinson, Mark R

    2012-05-01

    In the past two decades a trickle of manuscripts examining the non-neuronal central nervous system immune consequences of the drugs of abuse has now swollen to a significant body of work. Initially, these studies reported associative evidence of central nervous system proinflammation resulting from exposure to the drugs of abuse demonstrating key implications for neurotoxicity and disease progression associated with, for example, HIV infection. However, more recently this drug-induced activation of central immune signaling is now understood to contribute substantially to the pharmacodynamic actions of the drugs of abuse, by enhancing the engagement of classical mesolimbic dopamine reward pathways and withdrawal centers. This review will highlight the key in vivo animal, human, biological and molecular evidence of these central immune signaling actions of opioids, alcohol, cocaine, methamphetamine, and 3,4-methylenedioxymethamphetamine (MDMA). Excitingly, this new appreciation of central immune signaling activity of drugs of abuse provides novel therapeutic interventions and opportunities to identify 'at risk' individuals through the use of immunogenetics. Discussion will also cover the evidence of modulation of this signaling by existing clinical and pre-clinical drug candidates, and novel pharmacological targets. Finally, following examination of the breadth of central immune signaling actions of the drugs of abuse highlighted here, the current known common immune signaling components will be outlined and their impact on established addiction neurocircuitry discussed, thereby synthesizing a common neuroimmune hypothesis of addiction. Copyright © 2012 Elsevier Inc. All rights reserved.

  6. Use of Therapeutic Neuroscience Education to address psychosocial factors associated with acute low back pain: a case report.

    Science.gov (United States)

    Zimney, Kory; Louw, Adriaan; Puentedura, Emilio J

    2014-04-01

    Acute low back pain (LBP) from injuries is prevalent in the work place. It has been shown that patients with psychosocial factors often progress with persistent pain and lead to significant workers compensation costs. Therapeutic Neuroscience Education (TNE) has been shown to be beneficial in changing a patient's cognition regarding their pain state, which may result in decrease fear, anxiety and catastrophization. A 19-year-old female who developed LBP from a work injury was the patient for this case report. A physical examination, Numeric Pain Rating Scale (NRPS), Oswestry Disability Index (ODI), Fear-Avoidance Beliefs Questionnaire (FABQ), Keele STarT Back Screening Tool (Keele SBST) and Acute Low Back Pain Screening (ALBPS) Questionnaires were assessed during initial physical therapy visit and discharge. Treatment consisted of use of TNE, manual therapy and exercises. She attended five total visits over a 2-week period prior to full discharge. During the initial visit the patient reported NRPS = 3/10, ODI = 36%, FABQ-PA = 23, FABQ-W = 30, Keele SBST = 4/9, ALBPS = 101. At discharge the patient reported a 0 on all outcome questionnaires with ability to return to full work and no pain complaints.

  7. Angiographic study and therapeutic embolization of soft-tissue fibrosarcoma in a dog: case report and literature.

    Science.gov (United States)

    Sun, Fei; Hernández, Javier; Ezquerra, Javier; Durán, Esther; Pineda, Luis-Fernando; De Miguel, Carmen; Crisóstomo, Verónica; Usón, Jesús; Maynar, Manuel

    2002-01-01

    A case of soft-tissue fibrosarcoma with pulmonary metastases in a dog is reported. Although three attempts of fine-needle aspiration (FNA) biopsy failed to provide definitive tumor diagnosis, results of angiography strongly indicated a soft-tissue sarcoma. Transcatheter arterial embolization (TAE) using particles of gelatin sponge was performed following selective angiography. The mass was decreased in size on reevaluation 2 weeks after embolization. The dog was euthanized on the request of the owners due to overall failing health. Necropsy and pathological study confirmed the diagnosis of soft-tissue fibrosarcoma with pulmonary metastases. In a review of the literature, angiographic findings of soft-tissue sarcoma in the dog of this report were similar to those in human beings, suggesting a potential role for angiography in the differential diagnosis of suspect soft-tissue fibrosarcomas and for guiding FNA or surgical biopsy. Previous reports have also shown therapeutic embolization to be an effective treatment both in experimental animal study and in clinical practice in the human; therefore, TAE could be an effective adjunctive treatment of soft-tissue fibrosarcoma in the dog.

  8. [Lithiasis of soft appearance within a calyceal diverticulum in the right kidney. Report of one case and therapeutic management].

    Science.gov (United States)

    Hermida Pérez, José Alberto; Guerra Abrante, Pablo; Hernández Guerra, José Samuel; Ochoa Urdangarain, Otto

    2004-01-01

    To report the case of a 28-year-old female patient carrying a lithiasis of soft appearance located within a calyceal diverticulum in the right kidney which presented clinically during pregnancy, and to comment on therapeutic management, as well as the outcome one year after conservative treatment. 28-year-old female patient with history of renal colic during pregnancy, who presents at our clinics in the postpartum period with a recurrent abdominal and lumbar pain. Kidney-ureter-bladder (KUB) x-ray and intravenous urography (IVP) detected a lithiasis of soft appearance within a calyceal diverticulum in the right kidney. Treatment was conservative with potassium citrate/citric acid and follow-up controls with urine culture (every 3 months) and ultrasounds (every 8 months). Currently she is asymptomatic but the lithiasis persists on KUB and urine culture is positive (Escherichia coli) and receives treatment with cefuroxime 250 mg every 12 hours for 6 days and nitrofurantoin 100 mg every night for three months. Most urinary stones located within calyceal diverticula have an asymptomatic course, treatment not being necessary. The most frequent clinical presentations of these stones are flank pain, urinary infection demonstrated by positive urine culture, and incidental finding. IVU is an effective method for diagnosis. ESWL is not an effective treatment for them, being percutaneous techniques the most suitable for a single-surgical procedure resolution of both lithiasis and pyelocalyceal diverticulum.

  9. Clinicopathological features of primary diffuse large B-cell lymphoma of the central nervous system - strong EZH2 expression implying diagnostic and therapeutic implication.

    Science.gov (United States)

    Guo, Shuangping; Bai, Qingxian; Rohr, Joseph; Wang, Yingmei; Liu, Yang; Zeng, Kaixuan; Yu, Kangjie; Zhang, Xiumin; Wang, Zhe

    2016-12-01

    Primary diffuse large B-cell lymphoma of the central nervous system (CNS DLBCL) is a rare entity which is difficult to diagnose and treat. The histone methyltransferase EZH2 was reported to be involved in the tumorigenesis of systemic DLBCL but has not been implicated in primary CNS DLBCL. The clinicopathological features of 33 cases of primary CNS DLBCL and expression of EZH2 and Y641 mutation were assessed. The tumor cells of the majority cases resembled centroblasts, and intriguingly, three cases of rare anaplastic variant were observed. Immunophenotypically, 25/33 (75.8%) cases were non-germinal center B-cell-like type. Several cases (10/33; 30.3%) co-expressed BCL2 and MYC, 6/33 (18.2%) expressed both BCL6 and MYC, and 5/33 (15.2%) expressed BCL2, BCL6, and MYC. MYC expression alone and BCL2/MYC co-expression were associated with poor prognosis. EZH2 was strongly expressed in all 33 cases independent of Y641 mutation and was significantly associated with the tumor proliferative index Ki67. However, no association was found between the level of EZH2 expression and outcomes of patients. In summary, the clinicopathological features including three rare anaplastic variant of primary CNS DLBCL are described. Strong expression of EZH2 in all the primary CNS DLBCL and association with high proliferative index provides further information for treatment and diagnosis of this distinctive entity. © 2016 APMIS. Published by John Wiley & Sons Ltd.

  10. Super obese 33-week parturient undergoing an urgent laparoscopic bowel resection: A case report and review of anesthetic implications

    Directory of Open Access Journals (Sweden)

    Yury Khelemsky

    2011-01-01

    Full Text Available Approximately two percent of women undergo non-obstetric surgery during their pregnancies. The following case report describes the anesthetic management of a super obese parturient in her third trimester of pregnancy undergoing urgent laparoscopic (converted to open bowel resection. Such a case, which has not been previously reported, has multiple clinical implications for both mother and fetus and was further complicated by super obesity (BMI>50 and laparoscopy. The anesthetic implications for this patient population are reviewed.

  11. A Case Study Approach to Nursing Home Placement: Smooth and Difficult Cases and Implications for Nursing.

    Science.gov (United States)

    Koplow, Sarah M; Gallo, Agatha M; Knafl, Kathleen A; Vincent, Catherine; Paun, Olimpia; Gruss, Valerie

    2015-07-01

    Nursing home placement is one of the most challenging aspects of the caregiving journey. A case study approach was used to understand the experiences of caregivers during the first few months following nursing home placement. Two caregivers were selected from a larger qualitative descriptive study because their experiences exemplified smooth and difficult transitions for both themselves and their older family member. The caregivers were interviewed shortly after placement and 3 months post-placement. Four major contextual issues were identified that indicated the similarities and differences between the two cases, including (a) the caregiver's relationship with the older adult during the home caregiving time and post nursing home placement, (b) the circumstances surrounding placement, (c) support systems, and (d) continued involvement in care post-placement. Nursing home staff who understand these issues and address concerns through family-centered care can ease the transition and promote successful collaborations between staff and families. Copyright 2015, SLACK Incorporated.

  12. Comparison of Estimates between Cohort and Case-Control Studies in Meta-Analyses of Therapeutic Interventions: A Meta-Epidemiological Study.

    Science.gov (United States)

    Lanza, Amy; Ravaud, Philippe; Riveros, Carolina; Dechartres, Agnes

    2016-01-01

    Observational studies are increasingly being used for assessing therapeutic interventions. Case-control studies are generally considered to have greater risk of bias than cohort studies, but we lack evidence of differences in effect estimates between the 2 study types. We aimed to compare estimates between cohort and case-control studies in meta-analyses of observational studies of therapeutic interventions by using a meta-epidemiological study. We used a random sample of meta-analyses of therapeutic interventions published in 2013 that included both cohort and case-control studies assessing a binary outcome. For each meta-analysis, the ratio of estimates (RE) was calculated by comparing the estimate in case-control studies to that in cohort studies. Then, we used random-effects meta-analysis to estimate a combined RE across meta-analyses. An RE studies yielded larger estimates than cohort studies. The final analysis included 23 meta-analyses: 138 cohort and 133 case-control studies. Treatment effect estimates did not significantly differ between case-control and cohort studies (combined RE 0.97 [95% CI 0.86-1.09]). Heterogeneity was low, with between-meta-analysis variance τ2 = 0.0049. Estimates did not differ between case-control and prospective or retrospective cohort studies (RE = 1.05 [95% CI 0.96-1.15] and RE = 0.99 [95% CI, 0.83-1.19], respectively). Sensitivity analysis of studies reporting adjusted estimates also revealed no significant difference (RE = 1.03 [95% CI 0.91-1.16]). Heterogeneity was also low for these analyses. We found no significant difference in treatment effect estimates between case-control and cohort studies assessing therapeutic interventions.

  13. Cases of cutaneous diphtheria in New Zealand: implications for surveillance and management.

    Science.gov (United States)

    Sears, Ann; McLean, Margot; Hingston, David; Eddie, Barbara; Short, Pat; Jones, Mark

    2012-02-24

    Diphtheria is an acute bacterial illness caused by toxigenic strains of Corynebacterium diphtheriae (C. diphtheriae). We describe two epidemiologically-linked cases of skin infections from which toxigenic C. diphtheriae was isolated, and discuss implications for diphtheria surveillance and management in New Zealand. A public health investigation was undertaken to identify and manage close contacts of the index case. National and international guidelines on the surveillance and management of cutaneous diphtheria were reviewed, and data on toxigenic C. diphtheriae isolates identified in New Zealand from 1987-2009 were examined. The index case was an adult male who developed a cutaneous infection after being tattooed in Samoa. A wound swab taken from the infected tattoo grew a toxigenic strain of C. diphtheriae (var gravis). A secondary case of toxigenic cutaneous diphtheria was identified in a household contact. Instances of respiratory diphtheria associated with toxigenic cutaneous lesions have been reported in the literature. The review of surveillance data revealed inconsistencies in the notification of toxigenic strains of C. diphtheriae isolated from cutaneous sites. These cases are an important reminder that diphtheria remains a threat in New Zealand. All cases with toxigenic C. diphtheriae isolated from a clinical specimen, regardless of the site of infection, should be notified to a Medical Officer of Health.

  14. Ethical Implications of Case-Based Payment in China: A Systematic Analysis.

    Science.gov (United States)

    Jin, Pingyue; Biller-Andorno, Nikola; Wild, Verina

    2015-12-01

    How health care providers are paid affects how medicine is practiced. It is thus important to assess provider payment models not only from the economic perspective but also from the ethical perspective. China recently started to reform the provider payment model in the health care system from fee-for-service to case-based payment. This paper aims to examine this transition from an ethical perspective. We collected empirical studies on the impact of case-based payment in the Chinese health care system and applied a systematic ethical matrix that integrates clinical ethics and public health ethics to analyze the empirical findings. We identified eleven prominent ethical issues related to case-based payment. Some ethical problems of case-based payment in China are comparable to ethical problems of managed care and diagnosis related groups in high-income countries. However, in this paper we discuss in greater detail four specific ethical issues in the Chinese context: professionalism, the patient-physician relationship, access to care and patient autonomy. Based on the analysis, we cautiously infer that case-based payment is currently more ethically acceptable than fee-for-service in the context of China, mainly because it seems to lower financial barriers to access care. Nonetheless, it will be difficult to justify the implementation of case-based payment if no additional measures are taken to monitor and minimize its existing negative ethical implications. © 2014 John Wiley & Sons Ltd.

  15. Evaluation of approved and non-approved requests for therapeutic abortion in cases referred to legal medicine organization of Lorestan province in 2013

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    peyman Astaraki

    2015-09-01

    Full Text Available Background: Authorizing abortion in some cases of fetal and maternal diseases which was implemented by passing its law in 2005, a major change in therapeutic abortion was performed in Iran,s health system. Although there may be cases of illegal abortion, but our study examined legal abortion of Lorestan province in 2013, which led to increase in awareness of health professionals about indications of therapeutic abortion, the time to do it and answer to related questions. Materials and Methods: In this epidemiological and cross-sectional study, all applications for abortion permission, received by Lorestan legal organization in 2013, were studied. The data were recorded in a questionnaire and analyzed using SPSS software. Results: From 205 cases during a year, 144 of them obtained permission for abortion of which 88% issued for fetal abnormalities and 12% due to illness of the mother. The most common diseases in the fetus were, the brain and skull abnormalities, and in the mothers, cardiovascular diseases and hematologic abnormalities were the highest. In these cases, the most frequency belonged to the age group of 25-34 years. For 61 requests, permission for abortion had not been issued. High gestational age (26 cases and diseases of the brain and skull, were the most common reasons of request for abortion. Conclusion: Abortion means therapeutic abortion and with the increase in the authorized therapeutic abortion, the illegal abortion will be reduced and leads to increase in the health of pregnant women. By increasing awareness of the medical staff about permitted therapeutic abortion and related laws, a correct and better guidance of pregnant women, we can help them to have a healthy community. As well as the problems of obstetricians and gynecologists, in this field, will be decreased.

  16. [Orexin: clinical and therapeutic implications].

    Science.gov (United States)

    Mediavilla, Cristina; Risco, Severiano

    2014-02-01

    INTRODUCTION. Recent research has reported the existence of a new class of neuropeptides, called orexins or hypocretins, which are produced by a small group of neurons in the hypothalamus and whose actions are mediated by two types of receptors: OX1R and OX2R. More specifically, the orexinergic neurons have been located exclusively in cells in the lateral, dorsomedial and perifornical areas of the hypothalamus. Despite this highly specific anatomical origin, the orexinergic neurons are projected widely into a number of brainstem, cortical and limbic regions. DEVELOPMENT. This fuzzy pattern of distribution of the orexinergic fibres would be indicating the involvement of this peptidic system in a wide range of functions; indeed, it has been related with the mechanisms that enable regulation of the sleep-wake cycle, the ingestion of food and drink, and some particular types of learning, such as learning certain preferences regarding tastes. It has also been suggested that upsets in the functioning of the orexinergic system would explain the appearance of certain clinical disorders like narcolepsy, obesity or addiction to drug of abuse. CONCLUSIONS. Further research will help to determine the functioning of orexinergic neurons and the interaction between the systems that regulate emotion, energetic homeostasis and the reward mechanisms, on the one hand, and the systems that regulate the sleep-wake cycle on the other. That knowledge would almost certainly make it possible to develop new drugs that, by acting upon the orexinergic system, would be effective in the treatment of sleep disorders such as insomnia or narcolepsy, eating disorders or drug addiction.

  17. A case report of embryo donation: ethical and clinical implications for psychologists.

    Science.gov (United States)

    Rizk, Marianne; Pawlak, Stacey

    2016-10-01

    Third-party reproduction is a growing field, and an increasing body of literature considers the ethics of embryo donation. Due to the psychosocial complexities that generally accompany the donation and/or use of donor embryos, psychologists can play a pivotal role in these specialised fertility cases. While laws in the USA are in place to regulate the medical procedures involved in embryo donation, only unenforceable guidelines exist for psychologists specialising in fertility cases. The presentation of this case study aims to: (1) clarify the ethical concerns that fertility psychologists should consider in similar situations by assessing whether American Society of Reproductive Medicine (ASRM) and the American Psychological Association (APA) guidelines compete or complement one another within this case of embryo donation and (2) consider the interests, obligations and rights of all parties involved. Several principles, standards and guidelines that must be considered are described. Overall, the APA Ethics Code and the ASRM Guidelines appear to complement one another for most aspects of this case. Fertility psychologists should consider the clinical implications of the interests, rights and duties of all involved parties, including themselves. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  18. Standardised in vitro susceptibility testing of Borrelia burgdorferi against well-known and newly developed antimicrobial agents--possible implications for new therapeutic approaches to Lyme disease.

    Science.gov (United States)

    Hunfeld, Klaus-Peter; Kraiczy, Peter; Kekoukh, Elena; Schäfer, Volker; Brade, Volker

    2002-06-01

    Lyme disease represents a disorder of potentially chronic proportions, and relatively little is known about the in vivo pharmacodynamic interactions of antimicrobial agents with borreliae. So far, evidence-based drug regimens for the effective treatment of Lyme disease have not been definitively established. Moreover, therapeutic failures have been reported for almost every suitable antimicrobial agent currently available. Resistance to treatment and a protracted course of the disease, therefore, continue to pose problems for clinicians in the management of patients suffering from chronic Lyme disease. Further characterisation of the antibiotic susceptibility pattern and a better understanding of the interactions of B. burgdorferi with antimicrobial agents are urgently needed and continue to be crucial owing to considerable differences in the experimental conditions and test methods applied. The development of easily performed, new techniques for the sensitivity testing of B. burgdorferi provides the opportunity to study factors affecting the bacteriostatic and bactericidal action of recently introduced chemotherapeutic agents under more standardised conditions. For the first time, these studies provide direct evidence that, in addition to beta-lactams, macrolides, and tetracyclines which are recommended for stage-dependent treatment of Lyme borreliosis, other recently introduced substances, such as fluoroquinolones, everninomycins, and the ketolide family of antimicrobial agents, also show enhanced in vitro activity against borreliae. Some of these compounds, if effective in vivo as well, may prove to be useful agents in the treatment of certain manifestations of Lyme disease. As such, their potential role should be evaluated further by in vivo experiments and clinical trials. Finally, these antimicrobial agents may turn out to be very effective therapeutic alternatives on account of their oral availability, favourable pharmacodynamic profiles, and high tissue

  19. Comprehensive Review of Medicinal Marijuana, Cannabinoids, and Therapeutic Implications in Medicine and Headache: What a Long Strange Trip It's Been ….

    Science.gov (United States)

    Baron, Eric P

    2015-06-01

    The use of cannabis, or marijuana, for medicinal purposes is deeply rooted though history, dating back to ancient times. It once held a prominent position in the history of medicine, recommended by many eminent physicians for numerous diseases, particularly headache and migraine. Through the decades, this plant has taken a fascinating journey from a legal and frequently prescribed status to illegal, driven by political and social factors rather than by science. However, with an abundance of growing support for its multitude of medicinal uses, the misguided stigma of cannabis is fading, and there has been a dramatic push for legalizing medicinal cannabis and research. Almost half of the United States has now legalized medicinal cannabis, several states have legalized recreational use, and others have legalized cannabidiol-only use, which is one of many therapeutic cannabinoids extracted from cannabis. Physicians need to be educated on the history, pharmacology, clinical indications, and proper clinical use of cannabis, as patients will inevitably inquire about it for many diseases, including chronic pain and headache disorders for which there is some intriguing supportive evidence. To review the history of medicinal cannabis use, discuss the pharmacology and physiology of the endocannabinoid system and cannabis-derived cannabinoids, perform a comprehensive literature review of the clinical uses of medicinal cannabis and cannabinoids with a focus on migraine and other headache disorders, and outline general clinical practice guidelines. The literature suggests that the medicinal use of cannabis may have a therapeutic role for a multitude of diseases, particularly chronic pain disorders including headache. Supporting literature suggests a role for medicinal cannabis and cannabinoids in several types of headache disorders including migraine and cluster headache, although it is primarily limited to case based, anecdotal, or laboratory-based scientific research. Cannabis

  20. Implications of welfare reform on the elderly: a case study of provider, advocate, and consumer perspectives.

    Science.gov (United States)

    Estes, Carroll L; Goldberg, Sheryl; Wellin, Chris; Linkins, Karen W; Shostak, Sara; Beard, Renée L

    2006-01-01

    Whereas many studies of welfare reform have focused on effects on children and families, little research has examined the implications of welfare reform for the elderly. This case study incorporates interviews with service providers for the aging, members of advocacy organizations, and two focus groups of older consumers conducted in the multi-ethnic urban community of San Francisco. Study findings suggest that welfare reform has had both direct and indirect effects on the elderly and their services in the study community. Direct effects derive primarily from changes in the welfare reform legislation that had the effect of undermining both immigrants' eligibility for and claiming of public assistance benefits. Indirect effects on older persons include increased child-care demands upon grandparents. The case study data bear on a significant policy change within the broader trend of devolution at a historical point when anti-immigrant sentiment in the United States was running high.

  1. Diagnostic and therapeutic approach of congenital solitary coronary artery fistulas in adults : Dutch case series and review of literature

    NARCIS (Netherlands)

    Said, S. A. M.; Nijhuis, R. L. G.; op den Akker, Jeroen; Kimman, G. P.; Van Houwelingen, K. G.; Gerrits, D.; Huisman, A. B.; Slart, R. H. J. A.; Nicastia, D. M.; Koomen, E. M.; Tans, A. C.; Al-Windy, N. Y. Y.; Sonker, U.; Slagboom, T.; Pronk, A. C. B.

    Background Coronary artery fistulas (CAFs) are infrequent anomalies, coincidentally detected during coronary angiography (CAG). Aim To elucidate the currently used diagnostic imaging modalities and applied therapeutic approaches. Materials and Methods Five Dutch patients were found to have CAFs. A

  2. Public health implications of lead poisoning in backyard chickens and cattle: four cases

    Directory of Open Access Journals (Sweden)

    Roegner A

    2013-04-01

    Full Text Available Amber Roegner,1 Federico Giannitti,2 Leslie W Woods,2 Asli Mete,2 Birgit Puschner1,2 1Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA, USA; 2California Animal Health and Food Safety Laboratory System, School of Veterinary Medicine, University of California, Davis, CA, USA Abstract: Lead intoxication in livestock has historically been associated with cattle turned out to pasture and accidental ingestion of lead from drinking crankcase oil, licking grease from machinery, chewing on plumbing or batteries, or drinking water contaminated from leaching materials. Even with the decrease in manufactured items produced with lead, contaminants persist in the landscape and may enter the food supply through animal products. Changing patterns of open range herds moving to new pasture and the increased popularity of urban/suburban backyard chickens or other livestock necessitates public awareness about the clinical signs of lead intoxication, the potential for subclinical animals, public health concerns, particularly for exposure in children, and testing options available. Cases of lead intoxication in livestock demand a thorough case work-up to identify all sources of lead, address subclinical cases, evaluate risk to consumers, and make management suggestions for future prevention. We discuss four recent cases of confirmed lead poisoning in backyard chickens and open range cattle and assess the public health implications therein. Taken as a whole and considering the potential of the remaining herd or flock to be affected without necessarily showing signs, public health officials and veterinarians should be prepared to advise clients on case work-up and management and prevention considerations. Backyard chickens and cattle may not present for suspected lead poisoning as in several of the cases discussed herein yet may still contain concerning tissue or blood levels. The authors believe increased

  3. Implications of the obesity epidemic for lipid-lowering therapy: Non-HDL cholesterol should replace LDL cholesterol as the primary therapeutic target

    Directory of Open Access Journals (Sweden)

    Michel R Hoenig

    2008-02-01

    Full Text Available Michel R HoenigRoyal Brisbane and Women’s Hospital, Herston, Queensland, AustraliaAbstract: Obesity, metabolic syndrome and diabetes are conditions with increasing prevalence around the world. Cardiovascular risk in diabetics is often so high as to overlap with event rates observed in those with established coronary disease and this has lead to diabetes being classified as a coronary risk equivalent. However, despite the elevated risk of cardiovascular events associated with diabetes and the metabolic syndrome, these patients often have normal low density lipoprotein (LDL cholesterol despite frequent increases in apolipoprotein B, triglycerides and nonhigh density lipoprotein (HDL cholesterol. In contrast to LDL cholesterol, non-HDL cholesterol represents cardiovascular risk across all patient populations but is currently only recommended as a secondary target of therapy by the ATP III report for patients with hypertriglyceridemia. This article provides an overview of the studies that shown non-HDL cholesterol to be superior to LDL cholesterol in predicting cardiovascular events and presents the case for non-HDL cholesterol being the more appropriate primary target of therapy in the context of the obesity pandemic. Adopting non-HDL cholesterol as the primary therapeutic target for all patients will conceivably lead to an appropriate intensification of therapy for high risk patients with low LDL cholesterol.Keywords: obesity, coronary artery disease, non-HDL cholesterol, LDL cholesterol, metabolic syndrome, diabetes

  4. [Iatrogenic biliary ducts lesions after laparoscopic cholecystectomy: a medical technical error or a therapeutic failure in a routinely performed procedure. A medico-legal evaluation of selected cases].

    Science.gov (United States)

    Chowaniec, Czesław; Chowaniec, Małgorzata; Kobek, Mariusz; Nowak, Agnieszka

    2007-01-01

    Laparoscopic cholecystectomy due to cholelithiasis is associated with a higher risk of intraoperative lesions of biliary duct in comparison to classic surgery. Technical difficulties, a limited access to operating area, the presence of cholecystic adhesions and inflammatory lesions, as well as possible anomalies or anatomical variations of the extrahepatic biliary ducts pose the risk of damaging the biliary tract. At times, laparoscopic procedures are performed by surgeons with insufficient operator skills and qualifications. The medico-legal evaluation of intraoperative damage to the biliary tract with resulting complications--the so-called "biliary damage"--is very difficult. The presented analysis included six cases of intraoperative biliary ducts lesions evaluated by the Forensic Medicine Department, Medical University, Katowice. Three instances were associated with investigations carried out by public prosecutors in medical error cases, and in three others, civil cases were brought in the court, with the plaintiffs advancing a claim. While defining the scope of the management--both diagnostic, therapeutic and decision-making--in the pre-, intra- and postoperative period, attention was drawn to the prescriptive character of patient management in such cases, including indications for laparoscopic surgery, an increased potential therapeutic risk that also included a possibility of the patient developing "normal, typical" complications, referring the above factors to the scope and limits of the physician's professional and criminal liability and analyzing them to assess whether a medical error had been committed, or else the events had represented a therapeutic failure within the limits of the accepted therapeutic risk. A separate problem emphasized by the authors focused on difficulties in objective evaluation of health-associated consequences that might be defined in a tabular manner as long-term or permanent detriment to health.

  5. Therapeutic patient education and exercise therapy in patients with cervicogenic dizziness: a prospective case series clinical study

    Science.gov (United States)

    Minguez-Zuazo, Ana; Grande-Alonso, Mónica; Saiz, Beatriz Moral; La Touche, Roy; Lara, Sergio Lerma

    2016-01-01

    The purpose of this study was to evaluate the effectiveness of a treatment for patients with cervicogenic dizziness that consisted of therapeutic education and exercises. The Dizziness Handicap Inventory and Neck Disability Index were used. Secondary outcomes included range of motion, postural control, and psychological variables. Seven patients (two males and five females) aged 38.43±14.10 with cervicogenic dizziness were included. All the participants received eight treatment sessions. The treatment was performed twice a week during a four weeks period. Outcome measures included a questionnaire (demographic data, body chart, and questions about pain) and self-reported disability, pain, and psychological variables. Subjects were examined for cervical range of motion and postural control. All of these variables were assessed pre- and postintervention. Participants received eight sessions of therapeutic education patient and therapeutic exercise. The majority of participants showed an improvement in catastrophism (mean change, 11.57±7.13; 95% confidence interval [CI], 4.96–18.17; d=1.60), neck disability (mean change, 5.14±2.27.28; 95% CI, 3.04–7.24; d=1.32), and dizziness disability (mean change, 9.71±6.96; 95% CI, 3.26–16.15; d=1.01). Patients also showed improved range of motion in the right and left side. Therapeutic patient education in combination with therapeutic exercise was an effective treatment. Future research should investigate the efficacy of therapeutic patient education and exercise with larger sample sizes of patients with cervicogenic dizziness. PMID:27419118

  6. Immunohistochemical determination of HER-2/neu overexpression in malignant melanoma reveals no prognostic value, while c-Kit (CD117 overexpression exhibits potential therapeutic implications

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    Potti Anil

    2003-01-01

    Full Text Available Abstract Background HER-2/neu and c-kit (CD117 onco-protein are increasingly being recognized as targets for therapy in solid tumors, but data on their role in malignant melanoma is currently limited. We studied the prevalence of overexpression of HER-2/neu and c-Kit in 202 patients with malignant melanoma to evaluate a possible prognostic value of these molecular targets in malignant melanoma. Methods Overexpression of HER-2/neu and c-Kit was evaluated using immunohistochemical assays in 202 archival tissue specimens. Results Between 1991 and 2001, 202 subjects (109 males; 54% and 93 females; 46% with malignant melanoma were studied with a mean age of 57 years (age range: 15–101 years. The most common histologic type was amelanotic melanoma (n = 62; 30.7% followed by superficial spreading melanoma (n = 54; 26.7%. The depth of penetration of melanoma (Breslow thickness, pT Stage ranged from 0.4 mm (stage pT1 to 8.0 mm (stage pT4A. Mean thickness was 2.6 mm (stage pT3A. The ECOG performance scores ranged from 0 to 3. Only 2 patients (0.9% revealed HER-2/neu overexpression, whereas 46 (22.8% revealed c-Kit overexpression. Multivariate analysis performed did not show a significant difference in survival between c-Kit positive and negative groups (p = 0.36. Interestingly, not only was c-Kit more likely to be overexpressed in the superficial spreading type, a preliminary association between the presence or absence of c-Kit overexpression and the existence of another second primary tumor was also observed. Conclusions The results of our large study indicate that the HER-2/neu onco-protein neither has a role in melanogenesis nor is a potential target for clinical trials with monoclonal antibody therapy. This indicates there is no role for its testing in patients with malignant melanoma. Although c-Kit, expressed preferentially in the superficial spreading type, may not have prognostic value, it does have significant therapeutic implications as a

  7. Restructuring patient flow logistics around patient care needs: implications and practicalities from three critical cases.

    Science.gov (United States)

    Villa, Stefano; Barbieri, Marta; Lega, Federico

    2009-06-01

    To make hospitals more patient-centered it is necessary to intervene on patient flow logistics. The study analyzes three innovative redesign projects implemented at three Italian hospitals. The three hospitals have reorganized patient flow logistics around patient care needs using, as proxies, the expected length of stay and the level of nursing assistance. In order to do this, they have extensively revised their logistical configuration changing: (1) the organization of wards, (2) the hospital's physical lay-out, (3) the capacity planning system, and (4) the organizational roles supporting the patient flow management. The study describes the changes implemented as well as the results achieved and draws some general lessons that provide useful hints for those other hospitals involved in such type of redesign projects. The paper ends by discussing some policy implications. In fact, the results achieved in the three cases investigated provide interesting material for further discussion on clinical, operational, and economic issues.

  8. Implications of Pseudologia Fantastica in Criminal Forensic Evaluations: A Review and Case Report.

    Science.gov (United States)

    Frierson, Richard L; Joshi, Kaustubh G

    2017-08-15

    Pseudologia fantastica, a psychological phenomenon that has been described in the literature for at least a century, is an understudied and poorly understood entity. Sometimes referred to as pathological lying, pseudologia fantastica involves disproportionate fabrication that may be present for many years or a lifetime. In a forensic context, it can significantly complicate the evaluation of capacity to stand trial and, in certain jurisdictions, criminal responsibility. We review the current literature regarding pseudologia fantastica and present a case to highlight the clinical and forensic challenges it may create. We specifically discuss the complications that pseudologia fantastica may have on the assessment of a defendant's rational ability to consult with an attorney, a required element of capacity to stand trial. In addition, we discuss the implications of pseudologia fantastica in the evaluation of criminal responsibility. © 2017 American Academy of Forensic Sciences.

  9. Environmental implications of electricity purchase from independent power producers: a case study from Thailand

    Energy Technology Data Exchange (ETDEWEB)

    Shrestha, R.; Shrestha, R.M. [Asian Institute of Technology, Pathum Thani (Thailand). School for Environmental Resource & Development

    2003-07-01

    This paper analyses the effect on the environment of electricity purchase from independent power producers (IPPs) in the case of Thailand. The environmental implication is evaluated in terms of the net change in emission of air pollutants with electricity purchase from IPPs by a utility. The main finding of the study is that electricity purchase from a non-dispatchable IPP plant based on coal-fired generation would increase the net emissions compared with that without the purchase from IPPs. The study also shows that the lower plant factor of the IPP plant would also increase the emission of air pollutants. Furthermore, with non-dispatchable IPP plants, the total emission of air pollutants would increase, whereas with dispatchable IPP plants the total emission would decrease with the level of electricity purchases.

  10. Interviewing children in custody cases: implications of research and policy for practice.

    Science.gov (United States)

    Saywitz, Karen; Camparo, Lorinda B; Romanoff, Anna

    2010-01-01

    Research on child interviewing has burgeoned over the past 25 years as expectations about children's agency, competence, and participation in society have changed. This article identifies recent trends in research, policy, and theory with implications for the practice of interviewing children in cases of contested divorce and for the weight to be given the information children provide. A number of fields of relevant research are identified, including studies of families who have participated in the family law system, studies of child witnesses in the field, experimental studies of the effects of interview techniques on children's memory and suggestibility, and ethnographic methods that elicit children's views of their own experiences. Finally, a set of 10 principles for practice are delineated based on the best available science. Copyright 2010 John Wiley & Sons, Ltd.

  11. Isolated persistent left superior vena cava: A case report and its clinical implications

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    Samarjit Bisoyi

    2017-01-01

    Full Text Available The venous anomaly of a persistent left superior vena cava (PLSVC affects 0.3%-0.5% of the general population. PLSVC with absent right superior vena cava, also termed as "isolated PLSVC," is an extremely rare venous anomaly. Almost half of the patients with isolated PLSVC have cardiac anomalies in the form of atrial septal defect, endocardial cushion defects, or tetralogy of Fallot. Isolated PLSVC is usually innocuous. Its discovery, however, has important clinical implications. It can pose clinical difficulties with central venous access, cardiothoracic surgeries, and pacemaker implantation. When it drains to the left atrium, it may create a right to left shunt. In this case report, we present the incidental finding of isolated PLSVC in a patient who underwent aortic valve replacement. Awareness about this condition and its variations is important to avoid complications.

  12. Clinical implications of antiretroviral drug interactions with warfarin: a case-control study.

    Science.gov (United States)

    Esterly, John S; Darin, Kristin M; Gerzenshtein, Lana; Othman, Fidah; Postelnick, Michael J; Scarsi, Kimberly K

    2013-06-01

    Warfarin, a frequently prescribed anticoagulant with a narrow therapeutic index, is susceptible to drug-drug interactions with antiretroviral therapy (ART). This study compared the warfarin maintenance dose (WMD) between patients receiving and not receiving ART and evaluated predictors of warfarin dosage among those on ART. This was a case-control (1:2) study. Cases were HIV-infected patients receiving warfarin and protease inhibitor (PI)- and/or non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART. Controls were randomly selected HIV-uninfected patients receiving warfarin. The WMD was compared between cases and controls and between cases on varying ART regimens. Bivariate comparisons were performed and a linear regression model was developed to identify predictors of WMD. We identified 18 case and 36 control patients eligible for inclusion. Cases were younger than controls (mean age: 45.8 versus 63.1 years, P African American (50.0% versus 22.2%, P=0.04). ART was classified as PI-based (n=9), NNRTI-based (n=7) and PI + NNRTI-based (n=2). The WMD (mean ± SD) differed between cases and controls (8.6  ±  3.4 mg versus 5.1 ± 1.5 mg, P ART regimens (PI: 8.8  ±  4.5 mg; NNRTI: 8.6   ± 1.8 mg; PI + NNRTI: 7.3  ±  3.3 mg; P = 0.86). Race and ritonavir dose were independent predictors of WMD, predicting an increase of 3.9 mg (95% CI: 0.88-6.98, P = 0.02) if a patient was African American or 3.7 mg (95% CI: 0.53-6.89, P = 0.03) if the total daily ritonavir dose was 200 mg. The required WMD was significantly higher in patients receiving ART. Prompt dose titration to achieve a higher WMD with vigilant monitoring may be required due to these drug-drug interactions.

  13. Heel melanoma: the final result of wrong diagnostic and therapeutic approach in another bulgarian patient. First documented case from the board of the “adcrstr-association for dermatohistopathologic control, reevaluation and subsequent therapeutic recomme.

    Science.gov (United States)

    Chokoeva, A A; Tchernev, G; Gianfaldoni, S; Patterson, J W; Wollina, U; Lotti, T

    2015-01-01

    Difficulties with frequent misdiagnoses and incorrectly defined tumor thicknesses applied to the same histopathological preparation occurring among Bulgarian patients, has led to the creation of national and/or international associations or boards for control in problematic circumstances, particularly for patients with melanocytic and non melanocytic cutaneous tumors. Once again we report a problematic case of a patient with acral lentiginous melanomа, localized in the heel area of the right foot, in an otherwise healthy 69-year old woman. A pigmented lesion gradually developed in her heel area, where the patient had been previously treated several times with invasive therapeutic methods (cryosurgery, shave curettage) due to misdiagnosis as a verrucous lesion or as a viral wart in the absence of any prior histopathology report. Years later, the lesion progressed and changed in color, leading to surgical removal, followed by several histopathological evaluations that produced very different results on three separate occasions. The first result described the lesion as melanocytic nevus, and removed with tumor-free margins. The second report from the Department of Dermatology and Venereology, Military Academy in Sofia , Bulgaria, stated “no data for Verrucous carcinoma”. Only on the third assessment the correct diagnosis of “malignant melanoma” was given. A relapse of the melanoma occurred as only at the time of the last histopathologic evaluation, (following surgical resection of the lesion with adequate margins, performed in the “Onkoderma”- Policlinic for Dermatology, Venereology and Dermatologic Surgery, Sofia, Bulgaria) were criteria followed for appropriate pathological evaluation consistent with the recommendations of the AJCC for reporting of melanomas. Tumor thickness at that time was 1.31 mm. Removal of the draining lymph node, followed by inguinal lymphadenectomy was performed in the National Oncological Hospital in accordance with the

  14. The Case of Crimea in the Light of International Law: Its Nature and Implications

    Directory of Open Access Journals (Sweden)

    Maria Issaeva

    2015-01-01

    Full Text Available In March 2015, the Polish Academy of Science, the Institute of Law Studies, and the Centre for Polish-Russian Dialogue held a conference entitled The Case of Crimea in the Light of International Law: Its Nature and Implications. The conference took place against the backdrop of the first anniversary of Crimea’s ‘annexation’ / ‘reunification’2 by Russia, providing an opportunity for international legal scholars to discuss the legality of these events.Over two days, the conference saw around 35 presented papers on issues following five general themes: self-determination and secession; use of force, aggression and armed attack; the international community’s response to the situation in Crimea; non-recognition of unlawful situations; and international state and individual responsibility in the case of Crimea.The invited academics and practitioners who spoke at the conference came from Austria, Belarus, Bulgaria, France, Germany, Italy, Japan, Poland, Russia, Switzerland, The Netherlands, Ukraine, UK and USA.This review will explore selected presentations on the key issues of selfdetermination, secession, use of force and State responsibility.

  15. Therapeutic plasma exchange and pregnancy: A case report and guidelines for performing plasma exchange in a pregnant patient.

    Science.gov (United States)

    Cox, Jesse L; Koepsell, Scott A; Shunkwiler, Sara M

    2017-06-01

    Therapeutic plasma exchange (TPE) has been demonstrated to be of significant clinical value in a number of diseases and conditions, with well-established guidelines and recommendations. However, technical support in providing this procedure for pregnant patients is largely absent from these recommendations, leaving therapeutic apheresis practitioners without guidance to safely and adequately treat appropriate conditions in this important patient population. Here, we describe our experience in treating a 35-year-old pregnant patient with relapsing-remitting multiple sclerosis with TPE. Additionally, we outline the principle considerations when developing her treatment plan, and we provide recommendations for apheresis practitioners when performing TPE in pregnant patients. J. Clin. Apheresis 32:191-195, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  16. A Case Study with an Identified Bully: Policy and Practice Implications

    Directory of Open Access Journals (Sweden)

    Huddleston, Lillie

    2011-07-01

    Full Text Available Objective: Bullying is a serious public health problem that may include verbal or physical injury as well as social isolation or exclusion. As a result, research is needed to establish a database for policies and interventions designed to prevent bullying and its negative effects. This paper presented a case study that contributed to the literature by describing an intervention for bullies that has implications for research, practice and related policies regarding bullying.Methods: An individualized intervention for an identified bully was implemented using the Participatory Culture-Specific Intervention Model (PCSIM; Nastasi, Moore, & Varjas, 2004 with a seventh-grade middle school student. Ecological and culture-specific perspectives were used to develop and implement the intervention that included psychoeducational sessions with the student and consultation with the parent and school personnel. A mixed methods intervention design was used with the following informants: the target student, the mother of the student, a teacher and the school counselor. Qualitative data included semi-structured interviews with the parent, teacher and student, narrative classroom observations and evaluation/feedback forms filled out by the student and interventionist. Quantitative data included the following quantitative surveys (i.e., Child Posttraumatic Stress Reaction Index [CPTS-RI] and the Behavior Assessment Scale for Children, 2nd Edition. Both qualitative and quantitative data were used to evaluate the acceptability, integrity and efficacy of this intervention.Results: The process of intervention design, implementation and evaluation are described through an illustrative case study. Qualitative and quantitative findings indicated a decrease in internalizing, externalizing and bullying behaviors as reported by the teacher and the mother, and a high degree of acceptability and treatment integrity as reported by multiple stakeholders.Conclusion: This case

  17. Clinical characteristics and therapeutic response of objective tinnitus due to middle ear myoclonus: a large case series.

    Science.gov (United States)

    Park, Shi-Nae; Bae, Seong-Cheon; Lee, Guen-Ho; Song, Jee-nam; Park, Kyoung-Ho; Jeon, Eun-ju; Park, Young Soo; Yeo, Sang-Won

    2013-10-01

    To evaluate the clinical characteristics and therapeutic response of tinnitus due to middle ear myoclonus (MEM) and to suggest appropriate diagnostic methods. Retrospective chart review. This study included 58 patients with tinnitus diagnosed with MEM, who were seen from January 2004 to July 2011. Clinical and audiological characteristics were investigated. The therapeutic responses to counseling, medical therapy, and surgical therapy were evaluated. Patients had a mean age of 29.8 years (range, 6-70 years), 20.7% (n = 12) were stressful events or noise exposure were associated with the onset of MEM in 51.8% (n = 30) and 27.6% (n = 16) of patients, respectively. The most frequent nature of the tinnitus was a crackling sound. MEM associated with forceful eyelid closure was observed in 15% of patients. Impedance audiogram and otoendoscopic examinations of the tympanic membrane were helpful tools for diagnosing MEM. With medical therapy, more than 75% of patients exhibited complete or partial remission of their tinnitus. Patients with intractable MEM who underwent sectioning of the middle ear tendons had very good outcomes. Tinnitus due to middle ear myoclonus seems to occur in young patients and to be related to stress or noise. Information about the clinical characteristics and therapeutic response of this less-common type of tinnitus will help to ensure early and appropriate diagnosis and treatment of these patients. 4. Copyright © 2013 The American Laryngological, Rhinological, and Otological Society, Inc.

  18. Spinal Anesthesia with Low-Dose Bupivacaine for Therapeutic Abortion in a Patient with Eisenmenger’s Syndrome: A Case Report Study

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    Parviz Amri Maleh

    2014-06-01

    Full Text Available Background & objectives: Eisenmenger syndrome associated with pregnancy increases the maternal morbidity and mortality . Therefore, in the most of such patients the termination of pregnancy is recommended.   Case report: A 29 -year-old woman at the 7 th week of gestational age was candidate for therapeutic abortion with history of Eisenmenger syndrome due to atrial septal defect (ASD . Spinal a nesthesia was performed in sitting position at the L4-5 interspace with 10 mg of bupivacaine . The p atient was laid in the supine position after 2 minutes. The surgery lasted about an hour . Blood pressure and heart rate did not change significantly during operation.   Conclusion : Modified s pinal anesthesia with bupivacaine is recommended for therapeutic abortion in patients with Eisenmenger syndrome.

  19. Therapeutic Jurisprudence in Health Research: Enlisting Legal Theory as a Methodological Guide in an Interdisciplinary Case Study of Mental Health and Criminal Law.

    Science.gov (United States)

    Ferrazzi, Priscilla; Krupa, Terry

    2015-09-01

    Studies that seek to understand and improve health care systems benefit from qualitative methods that employ theory to add depth, complexity, and context to analysis. Theories used in health research typically emerge from social science, but these can be inadequate for studying complex health systems. Mental health rehabilitation programs for criminal courts are complicated by their integration within the criminal justice system and by their dual health-and-justice objectives. In a qualitative multiple case study exploring the potential for these mental health court programs in Arctic communities, we assess whether a legal theory, known as therapeutic jurisprudence, functions as a useful methodological theory. Therapeutic jurisprudence, recruited across discipline boundaries, succeeds in guiding our qualitative inquiry at the complex intersection of mental health care and criminal law by providing a framework foundation for directing the study's research questions and the related propositions that focus our analysis. © The Author(s) 2014.

  20. The implications of trade liberalization for diet and health: a case study from Central America

    Directory of Open Access Journals (Sweden)

    Hawkes Corinna

    2009-07-01

    Full Text Available Abstract Background Central America has undergone extensive trade liberalization over the past two decades, and has recently signed a Free Trade Agreement with the United States. The region is also experiencing a dual burden of malnutrition with the growth of dietary patterns associated with the global 'nutrition transition'. This study describes the relationship between trade liberalization policies and food imports and availability, and draws implications for diet and health, using Central America as a case study region. Methods Changes in tariff and non-tariff barriers for each country were documented, and compared with time-series graphs of import, production and availability data to show the outcome of changes in trade policy in relation to food imports and food availability. Results Changes in trade policy in Central America have directly affected food imports and availability via three avenues. First, the lowering of trade barriers has promoted availability by facilitating higher imports of a wide range of foods. Second, trade liberalization has affected food availability through promoting domestic meat production. Third, reductions in barriers to investment appear to be critical in expansion of processed food markets. This suggests that changes in trade policies have facilitated rising availability and consumption of meat, dairy products, processed foods and temperate (imported fruits in Central America. Conclusion This study indicates that the policies of trade liberalization in Central American countries over the past two decades, particularly in relation to the United States, have implications for health in the region. Specifically, they have been a factor in facilitating the "nutrition transition", which is associated with rising rates of obesity and chronic diseases such as cardiovascular disease and cancer. Given the significant cost of chronic disease for the health care system, individuals and the wider community, it is critical

  1. Ethical dilemmas among nurses as they transition to hospital case management: implications for organizational ethics, part I.

    Science.gov (United States)

    O'Donnell, Lolita T

    2007-01-01

    To describe the experiences of ethical concerns by clinical nurses as they transitioned into their new role in hospital case management. Through this study, an attempt was made to explore experiences of ethical concerns and identify the implications for organizational ethics. In this study, nurse case managers practicing in the acute hospital setting, military, not-for-profit community, and teaching hospitals were interviewed. The majority of the nurse case manager participants were engaged in hospital discharge planning and utilization review activities. An interpretive phenomenological approach was used to identify the themes inherent in ethical concerns and articulate them within the context of hospital nurse case management. Fifteen participants were interviewed to obtain a qualitative description of the nurse case managers' lived experiences of ethical dilemmas and how they were resolved. Nurse case managers' perceptions of solutions/options to resolve such ethical dilemmas were explored. As nurses transition into the expanded role of case management in the present healthcare delivery system, they frequently face situations demanding ethical choices and judgments to accommodate diverse patient interests and needs. These ethical decisions required in daily practice in case management represent ethical dilemmas to nurses. The insights derived from the analysis of the interviews have implications for nursing practice, education, policy, ethics, and research; recommendations for organizations employing nurse case managers in terms of recruitment, orientation, training, and continued need for educational support are identified. 1. The clinical decisions required in daily practice of case management represented challenges to the nurses. This highlights the critical role of adequate educational orientation to case management for beginning case managers. 2. Nurse case managers should be cognizant of the "disconnect" that could occur between their obligations to the

  2. Ethical dilemmas among nurses as they transition to hospital case management: implications for organizational ethics, part II.

    Science.gov (United States)

    O'Donnell, Lolita T

    2007-01-01

    The purpose of this study was to describe the experiences of ethical concerns by clinical nurses as they transitioned into their new role in hospital case management. Through this study, an attempt was made to explore experiences of ethical concerns and identify the implications for organizational ethics. In this study, nurse case managers practicing in the acute care setting, military, not-for-profit community, and teaching hospitals were interviewed. The majority of the nurse case manager participants were engaged in hospital discharge planning and utilization review activities. An interpretive phenomenological approach was used to identify the themes inherent in ethical concerns and articulate them within the context of hospital nurse case management. Fifteen participants were interviewed to obtain a qualitative description of the nurse case managers' lived experiences of ethical dilemmas and how they were resolved. Nurse case managers' perceptions of solutions/options to resolve such ethical dilemmas were explored. As nurses transition into the expanded role of case management in the present healthcare delivery system, they frequently face situations demanding ethical choices and judgments to accommodate diverse patient interests and needs. These ethical decisions required in daily practice of case management represent ethical dilemmas to nurses. The insights derived from the analysis of the interviews have implications for nursing practice, education, policy, ethics, and research; recommendations for organizations employing nurse case managers in terms of recruitment, orientation, training, and continued need for educational support are identified. 1. The clinical decisions required in daily practice of case management represented challenges to the nurses. This highlights the critical role of adequate educational orientation to case management for beginning case managers. 2. Nurse case managers should be cognizant of the "disconnect" that could occur between

  3. The therapeutic characteristics of serial casting on congenital scoliosis: a comparison with non-congenital cases from a single-center experience.

    Science.gov (United States)

    Cao, Jun; Zhang, Xue-Jun; Sun, Ning; Sun, Lin; Guo, Dong; Qi, Xin-Yu; Bai, Yun-Song; Sun, Bao-Sheng

    2017-04-04

    The therapeutic efficacy of serial casting on idiopathic scoliosis has been gradually documented. However, literatures on serial casting for congenital scoliosis (CS) remain extremely rare. This paper aimed to compare the treatment outcomes of serial casting between CS and non-CS patients to comprehensively evaluate the therapeutic characteristics of serial casting on CS patients. A total of 23 early-onset scoliosis cases were included and divided into congenital scoliosis (CS, n = 8) and non-congenital group (non-CS, n = 15). Therapeutic outcomes including the major curve Cobb angle, thoracic kyphosis angle, lumbar lodosis angle, and thoracic spine growing rate were compared between groups at precast, after the first cast, and at the latest follow-up, respectively. All patients received the first cast at the age of 3.25 ± 1.20 years and 5.70 ± 1.18 times of cast corrections. The average casting time was 17.17 ± 3.38 months, and the mean follow-up time was 23.91 ± 12.28 months. Both CS and non-CS groups had significant decrease in Cobb angle after the first cast and at the latest follow-up (all P < 0.05). Cobb angle was significantly lower in non-CS group than in CS group at both time points (all P < 0.01). The correction rate of Cobb angle was significantly higher in non-CS group than in CS group (around 50 vs. 20%, both P < 0.01). The mean thoracic growth rate was significantly lower in CS group than in non-CS group (0.72 ± 0.20 vs. 1.42 ± 0.22 cm/year, P < 0.001). At the latest follow-up, there are 2 cases receiving growing rod surgery, 8 cases wearing a brace, and 13 cases continuing serial casting. Although the therapeutic efficacy of casting on CS patients is not as good as that on non-CS patients, casting is still an efficient treatment option for CS patients to delay the need for initial surgery.

  4. Clinical case reports raise doubts about the therapeutic equivalence of an iron sucrose similar preparation compared with iron sucrose originator.

    Science.gov (United States)

    Stein, Jürgen; Dignass, Axel; Chow, Kai Uwe

    2012-02-01

    Intravenous iron sucrose has been used to treat iron deficiency and iron deficiency anaemia associated with different chronic diseases for several decades. Despite the complex structure of iron sucrose, copies called iron sucrose similars (ISSs) have been approved according to the generic approach and therefore, therapeutic equivalence is taken for granted. In February 2011, three patients who previously tolerated well the prescribed iron sucrose originator experienced urticaria, oedema and headache within 1 hour after infusion of an ISS that had been substituted for the originator at the pharmacy level. One patient collapsed due to severe hypovolaemic dysregulation and required hospitalisation. Due to emerging evidence that ISSs differ from the iron sucrose originator in safety and efficacy profiles, it seems prudent for physicians as well as patients who require intravenous (i.v.) iron to have available data on therapeutic equivalence of new ISS preparations versus the originator. This may be especially important in patients who are chronically ill and need iron supplementation on a regular, long-term basis.

  5. Nonconvulsive status epilepticus in the elderly associated with newer antidepressants used at therapeutic doses: A report of three cases

    Directory of Open Access Journals (Sweden)

    Go Taniguchi

    2015-01-01

    All three patients were male and were 73 years of age or older. One patient was recently diagnosed with temporal lobe epilepsy and treated with low-dose lamotrigine. In all patients, newer antidepressants were initiated because of depressive symptoms. After titrating to therapeutic doses (paroxetine 20 mg/day, sertraline 50 mg/day, and combination of sertraline 50 mg/day and mirtazapine 30 mg/day in one patient each, impaired consciousness appeared. Electroencephalography (EEG showed generalized slow waves with intermittent spike–slow-wave complexes. Intravenous injection of antiepileptic drugs improved EEG findings and clinical symptoms. After discontinuance of the abovementioned antidepressants, NCSE did not recur in any of patients. These reports raise the question of whether the newer antidepressants, like classic antidepressants, might also induce NCSE in the elderly, even when used at therapeutic doses. Physicians should consider monitoring for possible NCSE when using newer antidepressants in patients who may have low drug tolerability. Active continuous video-EEG monitoring is essential when behavioral and psychological symptoms or change in consciousness level is suspected.

  6. Martian sand sheet characterization and implications for formation: A case study

    Science.gov (United States)

    Runyon, Kirby D.; Bridges, Nathan T.; Newman, Claire E.

    2017-12-01

    Windblown sand and dust dominate surface geologic processes in Mars' current environment. Besides sand dune fields, areally extensive sand sheets are common across Mars, blanketing the underlying topography with several meters of rippled sand. Earth's sand sheets commonly form upwind or cross-wind to dunes and both partially trap and source sediment to downwind dunes. In contrast, Mars' sheets are frequently located downwind of active barchan and dome sand dunes, suggesting they cannot be a sediment source for the dunes as on Earth. Here, we characterize a Martian sand sheet and its geologic context, model the regional atmospheric circulation, and more broadly consider the implications for sand sheet formation on Mars. Our case study sand sheet in central Herschel Crater is geologic unit interpreted as outcrops of paleo-sand sheets is adjacent to the active sheets. Our observations and atmospheric modeling-which predict wind shear stresses above the sand suspension threshold-indicate that the upwind dunes may be eroding and their sand deposited downwind in sheets in what may be a cyclical process, possibly related to Mars' axial obliquity cycles.

  7. Modelling the black death. A historical case study and implications for the epidemiology of bubonic plague.

    Science.gov (United States)

    Monecke, Stefan; Monecke, Hannelore; Monecke, Jochen

    2009-12-01

    We analysed a plague outbreak in the mining town of Freiberg in Saxony which started in May 1613 and ended in February 1614. This epidemic was selected for study because of the high quality of contemporary sources. It was possible to identify 1400 individual victims meaning that more than 10% of the population of the city perished. The outbreak was modelled by 9 differential equations describing flea, rat, and human populations. This resulted in a close fit to the historical records of this outbreak. An interesting implication of the model is that the introduction of even a small number of immune rats into an otherwise unchanged setting results in an abortive outbreak with very few human victims. Hence, the percentage of immune rats directly influences the magnitude of a human epidemic by diverting search activities of the fleas. Thus, we conclude that the spread of Rattus norvegicus, which might acquire partial herd immunity by exposure to soil- or water-borne Yersinia species due to its preference for wet habitats, contributed to the disappearance of Black Death epidemics from Europe in the 18th century. In order to prove whether or not the parameter values obtained by fitting a given outbreak are also applicable to other cases, we modelled the plague outbreak in Bombay 1905/06 using the same parameter values except for the number of humans as well as of immune and susceptible rats.

  8. A rare variant of the ulnar artery with important clinical implications: a case report

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    Casal Diogo

    2012-11-01

    Full Text Available Abstract Background Variations in the major arteries of the upper limb are estimated to be present in up to one fifth of people, and may have significant clinical implications. Case presentation During routine cadaveric dissection of a 69-year-old fresh female cadaver, a superficial brachioulnar artery with an aberrant path was found bilaterally. The superficial brachioulnar artery originated at midarm level from the brachial artery, pierced the brachial fascia immediately proximal to the elbow, crossed superficial to the muscles that originated from the medial epicondyle, and ran over the pronator teres muscle in a doubling of the antebrachial fascia. It then dipped into the forearm fascia, in the gap between the flexor carpi radialis and the palmaris longus. Subsequently, it ran deep to the palmaris longus muscle belly, and superficially to the flexor digitorum superficialis muscle, reaching the gap between the latter and the flexor carpi ulnaris muscle, where it assumed is usual position lateral to the ulnar nerve. Conclusion As far as the authors could determine, this variant of the superficial brachioulnar artery has only been described twice before in the literature. The existence of such a variant is of particular clinical significance, as these arteries are more susceptible to trauma, and can be easily confused with superficial veins during medical and surgical procedures, potentially leading to iatrogenic distal limb ischemia.

  9. Breaking Therapeutic Inertia in Type 2 Diabetes: Active Detection of In-Patient Cases Allows Improvement of Metabolic Control at Midterm

    Directory of Open Access Journals (Sweden)

    Anna M. Lucas Martín

    2015-01-01

    Full Text Available Type 2 diabetes (T2D exists in 25–40% of hospitalized patients. Therapeutic inertia is the delay in the intensification of a treatment and it is frequent in T2D. The objectives of this study were to detect patients admitted to surgical wards with hyperglycaemia (HH; fasting glycaemia > 140 mg/dL as well as those with T2D and suboptimal chronic glycaemic control (SCGC and to assess the midterm impact of treatment modifications indicated at discharge. A total of 412 HH patients were detected in a period of 18 months; 86.6% (357 had a diagnosed T2D. Their preadmittance HbA1c was 7.7 ± 1.5%; 47% (189 had HbA1c ≥ 7.4% (SCGC and were moved to the upper step in the therapeutic algorithm at discharge. Another 15 subjects (3.6% of the cohort had T2D according to their current HbA1c. Ninety-four of the 189 SCGC patients were evaluated 3–6 months later. Their HbA1c before in-hospital-intervention was 8.6 ± 1.2% and 7.5 ± 1.2% at follow-up (P<0.004. Active detection of hyperglycaemia in patients admitted in conventional surgical beds permits the identification of T2D patients with SCGC as well as previously unknown cases. A shift to the upper step in the therapeutic algorithm at discharge improves this control. Hospitalization is an opportunity to break therapeutic inertia.

  10. [Etiopathogenetic differences and therapeutic possibillities of the carotid sinus syndrome. Report of two rare cases (author's transl)].

    Science.gov (United States)

    Dei Cas, L; Bianchi, G; Paini, G P; Effendy, F N; Brizzi, R; Visioli, O

    1978-06-01

    Two cases of carotid sinus syndrome with peculiar clinical and nosological characteristics are presented. The clinical symptoms were characterized by syncope with bradicardia and hypotension, which occurred contemporarily or independently of each other. The most valuable medical therapy to prevent or got over the syncopal attacks has proved to be one associating the sympathicomimetic drugs (high dosage dopamine, particularly on demande pacemaker. Complete decrease of symptoms following was obtained only after surgical treatment: denervation of carotid sinus in one case, intracranical section of the glosspharyngeal nerve and of the two vagal termination nearer to IX in the other case. This last result makes it possible to consider the case in question from an original nosological point of view exploiting the pathogenetic importance of stimulating the afferent nerve-fibres of the glossofaryngeal-nerve.

  11. Return to Competition in a Chronic Low Back Pain Runner: Beyond a Therapeutic Exercise Approach, a Case Report.

    Science.gov (United States)

    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.

  12. Comparing Online and Face-to-Face Student Counselling: What Therapeutic Goals Are Identifed and What Are the Implications for Educational Providers?

    Science.gov (United States)

    Hanley, Terry; Ersahin, Zehra; Sefi, Aaron; Hebron, Judith

    2017-01-01

    Online counselling is increasingly being used as an alternative to face-to-face student counselling. Using an exploratory mixed methods design, this project investigated the practice by examining the types of therapeutic goals that 11- to 25-year-olds identify online in routine practice. These goals were then compared to goals identified in…

  13. Therapeutic drug monitoring of ganciclovir for postnatal cytomegalovirus infection in an extremely low birth weight infant: a case report.

    Science.gov (United States)

    Sunada, Mariko; Kinoshita, Daisuke; Furukawa, Naoko; Kihara, Minako; Nishimura, Akira; Moriuchi, Masako; Moriuchi, Hiroyuki

    2016-08-22

    Ganciclovir is a therapeutic choice for extremely premature infants with severe postnatal cytomegalovirus disease, but little is known about its optimal dose size and dosing interval for them. We treated an extremely premature female infant with postnatal cytomegalovirus infection with intravenous administration of ganciclovir since 49 days of life (postmenstrual age of 31 weeks). After ganciclovir treatment was initiated at a dose of 5 mg/kg every 12 h, cytomegalovirus loads in the peripheral blood were markedly decreased. However, since plasma ganciclovir trough level was too high, the interval was extended to every 24 h. Subsequently, the trough level and the estimated 12-h area under the concentration-time curve (AUC0-12) were decreased from 3.5 mg/L to 0.3 mg/L and 53.9 mg · h/L to 19.2 mg · h/L, respectively, resulting in an exacerbation of viremia and clinical condition. Adjustment of dosing interval from 24 h to 12 h led to a peak level of 4.2 mg/L, trough level of 1.1 mg/L, and AUC0-12 of 31.8 mg · h/L, resulting in a marked suppression of viral load. Monitoring the therapeutic drug levels and cytomegalovirus loads is useful in obtaining a proper treatment effect and preventing overdosage during ganciclovir therapy in premature infants with postnatal cytomegalovirus infection.

  14. Surgical mistake causing an high recto-vaginal fistula. A case report with combined surgical and endoscopic approach: therapeutic considerations

    Science.gov (United States)

    2013-01-01

    Background Rectovaginal fistulas (RVFs) have multiple causes, size and location on which the surgical treatment depends. Description The Authors consider different approaches to RVFs and describe a clinical case of recurrent high RVF. Conclusions Most RVFs can be successfully repaired, although many interventions may be necessary. A colostomy with delayed repair may improve RVFs outcome. Moreover, several authors indicate Mucosal Advancement Flap and Babcock-Bacon technique as the treatments of choice respectively for low and high RVFs (complex and recurrent) and emphasize the placement of endoscopic prothesis in cases of difficult healing of the anastomosis. PMID:24266908

  15. [Comparison of therapeutic effects between patella replacement and patella osteotomy in total knee arthroplasty: a case-control study].

    Science.gov (United States)

    Tang, Xiao-Bo; Dong, Pei-Long; Wang, Jian

    2014-04-01

    To compare therapeutic effects between patella replacement and patella osteotomy in total knee arthroplasty. From April 2004 to April 2011, 52 patients (54 knees) were enrolled in the clinical trail of total knee arthroplasty, who received patella replacement (24 knees, including 13 males and 11 females,ranging in age from 53 to 78 years old or patella osteotomy (30 knees,including 16 males and 12 females,ranging in age from 55 to 79 years old. The average follow-up period was 56 months,ranging from 20 to 80 months. The American HSS Score for knee, the Feller score for patella, range of motion (ROM) for knee, patient satisfaction and complications related to the patella were used to evaluate therapeutic effects. In the patella replacement group,the preoperative and final follow-up HSS scores of patients were 38.4 +/- 8.2 and 91.2 +/- 8.6 respectively; Feller scores were 13.6 +/- 6.2 and 25.2 +/- 4.2; scores of anterior knee pain were 3.9 +/- 3.2 and 11.2 +/- 3.7; ROM were (78 +/- 26) degrees and(108 +/- 18) degrees. In the patella osteotomy group,the preoperative and final follow-up HSS scores of patients were 39.5 +/- 8.4 and 91.0 +/- 8.5 respectively;Feller scores were 13.4 +/- 6.5 and 25.6 +/- 4.0; scores of anterior knee pain were 3.7 +/- 3.1 and 11.3 +/- 3.6; ROM were (76 +/- 27) degrees and (110 +/- 19) degrees. In the patella replacement group,patient's satisfaction was 91%, and complication related to the patella was 16.7%; in the patella osteotomy group, patient's satisfaction was 89%, and complications related to the patella was 10.0%. There were no statistically significant differeneces in final follow-up HSS scores, Feller scores, scores of anterior knee pain and ROM between the two groups. However,there was no significant difference of patient's satisfaction between them. There was statistically significant differenece of patella-related complications between the two groups, and the complication rate in the patella replacement group was higher than

  16. Diagnostic and therapeutic challenges of an ambiguous cystic kidney disease in a resource limited setting: a case report.

    Science.gov (United States)

    Dimala, Christian Akem; Bechem, Ndemazie Nkafu; Kadia, Benjamin Momo; Feteh, Vitalis Fambombi; Choukem, Simeon Pierre

    2017-03-01

    Unilateral renal cystic disease is a rare condition that shares morphological similarities with multicystic dysplastic kidney, the former often distinguished from the latter on some clinical and histopathological grounds. However serious diagnostic and therapeutic dilemmas set in when there is a considerable overlap in the distinguishing features between these entities. A 19-year-old African female presented with a chronic severe debilitating right lower quadrant abdominal pain refractory to analgesics. Biochemical investigations and imaging studies revealed a non-functional polycystic right kidney and no identifiable pelvicalyceal system or ureter but with preserved renal function. The marked overlap in clinical presentation between unilateral renal cystic disease and multicystic dysplastic kidney in this patient necessitated further investigation to pose an appropriate diagnosis. A right nephrectomy was performed and histopathological analysis of the resected kidney done, the results of which were more consistent with unilateral renal cystic disease. The post-operative course was favorable. Unilateral renal cystic disease with an ipsilateral non-functional kidney and an atretic pelvicalyceal system is a very rare condition that needs to be distinguished from multicystic dysplastic kidney in order to guide management and set prognosis. A suspicion of either of these diseases therefore warrants a thorough clinical evaluation and the appropriate combination of biochemical and imaging investigations.

  17. Climate change and energy: The implications for the Spanish case; Cambio Climatico y Energia: Impliacaciones reciprocas en el caso Espanol

    Energy Technology Data Exchange (ETDEWEB)

    Perez Arriaga, J. I.

    2007-07-01

    This paper examines the mutual implications between the climate change problem and the actual energy-at-a-crossroads situation of the unsustainable world energy model. The implications for the Spanish case are studied as a case example. The paper provides a brief review of the scientific evidence on climate change, analyzes the causes of the present energy dilemma and characterizes the problem to be addressed. The principal challenge for the future climate regime is to identify the nature and level of commitment that will provide sufficient incentives for all countries, with such a diversity of interests. The paper also exposes the most plausible framework for the future climate regime, the basic components of such a regime, the role to be played by the major stake holders and some guidelines for future negotiations. (Author)

  18. The ISO 14001 EMS Implementation Process and Its Implications: A Case Study of Central Japan.

    Science.gov (United States)

    Mohammed

    2000-02-01

    / This study aims to investigate the ISO 14001 implementation process and its implications for regional environmental management. The region of Central Japan (known as Chubu in Japanese, which literally means center) was chosen for this case study. The study focuses on selected issues such as the: (1) trends and motives of private firms in the implementation of an ISO 14001-based environmental management system (EMS); (2) obstacles during system implementation; (3) role of the system in enhancing environmental performance within the certified organization; and (4) relation between the major stakeholders, local citizens, governments, and firms after adopting the system. To achieve these objectives, a questionnaire survey was mailed to all certified firms in the region. A 58% response was achieved overall. The results show that the main aims behind the adoption of ISO 14001 by firms in the Chubu region are to improve the environmental aspects within the enterprises and to enhance the employees' environmental awareness and capacity. The results have also shown that the ISO 14001-based EMS has had a great effect on a firm's environmental status as certified firms have claimed that natural resources such as fuel, water, and paper consumption have been more efficiently managed after adopting the system. Implementation of the system causes the firms to consider the role of the local people and the government in more effectively involving the local people in the firm's daily environmental activities. It also helps to enhance the environmental awareness among the local people. Adopting the system also promotes a better relation within the enterprises affiliated to the same group, such as more attention given by the parent firms (head offices) towards other firms working for the same group, or branches-mainly small and medium sized enterprises (SMEs)-in the field of EMS. Finally, the results show that firms give serious consideration to their final products' impacts on the

  19. Malaria case in Madagascar, probable implication of a new vector, Anopheles coustani.

    Science.gov (United States)

    Nepomichene, Thiery N J J; Tata, Etienne; Boyer, Sébastien

    2015-12-01

    Indoor spraying of insecticides and the use of insecticide-treated bed nets are key strategies for national malaria vector control in the central highlands of Madagascar. During the year 2013, malaria outbreaks were reported by the National Malaria Control Programme in the highlands, including the district of Ankazobe. Entomological trapping was carried out in April and May 2013 and in March 2014, using human landing catches, collection of mosquitoes resting in stables and in houses by oral aspirators, and Centers for Disease Control and Prevention light traps. Detection of Plasmodium in mosquitoes was carried out on head and thorax of anopheline females by ELISA, CSP and PCR (Plasmodium falciparum, Plasmodium malariae, Plasmodium vivax, or Plasmodium ovale). Human biting rate (HBR), sporozoite index and entomological infection rate (EIR) were calculated for Anopheles funestus, Anopheles arabiensis, Anopheles mascarensis, and Anopheles coustani. In Ankazobe district, the presence of malaria vectors such as An. funestus, An. arabiensis and An. mascarensis was confirmed, and a new and abundant potential vector, An. coustani was detected. Indeed, one individual of An. funestus and two An. coustani were detected positive with P. falciparum while one An. mascarensis and four An. coustani were positive with P. vivax. For An. coustani, in March 2014, the EIR varied from 0.01 infectious bites/person/month (ipm) outdoors to 0.11 ipm indoors. For An. funestus, in April 2013, the EIR was 0.13 ipm. The highest HBR value was observed for An. coustani, 86.13 ipm outdoors. The highest sporozoite rate was also for An. coustani, 9.5 % of An. coustani caught in stable was sporozoite positive. The implication of An. coustani in malaria transmission was not previously mentioned in Madagascar. Its very high abundance and the detection of Plasmodium coupled with an opportunistic feeding behaviour in villages with malaria cases supports its role in malaria transmission in Madagascar.

  20. Molecular profiling of patient-matched brain and extracranial melanoma metastases implicates the PI3K pathway as a therapeutic target.

    Science.gov (United States)

    Chen, Guo; Chakravarti, Nitin; Aardalen, Kimberly; Lazar, Alexander J; Tetzlaff, Michael T; Wubbenhorst, Bradley; Kim, Sang-Bae; Kopetz, Scott; Ledoux, Alicia A; Gopal, Y N Vashisht; Pereira, Cristiano Goncalves; Deng, Wanleng; Lee, Ju-Seog; Nathanson, Katherine L; Aldape, Kenneth D; Prieto, Victor G; Stuart, Darrin; Davies, Michael A

    2014-11-01

    An improved understanding of the molecular pathogenesis of brain metastases, one of the most common and devastating complications of advanced melanoma, may identify and prioritize rational therapeutic approaches for this disease. In particular, the identification of molecular differences between brain and extracranial metastases would support the need for the development of organ-specific therapeutic approaches. Hotspot mutations, copy number variations (CNV), global mRNA expression patterns, and quantitative analysis of protein expression and activation by reverse-phase protein array (RPPA) analysis were evaluated in pairs of melanoma brain metastases and extracranial metastases from patients who had undergone surgical resection for both types of tumors. The status of 154 previously reported hotspot mutations, including driver mutations in BRAF and NRAS, were concordant in all evaluable patient-matched pairs of tumors. Overall patterns of CNV, mRNA expression, and protein expression were largely similar between the paired samples for individual patients. However, brain metastases demonstrated increased expression of several activation-specific protein markers in the PI3K/AKT pathway compared with the extracranial metastases. These results add to the understanding of the molecular characteristics of melanoma brain metastases and support the rationale for additional testing of the PI3K/AKT pathway as a therapeutic target in these highly aggressive tumors. ©2014 American Association for Cancer Research.

  1. Severe iron overload and hyporegenerative anemia in a case with rhesus hemolytic disease: therapeutic approach to rare complications

    Directory of Open Access Journals (Sweden)

    Fatih Demircioğlu

    2010-09-01

    Full Text Available A 33 weeks’ gestation, a baby with rhesus hemolytic disease (RHD, who had received intrauterine transfusions twice, developed cholestatic hepatic disease and late hyporegenerative anemia. Her serum ferritin and bilirubin levels increased to 8842 ng/ml and 17.9 mg/dl, respectively. Liver biopsy showed cholestasis and severe iron overload. Treatment with recombinant erythropoietin (rHuEPO decreased the transfusion need, and intravenous deferoxamine resulted in a marked decreased in serum ferritin levels and normalization of liver function. In patients who have undergone intrauterine transfusions due to RHD, hyperferritinemia and late hyporegenerative anemia should be kept in mind. Chelation therapy in cases with symptomatic hyperferritinemia and rHuEPO treatment in cases with severe hyporegenerative anemia should be considered.

  2. Rituximab seems a promising therapeutic option in granulomatosis with polyangiitis with intestinal perforation: a case report and literature review.

    Science.gov (United States)

    Dag, Muhammet Sait; Pehlivan, Yavuz; Tutar, Ediz; Kisacik, Bunyamin

    2013-01-22

    Granulomatosis with polyangiitis (Wegener's) (GPA) is a chronic disease of unknown aetiology that leads to necrotising vasculitis in small and medium-sized vessels characterised by respiratory system and kidney involvement. Intestinal involvement is rare and perforation is even rarer in GPA. In this study, we are presenting a literature review of related cases, and a 29-year-old man referred from the emergency department with a multiple distal ileal perforation that was diagnosed with GPA, and successfully treated with rituximab.

  3. Cine MRI enables better therapeutic planning than CT in cases of possible lung cancer chest wall invasion.

    Science.gov (United States)

    Kajiwara, Naohiro; Akata, Soichi; Uchida, Osamu; Usuda, Jitsuo; Ohira, Tatsuo; Kawate, Norihiko; Ikeda, Norihiko

    2010-08-01

    To evaluate the hypothesis that lung cancer treatment planning (whether or not to use induction therapy) can be improved if respiratory dynamic cine magnetic resonance imaging (RD MR) is used. We studied 100 lung cancer patients, 76 men and 21 women, scheduled for thoracotomies between May 1997 and December 2006 wherein it was unclear preoperatively whether chest wall invasion would be found. We evaluated the accuracy of RD MR as compared with the findings at operation and postoperative pathology. The accuracy of RD MRI for evaluating chest wall invasion was compared with the efficacy of CT and MRI within our own group of patients and with data from the studies of other investigators. Concerning the evaluation of chest wall invasion, conventional computed tomography (CT) had 43.9% specificity, 60.0% sensitivity and 47.1% accuracy, while RD MR had 68.5% specificity, 100.0% sensitivity and 77.0% accuracy. RD MRI was particularly useful in the evaluation of cancers around 5 cm in diameter that were located adjacent to the diaphragm. Postoperative evaluation of superior sulcus tumor cases that had received induction therapy also showed that the RD MR procedure enabled an accurate decision in 87.5% of cases, and there were no false negative cases. RD MR is more useful than CT or standard MRI for evaluating thoracic wall invasion. This noninvasive method enhances the reliability of deciding whether induction therapy should be employed. Copyright 2009 Elsevier Ireland Ltd. All rights reserved.

  4. Therapeutic misadventure.

    Science.gov (United States)

    Langford, N J

    2010-10-01

    Therapeutic misadventure can be defined as an injury or an adverse event caused by medical management rather than by an underlying disease. Within the National Health Service there were over 86,000 reported adverse incidents in 2007. In the USA medication errors have been rated as the fourth highest cause of death. Unfortunately one of the greatest contributors to iatrogenic injury is human error. The potential types of misadventure are infinite. Medication errors are a major part of this, being responsible for over 70% of cases that cause serious harm. However, many medication errors caused by slips, lapses, technical errors and mistakes are preventable; intentional violations of safe operating procedures are not. While medication errors were tolerated by society in the past, the readiness to institute criminal proceedings against health-care professionals has increased greatly in the UK over the last decade. The medication process consists of writing prescriptions, dispensing the product, administering it and monitoring its effects. Prescription errors arise owing to incomplete information, lack of appropriate labelling, environmental factors and human blunders. Even with a perfect prescription the right medication must be dispensed and appropriately labelled. Dispensing errors are not uncommon and may be compounded by non-clinical considerations. Administration of a drug by injection is one of the most dangerous aspects of the medication process, especially in inexperienced hands. The final component of medication supply is monitoring the effect of the medication. With short courses of medication such monitoring is easy, but with long-term medication, particularly with potent drugs where the margin between efficacy and toxicity is small, active procedures may be required to ensure toxicity does not ensue. Despite the endeavour of health-care professions to stick to the rule of 'first, do no harm', in reality this is difficult to achieve all of the time. When

  5. Transient osteoporosis of pregnancy: A case report and review of anesthetic implications

    Directory of Open Access Journals (Sweden)

    Victor Eduardo Anillo Lombana

    2013-01-01

    We reviewed the anesthetic implications of this rare disease, particularly the use of a regional technique that removes the restrictive effect of the hip pain, and therefore increases the risk of a fracture.

  6. Autologous blood transfusion for hemodialysis patients: A case report and review of clinical reports and therapeutic features.

    Science.gov (United States)

    Suzuki, Yuhko; Okai, Ken; Ohashi, Hironori; Aota, Shigeo; Sakurai, Kaoru; Terawaki, Hiroyuki; Ohtsuka, Setsuko; Wakasugi, Minako; Nollet, Kenneth Eric; Ohto, Hitoshi

    2015-04-01

    We describe a hemodialysis (HD) patient who successfully underwent total hip arthroplasty with autologous blood transfusion (ABT). There were several problems with collecting ABT in this setting. A literature search for HD patients and ABT produced 8 articles describing 29 patients. Higher doses of erythropoietin stimulating agents were used to collect ABT than for a typical HD session. In 75% of the cases autologous blood was collected just after HD to collect better quality blood. The optimal clinical procedures for ABT in HD patients need to be clarified. Copyright © 2015 Elsevier Ltd. All rights reserved.

  7. Kant and therapeutic privilege.

    Science.gov (United States)

    Brown, Chris

    2008-08-01

    Given Kant's exceptionless moral prohibition on lying, one might suspect that he is committed to a similar prohibition on withholding diagnostic and prognostic information from patients. I confirm this suspicion by adapting arguments against therapeutic privilege from his arguments against lying. However, I show that all these arguments are importantly flawed and submit that they should be rejected. A more compelling Kantian take on informed consent and therapeutic privilege is achievable, I argue, by focusing on Kant's duty of beneficence, which requires us to aim at furthering others' ends. But I show that there are some cases in which furthering a patient's ends requires withholding material medical information from her. Although I concede that these cases are probably quite rare, I conclude that the best Kantian thinking agrees with that of therapeutic privilege's advocates.

  8. Therapeutic Implications of Black Seed and Its Constituent Thymoquinone in the Prevention of Cancer through Inactivation and Activation of Molecular Pathways

    Directory of Open Access Journals (Sweden)

    Arshad H. Rahmani

    2014-01-01

    Full Text Available The cancer is probably the most dreaded disease in both men and women and also major health problem worldwide. Despite its high prevalence, the exact molecular mechanisms of the development and progression are not fully understood. The current chemotherapy/radiotherapy regime used to treat cancer shows adverse side effect and may alter gene functions. Natural products are generally safe, effective, and less expensive substitutes of anticancer chemotherapeutics. Based on previous studies of their potential therapeutic uses, Nigella sativa and its constituents may be proved as good therapeutic options in the prevention of cancer. Black seeds are used as staple food in the Middle Eastern Countries for thousands of years and also in the treatment of diseases. Earlier studies have shown that N. sativa and its constituent thymoquinone (TQ have important roles in the prevention and treatment of cancer by modulating cell signaling pathways. In this review, we summarize the role of N. sativa and its constituents TQ in the prevention of cancer through the activation or inactivation of molecular cell signaling pathways.

  9. Metabolism and function of hepatitis B virus cccDNA: Implications for the development of cccDNA-targeting antiviral therapeutics.

    Science.gov (United States)

    Guo, Ju-Tao; Guo, Haitao

    2015-10-01

    Persistent hepatitis B virus (HBV) infection relies on the stable maintenance and proper functioning of a nuclear episomal form of the viral genome called covalently closed circular (ccc) DNA. One of the major reasons for the failure of currently available antiviral therapeutics to achieve a cure of chronic HBV infection is their inability to eradicate or inactivate cccDNA. In this review article, we summarize our current understanding of cccDNA metabolism in hepatocytes and the modulation of cccDNA by host pathophysiological and immunological cues. Perspectives on the future investigation of cccDNA biology, as well as strategies and progress in therapeutic elimination and/or transcriptional silencing of cccDNA through rational design and phenotypic screenings, are also discussed. This article forms part of a symposium in Antiviral Research on "An unfinished story: from the discovery of the Australia antigen to the development of new curative therapies for hepatitis B." Copyright © 2015 Elsevier B.V. All rights reserved.

  10. Implications for advanced safeguards derived from PR&PP case study results

    Energy Technology Data Exchange (ETDEWEB)

    Boyer, Brian D [Los Alamos National Laboratory

    2009-01-01

    The proliferation resistance and physical protection (PR and PP) working group produced a case study on the Example Sodium Fast Reactor (ESFR). The ESFR is a hypothetical nuclear energy system consisting of four sodium-cooled fast reactors of medium size collocated with an on-site dry fuel storage facility and a spent fuel reprocessing facility using pyroprocessing technology. This study revealed how safeguards would be applied at such site consisting of integrated multiple fuel cycle facilities and the implications of what safeguards technology and safeguards concepts would need to be adapted and developed to safeguard successfully this Generation IV nuclear energy system concept. The major safeguards concepts driving our safeguards analysis are timeliness goals and material quantity goals. Because the fresh transuranic (TRU) fuel to be produced in the ESFR fuel fabrication facility contains plutonium, the ESFR will be reprocessing, using in the reactor, and storing material on site that will have IAEA defined 'direct-use material' in it with stringent timeliness goals and material quantity goals that drive the safeguards implementation. Specifically, the TRU fresh fuel, pyroprocessing in process material, LWR spent fuel sent to the ESFR, and TRU spent fuel will contain plutonium. This material will need to be verified at interim intervals four times per year because the irradiated direct-use material, as defined previously, has three-month timeliness goals and 8 kg material quantity goals for plutonium. The TRU in-process material is, of course, irradiated direct-use material as defined by the IAEA. Keeping the plutonium and uranium together with TRu products should provide a radiation barrier. this radiation barrier slows down the ability to reprocess the fuel. Furthermore, the reprocessing technique, if it has some intrinsic proliferation resistance, will need major modifications to be able to separate plutonium from the uranium and TRU mixture. The

  11. Cryptococcosis in an Infectious Diseases Hospital of Buenos Aires, Argentina. Revision of 2041 cases: Diagnosis, clinical features and therapeutics.

    Science.gov (United States)

    Arechavala, Alicia; Negroni, Ricardo; Messina, Fernando; Romero, Mercedes; Marín, Emmanuel; Depardo, Roxana; Walker, Laura; Santiso, Gabriela

    2017-11-09

    Cryptococcosis is still a life-threatening mycosis that continues to be of serious concern in Latin American countries, especially among HIV+positive population. However, there is not any reliable information about the prevalence of this disease in this region. The aim of this study is to report data of 2041 patients with cryptococcosis that were attended at the Infectious Diseases Hospital F. J. Muñiz over a 30 year-period. Information about demographic and clinical data, survival time and the applied treatment, was taken from the Mycology Unit database. Mycological exams from different clinical samples were performed. Cryptococcal capsular antigen in serum and cerebrospinal fluid was detected through the latex agglutination technique. Cryptococcus isolates were phenotypically identified and the genotype was determined in some of them. Susceptibility tests were carried out following M27-A3 document. Seventy five percent of HIV+positive patients and 50% of the HIV-negative population were males. Mean ages were 34.1 in HIV+positive patients and 44.8 in the HIV-negative. Cryptococcosis was associated with AIDS in 98% of the cases. Meningeal compromise was seen in 90% of the patients. Although cerebrospinal fluid rendered more positive results, blood culture was the first diagnostic finding in some cases. Cryptococcal antigen showed positive results in 96.2% of the sera samples and in the 93.1% of the cerebrospinal fluid samples. Most of the isolates were Cryptococcus neoformans and belonged to genotype VNI. Minimal inhibitory concentration values were mostly below the epidemiological cutoff values. We observed that thanks to a high level of clinical suspicion, early diagnosis, combined therapy and intracranial pressure control by daily lumbar punctures, the global mortality rate has markedly decreased through the years in the analyzed period. Copyright © 2017 Asociación Española de Micología. Publicado por Elsevier España, S.L.U. All rights reserved.

  12. Therapeutic Nanodevices

    Science.gov (United States)

    Lee, Stephen; Ruegsegger, Mark; Barnes, Philip; Smith, Bryan; Ferrari, Mauro

    Therapeutic nanotechnology offers minimally invasive therapies with high densities of function concentrated in small volumes, features that may reduce patient morbidity and mortality. Unlike other areas of nanotechnology, novel physical properties associated with nanoscale dimensionality are not the raison d'être of therapeutic nanotechnology, whereas the aggregation of multiple biochemical (or comparably precise) functions into controlled nanoarchitectures is. Multifunctionality is a hallmark of emerging nanotherapeutic devices, and multifunctionality can allow nanotherapeutic devices to perform multistep work processes, with each functional component contributing to one or more nanodevice subroutine such that, in aggregate, subroutines sum to a cogent work process. Cannonical nanotherapeutic subroutines include tethering (targeting) to sites of disease, dispensing measured doses of drug (or bioactive compound), detection of residual disease after therapy and communication with an external clinician/operator. Emerging nanotherapeutics thus blur the boundaries between medical devices and traditional pharmaceuticals. Assembly of therapeutic nanodevices generally exploits either (bio)material self-assembly properties or chemoselective bioconjugation techniques, or both. Given the complexity, composition, and the necessity for their tight chemical and structural definition inherent in the nature of nanotherapeutics, their cost of goods (COGs) might exceed that of (already expensive) biologics. Early therapeutic nanodevices will likely be applied to disease states which exhibit significant unmet patient need (cancer and cardiovascular disease), while application to other disease states well-served by conventional therapy may await perfection of nanotherapeutic design and assembly protocols.

  13. Understanding the environmental implications of energy transitions. A case study for wind power

    Energy Technology Data Exchange (ETDEWEB)

    Arvesen, Anders

    2013-03-01

    A fundamental change in the ways in which we provide energy to run our economies, an energy transition, is needed to mitigate climate change. Wind power is an important part of future global energy supply in most energy scenarios. This thesis aims to contribute to a better understanding of the environmental implications of energy transitions, primarily by examining the case of wind power. This involves new investigations of both potential negative impacts of wind power and the positive role of the technology in emission reduction, as well as a critical review of past research. Three papers on wind power are presented: a comprehensive literature review of life cycle assessments (LCA) of wind power, a scenario-based LCA of large-scale adoption of wind power, and an LCA of an offshore wind farm. A hybrid LCA methodology is employed in the scenario-based LCA and LCA of an offshore wind farm. Another paper is presented which is not concerned with wind power in particular, but takes the form of an evaluation of limitations of climate change mitigation literature. It helps to achieve the aim stated above by bringing together knowledge of indirect effects of mitigation measures, and by elucidating how these effects may influence the viability of proposed mitigation strategies. The literature review aims to take stock of insights from past research, with a particular view to identifying remaining challenges. A survey of results indicates 0.063 ({+-}0.061) and 0.055 ({+-}0.037) kWh energy used and 20 ({+-}14) and 16 ({+-}10) Co2 emitted per kWh electricity for onshore and offshore cases. Evidence suggests strong positive effects of scale in the lower end of the turbine size spectrum, but is inconclusive for the megawatt range. LCAs tend to assume higher capacity factors than current real-world averages. Limitations of existing research are discussed; this includes poorly understood toxicity and resource depletion impacts, cut-off errors and seemingly inconsistent modelling

  14. Severe form of streptococcal necrotizing fasciitis of the upper limb - diagnostic and therapeutic challenge: A case report

    Directory of Open Access Journals (Sweden)

    Mikić Dragan

    2015-01-01

    Full Text Available Introduction. Since delay in recognition and effective treatment of necrotizing fasciitis (NF caused by invasive group A streptococcus increases the mortality and disability, the early diagnosis and management of this disease are essential for a better outcome. We presented a patient with a severe form of streptococcal NF of the left upper limb in whom amputation was performed as a life saving procedure. Case report. A 65-year-old man, previously healthy, suffered an injury to his left hand by sting on a fish bone. Two days after that the patient got fever, redness, swelling and pain in his left hand. Clinical examination of the patient after admission indicated NF that spread quickly to the entire left upper limb, left armpit, and the left side of the chest and abdomen. Despite the use of aggressive antibiotic and surgical therapy severe destruction of the skin and subcutaneous tissues developed with the development of gangrene of the left upper limb. In this situation, the team of specialists decided that the patient must be operated on submited to amputation of the left arm, at the shoulder. After amputation and aggressive debridement of soft tissue on the left side of the trunk, the patient completely recovered. β-hemolytic streptococcus group A was isolated from the skin and tissue obtained during the surgery. Conclusion. In the most severe forms of streptococcal NF of the extremities, adequate multidisciplinary treatment, including limb amputation, can save the life of a patient.

  15. Hepatoid Adenocarcinoma of the Stomach: A Challenging Diagnostic and Therapeutic Disease through a Case Report and Review of the Literature

    Directory of Open Access Journals (Sweden)

    Najla Fakhruddin

    2017-09-01

    Full Text Available Hepatoid adenocarcinoma of the stomach (HAS is a rare aggressive tumor with hepatocellular differentiation. HAS often produces alpha fetoprotein (AFP and metastasizes to the lymph nodes and the liver. Molecular studies revealed Her2 amplification and overexpression, association with p53 mutations, but no association with KRAS mutations. EGFR and BRAF mutations have not yet been evaluated in hepatoid carcinoma of the stomach so far. Hereby, we present a case of a 41-year-old female patient with HAS with high AFP level and liver metastases. Molecular analysis revealed Her2 overexpression by immunohistochemistry (IHC, but no EGFR, KRAS, or BRAF mutations were detected. The patient underwent chemotherapy type DCX (docetaxel, cisplatinum, and capecitabine every 3 weeks with partial response after two cycles, maintained for eight cycles, and then was on maintenance therapy with trastuzumab for 7 months before relapsing and dying 18 months from the day of diagnosis. Conclusively, HAS may be misdiagnosed as hepatocellular carcinoma; therefore, it should be considered in the differential diagnosis of multiple hepatic nodules with high AFP and no history of hepatitis, liver fibrosis or cirrhosis.

  16. Radiofrequency Ablation in the Management of Advanced Stage Thymomas: A Case Report on a Novel Multidisciplinary Therapeutic Approach

    Directory of Open Access Journals (Sweden)

    Panagiotis Paliogiannis

    2014-01-01

    Full Text Available We describe in this report a case of successful radiofrequency ablation of an unresectable stage III-type B3 thymoma, and we discuss the role of this novel approach in the management of patients with advanced stage thymoma. The patient, a 59-year-old Caucasian male underwent neoadjuvant chemotherapy with only a slight reduction of the mass. Subsequently, an explorative sternotomy and debulking were performed; before closing the thorax, radiofrequency ablation of the residual tumor was carried out and a partial necrosis of the mass was achieved. A further percutaneous radiofrequency ablation was performed subsequently, obtaining complete necrosis of the lesion. Successively, the patient underwent adjuvant radiotherapy. As a result of this multidisciplinary treatment, complete and stable response was obtained. It is hard to say which of the single treatments had the major impact on cure; nevertheless, the results obtained suggest that radiofrequency ablation must be taken into account for the treatment of advanced stage thymomas, and its effectiveness must be further assessed in future studies.

  17. Therapeutic and Ethical Dilemma of Puberty and Menstruation Problems in an Intellectually Disabled (Autistic) Female: a Case Report.

    Science.gov (United States)

    Memarian, Azadeh; Mehrpisheh, Shahrokh

    2015-10-01

    Intellectual disability is a term used when a person has certain limitations in mental functioning and skills. Autism is a group of developmental brain disorders, collectively called autism spectrum disorder (ASD). Teenagers with learning and physical disabilities are more likely to have menstrual problems compared to the general populations. The parents of a 12-year-old girl with autism spectrum disorder and intellectual disability referred to the coroner due to her numerous problems of puberty (menstruation) including: poor hygiene and polluting herself and the environment, not allowing to put or change the pads and changes in mood and physical health prior period, requested for the surgery (hysterectomy). In legal medicine organization after reviewing the medical records, physical exams and medical consultations with a gynecologist and psychiatric, surgery was not accepted. Hysterectomy (surgery) due to the age of the child, either physically or morally is not recommended. The use of hormone replacement therapy has side effects such as osteoporosis. In these cases, it seems noninvasive methods (behavioral therapy and learning care skills) under the welfare experts is also more effective and morally.

  18. Insights into the Molecular Pathogenesis of Activated B-Cell-like Diffuse Large B-Cell Lymphoma and Its Therapeutic Implications

    Directory of Open Access Journals (Sweden)

    Georg Lenz

    2015-05-01

    Full Text Available Within the last couple of years, the understanding of the molecular mechanisms that drive the pathogenesis of diffuse large B-cell lymphoma (DLBCL has significantly improved. Large-scale gene expression profiling studies have led to the discovery of several molecularly defined subtypes that are characterized by specific oncogene addictions and significant differences in their outcome. Next generation sequencing efforts combined with RNA interference screens frequently identify crucial oncogenes that lead to constitutive activation of various signaling pathways that drive lymphomagenesis. This review summarizes our current understanding of the molecular pathogenesis of the activated B-cell-like (ABC DLBCL subtype that is characterized by poor prognosis. A special emphasis is put on findings that might impact therapeutic strategies of affected patients.

  19. Insights into the Molecular Pathogenesis of Activated B-Cell-like Diffuse Large B-Cell Lymphoma and Its Therapeutic Implications

    Energy Technology Data Exchange (ETDEWEB)

    Lenz, Georg [Translational Oncology, Department of Medicine A, Albert-Schweitzer Campus 1, University Hospital Münster, 48149 Münster (Germany); Cluster of Excellence EXC 1003, Cells in Motion, 48149 Münster (Germany)

    2015-05-22

    Within the last couple of years, the understanding of the molecular mechanisms that drive the pathogenesis of diffuse large B-cell lymphoma (DLBCL) has significantly improved. Large-scale gene expression profiling studies have led to the discovery of several molecularly defined subtypes that are characterized by specific oncogene addictions and significant differences in their outcome. Next generation sequencing efforts combined with RNA interference screens frequently identify crucial oncogenes that lead to constitutive activation of various signaling pathways that drive lymphomagenesis. This review summarizes our current understanding of the molecular pathogenesis of the activated B-cell-like (ABC) DLBCL subtype that is characterized by poor prognosis. A special emphasis is put on findings that might impact therapeutic strategies of affected patients.

  20. Relationship between native-state solubility and non-native aggregation of recombinant human granulocyte colony stimulating factor: practical implications for protein therapeutic development.

    Science.gov (United States)

    Banks, Douglas D; Zhang, Jun; Siska, Christine C

    2014-10-06

    Prescreening methods are needed in the biotechnology industry for rapid selection of protein therapeutic candidates and formulations of low aggregation propensity. In recent reports solubility measurements have shown promise as one such method, although the connection between protein solubility and non-native aggregation is not well understood. In the present investigation, recombinant human granulocyte colony stimulating factor (rhGCSF) was used to explore this relationship since it was previously shown to rapidly undergo non-native aggregation/precipitation under physiological conditions in a reaction attenuated by the addition of sucrose [Krishnan, S.; et al. Biochemistry 2002, 41, 6422-6431]. Strong correlations were found between rhGCSF non-native aggregation and both solubility and thermal stability as a function of sucrose concentration. We believe these results make sense in the context of an rhGCSF aggregation mechanism where loss of monomer to insoluble aggregate is limited by association to an observable dimer from a less soluble (and aggregation competent) intermediate species that exists in a temperature sensitive pre-equilibrium with the native monomer. Both solubility and measures of conformational stability report on the position of this equilibrium and therefore the concentration of reactive intermediate. Interestingly, aggregation also correlated with rhGCSF solubility as a function of salting-in concentrations of phosphate since both are dependent on the colloidal stability of the reactive intermediate but not with conformational stability. In lieu of a complete understanding of the aggregation processes that limit protein therapeutic shelf life, these results highlight the potential of using simple solubility measurements as an additional tool in the biotechnology prescreening repertoire.

  1. Managing a female patient with left low back pain and sacroiliac joint pain with therapeutic exercise: a case report.

    Science.gov (United States)

    Boyle, Kyndall L

    2011-01-01

    The purpose of this case study is to describe the management of a female patient with chronic left low back pain and sacroiliac joint pain (LBP/SIJP) using unique unilateral exercises developed by the Postural Restoration Institute (PRI) to address pelvic asymmetry and left hip capsule restriction, which is consistent with a Right Handed and Left Anterior Interior Chain pattern of postural asymmetry.Client Description: The client was 65-year-old woman with a 10-month history of constant left LBP/SIJP and leg pain. The patient was seen six times to correct pelvic position/posture and left hip posterior capsule restriction via (1) muscle activation (left hamstrings, adductor magnus, and anterior gluteus medius) and (2) left hip adduction to lengthen the left posterior capsule/ischiofemoral ligament. Stabilization exercises included bilateral hamstrings, gluteus maximus, adductors, and abdominals to maintain pelvic position/posture.Measures and Outcome: Left Ober's test (initially positive) was negative at discharge. Pain as measured on the Numeric Pain Rating Scale (initially 1/10 at best and 8/10 at worst) was 0/10-0/10 at discharge. Oswestry Disability Index score (initially 20%) was 0% at discharge. The patient no longer had numbness in her left leg, and sexual intercourse had become pain free. INTERVENTIONs to restore and maintain the optimal position of pelvis and hip (femoral head in the acetabulum) may be beneficial for treating patients with chronic LBP/SIJP. The patient's pain was eliminated 13 days after she first performed three exercises to reposition the pelvis and restore left posterior hip capsule extensibility and internal rotation.

  2. Understanding therapeutic benefits of overground bionic ambulation: exploratory case series in persons with chronic, complete spinal cord injury.

    Science.gov (United States)

    Kressler, Jochen; Thomas, Christine K; Field-Fote, Edelle C; Sanchez, Justin; Widerström-Noga, Eva; Cilien, Deena C; Gant, Katie; Ginnety, Kelly; Gonzalez, Hernan; Martinez, Adriana; Anderson, Kimberley D; Nash, Mark S

    2014-10-01

    To explore responses to overground bionic ambulation (OBA) training from an interdisciplinary perspective including key components of neuromuscular activation, exercise conditioning, mobility capacity, and neuropathic pain. Case series. Academic research center. Persons (N=3; 2 men, 1 woman) aged 26 to 38 years with complete spinal cord injury (SCI) (American Spinal Injury Association Impairment Scale grade A) between the levels of T1 and T10 for ≥1 year. OBA 3d/wk for 6 weeks. To obtain a comprehensive understanding of responses to OBA, an array of measures were obtained while walking in the device, including walking speeds and distances, energy expenditure, exercise conditioning effects, and neuromuscular and cortical activity patterns. Changes in spasticity and pain severity related to OBA use were also assessed. With training, participants were able to achieve walking speeds and distances in the OBA device similar to those observed in persons with motor-incomplete SCI (10-m walk speed, .11-.33m/s; 2-min walk distance, 11-33m). The energy expenditure required for OBA was similar to walking in persons without disability (ie, 25%-41% of peak oxygen consumption). Subjects with lower soleus reflex excitability walked longer during training, but there was no change in the level or amount of muscle activity with training. There was no change in cortical activity patterns. Exercise conditioning effects were small or nonexistent. However, all participants reported an average reduction in pain severity over the study period ranging between -1.3 and 1.7 on a 0-to-6 numeric rating scale. OBA training improved mobility in the OBA device without significant changes in exercise conditioning or in neuromuscular or cortical activity. However, pain severity was reduced and no severe adverse events were encountered during training. OBA therefore opens the possibility to reduce the common consequences of chronic, complete SCI such as reduced functional mobility and neuropathic

  3. Clinical, prognostic, and therapeutic aspects of urachal carcinoma-A comprehensive review with meta-analysis of 1,010 cases.

    Science.gov (United States)

    Szarvas, Tibor; Módos, Orsolya; Niedworok, Christian; Reis, Henning; Szendröi, Attila; Szász, Marcell A; Nyirády, Péter

    2016-09-01

    Urachal carcinoma (UrC) is a rare and poorly investigated disease. Our current knowledge is mainly based on single-institutional studies. Despite growing interest in UrC, the included case numbers in recently published studies are still low. Therefore, we aimed to provide a comprehensive meta-analysis on the clinical, prognostic, and therapeutic aspects of UrC. A systematic Medline/PubMed search was performed on UrC using the terms "urachal carcinoma," "urachal cancer," and "urachus." Original articles and reviews in English language with case numbers>10 were selected. The vast majority (91%, 489/532) of UrCs are diagnosed at later stages (Sheldon≥III) when the tumor invades the urinary bladder. About 21% (136/646) of UrC patients have distant metastasis at first presentation. Although for patients with non-metastatic UrC surgical treatment provides an acceptable disease control, the systemic treatment of patients with progressed/metastatic UrC-in lack of prospective clinical trials-are less well established. Comparing cisplatin-based and 5-FU-based therapies in 74 published UrC cases, we found the latter to be superior in terms of radiographic response rates (9% vs. 44%, P = 0.043), but the combination of these 2 therapies provided the lowest progression rate (14%) with a similarly high response rate (43%). Owing to the lack of evidence-based guidelines, the therapy of UrC remains challenging. Given the infrequency of UrC, large prospective studies comparing different systemic therapies can hardly be conducted. Our metadata indicates that 5-FU-containing chemotherapy regimens are more effective than cisplatin-based treatment modalities, whereas their combination seems to provide the strongest antitumor effect. Nevertheless, in the lack of evidences from prospective clinical trials, therapeutic decision-making necessarily remains on an individual basis. In this situation, targeted therapies may provide a reasonable alternative. Therefore, better understanding of

  4. Possible therapeutic effect of orally administered ribavirin for respiratory syncytial virus-induced acute respiratory distress syndrome in an immunocompetent patient: a case report.

    Science.gov (United States)

    Yoon, Byung Woo; Lee, Seung Hyeun

    2017-12-20

    Human respiratory syncytial virus usually causes self-limiting upper respiratory infection and occasionally causes pneumonia in immunocompromised hosts. Respiratory syncytial virus-induced severe pneumonia or acute respiratory distress syndrome in immunocompetent adults has been rarely described. Unfortunately, optimal treatment has not been established for this potentially fatal condition. We report a case of respiratory syncytial virus-induced acute respiratory distress syndrome occurring in a previously healthy man successfully treated with orally administered ribavirin. An 81-year-old previously healthy Korean man presented with cough, dyspnea, and febrile sensation. He had hypoxemia with diffuse ground glass opacity evident on chest radiography, which progressed and required mechanical ventilation. All microbiological tests were negative except multiplex real-time reverse transcriptase polymerase chain reaction using respiratory specimen, which was positive for human adenovirus. Under the diagnosis of respiratory syncytial virus-induced acute respiratory distress syndrome, orally administered ribavirin was administered and he recuperated completely without complications. This case demonstrates the potential usefulness of orally administered ribavirin as a therapeutic option for severe respiratory syncytial virus infection, at least in an immunocompetent host.

  5. Implications of Financing Higher Education for Access and Equity: The Case of Syria

    Science.gov (United States)

    Kabbani, Nader; Salloum, Siba

    2011-01-01

    This article examines the implications for access and equity of the Syrian government's efforts to reform higher education in the country over the past decade. In the context of social and economic reforms that are moving the county from a state-controlled to a social market economy, it focuses on adequacy in financing higher education, as well as…

  6. Geoethical implications in the L'Aquila case: scientific knowledge and communication

    Science.gov (United States)

    Di Capua, Giuseppe

    2013-04-01

    effective evaluation of the errors of the prediction models. Furthermore, it has to include a commitment increasingly qualified in scientific communication, through the use of a simplified language but still scientifically correct and suitable for different users. Finally, it consists of taking care of the redefinition of relationships with policy makers and media, so that it is possible, also through the sharing of operational protocols, to establish areas of expertise helpful to clarify roles and responsibilities. Certainly a reflection arises from this sad affair: the unpredictability of natural hazards cannot be an excuse to acquit the science, as well as the legitimate need of citizens for reassurance has not to be used to exert pressure on those who have to make decisions in circumstances where the margins of error are still very high. This work aims to summarize some essential passages of the L'Aquila case, since the geoethical implications of this affair are important and paradigmatic.

  7. Factors of non-compliance with the therapeutic regimen among hypertensive men and women: a case-control study to investigate risk factors of stroke.

    Science.gov (United States)

    Baune, B Th; Aljeesh, Y; Bender, R

    2005-01-01

    To identify potential risk factors among the therapeutic regimen and life style which may increase the risk for stroke, a pair matched case-control study was conducted in Gaza Strip among 112 patients, who had been hospitalized for acute stroke and history of hypertension, and 224 controls with history of hypertension. Conditional logistic regression models show significant associations between stroke and medication not taking as prescribed (OR = 6.07; 95% CI: 1.53, 24.07), using excessive salt at meals (OR = 4.51; 95% CI: 2.05, 9.90), eating diet high in fat (OR = 4.67; 95% CI: 2.09, 10.40), and high level of stress (OR = 2.77; 95% CI: 1.43, 5.38). No significant association between smoking and the development of stroke (OR = 2.12; 95% CI: 0.82, 5.51) was found. Regular physical exercise was a protective factor (OR=0.26; 95% CI: 0.12, 0.57). Using excessive salt at meals was a significant risk factor (OR = 16.61; 95% CI: 4.40, 62.80) in people having low level of stress, whereas it was not significant in people having high level of stress. (OR = 1.76; 95% CI: 0.58, 5.33). Smoking in combination with low level of stress was a significant risk factor for stroke (OR = 9.88; 95% CI: 2.52, 38.78), but a non-significant protective factor in combination with high level of stress (OR=0.52; 95% CI: 0.14, 1.99). An increase in compliance with the pharmacological and non-pharmacological therapeutic regimen might be a key to a reduction of stroke incidence and prevalence among hypertensive patients.

  8. Disruption of autophagy by the histone deacetylase inhibitor MGCD0103 and its therapeutic implication in B-cell chronic lymphocytic leukemia.

    Science.gov (United States)

    El-Khoury, V; Pierson, S; Szwarcbart, E; Brons, N H C; Roland, O; Cherrier-De Wilde, S; Plawny, L; Van Dyck, E; Berchem, G

    2014-08-01

    Evading apoptosis is a hallmark of B-cell chronic lymphocytic leukemia (CLL) cells and an obstacle to current chemotherapeutic approaches. Inhibiting histone deacetylase (HDAC) has emerged as a promising strategy to induce cell death in malignant cells. We have previously reported that the HDAC inhibitor MGCD0103 induces CLL cell death by activating the intrinsic pathway of apoptosis. Here, we show that MGCD0103 decreases the autophagic flux in primary CLL cells. Activation of the PI3K/AKT/mTOR pathway, together with the activation of caspases, and to a minor extent CAPN1, resulting in cleavage of autophagy components, were involved in MGCD0103-mediated inhibition of autophagy. In addition, MGCD0103 directly modulated the expression of critical autophagy genes at the transcriptional level that may contribute to autophagy impairment. Besides, we demonstrate that autophagy is a pro-survival mechanism in CLL whose disruption potentiates cell death induced by anticancer molecules including HDAC and cyclin-dependent kinase inhibitors. In particular, our data highlight the therapeutic potential of MGCD0103 as not only an inducer of apoptosis but also an autophagy suppressor in both combination regimens with molecules like flavopiridol, known to induce protective autophagy in CLL cells, or as an alternative to circumvent undesired immunomodulatory effects seen in the clinic with conventional autophagy inhibitors.

  9. CRISPR/Cas9-Induced (CTG⋅CAG)nRepeat Instability in the Myotonic Dystrophy Type 1 Locus: Implications for Therapeutic Genome Editing.

    Science.gov (United States)

    van Agtmaal, Ellen L; André, Laurène M; Willemse, Marieke; Cumming, Sarah A; van Kessel, Ingeborg D G; van den Broek, Walther J A A; Gourdon, Geneviève; Furling, Denis; Mouly, Vincent; Monckton, Darren G; Wansink, Derick G; Wieringa, Bé

    2017-01-04

    Myotonic dystrophy type 1 (DM1) is caused by (CTG⋅CAG) n -repeat expansion within the DMPK gene and thought to be mediated by a toxic RNA gain of function. Current attempts to develop therapy for this disease mainly aim at destroying or blocking abnormal properties of mutant DMPK (CUG)n RNA. Here, we explored a DNA-directed strategy and demonstrate that single clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-cleavage in either its 5' or 3' unique flank promotes uncontrollable deletion of large segments from the expanded trinucleotide repeat, rather than formation of short indels usually seen after double-strand break repair. Complete and precise excision of the repeat tract from normal and large expanded DMPK alleles in myoblasts from unaffected individuals, DM1 patients, and a DM1 mouse model could be achieved at high frequency by dual CRISPR/Cas9-cleavage at either side of the (CTG⋅CAG)n sequence. Importantly, removal of the repeat appeared to have no detrimental effects on the expression of genes in the DM1 locus. Moreover, myogenic capacity, nucleocytoplasmic distribution, and abnormal RNP-binding behavior of transcripts from the edited DMPK gene were normalized. Dual sgRNA-guided excision of the (CTG⋅CAG)n tract by CRISPR/Cas9 technology is applicable for developing isogenic cell lines for research and may provide new therapeutic opportunities for patients with DM1. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  10. Transcription factors, transcriptional coregulators, and epigenetic modulation in the control of pulmonary vascular cell phenotype: therapeutic implications for pulmonary hypertension (2015 Grover Conference series).

    Science.gov (United States)

    Pullamsetti, Soni S; Perros, Frédéric; Chelladurai, Prakash; Yuan, Jason; Stenmark, Kurt

    2016-12-01

    Pulmonary hypertension (PH) is a complex and multifactorial disease involving genetic, epigenetic, and environmental factors. Numerous stimuli and pathological conditions facilitate severe vascular remodeling in PH by activation of a complex cascade of signaling pathways involving vascular cell proliferation, differentiation, and inflammation. Multiple signaling cascades modulate the activity of certain sequence-specific DNA-binding transcription factors (TFs) and coregulators that are critical for the transcriptional regulation of gene expression that facilitates PH-associated vascular cell phenotypes, as demonstrated by several studies summarized in this review. Past studies have largely focused on the role of the genetic component in the development of PH, while the presence of epigenetic alterations such as microRNAs, DNA methylation, histone levels, and histone deacetylases in PH is now also receiving increasing attention. Epigenetic regulation of chromatin structure is also recognized to influence gene expression in development or disease states. Therefore, a complete understanding of the mechanisms involved in altered gene expression in diseased cells is vital for the design of novel therapeutic strategies. Recent technological advances in DNA sequencing will provide a comprehensive improvement in our understanding of mechanisms involved in the development of PH. This review summarizes current concepts in TF and epigenetic control of cell phenotype in pulmonary vascular disease and discusses the current issues and possibilities in employing potential epigenetic or TF-based therapies for achieving complete reversal of PH.

  11. A Proposed Therapeutic Algorithm Based on Multiple Case Analysis Regarding the Repair Options of Iatrogenic Biliary Lesions Following Open and Laparoscopic Surgery

    Directory of Open Access Journals (Sweden)

    Cosmin Alec Moldovan

    2016-10-01

    Full Text Available Introduction: the problem of the iatrogenic lesions of the main biliary pathways is far from being completely clarified and still represents a serious surgical situation, during both open and laparoscopic surgeries. The outcome of these situations is closely linked with the actual moment of discovery of the lesion and the surgical methods for repairing such defects and implies a great number of options, such as reconstructive, derivative and substitutive techniques. Objectives: the goal of this paper is to present an algorithm of choices and their consequences for clinical conduit in the case of iatrogenic biliary lesions discovered in the course of open or laparoscopic procedures of the main biliary pathways, based on our experience. Material and method: We present a multicentric retrospective study of 53 cases of lesions following open and laparoscopic procedures, from a larger lot of 10.015 surgeries on extrahepatic biliary ducts recorded during a 40 years period of time, in 2 clinical hospitals. Out of these, 2127 interventions were strictly focused on the common bile duct, for various pathology. Conclusion: The choice of the optimum method is strictly correlated with the morphological nature of the lesion, which is different from one stage to the other, depending upon the moment of detection, and therefore have different surgical implications.

  12. Dispepsia funcional: Nuevos conocimientos en la fisiopatogenia con implicaciones terapéuticas Functional dyspepsia: New pathophysiologic knowledge with therapeutic implications

    Directory of Open Access Journals (Sweden)

    Ana C. Hernando-Harder

    2007-08-01

    the gastroduodenal region, in the absence of any organic, systemic, or metabolic disease that is likely to explain the symptoms. Pathogenetic features include disturbed gastric accommodation and emptying, duodenal dysmotility, heightened sensitivity, notably psychosocial disturbances and an association with a postinfective state. Increasing efforts are made to determine the etiopathogenesis of the disease, including new molecular and genetic aspects. However, the exact etiopathologic mechanism that causes the symptoms in an individual patient remains to be identified. The new Rome III criteria redefine and sub-characterize FD patients according to their main symptoms and this can be of value for standardized research, development and control of new therapeutic strategies and calculated therapeutic recommendations in the clinical practice. Various treatment modalities have been employed including dietary modifications, pharmacological agents directed at different targets within the gastrointestinal tract and central nervous system and psychological therapies including hypnotherapy. Unfortunately, to date, all of these therapies have yielded only marginal results. After excluding organic diseases, it is essential that the patient be assured about the benign nature and prognosis of the disease, and this can be sometimes the most helpful inversion for the patient and his/her physician.

  13. Optical microscopy of targeted drug delivery and local distribution in skin of a topical minocycline: implications in translational research and guidance for therapeutic dose selection (Conference Presentation)

    Science.gov (United States)

    Hermsmeier, Maiko; Sawant, Tanvee; Lac, Diana; Yamamoto, Akira; Chen, Xin; Huang, Susan Y.; Nagavarapu, Usha; Evans, Conor L.; Chan, Kin Foong; Daniels, AnnaMarie

    2017-02-01

    Acne vulgaris is a chronic inflammatory skin condition commonly resulting in negative aesthetic and social impacts on those affected. Minocycline, currently available as an oral antibiotic for moderate to severe acne, has a known minimum inhibitory concentration (MIC) for the acne-causing bacterium Propionibacterium acnes (P. acnes) in vitro, with its anti-inflammatory properties also eliciting inhibitory effects on pro-inflammatory molecules. A novel topical gel composition containing solubilized minocycline (BPX-01) has been developed to directly deliver the drug to the skin. Because minocycline is a known fluorophore, fluorescence microscopy and concurrent quantitative measurements were performed on excised human facial skin dosed with different concentrations, in order to determine the spatial distribution of the drug and quantification of its local concentration in the epidermis and the pilosebaceous unit where P. acnes generally reside. Local minocycline delivery confirmed achievement of an adequate therapeutic dose to support clinical studies. Subsequently, a 4-week double-blind, randomized, vehicle controlled clinical study was performed to assess the safety and efficacy of 1% minocycline BPX-01 applied daily. No instances of cutaneous toxicity were reported, and a greater than 1 log reduction of P. acnes count was observed at week 4 with statistical significance from baseline and vehicle control. In addition, no detectable amounts of minocycline in the plasma were reported, suggesting the potential of this new formulation to diminish the known systemic adverse effects associated with oral minocycline. Follow-on clinical plans are underway to further establish the safety of BPX-01 and to evaluate its efficacy against inflammatory acne lesions in a 225 patient multi-center dose-finding study.

  14. A cellular and molecular basis for the selective desmopressin-induced ACTH release in Cushing disease patients: key role of AVPR1b receptor and potential therapeutic implications.

    Science.gov (United States)

    Luque, R M; Ibáñez-Costa, A; López-Sánchez, L M; Jiménez-Reina, L; Venegas-Moreno, E; Gálvez, M A; Villa-Osaba, A; Madrazo-Atutxa, A M; Japón, M A; de la Riva, A; Cano, D A; Benito-López, P; Soto-Moreno, A; Gahete, M D; Leal-Cerro, A; Castaño, J P

    2013-10-01

    /exclusive desmopressin stimulatory pituitary effects observed in CD, thus opening the possibility of exploring AVPR1b antagonists as potential therapeutic tools for CD treatment.

  15. Role of protein kinase C β and vascular endothelial growth factor receptor in malignant pleural mesothelioma: Therapeutic implications and the usefulness of Caenorhabditis elegans model organism

    Directory of Open Access Journals (Sweden)

    Sivakumar Loganathan

    2011-01-01

    Full Text Available Purpose: To examine the role of both protein kinase C (PKC-β and vascular endothelial growth factor receptor (VEGFR-2 in malignant pleural mesothelioma (MPM using respective inhibitors, enzastaurin and KRN633. Materials and Methods: MPM cell lines, control cells, and a variety of archived MPM tumor samples were used to determine the protein expression levels of PKC-β, VEGFR-2, VEGF, and p-AKT. Effects of enzastaurin and KRN633 on phosphorylation status of key signaling molecules and viability of the mesothelioma cells were determined. The common soil nematode, Caenorhabditis elegans, was treated with enzastaurin to determine its suitability to screen for highly potent kinase inhibitors. Results: PKC-β1, PKC-β2 and VEGFR-2/KDR were overexpressed in MPM cell lines and MPM tumor tissues. Enzastaurin treatment resulted in significant loss in viability of VEGF induced cell proliferation; however, the effect of KRN633 was much less. Enzastaurin also dramatically decreased the phosphorylation of PKC-β, its downstream target p-AKT, and surprisingly, the upstream VEGFR-2. The combination of the two drugs at best was additive and similar results were obtained with respect to cell viability. Treatment of C. elegans with enzastaurin resulted in clear phenotypic changes and the worms were hypermotile with abnormal pattern and shape of eggs, suggesting altered fecundity. Conclusions: PKC-β1 and VEGFR-2 are both excellent therapeutic targets in MPM. Enzastaurin was better at killing MPM cells than KRN633 and the combination lacked synergy. In addition, we show here that C. elegans can be used to screen for the next generation inhibitors as treatment with enzastaurin resulted in clear phenotypic changes that could be assayed.

  16. Metabolic orchestration between cancer cells and tumor microenvironment as a co-evolutionary source of chemoresistance in ovarian cancer: a therapeutic implication.

    Science.gov (United States)

    Suh, Dong Hoon; Kim, Hee Seung; Kim, Boyun; Song, Yong Sang

    2014-11-01

    Our group reported a significant association between hexokinase II overexpression and chemoresistance in ovarian cancer, suggesting that aerobic glycolysis in the so-called Warburg effect might contribute to cancer progression. However, a growing body of evidence indicates contradictory findings with regard to the Warburg effect, such as high mitochondrial activity in highly invasive tumors and low ATP contribution of glycolysis in ovarian cancer. As a solution for the dilemma of the Warburg effect, the "reverse Warburg effect" was proposed in which aerobic glycolysis might occur in the stromal compartment of the tumor rather than in the cancer cells, indicating that the glycolytic tumor stroma feed the cancer cells through a type of symbiotic relationship. The reverse Warburg effect acting on the relationship between cancer cells and cancer-associated fibroblasts has evolved into dynamic interplay between cancer cells and multiple tumor stromal compartments, including cancer-associated fibroblasts, the extracellular matrix, endothelial cells, mesenchymal stem cells, adipocytes, and tumor-associated macrophages. Peritoneal cavities including ascites and the omentum also form a unique environment that is highly receptive for carcinomatosis in the advanced stages of ovarian cancer. The complicated but ingeniously orchestrated stroma-mediated cancer metabolism in ovarian cancer provides great heterogeneity in tumors with chemoresistance, which makes the disease thus far difficult to cure by single stromal-targeting agents. This review will discuss the experimental and clinical evidence of the cross-talk between cancer cells and various components of tumor stroma in terms of heterogeneous chemoresistance with focal points for therapeutic intervention in ovarian cancer. Copyright © 2014 Elsevier Inc. All rights reserved.

  17. A rare case of persistent metopic suture in an elderly individual: Incidental autopsy finding with clinical implications

    Directory of Open Access Journals (Sweden)

    S Vikram

    2014-01-01

    Full Text Available Metopic suture is a dense fibrous joint extending from the nasion to the bregma. Normally, closure of this suture takes place between 1-8 years of age. Failure of this closure beyond 8 years leads to persistent metopic suture. A rare case of persistent metopic suture in a 60-year-old male is documented, who committed suicide by alleged consumption of organophosphorous compound at District Govt. Wenlock Hospital, Mangalore, Karnataka, India. Metopic suture may mimic skull fracture and may mislead an inexperienced forensic expert. Neurosurgeon should also be aware of this anatomical variation while performing frontal craniotomy, as the persistent metopic suture may mimic vertical fracture of the skull. Hence, in this case report, the clinical and medico-legal implications of the persistent metopic sutures have been discussed.

  18. Reporting therapeutic discourse in a therapeutic community.

    Science.gov (United States)

    Chapman, G E

    1988-03-01

    Research in nurses' communications has concentrated on nurse to patient interactions. Those few studies which focus on nurse to nurse communications seem to be generated by a pragmatic and normative concern with effective information sharing. In this paper, which describes one aspect of a larger case study of a hospital-based therapeutic community, the description and analysis of nurses' reports flows not from a normative model of professional practice, but rather an exploration of how professional practice is articulated as discourse in nurses' written accounts. Foucault's ideas about therapeutic discourse inform the theoretical framework of the research. Ethnomethodological concerns with the importance of documentary analysis provide the methodological rationale for examining nurses' 24-hour report documents, as official discourse, reflecting therapeutic practice in this setting. A content analysis of nurses' reports, collected over a period of 4 months, demonstrated the importance of domesticity and ordinary everyday activities in nurses' accounts of hospital life. Disruption to the 'life as usual' domesticity in the community seemed to be associated with admission to and discharge from the hospital when interpersonal and interactional changes between patients occur. It is suggested that nurses in general hospital wards and more orthodox psychiatric settings might usefully consider the impact of admissions and discharges on the group of patients they manage, and make this a discursive focus of their work.

  19. Clinical picture and treatment implication in a child with Capgras syndrome: a case report.

    Science.gov (United States)

    Mazzone, Luigi; Armando, Marco; De Crescenzo, Franco; Demaria, Francesco; Valeri, Giovanni; Vicari, Stefano

    2012-11-27

    Capgras syndrome is a delusional misidentification syndrome characterized by the patient's belief that his or her relatives have been replaced by impostors. Here we describe the clinical picture and the therapeutic approach to an 11-year-old Caucasian girl with Capgras syndrome. A complete psychopathological assessment was conducted during the acute phase, at one month, two months and six months since diagnosis. Subsequent follow-up evaluations in this patient allowed us to detect improvements in the psychotic symptoms following treatment with risperidone and selective serotonin reuptake inhibitors, suggesting that this combined therapy may significantly improve the clinical outcome in patients who have Capgras syndrome.

  20. Antiviral Functions of Human Immunodeficiency Virus Type 1 (HIV-1)-Specific IgG Antibodies: Effects of Antiretroviral Therapy and Implications for Therapeutic HIV-1 Vaccine Design.

    Science.gov (United States)

    French, Martyn A; Tjiam, M Christian; Abudulai, Laila N; Fernandez, Sonia

    2017-01-01

    . As HIV-1 infects cells in GCs and induces GC dysfunction, which may persist during ART, strategies for boosting HIV-1-specific IgG antibody responses should include early commencement of ART and possibly the use of particular antiretroviral drugs to optimize drug levels in lymphoid follicles. Finally, enhancing particular functions of HIV-1-specific IgG antibody responses by using adjuvants or cytokines to modulate the IgG subclass content of the antibody response might be investigated in NHP models of HIV-1 infection and during trials of therapeutic vaccines in HIV patients.

  1. Immunophenotyping of Waldenströms macroglobulinemia cell lines reveals distinct patterns of surface antigen expression: potential biological and therapeutic implications.

    Science.gov (United States)

    Paulus, Aneel; Chitta, Kasyapa S; Wallace, Paul K; Advani, Pooja P; Akhtar, Sharoon; Kuranz-Blake, Maja; Ailawadhi, Sikander; Chanan-Khan, Asher A

    2015-01-01

    Waldenströms macroglobulinemia (WM) is a subtype of Non-Hodgkin's lymphoma in which the tumor cell population is markedly heterogeneous, consisting of immunoglobulin-M secreting B-lymphocytes, plasmacytoid lymphocytes and plasma cells. Due to rarity of disease and scarcity of reliable preclinical models, many facets of WM molecular and phenotypic architecture remain incompletely understood. Currently, there are 3 human WM cell lines that are routinely used in experimental studies, namely, BCWM.1, MWCL-1 and RPCI-WM1. During establishment of RPCI-WM1, we observed loss of the CD19 and CD20 antigens, which are typically present on WM cells. Intrigued by this observation and in an effort to better define the immunophenotypic makeup of this cell line, we conducted a more comprehensive analysis for the presence or absence of other cell surface antigens that are present on the RPCI-WM1 model, as well as those on the two other WM cell lines, BCWM.1 and MWCL-1. We examined expression of 65 extracellular and 4 intracellular antigens, comprising B-cell, plasma cell, T-cell, NK-cell, myeloid and hematopoietic stem cell surface markers by flow cytometry analysis. RPCI-WM1 cells demonstrated decreased expression of CD19, CD20, and CD23 with enhanced expression of CD28, CD38 and CD184, antigens that were differentially expressed on BCWM.1 and MWCL-1 cells. Due to increased expression of CD184/CXCR4 and CD38, RPCI-WM1 represents a valuable model in which to study the effects anti-CXCR4 or anti-CD38 targeted therapies that are actively being developed for treatment of hematologic cancers. Overall, differences in surface antigen expression across the 3 cell lines may reflect the tumor clone population predominant in the index patients, from whom the cell lines were developed. Our analysis defines the utility of the most commonly employed WM cell lines as based on their immunophenotype profiles, highlighting unique differences that can be further studied for therapeutic exploit.

  2. Sirtuin 6 suppresses hypoxia-induced inflammatory response in human osteoblasts via inhibition of reactive oxygen species production and glycolysis-A therapeutic implication in inflammatory bone resorption.

    Science.gov (United States)

    Hou, Kuo-Liang; Lin, Sze-Kwan; Chao, Ling-Hsiu; Hsiang-Hua Lai, Eddie; Chang, Cheng-Chi; Shun, Chia-Tung; Lu, Wan-Yu; Wang, Jyh-Horng; Hsiao, Michael; Hong, Chi-Yuan; Kok, Sang-Heng

    2017-03-01

    . Our findings suggest that SIRT6 suppresses inflammatory response in osteoblasts via modulation of glucose metabolism and redox homeostasis. SIRT6-based strategy may possess therapeutic potential for inflammatory bone resorption. © 2016 BioFactors, 43(2):170-180, 2017. © 2016 International Union of Biochemistry and Molecular Biology.

  3. Experimental approaches for elucidating co-agonist regulation of NMDA receptor in motor neurons: Therapeutic implications for amyotrophic lateral sclerosis (ALS).

    Science.gov (United States)

    Paul, Praveen; de Belleroche, Jackie

    2015-12-10

    Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease characterised by selective loss of motor neurons leading to fatal paralysis. Although most cases are sporadic, approximately 10% of cases are familial and the identification of mutations in these kindred has greatly accelerated our understanding of disease mechanisms. To date, the causal genes in over 70% of these families have been identified. Recently, we reported a mutation (R199W) in the enzyme that degrades d-serine, D-amino acid oxidase (DAO) and co-segregates with disease in familial ALS. Moreover, D-serine and DAO are abundant in human spinal cord and severely depleted in ALS. Using cell culture models, we have defined the effects of R199W-DAO, and shown that it activates autophagy, leads to the formation of ubiquitinated protein aggregates and promotes apoptosis, all of which processes are attenuated by a D-serine/glycine site antagonist of the N-methyl D-aspartate receptor (NMDAR). These findings suggest that the toxic effects of R199W-DAO are at least in part mediated via the NMDAR involving the D-serine/glycine site and that an excitotoxic mechanism may contribute to disease pathogenesis. Copyright © 2014 Elsevier B.V. All rights reserved.

  4. Cholera cases cluster in time and space in Matlab, Bangladesh: implications for targeted preventive interventions.

    Science.gov (United States)

    Debes, Amanda K; Ali, Mohammad; Azman, Andrew S; Yunus, Mohammad; Sack, David A

    2016-12-01

    : Cholera remains a serious public health threat in Asia, Africa and in parts of the Americas. Three World health Organization (WHO) pre-qualified oral cholera vaccines are now available but their supply is limited, so current supplies must be administered strategically. This requires an improved understanding of disease transmission and control strategies. : We used demographics and disease surveillance data collected from 1991 to 2000 in Matlab, Bangladesh, to estimate the spatial and temporal extent of the zone of increased risk around cholera cases. Specifically, we compare the cholera incidence among individuals living close to cholera cases with that among individuals living close to those without medically-attended cholera in this rural endemic setting. : Those living within 50 m of a confirmed cholera case had 36 times (95% confidence interval: 23-56) the risk of becoming a cholera case in the first 3 days (after case presentation) compared with risk elsewhere in the community. The relative risk gradually declined in space and time, but remained significantly high up to 450 me away within 3 days of case presentation, and up to 150 m away within 23 days from the date of presentation of the case. : These findings suggest that, if conducted rapidly, vaccinating individuals living close to a case (ring vaccination) could be an efficient and effective strategy to target vaccine to a high-risk population in an endemic setting.

  5. Considering photodynamic therapy as a therapeutic modality in selected cases of dome-shaped macula complicated by foveal serous retinal detachment.

    Science.gov (United States)

    Arapi, Ilir; Neri, Piergiorgio; Mariotti, Cesare; Gesuita, Rosaria; Pirani, Vittorio; Freddo, Francesco; Lutaj, Pajtim; Giovannini, Alfonso

    2015-02-01

    To study the role of photodynamic therapy (PDT) as a therapeutic modality in myopic patients with dome-shaped macula (DSM) associated with foveal serous retinal detachment (SRD). Retrospective interventional case series. The medical records of 10 consecutive myopic patients (10 eyes) with DSM associated with subfoveal SRD and treated with PDT were reviewed. Visual gain and loss were considered as increasing or decreasing of two or more lines of best corrected visual acuity (BCVA), respectively, and eyes with fluid resolution were deemed responsive to PDT. All eyes underwent several PDT treatments, with a median of three and a median follow-up time of 15.5 months. At final follow-up, six eyes (60%) showed complete resolution of the foveal SRD. The baseline hypocyanescent macular area observed during late indocyanine green angiography (ICGA) frames was significantly lower in the group of patients who responded to PDT and had an increase of at least two Snellen lines in BCVA (P = .01). Data suggest that myopic eyes associated with DSM and foveal SRD may be responsive to PDT, showing total resolution of fluid accumulation and positive BCVA changes if baseline ICGA findings show evidence of a limited hypocyanescent macular area. Copyright 2015, SLACK Incorporated.

  6. Human urine-based therapeutics in Spain from the early 20th century to the present: a historical literature overview and a present-day case study.

    Science.gov (United States)

    Vallejo, José Ramón; Aparicio Mena, Alfonso J; González, José Antonio

    2017-06-01

    Human urine is currently the subject of biomedical investigations as a potential therapeutic resource and it continues to be used in remedies in different cultures and societies, including the Spanish culture. In this study we gather etnomedical knowledge about urotherapy and determine their associated symbolisms in Spain. A literature overview and a case study were carried out to compile urine-based remedies and as a direct analysis of symbolic systems. Urotherapy is widespread in Spanish folk medicine. Among the 204 collected remedies, those related to treatment of diseases or skin conditions predominate (63%). Remedies have been reported for the treatment of skin diseases such as eczema, chloasma, alopecia, etc. to treat or alleviate burns, chilblains, wounds or skin chapping, and as a treatment of venomous bites. Most of the collected remedies have an associated naturalist symbolism, based on local traditions and the transmission of empirical initial knowledge. The use of urine in Spain is a result of the interaction of two types of practice: a local and traditional urotherapy, rural and with a utilitarian purpose, and a technical urotherapy, limited to an urban environment and a naturopathic medicine.

  7. The therapeutic effect of outpatient use of a peroneal nerve functional electrical stimulation neuroprosthesis in people with stroke: a case series.

    Science.gov (United States)

    Israel, Susan; Kotowski, Susan; Talbott, Nancy; Fisher, Keri; Dunning, Kari

    2011-01-01

    Foot drop is a common problem following a stroke. Although peroneal nerve functional electrical stimulation (pFES) for foot drop has been shown to improve function and gait, the majority of studies have used daily stimulation. There are few studies to show benefit and guide practice for less frequent dosing. Therefore, the purpose of this study was to examine the effect of gait training with pFES on ambulation and lower extremity kinematics when used on a schedule consistent with usual care in an outpatient therapy clinic. A pFES neuroprosthesis was used with overground gait training 3 times per week for 6 weeks in 2 subjects with foot drop due to chronic stroke (more than 6 months poststroke). Outcomes including functional gait (modified Emory Functional Ambulation Profile [mEFAP]), gait speed, and gait kinematics were assessed at baseline and at 6 weeks without the pFES (therapeutic effect). Both subjects demonstrated decreased ankle plantarflexion at initial heel contact during gait. Both subjects also showed decreased time to complete the mEFAP. Only 1 subject showed increased gait velocity. This case series suggests that the use of neuroprothesis pFES combined with overground gait training on a typical outpatient therapy schedule for 6 weeks may increase foot clearance during gait for persons with chronic stroke. Although the evidence is limited, it may be beneficial for clinicians to use pFES in creative ways during different aspects of treatment.

  8. Correlation between total vitamin D levels and psychotic psychopathology in patients with schizophrenia: therapeutic implications for add-on vitamin D augmentation.

    Science.gov (United States)

    Yüksel, Rabia Nazik; Altunsoy, Neslihan; Tikir, Baise; Cingi Külük, Merve; Unal, Kubranur; Goka, Sema; Aydemir, Cigdem; Goka, Erol

    2014-12-01

    Vitamin D deficiency is one of the implicated factors in ethio-pathogenesis of schizophrenia. Low serum vitamin D levels have been reported in many schizophrenia studies. However, the question is still not answered: Is there a correlation between disease activity and serum vitamin D levels? This is the first study evaluating the relationship between serum total vitamin D levels and disease activity, by comparing total vitamin D levels in two schizophrenia groups abruptly different in terms of disease activity. 41 patients with schizophrenia in remission, 40 patients with schizophrenia those in an acute episode and 40 age- and sex -matched controls with no major psychopatology were recruited in this study. Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impression - Severety scale (CGI-S) were used to evaluate disease activity. A demographic data form that included entries on age, gender, ethnicity, weight, skin color, daily duration of sun exposure and nutritional assessment were used. Blood samples were taken from all patients and controls. Total vitamin D (D2+D3), calcium, phosphor, parathyroid hormone values were measured. Patients in an acute episode had significantly lower vitamin D levels compared to patients in remission and to healthy controls (in terms of median values respectively, 7.18, 15.03, 15.02, p color, ethnicity or nutrition on total vitamin D levels. Even though important factors for vitamin D synthesis were similar, there was severe vitamin D deficiency in patients presenting with an acute episode, significantly different from those in remission. Is vitamin D deficiency the result or the cause of an acute episode? Our results contribute to the idea that vitamin D deficiency and schizophrenia may have interactions with an unknown pathway. Present data points out a possible influence at a genomic level. Future trials may investigate this association with longer follow up. We recommend that, serum vitamin D levels should be

  9. Self-neglect: a case study and implications for clinical practice.

    LENUS (Irish Health Repository)

    Day, Mary Rose

    2015-03-02

    Self-neglect is a worldwide and serious public health issue that can have serious adverse outcomes and is more common in older people. Cases can vary in presentation, but typically present as poor self-care, poor care of the environment and service refusal. Community nurses frequently encounter self-neglect cases and health and social care professionals play a key role in the identification, management and prevention of self-neglect. Self-neglect cases can give rise to ethical, personal and professional challenges. The aim of this article is to create a greater understanding of the concept of self-neglect among community nurses.

  10. Therapeutic Horseback Riding Outcomes of Parent-Identified Goals for Children with Autism Spectrum Disorder: An ABA' Multiple Case Design Examining Dosing and Generalization to the Home and Community

    Science.gov (United States)

    Holm, Margo B.; Baird, Joanne M.; Kim, Young Joo; Rajora, Kuwar B.; D'Silva, Delma; Podolinsky, Lin; Mazefsky, Carla; Minshew, Nancy

    2014-01-01

    We examined whether different doses of therapeutic riding influenced parent-nominated target behaviors of children with autism spectrum disorder (ASD) (a) during the session (b) at home, and (c) in the community. We used a single subject multiple Baseline, multiple case design, with dosing of 1, 3, and 5 times/week. Three boys with ASD, 6-8 years…

  11. How (not to draw philosophical implications from the cognitive nature of concepts: The case of intentionality

    Directory of Open Access Journals (Sweden)

    Kazuki eIijima

    2014-07-01

    Full Text Available Philosophers have often appealed to intuitive judgments in various thought experiments to support or reject particular theses. Experimental philosophy is an emerging discipline that examines the cognitive nature of such intuitive judgments. In this paper, we assess the methodological and epistemological status of experimental philosophy. We focus on the Knobe effect, in which our intuitive judgment of the intentionality of an action seems to depend on the perceived moral status of that action. The debate on the philosophical implications of the Knobe effect has been framed in terms of the distinction between the competence and performance of the concept of intentionality. Some scholars seem to suggest that the Knobe effect reflects the competence (or otherwise, the performance error of the concept of intentionality. However, we argue that these notions are purely functional and thus do not have philosophical implications, without assuming normativism, which we see as problematic in a psychological methodology. Finally, focusing on the gap between competence and rationality, we suggest future directions for experimental philosophy.

  12. Acquired lobar emphysema in a case of interstitial chronic lung disease. Surgical implications and review of the literature

    Directory of Open Access Journals (Sweden)

    Sancho Hernández Rogelio

    2014-07-01

    Full Text Available Acquired lobar interstitial emphysema (ALIE, initially described in infants with bronchopulmonary dysplasia is now known to occur in other conditions such as a secondary post-traumatic or inflammatory injury as in patients requiring ventilatory sup- port with chronic lung disease. The ALIE leads to progressive deterioration of lung function with massive distension and com- pression of lung parenchyma with consequent mediastinal shift in the course of chronic interstitial lung disease. This situation requires adequate clinical and radiological interpretation in order to make the proper patient selection i.e., between a candidate for lung biopsy for the benefit of a definitive diagnosis or one who in the course of a superimposed ALIE requires a diagnostic and therapeutic lobectomy. Two cases of this entity and descriptive decision-making diagnostic and surgical about pre-and intraop- erative findings are presented.

  13. Opioid Addiction: Social Problems Associated and Implications of Both Current and Possible Future Treatments, including Polymeric Therapeutics for Giving Up the Habit of Opioid Consumption

    Directory of Open Access Journals (Sweden)

    M. Cristina Benéitez

    2017-01-01

    Full Text Available Background. Detoxification programmes seek to implement the most secure and compassionate ways of withdrawing from opiates so that the inevitable withdrawal symptoms and other complications are minimized. Once detoxification has been achieved, the next stage is to enable the patient to overcome his or her drug addiction by ensuring consumption is permanently and completely abandoned, only after which can the subject be regarded as fully recovered. Methods. A systematic search on the common databases of relevant papers published until 2016 inclusive. Results and Conclusion. Our study of the available oral treatments for opioid dependence has revealed that no current treatment can actually claim to be fully effective. These treatments require daily oral administration and, consequently, regular visits to dispensaries, which in most cases results in a lack of patient compliance, which causes fluctuations in drug plasma levels. We then reviewed alternative treatments in the available scientific literature on polymeric sustained release formulations. Research has been done not only on release systems for detoxification but also on release systems for giving up the habit of taking opioids. These efforts have obtained the recent authorization of polymeric systems for use in patients that could help them to reduce their craving for drugs.

  14. Recovery Journeys of Counselors and Clients: A Case Study of the Therapeutic Alliance in a Drug Treatment and Rehabilitation Center in Malaysia

    Science.gov (United States)

    Amat, Mohamad Isa

    2013-01-01

    The therapeutic alliance is a significant research area in counseling. The understanding of the therapeutic alliance, particularly in drug treatment settings helps counselors and clients to increase the treatment outcomes and its treatment process. The present study investigated the journeys of recovering counselors and clients in a private…

  15. Incorporation of Therapeutic Interventions in Physiologically Based Pharmacokinetic Modeling of Human Clinical Case Reports of Accidental or Intentional Overdosing with Ethylene Glycol

    Energy Technology Data Exchange (ETDEWEB)

    Corley, Rick A.; McMartin, K. E.

    2005-05-16

    Ethylene glycol is a high production volume chemical used in the manufacture of resins and fibers, antifreeze, deicing fluids, heat transfer and hydraulic fluids. Although occupational uses of ethylene glycol have not been associated with adverse effects, there are case reports where humans have either intentionally or accidentally ingested large quantities of ethylene glycol, primarily from antifreeze. The acute toxicity of ethylene glycol in humans and animals and can proceed through three stages, each associated with a different metabolite: central nervous system depression (ethylene glycol), cardiopulmonary effects associated with metabolic acidosis (glycolic acid) and ultimately renal toxicity (oxalic acid), depending upon the total amounts consumed and effectiveness of therapeutic interventions. A physiologically based pharmacokinetic (PBPK) model developed in a companion paper (Corley et al., 2004) was refined in this study to include clinically relevant treatment regimens for ethylene glycol poisoning such as hemodialysis or metabolic inhibition with either ethanol or fomepizole. Such modifications enabled the model to describe several human case reports which included analysis of ethylene glycol and/or glycolic acid. Such data and model simulations provide important confirmation that the PBPK model developed previously can adequately describe the pharmacokinetics of ethylene glycol in humans following low, occupational or environmentally relevant inhalation exposures, as well as massive oral doses even under conditions where treatments have been employed that markedly affect the disposition of ethylene glycol and glycolic acid. By integrating the case report data sets with controlled studies in this PBPK model, it was demonstrated that fomepizole, if administered early enough in a clinical situation, can be more effective than ethanol or hemodialysis in preventing the metabolism of ethylene glycol to more toxic metabolites. Hemodialysis remains an

  16. Cumulative emission budgets and their implications: the case for SAFE carbon

    Science.gov (United States)

    Allen, Myles; Bowerman, Niel; Frame, David; Mason, Charles

    2010-05-01

    The risk of dangerous long-term climate change due to anthropogenic carbon dioxide emissions is predominantly determined by cumulative emissions over all time, not the rate of emission in any given year or commitment period. This has profound implications for climate mitigation policy: emission targets for specific years such as 2020 or 2050 provide no guarantee of meeting any overall cumulative emission budget. By focusing attention on short-term measures to reduce the flow of emissions, they may even exacerbate the overall long-term stock. Here we consider how climate policies might be designed explicitly to limit cumulative emissions to, for example, one trillion tonnes of carbon, a figure that has been estimated to give a most likely warming of two degrees above pre-industrial, with a likely range of 1.6-2.6 degrees. Three approaches are considered: tradable emission permits with the possibility of indefinite emission banking, carbon taxes explicitly linked to cumulative emissions and mandatory carbon sequestration. Framing mitigation policy around cumulative targets alleviates the apparent tension between climate protection and short-term consumption that bedevils any attempt to forge global agreement. We argue that the simplest and hence potentially the most effective approach might be a mandatory requirement on the fossil fuel industry to ensure that a steadily increasing fraction of fossil carbon extracted from the ground is artificially removed from the active carbon cycle through some form of sequestration. We define Sequestered Adequate Fraction of Extracted (SAFE) carbon as a source in which this sequestered fraction is anchored to cumulative emissions, increasing smoothly to reach 100% before we release the trillionth tonne. While adopting the use of SAFE carbon would increase the cost of fossil energy much as a system of emission permits or carbon taxes would, it could do so with much less explicit government intervention. We contrast this proposal

  17. An Appendiceal Neoplastic Lesion: Case Report and Implications for Colonoscopic Screening and Surveillance

    Directory of Open Access Journals (Sweden)

    Hugh J Freeman

    2009-01-01

    Full Text Available A 65-year-old man with a history of previously resected colonic adenomas had an apparent cecal lesion detected during colonoscopy. The polyp proved to be a tubulovillous adenoma with high-grade dysplasia involving most of the body of the appendix along with the base of the cecum. The appendiceal mucosa is biologically similar to the colonic mucosa, yet remains relatively ‘hidden’ in screening and surveillance studies, which suggests important implications for evolving detection strategies in the follow-up of patients with a previous colon polyp or cancer resections. Although endoscopic removal of the appendix has been reported, treatment of these localized appendiceal lesions requires a wide surgical excision.

  18. [Hyperemesis gravidarum: management and nutritional implications; case report and review of literature].

    Science.gov (United States)

    De Haro, Karina; Toledo, Karen; Fonseca, Yolanda; Arenas, Diego; Arenas, Humberto; Leonher, Karla

    2014-10-03

    Hyperemesis gravidarum is a state of severe nausea and vomiting during pregnancy, leading to dehydration, electrolyte and acid-base disorders, malnutrition and weight loss (> 5%). The prevalence of hyperemesis gravidarum is 0.3-2.3% of all pregnancies. To demonstrate the effectiveness of nutritional support in a case of a complicated hyperemesis gravidarum. A case of a 25 years old woman with hyperemesis gravidarum, who had weight loss of 17.7%, dehydration, electrolyte disorders and arrhythmias, managed with enteral and parenteral nutrition at home until week 26 of gestation reaching to cover 70% of her caloric requirements orally, getting a healthy product and a stable nutritionally mother in late pregnancy. The multidisciplinary management and specialized nutritional management in such cases it is compulsory to carry the patient and the product at the end of pregnancy in optimal conditions. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

  19. Specific antigen serologic tests in leprosy: implications for epidemiological surveillance of leprosy cases and household contacts.

    Science.gov (United States)

    Carvalho, Ana Paula Mendes; Coelho, Angélica da Conceição Oliveira; Correa-Oliveira, Rodrigo; Lana, Francisco Carlos Félix

    2017-09-01

    There is a lack of straightforward tests for field application and known biomarkers for predicting leprosy progression in infected individuals. The aim was to analyse the response to infection by Mycobacterium leprae based on the reactivity of specific antigens: natural disaccharide linked to human serum albumin via an octyl (NDOHSA), a semisynthetic phenolic glycolipid-I (PGL-I); Leprosy Infectious Disease Research Institute Diagnostic-1 (LID-1) and natural disaccharide octyl - Leprosy Infectious Disease Research Institute Diagnostic-1 (NDOLID). The study population consisted of 130 leprosy cases diagnosed between 2010 and 2015 and 277 household contacts. An enzyme-linked immunosorbent assay (ELISA) was used to analyse the reactivity of antibodies against NDOHSA, LID-1 and NDOLID. The samples and controls were tested in duplicate, and the antibody titer was expressed as an ELISA index. Data collection was made by home visits with application of questionnaire and dermatological evaluation of all household contacts to identify signs and symptoms of leprosy. Significant differences in the median ELISA results were observed among leprosy cases in treatment, leprosy cases that had completed treatment and household contacts. Higher proportions of seropositivity were observed in leprosy cases in treatment. Seropositivity was also higher in multibacillary in relation to paucibacillary, with the difference reaching statistical significance. Lower titers were observed among cases with a longer treatment time or discharge. For household contacts, the differences according to the clinical characteristics of the leprosy index case were less pronounced than expected. Other factors, such as the endemicity of leprosy, exposure outside the residence and genetic characteristics, appeared to have a greater influence on the seropositivity. Serologic tests could be used as auxiliary tools for determining the operational classification, in addition to identifying infected individuals

  20. Implications of the 750 GeV γγ Resonance as a Case Study for the International Linear Collider

    Energy Technology Data Exchange (ETDEWEB)

    Fujii, Keisuke [High Energy Accelerator Research Organization (KEK), Tsukuba (Japan); Grojean, Christophe [Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany); Univ. Autonoma de Barcelona (Spain). Inst. Catalana de Recerca i Estudis Avancats (ICREA) and Inst. de Fisica d' Altes Energies (IFAE); Peskin, Michael E. [SLAC National Accelerator Lab., Menlo Park, CA (United States); Barklow, Tim [SLAC National Accelerator Lab., Menlo Park, CA (United States); Gao, Yuanning [Tsinghua Univ., Beijing (China). Center for High Energy Physics; Kanemura, Shinya [Univ. of Toyama (Japan). Dept. of Physics; Kim, Hyungdo [Seoul National Univ. (Korea, Republic of). Dept. of Physics and Astronomy; List, Jenny [Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany); Nojiri, Mihoko [High Energy Accelerator Research Organization (KEK), Tsukuba (Japan); Univ. of Tokyo (Japan). Kavli Inst. for the Physics and Mathematics of the Universe; Perelstein, Maxim [Cornell Univ., Ithaca, NY (United States). Lab. for Elementary Particle Physics; Poschl, Roman [Univ. Paris-Sud, Orsay (France). Linear Accelerator Lab. (LAL). Centre Scientifique d' Orsay; Reuter, Jurgen [Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany); Simon, Frank [Max Planck Inst. for Physics (MPP), Munich (Germany); Tanabe, Tomohiko [Univ. of Tokyo (Japan). International Center for Elementary Particle Physics (ICEPP); Yu, Jaehoon [Univ. of Texas, Arlington, TX (United States). Dept. of Physics; Wells, James D. [Univ. of Michigan, Ann Arbor, MI (United States). Michigan Center for Theoretical Physics; Falkowski, Adam [Univ. Paris-Sud, Orsay (France). Lab. of Theoretical Physics (LPT); Matsumoto, Shigeki [Univ. of Tokyo (Japan). Kavli Inst. for the Physics and Mathematics of the Universe; Moroi, Takeo [Univ. of Tokyo (Japan). Dept. of Physics; Richard, Francois [Univ. Paris-Sud, Orsay (France). Linear Accelerator Lab. (LAL). Centre Scientifique d' Orsay; Tian, Junping [Univ. of Tokyo (Japan). International Center for Elementary Particle Physics (ICEPP); Vos, Marcel [Spanish National Research Council (CSIC), Valencia (Spain) and Univ. of Valencia (Spain). Inst. for Corpuscular Physics (IFIC); Yokoya, Hiroshi [Korean Inst. for Advanced Study (KIAS), Seoul (Korea, Republic of ). Quantum Universe Center; Murayama, Hitoshi [Univ. of Tokyo (Japan). Kavli Inst. for the Physics and Mathematics of the Universe; Univ. of California, Berkeley, CA (United States). Dept. of Physics; Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Yamamoto, Hitoshi [Tohoku Univ., Sendai (Japan). Dept. of Physics

    2016-07-14

    If the γγ resonance at 750 GeV suggested by 2015 LHC data turns out to be a real effect, what are the implications for the physics case and upgrade path of the International Linear Collider? Whether or not the resonance is confirmed, this question provides an interesting case study testing the robustness of the ILC physics case. In this note, we address this question with two points: (1) Almost all models proposed for the new 750 GeV particle require additional new particles with electroweak couplings. The key elements of the 500 GeV ILC physics program - precision measurements of the Higgs boson, the top quark, and 4-fermion interactions - will powerfully discriminate among these models. This information will be important in conjunction with new LHC data, or alone, if the new particles accompanying the 750 GeV resonance are beyond the mass reach of the LHC. (2) Over a longer term, the energy upgrade of the ILC to 1 TeV already discussed in the ILC TDR will enable experiments in γγ and e+e- collisions to directly produce and study the 750 GeV particle from these unique initial states.

  1. Child sexual abuse in Singapore with special reference to medico-legal implications: a review of 38 cases.

    Science.gov (United States)

    Yiming, Cai; Fung, Daniel

    2003-07-01

    There is a paucity of studies on child sexual abuse in Asia. This study reviews the trends of child sexual abuse in Singapore and discusses the medico-legal considerations in the identification, assessment and management (including forensic implications) of such cases. It is a retrospective case review of 38 consecutive cases of child sexual abuse seen at a child guidance clinic in Singapore. Our study showed that most of the children were young (74% below age 9) and female (78.9%) with perpetrators who are males and usually known to the victims. There is a need to have integrated protocols to streamline assessment and reduce the need for repeated questioning. Adequate support of the victims in the form of specialised handling during the Court proceedings and in the use of new technology (such as video conferencing) for obtaining the child's testimony may be necessary. A child's fitness to testify is determined by the credibility and competence of the child. Repressed memories are of questionable validity.

  2. Antifungal triazole alcohols: A comparative analysis of structure-activity, structure-teratogenicity and structure-therapeutic index relationships using the Multiple Computer-Automated Structure Evaluation (Multi-CASE) methodology

    Science.gov (United States)

    Klopman, Gilles; Ptchelintsev, Dmitri

    1993-06-01

    An increase in the opportunistic fungal infections necessitates a design of new more effective and safer antifungal agnets. Triazole alcohols are effective antifungals, but have a risk of teratogenicity associated with them. Therefore, successful design of drugs from this class depends on understanding the structure-activity and structure-teratogenicity relationships in conjunction. To this end, we applied the Multiple Computer-Automated Structure Evaluation (Multi-CASE) methodology to a study of the relationships between the structures of 71 triazole alcohols and their in vitro antifungal activity, teratogenicity, and therapeutic index. For each end point, several relevant structural descriptors were identified. A comparative analysis of the Multi-CASE results indicates that cyano, methoxy groups, and ortho-difluorination on the aromatic ring decrease antifungal activity, but not the therapeutic index because of the concomitant negative contribution to teratogenicity. Metabolically deactivating para-substitution in the benzene ring is beneficial for the therapeutic index in agreement with the idea of metabolically induced teratogenicity. Fluorinated para-alkyl substituents are most preferable. The pattern of ortho-substitution in the benzene ring affects both antifungal and teratogenic activity. This suggests that the relative orientation of the benzene ring with respect to the rest of the molecule may play a modulating role. The Multi-CASE model could correctly predict, a priori, the teratogenicity and antifungal potency of SCH 39304 and ICI 156,066 and be used to optimize the structure and therapeutic index of the latter.

  3. [Comprehensive management of a child with a post-traumatic brain stem and spinal cord injury. A case study and presentation of current therapeutic modalities].

    Science.gov (United States)

    Kobylarz, Krzysztof; Kwiatkowski, Stanisław; Inglot, Barbara; Mróz, Adam

    2008-01-01

    Less than twenty years ago, a high spinal cord injury accompanied by paralysis of the diaphragm and the resulting apnea and tetraplegia led to certain death within a short time after the trauma, mostly due to respiratory complications associated with ventilatory therapy in hospitals. The objective of this paper is to present the case of a paediatric brain stem trauma with spinal cord injury, consisting of spinal cord rupture in the upper cervical segment. Thanks to appropriate management at all treatment stages (prompt, fully professional assistance in the ambulance, followed by appropriate management at ICU), the child survived. Owing to currently available technical solutions, the boy has achieved considerable self-dependence and an opportunity of having post-traumatic complications treated using a diaphragm pacing stimulator and a baclofen pump. The report presents therapeutic problems encountered in children with post-traumatic spinal cord injury, emphasizing technical opportunities of managing diaphragm paralysis, as exemplified by the five-year treatment and rehabilitation process of a boy with spinal cord injury at C1 level managed at the University Children's Hospital of Cracow, Poland, in whom phrenic nerve stimulation was employed. The implanted stimulator and a specially constructed controller have allowed the boy to achieve mobility using a wheelchair, being able to use a PC and being taught by an individual teacher at home despite his tetraparesis. Recurrent respiratory tract infections and occasional decubitus required periodic hospitalizations. As the patient grew, in consequence of uncontrolled sudden increases of muscle tone of the trunk spine. Increased muscle tone was increasingly resistant to pharmacotherapy and negatively affected the effectiveness of home rehabilitation. In consequence, a decision was made to implant an intraspinal baclofen pump.

  4. Counseling a Student Presenting Borderline Personality Disorder in the Small College Context: Case Study and Implications

    Science.gov (United States)

    Draper, Matthew R.; Faulkner, Ginger E.

    2009-01-01

    This case study examines the dynamics and challenges associated with counseling a client experiencing borderline personality disorder in the small college institutional context. The work of counseling centers at small private institutions has been relatively unexplored in the extant college counseling literature. To help fill this gap, the current…

  5. Agreement between oral contraceptive users and prescribers: implications for case-control studies

    NARCIS (Netherlands)

    F.E. van Leeuwen; C.M. van Duijn (Cornelia); M.H. Camps; B.A. Kempers; M.F. Mentjens; H.B. Mulder; E.G. Schouten (Evert); R.M.L. Zwijsen; M.A. Rookus (Matti)

    1992-01-01

    textabstractCase-control studies examining the effects of oral contraceptives (OC) are prone to misclassification bias due to errors in assessment of OC use. Concern about inaccurate exposure histories has increased since current studies require women to recall OC use over prolonged periods of time.

  6. Methamphetamine Exposure, Iron Deficiency, and Implications for Cognitive-Communicative Function: A Case Study

    Science.gov (United States)

    Goldberg, Lynette R.; Heiss, Cynthia J.; White, Letitia; Kaf, Wafaa A.; Becker, Alan; Schindler, Jessica B.; Dion, Nancy; Oswalt, Jill

    2010-01-01

    Methamphetamine (meth) exposure during fetal development has the potential to adversely affect the development of multiple organ systems. An interdisciplinary case study of a 4-year 11-month-old child born to a mother addicted to meth revealed significant cognitive and communicative delays. Possible meth-related consequences for these delays…

  7. Congenital analbuminaemia: biochemical and clinical implications. A case report and literature review

    NARCIS (Netherlands)

    Koot, Bart G. P.; Houwen, Roderick; Pot, Dirk-Jan; Nauta, Jeroen

    2004-01-01

    Congenital analbuminaemia was diagnosed in a small-for-gestational-age neonate presenting with placental and body oedema, an unusual presentation of this rare autosomal recessive disorder. A review of 39 reported cases in the literature shows that the clinical symptoms are always remarkably mild and

  8. Educational Implications of the Subtle Late Effects of Childhood Leukemia Medical Treatment: A Case Study

    Science.gov (United States)

    Lavach, John F.; Hart, Juliet E.

    2008-01-01

    This paper presents a four-year longitudinal case study of a nine-year-old student when he was diagnosed with leukemia. Cognitive, neuropsychological, and affective functioning both pre and post chemotherapy treatment were assessed. Full neuropsychological evaluation revealed difficulties with processing speed, concentration, and organization…

  9. Manifestations, Treatment Implications and Speech-Language Consideration in Gorlin Syndrome: A Case Study.

    Science.gov (United States)

    Andrews, Alice E.; Stonestreet, Ruth H.

    This paper presents a case study of Gorlin Syndrome, also known as Basal Cell Nevus Syndrome, a rare genetic disorder characterized by widespread developmental defects. Criteria for diagnosis are listed, noting the presence of frequent basal cell carcinomas at a relatively young age and multiple cysts of the jaw. Speech and/or language impairments…

  10. Femoroacetabular impingement and its implications on range of motion: a case report

    Directory of Open Access Journals (Sweden)

    Bloem Rolf M

    2011-04-01

    Full Text Available Abstract Introduction Femoroacetabular impingement leads to limited hip motion, pain and progressive damage to the labrum. Assessment of the amount and location of excessive ossification can be difficult, and removal does not always lead to pain relief and an increase of function. One of the challenges ahead is to discover why certain cases have poor outcomes. Case presentation The technical and clinical results of two consecutive arthroscopic shavings of an osseous cam protrusion are described in our patient, a 50-year-old Caucasian man with complaints of femoroacetabular impingement. At 12 weeks after the first arthroscopic shaving, our patient still experienced pain. Using a range of motion simulation system based on computed tomography images the kinematics of his hip joint were analyzed. Bone that limited range of motion was removed in a second arthroscopic procedure. At six months post-operatively our patient is almost pain free and has regained a range of motion to a functional level. Conclusion This case demonstrates the relevance of range of motion simulation when the outcome of primary arthroscopic management is unsatisfactory. Such simulations may aid clinicians in determining the gain of a second operation. This claim is supported by the correlation of the simulations with clinical outcome, as shown in this case report.

  11. The economic implications of case-mix Medicaid reimbursement for nursing home care.

    Science.gov (United States)

    Grabowski, David C

    2002-01-01

    In recent years, there has been large growth in the nursing home industry in the use of case-mix adjusted Medicaid payment systems that employ resident characteristics to predict the relative use of resources in setting payment levels. Little attention has been paid to the access and quality incentives that these systems provide in the presence of excess demand conditions due to certificate-of-need (CON) and construction moratoria. Using 1991 to 1998 panel data for all certified U.S. nursing homes, a fixed-effects model indicates that adoption of a case-mix payment system led to increased access for more dependent residents, but the effect was modified in excess demand markets. Quality remained relatively stable with the introduction of case-mix reimbursement, regardless of the presence of excess demand conditions. These results suggest that CON and construction moratoria are still important barriers within the nursing home market, and recent quality assurance activities related to the introduction of case-mix payment systems may have been effective.

  12. Therapeutic options for visceral leishmaniasis.

    Science.gov (United States)

    Monge-Maillo, Begoña; López-Vélez, Rogelio

    2013-11-01

    Visceral leishmaniasis (VL), also known as Kala-Azar, is a disseminated protozoal infection caused principally by Leishmania donovani and Leishmania infantum (known as Leishmania chagasi in South America). The therapeutic options for VL are diverse and depend on different factors, such as the geographical area of the infection, development of resistance to habitual treatments, HIV co-infection, malnourishment and other concomitant infections. This article provides an exhaustive review of the literature regarding studies published on the treatment of VL, and gives therapeutic recommendations stratified according to their level of evidence, the species of Leishmania implicated and the geographical location of the infection.

  13. Policy implications of achievement testing using multilevel models: The case of Brazilian elementary schools

    Directory of Open Access Journals (Sweden)

    Igor Gomes Menezes

    2016-11-01

    Full Text Available Large-scale educational assessment has been established as source of descriptive, evaluative and interpretative information that influence educational policies worldwide throughout the last third of the 20th century. In the 1990s the Brazilian Ministry of Education developed the National Basic Education Assessment System (SAEB that regularly measures management, resource and contextual school features and academic achievement in public and private institutions. In 2005, after significant piloting and review of the SAEB, a new sampling strategy was taken and Prova Brasil became the new instrument used by the Ministry to assess skills in Portuguese (reading comprehension and Mathematics (problem solving, as well as collecting contextual information concerning the school, principal, teacher, and the students. This study aims to identify which variables are predictors of academic achievement of fifth grade students on Prova Brasil. Across a large sample of students, multilevel models tested a large number of variables relevant to student achievement. This approach uncovered critical variables not commonly seen as significant in light of other achievement determinants, including student habits, teacher ethnicity, and school technological resources. As such, this approach demonstrates the value of MLM to appropriately nuanced educational policies that reflect critical influences on student achievement. Its implications for wider application for psychology studies that may have relevant impacts for policy are also discussed.

  14. Implications of Switching Fossil Fuel Subsidies to Solar: A Case Study for the European Union

    Directory of Open Access Journals (Sweden)

    Jon Sampedro

    2017-12-01

    Full Text Available Fossil fuel subsidies (FFS constitute one of the most obvious barriers to tackling climate change, as they encourage inefficient energy consumption and divert investment away from clean energy sources. According to the International Monetary Fund, FFS amounted globally to $233 billion in 2014, over four times the value of subsidies awarded to promote renewable energy. In this study an integrated assessment model is used to analyse the CO2 implications in the European Union of eliminating FFS and recycling the revenues to promote rooftop PV. It is found that eliminating FFS would give rise to a small reduction in CO2 due to fuel-switching from coal to gas. If the revenues were recycled to promote solar, then the CO2 reduction would increase from 1.8% to 2.2% by 2030. Eliminating FFS is not a panacea from the mitigation point of view, even if the revenues are recycled, but other important objectives, such as those related to renewable energy promotion and the reduction of air pollution, are advanced at zero cost for the government.

  15. Investor to State Dispute Cases on the NAFTA: Facts and Implications

    Directory of Open Access Journals (Sweden)

    Kwan-Ho Kim

    1998-09-01

    Full Text Available Korea is about to take part in the MAI (Multilateral Agreement on Investment and sign the Korea-US investment agreement and so on. One major way to testify the possible trade dissensions we might face under these agreements is to observe the dissension cases under the NAFTA investment agreement which is similar to these agreements. The problems which found in NAFTA dissension cases, such as the discordant standing points among sections, the relationship between the central government and local governments, the coherence of the policies and the unreasonable domestic regulations are also our problems. The dissensions causing by the oversea investors might blemish the image of the country which attracts investments. The most ideal way is to prevent the dissensions. If it happened, it should be solved in a friendly way. This thesis discussed the grievance machinery or trouble shooter which was recently added into the investment promotion act and the effective operation of the foreign investment committee.

  16. Medicolegal Implications of Nosocomial Infections: A Case Report of Aspergillus Contamination during Cardiac Surgery.

    Science.gov (United States)

    Tuchtan, Lucile; Piercecchi-Marti, Marie-Dominique; Dumon, Henri; Métras, Dominique; Léonetti, Georges; Bartoli, Christophe

    2017-05-01

    Nosocomial infections have become a major issue of public health and lead to an increasing number of suits for damages. We present a rare case of Aspergillus contamination during cardiac surgery, describe the medicolegal investigation, and present the new system for compensation of bodily injury after nosocomial infection in France, based on the law of March 4, 2002 on patient rights and quality in the health system. This case demonstrates the limits of compensation for nosocomial infections on the grounds of national solidarity. The expert report requested by the regional commission for conciliation and compensation is of fundamental importance in enabling the commission to decide between fault and inherent risk of treatment. © 2016 American Academy of Forensic Sciences.

  17. Cytomegalovirus implicated in a case of progressive outer retinal necrosis (PORN).

    Science.gov (United States)

    Sfeir, Maroun

    2015-08-01

    Progressive outer retinal necrosis, also known as PORN, has been described as a variant of necrotizing herpetic retinopathy, occurring particularly in patients with acquired immune deficiency syndrome (AIDS). Although the etiologic organism has been reported to be Varicella-zoster virus, cytomegalovirus (CMV) can be an etiologic agent. Our case illustrates the occurrence of two opportunistic infections: PORN associated with CMV and Mycobacterium avium intracellulare duodenitis in a patient with uncontrolled HIV infection. Copyright © 2015 Elsevier B.V. All rights reserved.

  18. Pharmacogenomics and migraine: possible implications

    DEFF Research Database (Denmark)

    Tfelt-Hansen, P.; Brosen, K.

    2008-01-01

    Pharmacogenomics is the science about how inherited factors influence the effects of drugs. Drug response is always a result of mutually interacting genes with important modifications from environmental and constitutional factors. Based on the genetic variability of pharmacokinetic and in some...... cases pharmacodynamic variability we mention possible implications for the acute and preventive treatment of migraine. Pharmacogenomics will most likely in the future be one part of our therapeutic armamentarium and will provide a stronger scientific basis for optimizing drug therapy on the basis...

  19. The Use of Case Based Multiple Choice Questions for Assessing Large Group Teaching: Implications on Student's Learning

    Directory of Open Access Journals (Sweden)

    Christina Donnelly

    2014-06-01

    Full Text Available The practice of assessments in third level education is extremely important and a rarely disputed part of the university curriculum as a method to demonstrate a student’s learning. However, assessments to test a student’s knowledge and level of understanding are challenging to apply given recent trends which are showing that student numbers are increasing, student demographics are wide ranging and resources are being stretched. As a result of these emerging challenges, lecturers are required to develop a comprehensive assessment to effectively demonstrate student learning, whilst efficiently managing large class sizes. One form of assessment which has been used for efficient assessment is multiple choice questions (MCQs; however this method has been criticised for encouraging surface learning, in comparison to other methods such as essays or case studies. This research explores the impact of blended assessment methods on student learning. This study adopts a rigorous three-staged qualitative methodology to capture third level lecturers’ and students’ perception to (1 the level of learning when using MCQs; (2 the level of learning when blended assessment in the form of case based MCQs are used. The findings illuminate the positive impact of cased based MCQs as students and lecturers suggest that it leads to a higher level of learning and deeper information processing over that of MCQs without case studies. 2 The implications of this research is that this type of assessment contributes to the current thinking within literature on the use of assessments methods, as well as the blending of assessment methods to reach a higher level of learning. It further serves to reinforce the belief that assessments are the greatest influence on students’ learning, and the requirement for both universities and lecturers to reflect on the best form of assessment to test students’ level of understanding, whilst also balancing the real challenges of

  20. AIPL1 implicated in the pathogenesis of two cases of autosomal recessive retinal degeneration

    Science.gov (United States)

    Li, David; Jin, Chongfei; Jiao, Xiaodong; Li, Lin; Bushra, Tahmina; Naeem, Muhammad Asif; Butt, Nadeem H.; Husnain, Tayyab; Sieving, Paul A.; Riazuddin, Sheikh; Riazuddin, S. Amer

    2014-01-01

    Purpose To localize and identify the gene and mutations causing autosomal recessive retinal dystrophy in two consanguineous Pakistani families. Methods Consanguineous families from Pakistan were ascertained to be affected with autosomal recessive retinal degeneration. All affected individuals underwent thorough ophthalmologic examinations. Blood samples were collected, and genomic DNA was extracted using a salting out procedure. Genotyping was performed using microsatellite markers spaced at approximately 10 cM intervals. Two-point linkage analysis was performed with the lod score method. Direct DNA sequencing of amplified genomic DNA was performed for mutation screening of candidate genes. Results Genome-wide linkage scans yielded a lod score of 3.05 at θ=0 for D17S1832 and 3.82 at θ=0 for D17S938, localizing the disease gene to a 12.22 cM (6.64 Mb) region flanked by D17S1828 and D17S1852 for family 61032 and family 61227, which contains aryl hydrocarbon receptor interacting protein-like 1 (AIPL1), a gene previously implicated in recessive Leber congenital amaurosis and autosomal dominant cone-rod dystrophy. Sequencing of AIPL1 showed a homozygous c.773G>C (p.Arg258Pro) sequence change in all affected individuals of family 61032 and a homozygous c.465G>T (p.(H93_Q155del)) change in all affected members of family 61227. Conclusions The results strongly suggest that the c.773G>C (p.R258P) and c.465G>T (p.(H93_Q155del)) mutations in AIPL1 cause autosomal recessive retinal degeneration in these consanguineous Pakistani families. PMID:24426771

  1. Opioid overdose in a child: case report and discussion with emphasis on neurosurgical implications.

    Science.gov (United States)

    Reisner, Andrew; Hayes, Laura L; Holland, Christopher M; Wrubel, David M; Kebriaei, Meysam A; Geller, Robert J; Baum, Griffin R; Chern, Joshua J

    2015-12-01

    In environments in which opioids are increasingly abused for recreation, children are becoming more at risk for both accidental and nonaccidental intoxication. In toxic doses, opioids can cause potentially lethal acute leukoencephalopathy, which has a predilection for the cerebellum in young children. The authors present the case of a 2-year-old girl who suffered an accidental opioid overdose, presenting with altered mental status requiring cardiorespiratory support. She required emergency posterior fossa decompression, partial cerebellectomy, and CSF drainage due to cerebellar edema compressing the fourth ventricle. To the authors' knowledge, this is the first report of surgical decompression used to treat cerebellar edema associated with opioid overdose in a child.

  2. Anaesthetic Implications in Primary Hyperparathyroidism with Severe Hypercalcaemia; a Case Report

    Directory of Open Access Journals (Sweden)

    Pranav Bansal

    2013-07-01

    Full Text Available Primary hyperparathyroidism is a rare endocrinal disorder of excess production of parathormone. A wide array of presenting symptoms may occur from parathormone induced hypercalcaemia leading to nephrolithiasis, osteoporosis, muscle weakness and cardiac arrhythmias. We present a case of young female who presented with non union of an operated fracture femur and generalized bony pains and frequent complaints of vomiting, polyuria and polydipsia. She was diagnosed to have primary hyperparathyroidism with hypercalcaemia and underwent parathyroidectomy. The potential perioperative problems and anaesthetic concerns require a focused management and are discussed.

  3. Anaesthetic Implications in Primary Hyperparathyroidism with Severe Hypercalcaemia: a Case Report

    Directory of Open Access Journals (Sweden)

    Pranav Bansal

    2013-07-01

    Full Text Available Primary hyperparathyroidism is a rare endocrinal disorder of excess production of parathormone. A wide array of presenting symptoms may occur from parathormone induced hypercalcaemia leading to nephrolithiasis, osteoporosis, muscle weakness and cardiac arrhythmias. We present a case of young female who presented with non union of an operated fracture femur and generalized bony pains and frequent complaints of vomiting, polyuria and polydipsia. She was diagnosed to have primary hyperparathyroidism with hypercalcaemia and underwent parathyroidectomy. The potential perioperative problems and anaesthetic concerns are discussed.

  4. A case of impaired shape integration: Implications for models of visual object processing

    DEFF Research Database (Denmark)

    Gerlach, Christian; Marstrand, Lisbeth; Habekost, Thomas

    2005-01-01

    integration is not a prerequisite for normal object naming. However, on more demanding tests of visual object recognition, HE's performance deteriorated, with her performance being inversely related to the demand placed on integration of local elements into more elaborate shape descriptions. From this we...... conclude that shape integration is important for normal object recognition....... the notion that grouping may be divided into two general steps: (i) element clustering and (ii) shape configuration, with the latter operation being impaired in HE. As opposed to previous cases with shape integration deficits, HE was able to name objects accurately. Initially, this might suggest that shape...

  5. Teleology as Logical Phenomenology: Some Therapeutic Implications.

    Science.gov (United States)

    Rychlak, Joseph F.

    Phenomenology is an important force in the development of psychological theory, rather than a variant type of counseling method. A distinction must be drawn between the sensory phenomenology in which gestaltists focus on sensory receptors, and logical pheomenology in which the grounding of belief or self-identity is viewed as a prediction or…

  6. Imaging of penile traumas - therapeutic implications

    Energy Technology Data Exchange (ETDEWEB)

    Bertolotto, Michele; Calderan, Loretta; Cova, Maria Assunta [Universita di Trieste, UCO di Radiologia, Trieste (Italy)

    2005-12-01

    Injury to the penis may result from penetrating or nonpenetrating trauma. Nonpenetrating injury to the erect penis can produce albugineal tear, intracavernous hematoma or extraalbugineal hematoma from rupture of the dorsal vessels. Nonpenetrating injury to the flaccid penis usually follows blunt perineal traumas producing extratunical or cavernosal haematomas, or cavernosal artery tear followed by high flow priapism. Differential diagnosis between albugineal tear and other penile injuries must be obtained as soon as possible, since early surgical repair of albugineal tear reduces significantly the rate of postraumatic curvature and fibrosis. Ultrasonography (US) is able to detect the exact site of the tear in most patients as an interruption of the thin echogenic line of the tunica albuginea. Other imaging techniques are rarely required in the clinical practice. Color Doppler US is the imaging modality of choice to evaluate patients with high flow priapism. Focal or diffuse cavernosal fibrosis can be identified with US as echogenic areas in the cavernosal bodies. Postraumatic erectile dysfunction can result from fibrotic changes, nerve and vascular impairment or both. Doppler evaluation of penile vasculature is required in young patients with postraumatic impotence before surgical revascularization procedures. (orig.)

  7. Therapeutic implications of recombinant human erythropoietin in ...

    African Journals Online (AJOL)

    AJB SERVER

    2006-12-29

    Dec 29, 2006 ... brain and other exercise parameters such as muscle oxidative metabolism and fore arm vasodilation. ... ventricular hypertrophy and its associated mortality; it leads to the improvement of physical performance and .... tioning of skeletal muscle and O2 use as well as endothe- lial function (Mohan et al., 1999).

  8. Therapeutic implications of recombinant human erythropoietin in ...

    African Journals Online (AJOL)

    AJB SERVER

    2006-12-29

    Dec 29, 2006 ... brain and other exercise parameters such as muscle oxidative metabolism and fore arm vasodilation. .... in the effect of EPO on angiogenesis (Ashley et al.,. 2002). Recent studies have been conducted to .... EPO (7 x 109 plaque-forming units/kg) to the peritoneum of cotton rats caused a marked increase in.

  9. The Implications of Victimhood Identity: The Case of ‘Persecution’ of Swedish Hunters

    Directory of Open Access Journals (Sweden)

    Erica von Essen

    2017-06-01

    Full Text Available This ethnographically based study examines Swedish hunters’ claims to victimhood through appeal to the term ‘persecution’. Perceiving disenfranchisement, injustice and discrimination on the basis of wolf conservation policy, we present hunters’ self-styled predicament as victimhood-claimants of persecution at the hands of a state that has been co-opted by a conservationist, pro-wolf agenda that systematically disenfranchises rural and hunting interests and lifestyles. Through the phenomenological accounts of hunter respondents, our paper takes seriously the hunters’ perception of persecution and, likewise, considers the opposite case made by conservationists: that wolves have been, and continue to be, the real victims of persecution in the conflict. Nonetheless, we show that the persecution language as it is applied from opposing parties in the conflict is problematic inasmuch as it is focused around creating a moral panic and confusion among the Swedish public who are ultimately responsible, as a democratic body-politic, for assessing the legitimacy of claims to moral wrong-doing and legal redress for the wronged. Our case study joins scholarship that explores the pathologies of claims to victimization

  10. Case Study of R-1234yf Refrigerant: Implications for the Framework for Responsible Innovation.

    Science.gov (United States)

    Wodzisz, Rafał

    2015-12-01

    Safety and care for the natural environment are two of the most important values that drive scientific enterprise in twentieth century. Researchers and innovators often develop new technologies aimed at pollution reduction, and therefore satisfy the strive for fulfilment of these values. This work is often incentivized by policy makers. According to EU directive 2006/40/EC on mobile air conditioning since 2013 all newly approved vehicles have to be filled with refrigerant with low global warming potential (GWP). Extensive and expensive research financed by leading car manufacturers led to invention of R-1234yf refrigerant with GWP case it will be useful to refer it to the idea of responsible innovation (RI), which is now being developed and quickly attracts attention. I proceed in the following order. Firstly, I present the relevant properties of R-1234yf and discuss the controversy associated with its marketing. Secondly, I examine framework for responsible innovation. In greater detail I discuss the notions of care for future generations and collective responsibility. Thirdly, I apply the offered framework to the case study at hand. Finally, I draw some conclusions which go in two directions: one is to make some suggestions for improving the framework of RI, and the second is to identify missed opportunities for developing truly responsible refrigerant.

  11. Understanding congenital heart defects through abdominal fetal electrocardiography: case reports and clinical implications.

    Science.gov (United States)

    Velayo, Clarissa; Sato, Naoaki; Ito, Takuya; Chisaka, Hiroshi; Yaegashi, Nobuo; Okamura, Kunihiro; Kimura, Yoshitaka

    2011-05-01

    Congenital heart defects are the most common fetal structural anomalies of which a significant number remain unrecognized during postnatal life. Fetal electrocardiography (FECG) is an ideal clinical tool to complement ultrasonography for the screening and management of these cases where early and accurate diagnoses would allow definite rather than palliative treatment. The objective of this report was to correlate the particular FECG results found with the different types of congenital heart defects involved and to further demonstrate the usefulness of FECG in clinical settings. This is a report of four cases of prenatally diagnosed congenital heart defects seen at a university hospital in Sendai, Japan. Their complete and thorough evaluation included, among other tests, abdominal FECG analysis. The presence of premature ventricular contractions, a prolonged pre-ejection period (PEP > 75 msec), and prolonged QTc intervals (QTc > 440 msec) served as markers of hemodynamic alteration but were unlikely determinants of disease severity precluding further investigation. In practice, similar findings found on FECG should raise the index of suspicion for the presence of congenital heart disease and prompt a targeted ultrasound scan. © 2011 The Authors. Journal of Obstetrics and Gynaecology Research © 2011 Japan Society of Obstetrics and Gynecology.

  12. Geoethical implications for geoarchaeology. The Laacher See and AD 536 case studies

    Science.gov (United States)

    Riede, Felix; Price, Neil; Andersen, Per

    2017-04-01

    Environmental catastrophes represent profound challenges faced by societies today. Numerous scholars in the climate sciences as well as the Humanities have argued for a greater ethical engagement with these pressing issues. At the same time, several disciplines concerned with hazards are moving towards formalized ethical codes or promises that guide not only the dissemination of data but oblige scientists to relate to fundamentally political issues. With its starting point in the recently proposed geoethical promise, this paper reports on two case studies of how past natural hazards have affected vulnerable societies in Europe's past. We ask whether cases of past calamities and their societal effects should not play a greater role in public debates and whether geo-archaeologists working with past environmental hazards should be more outspoken in their ethical considerations. We offer no firm answers, but suggest that geo-archaeologists engage with debates of human-environment relations at this interface between politics, public affairs and science. We argue for greater communication between the human and natural sciences and further suggest that outreach institutions such as museums - both natural and cultural - could and perhaps should play a key role in staging such engagements.

  13. Mutation spectrum of RB1 mutations in retinoblastoma cases from Singapore with implications for genetic management and counselling.

    Directory of Open Access Journals (Sweden)

    Swati Tomar

    Full Text Available Retinoblastoma (RB is a rare childhood malignant disorder caused by the biallelic inactivation of RB1 gene. Early diagnosis and identification of carriers of heritable RB1 mutations can improve disease outcome and management. In this study, mutational analysis was conducted on fifty-nine matched tumor and peripheral blood samples from 18 bilateral and 41 unilateral unrelated RB cases by a combinatorial approach of Multiplex Ligation-dependent Probe Amplification (MLPA assay, deletion screening, direct sequencing, copy number gene dosage analysis and methylation assays. Screening of both blood and tumor samples yielded a mutation detection rate of 94.9% (56/59 while only 42.4% (25/59 of mutations were detected if blood samples alone were analyzed. Biallelic mutations were observed in 43/59 (72.9% of tumors screened. There were 3 cases (5.1% in which no mutations could be detected and germline mutations were detected in 19.5% (8/41 of unilateral cases. A total of 61 point mutations were identified, of which 10 were novel. There was a high incidence of previously reported recurrent mutations, occurring at 38.98% (23/59 of all cases. Of interest were three cases of mosaic RB1 mutations detected in the blood from patients with unilateral retinoblastoma. Additionally, two germline mutations previously reported to be associated with low-penetrance phenotypes: missense-c.1981C>T and splice variant-c.607+1G>T, were observed in a bilateral and a unilateral proband, respectively. These findings have implications for genetic counselling and risk prediction for the affected families. This is the first published report on the spectrum of mutations in RB patients from Singapore and shows that further improved mutation screening strategies are required in order to provide a definitive molecular diagnosis for every case of RB. Our findings also underscore the importance of genetic testing in supporting individualized disease management plans for patients and

  14. Mutation spectrum of RB1 mutations in retinoblastoma cases from Singapore with implications for genetic management and counselling.

    Science.gov (United States)

    Tomar, Swati; Sethi, Raman; Sundar, Gangadhara; Quah, Thuan Chong; Quah, Boon Long; Lai, Poh San

    2017-01-01

    Retinoblastoma (RB) is a rare childhood malignant disorder caused by the biallelic inactivation of RB1 gene. Early diagnosis and identification of carriers of heritable RB1 mutations can improve disease outcome and management. In this study, mutational analysis was conducted on fifty-nine matched tumor and peripheral blood samples from 18 bilateral and 41 unilateral unrelated RB cases by a combinatorial approach of Multiplex Ligation-dependent Probe Amplification (MLPA) assay, deletion screening, direct sequencing, copy number gene dosage analysis and methylation assays. Screening of both blood and tumor samples yielded a mutation detection rate of 94.9% (56/59) while only 42.4% (25/59) of mutations were detected if blood samples alone were analyzed. Biallelic mutations were observed in 43/59 (72.9%) of tumors screened. There were 3 cases (5.1%) in which no mutations could be detected and germline mutations were detected in 19.5% (8/41) of unilateral cases. A total of 61 point mutations were identified, of which 10 were novel. There was a high incidence of previously reported recurrent mutations, occurring at 38.98% (23/59) of all cases. Of interest were three cases of mosaic RB1 mutations detected in the blood from patients with unilateral retinoblastoma. Additionally, two germline mutations previously reported to be associated with low-penetrance phenotypes: missense-c.1981C>T and splice variant-c.607+1G>T, were observed in a bilateral and a unilateral proband, respectively. These findings have implications for genetic counselling and risk prediction for the affected families. This is the first published report on the spectrum of mutations in RB patients from Singapore and shows that further improved mutation screening strategies are required in order to provide a definitive molecular diagnosis for every case of RB. Our findings also underscore the importance of genetic testing in supporting individualized disease management plans for patients and asymptomatic

  15. Elementary teachers' acquisition of science knowledge: Case-studies and implications for teaching preparation

    Science.gov (United States)

    Stein, Morton

    Elementary school is a key time for students to develop their understanding of basic science concepts as well as their attitudes towards science and science learning. Yet many elementary teachers do not feel comfortable teaching science; as a result, they are likely to devote less time on that subject and to be less effective as science teachers. The literature suggests that weaknesses in elementary teachers' knowledge of science could be a main cause of this problem and, furthermore, that current elementary teacher preparation programs have contributed to this weakness. This study aims at gaining more knowledge about how elementary teachers who are successful in teaching science have acquired their science content knowledge and how such knowledge could be best acquired, with the ultimate goal of informing the design of more effective elementary teacher preparation programs. More specifically, this study addresses the following research questions: Which science learning experiences for elementary teachers seem most conducive to develop the kind of science content knowledge and pedagogical content knowledge needed to support the teaching of science as called for by the most recent national and state standards? Which of these experiences should be included in elementary teacher preparation programs, and how? The core of this study consists of case studies of eight elementary school teachers who were identified as successful in teaching science. These subjects were selected so as to ensure differences in their teacher preparation programs, as well as gender and years of teaching experience. Information about each teacher's self-efficacy and motivation with respect to teaching science, history of pre-service and in-service preparation with respect to science, and how his/her current science knowledge was acquired, was sought through a series of interviews with each subject and triangulated with data collected from other sources. A cross-case analysis revealed some

  16. Hydrotherapy for the long-term ventilated patient: A case study and implications for practice.

    Science.gov (United States)

    Wegner, Sally; Thomas, Peter; James, Christine

    2017-11-01

    Hydrotherapy of mechanically ventilated patients has been shown to be safe and feasible in both the acute stages of critical illness and in those requiring long term mechanical ventilation. This case study describes the hydrotherapy sessions of a 36 year old female, who after suffering complications of pneumococcal meningitis, became an incomplete quadriplegic and required long term mechanical ventilation. When implementing hydrotherapy with patients on mechanical ventilation a number of factors should be considered. These include staff resources and training, airway and ventilation management, patient preparation and safety procedures. Hydrotherapy can be safely utilised with mechanically ventilated patients, and may facilitate a patient's ability to participate in active exercise and rehabilitation. Copyright © 2017 Australian College of Critical Care Nurses Ltd. All rights reserved.

  17. [Two cases of congenital airway obstruction managed with ex utero intrapartum treatment procedures: anesthetic implications].

    Science.gov (United States)

    Manrique, S; Blasco, J; Munar, F; Andreu, E; Mateo, M D; Suescun, M C; López Gil, M V

    2007-01-01

    An ex utero intrapartum treatment (EXIT) procedure provides sufficient time to gain control of the potentially obstructed fetal upper airway while uterine placental circulation is maintained during cesarean section. We report 2 cases in which fetal congenital upper airway obstruction was managed without complications during EXIT procedures. We also discuss general considerations concerning the obstetric patient and the performance of intramuscular fetal anesthesia. Before the hysterotomy, sevoflurane at 1.5 minimum alveolar concentration was administered to assure sufficient uterine relaxation during EXIT. The 2 parturients remained hemodynamically stable during the procedure and uterine and placental perfusion was adequate. Nasotracheal intubation was possible in 1 fetus after a cervical mass was dissected. In the other, a tracheostomy was created. After the umbilical cord was clamped, the concentration of sevoflurane anesthetic gas was reduced and oxytocin and methylergometrine were administered to induce adequate uterine contractions within a few minutes. Both neonates survived the EXIT procedure with no complications.

  18. Unnecessary extractions in patients with hemicrania continua: case reports and implication for dentistry.

    Science.gov (United States)

    Prakash, Sanjay; Shah, Nilima D; Chavda, Bhavna V

    2010-01-01

    Headache and facial pain are both very high in the general population. Headache has been identified as one of the associated conditions in patients with chronic orofacial pain. The interrelation between the two has not been explored in the literature. Patients with facial pain often initially seek the care of a dentist. Misdiagnosis and multiple failed treatments (including invasive procedures) are very common in this population. This case report describes four patients whose condition fulfilled the International Headache Society's criteria for hemicrania continua but whose teeth were extracted because their pain was suspected to be of odontogenic origin. Each patient's records and the literature were reviewed for possible reasons for the unnecessary extractions. The findings suggest that initial treatment with drugs specific for primary headache disorders should be instituted before subjecting patients to invasive procedures.

  19. Implications of post-gadolinium MRI results in 13 cases with posterior reversible encephalopathy syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Ugurel, Mehmet Sahin [Department of Radiology, Gulhane Military Medical Academy and Medical Faculty, Ankara 06018 (Turkey)]. E-mail: sugurel@gata.edu.tr; Hayakawa, Minako [Department of Radiology, University of Iowa-College of Medicine, Iowa City, IA 52242 (United States)

    2005-03-01

    Background: There is a relative lack of definitive information about the contrast-enhancement characteristics of lesions in posterior reversible encephalopathy syndrome (PRES). Objective: Evaluation of contrast-enhanced MRI findings in PRES with a special emphasis on pathophysiology of post-gadolinium behavior of these lesions. Materials and methods: Contrast-enhanced 1.5 T MRI findings and relevant clinical data of the patients were retrospectively reviewed on 13 cases (six males, seven females; age range: 22-78; mean age 47). Although fluid attenuated inversion recovery (FLAIR) and diffusion-weighted MR images were considered for identification of the entity, primarily post-contrast T1-weighted MR images were searched for traces of enhancement in the lesions. Results: No definitely enhancing lesion was identified in the MR images obtained in 6-48 h after onset of symptoms (mostly headaches, seizures and cortical visual field deficits) in this series. Severity of disease indicated by small hemorrhages, confluence of lesions or progression to cytotoxic edema did not seem to alter this result. Typical lesion characteristics were consistent with vasogenic edema on FLAIR and diffusion MR images. Acute elevation of blood pressure on chronic hypertensive background was responsible in four, eclampsia in three, uremia with blood pressure fluctuations in three, and cyclosporine-toxicity in three cases. Conclusion: Although occasional enhancing brain lesions have been reported in the literature on PRES, contrast-enhancement of lesions may be a factor of scan timing and underlying etiology. Prospective studies with larger series on PRES are required for better evaluation of contrast-enhancement in MRI with respect to scan timing, which in turn may help understand its pathophysiology better.

  20. Formation of histamine and biogenic amines in cold-smoked tuna: An investigation of psychrotolerant bacteria from samples implicated in cases of histamine fish poisoning

    DEFF Research Database (Denmark)

    Emborg, Jette; Dalgaard, Paw

    2006-01-01

    Two outbreaks and a single case of histamine fish poisoning associated with cold-smoked tuna (CST) were reported in Denmark during 2004. The bacteria most likely responsible for histamine formation in CST implicated in histamine fish poisoning was identified for the first time in this study...

  1. Ablation of TNF-RI/RII expression in Alzheimer's disease mice leads to an unexpected enhancement of pathology: implications for chronic pan-TNF-α suppressive therapeutic strategies in the brain.

    Science.gov (United States)

    Montgomery, Sara L; Mastrangelo, Michael A; Habib, Diala; Narrow, Wade C; Knowlden, Sara A; Wright, Terry W; Bowers, William J

    2011-10-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by severe memory loss and cognitive impairment. Neuroinflammation, including the extensive production of pro-inflammatory molecules and the activation of microglia, has been implicated in the disease process. Tumor necrosis factor (TNF)-α, a prototypic pro-inflammatory cytokine, is elevated in AD, is neurotoxic, and colocalizes with amyloid plaques in AD animal models and human brains. We previously demonstrated that the expression of TNF-α is increased in AD mice at ages preceding the development of hallmark amyloid and tau pathological features and that long-term expression of this cytokine in these mice leads to marked neuronal death. Such observations suggest that TNF-α signaling promotes AD pathogenesis and that therapeutics suppressing this cytokine's activity may be beneficial. To dissect TNF-α receptor signaling requirements in AD, we generated triple-transgenic AD mice (3xTg-AD) lacking both TNF-α receptor 1 (TNF-RI) and 2 (TNF-RII), 3xTg-ADxTNF-RI/RII knock out, the cognate receptors of TNF-α. These mice exhibit enhanced amyloid and tau-related pathological features by the age of 15 months, in stark contrast to age-matched 3xTg-AD counterparts. Moreover, 3xTg-ADxTNF-RI/RII knock out-derived primary microglia reveal reduced amyloid-β phagocytic marker expression and phagocytosis activity, indicating that intact TNF-α receptor signaling is critical for microglial-mediated uptake of extracellular amyloid-β peptide pools. Overall, our results demonstrate that globally ablated TNF receptor signaling exacerbates pathogenesis and argues against long-term use of pan-anti-TNF-α inhibitors for the treatment of AD. Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  2. Estimating the effectiveness of ergonomics interventions through case studies: implications for predictive cost-benefit analysis.

    Science.gov (United States)

    Goggins, Richard W; Spielholz, Peregrin; Nothstein, Greg L

    2008-01-01

    Cost-benefit analysis (CBA) can help to justify an investment in ergonomics interventions. A predictive CBA model would allow practitioners to present a cost justification to management during the planning stages, but such a model requires reliable estimates of the benefits of ergonomics interventions. Through literature reviews and Internet searches, 250 case studies that reported the benefits of ergonomics programs and control measures were collected and summarized. Commonly reported benefits included reductions in the number of work-related musculoskeletal disorders (WMSDs) or their incidence rate, as well as related lost workdays, restricted workdays, and workers' compensation costs. Additional benefits reported were related to productivity, quality, turnover and absenteeism. Benefits reported were largely positive, and payback periods for ergonomics interventions were typically less than one year. The results of this review could be used to develop predictive CBA models for ergonomics programs and individual control measures. Cost-justifying ergonomics interventions prior to implementation may help to secure management support for proposed changes. Numbers used for the benefits side of a cost-benefit analysis (CBA) need to be based on "real world" data in order to be credible. The data presented in this paper may help in the development of simple cost-benefit models for ergonomics programs and control measures.

  3. Adaptive Transgenerational Plasticity in Plants: Case Studies, Mechanisms, and Implications for Natural Populations

    Science.gov (United States)

    Herman, Jacob J.; Sultan, Sonia E.

    2011-01-01

    Plants respond to environmental conditions not only by plastic changes to their own development and physiology, but also by altering the phenotypes expressed by their offspring. This transgenerational plasticity was initially considered to entail only negative effects of stressful parental environments, such as production of smaller seeds by resource- or temperature-stressed parent plants, and was therefore viewed as environmental noise. Recent evolutionary ecology studies have shown that in some cases, these inherited environmental effects can include specific growth adjustments that are functionally adaptive to the parental conditions that induced them, which can range from contrasting states of controlled laboratory environments to the complex habitat variation encountered by natural plant populations. Preliminary findings suggest that adaptive transgenerational effects can be transmitted by means of diverse mechanisms including changes to seed provisioning and biochemistry, and epigenetic modifications such as DNA methylation that can persist across multiple generations. These non-genetically inherited adaptations can influence the ecological breadth and evolutionary dynamics of plant taxa and promote the spread of invasive plants. Interdisciplinary studies that join mechanistic and evolutionary ecology approaches will be an important source of future insights. PMID:22639624

  4. Analysis of dental injuries with clinical implications: A forensic case report.

    Science.gov (United States)

    Tan, Si-Lei; Peng, Shu-Ya; Wan, Lei; Chen, Jie-Min; Xia, Wen-Tao

    2018-01-01

    Dental injuries, especially of the incisors, caused by punches in violent criminal attacks could be seen in daily forensic casework involving the identification of injuries to a living body. Sometimes, when there is neither circumstantial evidence nor information about the surrounding circumstances, it is difficult to discern the cause of these injuries and the manner in which they were inflicted. As an example of clinical forensic medicine, we present the case of a 58-year-old woman whose teeth were injured when fighting with her son-in-law over household affairs with no witnesses present. The two parties had conflicting stories about the cause of the woman's injury. The woman claimed that her teeth were lost while she was being beaten by her son-in-law, and the man argued that the damage to his mother-in-law's teeth was self-inflicted when she bit his fingers. The police attending the crime called for a forensic examination. Forensic practitioners analysed the mechanism of the tooth loss using multi-slice spiral computed tomography (MSCT) and imaging reconstruction technology. Local alveolar bone (medial alveolar) fracture and a small area of alveolar bone loss were found on MSCT. Thus, forensic medical experts speculated that the woman's lower central and lateral incisors were lost as a result of a violent attack and were not self-inflicted. Finally, forensic practitioners helped police in avoiding a miscarriage of justice and wrongful conviction.

  5. International service trade and its implications for human resources for health: a case study of Thailand

    Directory of Open Access Journals (Sweden)

    Pitayarangsarit Siriwan

    2004-06-01

    Full Text Available Abstract This study aims at analysing the impact of international service trade on the health care system, particularly in terms of human resources for health (HRH, using Thailand as a case study. Information was gathered through a literature review and interviews of relevant experts, as well as a brainstorming session. It was found that international service trade has greatly affected the Thai health care system and its HRH. From 1965 to 1975 there was massive emigration of physicians from Thailand in response to increasing demand in the United States of America. The country lost about 1,500 physicians, 20% of its total number, during that period. External migration of health professionals occurred without relation to agreements on trade in services. It was also found that free trade in service sectors other than health could seriously affect the health care system and HRH. Free trade in financial services with free flow of low-interest foreign loans, which started in 1993 in Thailand, resulted in the mushrooming of urban private hospitals between 1994 and 1997. This was followed by intensive internal migration of health professionals from rural public to urban private hospitals. After the economic crisis in 1997, with the resulting downturn of the private health sector, reverse brain drain was evident. At the same time, foreign investors started to invest in the bankrupt private hospitals. Since 2001, the return of economic growth and the influx of foreign patients have started another round of internal brain drain.

  6. The financial and service implications of splitting fixed-dose antiretroviral drugs - a case study.

    Science.gov (United States)

    Taylor, R; Carlin, E; Sadique, Z; Ahmed, I; Adams, E J

    2015-02-01

    In 2010/2011, regional commissioners withdrew payment for the fixed-dose combination Combivir, forcing a switch to component drugs. This was deemed clinically acceptable and annual savings of £44 k expected. We estimated the true costs of switching and examined patient outcomes. Information for 46 patients using Combivir was extracted from case notes for each clinical contact in the 12 months pre- and post-switch (clinician seen, tests, antiretrovirals). Post-switch care costs £93/patient more annually versus pre-switch (95% CI £424 to £609), yielding £4278/year more post-switch for all patients. Drug and pathology costs were more expensive post-switch and extra clinical visits required. None of these results were statistically significant. Forty-two per cent of patients switched directly or in the subsequent year to an alternative fixed-dose combination rather than generics. Costs in this group were significantly higher post-switch driven by drug cost. Six patients (13%) reported problems with the switch including confusion around dosing and new side effects. As less-expensive generic antiretroviral drugs become available, it may appear cheaper to switch from fixed-dose combinations to component drugs. However, the additional clinical costs involved may outweigh the initial cost savings of the drugs and switching may cause confusion for some patients, risking loss of adherence. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.