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Sample records for chronic ligand stimulation

  1. Stimulation of duodenal biopsies and whole blood from dogs with food-responsive chronic enteropathy and healthy dogs with Toll-like receptor ligands and probiotic Enterococcus faecium.

    Science.gov (United States)

    Schmitz, S; Henrich, M; Neiger, R; Werling, D; Allenspach, K

    2014-08-01

    The composition of the microbiome plays a significant role in the pathogenesis of inflammatory bowel disease (IBD) in humans and chronic enteropathies (CE) in dogs. The administration of probiotic micro-organisms is one way of modulating the microbiome, but experiments elucidating mechanisms of action of probiotics in the intestine of healthy and CE dogs are lacking. The aim of our study was to investigate the effects of different Toll-like receptor (TLR) ligands and Enterococcus faecium (EF) on ex vivo cultured duodenal samples and whole blood (WB) from dogs with food-responsive chronic enteropathy (FRE) when compared to healthy dogs. Biopsy stimulation was performed in 17 FRE and 11 healthy dogs; WB stimulation was performed in 16 FRE and 16 healthy dogs. Expression of TLR2, 4, 5 and 9, IL-17A, IL-22, IFNy, TNFα, IL-4, IL-10, TGFβ and PPARy was determined in biopsies by quantitative polymerase chain reaction (PCR). In addition, production of TNFα, IL-10, IFNy and IL-17A protein in WB and biopsy supernatants was assessed by ELISA. Treatment with individual TLR ligands or EF induced a variety of changes in the expression of different TLRs and cytokines, but not necessarily a consistent change with a single stimulating agent. Even though cytokine protein could not be detected in supernatants from ex vivo stimulated biopsies, we found TNFα protein responses in blood to be opposite of the transcriptional responses seen in the biopsies. Stimulation of canine duodenal biopsies with TLR ligands can potentially induce anti-inflammatory gene expression, especially in healthy tissue, whereas the effects of EF were limited.

  2. Spinal cord stimulation in chronic pain syndromes

    NARCIS (Netherlands)

    ten Vaarwerk, IAM; Staal, MJ

    1998-01-01

    Spinal cord stimulation (SCS) has been used for more than 30 years now, and although it has shown to be effective under certain well-described conditions of chronic pain, conclusive evidence on its effectiveness is still sparse. There is a need for more prospective and methodological good studies, i

  3. Dissociation and trafficking of rat GABAB receptor heterodimer upon chronic capsaicin stimulation.

    Science.gov (United States)

    Laffray, Sophie; Tan, Kelly; Dulluc, Josette; Bouali-Benazzouz, Rabia; Calver, Andrew R; Nagy, Frédéric; Landry, Marc

    2007-03-01

    Gamma-aminobutyric acid type B receptors (GABAB) are G-protein-coupled receptors that mediate GABAergic inhibition in the brain. Their functional expression is dependent upon the formation of heterodimers between GABAB1 and GABAB2 subunits, a process that occurs within the endoplasmic reticulum. However, the mechanisms that regulate GABAB receptor oligomerization at the plasma membrane remain largely unknown. We first characterized the functional cytoarchitecture of an organotypic co-culture model of rat dorsal root ganglia and spinal cord. Subsequently, we studied the interactions between GABAB subunits after chronic stimulation of sensory fibres with capsaicin. Surface labelling of recombinant proteins showed a decrease in subunit co-localization and GABAB2 labelling, after capsaicin treatment. In these conditions, fluorescence lifetime imaging measurements further demonstrated a loss of interactions between green fluorescent protein-GABAB1b and t-dimer discosoma sp red fluorescent protein-GABAB2 subunits. Finally, we established that the GABAB receptor undergoes clathrin-dependent internalization and rapid recycling to the plasma membrane following activation with baclofen, a GABAB agonist. However, in cultures chronically stimulated with capsaicin, the agonist-induced endocytosis was decreased, reflecting changes in the dimeric state of the receptor. Taken together, our results indicate that the chronic stimulation of sensory fibres can dissociate the GABAB heterodimer and alters its responsiveness to the endogenous ligand. Chronic stimulation thus modulates receptor oligomerization, providing additional levels of control of signalling.

  4. Transcriptome analysis of differentiating spermatogonia stimulated with kit ligand.

    Science.gov (United States)

    Rossi, Pellegrino; Lolicato, Francesca; Grimaldi, Paola; Dolci, Susanna; Di Sauro, Annarita; Filipponi, Doria; Geremia, Raffaele

    2008-01-01

    Kit ligand (KL) is a survival factor and a mitogenic stimulus for differentiating spermatogonia. However, it is not known whether KL also plays a role in the differentiative events that lead to meiotic entry of these cells. We performed a wide genome analysis of difference in gene expression induced by treatment with KL of spermatogonia from 7-day-old mice, using gene chips spanning the whole mouse genome. The analysis revealed that the pattern of RNA expression induced by KL is compatible with the qualitative changes of the cell cycle that occur during the subsequent cell divisions in type A and B spermatogonia, i.e. the progressive lengthening of the S phase and the shortening of the G2/M transition. Moreover, KL up-regulates in differentiating spermatogonia the expression of early meiotic genes (for instance: Lhx8, Nek1, Rnf141, Xrcc3, Tpo1, Tbca, Xrcc2, Mesp1, Phf7, Rtel1), whereas it down-regulates typical spermatogonial markers (for instance: Pole, Ptgs2, Zfpm2, Egr2, Egr3, Gsk3b, Hnrpa1, Fst, Ptch2). Since KL modifies the expression of several genes known to be up-regulated or down-regulated in spermatogonia during the transition from the mitotic to the meiotic cell cycle, these results are consistent with a role of the KL/kit interaction in the induction of their meiotic differentiation.

  5. CD40 Ligand Expression on Stimulated T-Helper Lymphocytes in Patients with Common Variable Immunodeficiency

    Directory of Open Access Journals (Sweden)

    Masoud Ravanbakhsh

    2007-09-01

    Full Text Available Common variable immunodeficiency (CVID is the most common symptomatic primary antibody deficiency, characterized by reduced serum immunoglobulins levels and increased susceptibility to recurrent pyogenic infections. In this study, we evaluated CD40 ligand expression on stimulated versus unstimulated T-helper lymphocytes of nine Common variable immunodeficient patients in comparison with fifteen normal controls. Phorbol myristate acetate (PMA and Ionomycin were used to stimulate cells in vitro. After six hours stimulation, the cells were subjected to surface staining with three-color staining procedure. Events were analyzed by flow cytometer, using FloMax software. Results were reported as the percentage of lymphocytes expressing CD markers. We did not find any significant statistical difference in CD40 ligand expression between patients and controls (p>0.05, despite having stimulation documented by CD69 expression as activation marker in each run. The results of this study are in agreement with some other studies, indicating that CD40 ligand expression on stimulated T-helper lymphocytes of Common variable immunodeficiency patients is similar to normal controls.  

  6. Stimulated anoxic biodegradation of aromatic hydrocarbons using Fe(III) ligands

    Science.gov (United States)

    Lovley, D.R.; Woodward, J.C.; Chapelle, F.H.

    1994-01-01

    Contamination of ground waters with water-soluble aromatic hydrocarbons, common components of petroleum pollution, often produces anoxic conditions under which microbial degradation of the aromatics is slow. Oxygen is often added to contaminated ground water to stimulate biodegradation, but this can be technically difficult and expensive. Insoluble Fe(III) oxides, which are generally abundant in shallow aquifers, are alternative potential oxidants, but are difficult for microorganisms to access. Here we report that adding organic ligands that bind to Fe(III) dramatically increases its bioavailability, and that in the presence of these ligands, rates of degradation of aromatic hydrocarbons in anoxic aquifer sediments are comparable to those in oxic sediments. We find that even benzene, which is notoriously refractory in the absence of oxygen, can be rapidly degraded. Our results suggest that increasing the bioavailability of Fe(III) by adding suitable ligands provides a potential alternative to oxygen addition for the bioremediation of petroleum-contaminated aquifers.Contamination of ground waters with water-soluble aromatic hydrocarbons, common components of petroleum pollution, often produces anoxic conditions under which microbial degradation of the aromatics is slow. Oxygen is often added to contaminated ground water to stimulate biodegradation, but this can be technically difficult and expensive. Insoluble Fe(III) oxides, which are generally abundant in shallow aquifers, are alternative potential oxidants, but are difficult for microorganisms to access. Here we report that adding organic ligands that bind to Fe(III) dramatically increases its bioavailability, and that in the presence of these ligands, rates of degradation of aromatic hydrocarbons in anoxic aquifer sediments are comparable to those in oxic sediments. We find that even benzene, which is notoriously refractory in the absence of oxygen, can be rapidly degraded. Our results suggest that increasing

  7. Anomia training and brain stimulation in chronic aphasia.

    Science.gov (United States)

    Cotelli, Maria; Fertonani, Anna; Miozzo, Antonio; Rosini, Sandra; Manenti, Rosa; Padovani, Alessandro; Ansaldo, Ana Ines; Cappa, Stefano F; Miniussi, Carlo

    2011-10-01

    Recent studies have reported enhanced performance on language tasks induced by non-invasive brain stimulation, i.e., repetitive transcranial magnetic stimulation (rTMS), or transcranial direct current stimulation (tDCS), in patients with aphasia due to stroke or Alzheimer's disease (AD). The first part of this article reviews brain stimulation studies related to language recovery in aphasic patients. The second part reports results from a pilot study with three chronic stroke patients who had non-fluent aphasia, where real or placebo rTMS was immediately followed by 25 minutes of individualised speech therapy. Real rTMS consisted of high-frequency rTMS over the left dorsolateral prefrontal cortex (BA 8/9) for 25 minutes. Each patient underwent a total of four weeks of intervention. P1 underwent four weeks of real rTMS (5 days/week) where individualised speech therapy was provided for 25 minutes immediately following each rTMS session. P2 and P3 each underwent two weeks of placebo rTMS, followed immediately by individualised speech therapy; then two weeks of real rTMS, followed immediately by individualised speech therapy. Assessments took place at 2, 4, 12, 24 and 48 weeks post-entry/baseline testing. Relative to entry/baseline testing, a significant improvement in object naming was observed at all testing times, from two weeks post-intervention in real rTMS plus speech therapy, or placebo rTMS plus speech therapy. Our findings suggest beneficial effects of targeted behavioural training in combination with brain stimulation in chronic aphasic patients. However, further work is required in order to verify whether optimal combination parameters (rTMS alone or speech therapy alone) and length of rTMS treatment may be found.

  8. 3D-printed wearable backpack stimulator for chronic in vivo aquatic stimulation.

    Science.gov (United States)

    Unguez, Graciela; Duran, Craig; Valles-Rosales, Delia; Harris, Michael; Salazar, Evan; McDowell, Michael; Tang, Wei

    2015-08-01

    The neural mechanisms underlying changes in gene expression in the interconversion between skeletal muscle and the non-contractile electrogenic cells of the electric organ in electric fishes require several days to be manifested. It is extremely challenging to study these non-immediate forms of plasticity in reduced preparations in cell culture due to the time requirements. To address this experimental obstacle we developed a 3D-printed wearable backpack that allows chronic electrical stimulation of aquatic teleost fish. The backpack holds a biphasic simulator using a full H-bridge driver structure. Stimulation amplitude is adjusted with a current source controlled by a micro potentiometer whereas the stimulation waveform is reconfigurable through a micro-controller. A 3.7 V Lithium Ion Polymer battery powers the entire circuit. This backpack system will allow underwater chronic stimulation experiments aimed to study the role that neuronal input exerts on cell phenotypes in a vertebrate species with high tissue regeneration and cell trans-differentiation capabilities.

  9. Small Molecule Inhibition of Ligand-Stimulated RAGE-DIAPH1 Signal Transduction

    Science.gov (United States)

    Manigrasso, Michaele B.; Pan, Jinhong; Rai, Vivek; Zhang, Jinghua; Reverdatto, Sergey; Quadri, Nosirudeen; DeVita, Robert J.; Ramasamy, Ravichandran; Shekhtman, Alexander; Schmidt, Ann Marie

    2016-01-01

    The receptor for advanced glycation endproducts (RAGE) binds diverse ligands linked to chronic inflammation and disease. NMR spectroscopy and x-ray crystallization studies of the extracellular domains of RAGE indicate that RAGE ligands bind by distinct charge- and hydrophobicity-dependent mechanisms. The cytoplasmic tail (ct) of RAGE is essential for RAGE ligand-mediated signal transduction and consequent modulation of gene expression and cellular properties. RAGE signaling requires interaction of ctRAGE with the intracellular effector, mammalian diaphanous 1 or DIAPH1. We screened a library of 58,000 small molecules and identified 13 small molecule competitive inhibitors of ctRAGE interaction with DIAPH1. These compounds, which exhibit in vitro and in vivo inhibition of RAGE-dependent molecular processes, present attractive molecular scaffolds for the development of therapeutics against RAGE-mediated diseases, such as those linked to diabetic complications, Alzheimer’s disease, and chronic inflammation, and provide support for the feasibility of inhibition of protein-protein interaction (PPI). PMID:26936329

  10. Small Molecule Inhibition of Ligand-Stimulated RAGE-DIAPH1 Signal Transduction.

    Science.gov (United States)

    Manigrasso, Michaele B; Pan, Jinhong; Rai, Vivek; Zhang, Jinghua; Reverdatto, Sergey; Quadri, Nosirudeen; DeVita, Robert J; Ramasamy, Ravichandran; Shekhtman, Alexander; Schmidt, Ann Marie

    2016-03-03

    The receptor for advanced glycation endproducts (RAGE) binds diverse ligands linked to chronic inflammation and disease. NMR spectroscopy and x-ray crystallization studies of the extracellular domains of RAGE indicate that RAGE ligands bind by distinct charge- and hydrophobicity-dependent mechanisms. The cytoplasmic tail (ct) of RAGE is essential for RAGE ligand-mediated signal transduction and consequent modulation of gene expression and cellular properties. RAGE signaling requires interaction of ctRAGE with the intracellular effector, mammalian diaphanous 1 or DIAPH1. We screened a library of 58,000 small molecules and identified 13 small molecule competitive inhibitors of ctRAGE interaction with DIAPH1. These compounds, which exhibit in vitro and in vivo inhibition of RAGE-dependent molecular processes, present attractive molecular scaffolds for the development of therapeutics against RAGE-mediated diseases, such as those linked to diabetic complications, Alzheimer's disease, and chronic inflammation, and provide support for the feasibility of inhibition of protein-protein interaction (PPI).

  11. Chronic Spinal Cord Electrical Stimulation Protects Against 6-hydroxydopamine Lesions

    Science.gov (United States)

    Yadav, Amol P.; Fuentes, Romulo; Zhang, Hao; Vinholo, Thais; Wang, Chi-Han; Freire, Marco Aurelio M.; Nicolelis, Miguel A. L.

    2014-01-01

    Although L-dopa continues to be the gold standard for treating motor symptoms of Parkinson's disease (PD), it presents long-term complications. Deep brain stimulation is effective, but only a small percentage of idiopathic PD patients are eligible. Based on results in animal models and a handful of patients, dorsal column stimulation (DCS) has been proposed as a potential therapy for PD. To date, the long-term effects of DCS in animal models have not been quantified. Here, we report that DCS applied twice a week in rats treated with bilateral 6-OHDA striatal infusions led to a significant improvement in symptoms. DCS-treated rats exhibited a higher density of dopaminergic innervation in the striatum and higher neuronal cell count in the substantia nigra pars compacta compared to a control group. These results suggest that DCS has a chronic therapeutical and neuroprotective effect, increasing its potential as a new clinical option for treating PD patients.

  12. Targeting the thyroid-stimulating hormone receptor with small molecule ligands and antibodies

    Science.gov (United States)

    Davies, Terry F; Latif, Rauf

    2015-01-01

    Introduction The thyroid-stimulating hormone receptor (TSHR) is the essential molecule for thyroid growth and thyroid hormone production. Since it is also a key autoantigen in Graves’ disease and is involved in thyroid cancer pathophysiology, the targeting of the TSHR offers a logical model for disease control. Areas covered We review the structure and function of the TSHR and the progress in both small molecule ligands and TSHR antibodies for their therapeutic potential. Expert opinion Stabilization of a preferential conformation for the TSHR by allosteric ligands and TSHR antibodies with selective modulation of the signaling pathways is now possible. These tools may be the next generation of therapeutics for controlling the pathophysiological consequences mediated by the effects of the TSHR in the thyroid and other extrathyroidal tissues. PMID:25768836

  13. Rational design of a synthetic mammalian riboswitch as a ligand-responsive -1 ribosomal frame-shifting stimulator

    Science.gov (United States)

    Lin, Ya-Hui; Chang, Kung-Yao

    2016-01-01

    Metabolite-responsive RNA pseudoknots derived from prokaryotic riboswitches have been shown to stimulate −1 programmed ribosomal frameshifting (PRF), suggesting −1 PRF as a promising gene expression platform to extend riboswitch applications in higher eukaryotes. However, its general application has been hampered by difficulty in identifying a specific ligand-responsive pseudoknot that also functions as a ligand-dependent -1 PRF stimulator. We addressed this problem by using the −1 PRF stimulation pseudoknot of SARS-CoV (SARS-PK) to build a ligand-dependent −1 PRF stimulator. In particular, the extra stem of SARS-PK was replaced by an RNA aptamer of theophylline and designed to couple theophylline binding with the stimulation of −1 PRF. Conformational and functional analyses indicate that the engineered theophylline-responsive RNA functions as a mammalian riboswitch with robust theophylline-dependent −1 PRF stimulation activity in a stable human 293T cell-line. Thus, RNA–ligand interaction repertoire provided by in vitro selection becomes accessible to ligand-specific −1 PRF stimulator engineering using SARS-PK as the scaffold for synthetic biology application. PMID:27521370

  14. DMPD: Toll-like receptors, Notch ligands, and cytokines drive the chronicity of lunginflammation. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 18073395 Toll-like receptors, Notch ligands, and cytokines drive the chronicity of ...2007 Dec;4(8):635-41. (.png) (.svg) (.html) (.csml) Show Toll-like receptors, Notch ligands, and cytokines d...rive the chronicity of lunginflammation. PubmedID 18073395 Title Toll-like receptors, Notch liga

  15. Erythropoiesis-stimulating agents in patients with chronic kidney disease

    Directory of Open Access Journals (Sweden)

    Mario Eandi

    2012-04-01

    Full Text Available Anemia is a frequent complication of chronic kidney disease (CKD due to the inability of the kidneys to release sufficient erythropoietin to regulate the production of red blood cells. Administration of erythropoiesis-stimulating agents (ESAs is highly effective in correcting anemia of CKD. The ESAs currently approved in Italy are epoetin alfa, epoetin beta, epoetin theta, darbepoetin alfa, CERA and biosimilars epoetin alfa and epoetin zeta. All the ESAs are effective in correcting renal anemia and increasing hemoglobin levels, but the choice of which to use should also take into account their pharmacokinetics and pharmacodynamics, their administration route, and economic issues. However, regarding the optimal use of ESAs an issue that remains controversial is the most appropriate dose conversion between epoetin alfa and darbepoetin alfa. In fact clinical experience demonstrates that the dose relationship between epoetin alfa and darbepoetin alfa is non proportional across the dosing spectrum. In this review is presented an update on the latest available evidence in the treatment of anemia in CKD patients, with particular reference to the definition of the correct conversion ratio EPO:DARB.

  16. Prostaglandin E2 stimulates Fas ligand expression via the EP1 receptor in colon cancer cells.

    LENUS (Irish Health Repository)

    O'Callaghan, G

    2012-02-03

    Fas ligand (FasL\\/CD95L) is a member of the tumour necrosis factor superfamily that triggers apoptosis following crosslinking of the Fas receptor. Despite studies strongly implicating tumour-expressed FasL as a major inhibitor of the anti-tumour immune response, little is known about the mechanisms that regulate FasL expression in tumours. In this study, we show that the cyclooxygenase (COX) signalling pathway, and in particular prostaglandin E(2) (PGE(2)), plays a role in the upregulation of FasL expression in colon cancer. Suppression of either COX-2 or COX-1 by RNA interference in HCA-7 and HT29 colon tumour cells reduced FasL expression at both the mRNA and protein level. Conversely, stimulation with PGE(2) increased FasL expression and these cells showed increased cytotoxicity against Fas-sensitive Jurkat T cells. Prostaglandin E(2)-induced FasL expression was mediated by signalling via the EP1 receptor. Moreover, immunohistochemical analysis using serial sections of human colon adenocarcinomas revealed a strong positive correlation between COX-2 and FasL (r=0.722; P<0.0001) expression, and between EP1 receptor and FasL (r=0.740; P<0.0001) expression, in the tumour cells. Thus, these findings indicate that PGE(2) positively regulates FasL expression in colon tumour cells, adding another pro-neoplastic activity to PGE(2).

  17. Evaluation of chronic immune system stimulation models in growing pigs.

    Science.gov (United States)

    Rakhshandeh, A; de Lange, C F M

    2012-02-01

    Two experiments (EXPs) were conducted to evaluate models of immune system stimulation (ISS) that can be used in nutrient metabolism studies in growing pigs. In EXP I, the pig's immune response to three non-pathogenic immunogens was evaluated, whereas in EXP II the pig's more general response to one of the immunogens was contrasted with observations on non-ISS pigs. In EXP I, nine growing barrows were fitted with a jugular catheter, and after recovery assigned to one of three treatments. Three immunogens were tested during a 10-day ISS period: (i) repeated injection of increasing amounts of Escherichia coli lipopolysaccharide (LPS); (ii) repeated subcutaneous injection of turpentine (TURP); and (iii) feeding grains naturally contaminated with mycotoxins (MYCO). In EXP II, 36 growing barrows were injected repeatedly with either saline (n = 12) or increasing amounts of LPS (n = 24) for 7 days (initial dose 60 μg/kg body weight). Treating pigs with TURP and LPS reduced feed intake (P < 0.02), whereas feed intake was not reduced in pigs on MYCO. Average daily gain (ADG; kg/day) of pigs on LPS (0.50) was higher than that of pigs on TURP (0.19), but lower than that of pigs on MYCO (0.61; P < 0.01). Body temperature was elevated in pigs on LPS and TURP, by 0.8°C and 0.7°C, respectively, relative to pre-ISS challenge values (39.3°C; P < 0.02), but remained unchanged in pigs on MYCO. Plasma concentrations of interleukin-1β were increased in pigs treated with LPS and TURP (56% and 55%, respectively, relative to 22.3 pg/ml for pre-ISS; P < 0.01), but not in MYCO-treated pigs. Plasma cortisol concentrations remained unchanged for pigs on MYCO and TURP, but were reduced in LPS-treated pigs (30% relative to 29.8 ng/ml for pre-ISS; P < 0.05). Red blood cell glutathione concentrations were lower in TURP-treated pigs (13% relative to 1.38 μM for pre-ISS; P < 0.05), but were unaffected in pigs on LPS and MYCO. In EXP I, TURP caused severe responses including skin ulceration and

  18. Treatment of Idiopathic Chronic Orchialgia with Transcutaneous Electrical Nerve Stimulation (TENS):A Preliminary Result

    OpenAIRE

    2016-01-01

    Purpose: Unilateral or bilateral testicular pain lasting more than 3 months is called as chronic orchialgia. Aproximately 25-50% of chronic orchialgia is idiopatic origin. This study aimed the effectiveness of Transcutaneous Electrical Nerve Stimulation (TENS) therapy due to Idiopathic Chronic Orchialgia (ICO). Methods: Five patients were included into this study with ICO that diagnosed with physical examination, urine analyses, urinary system x-ray film, and scrotal doppler ultrasound. Me...

  19. Glycogen depletion and resynthesis during 14 days of chronic low-frequency stimulation of rabbit muscle

    DEFF Research Database (Denmark)

    Prats, C; Bernal, C; Cadefau, J A;

    2002-01-01

    Electro-stimulation alters muscle metabolism and the extent of this change depends on application intensity and duration. The effect of 14 days of chronic electro-stimulation on glycogen turnover and on the regulation of glycogen synthase in fast-twitch muscle was studied. The results showed...... synthase was determined during electro-stimulation. The activity of this enzyme was measured at low UDPG concentration with either high or low Glu-6-P content. Western blots were performed against glycogen synthase over a range of stimulation periods. Activation of this enzyme was maximum before the net...

  20. Cultured Mesenchymal Stem Cells Stimulate an Immune Response by Providing Immune Cells with Toll-Like Receptor 2 Ligand.

    Science.gov (United States)

    Weinstock, Ada; Pevsner-Fischer, Meirav; Porat, Ziv; Selitrennik, Michael; Zipori, Dov

    2015-12-01

    Mesenchymal stem cells (MSCs) serve as supporting and regulatory cells, by providing tissues with multiple factors and are also known for their immunosuppressive capabilities. Our laboratory had previously shown that MSCs expressed toll-like receptor (TLR) 2 and are activated by its ligand Pam3Cys. TLR2 is an important component of the innate immune system, as it recognizes bacterial lipopeptides, thus priming a pro-inflammatory immune response. This study showed that Pam3Cys attached extensively to cells of both wild-type and TLR2 deficient cultured MSCs, thus, independently of TLR2. The TLR2 independent binding occurred through the adsorption of the palmitoyl moieties of Pam3Cys. It was further showed that Pam3Cys was transferred from cultured MSCs to immune cells. Moreover, Pam3Cys provided to the immune cells induced a pro-inflammatory response in vitro and in vivo. Overall, it is demonstrated herein that a TLR2 ligand bound to MSCs also through a TLR2 independent mechanism. Furthermore, the ligand incorporated by MSCs is subsequently released to stimulate an immune response both in vitro and in vivo. It is thus suggested that during bacterial infection, stromal cells may retain a reservoir of the TLR2 ligands, in a long-term manner, and release them slowly to maintain an immune response.

  1. Serum Levels of Soluble Fas Ligand and Soluble Fas Receptor in Patients with Chronic Congestive Heart Failure

    Institute of Scientific and Technical Information of China (English)

    李刚; 令狐华; 魏良明

    2002-01-01

    @@ To understand the pathophysiologic significances of soluble Fas Ligand (sFasL) and soluble Fas receptor (sFas) in chronic congestive heart failure (CHF) and to determine the relationship of circulating levels of sFasL and sFas to the severity of CHF, the serum sFasL and sfas levels were evaluated in patients with CHF.

  2. Interleukin-10 overexpression promotes Fas-ligand-dependent chronic macrophage-mediated demyelinating polyneuropathy.

    Directory of Open Access Journals (Sweden)

    Dru S Dace

    Full Text Available BACKGROUND: Demyelinating polyneuropathy is a debilitating, poorly understood disease that can exist in acute (Guillain-Barré syndrome or chronic forms. Interleukin-10 (IL-10, although traditionally considered an anti-inflammatory cytokine, has also been implicated in promoting abnormal angiogenesis in the eye and in the pathobiology of autoimmune diseases such as lupus and encephalomyelitis. PRINCIPAL FINDINGS: Overexpression of IL-10 in a transgenic mouse model leads to macrophage-mediated demyelinating polyneuropathy. IL-10 upregulates ICAM-1 within neural tissues, promoting massive macrophage influx, inflammation-induced demyelination, and subsequent loss of neural tissue resulting in muscle weakness and paralysis. The primary insult is to perineural myelin followed by secondary axonal loss. Infiltrating macrophages within the peripheral nerves demonstrate a highly pro-inflammatory signature. Macrophages are central players in the pathophysiology, as in vivo depletion of macrophages using clodronate liposomes reverses the phenotype, including progressive nerve loss and paralysis. Macrophage-mediate demyelination is dependent on Fas-ligand (FasL-mediated Schwann cell death. SIGNIFICANCE: These findings mimic the human disease chronic idiopathic demyelinating polyneuropathy (CIDP and may also promote further understanding of the pathobiology of related conditions such as acute idiopathic demyelinating polyneuropathy (AIDP or Guillain-Barré syndrome.

  3. Interleukin-34:A new ligand for Colony-stimulating factor-1Receptor%Interleukin-34: A new ligand for Colony-stimulating factor-1Receptor

    Institute of Scientific and Technical Information of China (English)

    CHEN Yao; Gang-Qing Yao

    2011-01-01

    1 IntroductionColony-stimulating factor-1 ( CSF1 ) is a important hematopoietic growth factor that is involved in the proliferation,differentiation,and survival of monocytes, macrophages, and bone marrow progenitor cells[1].Its receptor (c-Fms) is known as the c-Fmsproto-oncoprotein[2].By far the most definitive studies demonstrating biologic functions for CSF-1 in vivo are those in the op/op mutant mouse.The deficiency results from a single base-pair insertion in the coding region of the gene to product defective CSF-1[3-4].Mice homozygous for this mutation have significant osteopetrosis,low growth rate,low body weight as well as a toothless phenotype because of a severe deficiency of osteoclasts and mononuclear phagocytes[5-6],and are devoid of serum and tissue CSF-1 activity[7].

  4. Selective modulation of Wnt ligands and their receptors in adipose tissue by chronic hyperadiponectinemia.

    Directory of Open Access Journals (Sweden)

    Nobuhiko Wada

    Full Text Available BACKGROUND: Adiponectin-transgenic mice had many small adipocytes in both subcutaneous and visceral adipose tissues, and showed higher sensitivity to insulin, longer life span, and reduced chronic inflammation. We hypothesized that adiponectin regulates Wnt signaling in adipocytes and thereby modulates adipocyte proliferation and chronic inflammation in adipose tissue. MATERIALS AND METHODS: We examined the expression of all Wnt ligands and their receptors and the activity of Wnt signaling pathways in visceral adipose tissue from wild-type mice and two lines of adiponectin-transgenic mice. The effects of adiponectin were also investigated in cultured 3T3-L1 cells. RESULTS: The Wnt5b, Wnt6, Frizzled 6 (Fzd6, and Fzd9 genes were up-regulated in both lines of transgenic mice, whereas Wnt1, Wnt2, Wnt5a, Wnt9b, Wnt10b, Wnt11, Fzd1, Fzd2, Fzd4, Fzd7, and the Fzd coreceptor low-density-lipoprotein receptor-related protein 6 (Lrp6 were reduced. There was no difference in total β-catenin levels in whole-cell extracts, non-phospho-β-catenin levels in nuclear extracts, or mRNA levels of β-catenin target genes, indicating that hyperadiponectinemia did not affect canonical Wnt signaling. In contrast, phosphorylated calcium/calmodulin-dependent kinase II (p-CaMKII and phosphorylated Jun N-terminal kinase (p-JNK were markedly reduced in adipose tissue from the transgenic mice. The adipose tissue of the transgenic mice consisted of many small cells and had increased expression of adiponectin, whereas cyclooxygenase-2 expression was reduced. Wnt5b expression was elevated in preadipocytes of the transgenic mice and decreased in diet-induced obese mice, suggesting a role in adipocyte differentiation. Some Wnt genes, Fzd genes, and p-CaMKII protein were down-regulated in 3T3-L1 cells cultured with a high concentration of adiponectin. CONCLUSION: Chronic hyperadiponectinemia selectively modulated the expression of Wnt ligands, Fzd receptors and LRP coreceptors

  5. Occipital nerve stimulation in medically intractable, chronic cluster headache. The ICON study

    DEFF Research Database (Denmark)

    Wilbrink, Leopoldine A; Teernstra, Onno Pm; Haan, Joost

    2013-01-01

    BACKGROUND: About 10% of cluster headache patients have the chronic form. At least 10% of this chronic group is intractable to or cannot tolerate medical treatment. Open pilot studies suggest that occipital nerve stimulation (ONS) might offer effective prevention in these patients. Controlled...... in medically intractable, chronic cluster headache patients of high- versus low-amplitude ONS. Primary outcome measure is the mean number of attacks over the last four weeks. After a study period of six months there is an open extension phase of six months. Alongside the randomised trial an economic evaluation...... study is performed. DISCUSSION: The ICON study will show if ONS is an effective preventive therapy for patients suffering medically intractable chronic cluster headache and if there is a difference between high- and low-amplitude stimulation. The innovative design of the study will, for the first time...

  6. Cortical activation changes underlying stimulation-induced behavioural gains in chronic stroke.

    Science.gov (United States)

    Stagg, Charlotte Jane; Bachtiar, Velicia; O'Shea, Jacinta; Allman, Claire; Bosnell, Rosemary Ann; Kischka, Udo; Matthews, Paul McMahan; Johansen-Berg, Heidi

    2012-01-01

    Transcranial direct current stimulation, a form of non-invasive brain stimulation, is showing increasing promise as an adjunct therapy in rehabilitation following stroke. However, although significant behavioural improvements have been reported in proof-of-principle studies, the underlying mechanisms are poorly understood. The rationale for transcranial direct current stimulation as therapy for stroke is that therapeutic stimulation paradigms increase activity in ipsilesional motor cortical areas, but this has not previously been directly tested for conventional electrode placements. This study was performed to test directly whether increases in ipsilesional cortical activation with transcranial direct current stimulation are associated with behavioural improvements in chronic stroke patients. Patients at least 6 months post-first stroke participated in a behavioural experiment (n = 13) or a functional magnetic resonance imaging experiment (n = 11), each investigating the effects of three stimulation conditions in separate sessions: anodal stimulation to the ipsilesional hemisphere; cathodal stimulation to the contralesional hemisphere; and sham stimulation. Anodal (facilitatory) stimulation to the ipsilesional hemisphere led to significant improvements (5-10%) in response times with the affected hand in both experiments. This improvement was associated with an increase in movement-related cortical activity in the stimulated primary motor cortex and functionally interconnected regions. Cathodal (inhibitory) stimulation to the contralesional hemisphere led to a functional improvement only when compared with sham stimulation. We show for the first time that the significant behavioural improvements produced by anodal stimulation to the ipsilesional hemisphere are associated with a functionally relevant increase in activity within the ipsilesional primary motor cortex in patients with a wide range of disabilities following stroke.

  7. Potential mechanisms supporting the value of motor cortex stimulation to treat chronic pain syndromes

    Directory of Open Access Journals (Sweden)

    Marcos Fabio DosSantos

    2016-02-01

    Full Text Available Throughout the first years of the twenty-first century, neurotechnologies such as motor cortex stimulation (MCS, transcranial magnetic stimulation (TMS and transcranial direct current stimulation (tDCS have attracted scientific attention and been considered as potential tools to centrally modulate chronic pain, especially for those conditions more difficult to manage and refractory to all types of available pharmacological therapies. Interestingly, although the role of the motor cortex in pain has not been fully clarified, it is one of the cortical areas most commonly targeted by invasive and non-invasive neuromodulation technologies. Recent studies have provided significant advances concerning the establishment of the clinical effectiveness of primary motor cortex stimulation to treat different chronic pain syndromes. Concurrently, the neuromechanisms related to each method of primary motor cortex (M1 modulation have been unveiled. In this respect, the most consistent scientific evidence originates from MCS studies, which indicate the activation of top-down controls driven by M1 stimulation. This concept has also been applied to explain M1-TMS mechanisms. Nevertheless, activation of remote areas in the brain, including cortical and subcortical structures, has been reported with both invasive and non-invasive methods and the participation of major neurotransmitters (e.g. glutamate, GABA and serotonin as well as the release of endogenous opioids has been demonstrated. In this critical review, the putative mechanisms underlying the use of motor cortex stimulation to provide relief from chronic migraine and other types of chronic pain are discussed. Emphasis is placed on the most recent scientific evidence obtained from chronic pain research studies involving MCS and non-invasive neuromodulation methods (e.g. tDCS and TMS, which are analyzed comparatively.

  8. Cardiac responses of vagus nerve stimulation: Intraoperative bradycardia and subsequent chronic stimulation

    NARCIS (Netherlands)

    Ardesch, J.J.; Buschman, H.P.J.; Burgh, van der P.H.; Wagener-Schimmel, L.J.; Aa, van der H.E.; Hageman, G.

    2007-01-01

    OBJECTIVES: Few adverse events on heart rate have been reported with vagus nerve stimulation (VNS) for refractory epilepsy. We describe three cases with intraoperative bradycardia during device testing. PATIENTS AND METHODS: At our hospital 111 patients have received a VNS system. Intraoperative dev

  9. Quantitative changes in rat renin secretory granules after acute and chronic stimulation of the renin system

    DEFF Research Database (Denmark)

    Rasch, Ruth; Jensen, B L; Nyengaard, Jens Randel

    1998-01-01

    ) twofold, but did not significantly change the number of renin granules per arteriole or the renin-containing volume of the arteriole. Chronic stimulation was achieved by a combination of low-salt diet and inhibition of angiotensin-converting enzyme (ACE) for 14 days, and resulted in a 36-fold increase...

  10. Individualized treatment with transcranial direct current stimulation in patients with chronic nonfluent aphasia due to stroke

    Directory of Open Access Journals (Sweden)

    Priyanka eShah

    2015-04-01

    Full Text Available While evidence suggests that transcranial direct current stimulation (tDCS may facilitate language recovery in chronic post-stroke aphasia, individual variability in patient response to different patterns of stimulation remains largely unexplored. We sought to characterize this variability among chronic aphasic individuals, and to explore whether repeated stimulation with an individualized optimal montage could lead to persistent reduction of aphasia severity. In a two-phase study, we first stimulated patients with 4 active montages (left hemispheric anode or cathode; right hemispheric anode or cathode and one sham montage (Phase 1. We examined changes in picture naming ability to address 1 variability in response to different montages among our patients, and 2 whether individual patients responded optimally to at least one montage. During Phase 2, subjects who responded in Phase 1 were randomized to receive either real-tDCS or to receive sham stimulation (10 days; patients who were randomized to receive sham stimulation first were then crossed over to receive real-tDCS (10 days. In both phases, 2mA tDCS was administered for 20 minutes per real-tDCS sessions and patients performed a picture naming task during stimulation. Patients’ language ability was re-tested after 2-weeks and 2-months following real and sham tDCS in Phase 2.In Phase 1, despite considerable individual variability, the greatest average improvement was observed after left-cathodal stimulation. Seven out of 12 subjects responded optimally to at least 1 montage as demonstrated by transient improvement in picture-naming. In Phase 2, aphasia severity improved at 2-weeks and 2-months following real-tDCS but not sham.Despite individual variability with respect to optimal tDCS approach, certain montages result in consistent transient improvement in persons with chronic post-stroke aphasia. This preliminary study supports the notion that individualized tDCS treatment may enhance

  11. ASIC3 Mediates Itch Sensation in Response to Coincident Stimulation by Acid and Nonproton Ligand

    Directory of Open Access Journals (Sweden)

    Zhong Peng

    2015-10-01

    Full Text Available The regulation and mechanisms underlying itch sensation are complex. Here, we report a role for acid-sensing ion channel 3 (ASIC3 in mediating itch evoked by certain pruritogens during tissue acidosis. Co-administration of acid with Ser-Leu-Ile-Gly-Arg-Leu-NH2 (SL-NH2 increased scratching behavior in wild-type, but not ASIC3-null, mice, implicating the channel in coincident detection of acidosis and pruritogens. Mechanistically, SL-NH2 slowed desensitization of proton-evoked currents by targeting the previously identified nonproton ligand-sensing domain located in the extracellular region of ASIC3 channels in primary sensory neurons. Ablation of the ASIC3 gene reduced dry-skin-induced scratching behavior and pathological changes under conditions with concomitant inflammation. Taken together, our data suggest that ASIC3 mediates itch sensation via coincident detection of acidosis and nonproton ligands that act at the nonproton ligand-sensing domain of the channel.

  12. CaMKII induces permeability transition through Drp1 phosphorylation during chronic β-AR stimulation

    Science.gov (United States)

    Xu, Shangcheng; Wang, Pei; Zhang, Huiliang; Gong, Guohua; Gutierrez Cortes, Nicolas; Zhu, Weizhong; Yoon, Yisang; Tian, Rong; Wang, Wang

    2016-01-01

    Mitochondrial permeability transition pore (mPTP) is involved in cardiac dysfunction during chronic β-adrenergic receptor (β-AR) stimulation. The mechanism by which chronic β-AR stimulation leads to mPTP openings is elusive. Here, we show that chronic administration of isoproterenol (ISO) persistently increases the frequency of mPTP openings followed by mitochondrial damage and cardiac dysfunction. Mechanistically, this effect is mediated by phosphorylation of mitochondrial fission protein, dynamin-related protein 1 (Drp1), by Ca2+/calmodulin-dependent kinase II (CaMKII) at a serine 616 (S616) site. Mutating this phosphorylation site or inhibiting Drp1 activity blocks CaMKII- or ISO-induced mPTP opening and myocyte death in vitro and rescues heart hypertrophy in vivo. In human failing hearts, Drp1 phosphorylation at S616 is increased. These results uncover a pathway downstream of chronic β-AR stimulation that links CaMKII, Drp1 and mPTP to bridge cytosolic stress signal with mitochondrial dysfunction in the heart. PMID:27739424

  13. A partial hearing animal model for chronic electro-acoustic stimulation

    Science.gov (United States)

    Irving, S.; Wise, A. K.; Millard, R. E.; Shepherd, R. K.; Fallon, J. B.

    2014-08-01

    Objective. Cochlear implants (CIs) have provided some auditory function to hundreds of thousands of people around the world. Although traditionally carried out only in profoundly deaf patients, the eligibility criteria for implantation have recently been relaxed to include many partially-deaf patients with useful levels of hearing. These patients receive both electrical stimulation from their implant and acoustic stimulation via their residual hearing (electro-acoustic stimulation; EAS) and perform very well. It is unclear how EAS improves speech perception over electrical stimulation alone, and little evidence exists about the nature of the interactions between electric and acoustic stimuli. Furthermore, clinical results suggest that some patients that undergo cochlear implantation lose some, if not all, of their residual hearing, reducing the advantages of EAS over electrical stimulation alone. A reliable animal model with clinically-relevant partial deafness combined with clinical CIs is important to enable these issues to be studied. This paper outlines such a model that has been successfully used in our laboratory. Approach. This paper outlines a battery of techniques used in our laboratory to generate, validate and examine an animal model of partial deafness and chronic CI use. Main results. Ototoxic deafening produced bilaterally symmetrical hearing thresholds in neonatal and adult animals. Electrical activation of the auditory system was confirmed, and all animals were chronically stimulated via adapted clinical CIs. Acoustic compound action potentials (CAPs) were obtained from partially-hearing cochleae, using the CI amplifier. Immunohistochemical analysis allows the effects of deafness and electrical stimulation on cell survival to be studied. Significance. This animal model has applications in EAS research, including investigating the functional interactions between electric and acoustic stimulation, and the development of techniques to maintain residual

  14. Potential Mechanisms Supporting the Value of Motor Cortex Stimulation to Treat Chronic Pain Syndromes

    Science.gov (United States)

    DosSantos, Marcos F.; Ferreira, Natália; Toback, Rebecca L.; Carvalho, Antônio C.; DaSilva, Alexandre F.

    2016-01-01

    Throughout the first years of the twenty-first century, neurotechnologies such as motor cortex stimulation (MCS), transcranial magnetic stimulation (TMS), and transcranial direct current stimulation (tDCS) have attracted scientific attention and been considered as potential tools to centrally modulate chronic pain, especially for those conditions more difficult to manage and refractory to all types of available pharmacological therapies. Interestingly, although the role of the motor cortex in pain has not been fully clarified, it is one of the cortical areas most commonly targeted by invasive and non-invasive neuromodulation technologies. Recent studies have provided significant advances concerning the establishment of the clinical effectiveness of primary MCS to treat different chronic pain syndromes. Concurrently, the neuromechanisms related to each method of primary motor cortex (M1) modulation have been unveiled. In this respect, the most consistent scientific evidence originates from MCS studies, which indicate the activation of top-down controls driven by M1 stimulation. This concept has also been applied to explain M1-TMS mechanisms. Nevertheless, activation of remote areas in the brain, including cortical and subcortical structures, has been reported with both invasive and non-invasive methods and the participation of major neurotransmitters (e.g., glutamate, GABA, and serotonin) as well as the release of endogenous opioids has been demonstrated. In this critical review, the putative mechanisms underlying the use of MCS to provide relief from chronic migraine and other types of chronic pain are discussed. Emphasis is placed on the most recent scientific evidence obtained from chronic pain research studies involving MCS and non-invasive neuromodulation methods (e.g., tDCS and TMS), which are analyzed comparatively. PMID:26903788

  15. Rehabilitation interventions for chronic motor deficits with repetitive transcranial magnetic stimulation.

    Science.gov (United States)

    Paquette, C; Thiel, A

    2012-12-01

    Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive electrophysiological method to modulate cortical excitability. As such, rTMS can be used in conjunction with conventional physiotherapy or occupational therapy to facilitate rehabilitation of motor function in patients with focal brain lesions. This review summarizes the rationale for using rTMS in the rehabilitation of motor deficits as derived from imaging and electrophysiological studies of the human motor system. rTMS methodology and its various stimulation modalities are introduced and current evidence for rTMS as supportive therapy for the rehabilitation of chronic motor deficits is discussed.

  16. Effects of Anterior Thalamic Nucleus Deep Brain Stimulation in Chronic Epileptic Rats

    Science.gov (United States)

    Amorim, Beatriz; Cavarsan, Clarissa; Miranda, Maisa Ferreira; Aarão, Mayra C.; Madureira, Ana Paula; Rodrigues, Antônio M.; Nobrega, José N.; Mello, Luiz E.; Hamani, Clement

    2014-01-01

    Deep brain stimulation (DBS) has been investigated for the treatment of epilepsy. In rodents, an increase in the latency for the development of seizures and status epilepticus (SE) has been reported in different animal models but the consequences of delivering stimulation to chronic epileptic animals have not been extensively addressed. We study the effects of anterior thalamic nucleus (AN) stimulation at different current intensities in rats rendered epileptic following pilocarpine (Pilo) administration. Four months after Pilo-induced SE, chronic epileptic rats were bilaterally implanted with AN electrodes or had sham-surgery. Stimulation was delivered for 6 h/day, 5 days/week at 130 Hz, 90 µsec. and either 100 µA or 500 µA. The frequency of spontaneous recurrent seizures in animals receiving stimulation was compared to that recorded in the preoperative period and in rats given sham treatment. To investigate the effects of DBS on hippocampal excitability, brain slices from animals receiving AN DBS or sham surgery were studied with electrophysiology. We found that rats treated with AN DBS at 100 µA had a 52% non-significant reduction in the frequency of seizures as compared to sham-treated controls and 61% less seizures than at baseline. Animals given DBS at 500 µA had 5.1 times more seizures than controls and a 2.8 fold increase in seizure rate as compared to preoperative values. In non-stimulated controls, the average frequency of seizures before and after surgery remained unaltered. In vitro recordings have shown that slices from animals previously given DBS at 100 µA had a longer latency for the development of epileptiform activity, shorter and smaller DC shifts, and a smaller spike amplitude compared to non-stimulated controls. In contrast, a higher spike amplitude was recorded in slices from animals given AN DBS at 500 µA. PMID:24892420

  17. Psychological, neurophysiological and therapeutic aspects of chronic pain: preliminary results with transcutaneous electrical stimulation [proceeedings].

    Science.gov (United States)

    Hachen, H J

    1978-02-01

    Psychological, neurophysiological and therapeutic aspects of chronic pain are reviewed in the light of recent progress achieved in the respective fields (alpha-feedback training; gate-control theory; transcutaneous electrostimulation; percutaneous stereoactic radio-frequency cordotomy). The efficacy of selective large fibre stimulation has been evaluated in 39 spinal cord injury patients suffering from chronic intractable pain of 6 to 35 months's duration. Stimulation was applied daily for 6 consecutive hours. Pain reflief was assessed by verbal and visual analogue scales and McGill's pain questionaire. After 1 week, total or almost total relief of pain was reported by 49 per cent, moderate relief by 41 per cent and no improvement by 10 per cent of the cases; at a 3-months follow-up the figures were 28 per cent, 49 per cent and 23 per cent respectively.

  18. Numerical Characterization of Intraoperative and Chronic Electrodes in Deep Brain Stimulation

    Directory of Open Access Journals (Sweden)

    Alessandra ePaffi

    2015-02-01

    Full Text Available Intraoperative electrode is used in the Deep Brain stimulation (DBS technique to pinpoint the brain target and to choose the best parameters for the stimulating signal. However, when the intraoperative electrode is replaced with the chronic one, the observed effects do not always coincide with predictions.To investigate the causes of such discrepancies, in this work, a 3D model of the basal ganglia has been considered and realistic models of both intraoperative and chronic electrodes have been developed and numerically solved.Results of simulations on the electric potential and the activating function along neuronal fibers show that the different geometries and sizes of the two electrodes do not change shapes and polarities of these functions, but only the amplitudes. A similar effect is caused by the presence of different tissue layers (edema or glial tissue in the peri-electrode space. On the contrary, a not accurate positioning of the chronic electrode with respect to the intraoperative one (electric centers not coincident may induce a complete different electric stimulation on some groups of fibers.

  19. Strength improvement of knee extensor muscles in patients with chronic heart failure by neuromuscular electrical stimulation.

    Science.gov (United States)

    Quittan, M; Sochor, A; Wiesinger, G F; Kollmitzer, J; Sturm, B; Pacher, R; Mayr, W

    1999-05-01

    Patients with severe chronic heart failure (CHF) suffer from marked weakness of skeletal muscles. Neuromuscular electrical stimulation (NMES) proved to be an alternative to active strength training. The objective of this study was to test the feasibility and effectiveness of NMES in patients with chronic heart failure. Seven patients (56.0 +/- 5.0 years, CHF for 20 +/- 4 months, left ventricular ejection fraction 20.1 +/- 10.0%) finished an 8 week course of NMES of the knee extensor muscles. The stimulator delivered biphasic, symmetric, constant voltage impulses of 0.7 ms pulse width with a frequency of 50 Hz, 2 s on and 6 s off. No adverse effects occurred. After the stimulation period, the isokinetic peak torque of the knee extensor muscles increased by 13% from 101.0 +/- 8.7 Nm to 113.5 +/- 7.2 Nm (p = 0.004). The maximal isometric strength increased by 20% from 294.3 +/- 19.6 N to 354.14 +/- 15.7 N (p = 0.04). This increased muscle strength could be maintained in a 20 min fatigue test indicating decreased muscle fatigue. These results demonstrate that NMES of skeletal muscles in patients with severe chronic heart failure is a promising method for strength training in this group of patients.

  20. Determining the benefits of transcranial direct current stimulation on functional upper limb movement in chronic stroke.

    Science.gov (United States)

    Marquez, Jodie L; Conley, Alexander C; Karayanidis, Frini; Miller, James; Lagopoulos, Jim; Parsons, Mark W

    2017-02-13

    Transcranial direct current stimulation (tDCS) has been proposed as a tool to enhance stroke rehabilitation; however, evidence to support its use is lacking. The aim of this study was to investigate the effects of anodal and cathodal tDCS on upper limb function in chronic stroke patients. Twenty five participants were allocated to receive 20 min of 1 mA of anodal, cathodal or sham cortical stimulation in a random, counterbalanced order. Patients and assessors were blinded to the intervention at each time point. The primary outcome was upper limb performance as measured by the Jebsen Taylor Test of Hand Function (total score, fine motor subtest score and gross motor subtest score) as well as grip strength. Each outcome was assessed at baseline and at the conclusion of each intervention in both upper limbs. Neither anodal nor cathodal stimulation resulted in statistically significantly improved upper limb performance on any of the measured tasks compared with sham stimulation (P>0.05). When the data were analysed according to disability, participants with moderate/severe disability showed significantly improved gross motor function following cathodal stimulation compared with sham (P=0.014). However, this was accompanied by decreased key grip strength in the unaffected hand (P=0.003). We are unable to endorse the use of anodal and cathodal tDCS in the management of upper limb dysfunction in chronic stroke patients. Although there appears to be more potential for the use of cathodal stimulation in patients with severe disability, the effects were small and must be considered with caution as they were accompanied by unanticipated effects in the unaffected upper limb.

  1. Identification of a selective glucocorticoid receptor ligand for the treatment of chronic inflammation in type 2 diabetes mellitus.

    Science.gov (United States)

    Tan, Haifeng; Wang, Wei; Yin, Xiangang; Li, Yao; Yin, Rui

    2014-10-01

    The present study aimed to identify a new selective glucocorticoid receptor (GR) ligand for the treatment of chronic inflammation in type 2 diabetes mellitus. The IN Cell Analyzer 1000 platform was employed to screen for compounds that may promote GR nuclear translocation. A mammalian two-hybrid system and transactivation assay-were used to analyze the selected GR ligands and evaluate their activities for GR transcription and the recruitment of co-activators. A novel selective GR ligand, compound Q40, was identified that was able to promote GR nuclear translocation in a short period of time. It increased the ability of GR to recruit co-activators in a concentration-dependent manner, but had no positive effect on GR transcriptional activity. In conclusion, an increase in the expression levels of gluconeogeneic genes, induced by the transcriptional activation of GR, is the predisposing factor most commonly associated with the side-effects of glucocorticoids. The results suggest that compound Q40 is a ligand of the GR and exerts an agonistic action on the recruitment of co-activators without sugar dysmetabolism-related side-effects. Thus, compound Q40 has the potential to be used as an anti-inflammatory adjuvant therapy with minimal side-effects in patients with type 2 diabetes mellitus.

  2. PPAR-gamma ligands modulate effects of LPS in stimulated rat synovial fibroblasts.

    Science.gov (United States)

    Simonin, Marie-Agnès; Bordji, Karim; Boyault, Sandrine; Bianchi, Arnaud; Gouze, Elvire; Bécuwe, Philippe; Dauça, Michel; Netter, Patrick; Terlain, Bernard

    2002-01-01

    This work demonstrated the constitutive expression of peroxisome proliferator-activated receptor (PPAR)-gamma and PPAR-alpha in rat synovial fibroblasts at both mRNA and protein levels. A decrease in PPAR-gamma expression induced by 10 microg/ml lipopolysaccharide (LPS) was observed, whereas PPAR-alpha mRNA expression was not modified. 15-Deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) dose-dependently decreased LPS-induced cyclooxygenase (COX)-2 (-80%) and inducible nitric oxide synthase (iNOS) mRNA expression (-80%), whereas troglitazone (10 microM) only inhibited iNOS mRNA expression (-50%). 15d-PGJ(2) decreased LPS-induced interleukin (IL)-1 beta (-25%) and tumor necrosis factor (TNF)-alpha (-40%) expression. Interestingly, troglitazone strongly decreased TNF-alpha expression (-50%) but had no significant effect on IL-1 beta expression. 15d-PGJ(2) was able to inhibit DNA-binding activity of both nuclear factor (NF)-kappa B and AP-1. Troglitazone had no effect on NF-kappa B activation and was shown to increase LPS-induced AP-1 activation. 15d-PGJ(2) and troglitazone modulated the expression of LPS-induced iNOS, COX-2, and proinflammatory cytokines differently. Indeed, troglitazone seems to specifically target TNF-alpha and iNOS pathways. These results offer new insights in regard to the anti-inflammatory potential of the PPAR-gamma ligands and underline different mechanisms of action of 15d-PGJ(2) and troglitazone in synovial fibroblasts.

  3. Philadelphia chromosome detection in chronic myeloid leukemia: Utility of phytohemagglutinin-stimulated peripheral blood culture

    Directory of Open Access Journals (Sweden)

    Man Updesh Singh Sachdeva

    2012-01-01

    Full Text Available Background: The conventional cytogenetic approach to demonstrate Philadelphia (Ph chromosome at times does not yield enough number of metaphases or are of suboptimal quality. Further, the rapid molecular tests have completely pushed this simple technique into disrepute. Aims: This study aimed to evaluate usefulness of phytohemagglutinin (PHA-stimulated peripheral blood culture for detection of Ph chromosome in chronic myeloid leukemia (CML patients. Materials and Methods: Fifty-six patients, including 11 newly diagnosed cases of CML and 45 patients of CML on imatinib therapy showing the presence of Ph chromosome in unstimulated samples, were included in the study. Cytogenetic analysis was done on unstimulated samples, i.e. bone marrow aspirate, 24- and 48-h peripheral blood culture, and compared with PHA-stimulated 72-h peripheral blood culture. Results: The preparations from PHA-stimulated peripheral blood culture samples in all 56 patients yielded high number of good-quality metaphases. All the 11 (100% newly diagnosed patients and 39/45 (87% of the patients on imatinib therapy showed the presence of Ph chromosome in PHA-stimulated samples. Addition of PHA-stimulated 72-h peripheral blood culture preparation can be of use for increasing the diagnostic yield in cases of CML with suboptimal results on conventional cytogenetics from bone marrow aspirate sample.

  4. Epidural spinal cord stimulation in chronic non-reconstructible limb ischemia.

    Science.gov (United States)

    Neuhauser; Greiner; Kofler; Perkmann

    2004-04-01

    For patients with chronic non-reconstructible limb ischemia (chronic CLI), spinal-cord stimulation (SCS) has been advocated for the treatment of ischemic pain and prevention of amputation. The present clinical report was performed to evaluate the long-term effects of SCS on limb survival. A retrospective review was performed of 21 patients who had undergone SCS between December 1997 and July 2002 due to chronic CLI. The impulse generator used was the Itrel device (Medtronic, Inc). All conventional methods for revascularization and improvement of microcirculatory blood flow had been performed prior to SCS treatment. Patient selection was performed by clinical examination, pulse volume records, Doppler ankle/brachial measurements, angiography, and thoracic spine and lumbar spine x-ray. Since July 2000, additional TcpO2 measurements at the dorsum of the foot have been performed. SCS implantation was performed as a one-stage procedure in all cases. Patients are followed up to 57 months. Of 21 patients with chronic CLI, 20 (95%) were available for follow-up investigations. Four patients died one to fifteen months after implantation due to acute renal failure or myocardial infarction (19%). Major amputation could be avoided in 15 (71%) of 21 patients. Two electrode dislocation, one pulse-generator dislocation, and one wire disconnection occurred; no other complications were observed. SCS represents a safe and effective therapy for patients with chronic non-reconstructible critical limb ischemia.

  5. Chronic cadmium exposure stimulates SDF-1 expression in an ERα dependent manner.

    Science.gov (United States)

    Ponce, Esmeralda; Aquino, Natalie B; Louie, Maggie C

    2013-01-01

    Cadmium is an omnipotent environmental contaminant associated with the development of breast cancer. Studies suggest that cadmium functions as an endocrine disruptor, mimicking the actions of estrogen in breast cancer cells and activating the receptor to promote cell growth. Although acute cadmium exposure is known to promote estrogen receptor-mediated gene expression associated with growth, the consequence of chronic cadmium exposure is unclear. Since heavy metals are known to bioaccumulate, it is necessary to understand the effects of prolonged cadmium exposure. This study aims to investigate the effects of chronic cadmium exposure on breast cancer progression. A MCF7 breast cancer cell line chronically exposed to 10(-7) M CdCl2 serves as our model system. Data suggest that prolonged cadmium exposures result in the development of more aggressive cancer phenotypes - increased cell growth, migration and invasion. The results from this study show for the first time that chronic cadmium exposure stimulates the expression of SDF-1 by altering the molecular interactions between ERα, c-jun and c-fos. This study provides a mechanistic link between chronic cadmium exposure and ERα and demonstrates that prolonged, low-level cadmium exposure contributes to breast cancer progression.

  6. Chronic cadmium exposure stimulates SDF-1 expression in an ERα dependent manner.

    Directory of Open Access Journals (Sweden)

    Esmeralda Ponce

    Full Text Available Cadmium is an omnipotent environmental contaminant associated with the development of breast cancer. Studies suggest that cadmium functions as an endocrine disruptor, mimicking the actions of estrogen in breast cancer cells and activating the receptor to promote cell growth. Although acute cadmium exposure is known to promote estrogen receptor-mediated gene expression associated with growth, the consequence of chronic cadmium exposure is unclear. Since heavy metals are known to bioaccumulate, it is necessary to understand the effects of prolonged cadmium exposure. This study aims to investigate the effects of chronic cadmium exposure on breast cancer progression. A MCF7 breast cancer cell line chronically exposed to 10(-7 M CdCl2 serves as our model system. Data suggest that prolonged cadmium exposures result in the development of more aggressive cancer phenotypes - increased cell growth, migration and invasion. The results from this study show for the first time that chronic cadmium exposure stimulates the expression of SDF-1 by altering the molecular interactions between ERα, c-jun and c-fos. This study provides a mechanistic link between chronic cadmium exposure and ERα and demonstrates that prolonged, low-level cadmium exposure contributes to breast cancer progression.

  7. Effects of Abdominal Stimulation during Inspiratory Muscle Training on Respiratory Function of Chronic Stroke Patients.

    Science.gov (United States)

    Jung, Ju-Hyeon; Shim, Je-Myung; Kwon, Hae-Yeon; Kim, Ha-Roo; Kim, Bo-In

    2014-01-01

    [Purpose] The purpose of the present study was to verify a new method for improving respiratory functions by applying both abdominal stimulation and inspiratory muscle training (IMT) to train the inspiratory muscle and the expiratory muscle simultaneously, to improve the efficiency of IMT of chronic stroke patients. [Subjects] Eighteen stroke patients were randomly assigned to an experimental group (n = 9) and a control group (n = 9). [Methods] The experimental group was administered IMT with abdominal stimulation, and the control group was administered only IMT. During the intervention period, the experimental group and control group received training 20 min/day, 3 times/wk, for 4 weeks. To examine the lung functions of the subjects, FVC, FEV1, PEF, and FEF25-75 were measured using an electronic spirometer. The diaphragm thickness ratio was calculated from measurements made with a 7.5-MHz linear probe ultrasonic imaging system. [Result] The experimental group and the control group showed significant increases in diaphragm thickness ratio on the paretic side, but not on the non-paretic side. With regard to lung function, the experimental group showed significant increases in FEV1, PEF, and FEF25-75. The changes between before and after the intervention in the two groups were compared with each other, and the results showed significant differences in FEV1 and PEF. [Conclusion] The present study identified that IMT accompanied by abdominal stimulation improved the pulmonary function of chronic stroke patients.

  8. Occipital nerve stimulation in medically intractable, chronic cluster headache. The ICON study: Rationale and protocol of a randomised trial

    NARCIS (Netherlands)

    Wilbrink, Leopoldine A.; Teernstra, Onno P.M.; Haan, Joost; Zwet, van Erik W.; Evers, Silvia M.A.A.; Spincemaille, Geert H.; Veltink, Peter H.; Mulleners, Wim; Brand, Ronald; Huygen, Frank J.P.M.; Jensen, Rigmor H.; Paemeleire, Koen; Goadsby, Peter J.; Visser-Vandewalle, Veerle; Ferrari, Michel D.

    2013-01-01

    Background: About 10% of cluster headache patients have the chronic form. At least 10% of this chronic group is intractable to or cannot tolerate medical treatment. Open pilot studies suggest that occipital nerve stimulation (ONS) might offer effective prevention in these patients. Controlled neurom

  9. Management of chronic symphysis pubis pain following child birth with spinal cord stimulator.

    LENUS (Irish Health Repository)

    Idrees, Ahsan

    2012-01-01

    The case of a 39 year old woman who had diastasis of pubic symphysis following childbirth and later developed severe chronic neuropathic pain and disability is presented. She received extensive surgical and medical treatment for 6 years with no improvement of symptoms. The VNRS (Visual Numerical Rating Scale) pain score was 7\\/10 or more most of the time. This was quite disabling in terms of her quality of life. A spinal cord stimulator was inserted after failure of other modalities of pain management which resulted in dramatic improvement in the quality of life measured with SF-36 questionnaire. Her pain score became 0\\/10 VNRS and she was free from opioids and psychotropic medications within 3 months post insertion. Spinal cord stimulator can be considered for the management of pain due to diastasis of pubic symphysis, not amenable to other therapies.

  10. Management of chronic symphysis pubis pain following child birth with spinal cord stimulator.

    Science.gov (United States)

    Idrees, Ahsan

    2012-01-01

    The case of a 39 year old woman who had diastasis of pubic symphysis following childbirth and later developed severe chronic neuropathic pain and disability is presented. She received extensive surgical and medical treatment for 6 years with no improvement of symptoms. The VNRS (Visual Numerical Rating Scale) pain score was 7/10 or more most of the time. This was quite disabling in terms of her quality of life. A spinal cord stimulator was inserted after failure of other modalities of pain management which resulted in dramatic improvement in the quality of life measured with SF-36 questionnaire. Her pain score became 0/10 VNRS and she was free from opioids and psychotropic medications within 3 months post insertion. Spinal cord stimulator can be considered for the management of pain due to diastasis of pubic symphysis, not amenable to other therapies.

  11. [The treatment of vasospastic disease by chronic spinal cord stimulation. A case report].

    Science.gov (United States)

    Barba, A; Escribano, J V; García-Alfageme, A

    1992-01-01

    In 1976, by first time, Cook used the chronic medullar stimulation (CMS) for the treatment of chronic arteriopathies at the limbs in patients with distal ischemic ulcerations. Up to now, some studies about this procedure have been published. Results, poor at first, have presented an important improvement with the time and the better choosing of patients. In 1981, Neglio used by first time CMS as a treatment of vasospastic disease, with excellent results. With this procedure, pain and vasospastic crisis disappeared and re-epithelialization of ischemic ulcerations is found. In this article, we presented a case interesting because it show the different possibilities of this method as a symptomatic treatment of such kind of disease. Patient, with a Raynaud syndrome secondary to an sclerodermia treated previously by medical and surgical procedures, was treated, in different times, with CMS because of digital ischemic ulcerations in both hands. Results were positives and ulcerations healed.

  12. Electroconvulsive stimulation reverses anhedonia and cognitive impairments in rats exposed to chronic mild stress

    DEFF Research Database (Denmark)

    Henningsen, K; Woldbye, D P D; Wiborg, O

    2013-01-01

    Electroconvulsive therapy remains the most effective treatment for depression including a fast onset of action. However, this therapeutic approach suffers from some potential drawbacks. In the acute phase this includes amnesia. Electroconvulsive stimulation (ECS) has previously been shown...... to reverse a depression-like state in the chronic mild stress model of depression (CMS), but the effect of ECS on cognition has not previously been investigated. In this study the CMS model was used to induce a depressive-like condition in rats. The study was designed to investigate the acute effect of ECS...

  13. Preventing Ischial Pressure Ulcers: III. Clinical Pilot Study of Chronic Neuromuscular Electrical Stimulation

    Directory of Open Access Journals (Sweden)

    Hilton M. Kaplan

    2011-01-01

    Full Text Available Objective: BIONs™ (BIOnic Neurons are injectable, wireless microstimulators that make chronic BION Active Seating (BAS possible for pressure ulcer prevention (PUP. Neuromuscular electrical stimulation (NMES produces skeletal motion and activates trophic factors, counteracting three major etiological mechanisms leading to pressure ulcers (PUs: immobility, soft-tissue atrophy, and ischemia. Companion papers I and II reviewed prior experience with NMES for PUP, and analyzed the biomechanical considerations, respectively. This paper presents a treatment strategy derived from this analysis, and the clinical results of the first three cases.

  14. Chronic Enhancement of Serotonin Facilitates Excitatory Transcranial Direct Current Stimulation-Induced Neuroplasticity.

    Science.gov (United States)

    Kuo, Hsiao-I; Paulus, Walter; Batsikadze, Giorgi; Jamil, Asif; Kuo, Min-Fang; Nitsche, Michael A

    2016-04-01

    Serotonin affects memory formation via modulating long-term potentiation (LTP) and depression (LTD). Accordingly, acute selective serotonin reuptake inhibitor (SSRI) administration enhanced LTP-like plasticity induced by transcranial direct current stimulation (tDCS) in humans. However, it usually takes some time for SSRI to reduce clinical symptoms such as anxiety, negative mood, and related symptoms of depression and anxiety disorders. This might be related to an at least partially different effect of chronic serotonergic enhancement on plasticity, as compared with single-dose medication. Here we explored the impact of chronic application of the SSRI citalopram (CIT) on plasticity induced by tDCS in healthy humans in a partially double-blinded, placebo (PLC)-controlled, randomized crossover study. Furthermore, we explored the dependency of plasticity induction from the glutamatergic system via N-methyl-D-aspartate receptor antagonism. Twelve healthy subjects received PLC medication, combined with anodal or cathodal tDCS of the primary motor cortex. Afterwards, the same subjects took CIT (20 mg/day) consecutively for 35 days. During this period, four additional interventions were performed (CIT and PLC medication with anodal/cathodal tDCS, CIT and dextromethorphan (150 mg) with anodal/cathodal tDCS). Plasticity was monitored by motor-evoked potential amplitudes elicited by transcranial magnetic stimulation. Chronic application of CIT increased and prolonged the LTP-like plasticity induced by anodal tDCS for over 24 h, and converted cathodal tDCS-induced LTD-like plasticity into facilitation. These effects were abolished by dextromethorphan. Chronic serotonergic enhancement results in a strengthening of LTP-like glutamatergic plasticity, which might partially explain the therapeutic impact of SSRIs in depression and other neuropsychiatric diseases.

  15. Monocyte and plasma expression of TAM ligand and receptor in renal failure: Links to unregulated immunity and chronic inflammation.

    Science.gov (United States)

    Lee, Iris J; Hilliard, Brendan A; Ulas, Mehriban; Yu, Daohai; Vangala, Chandan; Rao, Swati; Lee, Jean; Gadegbeku, Crystal A; Cohen, Philip L

    2015-06-01

    Chronic inflammation is increased in patients with chronic kidney disease (CKD) and contributes to cardiovascular morbidity and mortality. Specific immune mechanisms and pathways that drive and maintain chronic inflammation in CKD are not well described. The TAM ligands (Gas6 and protein S) and receptors (Axl and Mer) have been recently recognized as playing a prominent role in immune regulation. The receptors exist in both soluble and cell-bound forms; the soluble receptors (sAxl and sMer) are believed to compete with the bound receptors and thus inhibit their function. In this study, we determined the expression of cell-bound and soluble TAM proteins in patients with CKD. CKD patients had significantly lower expression of Mer in monocytes, yet increased expression of soluble TAM receptors sAxl and sMer in plasma compared to controls. The metalloproteinase ADAM 17, responsible for cleavage of Mer to its soluble form, was increased in patient monocytes. Elevated levels of soluble TAM receptors were more evident in patients with progressive renal failure. These observations suggest that functional deficiency of TAM receptor-mediated regulation of inflammation may contribute to chronic inflammation in patients with CKD.

  16. Repeated transcranial direct current stimulation prevents abnormal behaviors associated with abstinence from chronic nicotine consumption.

    Science.gov (United States)

    Pedron, Solène; Monnin, Julie; Haffen, Emmanuel; Sechter, Daniel; Van Waes, Vincent

    2014-03-01

    Successful available treatments to quit smoking remain scarce. Recently, the potential of transcranial direct current stimulation (tDCS) as a tool to reduce craving for nicotine has gained interest. However, there is no documented animal model to assess the neurobiological mechanisms of tDCS on addiction-related behaviors. To address this topic, we have developed a model of repeated tDCS in mice and used it to validate its effectiveness in relieving nicotine addiction. Anodal repeated tDCS was applied over the frontal cortex of Swiss female mice. The stimulation electrode (anode) was fixed directly onto the cranium, and the reference electrode was placed onto the ventral thorax. A 2 × 20 min/day stimulation paradigm for five consecutive days was used (0.2 mA). In the first study, we screened for behaviors altered by the stimulation. Second, we tested whether tDCS could alleviate abnormal behaviors associated with abstinence from nicotine consumption. In naive animals, repeated tDCS had antidepressant-like properties 3 weeks after the last stimulation, improved working memory, and decreased conditioned place preference for nicotine without affecting locomotor activity and anxiety-related behavior. Importantly, abnormal behaviors associated with chronic nicotine exposure (ie, depression-like behavior, increase in nicotine-induced place preference) were normalized by repeated tDCS. Our data show for the first time in an animal model that repeated tDCS is a promising, non-expensive clinical tool that could be used to reduce smoking craving and facilitate smoking cessation. Our animal model will be useful to investigate the mechanisms underlying the effects of tDCS on addiction and other psychiatric disorders.

  17. An implantable device for neuropsychiatric rehabilitation by chronic deep brain stimulation in freely moving rats

    Science.gov (United States)

    Wang, Chenguang; Zhang, Fuqiang; Jia, Hong

    2017-01-01

    Successful practice of clinical deep brain stimulation (DBS) calls for basic research on the mechanisms and explorations of new indications in animals. In the article, a new implantable, single-channel, low-power miniature device is proposed, which may transmit pulses chronically into the brain nucleus of freely moving rats. The DBS system consists of an implantable pulse generator (IPG), a bipolar electrode, and an external programmer. The IPG circuit module is assembled as a 20-mm diameter circular board and fixed on a rat’s skull together with an electrode and battery. The rigid electrode may make its fabrication and implantation more easy. The external programmer is designed for bidirectional communication with the IPG by a telecontrol transceiver and adjusts stimulation parameters. A biological validation was performed in which the effects of electrical stimulation in brain nucleus accumbens were detected. The programmed parameters were accurate, implant steady, and power sufficient to allow stimulation for more than 3 months. The larger area of the electrode tip provided a moderate current or charge density and minimized the damage from electrochemistry and pyroelectricity. The rats implanted with the device showed a reduction in morphine-induced conditioned place preference after high-frequency stimulation. In conclusion, the DBS device is based on the criteria of simple technology, minimal invasion, low cost, small in size, light-weight, and wireless controlled. This shows that our DBS device is appropriate and can be used for preclinical studies, indicating its potential utility in the therapy and rehabilitation of neuropsychiatric disorders. PMID:28121810

  18. [Chronic high frequency deep brain stimulation of the globus pallidus internus for torsion dystonia].

    Science.gov (United States)

    Vesper, J; Klostermann, F; Funk, T; Bock, M

    2002-01-01

    Deep Brain Stimulation (DBS, chronic high frequency stimulation) is well established for Parkinson's disease and tremordominant movement disorders. Generalized dystonia is known as a type of movement disorder in which therapeutic options are very limited. A case of generalized dystonia is reported which was successfully treated by DBS in the Globus pallidus internus (GPI). A 26 years old male suffered from severe torsion dystonia of the lower limbs. The onset of symptoms was at age 7. It started with dystonia of the left foot. He very fast developed severe dystonia of the lower limbs. These complaints were initially treated by diazepam, later by baclofen (Lioresal ((R))) p.o em leader There was no L-DOPA response. Because of the rapid progression of the disease a cervical spinal cord stimulator was implanted with a transient success. Due to further progression of the disease the patient became wheelchair bounded and resistant for oral medication. Limited improvement of symptoms was achieved using continuous intrathecal administration of baclofen. Finally the patient was treated with 980 microgram intrathecal Baclofen (Lioresal ((R))) daily and up to 100 mg diazepam. Under these conditions the patient remained wheelchair bounded with severe lower limb dystonia. As an ultima ratio it was decided to treat the patient with stereotactic implantation of two electrodes (Medtronic 3387) and two neurostimulators (Medtronic ITREL ((R))II). The GPI was the bilateral target point. Intraoperative computerized tomography and ventriculography were used for target setting. Furthermore microrecordings were helpful to ensure the exact electrode positioning. Surgery was performed under sedation. Two weeks after surgery first improvement of symptoms was observed. Patient was able to stand with assistance. At the three months follow-up he could walk without assistance. Slight dystonic movement of the left ankle was the only remaining symptom under stimulation. The oral medication has

  19. NMR-based metabolomics Reveals Alterations of Electro-acupuncture Stimulations on Chronic Atrophic Gastritis Rats

    Science.gov (United States)

    Xu, Jingjing; Zheng, Xujuan; Cheng, Kian-Kai; Chang, Xiaorong; Shen, Guiping; Liu, Mi; Wang, Yadong; Shen, Jiacheng; Zhang, Yuan; He, Qida; Dong, Jiyang; Yang, Zongbao

    2017-01-01

    Chronic atrophic gastritis (CAG) is a common gastrointestinal disease which has been considered as precancerous lesions of gastric carcinoma. Previously, electro-acupuncture stimulation has been shown to be effective in ameliorating symptoms of CAG. However the underlying mechanism of this beneficial treatment is yet to be established. In the present study, an integrated histopathological examination along with molecular biological assay, as well as 1H NMR analysis of multiple biological samples (urine, serum, stomach, cortex and medulla) were employed to systematically assess the pathology of CAG and therapeutic effect of electro-acupuncture stimulation at Sibai (ST 2), Liangmen (ST 21), and Zusanli (ST 36) acupoints located in the stomach meridian using a rat model of CAG. The current results showed that CAG caused comprehensive metabolic alterations including the TCA cycle, glycolysis, membrane metabolism and catabolism, gut microbiota-related metabolism. On the other hand, electro-acupuncture treatment was found able to normalize a number of CAG-induced metabolomics changes by alleviating membrane catabolism, restoring function of neurotransmitter in brain and partially reverse the CAG-induced perturbation in gut microbiota metabolism. These findings provided new insights into the biochemistry of CAG and mechanism of the therapeutic effect of electro-acupuncture stimulations. PMID:28358020

  20. Chronic stress-like syndrome as a consequence of medial site subthalamic stimulation in Parkinson's disease.

    Science.gov (United States)

    Růžička, Filip; Jech, Robert; Nováková, Lucie; Urgošík, Dušan; Bezdíček, Ondřej; Vymazal, Josef; Růžička, Evžen

    2015-02-01

    Considering the functional organization of the subthalamic nucleus (STN), we hypothesized that subthalamic deep brain stimulation (STN-DBS) in Parkinson's disease might have a differential impact on the hypothalamic-pituitary-adrenal axis in relation to the position of active stimulating contact within the STN. In addition, we searched for any STN-DBS-related morning plasma cortisol changes in association with postoperative anxiety and weight gain. A plasma cortisol measurement was performed on the day of initiation of bilateral STN-DBS and repeated after 1 and 17 months in twenty patients with advanced Parkinson's disease. The body weight change and anxiety scores following the implantation were assessed as well. The electrode positions in the STN were determined on T1-weighted magnetic resonance images. After initiation of stimulation, cortisol levels significantly decreased and the cortisol changes after 1 and 17 months strongly correlated with the position of active contact in the subthalamic area. Patients with at least one contact located more medially in the STN experienced a significantly greater decrease of cortisol than those with one or both active contacts more laterally. Furthermore, the lower cortisol levels were strongly associated with higher trait anxiety and weight gain. These changes mimicked the effects of chronic stress and suggest the disturbing impact of STN-DBS on limbic and motivational systems.

  1. [Cytogenetics of chronic lymphocytic leukemia stimulated by CpG-oligodeoxynucleotides and IL-2].

    Science.gov (United States)

    Wang, Dong-Mei; Xu, Wei; Dong, Hua-Jie; Fang, Cheng; Zhu, Dan-Xia; Cao, Xin; Zhu, Hua-Yuan; Zhuang, Yun; Qiu, Hai-Rong; Yang, Hui; Li, Jian-Yong

    2010-10-01

    This study was to explore the stimulating effect of CpG-oligodeoxynucleotides (CpG-ODN) in combination with interleukin-2 (IL-2) on cytogenetic features of chronic lymphocytic leukemia (CLL) cells. Peripheral blood or bone marrow cells of 115 patients with CLL were cultured for 72 hours with CpG-ODN plus interleukin-2 (IL-2), and routine karyotype analysis was performed with R-banding technique. The metaphase number≥20 was considered as successful stimulation. The results showed that among the 115 CLL patients, successful stimulation rate was 74.8%. The rate of chromosome aberrations was 58.1%. One kind of aberration was detected in 21 cases (24.4%), two kinds of aberration in 6 cases (7.0%), complex aberrant karyotype in 23 cases (26.7%), included highly complex aberrant karyotype in 9 cases (10.5%), respectively. A total of 163 abnormalities of 102 kinds were detected in 86 patients. Number aberrations were 116 (71.2%), and structural abnormalities were 47 (28.8%). The most frequent number aberration was trisomy 12 (14.0%), and structural aberration was 15q+ (5.8%). It is concluded that most of CLL patients have chromosome abnormality, and the number abnormality are more frequent than the structural aberrations. CpG-ODN plus IL-2 can effectively raise the number of cells at metaphase and the detection rate of chromosome aberrations in CLL patients.

  2. Functional electrical stimulation therapy improves grasping in chronic cervical spinal cord injury: Two case studies

    Directory of Open Access Journals (Sweden)

    Miller Rosalynn C.

    2008-01-01

    Full Text Available OBJECTIVE AND IMPORTANCE: To present case studies of two individuals with chronic cervical spinal cord injury (SCI who participated in functional electrical stimulation (FES therapy with the objective to restore voluntary grasp function. CLINICAL PRESENTATION: Both individuals (right hand dominant males, age 24 and 31 had a sustained a cervical SCI (C6 and C4-5, respectively at least 8 years prior to participation in this study. INTERVENTION: Both individuals participated in an individualized FES therapy program for 6 weeks. FES therapy was administered through a regimen of three, one-hour sessions, per week for three months. A single arm of each participant (n = 2 was treated. FES therapy is an integrative intervention strategy combining muscle strengthening, functional movement training and stretching. The participant's hand movement abilities were assessed pre and post FES therapy using the Manual Muscle Test (MMT, a modified Sollerman Hand Function Test (mSHFT, and the Reach, Grasp, Transport and Release Task (RGTR. DISCUSSION: As the injuries of participants in the current study were chronic and thus neurologically stable, no spontaneous improvements/recovery in hand function was expected. However, FES as part of an integrated therapeutic approach affected restoration and improvement of hand function in both participants. CONCLUSION: The concurrent improvement in strength, integrated motor function and object contact following FES therapy, demonstrated that there is potential for affecting change in hand function of individuals with chronic SCI.

  3. Evaluating interhemispheric cortical responses to transcranial magnetic stimulation in chronic stroke: A TMS-EEG investigation.

    Science.gov (United States)

    Borich, Michael R; Wheaton, Lewis A; Brodie, Sonia M; Lakhani, Bimal; Boyd, Lara A

    2016-04-01

    TMS-evoked cortical responses can be measured using simultaneous electroencephalography (TMS-EEG) to directly quantify cortical connectivity in the human brain. The purpose of this study was to evaluate interhemispheric cortical connectivity between the primary motor cortices (M1s) in participants with chronic stroke and controls using TMS-EEG. Ten participants with chronic stroke and four controls were tested. TMS-evoked responses were recorded at rest and during a typical TMS assessment of transcallosal inhibition (TCI). EEG recordings from peri-central gyral electrodes (C3 and C4) were evaluated using imaginary phase coherence (IPC) analyses to quantify levels of effective interhemispheric connectivity. Significantly increased TMS-evoked beta (15-30Hz frequency range) IPC was observed in the stroke group during ipsilesional M1 stimulation compared to controls during TCI assessment but not at rest. TMS-evoked beta IPC values were associated with TMS measures of transcallosal inhibition across groups. These results suggest TMS-evoked EEG responses can index abnormal effective interhemispheric connectivity in chronic stroke.

  4. Fine-Tuned Expression of Programmed Death 1 Ligands in Mature Dendritic Cells Stimulated by CD40 Ligand is Critical for the Induction of an Efficient Tumor Specific Immune Response

    Institute of Scientific and Technical Information of China (English)

    Tao Gu; Yong Huang; Yuhua Qiu; Xueguang Zhang; Yibei Zhu; Cheng Chen; Min Li; Yongjing Chen; Gehua Yu; Yan Ge; Shiyong Zhou; Huan Zhou

    2008-01-01

    During maturation, murine myeloid dendritic cells(DCs)upregulated the expressions of CD11c, CD25, CD40, CD80, CD86.MHc II and programmed death 1 ligands 1 and 2(PD-L1 and PD-L2).Differential expression patterns of PD-L1 and PD. L2 were found when DCs were triggered by CD40 ligand and TNF-α.PD-L1 expression-was repressed and PD. L2 expression remained unchanged in mature CD40-ligated DCs, whereas TNF-αstimulted DCs kept high expression of PD. L1 and significantly enhanced PD-L2 expression on DCs. Proliferations of T lymphocytes stimulated by immature DCs were enhanced by blockade of the PD-1 and PD-1 ligand interaction. But inhibiitive effects were found in T lymphocytes stimulated by CD40-ligated DCs. With the tine-tuned expressions of the PD-L1 and PD-L2, CD40-ligated DCs could sustain a longer activation period and elicit a more efficient T lymphocyte activation. Cellular & Molecular Immunology. 2008;5(1):33-39.

  5. Treatment of Idiopathic Chronic Orchialgia with Transcutaneous Electrical Nerve Stimulation (TENS:A Preliminary Result

    Directory of Open Access Journals (Sweden)

    Ekrem Akdeniz

    2016-01-01

    Full Text Available Purpose: Unilateral or bilateral testicular pain lasting more than 3 months is called as chronic orchialgia. Aproximately 25-50% of chronic orchialgia is idiopatic origin. This study aimed the effectiveness of Transcutaneous Electrical Nerve Stimulation (TENS therapy due to Idiopathic Chronic Orchialgia (ICO. Methods: Five patients were included into this study with ICO that diagnosed with physical examination, urine analyses, urinary system x-ray film, and scrotal doppler ultrasound. Medical history revealed that multiple conservative therapy attempts failed to alleviate the pain. Two of the patients had right sided ICO. Traditional TENS device is placed to the most painful points. TENS applied 3 times in a week with duration 30 minutes for 4 weeks. Before and after TENS application, patients were evaluated by using Visual Analog Scale (VAS at first and third months. Results: Median age of patients was 26.20±2.38 (22-30. Mean VAS value was 6.52 ± 0.89 before the procedure. After 1 month VAS value was 3.82 ± 0.83 (p0.05. None of the patients needed any analgesics after during the one month. No complications, hyperemia or hypoesthesia of the scrotal or penile skin, occurred after the procedure. Conclusion: TENS reduces pain by increasing endorphin release in the spinal cord dorsal horn. TENS is very effective method for first 1 month in patients with ICO but its effect reduces by the time. There is no standard therapeutic protocol for idiopathic chronic orchialgia. Therefore TENS may be an alternative for patients who do not benefit from medical therapy and do not want invasive procedures. Short-term use of TENS and low number of the patients are the limitations of this study. Randomized, placebo-controlled, and longer follow-up period studies are needed to better assess the efficacy of TENS for ICO.

  6. Chronic Toxicity of a Novel Recombinant Human Granulocyte Colony-stimulating Factor in Rats

    Institute of Scientific and Technical Information of China (English)

    Fei Xia; Qing-yu Zhang; Yong-ping Jiang

    2011-01-01

    Objective To assess the severity and reversibility of the chronic toxicity of a novel recombinant human granulocyte colony-stimulating factor (rhG-CSFa) in rats and the dose-effect relationship. Methods A total of 100 Sprague-Dawley rats (equal numbers of male and female) were randomly divided into five groups (20 rats in each group): four groups were treated with rhG-CSFa at 500, 100,10, 1 μg/kg, respectively, and one group was treated with vehicle only to serve as the control. The rats were received subcutaneous injections of rhG-CSFa or vehicle daily for 13 weeks. During the course of the chronic toxicity study, the physical status, body weight, and food consumption were monitored. Half of the rats in each group (n= 10) were sacrificed after the last rhG-CSFa administration, and the other half were sacrificed at five weeks after the last rhG-CSFa administration. Urinalyses, blood biochemistry, hematological analysis, histopathological examination, and immunological tests were performed for each of the rats. Results The hematological analyses revealed that the mean white blood cells count, neutrophils count, and neutrophils percentage were increased in male rats at the dose of 10 μg/kg or higher, and these were related with the biological activity of rhG-CSFa. Some small abnormalities were observed in the spleen of a few rats when used highest dose (500 μg/kg, a dosage of 200 folds higher than the normal clinical dosage), but these abnormalities were recovered within S-week recovery period. No other rhG-CSFa-related abnormalities were observed in this chronic toxicity study.Conclusion No significant toxicity and immunogenicity are observed with rhG-CSFa administration to rats in the chronic toxicity studies.

  7. Electrical nerve stimulation and the relief of chronic pain through regulation of the accumulation of synaptic Arc protein.

    Science.gov (United States)

    Liu, Yue-peng; Liu, Su

    2013-08-01

    Electrical nerve stimulation (ENS) is used in clinical settings for the treatment of chronic pain, but the mechanism underlying its effects remains unknown. ENS has been found to mimic neural activity, inducing the accumulation of Arc in synapses. Activity-dependent synaptic accumulation of Arc protein has been shown to reduce synaptic strength by promoting endocytosis of the AMPA receptors in the synaptic membrane. These receptors play a decisive role in central sensitization, which is one of the main mechanisms underlying chronic pain. It is here hypothesized that ENS induces Arc expression in synapses, where Arc promotes endocytosis of membrane AMPARs that are up-regulated during chronic pain. High frequency and high intensity are characteristics of ENS, which may be effective in the treatment of chronic pain. Stimulation-site of ENS may also influence the outcome of ENS.

  8. CD8+ T cells of chronic HCV-infected patients express multiple negative immune checkpoints following stimulation with HCV peptides.

    Science.gov (United States)

    Barathan, Muttiah; Mohamed, Rosmawati; Vadivelu, Jamuna; Chang, Li Yen; Vignesh, Ramachandran; Krishnan, Jayalakshmi; Sigamani, Panneer; Saeidi, Alireza; Ram, M Ravishankar; Velu, Vijayakumar; Larsson, Marie; Shankar, Esaki M

    2017-03-01

    Hepatitis C virus (HCV)-specific CD4+ and CD8+ T cells are key to successful viral clearance in HCV disease. Accumulation of exhausted HCV-specific T cells during chronic infection results in considerable loss of protective functional immune responses. The role of T-cell exhaustion in chronic HCV disease remains poorly understood. Here, we studied the frequency of HCV peptide-stimulated T cells expressing negative immune checkpoints (PD-1, CTLA-4, TRAIL, TIM-3 and BTLA) by flow cytometry, and measured the levels of Th1/Th2/Th17 cytokines secreted by T cells by a commercial Multi-Analyte ELISArray™ following in vitro stimulation of T cells using HCV peptides and phytohemagglutinin (PHA). HCV peptide-stimulated CD4+ and CD8+ T cells of chronic HCV (CHC) patients showed significant increase of CTLA-4. Furthermore, HCV peptide-stimulated CD4+ T cells of CHC patients also displayed relatively higher levels of PD-1 and TRAIL, whereas TIM-3 was up-regulated on HCV peptide-stimulated CD8+ T cells. Whereas the levels of IL-10 and TGF-β1 were significantly increased, the levels of pro-inflammatory cytokines IL-2, TNF-α, IL-17A and IL-6 were markedly decreased in the T cell cultures of CHC patients. Chronic HCV infection results in functional exhaustion of CD4+ and CD8+ T cells likely contributing to viral persistence.

  9. Analgesic effectiveness of the association of transcutaneous electrical nerve stimulation and cryotherapy for chronic low back pain

    OpenAIRE

    Abreu,Eliziete Almeida de; Santos, Jean Douglas Moura dos; Ventura,Patrícia Lima

    2011-01-01

    BACKGROUND AND OBJECTIVES: Transcutaneous electrical nerve stimulation (TENS) and cryotherapy are physical therapy resources individually used, since there is the possibility of interaction between TENS and cryotherapy if they are associated. This study aimed at evaluating the analgesic effectiveness of the association or not of TENS and cryotherapy to relieve chronic low back pain. METHOD: Clinical trial involving six chronic low back pain patients distributed in three groups: cryotherapy, T...

  10. How process analysis could improve the implementation of spinal cord stimulation treatment for chronic pain.

    Science.gov (United States)

    Williams, Kayode A; McLeod, Julia C; Reinhardt, Gilles

    2012-05-01

    SUMMARY Spinal cord stimulation has been in clinical use for the treatment of chronic pain for over four decades. Since the initial use by Norman Shealy, the indications for its use have increased steadily over the decades to include neuropathic pain owing to failed back surgery syndrome, complex regional pain syndrome and painful diabetic peripheral neuropathies. To date, the precise mechanism of action of spinal cord stimulation remains unclear, yet it is still one of the most expensive interventional treatment modalities available in pain medicine with increasing application across the world. Given the worldwide focus on cost-effective care, there is an opportunity to focus on process analysis as a mechanism for optimizing the operations within and between all specialties engaged in the provision of care in pain medicine. Here, we propose a process analysis approach to model, measure and improve the delivery of disease-based care to enhance effective treatment with a costly modality. Systems-based process analysis is not widely utilized in pain medicine, and there is a limited body of evidence for its application. The purpose of this article is to generate interest in the discipline of process analysis in pain medicine, as it has found value in other healthcare settings and industries. We mention the applicability across countries and specialties that we hope will increase the awareness of this concept and possibly generate interest in further examination by investigators that will lead to the development of highly efficient and effective healthcare delivery processes and systems across the globe.

  11. Wearable light management system for light stimulated healing of large area chronic wounds (Conference Presentation)

    Science.gov (United States)

    Kallweit, David; Mayer, Jan; Fricke, Sören; Schnieper, Marc; Ferrini, Rolando

    2016-03-01

    Chronic wounds represent a significant burden to patients, health care professionals, and health care systems, affecting over 40 million patients and creating costs of approximately 40 billion € annually. We will present a medical device for photo-stimulated wound care based on a wearable large area flexible and disposable light management system consisting of a waveguide with incorporated micro- and nanometer scale optical structures for efficient light in-coupling, waveguiding and homogeneous illumination of large area wounds. The working principle of this innovative device is based on the therapeutic effects of visible light to facilitate the self-healing process of chronic wounds. On the one hand, light exposure in the red (656nm) induces growth of keratinocytes and fibroblasts in deeper layers of the skin. On the other hand, blue light (453nm) is known to have antibacterial effects predominately at the surface layers of the skin. In order to be compliant with medical requirements the system will consist of two elements: a disposable wound dressing with embedded flexible optical waveguides for the light management and illumination of the wound area, and a non-disposable compact module containing the light sources, a controller, a rechargeable battery, and a data transmission unit. In particular, we will report on the developed light management system. Finally, as a proof-of-concept, a demonstrator will be presented and its performances will be reported to demonstrate the potential of this innovative device.

  12. Sensorimotor plasticity after music-supported therapy in chronic stroke patients revealed by transcranial magnetic stimulation.

    Directory of Open Access Journals (Sweden)

    Julià L Amengual

    Full Text Available BACKGROUND: Several recently developed therapies targeting motor disabilities in stroke sufferers have shown to be more effective than standard neurorehabilitation approaches. In this context, several basic studies demonstrated that music training produces rapid neuroplastic changes in motor-related brain areas. Music-supported therapy has been recently developed as a new motor rehabilitation intervention. METHODS AND RESULTS: In order to explore the plasticity effects of music-supported therapy, this therapeutic intervention was applied to twenty chronic stroke patients. Before and after the music-supported therapy, transcranial magnetic stimulation was applied for the assessment of excitability changes in the motor cortex and a 3D movement analyzer was used for the assessment of motor performance parameters such as velocity, acceleration and smoothness in a set of diadochokinetic movement tasks. Our results suggest that the music-supported therapy produces changes in cortical plasticity leading the improvement of the subjects' motor performance. CONCLUSION: Our findings represent the first evidence of the neurophysiological changes induced by this therapy in chronic stroke patients, and their link with the amelioration of motor performance. Further studies are needed to confirm our observations.

  13. Re-evaluation of metal bioaccumulation and chronic toxicity in Hyalella azteca using saturation curves and the biotic ligand model

    Energy Technology Data Exchange (ETDEWEB)

    Borgmann, U.; Norwood, W.P.; Dixon, D.G

    2004-10-01

    Bioaccumulation by Hyalella of all metals studied so far in our laboratory was re-evaluated to determine if the data could be explained satisfactorily using saturation models. Saturation kinetics are predicted by the biotic ligand model (BLM), now widely used in modelling acute toxicity, and are a pre-requisite if the BLM is to be applied to chronic toxicity. Saturation models provided a good fit to all the data. Since these are mechanistically based, they provide additional insights into metal accumulation mechanisms not immediately apparent when using allometric models. For example, maximum Cd accumulation is dependent on the hardness of the water to which Hyalella are acclimated. The BLM may need to be modified when applied to chronic toxicity. Use of saturation models for bioaccumulation, however, also necessitates the need for using saturation models for dose-response relationships in order to produce unambiguous estimates of LC50 values based on water and body concentrations. This affects predictions of toxicity at very low metal concentrations and results in lower predicted toxicity of mixtures when many metals are present at low concentrations.

  14. The water channel aquaporin-1 contributes to renin cell recruitment during chronic stimulation of renin production.

    Science.gov (United States)

    Tinning, Anne R; Jensen, Boye L; Schweda, Frank; Machura, Katharina; Hansen, Pernille B L; Stubbe, Jane; Gramsbergen, Jan Bert; Madsen, Kirsten

    2014-12-01

    Both the processing and release of secretory granules involve water movement across granule membranes. It was hypothesized that the water channel aquaporin (AQP)1 directly contributes to the recruitment of renin-positive cells in the afferent arteriole. AQP1(-/-) and AQP1(+/+) mice were fed a low-salt (LS) diet [0.004% (wt/wt) NaCl] for 7 days and given enalapril [angiotensin-converting enzyme inhibitor (ACEI), 0.1 mg/ml] in drinking water for 3 days. There were no differences in plasma renin concentration at baseline. After LS-ACEI, plasma renin concentrations increased markedly in both genotypes but was significantly lower in AQP1(-/-) mice compared with AQP1(+/+) mice. Tissue renin concentrations were higher in AQP1(-/-) mice, and renin mRNA levels were not different between genotypes. Mean arterial blood pressure was not different at baseline and during LS diet but decreased significantly in both genotypes after the addition of ACEI; the response was faster in AQP1(-/-) mice but then stabilized at a similar level. Renin release after 200 μl blood withdrawal was not different. Isoprenaline-stimulated renin release from isolated perfused kidneys did not differ between genotypes. Cortical tissue norepinephrine concentrations were lower after LS-ACEI compared with baseline with no difference between genotypes. Plasma nitrite/nitrate concentrations were unaffected by genotype and LS-ACEI. In AQP1(-/-) mice, the number of afferent arterioles with recruitment was significantly lower compared with AQP1(+/+) mice after LS-ACEI. We conclude that AQP1 is not necessary for acutely stimulated renin secretion in vivo and from isolated perfused kidneys, whereas recruitment of renin-positive cells in response to chronic stimulation is attenuated or delayed in AQP1(-/-) mice.

  15. Chronic activation of NPFFR2 stimulates the stress-related depressive behaviors through HPA axis modulation.

    Science.gov (United States)

    Lin, Ya-Tin; Liu, Tzu-Yu; Yang, Ching-Yao; Yu, Yu-Lian; Chen, Ting-Chun; Day, Yuan-Ji; Chang, Che-Chien; Huang, Guo-Jen; Chen, Jin-Chung

    2016-09-01

    Neuropeptide FF (NPFF) is a morphine-modulating peptide that regulates the analgesic effect of opioids, and also controls food consumption and cardiovascular function through its interaction with two cognate receptors, NPFFR1 and NPFFR2. In the present study, we explore a novel modulatory role for NPFF-NPFFR2 in stress-related depressive behaviors. In a mouse model of chronic mild stress (CMS)-induced depression, the expression of NPFF significantly increased in the hypothalamus, hippocampus, medial prefrontal cortex (mPFC) and amygdala. In addition, transgenic (Tg) mice over-expressing NPFFR2 displayed clear depression and anxiety-like behaviors with hyperactivity in the hypothalamic-pituitary-adrenal (HPA) axis, reduced expression of glucocorticoid receptor (GR) and neurogenesis in the hippocampus. Furthermore, acute treatment of NPFFR2 agonists in wild-type (WT) mice enhanced the activity of the HPA axis, and chronic administration resulted in depressive and anxiety-like behaviors. Chronic stimulation of NPFFR2 also decreased the expression of hippocampal GR and led to persistent activation of the HPA axis. Strikingly, bilateral intra-paraventricular nucleus (PVN) injection of NPFFR2 shRNA predominately inhibits the depressive-like behavior in CMS-exposed mice. Antidepressants, fluoxetine and ketamine, effectively relieved the depressive behaviors of NPFFR2-Tg mice. We speculate that persistent NPFFR2 activation, in particular in the hypothalamus, up-regulates the HPA axis and results in long-lasting increases in circulating corticosterone (CORT), consequently damaging hippocampal function. This novel role of NPFFR2 in regulating the HPA axis and hippocampal function provides a new avenue for combating depression and anxiety-like disorder.

  16. The acute and chronic effect of vagus nerve stimulation in genetic absence epilepsy rats from Strasbourg (GAERS)

    NARCIS (Netherlands)

    S Dedeurwaerdere; K. Vonck; P Hese van; W.J. Wadman; P Boon

    2005-01-01

    PURPOSE: The aim of this study was to evaluate the efficacy of acute and chronic vagus nerve stimulation (VNS) in genetic absence epilepsy rats from Strasbourg (GAERS). This is a validated model for absence epilepsy, characterized by frequent spontaneous absences concomitant with spike and wave disc

  17. The effect of chronic heart failure and type 2 diabetes on insulin-stimulated endothelial function is similar and additive

    DEFF Research Database (Denmark)

    Falskov, Britt; Hermann, Thomas Steffen; Rask-Madsen, Christian;

    2011-01-01

    AIM: Chronic heart failure is associated with endothelial dysfunction and insulin resistance. The aim of this investigation was to study insulin-stimulated endothelial function and glucose uptake in skeletal muscles in patients with heart failure in comparison to patients with type 2 diabetes. ME...

  18. Individualized treatment with transcranial direct current stimulation in patients with chronic non-fluent aphasia due to stroke.

    Science.gov (United States)

    Shah-Basak, Priyanka P; Norise, Catherine; Garcia, Gabriella; Torres, Jose; Faseyitan, Olufunsho; Hamilton, Roy H

    2015-01-01

    While evidence suggests that transcranial direct current stimulation (tDCS) may facilitate language recovery in chronic post-stroke aphasia, individual variability in patient response to different patterns of stimulation remains largely unexplored. We sought to characterize this variability among chronic aphasic individuals, and to explore whether repeated stimulation with an individualized optimal montage could lead to persistent reduction of aphasia severity. In a two-phase study, we first stimulated patients with four active montages (left hemispheric anode or cathode; right hemispheric anode or cathode) and one sham montage (Phase 1). We examined changes in picture naming ability to address (1) variability in response to different montages among our patients, and (2) whether individual patients responded optimally to at least one montage. During Phase 2, subjects who responded in Phase 1 were randomized to receive either real-tDCS or to receive sham stimulation (10 days); patients who were randomized to receive sham stimulation first were then crossed over to receive real-tDCS (10 days). In both phases, 2 mA tDCS was administered for 20 min per real-tDCS sessions and patients performed a picture naming task during stimulation. Patients' language ability was re-tested after 2-weeks and 2-months following real and sham tDCS in Phase 2. In Phase 1, despite considerable individual variability, the greatest average improvement was observed after left-cathodal stimulation. Seven out of 12 subjects responded optimally to at least one montage as demonstrated by transient improvement in picture-naming. In Phase 2, aphasia severity improved at 2-weeks and 2-months following real-tDCS but not sham. Despite individual variability with respect to optimal tDCS approach, certain montages result in consistent transient improvement in persons with chronic post-stroke aphasia. This preliminary study supports the notion that individualized tDCS treatment may enhance aphasia

  19. Chronic morphine treatment enhances sciatic nerve stimulation-induced immediate early gene expression in the rat dorsal horn.

    Science.gov (United States)

    Bojovic, Ognjen; Bramham, Clive R; Tjølsen, Arne

    2015-01-01

    Synaptic plasticity is a property of neurons that can be induced by conditioning electrical stimulation (CS) of afferent fibers in the spinal cord. This is a widely studied property of spinal cord and hippocampal neurons. CS has been shown to trigger enhanced expression of immediate early gene proteins (IEGPs), with peak increases observed 2 hour post stimulation. Chronic morphine treatment has been shown to promoteinduce opioid-induced hyperalgesia, and also to increase CS-induced central sensitization in the dorsal horn. As IEGP expression may contribute to development of chronic pain states, we aimed to determine whether chronic morphine treatment affects the expression of IEGPs following sciatic nerve CS. Changes in expression of the IEGPs Arc, c-Fos or Zif268 were determined in cells of the lumbar dorsal horn of the spinal cord. Chronic Morphine pretreatment over 7 days led to a significant increase in the number of IEGP positive cells observed at both 2 h and 6 h after CS. The same pattern of immunoreactivity was obtained for all IEGPs, with peak increases occurring at 2 h post CS. In contrast, morphine treatment alone in sham operated animals had no effect on IEGP expression. We conclude that chronic morphine treatment enhances stimulus-induced expression of IEGPs in the lumbar dorsal horn. These data support the notion that morphine alters gene expression responses linked to nociceptive stimulation and plasticity.

  20. Peripheral nerve stimulation (PNS) in the trapezius muscle region alleviate chronic neuropathic pain after lower brachial plexus root avulsion lesion: A case report

    DEFF Research Database (Denmark)

    Sørensen, Jens Christian Hedemann; Meier, Kaare; Perinpam, Larshan;

    Peripheral nerve stimulation (PNS) in the trapezius muscle region alleviate chronic neuropathic pain after lower brachial plexus root avulsion lesion: A case report......Peripheral nerve stimulation (PNS) in the trapezius muscle region alleviate chronic neuropathic pain after lower brachial plexus root avulsion lesion: A case report...

  1. Chronic baclofen desensitizes GABA(B)-mediated G-protein activation and stimulates phosphorylation of kinases in mesocorticolimbic rat brain.

    Science.gov (United States)

    Keegan, Bradley M T; Beveridge, Thomas J R; Pezor, Jeffrey J; Xiao, Ruoyu; Sexton, Tammy; Childers, Steven R; Howlett, Allyn C

    2015-08-01

    The GABAB receptor is a therapeutic target for CNS and neuropathic disorders; however, few preclinical studies have explored effects of chronic stimulation. This study evaluated acute and chronic baclofen treatments on GABAB-activated G-proteins and signaling protein phosphorylation as indicators of GABAB signaling capacity. Brain sections from rats acutely administered baclofen (5 mg/kg, i.p.) showed no significant differences from controls in GABAB-stimulated GTPγS binding in any brain region, but displayed significantly greater phosphorylation/activation of focal adhesion kinase (pFAK(Tyr397)) in mesocorticolimbic regions (caudate putamen, cortex, hippocampus, thalamus) and elevated phosphorylated/activated glycogen synthase kinase 3-β (pGSK3β(Tyr216)) in the prefrontal cortex, cerebral cortex, caudate putamen, nucleus accumbens, thalamus, septum, and globus pallidus. In rats administered chronic baclofen (5 mg/kg, t.i.d. for five days), GABAB-stimulated GTPγS binding was significantly diminished in the prefrontal cortex, septum, amygdala, and parabrachial nucleus compared to controls. This effect was specific to GABAB receptors: there was no effect of chronic baclofen treatment on adenosine A1-stimulated GTPγS binding in any region. Chronically-treated rats also exhibited increases in pFAK(Tyr397) and pGSK3β(Tyr216) compared to controls, and displayed wide-spread elevations in phosphorylated dopamine- and cAMP-regulated phosphoprotein-32 (pDARPP-32(Thr34)) compared to acutely-treated or control rats. We postulate that those neuroadaptive effects of GABAB stimulation mediated by G-proteins and their sequelae correlate with tolerance to several of baclofen's effects, whereas sustained signaling via kinase cascades points to cross-talk between GABAB receptors and alternative mechanisms that are resistant to desensitization. Both desensitized and sustained signaling pathways should be considered in the development of pharmacotherapies targeting the GABA

  2. Demonstration of a setup for chronic optogenetic stimulation and recording across cortical areas in non-human primates

    Science.gov (United States)

    Yazdan-Shahmorad, Azadeh; Diaz-Botia, Camilo; Hanson, Tim; Ledochowitsch, Peter; Maharabiz, Michel M.; Sabes, Philip N.

    2015-03-01

    Although several studies have shown the feasibility of using optogenetics in non-human primates (NHP), reliable largescale chronic interfaces have not yet been reported for such studies in NHP. Here we introduce a chronic setup that permits repeated, daily optogenetic stimulation and large-scale recording from the same sites in NHP cortex. The setup combines optogenetics with a transparent artificial dura (AD) and high-density micro-electrocorticography (μECoG). To obtain expression across large areas of cortex, we infused AAV5-CamKIIa-C1V1-EYFP viral vector using an infusion technique based on convection-enhanced delivery (CED) in primary somatosensory (S1) and motor (M1) cortices. By epifluorescent imaging through AD we were able to confirm high levels of expression covering about 110 mm2 of S1 and M1. We then incorporated a 192-channel μECoG array spanning 192 mm2 into the AD for simultaneous electrophysiological recording during optical stimulation. The array consists of patterned Pt-Au-Pt metal traces embedded in ~10 μm Parylene-C insulator. The parylene is sufficiently transparent to allow minimally attenuated optical access for optogenetic stimulation. The array was chronically implanted over the opsin-expressing areas in M1 and S1 for over two weeks. Optical stimulation was delivered via a fiber optic placed on the surface of the AD. With this setup, we recorded reliable evoked activity following light stimulation at several locations. Similar responses were recorded across tens of days, however a decline in the light-evoked signal amplitude was observed during this period due to the growth of dural tissue over the array. These results show the feasibility of a chronic interface for combined largescale optogenetic stimulation and cortical recordings across days.

  3. Chronic immune activation in HIV-1 infection contributes to reduced interferon alpha production via enhanced CD40:CD40 ligand interaction.

    Directory of Open Access Journals (Sweden)

    Norbert Donhauser

    Full Text Available Although a signature of increased interferon (IFN-alpha production is observed in HIV-1 infection, the response of circulating plasmacytoid dendritic cells (PDC to Toll-like receptor ligand stimulation is substantially impaired. This functional PDC deficit, which we specifically observed in HIV-1 infected individuals with less than 500 CD4+ T cells/µl, is not well understood. We provide evidence that the peripheral IFN-alpha production in HIV-1 infection is actively suppressed by the enhanced interaction of CD40 ligand (CD40L, a member of the tumor necrosis factor family, and its receptor CD40, which are both upregulated upon immune activation. Plasma levels of soluble CD40L were significantly higher in untreated HIV-1 infected individuals (n = 52 than in subjects on long-term antiretroviral therapy (n = 62, p<0.03 and in uninfected control donors (n = 16, p<0.001. Concomitantly, cell-associated CD40L and the expression of the receptor CD40 on the PDC were significantly upregulated in HIV-1 infection (p<0.05. Soluble and cell-associated CD40L inhibited the PDC-derived IFN-alpha production by CpG oligodeoxynucleotides dose-dependently. This suppressive effect was observed at much lower, physiological CD40L concentrations in peripheral blood mononuclear cells (PBMC of HIV-1 infected individuals compared to controls (p<0.05. The CpG-induced IFN-alpha production in PBMC of HIV-1 infected donors was directly correlated with PDC and CD4+ T cell counts, and inversely correlated with the viral loads (p<0.001. In HIV-1 infected donors with less than 500 CD4+ T cells/µl, the CpG-induced IFN-alpha production was significantly correlated with the percentage of CD40-expressing PDC and the level of CD40 expression on these cells (p<0.05, whereas CD40L plasma levels played a minor role. In addition, low-dose CD40L contributed to the enhanced production of interleukin 6 and 8 in PBMC of HIV-1 infected donors compared to controls. Our data support

  4. Electrical stimulation therapy to promote healing of chronic wounds: a review of reviews

    Directory of Open Access Journals (Sweden)

    Houghton PE

    2017-01-01

    Full Text Available Pamela E Houghton School of Physical Therapy, Faculty of Health Sciences, Western University, London, ON, Canada Purpose: The overall objective of this study is to identify and appraise all of the existing clinical research literature that has evaluated the effect of electrical stimulation therapy (EST on wound healing outcomes in adults with various types of chronic wounds. Methods: A systematic and comprehensive search of four electronic databases and gray literature was carried out, and references included in related review articles were checked. Prospective and controlled clinical trials, systematic reviews (SRs, and meta-analyses that assessed the effects of EST on wound healing outcomes were described and appraised. A total PRISMA score was assigned for each included SR based on criteria included in the assessment of multiple systematic reviews (AMSTAR measurement tool. The percentage of available research that was identified in the SR was also calculated. Results: Sixty-two clinical research studies involving 2082 patients with pressure ulcers, venous leg ulcers, diabetic foot wounds, and arterial/ischemic wounds, and ulcers of mixed etiology were located. Thirty-three of the studies with 1370 patients compared wound size reduction after EST to a control group. Eighteen reviews that used a systematic approach to identify, select, and evaluate published studies on this topic have yielded conflicting results. Poorer quality SRs with a low total PRISMA score were more likely to yield negative or inconclusive findings. Most of these low-quality SRs had very vague research questions and included less than 50% of the available literature that was known to exist. Results from 22 well-designed randomized clinical trials and 10 high-quality SRs consistently support that EST can stimulate faster wound size reduction and/or produce a greater number of closed wounds compared to a group of similar patients receiving either standard wound care or sham

  5. Granulocyte-Macrophage Colony-Stimulating Factor Production and Tissue Eosinophilia in Chronic Rhinitis

    Directory of Open Access Journals (Sweden)

    Peric, Aleksandar

    2016-02-01

    Full Text Available Introduction Granulocyte-macrophage colony-stimulating factor (GM-CSF is a strong proinflammatory cytokine that takes part in allergic nasal inflammation as an eosinophil colony-stimulating factor. However, the role of GM-CSF in non-allergic rhinitis has not been fully explored. Objectives The aim of this investigation was to assess the concentration of GM-CSF in nasal secretions of patients with non-allergic rhinitis with eosinophilia syndrome (NARES in comparison to patients with perennial allergic rhinitis (PAR and healthy subjects, as well as to assess the relationship with the degree of eosinophilic inflammation and clinical characteristics of the patients. Methods Fourteen patients with diagnosis of NARES, 14 PAR patients, and 14 healthy subjects were included in this cross-sectional study. All patients underwent symptom score assessment, nasal endoscopy, allergy testing, and cytological evaluation. The concentration of GM-CSF in nasal secretions of all participants was measured by enzyme-linked immunosorbent assay (ELISA. Results We found significantly higher levels of GM-CSF in patients with NARES than in the control group (p = 0.035. The percent of eosinophils in nasal mucosa was higher in NARES patients in comparison to patients with PAR (p < 0.001 and control patients (p < 0.0001. We found positive correlations between GM-CSF levels and eosinophil counts only in NARES patients. Conclusion The concentrations of GM-CSF in nasal secretions correlate well with eosinophil counts in the nasal mucosa of NARES patients. These facts indicate a possible role of GM-CSF as a favorable marker for assessment of nasal disease severity and the degree of chronic eosinophilic inflammation in the nasal mucosa.

  6. Effects of restricted environmental stimulation: enhancement of hypnotizability for experimental and chronic pain control.

    Science.gov (United States)

    Barabasz, A F; Barabasz, M

    1989-07-01

    Enhancement of hypnotizability and pain tolerance has been demonstrated using restricted environmental stimulation therapy (REST) with university students as Ss (A. F. Barabasz, 1982). The purpose of the present study was to determine whether or not similar results could be obtained with chronic pain patients. Ss consisted of outpatients in treatment for conditions in which pain is prominent who also demonstrated low hypnotizability after repeated hypnosis plateau sessions. 2 groups of Ss were exposed to REST. Situational demand characteristics (Orne, 1962) favored an increase in hypnotizability for REST Group 1 (high demand). REST Group 2 (low demand) was exposed to situational demand characteristics designed to disguise the experimental hypothesis. 2 groups of control Ss were exposed to the same alternative demand characteristic manipulations as the experimental groups, but environmental stimulation was maintained. The Stanford Hypnotic Susceptibility Scale, Form C (SHSS:C) of Weitzenhoffer and E. R. Hilgard (1962), including a posthypnotic suggestion for an anesthetic reaction, and an ischemic pain test were administered prior to treatment and again immediately following treatment. After 6 hours of REST, significant increases in SHSS:C scores were found for high-demand and low-demand experimental Ss, as well as for high-demand control Ss. No such increase was found for low-demand controls. Significant decreases in pain scores were found for both high- and low-demand experimental groups. No significant pain score decreases were found for either control group, suggesting a relatively weak effect of demand characteristics. An independent postexperimental inquiry suggested all Ss believed they received active treatments. The inquiry, conducted 10-15 days after the experiment, also revealed a majority of experimental Ss were using hypnosis on a daily basis to reduce pain with a substantial decrease in pain medication. Only 2 control Ss (highest in hypnotizability

  7. NMDA receptor mediates chronic visceral pain induced by neonatal noxious somatic stimulation.

    Science.gov (United States)

    Miranda, Adrian; Mickle, Aaron; Bruckert, Mitchell; Kannampalli, Pradeep; Banerjee, Banani; Sengupta, Jyoti N

    2014-12-05

    NMDA receptors (NMDAR) are important in the development and maintenance of central sensitization. Our objective was to investigate the role of spinal neurons and NMDAR in the maintenance of chronic visceral pain. Neonatal rats were injected with acidic saline adjusted to pH 4.0 in the gastrocnemius muscle every other day for 12 days. In adult rats, NR1 and NR2B subunits were examined in the lumbo-sacral (LS) spinal cord. A baseline, visceromotor response (VMR) to graded colorectal distension (CRD) was recorded before and after administration of the NMDA antagonist, CGS-19755. Extracellular recordings were performed from CRD-sensitive LS spinal neurons and pelvic nerve afferents (PNA) before and after CGS-19755. Rats that received pH 4.0 saline injections demonstrated a significant increase in the expression NR2B subunits and VMR response to CRD>20 mmHg. CGS-19755 (i.v. or i.t.) had no effect in naïve rats, but significantly decreased the response to CRD in pH 4.0 saline injected rats. CGS-19755 had no effect on the spontaneous firing of SL-A, but decreased that of SL-S. Similarly, CGS-19755 attenuates the responses of SL-S neurons to CRD, but had no effect on SL-A neurons or on the response characteristics of PNA fibers. Neonatal noxious somatic stimulation results in chronic visceral hyperalgesia and sensitizes a specific subpopulation of CRD-sensitive spinal neurons. The sensitization of these SL-S spinal neurons is attenuated by the NMDAR antagonist. The results of this study suggest that spinal NMDARs play an important role in the development of hyperalgesia early in life.

  8. Motor cortex neurostimulation technologies for chronic post-stroke pain: implications of tissue damage on stimulation currents

    Directory of Open Access Journals (Sweden)

    Anthony Terrence O´Brien

    2016-11-01

    Full Text Available Background: Central post stroke pain (CPSP is a highly refractory syndrome that can occur after stroke. Primary motor cortex (M1 brain stimulation using epidural brain stimulation (EBS, transcranial magnetic stimulation (TMS, and transcranial direct current stimulation (tDCS have been explored as potential therapies for CPSP. These techniques have demonstrated variable clinical efficacy. It is hypothesized that changes in the stimulating currents that are caused by stroke-induced changes in brain tissue conductivity limit the efficacy of these techniques. Methods: We generated MRI-guided finite element models of the current density distributions in the human head and brain with and without chronic focal cortical infarctions during EBS, TMS, and tDCS. We studied the change in the stimulating current density distributions’ magnitude, orientation, and maxima locations between the different models. Results: Changes in electrical properties at stroke boundaries altered the distribution of stimulation currents in magnitude, location, and orientation. Current density magnitude alterations were larger for the non-invasive techniques (i.e., tDCS and TMS than for EBS. Nonetheless, the lesion also altered currents during EBS. The spatial shift of peak current density, relative to the size of the stimulation source, was largest for EBS.Conclusions: In order to maximize therapeutic efficiency, neurostimulation trials need to account for the impact of anatomically disrupted neural tissues on the location, orientation, and magnitude of exogenously applied currents. The relative current-neuronal structure should be considered when planning stimulation treatment, especially across techniques (e.g., using TMS to predict EBS response. We postulate that the effects of altered tissue properties in stroke regions may impact stimulation induced analgesic effects and/or lead to highly variable outcomes during brain stimulation treatments in CPSP.

  9. Neuromuscular electrical stimulation improves exercise tolerance in chronic obstructive pulmonary disease patients with better preserved fat-free mass

    Directory of Open Access Journals (Sweden)

    Lara Maris Nápolis

    2011-01-01

    Full Text Available BACKGROUND: High-frequency neuromuscular electrical stimulation increases exercise tolerance in patients with advanced chronic obstructive pulmonary disease (COPD patients. However, it is conceivable that its benefits are more prominent in patients with better-preserved peripheral muscle function and structure. OBJECTIVE: To investigate the effects of high-frequency neuromuscular electrical stimulation in COPD patients with better-preserved peripheral muscle function. Design: Prospective and cross-over study. METHODS: Thirty COPD patients were randomly assigned to either home-based, high-frequency neuromuscular electrical stimulation or sham stimulation for six weeks. The training intensity was adjusted according to each subject's tolerance. Fat-free mass, isometric strength, six-minute walking distance and time to exercise intolerance (Tlim were assessed. RESULTS: Thirteen (46.4% patients responded to high-frequency neuromuscular electrical stimulation; that is, they had a post/pre Δ Tlim >10% after stimulation (unimproved after sham stimulation. Responders had a higher baseline fat-free mass and six-minute walking distance than their seventeen (53.6% non-responding counterparts. Responders trained at higher stimulation intensities; their mean amplitude of stimulation during training was significantly related to their fat-free mass (r = 0.65; p<0.01. Logistic regression revealed that fat-free mass was the single independent predictor of Tlim improvement (odds ratio [95% CI] = 1.15 [1.04-1.26]; p<0.05. CONCLUSIONS: We conclude that high-frequency neuromuscular electrical stimulation improved the exercise capacity of COPD patients with better-preserved fat-free mass because they tolerated higher training stimulus levels. These data suggest that early training with high-frequency neuromuscular electrical stimulation before tissue wasting begins might enhance exercise tolerance in patients with less advanced COPD.

  10. Motor Cortex Neurostimulation Technologies for Chronic Post-stroke Pain: Implications of Tissue Damage on Stimulation Currents.

    Science.gov (United States)

    O'Brien, Anthony T; Amorim, Rivadavio; Rushmore, R Jarrett; Eden, Uri; Afifi, Linda; Dipietro, Laura; Wagner, Timothy; Valero-Cabré, Antoni

    2016-01-01

    Background: Central post stroke pain (CPSP) is a highly refractory syndrome that can occur after stroke. Primary motor cortex (M1) brain stimulation using epidural brain stimulation (EBS), transcranial magnetic stimulation (TMS), and transcranial direct current stimulation (tDCS) have been explored as potential therapies for CPSP. These techniques have demonstrated variable clinical efficacy. It is hypothesized that changes in the stimulating currents that are caused by stroke-induced changes in brain tissue conductivity limit the efficacy of these techniques. Methods: We generated MRI-guided finite element models of the current density distributions in the human head and brain with and without chronic focal cortical infarctions during EBS, TMS, and tDCS. We studied the change in the stimulating current density distributions' magnitude, orientation, and maxima locations between the different models. Results: Changes in electrical properties at stroke boundaries altered the distribution of stimulation currents in magnitude, location, and orientation. Current density magnitude alterations were larger for the non-invasive techniques (i.e., tDCS and TMS) than for EBS. Nonetheless, the lesion also altered currents during EBS. The spatial shift of peak current density, relative to the size of the stimulation source, was largest for EBS. Conclusion: In order to maximize therapeutic efficiency, neurostimulation trials need to account for the impact of anatomically disrupted neural tissues on the location, orientation, and magnitude of exogenously applied currents. The relative current-neuronal structure should be considered when planning stimulation treatment, especially across techniques (e.g., using TMS to predict EBS response). We postulate that the effects of altered tissue properties in stroke regions may impact stimulation induced analgesic effects and/or lead to highly variable outcomes during brain stimulation treatments in CPSP.

  11. Motor Cortex Neurostimulation Technologies for Chronic Post-stroke Pain: Implications of Tissue Damage on Stimulation Currents

    Science.gov (United States)

    O’Brien, Anthony T.; Amorim, Rivadavio; Rushmore, R. Jarrett; Eden, Uri; Afifi, Linda; Dipietro, Laura; Wagner, Timothy; Valero-Cabré, Antoni

    2016-01-01

    Background: Central post stroke pain (CPSP) is a highly refractory syndrome that can occur after stroke. Primary motor cortex (M1) brain stimulation using epidural brain stimulation (EBS), transcranial magnetic stimulation (TMS), and transcranial direct current stimulation (tDCS) have been explored as potential therapies for CPSP. These techniques have demonstrated variable clinical efficacy. It is hypothesized that changes in the stimulating currents that are caused by stroke-induced changes in brain tissue conductivity limit the efficacy of these techniques. Methods: We generated MRI-guided finite element models of the current density distributions in the human head and brain with and without chronic focal cortical infarctions during EBS, TMS, and tDCS. We studied the change in the stimulating current density distributions’ magnitude, orientation, and maxima locations between the different models. Results: Changes in electrical properties at stroke boundaries altered the distribution of stimulation currents in magnitude, location, and orientation. Current density magnitude alterations were larger for the non-invasive techniques (i.e., tDCS and TMS) than for EBS. Nonetheless, the lesion also altered currents during EBS. The spatial shift of peak current density, relative to the size of the stimulation source, was largest for EBS. Conclusion: In order to maximize therapeutic efficiency, neurostimulation trials need to account for the impact of anatomically disrupted neural tissues on the location, orientation, and magnitude of exogenously applied currents. The relative current-neuronal structure should be considered when planning stimulation treatment, especially across techniques (e.g., using TMS to predict EBS response). We postulate that the effects of altered tissue properties in stroke regions may impact stimulation induced analgesic effects and/or lead to highly variable outcomes during brain stimulation treatments in CPSP. PMID:27881958

  12. Transcranial Direct Current Stimulation Potentiates Improvements in Functional Ability in Patients With Chronic Stroke Receiving Constraint-Induced Movement Therapy

    DEFF Research Database (Denmark)

    Figlewski, Krystian; Blicher, Jakob Udby; Mortensen, Jesper;

    2017-01-01

    BACKGROUND AND PURPOSE: Transcranial direct current stimulation may enhance effect of rehabilitation in patients with chronic stroke. The objective was to evaluate the efficacy of anodal transcranial direct current stimulation combined with constraint-induced movement therapy of the paretic upper...... limb. METHODS: A total of 44 patients with stroke were randomly allocated to receive 2 weeks of constraint-induced movement therapy with either anodal or sham transcranial direct current stimulation. The primary outcome measure, Wolf Motor Function Test, was assessed at baseline and after...... the intervention by blinded investigators. RESULTS: Both groups improved significantly on all Wolf Motor Function Test scores. Group comparison showed improvement on Wolf Motor Function Test in the anodal group compared with the sham group. CONCLUSIONS: Anodal transcranial direct current stimulation combined...

  13. Combination of Transcranial Direct Current Stimulation and Neuromuscular Electrical Stimulation Improves Gait Ability in a Patient in Chronic Stage of Stroke

    Directory of Open Access Journals (Sweden)

    Takeshi Satow

    2016-02-01

    Full Text Available Background: Walking ability is important in stroke patients to maintain daily life. Nevertheless, its improvement is limited with conventional physical therapy in chronic stage. We report the case of a chronic stroke patient showing a remarkable improvement in gait function after a new neurorehabilitation protocol using transcranial direct current stimulation (tDCS and neuromuscular electrical stimulation (NMES. Case Presentation: A 62-year-old male with left putaminal hemorrhage suffered from severe right hemiparesis. He could move by himself with a wheelchair 1 year after the ictus. Anodal tDCS at the vertex (2 mA, 20 min with NMES at the anterior tibialis muscle had been applied for 3 weeks. The Timed Up and Go test and 10-meter walk test improved after the intervention, which had been maintained for at least 1 month. Conclusion: This single case suggests the possibility that tDCS with NMES could be a new rehabilitation approach to improve the gait ability in chronic stroke patients.

  14. A single trial of transcutaneous electrical nerve stimulation (TENS) improves spasticity and balance in patients with chronic stroke.

    Science.gov (United States)

    Cho, Hwi-young; In, Tae Sung; Cho, Ki Hun; Song, Chang Ho

    2013-01-01

    Spasticity management is pivotal for achieving functional recovery of stroke patients. The purpose of this study was to investigate the effects of a single trial of transcutaneous electrical nerve stimulation (TENS) on spasticity and balance in chronic stroke patients. Forty-two chronic stroke patients were randomly allocated into the TENS (n = 22) or the placebo-TENS (n = 20) group. TENS stimulation was applied to the gastrocnemius for 60 min at 100 Hz, 200 µs with 2 to 3 times the sensory threshold (the minimal threshold in detecting electrical stimulation for subjects) after received physical therapy for 30 min. In the placebo-TENS group, electrodes were placed but no electrical stimulation was administered. For measuring spasticity, the resistance encountered during passive muscle stretching of ankle joint was assessed using the Modified Ashworth Scale, and the Hand held dynamometer was used to assess the resistive force caused by spasticity. Balance ability was measured using a force platform that measures postural sway generated by postural imbalance. The TENS group showed a significantly greater reduction in spasticity of the gastrocnemius, compared to the placebo-TENS group (p TENS resulted in greater balance ability improvements, especially during the eyes closed condition (p TENS provides an immediately effective means of reducing spasticity and of improving balance in chronic stroke patients. The present data may be useful to establish the standard parameters for TENS application in the clinical setting of stroke.

  15. Responsiveness to erythropoiesis-stimulating agents in chronic kidney disease: does geography matter?

    Science.gov (United States)

    De Nicola, Luca; Locatelli, Francesco; Conte, Giuseppe; Minutolo, Roberto

    2014-02-01

    Management of renal anemia in the large and at-risk population of non-dialysis chronic kidney disease (CKD) patients is a critical issue. In particular, definition of the optimal hemoglobin (Hb) target for therapy is controversial but highly warranted by physicians and patients worldwide. Recently, international clinical practice guidelines have recommended delayed initiation of erythropoiesis-stimulating agents (ESA) and lower Hb target levels during maintenance therapy. However, geographical differences in terms of ESA dose needed to achieve a given Hb value can be evidenced, with US patients showing higher prevalence of ESA resistance. On the other hand, non-US patients are often maintained in a higher Hb range by means of low ESA doses. This critical point has never been addressed. Nevertheless, outside of the US, translating the restrictive recommendations of new guidelines, which are essentially based on trials in US patients, can lead to negative effects, such as an increased need for a blood transfusion, and worsening of quality of life. In this article we provide a reappraisal of current recommendations on anemia management in non-dialysis CKD in light of the geographical differences in individual responsiveness to ESA.

  16. Transcutaneous electrical nerve stimulation (TENS in the symptomatic management of chronic prostatitis/chronic pelvic pain syndrome: a placebo-control randomized trial

    Directory of Open Access Journals (Sweden)

    Sikiru Lamina

    2008-12-01

    Full Text Available OBJECTIVE: The aim of the study was to investigate the therapeutic efficacy of transcutaneous electrical nerve stimulation (TENS in the symptomatic management of chronic prostatitis pain/chronic pelvic pain syndrome. DESIGN: A pretest, posttest randomized double blind design was used in data collection. PARTICIPANT: Twenty-four patients diagnosed with chronic prostatitis- category IIIA and IIIB of the National Institute of Health Chronic Pain (NIH-CP were referred for physiotherapy from the Urology department. Intervention: Pre treatment pain level was assessed using the NIH-CP (pain domain index. The TENS group received TENS treatment, 5 times per week for a period of 4 weeks (mean treatment frequency, intensity, pulse width and duration of 60Hz, 100µS, 25mA and 20 minutes respectively. The Analgesic group received no TENS treatment but continued analgesics; the Control group received no TENS and Analgesic but placebo. All subjects were placed on antibiotics throughout the treatment period. Outcome measures: Post-treatment pain level was also assessed using NIH-CP pain index. RESULT: Findings of the study revealed significant effect of TENS on chronic prostatitis pain at p < 0.05. CONCLUSION: TENS is an effective means of non-invasive symptomatic management of chronic prostatitis pain.

  17. Low-frequency electrical stimulation induces long-term depression in patients with chronic tension-type headache

    DEFF Research Database (Denmark)

    Lindelof, Kim; Jung, Kerstin; Ellrich, Jens;

    2010-01-01

    Repetitive low-frequency electrical stimulation (LFS) induces pain inhibition in healthy volunteers and in animals, but it is unknown whether it has an analgesic effect in patients with headache. The aim of this study was to investigate if LFS could induce prolonged pain inhibition, called long......-term depression (LTD), in patients with chronic tension-type headache (CTTH). Twenty CTTH patients and 20 healthy volunteers were exposed to 20 min LFS (1 Hz) to the forehead. LTD was measured as a decrease in pain response to electrical stimulation in a 1-h post-LFS period following LFS. The LFS induced...

  18. Cortical activation changes underlying stimulation-induced behavioural gains in chronic stroke

    OpenAIRE

    Stagg, Charlotte Jane; Bachtiar, Velicia; O'Shea, Jacinta; Allman, Claire; Bosnell, Rosemary Ann; Kischka, Udo; Matthews, Paul McMahan; Johansen-Berg, Heidi

    2011-01-01

    Transcranial direct current stimulation, a form of non-invasive brain stimulation, is showing increasing promise as an adjunct therapy in rehabilitation following stroke. However, although significant behavioural improvements have been reported in proof-of-principle studies, the underlying mechanisms are poorly understood. The rationale for transcranial direct current stimulation as therapy for stroke is that therapeutic stimulation paradigms increase activity in ipsilesional motor cortical a...

  19. Erythropoiesis-stimulating agents increase the risk of acute stroke in patients with chronic kidney disease

    Science.gov (United States)

    Seliger, Stephen L.; Zhang, Amy D.; Weir, Matthew R.; Walker, Loreen; Hsu, Van Doren; Parsa, Afshin; Diamantidis, Clarissa; Fink, Jeffrey C.

    2013-01-01

    Erythropoiesis-stimulating agents (ESAs) are effective in ameliorating anemia in chronic kidney disease (CKD). However, a recent trial in diabetic CKD patients suggested a greater stroke risk associated with full correction of anemia using ESAs. We performed a case-control study examining the association of incident ESA use with acute stroke in CKD patients, using national Veterans Affairs data. Patients with eGFR<60 cc/min/1.73m2 and outpatient hemoglobin (Hb)<12g/dL were included. Acute hospitalized stroke cases (N=2071) were identified using diagnosis codes and matched 1:5 to controls without stroke. Conditional logistic regression was used to estimate the association of ESA use with stroke, adjusting for potential confounders. After multivariate adjustment, ESA use (N=1026, 8.3%) was associated with 30% greater odds of stroke (odds ratio[OR]=1.30, 95% confidence interval[CI]: 1.06, 1.58). There was significant interaction (p=.015) between ESA use and cancer; ESA use was associated with 85% greater odds of stroke in cancer patients (95% CI: 1.26, 2.65), but not associated with stroke in patients without cancer (OR=1.07, 95% CI: 0.85, 1.35). ESA-treated patients with cancer received a median initial dose 2.5 to 4 times greater than ESA patients without cancer, but pre-ESA Hb and rate of Hb change did not differ between groups. Among a large national sample of anemic CKD patients, ESA treatment is associated with an increased risk of acute stroke, with the greatest effect among patients with cancer. PMID:21389972

  20. Erythropoiesis-stimulating Agents and Anemia in Patients with Non-dialytic Chronic Kidney Disease.

    Science.gov (United States)

    Kim, Sun Moon; Kim, Kyeong Min; Kwon, Soon Kil; Kim, Hye-Young

    2016-01-01

    Anemia is common in patients with advanced chronic kidney disease (CKD). Though erythropoiesis-stimulating agents (ESAs) have been strongly endorsed in guidelines, it is of particular financial interest. Recently, the reimbursement of ESAs in non-dialytic patients was started by the Korean National Health Insurance System. Thus, we investigated the impact of the reimbursement of ESAs on the anemia care in non-dialytic CKD patients. Medical records of patients with advanced CKD (estimated GFR <30 mL/min/1.73 m(2)) were reviewed. Use of ESAs, blood transfusion, and hemoglobin concentrations were analyzed from one year prior to reimbursement to three years following. We used multivariable modified Poisson regression to estimate the utilization prevalence ratio (PRs). A total of 1,791 medical records were analyzed. The proportion of patients receiving ESAs increased from 14.8% before reimbursement to a peak 33.6% in 1 yr after reimbursement; thereafter, ESA use decreased to 22.4% in 3 yr after reimbursement (compared with baseline; PR, 2.19 [95% CI, 1.40-3.42]). In patients with Hb <10 g/dL, the proportion of receiving ESAs increased from 32.1% before reimbursement to 66.7% in 3 yr after reimbursement (compared with baseline; PR, 2.04 [95% CI, 1.25-3.32]). Mean hemoglobin concentrations were 10.06±1.54 g/dL before reimbursement and increased to 10.78±1.51 g/dL in 3 yr after the reimbursement change (P=0.001). However, the requirement of blood transfusion was not changed over time. With the reimbursement of ESAs, the advanced CKD patients were more likely to be treated with ESAs, and the hemoglobin concentrations increased.

  1. Aggressive cutaneous vasculitis in a patient with chronic lymphatic leukemia following granulocyte colony stimulating factor injection: a case report

    Directory of Open Access Journals (Sweden)

    El Husseiny Noha M

    2011-03-01

    Full Text Available Abstract Introduction Vasculitis has been reported in a few cases of chronic lymphatic leukemia and with granulocytic colony-stimulating factor therapy. Those with granulocytic colony-stimulating factor occurred after prolonged therapy and there was a rise in total leukocyte count unlike that in our patient who received just a single injection for the first time. Case presentation We report the case of a 64-year-old Egyptian man with chronic lymphatic leukemia who developed progressive cutaneous vasculitic lesions following injection of a single dose of a granulocytic colony stimulating factor before a third cycle of chemotherapy to improve neutropenia. This is an unusual case and the pathogenesis is not fully understood. Our patient was not on any medical treatment except for bisoprolol for ischemic heart disease. Although aggressive management with steroids, anticoagulation and plasmapheresis had been carried out, the condition was aggressive and the patient's consciousness deteriorated. A magnetic resonance imaging scan of his brain revealed multiple ischemic foci that could be attributed to vasculitis of the brain. Conclusion The aim of this case report is to highlight the importance of monitoring patients on granulocytic colony-stimulating factor therapy, especially in the context of other conditions (such as a hematological malignancy that may lead to an adverse outcome.

  2. The Serum Levels of Soluble Fas Ligand and Soluble Fas Receptor in Patients with chronic congestive heart failure

    Institute of Scientific and Technical Information of China (English)

    李刚; 令狐华; 魏良明; 陈运贞

    2002-01-01

    Objectives To investigate the association of soluble Fas ligand(sFasL) andsoluble Fas receptor(sFas)with human chronic congestive heart failure(CHF). Methods The serumlevel of sFasL and sFas in 33 patients with CHF (13in cardiac function class Ⅱ, 17 in class Ⅲ, 3 inclass IV, NYHA) was assessed with enzyme- linkedimmunosorbent assay, and was compared with that of18 age-, blood pressure- matched patients with cardiac function class I (NYHA). Results There wasno difference in the level of sFasL between the twogroups [CHF group: 231.50 + / - 84.50 (cardiacfunction class Ⅱ 216.50+/-96.00 , class Ⅲ226.80 + / - 85.70, class IV 244. 00 + / - 73.00 )vs. cardiac function class I group: 217.50+ /-89. 00 pg/mL, P>0. 05 ]. However, the level of sFaswas significantly higher in the patients with CHF thanthose of cardiac function class I group [CHF group:1353.30+/-507.71 (cardiac function class Ⅱ1154.85+/-371.20 , class Ⅲ 1412.88+/-493.62, class IV1875.67 + / - 806. 10) vs, cardiacfunction class I group: 983.11 + / -461.26 pg/mL,P<0. 05 ]. Conclusions sFasL was not associatedwith human CHF. However, the elevation of serumlevel of sFas was proportion to the severity of humanCHF. sFas may play an important role in the patho-genesis of human CHF.

  3. Characterization of postsynaptic potentials evoked by sural nerve stimulation in hindlimb motoneurons from acute and chronic spinal cats.

    Science.gov (United States)

    Baker, L L; Chandler, S H

    1987-09-15

    The purpose of this study was to characterize the changes in postsynaptic potentials recorded in ankle extensor motoneurons resulting from activation of the sural nerve after spinal cord transection in the adult cat. Eight acute and nine chronic animals were spinalized at T12. Intracellular recordings from motoneurons innervating the triceps surae were performed. Sural nerve stimulation evoked complex synaptic potentials consisting of early and late components in all motoneurons. Early excitatory and inhibitory postsynaptic potentials (PSPs), as well as long latency excitatory postsynaptic potentials were recorded and averaged for assessment of PSP amplitude and duration. Early PSPs, both excitatory and inhibitory, were significantly larger in the motoneurons of cats spinalized 4-6 months earlier. Central latency of excitatory potentials were similar in the two samples of motoneurons, but the central latency associated with the initial inhibitory PSP was significantly shorter in the recordings from motoneurons of chronic spinal cats. In most recordings, an additional inhibitory PSP followed the initial excitatory PSP in motoneurons, and this secondary inhibitory PSP was similar in peak amplitude and duration in both samples of motoneurons. Also, a long latency excitatory PSP was recorded in a large percentage of motoneurons from both samples. This potential was typically of greater amplitude and longer duration in the motoneurons from chronic animals, when compared to recordings from acute animals. Although changes in amplitude and duration of PSP activity could be documented, there was no marked alteration in the frequency of occurrence of each PSP pattern recorded from the two preparations. This suggests that the synaptic pathways mediating the sural nerve reflexes have not qualitatively changed in the chronic spinal animal. The changes in amplitudes and durations of the PSPs in the chronic spinal cat indicate, however, that quantitative changes have occurred

  4. Chronic inflammatory diseases are stimulated by current lifestyle: how diet, stress levels and medication prevent our body from recovering

    Directory of Open Access Journals (Sweden)

    Bosma-den Boer Margarethe M

    2012-04-01

    Full Text Available Abstract Serhan and colleagues introduced the term "Resoleomics" in 1996 as the process of inflammation resolution. The major discovery of Serhan's work is that onset to conclusion of an inflammation is a controlled process of the immune system (IS and not simply the consequence of an extinguished or "exhausted" immune reaction. Resoleomics can be considered as the evolutionary mechanism of restoring homeostatic balances after injury, inflammation and infection. Under normal circumstances, Resoleomics should be able to conclude inflammatory responses. Considering the modern pandemic increase of chronic medical and psychiatric illnesses involving chronic inflammation, it has become apparent that Resoleomics is not fulfilling its potential resolving capacity. We suggest that recent drastic changes in lifestyle, including diet and psycho-emotional stress, are responsible for inflammation and for disturbances in Resoleomics. In addition, current interventions, like chronic use of anti-inflammatory medication, suppress Resoleomics. These new lifestyle factors, including the use of medication, should be considered health hazards, as they are capable of long-term or chronic activation of the central stress axes. The IS is designed to produce solutions for fast, intensive hazards, not to cope with long-term, chronic stimulation. The never-ending stress factors of recent lifestyle changes have pushed the IS and the central stress system into a constant state of activity, leading to chronically unresolved inflammation and increased vulnerability for chronic disease. Our hypothesis is that modern diet, increased psycho-emotional stress and chronic use of anti-inflammatory medication disrupt the natural process of inflammation resolution ie Resoleomics.

  5. Using the new board game SeCZ TaLK to stimulate the communication on sexual health for adolescents with chronic conditions

    NARCIS (Netherlands)

    Stege, H.A. van der; Staa, A.L. van; Hilberink, S.R.; Visser, A.

    2010-01-01

    This study evaluated the feasibility and appreciation of a new educational board game (SeCZ TaLK) that stimulates communication on sexuality and intimate relationships in youth with chronic conditions.

  6. Chronic endocannabinoid system stimulation induces muscle macrophage and lipid accumulation in type 2 diabetic mice independently of metabolic endotoxaemia.

    Directory of Open Access Journals (Sweden)

    Lucie Geurts

    Full Text Available AIMS: Obesity and type 2 diabetes are characterised by low-grade inflammation, metabolic endotoxaemia (i.e., increased plasma lipopolysaccharides [LPS] levels and altered endocannabinoid (eCB-system tone. The aim of this study was to decipher the specific role of eCB-system stimulation or metabolic endotoxaemia in the onset of glucose intolerance, metabolic inflammation and altered lipid metabolism. METHODS: Mice were treated with either a cannabinoid (CB receptor agonist (HU210 or low-dose LPS using subcutaneous mini-pumps for 6 weeks. After 3 weeks of the treatment under control (CT diet, one-half of each group of mice were challenged with a high fat (HF diet for the following 3-week period. RESULTS: Under basal conditions (control diet, chronic CB receptor agonist treatment (i.e., 6 weeks induced glucose intolerance, stimulated metabolic endotoxaemia, and increased macrophage infiltration (CD11c and F4/80 expression in the muscles; this phenomenon was associated with an altered lipid metabolism (increased PGC-1α expression and decreased CPT-1b expression in this tissue. Chronic LPS treatment tended to increase the body weight and fat mass, with minor effects on the other metabolic parameters. Challenging mice with an HF diet following pre-treatment with the CB agonist exacerbated the HF diet-induced glucose intolerance, the muscle macrophage infiltration and the muscle's lipid content without affecting the body weight or the fat mass. CONCLUSION: Chronic CB receptor stimulation under basal conditions induces glucose intolerance, stimulates metabolic inflammation and alters lipid metabolism in the muscles. These effects worsen following the concomitant ingestion of an HF diet. Here, we highlight the central roles played by the eCB system and LPS in the pathophysiology of several hallmarks of obesity and type 2 diabetes.

  7. Utilizing repetitive transcranial magnetic stimulation to improve language function in stroke patients with chronic non-fluent aphasia.

    Science.gov (United States)

    Garcia, Gabriella; Norise, Catherine; Faseyitan, Olufunsho; Naeser, Margaret A; Hamilton, Roy H

    2013-07-02

    Transcranial magnetic stimulation (TMS) has been shown to significantly improve language function in patients with non-fluent aphasia(1). In this experiment, we demonstrate the administration of low-frequency repetitive TMS (rTMS) to an optimal stimulation site in the right hemisphere in patients with chronic non-fluent aphasia. A battery of standardized language measures is administered in order to assess baseline performance. Patients are subsequently randomized to either receive real rTMS or initial sham stimulation. Patients in the real stimulation undergo a site-finding phase, comprised of a series of six rTMS sessions administered over five days; stimulation is delivered to a different site in the right frontal lobe during each of these sessions. Each site-finding session consists of 600 pulses of 1 Hz rTMS, preceded and followed by a picture-naming task. By comparing the degree of transient change in naming ability elicited by stimulation of candidate sites, we are able to locate the area of optimal response for each individual patient. We then administer rTMS to this site during the treatment phase. During treatment, patients undergo a total of ten days of stimulation over the span of two weeks; each session is comprised of 20 min of 1 Hz rTMS delivered at 90% resting motor threshold. Stimulation is paired with an fMRI-naming task on the first and last days of treatment. After the treatment phase is complete, the language battery obtained at baseline is repeated two and six months following stimulation in order to identify rTMS-induced changes in performance. The fMRI-naming task is also repeated two and six months following treatment. Patients who are randomized to the sham arm of the study undergo sham site-finding, sham treatment, fMRI-naming studies, and repeat language testing two months after completing sham treatment. Sham patients then cross over into the real stimulation arm, completing real site-finding, real treatment, fMRI, and two- and six

  8. Stimulation of the B-cell receptor activates the JAK2/STAT3 signaling pathway in chronic lymphocytic leukemia cells.

    Science.gov (United States)

    Rozovski, Uri; Wu, Ji Yuan; Harris, David M; Liu, Zhiming; Li, Ping; Hazan-Halevy, Inbal; Ferrajoli, Alessandra; Burger, Jan A; O'Brien, Susan; Jain, Nitin; Verstovsek, Srdan; Wierda, William G; Keating, Michael J; Estrov, Zeev

    2014-06-12

    In chronic lymphocytic leukemia (CLL), stimulation of the B-cell receptor (BCR) triggers survival signals. Because in various cells activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway provides cells with survival advantage, we wondered whether BCR stimulation activates the JAK/STAT pathway in CLL cells. To stimulate the BCR we incubated CLL cells with anti-IgM antibodies. Anti-IgM antibodies induced transient tyrosine phosphorylation and nuclear localization of phosphorylated (p) STAT3. Immunoprecipitation studies revealed that anti-JAK2 antibodies coimmunoprecipitated pSTAT3 and pJAK2 in IgM-stimulated but not unstimulated CLL cells, suggesting that activation of the BCR induces activation of JAK2, which phosphorylates STAT3. Incubation of CLL cells with the JAK1/2 inhibitor ruxolitinib inhibited IgM-induced STAT3 phosphorylation and induced apoptosis of IgM-stimulated but not unstimulated CLL cells in a dose- and time-dependent manner. Whether ruxolitinib treatment would benefit patients with CLL remains to be determined.

  9. Exocrine and endocrine functional reserve in the course of chronic pancreatitis as studied by maximal stimulation tests.

    Science.gov (United States)

    Cavallini, G; Bovo, P; Zamboni, M; Bosello, O; Filippini, M; Riela, A; Brocco, G; Rossi, L; Pelle, C; Chiavenato, A

    1992-01-01

    Thirty patients suffering from chronic alcoholic pancreatitis (18 calcified) were entered into a study of exocrine and endocrine pancreatic function based on two maximal stimulation tests, namely the secretin-cerulein test and the glucagon test with serum assays of C peptide. The glucagon test was also performed in 19 control subjects. In addition, 10 chronic pancreatitis patients and nine controls were subjected to an oral glucose tolerance test (OGTT) with serum insulin determinations. C peptide basal values were decreased only in patients with severe pancreatic exocrine insufficiency (P less than 0.001), while delta C peptide values were also reduced in patients with moderate exocrine insufficiency (P less than 0.001). Lipase output correlated very well with delta C peptide values (P less than 0.001). While serum insulin levels during OGTT and C peptide basal values showed no significant differences between the chronic pancreatitis and control groups, delta C peptide values were significantly reduced in chronic pancreatitis patients (P less than 0.02). Both endocrine and exocrine function are impaired in chronic pancreatitis, as demonstrated by maximal tests, even in early stages of the disease.

  10. Hepcidin as a predictive factor and therapeutic target in erythropoiesis-stimulating agent treatment for anemia of chronic disease in rats.

    Science.gov (United States)

    Theurl, Milan; Nairz, Manfred; Schroll, Andrea; Sonnweber, Thomas; Asshoff, Malte; Haschka, David; Seifert, Markus; Willenbacher, Wolfgang; Wilflingseder, Doris; Posch, Wilfried; Murphy, Anthony T; Witcher, Derrick R; Theurl, Igor; Weiss, Günter

    2014-09-01

    Anemia of chronic disease is a multifactorial disorder, resulting mainly from inflammation-driven reticuloendothelial iron retention, impaired erythropoiesis, and reduced biological activity of erythropoietin. Erythropoiesis-stimulating agents have been used for the treatment of anemia of chronic disease, although with varying response rates and potential adverse effects. Serum concentrations of hepcidin, a key regulator of iron homeostasis, are increased in patients with anemia of chronic disease and linked to the pathogenesis of this disease, because hepcidin blocks cellular iron egress, thus limiting availability of iron for erythropoiesis. We tested whether serum hepcidin levels can predict and affect the therapeutic efficacy of erythropoiesis-stimulating agent treatment using a well-established rat model of anemia of chronic disease. We found that high pre-treatment hepcidin levels correlated with an impaired hematologic response to an erythropoiesis-stimulating agent in rats with anemia of chronic disease. Combined treatment with an erythropoiesis-stimulating agent and an inhibitor of hepcidin expression, LDN-193189, significantly reduced serum hepcidin levels, mobilized iron from tissue stores, increased serum iron levels and improved hemoglobin levels more effectively than did the erythropoiesis-stimulating agent or LDN-193189 monotherapy. In parallel, both the erythropoiesis-stimulating agent and erythropoiesis-stimulating agent/LDN-193189 combined reduced the expression of cytokines known to inhibit erythropoiesis. We conclude that serum hepcidin levels can predict the hematologic responsiveness to erythropoiesis-stimulating agent therapy in anemia of chronic disease. Pharmacological inhibition of hepcidin formation improves the erythropoiesis-stimulating agent's therapeutic efficacy, which may favor a reduction of erythropoiesis-stimulating agent dosages, costs and side effects.

  11. Fixed-site high-frequency transcutaneous electrical nerve stimulation for treatment of chronic low back and lower extremity pain

    Science.gov (United States)

    Gozani, Shai N

    2016-01-01

    Objective The objective of this study was to determine if fixed-site high-frequency transcutaneous electrical nerve stimulation (FS-TENS) is effective in treating chronic low back and lower extremity pain. Background Transcutaneous electrical nerve stimulation is widely used for treatment of chronic pain. General-purpose transcutaneous electrical nerve stimulation devices are designed for stimulation anywhere on the body and often cannot be used while the user is active or sleeping. FS-TENS devices are designed for placement at a pre-determined location, which enables development of a wearable device for use over extended time periods. Methods Study participants with chronic low back and/or lower extremity pain self-administered an FS-TENS device for 60 days. Baseline, 30-, and 60-day follow-up data were obtained through an online questionnaire. The primary outcome measure was the patient global impression of change. Pain intensity and interference were assessed using the Brief Pain Inventory. Changes in use of concomitant pain medications were evaluated with a single-item global self-rating. Results One hundred and thirty participants were enrolled, with 88 completing the 60-day follow-up questionnaire. Most participants (73.9%) were 50 years of age or older. At baseline, low back pain was identified by 85.3%, lower extremity pain by 71.6%, and upper extremity pain by 62.5%. Participants reported widespread pain, at baseline, with a mean of 3.4 (standard deviation 1.1) pain sites. At the 60-day follow-up, 80.7% of participants reported that their chronic pain had improved and they were classified as responders. Baseline characteristics did not differentiate non-responders from responders. There were numerical trends toward reduced pain interference with walking ability and sleep, and greater pain relief in responders. There was a large difference in use of concomitant pain medications, with 80.3% of responders reporting a reduction compared to 11.8% of non

  12. Can angiogenesis induced by chronic electrical stimulation enhance latissimus dorsi muscle flap survival for application in cardiomyoplasty?

    Science.gov (United States)

    Overgoor, Max L E; Carroll, Sean M; Papanicolau, George; Carroll, Camilla M A; Ustüner, Tuncay E T; Stremel, Richard W; Anderson, Gary L; Franken, Ralph J P M; Kon, Moshe; Barker, John H

    2003-01-01

    In cardiomyoplasty, the latissimus dorsi muscle is lifted on its primary neurovascular pedicle and wrapped around a failing heart. After 2 weeks, it is trained for 6 weeks using chronic electrical stimulation, which transforms the latissimus dorsi muscle into a fatigue-resistant muscle that can contract in synchrony with the beating heart without tiring. In over 600 cardiomyoplasty procedures performed clinically to date, the outcomes have varied. Given the data obtained in animal experiments, the authors believe these variable outcomes are attributable to distal latissimus dorsi muscle flap necrosis. The aim of the present study was to investigate whether the chronic electrical stimulation training used to transform the latissimus dorsi muscle into fatigue-resistant muscle could also be used to induce angiogenesis, increase perfusion, and thus protect the latissimus dorsi muscle flap from distal necrosis. After 14 days of chronic electrical stimulation (10 Hz, 330 microsec, 4 to 6 V continuous, 8 hours/day) of the right or left latissimus dorsi muscle (randomly selected) in 11 rats, both latissimus dorsi muscles were lifted on their thoracodorsal pedicles and returned to their anatomical beds. Four days later, the resulting amount of distal flap necrosis was measured. Also, at predetermined time intervals throughout the experiment, muscle surface blood perfusion was measured using scanning laser Doppler flowmetry. Finally, latissimus dorsi muscles were excised in four additional stimulated rats, to measure angiogenesis (capillary-to-fiber ratio), fiber type (oxidative or glycolytic), and fiber size using histologic specimens. The authors found that chronic electrical stimulation (1) significantly (p < 0.05) increased angiogenesis (mean capillary-to-fiber ratio) by 82 percent and blood perfusion by 36 percent; (2) did not reduce the amount of distal flap necrosis compared with nonchronic electrical stimulation controls (29 +/- 5.3 percent versus 26.6 +/- 5

  13. Stability and selectivity of a chronic, multi-contact cuff electrode for sensory stimulation in human amputees

    Science.gov (United States)

    Tan, Daniel W.; Schiefer, Matthew A.; Keith, Michael W.; Anderson, J. Robert; Tyler, Dustin J.

    2015-04-01

    Objective. Stability and selectivity are important when restoring long-term, functional sensory feedback in individuals with limb-loss. Our objective is to demonstrate a chronic, clinical neural stimulation system for providing selective sensory response in two upper-limb amputees. Approach. Multi-contact cuff electrodes were implanted in the median, ulnar, and radial nerves of the upper-limb. Main results. Nerve stimulation produced a selective sensory response on 19 of 20 contacts and 16 of 16 contacts in subjects 1 and 2, respectively. Stimulation elicited multiple, distinct percept areas on the phantom and residual limb. Consistent threshold, impedance, and percept areas have demonstrated that the neural interface is stable for the duration of this on-going, chronic study. Significance. We have achieved selective nerve response from multi-contact cuff electrodes by demonstrating characteristic percept areas and thresholds for each contact. Selective sensory response remains consistent in two upper-limb amputees for 1 and 2 years, the longest multi-contact sensory feedback system to date. Our approach demonstrates selectivity and stability can be achieved through an extraneural interface, which can provide sensory feedback to amputees.

  14. Paramecium tetraurelia growth stimulation under low-level chronic irradiation: investigations on a possible mechanism. [/sup 60/Co

    Energy Technology Data Exchange (ETDEWEB)

    Croute, F.; Soleilhavoup, J.P.; Vidal, S.; Dupouy, D.; Planel, H.

    1982-12-01

    Experiments were carried out to demonstrate the effects of low-level chronic irradiation on Paramecium tetraurelia proliferation. Biological effects were strongly dependent on the bacterial density of culture medium and more exactly on the catalase content of the medium. Significant growth stimulation was found under /sup 60/Co chronic irradiation at a dose rate of 2 rad/year when paramecia were grown in a medium containing a high bacterial concentration (2.5 x 10/sup 2/ cells/m) or supplemented with catalase (300 U/ml). In a medium with a low bacterial density (1 x 10/sup 6/ cell/ml) or supplemented with a catalase activity inhibitor, growth simulation was preceded by a transitory inhibiting effect which could be correlated with extracellularly radioproduced H/sub 2/O/sub 2/. H/sub 2/O/sub 2/ addition appeared to be able to simulate the biological effects of chronic irradiation. A possible mechanism is discussed.We proposed that the stimulating effects were the result of intracellular enzymatic scavenging of radioproduced H/sub 2/O/sub 2/.

  15. Human macrophages chronically exposed to LPS can be reactivated by stimulation with MDP to acquire an antimicrobial phenotype.

    Science.gov (United States)

    Guzmán-Beltrán, Silvia; Torres, Martha; Arellano, Monserrat; Juárez, Esmeralda

    2017-02-21

    Macrophages are important in host defense and can differentiate into functionally distinct subsets named classically (M1) or alternatively (M2) activated. In several inflammatory disorders, macrophages become tolerized to prevent deleterious consequences. This tolerization reduces the ability of macrophages to respond to bacterial components (e.g., LPS) maintaining a low level of inflammation but compromising the ability of macrophages to mount an effective immune response during subsequent pathogen encounters. In this study, we aimed to reactivate human monocyte-derived macrophages chronically exposed to LPS by re-stimulation with muramyl dipeptide (MDP). We observed an undefined profile of cell surface marker expression during endotoxin tolerance and absence of TNFα production. Stimulating macrophages chronically exposed to LPS with LPS+MDP restored TNFα, production together with an increased production of IL1, IL6, IFNγ, IL4, IL5 and IL10. These results suggest that macrophages chronically exposed to LPS possess a mixed M1-M2 phenotype with sufficient antimicrobial and homeostatic potential.

  16. Effect of Vericiguat, a Soluble Guanylate Cyclase Stimulator, on Natriuretic Peptide Levels in Patients With Worsening Chronic Heart Failure and Reduced Ejection Fraction

    DEFF Research Database (Denmark)

    Gheorghiade, Mihai; Greene, Stephen J; Butler, Javed;

    2015-01-01

    IMPORTANCE: Worsening chronic heart failure (HF) is a major public health problem. OBJECTIVE: To determine the optimal dose and tolerability of vericiguat, a soluble guanylate cyclase stimulator, in patients with worsening chronic HF and reduced left ventricular ejection fraction (LVEF). DESIGN, ...

  17. Effectiveness of anodal transcranial direct current stimulation in patients with chronic low back pain: Design, method and protocol for a randomised controlled trial

    Directory of Open Access Journals (Sweden)

    Luedtke Kerstin

    2011-12-01

    Full Text Available Abstract Background Electrical stimulation of central nervous system areas with surgically implanted stimulators has been shown to result in pain relief. To avoid the risks and side effects of surgery, transcranial direct current stimulation is an option to electrically stimulate the motor cortex through the skull. Previous research has shown that transcranial direct current stimulation relieves pain in patients with fibromyalgia, chronic neuropathic pain and chronic pelvic pain. Evidence indicates that the method is pain free, safe and inexpensive. Methods/Design A randomised controlled trial has been designed to evaluate the effect of transcranial direct current stimulation over the motor cortex for pain reduction in patients with chronic low back pain. It will also investigate whether transcranial direct current stimulation as a prior treatment enhances the symptom reduction achieved by a cognitive-behavioural group intervention. Participants will be randomised to receive a series of 5 days of transcranial direct current stimulation (2 mA, 20 mins or 20 mins of sham stimulation; followed by a cognitive-behavioural group programme. The primary outcome parameters will measure pain (Visual Analog Scale and disability (Oswestry Disability Index. Secondary outcome parameters will include the Fear Avoidance Beliefs Questionnaire, the Funktionsfragebogen Hannover (perceived function, Hospital Anxiety Depression Scale, bothersomeness and Health Related Quality of Life (SF 36, as well as Patient-Perceived Satisfactory Improvement. Assessments will take place immediately prior to the first application of transcranial direct current stimulation or sham, after 5 consecutive days of stimulation, immediately after the cognitive-behavioural group programme and at 4 weeks, 12 weeks and 24 weeks follow-up. Discussion This trial will help to determine, whether transcranial direct current stimulation is an effective treatment for patients with chronic low back

  18. Chronic infection drives expression of the inhibitory receptor CD200R, and its ligand CD200, by mouse and human CD4 T cells.

    Directory of Open Access Journals (Sweden)

    Stefano Caserta

    Full Text Available Certain parasites have evolved to evade the immune response and establish chronic infections that may persist for many years. T cell responses in these conditions become muted despite ongoing infection. Upregulation of surface receptors with inhibitory properties provides an immune cell-intrinsic mechanism that, under conditions of chronic infection, regulates immune responses and limits cellular activation and associated pathology. The negative regulator, CD200 receptor, and its ligand, CD200, have been shown to regulate macrophage activation and reduce pathology following infection. We show that CD4 T cells also increase expression of inhibitory CD200 receptors (CD200R in response to chronic infection. CD200R was upregulated on murine effector T cells in response to infection with bacterial, Salmonella enterica, or helminth, Schistosoma mansoni, pathogens that respectively drive predominant Th1- or Th2-responses. In vitro chronic and prolonged stimuli were required for the sustained upregulation of CD200R, and its expression coincided with loss of multifunctional potential in T effector cells during infection. Importantly, we show an association between IL-4 production and CD200R expression on T effector cells from humans infected with Schistosoma haematobium that correlated effectively with egg burden and, thus infection intensity. Our results indicate a role of CD200R:CD200 in T cell responses to helminths which has diagnostic and prognostic relevance as a marker of infection for chronic schistosomiasis in mouse and man.

  19. Lesion correlates of transcranial direct current stimulation (tDCS in chronic nonfluent aphasia

    Directory of Open Access Journals (Sweden)

    PRIYANKA P SHAH

    2014-04-01

    We conclude that patients exhibiting differential patterns of damage involving the frontotemporal language areas may respond to stimulation differently. Integrity of left temporal language areas appears crucial for responsiveness to the anodal or excitatory stimulation of the damaged, left frontal areas. If temporal areas are not spared, extensive damage in specific frontotemporal areas including the surrounding white matter predicts responsiveness to cathodal or inhibitory stimulation of the left frontal areas. We posit that tDCS-induced normalization of the intra-hemispheric inhibition [3] may be the underlying mechanism of improvement in these patients.

  20. Electrical stimulation of skeletal muscles. An alternative to aerobic exercise training in patients with chronic heart failure?

    Science.gov (United States)

    Dobsák, Petr; Nováková, Marie; Fiser, Bohumil; Siegelová, Jarmila; Balcárková, Pavla; Spinarová, Lenka; Vítovec, Jirí; Minami, Naoyoshi; Nagasaka, Makoto; Kohzuki, Masahiro; Yambe, Tomoyuki; Imachi, Kou; Nitta, Shin-ichi; Eicher, Jean-Christophe; Wolf, Jean-Eric

    2006-05-01

    The aim of this study was to investigate whether electrical stimulation of skeletal muscles could represent a rehabilitation alternative for patients with chronic heart failure (CHF). Thirty patients with CHF and NYHA class II-III were randomly assigned to a rehabilitation program using either electrical stimulation of skeletal muscles or bicycle training. Patients in the first group (n = 15) had 8 weeks of home-based low-frequency electrical stimulation (LFES) applied simultaneously to the quadriceps and calf muscles of both legs (1 h/day for 7 days/week); patients in the second group (n = 15) underwent 8 weeks of 40 minute aerobic exercise (3 times a week). After the 8-week period significant increases in several functional parameters were observed in both groups: maximal VO2 uptake (LFES group: from 17.5 +/- 4.4 mL/kg/min to 18.3 +/- 4.2 mL/kg/min, P bicycle group: from 18.1 +/- 3.9 mL/kg/min to 19.3 +/- 4.1 mL/kg/min, P bicycle group: from 91.2 +/- 13.4 W to 112.9 +/- 10.8 W, P bicycle group: from 425 +/- 118 m to 483 +/- 120 m, P bicycle group: from 510 +/- 90 seconds to 611 +/- 112 seconds, P electrical stimulation. LFES should be considered as a valuable alternative to classical exercise training in patients with CHF.

  1. Regulation of activity-regulated cytoskeleton protein (Arc) mRNA after acute and chronic electroconvulsive stimulation in the rat

    DEFF Research Database (Denmark)

    Larsen, M H; Olesen, M; Woldbye, D P D

    2005-01-01

    The temporal profile of Arc gene expression after acute and chronic electroconvulsive stimulations (ECS) was studied using semi-quantitative in situ hybridisation in the rat cortex. A single ECS strongly and temporarily increased Arc mRNA levels in dentate granular cells with maximal induction se......, but not accumulated by long term repetitive ECS and therefore not a molecular biomarker for antidepressant properties. More likely, Arc is likely a molecular link to the decline in memory consolidation seen in depressive patients subjected to electroconvulsive therapy....

  2. Reduction of chronic abdominal pain in patients with inflammatory bowel disease through transcranial direct current stimulation: a randomized controlled trial.

    Science.gov (United States)

    Volz, Magdalena S; Farmer, Annabelle; Siegmund, Britta

    2016-02-01

    Inflammatory bowel disease (IBD) is frequently associated with chronic abdominal pain (CAP). Transcranial direct current stimulation (tDCS) has been proven to reduce chronic pain. This study aimed to investigate the effects of tDCS in patients with CAP due to IBD. This randomized, sham-controlled, double blind, parallel-designed study included 20 patients with either Crohn disease or ulcerative colitis with CAP (≥3/10 on the visual analog scale (VAS) in 3/6 months). Anodal or sham tDCS was applied over the primary motor cortex for 5 consecutive days (2 mA, 20 minutes). Assessments included VAS, pressure pain threshold, inflammatory markers, and questionnaires on quality of life, functional and disease specific symptoms (Irritable Bowel Syndrome-Severity Scoring System [IBS-SSS]), disease activity, and pain catastrophizing. Follow-up data were collected 1 week after the end of the stimulation. Statistical analyses were performed using analysis of variance and t tests. There was a significant reduction of abdominal pain in the anodal tDCS group compared with sham tDCS. This effect was evident in changes in VAS and pressure pain threshold on the left and right sides of the abdomen. In addition, 1 week after stimulation, pain reduction remained significantly decreased in the right side of the abdomen. There was also a significant reduction in scores on pain catastrophizing and on IBS-SSS when comparing both groups. Inflammatory markers and disease activity did not differ significantly between groups throughout the experiment. Transcranial direct current stimulation proved to be an effective and clinically relevant therapeutic strategy for CAP in IBD. The analgesic effects observed are unrelated to inflammation and disease activity, which emphasizes central pain mechanisms in CAP.

  3. Chronic electrical stimulation drives mitochondrial biogenesis in skeletal muscle of a lizard, Varanus exanthematicus.

    Science.gov (United States)

    Schaeffer, Paul J; Nichols, Scott D; Lindstedt, Stan L

    2007-10-01

    We investigated the capacity for phenotypic plasticity of skeletal muscle from Varanus exanthematicus, the savannah monitor lizard. Iliofibularis muscle from one leg of each lizard was electrically stimulated for 8 weeks. Both stimulated and contralateral control muscles were collected and processed for electron microscopy. We used stereological analysis of muscle cross-sections to quantify the volume densities of contractile elements, sarcoplasmic reticulum, mitochondria and intracellular lipids. We found that mitochondrial volume density was approximately fourfold higher in the stimulated muscle compared to controls, which were similar to previously reported values. Sarcoplasmic reticulum volume density was reduced by an amount similar to the increase in mitochondrial volume density while the volume density of contractile elements remained unchanged. Intracellular lipid accumulation was visibly apparent in many stimulated muscle sections but the volume density of lipids did not reach a significant difference. Although monitor lizards lack the highly developed aerobic metabolism of mammals, they appear to possess the capacity for muscle plasticity.

  4. Hedgehog signaling is synergistically enhanced by nutritional deprivation and ligand stimulation in human fibroblasts of Gorlin syndrome.

    Science.gov (United States)

    Mizuochi, Hiromi; Fujii, Katsunori; Shiohama, Tadashi; Uchikawa, Hideki; Shimojo, Naoki

    2015-02-13

    Hedgehog signaling is a pivotal developmental pathway that comprises hedgehog, PTCH1, SMO, and GLI proteins. Mutations in PTCH1 are responsible for Gorlin syndrome, which is characterized by developmental defects and tumorigenicity. Although the hedgehog pathway has been investigated extensively in Drosophila and mice, its functional roles have not yet been determined in human cells. In order to elucidate the mechanism by which transduction of the hedgehog signal is regulated in human tissues, we employed human fibroblasts derived from three Gorlin syndrome patients and normal controls. We investigated GLI1 transcription, downstream of hedgehog signaling, to assess native signal transduction, and then treated fibroblasts with a recombinant human hedgehog protein with or without serum deprivation. We also examined the transcriptional levels of hedgehog-related genes under these conditions. The expression of GLI1 mRNA was significantly higher in Gorlin syndrome-derived fibroblasts than in control cells. Hedgehog stimulation and nutritional deprivation synergistically enhanced GLI1 transcription levels, and this was blocked more efficiently by vismodegib, a SMO inhibitor, than by the natural compound, cyclopamine. Messenger RNA profiling revealed the increased expression of Wnt signaling and morphogenetic molecules in these fibroblasts. These results indicated that the hedgehog stimulation and nutritional deprivation synergistically activated the hedgehog signaling pathway in Gorlin syndrome fibroblasts, and this was associated with increments in the transcription levels of hedgehog-related genes such as those involved in Wnt signaling. These fibroblasts may become a significant tool for predicting the efficacies of hedgehog molecular-targeted therapies such as vismodegib.

  5. Human thymus medullary epithelial cells promote regulatory T-cell generation by stimulating interleukin-2 production via ICOS ligand.

    Science.gov (United States)

    Nazzal, D; Gradolatto, A; Truffault, F; Bismuth, J; Berrih-Aknin, S

    2014-09-11

    Natural thymic T regulatory (tTreg) cells maintain tolerance to self-antigen. These cells are generated in the thymus, but how this generation occurs is still controversial. Furthermore, the contribution of thymus epithelial cells to this process is still unclear, especially in humans. Using an exceptional panel of human thymic samples, we demonstrated that medullary thymus epithelial cells (mTECs) promote the generation of tTreg cells and favor their function. These effects were mediated through soluble factors and were mTEC specific since other cell types had no such effect. By evaluating the effects of mTECs on the absolute number of Treg cells and their state of proliferation or cell death, we conclude that mTECs promote the proliferation of newly generated CD25+ cells from CD4+CD25- cells and protect Treg cells from cell death. This observation implicates Bcl-2 and mitochondrial membrane potential changes, indicating that the intrinsic cell death pathway is involved in Treg protection by mTECs. Interestingly, when the mTECs were cultured directly with purified Treg cells, they were able to promote their phenotype but not their expansion, suggesting that CD4+CD25- cells have a role in the expansion process. To explore the mechanisms involved, several neutralizing antibodies were tested. The effects of mTECs on Treg cells were essentially due to interleukin (IL)-2 overproduction by thymus CD4+ T cells. We then searched for a soluble factor produced by mTECs able to increase IL-2 production by CD4+ cells and could identify the inducible T-cell costimulator ligand (ICOSL). Our data strongly suggest a « ménage à trois »: mTEC cells (via ICOSL) induce overproduction of IL-2 by CD25- T cells leading to the expansion of tTreg cells. Altogether, these results demonstrate for the first time a role of mTECs in promoting Treg cell expansion in the human thymus and implicate IL-2 and ICOSL in this process.

  6. Electrical stimulation of the aortic depressor nerve in conscious rats overcomes the attenuation of the baroreflex in chronic heart failure.

    Science.gov (United States)

    Pinto, Tomás O C Teixeira; Lataro, Renata M; Castania, Jaci A; Durand, Marina T; Silva, Carlos A A; Patel, Kaushik P; Fazan, Rubens; Salgado, Helio C

    2016-04-01

    Chronic heart failure (CHF) is characterized by autonomic dysfunction combined with baroreflex attenuation. The hypotensive and bradycardic responses produced by electrical stimulation of the aortic depressor nerve (ADN) were examined in conscious CHF and control male Wistar rats (12-13 wk old). Furthermore, the role of parasympathetic and sympathetic nervous system in mediating the cardiovascular responses to baroreflex activation was evaluated by selective β1-adrenergic and muscarinic receptor antagonists. CHF was induced by myocardial infarction. After 6 wk, the subjects were implanted with electrodes for ADN stimulation. Twenty-four hours later, electrical stimulation of the ADN was applied for 20 s using five different frequencies (5, 15, 30, 60, and 90 Hz), while the arterial pressure was recorded by a catheter implanted into the femoral artery. Electrical stimulation of the ADN elicited progressive and similar hypotensive and bradycardic responses in control (n = 12) and CHF (n = 11) rats, while the hypotensive response was not affected by methylatropine. Nevertheless, the reflex bradycardia was attenuated by methylatropine in control, but not in CHF rats. Atenolol did not affect the hypotensive or bradycardic response in either group. The ADN function was examined under anesthesia through electroneurographic recordings. The arterial pressure-ADN activity relationship was attenuated in CHF rats. In conclusion, despite the attenuation of baroreceptor function in CHF rats, the electrical stimulation of the ADN elicited a stimulus-dependent hypotension and bradycardia of similar magnitude as observed in control rats. Therefore, electrical activation of the aortic baroreflex overcomes both the attenuation of parasympathetic function and the sympathetic overdrive.

  7. Increased adrenergic signaling is responsible for decreased glucose-stimulated insulin secretion in the chronically hyperinsulinemic ovine fetus.

    Science.gov (United States)

    Andrews, Sasha E; Brown, Laura D; Thorn, Stephanie R; Limesand, Sean W; Davis, Melissa; Hay, William W; Rozance, Paul J

    2015-01-01

    Insulin may stimulate its own insulin secretion and is a potent growth factor for the pancreatic β-cell. Complications of pregnancy, such as diabetes and intrauterine growth restriction, are associated with changes in fetal insulin concentrations, secretion, and β-cell mass. However, glucose concentrations are also abnormal in these conditions. The direct effect of chronic fetal hyperinsulinemia with euglycemia on fetal insulin secretion and β-cell mass has not been tested. We hypothesized that chronic fetal hyperinsulinemia with euglycemia would increase glucose-stimulated insulin secretion (GSIS) and β-cell mass in the ovine fetus. Singleton ovine fetuses were infused with iv insulin to produce high physiological insulin concentrations, or saline for 7-10 days. The hyperinsulinemic animals also received a direct glucose infusion to maintain euglycemia. GSIS, measured at 133 ± 1 days of gestation, was significantly attenuated in the hyperinsulinemic fetuses (P < .05). There was no change in β-cell mass. The hyperinsulinemic fetuses also had decreased oxygen (P < .05) and higher norepinephrine (1160 ± 438 vs 522 ± 106 pg/mL; P < .005). Acute pharmacologic adrenergic blockade restored GSIS in the hyperinsulinemic-euglycemic fetuses, demonstrating that increased adrenergic signaling mediates decreased GSIS in these fetuses.

  8. Influence of a pre-stimulation with chronic low-dose UVB on stress response mechanisms in human skin fibroblasts.

    Science.gov (United States)

    Drigeard Desgarnier, Marie-Catherine; Fournier, Frédéric; Droit, Arnaud; Rochette, Patrick J

    2017-01-01

    Exposure to solar ultraviolet type B (UVB), through the induction of cyclobutane pyrimidine dimer (CPD), is the major risk factor for cutaneous cancer. Cells respond to UV-induced CPD by triggering the DNA damage response (DDR) responsible for signaling DNA repair, programmed cell death and cell cycle arrest. Underlying mechanisms implicated in the DDR have been extensively studied using single acute UVB irradiation. However, little is known concerning the consequences of chronic low-dose of UVB (CLUV) on the DDR. Thus, we have investigated the effect of a CLUV pre-stimulation on the different stress response pathways. We found that CLUV pre-stimulation enhances CPD repair capacity and leads to a cell cycle delay but leave residual unrepaired CPD. We further analyzed the consequence of the CLUV regimen on general gene and protein expression. We found that CLUV treatment influences biological processes related to the response to stress at the transcriptomic and proteomic levels. This overview study represents the first demonstration that human cells respond to chronic UV irradiation by modulating their genotoxic stress response mechanisms.

  9. Receptor activator of nuclear factor kappa B ligand and osteoprotegerin expression in chronic apical periodontitis:possible association with inflammatory cells

    Institute of Scientific and Technical Information of China (English)

    FAN Rong; SUN Bin; ZHANG Cheng-fei; L(U) Ya-lin; XUAN Wei; WANG Qian-qian; YIN Xing-zhe

    2011-01-01

    Background Receptor activator of nuclear factor kappa B (NF-κB) ligand (RANKL) and osteoprotegerin (OPG) have been recently shown to play important roles in bone resorption. The aim of this study was to investigate the possible association between the expression of bone resorption regulators (RANKL and OPG) and inflammatory cell infiltration in chronic apical periodontitis.Methods The samples of chronic periapical lesions (n=40) and healthy periapical tissues (n=10) were examined for immunohistochemical analysis of RANKL and OPG. Lesion samples were further analyzed for the inflammatory infiltration condition. The inflammatory cell infiltration was scored in relation to immunohistochemical reactivity for CD3, CD20 and CD68.Results The number of RANKL-positive cells and the ratio of RANKL/OPG in chronic apical periodontitis were significantly higher than those in healthy periapical tissues (P<0.001). The number of RANKL-positive cells was higher in lesions with severe inflammatory infiltration than in those with light inflammatory infiltration (P<0.05). Significantly increased RANKL expression was found with T lymphocytes (CD3+), macrophages (CD68+) and B lymphocytes (CD20+)infiltration (P<0.05). No association was found between the ratio of RANKL/OPG and inflammatory cell infiltration.Conclusions RANKL expression was increased with T, B lymphocytes and macrophages infiltration, respectively in chronic periapical lesions. RANKL appears to be closely related to periapical inflammatory infiltrates. The relative ratio of RANKL/OPG may be a key determinant of RANKL-mediated bone resorption.

  10. MEG can map short and long-term changes in brain activity following deep brain stimulation for chronic pain.

    Directory of Open Access Journals (Sweden)

    Hamid R Mohseni

    Full Text Available Deep brain stimulation (DBS has been shown to be clinically effective for some forms of treatment-resistant chronic pain, but the precise mechanisms of action are not well understood. Here, we present an analysis of magnetoencephalography (MEG data from a patient with whole-body chronic pain, in order to investigate changes in neural activity induced by DBS for pain relief over both short- and long-term. This patient is one of the few cases treated using DBS of the anterior cingulate cortex (ACC. We demonstrate that a novel method, null-beamforming, can be used to localise accurately brain activity despite the artefacts caused by the presence of DBS electrodes and stimulus pulses. The accuracy of our source localisation was verified by correlating the predicted DBS electrode positions with their actual positions. Using this beamforming method, we examined changes in whole-brain activity comparing pain relief achieved with deep brain stimulation (DBS ON and compared with pain experienced with no stimulation (DBS OFF. We found significant changes in activity in pain-related regions including the pre-supplementary motor area, brainstem (periaqueductal gray and dissociable parts of caudal and rostral ACC. In particular, when the patient reported experiencing pain, there was increased activity in different regions of ACC compared to when he experienced pain relief. We were also able to demonstrate long-term functional brain changes as a result of continuous DBS over one year, leading to specific changes in the activity in dissociable regions of caudal and rostral ACC. These results broaden our understanding of the underlying mechanisms of DBS in the human brain.

  11. Requirement for the POZ/BTB protein NAC1 in acute but not chronic psychomotor stimulant response.

    Science.gov (United States)

    Mackler, Scott; Pacchioni, Alejandra; Degnan, Ryan; Homan, Ying; Conti, Alana C; Kalivas, Peter; Blendy, Julie A

    2008-02-11

    NAC1 is a novel member of the POZ/BTB (Pox virus and Zinc finger/Bric-a-bracTramtrack Broad complex) but varies from other proteins of this class in that it lacks the characteristic DNA-binding motif, suggesting a novel role. We have employed constitutive gene deletion to elucidate the role of NAC1 in vivo. Nac1 mutant mice are viable with no obvious developmental or physiological impairments. Previous studies suggest a role for NAC1 in cocaine-mediated behaviors. Therefore, we evaluated a variety of behaviors associated with psychomotor stimulant effects in Nac1 mutant mice. Acute locomotor activating effects of cocaine or amphetamine are absent in Nac1 mutant mice, however longer exposure to these psychomotor stimulants result in the development of behavioral sensitization. Acute rewarding properties of cocaine and amphetamine are also blunted in mutant mice, yet repeated exposure resulted in conditioned place preference similar to that observed in wild-type mice. Lastly, increases in extracellular dopamine in the nucleus accumbens, which accompany acute cocaine administration, are blunted in mutant mice, but following chronic cocaine extracellular dopamine levels are increased to the same extent as in wild-type mice. Together these data indicate involvement of NAC1 in the acute behavioral and neurochemical responses to psychomotor stimulants.

  12. Long term clinical outcome of peripheral nerve stimulation in patients with chronic peripheral neuropathic pain

    DEFF Research Database (Denmark)

    Calenbergh, F. Van; Gybels, J.; Laere, K. Van;

    2009-01-01

    examination. The assessments were done both during habitual use of PNS and with the stimulator off. RESULTS: Average pain intensity and pain unpleasantness ratings as assessed with visual analog and verbal rating scales showed significant beneficial effects of PNS. Quality of life measures (sleep and daily...

  13. Effects of Cholinergic Stimulation with Pyridostigmine Bromide on Chronic Chagasic Cardiomyopathic Mice

    Directory of Open Access Journals (Sweden)

    Marília Beatriz de Cuba

    2014-01-01

    Full Text Available The aim of the present study was to assess the effects of an anticholinesterase agent, pyridostigmine bromide (Pyrido, on experimental chronic Chagas heart disease in mice. To this end, male C57BL/6J mice noninfected (control:Con or chronically infected (5 months with Trypanosoma cruzi (chagasic:Chg were treated or not (NT with Pyrido for one month. At the end of this period, electrocardiogram (ECG; cardiac autonomic function; heart histopathology; serum cytokines; and the presence of blood and tissue parasites by means of immunohistochemistry and PCR were assessed. In NT-Chg mice, significant changes in the electrocardiographic, autonomic, and cardiac histopathological profiles were observed confirming a chronic inflammatory response. Treatment with Pyrido in Chagasic mice caused a significant reduction of myocardial inflammatory infiltration, fibrosis, and hypertrophy, which was accompanied by a decrease in serum levels of IFNγ with no change in IL-10 levels, suggesting a shift of immune response toward an anti-inflammatory profile. Lower nondifferent numbers of parasite DNA copies were observed in both treated and nontreated chagasic mice. In conclusion, our findings confirm the marked neuroimmunomodulatory role played by the parasympathetic autonomic nervous system in the evolution of the inflammatory-immune response to T. cruzi during experimental chronic Chagas heart disease in mice.

  14. Erythropoiesis-stimulating agents for anaemia in chronic heart failure patients

    NARCIS (Netherlands)

    Ngo, Katherine; Kotecha, Dipak; Walters, Julia A. E.; Manzano, Luis; Palazzuoli, Alberto; van Veldhuisen, Dirk J.; Flather, Marcus

    2010-01-01

    Background Chronic heart failure (CHF) is a leading cause of morbidity and mortality worldwide. Anaemia is a common (12-55%) co-morbid condition and is associated with worsening symptoms and increased mortality. Anaemia is treatable and can be targeted in the treatment of patients with CHF. Erythrop

  15. eHealth to stimulate physical activity in patients with chronic obstructive pulmonary disease

    NARCIS (Netherlands)

    Vorrink, S.N.W.

    2016-01-01

    Persons with Chronic Obstructive Pulmonary Disease (COPD) demonstrate reduced physical activity (PA) levels compared to healthy age-matched controls. Regular PA is associated with positive health outcomes. Inactivity leads to deconditioning, which leads to increased symptoms and a further reduction

  16. Effects of Lumbosacral Spinal Cord Epidural Stimulation for Standing after Chronic Complete Paralysis in Humans.

    Directory of Open Access Journals (Sweden)

    Enrico Rejc

    Full Text Available Sensory and motor complete spinal cord injury (SCI has been considered functionally complete resulting in permanent paralysis with no recovery of voluntary movement, standing or walking. Previous findings demonstrated that lumbosacral spinal cord epidural stimulation can activate the spinal neural networks in one individual with motor complete, but sensory incomplete SCI, who achieved full body weight-bearing standing with independent knee extension, minimal self-assistance for balance and minimal external assistance for facilitating hip extension. In this study, we showed that two clinically sensory and motor complete participants were able to stand over-ground bearing full body-weight without any external assistance, using their hands to assist balance. The two clinically motor complete, but sensory incomplete participants also used minimal external assistance for hip extension. Standing with the least amount of assistance was achieved with individual-specific stimulation parameters, which promoted overall continuous EMG patterns in the lower limbs' muscles. Stimulation parameters optimized for one individual resulted in poor standing and additional need of external assistance for hip and knee extension in the other participants. During sitting, little or negligible EMG activity of lower limb muscles was induced by epidural stimulation, showing that the weight-bearing related sensory information was needed to generate sufficient EMG patterns to effectively support full weight-bearing standing. In general, electrode configurations with cathodes selected in the caudal region of the array at relatively higher frequencies (25-60 Hz resulted in the more effective EMG patterns for standing. These results show that human spinal circuitry can generate motor patterns effective for standing in the absence of functional supraspinal connections; however the appropriate selection of stimulation parameters is critical.

  17. Effects of Lumbosacral Spinal Cord Epidural Stimulation for Standing after Chronic Complete Paralysis in Humans.

    Science.gov (United States)

    Rejc, Enrico; Angeli, Claudia; Harkema, Susan

    2015-01-01

    Sensory and motor complete spinal cord injury (SCI) has been considered functionally complete resulting in permanent paralysis with no recovery of voluntary movement, standing or walking. Previous findings demonstrated that lumbosacral spinal cord epidural stimulation can activate the spinal neural networks in one individual with motor complete, but sensory incomplete SCI, who achieved full body weight-bearing standing with independent knee extension, minimal self-assistance for balance and minimal external assistance for facilitating hip extension. In this study, we showed that two clinically sensory and motor complete participants were able to stand over-ground bearing full body-weight without any external assistance, using their hands to assist balance. The two clinically motor complete, but sensory incomplete participants also used minimal external assistance for hip extension. Standing with the least amount of assistance was achieved with individual-specific stimulation parameters, which promoted overall continuous EMG patterns in the lower limbs' muscles. Stimulation parameters optimized for one individual resulted in poor standing and additional need of external assistance for hip and knee extension in the other participants. During sitting, little or negligible EMG activity of lower limb muscles was induced by epidural stimulation, showing that the weight-bearing related sensory information was needed to generate sufficient EMG patterns to effectively support full weight-bearing standing. In general, electrode configurations with cathodes selected in the caudal region of the array at relatively higher frequencies (25-60 Hz) resulted in the more effective EMG patterns for standing. These results show that human spinal circuitry can generate motor patterns effective for standing in the absence of functional supraspinal connections; however the appropriate selection of stimulation parameters is critical.

  18. F1t3 RECEPTOR EXPRESSION ON THE SURFACE OF MALIGNANT HEMATOPOIETIC CELLS AND RESPONSES TO F1t3 LIGAND STIMULATION

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Objective: To investigate the F1t3 receptor expression on the surface of malignant hematopoietic cells, the effect of TNFa and dexamethasone (DXM) on its expression and the responses of those cells to recombinant human F1t3 ligand (rhFL). Methods: Eighteen malignant hematopoietic cell lines were determined for the F1t3 receptor expression by flow cytometric analysis. The effect of rhFL on the proliferation of malignant hematopoietic cells in vitro was measured using MTT assay. Results: The expressions of F1t3 receptor on the surface of Raji, Daudi, HL-60, 8266 and XG-6 cells were detected by flow cytometric analysis. Following incubation with 20 ng/ml TNFa for 24h, the number of F1t3 receptor positive cells decreased in Raji and 8266, increased in HL-60 and XG-6, and no difference in Daudi cells. After incubation with 10-6 mol/L DXM for 24h, the number of F1t3 receptor positive cells decreased in all the 5 F1t3 receptor positive cell lines. rhFL stimulated the proliferation of HL-60 and Raji cells. Conclusion: For most of the malignant hematopoietic cells, there was neither the expression of F1t3 receptor nor the response to rhFL. DXM may be useful to reduce the effect of FL on the proliferation of some F1t3 receptor positive malignant hematopoietic cells in vitro and in vivo.

  19. NOD1 and NOD2 receptors in mrigal (Cirrhinus mrigala): Inductive expression and downstream signalling in ligand stimulation and bacterial infections

    Indian Academy of Sciences (India)

    Banikalyan Swain; Madhubanti Basu; Mrinal Samanta

    2013-09-01

    Nucleotide binding and oligomerization domain (NOD)1 and NOD2 are important cytoplasmic pattern recognition receptors (PRRs) and key members of the NOD-like receptor (NLR) family. They sense a wide range of bacteria or their products and play a key role in inducing innate immunity. This report describes the role of NOD1 and NOD2 receptors signalling in innate immunity in the Indian major carp, mrigal (Cirrhinus mrigala). Tissue-specific expression analysis of NOD1 and NOD2 genes by quantitative real-time PCR (qRT-PCR) revealed their wide distribution in various organs/tissues. In the untreated fish, the highest expression of NOD1 and NOD2 was detected in liver and blood, respectively. Stimulation with NOD1- and NOD2-specific ligands, i.e. iE-DAP and MDP, activated NOD1 and NOD2 receptor signalling in vivo and in vitro resulting in significant ( < 0.05) induction of downstream signalling molecule RICK, and the effector molecules IL-1, IL-8 and IFN- in the treated group as compared to their controls. In response to both Gram-positive and Gram-negative bacterial infections, NOD1 and NOD2 receptors signalling were activated and IL-1, IL-8 and IFN- were induced. These findings highlight the important role of NOD receptors in eliciting innate immune response during the pathogenic invasion to the fish.

  20. Long-term effects of transcranial direct-current stimulation in chronic post-stroke aphasia: a pilot study.

    Science.gov (United States)

    Vestito, Lucilla; Rosellini, Sara; Mantero, Massimo; Bandini, Fabio

    2014-01-01

    Transcranial direct-current stimulation (tDCS) has been suggested to improve language function in patients with post-stroke aphasia. Most studies on aphasic patients, however, were conducted with a very limited follow-up period, if any. In this pilot, single-blind study on chronic post-stroke aphasic patients, we aimed to verify whether or not tDCS is able to extend its beneficial effects for a longer period of time (21 weeks after the end of stimulation). Three aphasic patients underwent anodal tDCS (A-tDCS, 20 min, 1.5 mA) and sham stimulation (S-tDCS) over the left frontal (perilesional) region, coupled with a simultaneous naming training (on-line tDCS). Ten consecutive sessions (5 days per week for 2 weeks) were implemented. In the first five sessions, we used a list of 40 figures, while in the subsequent five sessions we utilized a second set of 40 figures differing in word difficulty. At the end of the stimulation period, we found a significant beneficial effect of A-tDCS (as compared to baseline and S-tDCS) in all our subjects, regardless of word difficulty, although with some inter-individual differences. In the follow-up period, the percentage of correct responses persisted significantly better until the 16th week, when an initial decline in naming performance was observed. Up to the 21st week, the number of correct responses, though no longer significant, was still above the baseline level. These results in a small group of aphasic patients suggest a long-term beneficial effect of on-line A-tDCS.

  1. LONG-TERM EFFECTS OF TRANSCRANIAL DIRECT CURRENT STIMULATION IN CHRONIC POST-STROKE APHASIA: A PILOT STUDY

    Directory of Open Access Journals (Sweden)

    Lucilla eVestito

    2014-10-01

    Full Text Available Transcranial direct current stimulation (tDCS has been suggested to improve language function in patients with post-stroke aphasia. Most studies on aphasic patients, however, were conducted with a very limited follow-up period, if any. In this pilot, single-blind study on chronic post-stroke aphasic patients, we aimed to verify whether or not tDCS is able to extend its beneficial effects for a longer period of time (21 weeks after the end of stimulation. Three aphasic patients underwent anodal tDCS (A-tDCS, 20 min, 1.5 mA and sham stimulation (S-tDCS over the left frontal (perilesional region, coupled with a simultaneous naming training (on-line tDCS. Ten consecutive sessions (five days per week for two weeks were implemented. In the first five sessions we used a list of 40 figures, while in the subsequent five sessions we utilized a second set of 40 figures differing in word difficulty. At the end of the stimulation period we found a significant beneficial effect of A-tDCS (as compared to baseline and S-tDCS in all our subjects, regardless of word difficulty, although with some inter-individual differences. In the follow-up period, the percentage of correct responses persisted significantly better until the 16th week, when an initial decline in naming performance was observed. Up to the 21st week, the number of correct responses, though no longer significant, was still above the baseline level. These results in a small group of aphasic patients suggest a long-term beneficial effect of on-line A-tDCS.

  2. Electroconvulsive Stimulation, but not Chronic Restraint Stress, Causes Structural Alterations in Adult Rat Hippocampus

    DEFF Research Database (Denmark)

    Olesen, Mikkel V.; Wörtwein, Gitta; Pakkenberg, Bente

    2015-01-01

    The neurobiological mechanisms underlying depression are not fully understood. Only a few previous studies have used validated stereological methods to test how stress and animal paradigms of depression affect adult hippocampal neurogenesis and whether antidepressant therapy can counteract possible...... changes in an animal model. Thus, in this study we applied methods that are state of the art in regard to stereological cell counting methods. Using a validated rat model of depression in combination with a clinically relevant schedule of electroconvulsive stimulation, we estimated the total number...... induces depression-like behavior, without significantly changing neurogenesis, the total number of neurons or the volume of the hippocampus. Further, electroconvulsive stimulation prevents stress-induced depression-like behavior and increases neurogenesis. The total number of neurons and the granule cell...

  3. Chronic Cadmium Exposure Stimulates SDF-1 Expression in an ERα Dependent Manner

    OpenAIRE

    2013-01-01

    Cadmium is an omnipotent environmental contaminant associated with the development of breast cancer. Studies suggest that cadmium functions as an endocrine disruptor, mimicking the actions of estrogen in breast cancer cells and activating the receptor to promote cell growth. Although acute cadmium exposure is known to promote estrogen receptor-mediated gene expression associated with growth, the consequence of chronic cadmium exposure is unclear. Since heavy metals are known to bioaccumulate,...

  4. Electrical stimulation for chronic non-specific low back pain in a working-age population: a 12-week double blinded randomized controlled trial

    OpenAIRE

    2013-01-01

    Background Non-invasive electrotherapy is commonly used for treatment of chronic low back pain. Evidence for efficacy of most electrotherapy modalities is weak or lacking. This study aims to execute a high-quality, double-blinded randomized controlled clinical trial comparing 1) H-Wave® Device stimulation plus usual care with 2) transcutaneous electrical nerve stimulation (TENS) plus usual care, and 3) Sham electrotherapy plus usual care to determine comparative efficacy for treatment of chro...

  5. Report of leucine-rich repeats (LRRs) from Scylla serrata: Ontogeny, molecular cloning, characterization and expression analysis following ligand stimulation, and upon bacterial and viral infections.

    Science.gov (United States)

    Vidya, R; Makesh, M; Purushothaman, C S; Chaudhari, A; Gireesh-Babu, P; Rajendran, K V

    2016-09-15

    Leucine-rich repeat (LRR) proteins are present in all living organisms, and their participation in signal transduction and defense mechanisms has been elucidated in humans and mosquitoes. LRRs possibly involve in protein-protein interactions also and show differential expression pattern upon challenge with pathogens. In the present study, a new LRR gene was identified in mud crab, Scylla serrata. LRR gene mRNA levels in different developmental stages and various tissues of S. serrata were analysed. Further, the response of the gene against different ligands, Gram-negative bacterium, and white spot syndrome virus (WSSV) was investigated in vitro and in vivo. Full-length cDNA sequence of S. serrata LRR (SsLRR) was found to be 2290 nucleotide long with an open reading frame of 1893bp. SsLRR encodes for a protein containing 630 deduced amino acids with 17 conserved LRR domains and exhibits significant similarity with crustacean LRRs so that these could be clustered into a branch in the phylogenetic tree. SsLRR mRNA transcripts were detected in all the developmental stages (egg, Zoea1-5, megalopa and crab instar), haemocytes and various tissues such as, stomach, gill, muscle, hepatopancreas, hematopoietic organ, heart, epithelial layer and testis by reverse-transcriptase PCR. SsLRR transcripts in cultured haemocytes showed a 2-fold increase in expression at 1.5 and 12h upon Poly I:C induction. WSSV challenge resulted in significant early up-regulation at 3h in-vitro and late up-regulation at 72h in-vivo. Peptidoglycan (PGN)-induction resulted in marginal up-regulation of SsLRR at timepoints, 6, 12 and 24h (fold change below 1.5) and no significant change in the expression at early timepoints. LPS-stimulation, on the other hand, showed either down-regulation or normal level of expression at all timepoints. However, a delayed 5-fold up-regulation was observed in vivo against Vibrio parahaemolyticus infection at 72hpi. The constitutive expression of the LRR gene in all the

  6. Fludarabine, cyclophosphamide and rituximab plus granulocyte macrophage colony-stimulating factor as frontline treatment for patients with chronic lymphocytic leukemia.

    Science.gov (United States)

    Strati, Paolo; Ferrajoli, Alessandra; Lerner, Susan; O'Brien, Susan; Wierda, William; Keating, Michael J; Faderl, Stefan

    2014-04-01

    Fludarabine, cyclophosphamide and rituximab (FCR), the standard of care for the frontline treatment of patients with chronic lymphocytic leukemia (CLL), is associated with a high rate of neutropenia and infectious complications. Granulocyte macrophage colony-stimulating factor (GM-CSF) reduces myelosuppression and can potentiate rituximab activity. We conducted a clinical trial combining GM-CSF with FCR for frontline treatment of 60 patients with CLL. Eighty-six percent completed all six courses and 18% discontinued GM-CSF for toxicity: grade 3-4 neutropenia was observed in 30% of cycles, and severe infections in 16% of cases. The overall response rate was 100%. Both median event-free survival (EFS) and overall survival (OS) have not been reached. Longer EFS was associated with favorable cytogenetics. GM-CSF led to a lower frequency of infectious complications than in the historical FCR group, albeit similar EFS and OS.

  7. Functional improvement and maturation of rat and human engineered heart tissue by chronic electrical stimulation.

    Science.gov (United States)

    Hirt, Marc N; Boeddinghaus, Jasper; Mitchell, Alice; Schaaf, Sebastian; Börnchen, Christian; Müller, Christian; Schulz, Herbert; Hubner, Norbert; Stenzig, Justus; Stoehr, Andrea; Neuber, Christiane; Eder, Alexandra; Luther, Pradeep K; Hansen, Arne; Eschenhagen, Thomas

    2014-09-01

    Spontaneously beating engineered heart tissue (EHT) represents an advanced in vitro model for drug testing and disease modeling, but cardiomyocytes in EHTs are less mature and generate lower forces than in the adult heart. We devised a novel pacing system integrated in a setup for videooptical recording of EHT contractile function over time and investigated whether sustained electrical field stimulation improved EHT properties. EHTs were generated from neonatal rat heart cells (rEHT, n=96) or human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (hEHT, n=19). Pacing with biphasic pulses was initiated on day 4 of culture. REHT continuously paced for 16-18 days at 0.5Hz developed 2.2× higher forces than nonstimulated rEHT. This was reflected by higher cardiomyocyte density in the center of EHTs, increased connexin-43 abundance as investigated by two-photon microscopy and remarkably improved sarcomere ultrastructure including regular M-bands. Further signs of tissue maturation include a rightward shift (to more physiological values) of the Ca(2+)-response curve, increased force response to isoprenaline and decreased spontaneous beating activity. Human EHTs stimulated at 2Hz in the first week and 1.5Hz thereafter developed 1.5× higher forces than nonstimulated hEHT on day 14, an ameliorated muscular network of longitudinally oriented cardiomyocytes and a higher cytoplasm-to-nucleus ratio. Taken together, continuous pacing improved structural and functional properties of rEHTs and hEHTs to an unprecedented level. Electrical stimulation appears to be an important step toward the generation of fully mature EHT.

  8. Metabolic activity of brown, "beige," and white adipose tissues in response to chronic adrenergic stimulation in male mice.

    Science.gov (United States)

    Labbé, Sébastien M; Caron, Alexandre; Chechi, Kanta; Laplante, Mathieu; Lecomte, Roger; Richard, Denis

    2016-07-01

    Classical brown adipocytes such as those found in interscapular brown adipose tissue (iBAT) represent energy-burning cells, which have been postulated to play a pivotal role in energy metabolism. Brown adipocytes can also be found in white adipose tissue (WAT) depots [e.g., inguinal WAT (iWAT)] following adrenergic stimulation, and they have been referred to as "beige" adipocytes. Whether the presence of these adipocytes, which gives iWAT a beige appearance, can confer a white depot with some thermogenic activity remains to be seen. In consequence, we designed the present study to investigate the metabolic activity of iBAT, iWAT, and epididymal white depots in mice. Mice were either 1) kept at thermoneutrality (30°C), 2) kept at 30°C and treated daily for 14 days with an adrenergic agonist [CL-316,243 (CL)], or 3) housed at 10°C for 14 days. Metabolic activity was assessed using positron emission tomography imaging with fluoro-[(18)F]deoxyglucose (glucose uptake), fluoro-[(18)F]thiaheptadecanoic acid (fatty acid uptake), and [(11)C]acetate (oxidative activity). In each group, substrate uptakes and oxidative activity were measured in anesthetized mice in response to acute CL. Our results revealed iBAT as a major site of metabolic activity, which exhibited enhanced glucose and nonesterified fatty acid uptakes and oxidative activity in response to chronic cold and CL. On the other hand, beige adipose tissue failed to exhibit appreciable increase in oxidative activity in response to chronic cold and CL. Altogether, our results suggest that the contribution of beige fat to acute-CL-induced metabolic activity is low compared with that of iBAT, even after sustained adrenergic stimulation.

  9. Bilateral Repetitive Transcranial Magnetic Stimulation Combined with Intensive Swallowing Rehabilitation for Chronic Stroke Dysphagia: A Case Series Study

    Directory of Open Access Journals (Sweden)

    Ryo Momosaki

    2014-03-01

    Full Text Available The purpose of this study was to clarify the safety and feasibility of a 6-day protocol of bilateral repetitive transcranial magnetic stimulation (rTMS combined with intensive swallowing rehabilitation for chronic poststroke dysphagia. In-hospital treatment was provided to 4 poststroke patients (age at treatment: 56-80 years; interval between onset of stroke and treatment: 24-37 months with dysphagia. Over 6 consecutive days, each patient received 10 sessions of rTMS at 3 Hz applied to the pharyngeal motor cortex bilaterally, followed by 20 min of intensive swallowing rehabilitation exercise. The swallowing function was evaluated by the Penetration Aspiration Scale (PAS, Modified Mann Assessment of Swallowing Ability (MMASA, Functional Oral Intake Scale (FOIS, laryngeal elevation delay time (LEDT and Repetitive Saliva-Swallowing Test (RSST on admission and at discharge. All patients completed the 6-day treatment protocol and none showed any adverse reactions throughout the treatment. The combination treatment improved laryngeal elevation delay time in all patients. Our proposed protocol of rTMS plus swallowing rehabilitation exercise seems to be safe and feasible for chronic stroke dysphagia, although its efficacy needs to be confirmed in a large number of patients.

  10. Chronic Trigeminal Nerve Stimulation Protects Against Seizures, Cognitive Impairments, Hippocampal Apoptosis, and Inflammatory Responses in Epileptic Rats.

    Science.gov (United States)

    Wang, Qian-Qian; Zhu, Li-Jun; Wang, Xian-Hong; Zuo, Jian; He, Hui-Yan; Tian, Miao-Miao; Wang, Lei; Liang, Gui-Ling; Wang, Yu

    2016-05-01

    Trigeminal nerve stimulation (TNS) has recently been demonstrated effective in the treatment of epilepsy and mood disorders. Here, we aim to determine the effects of TNS on epileptogenesis, cognitive function, and the associated hippocampal apoptosis and inflammatory responses. Rats were injected with pilocarpine to produce status epilepticus (SE) and the following chronic epilepsy. After SE induction, TNS treatment was conducted for 4 consecutive weeks. A pilocarpine re-injection was then used to induce a seizure in the epileptic rats. The hippocampal neuronal apoptosis induced by seizure was assessed by TUNEL staining and inflammatory responses by immunohistochemistry and enzyme-linked immunosorbent assay (ELISA). The spontaneous recurrent seizure (SRS) number was counted through video monitoring, and the cognitive function assessed through Morris Water Maze (MWM) test. TNS treatment attenuated the SRS attacks and improved the cognitive impairment in epileptic rats. A pilocarpine re-injection resulted in less hippocampal neuronal apoptosis and reduced level of interleukin-1 beta (IL-1β), tumor necrosis factor-α (TNF-α), and microglial activation in epileptic rats with TNS treatment in comparison to the epileptic rats without TNS treatment. It is concluded that TNS treatment shortly after SE not only protected against the chronic spontaneous seizures but also improved cognitive impairments. These antiepileptic properties of TNS may be related to its attenuating effects on hippocampal apoptosis and pro-inflammatory responses.

  11. Bilateral Repetitive Transcranial Magnetic Stimulation Combined with Intensive Swallowing Rehabilitation for Chronic Stroke Dysphagia: A Case Series Study

    Science.gov (United States)

    Momosaki, Ryo; Abo, Masahiro; Kakuda, Wataru

    2014-01-01

    The purpose of this study was to clarify the safety and feasibility of a 6-day protocol of bilateral repetitive transcranial magnetic stimulation (rTMS) combined with intensive swallowing rehabilitation for chronic poststroke dysphagia. In-hospital treatment was provided to 4 poststroke patients (age at treatment: 56–80 years; interval between onset of stroke and treatment: 24–37 months) with dysphagia. Over 6 consecutive days, each patient received 10 sessions of rTMS at 3 Hz applied to the pharyngeal motor cortex bilaterally, followed by 20 min of intensive swallowing rehabilitation exercise. The swallowing function was evaluated by the Penetration Aspiration Scale (PAS), Modified Mann Assessment of Swallowing Ability (MMASA), Functional Oral Intake Scale (FOIS), laryngeal elevation delay time (LEDT) and Repetitive Saliva-Swallowing Test (RSST) on admission and at discharge. All patients completed the 6-day treatment protocol and none showed any adverse reactions throughout the treatment. The combination treatment improved laryngeal elevation delay time in all patients. Our proposed protocol of rTMS plus swallowing rehabilitation exercise seems to be safe and feasible for chronic stroke dysphagia, although its efficacy needs to be confirmed in a large number of patients. PMID:24803904

  12. Functional electrical stimulation mediated by iterative learning control and 3D robotics reduces motor impairment in chronic stroke

    Directory of Open Access Journals (Sweden)

    Meadmore Katie L

    2012-06-01

    Full Text Available Abstract Background Novel stroke rehabilitation techniques that employ electrical stimulation (ES and robotic technologies are effective in reducing upper limb impairments. ES is most effective when it is applied to support the patients’ voluntary effort; however, current systems fail to fully exploit this connection. This study builds on previous work using advanced ES controllers, and aims to investigate the feasibility of Stimulation Assistance through Iterative Learning (SAIL, a novel upper limb stroke rehabilitation system which utilises robotic support, ES, and voluntary effort. Methods Five hemiparetic, chronic stroke participants with impaired upper limb function attended 18, 1 hour intervention sessions. Participants completed virtual reality tracking tasks whereby they moved their impaired arm to follow a slowly moving sphere along a specified trajectory. To do this, the participants’ arm was supported by a robot. ES, mediated by advanced iterative learning control (ILC algorithms, was applied to the triceps and anterior deltoid muscles. Each movement was repeated 6 times and ILC adjusted the amount of stimulation applied on each trial to improve accuracy and maximise voluntary effort. Participants completed clinical assessments (Fugl-Meyer, Action Research Arm Test at baseline and post-intervention, as well as unassisted tracking tasks at the beginning and end of each intervention session. Data were analysed using t-tests and linear regression. Results From baseline to post-intervention, Fugl-Meyer scores improved, assisted and unassisted tracking performance improved, and the amount of ES required to assist tracking reduced. Conclusions The concept of minimising support from ES using ILC algorithms was demonstrated. The positive results are promising with respect to reducing upper limb impairments following stroke, however, a larger study is required to confirm this.

  13. Hepcidin-25 in chronic hemodialysis patients is related to residual kidney function and not to treatment with erythropoiesis stimulating agents.

    Directory of Open Access Journals (Sweden)

    Neelke C van der Weerd

    Full Text Available Hepcidin-25, the bioactive form of hepcidin, is a key regulator of iron homeostasis as it induces internalization and degradation of ferroportin, a cellular iron exporter on enterocytes, macrophages and hepatocytes. Hepcidin levels are increased in chronic hemodialysis (HD patients, but as of yet, limited information on factors associated with hepcidin-25 in these patients is available. In the current cross-sectional study, potential patient-, laboratory- and treatment-related determinants of serum hepcidin-20 and -25, were assessed in a large cohort of stable, prevalent HD patients. Baseline data from 405 patients (62% male; age 63.7 ± 13.9 [mean SD] enrolled in the CONvective TRAnsport STudy (CONTRAST; NCT00205556 were studied. Predialysis hepcidin concentrations were measured centrally with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Patient-, laboratory- and treatment related characteristics were entered in a backward multivariable linear regression model. Hepcidin-25 levels were independently and positively associated with ferritin (p<0.001, hsCRP (p<0.001 and the presence of diabetes (p = 0.02 and inversely with the estimated glomerular filtration rate (p = 0.01, absolute reticulocyte count (p = 0.02 and soluble transferrin receptor (p<0.001. Men had lower hepcidin-25 levels as compared to women (p = 0.03. Hepcidin-25 was not associated with the maintenance dose of erythropoiesis stimulating agents (ESA or iron therapy. In conclusion, in the currently studied cohort of chronic HD patients, hepcidin-25 was a marker for iron stores and erythropoiesis and was associated with inflammation. Furthermore, hepcidin-25 levels were influenced by residual kidney function. Hepcidin-25 did not reflect ESA or iron dose in chronic stable HD patients on maintenance therapy. These results suggest that hepcidin is involved in the pathophysiological pathway of renal anemia and iron availability in these patients, but

  14. Identification of Nod like receptor C3 (NLRC3) in Asian seabass, Lates calcarifer: Characterisation, ontogeny and expression analysis after experimental infection and ligand stimulation.

    Science.gov (United States)

    Paria, Anutosh; Deepika, A; Sreedharan, K; Makesh, M; Chaudhari, Aparna; Purushothaman, C S; Thirunavukkarasu, A R; Rajendran, K V

    2016-08-01

    Nod like receptors (NLRs) are a large group of cytoplasmic PRRs believed to play an important role in bacterial recognition in higher vertebrates. In this study, a novel Nod like receptor C3 (AsNLRC3) has been identified, cloned and characterised from Asian seabass, Lates calcarifer. The full-length AsNLRC3 transcript composed of a 4142 bp nucleic acid sequence encode for a protein of 1134 deduced amino acids. Three signature domains identified are conserved NACHT-domain, C-terminal LLR domain and N-terminal CARD effector domain. From the domain architecture and phylogenetic analysis, it was quite evident that AsNLRC3 is different from the NLR subfamily C of other teleosts. AsNLRC3 expressed in all the 11 tissues tested but highly expressed in tissues facing external environment such as gill, hindgut and midgut. The ontogenic expression profile of this receptor showed constitutive expression throughout the embryonic and larval developmental stages, which could be an innate immune strategy against different marine pathogens for larval survival. Infection with Vibrio alginolyticus and poly I:C induction showed an alteration of expression pattern in different tissues but did not show significant alteration in expression with Staphylococcus aureus infection. In vitro study in Asian seabass kidney cell line (SISK) stimulated with different ligands such as LPS, PGN and poly I:C showed considerable up-regulation at some of the time-points tested. These results suggest that AsNLRC3 can be a pivotal cytosolic innate immune receptor for recognizing wide array of pathogens in a euryhaline teleost model like Asian seabass in diverse environmental conditions.

  15. A dual pH/Redox responsive copper-ligand nanoliposome bioactive complex for the treatment of chronic inflammation.

    Science.gov (United States)

    Mavuso, Simphiwe; Choonara, Yahya E; Marimuthu, Thashree; Kumar, Pradeep; du Toit, Lisa C; Kondiah, Pierre P D; Pillay, Viness

    2016-07-25

    A novel dual pH/redox-responsive polymeric nanoliposome system (NLs) loaded with a copper-liganded bioactive complex was prepared and designed as a controlled delivery system for the management of inflammation. The NLs were synthesised after preparation of the copper-glyglycine-prednisolone succinate] ([(Cu(glygly)(PS)]) complex, and the dual pH/redox responsive biopolymer respectively. The methodology undertaken for the development of the drug delivery system involved coordination of the bioactive to Copper (II), preparation of dual pH/redox responsive biopolymer, and the synthesis of dual pH/redox nanoliposomes. Characterisations of the prepared copper-liganded bioactive [Copper-glyglycine-prednisolone succinate] ([(Cu(glygly)(PS)]) complex, dual pH/redox responsive biopolymer (Eudragit E100-cystamine) and [(Cu(glygly)(PS)]-loaded NLs were carried out using spectroscopic and physicochemical techniques. Results indicated a high inflammatory/oxidant inhibitory activity of [Cu(glygly)(PS)] in comparison to the free PS drug. The [Cu(glygly)(PS)] complex exhibited a significant free radical-scavenging activity (60.1±1.2%) and lipoxygenase (LOX-5) inhibitory activity (36.6±1.3%) in comparison to PS which resulted in activity of 4.4±1.4% and inhibition of 6.1±2.6% respectively. The [Cu(glygly)(PS)] loaded NLs demonstrated low release profiles of 22.9±5.4% in 6h at pH 7.4, in comparison to a significant accelerated release at pH 5 in a reducing environment of 75.9±3.7% over 6h duration. Results suggest that the novel copper-liganded bioactive delivery system with controlled drug release mechanism could serve as a potential drug delivery system candidate in the management of inflammation.

  16. Long-term changes in sleep and electroencephalographic activity by chronic vagus nerve stimulation in cats.

    Science.gov (United States)

    Valdés-Cruz, Alejandro; Magdaleno-Madrigal, Victor M; Martínez-Vargas, David; Fernández-Mas, Rodrigo; Almazán-Alvarado, Salvador

    2008-04-01

    We previously reported the effect of vagus nerve electrical stimulation (VNS) on sleep and behavior in cats. The aim of the present study is to analyze the long-term effects of VNS on the electroencephalographic (EEG) power spectrum and on the different stages of the sleep-wakefulness cycle in the freely moving cat. To achieve this, six male cats were implanted with electrodes on the left vagal nerve and submitted to 15 rounds of 23 h continuous sleep recordings in three categories: baseline (BL), VNS and post-stimulus recording (PSR). The following parameters were analyzed: EEG power spectrum, total time and number of sleep phases, ponto-geniculo-occipital (PGO) wave density of the rapid eye movement (REM) sleep, and the number of times the narcoleptic reflex was present (sudden transition from wakefulness to REM sleep). Significant changes were detected, such as an enhancement of slow-wave sleep (SWS) stage II; a power increase in the bands corresponding to sleep spindles (8-14 Hz) and delta waves (1-4 Hz) with VNS and PSR; an increase in the total time, number of stages, and density of PGO wave in REM sleep with VNS; a decrease of wakefulness in PSR, and the eventual appearance of the narcoleptic reflex with VNS. The results show that the effect of the VNS changes during different stages of the sleep-wakefulness cycle. In REM sleep, the effect was present only during VNS, while the SWS II was affected beyond VNS periods. This suggests that ponto-medullar and thalamic mechanisms of slow EEG activity may be due to plastic changes elicited by vagal stimulation.

  17. Different mechanisms for the short-term effects of real versus sham transcutaneous electrical nerve stimulation (TENS) in patients with chronic pain: a pilot study.

    NARCIS (Netherlands)

    Oosterhof, J.; Wilder-Smith, O.H.G.; Oostendorp, R.A.B.; Crul, B.J.P.

    2012-01-01

    Transcutaneous electrical nerve stimulation (TENS) has existed since the early 1970s. However, randomized placebo controlled studies show inconclusive results in the treatment of chronic pain. These results could be explained by assuming that TENS elicits a placebo response. However, in animal resea

  18. Outcome of transcutaneous electrical nerve stimulation in chronic pain: short-term results of a double-blind, randomised, placebo-controlled trial.

    NARCIS (Netherlands)

    Oosterhof, J.; Boo, T.M. de; Oostendorp, R.A.B.; Wilder-Smith, O.H.G.; Crul, B.J.P.

    2006-01-01

    The aim of this study was to test the efficacy of shortterm transcutaneous electrical nerve stimulation (TENS) treatment in chronic pain with respect to pain intensity and patients' satisfaction with treatment results. We therefore performed a randomised controlled trial comparing TENS and sham TENS

  19. Percutaneous neuromuscular electrical stimulation (P-NMES) for treating shoulder pain in chronic hemiplegia. Effects on shoulder pain and quality of life

    NARCIS (Netherlands)

    Renzenbrink, Gerbert J.; IJzerman, Maarten J.

    2004-01-01

    Objective: To evaluate the effect of percutaneous neuromuscular electrical stimulation (P-NMES) of the shoulder muscles on shoulder pain intensity and health-related quality of life in chronic hemiplegia. Design: Prospective, open label design. Setting: The outpatient services of a large teachin

  20. Chronic preclinical safety evaluation of EPO-018B, a pegylated peptidic erythropoiesis-stimulating agent in monkeys and rats.

    Science.gov (United States)

    Gong, Xue-Lian; Gu, Xiao-Lei; Chen, Yong-Chun; Zhu, Hai; Xia, Zhen-Na; Li, Jian-Zhong; Lu, Guo-Cai

    2016-09-15

    EPO-018B, a synthetic peptide-based erythropoiesis stimulating agent (ESA), is mainly designed for treatment of anemia caused by chronic renal failure and chemotherapy against cancer. It overcomes the deficiencies of currently approved ESA, including the frequent administration of temperature-sensitive recombinant protein and anti-EPO antibody-mediated pure red cell aplasia (PRCA). This study was designed to evaluate the potential chronic toxicity of EPO-018B. Subcutaneous administration doses were designed as 0, 0.2, 1 and 10mg/kg for six months for 160 rats (20/gender/group) and 0, 0.3, 3 and 20mg/kg for nine months for 32 monkeys (4/gender/group) once every three weeks. The vehicles received the same volume of physiological saline injection. All animals survived to the scheduled necropsies after six weeks (for rats) and fourteen weeks (for monkeys) recovery period, except for the two high-dose female rats and two high-dose male monkeys, which were considered related to the increased RBCs, chronic blood hyperviscosity and chronic cardiac injury. EPO-018B is supposed to be subcutaneously injected once every month and the intended human therapeutic dose is 0.025mg/kg. The study findings at 0.2mg/kg for rats and 0.3mg/kg for monkeys were considered to be the study NOAEL (the no observed adverse effect level), which were more than ten times the intended human therapeutic dose. Higher doses caused adverse effects related to the liver toxicity, cardiotoxicity, appearance of neutralizing antibodies of EPO-018B and the decrease of serum glucose and cholesterol. Most treatment-induced effects were reversible or revealed ongoing recovery upon the discontinuation of treatment. The sequelae occurred in rats and monkeys were considered secondary to exaggerated pharmacology and would less likely occur in the intended patient population. As to the differences between human beings and animals, the safety of EPO-018B need to be further confirmed in the future clinical studies.

  1. Distinct effects of chronic dopaminergic stimulation on hippocampal neurogenesis and striatal doublecortin expression in adult mice

    Directory of Open Access Journals (Sweden)

    Rachele eSalvi

    2016-03-01

    Full Text Available While adult neurogenesis is considered to be restricted to the hippocampal dentate gyrus (DG and the subventricular zone (SVZ, recent studies in humans and rodents provide evidence for newly generated neurons in regions generally considered as non-neurogenic, e.g. the striatum. Stimulating dopaminergic neurotransmission has the potential to enhance adult neurogenesis in the SVZ and the DG most likely via D2/D3 dopamine (DA receptors. Here, we investigated the effect of two distinct preferential D2/D3 DA agonists, Pramipexole (PPX and Ropinirole (ROP, on adult neurogenesis in the hippocampus and striatum of adult naïve mice. To determine newly generated cells in the DG incorporating 5-bromo-2'-deoxyuridine (BrdU a proliferation paradigm was performed in which two BrdU injections (100 mg/kg were applied intraperitoneally within 12 hours after a 14-day-DA agonist treatment. Interestingly, PPX, but not ROP significantly enhanced the proliferation in the DG by 42% compared to phosphate buffered saline (PBS-injected control mice. To analyze the proportion of newly generated cells differentiating into mature neurons, we quantified cells co-expressing BrdU and NeuN 32 days after the last of five BrdU injections (50 mg/kg applied at the beginning of 14-day DA agonist or PBS administration. Again, PPX only enhanced neurogenesis in the DG significantly compared to ROP- and PBS-injected mice. Moreover, we explored the pro-neurogenic effect of both DA agonists in the striatum by quantifying neuroblasts expressing doublecortin (DCX in the entire striatum, as well as in the dorsal and ventral sub-regions separately. We observed a significantly higher number of DCX+ neuroblasts in the dorsal compared to the ventral sub-region of the striatum in PPX-injected mice. These results suggest that the stimulation of hippocampal and dorsal striatal neurogenesis may be up-regulated by PPX. The increased generation of neural cells, both in constitutively active and

  2. Chronic warming stimulates growth of marsh grasses more than mangroves in a coastal wetland ecotone.

    Science.gov (United States)

    Coldren, G A; Barreto, C R; Wykoff, D D; Morrissey, E M; Langley, J A; Feller, I C; Chapman, S K

    2016-11-01

    Increasing temperatures and a reduction in the frequency and severity of freezing events have been linked to species distribution shifts. Across the globe, mangrove ranges are expanding toward higher latitudes, likely due to diminishing frequency of freezing events associated with climate change. Continued warming will alter coastal wetland plant dynamics both above- and belowground, potentially altering plant capacity to keep up with sea level rise. We conducted an in situ warming experiment, in northeast Florida, to determine how increased temperature (+2°C) influences co-occurring mangrove and salt marsh plants. Warming was achieved using passive warming with three treatment levels (ambient, shade control, warmed). Avicennia germinans, the black mangrove, exhibited no differences in growth or height due to experimental warming, but displayed a warming-induced increase in leaf production (48%). Surprisingly, Distichlis spicata, the dominant salt marsh grass, increased in biomass (53% in 2013 and 70% in 2014), density (41%) and height (18%) with warming during summer months. Warming decreased plant root mass at depth and changed abundances of anaerobic bacterial taxa. Even while the poleward shift of mangroves is clearly controlled by the occurrences of severe freezes, chronic warming between these freeze events may slow the progression of mangrove dominance within ecotones.

  3. Renin-angiotensin system stimulates erythropoietin secretion in chronic hemodialysis patients.

    Science.gov (United States)

    Vlahakos, D V; Balodimos, C; Papachristopoulos, V; Vassilakos, P; Hinari, E; Vlachojannis, J G

    1995-01-01

    A series of observations suggests an interrelationship between the renin-angiotensin system (RAS) and erythropoietin (EPO) secretion. To further evaluate the role of RAS in erythropoiesis of chronic hemodialysis patients, we studied two groups of such patients: Group A consisted of 16 patients (14 male and 2 female, 54.7 +/- 3.3 years old), who maintained a target hematocrit value of 0.30 (0.32 +/- 0.01), without recombinant human EPO (rhEPO) supplementation. Group B consisted of 14 patients (7 male and 7 female, 50 +/- 5.3 years old), who required subcutaneous injections of rhEPO (90.8 +/- 10 IU.kg-1.week-1), to maintain the same target hematocrit value of 0.30 (30 +/- 0.01). Plasma renin activity (PRA) was found to be the major feature to distinguish patients in these two Groups and it was five times higher in Group A (10 +/- 2 ng.ml-1.h-1) compared to Group B patients (1.8 +/- 0.6 ng.ml-1.h-1) (p < 0.001). Moreover, activation of RAS in Group A patients by volume depletion (2.2 +/- 0.2 l) during hemodialysis resulted in a 118 +/- 33 percent increment of PRA (p < 0.01) which was accompanied by a 69 +/- 25 percent increment of serum EPO levels (p < 0.05). Repetition of the same protocol after inhibiting the converting enzyme with 50 mg of Captopril prior to dialysis session, resulted in a 315 +/- 64 percent increment of PRA (p < 0.001), while at the same time completely blocked the expected rise in serum EPO levels (1.25 +/- 12.5 percent increment).(ABSTRACT TRUNCATED AT 250 WORDS)

  4. Toll-like receptor 22 in Labeo rohita: molecular cloning, characterization, 3D modeling, and expression analysis following ligands stimulation and bacterial infection.

    Science.gov (United States)

    Samanta, Mrinal; Swain, Banikalyan; Basu, Madhubanti; Mahapatra, Girishbala; Sahoo, Bikash R; Paichha, Mahismita; Lenka, Saswati S; Jayasankar, Pallipuram

    2014-09-01

    Toll-like receptors (TLRs) are a class of innate immune receptors that sense pathogens or their molecular signatures and activate signaling cascades to induce a quick and non-specific immune response in the host. Among various types of TLRs, TLR22 is exclusively present in teleosts and amphibians and is expected to play the distinctive role in innate immunity. This report describes molecular cloning, three-dimensional (3D) modeling, and expression analysis of TLR22 in rohu (Labeo rohita), the most commercially important freshwater fish species in the Indian subcontinent. The open reading frame (ORF) of rohu TLR22 (LrTLR22) comprised of 2,838 nucleotides (nt), encoding 946 amino acid (aa) residues with the molecular mass of ∼ 107.6 kDa. The secondary structure of deduced LrTLR22 exhibited the presence of signal peptide (1-22 aa), 18 leucine-rich repeat (LRR) regions (79-736 aa), and TIR domain (792-935 aa). The 3D model of LrTLR22-LRR regions together elucidated the horse-shoe-shaped structure having parallel β-strands at the concave surface and few α-helices at the convex surface. The TIR domain structure revealed alternate presence of five α-helices and β-sheets. Phylogenetically, LrTLR22 was closely related to common carp and exhibited significant similarity (92.2 %) and identity (86.1 %) in their amino acids. In rohu, TLR22 was constitutively expressed in all embryonic developmental stages, and tissue-specific analysis illustrated its expression in all examined tissues, highest was in liver and lowest in brain. In vivo modulation of TLR22 gene expression was analyzed by quantitative real-time PCR (qRT-PCR) assay following stimulation with lipopolysaccharide (LPS), synthetic double stranded RNA (polyinosinic-polycytidylic acid), and bacterial (Aeromonas hydrophila) RNA. Among these ligands, bacterial RNA most significantly (p < 0.05) induced TLR22 gene expression in most of the tested tissues. In A. hydrophila infection, induction of TLR22 gene expression

  5. Different mechanisms for the short-term effects of real versus sham transcutaneous electrical nerve stimulation (TENS) in patients with chronic pain: a pilot study.

    Science.gov (United States)

    Oosterhof, Jan; Wilder-Smith, Oliver H; Oostendorp, Rob A; Crul, Ben J

    2012-01-01

    Transcutaneous electrical nerve stimulation (TENS) has existed since the early 1970s. However, randomized placebo controlled studies show inconclusive results in the treatment of chronic pain. These results could be explained by assuming that TENS elicits a placebo response. However, in animal research TENS has been found to decrease hyperalgesia, which contradicts this assumption. The aim of this study is to use quantitative sensory testing to explore changes in pain processing during sham versus real TENS in patients with chronic pain. Patients with chronic pain (N = 20) were randomly allocated to real TENS or sham TENS application. Electrical pain thresholds (EPTs) were determined inside and outside the segment stimulated, before and after the first 20 minutes of the intervention, and after a period of 10 days of daily real/sham TENS application. Pain relief did not differ significantly for real versus sham TENS. However, by comparing time courses of EPTs, it was found that EPT values outside the segment of stimulation increased for sham TENS, whereas for real TENS these values decreased. There were, however, no differences for EPT measurements inside the segment stimulated. These results illustrate the importance of including mechanism-reflecting parameters in addition to symptoms when conducting pain research.

  6. Transcranial Alternating Current Stimulation in Patients with Chronic Disorder of Consciousness: A Possible Way to Cut the Diagnostic Gordian Knot?

    Science.gov (United States)

    Naro, Antonino; Bramanti, Placido; Leo, Antonino; Russo, Margherita; Calabrò, Rocco Salvatore

    2016-07-01

    Unresponsive wakefulness syndrome (UWS) is a chronic disorder of consciousness (DOC) characterized by a lack of awareness and purposeful motor behaviors, owing to an extensive brain connectivity impairment. Nevertheless, some UWS patients may retain residual brain connectivity patterns, which may sustain a covert awareness, namely functional locked-in syndrome (fLIS). We evaluated the possibility of bringing to light such residual neural networks using a non-invasive neurostimulation protocol. To this end, we enrolled 15 healthy individuals and 26 DOC patients (minimally conscious state-MCS- and UWS), who underwent a γ-band transcranial alternating current stimulation (tACS) over the right dorsolateral prefrontal cortex. We measured the effects of tACS on power and partial-directed coherence within local and long-range cortical networks, before and after the protocol application. tACS was able to specifically modulate large-scale cortical effective connectivity and excitability in all the MCS participants and some UWS patients, who could be, therefore, considered as suffering from fLIS. Hence, tACS could be a useful approach in supporting a DOC differential diagnosis, depending on the level of preservation of the cortical large-scale effective connectivity.

  7. Analgesic effect of repetitive transcranial magnetic stimulation (rTMS) in patients with chronic low back pain.

    Science.gov (United States)

    Ambriz-Tututi, Mónica; Alvarado-Reynoso, Beatriz; Drucker-Colín, René

    2016-08-22

    The objective of the present study was to assess the benefits of 1-week repetitive transcranial magnetic stimulation (rTMS) in patients with chronic low back pain (LBP). The visual analogue scale (VAS), Short Form McGill pain questionnaire (SF-MPQ), and Short Form 36 Health Survey were used to evaluate the effect of this treatment. Eighty-two patients diagnosed with LBP were divided randomly into three groups: rTMS-treated group, sham group, and physical therapy-treated group. We observed a significant reduction in VAS and SF-MPQ scores in the rTMS-treated group, but not in the sham group. Moreover, patients who received rTMS had a lower mean pain score than patients treated with physical therapy. Our study suggests that rTMS produces safe, significant, and long-term relief in patients with LBP without evident side effects. This study shows for the first time that long-term repeated sessions of rTMS decrease pain perception of LBP. Bioelectromagnetics. © 2016 Wiley Periodicals, Inc.

  8. Rational design and synthesis of altered peptide ligands based on human myelin oligodendrocyte glycoprotein 35-55 epitope: inhibition of chronic experimental autoimmune encephalomyelitis in mice.

    Science.gov (United States)

    Tselios, Theodore; Aggelidakis, Mihalis; Tapeinou, Anthi; Tseveleki, Vivian; Kanistras, Ioannis; Gatos, Dimitrios; Matsoukas, John

    2014-11-04

    Experimental autoimmune encephalomyelitis (EAE) is a demyelinating disease of the central nervous system and is an animal model of multiple sclerosis (MS). Although the etiology of MS remains unclear, there is evidence T-cell recognition of immunodominant epitopes of myelin proteins, such as the 35-55 epitope of myelin oligodendrocyte glycoprotein (MOG), plays a pathogenic role in the induction of chronic EAE. Cyclization of peptides is of great interest since the limited stability of linear peptides restricts their potential use as therapeutic agents. Herein, we have designed and synthesized a number of linear and cyclic peptides by mutating crucial T cell receptor (TCR) contact residues of the human MOG35-55 epitope. In particular, we have designed and synthesized cyclic altered peptide ligands (APLs) by mutating Arg41 with Ala or Arg41 and Arg46 with Ala. The peptides were synthesized in solid phase on 2-chlorotrityl chloride resin (CLTR-Cl) using the Fmoc/t-Bu methodology. The purity of final products was verified by RP-HPLC and their identification was achieved by ESI-MS. It was found that the substitutions of Arg at positions 41 and 46 with Ala results in peptide analogues that reduce the severity of MOG-induced EAE clinical symptoms in C57BL/6 mice when co-administered with mouse MOG35-55 peptide at the time of immunization.

  9. Rational Design and Synthesis of Altered Peptide Ligands based on Human Myelin Oligodendrocyte Glycoprotein 35–55 Epitope: Inhibition of Chronic Experimental Autoimmune Encephalomyelitis in Mice

    Directory of Open Access Journals (Sweden)

    Theodore Tselios

    2014-11-01

    Full Text Available Experimental autoimmune encephalomyelitis (EAE is a demyelinating disease of the central nervous system and is an animal model of multiple sclerosis (MS. Although the etiology of MS remains unclear, there is evidence T-cell recognition of immunodominant epitopes of myelin proteins, such as the 35–55 epitope of myelin oligodendrocyte glycoprotein (MOG, plays a pathogenic role in the induction of chronic EAE. Cyclization of peptides is of great interest since the limited stability of linear peptides restricts their potential use as therapeutic agents. Herein, we have designed and synthesized a number of linear and cyclic peptides by mutating crucial T cell receptor (TCR contact residues of the human MOG35–55 epitope. In particular, we have designed and synthesized cyclic altered peptide ligands (APLs by mutating Arg41 with Ala or Arg41 and Arg46 with Ala. The peptides were synthesized in solid phase on 2-chlorotrityl chloride resin (CLTR-Cl using the Fmoc/t-Bu methodology. The purity of final products was verified by RP-HPLC and their identification was achieved by ESI-MS. It was found that the substitutions of Arg at positions 41 and 46 with Ala results in peptide analogues that reduce the severity of MOG-induced EAE clinical symptoms in C57BL/6 mice when co-administered with mouse MOG35–55 peptide at the time of immunization.

  10. Cerebral responses to innocuous somatic pressure stimulation following aerobic exercise rehabilitation in chronic pain patients: a functional magnetic resonance imaging study

    Directory of Open Access Journals (Sweden)

    Micalos PS

    2014-08-01

    Full Text Available Peter S Micalos,1 Mayuresh S Korgaonkar,2 Eric J Drinkwater,3 Jack Cannon,3 Frank E Marino3 1School of Biomedical Sciences, Charles Sturt University, Bathurst, 2Brain Dynamics Centre, Westmead Millennium Institute, University of Sydney Medical School, Sydney, 3School of Human Movement Studies, Charles Sturt University, Bathurst, NSW, Australia Objective: The purpose of this research was to assess the functional brain activity and perceptual rating of innocuous somatic pressure stimulation before and after exercise rehabilitation in patients with chronic pain. Materials and methods: Eleven chronic pain patients and eight healthy pain-free controls completed 12 weeks of supervised aerobic exercise intervention. Perceptual rating of standardized somatic pressure stimulation (2 kg on the right anterior mid-thigh and brain responses during functional magnetic resonance imaging (fMRI were assessed at pre- and postexercise rehabilitation. Results: There was a significant difference in the perceptual rating of innocuous somatic pressure stimulation between the chronic pain and control groups (P=0.02 but no difference following exercise rehabilitation. Whole brain voxel-wise analysis with correction for multiple comparisons revealed trends for differences in fMRI responses between the chronic pain and control groups in the superior temporal gyrus (chronic pain > control, corrected P=0.30, thalamus, and caudate (control > chronic, corrected P=0.23. Repeated measures of the regions of interest (5 mm radius for blood oxygen level-dependent signal response revealed trend differences for superior temporal gyrus (P=0.06, thalamus (P=0.04, and caudate (P=0.21. Group-by-time interactions revealed trend differences in the caudate (P=0.10 and superior temporal gyrus (P=0.29. Conclusion: Augmented perceptual and brain responses to innocuous somatic pressure stimulation were shown in the chronic pain group compared to the control group; however, 12-weeks of exercise

  11. Mechanisms underlying enhancements in muscle force and power output during maximal cycle ergometer exercise induced by chronic β2-adrenergic stimulation in men

    DEFF Research Database (Denmark)

    Hostrup, Morten; Kalsen, Anders; Onslev, Johan;

    2015-01-01

    The study was a randomized placebo-controlled trial investigating mechanisms by which chronic β2-adrenergic stimulation enhances muscle force and power output during maximal cycle ergometer exercise in young men. Eighteen trained men were assigned to an experimental group [oral terbutaline 5 mg/3...... that muscle hypertrophy is the primary mechanism underlying enhancements in muscle force and peak power during maximal cycling induced by chronic β2-adrenergic stimulation in humans.......The study was a randomized placebo-controlled trial investigating mechanisms by which chronic β2-adrenergic stimulation enhances muscle force and power output during maximal cycle ergometer exercise in young men. Eighteen trained men were assigned to an experimental group [oral terbutaline 5 mg/30...... kg body weight (bw) twice daily (TER); n = 9] or a control group [placebo (PLA); n = 9] for a 4-wk intervention. No changes were observed with the intervention in PLA. Isometric muscle force of the quadriceps increased (P ≤ 0.01) by 97 ± 29 N (means ± SE) with the intervention in TER compared...

  12. Occipital peripheral nerve stimulation in the management of chronic intractable occipital neuralgia in a patient with neurofibromatosis type 1: a case report

    Directory of Open Access Journals (Sweden)

    Calvillo Octavio

    2011-05-01

    Full Text Available Abstract Introduction Occipital peripheral nerve stimulation is an interventional pain management therapy that provides beneficial results in the treatment of refractory chronic occipital neuralgia. Herein we present a first-of-its-kind case study of a patient with neurofibromatosis type 1 and bilateral occipital neuralgia treated with occipital peripheral nerve stimulation. Case presentation A 42-year-old Caucasian woman presented with bilateral occipital neuralgia refractory to various conventional treatments, and she was referred for possible treatment with occipital peripheral nerve stimulation. She was found to be a suitable candidate for the procedure, and she underwent implantation of two octapolar stimulating leads and a rechargeable, programmable, implantable generator. The intensity, severity, and frequency of her symptoms resolved by more than 80%, but an infection developed at the implantation site two months after the procedure that required explantation and reimplantation of new stimulating leads three months later. To date she continues to experience symptom resolution of more than 60%. Conclusion These results demonstrate the significance of peripheral nerve stimulation in the management of refractory occipital neuralgias in patients with neurofibromatosis type 1 and the possible role of neurofibromata in the development of occipital neuralgia in these patients.

  13. A comparison of the effects of repetitive transcranial magnetic stimulation (rTMS) by number of stimulation sessions on hemispatial neglect in chronic stroke patients.

    Science.gov (United States)

    Kim, Yong Kyun; Jung, Jae Hwan; Shin, Sung Hun

    2015-01-01

    We investigated the effect of repetitive transcranial magnetic stimulation (rTMS) applied either during one session of stimulation, or by ten sessions of low-frequency stimulation over the left parietal cortex, on hemispatial neglect in stroke patients. We enrolled 34 subjects that had experienced a stroke. All subjects received 1,200 real rTMS over the left parietal cortex at an intensity of 90% of motor thresholds with 1 Hz. Subjects were divided into two groups. One group of subjects (n = 19) received real rTMS over the left parietal cortex in a single session of stimulation, and the other group (n = 15), underwent a total of ten sessions of daily stimulations for 2 weeks. Letter cancelation test, line bisection test, and Ota's task were administered to compare the effects of different rTMS protocols, before and after rTMS. The results showed no difference in baseline value between the single session group and the ten sessions group. Total ten sessions of low-frequency rTMS over the left parietal cortex, compared with the single session of rTMS, significantly improved hemispatial neglect in letter cancelation, line bisection, and Ota's task (P rTMS can be used in treatment by rTMS for patients suffering from hemispatial neglect after stroke.

  14. Chronic TNFalpha and cAMP pre-treatment of human adipocytes alter HSL, ATGL and perilipin to regulate basal and stimulated lipolysis.

    Science.gov (United States)

    Bézaire, Véronic; Mairal, Aline; Anesia, Rodica; Lefort, Corinne; Langin, Dominique

    2009-09-17

    We examined the effects of chronic TNFalpha and dibutyryl-cAMP (Db-cAMP) pre-treatment on the lipolytic machinery of human hMADS adipocytes. TNFalpha decreased adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) protein content and triglycerides (TG)-hydrolase activity but increased basal lipolysis due to a marked reduction in perilipin (PLIN) protein content. Conversely, Db-cAMP increased ATGL and HSL protein content but prevented PLIN phosphorylation, the net result being accentuated basal lipolysis. In forskolin-stimulated conditions, TNFalpha and Db-cAMP pre-treatment decreased stimulated TG-hydrolase activity and impaired PLIN phosphorylation. Together, this resulted in a severely attenuated response to forskolin-stimulated lipolysis.

  15. Taking Sides: An Integrative Review of the Impact of Laterality and Polarity on Efficacy of Therapeutic Transcranial Direct Current Stimulation for Anomia in Chronic Poststroke Aphasia

    Directory of Open Access Journals (Sweden)

    Margaret Sandars

    2016-01-01

    Full Text Available Anomia is a frequent and persistent symptom of poststroke aphasia, resulting from damage to areas of the brain involved in language production. Cortical neuroplasticity plays a significant role in language recovery following stroke and can be facilitated by behavioral speech and language therapy. Recent research suggests that complementing therapy with neurostimulation techniques may enhance functional gains, even amongst those with chronic aphasia. The current review focuses on the use of transcranial Direct Current Stimulation (tDCS as an adjunct to naming therapy for individuals with chronic poststroke aphasia. Our survey of the literature indicates that combining therapy with anodal (excitatory stimulation to the left hemisphere and/or cathodal (inhibitory stimulation to the right hemisphere can increase both naming accuracy and speed when compared to the effects of therapy alone. However, the benefits of tDCS as a complement to therapy have not been yet systematically investigated with respect to site and polarity of stimulation. Recommendations for future research to help determine optimal protocols for combined therapy and tDCS are outlined.

  16. Taking Sides: An Integrative Review of the Impact of Laterality and Polarity on Efficacy of Therapeutic Transcranial Direct Current Stimulation for Anomia in Chronic Poststroke Aphasia.

    Science.gov (United States)

    Sandars, Margaret; Cloutman, Lauren; Woollams, Anna M

    2016-01-01

    Anomia is a frequent and persistent symptom of poststroke aphasia, resulting from damage to areas of the brain involved in language production. Cortical neuroplasticity plays a significant role in language recovery following stroke and can be facilitated by behavioral speech and language therapy. Recent research suggests that complementing therapy with neurostimulation techniques may enhance functional gains, even amongst those with chronic aphasia. The current review focuses on the use of transcranial Direct Current Stimulation (tDCS) as an adjunct to naming therapy for individuals with chronic poststroke aphasia. Our survey of the literature indicates that combining therapy with anodal (excitatory) stimulation to the left hemisphere and/or cathodal (inhibitory) stimulation to the right hemisphere can increase both naming accuracy and speed when compared to the effects of therapy alone. However, the benefits of tDCS as a complement to therapy have not been yet systematically investigated with respect to site and polarity of stimulation. Recommendations for future research to help determine optimal protocols for combined therapy and tDCS are outlined.

  17. Chronic ethanol intake modifies pyrrolidon carboxypeptidase activity in mouse frontal cortex synaptosomes under resting and K+ -stimulated conditions: role of calcium.

    Science.gov (United States)

    Mayas, María Dolores; Ramírez-Expósito, María Jesús; García-López, María Jesús; Carrera, María Pilar; Martínez-Martos, José Manuel

    2008-07-04

    Pyrrolidon carboxypeptidase (Pcp) is an omega peptidase that removes pyroglutamyl N-terminal residues of peptides such as thyrotrophin-releasing hormone (TRH), which is one of the neuropeptides that has been localized into many areas of the brain and acts as an endogenous neuromodulator of several parameters related to ethanol (EtOH) consumption. In this study, we analysed the effects of chronic EtOH intake on Pcp activity on mouse frontal cortex synaptosomes and their corresponding supernatant under basal and K+ -stimulated conditions, in presence and absence of calcium (Ca2+) to know the regulation of Pcp on TRH. In basal conditions, chronic EtOH intake significantly decreased synaptosomes Pcp activity but only in absence of Ca2+. However, supernatant Pcp activity is also decreased in presence and absence of calcium. Under K+-stimulated conditions, chronic EtOH intake decreased synaptosomes Pcp activity but only in absence of Ca2+, whereas supernatant Pcp activity was significantly decreased only in presence of Ca2+. The general inhibitory effect of chronic EtOH intake on Pcp activity suggests an inhibition of TRH metabolism and an enhancement of TRH neurotransmitter/neuromodulator functions, which could be related to putative processes of tolerance to EtOH in which TRH has been involved. Our data may also indicate that active peptides and their degrading peptidases are released together to the synaptic cleft to regulate the neurotransmitter/neuromodulator functions of these peptides, through a Ca2+ -dependent mechanism.

  18. Enhanced interleukin-1beta production of PBMCs from patients with gout after stimulation with Toll-like receptor-2 ligands and urate crystals

    NARCIS (Netherlands)

    Mylona, E.E.; Mouktaroudi, M.; Crisan, T.O.; Makri, S.; Pistiki, A.; Georgitsi, M.; Savva, A.; Netea, M.G.; Meer, J.W. van der; Giamarellos-Bourboulis, E.J.; Joosten, L.A.B.

    2012-01-01

    ABSTRACT: INTRODUCTION: Monosodium urate monohydrate (MSU) crystals synergize with various toll-like receptor (TLR) ligands to induce cytokine production via activation of the NOD-like receptor (NLR) family, pyrin domain-containing 3 (NLPR3) inflammasome. This has been demonstrated in vitro using hu

  19. Repetitive transcranial magnetic stimulation for the treatment of chronic tinnitus after traumatic brain injury: a case study.

    Science.gov (United States)

    Kreuzer, Peter Michael; Landgrebe, Michael; Frank, Elmar; Langguth, Berthold

    2013-01-01

    Tinnitus is a frequent symptom of traumatic brain injury, which is difficult to treat. Repetitive transcranial magnetic stimulation has shown beneficial effects in some forms of tinnitus. However, traumatic brain injury in the past has been considered as a relative contraindication for repetitive transcranial magnetic stimulation because of the increased risk of seizures. Here we present the case of a 53-year-old male patient suffering from severe tinnitus after traumatic brain injury with comorbid depression and alcohol abuse, who received 5 treatment series of repetitive transcranial magnetic stimulation (1 Hz stimulation protocol over left primary auditory cortex, 10 sessions of 2000 stimuli each, stimulation intensity 110% resting motor threshold). Repetitive transcranial magnetic stimulation was tolerated without any side effects and tinnitus complaints (measured by a validated tinnitus questionnaire and numeric rating scales) were improved in a replicable way throughout 5 courses of transcranial magnetic stimulation up to now.

  20. The effect of transcranial direct current stimulation on the expression of the flexor synergy in the paretic arm in chronic stroke is dependent on shoulder abduction loading.

    Science.gov (United States)

    Yao, Jun; Drogos, Justin; Veltink, Fleur; Anderson, Caitlyn; Concha Urday Zaa, Janny; Hanson, Laura Imming; Dewald, Julius P A

    2015-01-01

    Reaching ability of the paretic upper extremity in individuals with stroke decreases with increased shoulder abduction (SABD) loads. Transcranial direct current stimulation (tDCS) has been implemented to improve movement ability following stroke. However, results from previous studies vary, perhaps due to the influence of impairment level and the type of motor tasks that were used to study the effects of tDCS. This study specifically examines the impact of SABD loading on the effects of tDCS in 9 individuals with moderate to severe chronic stroke. In 3 different sessions, participants repeated a reaching assessment with various SABD loads (supported on a haptic table, 25%, and 50% of maximum voluntary SABD torque) in random order, pre and post one of the following 15-min tDCS protocols: anodal stimulation of lesioned M1, cathodal stimulation of non-lesioned M1, or anodal stimulation of non-lesioned M1. Sham stimulation was also conducted preceding one of the tDCS sessions. The averaged maximum reaching distance over valid trials was calculated for each condition. We observed significant interactions between SABD load, tDCS protocol and time (i.e., pre or post-tDCS). Post hoc test showed that anodal stimulation of the lesioned M1 caused a clear trend (p = 0.058) of increasing the reaching ability at a medium level of SABD loading (25%), but not for higher loads (50%). This suggests that anodal stimulation increases residual corticospinal tract activity, which successfully increases reaching ability at moderate loads; however, is insufficient to make significant changes at higher SABD loads. We also found that cathodal stimulation of the non-lesioned M1 significantly (p = 0.018) decreased the reaching distance at a high level of SABD loading (50%). This study demonstrated, for the first time, that the effect of tDCS on the reaching ability is dependent on SABD loads in individuals with moderate to severe stroke.

  1. Donor-Recipient Matching for KIR Genotypes Reduces Chronic GVHD and Missing Inhibitory KIR Ligands Protect against Relapse after Myeloablative, HLA Matched Hematopoietic Cell Transplantation.

    Directory of Open Access Journals (Sweden)

    Rehan Mujeeb Faridi

    Full Text Available Allogeneic hematopoietic cell transplantation (HCT can be curative for many hematologic diseases. However, complications such as graft-versus-host disease (GVHD and relapse of primary malignancy remain significant and are the leading causes of morbidity and mortality. Effects of killer Ig-like receptors (KIR-influenced NK cells on HCT outcomes have been extensively pursued over the last decade. However, the relevance of the reported algorithms on HLA matched myeloablative HCT with rabbit antithymocyte globulin (ATG is used for GVHD prophylaxis remains elusive. Here we examined the role of KIR and KIR-ligands of donor-recipient pairs in modifying the outcomes of ATG conditioned HLA matched sibling and unrelated donor HCT.The study cohort consisted of 281 HLA matched sibling and unrelated donor-recipient pairs of first allogeneic marrow or blood stem cell transplantation allocated into 'discovery' (135 pairs and 'validation' (146 pairs cohorts. High resolution HLA typing was obtained from the medical charts and KIR gene repertoires were obtained by a Luminex® based SSO method. All surviving patients were followed-up for a minimum of two years. KIR and HLA class I distributions of HCT pairs were stratified as per applicable definitions and were tested for their association with cause specific outcomes [acute GVHD grade II-IV (aGVHD, chronic GVHD needing systemic therapy (cGVHD and relapse] using a multivariate competing risks regression model as well as with survival outcomes [relapse-free survival (RFS, cGVHD & relapse free survival (cGRFS and overall survival (OS] by multivariate Cox proportional hazards regression model. A significant association between KIR genotype mismatching (KIR-B/x donor into KIR-AA recipient or vice versa and cGVHD was found in both discovery (p = 0.001; SHR = 2.78; 95%CI: 1.50-5.17 and validation cohorts (p = 0.005; SHR = 2.61; 95%CI: 1.33-5.11. High incidence of cGVHD associated with KIR genotype mismatching was

  2. Stimulation of allergen-loaded macrophages by TLR9-ligand potentiates IL-10-mediated suppression of allergic airway inflammation in mice

    Directory of Open Access Journals (Sweden)

    Hofman Gerard A

    2004-11-01

    Full Text Available Abstract Background Previously, we demonstrated that OVA-loaded macrophages (OVA-Mφ partially suppress OVA-induced airway manifestations of asthma in BALB/c mice. In vitro studies showed that OVA-Mφ start to produce IL-10 upon interaction with allergen-specific T cells, which might mediate their immunosuppressive effects. Herein, we examined whether IL-10 is essential for the immunosuppressive effects of OVA-Mφ in vivo, and whether ex vivo stimulation of the IL-10 production by OVA-Mφ could enhance these effects. Methods Peritoneal Mφ were loaded with OVA and stimulated with LPS or immunostimulatory sequence oligodeoxynucleotide (ISS-ODN in vitro. The increase of IL-10 production was examined and, subsequently, ex vivo stimulated OVA-Mφ were used to treat (i.v. OVA-sensitized mice. To further explore whether Mφ-derived IL-10 mediates the immunosuppressive effects, Mφ isolated from IL-10-/- mice were used for treatment. Results We found that stimulation with LPS or ISS-ODN highly increased the IL-10 production by OVA-Mφ (2.5-fold and 4.5-fold increase, respectively. ISS-ODN stimulation of OVA-Mφ significantly potentiated the suppressive effects on allergic airway inflammation. Compared to sham-treatment, ISS-ODN-stimulated OVA-Mφ suppressed the airway eosinophilia by 85% (vs. 30% by unstimulated OVA-Mφ, IL-5 levels in bronchoalveolar lavage fluid by 80% (vs. 50% and serum OVA-specific IgE levels by 60% (vs. 30%. Importantly, IL-10-/-Mφ that were loaded with OVA and stimulated with ISS-ODN ex vivo, failed to suppress OVA-induced airway inflammation. Conclusions These results demonstrate that Mφ-derived IL-10 mediates anti-inflammatory responses in a mouse model of allergic asthma, which both can be potentiated by stimulation with ISS-ODN.

  3. β-adrenergic response modulated by κ-opioid receptor stimulation is attenuated in the cardiomyocytes of rats following chronic hypoxia

    Institute of Scientific and Technical Information of China (English)

    裴建明; 毕辉; 王跃民; 朱妙章; 周京军; 朱运龙

    2003-01-01

    Objective: To study cross-talk between β-opioid receptor and β-adrenoceptor through determination of the intracellular calcium ([Ca2+]i) and cAMP responses in ventricular myocytes of rats subjected to chronic hypoxia for 4 weeks.Methods: Electrically-induced [Ca2+]i transient was measured in single right ventricular myocytes isolated from hearts of chronically hypoxic rats and the age-matched normoxic rats, by using a spectrofluorometric method.Results: β-adrenoceptor stimulation with isoproterenol increased the electrically-induced [Ca2+]i transient and cAMP in myocytes of normoxic rats.U50,488H, a selective β-opioid receptor agonist, at dose (1 μmol/L) which itself had no effect on the [Ca2+]i transient and cAMP, significantly inhibited the effect of isoproterenol.This inhibition was completely abolished in the presence of nor-BNI, a selective κ-opioid receptor antagonist.In the ventricular myocytes of chronically hypoxic rats, the inhibition of U50,488H on the increased [Ca2+]i transient and cAMP with isoproterenol was blunted.Conclusion: Results indicate that the cross-talk between the κ-opioid receptor and β-adrenoceptor is attenuated in the right ventricular myocytes of chronically hypoxic rat.This may be a self-protective mechanism of the heart following chronic hypoxia, which prevents the further decrease of the cardiac function.

  4. The Effect of Radial Extracorporeal Shock Wave Stimulation on Upper Limb Spasticity in Chronic Stroke Patients: A Single-Blind, Randomized, Placebo-Controlled Study.

    Science.gov (United States)

    Dymarek, Robert; Taradaj, Jakub; Rosińczuk, Joanna

    2016-08-01

    The main purpose of this study was to determine the clinical, electrophysiological and thermal effects of radial extracorporeal shock wave (rESW) stimulation on upper limb muscles affected by spasticity in patients with chronic stroke. Patients included in the study were randomly assigned into the following two groups: 30 patients stimulated with active rESW (A); and 30 patients stimulated with placebo rESW (B). All patients were analyzed using the Modified Ashworth Scale (MAS) to test the spasticity levels of the elbow (E), radio carpal (RC) and fingers (FF) joints; surface electromyography (sEMG) was performed for the resting bioelectrical activity registration of the flexor carpi radialis (FCR) and flexor carpi ulnaris (FCU) muscles; and infrared thermal imaging (IRT) was used to assess the temperature distributions of the carpal flexor muscles (CFM). All assessments were performed at baseline (t0), immediately after rESW (t1) as well as 1 and 24 h following its finalization (t2 and t3). Patients treated with active rESW showed a statistically significant reduction in the MAS score for the RC joint at t1 and for the FF joints at t1, t2 and t3 (p  0.05). Applications of rESW demonstrating positive effects at reducing the level of spastic hypertonia of the upper limb muscles in patients with chronic stroke. ESW treatments should be considered as a potential anti-spastic effect to regulate vasculature.

  5. Modelling motor cortex stimulation for chronic pain control. electrical potential field, activating functions and responses of simple nerve fibre models

    NARCIS (Netherlands)

    Manola, L.; Roelofsen, B.H.; Holsheimer, J.; Marani, E.; Geelen, J.A.G.

    2005-01-01

    This computer modelling study on motor cortex stimulation (MCS) introduced a motor cortex model, developed to calculate the imposed electrical potential field characteristics and the initial response of simple fibre models to stimulation of the precentral gyrus by an epidural electrode, as applied i

  6. Modulation of N400 in chronic non-fluent aphasia using low frequency Repetitive Transcranial Magnetic Stimulation (rTMS).

    Science.gov (United States)

    Barwood, Caroline H S; Murdoch, Bruce E; Whelan, Brooke-Mai; Lloyd, David; Riek, Stephan; O'Sullivan, John D; Coulthard, Alan; Wong, Andrew

    2011-03-01

    Low frequency Repetitive Transcranial Magnetic Stimulation (rTMS) has previously been applied to language homologues in non-fluent populations of persons with aphasia yielding significant improvements in behavioral language function up to 43 months post stimulation. The present study aimed to investigate the electrophysiological correlates associated with the application of rTMS through measurement of the semantic based N400 Event-related brain potentials (ERP) component. Low frequency (1 Hz) rTMS was applied to the anterior portion of the homologue to Broca's area (pars triangularis), for 20 min per day for 10 days, using a stereotactic neuronavigational system. Twelve non-fluent persons with aphasia, 2-6 years post stroke were stimulated. Six participants were randomly assigned to receive real stimulation and six participants were randomly assigned to receive a blind sham control condition. ERP measures were recorded at baseline, 1 week and 2 months subsequent to stimulation. The findings demonstrate treatment related changes observed in the stimulation group when compared to the placebo control group at 2 months post stimulation indicating neuromodulation of N400 as a result of rTMS. No treatment related changes were identified in the stimulation group, when compared to the sham group from baseline to 1 week post stimulation. The electrophysiological results represent the capacity of rTMS to modulate neural language networks and measures of lexical-semantic function in participants with non-fluent aphasia and suggest that time may be an important factor in brain reorganization subsequent to rTMS.

  7. Modulation of event-related desynchronization during motor imagery with transcranial direct current stimulation (tDCS) in patients with chronic hemiparetic stroke.

    Science.gov (United States)

    Kasashima, Yuko; Fujiwara, Toshiyuki; Matsushika, Yayoi; Tsuji, Tetsuya; Hase, Kimitaka; Ushiyama, Junichi; Ushiba, Junichi; Liu, Meigen

    2012-09-01

    Electroencephalogram-based brain-computer interface (BCI) has been developed as a new neurorehabilitative tool for patients with severe hemiparesis. However, its application has been limited because of difficulty detecting stable brain signals from the affected hemisphere. It has been reported that transcranial direct current stimulation (tDCS) can modulate event-related desynchronization (ERD) in healthy persons. The objective of this study was to test the hypothesis that anodal tDCS could modulate ERD in patients with severe hemiparetic stroke. The participants were six patients with chronic hemiparetic stroke (mean age, 56.8 ± 9.5 years; mean time from the onset, 70.0 ± 19.6 months; Fugl-Meyer Assessment upper extremity motor score, 30.8 ± 16.5). We applied anodal tDCS (10 min, 1 mA) and sham stimulation over the affected primary motor cortex in a random order. ERD of the mu rhythm (mu ERD) with motor imagery of extension of the affected finger was assessed before and after anodal tDCS and sham stimulation. Mu ERD of the affected hemisphere increased significantly after anodal tDCS, whereas it did not change after sham stimulation. Our results show that anodal tDCS can increase mu ERD in patients with hemiparetic stroke, indicating that anodal tDCS could be used as a conditioning tool for BCI in stroke patients.

  8. Chronic stimulation of the semicircular canals using a multichannel vestibular prosthesis: effects on locomotion and angular vestibulo-ocular reflex in chinchillas.

    Science.gov (United States)

    Sun, Daniel Q; Rahman, Mehdi A; Fridman, Gene; Dai, Chenkai; Chiang, Bryce; Della Santina, Charles C

    2011-01-01

    Bilateral loss of vestibular sensation causes difficulty maintaining stable vision, posture and gait. An implantable prosthesis that partly restores vestibular sensation could significantly improve quality of life for individuals disabled by this disorder. We have developed a head-mounted multichannel vestibular prosthesis (MVP) that restores sufficient semicircular canal function to recreate a 3D angular vestibulo-ocular reflex (aVOR). In this study, we evaluated effects of chronic MVP stimulation on locomotion in chinchillas. Two of three animals examined exhibited significant improvements in both locomotion and aVOR.

  9. The Benefit of a Mechanical Needle Stimulation Pad in Patients with Chronic Neck and Lower Back Pain: Two Randomized Controlled Pilot Studies

    Directory of Open Access Journals (Sweden)

    Claudia Hohmann

    2012-01-01

    Full Text Available Objectives. The objective was to investigate whether a treatment with a needle stimulation pad (NSP changes perceived pain and/or sensory thresholds in patients with chronic neck (NP and lower back pain (BP. Methods. 40 patients with chronic NP and 42 patients with chronic BP were equally randomized to either treatment or waiting list control group. The treatment group self-administered a NSP over a period of 14 days. Pain ratings were recorded on numerical rating scales (NRSs. Mechanical detection thresholds (MDTs and pressure pain thresholds (PPTs were determined at the site of maximal pain and in the adjacent region, vibration detection thresholds (VDT were measured at close spinal processes. The Northwick Park Neck Pain Questionnaire (NPQ and the Oswestry Disability Index (ODI were utilized for the NP and BP study, respectively. Results. NRS ratings were significantly reduced for the treatment groups compared to the control groups (NP: P=.021 and BP: P<.001, accompanied by a significant increase of PPT at pain maximum (NP: P=.032 and BP: P=.013. There was no effect on VDT and MDT. The NPQ showed also a significant improvement, but not the ODI. Conclusions. The mechanical NSP seems to be an effective treatment method for chronic NP and BP.

  10. Efficacy and safety of bilateral continuous theta burst stimulation (cTBS for the treatment of chronic tinnitus: design of a three-armed randomized controlled trial

    Directory of Open Access Journals (Sweden)

    Plontke Stefan K

    2009-08-01

    Full Text Available Abstract Background Tinnitus, the perception of sound and noise in absence of an auditory stimulus, has been shown to be associated with maladaptive neuronal reorganization and increased activity of the temporoparietal cortex. Transient modulation of tinnitus by repetitive transcranial magnetic stimulation (rTMS indicated that these areas are critically involved in the pathophysiology of tinnitus and suggested new treatment strategies. However, the therapeutic efficacy of rTMS in tinnitus is still unclear, individual response is variable, and the optimal stimulation area disputable. Recently, continuous theta burst stimulation (cTBS has been put forward as an effective rTMS protocol for the reduction of pathologically enhanced cortical excitability. Methods 48 patients with chronic subjective tinnitus will be included in this randomized, placebo controlled, three-arm trial. The treatment consists of two trains of cTBS applied bilaterally to the secondary auditory cortex, the temporoparietal associaction cortex, or to the lower occiput (sham condition every working day for four weeks. Primary outcome measure is the change of tinnitus distress as quantified by the Tinnitus Questionnaire (TQ. Secondary outcome measures are tinnitus loudness and annoyance as well as tinnitus change during and after treatment. Audiologic and speech audiometric measurements will be performed to assess potential side effects. The aim of the present trail is to investigate effectiveness and safety of a four weeks cTBS treatment on chronic tinnitus and to compare two areas of stimulation. The results will contribute to clarify the therapeutic capacity of rTMS in tinnitus. Trial registration The trial was registered with the clinical trials register of http://www.clinicaltrials.gov (NCT00518024.

  11. The Effect of Transcranial Direct Current Stimulation on the Expression of the Flexor Synergy in the Paretic Arm in Chronic Stroke is Dependent on Shoulder Abduction Loading

    Directory of Open Access Journals (Sweden)

    Jun eYao

    2015-05-01

    Full Text Available Reaching ability of the paretic upper extremity in individuals with stroke decreases with increased shoulder abduction (SABD loads. Transcranial direct current stimulation (tDCS has been implemented to improve movement ability following stroke. However, results from previous studies vary, perhaps due to the influence of impairment level and the type of motor tasks that were used to study the effects of tDCS. This study specifically examines the impact of SABD loading on the effects of tDCS in 9 individuals with moderate to severe chronic stroke.In 3 different sessions, participants repeated a reaching assessment with various SABD loads (supported on a haptic table, 25%, and 50% of maximum voluntary SABD torque in random order, pre and post one of the following 15-minute tDCS protocols: anodal stimulation of lesioned M1, cathodal stimulation of non-lesioned M1, or anodal stimulation of non-lesioned M1. Sham stimulation was also conducted preceding one of the tDCS sessions. The averaged maximum reaching distance over valid trials was calculated for each condition.We observed significant interactions between SABD load, tDCS protocol and time (i.e. pre or post-tDCS. Post-hoc test showed that anodal stimulation of the lesioned M1 caused a clear trend (p=0.058 of increasing the reaching ability at a medium level of SABD loading (25%, but not for higher loads (50%. This suggests that anodal stimulation increases residual corticospinal tract activity, which successfully increases reaching ability at moderate loads; however, is insufficient to make significant changes at higher SABD loads. We also found that cathodal stimulation of the non-lesioned M1 significantly (p=0.018 decreased the reaching distance with high level of SABD loading (50%. This study demonstrated, for the first time, that the effect of tDCS on the reaching ability is dependent on shoulder abduction loads in individuals with moderate to severe stroke.

  12. Conditional ligands for Asian HLA variants facilitate the definition of CD8+ T-cell responses in acute and chronic viral diseases

    DEFF Research Database (Denmark)

    Chang, Cynthia X L; Tan, Anthony T; Or, Ming Yan

    2013-01-01

    Conditional ligands have enabled the high-throughput production of human leukocyte antigen (HLA) libraries that present defined peptides. Immunomonitoring platforms typically concentrate on restriction elements associated with European ancestry, and such tools are scarce for Asian HLA variants. W...

  13. Caloric Vestibular Stimulation Reduces Pain and Somatoparaphrenia in a Severe Chronic Central Post-Stroke Pain Patient: A Case Study.

    Science.gov (United States)

    Spitoni, Grazia Fernanda; Pireddu, Giorgio; Galati, Gaspare; Sulpizio, Valentina; Paolucci, Stefano; Pizzamiglio, Luigi

    2016-01-01

    Central post-stroke pain is a neuropathic syndrome characterized by intolerable contralesional pain and, in rare cases, somatic delusions. To date, there is limited evidence for the effective treatments of this disease. Here we used caloric vestibular stimulation to reduce pain and somatoparaphrenia in a 57-year-old woman suffering from central post-stroke pain. Resting-state functional magnetic resonance imaging was used to assess the neurological effects of this treatment. Following vestibular stimulation we observed impressive improvements in motor skills, pain, and somatic delusions. In the functional connectivity study before the vestibular stimulation, we observed differences in the patient's left thalamus functional connectivity, with respect to the thalamus connectivity of a control group (N = 20), in the bilateral cingulate cortex and left insula. After the caloric stimulation, the left thalamus functional connectivity with these regions, which are known to be involved in the cortical response to pain, disappeared as in the control group. The beneficial use of vestibular stimulation in the reduction of pain and somatic delusion in a CPSP patient is now documented by behavioral and imaging data. This evidence can be applied to theoretical models of pain and body delusions.

  14. Caloric Vestibular Stimulation Reduces Pain and Somatoparaphrenia in a Severe Chronic Central Post-Stroke Pain Patient: A Case Study.

    Directory of Open Access Journals (Sweden)

    Grazia Fernanda Spitoni

    Full Text Available Central post-stroke pain is a neuropathic syndrome characterized by intolerable contralesional pain and, in rare cases, somatic delusions. To date, there is limited evidence for the effective treatments of this disease. Here we used caloric vestibular stimulation to reduce pain and somatoparaphrenia in a 57-year-old woman suffering from central post-stroke pain. Resting-state functional magnetic resonance imaging was used to assess the neurological effects of this treatment. Following vestibular stimulation we observed impressive improvements in motor skills, pain, and somatic delusions. In the functional connectivity study before the vestibular stimulation, we observed differences in the patient's left thalamus functional connectivity, with respect to the thalamus connectivity of a control group (N = 20, in the bilateral cingulate cortex and left insula. After the caloric stimulation, the left thalamus functional connectivity with these regions, which are known to be involved in the cortical response to pain, disappeared as in the control group. The beneficial use of vestibular stimulation in the reduction of pain and somatic delusion in a CPSP patient is now documented by behavioral and imaging data. This evidence can be applied to theoretical models of pain and body delusions.

  15. Effects of Robot-assisted Gait Training Combined with Functional Electrical Stimulation on Recovery of Locomotor Mobility in Chronic Stroke Patients: A Randomized Controlled Trial.

    Science.gov (United States)

    Bae, Young-Hyeon; Ko, Young Jun; Chang, Won Hyuk; Lee, Ju Hyeok; Lee, Kyeong Bong; Park, Yoo Jung; Ha, Hyun Geun; Kim, Yun-Hee

    2014-12-01

    [Purpose] The purpose of the present study was to investigate the effects of robot-assisted gait training combined with functional electrical stimulation on locomotor recovery in patients with chronic stroke. [Subjects] The 20 subjects were randomly assigned into either an experimental group (n = 10) that received a combination of robot-assisted gait training and functional electrical stimulation on the ankle dorsiflexor of the affected side or a control group (n = 10) that received robot-assisted gait training only. [Methods] Both groups received the respective therapies for 30 min/day, 3 days/week for 5 weeks. The outcome was measured using the Modified Motor Assessment Scale (MMAS), Timed Up-and-Go Test (TUG), Berg Balance Scale (BBS), and gait parameters through gait analysis (Vicon 370 motion analysis system, Oxford Metrics Ltd., Oxford, UK). All the variables were measured before and after training. [Results] Step length and maximal knee extension were significantly greater than those before training in the experimental group only. Maximal Knee flexion showed a significant difference between the experimental and control groups. The MMAS, BBS, and TUG scores improved significantly after training compared with before training in both groups. [Conclusion] We suggest that the combination of robot-assisted gait training and functional electrical stimulation encourages patients to actively participate in training because it facilitates locomotor recovery without the risk of adverse effects.

  16. Chronic Brucellosis Patients Retain Low Frequency of CD4+ T-Lymphocytes Expressing CD25 and CD28 after Escherichia coli LPS Stimulation of PHA-Cultured PBMCs

    Directory of Open Access Journals (Sweden)

    Panagiotis Skendros

    2008-01-01

    Full Text Available Chronic brucellosis patients display a defective Th1 response to PHA. We have previously shown that heat-killed B. abortus (HKBA can downregulate the PHA-induced increase of CD4+/CD25+ and CD14+/CD80+ cells of brucellosis patients. In the present study, we investigate the effect of E. coli LPS, as a potent stimulant of monocytes and autologous T-lymphocytes, on the PHA-cultured PBMCs of the same groups of patients. Thirteen acute brucellosis (AB patients, 22 chronic brucellosis (CB patients, 11 “cured” subjects, and 15 healthy volunteers were studied. The percentage of CD4+/CD25+ and CD4+/CD28+ T-lymphocytes as well as CD14+/CD80+ monocytes were analyzed by flow cytometry after PBMCs culture with PHA plus E. coli LPS. A significant decrease in the percentage of CD4+/CD25+ and CD4+/CD28+ T-lymphocytes was observed in CB compared to AB. In HKBA cultures, compared to E. coli LPS-cultures, there was a significant reduction of CD4+/CD25+ T-lymphocytes in all groups and CD14+/CD80+ in patients groups. We suggest that Brucella can modulate host immune response, leading to T-cell anergy and chronic infection.

  17. Low-frequency electrical stimulation induces long-term depression in patients with chronic tension-type headache

    DEFF Research Database (Denmark)

    Lindelof, Kim; Jung, Kerstin; Ellrich, Jens;

    2010-01-01

    Repetitive low-frequency electrical stimulation (LFS) induces pain inhibition in healthy volunteers and in animals, but it is unknown whether it has an analgesic effect in patients with headache. The aim of this study was to investigate if LFS could induce prolonged pain inhibition, called long-t...

  18. A Lactobacillus rhamnosus GG-derived soluble protein, p40, stimulates ligand release from intestinal epithelial cells to transactivate epidermal growth factor receptor.

    Science.gov (United States)

    Yan, Fang; Liu, Liping; Dempsey, Peter J; Tsai, Yu-Hwai; Raines, Elaine W; Wilson, Carole L; Cao, Hailong; Cao, Zheng; Liu, LinShu; Polk, D Brent

    2013-10-18

    p40, a Lactobacillus rhamnosus GG (LGG)-derived soluble protein, ameliorates intestinal injury and colitis, reduces apoptosis, and preserves barrier function by transactivation of the EGF receptor (EGFR) in intestinal epithelial cells. The aim of this study is to determine the mechanisms by which p40 transactivates the EGFR in intestinal epithelial cells. Here we show that p40-conditioned medium activates EGFR in young adult mouse colon epithelial cells and human colonic epithelial cell line, T84 cells. p40 up-regulates a disintegrin and metalloproteinase domain-containing protein 17 (ADAM17) catalytic activity, and broad spectrum metalloproteinase inhibitors block EGFR transactivation by p40 in these two cell lines. In ADAM17-deficient mouse colonic epithelial (ADAM17(-/-) MCE) cells, p40 transactivation of EGFR is blocked, but can be rescued by re-expression with WT ADAM17. Furthermore, p40 stimulates release of heparin binding (HB)-EGF, but not transforming growth factor (TGF)α or amphiregulin, in young adult mouse colon cells and ADAM17(-/-) MCE cells overexpressing WT ADAM17. Knockdown of HB-EGF expression by siRNA suppresses p40 effects on transactivating EGFR and Akt, preventing apoptosis, and preserving tight junction function. The effects of p40 on HB-EGF release and ADAM17 activation in vivo are examined after administration of p40-containing pectin/zein hydrogel beads to mice. p40 stimulates ADAM17 activity and EGFR activation in colonic epithelial cells and increases HB-EGF levels in blood from WT mice, but not from mice with intestinal epithelial cell-specific ADAM17 deletion. Thus, these data define a mechanism of a probiotic-derived soluble protein in modulating intestinal epithelial cell homeostasis through ADAM17-mediated HB-EGF release, leading to transactivation of EGFR.

  19. Chronic vagus nerve stimulation attenuates vascular endothelial impairments and reduces the inflammatory profile via inhibition of the NF-κB signaling pathway in ovariectomized rats.

    Science.gov (United States)

    Li, Ping; Liu, Huaipu; Sun, Peng; Wang, Xiaoyu; Wang, Chen; Wang, Ling; Wang, Tinghuai

    2016-02-01

    Vagus nerve stimulation (VNS), a method for activating cholinergic anti-inflammatory pathways, could suppress endothelial activation and minimize tissue injury during inflammation. The aim of this study was to investigate the effects of chronic VNS on endothelial impairments and the inflammatory profile in ovariectomized (OVX) rats. Sprague-Dawley rats (7-8 months old) were randomly assigned to the following four groups: sham-OVX, OVX, OVX+sham-VNS, and OVX+VNS. Throughout the experimental period, the OVX+VNS group received VNS for 3h (20.0 Hz, 1.0 mA, and 10.00 ms pulse width) at the same time every other day. After 12 weeks of VNS, blood samples and thoracic aortas were collected for further analyses. Light microscopy and electron microscopy analyses showed that chronic VNS prevented endothelial swelling, desquamation and even necrosis in the OVX rats. In addition, it obviously improved endothelial function in the OVX rats by restoring the endothelial nitric oxide synthase (e-NOS) and serum endothelin-1 level. Increased expression of cell adhesion molecules (VCAM-1, ICAM-1 and E-selectin) in the thoracic aortas and increases in the levels of circulating cytokines (TNF-α, IL-6, MCP-1, and CINC/KC) were also observed in the OVX rats. Chronic VNS significantly restored these detrimental changes partly by increasing the ACh concentrations in vascular walls and blocking NF-κB pathway activity. The results of this in vivo study have shown that the administration of chronic VNS during, in the early stage of estrogen deficiency, protects OVX rats from endothelial impairments and the inflammatory profile. These findings indicate that activation of the vagus nerve could be a promising supplemental therapy for reducing the risks of suffering from further CVDs in postmenopausal women.

  20. Effectiveness of combined counseling and low-level laser stimulation in the treatment of disturbing chronic tinnitus.

    Science.gov (United States)

    Cuda, Domenico; De Caria, Antonio

    2008-01-01

    We recruited 46 adult patients affected by disturbing tinnitus lasting for at least 3 years. All were treated with a combined counseling protocol constituting hypnotherapeutic and muscle relaxation techniques. We randomly assigned 26 patients to the group receiving low-level laser stimulation treatment and 20 to the placebo group. The laser power was 5 mV and the wavelength 650 nm. The irradiation lasted 20 minutes daily for 3 months. The Tinnitus Handicap Inventory (THI) questionnaire was submitted at the beginning and at the end of treatment. The THI scores improved in the entire sample after treatment but more significantly in the group receiving low-level laser stimulation. From the point of view of clinical classification, approximately 61% of irradiated patients had tinnitus severity decreased by one class, in comparison to 35% of the placebo group.

  1. A STUDY TO COMPARE THE EFFECTIVENESS OF TRANSCUTANEOUS ELECTRICAL NERVE STIMULATION WITH RETRO - WALKING VERSUS ULTRASOUND THERAPY WITH RETRO - WALKING IN CHRONIC OSTEOARTHRITIS OF KNEE

    Directory of Open Access Journals (Sweden)

    Somashekar

    2015-07-01

    Full Text Available BACKGROUND AND OBJECTIVES: Knee osteoarthritis (OA is a painful and degenerative joint diseases, the pain, joint stiffness associated with this condition have a dramatic impact on physical mobility and function. This study was done to assess the effectiveness of TENS and retro walking versus ultrasound therapy with retro walking in patients suffering from chronic knee osteoarthritis. METHODS: All the subjects were clinically diagnosed by orthopaedician with chronic knee osteoarthritis were screen ed after finding their suitability as per the inclusion criteria and were requested to participate in the study. Participants in the study were briefed about the nature of the study and their intervention. After briefing them about the study, their informe d written consent was taken. 60 chronic knee osteoarthritis patient were randomly divided into two groups with n=30 in each group, Group A - received TENS transcutaneous electrical nerve stimulation and retro walking, where group B - received ultrasound therap y with retro walking. The treatment was given 5 days a week. The total duration of treatment was 3 weeks. OUTCOMES MEASURES: The patie n ts were evaluated at the beginning of the intervention program, Day 1st, end of 1st week, end of 2nd week and end of 3rd week. All the Patients were requested to come for a follow up measurement after 3rd week of treatment program. All the patients were assessed for pain, functional outcome and range of motion by taking their VAS scale, WOMAC scale and universal goniometer. RESULTS: Both the groups showed statistically significant improvement in all three parameters (VAS, WOMAC and Range of motion by repeated test ANOVA. Independent t - test analysis of outcome measures when compared between the two groups showed that Group B outcome measures were significantly far better than the outcome measures of Group A. CONCLUSION: Transcutaneous electrical nerve stimulation TENS with retro walking and therapeutic

  2. Acupuncture and transcutaneous electric nerve stimulation in the treatment of pain associated with chronic pancreatitis. A randomized study

    DEFF Research Database (Denmark)

    Ballegaard, Søren; Christophersen, S J; Dawids, Steen

    1985-01-01

    In 23 patients with pancreatitis, daily pain for at least 3 months, and no abuse of alcohol, the pain-relieving effect of electroacupuncture (13 patients) or transcutaneous electric nerve stimulation (TENS) (16 patients) was studied. In two prospective studies with a cross-over design, active acu...... acupuncture was compared with sham acupuncture, and TENS of the segmental points of the pancreas with sham treatment. Neither electroacupuncture nor TENS brought about pain relief that could substitute for or supplement medical treatment....

  3. Amniotic Membrane Modifies the Genetic Program Induced by TGFß, Stimulating Keratinocyte Proliferation and Migration in Chronic Wounds.

    Directory of Open Access Journals (Sweden)

    Antonia Alcaraz

    Full Text Available Post-traumatic large-surface or deep wounds often cannot progress to reepithelialisation because they become irresponsive in the inflammatory stage, so intervention is necessary to provide the final sealing epidermis. Previously we have shown that Amniotic Membrane (AM induced a robust epithelialisation in deep traumatic wounds.To better understand this phenomenon, we used keratinocytes to investigate the effect of AM on chronic wounds. Using keratinocytes, we saw that AM treatment is able to exert an attenuating effect upon Smad2 and Smad3 TGFß-induced phosphorylation while triggering the activation of several MAPK signalling pathways, including ERK and JNK1, 2. This also has a consequence for TGFß-induced regulation on cell cycle control key players CDK1A (p21 and CDK2B (p15. The study of a wider set of TGFß regulated genes showed that the effect of AM was not wide but very concrete for some genes. TGFß exerted a powerful cell cycle arrest; the presence of AM however prevented TGFß-induced cell cycle arrest. Moreover, AM induced a powerful cell migration response that correlates well with the expression of c-Jun protein at the border of the healing assay. Consistently, the treatment with AM of human chronic wounds induced a robust expression of c-Jun at the wound border.The effect of AM on the modulation of TGFß responses in keratinocytes that favours proliferation together with AM-induced keratinocyte migration is the perfect match that allows chronic wounds to move on from their non-healing state and progress into epithelialization. Our results may explain why the application of AM on chronic wounds is able to promote epithelialisation.

  4. Electroconvulsive stimulations prevent chronic stress-induced increases in L-type calcium channel mRNAs in the hippocampus and basolateral amygdala

    DEFF Research Database (Denmark)

    Maigaard, Katrine; Pedersen, Ida Hageman; Jørgensen, Anders;

    2012-01-01

    Although affective disorders have high prevalence, morbidity and mortality, we do not fully understand disease etiopathology, nor have we determined the exact mechanisms by which treatment works. Recent research indicates that intracellular calcium ion dysfunction might be involved. Here we use...... the chronic restraint stress model of affective disorder (6 h restraint per day for 21 days) in combination with electroconvulsive stimulations to examine the effects of stress and an effective antidepressive treatment modality on L-type voltage gated calcium channel subunit mRNA expression patterns......, while stress only upregulated Ca(v)1.3 channel expression significantly in the dentate gyrus. ECS effects on Ca(v)1.2 channel expression were generally specific to stressed animals. Our findings are consistent with and extent previous studies on the involvement of intracellular calcium ion dysfunction...

  5. Mechanisms underlying enhancements in muscle force and power output during maximal cycle ergometer exercise induced by chronic β2-adrenergic stimulation in men.

    Science.gov (United States)

    Hostrup, Morten; Kalsen, Anders; Onslev, Johan; Jessen, Søren; Haase, Christoffer; Habib, Sajad; Ørtenblad, Niels; Backer, Vibeke; Bangsbo, Jens

    2015-09-01

    The study was a randomized placebo-controlled trial investigating mechanisms by which chronic β2-adrenergic stimulation enhances muscle force and power output during maximal cycle ergometer exercise in young men. Eighteen trained men were assigned to an experimental group [oral terbutaline 5 mg/30 kg body weight (bw) twice daily (TER); n = 9] or a control group [placebo (PLA); n = 9] for a 4-wk intervention. No changes were observed with the intervention in PLA. Isometric muscle force of the quadriceps increased (P ≤ 0.01) by 97 ± 29 N (means ± SE) with the intervention in TER compared with PLA. Peak and mean power output during 30 s of maximal cycling increased (P ≤ 0.01) by 32 ± 8 and 25 ± 9 W, respectively, with the intervention in TER compared with PLA. Maximal oxygen consumption (V̇o2max) and time to fatigue during incremental cycling did not change with the intervention. Lean body mass increased by 1.95 ± 0.8 kg (P ≤ 0.05) with the intervention in TER compared with PLA. Change in single fiber cross-sectional area of myosin heavy chain (MHC) I (1,205 ± 558 μm(2); P ≤ 0.01) and MHC II fibers (1,277 ± 595 μm(2); P ≤ 0.05) of the vastus lateralis muscle was higher for TER than PLA with the intervention, whereas no changes were observed in MHC isoform distribution. Expression of muscle proteins involved in growth, ion handling, lactate production, and clearance increased (P ≤ 0.05) with the intervention in TER compared with PLA, with no change in oxidative enzymes. Our observations suggest that muscle hypertrophy is the primary mechanism underlying enhancements in muscle force and peak power during maximal cycling induced by chronic β2-adrenergic stimulation in humans.

  6. Neuroplastic effects of transcranial direct current stimulation on painful symptoms reduction in chronic Hepatitis C: a phase II randomized, double blind, sham controlled trial

    Directory of Open Access Journals (Sweden)

    Aline Patricia Brietzke

    2016-01-01

    Full Text Available Introduction: Pegylated Interferon Alpha (Peg-IFN in combination with other drugs is the standard treatment for chronic hepatitis C infection (HCV and is related to severe painful symptoms. The aim of this study was access the efficacy of transcranial direct current stimulation (tDCS in controlling the painful symptoms related to Peg-IFN side effects. Material and Methods: In this phase II double-blind trial, twenty eight (n=28 HCV subjects were randomized to receive either five consecutive days of active tDCS (n=14 or sham (n=14 during five consecutive days with anodal stimulation over the primary motor cortex region using 2 mA for 20 minutes. The primary outcomes were visual analogue scale (VAS pain and brain-derived neurotrophic factor (BDNF serum levels. Secondary outcomes were the pressure-pain threshold (PPT, the Brazilian Profile of Chronic Pain: Screen (B-PCP:S and drug analgesics use. Results: tDCS reduced the VAS scores (P<0.003, with a mean pain drop of 56% (p<0.001. Furthermore, tDCS was able to enhance BDNF levels (p<0.01. The mean increase was 37.48% in the active group. Finally, tDCS raised PPT (p<0.001 and reduced the B-PCP:S scores and analgesic use (p<0.05. Conclusions: Five sessions of tDCS were effective in reducing the painful symptoms in HCV patients undergoing Peg-IFN treatment. These findings support the efficacy of tDCS as a promising therapeutic tool to improve the tolerance of the side effects related to the use of Peg-IFN. Future larger studies (phase III and IV trials are needed to confirm the clinical use of the therapeutic effects of tDCS in such condition. Trial registration: Brazilian Human Health Regulator for Research with the approval number CAAE 07802012.0.0000.5327

  7. Long-term sensory stimulation therapy improves hand function and restores cortical responsiveness in patients with chronic cerebral lesions. Three single case studies.

    Directory of Open Access Journals (Sweden)

    Jan-Christoph eKattenstroth

    2012-08-01

    Full Text Available Rehabilitation of sensorimotor impairment resulting from cerebral lesion (CL utilizes task specific training and massed practice to drive reorganization and sensorimotor improvement due to induction of neuroplasticity mechanisms. Loss of sensory abilities often complicates recovery, and thus the individual’s ability to use the affected body part for functional tasks. Therefore, the development of additional and alternative approaches that supplement, enhance, or even replace conventional training procedures would be advantageous. Repetitive sensory stimulation protocols (rSS have been shown to evoke sensorimotor improvements of the affected limb in patients with chronic stroke. However, the possible impact of long-term rSS on sensorimotor performance of patients with CL, where the incident dated back many years remains unclear. The particular advantage of rSS is its passive nature, which does not require active participation of the subjects. Therefore, rSS can be applied parallel to other occupations, making the intervention easier to implement and more acceptable to the individual. Here we report the effects of applying rSS for 8, 36 and 76 weeks on the paretic hand of 3 long-term patients with different types of CL. Different behavioral tests were used to assess sensory and/or sensorimotor performance of the upper extremities prior, after, and during the intervention. In one patient, the impact of long-term rSS on restoration of cortical activation was investigated by recording somatosensory evoked potentials. After long-term rSS all three patients showed considerable improvements of their sensory and motor abilities. In addition, almost normal evoked potentials could be recorded after rSS in one patient. Our data show that long-term rSS applied to patients with chronic CL can improve tactile and sensorimotor functions, which, however, developed in some cases only after many weeks of stimulation, and continued to further improve on a time

  8. Thermo-responsive cell culture carriers based on poly(vinyl methyl ether)—the effect of biomolecular ligands to balance cell adhesion and stimulated detachment

    Science.gov (United States)

    Teichmann, Juliane; Nitschke, Mirko; Pette, Dagmar; Valtink, Monika; Gramm, Stefan; Härtel, Frauke V.; Noll, Thomas; Funk, Richard H. W.; Engelmann, Katrin; Werner, Carsten

    2015-08-01

    Two established material systems for thermally stimulated detachment of adherent cells were combined in a cross-linked polymer blend to merge favorable properties. Through this approach poly(N-isopropylacrylamide) (PNiPAAm) with its superior switching characteristic was paired with a poly(vinyl methyl ether)-based composition that allows adjusting physico-chemical and biomolecular properties in a wide range. Beyond pure PNiPAAm, the proposed thermo-responsive coating provides thickness, stiffness and swelling behavior, as well as an apposite density of reactive sites for biomolecular functionalization, as effective tuning parameters to meet specific requirements of a particular cell type regarding initial adhesion and ease of detachment. To illustrate the strength of this approach, the novel cell culture carrier was applied to generate transplantable sheets of human corneal endothelial cells (HCEC). Sheets were grown, detached, and transferred onto planar targets. Cell morphology, viability and functionality were analyzed by immunocytochemistry and determination of transepithelial electrical resistance (TEER) before and after sheet detachment and transfer. HCEC layers showed regular morphology with appropriate TEER. Cells were positive for function-associated marker proteins ZO-1, Na+/K+-ATPase, and paxillin, and extracellular matrix proteins fibronectin, laminin and collagen type IV before and after transfer. Sheet detachment and transfer did not impair cell viability. Subsequently, a potential application in ophthalmology was demonstrated by transplantation onto de-endothelialized porcine corneas in vitro. The novel thermo-responsive cell culture carrier facilitates the generation and transfer of functional HCEC sheets. This paves the way to generate tissue engineered human corneal endothelium as an alternative transplant source for endothelial keratoplasty.

  9. Chronic kisspeptin administration stimulated gonadal development in pre-pubertal male yellowtail kingfish (Seriola lalandi; Perciformes) during the breeding and non-breeding season.

    Science.gov (United States)

    Nocillado, Josephine N; Zohar, Yonathan; Biran, Jakob; Levavi-Sivan, Berta; Elizur, Abigail

    2013-09-15

    The kisspeptin system is now accepted as a key regulator of vertebrate reproductive function, particularly the onset of puberty. In teleosts, the stimulatory effect of exogenous kisspeptins has been demonstrated mainly at the hypothalamic and pituitary levels of the reproductive axis, with very limited information pertaining to gonadal response. We determined the effect of chronic peripheral administration of the conserved kisspeptin decapeptides (YNLNSFGLRY or Kiss1-10; and FNFNPFGLRF or Kiss2-10) on gonadal development of pre-pubertal yellowtail kingfish (Seriola lalandi), a Perciform teleost, during the breeding and non-breeding season. We utilized slow-release implants to chronically deliver the synthesized peptides, which were based on the yellowtail kingfish kiss1 and kiss2 cDNA sequences that we isolated. The expression level of kiss2r and gnrh1 in the brain or hypothalamus did not vary between treated and control groups. Pituitary expression of fshβ and lhβ was upregulated only with Kiss1-10 treatment regardless of the season. Based on histological evidence, gonadal development was stimulated in male fish with either Kiss1-10 or Kiss2-10, with Kiss2-10 being more effective during the non-breeding period. Overall, our results suggest that kisspeptins modulate the early gonadal development of male yellowtail kingfish, however that may vary with the breeding season.

  10. Granulocyte Colony-stimulating Factor-primed Bone Marrow: An Excellent Stem-cell Source for Transplantation in Acute Myelocytic Leukemia and Chronic Myelocytic Leukemia

    Directory of Open Access Journals (Sweden)

    Yuhang Li

    2015-01-01

    Full Text Available Background: Steady-state bone marrow (SS-BM and granulocyte colony-stimulating growth factor-primed BM/peripheral blood stem-cell (G-BM/G-PBSC are the main stem-cell sources used in allogeneic hematopoietic stem-cell transplantation. Here, we evaluated the treatment effects of SS-BM and G-BM/G-PBSC in human leucocyte antigen (HLA-identical sibling transplantation. Methods: A total of 226 patients (acute myelogenous leukemia-complete remission 1, chronic myelogenous leukemia-chronic phase 1 received SS-BM, G-BM, or G-PBSC from an HLA-identical sibling. Clinical outcomes (graft-versus-host disease [GVHD], overall survival, transplant-related mortality [TRM], and leukemia-free survival [LFS] were analyzed. Results: When compared to SS-BM, G-BM gave faster recovery time to neutrophil or platelet (P 0.05. Conclusions: G-CSF-primed bone marrow shared the advantages of G-PBSC and SS-BM. We conclude that G-BM is an excellent stem-cell source that may be preferable to G-PBSC or SS-BM in patients receiving HLA-identical sibling hematopoietic stem-cell transplantation.

  11. Heat pain thresholds and cerebral event-related potentials following painful CO2 laser stimulation in chronic tension-type headache.

    Science.gov (United States)

    de Tommaso, Marina; Libro, Giuseppe; Guido, Marco; Sciruicchio, Vittorio; Losito, Luciana; Puca, Francomichele

    2003-07-01

    Current opinion concerning the pathophysiology of tension-type headache (TTH) and its related pericranial muscle tenderness proposes a primary role of central sensitization at the level of dorsalhorn/trigeminal nucleus as well as the supraspinal level. Investigation of these phenomena can be conducted using laser-evoked potentials (LEPs), which are objective and quantitative neurophysiological tools for the assessment of pain perception. In the present study we examined features of LEPs, as well as cutaneous heat-pain thresholds to laser stimulation, in relation to the tenderness of pericranial muscles in chronic TTH resulting from pericranial muscle disorder, during a pain-free phase. Twelve patients with TTH and 11 healthy controls were examined using the Total Tenderness Scoring (TTS) system. The stimulus was a laser pulse generated by a CO(2) laser. The dorsum of the hand and the cutaneous zones corresponding to pericranial muscles were stimulated. Subjective perception of stimulus intensity was assessed by a visual analogue scale. Two responses, the earlier named N2a and the last named P2, were considered; the absolute latency was measured at the highest peak of each response. The N2a-P2 components' peak-to-peak amplitude was detected. The heat pain threshold was similar in TTH patients and controls at the level of both the hand and pericranial skin. The TTS scores at almost all pericranial sites were higher in TTH patients than in normal controls. The amplitude of the N2a-P2 complex elicited by stimulation of the pericranial zone was greater in TTH patients than in controls; the amplitude increase was significantly associated with the TTS score. Our findings suggest that pericranial tenderness may be a primary phenomenon that precedes headache, and is mediated by a greater pain-specific hypervigilance at the cortical level.

  12. Granulocyte Colony-stimulating Factor-primed Bone Marrow: An Excellent Stem-cell Source for Transplantation in Acute Myelocytic Leukemia and Chronic Myelocytic Leukemia

    Institute of Scientific and Technical Information of China (English)

    Yuhang Li; Min Jiang; Chen Xu; Jianlin Chen; Botao Li; Jun Wang; Jiangwei Hu

    2015-01-01

    Background:Steady-state bone marrow (SS-BM) and granulocyte colony-stimulating growth factor-primed BM/peripheral blood stem-cell (G-BM/G-PBSC) are the main stem-cell sources used in allogeneic hematopoietic stem-cell transplantation.Here,we evaluated the treatment effects of SS-BM and G-BM/G-PBSC in human leucocyte antigen (HLA)-identical sibling transplantation.Methods:A total of 226 patients (acute myelogenous leukemia-complete remission 1,chronic myelogenous leukemia-chronic phase 1) received SS-BM,G-BM,or G-PBSC from an HLA-identical sibling.Clinical outcomes (graft-versus-host disease [GVHD],overall survival,transplant-related mortality [TRM],and leukemia-free survival [LFS]) were analyzed.Results:When compared to SS-BM,G-BM gave faster recovery time to neutrophil or platelet (P < 0.05).Incidence of grade Ⅲ-Ⅳ acute GVHD and extensive chronic GVHD (cGVHD) was lower than seen with SS-BM (P < 0.05) and similar to G-PBSC.Although the incidence of cGVHD in the G-BM group was similar to SS-BM,both were lower than G-PBSC (P < 0.05).G-BM and G-PBSC exhibited similar survival,LFS,and TRM,but were significantly different from SS-BM (P < 0.05).There were no significant differences in leukemia relapse rates among the groups (P > 0.05).Conclusions:G-CSF-primed bone marrow shared the advantages of G-PBSC and SS-BM.We conclude that G-BM is an excellent stem-cell source that may be preferable to G-PBSC or SS-BM in patients receiving HLA-identical sibling hematopoietic stem-cell transplantation.

  13. Chronic improvement of amino acid nutrition stimulates initiation of global messenger ribonucleic acid translation in tissues of sheep without affecting protein elongation.

    Science.gov (United States)

    Connors, M T; Poppi, D P; Cant, J P

    2010-02-01

    Initiation of mRNA translation and elongation of the polypeptide chain are 2 regulated processes responsible for the short-term postprandial acceleration of protein synthesis in animal tissues. It is known that a chronic increase in the absorptive supply of AA stimulates protein synthesis in ruminant animals, but effects on translation initiation and elongation are unknown. To determine whether initiation or elongation phases of global mRNA translation are affected by chronic elevation of AA supply, 24 ewe lambs of 25.9 +/- 2.5 kg of BW were randomly allocated to 4 treatment groups of 6 lambs each. All lambs received a basal diet of barley and hay at 1.2 times maintenance ME intake. Treatments were an intravenous (i.v.) saline infusion as a control, i.v. infusion of 6 essential AA (EAA; Arg, Lys, His, Thr, Met, Cys) for 10 d, i.v. infusion of the same EAA excluding Met and Cys (EAA-SAA) for 10 d, and an oral drench of fishmeal twice daily for 17 d. Fishmeal supplementation supplied an extra 719 mg of N x kg(-0.75) x d(-1) and N retention was increased 519 mg x kg(-0.75) x d(-1) over the control. The EAA treatment supplied an extra 343 mg of N x kg(-0.75) x d(-1) directly into the blood, and N balance was increased by 268 mg x kg(-0.75) x d(-1). Deletion of Met plus Cys from EAA had no effect on N balance. The results indicate that Met plus Cys did not limit body protein gain on the basal diet alone or the basal diet plus 6 AA. Protein fractional synthesis rates in liver, duodenum, skin, rumen, semimembranosus, and LM were measured by a flooding dose procedure using L-[ring-2,6-(3)H]-Phe. Ribosome transit times were estimated from the ratio of nascent to total protein-bound radioactivities. Fishmeal and EAA treatments had no effect on RNA, DNA, or protein contents of tissues, but fractional synthesis rate, translational efficiency, and concentrations of active ribosomes were consistently elevated. Ribosome transit time was not affected by long-term AA supply. We

  14. Expression profiling of skeletal muscle following acute and chronic β2-adrenergic stimulation: implications for hypertrophy, metabolism and circadian rhythm

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    Lynch Gordon S

    2009-09-01

    Full Text Available Abstract Background Systemic administration of β-adrenoceptor (β-AR agonists has been found to induce skeletal muscle hypertrophy and significant metabolic changes. In the context of energy homeostasis, the importance of β-AR signaling has been highlighted by the inability of β1-3-AR-deficient mice to regulate energy expenditure and susceptibility to diet induced obesity. However, the molecular pathways and gene expression changes that initiate and maintain these phenotypic modulations are poorly understood. Therefore, the aim of this study was to identify differential changes in gene expression in murine skeletal muscle associated with systemic (acute and chronic administration of the β2-AR agonist formoterol. Results Skeletal muscle gene expression (from murine tibialis anterior was profiled at both 1 and 4 hours following systemic administration of the β2-AR agonist formoterol, using Illumina 46K mouse BeadArrays. Illumina expression profiling revealed significant expression changes in genes associated with skeletal muscle hypertrophy, myoblast differentiation, metabolism, circadian rhythm, transcription, histones, and oxidative stress. Differentially expressed genes relevant to the regulation of muscle mass and metabolism (in the context of the hypertrophic phenotype were further validated by quantitative RT-PCR to examine gene expression in response to both acute (1-24 h and chronic administration (1-28 days of formoterol at multiple timepoints. In terms of skeletal muscle hypertrophy, attenuation of myostatin signaling (including differential expression of myostatin, activin receptor IIB, phospho-Smad3 etc was observed following acute and chronic administration of formoterol. Acute (but not chronic administration of formoterol also significantly induced the expression of genes involved in oxidative metabolism, including hexokinase 2, sorbin and SH3 domain containing 1, and uncoupling protein 3. Interestingly, formoterol

  15. Now you feel both: Galvanic vestibular stimulation induces lasting improvements in the rehabilitation of chronic tactile extinction

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    Lena eSchmidt

    2013-03-01

    Full Text Available Tactile extinction is frequent, debilitating and often persistent after brain damage. Currently, there is no treatment available for this disorder. In two previous case studies we showed an influence of galvanic vestibular stimulation (GVS on tactile extinction. Here, we evaluated in further patients the immediate and lasting effects of GVS on tactile extinction. GVS is known to induce polarity-specific changes in cerebral excitability in the vestibular cortices and adjacent cortical areas. Tactile extinction was examined with the Quality Extinction Test (QET where subjects have to discriminate six different tactile fabrics in bilateral, double simultaneous stimulations (DSS on their dorsum of hands with identical or different tactile fabrics. Twelve patients with stable left-sided tactile extinction after unilateral right-hemisphere lesions were divided into two groups. The GVS group (N=6 performed the QET under six different experimental conditions (two Baselines, Sham-GVS, left-cathodal/right-anodal GVS, right-cathodal/left-anodal GVS, and a follow-up test. The second group of patients with left-sided extinction (N=6 performed the QET six times repetitively, but without receiving GVS (control group. Both right-cathodal/left-anodal as well as left-cathodal/right-anodal GVS (mean: 0.67 mA improved tactile identification of identical and different stimuli in the experimental group. These results show a generic effect of GVS on tactile extinction, but not in a polarity-specific way. These observed effects persisted at Follow-up. Sham-GVS had no significant effect on extinction. In the control group, no significant improvements were seen in the QET after the six measurements of the QET, thus ruling out test repetition effects. In conclusion, GVS improved bodily awareness permanently for the contralesional body side in patients with tactile extinction and thus offers a novel treatment option for these patients.

  16. Chronic electroconvulsive stimulation but not chronic restraint stress modulates mRNA expression of voltage-dependent potassium channels Kv7.2 and Kv11.1 in the rat piriform cortex

    DEFF Research Database (Denmark)

    Hjæresen, Marie-Louise; Hageman, Ida; Plenge, Per;

    2008-01-01

    The mechanisms by which stress and electroconvulsive therapy exert opposite effects on the course of major depression are not known. Potential candidates might include the voltage-dependent potassium channels. Potassium channels play an important role in maintaining the resting membrane potential...... and controlling neuronal excitability. To explore this hypothesis, we examined the effects of one or several electroconvulsive stimulations and chronic restraint stress (6 h/day for 21 days) on the expression of voltage-dependent potassium channel Kv7.2, Kv11.1, and Kv11.3 mRNA in the rat brain using in situ...... hybridization. Repeated, but not acute, electroconvulsive stimulation increased Kv7.2 and Kv11.1 mRNA levels in the piriform cortex. In contrast, restraint stress had no significant effect on mRNA expression of Kv7.2, Kv11.1, or Kv11.3 in any of the brain regions examined. Thus, it appears that the investigated...

  17. Multi-linear regression analysis, preliminary biotic ligand modeling, and cross species comparison of the effects of water chemistry on chronic lead toxicity in invertebrates.

    Science.gov (United States)

    Esbaugh, A J; Brix, K V; Mager, E M; De Schamphelaere, K; Grosell, M

    2012-03-01

    The current study examined the chronic toxicity of lead (Pb) to three invertebrate species: the cladoceran Ceriodaphnia dubia, the snail Lymnaea stagnalis and the rotifer Philodina rapida. The test media consisted of natural waters from across North America, varying in pertinent water chemistry parameters including dissolved organic carbon (DOC), calcium, pH and total CO(2). Chronic toxicity was assessed using reproductive endpoints for C. dubia and P. rapida while growth was assessed for L. stagnalis, with chronic toxicity varying markedly according to water chemistry. A multi-linear regression (MLR) approach was used to identify the relative importance of individual water chemistry components in predicting chronic Pb toxicity for each species. DOC was an integral component of MLR models for C. dubia and L. stagnalis, but surprisingly had no predictive impact on chronic Pb toxicity for P. rapida. Furthermore, sodium and total CO(2) were also identified as important factors affecting C. dubia toxicity; no other factors were predictive for L. stagnalis. The Pb toxicity of P. rapida was predicted by calcium and pH. The predictive power of the C. dubia and L. stagnalis MLR models was generally similar to that of the current C. dubia BLM, with R(2) values of 0.55 and 0.82 for the respective MLR models, compared to 0.45 and 0.79 for the respective BLMs. In contrast the BLM poorly predicted P. rapida toxicity (R(2)=0.19), as compared to the MLR (R(2)=0.92). The cross species variability in the effects of water chemistry, especially with respect to rotifers, suggests that cross species modeling of invertebrate chronic Pb toxicity using a C. dubia model may not always be appropriate.

  18. The frequencies of Killer immunoglobulin-like receptors and their HLA ligands in chronic inflammatory demyelinating polyradiculoneuropathy are similar to those in Guillian Barre syndrome but differ from those of controls, suggesting a role for NK cells in pathogenesis.

    Science.gov (United States)

    Blum, Stefan; Csurhes, Peter; McCombe, Pamela

    2015-08-15

    Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an acquired inflammatory neuropathy, which has similar clinical and pathological features to Guillain-Barré Syndrome (GBS), but differs in time course. We investigated the frequency of genes encoding Killer immunoglobulin-like receptors and their HLA ligands in subjects with CIDP, in subjects with GBS and in healthy controls. There were no differences in KIR gene frequency among the 3 groups. The gene frequencies for HLA-B Bw4-I were significantly greater in CIDP than HC, but did not differ from GBS. The frequency of the combination of 3DL1/HLA-B Bw4I was greater in CIDP than HC, but did not differ from that of GBS. These data raise the possibility of NK cell function being an important factor in the pathogenesis of CIDP.

  19. [Immunologic disorders in pathogenesis of chronic generalized parodontitis].

    Science.gov (United States)

    Volozhin, A I; Poriadin, G V; Kazimiski, T I; Barer, G M; Askerova, S Sh; Salmasi, Zh M

    2005-01-01

    Systemic immunity was studied in patients with chronic generalized parodontitis. This group of patients had distinct changes in immunologic system: depression of T- and stimulation of B-cellular immunity without accumulation of plasma cells and initiation of effective humoral response. Increased peripheral blood number of lymphocytes expressing induction of apoptosis CD95 receptors and ligand for this receptor CD95L (Fas-L) can lead to intensification of lymphocyte apoptosis and may be the reason for T-cell deficit development. The results of the study confirm the important role of immune system disturbances in pathogenesis of chronic generalized parodontitis.

  20. Effect of chronic electrical stimulation of the centromedian thalamic nuclei on various intractable seizure patterns: I. Clinical seizures and paroxysmal EEG activity.

    Science.gov (United States)

    Velasco, F; Velasco, M; Velasco, A L; Jiménez, F

    1993-01-01

    Twenty-three patients with various intractable seizure patterns were divided into four groups based on their most frequent seizure type and their clinical and EEG response to chronic electrical stimulation of the centromedian thalamic nuclei (ESCM): group A, generalized tonic-clonic (GTC, n = 9); group B, partial motor (Rasmussen type) (n = 3); group C, complex partial seizures (CPS, n = 5); and group D, generalized tonic seizures (Lennox-Gastaut type) (n = 6). CM were radiologically and electrophysiologically localized by means of stereotaxic landmarks and by thalamically induced scalp recruiting-like responses and desynchronization. ESCM consisted of daily 2-h stimulation sessions for 3 months. Each stimulus consisted of a 1-min train of square pulses with a 4-min interstimulus interval, alternating right and left CM. Each pulse was 1.0 ms in duration at 60/s frequency and 8-15 V (400-1,250 microA) amplitude. Voltage (V), current flow (microA) and impedance (k omega) at the electrode tips were kept constant. A significant decrease in the number of seizures per month and paroxysmal EEG waves per 10-s spochs occurred in group A patients between the baseline period (BL) and the ESCM period. These changes persisted for > 3 months after discontinuation of ESCM (poststimulation period, Post). Post was accompanied by a significant decrease in the number of paroxysmal EEG discharges. A substantial decrease in seizures and paroxysmal discharges was also observed in patients of group B. In contrast, patients of groups C and D showed no significant changes from BL to ESCM and Post periods, except for a significant decrease in the number of seizures in group D patients from BL to Post periods.

  1. Effects of transcutaneous electrical nerve stimulation (TENS and interferential currents (IFC in patients with nonspecific chronic low back pain: randomized clinical trial

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    Ligia Maria Facci

    Full Text Available CONTEXT AND OBJECTIVE: Transcutaneous electrical nerve stimulation (TENS and interferential current are the most used electrotherapy methods, although there is little scientific evidence to support their use. The aim of this study was to compare the effects of TENS and interferential current among patients with nonspecific chronic low back pain. DESIGN AND SETTING: Single-blind randomized controlled trial in the Department of Physiotherapy, Centro Universitário de Maringá. METHODS: One hundred and fifty patients were randomly divided into three groups: TENS (group 1, interferential current (group 2 and controls (group 3. The patients designated for electrotherapy received ten 30-minute sessions, while the control group remained untreated. All patients and controls were evaluated before and after treatment using a visual analog scale and the McGill Pain and Roland Morris questionnaires, and regarding their use of additional medications. RESULTS: There was a mean reduction on the visual analog scale of 39.18 mm with TENS, 44.86 mm with interferential current and 8.53 mm among the controls. In the Roland Morris questionnaire, group 1 had a mean reduction of 6.59; group 2, 7.20; and group 3, 0.70 points. In group 1, 84% of the patients stopped using medications after the treatment; in group 2, 75%; and in group 3, 34%. There was no statistically significant difference between the TENS and interferential current groups (P > 0.05; a difference was only found between these groups and the controls (P < 0.0001. CONCLUSION: There was no difference between TENS and interferential current for chronic low back pain treatment. CLINICAL TRIAL REGISTRATION: NCT01017913.

  2. Involvement of MAPK/NF-κB signaling in the activation of the cholinergic anti-inflammatory pathway in experimental colitis by chronic vagus nerve stimulation.

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    Peng Sun

    Full Text Available BACKGROUND: Autonomic nervous system dysfunction is implicated in the etiopathogenesis of inflammatory bowel diseases (IBD. Therapies that increase cardiovagal activity, such as Mind-Body interventions, are currently confirmed to be effective in clinical trials in IBD. However, a poor understanding of pathophysiological mechanisms limits the popularization of therapies in clinical practice. The aim of the present study was to explore the mechanisms of these therapies against 2,4,6-trinitrobenzenesulfonic acid (TNBS-induced colitis in rats using a chronic vagus nerve stimulation model in vivo, as well as the lipopolysaccharide (LPS-induced inflammatory response in human epithelial colorectal adenocarcinoma cells (Caco-2 by acetylcholine in vitro. METHODS AND RESULTS: Colitis was induced in rats with rectal instillation of TNBS, and the effect of chronic VNS (0.25 mA, 20 Hz, 500 ms on colonic inflammation was evaluated. Inflammatory responses were assessed by disease activity index (DAI, histological scores, myeloperoxidase (MPO activity, inducible nitric oxide synthase (iNOS, TNF-α and IL-6 production. The expression of Mitogen-activated protein kinases (MAPK family members, IκB-α, and nuclear NF-κB p65 were studied by immunoblotting. Heart rate variability (HRV analysis was also applied to assess the sympathetic-vagal balance. DAI, histological scores, MPO activity, iNOS, TNF-α and IL-6 levels were significantly decreased by chronic VNS. Moreover, both VNS and acetylcholine reduced the phosphorylation of MAPKs and prevented the nuclear translocation of NF-κB p65. Methyllycaconitine (MLA only reversed the inhibitory effect on p-ERK and intranuclear NF-κB p65 expression by ACh in vitro, no significant change was observed in the expression of p-p38 MAPK or p-JNK by MLA. CONCLUSION: Vagal activity modification contributes to the beneficial effects of the cholinergic anti-inflammatory pathway in IBD-related inflamed colonic mucosa based on the

  3. Creatine loading elevates the intracellular phosphorylation potential and alters adaptive responses of rat fast-twitch muscle to chronic low-frequency stimulation.

    Science.gov (United States)

    Putman, Charles T; Gallo, Maria; Martins, Karen J B; MacLean, Ian M; Jendral, Michelle J; Gordon, Tessa; Syrotuik, Daniel G; Dixon, Walter T

    2015-07-01

    This study tested the hypothesis that elevating the intracellular phosphorylation potential (IPP = [ATP]/[ADP]free) within rat fast-twitch tibialis anterior muscles by creatine (Cr) loading would prevent fast-to-slow fibre transitions induced by chronic low-frequency electrical stimulation (CLFS, 10 Hz, 12 h/day). Creatine-control and creatine-CLFS groups drank a solution of 1% Cr + 5% dextrose, ad libitum, for 10 days before and during 10 days of CLFS; dextrose-control and dextrose-CLFS groups drank 5% dextrose. Cr loading increased total Cr (P creatine-CLFS than in dextrose-CLFS. Higher IPP was confirmed by a 58% reduction in phospho-AMP-activated protein kinase α (Thr172) (P creatine-CLFS, MyHC-I and MyHC-IIa mRNA were unchanged and MyHC-IIb mRNA decreased by 75% (P creatine-CLFS, but reciprocal reductions in glycolytic reference enzymes occurred only in dextrose-CLFS (P creatine-CLFS coincided with prolonged time to peak tension and half-rise time (P < 0.01). These results highlight the IPP as an important physiological regulator of muscle fibre plasticity and demonstrate that training-induced changes typically associated with improvements in muscular endurance or increased power output are not mutually exclusive in Cr-loaded muscles.

  4. Reverse left ventricular remodeling is more likely in non ischemic cardiomyopathy patients upgraded to biventricular stimulation after chronic right ventricular pacing

    Directory of Open Access Journals (Sweden)

    Morales Maria-Aurora

    2011-12-01

    Full Text Available Abstract Background Chronic right ventricular (RV apical pacing may lead to left ventricular (LV dyssynchrony and LV dysfunction. In heart failure due to RV pacing, upgrading to biventricular stimulation (CRT can improve NYHA Class and LV function. A proportion of patients do not respond to upgrading. Aim was to assess whether etiology of LV dysfunction accounts for responses to CRT in RV-paced patients. Methods Sixty-two patients treated by CRT, under RV pacing from 50.2 ± 5.4 months, were studied. Cause of LV dysfunction was non-ischemic (NIC in 28 and ischemic cardiomyopathy (IC in 34 patients. Clinical and conventional echocardiographic parameters were available within 1 month before RV pacing, within 1 month before CRT and at 12 ± 2 months of follow-up (FU. Results Decreased LVEF (from 37.0 ± 8.8 to 25.6 ± 6.1%, p 10% decrease in LVESD was observed in 24 patients: 5 with IC, 19 with NIC (p 10% decrease in LVESD remained highly significant (p Conclusions CRT improves functional class even after long-lasting pacing. Reverse remodeling is evident in a small population, more likely with NIC.

  5. Expression of Fos protein in the rat central nervous system in response to noxious stimulation: effects of chronic inflammation of the superior cervical ganglion

    Directory of Open Access Journals (Sweden)

    Laudanna A.

    1998-01-01

    Full Text Available The aim of this study was to investigate the possible interactions between the nociceptive system, the sympathetic system and the inflammatory process. Thus, the superior cervical ganglion of rats was submitted to chronic inflammation and Fos expression was used as a marker for neuronal activity throughout central neurons following painful peripheral stimulation. The painful stimulus consisted of subcutaneously injected formalin applied to the supra-ocular region. Fos-positive neurons were identified by conventional immunohistochemical techniques, and analyzed from the obex through the cervical levels of the spinal cord. In the caudal sub-nucleus of the spinal trigeminal nuclear complex, the number of Fos-positive neurons was much higher in rats with inflammation of the superior cervical ganglion than in control rats, either sham-operated or with saline applied to the ganglion. There was a highly significant difference in the density of Fos-positive neurons between the inflamed and control groups. No significant difference was found between control groups. These results suggest that the inflammation of the superior cervical ganglion generated an increased responsiveness to painful stimuli, which may have been due to a diminished sympathetic influence upon the sensory peripheral innervation.

  6. The relationships of motor-evoked potentials to hand dexterity, motor function, and spasticity in chronic stroke patients: a transcranial magnetic stimulation study.

    Science.gov (United States)

    Cakar, Engin; Akyuz, Gulseren; Durmus, Oguz; Bayman, Levent; Yagci, Ilker; Karadag-Saygi, Evrim; Gunduz, Osman Hakan

    2016-12-01

    The standardization of patient evaluation and monitoring methods has a special importance in evaluating the effectiveness of therapeutic methods using drugs or rehabilitative techniques in stroke rehabilitation. The aim of this study was to investigate the relationships between clinical instruments and transcranial magnetic stimulation (TMS)-evoked neurophysiological parameters in stroke patients. This study included 22 chronic post-stroke patients who were clinically assessed using the Motricity Index (MI), finger-tapping test (FTT), Motor Activity Log (MAL) 28, Brunnstrom motor staging and Ashworth Scale (ASH). Motor-evoked potential (MEP) latency and amplitude, resting motor threshold (rMT) and central motor conduction time (CMCT) were measured with TMS. Shorter MEP-latency, shorter CMCT, higher motor-evoked potential amplitude, and diminished rMT exhibited significant correlations with clinical measures evaluating motor stage, dexterity, and daily life functionality. rMT exhibited a negative correlation with hand and lower extremity Brunnstrom stages (r = -0.64, r = -0.51, respectively), MI score (r = -0.48), FTT score (r = -0.69), and also with amount of use scale and quality of movement scale of MAL 28 scores (r = -0.61, r = -0.62, respectively). Higher MEP amplitude and diminished rMT showed positive correlations with reduced ASH score (r = -0.65, r = 0.44, respectively). The TMS-evoked neurophysiologic parameters including MEP latency, amplitude, rMT and CMCT generally have positive correlation with clinical measures which evaluate motor stage, dexterity and daily life functionality. Additionally, spasticity has also remarkable relationships with MEP amplitude and rMT. These results suggest that TMS-evoked neurophysiological parameters were useful measures for monitoring post-stroke patients.

  7. Improved detection of chromosomal abnormalities in chronic lymphocytic leukemia by conventional cytogenetics using CpG oligonucleotide and interleukin-2 stimulation: A Belgian multicentric study.

    Science.gov (United States)

    Put, Natalie; Konings, Peter; Rack, Katrina; Jamar, Mauricette; Van Roy, Nadine; Libouton, Jeanne-Marie; Vannuffel, Pascal; Sartenaer, Daniel; Ameye, Geneviève; Speleman, Frank; Herens, Christian; Poirel, Hélène A; Moreau, Yves; Hagemeijer, Anne; Vandenberghe, Peter; Michaux, Lucienne

    2009-10-01

    We performed a multicentric study to assess the impact of two different culture procedures on the detection of chromosomal abnormalities in 217 consecutive unselected cases with chronic lymphocytic leukemia (CLL) referred for routine analysis either at the time of diagnosis (n = 172) or during disease evolution (n = 45). Parallel cultures of peripheral blood or bone marrow were set up with the addition of either the conventional B-cell mitogen 12-O-tetradecanoyl-phorbol-13-acetate (TPA) or a combination of CpG oligonucleotide (CpG) and interleukin-2 (IL-2). Cytogenetic analyses were performed on both cultures. Clonal abnormalities were identified in 116 cases (53%). In 78 cases (36%), the aberrant clone was detected in both cultures. Among these, the percentages of aberrant metaphases were similar in both conditions in 17 cases, higher in the CpG/IL-2 culture in 43 cases, and higher in the TPA culture in 18 cases. Clonal aberrations were detected in only one culture, either in CpG/IL-2 or TPA in 33 (15%) and 5 (2%) cases, respectively. Taken together, abnormal karyotypes were observed in 51% with CpG/IL-2 and 38% with TPA (P cytogenetic analysis in 80 cases: del(13q) (n = 71), del(11q) (n = 5), +12 (n = 2), del(14q) (n = 1), and del(17p) (n = 1). In conclusion, our results confirm that CpG/IL-2 stimulation increases the detection rate of chromosomal abnormalities in CLL compared with TPA and that further improvement can be obtained by FISH. However, neither conventional cytogenetics nor FISH detected all aberrations, demonstrating the complementary nature of these techniques.

  8. Role of the insula and vestibular system in patients with chronic subjective dizziness: An fMRI study using sound-evoked vestibular stimulation

    Directory of Open Access Journals (Sweden)

    Iole eIndovina

    2015-12-01

    Full Text Available Chronic subjective dizziness (CSD is a common vestibular disorder characterized by persistent non-vertiginous dizziness, unsteadiness, and heightened sensitivity to motion stimuli that may last for months to years after events that cause acute vestibular symptoms or disrupt balance. CSD is not associated with abnormalities of basic vestibular or oculomotor reflexes. Rather, it is thought to arise from persistent use of high-threat postural control strategies and greater reliance on visual cues for spatial orientation (i.e., visual dependence, long after triggering events resolve. Anxiety-related personality traits confer vulnerability to CSD. Anomalous interactions between the central vestibular system and neural structures related to anxiety may sustain it. Vestibular- and anxiety-related processes overlap in the brain, particularly in the insula and hippocampus. Alterations in activity and connectivity in these brain regions in response to vestibular stimuli may be the neural basis of CSD.We examined this hypothesis by comparing brain activity from 18 patients with CSD and 18 healthy controls measured by functional magnetic resonance imaging during loud short tone bursts, which are auditory stimuli that evoke robust vestibular responses. Relative to controls, patients with CSD showed reduced activations to sound-evoked vestibular stimulation in the parieto-insular vestibular cortex (PIVC including the posterior insula, and in the anterior insula, inferior frontal gyrus, hippocampus, and anterior cingulate cortex. Patients with CSD also showed altered connectivity between the anterior insula and PIVC, anterior insula and middle occipital cortex, hippocampus and PIVC, and anterior cingulate cortex and PIVC.We conclude that reduced activation in PIVC, hippocampus, anterior insula, inferior frontal gyrus, and anterior cingulate cortex, as well as connectivity changes among these regions, may be linked to long-term vestibular symptoms in patients

  9. Serum FLT-3 ligand in a busulphan-induced model of chronic bone marrow hypoplasia in the female CD-1 mouse.

    Science.gov (United States)

    Molyneux, Gemma; Gibson, Frances M; Whayman, Matthew; Turton, John A

    2008-04-01

    The concentration of the cytokine fms-like tyrosine kinase-3 ligand (FL) is elevated in the plasma of patients treated with chemotherapy or radiotherapy for malignant conditions. In addition, plasma FL is increased in patients with bone marrow failure resulting from stem-cell defects (e.g. aplastic anaemia). Our goal in the present study was to measure the concentration of serum FL in mice treated with the chemotherapeutic agent busulphan (BU) to induce bone marrow depression and relate changes in FL to effects on haemopoiesis. Female CD-1 mice were treated with BU (9.0 mg/kg) or vehicle by intraperitoneal injection on 10 occasions over 21 days. Animals were autopsied on days 1, 23, 72, 119 and 177 postdosing. A full blood count was performed, and serum prepared for FL analysis. Femoral marrow cell suspensions were prepared to assess the total femoral nucleated cell count (FNCC) and the number of committed haemopoietic progenitor cells (CFU-C). On days 1 and 23 postdosing, significant decreases were evident in many peripheral blood parameters; the FNCC and CFU-C were also reduced in BU-treated mice, in conjunction with increases in serum FL levels. On days 72, 119 and 177 postdosing, several peripheral blood and bone marrow parameters remained reduced and the concentration of serum FL continued to be significantly increased. Linear regression analysis demonstrated significant correlations between the concentration of serum FL in BU-treated mice and peripheral blood and bone marrow parameters; this suggests the possible use of serum FL as a potential biomarker for drug-induced bone marrow injury.

  10. Effects of neuromuscular electrical stimulation and aerobic exercise training on arterial stiffness and autonomic functions in patients with chronic heart failure.

    Science.gov (United States)

    Dobšák, Petr; Tomandl, Josef; Spinarova, Lenka; Vitovec, Jiri; Dusek, Ladislav; Novakova, Marie; Jarkovsky, Jiri; Krejci, Jan; Hude, Petr; Honek, Tomáš; Siegelova, Jarmila; Homolka, Pavel

    2012-10-01

    Neuromuscular electrical stimulation (NMES) of leg muscles has been introduced in clinical practice as a rehabilitation (RHB) method in patients with chronic heart failure (CHF); however, the role of NMES on the reduction of arterial stiffness and autonomic disbalance in these patients has not yet been studied. Sixty-one patients with stable CHF (mean age 58.9 [2.1] years; mean ejection fraction 31 [4.2]%, New York Heart Association II-III) were randomly assigned into two groups. Patients in (i) exercise training group (ET; n = 30) underwent 12 weeks of bicycle ET (3 × 40 min/week); (ii) group NMES (n = 31) performed 12 weeks of NMES of quadriceps and calf muscles (frequency 10 Hz, mode "20 s on-20 s off," intensity 60 mA), 2 × 60 min/day. Noninvasive assessment of arterial stiffness was done using the cardio-ankle vascular index (CAVI). CAVI and heart rate variability (HRV) and ·VO(2peak) were evaluated before and after RHB program. Both types of RHB reduced significantly CAVI (ET from 9.6 [0.2] to 8.9 [0.2], P < 0.012; NMES from 9.3 [0.2] to 8.7 [0.2], P < 0.013), increased high frequency (HF) component of HRV (+65.6%; P = 0.001) and decreased ratio of low frequency (LF) component with HF component (LF/HF ratio) in group ET (-39.8%; P < 0.001). Changes of HRV parameters in group NMES were not significant; however, a marked tendency to autonomic stabilization was present. Both types of RHB led also to significant increase of ·VO(2peak) (ET from 18.7 [0.7] to 20.8 [0.7] mL/kg/min, P < 0.004; NMES from 17.3 [0.7] to 19.0 [0.7] mL/kg/min, P < 0.001). ET or NMES has been shown to improve significantly arterial stiffness and to stabilize autonomic balance.

  11. Chronic treatment with 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside increases insulin-stimulated glucose uptake and GLUT4 translocation in rat skeletal muscles in a fiber type-specific manner.

    Science.gov (United States)

    Buhl, E S; Jessen, N; Schmitz, O; Pedersen, S B; Pedersen, O; Holman, G D; Lund, S

    2001-01-01

    Recent studies have demonstrated that chronic administration of AICAR (5-aminoimidazole-4-carboxamide- 1-beta-D-ribofuranoside), an activator of the AMP-activated protein kinase, increases hexokinase activity and the contents of total GLUT4 and glycogen in rat skeletal muscles. To explore whether AICAR also affects insulin-stimulated glucose transport and GLUT4 cell surface content, Wistar rats were subcutaneously injected with AICAR for 5 days in succession (1 mg/g body wt). Maximally insulin-stimulated (60 nmol/l) glucose uptake was markedly increased in epitrochlearis (EPI) muscle (average 63%, P fiber type-specific increase in insulin-stimulated glucose uptake and GLUT4 cell surface content in rat skeletal muscle with the greatest effect observed on white fast-twitch glycolytic muscles (EPI). These results are comparable with the effects of chronic exercise training, and it brings the AMP-activated protein kinase into focus as a new interesting target for future pharmacological intervention in insulin-resistant conditions.

  12. Preliminary Evidence of the Effects of High-frequency Repetitive Transcranial Magnetic Stimulation (rTMS) on Swallowing Functions in Post-Stroke Individuals with Chronic Dysphagia

    Science.gov (United States)

    Cheng, Ivy K. Y.; Chan, Karen M. K.; Wong, C. S.; Cheung, Raymond T. F.

    2015-01-01

    Background: There is growing evidence of potential benefits of repetitive transcranial magnetic stimulation (rTMS) in the rehabilitation of dysphagia. However, the site and frequency of stimulation for optimal effects are not clear. Aims: The aim of this pilot study is to investigate the short-term effects of high-frequency 5 Hz rTMS applied to…

  13. Are there guidelines for implantable spinal cord stimulator therapy in patients using chronic anticoagulation therapy? - A review of decision-making in the high-risk patient

    Directory of Open Access Journals (Sweden)

    Ramsis F Ghaly

    2016-01-01

    Conclusion: Our literature search did not reveal any evidence of SCS therapy among patients with chronic anticoagulation. This case illustrated a complicated clinical case scenario wherein a percutaneous SCS implantation would normally be contraindicated due to severe thoracic spinal stenosis and chronic anticoagulation which could lead to possible paralysis or even a lethal consequences associated with the possible formation of a thoracic epidural hematoma.

  14. Stress stimulation and signal pathways of osteoprotegerin, receptor activator of nuclear factor kappa B and its ligand in bone metabolism%应力刺激与骨保护蛋白、核因子κB受体活化因子及其配体骨代谢信号通路

    Institute of Scientific and Technical Information of China (English)

    王丹; 鲍捷; 王国祥

    2012-01-01

    背景:骨保护蛋白、核因子κB 受体活化因子及其配体(osteoprote-gerin/ ligand of receptor activator of NF-κB/receptoractivator of NF-κB,OPG/RANKL/RANK)骨代谢信号通路是对应力敏感的通路之一.不同性质的运动会产生不同的机械应力刺激,影响骨代谢信号通路.目的:观察不同性质的运动对OPG/RANKL/RANK 信号通路的影响.方法:由第一作者于2000/2011 通过计算机检索 CNKI,HighWire 和Elsevier 数据库中关于" 应力刺激与OPG/RANKL/RANK"的相关的论文报告.以"应力刺激,OPG/RANKL/RANK"或"应力刺激,骨代谢"为检索词进行检索.选择的文章内容与应力刺激对信号通路的影响有关,选择相关近期发表的文献或者是发表在权威期刊的文献.共检索到215 篇文章,按纳入和排除标准对文献进行筛选,共纳入31 篇文章.结果与结论:运动对骨骼不断产生机械应力刺激,这种机械应力刺激可以通过影响成骨细胞和破骨细胞的OPG/RNAKL/RANK 信号调节系统而调节骨组织代谢.但是相关文献中的研究结果不一致,有待进一步的研究.%BACKGROUND: Signal pathway of osteoprotegerin, receptor activator of nuclear factor kappa B and its ligand in bone metabolismis one of the accesses to cope with the stress sensitivity. Different types of the exercise can produce different types of stressstimulation, and influence the signal pathways in bone metabolism.OBJECTIVE: To explore the influence of different types of exercise on the signal pathways of osteoprotegerin, receptor activator ofnuclear factor kappa B and its ligand in bone metabolism.METHODS: An online search of CNKI, HighWire and Elsevier databases was performed for articles related to "stress stimulation,osteoprotegerin, receptor activator of nuclear factor kappa B and its ligand". Articles published from 2000 to 2011 with thekeywords of "stress stimulation, osteoprotegerin, receptor activator of nuclear factor kappa B and its ligand" or

  15. Mast Cell Growth Factor (C-Kit Ligand) in Combination with Granulocytemacrophage Colony-Stimulating Factor and Interleukin-3: In Vivo Hemopoietic Effects in Irradiated Mice Compared to in Vitro Effects

    Science.gov (United States)

    1994-01-01

    ligand, henceforth thermore, the macrocytic anemia , deficiencies referred to as MGF, was provided by Immunex in tissue mast cells, abnormalities in...Keighley G. Two hereditary Exp Hematol 1992; 20: 276-9. mouse anemias (SI/SId and W/W’) deficient in response 32. Urdal DL, Mochizuki D, Conlon PJ, March CJ

  16. Presence of Rheumatoid Factor during Chronic HCV Infection Is Associated with Expansion of Mature Activated Memory B-Cells that Are Hypo-Responsive to B-Cell Receptor Stimulation and Persist during the Early Stage of IFN Free Therapy.

    Science.gov (United States)

    Reyes-Avilés, Elane; Kostadinova, Lenche; Rusterholtz, Anne; Cruz-Lebrón, Angelica; Falck-Ytter, Yngve; Anthony, Donald D

    2015-01-01

    Approximately half of those with chronic hepatitis C virus (HCV) infection have circulating rheumatoid factor (RF), and a portion of these individuals develop cryoglobulinemic vasculitis. B cell phenotype/function in relation to RF in serum has been unclear. We examined B cell subset distribution, activation state (CD86), cell cycle state (Ki67), and ex-vivo response to BCR, TLR9 and TLR7/8 stimulation, in chronic HCV-infected donors with or without RF, and uninfected donors. Mature-activated B-cells of HCV-infected donors had lower CD86 expression compared to uninfected donors, and in the presence of RF they also showed reduced CD86 expression in response to BCR and TLR9 stimulation. Additionally, mature activated memory B cells of HCV RF+ donors less commonly expressed Ki67+ than HCV RF- donors, and did not proliferate as well in response to BCR stimulation. Proportions of mature-activated B cells were enhanced, while naïve B-cells were lower in the peripheral blood of HCV-RF+ compared to RF- and uninfected donors. None of these parameters normalize by week 8 of IFN free direct acting antiviral (DAA) therapy in HCV RF+ donors, while in RF- donors, mature activated B cell proportions did normalize. These data indicate that while chronic HCV infection alone results in a lower state of activation in mature activated memory B cells, the presence of RF in serum is associated with a more pronounced state of unresponsiveness and an overrepresentation of these B cells in the blood. This phenotype persists at least during the early time window after removal of HCV from the host.

  17. Experimental chronic Pseudomonas aeruginosa lung infection in rats. Non-specific stimulation with LPS reduces lethality as efficiently as specific immunization

    DEFF Research Database (Denmark)

    Lange, K H; Hougen, H P; Høiby, N

    1995-01-01

    stimulation of the non-specific defence mechanisms by Escherichia coli lipopolysaccharide (LPS) or P. aeruginosa sonicate, or the acquired specific immune response by vaccination with the same bacterial antigens. One day prior to challenge with P. aeruginosa embedded in alginate beads, rats were stimulated...... to earlier recruitment of PMNs most likely mediated by either cytokines and other chemotactic factors (stimulated group) or the immune response in concert with the complement cascade (vaccinated group). The results of the present and previous vaccination studies show that it is possible to improve survival...

  18. Design of Ligands for Affinity Purification of G-CSF Based on Peptide Ligands Derived from a Peptide Library

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Combinatorial peptide libraries have become powerful tools to screen functional ligands by the principle of affinity selection. We screened in a phage peptide library to investigate potential peptide affinity ligands for the purification of human granulocyte colony-stimulation factor(hG-CSF). Peptide ligands will be promising to replace monoclonal antibodies as they have advantages of high stability, efficiency, selectivity and low price.

  19. Gait analysis in patients with advanced Parkinson disease: different or additive effects on gait induced by levodopa and chronic STN stimulation.

    Science.gov (United States)

    Lubik, S; Fogel, W; Tronnier, V; Krause, M; König, J; Jost, W H

    2006-02-01

    The aim of our study was to observe the effects on gait parameters induced by STN stimulation and levodopa medication in patients with advanced Parkinson's disease in order to determine different or additive effects. Therefore we examined 12 patients with advanced Parkinson disease after bilateral implantation of DBS into the STN. We assessed the motor score of the UPDRS and quantitative gait analysis under 4 treatment conditions: with and without stimulation as well as with and without levodopa. The mean improvement of the UPDRS motor score was almost the same with levodopa and DBS. Combining both therapies we saw a further improvement of the motor score. Gait parameters of patients with PD treated either with levodopa or STN stimulation were greatly improved. A significant difference between levodopa and STN stimulation could only be shown for the parameters velocity and step length. These parameters improved more with levodopa than with stimulation. The combination of both therapeutic methods showed the best results on the UPDRS motor score and gait parameters.

  20. Evaluation of CD4+CD25+ T lymphocyte response time kinetics in patients with chronic Chagas disease after in vitro stimulation with recombinant Trypanosoma cruzi antigens

    Directory of Open Access Journals (Sweden)

    Suellen Carvalho de Moura Braz

    2013-05-01

    Full Text Available Introduction CD4+CD25+ T lymphocytes have been implicated in the regulation of host inflammatory response against Trypanosoma cruzi, and may be involved in the clinical course of the disease. Methods Peripheral blood mononuclear cells from patients with chronic Chagas disease were cultured in the presence of T. cruzi recombinant antigens and assayed for lymphocytes at distinct time points. Results It was possible to differentiate clinical forms of chronic Chagas disease at days 3 and 5 according to presence of CD4+CD25+ T cells in cell cultures. Conclusions Longer periods of cell culture proved to be potentially valuable for prospective evaluations of CD4+CD25+ T lymphocytes in patients with chronic Chagas disease.

  1. Chronic hypoxia induces the activation of the Wnt/β-catenin signaling pathway and stimulates hippocampal neurogenesis in wild-type and APPswe-PS1ΔE9 transgenic mice in vivo

    Science.gov (United States)

    Varela-Nallar, Lorena; Rojas-Abalos, Macarena; Abbott, Ana C.; Moya, Esteban A.; Iturriaga, Rodrigo; Inestrosa, Nibaldo C.

    2014-01-01

    Hypoxia modulates proliferation and differentiation of cultured embryonic and adult stem cells, an effect that includes β-catenin, a key component of the canonical Wnt signaling pathway. Here we studied the effect of mild hypoxia on the activity of the Wnt/β-catenin signaling pathway in the hippocampus of adult mice in vivo. The hypoxia-inducible transcription factor-1α (HIF-1α) was analyzed as a molecular control of the physiological hypoxic response. Exposure to chronic hypoxia (10% oxygen for 6–72 h) stimulated the activation of the Wnt/β-catenin signaling pathway. Because the Wnt/β-catenin pathway is a positive modulator of adult neurogenesis, we evaluated whether chronic hypoxia was able to stimulate neurogenesis in the subgranular zone (SGZ) of the hippocampal dentate gyrus. Results indicate that hypoxia increased cell proliferation and neurogenesis in adult wild-type mice as determined by Ki67 staining, Bromodeoxyuridine (BrdU) incorporation and double labeling with doublecortin (DCX). Chronic hypoxia also induced neurogenesis in a double transgenic APPswe-PS1ΔE9 mouse model of Alzheimer’s disease (AD), which shows decreased levels of neurogenesis in the SGZ. Our results show for the first time that exposure to hypoxia in vivo can induce the activation of the Wnt/β-catenin signaling cascade in the hippocampus, suggesting that mild hypoxia may have a therapeutic value in neurodegenerative disorders associated with altered Wnt signaling in the brain and also in pathological conditions in which hippocampal neurogenesis is impaired. PMID:24574965

  2. Decrease of D2 receptor binding but increase in D2-stimulated G-protein activation, dopamine transporter binding and behavioural sensitization in brains of mice treated with a chronic escalating dose 'binge' cocaine administration paradigm.

    Science.gov (United States)

    Bailey, A; Metaxas, A; Yoo, J H; McGee, T; Kitchen, I

    2008-08-01

    Understanding the neurobiology of the transition from initial drug use to excessive drug use has been a challenge in drug addiction. We examined the effect of chronic 'binge' escalating dose cocaine administration, which mimics human compulsive drug use, on behavioural responses and the dopaminergic system of mice and compared it with a chronic steady dose (3 x 15 mg/kg/day) 'binge' cocaine administration paradigm. Male C57BL/6J mice were injected with saline or cocaine in an escalating dose paradigm for 14 days. Locomotor and stereotypy activity were measured and quantitative autoradiographic mapping of D(1) and D(2) receptors, dopamine transporters and D(2)-stimulated [(35)S]GTPgammaS binding was performed in the brains of mice treated with this escalating and steady dose paradigm. An initial sensitization to the locomotor effects of cocaine followed by a dose-dependent increase in the duration of the locomotor effect of cocaine was observed in the escalating but not the steady dose paradigm. Sensitization to the stereotypy effect of cocaine and an increase in cocaine-induced stereotypy score was observed from 3 x 20 to 3 x 25 mg/kg/day cocaine. There was a significant decrease in D(2) receptor density, but an increase in D(2)-stimulated G-protein activity and dopamine transporter density in the striatum of cocaine-treated mice, which was not observed in our steady dose paradigm. Our results document that chronic 'binge' escalating dose cocaine treatment triggers profound behavioural and neurochemical changes in the dopaminergic system, which might underlie the transition from drug use to compulsive drug use associated with addiction, which is a process of escalation.

  3. Chronic hypoxia induces the in vivo activation of the Wnt/β-catenin signaling pathway and stimulates hippocampal neurogenesis in wild-type and APPswe-PS1deltaE9 transgenic mice

    Directory of Open Access Journals (Sweden)

    Lorena eVarela-Nallar

    2014-02-01

    Full Text Available Hypoxia modulates proliferation and differentiation of cultured embryonic and adult stem cells, an effect that includes β-catenin a key component of the canonical Wnt signaling pathway. Here we studied in vivo the effect of mild hypoxia on the activity of the Wnt/β-catenin signaling pathway in the hippocampus of adult mice. As a molecular control of the physiological hypoxic response the hypoxia-inducible transcription factor-1α (HIF-1α was analyzed. Exposure to chronic hypoxia (10% oxygen for 6-72 h stimulated the activation of the Wnt/β-catenin signaling pathway. Because the Wnt/β-catenin pathway is a positive modulator of adult neurogenesis, we evaluated whether chronic hypoxia was able to stimulate neurogenesis in the subgranular zone (SGZ of the hippocampal dentate gyrus. Results indicate that hypoxia increased cell proliferation and neurogenesis in adult wild-type mice as determined by Ki67 staining, BrdU incorporation and double labeling with doublecortin. Chronic hypoxia also induced neurogenesis in double transgenic APPswe-PS1deltaE9 mouse model of Alzheimer’s disease (AD, which shows decreased levels of neurogenesis at the SGZ. Our results show for the first time that in vivo exposure to hypoxia can induce the activation of the Wnt/β-catenin signaling cascade in the hippocampus, suggesting that mild hypoxia may have a therapeutic value in neurodegenerative disorder associated with altered Wnt signaling in the brain and also in pathological conditions in which hippocampal neurogenesis is impaired.

  4. A Mobile Phone App to Stimulate Daily Physical Activity in Patients with Chronic Obstructive Pulmonary Disease : Development, Feasibility, and Pilot Studies

    NARCIS (Netherlands)

    Vorrink, SNW; Kort, Helianthe Sm; Troosters, Thierry; Lammers, Jan-Willem J

    2016-01-01

    BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) demonstrate reduced levels of daily physical activity (DPA) compared to healthy controls. This results in a higher risk of hospital admission and shorter survival. Performing regular DPA reduces these risks. OBJECTIVE: To develop

  5. A mobile phone application to stimulate daily physical activity in patients with chronic obstructive pulmonary disease: development, feasibility and pilot studies

    NARCIS (Netherlands)

    Vorrink, Sigrid N.W.; Kort, Helianthe S.M.; Troosters, Thierry; Lammers, Jan-Willem J.

    2016-01-01

    Background: Patients with chronic obstructive pulmonary disease (COPD) demonstrate reduced levels of daily physical activity (DPA) compared to healthy controls. This results in a higher risk of hospital admission and shorter survival. Performing regular DPA reduces these risks. Objective: To develop

  6. Internalization mechanisms of the epidermal growth factor receptor after activation with different ligands

    DEFF Research Database (Denmark)

    Henriksen, Lasse; Grandal, Michael Vibo; Knudsen, Stine Louise Jeppe

    2013-01-01

    fully inhibits EGFR degradation after all ligands tested. Furthermore, inhibition of dynamin function blocked EGFR internalization after stimulation with all ligands. Knocking out a number of clathrin-independent dynamin-dependent pathways of internalization had no effect on the ligand...

  7. Efficacy of biofeedback and electrical stimulation combined with drugs for chronic prostatitis/chronic pelvic pain syndrome%生物反馈电刺激联合药物治疗慢性前列腺炎/慢性骨盆疼痛综合征的临床研究

    Institute of Scientific and Technical Information of China (English)

    唐荣; 安瑞华

    2012-01-01

    目的 探讨生物反馈电刺激联合药物治疗慢性前列腺炎/慢性骨盆疼痛综合征(CP/CPPS)的效果.方法 符合入选标准的患者随机分为药物组(A组)、药物+生物反馈电刺激组(B组),每组25例,另单设一单纯药物治疗无效组(C组)25例.B、C两组均采用生物反馈电刺激治疗仪治疗,B组加常规药物治疗,A组应用常规药物治疗.结果 A组和B组治疗后患者的临床症状较治疗前均有显著改善(P<0.05);且B组优于A组.C组治疗后的临床症状亦较治疗前有显著改善(P<0.05).结论 生物反馈电刺激治疗能明显改善慢性前列腺炎/慢性盆底疼痛综合征患者的临床症状及性功能,且能改善药物治疗无效的顽固性前列腺炎症状.%Objective To investigate the effect of biofeedback and electrical stimulation combined with drugs on chronic prostatitis/chronic pelvic pain syndrome ( CP/CPPS). Methods Seventy five eligible patients were randomly divided into 3 groups (each 25 patients) ; group A received routine drugs, group B received biofeedback and electrical stimulation combined with ' routine drugs. Patients in group C were treated ineffectively with routine drugs,and received biofeedback and electrical stimulation therapy only. Results The clinical symptoms of patients in group A and group B after treatment were both significantly improved than before treatment (P <0.05), clinical symptoms of patients in group B were better than in group A. The clinical symptoms of patients in group C after treatment compared with that before treatment were significantly improved (P < 0. 05). Conclusion Biofeedback electrical stimulation therapy may significantly improve the clinical symptoms and sexual function of patients with chronic prostatitis/chronic pelvic pain syndrome. It also can improve the clinical symptoms of patients with refractory prostatitis who were treated ineffectively with routine drugs.

  8. Cross-axis adaptation improves 3D vestibulo-ocular reflex alignment during chronic stimulation via a head-mounted multichannel vestibular prosthesis.

    Science.gov (United States)

    Dai, Chenkai; Fridman, Gene Y; Chiang, Bryce; Davidovics, Natan S; Melvin, Thuy-Anh; Cullen, Kathleen E; Della Santina, Charles C

    2011-05-01

    By sensing three-dimensional (3D) head rotation and electrically stimulating the three ampullary branches of a vestibular nerve to encode head angular velocity, a multichannel vestibular prosthesis (MVP) can restore vestibular sensation to individuals disabled by loss of vestibular hair cell function. However, current spread to afferent fibers innervating non-targeted canals and otolith end organs can distort the vestibular nerve activation pattern, causing misalignment between the perceived and actual axis of head rotation. We hypothesized that over time, central neural mechanisms can adapt to correct this misalignment. To test this, we rendered five chinchillas vestibular deficient via bilateral gentamicin treatment and unilaterally implanted them with a head-mounted MVP. Comparison of 3D angular vestibulo-ocular reflex (aVOR) responses during 2 Hz, 50°/s peak horizontal sinusoidal head rotations in darkness on the first, third, and seventh days of continual MVP use revealed that eye responses about the intended axis remained stable (at about 70% of the normal gain) while misalignment improved significantly by the end of 1 week of prosthetic stimulation. A comparable time course of improvement was also observed for head rotations about the other two semicircular canal axes and at every stimulus frequency examined (0.2-5 Hz). In addition, the extent of disconjugacy between the two eyes progressively improved during the same time window. These results indicate that the central nervous system rapidly adapts to multichannel prosthetic vestibular stimulation to markedly improve 3D aVOR alignment within the first week after activation. Similar adaptive improvements are likely to occur in other species, including humans.

  9. Successful Management of Neutropenia in a Patient with CD40 Ligand Deficiency by Immunoglobulin Replacement Therapy

    Directory of Open Access Journals (Sweden)

    Lida Atarod

    2007-03-01

    Full Text Available Hyper-IgM syndromes are characterized by profound reduction of serum IgG, IgA, and IgE levels with normal or increased concentrations of serum IgM. CD40 ligand deficiency is X-linked form of the disease, which results in a lack of immunoglobulin class switching from IgM to IgG in B cells. In addition to the recurrent infections, a number of patients suffer from neutropenia. There are some evidences indicating the effect of G-CSF in combination with intravenous immunoglobulin (IVIG in improvement of neutrophil counts, which has become the most common procedure to control neutropenia.In this report we present a 6 year-old patient of CD40 ligand deficiency, who suffered from chronic, severe neutropenia. Administration of IVIG was started for him when the diagnosis was made at the age of 1.5 years and he was on the regular IVIG therapy after that time untill now for a period of 4.5 years. IVIG and prophylactic antibiotic therapy, despite cessation of granulocyte colony-stimulating factor, injection after one month, corrected the severe neutropenic state of this patient. It seems that regular administration of sufficient doses of IVIG can be useful in the management of neutropenia in CD40 ligand deficiency, which results in better quality of life with decreasing occurrence of infection.

  10. Chronic ultra-low dose follicle-stimulating hormone regimen for patients with polycystic ovary syndrome: one click, one follicle, one pregnancy.

    Science.gov (United States)

    Orvieto, Raoul; Homburg, Roy

    2009-04-01

    In the present study we demonstrate that using a weekly incremental dose as small as 8.3 IU of FSH in a chronic ultra low-dose step-up protocol for anovulatory polycystic ovary syndrome (PCOS) produces very good clinical results with an excellent safety profile. Although using a significantly lower incremental (16.6% of the initial dose) and total (622 +/- 286 IU) gonadotropin dose, compared with the widely used and accepted low-dose gonadotropins regimen, a clinical pregnancy rate (PR) of almost 30% per started cycle has been achieved with just one twin gestation and no case of even mild ovarian hyperstimulation syndrome (OHSS).

  11. Maltodextrin/ascorbic acid stimulates wound closure by increasing collagen turnover and TGF-β1 expression in vitro and changing the stage of inflammation from chronic to acute in vivo.

    Science.gov (United States)

    Salgado, Rosa M; Cruz-Castañeda, Otilia; Elizondo-Vázquez, Francisco; Pat, Lucia; De la Garza, Anabel; Cano-Colín, Saúl; Baena-Ocampo, Leticia; Krötzsch, Edgar

    2017-02-01

    It has been reported that carbohydrates confer physicochemical properties to the wound environment that improves tissue repair. We evaluated in vitro and in vivo wound healing during maltodextrin/ascorbic acid treatment. In a fibroblast monolayer scratch assay, we demonstrated that maltodextrin/ascorbic acid stimulated monolayer repair by increasing collagen turnover coordinately with TGF-β1 expression (rising TGF-β1 and MMP-1 expression, as well as gelatinase activity, while TIMP-1 was diminished), similar to in vivo trends. On the other hand, we observed that venous leg ulcers treated with maltodextrin/ascorbic acid diminished microorganism population and improved wound repair during a 12 week period. When maltodextrin/ascorbic acid treatment was compared with zinc oxide, almost four fold wound closure was evidenced. Tissue architecture and granulation were improved after the carbohydrate treatment also, since patients that received maltodextrin/ascorbic acid showed lower type I collagen fiber levels and increased extracellular alkaline phosphatase activity and blood vessels than those treated with zinc oxide. We hypothesize that maltodextrin/ascorbic acid treatment stimulated tissue repair of chronic wounds by changing the stage of inflammation and modifying collagen turnover directly through fibroblast response.

  12. Chronic pancreatitis

    Science.gov (United States)

    Chronic pancreatitis - chronic; Pancreatitis - chronic - discharge; Pancreatic insufficiency - chronic; Acute pancreatitis - chronic ... alcohol abuse over many years. Repeated episodes of acute ... chronic pancreatitis. Genetics may be a factor in some cases. ...

  13. Impaired toll like receptor-7 and 9 induced immune activation in chronic spinal cord injured patients contributes to immune dysfunction

    Science.gov (United States)

    Gungor, Bilgi; Kahraman, Tamer; Gursel, Mayda; Yilmaz, Bilge

    2017-01-01

    Reduced immune activation or immunosuppression is seen in patients withneurological diseases. Urinary and respiratory infections mainly manifested as septicemia and pneumonia are the most frequent complications following spinal cord injuries and they account for the majority of deaths. The underlying reason of these losses is believed to arise due to impaired immune responses to pathogens. Here, we hypothesized that susceptibility to infections of chronic spinal cord injured (SCI) patients might be due to impairment in recognition of pathogen associated molecular patterns and subsequently declining innate and adaptive immune responses that lead to immune dysfunction. We tested our hypothesis on healthy and chronic SCI patients with a level of injury above T-6. Donor PBMCs were isolated and stimulated with different toll like receptor ligands and T-cell inducers aiming to investigate whether chronic SCI patients display differential immune activation to multiple innate and adaptive immune cell stimulants. We demonstrate that SCI patients' B-cell and plasmacytoid dendritic cells retain their functionality in response to TLR7 and TLR9 ligand stimulation as they secreted similar levels of IL6 and IFNα. The immune dysfunction is not probably due to impaired T-cell function, since neither CD4+ T-cell dependent IFNγ producing cell number nor IL10 producing regulatory T-cells resulted different outcomes in response to PMA-Ionomycin and PHA-LPS stimulation, respectively. We showed that TLR7 dependent IFNγ and IP10 levels and TLR9 mediated APC function reduced substantially in SCI patients compared to healthy subjects. More importantly, IP10 producing monocytes were significantly fewer compared to healthy subjects in response to TLR7 and TLR9 stimulation of SCI PBMCs. When taken together this work implicated that these defects could contribute to persistent complications due to increased susceptibility to infections of chronic SCI patients. PMID:28170444

  14. Effects of chronic treatment with the eNOS stimulator Impaza on penis length and sexual behaviors in rats with a high baseline of sexual activity.

    Science.gov (United States)

    Chu, X; Zhavbert, E S; Dugina, J L; Kheyfets, I A; Sergeeva, S A; Epstein, O I; Agmo, A

    2014-01-01

    Endothelial nitric oxide synthase (eNOS) has an important role in erection, and it also affects aspects of sexual behavior. In this experiment, we determined whether a compound enhancing the activity of eNOS, Impaza, could stimulate any aspect of sexual behavior and increase penis length in rats with a high baseline of sexual activity. For comparison, the PDE5 inhibitor sildenafil was included. Male rats were orally treated with Impaza or sildenafil for 28 days. Impaza (3 ml kg(-1)) was given daily while sildenafil (3 mg kg(-1)) was given twice weekly. Tests for sexual incentive motivation and copulatory behavior were performed just before drug treatment and at days 7, 14 and 28 of treatment. In addition, the length of the protruding penis at mount, intromission and ejaculation was measured. Impaza but not sildenafil increased penis length at mount after 14 and 28 days of treatment. The compounds failed to modify sexual incentive motivation or copulatory behavior. It is suggested that Impaza enhanced intracavernous pressure, as such a pressure increase is the most likely explanation for enhanced penis length at mount. This effect, together with an absence of motivational actions, suggests that Impaza may be the most valuable treatment for erectile dysfunction.

  15. CB receptor ligands from plants.

    Science.gov (United States)

    Woelkart, Karin; Salo-Ahen, Outi M H; Bauer, Rudolf

    2008-01-01

    Advances in understanding the physiology and pharmacology of the endogenous cannabinoid system have potentiated the interest of cannabinoid receptors as potential therapeutic targets. Cannabinoids have been shown to modulate a variety of immune cell functions and have therapeutic implications on central nervous system (CNS) inflammation, chronic inflammatory conditions such as arthritis, and may be therapeutically useful in treating autoimmune conditions such as multiple sclerosis. Many of these drug effects occur through cannabinoid receptor signalling mechanisms and the modulation of cytokines and other gene products. Further, endocannabinoids have been found to have many physiological and patho-physiological functions, including mood alteration and analgesia, control of energy balance, gut motility, motor and co-ordination activities, as well as alleviation of neurological, psychiatric and eating disorders. Plants offer a wide range of chemical diversity and have been a growing domain in the search for effective cannabinoid ligands. Cannabis sativa L. with the known plant cannabinoid, Delta(9-)tetrahydrocannabinol (THC) and Echinacea species with the cannabinoid (CB) receptor-binding lipophilic alkamides are the best known herbal cannabimimetics. This review focuses on the state of the art in CB ligands from plants, as well their possible therapeutic and immunomodulatory effects.

  16. Ligand modeling and design

    Energy Technology Data Exchange (ETDEWEB)

    Hay, B.P. [Pacific Northwest National Lab., Richland, WA (United States)

    1997-10-01

    The purpose of this work is to develop and implement a molecular design basis for selecting organic ligands that would be used in the cost-effective removal of specific radionuclides from nuclear waste streams. Organic ligands with metal ion specificity are critical components in the development of solvent extraction and ion exchange processes that are highly selective for targeted radionuclides. The traditional approach to the development of such ligands involves lengthy programs of organic synthesis and testing, which in the absence of reliable methods for screening compounds before synthesis, results in wasted research effort. The author`s approach breaks down and simplifies this costly process with the aid of computer-based molecular modeling techniques. Commercial software for organic molecular modeling is being configured to examine the interactions between organic ligands and metal ions, yielding an inexpensive, commercially or readily available computational tool that can be used to predict the structures and energies of ligand-metal complexes. Users will be able to correlate the large body of existing experimental data on structure, solution binding affinity, and metal ion selectivity to develop structural design criteria. These criteria will provide a basis for selecting ligands that can be implemented in separations technologies through collaboration with other DOE national laboratories and private industry. The initial focus will be to select ether-based ligands that can be applied to the recovery and concentration of the alkali and alkaline earth metal ions including cesium, strontium, and radium.

  17. Nonconventional interventions for chronic post-traumatic stress disorder: Ketamine, repetitive trans-cranial magnetic stimulation (rTMS), and alternative approaches.

    Science.gov (United States)

    Pradhan, Basant; Kluewer D'Amico, Jessica; Makani, Ramkrishna; Parikh, Tapan

    2016-01-01

    It is alarming that only 59% of those who have post-traumatic stress disorder (PTSD) respond to selective serotonin reuptake inhibitors. Many existing treatments, both pharmacological and nonpharmacological, do not directly target trauma memories that lay at the core of the PTSD pathogenesis. Notable exceptions are medications like ketamine and propranolol and trauma-focused psychotherapies like eye-movement desensitization and reprocessing therapy (developed by Shapiro) and Trauma Interventions using Mindfulness Based Extinction and Reconsolidation (TIMBER) for trauma memories (developed by Pradhan). Although the antidepressant effects of ketamine are no longer news, ketamine's effects on treatment refractory PTSD (TR-PTSD) is a recent concept. As TR-PTSD has a marked public health burden and significant limitations in terms of treatment interventions, a thorough assessment of current strategies is required. Research to bring clarity to the underlying pathophysiology and neurobiology of TR-PTSD delineating the chemical, structural, and circuitry abnormalities will take time. In the interim, in the absence of a 1-size-fits-all therapeutic approach, pragmatically parallel lines of research can be pursued using the pharmacological and nonpharmacological treatments that have a strong theoretical rationale for efficacy. This article aims to review the current literature on interventions for PTSD, most notably ketamine, trans-cranial magnetic stimulation treatment, yoga and mindfulness interventions, and TIMBER. We present an outline for their future use, alone as well as in combination, with a hope of providing additional insights as well as advocating for developing more effective therapeutic intervention for this treatment-resistant and debilitating condition.

  18. Superior serum half life of albumin tagged TNF ligands

    Energy Technology Data Exchange (ETDEWEB)

    Mueller, Nicole [Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Wuerzburg, Roentgenring 11, 97070 Wuerzburg (Germany); Schneider, Britta; Pfizenmaier, Klaus [Institute of Cell Biology and Immunology, University of Stuttgart, Allmandring 31, 70569 Stuttgart (Germany); Wajant, Harald, E-mail: harald.wajant@mail.uni-wuerzburg.de [Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Wuerzburg, Roentgenring 11, 97070 Wuerzburg (Germany)

    2010-06-11

    Due to their immune stimulating and apoptosis inducing properties, ligands of the TNF family attract increasing interest as therapeutic proteins. A general limitation of in vivo applications of recombinant soluble TNF ligands is their notoriously rapid clearance from circulation. To improve the serum half life of the TNF family members TNF, TWEAK and TRAIL, we genetically fused soluble variants of these molecules to human serum albumin (HSA). The serum albumin-TNF ligand fusion proteins were found to be of similar bioactivity as the corresponding HSA-less counterparts. Upon intravenous injection (i.v.), serum half life of HSA-TNF ligand fusion proteins, as determined by ELISA, was around 15 h as compared to approximately 1 h for all of the recombinant control TNF ligands without HSA domain. Moreover, serum samples collected 6 or 24 h after i.v. injection still contained high TNF ligand bioactivity, demonstrating that there is only limited degradation/inactivation of circulating HSA-TNF ligand fusion proteins in vivo. In a xenotransplantation model, significantly less of the HSA-TRAIL fusion protein compared to the respective control TRAIL protein was required to achieve inhibition of tumor growth indicating that the increased half life of HSA-TNF ligand fusion proteins translates into better therapeutic action in vivo. In conclusion, our data suggest that genetic fusion to serum albumin is a powerful and generally applicable mean to improve bioavailability and in vivo activity of TNF ligands.

  19. Peripheral neuromodulation in chronic migraine.

    Science.gov (United States)

    Perini, F; De Boni, A

    2012-05-01

    Patients with chronic migraines are often refractory to medical treatment. Therefore, they might need other strategies to modulate their pain, according to their level of disability. Neuromodulation can be achieved with several tools: meditation, biofeedback, physical therapy, drugs and electric neurostimulation (ENS). ENS can be applied to the central nervous system (brain and spinal cord), either invasively (cortical or deep brain) or non-invasively [cranial electrotherapy stimulation, transcranial direct current stimulation and transcranial magnetic stimulation]. Among chronic primary headaches, cluster headaches are most often treated either through deep brain stimulation or occipital nerve stimulation because there is a high level of disability related to this condition. ENS, employed through several modalities such as transcutaneous electrical nerve stimulation, interferential currents and pulsed radiofrequency, has been applied to the peripheral nervous system at several sites. We briefly review the indications for the use of peripheral ENS at the site of the occipital nerves for the treatment of chronic migraine.

  20. Ligand modeling and design

    Energy Technology Data Exchange (ETDEWEB)

    Hay, B. [Pacific Northwest Lab., Richland, WA (United States)

    1996-10-01

    The purpose of this work is to develop and implement a molecular design basis for selecting organic ligands that would be used tin applications for the cost-effective removal of specific radionuclides from nuclear waste streams.

  1. Programmed death-1/programmed death-ligand 1 pathway and its regulation on oral chronic diseases%程序性细胞死亡-1/程序性细胞死亡配体-1信号途径及其对口腔慢性疾病的作用

    Institute of Scientific and Technical Information of China (English)

    张静

    2012-01-01

    程序性细胞死亡-1 (PD-1)/程序性细胞死亡配体-1 (PD-L1)作为B7-CD28家族的重要负性共刺激信号途径,已证实能够通过抑制T细胞的活化增殖及细胞因子的产生来负调控免疫应答,参与免疫耐受及自身免疫性疾病、慢性感染、肿瘤等慢性疾病.本文综述了PD-1/PD-L1信号途径的生物学特点和功能及其在口腔扁平苔藓、慢性牙周炎、口腔恶性肿瘤等口腔慢性疾病中的研究,并探讨了调节该通路为口腔慢性疾病提供治疗的可能性.%Programmed death-1(PD-l)/programmed death-ligand 1(PD-L1), as the important member of B7-CD28 family, is a newly identified negative co-stimulatory pathway. It may play a critical immunoregulatory role, through inhibiting T cells activation and proliferation as well as cytokines production, in chronic diseases such as autoimmune diseases, chronic infections and tumors. Besides discussing the biological. Characteristics and functions of PD-1/PO-L1, this review mainly explores its regulation on oral chronic diseases including oral lichen planus, chronic periodontitis as well as oral malignant tumors and the therapeutic potential of PD-1/PD-L1 modulation in this filed.

  2. Progress in the study of purinergic ligand-gated ion channel 7 receptors in chronic pain%嘌呤能离子通道型受体7在病理性疼痛中的作用研究进展

    Institute of Scientific and Technical Information of China (English)

    李娜娜; 杨玲; 姚永兴

    2014-01-01

    背景 三磷酸腺苷(adenosine triphosphate,ATP)是一种普遍存在于周围和中枢神经系统的神经递质,以此类神经递质作为配体的受体称为嘌呤能受体.嘌呤能受体可分为离子通道型受体和代谢型受体.嘌呤能离子通道型受体7(purinergic ligand-gated ion channel 7,P2X7)属于配体门控型非选择性离子通道.因其独特的结构、功能和分布特点,在炎症和疼痛中发挥着重要作用. 目的 综述P2X7受体在神经病理性疼痛方面的研究进展. 内容 P2X7受体的结构与分布;P2X7受体的生理功能;P2X7受体在病理性疼痛中的作用以及P2X7受体介导病理性疼痛的可能机制. 趋向 对P2X7受体与病理性疼痛的深入研究将为开发新一代镇痛药物提供理论依据.%Background Adenosine triphosphate (ATP),is a neurotransmitter commonly found in and around the central nervous system,and such neurotransmitter by combining body called purinergic receptors.These receptors can be divided into ion channel type receptors and metabotropic receptors.Purinergic ligand-gated ion channel 7 (P2X7) receptor is one of purinergic receptors,and belongs to ligand gating non selective ion channel.Because of its unique structure,function and distribution characteristics,it plays an important role in inflammation and chronic pain.Objective Progress in the study of P2X7 receptor in chronic pain was reviewed.Content Acting as an ion channel receptor,P2X7 receptor plays a critical role in chronic pain.Progress in the structure and expressing profile,the alteration of expressing following chronic inflammation and nerve injury,and the effect of inhibitors on chronic pain were reviewed.Trend Progress in the study of P2X7 receptor may provide theoretical foundation for the discovery of new analgesic agents.

  3. Trulance Approved for Chronic Constipation

    Science.gov (United States)

    ... news/fullstory_163171.html Trulance Approved for Chronic Constipation Drug designed to stimulate upper gastrointestinal tract To ... U.S. Food and Drug Administration to treat persistent constipation of unknown (idiopathic) cause in adults. Some 42 ...

  4. 双侧丘脑底核慢性电刺激治疗原发性帕金森病%Treatment of idiopathic Parkinson's disease with chronic electronic deep brain stimulation of bilateral subthalamic nucleus

    Institute of Scientific and Technical Information of China (English)

    骆承章; 曹胜武; 赵春生

    2013-01-01

    Objective To evaluate the surgical approaches and clinical efficacy of electronic deep brain stimulation(DBS) in bilateral subthalamic nucleus (STN) for the treatment of Parkinson's disease.Methods Fourteen patients with idiopathic Parkinson's disease were treated with chronic electronic bilateral subthalamic nucleus deep brain stimulation(STN-DBS).The target was established by cranial magnetic resonance(MRI) and intraoperative microelectrode recording(MER).The patients were followed up for 6 months to 8 years.The outcomes of motor symptoms and medication dose in the 6th month after surgery were analyzed.Results The Unified Parkinson's Disease Rating Scale (UPDRS) motor score was significantly improved in the 6th month after surgery (P<0.05).The UPDRS motor score was improved on an average by 41.8% under on-status and 51.6% under offstatus.Patients were able to gain a better life quality by a long-term stimulation parameters and medication dose adjustment.The medication dose was reduced averagely by 55.6% in the 6th month after surgery.Conclusion The bilateral subthalamic nucleus stimulation is an effective method for the treatment of idiopathic Parkinson's disease.%目的 探讨双侧丘脑底核-脑深部电刺激(STN-DBS)治疗原发性帕金森病(PD)的手术方法及临床疗效.方法 采用头颅核磁共振及术中微电极记录电生理技术明确靶点定位,对14例原发性PD患者行STN-DBS手术.随访6个月-8年,评估手术对患者运动症状的改善及术后6个月患者服药剂量减少情况.结果 术后6个月患者统一用帕金森评分量表(UPDRS),运动检查评分有明显改善(P<0.05):“开”状态下平均改善率为41.8%,“关”状态下平均改善率为51.6%.患者术后通过调整刺激参数及药物剂量,均能获得满意的生活质量.于术后6个月左右评估,患者服用抗帕金森药物剂量平均减少55.6% (P<0.05).结论 STN-DBS术治疗原发性PD疗效确切.

  5. Dimeric ligands for GPCRs involved in human reproduction : synthesis and biological evaluation

    NARCIS (Netherlands)

    Bonger, Kimberly Michelle

    2008-01-01

    Dimeric ligands for G-protein coupled receptors that are involved in human reproduction, namely the gonadotropin releasing hormone receptor, the luteinizing hormone receptor and the follicle-stimulating hormone receptor, were synthesized and biologically evaluated.

  6. Growth Stimulants

    OpenAIRE

    Matthews, Nyle J.

    1989-01-01

    A tiny pellet inserted under the skin of a calf's ear may increase weight gains as much as 15 to 20 percent. This same result would take years to accomplish through breeding and selection. These tiny pellets are growth stimulants. They are made of hormones that are constructed to slowly release minute amounts into the blood stream that stimulate the animal to produce natural body hormones. One of these hormones is a growth hormone. It regulates the rate of growth of the animal. Increasing the...

  7. The imidazoline receptors and ligands in pain modulation

    Directory of Open Access Journals (Sweden)

    Nurcan Bektas

    2015-01-01

    Full Text Available Pain is an unpleasant experience and effects daily routine negatively. Although there are various drugs, many of them are not entirely successful in relieving pain, since pain modulation is a complex process involving numerous mediators and receptors. Therefore, it is a rational approach to identify the factors involved in the complex process and develop new agents that act on these pain producing mechanisms. In this respect, the involvement of the imidazoline receptors in pain modulation has drawn attention in recent years. In this review, it is aimed to focus on the imidazoline receptors and their ligands which contribute to the pain modulation. It is demonstrated that imidazoline-2 (I2 receptors are steady new drug targets for analgesics. Even if the mechanism of I2receptor is not well known in the modulation of pain, it is known that it plays a role in tonic and chronic pain but not in acute phasic pain. Moreover, the I2receptor ligands increase the analgesic effects of opioids in both acute and chronic pain and prevent the development of opioid tolerance. So, they are valuable for the chronic pain treatment and also therapeutic coadjuvants in the management of chronic pain with opiate drugs due to the attenuation of opioid tolerance and addiction. Thus, the use of the ligands which bind to the imidazoline receptors is an effective strategy for relieving pain. This educational forum exhibits the role of imidazoline receptors and ligands in pain process by utilizing experimental studies.

  8. Hepatic IFNL4 expression is associated with non-response to interferon-based therapy through the regulation of basal interferon-stimulated gene expression in chronic hepatitis C patients.

    Science.gov (United States)

    Murakawa, Miyako; Asahina, Yasuhiro; Kawai-Kitahata, Fukiko; Nakagawa, Mina; Nitta, Sayuri; Otani, Satoshi; Nagata, Hiroko; Kaneko, Shun; Asano, Yu; Tsunoda, Tomoyuki; Miyoshi, Masato; Itsui, Yasuhiro; Azuma, Seishin; Kakinuma, Sei; Tanaka, Yasuhito; Iijima, Sayuki; Tsuchiya, Kaoru; Izumi, Namiki; Tohda, Shuji; Watanabe, Mamoru

    2016-12-30

    Single nucleotide polymorphisms (SNPs) within or near interferon lambda 4 (IFNL4) gene located upstream of IFNL3 are associated with response to anti-HCV therapy both in interferon (IFN)-based and IFN-free regimens. IFNL4 encodes IFNλ4, a newly discovered type III IFN, and its expression is controlled by rs368234815-TT/ΔG, which is in strong linkage disequilibrium (LD) with other tag SNPs within or near IFNL4 such as rs12979860 and rs8099917. Intrahepatic expression levels of IFN-stimulated genes (ISGs) affect the responsiveness to IFNα and are also associated with IFNL4 genotype. However, IFNL4 expressions and its role in intrinsic antiviral innate immunity remain unclear. This study evaluated the effect of IFNL4 on intrahepatic ISG expression and investigated its relationship with treatment outcomes in liver samples obtained from 49 chronic hepatitis C patients treated with pegylated (PEG)-IFN/ribavirin therapy. IFNL4 mRNA was detected in 11 of 22 patients with IFNL4-unfavorable SNPs but not in patients with favorable genotypes. IFNL4 expression was associated with non-response to PEG-IFN/ribavirin therapy. Intrahepatic expression of antiviral ISGs (ISG15 and MX1) was significantly higher in IFNL4-unfavorable patients with detectable IFNL4 mRNA than in patients with undetectable IFNL4 mRNA, whereas the expression of suppressive ISGs (RNF125, SOCS1, SOCS3, and RNF11) was lower in patients with detectable IFNL4 mRNA. In summary, intrahepatic expression of IFNL4 was associated with increased antiviral ISG expression and decreased suppressive ISG expression at baseline, resulting in poor responsiveness to IFNα-based therapy in HCV infection.

  9. Ligand fitting with CCP4

    Science.gov (United States)

    2017-01-01

    Crystal structures of protein–ligand complexes are often used to infer biology and inform structure-based drug discovery. Hence, it is important to build accurate, reliable models of ligands that give confidence in the interpretation of the respective protein–ligand complex. This paper discusses key stages in the ligand-fitting process, including ligand binding-site identification, ligand description and conformer generation, ligand fitting, refinement and subsequent validation. The CCP4 suite contains a number of software tools that facilitate this task: AceDRG for the creation of ligand descriptions and conformers, Lidia and JLigand for two-dimensional and three-dimensional ligand editing and visual analysis, Coot for density interpretation, ligand fitting, analysis and validation, and REFMAC5 for macromolecular refinement. In addition to recent advancements in automatic carbohydrate building in Coot (LO/Carb) and ligand-validation tools (FLEV), the release of the CCP4i2 GUI provides an integrated solution that streamlines the ligand-fitting workflow, seamlessly passing results from one program to the next. The ligand-fitting process is illustrated using instructive practical examples, including problematic cases such as post-translational modifications, highlighting the need for careful analysis and rigorous validation. PMID:28177312

  10. Preliminary results of transcutaneous vagus nerve stimulation for chronic subjective tinnitus:A controlled clinical study%经皮迷走神经刺激术治疗慢性耳鸣的初步研究

    Institute of Scientific and Technical Information of China (English)

    曾祥丽; 招柏明; 张姝琪; 黎志成; 岑锦添; 顾晶; 袁涛; 李水颜

    2016-01-01

    Objective To report the efficacy and safety of transcutaneous vagus nerve stimulation (T-VNS) for treat-ment of chronic subjective tinnitus. Methods Chronic subjective tinnitus patients whose THI score was≥38 points, and with a tinnitus history of ≥6 months, were randomly divided into a T-VNS and a control groups. For patients in the T-VNS group, in addition to routine treatments, T-VNS was added using a G6805-type I cupping therapy apparatus, while only routine treatment were provided to patients in the control group. Treatment efficacy was evaluated with the Tinnitus Handicap Inventory (THI), Pittsburgh Sleep Quality Index (PSQI) and Depression and Anxiety-Stress Scale-21 (DASS-21) administered before and after treatment. Results Tinnitus symptoms improved more in the T-VNS group than in the control group during the 10 days of T-VNS treatment (p<0.05), with significantly improved PSQI scores, al-though there was a mild rebound of the scores at 3 months follow-up. DASS-21 scores showed decreased anxiety in the T-VNS group during VNS therapy, but no change in the control group. THI scores showed no significant difference be-tween the T-VNS and control groups either during treatment or at 3 months follow-up, although within the T-VNS group, THI scores reduced after T-VNS therapy (with no statistically significant difference) and at 3 months follow-up (statistically significant). Conclusion T-VNS may improve anxiety and sleep quality in patients who suffer from chron-ic subjective tinnitus. The primary study showed that this therapy was safe, with only transient cough or ear tingling dur-ing treatment in a minority of patients, while partially improving tinnitus distress over the 10-days treatment. Stimula-tion parameters and treatment course remain to be further investigated.%目的:探讨经皮外耳道迷走神经刺激术对慢性主观性耳鸣的治疗效果、安全性及可行性。方法选取THI评分≥38分,病史6≥个月的慢性主观性耳

  11. [Occipital nerve stimulation for refractory chronic migraine].

    Science.gov (United States)

    Bermejo, Pedro E; Torres, Cristina V; Sola, Rafael G

    2015-06-01

    Introduccion. La estimulacion de nervios occipitales (ENO) es un tratamiento preventivo de la migraña cronica refractaria que esta adquiriendo una importancia creciente en los ultimos años. Objetivo. Evaluar el mecanismo de accion, estudios clinicos, tecnica de implantacion y criterios de inclusion de la ENO en el tratamiento preventivo de la migraña. Desarrollo. Se realiza una revision no sistematica de la bibliografia sobre los aspectos anteriormente expuestos en la ENO como tratamiento para la migraña cronica. Esta patologia afecta aproximadamente al 2% de la poblacion y da lugar a una importante disminucion de la calidad de vida e interferencia con las actividades laborales y sociales. La ENO es una terapia emergente y prometedora para el tratamiento de la migraña cronica que ha demostrado una disminucion superior al 50% en el dolor en la mayoria de los estudios abiertos y ensayos clinicos publicados. Aunque el mecanismo de accion es desconocido, parece existir una neuromodulacion de la informacion nociceptiva trigeminal en el nucleo caudal del trigemino explicada mediante la teoria de la puerta de entrada de Melzack y Wall. La ENO es un tratamiento seguro y bien tolerado, y los efectos secundarios son habitualmente locales, como desplazamiento de los electrodos o infecciones de la herida quirurgica, que habitualmente no requieren su retirada. Conclusiones. La ENO es un tratamiento eficaz, bien tolerado y seguro en la prevencion de la migraña cronica, y supone una opcion util para aquellos pacientes con migraña cronica refractaria a los tratamientos medicos convencionales.

  12. CD40 ligand immunotherapy in cancer: an efficient approach.

    Science.gov (United States)

    Kuwashima, N; Kageyama, S; Eto, Y; Urashima, M

    2001-01-01

    Cancer cells do not elicit a clinically sufficient anti-tumor immune response that results in tumor rejection. Recently, many investigators have been trying to enhance anti-tumor immunity and encouraging results have been reported. This review will discuss current anti-cancer immunotherapy; interleukin-2 therapy, tumor vaccine secreting Granulocyte macrophage-colony stimulating factor, dendritic cells fused with tumor cells, and CD40 ligand immunotherapy. Moreover, we introduce our two kinds of CD40 ligand immuno-genetherapy; (1) oral CD40 ligand gene therapy against lymphoma using attenuated Salmonella typhimurium (published in BLOOD 2000), (2) cancer vaccine transfected with CD40 ligand ex vivo for neuroblastoma (unpublished). Both approaches resulted in a high degree of protection against the tumor progression and they are simple and safe in the murine system.

  13. Neural stimulation and recording electrodes.

    Science.gov (United States)

    Cogan, Stuart F

    2008-01-01

    Electrical stimulation of nerve tissue and recording of neural electrical activity are the basis of emerging prostheses and treatments for spinal cord injury, stroke, sensory deficits, and neurological disorders. An understanding of the electrochemical mechanisms underlying the behavior of neural stimulation and recording electrodes is important for the development of chronically implanted devices, particularly those employing large numbers of microelectrodes. For stimulation, materials that support charge injection by capacitive and faradaic mechanisms are available. These include titanium nitride, platinum, and iridium oxide, each with certain advantages and limitations. The use of charge-balanced waveforms and maximum electrochemical potential excursions as criteria for reversible charge injection with these electrode materials are described and critiqued. Techniques for characterizing electrochemical properties relevant to stimulation and recording are described with examples of differences in the in vitro and in vivo response of electrodes.

  14. LigandRNA: computational predictor of RNA-ligand interactions.

    Science.gov (United States)

    Philips, Anna; Milanowska, Kaja; Lach, Grzegorz; Bujnicki, Janusz M

    2013-12-01

    RNA molecules have recently become attractive as potential drug targets due to the increased awareness of their importance in key biological processes. The increase of the number of experimentally determined RNA 3D structures enabled structure-based searches for small molecules that can specifically bind to defined sites in RNA molecules, thereby blocking or otherwise modulating their function. However, as of yet, computational methods for structure-based docking of small molecule ligands to RNA molecules are not as well established as analogous methods for protein-ligand docking. This motivated us to create LigandRNA, a scoring function for the prediction of RNA-small molecule interactions. Our method employs a grid-based algorithm and a knowledge-based potential derived from ligand-binding sites in the experimentally solved RNA-ligand complexes. As an input, LigandRNA takes an RNA receptor file and a file with ligand poses. As an output, it returns a ranking of the poses according to their score. The predictive power of LigandRNA favorably compares to five other publicly available methods. We found that the combination of LigandRNA and Dock6 into a "meta-predictor" leads to further improvement in the identification of near-native ligand poses. The LigandRNA program is available free of charge as a web server at http://ligandrna.genesilico.pl.

  15. Myeloperoxidase formation of PAF receptor ligands induces PAF receptor-dependent kidney injury during ethanol consumption.

    Science.gov (United States)

    Latchoumycandane, Calivarathan; Nagy, Laura E; McIntyre, Thomas M

    2015-09-01

    Cytochrome P450 2E1 (CYP2E1) induction and oxidative metabolism of ethanol in hepatocytes inflame and damage liver. Chronic ethanol ingestion also induces kidney dysfunction, which is associated with mortality from alcoholic hepatitis. Whether the kidney is directly affected by ethanol or is secondary to liver damage is not established. We found that CYP2E1 was induced in kidney tubules of mice chronically ingesting a modified Lieber-deCarli liquid ethanol diet. Phospholipids of kidney tubules were oxidized and fragmented in ethanol-fed mice with accumulation of azelaoyl phosphatidylcholine (Az-PC), a nonbiosynthetic product formed only by oxidative truncation of polyunsaturated phosphatidylcholine. Az-PC stimulates the inflammatory PAF receptor (PTAFR) abundantly expressed by neutrophils and kidney tubules, and inflammatory cells and myeloperoxidase-containing neutrophils accumulated in the kidneys of ethanol-fed mice after significant hysteresis. Decreased kidney filtration and induction of the acute kidney injury biomarker KIM-1 in tubules temporally correlated with leukocyte infiltration. Genetic ablation of PTAFR reduced accumulation of PTAFR ligands and reduced leukocyte infiltration into kidneys. Loss of this receptor in PTAFR(-/-) mice also suppressed oxidative damage and kidney dysfunction without affecting CYP2E1 induction. Neutrophilic inflammation was responsible for ethanol-induced kidney damage, because loss of neutrophil myeloperoxidase in MPO(-/-) mice was similarly protective. We conclude that ethanol catabolism in renal tubules results in a self-perpetuating cycle of CYP2E1 induction, local PTAFR ligand formation, and neutrophil infiltration and activation that leads to myeloperoxidase-dependent oxidation and damage to kidney function. Hepatocytes do not express PTAFR, so this oxidative cycle is a local response to ethanol catabolism in the kidney.

  16. Movement disorders induced by deep brain stimulation.

    Science.gov (United States)

    Baizabal-Carvallo, José Fidel; Jankovic, Joseph

    2016-04-01

    Deep brain stimulation represents a major advance in the treatment of several types of movement disorders. However, during stimulation new movement disorders may emerge, thus limiting the positive effects of this therapy. These movement disorders may be induced by: 1) stimulation of the targeted nucleus, 2) stimulation of surrounding tracts and nuclei, and 3) as a result of dose adjustment of accompanying medications, such as reduction of dopaminergic drugs in patients with Parkinson's disease. Various dyskinesias, blepharospasm, and apraxia of eyelid opening have been described mainly with subthalamic nucleus stimulation, whereas hypokinesia and freezing of gait have been observed with stimulation of the globus pallidus internus. Other deep brain stimulation-related movement disorders include dyskinesias associated with stimulation of the globus pallidus externus and ataxic gait as a side effect of chronic bilateral stimulation of the ventral intermediate nucleus of thalamus. These movement disorders are generally reversible and usually resolved once the stimulation is reduced or turned off. This, however, typically leads to loss of benefit of the underlying movement disorder which can be re-gained by using different contacts, changing targets or stimulation parameters, and adjusting pharmacological therapy. New and innovative emerging technologies and stimulation techniques may help to prevent or overcome the various deep brain stimulation-induced movement disorders. In this review we aim to describe the clinical features, frequency, pathophysiology, and strategies for treatment of these iatrogenic movement disorders.

  17. Ligand-Receptor Interactions

    CERN Document Server

    Bongrand, Pierre

    2008-01-01

    The formation and dissociation of specific noncovalent interactions between a variety of macromolecules play a crucial role in the function of biological systems. During the last few years, three main lines of research led to a dramatic improvement of our understanding of these important phenomena. First, combination of genetic engineering and X ray cristallography made available a simultaneous knowledg of the precise structure and affinity of series or related ligand-receptor systems differing by a few well-defined atoms. Second, improvement of computer power and simulation techniques allowed extended exploration of the interaction of realistic macromolecules. Third, simultaneous development of a variety of techniques based on atomic force microscopy, hydrodynamic flow, biomembrane probes, optical tweezers, magnetic fields or flexible transducers yielded direct experimental information of the behavior of single ligand receptor bonds. At the same time, investigation of well defined cellular models raised the ...

  18. Local Innate Responses to TLR Ligands in the Chicken Trachea

    Directory of Open Access Journals (Sweden)

    Neda Barjesteh

    2016-07-01

    Full Text Available The chicken upper respiratory tract is the portal of entry for respiratory pathogens, such as avian influenza virus (AIV. The presence of microorganisms is sensed by pathogen recognition receptors (such as Toll-like receptors (TLRs of the innate immune defenses. Innate responses are essential for subsequent induction of potent adaptive immune responses, but little information is available about innate antiviral responses of the chicken trachea. We hypothesized that TLR ligands induce innate antiviral responses in the chicken trachea. Tracheal organ cultures (TOC were used to investigate localized innate responses to TLR ligands. Expression of candidate genes, which play a role in antiviral responses, was quantified. To confirm the antiviral responses of stimulated TOC, chicken macrophages were treated with supernatants from stimulated TOC, prior to infection with AIV. The results demonstrated that TLR ligands induced the expression of pro-inflammatory cytokines, type I interferons and interferon stimulated genes in the chicken trachea. In conclusion, TLR ligands induce functional antiviral responses in the chicken trachea, which may act against some pathogens, such as AIV.

  19. Comparative Effectiveness of Biosimilar, Reference Product and Other Erythropoiesis-Stimulating Agents (ESAs Still Covered by Patent in Chronic Kidney Disease and Cancer Patients: An Italian Population-Based Study.

    Directory of Open Access Journals (Sweden)

    Ylenia Ingrasciotta

    Full Text Available Since 2007 biosimilars of erythropoiesis-stimulating agents (ESAs are available on the Italian market. Very limited post-marketing data exist on the comparative effectiveness of biosimilar and originator ESAs.This population-based study was aimed to compare the effects of biosimilars, reference product and other ESAs still covered by patent on hemoglobinemia in chronic kidney disease (CKD and cancer patients in a Local Health Unit (LHU from Northern Italy.A retrospective cohort study was conducted during the years 2009-2014 using data from Treviso LHU administrative database. Incident ESA users (no ESA dispensing within 6 months prior to treatment start, i.e. index date (ID with at least one hemoglobin measurement within one month prior to ID (baseline Hb value and another measurement between 2nd and 3rd month after ID (follow-up Hb value were identified. The strength of the consumption (as total number of defined daily dose (DDD dispensed during the follow-up divided by days of follow-up and the difference between follow-up and baseline Hb values [delta Hb (ΔHb] were evaluated. Based on Hb changes, ESA users were classified as non-responders (ΔHb≤0 g/dl, responders (02 g/dl. A multivariate ordinal logistic regression model to identify predictors for responsiveness to treatment was performed. All analyses were stratified by indication for use and type of dispensed ESA at ID.Overall, 1,003 incident ESA users (reference product: 252, 25.1%; other ESAs covered by patent: 303, 30.2%; biosimilars: 448, 44.7% with CKD or cancer were eligible for the study. No statistically significant difference in the amount of dose dispensed during the follow-up among biosimilars, reference product and other ESAs covered by patent was found in both CKD and cancer. After three months from treatment start, all ESAs increased Hb values on average by 2g/dl. No differences in ΔHb as well as in frequency of non-responders, responders and highly responders among

  20. Lipoteichoic acid induces unique inflammatory responses when compared to other toll-like receptor 2 ligands.

    Directory of Open Access Journals (Sweden)

    Elizabeth M Long

    Full Text Available Toll-like receptors (TLRs recognize evolutionarily-conserved molecular patterns originating from invading microbes. In this study, we were interested in determining if microbial ligands, which use distinct TLR2-containing receptor complexes, represent unique signals to the cell and can thereby stimulate unique cellular responses. Using the TLR2 ligands, R-FSL1, S-FSL1, Pam2CSK4, Pam3CSK4, and lipoteichoic acid (LTA, we demonstrate that these ligands activate NF-kappaB and MAP Kinase pathways with ligand-specific differential kinetics in murine macrophages. Most strikingly, LTA stimulation of these pathways was substantially delayed when compared with the other TLR2 ligands. These kinetics differences were associated with a delay in the LTA-induced expression of a subset of genes as compared with another TLR2 ligand, R-FSL1. However, this did not translate to overall differences in gene expression patterns four hours following stimulation with different TLR2 ligands. We extended this study to evaluate the in vivo responses to distinct TLR2 ligands using a murine model of acute inflammation, which employs intravital microscopy to monitor leukocyte recruitment into the cremaster muscle. We found that, although R-FSL1, S-FSL1, Pam2CSK4, and Pam3CSK4 were all able to stimulate robust leukocyte recruitment in vivo, LTA remained functionally inert in this in vivo model. Therefore distinct TLR2 ligands elicit unique cellular responses, as evidenced by differences in the kinetic profiles of signaling and gene expression responses in vitro, as well as the physiologically relevant differences in the in vivo responses to these ligands.

  1. Bexarotene ligand pharmaceuticals.

    Science.gov (United States)

    Hurst, R E

    2000-12-01

    Bexarotene (LGD-1069), from Ligand, was the first retinoid X receptor (RXR)-selective, antitumor retinoid to enter clinical trials. The company launched the drug for the treatment of cutaneous T-cell lymphoma (CTCL), as Targretin capsules, in the US in January 2000 [359023]. The company filed an NDA for Targretin capsules in June 1999, and for topical gel in December 1999 [329011], [349982] specifically for once-daily oral administration for the treatment of patients with early-stage CTCL who have not tolerated other therapies, patients with refractory or persistent early stage CTCL and patients with refractory advanced stage CTCL. The FDA approved Targretin capsules at the end of December 1999 for once-daily oral treatment of all stages of CTCL in patients refractory to at least one prior systemic therapy, at an initial dose of 300 mg/m2/day. After an NDA was submitted in December 1999 for Targretin gel, the drug received Priority Review status for use as a treatment of cutaneous lesions in patients with stage IA, IB or IIA CTCL [354836]. The FDA issued an approvable letter in June 2000, and granted marketing clearance for CTCL in the same month [370687], [372768], [372769], [373279]. Ligand had received Orphan Drug designation for this indication [329011]. At the request of the FDA, Ligand agreed to carry out certain post-approval phase IV and pharmacokinetic studies [351604]. The company filed an MAA with the EMEA for Targretin Capsules to treat lymphoma in November 1999 [348944]. The NDA for Targretin gel is based on a multicenter phase III trial that was conducted in the US, Canada, Europe and Australia involving 50 patients and a multicenter phase I/II clinical program involving 67 patients. Targretin gel was evaluated for the treatment of patients with early stage CTCL (IA-IIA) who were refractory to, intolerant to, or reached a response plateau for at least 6 months on at least two prior therapies. Efficacy results exceeded the protocol-defined response

  2. Chronic myelogenous leukemia (CML)

    Science.gov (United States)

    CML; Chronic myeloid leukemia; Chronic granulocytic leukemia; Leukemia - chronic granulocytic ... Chronic myelogenous leukemia is grouped into phases: Chronic Accelerated Blast crisis The chronic phase can last for ...

  3. Increased interleukin-18 in the gingival tissues evokes chronic periodontitis after bacterial infection.

    Science.gov (United States)

    Yoshinaka, Kotaro; Shoji, Noriaki; Nishioka, Takashi; Sugawara, Yumiko; Hoshino, Tomoaki; Sugawara, Shunji; Sasano, Takashi

    2014-01-01

    Periodontal disease is a chronic inflammatory disease that results in the breakdown of the tooth-supporting tissues, and can ultimately lead to resorption of the alveolar bone. Recently, several studies have shown a close relationship between increased interleukin-18 (IL-18) levels and the pathogenesis of chronic periodontitis, a major cause of tooth loss. However, it has yet to be shown whether chronic periodontitis results from or causes an increase in IL-18 after bacterial infection. In the present study, we investigated how IL-18 overexpression relates to periodontal disease using IL-18 transgenic (Tg) mice. IL-18Tg and wild-type mice were inoculated intraorally with Porphyromonas (P.) gingivalis, which has been implicated in the etiology of chronic periodontitis. Seventy days after P. gingivalis infection, alveolar bone loss and gingival cytokine levels were assessed using histo-morphological analysis and enzyme-linked immuno-absorbent assay, respectively. Periodontal bone loss was evoked in IL-18Tg mice, but not in wild-type mice. Interestingly, levels of bone-resorptive cytokines, including IL-1α, IL-1β, tumor necrosis factor-α, and IL-6, were unchanged in the gingival tissues of IL-18Tg mice infected with P. gingivalis, although levels of interferon γ (a proinflammatory T-helper 1 cytokine) decreased. RT-PCR analysis showed elevated expression of mRNAs for receptor activator of nuclear factor kappa-B ligand (a key stimulator of osteoclast development and activation) and CD40 ligand (a marker of T cell activation) in the gingiva of IL-18Tg mice infected with P. gingivalis. We conclude that increased IL-18 in the gingival tissues evokes chronic periodontitis after bacterial infection, presumably via a T cell-mediated pathway.

  4. Expression of programmed death-1 and programmed death ligand-1 in the peripheral T-lymphocytes from patients with chronic periodontitis%慢性牙周炎患者外周血T淋巴细胞表面程序性死亡分子1及其配体的表达

    Institute of Scientific and Technical Information of China (English)

    朱德星; 刘汾; 戴芳; 罗雪晴; 洪宝枝

    2014-01-01

    目的 探讨慢性牙周炎患者外周血淋巴细胞程序性死亡分子1(programmed death-1,PD-1)及其主要配体程序性死亡分子配体1(programmed death ligand-1,PD-L1)的表达及其意义,以阐明其在慢性牙周炎发生和发展中的作用.方法 采用流式细胞术检测30例慢性牙周炎患者(牙周炎组)、25慢性牙龈炎患者(牙龈炎组)及18例牙周健康对照者(健康对照组)外周血CD4+和CD8+T淋巴细胞表面PD-1及PD-L1的表达,并检测16例慢性牙周炎患者进行牙周基础治疗6周后外周血CD4+和CD8+T淋巴细胞PD-1及PD-L1的表达.两组间比较采用t检验,多组间比较采用方差分析,多个样本间的两两比较采用LSD-t检验或x2检验.结果 牙周炎组外周血CD4+、CD8+T淋巴细胞表面PD-1的阳性表达率[(16.7±5.5)%、(20.8±5.1)%]及牙龈炎组二者的表达率[(14.2±6.1)%、(14.5±4.3)%]均显著高于健康对照组[分别为(9.5±2.1)%、(8.1±1.9)%](P值均<0.05);牙周炎组外周血CD4+、CD8+T淋巴细胞表面PD-L1的阳性表达率[(24.2±7.1)%、(15.3±6.8)%]及牙龈炎组二者的表达率[(12.4±6.0)%、(11.2±5.5)%]均显著高于健康对照组[(4.7±1.2)%和(3.2±2.3)%](P值均<0.05).牙周基础治疗6周后,16例慢性牙周炎患者CD4+和CD8+T淋巴细胞PD-1、PD-L1的阳性表达率均显著降低,与治疗前相比差异均有统计学意义(P值均<0.05).结论 慢性牙周炎患者外周血CD4+和CD8+T淋巴细胞PD-1及PD-L1表达水平显著升高,与牙周炎症水平密切相关,牙周基础治疗可以下调慢性牙周炎患者外周血CD4+和CD8+T细胞表面PD-1及PD-L1的表达.%Objective To investigate the expression of programmed death-1(PD-1) and programmed death ligand-1 (PD-L1) in peripheral T-lymphocytes from patients with chronic periodontitis and its significance and to clarify its role in the development of chronic periodontitis.Methods A total of 73 subjects were included in the study and divided

  5. Electrical stimulation in exercise training

    Science.gov (United States)

    Kroll, Walter

    1994-01-01

    Electrical stimulation has a long history of use in medicine dating back to 46 A.D. when the Roman physician Largus found the electrical discharge of torpedo fishes useful in the treatment of pain produced by headache and gout. A rival Greek physician, Dioscorides, discounted the value of the torpedo fish for headache relief but did recommend its use in the treatment of hemorrhoids. In 1745, the Leyden jar and various sized electrostatic generators were used to treat angina pectoris, epilepsy, hemiplegia, kidney stones, and sciatica. Benjamin Franklin used an electrical device to treat successfully a young woman suffering from convulsive fits. In the late 1800's battery powered hydroelectric baths were used to treat chronic inflammation of the uterus while electrified athletic supporters were advertised for the treatment of male problems. Fortunately, such an amusing early history of the simple beginnings of electrical stimulation did not prevent eventual development of a variety of useful therapeutic and rehabilitative applications of electrical stimulation. Over the centuries electrical stimulation has survived as a modality in the treatment of various medical disorders with its primary application being in the rehabilitation area. Recently, a surge of new interest in electrical stimulation has been kindled by the work of a Russian sport scientist who reported remarkable muscle strength and endurance improvements in elite athletes. Yakov Kots reported his research on electric stimulation and strength improvements in 1977 at a Canadian-Soviet Exchange Symposium held at Concordia University in Montreal. Since then an explosion of new studies has been seen in both sport science and in medicine. Based upon the reported works of Kots and the present surge of new investigations, one could be misled as to the origin of electrical stimulation as a technique to increase muscle strength. As a matter of fact, electric stimulation has been used as a technique to improve

  6. A PET study on brain of chronic unpredictable mild stimulations (CUMS)-induced depressive rats%慢性不可预见性温和刺激抑郁症模型大鼠的脑PET成像研究

    Institute of Scientific and Technical Information of China (English)

    刘金鹏; 刘华; 高峻钰; 刘少君

    2015-01-01

    目的:通过PET成像技术研究慢性不可预见性温和刺激( CUMS)致抑郁症大鼠的全脑代谢特点。方法实验组大鼠给予CUMS 4周后,通过糖水偏嗜度、自发活动距离、体质量等指标分为刺激后抑郁大鼠( D组)及刺激后非抑郁大鼠( ND组),并与正常对照组大鼠( CON组)一起行PET检查,比较不同组大鼠之间全脑的代谢变化。结果(1)D组大鼠的双侧S1、丘脑、苍白球、岛叶、M2、左屏状核较CON组代谢升高,右侧下丘、胼胝体压部、小脑则代谢降低;(2)D组大鼠双侧海马CA3区、M1、M2、纹状体、S1、嗅球等区较ND组代谢增高,左侧楔状核及海马则代谢降低;(3) ND组大鼠与CON组相比,无代谢升高的脑区,而外侧隔核、双侧纹状体、下丘脑室旁核、双侧S1、右侧苍白球则代谢降低。结论以前囟后4 mm处为界,抑郁大鼠脑代谢特点是前高后低,左右大致对称。抑郁症的发生可能与多个脑区功能的异常相互作用有关。%Objective To observe the metabolic changes in the whole brain of chronic unpredictable mild stimulations ( CUMS)-induced depressive rats using PET imaging technology.Methods After 4 weeks’ of CUMS, rats of experimental group were divided into two groups:Group D( depression) and Group ND( no depression) , according to the degree of sugar addiction, distance of spontaneous activity and relative body mass.Then metabolic changes in the whole brain of these rats and those in control group ( CON) were observed using PET technology, and the differences were companred between the threegroups.Results (1)ComparedwithGroupCON,metabolismofGroupDwaselevatedinbilateralS1,thalamus, globus pallidus, insula, M2 and left claustrum, but descended in right inferior colliculus, splenium of corpus callosum and cerebellum.(2) Metabolism of Group D increased in the bilateral CA3 region of hippocampus, M1, M2, striatum, S1 and olfactory bulb

  7. [Neurosurgical treatment of chronic pain].

    Science.gov (United States)

    Fontaine, D; Blond, S; Mertens, P; Lanteri-Minet, M

    2015-02-01

    Neurosurgical treatment of pain used two kind of techniques: 1) Lesional techniques interrupt the transmission of nociceptive neural input by lesionning the nociceptive pathways (drezotomy, cordotomy, tractotomy…). They are indicated to treat morphine-resistant cancer pain and few cases of selected neuropathic pain. 2) Neuromodulation techniques try to decrease pain by reinforcing inhibitory and/or to limit activatory mechanisms. Chronic electrical stimulation of the nervous system (peripheral nerve stimulation, spinal cord stimulation, motor cortex stimulation…) is used to treat chronic neuropathic pain. Intrathecal infusion of analgesics (morphine, ziconotide…), using implantable pumps, allows to increase their efficacy and to reduce their side effects. These techniques can improve, sometimes dramatically, selected patients with severe and chronic pain, refractory to all other treatments. The quality of the analgesic outcome depends on the relevance of the indications.

  8. Melatonin: functions and ligands.

    Science.gov (United States)

    Singh, Mahaveer; Jadhav, Hemant R

    2014-09-01

    Melatonin is a chronobiotic substance that acts as synchronizer by stabilizing bodily rhythms. Its synthesis occurs in various locations throughout the body, including the pineal gland, skin, lymphocytes and gastrointestinal tract (GIT). Its synthesis and secretion is controlled by light and dark conditions, whereby light decreases and darkness increases its production. Thus, melatonin is also known as the 'hormone of darkness'. Melatonin and analogs that bind to the melatonin receptors are important because of their role in the management of depression, insomnia, epilepsy, Alzheimer's disease (AD), diabetes, obesity, alopecia, migraine, cancer, and immune and cardiac disorders. In this review, we discuss the mechanism of action of melatonin in these disorders, which could aid in the design of novel melatonin receptor ligands.

  9. Neuromodulation of chronic headaches

    DEFF Research Database (Denmark)

    Martelletti, Paolo; Jensen, Rigmor H; Antal, Andrea

    2013-01-01

    stimulation, occipital nerve stimulation, stimulation of sphenopalatine ganglion, cervical spinal cord stimulation, vagus nerve stimulation, transcranial direct current stimulation, repetitive transcranial magnetic stimulation, and transcutaneous electrical nerve stimulation are extensively published although...

  10. Deep brain stimulation for cluster headache

    DEFF Research Database (Denmark)

    Grover, Patrick J; Pereira, Erlick A C; Green, Alexander L

    2009-01-01

    Cluster headache is a severely debilitating disorder that can remain unrelieved by current pharmacotherapy. Alongside ablative neurosurgical procedures, neuromodulatory treatments of deep brain stimulation (DBS) and occipital nerve simulation have emerged in the last few years as effective...... circumstances to intervene. Here we review current data on neurosurgical interventions for chronic cluster headache focusing upon DBS and occipital nerve stimulation, and discuss the indications for and putative mechanisms of DBS including translational insights from functional neuroimaging, diffusion weighted...

  11. 视动力刺激对下背痛患者姿势控制的影响%The clinical study of the optokinetic stimulation on postural control in subjects with chronic low back pain

    Institute of Scientific and Technical Information of China (English)

    李睿; 王宁华; 魏坤琳; 颜翔

    2012-01-01

    Objective: To investigate the characteristic of chronic nonspecific low back pain(CNLBP)'s posture control in different surfaces by optokinetio stimulation of different velocities, so as to provide new theory and experiment data for further recognizing the CNLBP and enrich Us' treatment. Method: Thirteen individuals with CNLBP (age range 25-40 years) and thirteen age,gender-matched control subjects were recruited. Every subject was exposed to random-dot patterns projected on a large screen, the dots' moving direction were contraction(-) and expansion(+), the dots' velocity included 80°/s,40°/s and 20%. The visual stimulus used "stimuli-interval" pattern, and applied the force platform to rerord the peak velocity and different phases' standard deviation (SD) of anterior-posterior center of pressure (COP) displacements and total length of medial-lateral COP sway on the stable surface and soft surface. Result: No difference in COP parameters were observed when standing on the stable surface between the two groups (P>0.05). However, significant more SD of amplitude in the middle phase was seen in the persons with CNLBP when confronting the +40°/s stimuli on the soft surface (3.74 ± L22) compared to the healthy individuals (2.83 ± 0.75), (P<0.05). Besides, when confronting the same stimuli, the parameters of COP displacement on the soft plane were more than that on the stable surface in each group (/V0.001). Conclusion: The subjects of LBP had visual-dependent phenomenon and decreased the efficiency of postural adjustment in the more complicated task and environment, especially optokinectic stimulation in the expansion direction. This result suggested thai the treatment to the abnormal motor pattern in LBP patients should take the properties of task and environment factor into account.%目的:研究下背痛患者站于不同支撑面接受视动力刺激时的姿势控制特征,为进一步认识下背痛和丰富治疗方案提供新

  12. Macrocyclic G-quadruplex ligands

    DEFF Research Database (Denmark)

    Nielsen, M C; Ulven, Trond

    2010-01-01

    G-quadruplex stabilizing compounds have recently received increased interest due to their potential application as anticancer therapeutics. A significant number of structurally diverse G-quadruplex ligands have been developed. Some of the most potent and selective ligands currently known are macr...

  13. Identification of beryllium-dependent peptides recognized by CD4+ T cells in chronic beryllium disease.

    Science.gov (United States)

    Falta, Michael T; Pinilla, Clemencia; Mack, Douglas G; Tinega, Alex N; Crawford, Frances; Giulianotti, Marc; Santos, Radleigh; Clayton, Gina M; Wang, Yuxiao; Zhang, Xuewu; Maier, Lisa A; Marrack, Philippa; Kappler, John W; Fontenot, Andrew P

    2013-07-01

    Chronic beryllium disease (CBD) is a granulomatous disorder characterized by an influx of beryllium (Be)-specific CD4⁺ T cells into the lung. The vast majority of these T cells recognize Be in an HLA-DP–restricted manner, and peptide is required for T cell recognition. However, the peptides that stimulate Be-specific T cells are unknown. Using positional scanning libraries and fibroblasts expressing HLA-DP2, the most prevalent HLA-DP molecule linked to disease, we identified mimotopes and endogenous self-peptides that bind to MHCII and Be, forming a complex recognized by pathogenic CD4⁺ T cells in CBD. These peptides possess aspartic and glutamic acid residues at p4 and p7, respectively, that surround the putative Be-binding site and cooperate with HLA-DP2 in Be coordination. Endogenous plexin A peptides and proteins, which share the core motif and are expressed in lung, also stimulate these TCRs. Be-loaded HLA-DP2–mimotope and HLA-DP2–plexin A4 tetramers detected high frequencies of CD4⁺ T cells specific for these ligands in all HLADP2+ CBD patients tested. Thus, our findings identify the first ligand for a CD4⁺ T cell involved in metal-induced hypersensitivity and suggest a unique role of these peptides in metal ion coordination and the generation of a common antigen specificity in CBD.

  14. Electrical Stimulation of the Upper Limb in Stroke: Stimulation of the Extensors of the Hand vs. Alternate Stimulation of Flexors and Extensors

    NARCIS (Netherlands)

    Kroon, de J.R.; IJzerman, M.J.; Lankhorst, G.J.; Zilvold, G.

    2004-01-01

    Objective: To investigate whether there is a difference in functional improvement in the affected arm of chronic stroke patients when comparing two methods of electrical stimulation. Design: Explanatory trial in which 30 chronic stroke patients with impaired arm function were randomly allocated

  15. Glutamate receptor ligands

    DEFF Research Database (Denmark)

    Guldbrandt, Mette; Johansen, Tommy N; Frydenvang, Karla Andrea;

    2002-01-01

    Homologation and substitution on the carbon backbone of (S)-glutamic acid [(S)-Glu, 1], as well as absolute stereochemistry, are structural parameters of key importance for the pharmacological profile of (S)-Glu receptor ligands. We describe a series of methyl-substituted 2-aminoadipic acid (AA......-ray crystallographic analyses, chemical correlation, and CD spectral analyses. The effects of the individual stereoisomers at ionotropic and metabotropic (S)-Glu receptors (iGluRs and mGluRs) were characterized. Compounds with S-configuration at the alpha-carbon generally showed mGluR2 agonist activity of similar...... limited effect on pharmacology. Structure-activity relationships at iGluRs in the rat cortical wedge preparation showed a complex pattern, some compounds being NMDA receptor agonists [e.g., EC(50) =110 microM for (2S,5RS)-5-methyl-AA (6a,b)] and some compounds showing NMDA receptor antagonist effects [e...

  16. Activation profiles of opioid ligands in HEK cells expressing δ opioid receptors

    OpenAIRE

    Clark J; Demirci Hasan; Gharagozlou Parham; Lameh Jelveh

    2002-01-01

    Abstract Background The aim of the present study was to characterize the activation profiles of 15 opioid ligands in transfected human embryonic kidney cells expressing only δ opioid receptors. Activation profiles of most of these ligands at δ opioid receptors had not been previously characterized in vitro. Receptor activation was assessed by measuring the inhibition of forskolin-stimulated cAMP production. Results Naltrexone and nalorphine were classified as antagonists at δ opioid receptor....

  17. Chronic cholecystitis

    Science.gov (United States)

    Cholecystitis - chronic ... Most of the time, chronic cholecystitis is caused by repeated attacks of acute (sudden) cholecystitis. Most of these attacks are caused by gallstones in the gallbladder. These ...

  18. Chronic Pain

    Science.gov (United States)

    ... pain. Psychotherapy, relaxation and medication therapies, biofeedback, and behavior modification may also be employed to treat chronic pain. × ... pain. Psychotherapy, relaxation and medication therapies, biofeedback, and behavior modification may also be employed to treat chronic pain. ...

  19. Chronic Pain

    Science.gov (United States)

    ... a problem you need to take care of. Chronic pain is different. The pain signals go on ... there is no clear cause. Problems that cause chronic pain include Headache Low back strain Cancer Arthritis ...

  20. Vagus Nerve Stimulation

    Science.gov (United States)

    Vagus nerve stimulation Overview By Mayo Clinic Staff Vagus nerve stimulation is a procedure that involves implantation of a device that stimulates the vagus nerve with electrical impulses. There's one vagus nerve on ...

  1. Chronic prostatitis

    OpenAIRE

    Le, Brian; Schaeffer, Anthony J.

    2011-01-01

    Chronic prostatitis can cause pain and urinary symptoms, and usually occurs without positive bacterial cultures from prostatic secretions (known as chronic abacterial prostatitis or chronic pelvic pain syndrome [CP/CPPS]). Bacterial infection can result from urinary tract instrumentation, but the cause and natural history of CP/CPPS are unknown.

  2. Chronic prostatitis

    OpenAIRE

    Erickson, Bradley A.; Schaeffer, Anthony J.; Le, Brian

    2008-01-01

    Chronic prostatitis can cause pain and urinary symptoms, and usually occurs without positive bacterial cultures from prostatic secretions (known as chronic abacterial prostatitis or chronic pelvic pain syndrome, CP/CPPS). Bacterial infection can result from urinary tract instrumentation, but the cause and natural history of CP/CPPS are unknown.

  3. Comparative Effectiveness of Biosimilar, Reference Product and Other Erythropoiesis-Stimulating Agents (ESAs) Still Covered by Patent in Chronic Kidney Disease and Cancer Patients: An Italian Population-Based Study

    NARCIS (Netherlands)

    Y. Ingrasciotta (Ylenia); F. Giorgianni (Francesco); I. Marcianò (Ilaria); J. Bolcato (Jenny); R. Pirolo (Roberta); A. Chinellato (Alessandro); V. Ientile (Valentina); D. Santoro (Domenico); A.A. Genazzani (Armando A.); A. Alibrandi (Angela); A. Fontana (Andrea); A.P. Caputi (Achille); G. Trifirò (Gianluca)

    2016-01-01

    textabstractBackground Since 2007 biosimilars of erythropoiesis-stimulating agents (ESAs) are available on the Italian market. Very limited post-marketing data exist on the comparative effectiveness of biosimilar and originator ESAs. Aim This population-based study was aimed to compare the effects o

  4. Species difference of CD137 ligand signaling in human and murine monocytes.

    Directory of Open Access Journals (Sweden)

    Qianqiao Tang

    Full Text Available BACKGROUND: Stimulation of CD137 ligand on human monocytes has been shown to induce DC differentiation, and these CD137L-DCs are more potent than classical DCs, in stimulating T cell responses in vitro. To allow an in vivo evaluation of the potency of CD137L-DCs in murine models we aimed at generating murine CD137L-DCs. METHODOLOGY/PRINCIPAL FINDINGS: When stimulated through CD137 ligand murine monocytes responded just as human monocytes with an increased adherence, morphological changes, proliferation and an increase in viable cell numbers. But CD137 ligand signaling did not induce expression of inflammatory cytokines and costimulatory molecules in murine monocytes and these cells had no T cell stimulatory activity. Murine monocytes did not differentiate to inflammatory DCs upon CD137 ligand signaling. Furthermore, while CD137 ligand signaling induces maturation of human immature classical DCs it failed to do so with murine immature classical DCs. CONCLUSIONS/SIGNIFICANCE: These data demonstrate that both human and murine monocytes become activated by CD137 ligand signaling but only human and not murine monocytes differentiate to inflammatory DCs.

  5. Electrical stimulation for epilepsy: stimulation of hippocampal foci.

    Science.gov (United States)

    Velasco, F; Velasco, M; Velasco, A L; Menez, D; Rocha, L

    2001-01-01

    Subacute and chronic continuous electrical stimulation at the epileptic focus in the hippocampus or parahippocampal cortex at 130 Hz, 0.21-1.0 ms, 2.5-3.5 V (about 200-300 microA) induces a decrease in focal EEG epileptic interictal activity and also in the occurrence of clinical seizures. This may represent an alternative for the treatment of temporal lobe seizures originated in bilateral independent temporal lobe foci or occurring in patients where one is uncertain whether memory deficit might result from ablative procedures.

  6. Effects of acute and chronic attenuation of postprandial hyperglycemia on postglucose-load endothelial function in insulin resistant individuals: is stimulation of first phase insulin secretion beneficial for the endothelial function?

    DEFF Research Database (Denmark)

    Major-Pedersen, A; Ihlemann, N; Hermann, T S;

    2008-01-01

    The aim of the study is to determine if attenuation of postprandial hyperglycemia, by acutely and chronically enhancing postprandial insulin secretion in insulin-resistant individuals, improves the endothelial dysfunction. We assessed postoral glucose-load endothelial function in 56 insulin....... We found no relationship between postprandial hyperglycemia and post-OGL FMD....

  7. Role of the T cell receptor ligand affinity in T cell activation by bacterial superantigens

    DEFF Research Database (Denmark)

    Andersen, P S; Geisler, C; Buus, S

    2001-01-01

    Similar to native peptide/MHC ligands, bacterial superantigens have been found to bind with low affinity to the T cell receptor (TCR). It has been hypothesized that low ligand affinity is required to allow optimal TCR signaling. To test this, we generated variants of Staphylococcus enterotoxin C3...... (SEC3) with up to a 150-fold increase in TCR affinity. By stimulating T cells with SEC3 molecules immobilized onto plastic surfaces, we demonstrate that increasing the affinity of the SEC3/TCR interaction caused a proportional increase in the ability of SEC3 to activate T cells. Thus, the potency...... correlation between ligand affinity and ligand potency indicating that it is the density of receptor-ligand complexes in the T cell contact area that determines TCR signaling strength....

  8. Recent development of CB2 selective and peripheral CB1/CB2 cannabinoid receptor ligands.

    Science.gov (United States)

    Nevalainen, Tapio

    2014-01-01

    Cannabinoids have potential therapeutic value e.g. in pain relief, cancer therapy, control of nausea and vomiting, and appetite stimulation, but their therapeutic benefits are limited by unwanted central nervous system (CNS) side-effects. Separating the therapeutic effects of cannabinoid agonists from their undesired CNS effects can be achieved by either increasing the selectivity of the ligands for the CB2 receptor or by developing peripherally restricted CB1/CB2 ligands. A vast number of structurally diverse CB2 ligands have been developed during the past 3 years, stemming from the screening hits, which are further optimized towards lead compounds and drug candidates. Some of CB2 ligands may ultimately enter into clinical use as pain relief, anticancer, or antipruritic agents. This review focuses on the recent literature dealing with selective CB2 receptor ligands, with a particular emphasis on the CB2 agonists developed from 2009 onwards.

  9. LPCES对慢性低压缺氧兔颏舌肌肌球蛋白重链和SR Ca2+摄取-释放动力学的影响%Electrical stimulation at lower physiological frequency induces myosin heavy chain isoform transformation and improves sarcoplasmic reticulum Ca2+ uptake/release in genioglossus of rabbits exposed to chronic hypoxia

    Institute of Scientific and Technical Information of China (English)

    刘熙; 刘刚; 张妮; 欧娜; 张鹏

    2011-01-01

    Objective To identify the effect of chronic electrical stimulation at a lower physiological frequency on the expressions of myosin heavy chain (MHC) isoforms and kinetics of sarcoplasmic reticulum (SR) Ca2 + uptake/release in the genioglossus of rabbits exposed to chronic hypoxia. Methods Twenty-four adult rabbits were randomized into control group ( A), chronic hypoxia group ( B ), 2.5 Hz electrical stimulation group (C) and (2.5 + 40) Hz electrical stimulation group (low frequency plus physical frequency, D).After the rabbits from group B, C and D had been fed with free access to food and water in a hypoxia cabin ( simulating 5 000 m altitude) in 10 h a day for 4 weeks, the rabbits in group C and D received electrical stimulation in their genioglossus at a frequency of 2.5 Hz and (2.5 +40) Hz respectively in 10 h per day for 14 d,while those in group B received no electrical stimulation. Expressions of MHC isoforms in the genioglossus of rabbits in 4 groups were detected by Western blotting, and Fura-2 fluorophotometry was used to assay the kinetics changes of SR Ca2 + uptake-release. Restlts The expression level of MHC l a was significantly higher while that of MHC I was significantly lower in group B than that in group A (P < 0.05 ). Meanwhile,the genioglossus SR Ca2+ uptake/release velocity in group B was significantly decreased compared with that in group A ( P < 0. 05 ). The expression levels of MHC Ⅱ a and MHC I in group C and D after electrical stimulation were significantly higher, while those of MHC Ⅱ b, especially in group D, were significantly lower than those in group B (P < 0.05 ). The genioglossus SR Ca2+ uptake/release velocity in group C and D, especially in group D, was significantly increased compared with that in group B ( P < 0.05 ). No significant difference was found in expression levels of MHC Ⅱ a and MHC I between group C and D after electrical stimulation ( P > 0.05). Conclusion MHC Ⅱb in the genioglossus of rabbits with

  10. Ligand-dependent exciton dynamics and photovoltaic properties of PbS quantum dot heterojunction solar cells.

    Science.gov (United States)

    Chang, Jin; Ogomi, Yuhei; Ding, Chao; Zhang, Yao Hong; Toyoda, Taro; Hayase, Shuzi; Katayama, Kenji; Shen, Qing

    2017-03-01

    The surface chemistry of colloidal quantum dots (QDs) plays an important role in determining the photoelectric properties of QD films and the corresponding quantum dot heterojunction solar cells (QDHSCs). To investigate the effects of the ligand structure on the photovoltaic performance and exciton dynamics of QDHSCs, PbS QDHSCs were fabricated by the solid state ligand exchange method with mercaptoalkanoic acid as the cross-linking ligand. Temperature-dependent photoluminescence and ultrafast transient absorption spectra show that the electronic coupling and charge transfer rate within QD ensembles were monotonically enhanced as the ligand length decreased. However, in practical QDHSCs, the second shortest ligand 3-mercaptopropionic acid (MPA) showed higher power conversion efficiency than the shortest ligand thioglycolic acid (TGA). This could be attributed to the difference in their surface trap states, supported by thermally stimulated current measurements. Moreover, compared with the non-conjugated ligand MPA, the conjugated ligand 4-mercaptobenzoic acid (MBA) introduces less trap states and has a similar charge transfer rate in QD ensembles, but has poor photovoltaic properties. This unexpected result could be contributed by the QD-ligand orbital mixing, leading to the charge transfer from QDs to ligands instead of charge transfer between adjacent QDs. This work highlights the significant effects of ligand structures on the photovoltaic properties and exciton dynamics of QDHSCs, which would shed light on the further development of QD-based photoelectric devices.

  11. Immunoglobulin gene repertoire in ocular adnexal lymphomas: hints on the nature of the antigenic stimulation.

    Science.gov (United States)

    Dagklis, A; Ponzoni, M; Govi, S; Cangi, M G; Pasini, E; Charlotte, F; Vino, A; Doglioni, C; Davì, F; Lossos, I S; Ntountas, I; Papadaki, T; Dolcetti, R; Ferreri, A J M; Stamatopoulos, K; Ghia, P

    2012-04-01

    Evidence from certain geographical areas links lymphomas of the ocular adnexa marginal zone B-cell lymphomas (OAMZL) with Chlamydophila psittaci (Cp) infection, suggesting that lymphoma development is dependent upon chronic stimulation by persistent infections. Notwithstanding that, the actual immunopathogenetical mechanisms have not yet been elucidated. As in other B-cell lymphomas, insight into this issue, especially with regard to potential selecting ligands, could be provided by analysis of the immunoglobulin (IG) receptors of the malignant clones. To this end, we studied the molecular features of IGs in 44 patients with OAMZL (40% Cp-positive), identifying features suggestive of a pathogenic mechanism of autoreactivity. Herein, we show that lymphoma cells express a distinctive IG repertoire, with electropositive antigen (Ag)-binding sites, reminiscent of autoantibodies (auto-Abs) recognizing DNA. Additionally, five (11%) cases of OAMZL expressed IGs homologous with autoreactive Abs or IGs of patients with chronic lymphocytic leukemia, a disease known for the expression of autoreactive IGs by neoplastic cells. In contrast, no similarity with known anti-Chlamydophila Abs was found. Taken together, these results strongly indicate that OAMZL may originate from B cells selected for their capability to bind Ags and, in particular, auto-Ags. In OAMZL associated with Cp infection, the pathogen likely acts indirectly on the malignant B cells, promoting the development of an inflammatory milieu, where auto-Ags could be exposed and presented, driving proliferation and expansion of self-reactive B cells.

  12. Visualization of Metal-to-Ligand and Ligand-to-Ligand Charge Transfer in Metal-Ligand Complexes

    Institute of Scientific and Technical Information of China (English)

    Yong Ding; Jian-xiu Guo; Xiang-si Wang; Sha-sha Liu; Feng-cai Ma

    2009-01-01

    Three methods including the atomic resolved density of state, charge difference density, and the transition density matrix are used to visualize metal to ligand charge transfer (MLCT) in ruthenium(Ⅱ) ammine complex. The atomic resolved density of state shows that there is density of Ru on the HOMOs. All the density is localized on the ammine, which reveals that the excited electrons in the Ru complex are delocalized over the ammine ligand. The charge difference density shows that all the holes are localized on the Ru and the electrons on the ammine. The localization explains the MLCT on excitation. The transition density matrix shows that there is electron-hole coherence between Ru and ammine. These methods are also used to examine the MLCT in Os(bpy)(p0p)Cl ("Osp0p"; bpy=2,2'-bipyridyl; p0p=4,4'-bipyridyl) and the ligand-to-ligand charge transfer (LLCT) in Alq3. The calculated results show that these methods are powerful to examine MLCT and LLCT in the metal-ligand system.

  13. IDENTIFICATION OF SPECIFIC PEPTIDE LIGANDS FOR B-LYMPHOMA CELL AND ITS EFFECT ON TYROSINE PHOSPHORYLATION AND CELL APOPTOSIS

    Institute of Scientific and Technical Information of China (English)

    宋良文; 马宪梅; 崔雪梅; 李扬; 王晓民

    2004-01-01

    Objective To search novel method for diagnosis and therapy of B-lymphoma, specific small molecular peptide ligands against binding site of tumor cells were screened and its effects on signal transduction and cell apoptosis were tested. Methods Specific peptide ligands were screened by binding with site of human B lymphoma cell (OC1LY8) using peptide-bead libraries. The identified peptides were characterized with responsible cells by rebinding test. The role of tyrosine phosphorylation of peptide ligand was tested by Western blot;and its apoptosispromoting role was observed by confocal fluorescent microscope. Results Specific peptide ligand was able to bind specifically to site on cell surface and enter into cytoplasm. Tetrameric peptide ligand was able to strongly trigger signal transduction resulting in tyrosine phosphorylation and cellular apoptosis in OC1LY8 cell line.Conclusion Screened peptide ligand can effectively bind with OC1LY8 cell, stimulate cellular tyrosine phosphorylation and induce cellular apoptosis.

  14. Non-Ligand-Induced Dimerization is Sufficient to Initiate the Signalling and Endocytosis of EGF Receptor

    OpenAIRE

    Kourouniotis, George; Wang, Yi; Pennock, Steven; Chen, Xinmei; Wang, Zhixiang

    2016-01-01

    The binding of epidermal growth factor (EGF) to EGF receptor (EGFR) stimulates cell mitogenesis and survival through various signalling cascades. EGF also stimulates rapid EGFR endocytosis and its eventual degradation in lysosomes. The immediate events induced by ligand binding include receptor dimerization, activation of intrinsic tyrosine kinase and autophosphorylation. However, in spite of intensified efforts, the results regarding the roles of these events in EGFR signalling and internali...

  15. Chronic Constipation: Current Treatment Options

    Directory of Open Access Journals (Sweden)

    Louis Wing Cheong Liu

    2011-01-01

    Full Text Available Chronic constipation is a common functional gastrointestinal disorder that affects patients of all ages. In 2007, a consensus group of 10 Canadian gastroenterologists developed a set of recommendations pertaining to the management of chronic constipation and constipation-dominant irritable bowel syndrome. Since then, tegaserod has been withdrawn from the Canadian market. A new, highly selective serotonin receptor subtype 4 agonist, prucalopride, has been examined in several large, randomized, placebo-controlled trials demonstrating its efficacy and safety in the management of patients with chronic constipation. Additional studies evaluating the use of stimulant laxatives, polyethylene glycol and probiotics in the management of chronic constipation have also been published. The present review summarizes the previous recommendations and new evidence supporting different treatment modalities – namely, diet and lifestyle, bulking agents, stool softeners, osmotic and stimulant laxatives, prucalopride and probiotics in the management of chronic constipation. A brief summary of lubiprostone and linaclotide is also presented. The quality of evidence is presented by adopting the Grading of Recommendations, Assessment, Development and Evaluation system. Finally, a management pyramid for patients with chronic constipation is proposed based on the quality of evidence, impact of each modality on constipation and on general health, and their availabilities in Canada.

  16. Central nicotinic receptors: structure, function, ligands, and therapeutic potential.

    Science.gov (United States)

    Romanelli, M Novella; Gratteri, Paola; Guandalini, Luca; Martini, Elisabetta; Bonaccini, Claudia; Gualtieri, Fulvio

    2007-06-01

    The growing interest in nicotinic receptors, because of their wide expression in neuronal and non-neuronal tissues and their involvement in several important CNS pathologies, has stimulated the synthesis of a high number of ligands able to modulate their function. These membrane proteins appear to be highly heterogeneous, and still only incomplete information is available on their structure, subunit composition, and stoichiometry. This is due to the lack of selective ligands to study the role of nAChR under physiological or pathological conditions; so far, only compounds showing selectivity between alpha4beta2 and alpha7 receptors have been obtained. The nicotinic receptor ligands have been designed starting from lead compounds from natural sources such as nicotine, cytisine, or epibatidine, and, more recently, through the high-throughput screening of chemical libraries. This review focuses on the structure of the new agonists, antagonists, and allosteric ligands of nicotinic receptors, it highlights the current knowledge on the binding site models as a molecular modeling approach to design new compounds, and it discusses the nAChR modulators which have entered clinical trials.

  17. Why mercury prefers soft ligands

    Energy Technology Data Exchange (ETDEWEB)

    Riccardi, Demian M [ORNL; Guo, Hao-Bo [ORNL; Gu, Baohua [ORNL; Parks, Jerry M [ORNL; Summers, Anne [University of Georgia, Athens, GA; Miller, S [University of California, San Francisco; Liang, Liyuan [ORNL; Smith, Jeremy C [ORNL

    2013-01-01

    Mercury (Hg) is a major global pollutant arising from both natural and anthropogenic sources. Defining the factors that determine the relative affinities of different ligands for the mercuric ion, Hg2+, is critical to understanding its speciation, transformation, and bioaccumulation in the environment. Here, we use quantum chemistry to dissect the relative binding free energies for a series of inorganic anion complexes of Hg2+. Comparison of Hg2+ ligand interactions in the gaseous and aqueous phases shows that differences in interactions with a few, local water molecules led to a clear periodic trend within the chalcogenide and halide groups and resulted in the well-known experimentally observed preference of Hg2+ for soft ligands such as thiols. Our approach establishes a basis for understanding Hg speciation in the biosphere.

  18. Molecular Recognition and Ligand Association

    Science.gov (United States)

    Baron, Riccardo; McCammon, J. Andrew

    2013-04-01

    We review recent developments in our understanding of molecular recognition and ligand association, focusing on two major viewpoints: (a) studies that highlight new physical insight into the molecular recognition process and the driving forces determining thermodynamic signatures of binding and (b) recent methodological advances in applications to protein-ligand binding. In particular, we highlight the challenges posed by compensating enthalpic and entropic terms, competing solute and solvent contributions, and the relevance of complex configurational ensembles comprising multiple protein, ligand, and solvent intermediate states. As more complete physics is taken into account, computational approaches increase their ability to complement experimental measurements, by providing a microscopic, dynamic view of ensemble-averaged experimental observables. Physics-based approaches are increasingly expanding their power in pharmacology applications.

  19. Effect of mobilization of bone marrow stem cells by granulocyte colony stimulating factor on clinical symptoms, left ventricular perfusion and function in patients with severe chronic ischemic heart disease

    DEFF Research Database (Denmark)

    Wang, Yongzhong; Tägil, Kristina; Ripa, Rasmus S.

    2005-01-01

    OBJECTIVES: A phase I safety and efficacy study with granulocyte colony stimulating factor (G-CSF) mobilization of bone marrow stem cells to induce vasculogenesis in patients with severe ischemic heart disease (IHD) was conducted. DESIGN, PATIENTS AND RESULTS: 29 patients with IHD participated...... in 'mobilizers'. At the follow-up, G-CSF treated had improved in CCS classification, NTG consumption and angina attacks, but the controls only in CCS classification. No difference was seen between the two groups. The decline in NTG consumption tended to be significant in 'mobilizers' compared to controls...

  20. MULTIDENTATE TEREPHTHALAMIDATE AND HYDROXYPYRIDONATE LIGANDS: TOWARDS NEW ORALLY ACTIVE CHELATORS

    Energy Technology Data Exchange (ETDEWEB)

    Abergel, Rebecca J.; Raymond, Kenneth N.

    2011-07-13

    The limitations of current therapies for the treatment of iron overload or radioisotope contamination have stimulated efforts to develop new orally bioavailable iron and actinide chelators. Siderophore-inspired tetradentate, hexadentate and octadentate terephthalamidate and hydroxypyridonate ligands were evaluated in vivo as selective and efficacious iron or actinide chelating agents, with several metal loading and ligand assessment procedures, using {sup 59}Fe, {sup 238}Pu, and {sup 241}Am as radioactive tracers. The compounds presented in this study were compared to commercially available therapeutic sequestering agents [deferoxamine (DFO) for iron and diethylenetriaminepentaacetic acid (DPTA) for actinides] and are unrivaled in terms of affinity, selectivity and decorporation efficacy, which attests to the fact that high metal affinity may overcome the low bioavailability properties commonly associated to multidenticity.

  1. [Chronicity, chronicization, systematization of delusions].

    Science.gov (United States)

    Trapet, P; Fernandez, C; Galtier, M C; Gisselmann, A

    1984-05-01

    Chronicity in psychopathology is indicative of a term, a decay. Chronicization only leads the way to this term. Here, chronicization is taken literally as an inscription in the time course of delusions. The mechanism of systematization seems to be a central mark in the approach to chronic delusions. It is not an alienation or an irreversible closing but an attempted accommodation with reality in the life of psychotic subjects, irrespective of the delusional structure. The role of therapy and drug treatment as a follow-up may in that case assume another meaning.

  2. Chronic pancreatitis

    OpenAIRE

    Kocher, Hemant M.; Froeling, Fieke EM

    2008-01-01

    Chronic pancreatitis is characterised by long-standing inflammation of the pancreas owing to a wide variety of causes, including recurrent acute attacks of pancreatitis. Chronic pancreatitis affects 3–9 people in 100,000; 70% of cases are alcohol-induced.

  3. Chronic pancreatitis

    OpenAIRE

    Kocher, Hemant M.; Kadaba, Raghu

    2011-01-01

    Chronic pancreatitis is characterised by long-standing inflammation of the pancreas due to a wide variety of causes, including recurrent acute attacks of pancreatitis. Chronic pancreatitis affects between 3 and 9 people in 100,000; 70% of cases are alcohol-induced.

  4. Electrical stimulation of the upper extremity in stroke: cyclic versus EMG-triggered stimulation

    NARCIS (Netherlands)

    Kroon, de Joke R.; IJzerman, Maarten J.

    2008-01-01

    Objective: To compare the effect of cyclic and electromyography (EMG)-triggered electrical stimulation on motor impairment and function of the affected upper extremity in chronic stroke. Design: Randomized controlled trial. Setting: Outpatient clinic of a rehabilitation centre. Subjects and inte

  5. Internalization mechanisms of the epidermal growth factor receptor after activation with different ligands.

    Directory of Open Access Journals (Sweden)

    Lasse Henriksen

    Full Text Available The epidermal growth factor receptor (EGFR regulates normal growth and differentiation, but dysregulation of the receptor or one of the EGFR ligands is involved in the pathogenesis of many cancers. There are eight ligands for EGFR, however most of the research into trafficking of the receptor after ligand activation focuses on the effect of epidermal growth factor (EGF and transforming growth factor-α (TGF-α. For a long time it was believed that clathrin-mediated endocytosis was the major pathway for internalization of the receptor, but recent work suggests that different pathways exist. Here we show that clathrin ablation completely inhibits internalization of EGF- and TGF-α-stimulated receptor, however the inhibition of receptor internalization in cells treated with heparin-binding EGF-like growth factor (HB-EGF or betacellulin (BTC was only partial. In contrast, clathrin knockdown fully inhibits EGFR degradation after all ligands tested. Furthermore, inhibition of dynamin function blocked EGFR internalization after stimulation with all ligands. Knocking out a number of clathrin-independent dynamin-dependent pathways of internalization had no effect on the ligand-induced endocytosis of the EGFR. We suggest that EGF and TGF-α lead to EGFR endocytosis mainly via the clathrin-mediated pathway. Furthermore, we suggest that HB-EGF and BTC also lead to EGFR endocytosis via a clathrin-mediated pathway, but can additionally use an unidentified internalization pathway or better recruit the small amount of clathrin remaining after clathrin knockdown.

  6. A race for RAGE ligands.

    Science.gov (United States)

    Schleicher, Erwin D

    2010-08-01

    In experimental animals a causal involvement of the multiligand receptor for advanced glycation end products (RAGE) in the development of diabetic vascular complications has been demonstrated. However, the nature of RAGE ligands present in patients with diabetic nephropathy has not yet been defined; this leaves open the relevance of the RAGE system to the human disease.

  7. Brain Stimulation Therapies

    Science.gov (United States)

    ... is preferred by many doctors, patients and families. Vagus Nerve Stimulation Vagus nerve stimulation (VNS) works through a device implanted under ... skin that sends electrical pulses through the left vagus nerve, half of a prominent pair of nerves that ...

  8. Feldspar, Infrared Stimulated Luminescence

    DEFF Research Database (Denmark)

    Jain, Mayank

    2014-01-01

    This entry primarily concerns the characteristics and the origins of infrared-stimulated luminescence in feldspars.......This entry primarily concerns the characteristics and the origins of infrared-stimulated luminescence in feldspars....

  9. An Overview of Stimulators

    OpenAIRE

    Mohd. Suhaib Kidwai; Mohd Maroof Siddiqui; Ahmad Nafees; Qazi saeed Ahmad

    2012-01-01

    This paper aims to bring forth the significance of stimulators , recent advancements in the field of stimulators and how electrical signals can be utilized for pain relief and to cure other diseases of human body ,by using stimulators. This paper aims to create awareness about stimulators and also focuses on their advantages as compared to theconventional medicine .Moreover,it also bring forth that how an electrical signal can be utilized for treating various human disorders and diseases.

  10. 21 CFR 882.5830 - Implanted diaphragmatic/phrenic nerve stimulator.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Implanted diaphragmatic/phrenic nerve stimulator... Implanted diaphragmatic/phrenic nerve stimulator. (a) Identification. An implanted diaphragmatic/phrenic... spinal cord injury, or chronic lung disease. The stimulator consists of an implanted receiver...

  11. Structure-based virtual screening campaigns on curcuminoids as potent ligands for histone deacetylase-2

    Directory of Open Access Journals (Sweden)

    Enade Perdana Istyastono

    2016-03-01

    Full Text Available Curcumin was reported to reverse the decrease in histone deacetylase-2 (HDAC2 protein expression in inflammatory diseases of the lung, including chronic obstructive pulmonary disease (COPD, severe asthma, and asthma in smokers. This indicates that curcumin is a potent ligand for HDAC2. The construction and retrospective validation of a structure-based virtual screening (SBVS protocol to identify potent ligands for HDAC2 are presented in this article. The validated protocol was subsequently employed to screen curcumin and other curcuminoids found in Curcuma longa, i.e. demethoxy curcumin and bis-demethoxy curcumin, and to examine their interactions to HDAC2 in the atomic level. The results show that curcumin, demethoxy curcumin and bis-demethoxy curcumin are potent HDAC2 ligands. The insights from their interactions to HDAC2 resulted from the molecular docking simulations presented in this article could be employed further in the design and discovery potent HDAC2 ligands.

  12. Ligand-induced internalization of the type 1 cholecystokinin receptor independent of recognized signaling activity.

    Science.gov (United States)

    Cawston, Erin E; Harikumar, Kaleeckal G; Miller, Laurence J

    2012-02-01

    Receptor ligands, identified as antagonists, based on the absence of stimulation of signaling, can rarely stimulate receptor internalization. d-Tyr-Gly-[(Nle(28,31),d-Trp(30))CCK-26-32]-2-phenylethyl ester (d-Trp-OPE) is such a ligand that binds to the cholecystokinin (CCK) receptor and stimulates internalization. Here, the molecular basis of this trafficking event is explored, with the assumption that ligand binding initiates conformational change, exposing an epitope to direct endocytosis. Ligand-stimulated internalization was studied morphologically using fluorescent CCK and d-Trp-OPE. d-Trp-OPE occupation of Chinese hamster ovary cell receptors stimulated internalization into the same region as CCK. Arrestin-biased action was ruled out using morphological translocation of fluorescent arrestin 2 and arrestin 3, moving to the membrane in response to CCK, but not d-Trp-OPE. Possible roles of the carboxyl terminus were studied using truncated receptor constructs, eliminating the proline-rich distal tail, the serine/threonine-rich midregion, and the remainder to the vicinal cysteines. None of these constructs disrupted d-Trp-OPE-stimulated internalization. Possible contributions of transmembrane segments were studied using competitive inhibition with peptides that also had no effect. Intracellular regions were studied with a similar strategy using coexpressing cell lines. Peptides corresponding to ends of each loop region were studied, with only the peptide at the carboxyl end of the third loop inhibiting d-Trp-OPE-stimulated internalization but having no effect on CCK-stimulated internalization. The region contributing to this effect was refined to peptide 309-323, located below the recognized G protein-association motif. While a receptor in which this segment was deleted did internalize in response to d-Trp-OPE, it exhibited abnormal ligand binding and did not signal in response to CCK, suggesting an abnormal conformation and possible mechanism of internalization

  13. DARPP-32 expression in rat brain after electroconvulsive stimulation.

    Science.gov (United States)

    Rosa, Daniela V F; Souza, Renan P; Souza, Bruno R; Motta, Bernardo S; Caetano, Fernando; Jornada, Luciano K; Feier, Gustavo; Gomez, Marcus V; Quevedo, João; Romano-Silva, Marco A

    2007-11-07

    Although electroconvulsive therapy (ECT) has been used as a treatment for mental disorder since 1930s, little progress has been made in the mechanisms underlying its therapeutic or adverse effects. The aim of this work was to analyze the expression of DARPP-32 (a protein with a central role in dopaminergic signaling) in striatum, cortex, hippocampus and cerebellum of Wistar rats subjected to acute or chronic electroconvulsive stimulation (ECS). Rats were submitted to a single stimulation (acute) or to a series of eight stimulations, applied one every 48 h (chronic). Animals were killed for collection of tissue samples at time zero, 0.5, 3, 12, 24 and 48 h after stimulation in the acute model and at the same time intervals after the last stimulation in the chronic model. Our results indicated that acute ECS produces smaller changes in the expression of DARPP-32 but, interestingly, chronic ECS increased transient expression of DARPP-32 in several time frames, in striatum and hippocampus, after the last stimulation. Results on the expression of proteins involved in signaling pathways are relevant for neuropsychiatric disorders and treatment, in particular ECT, and can contribute to shed light on the mechanisms related to therapeutic and adverse effects.

  14. Endogenous IGF-I and alpha v beta3 integrin ligands regulate increased smooth muscle growth in TNBS-induced colitis.

    Science.gov (United States)

    Hazelgrove, Krystina B; Flynn, Robert S; Qiao, Li-Ya; Grider, John R; Kuemmerle, John F

    2009-06-01

    Endogenous insulin-like growth factor-I (IGF-I) regulates intestinal smooth muscle growth by concomitantly stimulating proliferation and inhibiting apoptosis. IGF-I-stimulated growth is augmented by the alpha(v)beta(3) integrin ligands vitronectin and fibronectin. IGF-I expression in smooth muscle is increased in both TNBS-induced colitis and Crohn's disease. We hypothesized that intestinal inflammation increased vitronectin and fibronectin expression by smooth muscle and, along with IGF-I upregulation, increased intestinal muscle growth. Intestinal smooth muscle cells were examined 7 days following the induction of TNBS-induced colitis. Although alpha(v)beta(3) integrin expression was not altered by TNBS-induced colitis, vitronectin and fibronectin levels were increased by 80 +/- 10% and 90 +/- 15%, above control levels, respectively. Basal IGF-I receptor phosphorylation in inflamed muscle from TNBS-treated rats was increased by 86 +/- 8% over vehicle-treated controls. Basal ERK1/2, p70S6 kinase, and GSK-3beta phosphorylation in muscle cells of TNBS-treated rats were also increased by 140-180%. TNBS treatment increased basal muscle cell proliferation by 130 +/- 15% and decreased apoptosis by 20 +/- 2% compared with that in vehicle-treated controls. The changes in proliferation and apoptosis were reversed by an IGF-I receptor tyrosine kinase inhibitor or an alpha(v)beta(3) integrin antagonist. The results suggest that smooth muscle hyperplasia in TNBS-induced colitis partly results from the upregulation of endogenous IGF-I and ligands of alpha(v)beta(3) integrin that mediate increased smooth muscle cell proliferation and decreased apoptosis. This paper has identified one mechanism regulating smooth muscle hyperplasia, a feature of stricture formation that occurs in the chronically inflamed intestine of TNBS-induced colitis and potentially Crohn's disease.

  15. Ear infection - chronic

    Science.gov (United States)

    Middle ear infection - chronic; Otitis media - chronic; Chronic otitis media; Chronic ear infection ... up. When this happens, infection can occur. A chronic ear infection develops when fluid or an infection ...

  16. Immune evasion activities of accessory proteins Vpu, Nef and Vif are conserved in acute and chronic HIV-1 infection.

    Science.gov (United States)

    Mlcochova, Petra; Apolonia, Luis; Kluge, Silvia F; Sridharan, Aishwarya; Kirchhoff, Frank; Malim, Michael H; Sauter, Daniel; Gupta, Ravindra K

    2015-08-01

    Heterosexual HIV-1 transmission has been identified as a genetic bottleneck and a single transmitted/founder (T/F) variant with reduced sensitivity to type I interferon initiates productive infection in most cases. We hypothesized that particularly active accessory protein(s) may confer T/F viruses with a selective advantage in establishing HIV infection. Thus, we tested vpu, vif and nef alleles from six T/F and six chronic (CC) viruses in assays for 9 immune evasion activities involving the counteraction of interferon-stimulated genes and modulation of ligands known to activate innate immune cells. All functions were highly conserved with no significant differences between T/F and CC viruses, suggesting that these accessory protein functions are important throughout the course of infection.

  17. Controlled-deactivation cannabinergic ligands.

    Science.gov (United States)

    Sharma, Rishi; Nikas, Spyros P; Paronis, Carol A; Wood, Jodianne T; Halikhedkar, Aneetha; Guo, Jason Jianxin; Thakur, Ganesh A; Kulkarni, Shashank; Benchama, Othman; Raghav, Jimit Girish; Gifford, Roger S; Järbe, Torbjörn U C; Bergman, Jack; Makriyannis, Alexandros

    2013-12-27

    We report an approach for obtaining novel cannabinoid analogues with controllable deactivation and improved druggability. Our design involves the incorporation of a metabolically labile ester group at the 2'-position on a series of (-)-Δ(8)-THC analogues. We have sought to introduce benzylic substituents α to the ester group which affect the half-lives of deactivation through enzymatic activity while enhancing the affinities and efficacies of individual ligands for the CB1 and CB2 receptors. The 1'-(S)-methyl, 1'-gem-dimethyl, and 1'-cyclobutyl analogues exhibit remarkably high affinities for both CB receptors. The novel ligands are susceptible to enzymatic hydrolysis by plasma esterases in a controllable manner, while their metabolites are inactive at the CB receptors. In further in vitro and in vivo experiments key analogues were shown to be potent CB1 receptor agonists and to exhibit CB1-mediated hypothermic and analgesic effects.

  18. Abnormal B-cell activation associated with TALL-1 over-expression and SOCS-1 suppression during chronic hepatitis C virus infection.

    Science.gov (United States)

    Moorman, Jonathan; Dong, Zhi P; Ni, Lei; Zhang, Chunlan; Borthwick, Thomas; Yao, Zhi Q

    2009-10-01

    Chronic hepatitis C virus (HCV) infection is associated with cirrhosis, autoimmunity and lymphoproliferative disorders. We have previously reported a differential regulation of T and B lymphocytes by HCV core protein in vitro. In this report, we employed a translational approach to characterize the activation status of peripheral B cells from individuals with chronic HCV infection and to explore potential mechanisms for B-cell dysregulation in the setting of HCV infection. In contrast to the T-cell suppression observed in HCV-infected individuals, B cells exhibit a non-specific polyclonal activation phenotype, characterized by significantly higher levels of (1) the early activation marker, CD69, (2) the costimulatory molecule, CD86, and (3) the CCR5 chemokine receptor, CD195, when compared with B cells from healthy donors in response to phytohaemagglutinin (PHA) stimulation. Importantly, tumour necrosis factor- and Apo-L-related leucocyte-expressed ligand-1 (TALL-1), also known as B-lymphocyte stimulator (BLYS), was found to be up-regulated on the surface of B cells from HCV patients in response to PHA as well as HCV core antigen stimulation. This up-regulation of TALL-1 was associated with vigorous memory B-cell responses to viral antigenic stimulation. Additionally, suppressor of cytokine signalling-1 (SOCS-1), a negative feedback immunoregulator that is inhibited in B lymphocytes by HCV core in vitro, was also inhibited in B cells from HCV patients when compared with healthy donors. These findings suggest that TALL-1 over-expression and SOCS-1 suppression are associated with aberrant B-cell activation, providing a plausible basis for the B-cell clonal expansion underlying the lymphoproliferative disorders and autoimmune phenomena observed during chronic HCV infection.

  19. Privileged chiral ligands and catalysts

    CERN Document Server

    Zhou, Qi-Lin

    2011-01-01

    This ultimate ""must have"" and long awaited reference for every chemist working in the field of asymmetric catalysis starts with the core structure of the catalysts, explaining why a certain ligand or catalyst is so successful. It describes in detail the history, the basic structural characteristics, and the applications of these ""privileged catalysts"". A novel concept that gives readers a much deeper insight into the topic.

  20. Tumor targeting via integrin ligands

    Directory of Open Access Journals (Sweden)

    Udaya Kiran eMarelli

    2013-08-01

    Full Text Available Selective and targeted delivery of drugs to tumors is a major challenge for an effective cancer therapy and also to overcome the side effects associated with current treatments. Overexpression of various receptors on tumor cells is a characteristic structural and biochemical aspect of tumors and distinguishes them from physiologically normal cells. This abnormal feature is therefore suitable for selectively directing anticancer molecules to tumors by using ligands that can preferentially recognize such receptors. Several subtypes of integrin receptors that are crucial for cell adhesion, cell signaling, cell viability and motility have been shown to have an upregulated expression on cancer cells. Thus, ligands that recognize specific integrin subtypes represent excellent candidates to be conjugated to drugs or drug carrier systems and be targeted to tumors. In this regard, integrins recognizing the RGD cell adhesive sequence have been extensively targeted for tumor specific drug delivery. Here we review key recent examples on the presentation of RGD-based integrin ligands by means of distinct drug delivery systems, and discuss the prospects of such therapies to specifically target tumor cells.

  1. 急慢性迷走神经刺激对大鼠海洛因复吸行为的影响及作用机制%Effect and mechanism of acute and chronic vagus nerve stimulation on heroin relapse in rats

    Institute of Scientific and Technical Information of China (English)

    朱华强; 于静; 陈为升; 唐甩恩; 符丹; 刘惠芬; 周文华

    2012-01-01

    目的:探讨急慢性迷走神经刺激(VNS)对大鼠海洛因复吸行为可能的干预作用及机制.方法:SD大鼠每天进行4h的海洛因自身给药训练,持续14d,建立具有强迫性觅药和给药特征的自身给药模型.随后所有大鼠植入VNS电极,恢复后进行10 d的海洛因觅药行为消退训练,期间分组给予急性VNS、慢性VNS或假刺激.消退结束后测定各组大鼠条件性线索诱导下的海洛因觅药行为的恢复(即海洛因复吸行为).免疫荧光法检测中枢核团c-Fos的表达水平.结果:海洛因复吸行为测定结果显示,与假刺激对照组比较,急性VNS组和慢性VNS组的有效鼻触数均明显降低(P<0.01).免疫荧光的结果显示,与对照组比较,急性VNS组(P<0.05)和慢性VNS组(P<0.01)中央杏仁核(Ce)的c-Fos表达水平均明显降低,而边缘下区(IL)的c-Fos表达水平均明显升高(P<0.05).结论:急慢性VNS均能够显著抑制大鼠的海洛因复吸行为,其机制可能与Ce和IL脑区神经元激活的改变有关.%AIM: To investigate the therapeutic effect of vagus nerve stimulation ( VNS) on heroin relapse in rats and its possible mechanism. METHODS: The SD rats were trained to self-administer heroin by nose-poking in a daily 4 hours session for consecutive 14 days, to establish an animal model of compulsive drug-seeking and drug-taking. The electrode was implanted into the left vagus nerve and followed by several days recovery, all rats were then trained to 10 daily extinction session and divided into 3 groups: sham control, acute VNS and chronic VNS. The rats in the chronic VNS group were given VNS 2 hours before all extinction and relapse test session, while the rats in the acute VNS group were given VNS 2 hours only before relapse test session. Cue-induced heroin relapse test were measured 24 hours after last extinction session. After relapse testing, c-Fos levels in brain regions of rats were measured by immuno- fluorescence. RESULTS

  2. PEG10 Activation by Co-Stimulation of CXCR5 and CCR7 Essentially Contributes to Resistance to Apoptosis in CD19+CD34+ B Cells from Patients with B Cell Lineage Acute and Chronic Lymphocytic Leukemia

    Institute of Scientific and Technical Information of China (English)

    ChunsongHu; JeiXiong; LinjeiZhang; BaojunHuang; QiupingZhang; QunLi; MingzhenYang; YaouWu; QunWu; QianShen; QingpingGao; KejianZhang; ZhiminSun; JunyanLin; YouxinJin

    2004-01-01

    We investigated CD19+CD34+ and CD19+CD34 B cells from cord blood (CB) and typical patients with B cell lineage acute and chronic lymphocytic leukemia (B-ALL and B-CLL) in terms of expression and functions of CXCR5/CXCL13 and CCR7/CCL19. CXCR5 and CCR7 were selectively frequent expressed on B-ALL, B-CLL and CB CD19+CD34+ B cells, but not on CD19+CD34- B cells. Instead of induction of impressive chemotactic responsiveness, CXCL13 and CCL19 together induced significant resistance to TNF-α-mediated apoptosis in B-ALL and B-CLL but not CB CD19+CD34+ B cells. B-ALL and B-CLL CD19+CD34+ B cells expressed elevatedlevel of Paternally Expressed Gene 10 (PEG10), and CXCL13 and CCL19 together significantly up-regulated PEG10 expression in the cells. We found that CXCL13 and CCL19 together by means of activation of CXCR5 and CCR7 up-regulated PEG10 expression and function, subsequent stabilized caspase-3 and caspase-8 in B-ALL and B-CLL CD19+CD34+ B cells, and rescued the cells from TNF-α-mediated apoptosis. We suggested that normal lymphocytes, especially naive B and T cells, utilized CXCR5/CXCL13 and CCR7/CCL19 for migration, homing, maturation, and cell homeostasis as well as secondary lymphoid tissues organogenesis. Meanwhile certain malignant cells took advantages of CXCR5/CXCL13 and CCR7/CCL19 for infiltration, resistance to apoptosis, and inappropriate proliferation. Cellular & Molecular Immunology.

  3. PEG10 Activation by Co-Stimulation of CXCR5 and CCR7 Essentially Contributes to Resistance to Apoptosis in CD19+CD34+ B Cells from Patients with B Cell Lineage Acute and Chronic Lymphocytic Leukemia

    Institute of Scientific and Technical Information of China (English)

    Chunsong Hu; Qian Shen; Qingping Gao; Kejian Zhang; Zhimin Sun; Junyan Liu; Youxin Jin; Jinquan Tan; Jei Xiong; Linjei zhang; Baojun Huang; Qiuping Zhang; Qun Li; Mingzhen Yang; Yaou Wu; Qun Wu

    2004-01-01

    We investigated CD19+CD34+ and CD19+CD34- B cells from cord blood (CB) and typical patients with B cell lineage acute and chronic lymphocytic leukemia (B-ALL and B-CLL) in terms of expression and functions of CXCR5/CXCL13 and CCR7/CCL19. CXCR5 and CCR7 were selectively frequent expressed on B-ALL, B-CLL and CB CD19+CD34+ B cells, but not on CD19+CD34- B cells. Instead of induction of impressive chemotactic responsiveness, CXCL13 and CCL19 together induced significant resistance to TNF-α-mediated apoptosis in B-ALL and B-CLL but not CB CD19+CD34+ B cells. B-ALL and B-CLL CD19+CD34+ B cells expressed elevated level of Paternally Expressed Gene 10 (PEG10), and CXCL13 and CCL19 together significantly up-regulated PEG10 expression in the cells. We found that CXCL13 and CCL19 together by means of activation of CXCR5 and CCR7 up-regulated PEG10 expression and function, subsequent stabilized caspase-3 and caspase-8 in B-ALL and B-CLL CD19+CD34+ B cells, and rescued the cells from TNF-α-mediated apoptosis. We suggested that normal lymphocytes, especially na(I)ve B and T cells, utilized CXCR5/CXCL13 and CCR7/CCL19 for migration, homing, maturation, and cell homeostasis as well as secondary lymphoid tissues organogenesis.Meanwhile certain malignant cells took advantages of CXCR5/CXCL13 and CCR7/CCL19 for infiltration,resistance to apoptosis, and inappropriate proliferation.

  4. Serotonergic system and its role in epilepsy and neuropathic pain treatment: a review based on receptor ligands.

    Science.gov (United States)

    Panczyk, Katarzyna; Golda, Sylwia; Waszkielewicz, Anna; Zelaszczyk, Dorota; Gunia-Krzyzak, Agnieszka; Marona, Henryk

    2015-01-01

    The serotonergic system is involved in pathomechanisms of both epilepsy and neuropathic pain. So far, participation in the epileptogenesis and maintenance of epilepsy was proved for 5-HT1A, 5-HT2C, 5-HT3, 5-HT4 and 5-HT7 receptors as well as 5-HTT serotonin transporter. Depending on the receptor type or its localization, its stimulation may increase or decrease neuronal excitability. According to the available data, neuropathic pain mechanisms involve 5-HT1A/1B/1D, 5-HT2A/2B/2C, 5-HT3, 5-HT4, 5-HT6, 5-HT7 receptors and 5-HTT serotonin transporter. Changes in their expression modulate pain mainly by affecting the transmission through serotonergic descending pathways. Several compounds, whose mechanisms of action base on influence on the serotonergic system, are already in use. These are 5-HT3 agonists (triptans) in case of migraine, tricyclic antidepressants or monoamine reuptake inhibitors in neuropathic pain treatment. In addition, selective and non-selective ligands are tested for their anticonvulsant or analgesic properties. Some ED50 values have been already obtained in such animal models as maximal electroshock (MES)-induced seizures (epilepsy), spinal nerve ligation (SNL), chronic constriction injury (CCI) or formalin (neuropathic pain). This review shows that in case of drug discovery within the serotonergic system one must take into account special significance of factors such as: the species, the type of model, the route of administration, and the dose range.

  5. Mechanisms of chronic pain from whiplash injury.

    Science.gov (United States)

    Davis, Charles G

    2013-02-01

    This article is to provide insights into the mechanisms underlying chronic pain from whiplash injury. Studies show that injury produces plasticity changes of different neuronal structures that are responsible for amplification of nociception and exaggerated pain responses. There is consistent evidence for hypersensitivity of the central nervous system to sensory stimulation in chronic pain after whiplash injury. Tissue damage, detected or not by the available diagnostic methods, is probably the main determinant of central hypersensitivity. Different mechanisms underlie and co-exist in the chronic whiplash condition. Spinal cord hyperexcitability in patients with chronic pain after whiplash injury can cause exaggerated pain following low intensity nociceptive or innocuous peripheral stimulation. Spinal hypersensitivity may explain pain in the absence of detectable tissue damage. Whiplash is a heterogeneous condition with some individuals showing features suggestive of neuropathic pain. A predominantly neuropathic pain component is related to a higher pain/disability level.

  6. [Chronic hepatitis].

    Science.gov (United States)

    Figueroa Barrios, R

    1995-01-01

    Medical literature about chronic hepatitis is reviewed. This unresolving disease caused by viruses, drugs or unknown factors may progress to in cirrhosis and hepatocarcinoma. A classification based on liver biopsy histology into chronic persistent and chronic active types has been largely abandoned and emphasis is placed on recognizing the etiology of the various types. One is associated with continuing hepatitis B virus infection; another is related to chronic hepatitis C virus infection and the third is termed autoinmune, because of the association with positive serum autoantibodies. A fourth type with similar clinical functional and morphologic features is found with some drug reactions. Long term corticoesteroid therapy is usually successful in autoinmune type. Associations between antibodies to liver-kidney microsomes and the hepatitis C virus can cause diagnostic difficulties. Antiviral treatment of chronic hepatitis B and C with interpheron alfa is employed, controlling symptoms and abnormal biochemistry and the progression to cirrhosis and liver cancer in 30 to 40% patients. Alternative therapies or combinations with interpheron are being evaluated waiting for final results.

  7. Lubiprostone stimulates small intestinal mucin release

    Directory of Open Access Journals (Sweden)

    De Lisle Robert C

    2012-11-01

    Full Text Available Abstract Background Lubiprostone is a synthetic bicyclic fatty acid derivative of prostaglandin E1 (PGE1 used for chronic constipation. The best known action of lubiprostone is simulation of Cl- dependent fluid secretion. In a mouse model of the genetic disease cystic fibrosis, we previously showed that in vivo administration of lubiprostone resulted in greater mucus accumulation in the small intestine. The aim of this study was to directly test whether lubiprostone stimulates intestinal mucin release. Methods Mucin release was measured by mounting segments (4-5 cm of mouse proximal-mid small intestine in an organ bath, allowing access to the perfusate (luminal and the bath (serosal solutions. Nifedipine (10-6 M and indomethacin (10-5 M were included in all solutions to inhibit smooth muscle activity and endogenous prostaglandin production, respectively. The tissue was equilibrated under flow for 30 min, using the perfusate collected during the final 10 min of the equilibration period to measure unstimulated release rate. Stimulus was then added to either the perfusate or the bath and the perfusate was collected for another 30 min to measure the stimulated mucin release rate. Mucin in perfusates was quantified by periodic acid-Schiff's base dot-blot assay, using purified pig gastric mucin as a standard. Results When applied luminally at 1 μM lubiprostone was ineffective at stimulating mucin release. When added to the serosal solution, 1 μM lubiprostone stimulated mucin release to ~300% of the unstimulated rate. As a positive control, serosal 1 μM prostaglandin E2 increased mucin release to ~400% of the unstimulated rate. Conclusions These results support the idea that lubiprostone has prostaglandin-like actions on the intestine, which includes stimulation of mucin release. Stimulation of mucin release by lubiprostone may be protective in gastrointestinal conditions where loss of mucus is believed to contribute to pathogenesis. Thus, in

  8. Chronic Cough in Otorhinolaryngologic Routine

    Directory of Open Access Journals (Sweden)

    Palheta Neto, Francisco Xavier

    2011-04-01

    Full Text Available Introduction: The chronic cough is sometimes manifested as an imprecise symptom, but of great importance for both the diagnosis and the prognosis. In an otorhinolaryngologic approach, several illnesses that can occur with it can be numbered, including 2 of the 3 main causes of chronic cough. Objective: To identify the main otorhinolaryngologic diseases showing the chronic cough as one of their manifestations. Method: A literature's revision was performed in several scientific articles, specialized books and consultation in Birene and Scielo databases. Literature's revision: cough production in the upper airways is usually associated with an inflammatory reaction by stimulating sensitive receptors of these areas or by mechanic stimulus. The main cause of the chronic cough in the otorhinolaryngology day-to-day is the post-nasal drip, gathering together by itself 02 of the most common diseases: rhinitis and sinusitis. Laryngitis as a result of gastroesophageal reflux (GER stands out in the index of chronic cough etiology, but it is not as severe as GER . Neoplasias are also somewhat frequent causes of cough, and the difficulty in diagnosing the cough cause is common in this disease group. Motility disorder, laryngeal irritation persistence, parasitic disease and injuries by inhalation of toxic products were also found as a cause of cough for longer than 03 months. Conclusion:Chronic cough is a frequent and important finding in otorhinolaryngology and cannot be underestimated, and a careful anamnesis is the best way to determine the etiology and perform a correct treatment for the patient's disease.

  9. Fcγ receptors and ligands and cardiovascular disease.

    Science.gov (United States)

    Tanigaki, Keiji; Sundgren, Nathan; Khera, Amit; Vongpatanasin, Wanpen; Mineo, Chieko; Shaul, Philip W

    2015-01-16

    Fcγ receptors (FcγRs) classically modulate intracellular signaling on binding of the Fc region of IgG in immune response cells. How FcγR and their ligands affect cardiovascular health and disease has been interrogated recently in both preclinical and clinical studies. The stimulation of activating FcγR in endothelial cells, vascular smooth muscle cells, and monocytes/macrophages causes a variety of cellular responses that may contribute to vascular disease pathogenesis. Stimulation of the lone inhibitory FγcR, FcγRIIB, also has adverse consequences in endothelial cells, antagonizing NO production and reparative mechanisms. In preclinical disease models, activating FcγRs promote atherosclerosis, whereas FcγRIIB is protective, and activating FcγRs also enhance thrombotic and nonthrombotic vascular occlusion. The FcγR ligand C-reactive protein (CRP) has undergone intense study. Although in rodents CRP does not affect atherosclerosis, it causes hypertension and insulin resistance and worsens myocardial infarction. Massive data have accumulated indicating an association between increases in circulating CRP and coronary heart disease in humans. However, Mendelian randomization studies reveal that CRP is not likely a disease mediator. CRP genetics and hypertension warrant further investigation. To date, studies of genetic variants of activating FcγRs are insufficient to implicate the receptors in coronary heart disease pathogenesis in humans. However, a link between FcγRIIB and human hypertension may be emerging. Further knowledge of the vascular biology of FcγR and their ligands will potentially enhance our understanding of cardiovascular disorders, particularly in patients whose greater predisposition for disease is not explained by traditional risk factors, such as individuals with autoimmune disorders.

  10. CD137 is induced by the CD40 signal on chronic lymphocytic leukemia B cells and transduces the survival signal via NF-κB activation.

    Directory of Open Access Journals (Sweden)

    Yukana Nakaima

    Full Text Available CD137 is a member of the tumor necrosis factor receptor family that is expressed on activated T cells. This molecule provides a co-stimulatory signal that enhances the survival, and differentiation of cells, and has a crucial role in the development of CD8 cytotoxic T cells and anti-tumor immunity. Here we report that CD137 expression is also induced on normal or malignant human B cells by CD40 ligation by its ligand CD154. This CD137 induction was more prominent in chronic lymphocytic leukemia (CLL cells than in other types of B cells. CD137 stimulation on B cells by its ligand induced the nuclear translocation of p52 (a non-canonical NF-κB factor. In agreement with this finding, expression of the survival factor BCL-XL was upregulated. Consequently, the CD137 signal augmented the survival of CD154-stimulated CLL B cells in vitro. This unexpected induction of CD137 on B cells by CD40 signal may influence the clinical course of CLL.

  11. Ligand placement based on prior structures: the guided ligand-replacement method

    Energy Technology Data Exchange (ETDEWEB)

    Klei, Herbert E. [Lawrence Berkeley National Laboratory, Berkeley, CA 94720 (United States); Bristol-Myers Squibb, Princeton, NJ 08543-4000 (United States); Moriarty, Nigel W., E-mail: nwmoriarty@lbl.gov; Echols, Nathaniel [Lawrence Berkeley National Laboratory, Berkeley, CA 94720 (United States); Terwilliger, Thomas C. [Los Alamos National Laboratory, Los Alamos, NM 87545-0001 (United States); Baldwin, Eric T. [Bristol-Myers Squibb, Princeton, NJ 08543-4000 (United States); Natural Discovery LLC, Princeton, NJ 08542-0096 (United States); Pokross, Matt; Posy, Shana [Bristol-Myers Squibb, Princeton, NJ 08543-4000 (United States); Adams, Paul D. [Lawrence Berkeley National Laboratory, Berkeley, CA 94720 (United States); University of California at Berkeley, Berkeley, CA 94720-1762 (United States)

    2014-01-01

    A new module, Guided Ligand Replacement (GLR), has been developed in Phenix to increase the ease and success rate of ligand placement when prior protein-ligand complexes are available. The process of iterative structure-based drug design involves the X-ray crystal structure determination of upwards of 100 ligands with the same general scaffold (i.e. chemotype) complexed with very similar, if not identical, protein targets. In conjunction with insights from computational models and assays, this collection of crystal structures is analyzed to improve potency, to achieve better selectivity and to reduce liabilities such as absorption, distribution, metabolism, excretion and toxicology. Current methods for modeling ligands into electron-density maps typically do not utilize information on how similar ligands bound in related structures. Even if the electron density is of sufficient quality and resolution to allow de novo placement, the process can take considerable time as the size, complexity and torsional degrees of freedom of the ligands increase. A new module, Guided Ligand Replacement (GLR), was developed in Phenix to increase the ease and success rate of ligand placement when prior protein–ligand complexes are available. At the heart of GLR is an algorithm based on graph theory that associates atoms in the target ligand with analogous atoms in the reference ligand. Based on this correspondence, a set of coordinates is generated for the target ligand. GLR is especially useful in two situations: (i) modeling a series of large, flexible, complicated or macrocyclic ligands in successive structures and (ii) modeling ligands as part of a refinement pipeline that can automatically select a reference structure. Even in those cases for which no reference structure is available, if there are multiple copies of the bound ligand per asymmetric unit GLR offers an efficient way to complete the model after the first ligand has been placed. In all of these applications, GLR

  12. Vagus Nerve Stimulation Affects Pain Perception in Depressed Adults

    Directory of Open Access Journals (Sweden)

    Jeffrey J Borckardt

    2005-01-01

    Full Text Available BACKGROUND: Previous research suggests that vagus nerve stimulation (VNS affects pain perception in epilepsy patients, with acute VNS decreasing pain thresholds and chronic VNS treatment increasing pain thresholds. However, no studies have investigated the effects of VNS on pain perception in chronically depressed adults, nor have controlled, systematic investigations been published on the differential effects of certain VNS device parameters on pain perception.

  13. Chronic gastritis.

    Science.gov (United States)

    Sipponen, Pentti; Maaroos, Heidi-Ingrid

    2015-06-01

    Prevalence of chronic gastritis has markedly declined in developed populations during the past decades. However, chronic gastritis is still one of the most common serious pandemic infections with such severe killing sequelae as peptic ulcer or gastric cancer. Globally, on average, even more than half of people may have a chronic gastritis at present. Helicobacter pylori infection in childhood is the main cause of chronic gastritis, which microbial origin is the key for the understanding of the bizarre epidemiology and course of the disease. A life-long and aggressive inflammation in gastritis results in destruction (atrophic gastritis) of stomach mucosa with time (years and decades). The progressive worsening of atrophic gastritis results subsequently in dysfunctions of stomach mucosa. Atrophic gastritis will finally end up in a permanently acid-free stomach in the most extreme cases. Severe atrophic gastritis and acid-free stomach are the highest independent risk conditions for gastric cancer known so far. In addition to the risks of malignancy and peptic ulcer, acid-free stomach and severe forms of atrophic gastritis may associate with failures in absorption of essential vitamins, like vitamin B12, micronutrients (like iron, calcium, magnesium and zinc), diet and medicines.

  14. Chronic Bronchitis

    Science.gov (United States)

    ... breathing. You may also have other tests. Chronic bronchitis is a long-term condition that keeps coming back or never goes away completely. If you smoke, it is important to quit. Treatment can help with your symptoms. It often includes ...

  15. Manipulation of P2X Receptor Activities by Light Stimulation

    Directory of Open Access Journals (Sweden)

    Sang Seong Kim

    2016-01-01

    Full Text Available P2X receptors are involved in amplification of inflammatory responses in peripheral nociceptive fibers and in mediating pain-related signals to the CNS. Control of P2X activation has significant importance in managing unwanted hypersensitive neuron responses. To overcome the limitations of chemical ligand treatment, optical stimulation methods of optogenetics and photoswitching achieve efficient control of P2X activation while allowing specificity at the target site and convenient stimulation by light illumination. There are many potential applications for photosensitive elements, such as improved uncaging methods, photoisomerizable ligands, photoswitches, and gold nanoparticles. Each technique has both advantages and downsides, and techniques are selected according to the purpose of the application. Technical advances not only provide novel approaches to manage inflammation or pain mediated by P2X receptors but also suggest a similar approach for controlling other ion channels.

  16. The use of repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) to relieve pain.

    Science.gov (United States)

    Lefaucheur, Jean-Pascal; Antal, Andrea; Ahdab, Rechdi; Ciampi de Andrade, Daniel; Fregni, Felipe; Khedr, Eman M; Nitsche, Michael; Paulus, Walter

    2008-10-01

    Chronic pain resulting from injury of the peripheral or central nervous system may be associated with a significant dysfunction of extensive neural networks. Noninvasive stimulation techniques, such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) may be suitable to treat chronic pain as they can act on these networks by modulating neural activities not only in the stimulated area, but also in remote regions that are interconnected to the site of stimulation. Motor cortex was the first cortical target that was proved to be efficacious in chronic pain treatment. At present, significant analgesic effects were also shown to occur after the stimulation of other cortical targets (including prefrontal and parietal areas) in acute provoked pain, chronic neuropathic pain, fibromyalgia, or visceral pain. Therapeutic applications of rTMS in pain syndromes are limited by the short duration of the induced effects, but prolonged pain relief can be obtained by repeating rTMS sessions every day for several weeks. Recent tDCS studies also showed some effects on various types of chronic pain. We review the evidence to date of these two techniques of noninvasive brain stimulation for the treatment of pain.

  17. Ligand photo-isomerization triggers conformational changes in iGluR2 ligand binding domain.

    Directory of Open Access Journals (Sweden)

    Tino Wolter

    Full Text Available Neurological glutamate receptors bind a variety of artificial ligands, both agonistic and antagonistic, in addition to glutamate. Studying their small molecule binding properties increases our understanding of the central nervous system and a variety of associated pathologies. The large, oligomeric multidomain membrane protein contains a large and flexible ligand binding domains which undergoes large conformational changes upon binding different ligands. A recent application of glutamate receptors is their activation or inhibition via photo-switchable ligands, making them key systems in the emerging field of optochemical genetics. In this work, we present a theoretical study on the binding mode and complex stability of a novel photo-switchable ligand, ATA-3, which reversibly binds to glutamate receptors ligand binding domains (LBDs. We propose two possible binding modes for this ligand based on flexible ligand docking calculations and show one of them to be analogues to the binding mode of a similar ligand, 2-BnTetAMPA. In long MD simulations, it was observed that transitions between both binding poses involve breaking and reforming the T686-E402 protein hydrogen bond. Simulating the ligand photo-isomerization process shows that the two possible configurations of the ligand azo-group have markedly different complex stabilities and equilibrium binding modes. A strong but slow protein response is observed after ligand configuration changes. This provides a microscopic foundation for the observed difference in ligand activity upon light-switching.

  18. Measurement of protein-ligand complex formation.

    Science.gov (United States)

    Lowe, Peter N; Vaughan, Cara K; Daviter, Tina

    2013-01-01

    Experimental approaches to detect, measure, and quantify protein-ligand binding, along with their theoretical bases, are described. A range of methods for detection of protein-ligand interactions is summarized. Specific protocols are provided for a nonequilibrium procedure pull-down assay, for an equilibrium direct binding method and its modification into a competition-based measurement and for steady-state measurements based on the effects of ligands on enzyme catalysis.

  19. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura : a double-blind randomised controlled trial

    NARCIS (Netherlands)

    Kuter, David J.; Bussel, James B.; Lyons, Roger M.; Pullarkat, Vinod; Gernsheimer, Terry B.; Senecal, Francis M.; Aledort, Louis M.; George, James N.; Kessler, Craig M.; Sanz, Miguel A.; Liebman, Howard A.; Slovick, Frank T.; de Wolf, J. Th M.; Bourgeois, Emmanuelle; Guthrie, Troy H.; Newland, Adrian; Wasser, Jeffrey S.; Hamburg, Solomon I.; Grande, Carlos; Lefrere, Francois; Lichtin, Alan Eli; Tarantino, Michael D.; Terebelo, Howard R.; Viallard, Jean-Francois; Cuevas, Francis J.; Go, Ronald S.; Henry, David H.; Redner, Robert L.; Rice, Lawrence; Schipperus, Martin R.; Guo, D. Matthew; Nichol, Janet L.

    2008-01-01

    Background Chronic immune thrombocytopenic purpura (ITP) is characterised by accelerated platelet destruction and decreased platelet production. Short-term administration of the thrombopoiesis-stimulating protein, romiplostim, has been shown to increase platelet counts in most patients with chronic

  20. Chronic Pancreatitis in Children

    Science.gov (United States)

    ... Information > Children/Pediatric > Chronic Pancreatitis in Children test Chronic Pancreatitis in Children What symptoms would my child ... pancreatitis will develop diabetes in adolescence. Who gets chronic pancreatitis? Those at risk for chronic pancreatitis are ...

  1. Chronic Beryllium Disease

    Science.gov (United States)

    ... Science Education & Training Home Conditions Chronic Beryllium Disease Chronic Beryllium Disease Make an Appointment Find a Doctor ... MD, MSPH, FCCP (February 01, 2016) What is chronic beryllium disease (CBD)? Chronic beryllium disease (CBD) is ...

  2. Chronic motor tic disorder

    Science.gov (United States)

    Chronic vocal tic disorder; Tic - chronic motor tic disorder ... Chronic motor tic disorder is more common than Tourette syndrome . Chronic tics may be forms of Tourette syndrome. Tics usually start ...

  3. Chronic Pelvic Pain

    Science.gov (United States)

    ... Education & Events Advocacy For Patients About ACOG Chronic Pelvic Pain Home For Patients Search FAQs Chronic Pelvic Pain ... Pelvic Pain FAQ099, August 2011 PDF Format Chronic Pelvic Pain Gynecologic Problems What is chronic pelvic pain? What ...

  4. Evaluation of intradural stimulation efficiency and selectivity in a computational model of spinal cord stimulation.

    Directory of Open Access Journals (Sweden)

    Bryan Howell

    Full Text Available Spinal cord stimulation (SCS is an alternative or adjunct therapy to treat chronic pain, a prevalent and clinically challenging condition. Although SCS has substantial clinical success, the therapy is still prone to failures, including lead breakage, lead migration, and poor pain relief. The goal of this study was to develop a computational model of SCS and use the model to compare activation of neural elements during intradural and extradural electrode placement. We constructed five patient-specific models of SCS. Stimulation thresholds predicted by the model were compared to stimulation thresholds measured intraoperatively, and we used these models to quantify the efficiency and selectivity of intradural and extradural SCS. Intradural placement dramatically increased stimulation efficiency and reduced the power required to stimulate the dorsal columns by more than 90%. Intradural placement also increased selectivity, allowing activation of a greater proportion of dorsal column fibers before spread of activation to dorsal root fibers, as well as more selective activation of individual dermatomes at different lateral deviations from the midline. Further, the results suggest that current electrode designs used for extradural SCS are not optimal for intradural SCS, and a novel azimuthal tripolar design increased stimulation selectivity, even beyond that achieved with an intradural paddle array. Increased stimulation efficiency is expected to increase the battery life of implantable pulse generators, increase the recharge interval of rechargeable implantable pulse generators, and potentially reduce stimulator volume. The greater selectivity of intradural stimulation may improve the success rate of SCS by mitigating the sensitivity of pain relief to malpositioning of the electrode. The outcome of this effort is a better quantitative understanding of how intradural electrode placement can potentially increase the selectivity and efficiency of SCS

  5. Chronic thyroiditis (Hashimoto disease)

    Science.gov (United States)

    Hashimoto thyroiditis; Chronic lymphocytic thyroiditis; Autoimmune thyroiditis; Chronic autoimmune thyroiditis; Lymphadenoid goiter - Hashimoto; Hypothyroidism - Hashimoto; Type 2 polyglandular autoimmune ...

  6. Stimulate your creativity

    Energy Technology Data Exchange (ETDEWEB)

    Raudsepp, E.

    1983-02-01

    Aids in idea stimulation and problem solving are presented. The forced relation technique forces random words together to stimulate thought. This can be done by the catalog method or by listing characteristics and alternatives until a novel idea occurs. A checklist designed for mathematical problem solving is given. The forms of questioning it provides include understanding the unknown and finding a connection between the data and the unknown. A vice-versa checklist, where consideration of the opposite encourages new ideas, is suggested. A self-questioning attitude is necessary for problem-solving. A word stimulation by checklist is also suggested.

  7. Uso de la estimulación espinal en pacientes con dolor crónico intratable en la Clínica del Dolor del C.M.N "20 de Noviembre" del ISSSTE: Nuestra experiencia Use of the Spinal Cord Stimulation in patients with severe chronic pain in the C.M.N "20 of November" Pain Unit: Our experience

    Directory of Open Access Journals (Sweden)

    A. A. Medina-Gutiérrez

    2008-03-01

    ón de los candidatos.Introduction and objectives: The patients with chronic intractable pain needs multimodal therapuetic approach. The spinal cord stimulation is part of the therapuetic interventions in this tipe of patients.The aim of our study is to know the utility of the spinal cord stimulation for the control of pain and its impact in the quality of life in the Pain clinic of the C.M:N. "20 de Noviembre". Methods: 31 patients with chronic intractable refractory pain and disability, measure with Visual Analogue Scale, Oswestry Questionaire for dissablity, previous to the implantaction fo the spinal cord stimulation electrode. Follow up from 3 moths up to 3 years. Statistical análisis with descriptive tests and Anova (p=0.005 SS. Results: 31 patients, mean age 53.7 years, female gender in 67.74%, male gender in 32.26%, with postlaminectomy syndrome in 67.74 % mean VAS previous to the SCS electrode implantaction of 8.3 (SD 0.877, mean inicial Oswestry índex of 31.9 (SD 3.714 equivalent to a 63.6% disability. 3 months follow up after the SCS electrode implantaction we observe a mean reduction in the VAS of 2.81, (SD 1.166 was statistical significant (p=0.003 the patients report a mean of 18.29 (SD 1.918 in the Oswestry índex (36.58% dissability. 6.45% of the patients presented minor complications after the implantaction. In 6.45% we found migration of the electrode, and 2 (6.45% presented complications related to the equipment. Discussion and conclusions: Our results are similar to the ones reported by other authors, we found that the VAS reduction was statistical significant even do the small number of patients in our study, The complications due to the impantaction are similar and between the reported ranges. We consider that the spinal cord stimulation is a good option in patients with chronic intractable pain, when a carefull sellection of candidates are made.

  8. Advanced glycation endproducts in chronic heart failure

    NARCIS (Netherlands)

    Smit, Andries J.; Hartog, Jasper W. L.; Voors, Adriaan A.; van Veldhuisen, Dirk J.; Schleicher, E; Somoza,; Shieberle, P

    2008-01-01

    Advanced glycation endproducts (AGEs) have been proposed as factors involved in the development and progression of chronic heart failure (CHF). Cross-linking by AGEs results in vascular and myocardial stiffening, which are hallmarks in the pathogenesis of CHE Additionally, stimulation of receptors b

  9. ACTH stimulation test

    Science.gov (United States)

    ... Groot LJ, de Kretser DM, et al, eds. Endocrinology: Adult and Pediatric . 7th ed. Philadelphia, PA: Elsevier Saunders; 2016:chap 102. Chernecky CC, Berger BJ. ACTH stimulation test - diagnostic. In: ... . 13th ed. Philadelphia, PA: Elsevier Saunders; 2016:chap ...

  10. Geothermal Well Stimulation

    Energy Technology Data Exchange (ETDEWEB)

    Campbell, D. A.; Morris, C. W.; Sinclair, A. R.; Hanold, R. J.; Vetter, O. J.

    1981-03-01

    The stimulation of geothermal wells presents some new and challenging problems. Formation temperatures in the 300-600 F range can be expected. The behavior of stimulation fluids, frac proppants, and equipment at these temperatures in a hostile brine environment must be carefully evaluated before performance expectations can be determined. In order to avoid possible damage to the producing horizon of the formation, high temperature chemical compatibility between the in situ materials and the stimulation materials must be verified. Perhaps most significant of all, in geothermal wells the required techniques must be capable of bringing about the production of very large amounts of fluid. This necessity for high flow rates represents a significant departure from conventional petroleum well stimulation and demands the creation of very high near-wellbore permeability and/or fractures with very high flow conductivity.

  11. Deep brain stimulation

    Science.gov (United States)

    ... a device called a neurostimulator to deliver electrical signals to the areas of the brain that control ... neurostimulator, which puts out the electric current. The stimulator is similar to a heart ...

  12. Beryllium-stimulated apoptosis in macrophage cell lines.

    Science.gov (United States)

    Sawyer, R T; Fadok, V A; Kittle, L A; Maier, L A; Newman, L S

    2000-08-21

    In vitro stimulation of bronchoalveolar lavage cells from patients with chronic beryllium disease (CBD) induces the production of TNF-alpha. We tested the hypothesis that beryllium (Be)-stimulated TNF-alpha might induce apoptosis in mouse and human macrophage cell lines. These cell lines were selected because they produce a range of Be-stimulated TNF-alpha. The mouse macrophage cell line H36.12j produces high levels of Be-stimulated TNF-alpha. The mouse macrophage cell line P388D.1 produces low, constitutive, levels of TNF-alpha and does not up-regulate Be-stimulated TNF-alpha production. The DEOHS-1 human CBD macrophage cell line does not produce constitutive or Be-stimulated TNF-alpha. Apoptosis was determined by microscopic observation of propidium iodide stained fragmented nuclei in unstimulated and BeSO(4)-stimulated macrophage cell lines. BeSO(4) induced apoptosis in all macrophage cell lines tested. Beryllium-stimulated apoptosis was dose-responsive and maximal after 24 h of exposure to 100 microM BeSO(4). In contrast, unstimulated and Al(2)(SO(4))(3)-stimulated macrophage cell lines did not undergo apoptosis. The general caspase inhibitor BD-fmk inhibited Be-stimulated macrophage cell line apoptosis at concentrations above 50 microM. Our data show that Be-stimulated macrophage cell line apoptosis was caspase-dependent and not solely dependent on Be-stimulated TNF-alpha levels. We speculate that the release of Be-antigen from apoptotic macrophages may serve to re-introduce Be material back into the lung microenvironment, make it available for uptake by new macrophages, and thereby amplify Be-stimulated cytokine production, promoting ongoing inflammation and granuloma maintenance in CBD.

  13. Rhodium olefin complexes of diiminate type ligands

    NARCIS (Netherlands)

    Willems, Sander Theodorus Hermanus

    2003-01-01

    The mono-anionic beta-diiminate ligand (ArNC(CH3)CHC(CH3)NAr) on several previous occasions proved useful in stabilising low coordination numbers for both early and late transition metals. In this thesis the reactivity of the rhodium olefin complexes of one of these beta-diiminate ligands (Ar = 2,6-

  14. Ligand sphere conversions in terminal carbide complexes

    DEFF Research Database (Denmark)

    Morsing, Thorbjørn Juul; Reinholdt, Anders; Sauer, Stephan P. A.

    2016-01-01

    Metathesis is introduced as a preparative route to terminal carbide complexes. The chloride ligands of the terminal carbide complex [RuC(Cl)2(PCy3)2] (RuC) can be exchanged, paving the way for a systematic variation of the ligand sphere. A series of substituted complexes, including the first exam...

  15. Flexible Ligand Docking Using Evolutionary Algorithms

    DEFF Research Database (Denmark)

    Thomsen, Rene

    2003-01-01

    The docking of ligands to proteins can be formulated as a computational problem where the task is to find the most favorable energetic conformation among the large space of possible protein–ligand complexes. Stochastic search methods such as evolutionary algorithms (EAs) can be used to sample large...

  16. Production, purification, and characterization of scFv TNF ligand fusion proteins.

    Science.gov (United States)

    Fick, Andrea; Wyzgol, Agnes; Wajant, Harald

    2012-01-01

    Single-chain variable fragments (scFvs) specific for tumor-associated cell surface antigens are the most broadly used reagents to direct therapeutic or diagnostic effector molecules, such as toxins, radioisotopes, and CD3-stimulating scFvs, to tumors. One novel class of effector molecules that can be targeted to tumors by scFvs are ligands of the tumor necrosis factor (TNF) family. Typically, these molecules have apoptosis inducing and/or immune stimulating properties and are therefore highly attractive for cancer treatment. N-terminal fusion of scFvs does not interfere with the receptor binding capabilities of TNF ligands and thus allows the straightforward generation of scFv TNF ligand fusion proteins. We report here a protocol for the purification of eukaryotically produced scFv TNF ligand fusion proteins based on affinity chromatography on anti-Flag agarose and further describe assays for the determination of the targeting index of this type of scFv-targeted proteins.

  17. Ligand binding mechanics of maltose binding protein.

    Science.gov (United States)

    Bertz, Morten; Rief, Matthias

    2009-11-13

    In the past decade, single-molecule force spectroscopy has provided new insights into the key interactions stabilizing folded proteins. A few recent studies probing the effects of ligand binding on mechanical protein stability have come to quite different conclusions. While some proteins seem to be stabilized considerably by a bound ligand, others appear to be unaffected. Since force acts as a vector in space, it is conceivable that mechanical stabilization by ligand binding is dependent on the direction of force application. In this study, we vary the direction of the force to investigate the effect of ligand binding on the stability of maltose binding protein (MBP). MBP consists of two lobes connected by a hinge region that move from an open to a closed conformation when the ligand maltose binds. Previous mechanical experiments, where load was applied to the N and C termini, have demonstrated that MBP is built up of four building blocks (unfoldons) that sequentially detach from the folded structure. In this study, we design the pulling direction so that force application moves the two MBP lobes apart along the hinge axis. Mechanical unfolding in this geometry proceeds via an intermediate state whose boundaries coincide with previously reported MBP unfoldons. We find that in contrast to N-C-terminal pulling experiments, the mechanical stability of MBP is increased by ligand binding when load is applied to the two lobes and force breaks the protein-ligand interactions directly. Contour length measurements indicate that MBP is forced into an open conformation before unfolding even if ligand is bound. Using mutagenesis experiments, we demonstrate that the mechanical stabilization effect is due to only a few key interactions of the protein with its ligand. This work illustrates how varying the direction of the applied force allows revealing important details about the ligand binding mechanics of a large protein.

  18. Spinal cord stimulation: Background and clinical application

    DEFF Research Database (Denmark)

    Meier, Kaare

    2014-01-01

    Background Spinal cord stimulation (SCS) is a surgical treatment for chronic neuropathic pain refractory to conventional treatment. SCS treatment consists of one or more leads implanted in the epidural space of the spinal canal, connected to an implantable pulse generator (IPG). Each lead carries...... for the treatment include pregnancy, coagulopathy, severe addiction to psychoactive substances, and lack of ability to cooperate (e.g. due to active psychosis or cognitive impairment). Most common complications to the treatment include lead migration, lead breakage, infection, pain over the implant, and dural...... is described in detail and illustrated with a series of intraoperative pictures. Finally, indications for SCS are discussed along with some of the controversies surrounding the therapy. Implications The reader is presented with a broad overview of spinal cord stimulation, including the historical...

  19. Non-Ligand-Induced Dimerization is Sufficient to Initiate the Signalling and Endocytosis of EGF Receptor

    Directory of Open Access Journals (Sweden)

    George Kourouniotis

    2016-07-01

    Full Text Available The binding of epidermal growth factor (EGF to EGF receptor (EGFR stimulates cell mitogenesis and survival through various signalling cascades. EGF also stimulates rapid EGFR endocytosis and its eventual degradation in lysosomes. The immediate events induced by ligand binding include receptor dimerization, activation of intrinsic tyrosine kinase and autophosphorylation. However, in spite of intensified efforts, the results regarding the roles of these events in EGFR signalling and internalization is still very controversial. In this study, we constructed a chimeric EGFR by replacing its extracellular domain with leucine zipper (LZ and tagged a green fluorescent protein (GFP at its C-terminus. We showed that the chimeric LZ-EGFR-GFP was constitutively dimerized. The LZ-EGFR-GFP dimer autophosphorylated each of its five well-defined C-terminal tyrosine residues as the ligand-induced EGFR dimer does. Phosphorylated LZ-EGFR-GFP was localized to both the plasma membrane and endosomes, suggesting it is capable of endocytosis. We also showed that LZ-EGFR-GFP activated major signalling proteins including Src homology collagen-like (Shc, extracellular signal-regulated kinase (ERK and Akt. Moreover, LZ-EGFR-GFP was able to stimulate cell proliferation. These results indicate that non-ligand induced dimerization is sufficient to activate EGFR and initiate cell signalling and EGFR endocytosis. We conclude that receptor dimerization is a critical event in EGF-induced cell signalling and EGFR endocytosis.

  20. Multimodal pain stimulation of the gastrointestinal tract

    Institute of Scientific and Technical Information of China (English)

    Asbjφrn Mohr Drewes; Hans Gregersen

    2006-01-01

    Understanding and characterization of pain and other sensory symptoms are among the most important issues in the diagnosis and assessment of patient with gastrointestinal disorders. Methods to evoke and assess experimental pain have recently developed into a new area with the possibility for multimodal stimulation (e.g.,electrical, mechanical, thermal and chemical stimulation)of different nerves and pain pathways in the human gut. Such methods mimic to a high degree the pain experienced in the clinic. Multimodal pain methods have increased our basic understanding of different peripheral receptors in the gut in health and disease. Together with advanced muscle analysis, the methods have increased our understanding of receptors sensitive to mechanical,chemical and temperature stimuli in diseases, such as systemic sclerosis and diabetes. The methods can also be used to unravel central pain mechanisms, such as those involved in allodynia, hyperalgesia and referred pain. Abnormalities in central pain mechanisms are often seen in patients with chronic gut pain and hence methods relying on multimodal pain stimulation may help to understand the symptoms in these patients.Sex differences have been observed in several diseases of the gut, and differences in central pain processing between males and females have been hypothesized using multimodal pain stimulations. Finally, multimodal methods have recently been used to gain more insight into the effect of drugs against pain in the GI tract.Hence, the multimodal methods undoubtedly represents a major step forward in the future characterization and treatment of patients with various diseases of the gut.

  1. Chronic Stimulation-Induced Changes in the Rodent Thyroarytenoid Muscle

    Science.gov (United States)

    McMullen, Colleen A.; Butterfield, Timothy A.; Dietrich, Maria; Andreatta, Richard D.; Andrade, Francisco H.; Fry, Lisa; Stemple, Joseph C.

    2011-01-01

    Purpose: Therapies for certain voice disorders purport principles of skeletal muscle rehabilitation to increase muscle mass, strength, and endurance. However, applicability of limb muscle rehabilitation to the laryngeal muscles has not been tested. In this study, the authors examined the feasibility of the rat thyroarytenoid muscle to remodel as a…

  2. Correcting ligands, metabolites, and pathways

    Directory of Open Access Journals (Sweden)

    Vriend Gert

    2006-11-01

    Full Text Available Abstract Background A wide range of research areas in bioinformatics, molecular biology and medicinal chemistry require precise chemical structure information about molecules and reactions, e.g. drug design, ligand docking, metabolic network reconstruction, and systems biology. Most available databases, however, treat chemical structures more as illustrations than as a datafield in its own right. Lack of chemical accuracy impedes progress in the areas mentioned above. We present a database of metabolites called BioMeta that augments the existing pathway databases by explicitly assessing the validity, correctness, and completeness of chemical structure and reaction information. Description The main bulk of the data in BioMeta were obtained from the KEGG Ligand database. We developed a tool for chemical structure validation which assesses the chemical validity and stereochemical completeness of a molecule description. The validation tool was used to examine the compounds in BioMeta, showing that a relatively small number of compounds had an incorrect constitution (connectivity only, not considering stereochemistry and that a considerable number (about one third had incomplete or even incorrect stereochemistry. We made a large effort to correct the errors and to complete the structural descriptions. A total of 1468 structures were corrected and/or completed. We also established the reaction balance of the reactions in BioMeta and corrected 55% of the unbalanced (stoichiometrically incorrect reactions in an automatic procedure. The BioMeta database was implemented in PostgreSQL and provided with a web-based interface. Conclusion We demonstrate that the validation of metabolite structures and reactions is a feasible and worthwhile undertaking, and that the validation results can be used to trigger corrections and improvements to BioMeta, our metabolite database. BioMeta provides some tools for rational drug design, reaction searches, and

  3. TSPO PIGA Ligands Promote Neurosteroidogenesis and Human Astrocyte Well-Being

    Directory of Open Access Journals (Sweden)

    Eleonora Da Pozzo

    2016-06-01

    Full Text Available The steroidogenic 18 kDa translocator protein (TSPO is an emerging, attractive therapeutic tool for several pathological conditions of the nervous system. Here, 13 high affinity TSPO ligands belonging to our previously described N,N-dialkyl-2-phenylindol-3-ylglyoxylamide (PIGA class were evaluated for their potential ability to affect the cellular Oxidative Metabolism Activity/Proliferation index, which is used as a measure of astrocyte well-being. The most active PIGA ligands were also assessed for steroidogenic activity in terms of pregnenolone production, and the values were related to the metabolic index in rat and human models. The results showed a positive correlation between the increase in the Oxidative Metabolism Activity/Proliferation index and the pharmacologically induced stimulation of steroidogenesis. The specific involvement of steroid molecules in mediating the metabolic effects of the PIGA ligands was demonstrated using aminoglutethimide, a specific inhibitor of the first step of steroid biosynthesis. The most promising steroidogenic PIGA ligands were the 2-naphthyl derivatives that showed a long residence time to the target, in agreement with our previous data. In conclusion, TSPO ligand-induced neurosteroidogenesis was involved in astrocyte well-being.

  4. Twiddler's syndrome in a patient with a deep brain stimulation device for generalized dystonia

    DEFF Research Database (Denmark)

    Astradsson, Arnar; Schweder, Patrick M; Joint, Carole

    2011-01-01

    Deep brain stimulation (DBS) is the technique of neurostimulation of deep brain structures for the treatment of conditions such as essential tremor, dystonia, Parkinson's disease and chronic pain syndromes. The procedure uses implanted deep brain stimulation electrodes connected to extension leads...

  5. Effects of imipramine or GABA(B) receptor ligands on the immobility, swimming and climbing in the forced swim test in rats following discontinuation of cocaine self-administration.

    Science.gov (United States)

    Frankowska, Małgorzata; Gołda, Anna; Wydra, Karolina; Gruca, Piotr; Papp, Mariusz; Filip, Małgorzata

    2010-02-10

    We tested if discontinuation of cocaine self-administration can lead to the development of depressive-like symptoms in the forced swim test expressed as changes in immobility, swimming and climbing behaviors in rats. A "yoked" procedure in which rats were run simultaneously in groups of three, with two rats received the passive injection of cocaine or saline, was employed. Later, we examined whether acute treatment with the classical antidepressant imipramine or GABA(B) receptor ligands could alter the increases in immobility recorded after discontinuation of self-administered cocaine. We found a significant increase (44%) in the immobility time 3 days following discontinuation of cocaine (0.5mg/kg/infusion/2h daily) self-administration for 14 days; such enhancement resembled that observed in rats following the chronic mild stress. Acute administration with imipramine (15 or 30 mg/kg), the GABA(B) receptor agonists baclofen (0.125 mg/kg) and SKF 97541 (0.005 mg/kg), the positive allosteric modulator CGP 7930 (0.3mg/kg) or the antagonist SCH 50911 (0.3mg/kg) counteracted the cocaine discontinuation-induced enhancement in the immobility time. The enhanced immobility time in rats that self-administered cocaine (but not given cocaine passively) may reflect the motivated or cognitive processes of reinforced responding of cocaine and could be a potential driver of the addiction process per se. Moreover, either blockade or stimulation of GABA(B) receptors by their ligands in very low doses attenuated the enhanced immobility time in rats after discontinuation of cocaine self-administration and these findings extend preclinical studies demonstrating the potential involvement of GABA(B) receptor ligands to reduce cocaine craving.

  6. Multicomponent mixtures for cryoprotection and ligand solubilization

    Directory of Open Access Journals (Sweden)

    Lidia Ciccone

    2015-09-01

    Full Text Available Mixed cryoprotectants have been developed for the solubilization of ligands for crystallization of protein–ligand complexes and for crystal soaking. Low affinity lead compounds with poor solubility are problematic for structural studies. Complete ligand solubilization is required for co-crystallization and crystal soaking experiments to obtain interpretable electron density maps for the ligand. Mixed cryo-preserving compounds are needed prior to X-ray data collection to reduce radiation damage at synchrotron sources. Here we present dual-use mixes that act as cryoprotectants and also promote the aqueous solubility of hydrophobic ligands. Unlike glycerol that increases protein solubility and can cause crystal melting the mixed solutions of cryo-preserving compounds that include precipitants and solubilizers, allow for worry-free crystal preservation while simultaneously solubilizing relatively hydrophobic ligands, typical of ligands obtained in high-throughput screening. The effectiveness of these mixture has been confirmed on a human transthyretin crystals both during crystallization and in flash freezing of crystals.

  7. Coordinate unsaturation with fluorinated ligands

    Energy Technology Data Exchange (ETDEWEB)

    Rack, J.L.; Hurlburt, P.K.; Anderson, O.P.; Strauss, S.H. [Colorado State Univ., Ft. Collins, CO (United States)

    1993-12-31

    The preparation and characterization of Zn(OTeF{sub 5}){sub 2} has resulted in a model compound with which to explore the concept of coordinative unsaturation. The coordination of solvents of varying donicity and dielectric constant to the Zn(II) ions in Zn(OTeF{sub 5}){sub 2} was studied by vapor phase monometry, NMR and IR spectroscopy, conductimetry, and X-Ray crystallography. The structures of [Zn(C{sub 6}H{sub 5}NO{sub 2}){sub 2}(OTeF{sub 5})2]2 and Zn(C{sub 6}H{sub 5}NO{sub 2}){sub 3}(OTEF{sub 5}){sub 2} demonstrate the electronic flexibility of some weakly coordinating solvents in that nitrobenzene can function as either an {eta}{sup 1}O or {eta}{sup 2}O,O`-ligand. The dependence of the number of bound solvent molecules and the degree of OTeF{sub 5}{minus} dissociation on solvent donor number and dielectric constant will be presented.

  8. The chronic kidney disease - Mineral bone disorder (CKD-MBD): Advances in pathophysiology.

    Science.gov (United States)

    Hruska, Keith A; Sugatani, Toshifumi; Agapova, Olga; Fang, Yifu

    2017-01-21

    The causes of excess cardiovascular mortality associated with chronic kidney disease (CKD) have been attributed in part to the CKD-mineral bone disorder syndrome (CKD-MBD), wherein, novel cardiovascular risk factors have been identified. New advances in the causes of the CKD-MBD are discussed in this review. They demonstrate that repair and disease processes in the kidneys release factors to the circulation that cause the systemic complications of CKD. The discovery of WNT inhibitors, especially Dickkopf 1 (Dkk1), produced during renal repair as participating in the pathogenesis of the vascular and skeletal components of the CKD-MBD implied that additional pathogenic factors are critical. This lead to the discovery that activin A is a second renal repair factor circulating in increased levels during CKD. Activin A derives from peritubular myofibroblasts of diseased kidneys, wherein it stimulates fibrosis, and decreases tubular klotho expression. Activin A binds to the type 2 activin A receptor, ActRIIA, which is variably affected by CKD in the vasculature. In diabetic/atherosclerotic aortas, specifically in vascular smooth muscle cells (VSMC), ActRIIA signaling is inhibited and contributes to CKD induced VSMC dedifferentiation, osteogenic transition and neointimal atherosclerotic calcification. In nondiabetic/nonatherosclerotic aortas, CKD increases VSMC ActRIIA signaling, and vascular fibroblast signaling causing the latter to undergo osteogenic transition and stimulate vascular calcification. In both vascular situations, a ligand trap for ActRIIA prevented vascular calcification. In the skeleton, activin A is responsible for CKD stimulation of osteoclastogenesis and bone remodeling increasing bone turnover. These studies demonstrate that circulating renal repair and injury factors are causal of the CKD-MBD and CKD associated cardiovascular disease.

  9. PD-1/PD-L1 signal pathway participates in HCV F protein-induced T cell dysfunction in chronic HCV infection.

    Science.gov (United States)

    Xiao, Wen; Jiang, Long Feng; Deng, Xiao Zhao; Zhu, Dan Yan; Pei, Jia Ping; Xu, Mao Lei; Li, Bing Jun; Wang, Chang Jun; Zhang, Jing Hai; Zhang, Qi; Zhou, Zhen Xian; Ding, Wei Liang; Xu, Xiao Dong; Yue, Ming

    2016-04-01

    Programmed cell death-1/programmed cell death-1 ligand 1 (PD-1/PD-L1) inhibitory signal pathway has been verified to be involved in the establishment of persistent viral infections. Blockade of PD-1/PD-L1 engagement to reinvigorate T cell activity is supposed to be a potential therapeutic scheme. Studies have verified the participation of PD-1/PD-L1 in hepatitis C virus (HCV) core protein-regulated immune response. To determine the roles of PD-1/PD-L1 signal pathway in HCV F protein-induced immunoreaction in chronic HCV infection, variations in T cells were examined. The results showed that PD-1 expression on CD8(+) and CD4(+) T cells was increased with HCV F stimulation in both chronic HCV patients and healthy controls, and could be reduced partly by PD-1/PD-L1 blocking. Additionally, by PD-1/PD-L1 blocking, HCV F-induced inhibition of T cell proliferation and promotion of cellular apoptosis were partly or even totally recovered. Furthermore, levels of both Th1 and Th2 cytokines were elevated in the presence of anti-PD-L1 antibody. All these results indicated that PD-1/PD-L1 signal pathway also participates in HCV F protein-induced immunoregulation. PD-1/PD-L1 blocking plays important roles in the restoration of effective functionality of the impaired T cells in chronic HCV patients.

  10. New York Canyon Stimulation

    Energy Technology Data Exchange (ETDEWEB)

    Raemy, Bernard

    2012-06-21

    The New York Canyon Stimulation Project was to demonstrate the commercial application of Enhanced Geothermal System techniques in Buena Vista Valley area of Pershing County, Nevada. From October 2009 to early 2012, TGP Development Company aggressively implemented Phase I of Pre-Stimulation and Site/Wellbore readiness. This included: geological studies; water studies and analyses and procurement of initial permits for drilling. Oversubscription of water rights and lack of water needed for implementation of EGS were identified and remained primary obstacles. Despite extended efforts to find alternative solutions, the water supply circumstances could not be overcome and led TGP to determine a "No Go" decision and initiate project termination in April 2012.

  11. Mechanisms of impaired gallbladder contractile response in chronic acalculous cholecystitis.

    Science.gov (United States)

    Merg, Anders R; Kalinowski, Scott E; Hinkhouse, Marilyn M; Mitros, Frank A; Ephgrave, Kimberly S; Cullen, Joseph J

    2002-01-01

    The mechanisms involved in the impaired gallbladder contractile response in chronic acalculous cholecystitis are unknown. To determine the mechanisms that may lead to impaired gallbladder emptying in chronic acalculous cholecystitis, gallbladder specimens removed during hepatic resection (controls) and after cholecystectomy for chronic acalculous cholecystitis were attached to force transducers and placed in tissue baths with oxygenated Krebs solution. Electrical field stimulation (EFS) (1 to 10 Hz, 0.1 msec, 70 V) or the contractile agonists, CCK-8 (10(-9) to 10(-5)) or K(+) (80 mmol/L), were placed separately in the tissue baths and changes in tension were determined. Patients with chronic acalculous cholecystitis had a mean gallbladder ejection fraction of 12% +/- 4%. Pathologic examination of all gallbladders removed for chronic acalculous cholecystitis revealed chronic cholecystitis. Spontaneous contractile activity was present in gallbladder strips in 83% of control specimens but only 29% of gallbladder strips from patients with chronic acalculous cholecystitis (P < 0.05 vs. controls). CCK-8 contractions were decreased by 54% and EFS-stimulated contractions were decreased by 50% in the presence of chronic acalculous cholecystitis (P < 0.05 vs. controls). K(+)-induced contractions were similar between control and chronic acalculous cholecystitis gallbladder strips. The impaired gallbladder emptying in chronic acalculous cholecystitis appears to be due to diminished spontaneous contractile activity and decreased contractile responsiveness to both CCK and EFS.

  12. Magnetic Stimulation and Epilepsy

    Science.gov (United States)

    2013-10-14

    investigated using behavioral recording and electroencephalographic (EEG) recording. The results (Figures 1~7) obtained have been submitted to Epilepsia ...Magnetic Stimulation on Penicillin-Induced Seizures in Rats. Epilepsia (submitted). * corresponding author. IV. OTHER CHANGES N/A V. FUTURE PLANS

  13. Chronic inflammatory demyelinating polyneuropathy

    Science.gov (United States)

    Polyneuropathy - chronic inflammatory; CIDP; Chronic inflammatory polyneuropathy; Guillain-Barré - CIDP ... Health care providers also consider CIDP as the chronic form of Guillain-Barré syndrome. The specific triggers ...

  14. Dealing with chronic cancer

    Science.gov (United States)

    ... medlineplus.gov/ency/patientinstructions/000933.htm Dealing with chronic cancer To use the sharing features on this ... be controlled for a period of time. Controlling Chronic Cancer When you have a chronic cancer, the ...

  15. Spinal Cord Stimulation

    DEFF Research Database (Denmark)

    Meier, Kaare

    2014-01-01

    pain after failed back surgery syndrome (FBSS)(4), pain due to peripheral nerve injury, stump pain(5), peripheral vascular disease(6) and diabetic neuropathy(7,8); whereas phantom pain(9), postherpetic neuralgia(10), chronic visceral pain(11), and pain after partial spinal cord injury(12) remain more...

  16. Secretin stimulation test

    Science.gov (United States)

    ... done to check the digestive function of the pancreas. The following diseases may prevent the pancreas from working properly: Chronic ... Related MedlinePlus Health Topics Cystic Fibrosis Pancreatic Cancer Pancreatic Diseases Browse the Encyclopedia A.D.A.M., Inc. ...

  17. Ligand inducible assembly of a DNA tetrahedron.

    Science.gov (United States)

    Dohno, Chikara; Atsumi, Hiroshi; Nakatani, Kazuhiko

    2011-03-28

    Here we show that a small synthetic ligand can be used as a key building component for DNA nanofabrication. Using naphthyridinecarbamate dimer (NCD) as a molecular glue for DNA hybridization, we demonstrate NCD-triggered formation of a DNA tetrahedron.

  18. [New insights on hepcidin in anemia of chronic disease].

    Science.gov (United States)

    Wang, Feng-Dan; Zhou, Dao-Bin

    2009-12-01

    Anemia of chronic disease is normocytic and normochromic. One of the mechanisms is misbalance of iron metabolism. Hepcidin, a kind of protein secreted by liver is considered to be the hormone regulating iron metabolism. It binds to ferroportin and induces the latter one's internalization. Thus, iron transportation from iron storage cells to serum is reduced. Cytokines are elevated in chronic disease. They stimulate hepcidin expression in liver through JAK2/STAT3 pathway. As a result, iron absorption and reabsorption is blocked, which leads to the misbalance of iron metabolism in anemia of chronic disease. In this article, the hepcidin and its relation to iron metabolism and anemia in chronic disease are reviewed.

  19. Nye ligander for Pt-MOF strukturer

    OpenAIRE

    Jakobsen, Søren

    2006-01-01

    Metalorganic frameworks (MOFs) are a new type of compounds which have been intensely investigated during the last few years. They have been synthesized using a wide variety of metals and ligands constructing a vast number of 1, 2 and 3 dimensional structures, some of which possess zeolite-type physics and chemistry. Our approach is to incorporate platinum metal sites into the structures making them bimetallic and potentially catalytically active. Therefore a number of N-N-type ligands (dii...

  20. Designer TGFβ superfamily ligands with diversified functionality.

    Directory of Open Access Journals (Sweden)

    George P Allendorph

    Full Text Available Transforming Growth Factor--beta (TGFβ superfamily ligands, including Activins, Growth and Differentiation Factors (GDFs, and Bone Morphogenetic Proteins (BMPs, are excellent targets for protein-based therapeutics because of their pervasiveness in numerous developmental and cellular processes. We developed a strategy termed RASCH (Random Assembly of Segmental Chimera and Heteromer, to engineer chemically-refoldable TGFβ superfamily ligands with unique signaling properties. One of these engineered ligands, AB208, created from Activin-βA and BMP-2 sequences, exhibits the refolding characteristics of BMP-2 while possessing Activin-like signaling attributes. Further, we find several additional ligands, AB204, AB211, and AB215, which initiate the intracellular Smad1-mediated signaling pathways more strongly than BMP-2 but show no sensitivity to the natural BMP antagonist Noggin unlike natural BMP-2. In another design, incorporation of a short N-terminal segment from BMP-2 was sufficient to enable chemical refolding of BMP-9, without which was never produced nor refolded. Our studies show that the RASCH strategy enables us to expand the functional repertoire of TGFβ superfamily ligands through development of novel chimeric TGFβ ligands with diverse biological and clinical values.

  1. RAGE: a new frontier in chronic airways disease.

    Science.gov (United States)

    Sukkar, Maria B; Ullah, Md Ashik; Gan, Wan Jun; Wark, Peter A B; Chung, Kian Fan; Hughes, J Margaret; Armour, Carol L; Phipps, Simon

    2012-11-01

    Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous inflammatory disorders of the respiratory tract characterized by airflow obstruction. It is now clear that the environmental factors that drive airway pathology in asthma and COPD, including allergens, viruses, ozone and cigarette smoke, activate innate immune receptors known as pattern-recognition receptors, either directly or indirectly by causing the release of endogenous ligands. Thus, there is now intense research activity focused around understanding the mechanisms by which pattern-recognition receptors sustain the airway inflammatory response, and how these mechanisms might be targeted therapeutically. One pattern-recognition receptor that has recently come to attention in chronic airways disease is the receptor for advanced glycation end products (RAGE). RAGE is a member of the immunoglobulin superfamily of cell surface receptors that recognizes pathogen- and host-derived endogenous ligands to initiate the immune response to tissue injury, infection and inflammation. Although the role of RAGE in lung physiology and pathophysiology is not well understood, recent genome-wide association studies have linked RAGE gene polymorphisms with airflow obstruction. In addition, accumulating data from animal and clinical investigations reveal increased expression of RAGE and its ligands, together with reduced expression of soluble RAGE, an endogenous inhibitor of RAGE signalling, in chronic airways disease. In this review, we discuss recent studies of the ligand-RAGE axis in asthma and COPD, highlight important areas for future research and discuss how this axis might potentially be harnessed for therapeutic benefit in these conditions.

  2. Chronic mucus hypersecretion

    DEFF Research Database (Denmark)

    Harmsen, L; Thomsen, S F; Sylvan Ingebrigtsen, Truls;

    2010-01-01

    Chronic mucus hypersecretion (CMH) is a common condition in patients with chronic respiratory diseases. Little is known about the incidence, prevalence and determinants of CMH in younger individuals....

  3. Fully Flexible Docking of Medium Sized Ligand Libraries with RosettaLigand.

    Directory of Open Access Journals (Sweden)

    Samuel DeLuca

    Full Text Available RosettaLigand has been successfully used to predict binding poses in protein-small molecule complexes. However, the RosettaLigand docking protocol is comparatively slow in identifying an initial starting pose for the small molecule (ligand making it unfeasible for use in virtual High Throughput Screening (vHTS. To overcome this limitation, we developed a new sampling approach for placing the ligand in the protein binding site during the initial 'low-resolution' docking step. It combines the translational and rotational adjustments to the ligand pose in a single transformation step. The new algorithm is both more accurate and more time-efficient. The docking success rate is improved by 10-15% in a benchmark set of 43 protein/ligand complexes, reducing the number of models that typically need to be generated from 1000 to 150. The average time to generate a model is reduced from 50 seconds to 10 seconds. As a result we observe an effective 30-fold speed increase, making RosettaLigand appropriate for docking medium sized ligand libraries. We demonstrate that this improved initial placement of the ligand is critical for successful prediction of an accurate binding position in the 'high-resolution' full atom refinement step.

  4. LigandRFs: random forest ensemble to identify ligand-binding residues from sequence information alone

    KAUST Repository

    Chen, Peng

    2014-12-03

    Background Protein-ligand binding is important for some proteins to perform their functions. Protein-ligand binding sites are the residues of proteins that physically bind to ligands. Despite of the recent advances in computational prediction for protein-ligand binding sites, the state-of-the-art methods search for similar, known structures of the query and predict the binding sites based on the solved structures. However, such structural information is not commonly available. Results In this paper, we propose a sequence-based approach to identify protein-ligand binding residues. We propose a combination technique to reduce the effects of different sliding residue windows in the process of encoding input feature vectors. Moreover, due to the highly imbalanced samples between the ligand-binding sites and non ligand-binding sites, we construct several balanced data sets, for each of which a random forest (RF)-based classifier is trained. The ensemble of these RF classifiers forms a sequence-based protein-ligand binding site predictor. Conclusions Experimental results on CASP9 and CASP8 data sets demonstrate that our method compares favorably with the state-of-the-art protein-ligand binding site prediction methods.

  5. 重复经颅磁刺激(rTMS)治疗慢性主观性耳鸣的短期疗效分析%The Short-term Effect Analysis of Repetitive Transcranial Magnetic Stimulation (rTMS) in Chronic Tinnitus

    Institute of Scientific and Technical Information of China (English)

    杨海弟; 郑亿庆; 区永康; 黄夏茵

    2015-01-01

    Objective Evaluate the therapeutic effect of 1-Hz repetitive transcranial magnetic stimulation (rTMS) on tinnitus. Methods 46 chronic tinnitus patients were treated with repetitive transcranial magnetic stimulation for two weeks and the therapeutic effects were assessed afterward. Results rTMS treatment could improve tinnitus obviously. The overall effec⁃tive rate is 63.1%in subjective tinnitus, The effective rate is higher in decompensated tinnitus(THI≥40) than compensatory tinnitus (THI<40) (77%vs 45%;P<0.001), The THI score of tinnitus patients before and after treatment were r 51.8 ± 23.5 and 37 ± 18.8;espectively (t=5.94, p<0.001), VAS were 6.3 ± 2.4 and 4.9 ± 1.8;(t=5.27, p<0.01.) The difference of the changes of THI between decompensated tinnitus and compensated tinnitus group after rTMS treatment was 19.4 ± 8.5 (df=42, T=4.95, P<0.001). Conclusions rTMS could improve tinnitus, especially for decompensated tinnitus patients.%目的:采取1Hz低频重复经颅磁刺激(rTMS)治疗慢性主观性耳鸣并评价其治疗效果。方法对慢性主观性耳鸣患者46例行1Hz低频rTMS连续治疗2周,治疗前后分别行耳鸣残疾量表评分(THI)评分及主观疗效评估。结果 rTMS对耳鸣治疗有明显效果,对主观耳鸣症状总体有效率为63.1%,其中失代偿性耳鸣(THI≥40)的有效率明显高于代偿性耳鸣(THI<40)(77%vs 45%;P<0.001),耳鸣患者治疗前后THI为(51.8±23.5 vs 37.0±18.8;t=5.94,p<0.001), VAS为(6.3±2.4 vs 4.9±1.8;t=5.27,p<0.01),治疗前后有统计学差异。失代偿组与代偿组耳鸣rTMS治疗后THI变化存在显著差异,两组差值为19.4±8.5(df=42,T=4.95,P<0.001)。结论 rTMS治疗耳鸣有效,可明显降低THI得分,改善耳鸣症状,特别在失代偿性耳鸣效果更明显。

  6. Estimulación eléctrica medular en pacientes con dolor crónico: evaluación de la discapacidad y la calidad de vida Spinal cord stimulation in patients with chronic pain: disability and quality of life evaluation

    Directory of Open Access Journals (Sweden)

    A. Jiménez-Ramos

    2010-04-01

    Full Text Available Introducción: La estimulación eléctrica medular (EEM definitiva es un procedimiento para pacientes con dolor crónico de predominio neuropático. El objetivo fue analizar la respuesta a la EEM en el dolor y los índices de calidad de vida. Material y métodos: Se trata de un estudio de serie de pacientes retrospectiva, longitudinal y descriptiva, en el que se incluyó a 40 pacientes de ambos sexos, con edades entre los 18 y los 85 años, a los que se implantó un sistema de EEM. Se evaluó la intensidad del dolor mediante la escala visual analógica (EVA previamente, al mes y a los 6 meses de implantado. Se aplicó el índice de discapacidad de Oswestry y el Fast-Espiditest previo a la implantación y a los 6 meses. Se utilizó estadística descriptiva, con prueba de ANOVA, para lo que se consideró como significativo un valor de p Introduction: Spinal Cord Stimulation (SCS is a procedure for patients with chronic intractable pain of neuropathic predominance. The objective was to evaluate the disability and quality of life in patients with SCS. Material and methods: A retrospective, descriptive and longitudinal research study with 40 male and female patients from 30 to 70 years of age with a SCS system. The intensity of pain was assessed by means of Visual Analogue Scale (VAS, 1 month before and at 6 months after the implant. The Oswestry and the Fast-Espiditest disability indexes were used before and 6 months after the implantation. The statistical analysis of the results was performed using the ANOVA test using a p < 0.05 as significant. Results: A total of 88% of patients had neuropathic pain with an aetiological diagnosis of failed back surgery syndrome (67.5%. The baseline VAS score was 8.8 ± 1.1, at 1 month 3.5 ± 2.3 and 3.9 ± 2.0 at the 6th month (p < 0.001. The initial Oswestry Index was 65.5 ± 8.5 and the final one 43.8 ± 11.4 (p < 0.001. Using the Fast-Espiditest 10% of patients had moderate pain and 90% had intense pain at

  7. Electrophysiologic study of chronic inflammatory demyelinating polyneuropathy by using segmental stimulation in the median nerve and ulnar nerve%正中神经和尺神经分段刺激在慢性炎性脱髓鞘性多发性神经病中的电生理研究

    Institute of Scientific and Technical Information of China (English)

    王晋荣; 王进华; 叶憬; 杨伟丽

    2013-01-01

    目的 探讨运动神经传导速度(MCV)、复合肌肉动作电位(CMAP)与肌力减退的关系和传导阻滞(CB)在慢性炎性脱髓鞘性多发性神经病(chronic inflammatory demyelinating polyradiculoneuritis,CIDP)中的表现特点.方法 30例CIDP患者在进行常规MCV、远端潜伏期(DML)、F波、感觉神经传导速度(SCV)、肌电图(EMG)测定的基础上,在正中神经采用由远到近的“腕-肘-腋-Erb's点”4点3段刺激,尺神经采用由远到近的“腕-肘下-肘上-腋-Erb's点”5点4段刺激,记录各段刺激后CMAP各参数及MCV的变化.结果 CMAP波幅衰减、面积衰减、时程增加以及MCV减慢与临床肌力减退无相关性,dCMAP波幅与上肢远端肌力呈正相关;患者中80.00%在正中神经、73.33%在尺神经发现了1个或多个节段的CB,且出现节段无明显选择性.结论 dCMAP波幅降低与CIDP患者肌力减退有相关性.在CIDP中CB出现率高,且较为弥散地在各节段中出现.%Objective To investigate the relationship between motor conduction velocity (MCV) and compound muscle action potential (CMAP) and muscle strength impairment; and to study the characteristics of conduction block (CB) in chronic inflammatory demyelinating polyneuropathy (CIDP). Methods 30 patients with CIDP formed the study population. All patients were examined by MCV, distal motor latency (DML), F wave, sensory nerve conduction velocity (SCV) and electromyography (EMG). Stimulations were perfomed at 4 sites of the median nerve from distal to proximal (wrist, elbow, axilla, Erb' s point) and 5 sites of the ulnar nerve (wrist, below elbow, above elbow, axilla, Erb' s point), while all the parameters of CMAP and MCV were recorded. Results There were no correlations between the CAMP amplitude attenuation, area, duration increase, MCV reduction and the clinical muscle strength. However, there was positive correlation between the amplitude of the dCMAP and the distal muscle strength in the upper

  8. 呼吸兴奋剂联合无创通气对慢性阻塞性肺疾病急性加重患者酸碱平衡与电解质的影响研究%The influence of respiratory stimulant joint noninvasive ventilation on acid - base balance and electrolyte of patients with chronic obstructive pulmonary diseases acute exacerbation

    Institute of Scientific and Technical Information of China (English)

    郑世珍; 王超; 徐治波

    2016-01-01

    Objective The study the influence of respiratory stimulant joint noninvasive ventilation on acid - base bal-ance and electrolyte of patients with chronic obstructive pulmonary diseases acute exacerbation(AECOPD). Methods A total of 50 patients with AECOPD were selected from January 2013 to January 2015 in the Second People's Hosppital of Chengdu, which were randomly divide into control group and observation group,25 cases in each group. Control group were treated with noninvasive ventilation, observation group were treated with noninvasive ventilation combined with respiratory stimu-lant. Compared the two groups before and after treatment arterial blood gas analysis index〔pH,partial pressure of carbon dioxide in artery(PaCO2 ),arterial partial pressure of oxygen(PaO2 )〕,electrolyte(Na + ,K + ),prevalence of metabolic alkalosis. Results Before treatment,pH,PaO2 ,PaCO2 between two groups showed no significant differences(P > 0. 05);after treat-ment,pH、PaO2 of observation group were higher than control group,PaCO2 was lower than control group(P 0. 05);after treatment,Na + of observation group was higher than control group,K + was lower than control group(P 0. 05);after treatment,pressure rate of carbon dioxide of observation group was higher than control group(P < 0. 05). Conclusion The influence of respiratory stimulant joint noninva-sive ventilation in the treatment of AECOPD easily lead to acid - base balance disorders and alkalosis,need to control the using of respiratory stimulant.%目的:探讨呼吸兴奋剂联合无创通气对慢性阻塞性肺疾病急性加重(AECOPD)患者酸碱平衡与电解质的影响。方法选取成都市第二人民医院2013年1月—2015年1月收治的 AECOPD 患者50例,随机分为对照组与观察组,各25例。对照组予以无创性通气治疗,观察组在对照组基础上予以可拉明+洛贝林治疗,两组患者治疗疗程为7d。比较两组患者治疗前后血气分析指标〔pH 值、动

  9. Efeito da estimulação elétrica nervosa transcutânea no tratamento da dor no ombro de pacientes com doença renal crônica: relato de casos Effect of transcutaneous electrical nerve stimulation in the treatment of pain in the shoulder of patients with chronic kidney disease: a two-case report

    Directory of Open Access Journals (Sweden)

    Patrícia Ribeiro Bertoli

    2009-09-01

    Full Text Available A doença renal crônica (DRC pode causar muitas complicações clínicas associadas ao tempo de diálise. A amiloidose é uma dessas complicações e pode levar à dor no ombro, comum em pacientes com DRC. Só foram encontrados na literatura relatos de tratamento cirúrgico e/ou medicamentoso para esse tipo de dor. O objetivo aqui foi avaliar o benefício da estimulação elétrica nervosa transcutânea (TENS no tratamento da dor no ombro devida à amiloidose em pacientes com DRC. Duas pacientes foram avaliadas quatro vezes num período de três meses. Na avaliação inicial as pacientes foram orientadas e receberam um aparelho de TENS para uso domiciliar (10Hz, 150 µs, duas vezes por dia, por 40 minutos durante três meses. A dor foi avaliada utilizando-se uma escala visual analógica e o questionário de dor de Wisconsin. Os resultados mostram que o tratamento com TENS reduziu a dor no ombro em ambas as pacientes. O tratamento com a TENS pode pois ser eficaz em reduzir a dor no ombro em pacientes com DRC.Chronic kidney disease (CKD may bring about several clinical complications associated to long-term dialysis. Amyloidosis is one of such complications and may lead to shoulder pain, common among CKD patients, for which no studies could be found in literature on the use of transcutaneous electrical nerve stimulation (TENS - only surgical and medicine treatments are reported. The purpose here was to assess benefits of TENS in treating shoulder pain due to amyloidosis in patients with CKD. Two female patients were assessed four times in a three-month period. At the initial evaluation, patients were guided as to its use and given a TENS device for use at home (10 Hz, 150 µs, twice a day, for 40 minutes for three months. Pain was assessed by means of a visual analog scale and of the Wisconsin brief pain questionnaire. Results show that TENS reduced shoulder pain in both patients. Treatment with TENS may hence be effective in reducing shoulder

  10. Evidence-based pharmacological management of chronic neuropathic pain

    Directory of Open Access Journals (Sweden)

    Zarrin Ansari

    2013-06-01

    Full Text Available Neuropathic pain (NP is a chronic, debilitating symptomatology of lesions/injuries of the central and peripheral nervous system. As per pooled estimates, the prevalence is 7-8% in the general population; however, the prevalence varies with different neuropathic conditions. The aetiology can range from peripheral neuropathic conditions viz. peripheral diabetic neuropathic pain (PDNP, post-herpetic neuralgia (PHN, trigeminal neuralgia, HIV- associated polyneuropathy, cervical radiculopathy to central neuropathic conditions, viz. central post-stroke pain, spinal cord injury and the neuropathic pain associated with multiple sclerosis. Apart from the symptomatic perception of pain, neuropathic pain affects the cognitive and emotional aspects of the affected individual. The pain, being debilitating and resistant to over-the-counter analgesics, diminishes the quality of life, disrupts sleep and leads to psychiatric complications such as comorbid anxiety and depression. The management is palliative and involves drugs, psychological intervention, stimulations and nerve-blocking techniques. This review concentrates on the pharmacological therapeutic options available and focuses on the selection of the agent/s in accordance with the evidence. The first-line treatment includes the tricyclic antidepressants ([TCAs]; amitriptyline, nortriptyline, selective serotonin norepinephrine inhibitors ([SNRIs]; duloxetine, venlafaxine, calcium channel alpha 2 - delta ligands (pregabalin, gabapentin, carbamazepine and oxcarbazepine. Lidocaine plasters are first-line options for specific focal conditions such as post-herpetic neuralgia. The second-line therapy includes the opioid analgesics and tramadol. The choice of drug selection should complement the patient’s age, type of neuropathic condition, tolerability to an agent, comorbid condition and cost-effectiveness. Management must be individualized with a realistic and composite goal of making the pain tolerable and

  11. Chronic urticaria

    Directory of Open Access Journals (Sweden)

    Sandeep Sachdeva

    2011-01-01

    Full Text Available Chronic urticaria (CU is a disturbing allergic condition of the skin. Although frequently benign, it may sometimes be a red flag sign of a serious internal disease. A multitude of etiologies have been implicated in the causation of CU, including physical, infective, vasculitic, psychological and idiopathic. An autoimmune basis of most of the ′idiopathic′ forms is now hypothesized. Histamine released from mast cells is the major effector in pathogenesis and it is clinically characterized by wheals that have a tendency to recur. Laboratory investigations aimed at a specific etiology are not always conclusive, though may be suggestive of an underlying condition. A clinical search for associated systemic disease is strongly advocated under appropriate circumstances. The mainstay of treatment remains H1 antihistaminics. These may be combined with complementary pharmacopeia in the form of H2 blockers, doxepin, nifedipine and leukotriene inhibitors. More radical therapy in the form of immunoglobulins, plasmapheresis and cyclophosphamide may be required for recalcitrant cases. Autologous transfusion and alternative remedies like acupuncture have prospects for future. A stepwise management results in favorable outcomes. An update on CU based on our experience with patients at a tertiary care centre is presented.

  12. Synthesis and characterization of mixed ligand chiral nanoclusters

    KAUST Repository

    Guven, Zekiye P.

    2016-06-22

    Chiral mixed ligand silver nanoclusters were synthesized in the presence of a chiral and an achiral ligand. While the chiral ligand led mostly to the formation of nanoparticles, the presence of the achiral ligand drastically increased the yield of nanoclusters with enhanced chiral properties. © 2016 The Royal Society of Chemistry.

  13. Sacral nerve stimulation.

    Science.gov (United States)

    Matzel, K E; Stadelmaier, U; Besendörfer, M

    2004-01-01

    The current concept of recruiting residual function of an inadequate pelvic organ by electrostimulation involves stimulation of the sacral spinal nerves at the level of the sacral canal. The rationale for applying SNS to fecal incontinence was based on clinical observations of its effect on bowel habits and anorectal continence function in urologic patients (increased anorectal angulation and anal canal closure pressure) and on anatomic considerations: dissection demonstrated a dual peripheral nerve supply of the striated pelvic floor muscles that govern these functions. Because the sacral spinal nerve site is the most distal common location of this dual nerve supply, stimulating here can elicit both functions. Since the first application of SNS in fecal incontinence in 1994, this technique has been improved, the patient selection process modified, and the spectrum of indications expanded. At present SNS has been applied in more than 1300 patients with fecal incontinence limited.

  14. Cognitive stimulation in brainstorming.

    Science.gov (United States)

    Dugosh, K L; Paulus, P B; Roland, E J; Yang, H C

    2000-11-01

    Research on group brainstorming has demonstrated that it is less effective for generating large numbers of ideas than individual brainstorming, yet various scholars have presumed that group idea sharing should enhance cognitive stimulation and idea production. Three experiments examined the potential of cognitive stimulation in brainstorming. Experiments 1 and 2 used a paradigm in which individuals were exposed to ideas on audiotape as they were brainstorming, and Experiment 3 used the electronic brainstorming paradigm. Evidence was obtained for enhanced idea generation both during and after idea exposure. The attentional set of the participant and the content of the exposure manipulation (number of ideas, presence of irrelevant information) influenced this effect. These results are consistent with a cognitive perspective on group brainstorming.

  15. Interleukin 3 stimulates proliferation and triggers endothelial-leukocyte adhesion molecule 1 gene activation of human endothelial cells.

    Science.gov (United States)

    Brizzi, M F; Garbarino, G; Rossi, P R; Pagliardi, G L; Arduino, C; Avanzi, G C; Pegoraro, L

    1993-06-01

    Proliferation and functional activation of endothelial cells within a tissue site of inflammation are regulated by humoral factors released by cells, such as T lymphocytes and monocytes, infiltrating the perivascular space. In the present study we investigated the effects of interleukin 3 (IL-3), an activated T lymphocyte-derived cytokine, on cultured human umbilical vein endothelial cells (HUVEC). Proliferative activity, evaluated both by estimation of the fraction of cells in the S phase and by direct cell count demonstrated that IL-3, at the dose of 25 ng/ml, enhances more than threefold both DNA synthesis and cell proliferation above baseline control conditions. Binding studies with radioiodinated ligand demonstrated that HUVEC constitutively express a smaller number of IL-3 binding sites (approximately 99 binding sites per cell, with an apparent Kd of 149 pM). Accordingly, molecular analysis showed the presence of transcripts for both alpha and beta subunits of the IL-3 receptor. Functional activation of endothelial cells was evaluated by the expression of the endothelial-leukocyte adhesion molecule 1 (ELAM-1) transcript and by leukocyte adhesion. The ELAM-1 gene transcript was clearly detectable 4 h after IL-3 addition and started to decrease after 12 h. Moreover, IL-3-induced ELAM-1 transcription was followed by enhanced adhesion of neutrophils and CD4+ T cells to HUVEC. The findings that IL-3 can stimulate both proliferation and functional activation of endothelial cells suggest that this cytokine can be involved in sustaining the process of chronic inflammation.

  16. Prolonged calcitonin receptor signaling by salmon, but not human calcitonin, reveals ligand bias.

    Directory of Open Access Journals (Sweden)

    Kim Vietz Andreassen

    Full Text Available Salmon calcitonin (sCT and human calcitonin (hCT are pharmacologically distinct. However, the reason for the differences is unclear. Here we analyze the differences between sCT and hCT on the human calcitonin receptor (CT(aR with respect to activation of cAMP signaling, β-arrestin recruitment, ligand binding kinetics and internalization. The study was conducted using mammalian cell lines heterologously expressing the human CT(a receptor. CT(aR downstream signaling was investigated with dose response profiles for cAMP production and β-arrestin recruitment for sCT and hCT during short term (<2 hours and prolonged (up to 72 hours stimulation. CT(aR kinetics and internalization was investigated with radio-labeled sCT and hCT ligands on cultured cells and isolated membrane preparations from the same cell line. We found that sCT and hCT are equipotent during short-term stimulations with differences manifesting themselves only during long-term stimulation with sCT inducing a prolonged activation up to 72 hours, while hCT loses activity markedly earlier. The prolonged sCT stimulation of both cAMP accumulation and β-arrestin recruitment was attenuated, but not abrogated by acid wash, suggesting a role for sCT activated internalized receptors. We have demonstrated a novel phenomenon, namely that two distinct CT(aR downstream signaling activation patterns are activated by two related ligands, thereby highlighting qualitatively different signaling responses in vitro that could have implications for sCT use in vivo.

  17. Prolonged calcitonin receptor signaling by salmon, but not human calcitonin, reveals ligand bias.

    Science.gov (United States)

    Andreassen, Kim Vietz; Hjuler, Sara Toftegaard; Furness, Sebastian G; Sexton, Patrick M; Christopoulos, Arthur; Nosjean, Olivier; Karsdal, Morten Asser; Henriksen, Kim

    2014-01-01

    Salmon calcitonin (sCT) and human calcitonin (hCT) are pharmacologically distinct. However, the reason for the differences is unclear. Here we analyze the differences between sCT and hCT on the human calcitonin receptor (CT(a)R) with respect to activation of cAMP signaling, β-arrestin recruitment, ligand binding kinetics and internalization. The study was conducted using mammalian cell lines heterologously expressing the human CT(a) receptor. CT(a)R downstream signaling was investigated with dose response profiles for cAMP production and β-arrestin recruitment for sCT and hCT during short term (<2 hours) and prolonged (up to 72 hours) stimulation. CT(a)R kinetics and internalization was investigated with radio-labeled sCT and hCT ligands on cultured cells and isolated membrane preparations from the same cell line. We found that sCT and hCT are equipotent during short-term stimulations with differences manifesting themselves only during long-term stimulation with sCT inducing a prolonged activation up to 72 hours, while hCT loses activity markedly earlier. The prolonged sCT stimulation of both cAMP accumulation and β-arrestin recruitment was attenuated, but not abrogated by acid wash, suggesting a role for sCT activated internalized receptors. We have demonstrated a novel phenomenon, namely that two distinct CT(a)R downstream signaling activation patterns are activated by two related ligands, thereby highlighting qualitatively different signaling responses in vitro that could have implications for sCT use in vivo.

  18. Raft River well stimulation experiments: geothermal reservoir well stimulation program

    Energy Technology Data Exchange (ETDEWEB)

    1980-08-01

    The Geothermal Reservoir Well Stimulation Program (GRWSP) performed two field experiments at the Raft River KGRA in 1979. Wells RRGP-4 and RRGP-5 were selected for the hydraulic fracture stimulation treatments. The well selection process, fracture treatment design, field execution, stimulation results, and pre- and post-job evaluations are presented.

  19. Macrophage-elicited osteoclastogenesis in response to bacterial stimulation requires Toll-like receptor 2-dependent tumor necrosis factor-alpha production.

    Science.gov (United States)

    Ukai, Takashi; Yumoto, Hiromichi; Gibson, Frank C; Genco, Caroline Attardo

    2008-02-01

    The receptor activator of NF-kappaB ligand (RANKL) and the proinflammatory cytokines are believed to play important roles in osteoclastogenesis. We recently reported that the innate immune recognition receptor, Toll-like receptor 2 (TLR2), is crucial for inflammatory bone loss in response to infection by Porphyromonas gingivalis, the primary organism associated with chronic inflammatory periodontal disease. However, the contribution of macrophage-expressed TLRs to osteoclastogenesis has not been defined. In this study, we defined a requirement for TLR2 in tumor necrosis factor-alpha (TNF-alpha)-elicited osteoclastogenesis in response to exposure to P. gingivalis. Culture supernatant (CS) fluids from P. gingivalis-stimulated macrophages induced bone marrow macrophage-derived osteoclastogenesis. This activity was dependent on TNF-alpha and occurred independently of RANKL, interleukin-1beta (IL-1beta), and IL-6. CS fluids from P. gingivalis-stimulated TLR2(-/-) macrophages failed to express TNF-alpha, and these fluids induced significantly less osteoclast formation compared with that of the wild-type or the TLR4(-/-) macrophages. In addition, P. gingivalis exposure induced up-regulation of TLR2 expression on the cell surface of macrophages, which was demonstrated to functionally react to reexposure to P. gingivalis, as measured by a further increase in TNF-alpha production. These results demonstrate that macrophage-dependent TLR2 signaling is crucial for TNF-alpha-dependent/RANKL-independent osteoclastogenesis in response to P. gingivalis infection. Furthermore, the ability of P. gingivalis to induce the cell surface expression of TLR2 may contribute to the chronic inflammatory state induced by this pathogen.

  20. Nitrosamines as nicotinic receptor ligands.

    Science.gov (United States)

    Schuller, Hildegard M

    2007-05-30

    Nitrosamines are carcinogens formed in the mammalian organism from amine precursors contained in food, beverages, cosmetics and drugs. The potent carcinogen, NNK, and the weaker carcinogen, NNN, are nitrosamines formed from nicotine. Metabolites of the nitrosamines react with DNA to form adducts responsible for genotoxic effects. We have identified NNK as a high affinity agonist for the alpha7 nicotinic acetylcholine receptor (alpha7nAChR) whereas NNN bound with high affinity to epibatidine-sensitive nAChRs. Diethylnitrosamine (DEN) bound to both receptors but with lower affinity. High levels of the alpha7nAChR were expressed in human small cell lung cancer (SCLC) cell lines and in hamster pulmonary neuroendocrine cells (PNECs), which serve as a model for the cell of origin of human SCLC. Exposure of SCLC or PNECs to NNK or nicotine increased expression of the alpha7nAChR and caused influx of Ca(2+), activation of PKC, Raf-1, ERK1/2, and c-myc, resulting in the stimulation of cell proliferation. Signaling via the alpha7nAChR was enhanced when cells were maintained in an environment of 10-15% CO(2) similar to that in the diseased lung. Hamsters with hyperoxia-induced pulmonary fibrosis developed neuroendocrine lung carcinomas similar to human SCLC when treated with NNK, DEN, or nicotine. The development of the NNK-induced tumors was prevented by green tea or theophylline. The beta-adrenergic receptor agonist, isoproterenol or theophylline blocked NNK-induced cell proliferation in vitro. NNK and nicotine-induced hyperactivity of the alpha7nAChR/RAF/ERK1/2 pathway thus appears to play a crucial role in the development of SCLC in smokers and could be targeted for cancer prevention.

  1. Immobilisation of ligands by radio-derivatized polymers; Immobilisering av ligander med radioderiverte polymerer

    Energy Technology Data Exchange (ETDEWEB)

    Varga, J.M.; Fritsch, P.

    1995-01-30

    The invention relates to radio-derivatized polymers and a method of producing them by contacting non-polymerizable conjugands with radiolysable polymers in the presence of irradiation. The resulting radio-derivatized polymers can be further linked with ligand of organic or inorganic nature to immobilize such ligands. 2 figs., 5 tabs.

  2. Multiple ligand simultaneous docking: orchestrated dancing of ligands in binding sites of protein.

    Science.gov (United States)

    Li, Huameng; Li, Chenglong

    2010-07-30

    Present docking methodologies simulate only one single ligand at a time during docking process. In reality, the molecular recognition process always involves multiple molecular species. Typical protein-ligand interactions are, for example, substrate and cofactor in catalytic cycle; metal ion coordination together with ligand(s); and ligand binding with water molecules. To simulate the real molecular binding processes, we propose a novel multiple ligand simultaneous docking (MLSD) strategy, which can deal with all the above processes, vastly improving docking sampling and binding free energy scoring. The work also compares two search strategies: Lamarckian genetic algorithm and particle swarm optimization, which have respective advantages depending on the specific systems. The methodology proves robust through systematic testing against several diverse model systems: E. coli purine nucleoside phosphorylase (PNP) complex with two substrates, SHP2NSH2 complex with two peptides and Bcl-xL complex with ABT-737 fragments. In all cases, the final correct docking poses and relative binding free energies were obtained. In PNP case, the simulations also capture the binding intermediates and reveal the binding dynamics during the recognition processes, which are consistent with the proposed enzymatic mechanism. In the other two cases, conventional single-ligand docking fails due to energetic and dynamic coupling among ligands, whereas MLSD results in the correct binding modes. These three cases also represent potential applications in the areas of exploring enzymatic mechanism, interpreting noisy X-ray crystallographic maps, and aiding fragment-based drug design, respectively.

  3. A new feature of Mpl receptor: ligand-induced transforming activity in FRE rat fibroblasts.

    Science.gov (United States)

    Challier, C; Cocault, L; Flon, M; Pauchard, M; Porteu, F; Gisselbrecht, S; Souyri, M

    2000-04-13

    Mpl is the receptor for thrombopoietin, the primary regulator of platelet production by megakaryocytes. Upon stimulation by its ligand, Mpl receptor induces proliferation and differentiation of hematopoietic cell lines of various origins. In this paper, we show that Mpl is also able to transform FRE rat fibroblasts in the presence of MGDF (pegylated Megakaryocyte Growth and Development Factor), a modified form of its ligand. We also demonstrate that upon MGDF stimulation Mpl receptor activates the classical transduction pathways described for hematopoietic cell lines in FRE cells. Introduction of Mpl deletion mutants in FRE cells allowed us to demonstrate that the C-terminal region of the Mpl intracytoplasmic domain, which is involved in hematopoietic differentiation, is necessary for the transformation process. Within that region, site-directed mutagenesis showed that the Y112 residue, which is required for Shc phosphorylation, is essential for rat fibroblast transformation by Mpl/MGDF, suggesting the involvement of Shc in Mpl-mediated transformation. Interestingly, we showed that transformation correlated with strong and sustained MAPK activation. Neither Jak2, Stat3 nor Stat5 phosphorylation was sufficient to induce the transformation process. Taken altogether, our results suggest the oncogenicity of Mpl in fibroblastic cells in the presence of its ligand.

  4. Organotellurium ligands - designing and complexation reactions

    Indian Academy of Sciences (India)

    Ajai K Singh

    2002-08-01

    A variety of tellurium ligands has been designed and studied for their complexation reactions in the last decade. Of these hybrid telluroethers, halotellurium ligands and polytellurides are the most notable ones. RTe- and polytelluride ions have also been used to design clusters. Ligation of ditelluroethers and several hybrid telluroethers is extensively studied in our laboratories. The ditelluroether ligand RTeCH2TeR (where R = 4-MeOC6H4) (1), similar to dppm [1,2-bis(diphenylphosphino) methane], has been synthesized in good yield (∼80 %) by reacting CHCl3 with RTe- (generated in situ by borohydride reduction of R2Te2). Iodine reacts with 1 to give tetra-iodo derivative, which has intermolecular Te$\\cdots$I interactions resulting in a macro structure containing rectangular Te-I$\\cdots$Te bridges. 1 readily forms four membered rings with Pd(II) and Ru(II). On the formation of this chelate ring, the signal in 125Te NMR spectra shifts significantly upfield (50-60 ppm). The bridging mode of 1 has been shown in [Ru(-cymene)Cl2](-1)[Ru(-cymene)Cl2]. The hybrid telluroether ligands explored are of the types (Te, S), (Te, N) and (Te, O). The tellurium donor site has strong trans influence, which is manifested more strongly in square planar complexes of palladium(II). The morpholine N-donor site has been found to have weaker donor characteristics in (Te, N) ligands than pyridine and alkylamine donor sites of analogous ligands. The singlet oxygen readily oxidises the coordinated Te. This oxidation follows first order kinetics. The complexation reaction of RuCl3.H2O with N-[2-(4-methoxyphenyltelluro)ethyl]phthalimide (2) results in a novel (Te, N, O)-heterocycle, Te-chloro,Te-anisyl-1a-aza-4-oxa-3-tellura-1H, 2H, 4aH-9 fluorenone. The (Te, O) ligands can be used as hemilabile ligands, the oxygen atom temporarily protects the vacant coordination site before the arrival of the substrate. The chelate shifts observed in 125Te NMR spectra of metal complexes of Te-ligands have

  5. Determination of stimulation focality in heterogeneous head models during transcranial magnetic stimulation (TMS)

    Science.gov (United States)

    Lee, Erik; Hadimani, Ravi; Jiles, David

    2015-03-01

    Transcranial Magnetic Stimulation (TMS) is an increasingly popular tool used by both the scientific and medical community to understand and treat the brain. TMS has the potential to help people with a wide range of diseases such as Parkinson's, Alzheimer's, and PTSD, while currently being used to treat people with chronic, drug-resistant depression. Through computer simulations, we are able to see the electric field that TMS induces in anatomical human models, but there is no measure to quantify this electric field in a way that relates to a specific patient undergoing TMS therapy. We propose a way to quantify the focality of the induced electric field in a heterogeneous head model during TMS by relating the surface area of the brain being stimulated to the total volume of the brain being stimulated. This figure would be obtained by conducting finite element analysis (FEA) simulations of TMS therapy on a patient specific head model. Using this figure to assist in TMS therapy will allow clinicians and researchers to more accurately stimulate the desired region of a patient's brain and be more equipped to do comparative studies on the effects of TMS across different patients. This work was funded by the Carver Charitable Trust.

  6. Cranial electrotherapy stimulation and fibromyalgia.

    Science.gov (United States)

    Gilula, Marshall F

    2007-07-01

    Cranial electrotherapy stimulation (CES) is a well-documented neuroelectrical modality that has been proven effective in some good studies of fibromyalgia (FM) patients. CES is no panacea but, for some FM patients, the modality can be valuable. This article discusses aspects of both CES and FM and how they relate to the individual with the condition. FM frequently has many comorbidities such as anxiety, depression, insomnia and a great variety of different rheumatologic and neurological symptoms that often resemble multiple sclerosis, dysautonomias, chronic fatigue syndrome and others. However, despite long-standing criteria from the American College of Rheumatology for FM, some physicians believe there is probably no single homogeneous condition that can be labeled as FM. Whether it is a disease, a syndrome or something else, sufferers feel like they are living one disaster after another. Active self-involvement in care usually enhances the therapeutic results of various treatments and also improves the patient's sense of being in control of the condition. D-ribose supplementation may prove to significantly enhance energy, sleep, mental clarity, pain control and well-being in FM patients. A form of evoked potential biofeedback, the EPFX, is a powerful stress reduction technique which assesses the chief stressors and risk factors for illness that can impede the FM patient's built-in healing abilities. Future healthcare will likely expand the diagnostic criteria of FM and/or illuminate a group of related conditions and the ways in which the conditions relate to each other. Future medicine for FM and related conditions may increasingly involve multimodality treatment that features CES as one significant part of the therapeutic regimen. Future medicine may also include CES as an invaluable, cost-effective add-on to many facets of clinical pharmacology and medical therapeutics.

  7. Dockomatic - automated ligand creation and docking

    Directory of Open Access Journals (Sweden)

    Hampikian Greg

    2010-11-01

    Full Text Available Abstract Background The application of computational modeling to rationally design drugs and characterize macro biomolecular receptors has proven increasingly useful due to the accessibility of computing clusters and clouds. AutoDock is a well-known and powerful software program used to model ligand to receptor binding interactions. In its current version, AutoDock requires significant amounts of user time to setup and run jobs, and collect results. This paper presents DockoMatic, a user friendly Graphical User Interface (GUI application that eases and automates the creation and management of AutoDock jobs for high throughput screening of ligand to receptor interactions. Results DockoMatic allows the user to invoke and manage AutoDock jobs on a single computer or cluster, including jobs for evaluating secondary ligand interactions. It also automates the process of collecting, summarizing, and viewing results. In addition, DockoMatic automates creation of peptide ligand .pdb files from strings of single-letter amino acid abbreviations. Conclusions DockoMatic significantly reduces the complexity of managing multiple AutoDock jobs by facilitating ligand and AutoDock job creation and management.

  8. A new class of PN3-pincer ligands for metal–ligand cooperative catalysis

    KAUST Repository

    Li, Huaifeng

    2014-12-01

    Work on a new class of PN3-pincer ligands for metal-ligand cooperative catalysis is reviewed. While the field of the pyridine-based PN3-transition metal pincer complexes is still relatively young, many important applications of these complexes have already emerged. In several cases, the PN3-pincer complexes for metal-ligand cooperative catalysis result in significantly improved or unprecedented activities. The synthesis and coordination chemistry of PN3-pincer ligands are briefly summarized first to cover the synthetic routes for their preparation, followed by a focus review on their applications in catalysis. A specific emphasis is placed on the later section about the role of PN3-pincer ligands\\' dearomatization-rearomatization steps during the catalytic cycles. The mechanistic insights from density functional theory (DFT) calculations are also discussed.

  9. Sliding tethered ligands add topological interactions to the toolbox of ligand-receptor design

    Science.gov (United States)

    Bauer, Martin; Kékicheff, Patrick; Iss, Jean; Fajolles, Christophe; Charitat, Thierry; Daillant, Jean; Marques, Carlos M.

    2015-09-01

    Adhesion in the biological realm is mediated by specific lock-and-key interactions between ligand-receptor pairs. These complementary moieties are ubiquitously anchored to substrates by tethers that control the interaction range and the mobility of the ligands and receptors, thus tuning the kinetics and strength of the binding events. Here we add sliding anchoring to the toolbox of ligand-receptor design by developing a family of tethered ligands for which the spacer can slide at the anchoring point. Our results show that this additional sliding degree of freedom changes the nature of the adhesive contact by extending the spatial range over which binding may sustain a significant force. By introducing sliding tethered ligands with self-regulating length, this work paves the way for the development of versatile and reusable bio-adhesive substrates with potential applications for drug delivery and tissue engineering.

  10. Ferumoxytol: a silver lining in the treatment of anemia of chronic kidney disease or another dark cloud?

    OpenAIRE

    Barton Pai A; Garba AO

    2012-01-01

    Amy Barton Pai, Adinoyi O GarbaAlbany College of Pharmacy and Health Sciences, Albany, New York, NY, USAAbstract: Intravenous iron therapy is pivotal in the treatment of anemia of chronic kidney disease to optimize the response of hemoglobin to erythropoiesis-stimulating agents. Intravenous iron use in patients with chronic kidney disease is on the rise. Recent clinical trial data prompting safety concerns regarding the use of erythropoiesis-stimulating agents has stimulated new US Food and D...

  11. Chronic pain after hysterectomy

    DEFF Research Database (Denmark)

    Brandsborg, B.; Nikolajsen, L.; Kehlet, H.;

    2008-01-01

    BACKGROUND: Chronic pain is a well-known adverse effect of surgery, but the risk of chronic pain after gynaecological surgery is less established. METHOD: This review summarizes studies on chronic pain following hysterectomy. The underlying mechanisms and risk factors for the development of chronic...... post-hysterectomy pain are discussed. RESULTS AND CONCLUSION: Chronic pain is reported by 5-32% of women after hysterectomy. A guideline is proposed for future prospective studies Udgivelsesdato: 2008/3...

  12. Chronic pain after hysterectomy

    DEFF Research Database (Denmark)

    Brandsborg, B; Nikolajsen, L; Kehlet, Henrik;

    2008-01-01

    BACKGROUND: Chronic pain is a well-known adverse effect of surgery, but the risk of chronic pain after gynaecological surgery is less established. METHOD: This review summarizes studies on chronic pain following hysterectomy. The underlying mechanisms and risk factors for the development of chronic...... post-hysterectomy pain are discussed. RESULTS AND CONCLUSION: Chronic pain is reported by 5-32% of women after hysterectomy. A guideline is proposed for future prospective studies. Udgivelsesdato: 2008-Mar...

  13. Molecular Dynamics Simulations Reveal the Mechanisms of Allosteric Activation of Hsp90 by Designed Ligands.

    Science.gov (United States)

    Vettoretti, Gerolamo; Moroni, Elisabetta; Sattin, Sara; Tao, Jiahui; Agard, David A; Bernardi, Anna; Colombo, Giorgio

    2016-04-01

    Controlling biochemical pathways through chemically designed modulators may provide novel opportunities to develop therapeutic drugs and chemical tools. The underlying challenge is to design new molecular entities able to act as allosteric chemical switches that selectively turn on/off functions by modulating the conformational dynamics of their target protein. We examine the origins of the stimulation of ATPase and closure kinetics in the molecular chaperone Hsp90 by allosteric modulators through atomistic molecular dynamics (MD) simulations and analysis of protein-ligand interactions. In particular, we focus on the cross-talk between allosteric ligands and protein conformations and its effect on the dynamic properties of the chaperone's active state. We examine the impact of different allosteric modulators on the stability, structural and internal dynamics properties of Hsp90 closed state. A critical aspect of this study is the development of a quantitative model that correlates Hsp90 activation to the presence of a certain compound, making use of information on the dynamic adaptation of protein conformations to the presence of the ligand, which allows to capture conformational states relevant in the activation process. We discuss the implications of considering the conformational dialogue between allosteric ligands and protein conformations for the design of new functional modulators.

  14. Binding capacity of ER-α ligands and SERMs: comparison of the human, dog and cat.

    Science.gov (United States)

    Toniti, Waraphan; Suthiyotha, Nareuthorn; Puchadapirom, Pranom; Jenwitheesuk, Ekachai

    2011-01-01

    The estrogen molecule is the major risk factor related to mammary gland tumors, with estrogen receptor alpha (ER- α) as the important target stimulating growth. Therefore one alternative approach to treatment of breast cancer is to use selective estrogen receptor modulator (SERM), hormonal therapy. In this study, the structures of ER- α in humans, dogs and cats were predicted using the amino acid sequencing data bank and corrected for general protein structures, receptor sites and docking by adding 2,344 ligands with 15 SERMs into the database and calculating estimated inhibition constants (Ki). Thereby, ranking of best ligands of SERMs in humans, dogs and cats could be achieved. The results show that the shapes of ER- α differ between species but the major pocket sites are the same. Bazedoxifene, a new SERM proved to be the best estrogen antagonist and ER- α inhibitor in all species (human, dog, cat) with the lowest Ki. The other good ligands for dogs and cats are Neohesperidin, Dihydrochalcone, and Schreiber2. The differences in these protein structures may explain why there are only a few SERMs or other ligands which can be used as anti-cancer drugs.

  15. B淋巴细胞刺激因子对慢性特发性荨麻疹患者产生抗FcεRI抗体和抗IgE抗体的影响%Influence of B lymphocyte stimulator on the production of anti-FcεRI and anti-IgE antibodies by B lymphocytes from patients with chronic idiopathic urticaria

    Institute of Scientific and Technical Information of China (English)

    康尔恂; 李杰; 孙丽伟; 韩春玉; 闫丽萍; 杨建

    2013-01-01

    目的 探讨B淋巴细胞刺激因子(BlyS)能否刺激慢性特发性荨麻疹(CIU)患者B淋巴细胞产生抗FcεRI抗体或抗IgE抗体.方法 设CIU患者组和健康对照组.ELISA法测定血清中BlyS、抗FcεRI抗体和抗IgE抗体水平,分离培养受试者外周血B淋巴细胞,在培养液中加入BlyS,检测培养液中抗FcεRI抗体和抗IgE抗体水平,分析BlyS与抗FcεRI抗体和抗IgE抗体产生的相关性.结果 CIU患者血清BlyS水平显著高于健康对照组(t=3.04,P< 0.01),抗FcεRI抗体和抗IgE抗体水平均显著高于健康对照组(t=3.51,P<0.01;t=3.29,P< 0.01).CIU患者血清中抗FcεRI抗体和抗IgE抗体水平与BlyS水平呈正相关(r=0.93,P<0.01;r=0.91,P< 0.01);CIU患者外周血B淋巴细胞培养液中加入有效浓度BlyS后,B淋巴细胞培养液中抗FcεRI抗体和抗IgE抗体水平均显著高于不加BlyS的空白对照(t=3.67,P< 0.01;t=3.56,P< 0.01),2种抗体在培养液中的水平与BlyS浓度呈正相关(r=0.96,P< 0.01;r=0.91,P< 0.01);抗FcεRI抗体和抗IgE抗体在CIU患者血清与培养液中的检出符合率分别为94.76%和87.84%.结论 CIU患者血液中BlyS水平增高可刺激B淋巴细胞产生抗FcεRI抗体或抗IgE抗体,可能与CIU发病有关.%Objective To explore if B lymphocyte stimulator (BlyS) stimulates B lymphocytes from patients with chronic idiopathic urticaria (CIU) to produce anti-high affinity IgE receptor (FcεRI) or anti-IgE antibodies.Methods Totally,300 CIU patients and 300 health controls were enrolled in this study.Blood samples were obtained from these subjects.Peripheral blood B lymphocytes were isolated and cultured in vitro for 72 hours.Then,BlyS of various concentrations (2,4,8,16 ng/ml) was added to the culture medium of B lymphocytes followed by another 72-hour culture.Enzyme-linked immunosorbent assay was performed to determine the serum levels of BlyS,anti-FcεRI and anti-IgE antibodies,as well as the supernatant levels of anti

  16. Receptor for Advanced Glycation End Products and its Inflammatory Ligands are Upregulated in Amyotrophic Lateral Sclerosis

    Directory of Open Access Journals (Sweden)

    Judyta eJuranek

    2015-12-01

    Full Text Available Amyotrophic lateral sclerosis (ALS is a fatal motor neuron disorder of largely unknown pathogenesis. Recent studies suggest that enhanced oxidative stress and neuroinflammation contribute to the progression of the disease. Mounting evidence implicates the receptor for advanced glycation end-products (RAGE as a significant contributor to the pathogenesis of certain neurodegenerative diseases and chronic conditions. It is hypothesized that detrimental actions of RAGE are triggered upon binding to its ligands, such as AGEs (advanced glycation end products, S100/calgranulin family members, and High Mobility Group Box-1 (HMGB1 proteins. Here, we examined the expression of RAGE and its ligands in human ALS spinal cord. Tissue samples from age-matched human control and ALS spinal cords were tested for the expression of RAGE, carboxymethyllysine (CML AGE, S100B and HMGB1, and intensity of the immunofluorescent and immunoblotting signals was assessed. We found that the expression of both RAGE and its ligands was significantly increased in the spinal cords of ALS patients versus age-matched control subjects. Our study is the first report describing co-expression of both RAGE and its ligands in human ALS spinal cords. These findings suggest that further probing of RAGE as a mechanism of neurodegeneration in human ALS is rational.

  17. Cationic ruthenium alkylidene catalysts bearing phosphine ligands.

    Science.gov (United States)

    Endo, Koji; Grubbs, Robert H

    2016-02-28

    The discovery of highly active catalysts and the success of ionic liquid immobilized systems have accelerated attention to a new class of cationic metathesis catalysts. We herein report the facile syntheses of cationic ruthenium catalysts bearing bulky phosphine ligands. Simple ligand exchange using silver(i) salts of non-coordinating or weakly coordinating anions provided either PPh3 or chelating Ph2P(CH2)nPPh2 (n = 2 or 3) ligated cationic catalysts. The structures of these newly reported catalysts feature unique geometries caused by ligation of the bulky phosphine ligands. Their activities and selectivities in standard metathesis reactions were also investigated. These cationic ruthenium alkylidene catalysts reported here showed moderate activity and very similar stereoselectivity when compared to the second generation ruthenium dichloride catalyst in ring-closing metathesis, cross metathesis, and ring-opening metathesis polymerization assays.

  18. Stimulation of GLP-1 secretion downstream of the ligand-gated ion channel TRPA1.

    Science.gov (United States)

    Emery, Edward C; Diakogiannaki, Eleftheria; Gentry, Clive; Psichas, Arianna; Habib, Abdella M; Bevan, Stuart; Fischer, Michael J M; Reimann, Frank; Gribble, Fiona M

    2015-04-01

    Stimulus-coupled incretin secretion from enteroendocrine cells plays a fundamental role in glucose homeostasis and could be targeted for the treatment of type 2 diabetes. Here, we investigated the expression and function of transient receptor potential (TRP) ion channels in enteroendocrine L cells producing GLP-1. By microarray and quantitative PCR analysis, we identified trpa1 as an L cell-enriched transcript in the small intestine. Calcium imaging of primary L cells and the model cell line GLUTag revealed responses triggered by the TRPA1 agonists allyl-isothiocyanate (mustard oil), carvacrol, and polyunsaturated fatty acids, which were blocked by TRPA1 antagonists. Electrophysiology in GLUTag cells showed that carvacrol induced a current with characteristics typical of TRPA1 and triggered the firing of action potentials. TRPA1 activation caused an increase in GLP-1 secretion from primary murine intestinal cultures and GLUTag cells, an effect that was abolished in cultures from trpa1(-/-) mice or by pharmacological TRPA1 inhibition. These findings present TRPA1 as a novel sensory mechanism in enteroendocrine L cells, coupled to the facilitation of GLP-1 release, which may be exploitable as a target for treating diabetes.

  19. Genome-wide analysis of TIAR RNA ligands in mouse macrophages before and after LPS stimulation

    Directory of Open Access Journals (Sweden)

    Yacine Kharraz

    2016-03-01

    Full Text Available TIA-1 related protein (TIAR is a RNA-binding protein involved in several steps of gene expression such as RNA splicing Aznarez et al. (2008 [1] and translation Piecyk et al. (2000 [2]. TIAR contains three RNA recognition motifs (RRMs allowing its interaction with specific sequences localized in the untranslated regions (UTRs of several mRNAs. In myeloid cells, TIAR has been shown to bind and regulate the translation and stability of various mRNA-encoding proteins important for the inflammatory response, such as TNFα Piecyk et al. (2000, Gueydan et al. (1999 [2,3], Cox-2 Cok et al. (2003 [4] or IL-8 Suswam et al. (2005 [5]. Here, we generated two macrophage-like RAW 264.7 cell lines expressing either a tagged full-length TIAR protein or a RRM2-truncated mutant unable to bind RNA with high affinity Dember et al. (1996, Kim et al. (2013 . By a combination of RNA-IP and microarray analysis (RIP-chip, we identified mRNAs specifically bound by the full-length protein both in basal conditions and in response to LPS (GSE77577.

  20. CD40 and OX40 ligand are increased on stimulated asthmatic airway smooth muscle

    NARCIS (Netherlands)

    Burgess, Janette K; Blake, Anita E; Boustany, Sarah; Johnson, Peter R A; Armour, Carol L; Black, Judith L; Hunt, Nicholas H; Hughes, J Margaret

    2005-01-01

    BACKGROUND: Severe, persistent asthma is characterized by airway smooth muscle hyperplasia, inflammatory cell infiltration into the smooth muscle, and increased expression of many cytokines, including IL-4, IL-13, IL-1beta, and TNF-alpha. These cytokines have the potential to alter the expression of

  1. Coordination- and Redox-Noninnocent Behavior of Ambiphilic Ligands Containing Antimony.

    Science.gov (United States)

    Jones, J Stuart; Gabbaï, François P

    2016-05-17

    Stimulated by applications in catalysis, the chemistry of ambiphilic ligands featuring both donor and acceptor functionalities has experienced substantial growth in the past several years. The unique opportunities in catalysis offered by ambiphilic ligands stem from the ability of their acceptor functionalities to play key roles via metal-ligand cooperation or modulation of the reactivity of the metal center. Ligands featuring group 13 centers, most notably boranes, as their acceptor functionalities have undoubtedly spearheaded these developments, with remarkable results having been achieved in catalytic hydrogenation and hydrosilylation. Motivated by these developments as well as by our fundamental interest in the chemistry of heavy group 15 elements, we became fascinated by the possibility of employing antimony centers as Lewis acids within ambiphilic ligands. The chemistry of antimony-based ligands, most often encountered as trivalent stibines, has historically been considered to mirror that of their lighter phosphorus-based congeners. There is growing evidence, however, that antimony-based ligands may display unique coordination behavior and reactivity. Additionally, despite the diverse Lewis acid and redox chemistry that antimony exhibits, there have been only limited efforts to explore this chemistry within the coordination sphere of a transition metal. By incorporation of antimony into the framework of polydentate ligands in order to enforce the main group metal-transition metal interaction, the effect of redox and coordination events at the antimony center on the structure, electronics, and reactivity of the metal complex may be investigated. This Account describes our group's continuing efforts to probe the coordination behavior, reactivity, and application of ambiphilic ligands incorporating antimony centers. Structural and theoretical studies have established that both Sb(III) and Sb(V) centers in polydentate ligands may act as Z-type ligands toward late

  2. Towards understanding and managing chronic cough.

    Science.gov (United States)

    Satia, Imran; Badri, Huda; Al-Sheklly, Bashar; Smith, Jaclyn Ann; Woodcock, Ashley A

    2016-12-01

    Chronic cough is a common and troublesome condition affecting approximately 12% of the general population. It is associated with poor quality of life with psychological, social and physical consequences. Patients typically complain of a dry irritating cough, driven by a strong urge to cough associated with a sensation or irritation located in the throat. Treatment of potential 'causes', ie asthma, gastro-oesophageal reflux disease and rhino-sinusitis, may produce a complete or partial response, but the response of some patients to opiates and alpha-2-delta ligand antagonists (gabapentin and pregabalin) supports the concept that this is primarily a neurological disorder, characterised by hyper-responsiveness of the nerves. Novel and highly effective neuronal treatments are in development and offer hope of better symptom control with fewer side effects within a few years. This review focuses on understanding the mechanism of chronic cough, current management approaches and research that may lead to novel therapies.

  3. Differential changes in gingival somatosensory sensitivity after painful electrical tooth stimulation.

    Science.gov (United States)

    Baad-Hansen, Lene; Lu, Shengyi; Kemppainen, Pentti; List, Thomas; Zhang, Zhenting; Svensson, Peter

    2015-04-01

    We aimed to evaluate the effect of painful tooth stimulation on gingival somatosensory sensitivity of healthy volunteers in a randomized, controlled design. Thirteen healthy volunteers (six women, seven men; 28.4 ± 5.0 years) were included for two experimental sessions of electrical tooth stimulation: painful tooth stimulation and tooth stimulation below the sensory threshold (control). Eight of the human subjects participated in a third session without tooth stimulation. In all sessions, the somatosensory sensitivity of the gingiva adjacent to the stimulated tooth was evaluated with a standardized battery of quantitative sensory tests (QST) before, immediately after and 30 min after tooth stimulation. Painful tooth stimulation evoked significant decreases in warmth and heat pain thresholds (P 0.086). No QST changes were detected in the session without tooth stimulation (P > 0.060). In conclusion, modest increased gingival sensitivity to warmth, painful heat and pressure stimuli as well as desensitization to non-painful mechanical stimulation were demonstrated after tooth stimulation. This suggests involvement of competing heterotopic facilitatory and inhibitory mechanisms. Furthermore, stimulation below the sensory threshold induced similar thermal sensitization suggesting the possibility of activation of axon-reflex-like mechanisms even at intensities below the perception threshold. These findings may have implications for interpretation of somatosensory results in patients with chronic intraoral pain.

  4. Efficient chemoenzymatic synthesis of chiral pincer ligands.

    Science.gov (United States)

    Felluga, Fulvia; Baratta, Walter; Fanfoni, Lidia; Pitacco, Giuliana; Rigo, Pierluigi; Benedetti, Fabio

    2009-05-01

    Chiral, nonracemic pincer ligands based on the 6-phenyl-2-aminomethylpyridine and 2-aminomethylbenzo[h]quinoline scaffolds were obtained by a chemoenzymatic approach starting from 2-pyridyl and 2-benzoquinolyl ethanone. In the enantiodifferentiating step, secondary alcohols of opposite absolute configuration were obtained by a baker's yeast reduction of the ketones and by lipase-mediated dynamic kinetic resolution of the racemic alcohols. Their transformation into homochiral 1-methyl-1-heteroarylethanamines occurred without loss of optical purity, giving access to pincer ligands used in enantioselective catalysis.

  5. [Chronic otitis mediaChronic Otitis Media].

    Science.gov (United States)

    Kohles, N; Schulz, T; Eßer, D

    2015-11-01

    There are 2 different kinds of chronic otitis media: Otitis media chronica mesotympanalis and otitis media chronica epitympanalis (cholesteatoma). The incidence of chronic otitis media as reported in literature differs in a wide range. The incidence rates vary between 0.45 and 46%. Both, otitis media chronica mesotympanalis and cholesteatoma, lead to eardrum perforation due to lengthy and recurring inflammations. Furthermore, chronic otitis media is characterized by frequently recurring otorrhea and conductive hearing loss.

  6. Fibrocyte-like cells from intrauterine growth restriction placentas have a reduced ability to stimulate angiogenesis.

    Science.gov (United States)

    Riddell, Meghan R; Winkler-Lowen, Bonnie; Jiang, Yanyan; Guilbert, Larry J; Davidge, Sandra T

    2013-09-01

    Intrauterine growth restriction (IUGR) is a common complication of pregnancy whereby the fetus fails to achieve its genetic growth potential. Malformation of the placental vasculature is observed in IUGR and may be due to the development of the placenta in a chronically hypoxic environment. Recently, we identified that the predominant stromal cells in the angiogenic zones of the placenta are fibrocyte-like cells. The conditioned medium from fibrocyte-like cells (FcCM) has been shown to stimulate angiogenesis in vitro. Thus, we hypothesized that FcCM from IUGR cells would have a reduced ability to stimulate angiogenesis and that chronic hypoxia would decrease the ability of both normal and IUGR fibrocyte-like cells to stimulate angiogenesis. IUGR FcCM had a reduced ability to stimulate endothelial tubule-like structure formation and an increased ability to stimulate endothelial migration compared with normal FcCM. However, normal and IUGR FcCM produced in chronic hypoxia did not alter endothelial proliferation, migration, or tubule-like structure formation. IUGR FcCM was found to have reduced levels of the pro-angiogenic cytokine IL-8 and increased levels of the anti-angiogenic factors activin-A and pigment epithelium-derived growth factor. Thus, alterations in the ability of IUGR fibrocyte-like cells to stimulate angiogenesis may contribute to the development of vascular malformation in IUGR, but in vitro these changes cannot be attributed to a chronically hypoxic environment.

  7. Synthesis and biological activity of novel small peptides with aminophosphonates moiety as NOP receptor ligands.

    Science.gov (United States)

    Naydenova, Emilia D; Todorov, Petar T; Mateeva, Polina I; Zamfirova, Rositza N; Pavlov, Nikola D; Todorov, Simeon B

    2010-11-01

    The aim of the present study was the synthesis and the biological screening of new analogs of Ac-RYYRWK-NH2, modified at the N-terminal with 1-[(methoxyphosphono)methylamino]cycloalkanecarboxylic acids. The four newly synthesized ligands for the nociceptin/orphanin FQ (N/OFQ) receptor (NOP) have been prepared by solid-phase peptide synthesis--Fmoc-strategy. These compounds were tested for agonistic activity in vitro on electrically stimulated smooth-muscle preparations isolated from vas deferens of Wistar rats. Our data showed that substitution of Arg at position 1 with aminophosphonates moiety decreased significantly the affinity of ligands to the NOP receptor. Furthermore, the enlargement of the cycle (with 5-8 carbon atoms) additionally diminished both the activity and the selectivity for NOP-receptor.

  8. Emerging Roles for CSF-1 Receptor and its Ligands in the Nervous System.

    Science.gov (United States)

    Chitu, Violeta; Gokhan, Şölen; Nandi, Sayan; Mehler, Mark F; Stanley, E Richard

    2016-06-01

    The colony-stimulating factor-1 receptor (CSF-1R) kinase regulates tissue macrophage homeostasis, osteoclastogenesis, and Paneth cell development. However, recent studies in mice have revealed that CSF-1R signaling directly controls the development and maintenance of microglia, and cell autonomously regulates neuronal differentiation and survival. While the CSF-1R-cognate ligands, CSF-1 and interleukin-34 (IL-34) compete for binding to the CSF-1R, they are expressed in a largely non-overlapping manner by mature neurons. The recent identification of a dominantly inherited, adult-onset, progressive dementia associated with inactivating mutations in the CSF-1R highlights the importance of CSF-1R signaling in the brain. We review the roles of the CSF-1R and its ligands in microglial and neural development and function, and their relevance to our understanding of neurodegenerative disease.

  9. CLiBE: a database of computed ligand binding energy for ligand-receptor complexes.

    Science.gov (United States)

    Chen, X; Ji, Z L; Zhi, D G; Chen, Y Z

    2002-11-01

    Consideration of binding competitiveness of a drug candidate against natural ligands and other drugs that bind to the same receptor site may facilitate the rational development of a candidate into a potent drug. A strategy that can be applied to computer-aided drug design is to evaluate ligand-receptor interaction energy or other scoring functions of a designed drug with that of the relevant ligands known to bind to the same binding site. As a tool to facilitate such a strategy, a database of ligand-receptor interaction energy is developed from known ligand-receptor 3D structural entries in the Protein Databank (PDB). The Energy is computed based on a molecular mechanics force field that has been used in the prediction of therapeutic and toxicity targets of drugs. This database also contains information about ligand function and other properties and it can be accessed at http://xin.cz3.nus.edu.sg/group/CLiBE.asp. The computed energy components may facilitate the probing of the mode of action and other profiles of binding. A number of computed energies of some PDB ligand-receptor complexes in this database are studied and compared to experimental binding affinity. A certain degree of correlation between the computed energy and experimental binding affinity is found, which suggests that the computed energy may be useful in facilitating a qualitative analysis of drug binding competitiveness.

  10. Ligand-induced Ordering of the C-terminal Tail Primes STING for Phosphorylation by TBK1

    Directory of Open Access Journals (Sweden)

    Yuko Tsuchiya

    2016-07-01

    Full Text Available The innate immune protein Stimulator of interferon genes (STING promotes the induction of interferon beta (IFN-β production via the phosphorylation of its C-terminal tail (CTT by TANK-binding kinase 1 (TBK1. Potent ligands of STING are, therefore, promising candidates for novel anti-cancer drugs or vaccine adjuvants. However, the intrinsically flexible CTT poses serious problems in in silico drug discovery. Here, we performed molecular dynamics simulations of the STING fragment containing the CTT in ligand-bound and unbound forms and observed that the binding of a potent ligand cyclic GMP-AMP (cGAMP induced a local structure in the CTT, reminiscent of the known structure of a TBK1 substrate. The subsequent molecular biological experiments confirmed the observed dynamics of the CTT and identified essential residues for the activation of the IFN-β promoter, leading us to propose a new mechanism of STING activation.

  11. Neuromodulation of chronic headaches: position statement from the European Headache Federation.

    Science.gov (United States)

    Martelletti, Paolo; Jensen, Rigmor H; Antal, Andrea; Arcioni, Roberto; Brighina, Filippo; de Tommaso, Marina; Franzini, Angelo; Fontaine, Denys; Heiland, Max; Jürgens, Tim P; Leone, Massimo; Magis, Delphine; Paemeleire, Koen; Palmisani, Stefano; Paulus, Walter; May, Arne

    2013-10-21

    The medical treatment of patients with chronic primary headache syndromes (chronic migraine, chronic tension-type headache, chronic cluster headache, hemicrania continua) is challenging as serious side effects frequently complicate the course of medical treatment and some patients may be even medically intractable. When a definitive lack of responsiveness to conservative treatments is ascertained and medication overuse headache is excluded, neuromodulation options can be considered in selected cases. Here, the various invasive and non-invasive approaches, such as hypothalamic deep brain stimulation, occipital nerve stimulation, stimulation of sphenopalatine ganglion, cervical spinal cord stimulation, vagus nerve stimulation, transcranial direct current stimulation, repetitive transcranial magnetic stimulation, and transcutaneous electrical nerve stimulation are extensively published although proper RCT-based evidence is limited. The European Headache Federation herewith provides a consensus statement on the clinical use of neuromodulation in headache, based on theoretical background, clinical data, and side effect of each method. This international consensus further gives recommendations for future studies on these new approaches. In spite of a growing field of stimulation devices in headaches treatment, further controlled studies to validate, strengthen and disseminate the use of neurostimulation are clearly warranted. Consequently, until these data are available any neurostimulation device should only be used in patients with medically intractable syndromes from tertiary headache centers either as part of a valid study or have shown to be effective in such controlled studies with an acceptable side effect profile.

  12. Abundance of Flt3 and its ligand in astrocytic tumors

    Directory of Open Access Journals (Sweden)

    Eßbach C

    2013-05-01

    Full Text Available C Eßbach,1 N Andrae,1 D Pachow,1 J-P Warnke,2 A Wilisch-Neumann,1 E Kirches,1 C Mawrin11Department of Neuropathology, Otto-von-Guericke University, Magdeburg, 2Department of Neurosurgery, Paracelsus Hospital, Zwickau, GermanyBackground: Molecular targeted therapies for astrocytic tumors are the subject of growing research interest, due to the limited response of these tumors, especially glioblastoma multiforme, to conventional chemotherapeutic regimens. Several of these approaches exploit the inhibition of receptor tyrosine kinases. To date, it has not been elucidated if fms-like tyrosine kinase-3 (Flt3 and its natural ligand (Flt3L are expressed in astrocytic tumors, although some of the clinically intended small-molecule receptor tyrosine kinase inhibitors affect Flt3, while others do not. More importantly, the recent proof of principle for successful stimulation of the immune system against gliomas in preclinical models via local Flt3L application requires elucidation of this receptor tyrosine kinase pathway in these tumors in more detail. This therapy is based on recruitment of Flt3-positive dendritic cells, but may be corroborated by activity of this signaling pathway in glioma cells.Methods: Receptor and ligand expression was analyzed by real-time polymerase chain reaction in 31 astrocytic tumors (six diffuse and 11 anaplastic astrocytomas, 14 glioblastomas derived from patients of both genders and in glioblastoma cell lines. The two most common activating mutations of the Flt3 gene, ie, internal tandem duplication and D835 point mutation, were assessed by specific polymerase chain reaction.Results: A relatively high abundance of Flt3L mRNA (4%–6% of the reference, β2 microglobulin could be demonstrated in all tumor samples. Flt3 expression could generally be demonstrated by 40 specific polymerase chain reaction cycles and gel electrophoresis in 87% of the tumors, including all grades, although the small quantities of the receptor did

  13. Lubiprostone: a novel treatment for chronic constipation.

    Science.gov (United States)

    Lacy, Brian E; Levy, L Campbell

    2008-01-01

    Chronic constipation is highly prevalent, reduces patients' quality of life, and imposes a significant health care burden on society. Lifestyle modifications and over-the-counter agents improve symptoms of constipation in some patients, however many patients have persistent symptoms and require the use of prescription medications. Three prescription medications are currently Food and Drug Administration (FDA) approved and available for the treatment of chronic constipation in adults. This review will focus on lubiprostone, the newest medication available for the treatment of chronic constipation. Lubiprostone is a bicyclic fatty acid metabolite analogue ofprostaglandin E1. It activates specific chloride channels in the gastrointestinal tract to stimulate intestinal fluid secretion, increase gastrointestinal transit, and improve symptoms of constipation. This article will provide a brief overview on chloride channel function in the gastrointestinal tract, describe the structure, function, and pharmacokinetics of lubiprostone, and discuss the safety and efficacy of this new medication.

  14. Neurite outgrowth induced by a synthetic peptide ligand of neural cell adhesion molecule requires fibroblast growth factor receptor activation

    DEFF Research Database (Denmark)

    Rønn, L C; Doherty, P; Holm, A;

    2000-01-01

    The neural cell adhesion molecule NCAM is involved in axonal outgrowth and target recognition in the developing nervous system. In vitro, NCAM-NCAM binding has been shown to induce neurite outgrowth, presumably through an activation of fibroblast growth factor receptors (FGFRs). We have recently...... identified a neuritogenic ligand, termed the C3 peptide, of the first immunoglobulin (lg) module of NCAM using a combinatorial library of synthetic peptides. Here we investigate whether stimulation of neurite outgrowth by this synthetic ligand of NCAM involves FGFRs. In primary cultures of cerebellar neurons...... from wild-type mice, the C3 peptide stimulated neurite outgrowth. This response was virtually absent in cultures of cerebellar neurons from transgenic mice expressing a dominant-negative form of the FGFR1. Likewise, in PC12E2 cells transiently expressing a dominant-negative form of the mouse FGFR1...

  15. Effects of the addition of functional electrical stimulation to ground level gait training with body weight support after chronic stroke Efeitos da adição da estimulação elétrica funcional ao treino de marcha em piso fixo com suporte parcial de peso após acidente vascular encefálico crônico

    Directory of Open Access Journals (Sweden)

    Christiane L. Prado-Medeiros

    2011-12-01

    Full Text Available BACKGROUND: The addition of functional electrical stimulation (FES to treadmill gait training with partial body weight support (BWS has been proposed as a strategy to facilitate gait training in people with hemiparesis. However, there is a lack of studies that evaluate the effectiveness of FES addition on ground level gait training with BWS, which is the most common locomotion surface. OBJECTIVE: To investigate the additional effects of commum peroneal nerve FES combined with gait training and BWS on ground level, on spatial-temporal gait parameters, segmental angles, and motor function. METHODS: Twelve people with chronic hemiparesis participated in the study. An A1-B-A2 design was applied. A1 and A2 corresponded to ground level gait training using BWS, and B corresponded to the same training with the addition of FES. The assessments were performed using the Modified Ashworth Scale (MAS, Functional Ambulation Category (FAC, Rivermead Motor Assessment (RMA, and filming. The kinematics analyzed variables were mean walking speed of locomotion; step length; stride length, speed and duration; initial and final double support duration; single-limb support duration; swing period; range of motion (ROM, maximum and minimum angles of foot, leg, thigh, and trunk segments. RESULTS: There were not changes between phases for the functional assessment of RMA, for the spatial-temporal gait variables and segmental angles, no changes were observed after the addition of FES. CONCLUSION: The use of FES on ground level gait training with BWS did not provide additional benefits for all assessed parameters.CONTEXTUALIZAÇÃO: A adição da estimulação elétrica funcional (EEF ao treino de marcha em esteira, com sistema de suporte parcial de peso corporal (SPPC, tem sido proposta como estratégia para melhorar a marcha em hemiparéticos. Entretanto, nenhum estudo verificou a eficácia da adição da EEF ao treino de marcha com SPPC em piso fixo, a superfície mais

  16. Use of intravenous iron supplementation in chronic kidney disease: an update.

    Science.gov (United States)

    Macdougall, Iain C; Geisser, Peter

    2013-01-01

    Iron deficiency is an important clinical concern in chronic kidney disease (CKD), giving rise to iron-deficiency anemia and impaired cellular function. Oral supplementation, in particular with ferrous salts, is associated with a high rate of gastrointestinal side effects and is poorly absorbed, a problem that is avoided with intravenous iron. The most stable intravenous iron complexes (eg, iron dextran, ferric carboxymaltose, ferumoxytol, and iron isomaltoside 1000) can be given in higher single doses and more rapidly than less stable preparations (eg, sodium ferric gluconate). Iron complexes that contain dextran or dextran-derived ligands can cause dextran-induced anaphylactic reactions, which cannot occur with dextran-free preparations such as ferric carboxymaltose and iron sucrose. Test doses are advisable for conventional dextran-containing compounds. Iron supplementation is recommended for all CKD patients with anemia who receive erythropoiesis-stimulating agents, whether or not they require dialysis. Intravenous iron is the preferred route of administration in hemodialysis patients, with randomized trials showing a significantly greater increase in hemoglobin levels for intravenous versus oral iron and a low rate of treatment-related adverse events. In the nondialysis CKD population, the erythropoietic response is also significantly higher using intravenous versus oral iron, and tolerability is at least as good. Moreover, in some nondialysis patients intravenous iron supplementation can avoid, or at least delay, the need for erythropoiesis-stimulating agents. In conclusion, we now have the ability to achieve iron replenishment rapidly and conveniently in dialysis-dependent and nondialysis-dependent CKD patients without compromising safety.

  17. Transcranial brain stimulation: closing the loop between brain and stimulation

    DEFF Research Database (Denmark)

    Karabanov, Anke; Thielscher, Axel; Siebner, Hartwig Roman

    2016-01-01

    PURPOSE OF REVIEW: To discuss recent strategies for boosting the efficacy of noninvasive transcranial brain stimulation to improve human brain function. RECENT FINDINGS: Recent research exposed substantial intra- and inter-individual variability in response to plasticity-inducing transcranial brain...... transcranial brain stimulation. Priming interventions or paired associative stimulation can be used to ‘standardize’ the brain-state and hereby, homogenize the group response to stimulation. Neuroanatomical and neurochemical profiling based on magnetic resonance imaging and spectroscopy can capture trait......-related and state-related variability. Fluctuations in brain-states can be traced online with functional brain imaging and inform the timing or other settings of transcranial brain stimulation. State-informed open-loop stimulation is aligned to the expression of a predefined brain state, according to prespecified...

  18. Costimulatory molecule programmed death-1 in the cytotoxic response during chronic hepatitis C

    Institute of Scientific and Technical Information of China (English)

    Juan Ramón Larrubia; Selma Benito-Martínez; Joaquín Miquel; Miryam Calvino; Eduardo Sanz-de-Villalobos; Trinidad Parra-Cid

    2009-01-01

    Hepatitis C virus (HCV)-specific CD8~+ T cells play an important role in the resolution of HCV infection. Nevertheless, during chronic hepatitis C these cells lack their effector functions and fail to control the virus.HCV has developed several mechanisms to escape immune control. One of these strategies is the upregulation of negative co-stimulatory molecules such us programmed death-1 (PD-1). This molecule is upregulated on intrahepatic and peripheral HCV-specific cytotoxic T cells during acute and chronic phases of the disease, whereas PD-1 expression is low in resolved infection. PD-1 expressing HCV-specific CD8~+ T cells are exhausted with impairment of several effector mechanisms, such as: type-1 cytokine production, expansion ability after antigen encounter and cytotoxic ability. However, PD-1 associated exhaustion can be restored by blocking the interaction between PD-1 and its ligand (PD-L1). After this blockade, HCV-specific CD8~+ T cells reacquire their functionality. Nevertheless,functional restoration depends on PD-1 expression level.High PD-1-expressing intrahepatic HCV-specific CD8~+ T cells do not restore their effector abilities after PD-1/ PD-L1 blockade. The mechanisms by which HCV is able to induce PD-1 up-regulation to escape immune control are unknown. Persistent TCR stimulation by a high level of HCV antigens could favour early PD-1 induction, but the interaction between HCV core protein and gC1q receptor could also participate in this process. The PD-1/PD-L1 pathway modulation could be a therapeutic strategy, in conjunction with the regulation of others co-stimulatory pathways, in order to restore immune response against HCV to succeed in clearing the infection.

  19. Polyphasic innate immune responses to acute and chronic LCMV infection: Innate immunity to acute & chronic viral infection

    OpenAIRE

    Norris, Brian A; Uebelhoer, Luke S.; Nakaya, Helder I.; Price, Aryn A; Grakoui, Arash; Pulendran, Bali

    2013-01-01

    Resolution of acute and chronic viral infections requires activation of innate cells to initiate and maintain adaptive immune responses. Here we report that infection with acute Armstrong (ARM) or chronic Clone 13 (C13) strains of lymphocytic choriomeningitis virus (LCMV) led to two distinct phases of innate immune response. During the first 72hr of infection, dendritic cells upregulated activation markers, and stimulated anti-viral CD8+ T cells, independent of viral strain. Seven days after ...

  20. The effect of repetitive transcranial magnetic stimulation on the changes of depressive like behaviors in chronic unpredictable mild stress model rats and its possible mechanism%重复经颅磁刺激对抑郁模型大鼠行为的改善作用及机制

    Institute of Scientific and Technical Information of China (English)

    刘高华; 陈冠婕; 陈怡环; 杨帆; 张瑞国; 彭正午; 谭庆荣

    2013-01-01

    Objective To investigate the effect of repetitive transcranial magnetic stimulation (rTMS) on the depressive like behaviors and expression of brain derived neurotrophic factor (BDNF),IL-1β and NF-κB of hippocampal in chronic unpredictable mild stress (CUMS) rats.Methods Thirty-two adult male rats were randomly divided into four groups (n =8):Control group,Control + rTMS group,CUMS group and CUMS + rTMS group.The sucrose preference test,forced swim test and open field test were used to evaluate depressive like behaviors for each groups.In addition,the expression of BDNF,NF-κB and IL-1 β in hippocampal were detected by western blot and ELISA after behavioral test,respectively.Results 1.The effects of rTMS on depressive like behaviors of CUMS rats:in the sucrose preference test,the sucrose preference rate of CUMS rats (0.67 ± 0.06) was significantly lower than Control group (0.91 ± 0.04),which was higher in the CUMS + rTMS group (0.83 ±0.08).In the forced swim test,the immobility time of CUMS group ((26.88 ± 11.33) s) was longer than Control group ((15.22 ± 6.75) s) and CUMS + rTMS group ((18.41 ± 6.95) s).In the open field test,both the total distance travelled and number of central area entry times of CUMS group((849.165 ± 769.01) cm,(7.42 ± 5.68))were significantly shorter ((6224.81 ± 1403.2) cm) and smaller (22.86 ± 3.72) than Control group,and those of the CUMS + rTMS were longer ((4105.57 ± 1516.92)cm) and larger (21.25 ± 3.45).All the behavioral results were statistically significant (P< 0.05).And of all the aforementioned behavioral parameters,there were no significant differences between Control group and Control + rTMS group(P>0.05).2.The effects of rTMS on the hippocampal expressions of BDNF,NF-κB and IL-1β in CUMS rats:compared with Control group,the hippocampal expression of BDNF in CUMS rats was significantly decreased,while the expressions of NF-κB and IL-1β in the hippocampus were significantly increased (P< 0.05).Compared

  1. Supramolecular architectures constructed using angular bipyridyl ligands

    CERN Document Server

    Barnett, S A

    2003-01-01

    This work details the synthesis and characterization of a series of coordination frameworks that are formed using bidentate angular N-donor ligands. Pyrimidine was reacted with metal(ll) nitrate salts. Reactions using Cd(NO sub 3) sub 2 receive particular focus and the analogous reactions using the linear ligand, pyrazine, were studied for comparison. In all cases, two-dimensional coordination networks were prepared. Structural diversity is observed for the Cd(ll) centres including metal-nitrate bridging. In contrast, first row transition metal nitrates form isostructural one-dimensional chains with only the bridging N-donor ligands generating polymeric propagation. The angular ligand, 2,4-bis(4-pyridyl)-1,3,5-triazine (dpt), was reacted with Cd(NO sub 3) sub 2 and Zn(NO sub 3) sub 2. Whereas Zn(NO sub 3) sub 2 compounds exhibit solvent mediated polymorphism, a range of structures were obtained for the reactions with Cd(NO sub 3) sub 2 , including the first example of a doubly parallel interpenetrated 4.8 sup...

  2. [Functional selectivity of opioid receptors ligands].

    Science.gov (United States)

    Audet, Nicolas; Archer-Lahlou, Elodie; Richard-Lalonde, Mélissa; Piñeyro-Filpo, Graciela

    2010-01-01

    Opiates are the most effective analgesics available for the treatment of severe pain. However, their clinical use is restricted by unwanted side effects such as tolerance, physical dependence and respiratory depression. The strategy to develop new opiates with reduced side effects has mainly focused on the study and production of ligands that specifically bind to different opiate receptors subtypes. However, this strategy has not allowed the production of novel therapeutic ligands with a better side effects profile. Thus, other research strategies need to be explored. One which is receiving increasing attention is the possibility of exploiting ligand ability to stabilize different receptor conformations with distinct signalling profiles. This newly described property, termed functional selectivity, provides a potential means of directing the stimulus generated by an activated receptor towards a specific cellular response. Here we summarize evidence supporting the existence of ligand-specific active conformations for two opioid receptors subtypes (delta and mu), and analyze how functional selectivity may contribute in the production of longer lasting, better tolerated opiate analgesics. double dagger.

  3. A versatile dinucleating ligand containing sulfonamide groups

    DEFF Research Database (Denmark)

    Sundberg, Jonas; Witt, Hannes; Cameron, Lisa

    2014-01-01

    Copper, iron, and gallium coordination chemistries of the new pentadentate bis-sulfonamide ligand 2,6-bis(N-2-pyridylmethylsulfonamido)-4-methylphenol (psmpH3) were investigated. PsmpH3 is capable of varying degrees of deprotonation, and notably, complexes containing the fully trideprotonated...

  4. Flexible Ligand Docking Using Differential Evolution

    DEFF Research Database (Denmark)

    Thomsen, René

    2003-01-01

    Molecular docking of biomolecules is becoming an increasingly important part in the process of developing new drugs, as well as searching compound databases for promising drug candidates. The docking of ligands to proteins can be formulated as an optimization problem where the task is to find...

  5. Receptor Binding Ligands to Image Infection

    NARCIS (Netherlands)

    Chianelli, M.; Boerman, O. C.; Malviya, G.; Galli, F.; Oyen, W. J. G.; Signore, A.

    2008-01-01

    The current gold standard for imaging infection is radiolabeled white blood cells. For reasons of safety, simplicity and cost, it would be desirable to have a receptor-specific ligand that could be used for imaging infection and that would allow a differential diagnosis between sterile and septic in

  6. Ligand iron catalysts for selective hydrogenation

    Science.gov (United States)

    Casey, Charles P.; Guan, Hairong

    2010-11-16

    Disclosed are iron ligand catalysts for selective hydrogenation of aldehydes, ketones and imines. A catalyst such as dicarbonyl iron hydride hydroxycyclopentadiene) complex uses the OH on the five member ring and hydrogen linked to the iron to facilitate hydrogenation reactions, particularly in the presence of hydrogen gas.

  7. Impact of spinal cord stimulation on sensory characteristics in complex regional pain syndrome type I - A randomized trial

    NARCIS (Netherlands)

    Kemler, MA; Reulen, JPH; Barendse, GAM; van Kleef, M; de Vet, HCW; van den Wildenberg, FAJM

    2001-01-01

    Background: A randomized trial was performed to assess the effect of spinal cord stimulation (SCS) on detection and pain thresholds for pressure, warmth, and cold and on the extent of mechanical hyperalgesia in patients with chronic complex regional pain syndrome type I. Methods: Fifty-four chronic

  8. Caloric vestibular stimulation in aphasic syndrome

    Directory of Open Access Journals (Sweden)

    David eWilkinson

    2013-12-01

    Full Text Available Caloric vestibular stimulation (CVS is commonly used to diagnose brainstem disorder but its therapeutic application is much less established. Based on the finding that CVS increases blood flow to brain structures associated with language and communication, we assessed whether the procedure has potential to relieve symptoms of post-stroke aphasia. Three participants, each presenting with chronic, unilateral lesions to the left hemisphere, were administered daily CVS for 4 consecutive weeks. Relative to their pre-treatment baseline scores, two of the three participants showed significant improvement on both picture and responsive naming at immediate and one-week follow-up. One of these participants also showed improved sentence repetition, and another showed improved auditory word discrimination. No adverse reactions were reported. These data provide the first, albeit tentative, evidence that CVS may relieve expressive and receptive symptoms of aphasia. A larger, sham-controlled study is now needed to further assess efficacy.

  9. Inhibitory effect on hepatitis B virus in vitro by a peroxisome proliferator-activated receptor-{gamma} ligand, rosiglitazone

    Energy Technology Data Exchange (ETDEWEB)

    Wakui, Yuta; Inoue, Jun [Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aobaku, Sendai 980-8574 (Japan); Ueno, Yoshiyuki, E-mail: yueno@mail.tains.tohoku.ac.jp [Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aobaku, Sendai 980-8574 (Japan); Fukushima, Koji; Kondo, Yasuteru; Kakazu, Eiji; Obara, Noriyuki; Kimura, Osamu; Shimosegawa, Tooru [Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aobaku, Sendai 980-8574 (Japan)

    2010-05-28

    Although chronic infection of hepatitis B virus (HBV) is currently managed with nucleot(s)ide analogues or interferon-{alpha}, the control of HBV infection still remains a clinical challenge. Peroxisome proliferator-activated receptor (PPAR) is a ligand-activated transcription factor, that plays a role in glucose and lipid metabolism, immune reactions, and inflammation. In this study, the suppressive effect of PPAR ligands on HBV replication was examined in vitro using a PPAR{alpha} ligand, bezafibrate, and a PPAR{gamma} ligand, rosiglitazone. The effects were examined in HepG2 cells transfected with a plasmid containing 1.3-fold HBV genome. Whereas bezafibrate showed no effect against HBV replication, rosiglitazone reduced the amount of HBV DNA, hepatitis B surface antigen, and hepatitis B e antigen in the culture supernatant. Southern blot analysis showed that the replicative intermediates of HBV in the cells were also inhibited. It was confirmed that GW9662, an antagonist of PPAR{gamma}, reduced the suppressive effect of rosiglitazone on HBV. Moreover, rosiglitazone showed a synergistic effect on HBV replication with lamivudine or interferon-{alpha}-2b. In conclusion, this study showed that rosiglitazone inhibited the replication of HBV in vitro, and suggested that the combination therapy of rosiglitazone and nucleot(s)ide analogues or interferon could be a therapeutic option for chronic HBV infection.

  10. Brain stimulation for intractable epilepsy: Anterior thalamus and responsive stimulation

    Directory of Open Access Journals (Sweden)

    Vibhor Krishna

    2014-01-01

    Full Text Available Despite medications, resective surgery, and vagal nerve stimulation, some patients with epilepsy continue to have seizures. In these patients, other approaches are urgently needed. The biological basis of stimulation of anterior thalamic nucleus and epileptogenic focus is presented. Results from two large randomized controlled trials Stimulation of Anterior Nucleus of Thalamus for Epilepsy (SANTE and Neuropace pivotal trial are discussed. Neuromodulation provides effective treatment for a select group of refractory epilepsy patients. Future investigations into the mechanism underlying ′response′ to brain stimulation are desired.

  11. Catalposide is a natural agonistic ligand of peroxisome proliferator-activated receptor-{alpha}

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Ji Hae; Jun, Hee-jin; Hoang, Minh-Hien; Jia, Yaoyao [Division of Food Bioscience and Technology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of); Department of Biotechnology, Graduate School of Life Sciences and Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of); Han, Xiang Hua [College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk 361-763 (Korea, Republic of); Lee, Dong-Ho [Department of Biotechnology, Graduate School of Life Sciences and Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of); Lee, Hak-Ju [Division of Green Business Management, Department of Forest Resources Utilization, Korean Forest Research Institute, Seoul 130-712 (Korea, Republic of); Hwang, Bang Yeon, E-mail: byhwang@chungbuk.ac.kr [College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk 361-763 (Korea, Republic of); Lee, Sung-Joon, E-mail: junelee@korea.ac.kr [Division of Food Bioscience and Technology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of); Department of Biotechnology, Graduate School of Life Sciences and Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of)

    2012-06-15

    Highlights: Black-Right-Pointing-Pointer Catalposide is a novel ligand for PPAR{alpha}. Black-Right-Pointing-Pointer Cell stimulated with catalposide improved fatty acid uptake, regulated target genes in fatty acid {beta}-oxidation and synthesis. Black-Right-Pointing-Pointer Catalposdie reduces hepatic triacylglycerides. Black-Right-Pointing-Pointer Theses demonstrate catalposide could ameliorate hyperlipidemia and hepatic steatosis. -- Abstract: Peroxisome proliferator-activated receptor-alpha (PPAR{alpha}) is a nuclear receptor that regulates the expression of genes related to cellular lipid uptake and oxidation. Thus, PPAR{alpha} agonists may be important in the treatment of hypertriglyceridemia and hepatic steatosis. In this study, we demonstrated that catalposide is a novel natural PPAR{alpha} agonist, identified from reporter gene assay-based activity screening with approximately 900 natural plant and seaweed extracts. Results of time-resolved fluorescence resonance energy transfer analyses suggested that the compound interacted directly with the ligand-binding domain of PPAR{alpha}. Cultured hepatocytes stimulated with catalposide exhibited significantly reduced cellular triglyceride concentrations, by 21%, while cellular uptake of fatty acids was increased, by 70% (P < 0.05). Quantitative PCR analysis revealed that the increase in cellular fatty acid uptake was due to upregulation of fatty acid transporter protein-4 (+19% vs. the control) in cells stimulated with catalposide. Additionally, expression of genes related to fatty acid oxidation and high-density lipoprotein metabolism were upregulated, while that of genes related to fatty acid synthesis were suppressed. In conclusion, catalposide is hypolipidemic by activation of PPAR{alpha} via a ligand-mediated mechanism that modulates the expression of in lipid metabolism genes in hepatocytes.

  12. The Positron Emission Tomography Ligand DAA1106 Binds With High Affinity to Activated Microglia in Human Neurological Disorders

    OpenAIRE

    2008-01-01

    Chronic microglial activation is an important component of many neurological disorders, and imaging activated microglia in vivo will enable the detection and improved treatment of neuroinflammation. 1-(2-Chlorphenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline-carbox-amide (PK11195), a peripheral benzodiazepine receptor ligand, has been used to image neuroinflammation, but the extent to which PK11195 binding distinguishes activated microglia and reactive astrocytes is unclear. Moreover, PK1119...

  13. Stimulated Cavity-Optomechanics

    CERN Document Server

    Bahl, Gaurav; Tomes, Matthew; Carmon, Tal

    2011-01-01

    Stimulated Brillouin interaction between sound and light, known to be the strongest optical nonlinearity common to all amorphous and crystalline dielectrics, has been widely studied in fibers and bulk materials but rarely in optical microresonators. The possibility of experimentally extending this principle to excite mechanical resonances in photonic microsystems, for sensing and frequency reference applications, has remained largely unexplored. The challenge lies in the fact that microresonators inherently have large free spectral range, while the phase matching considerations for the Brillouin process require optical modes of nearby frequencies but with different wavevectors. We rely on high-order transverse optical modes to relax this limitation. Here we report on the experimental excitation of mechanical resonances ranging from 49 to 1400 MHz by using forward Brillouin scattering. These natural mechanical resonances are excited in ~100 um silica microspheres, and are of a surface-acoustic whispering-galle...

  14. Collective stimulated Brillouin backscatter

    CERN Document Server

    Lushnikov, Pavel M

    2007-01-01

    We develop the statistical theory of the stimulated Brillouin backscatter (BSBS) instability of a spatially and temporally partially incoherent laser beam for laser fusion relevant plasma. We find a new regime of BSBS which has a much larger threshold than the classical threshold of a coherent beam in long-scale-length laser fusion plasma. Instability is collective because it does not depend on the dynamics of isolated speckles of laser intensity, but rather depends on averaged beam intensity. We identify convective and absolute instability regimes. Well above the incoherent threshold the coherent instability growth rate is recovered. The threshold of convective instability is inside the typical parameter region of National Ignition Facility (NIF) designs although current NIF bandwidth is not large enough to insure dominance of collective instability and suggests lower instability threshold due to speckle contribution. In contrast, we estimate that the bandwidth of KrF-laser-based fusion systems would be larg...

  15. Myeloperoxidase Stimulates Neutrophil Degranulation.

    Science.gov (United States)

    Grigorieva, D V; Gorudko, I V; Sokolov, A V; Kostevich, V A; Vasilyev, V B; Cherenkevich, S N; Panasenko, O M

    2016-08-01

    Myeloperoxidase, heme enzyme of azurophilic granules in neutrophils, is released into the extracellular space in the inflammation foci. In neutrophils, it stimulates a dose-dependent release of lactoferrin (a protein of specific granules), lysozyme (a protein of specific and azurophilic granules), and elastase (a protein of azurophilic granules). 4-Aminobenzoic acid hydrazide, a potent inhibitor of peroxidase activity of myeloperoxidase, produced no effect on neutrophil degranulation. Using signal transduction inhibitors (genistein, methoxyverapamil, wortmannin, and NiCl2), we demonstrated that myeloperoxidase-induced degranulation of neutrophils resulted from enzyme interaction with the plasma membrane and depends on activation of tyrosine kinases, phosphatidylinositol 3-kinases (PI3K), and calcium signaling. Myeloperoxidase modified by oxidative/halogenation stress (chlorinated and monomeric forms of the enzyme) lost the potency to activate neutrophil degranulation.

  16. Collective stimulated Brillouin scatter

    CERN Document Server

    Korotkevich, Alexander O; Rose, Harvey A

    2011-01-01

    We develop a statistical theory of stimulated Brillouin backscatter (BSBS) of a spatially and temporally partially incoherent laser beam for laser fusion relevant plasma. We find a new collective regime of BSBS which has a much larger threshold than the classical threshold of a coherent beam in long-scale-length laser fusion plasma. We identify two contributions to BSBS convective instability increment. The first is collective with intensity threshold independent of the laser correlation time and controlled by diffraction. The second is independent of diffraction, it grows with increase of the correlation time and does not have an intensity threshold. The instability threshold is inside the typical parameter region of National Ignition Facility (NIF). We also find that the bandwidth of KrF-laser-based fusion systems would be large enough to allow additional suppression of BSBS.

  17. Stimulated coherent transition radiation

    Energy Technology Data Exchange (ETDEWEB)

    Hung-chi Lihn

    1996-03-01

    Coherent radiation emitted from a relativistic electron bunch consists of wavelengths longer than or comparable to the bunch length. The intensity of this radiation out-numbers that of its incoherent counterpart, which extends to wavelengths shorter than the bunch length, by a factor equal to the number of electrons in the bunch. In typical accelerators, this factor is about 8 to 11 orders of magnitude. The spectrum of the coherent radiation is determined by the Fourier transform of the electron bunch distribution and, therefore, contains information of the bunch distribution. Coherent transition radiation emitted from subpicosecond electron bunches at the Stanford SUNSHINE facility is observed in the far-infrared regime through a room-temperature pyroelectric bolometer and characterized through the electron bunch-length study. To measure the bunch length, a new frequency-resolved subpicosecond bunch-length measuring system is developed. This system uses a far-infrared Michelson interferometer to measure the spectrum of coherent transition radiation through optical autocorrelation with resolution far better than existing time-resolved methods. Hence, the radiation spectrum and the bunch length are deduced from the autocorrelation measurement. To study the stimulation of coherent transition radiation, a special cavity named BRAICER is invented. Far-infrared light pulses of coherent transition radiation emitted from electron bunches are delayed and circulated in the cavity to coincide with subsequent incoming electron bunches. This coincidence of light pulses with electron bunches enables the light to do work on electrons, and thus stimulates more radiated energy. The possibilities of extending the bunch-length measuring system to measure the three-dimensional bunch distribution and making the BRAICER cavity a broadband, high-intensity, coherent, far-infrared light source are also discussed.

  18. 先天抑郁对大鼠幼年结肠乙酸刺激致慢性内脏高敏感的影响%Effect of inherent depression on chronic visceral hypersensitivity induced by colon acetate stimulation in neonatal rats

    Institute of Scientific and Technical Information of China (English)

    刘懿萱; 张永燊; 段丽萍; 张璐; 杨长青

    2015-01-01

    Objective:To explore the effect of inherent depression on chronic visceral hypersensitivity. The differences of visceral sensitivity, colitis, and brain activation between Fawn-Hooded ( FH/Wjd) and Sprague-Dawley( SD) rats were identified after neonatal colon acetate stimulation.Methods:The specific pathogen free Fawn-Hooded (FH/Wjd) and Sprague-Dawley(SD) rats were used to establish irritable bowel syndrome (IBS) model.The visceral sensitivity was measured by colorectal distension (CRD). The expression of 5-hydroxytryptamine (5-HT), mast cell (MC), indoleamine 2,3-dioxygenase (IDO) in colon and IDO in specific cerebral regions were detected through immunohistochemistry.Results:Ab-dominal withdrawal reflex ( AWR) scores showed that visceral sensitivity of acetate-enema groups was sig-nificantly higher than that of saline-enema groups ( FH/Wjd:2.44 ±0.04 vs.1.96 ±0.07, P Besides, the MC amounts of control and IBS group of FH/Wjd rats were significantly more than that of SD IBS group rats ( P<0 .01 ) .The IDO and 5-HT positive cells in colonic mucosa of IBS group of both SD and FH/Wjd rats were significantly more than those of their control groups, respectively(P <0.01). The IDO, 5-HT positive cells in colonic mucosa of both control and IBS group of FH/Wjd rats were significantly more than those of both control and IBS group of SD rats ( control:IDO,24.64 ±2.22 vs. 15.52 ±1.39;5-HT,21.32 ±1.26 vs.12.72 ±1.12.IBS: IDO,44.92 ±2.31 vs.20.85 ±1.72;5-HT, 31.84 ±1.57 vs.19.65 ±1.09.P <0.01).The expression of IDO in prelimbic cortex (PrL) areas of FH/Wjd IBS rats was significantly higher than that of IBS group of SD rats (49.60 ±4.31 vs. 35.60 ±2.42, P <0.01) , and the expression of IDO in rostral anterior cingulate cortex ( rACC) areas of FH/Wjd IBS rats was significantly more than that of FH/Wjd control rats (45.44 ±1.16 vs.34.08 ± 2.76, P <0.01) .Conclusion:Inherent depressive FH/Wjd rats were more sensitive to neonatal colon acetate stimulation, presenting

  19. [Conditioning of emotional behavior caused by hypothalamic stimulation (3): The learned behavior caused by hypothalamic stimulation in rabbits].

    Science.gov (United States)

    Yanaura, S; Funada, K; Abe, Y; Hosokawa, T

    1976-09-01

    In the present study, the learned behavior caused by hypothalamic electrical stimulation was examined in order to determine the effects of psychotropic drugs. Subjects were albino male rabbits with electrodes chronically implanted in the hypothalamic area. A shuttle box, which was adjusted for behavioral pharmacological estimation of drugs in rabbits, was used. A buzzer sound (85dB) and electrical stimulation of hypothalamus (100 HZ, 1 msec, 1.2-2.0V) were used as the conditional stimulation (CS) and unconditional stimulation (UCS), respectively. The same animal was trained in habituation to a buzzer sound as the CS. For avoidance conditioning in a two-compartment situation, the animal was placed in a shuttle box divided by a hurdle situated at the middle of two-compartments. After the CS was presented for 10 sec, the UCS was given. The animals were subjected to 15 conditioning trials per day. The avoidance and escape behavior model became as distinct by hypothalamic stimulation as by UCS. After termination of the experiments, extinction trials were carried out after which the animals were sacrificed, and localization of the stimulating electrodes was determined histologically.

  20. Chronic Kidney Diseases

    Science.gov (United States)

    ... Room? What Happens in the Operating Room? Chronic Kidney Diseases KidsHealth > For Kids > Chronic Kidney Diseases Print ... re talking about your kidneys. What Are the Kidneys? Your kidneys are tucked under your lower ribs ...

  1. Diet - chronic kidney disease

    Science.gov (United States)

    ... page: //medlineplus.gov/ency/article/002442.htm Diet - chronic kidney disease To use the sharing features on this page, ... make changes to your diet when you have chronic kidney disease. These changes may include limiting fluids, eating a ...

  2. Chronic granulomatous disease

    Science.gov (United States)

    CGD; Fatal granulomatosis of childhood; Chronic granulomatous disease of childhood; Progressive septic granulomatosis ... In chronic granulomatous disease (CGD), immune system cells called phagocytes are unable to kill some types of bacteria and ...

  3. Chronic mucus hypersecretion

    DEFF Research Database (Denmark)

    Ulrik, Charlotte Suppli; von Linstow, Marie-Louise; Nepper-Christensen, Steen;

    2005-01-01

    To investigate if chronic mucus hypersecretion (CMH) can be used as a marker of asthma in young adults.......To investigate if chronic mucus hypersecretion (CMH) can be used as a marker of asthma in young adults....

  4. Chronic tophaceous gout

    Directory of Open Access Journals (Sweden)

    Thappa D

    1993-01-01

    Full Text Available A rare case of chronic tophaceous gout, in a 27-year-old female on diuretics for chronic congestive cardiac failure with characteristic histopathological and radiological changes is reported.

  5. Chronic Pancreatitis in Children

    Science.gov (United States)

    ... maintaining good health. Can chronic pancreatitis give my child cancer? If your child has chronic pancreatitis, he or she will be at an increased risk of developing pancreatic cancer compared to the general population. The degree of ...

  6. People Experiencing Chronic Homelessness

    Science.gov (United States)

    ... Goals Ending Chronic Homelessness Share This: Ending Chronic Homelessness Last updated on January 19, 2017 We can ... the USICH newsletter. We know how to end homelessness. Let's do it, together. Sign up for our ...

  7. Targeting Ligand-Dependent and Ligand-Independent Androgen Receptor Signaling in Prostate Cancer

    Science.gov (United States)

    2015-10-01

    Award Number: W81XWH-12-1-0288 TITLE: Targeting Ligand-Dependent and Ligand-Independent Androgen Receptor Signaling in Prostate Cancer...average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed...and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of

  8. Effect of the different winding methods of coil on electromagnetic field during transcranial magnetic stimulation.

    Science.gov (United States)

    Yang, Shuo; Xu, Guizhi; Wang, Lei; Zhang, Xiu

    2008-01-01

    Transcranial magnetic stimulation (TMS) is a powerful, non-invasive tool for investigating functions in the brain. The target inside the head is stimulated with eddy currents induced in the tissues by the time-varying magnetic field. TMS has been used in several applications in medical and clinical research which include brain mapping, treatment of mood disorder and schizophrenia, treatment of epilepsy, treatment of chronic pain and so on. The stimulation effect can be affected by the stimulation intensity. For coils with the same shape, different winding methods make the coil have different stimulation intensity. In this paper, three different methods for winding circular coils are discussed. The electromagnetic fields induced by the three different circular coils were analyzed. The results show that the circular coil with the pancake coil winding has the strongest stimulation intensity.

  9. Neuropeptides and neuropeptide receptors: drug targets, and peptide and non-peptide ligands: a tribute to Prof. Dieter Seebach.

    Science.gov (United States)

    Hoyer, Daniel; Bartfai, Tamas

    2012-11-01

    both central and peripheral nervous system disorders. Both, receptor subtype-selective antagonists and agonists are being developed, as illustrated by the success of somatostatin agonists, angiotensin, and endothelin antagonists, and the expected clinical applications of NK-1/2/3 (substance P) receptor antagonists, CRF, vasopressin, NPY, neurotensin, orexin antagonists, or neuropeptide receptor modulators; such ligands have efficacy in preclinical or clinical models of pain and neuropsychiatric diseases, such as migraine, chronic/neuropathic pain, anxiety, sleep disorders, depression, and schizophrenia. In addition, both positive and negative allosteric modulators have been described with interesting in vivo activities (e.g., at galanin receptors). The field has become more complex now that an increasing number of heteromeric neuropeptide receptors are described, e.g., ghrelin receptors with 5-HT(2C) or dopamine D(1), D(2) receptors. At long last, structure-based drug discovery can now be envisaged with confidence, since crystal or solution structure of GPCRs and GPCR-ligand complexes, including peptide receptors, are published almost on a monthly basis. Finally, although most compounds acting at peptide receptors are still peptidomimetics, the last decade has seen the emergence of low-molecular-weight nonpeptide ligands (e.g., for orexin, ghrelin, or neurokinin receptors), and surprising progress has been made with β- and γ-peptides as very stable and potent mimetics of, e.g., somatostatin (SRIF), where the native SRIF has a half-life limited to 2-3 min. This last point will be illustrated more specifically, as we have had a long-standing collaboration with Prof. D. Seebach to whom this review is dedicated at the occasion of his 75th birthday.

  10. The effect of TSH change per year on the risk of incident chronic kidney disease in euthyroid subjects.

    Science.gov (United States)

    Lee, Da Young; Jee, Jae Hwan; Jun, Ji Eun; Kim, Tae Hyuk; Jin, Sang-Man; Hur, Kyu Yeon; Kim, Sun Wook; Chung, Jae Hoon; Lee, Moon-Kyu; Kim, Jae Hyeon

    2017-02-01

    The objective of this study is to evaluate the predictive values of baseline thyroid-stimulating hormone and the rate of thyroid-stimulating hormone change within the euthyroid state on the development of chronic kidney disease. We conducted a longitudinal study in 17,067 Korean adults with normal thyroid function and no history of thyroid disease. Incident chronic kidney disease was defined as an estimated glomerular filtration rate chronic kidney disease or at the final visit in subjects without chronic kidney disease, divided by the observation period (years). Subjects were stratified into quintiles according to rates of thyroid-stimulating hormone change. During 86,583 person-years of follow-up (median follow-up 5.2 years), there were 561 incident cases of chronic kidney disease. The risk of incident chronic kidney disease was significantly higher in subjects with rapid increases (quintile 5) or decreases (quintile 1) in thyroid-stimulating hormone levels compared to the reference group (quintile 3). In fully adjusted models, the hazard ratios of quintiles 1 and 5 were 3.15 (95 % confidence interval 2.34 to 4.24; p chronic kidney disease. The development of chronic kidney disease is associated with the rate of changes in thyroid-stimulating hormone level rather than with baseline thyroid-stimulating hormone levels.

  11. Fusion of ligand-coated nanoparticles with lipid bilayers: effect of ligand flexibility.

    Science.gov (United States)

    Van Lehn, Reid C; Alexander-Katz, Alfredo

    2014-08-07

    Amphiphilic, monolayer-protected gold nanoparticles (AuNPs) have recently been shown to insert into and fuse with lipid bilayers, driven by the hydrophobic effect. The inserted transmembrane state is stabilized by the "snorkeling" of charged ligand end groups out of the bilayer interior. This snorkeling process is facilitated by the backbone flexibility of the alkanethiol ligands that comprise the monolayer. In this work, we show that fusion is favorable even in the absence of backbone flexibility by modeling the ligands as rigid rods. For rigid ligands, snorkeling is still accommodated by rotations of the ligand with respect to the grafting point, but the process incurs a more significant free energy penalty than if the backbone were fully flexible. We show that the rigid rod model predicts similar trends in the free energy change for insertion as the previous flexible model when the size of the AuNPs is varied. However, the rigidity of the ligand backbone reduces the overall magnitude of the free energy change compared to that of the flexible model. These results thus generalize previous findings to systems with hindered backbone flexibility due to either structural constraints or low temperature.

  12. Disruption of Immune Regulation by Microbial Pathogens and Resulting Chronic Inflammation

    OpenAIRE

    2013-01-01

    Activation of the immune response is a tightly regulated, coordinated effort that functions to control and eradicate exogenous microorganisms, while also responding to endogenous ligands. Determining the proper balance of inflammation is essential, as chronic inflammation leads to a wide array of host pathologies. Bacterial pathogens can instigate chronic inflammation via an extensive repertoire of evolved evasion strategies that perturb immune regulation. In this review, we discuss two model...

  13. Optically stimulated differential impedance spectroscopy

    Science.gov (United States)

    Maxey, Lonnie C; Parks, II, James E; Lewis, Sr., Samuel A; Partridge, Jr., William P

    2014-02-18

    Methods and apparatuses for evaluating a material are described. Embodiments typically involve use of an impedance measurement sensor to measure the impedance of a sample of the material under at least two different states of illumination. The states of illumination may include (a) substantially no optical stimulation, (b) substantial optical stimulation, (c) optical stimulation at a first wavelength of light, (d) optical stimulation at a second wavelength of light, (e) a first level of light intensity, and (f) a second level of light intensity. Typically a difference in impedance between the impedance of the sample at the two states of illumination is measured to determine a characteristic of the material.

  14. Deep Brain Electrical Stimulation in Epilepsy

    Science.gov (United States)

    Rocha, Luisa L.

    2008-11-01

    The deep brain electrical stimulation has been used for the treatment of neurological disorders such as Parkinson's disease, chronic pain, depression and epilepsy. Studies carried out in human brain indicate that the application of high frequency electrical stimulation (HFS) at 130 Hz in limbic structures of patients with intractable temporal lobe epilepsy abolished clinical seizures and significantly decreased the number of interictal spikes at focus. The anticonvulsant effects of HFS seem to be more effective in patients with less severe epilepsy, an effect associated with a high GABA tissue content and a low rate of cell loss. In addition, experiments using models of epilepsy indicate that HFS (pulses of 60 μs width at 130 Hz at subthreshold current intensity) of specific brain areas avoids the acquisition of generalized seizures and enhances the postictal seizure suppression. HFS is also able to modify the status epilepticus. It is concluded that the effects of HFS may be a good strategy to reduce or avoid the epileptic activity.