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Sample records for activation therapy pat

  1. Photon activated therapy (PAT) using monochromatic Synchrotron x-rays and iron oxide nanoparticles in a mouse tumor model: feasibility study of PAT for the treatment of superficial malignancy

    PubMed Central

    2012-01-01

    Background X-rays are known to interact with metallic nanoparticles, producing photoelectric species as radiosensitizing effects, and have been exploited in vivo mainly with gold nanoparticles. The purpose of this study was to investigate the potential of sensitizing effect of iron oxide nanoparticles for photon activated therapy. Methods X-rays photon activated therapy (PAT) was studied by treating CT26 tumor cells and CT26 tumor-bearing mice loaded with 13-nm diameter FeO NP, and irradiating them at 7.1 keV near the Fe K-edge using synchrotron x-rays radiation. Survival of cells was determined by MTT assay, and tumor regression assay was performed for in vivo model experiment. The results of PAT treated groups were compared with x-rays alone control groups. Results A more significant reduction in viability and damage was observed in the FeO NP-treated irradiated cells, compared to the radiation alone group (p < 0.04). Injection of FeO NP (100 mg/kg) 30 min prior to irradiation elevated the tumor concentration of magnetite to 40 μg of Fe/g tissue, with a tumor-to-muscle ratio of 17.4. The group receiving FeO NP and radiation of 10 Gy showed 80% complete tumor regression (CTR) after 15–35 days and relapse-free survival for up to 6 months, compared to the control group, which showed growth retardation, resulting in 80% fatality. The group receiving radiation of 40 Gy showed 100% CTR in all cases irrespective of the presence of FeO NP, but CTR was achieved earlier in the PAT-treated group compared with the radiation alone group. Conclusions An iron oxide nanoparticle enhanced therapeutic effect with relatively low tissue concentration of iron and 10 Gy of monochromatic X-rays. Since 7.1 keV X-rays is attenuated very sharply in the tissue, FeO NP-PAT may have promise as a potent treatment option for superficial malignancies in the skin, like chest wall recurrence of breast cancer. PMID:23111059

  2. Use of modified Fraser's stain in Promoting Activity Test (PAT).

    PubMed

    Borràs, M

    1988-09-01

    The Promoting Activity Test (PAT) requires a staining procedure that allows rapid, accurate and reliable counting of mitotic figures. We propose use of Fraser's kernechtrot-crystal violet technique, but eliminating the picric-alcoholic differentiation to avoid fading. This modified protocol gives higher mitotic counts in adult mouse adrenal cortex than the hematoxylin-eosin originally used, especially with respect to less conspicuous prophases. PMID:2464217

  3. Pat Mora.

    ERIC Educational Resources Information Center

    Corsaro, Julie

    1997-01-01

    Discusses Pat Mora's career as a children's book author and aspects of her work: the Latino experience, bilingualism, family life, desert landscape, and folk tales. Provides classroom activities in art, creative writing, social studies, geography, drama. Provides a selected bibliography of Mora's work. (PEN)

  4. Photon-activation therapy

    SciTech Connect

    Fairchild, R.G.; Bond, V.P.

    1982-01-01

    Photon Activation Therapy (PAT) is a technique in which radiation dose to tumor is enhanced via introduction of stable /sup 127/I in the form of iodinated deoxyuridine (IdUrd). Stimulation of cytotoxic effects from IdUrd is accomplished by activation with external (or implanted) radiation sources. Thus, accumulations of this nucleoside in actively competing cellpools do not preclude therapy in so far as such tissues can be excluded from the radiation field. Calculations show that 5% replacement of thymidine (Tyd) in tumor DNA should enhance the biological effectiveness of a given photon radiotherapy dose by a factor of approx. 3. Proportionally higher gains would result from higher replacements of Tyd and IdUrd. In addition, biological response is enhanced by chemical sensitization with IdUrd. The data indicate that damage from photon activation as well as chemical sensitization does not repair. Thus, at low dose rates, a further increase in therapeutic gain should accrue as normal tissues are allowed to repair and regenerate. A samarium-145 source has been developed for PAT, with activating x-ray energies of from 38 to 45 keV. Favorable clinical results can be expected through the use of IdUrd and protracted irradiations with low energy x-rays. In particular, PAT may provide unique advantages at selected sites such as brain, or head and neck tumors. (ERB)

  5. Workshop on photon activation therapy: proceedings

    SciTech Connect

    Fairchild, R.G.

    1985-04-18

    This Workshop was held concurrently with an IAEA Research Coordination Meeting on Exploration of the Possibility of High-LET Radiation for Non-conventional Radiotherapy in Cancer. The Workshop on Photon Activation Therapy (PAT) was given as a special session on April 18, as it was thoght PAT might eventually be found to be attractive to developing countries, which is a major concern of the IAEA. An effort was made to bring together representatives of the various groups known to be actively working on PAT; these included investigators from Sweden and Japan as well as the US. It is hoped that this compendium of papers will be of use to those currently active in this developing field, as well as to those who might join this area of endeavor in the future.

  6. Implementing PAT with Standards

    NASA Astrophysics Data System (ADS)

    Chandramohan, Laakshmana Sabari; Doolla, Suryanarayana; Khaparde, S. A.

    2016-02-01

    Perform Achieve Trade (PAT) is a market-based incentive mechanism to promote energy efficiency. The purpose of this work is to address the challenges inherent to inconsistent representation of business processes, and interoperability issues in PAT like cap-and-trade mechanisms especially when scaled. Studies by various agencies have highlighted that as the mechanism evolves including more industrial sectors and industries in its ambit, implementation will become more challenging. This paper analyses the major needs of PAT (namely tracking, monitoring, auditing & verifying energy-saving reports, and providing technical support & guidance to stakeholders); and how the aforesaid reasons affect them. Though current technologies can handle these challenges to an extent, standardization activities for implementation have been scanty for PAT and this work attempts to evolve them. The inconsistent modification of business processes, rules, and procedures across stakeholders, and interoperability among heterogeneous systems are addressed. This paper proposes the adoption of specifically two standards into PAT, namely Business Process Model and Notation for maintaining consistency in business process modelling, and Common Information Model (IEC 61970, 61968, 62325 combined) for information exchange. Detailed architecture and organization of these adoptions are reported. The work can be used by PAT implementing agencies, stakeholders, and standardization bodies.

  7. Functional dissection and evidence for intercellular transfer of the heterocyst-differentiation PatS morphogen.

    PubMed

    Corrales-Guerrero, Laura; Mariscal, Vicente; Flores, Enrique; Herrero, Antonia

    2013-06-01

    The formation of a diazotrophic cyanobacterial filament represents a simple example of biological development. In Anabaena, a non-random pattern of one nitrogen-fixing heterocyst separated by about 10 photosynthetic vegetative cells results from lateral inhibition elicited by the cells differentiating into heterocysts. Key to this process is the patS gene, which has been shown to produce an inhibitor of heterocyst differentiation that involves the C-terminal RGSGR pentapeptide. Complementation of a ΔpatS Anabaena mutant with different versions of PatS, including point mutations or tag fusions, showed that patS is translated into a 17-amino acid polypeptide. Alterations in the N-terminal part of PatS produced inhibition of heterocyst differentiation, thus this part of the peptide appears necessary for proper processing and self-immunity in the producing cells. Alterations in the C-terminal part of PatS led to over-differentiation, thus supporting its role in inhibition of heterocyst differentiation. A polypeptide, produced in proheterocysts, consisting of a methionine followed by the eight, but not the five, terminal amino acids of PatS recreated the full activity of the native peptide. Immunofluorescence detection showed that an RGSGR-containing peptide accumulated in the cells adjacent to the producing proheterocysts, illustrating intercellular transfer of a morphogen in the cyanobacterial filaments. PMID:23663167

  8. Patent information analysis methods and their effective use : A study through activities of PAT-LIST Research Workshop adviser

    NASA Astrophysics Data System (ADS)

    Nakamura, Sakae

    For effective use of technical information, various analytical tools and methods (e.g., patent map analysis) have been proposed. It was against this background that the “PAT-LIST Research Workshop” (supported by Raytec Co., Ltd.) was established in 2006. This article discusses, as an example, some actual research subject that the author as an adviser to the forum has studied through our activities in the past six years, especially the subject for 2010 (unveiling intellectual property strategies of specified enterprises from technical information analysis results). Practically useful analysis methods will be proposed showing some points of notes in analysis about the methods. What is also introduced is macroanalysis using text mining tools and the significance of controlled technical classification in a problem/solution map for determining critical fields.

  9. Ten-year follow-up of a prospective trial for the targeted therapy of gastric cancer with the human monoclonal antibody PAT-SC1.

    PubMed

    Hensel, Frank; Timmermann, Wolfgang; von Rahden, Burkhard H A; Rosenwald, Andreas; Brändlein, Stephanie; Illert, Bertram

    2014-03-01

    The fully human monoclonal antibody PAT-SC1 is specific for an isoform of CD55 (decay-accelerating factor) designated CD55PAT-SC1. This antigen is expressed in the majority (80%) of gastric cancers (GCs), and the antibody induces tumour cell-specific apoptosis in vitro as well as in vivo. PAT-SC1, therefore, has been deemed promising as a therapeutic agent. Here, we describe the results of an academic clinical study performed in a neoadjuvant setting with resectable GC patients. Patients undergoing treatment for GC between 1997 and 2001 were tested for CD55PAT-SC1 expression. Fifty-one resectable patients that tested positively received a single administration of 20 mg PAT-SC1 48 h prior to surgery. They underwent standard surgery with either subtotal or total gastrectomy with bursectomy, omentectomy and a modified D2-lymphadenectomy, aimed at R0 resection. Primary endpoints of the present study were to evaluate side-effects of the PAT-SC1 antibody treatment and to evaluate histopathological effects such as tumour regression and induction of apoptosis. Long-term survival was a secondary endpoint. Administration of PAT-SC1 appeared safe with only reversible side-effects according to WHO grade I and II. Despite the low‑dose of the antibody, 81.6% of the patients showed signs of increased apoptosis within the primary tumour and 60% showed signs of tumour cell regression. Comparison of the 10-year survival rates of the R0-resected CD55PAT-SC1-positive patients treated with the PAT-SC1 antibody with a historical collective of R0-resected CD55PAT-SC1-positive patients not treated with PAT-SC1 indicated a survival benefit in the treated patients. Furthermore, comparison of the patient survival of CD55PAT‑SC1-positive vs. CD55PAT-SC1-negative groups suggested that CD55PAT-SC1 antigen expression is an independent predictor of poor survival in a Cox regression analysis. Antibody PAT-SC1 may be a useful additive therapeutic agent in the treatment of patients with CD55PAT

  10. Role of gibberellins in parthenocarpic fruit development induced by the genetic system pat-3/pat-4 in tomato.

    PubMed

    Fos, Mariano; Proaño, Karina; Nuez, Fernando; García-Martínez, José L.

    2001-04-01

    The role of gibberellins (GAs) in the induction of parthenocarpic fruit-set and growth by the pat-3/pat-4 genetic system in tomato (Lycopersicon esculentum Mill.) was investigated using wild type (WT; Cuarenteno) and a near-isogenic line derived from the German line RP75/59 (the source of pat-3/pat-4 parthenocarpy). Unpollinated WT ovaries degenerated but GA3 application induced parthenocarpic fruit growth. On the contrary, parthenocarpic growth of pat-3/pat-4 fruits, which occurs in the absence of pollination and hormone treatment, was not affected by applied GA3. Unpollinated pat-3/pat-4 fruit growth was negated by paclobutrazol, an inhibitor of ent-kaurene oxidase, and this inhibitory effect was negated by GA3. The quantification of the main GAs of the early 13-hydroxylation pathway (GA1, GA8, GA19, GA20, GA29 and GA44) in unpollinated ovaries at 3 developmental stages (flower bud, FB; pre-anthesis, PR; and anthesis, AN), by gas chromatography-selected ion monitoring, showed that the concentration of most of them was higher in pat-3/pat-4 than in WT ovaries at PR and AN stages. The concentration of GA1, suggested previously to be the active GA in tomate, was 2-4 times higher. Unpollinated pat-3/pat-4 ovaries at FB, PR and AN stages also contained relatively high amounts (5-12 ng g-1) of GA3, a GA found at less than 0.5 ng g-1 in WT ovaries. It is concluded that the mutations pat-3/pat-4 may induce natural facultative parthenocarpy capacity in tomato by increasing the concentration of GA1 and GA3 in the ovaries before pollination. PMID:11299021

  11. Role of gibberellins in parthenocarpic fruit development induced by the genetic system pat-3/pat-4 in tomato.

    PubMed

    Fos, Mariano; Proaño, Karina; Nuez, Fernando; García-Martínez, José L.

    2001-04-01

    The role of gibberellins (GAs) in the induction of parthenocarpic fruit-set and growth by the pat-3/pat-4 genetic system in tomato (Lycopersicon esculentum Mill.) was investigated using wild type (WT; Cuarenteno) and a near-isogenic line derived from the German line RP75/59 (the source of pat-3/pat-4 parthenocarpy). Unpollinated WT ovaries degenerated but GA3 application induced parthenocarpic fruit growth. On the contrary, parthenocarpic growth of pat-3/pat-4 fruits, which occurs in the absence of pollination and hormone treatment, was not affected by applied GA3. Unpollinated pat-3/pat-4 fruit growth was negated by paclobutrazol, an inhibitor of ent-kaurene oxidase, and this inhibitory effect was negated by GA3. The quantification of the main GAs of the early 13-hydroxylation pathway (GA1, GA8, GA19, GA20, GA29 and GA44) in unpollinated ovaries at 3 developmental stages (flower bud, FB; pre-anthesis, PR; and anthesis, AN), by gas chromatography-selected ion monitoring, showed that the concentration of most of them was higher in pat-3/pat-4 than in WT ovaries at PR and AN stages. The concentration of GA1, suggested previously to be the active GA in tomate, was 2-4 times higher. Unpollinated pat-3/pat-4 ovaries at FB, PR and AN stages also contained relatively high amounts (5-12 ng g-1) of GA3, a GA found at less than 0.5 ng g-1 in WT ovaries. It is concluded that the mutations pat-3/pat-4 may induce natural facultative parthenocarpy capacity in tomato by increasing the concentration of GA1 and GA3 in the ovaries before pollination.

  12. Green synthesis and antimicrobial activity of silver nanoparticles using wild medicinal mushroom Ganoderma applanatum (Pers.) Pat. from Similipal Biosphere Reserve, Odisha, India.

    PubMed

    Mohanta, Yugal Kishore; Singdevsachan, Sameer Kumar; Parida, Umesh Kumar; Panda, Sujogya Kumar; Mohanta, Tapan Kumar; Bae, Hanhong

    2016-08-01

    In the present study, green synthesis and cost effective approach of silver nanoparticles using wild medicinal mushroom Ganoderma applanatum (Pers.) Pat. from Similipal Biosphere Reserve, Odisha, India is reported. The biosynthesised AgNPs were characterised using UV-visible spectroscopy, particle analyser and scanning electron microscopy studies. It was found by dynamic light scattering analysis, that the average size and charges of the AgNPs were 133.0 ± 0.361 nm and -6.01 ± 5.30 mV, respectively. Moreover, the Fourier transform infrared study was also conducted to identify the biomolecules or functional groups responsible for the reduction of Ag and stabilisation of the AgNPs. The potential biomedical application with reference to antimicrobial activity of the synthesised AgNPs was investigated against some pathogenic microorganisms viz. Escherichia coli, Bacillus subtilis, Staphylococcus epidermidis, Vibrio cholerae, Staphylococcus aureus and Shigella flexneri.

  13. Green synthesis and antimicrobial activity of silver nanoparticles using wild medicinal mushroom Ganoderma applanatum (Pers.) Pat. from Similipal Biosphere Reserve, Odisha, India.

    PubMed

    Mohanta, Yugal Kishore; Singdevsachan, Sameer Kumar; Parida, Umesh Kumar; Panda, Sujogya Kumar; Mohanta, Tapan Kumar; Bae, Hanhong

    2016-08-01

    In the present study, green synthesis and cost effective approach of silver nanoparticles using wild medicinal mushroom Ganoderma applanatum (Pers.) Pat. from Similipal Biosphere Reserve, Odisha, India is reported. The biosynthesised AgNPs were characterised using UV-visible spectroscopy, particle analyser and scanning electron microscopy studies. It was found by dynamic light scattering analysis, that the average size and charges of the AgNPs were 133.0 ± 0.361 nm and -6.01 ± 5.30 mV, respectively. Moreover, the Fourier transform infrared study was also conducted to identify the biomolecules or functional groups responsible for the reduction of Ag and stabilisation of the AgNPs. The potential biomedical application with reference to antimicrobial activity of the synthesised AgNPs was investigated against some pathogenic microorganisms viz. Escherichia coli, Bacillus subtilis, Staphylococcus epidermidis, Vibrio cholerae, Staphylococcus aureus and Shigella flexneri. PMID:27463787

  14. Differential expression of proton-assisted amino acid transporters (PAT[1] and PAT[2]) in tissues of neonatal pigs

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The PATs have been identified as growth-regulatory nutrient sensors in Drosophila and as activators of mammalian target of rapamycin (mTOR) in mammalian cell cultures. These studies suggest that, beyond their classical function as transporters of simple amino acids (AA), the PATs act as tranceptors,...

  15. Photon activation therapy.

    PubMed

    Fairchild, R G; Bond, V P

    1984-12-01

    It is suggested here that significant advantages should accrue from the use of 40 keV photons from implanted sources of 145Sm. These energies should stimulate Auger electron cascades from IdUrd, as well as produce non-repairable damage from radiosensitization. The use of low dose rates (approximately 10 rd/hr) should allow repair in normal tissues exposed to the activating photons. Utilization of this technique with brain tumors should minimize problems associated with radiosensitization of normal tissues, as CNS tissues do not synthesize DNA. The deposition of high LET radiations selectively in tumor cells provides unique advantages not available to either conventional therapy or other forms of particle therapy (fast neutrons, protons, pions, heavy ions). PMID:6515666

  16. Activity Therapy: An Alternative Therapy for Adolescents.

    ERIC Educational Resources Information Center

    Kottman, Terry T.; And Others

    1987-01-01

    Discusses the benefits of activity therapy for preteens and adolescents, where the client is engaged in nonverbal modes of relationship--games, free play, movement, drama, music, art or other activities, as the chief therapeutic media in which conflicts are resolved and intellectual and emotional energies freed. Reviews the literature, describes…

  17. Determinants within the C-terminal domain of Streptomyces lividans acetyl-CoA synthetase that block acetylation of its active site lysine in vitro by the protein acetyltransferase (Pat) enzyme.

    PubMed

    Tucker, Alex C; Escalante-Semerena, Jorge C

    2014-01-01

    Reversible lysine acetylation (RLA) is a widespread regulatory mechanism that modulates the function of proteins involved in diverse cellular processes. A strong case has been made for RLA control exerted by homologues of the Salmonella enterica protein acetyltransferase (SePat) enzyme on the broadly distributed AMP-forming CoA ligase (a.k.a. acyl-CoA synthetases) family of metabolic enzymes, with acetyl-CoA synthetase (Acs) being the paradigm in the field. Here we investigate why the Acs homologue in Streptomyces lividans (SlAcs) is poorly acetylated in vitro by the S. lividans protein acetyltransferase (SlPat) enzyme. Chimeras of S. enterica Acs (SeAcs) and S. lividans Acs (SlAcs) constructed during the course of this work were acetylated by SlPatA in vitro, retained most of their activity, and were under RLA control in a heterologous host. We identified SeAcs residues N- and C-terminal to the target lysine that when introduced into SlAcs, rendered the latter under RLA control. These results lend further support to the idea that Pat enzymes interact with extensive surfaces of their substrates. Finally, we suggest that acetylation of SlAcs depends on factors or conditions other than those present in our in vitro system. We also discuss possible explanations why SlAcs is not controlled by RLA as defined in other bacterial species.

  18. Both Sm-domain and C-terminal extension of Lsm1 are important for the RNA-binding activity of the Lsm1-7-Pat1 complex.

    PubMed

    Chowdhury, Ashis; Raju, Kalidindi K; Kalurupalle, Swathi; Tharun, Sundaresan

    2012-05-01

    Lsm proteins are a ubiquitous family of proteins characterized by the Sm-domain. They exist as hexa- or heptameric RNA-binding complexes and carry out RNA-related functions. The Sm-domain is thought to be sufficient for the RNA-binding activity of these proteins. The highly conserved eukaryotic Lsm1 through Lsm7 proteins are part of the cytoplasmic Lsm1-7-Pat1 complex, which is an activator of decapping in the conserved 5'-3' mRNA decay pathway. This complex also protects mRNA 3'-ends from trimming in vivo. Purified Lsm1-7-Pat1 complex is able to bind RNA in vitro and exhibits a unique binding preference for oligoadenylated RNA (over polyadenylated and unadenylated RNA). Lsm1 is a key subunit that determines the RNA-binding properties of this complex. The normal RNA-binding activity of this complex is crucial for mRNA decay and 3'-end protection in vivo and requires the intact Sm-domain of Lsm1. Here, we show that though necessary, the Sm-domain of Lsm1 is not sufficient for the normal RNA-binding ability of the Lsm1-7-Pat1 complex. Deletion of the C-terminal domain (CTD) of Lsm1 (while keeping the Sm-domain intact) impairs mRNA decay in vivo and results in Lsm1-7-Pat1 complexes that are severely impaired in RNA binding in vitro. Interestingly, the mRNA decay and 3'-end protection defects of such CTD-truncated lsm1 mutants could be suppressed in trans by overexpression of the CTD polypeptide. Thus, unlike most Sm-like proteins, Lsm1 uniquely requires both its Sm-domain and CTD for its normal RNA-binding function.

  19. Activation of hormone-sensitive lipase requires two steps, protein phosphorylation and binding to the PAT-1 domain of lipid droplet coat proteins.

    PubMed

    Wang, Hong; Hu, Liping; Dalen, Knut; Dorward, Heidi; Marcinkiewicz, Amy; Russell, Deanna; Gong, Dawei; Londos, Constantine; Yamaguchi, Tomohiro; Holm, Cecilia; Rizzo, Mark A; Brasaemle, Dawn; Sztalryd, Carole

    2009-11-13

    Lipolysis is an important metabolic pathway controlling energy homeostasis through degradation of triglycerides stored in lipid droplets and release of fatty acids. Lipid droplets of mammalian cells are coated with one or more members of the PAT protein family, which serve important functions in regulating lipolysis. In this study, we investigate the mechanisms by which PAT family members, perilipin A, adipose differentiation-related protein (ADFP), and LSDP5, control lipolysis catalyzed by hormone-sensitive lipase (HSL), a major lipase in adipocytes and several non-adipose cells. We applied fluorescence microscopic tools to analyze proteins in situ in cultured Chinese hamster ovary cells using fluorescence recovery after photobleaching and anisotropy Forster resonance energy transfer. Fluorescence recovery after photobleaching data show that ADFP and LSDP5 exchange between lipid droplet and cytoplasmic pools, whereas perilipin A does not. Differences in protein mobility do not correlate with PAT protein-mediated control of lipolysis catalyzed by HSL or endogenous lipases. Forster resonance energy transfer and co-immunoprecipitation experiments reveal that each of the three PAT proteins bind HSL through interaction of the lipase with amino acids within the highly conserved amino-terminal PAT-1 domain. ADFP and LSDP5 bind HSL under basal conditions, whereas phosphorylation of serine residues within three amino-terminal protein kinase A consensus sequences of perilipin A is required for HSL binding and maximal lipolysis. Finally, protein kinase A-mediated phosphorylation of HSL increases lipolysis in cells expressing ADFP or LSDP5; in contrast, phosphorylation of perilipin A exerts the major control over HSL-mediated lipolysis when perilipin is the main lipid droplet protein. PMID:19717842

  20. Effects of the Activity of Coprophagous Insects on Greenhouse Gas Emissions from Cattle Dung Pats and Changes in Amounts of Nitrogen, Carbon, and Energy.

    PubMed

    Iwasa, Mitsuhiro; Moki, Yukari; Takahashi, Junichi

    2015-02-01

    Effects of coprophagous insects on greenhouse gas emissions from cattle dung pats were investigated during the initial stage in the decomposition of dung, with accompanying changes in nitrogen, carbon, and energy content. We set up three treatments with adults of Caccobius jessoensis Harold (dung beetle) and larvae of the fly Neomyia cornicina (F.): 1) dung with dung beetles; 2) dung with fly larvae; and 3) dung without insects. In these treatments, the gas flux was measured from air flow exiting the glass containers connected with an in vitro continuous gas analysis system. Total gas fluxes from dung pats with fly larvae were lowest in carbon dioxide (CO2), methane (CH4), and nitrous oxide (N2O). The presence of dung beetles significantly increased CO2 flux from dung, but reduced CH4 flux compared with dung without insects. Fluxes of N2O from dung pats with dung beetles and without insects had distinct peaks at different times after the start of the experiment, while N2O from dung with fly larvae was emitted in extremely low levels throughout the experiment. Carbon (C) content in dung with beetles was significantly lower than that of untreated dung pats designated as fresh dung, whereas that of dung with fly larvae was higher than dung with beetles and without insects. Nitrogen (N) content was significantly lower in dung with fly larvae than the other treatments. Contents of C and N in fly pupae were 35.87 and 8.05%, respectively. During the larval growth of the fly, energy accumulated in the fly body was 2,830 J/g.

  1. Effects of the Activity of Coprophagous Insects on Greenhouse Gas Emissions from Cattle Dung Pats and Changes in Amounts of Nitrogen, Carbon, and Energy.

    PubMed

    Iwasa, Mitsuhiro; Moki, Yukari; Takahashi, Junichi

    2015-02-01

    Effects of coprophagous insects on greenhouse gas emissions from cattle dung pats were investigated during the initial stage in the decomposition of dung, with accompanying changes in nitrogen, carbon, and energy content. We set up three treatments with adults of Caccobius jessoensis Harold (dung beetle) and larvae of the fly Neomyia cornicina (F.): 1) dung with dung beetles; 2) dung with fly larvae; and 3) dung without insects. In these treatments, the gas flux was measured from air flow exiting the glass containers connected with an in vitro continuous gas analysis system. Total gas fluxes from dung pats with fly larvae were lowest in carbon dioxide (CO2), methane (CH4), and nitrous oxide (N2O). The presence of dung beetles significantly increased CO2 flux from dung, but reduced CH4 flux compared with dung without insects. Fluxes of N2O from dung pats with dung beetles and without insects had distinct peaks at different times after the start of the experiment, while N2O from dung with fly larvae was emitted in extremely low levels throughout the experiment. Carbon (C) content in dung with beetles was significantly lower than that of untreated dung pats designated as fresh dung, whereas that of dung with fly larvae was higher than dung with beetles and without insects. Nitrogen (N) content was significantly lower in dung with fly larvae than the other treatments. Contents of C and N in fly pupae were 35.87 and 8.05%, respectively. During the larval growth of the fly, energy accumulated in the fly body was 2,830 J/g. PMID:26308812

  2. Analysis of deaths caused by pat-pat accidents in Turkey.

    PubMed

    Küçüker, Hüdaverdi

    2012-01-01

    This study deals with deaths during the period 2004 to 2009 that occurred during the use of a vehicle known as pat-pat, which is an unusual vehicle, similar to a tractor-trailer used in agricultural production and transportation The records of crime scene investigation and autopsies of 28 cases of death due to pat-pat-related crushes were evaluated. Of all cases, 60.7 percent were drivers and the remaining 39.3% were passengers. The most common cause of death (in 39.3% of cases) was brain-spinal cord injury due to blunt trauma of the head and neck. Implementing legislation regarding safety measures or limitation of the use for transportation should be performed for pat-pats, of which thousands are currently in use.

  3. Polyamine metabolism is altered in unpollinated parthenocarpic pat-2 tomato ovaries.

    PubMed

    Fos, Mariano; Proaño, Karina; Alabadí, David; Nuez, Fernando; Carbonell, Juan; García-Martínez, José L

    2003-01-01

    Facultative parthenocarpy induced by the recessive mutation pat-2 in tomato (Lycopersicon esculentum Mill.) depends on gibberellins (GAs) and is associated with changes in GA content in unpollinated ovaries. Polyamines (PAs) have also been proposed to play a role in early tomato fruit development. We therefore investigated whether PAs are able to induce parthenocarpy and whether the pat-2 mutation alters the content and metabolism of PAs in unpollinated ovaries. Application of putrescine, spermidine, and spermine to wild-type unpollinated tomato ovaries (cv Madrigal [MA/wt]) induced partial parthenocarpy. Parthenocarpic growth of MA/pat-2 (a parthenocarpic near-isogenic line to MA/wt) ovaries was negated by paclobutrazol (GA biosynthesis inhibitor), and this inhibition was counteracted by spermidine. Application of alpha-difluoromethyl-ornithine (-Orn) and/or alpha-difluoromethyl-arginine (-Arg), irreversible inhibitors of the putrescine biosynthesis enzymes Orn decarboxylase (ODC) and Arg decarboxylase, respectively, prevented growth of unpollinated MA/pat-2 ovaries. Alpha-difluoromethyl-Arg inhibition was counteracted by putrescine and GA(3), whereas that of alpha-difluoromethyl-Orn was counteracted by GA(3) but not by putrescine or spermidine. In unpollinated MA/pat-2 ovaries, the content of free spermine was significantly higher than in MA/wt ovaries. ODC activity was higher in pat-2 ovaries than in MA/wt. Transcript levels of genes encoding ODC and spermidine synthase were also higher in MA/pat-2. All together, these results strongly suggest that the parthenocarpic ability of pat-2 mutants depends on elevated PAs levels in unpollinated mutant ovaries, which correlate with an activation of the ODC pathway, probably as a consequence of elevated GA content in unpollinated pat-2 tomato ovaries. PMID:12529543

  4. Polyamine metabolism is altered in unpollinated parthenocarpic pat-2 tomato ovaries.

    PubMed

    Fos, Mariano; Proaño, Karina; Alabadí, David; Nuez, Fernando; Carbonell, Juan; García-Martínez, José L

    2003-01-01

    Facultative parthenocarpy induced by the recessive mutation pat-2 in tomato (Lycopersicon esculentum Mill.) depends on gibberellins (GAs) and is associated with changes in GA content in unpollinated ovaries. Polyamines (PAs) have also been proposed to play a role in early tomato fruit development. We therefore investigated whether PAs are able to induce parthenocarpy and whether the pat-2 mutation alters the content and metabolism of PAs in unpollinated ovaries. Application of putrescine, spermidine, and spermine to wild-type unpollinated tomato ovaries (cv Madrigal [MA/wt]) induced partial parthenocarpy. Parthenocarpic growth of MA/pat-2 (a parthenocarpic near-isogenic line to MA/wt) ovaries was negated by paclobutrazol (GA biosynthesis inhibitor), and this inhibition was counteracted by spermidine. Application of alpha-difluoromethyl-ornithine (-Orn) and/or alpha-difluoromethyl-arginine (-Arg), irreversible inhibitors of the putrescine biosynthesis enzymes Orn decarboxylase (ODC) and Arg decarboxylase, respectively, prevented growth of unpollinated MA/pat-2 ovaries. Alpha-difluoromethyl-Arg inhibition was counteracted by putrescine and GA(3), whereas that of alpha-difluoromethyl-Orn was counteracted by GA(3) but not by putrescine or spermidine. In unpollinated MA/pat-2 ovaries, the content of free spermine was significantly higher than in MA/wt ovaries. ODC activity was higher in pat-2 ovaries than in MA/wt. Transcript levels of genes encoding ODC and spermidine synthase were also higher in MA/pat-2. All together, these results strongly suggest that the parthenocarpic ability of pat-2 mutants depends on elevated PAs levels in unpollinated mutant ovaries, which correlate with an activation of the ODC pathway, probably as a consequence of elevated GA content in unpollinated pat-2 tomato ovaries.

  5. Polyamine Metabolism Is Altered in Unpollinated Parthenocarpic pat-2 Tomato Ovaries1

    PubMed Central

    Fos, Mariano; Proaño, Karina; Alabadí, David; Nuez, Fernando; Carbonell, Juan; García-Martínez, José L.

    2003-01-01

    Facultative parthenocarpy induced by the recessive mutation pat-2 in tomato (Lycopersicon esculentum Mill.) depends on gibberellins (GAs) and is associated with changes in GA content in unpollinated ovaries. Polyamines (PAs) have also been proposed to play a role in early tomato fruit development. We therefore investigated whether PAs are able to induce parthenocarpy and whether the pat-2 mutation alters the content and metabolism of PAs in unpollinated ovaries. Application of putrescine, spermidine, and spermine to wild-type unpollinated tomato ovaries (cv Madrigal [MA/wt]) induced partial parthenocarpy. Parthenocarpic growth of MA/pat-2 (a parthenocarpic near-isogenic line to MA/wt) ovaries was negated by paclobutrazol (GA biosynthesis inhibitor), and this inhibition was counteracted by spermidine. Application of α-difluoromethyl-ornithine (-Orn) and/or α-difluoromethyl-arginine (-Arg), irreversible inhibitors of the putrescine biosynthesis enzymes Orn decarboxylase (ODC) and Arg decarboxylase, respectively, prevented growth of unpollinated MA/pat-2 ovaries. α-Difluoromethyl-Arg inhibition was counteracted by putrescine and GA3, whereas that of α-difluoromethyl-Orn was counteracted by GA3 but not by putrescine or spermidine. In unpollinated MA/pat-2 ovaries, the content of free spermine was significantly higher than in MA/wt ovaries. ODC activity was higher in pat-2 ovaries than in MA/wt. Transcript levels of genes encoding ODC and spermidine synthase were also higher in MA/pat-2. All together, these results strongly suggest that the parthenocarpic ability of pat-2 mutants depends on elevated PAs levels in unpollinated mutant ovaries, which correlate with an activation of the ODC pathway, probably as a consequence of elevated GA content in unpollinated pat-2 tomato ovaries. PMID:12529543

  6. Antimatter/HiPAT Support Services

    NASA Technical Reports Server (NTRS)

    Lewis, Raymond A.

    2001-01-01

    Techniques were developed for trapping normal matter in the High Performance Antiproton Trap (HiPAT). Situations encountered included discharge phenomena, charge exchange and radial diffusion processes. It is important to identify these problems, since they will also limit the performance in trapping antimatter next year.

  7. A Poetry Workshop in Print: Pat Mora

    ERIC Educational Resources Information Center

    Hopkins, Lee Bennett

    2006-01-01

    After a successful career as a writer for adults, Pat Mora began creating books for children. Her first picture book, "Tomas and The Library Lady" (Knopf, 1997) is a tender story of a young migrant worker who unearths new worlds when he discovers the magic a public library holds. The text, cleverly interspersed with foreign words, became a…

  8. Overview of the High Performance Antiproton (HiPAT) Experiment

    NASA Technical Reports Server (NTRS)

    Martin, James J.; Sims, William H.; Chakrabarti, Suman; Pearson, Boise; Fant, Wallace E.; Lewis, Raymond A.; Rodgers, Stephen (Technical Monitor)

    2002-01-01

    The annihilation of matter with antimatter represents the highest energy density of any known reaction, producing 10(exp 8) MJ/g, approximately 10 orders of magnitude more energy per unit mass than chemical based combustion. To take the first step towards using this energy for propulsion applications the NASA MSFC Propulsion Research Center (PRC) has initiated a research activity examining the storage of low energy antiprotons. Storage was identified as a key enabling technology since it builds the experience base necessary to understand the handling of antiprotons for virtually all utilization and high-density storage concepts. To address this need, a device referred to as the High Performance Antiproton Trap (HiPAT) is under development at the NASA MSFC PRC. The HiPAT is an electromagnetic system (Penning-Malmberg design) consisting of a 4 Tesla superconductor, a high voltage confinement electrode system (operation up to 20 KV), and an ultra high vacuum test section (operating in the 10(exp -12) torr range). The system was designed to be portable with an ultimate goal of maintaining 10(exp 12) charged particles with a half-life of 18 days. Currently, this system is being experimentally evaluated using normal matter ions which are cheap to produce and relatively easy to handle. These normal ions provide a good indication of overall trap behavior, with the exception of assessing annihilation losses. The ions are produced external to HiPAT using two hydrogen ion sources, with adjustable beam energy and current. Ion are transported in a beam line and controlled through the use of electrostatic optics. These optics serve to both focus and gate the incoming ions, providing microsecond-timed pulses that are dynamically captured by cycling the HiPAT electric containment field like a 'trap door'. The layout of this system more closely simulates the operations expected at an actual antiproton production facility where 'packets' of antiprotons with pulse widths measured in

  9. Innovative Approaches to Plasminogen Activator Therapy

    NASA Astrophysics Data System (ADS)

    Haber, Edgar; Quertermous, Thomas; Matsueda, Gary R.; Runge, Marschall S.

    1989-01-01

    Plasminogen activator therapy for acute myocardial infarction has become standard medical practice. Bleeding complications, however, limit the utility of the currently available agents. This article reviews how the tools of molecular biology and protein engineering are being used to develop safer and more effective plasminogen activators.

  10. Horticulture Therapy Activities for Exceptional Students.

    ERIC Educational Resources Information Center

    Airhart, Douglas L.; And Others

    1988-01-01

    The Tennessee Technological University's Program of Special Education sponsors a "Super Saturday" of enrichment activities for gifted and talented students as well as students with learning disabilities. A session on horticulture was planned and arranged by students in a class on horticultural therapy who designed learning activities of two types:…

  11. The gene pat-2, which induces natural parthenocarpy, alters the gibberellin content in unpollinated tomato ovaries.

    PubMed

    Fos, M; Nuez, F; García-Martínez, J L

    2000-02-01

    We investigated the role of gibberellins (GAs) in the effect of pat-2, a recessive mutation that induces facultative parthenocarpic fruit development in tomato (Lycopersicon esculentum Mill.) using near-isogenic lines with two different genetic backgrounds. Unpollinated wild-type Madrigal (MA/wt) and Cuarenteno (CU/wt) ovaries degenerated, but GA(3) application induced parthenocarpic fruit growth. On the contrary, parthenocarpic growth of MA/pat-2 and CU/pat-2 fruits, which occurs in the absence of pollination and hormone application, was not affected by GA(3). Pollinated MA/wt and parthenocarpic MA/pat-2 ovary development was negated by paclobutrazol, and this inhibitory effect was counteracted by GA(3). The main GAs of the early-13-hydroxylation pathway (GA(1), GA(3), GA(8), GA(19), GA(20), GA(29), GA(44), GA(53), and, tentatively, GA(81)) and two GAs of the non-13-hydroxylation pathway (GA(9) and GA(34)) were identified in MA/wt ovaries by gas chromatography-selected ion monitoring. GAs were quantified in unpollinated ovaries at flower bud, pre-anthesis, and anthesis. In unpollinated MA/pat-2 and CU/pat-2 ovaries, the GA(20) content was much higher (up to 160 times higher) and the GA(19) content was lower than in the corresponding non-parthenocarpic ovaries. The application of an inhibitor of 2-oxoglutarate-dependent dioxygenases suggested that GA(20) is not active per se. The pat-2 mutation may increase GA 20-oxidase activity in unpollinated ovaries, leading to a higher synthesis of GA(20), the precursor of an active GA. PMID:10677440

  12. The gene pat-2, which induces natural parthenocarpy, alters the gibberellin content in unpollinated tomato ovaries.

    PubMed

    Fos, M; Nuez, F; García-Martínez, J L

    2000-02-01

    We investigated the role of gibberellins (GAs) in the effect of pat-2, a recessive mutation that induces facultative parthenocarpic fruit development in tomato (Lycopersicon esculentum Mill.) using near-isogenic lines with two different genetic backgrounds. Unpollinated wild-type Madrigal (MA/wt) and Cuarenteno (CU/wt) ovaries degenerated, but GA(3) application induced parthenocarpic fruit growth. On the contrary, parthenocarpic growth of MA/pat-2 and CU/pat-2 fruits, which occurs in the absence of pollination and hormone application, was not affected by GA(3). Pollinated MA/wt and parthenocarpic MA/pat-2 ovary development was negated by paclobutrazol, and this inhibitory effect was counteracted by GA(3). The main GAs of the early-13-hydroxylation pathway (GA(1), GA(3), GA(8), GA(19), GA(20), GA(29), GA(44), GA(53), and, tentatively, GA(81)) and two GAs of the non-13-hydroxylation pathway (GA(9) and GA(34)) were identified in MA/wt ovaries by gas chromatography-selected ion monitoring. GAs were quantified in unpollinated ovaries at flower bud, pre-anthesis, and anthesis. In unpollinated MA/pat-2 and CU/pat-2 ovaries, the GA(20) content was much higher (up to 160 times higher) and the GA(19) content was lower than in the corresponding non-parthenocarpic ovaries. The application of an inhibitor of 2-oxoglutarate-dependent dioxygenases suggested that GA(20) is not active per se. The pat-2 mutation may increase GA 20-oxidase activity in unpollinated ovaries, leading to a higher synthesis of GA(20), the precursor of an active GA.

  13. The Protein Acetyltransferase PatZ from Escherichia coli Is Regulated by Autoacetylation-induced Oligomerization*

    PubMed Central

    de Diego Puente, Teresa; Gallego-Jara, Julia; Castaño-Cerezo, Sara; Bernal Sánchez, Vicente; Fernández Espín, Vanesa; García de la Torre, José; Manjón Rubio, Arturo; Cánovas Díaz, Manuel

    2015-01-01

    Lysine acetylation is an important post-translational modification in the metabolic regulation of both prokaryotes and eukaryotes. In Escherichia coli, PatZ (formerly YfiQ) is the only known acetyltransferase protein and is responsible for acetyl-CoA synthetase acetylation. In this study, we demonstrated PatZ-positive cooperativity in response to acetyl-CoA and the regulation of acetyl-CoA synthetase activity by the acetylation level. Furthermore, functional analysis of an E809A mutant showed that the conserved glutamate residue is not relevant for the PatZ catalytic mechanism. Biophysical studies demonstrated that PatZ is a stable tetramer in solution and is transformed to its octameric form by autoacetylation. Moreover, this modification is reversed by the sirtuin CobB. Finally, an in silico PatZ tetramerization model based on hydrophobic and electrostatic interactions is proposed and validated by three-dimensional hydrodynamic analysis. These data reveal, for the first time, the structural regulation of an acetyltransferase by autoacetylation in a prokaryotic organism. PMID:26251518

  14. The Protein Acetyltransferase PatZ from Escherichia coli Is Regulated by Autoacetylation-induced Oligomerization.

    PubMed

    de Diego Puente, Teresa; Gallego-Jara, Julia; Castaño-Cerezo, Sara; Bernal Sánchez, Vicente; Fernández Espín, Vanesa; García de la Torre, José; Manjón Rubio, Arturo; Cánovas Díaz, Manuel

    2015-09-18

    Lysine acetylation is an important post-translational modification in the metabolic regulation of both prokaryotes and eukaryotes. In Escherichia coli, PatZ (formerly YfiQ) is the only known acetyltransferase protein and is responsible for acetyl-CoA synthetase acetylation. In this study, we demonstrated PatZ-positive cooperativity in response to acetyl-CoA and the regulation of acetyl-CoA synthetase activity by the acetylation level. Furthermore, functional analysis of an E809A mutant showed that the conserved glutamate residue is not relevant for the PatZ catalytic mechanism. Biophysical studies demonstrated that PatZ is a stable tetramer in solution and is transformed to its octameric form by autoacetylation. Moreover, this modification is reversed by the sirtuin CobB. Finally, an in silico PatZ tetramerization model based on hydrophobic and electrostatic interactions is proposed and validated by three-dimensional hydrodynamic analysis. These data reveal, for the first time, the structural regulation of an acetyltransferase by autoacetylation in a prokaryotic organism.

  15. The effects of PAT on the Savannah River ecosystem, particularly fisheries

    SciTech Connect

    Patrick, R.

    1994-03-01

    The main purpose of this study was to determine whether or not the pre-startup activities at K-Reactor, i.e., Power Ascension Testing (PAT), have caused damage because of temperature rises in the Savannah River. Therefore, the biological studies were mainly aimed at providing information as to changes that might cause the damage of the fish population, and to other important organisms in the ecosystem. To determine if deleterious effects had occurred, one had to review the past studies to determine the condition and diversity of aquatic life before these PAT studies started. Therefore old reports were reviewed and a current study made in 1992.

  16. PAT-1 safety analysis report addendum.

    SciTech Connect

    Weiner, Ruth F.; Schmale, David T.; Kalan, Robert J.; Akin, Lili A.; Miller, David Russell; Knorovsky, Gerald Albert; Yoshimura, Richard Hiroyuki; Lopez, Carlos; Harding, David Cameron; Jones, Perry L.; Morrow, Charles W.

    2010-09-01

    The Plutonium Air Transportable Package, Model PAT-1, is certified under Title 10, Code of Federal Regulations Part 71 by the U.S. Nuclear Regulatory Commission (NRC) per Certificate of Compliance (CoC) USA/0361B(U)F-96 (currently Revision 9). The purpose of this SAR Addendum is to incorporate plutonium (Pu) metal as a new payload for the PAT-1 package. The Pu metal is packed in an inner container (designated the T-Ampoule) that replaces the PC-1 inner container. The documentation and results from analysis contained in this addendum demonstrate that the replacement of the PC-1 and associated packaging material with the T-Ampoule and associated packaging with the addition of the plutonium metal content are not significant with respect to the design, operating characteristics, or safe performance of the containment system and prevention of criticality when the package is subjected to the tests specified in 10 CFR 71.71, 71.73 and 71.74.

  17. Active music therapy and Parkinson's disease: methods.

    PubMed

    Pacchetti, C; Aglieri, R; Mancini, F; Martignoni, E; Nappi, G

    1998-01-01

    Music therapy (MT) is an unconventional, multisensorial therapy poorly assessed in medical care but widely used to different ends in a variety of settings. MT has two branches: active and passive. In active MT the utilisation of instruments is structured to correspond to all sensory organs so as to obtain suitable motor and emotional responses. We conducted a prospective study to evaluate the effects of MT in the neurorehabilitation of patients with Parkinson's Disease (PD), a common degenerative disorder involving movement and emotional impairment. Sixteen PD patients took part in 13 weekly sessions of MT each lasting 2 hours. At the beginning and at the end of the session, every 2 weeks, the patients were evaluated by a neurologist, who assessed PD severity with UPDRS, emotional functions with Happiness Measures (HM) and quality of life using the Parkinson's Disease Quality of Life Questionnaire (PDQL). After every session a significant improvement in motor function, particularly in relation to hypokinesia, was observed both in the overall and in the pre-post session evaluations. HM, UPDRS-ADL and PDQL changes confirmed an improving effect of MT on emotional functions, activities of daily living and quality of life. In conclusion, active MT, operating at a multisensorial level, stimulates motor, affective and behavioural functions. Finally, we propose active MT as new method to include in PD rehabilitation programmes. This article describes the methods adopted during MT sessions with PD patients. PMID:9584875

  18. The Gene pat-2, Which Induces Natural Parthenocarpy, Alters the Gibberellin Content in Unpollinated Tomato Ovaries1

    PubMed Central

    Fos, Mariano; Nuez, Fernando; García-Martínez, José L.

    2000-01-01

    We investigated the role of gibberellins (GAs) in the effect of pat-2, a recessive mutation that induces facultative parthenocarpic fruit development in tomato (Lycopersicon esculentum Mill.) using near-isogenic lines with two different genetic backgrounds. Unpollinated wild-type Madrigal (MA/wt) and Cuarenteno (CU/wt) ovaries degenerated, but GA3 application induced parthenocarpic fruit growth. On the contrary, parthenocarpic growth of MA/pat-2 and CU/pat-2 fruits, which occurs in the absence of pollination and hormone application, was not affected by GA3. Pollinated MA/wt and parthenocarpic MA/pat-2 ovary development was negated by paclobutrazol, and this inhibitory effect was counteracted by GA3. The main GAs of the early-13-hydroxylation pathway (GA1, GA3, GA8, GA19, GA20, GA29, GA44, GA53, and, tentatively, GA81) and two GAs of the non-13-hydroxylation pathway (GA9 and GA34) were identified in MA/wt ovaries by gas chromatography-selected ion monitoring. GAs were quantified in unpollinated ovaries at flower bud, pre-anthesis, and anthesis. In unpollinated MA/pat-2 and CU/pat-2 ovaries, the GA20 content was much higher (up to 160 times higher) and the GA19 content was lower than in the corresponding non-parthenocarpic ovaries. The application of an inhibitor of 2-oxoglutarate-dependent dioxygenases suggested that GA20 is not active per se. The pat-2 mutation may increase GA 20-oxidase activity in unpollinated ovaries, leading to a higher synthesis of GA20, the precursor of an active GA. PMID:10677440

  19. The 3' overhangs at Tetrahymena thermophila telomeres are packaged by four proteins, Pot1a, Tpt1, Pat1, and Pat2.

    PubMed

    Premkumar, Vidjaya Letchoumy; Cranert, Stacey; Linger, Benjamin R; Morin, Gregg B; Minium, Sasha; Price, Carolyn

    2014-02-01

    Although studies with the ciliate Tetrahymena thermophila have played a central role in advancing our understanding of telomere biology and telomerase mechanisms and composition, the full complement of Tetrahymena telomere proteins has not yet been identified. Previously, we demonstrated that in Tetrahymena, the telomeric 3' overhang is protected by a three-protein complex composed of Pot1a, Tpt1, and Pat1. Here we show that Tpt1 and Pat1 associate with a fourth protein, Pat2 (Pot1 associated Tetrahymena 2). Mass spectrometry of proteins copurifying with Pat1 or Tpt1 identified peptides from Pat2, Pot1a, Tpt1, and Pat1. The lack of other proteins copurifying with Pat1 or Tpt1 implies that the overhang is protected by a four-protein Pot1a-Tpt1-Pat1-Pat2 complex. We verified that Pat2 localizes to telomeres, but we were unable to detect direct binding to telomeric DNA. Cells depleted of Pat2 continue to divide, but the telomeres exhibit gradual shortening. The lack of growth arrest indicates that, in contrast to Pot1a and Tpt1, Pat2 is not required for the sequestration of the telomere from the DNA repair machinery. Instead, Pat2 is needed to regulate telomere length, most likely by acting in conjunction with Pat1 to allow telomerase access to the telomere.

  20. Pat Thiel talks about Nobel Prize winner Dan Shechtman

    ScienceCinema

    Thiel, Pat

    2016-07-12

    Ames Laboratory senior scientist and Iowa State University Distinguished Professor of Chemistry Pat Thiel talks about her friend and colleague Dan Shechtman who received the 2011 Nobel Prize for Chemistry.

  1. Overexpression of patA and patB, Which Encode ABC Transporters, Is Associated with Fluoroquinolone Resistance in Clinical Isolates of Streptococcus pneumoniae▿

    PubMed Central

    Garvey, Mark I.; Baylay, Alison J.; Wong, Ryan L.; Piddock, Laura J. V.

    2011-01-01

    Fifty-seven clinical isolates of Streptococcus pneumoniae were divided into four groups based on their susceptibilities to the fluoroquinolones ciprofloxacin and norfloxacin and the dyes ethidium bromide and acriflavine. Comparative reverse transcription-PCR was used to determine the level of expression of the genes patA and patB, which encode putative ABC transporters. Overexpression was observed in 14 of the 15 isolates that were resistant to both fluoroquinolones and dyes and in only 3 of 24 of those resistant to fluoroquinolones only. Isolates overexpressing patA and patB accumulated significantly less of the fluorescent dye Hoechst 33342 than wild-type isolates, suggesting that PatA and PatB are involved in efflux. Inactivation of patA and patB by in vitro mariner mutagenesis conferred hypersusceptibility to ethidium bromide and acriflavine in all isolates tested and lowered the MICs of ciprofloxacin in the patAB-overproducing and/or fluoroquinolone-resistant isolates. These data represent the first observation of overexpression of patA and patB in clinical isolates and show that PatA and PatB play a clinically relevant role in fluoroquinolone resistance. PMID:20937787

  2. Photodynamic Therapy in Pediatric Dentistry

    PubMed Central

    da Silva Barbosa, Patricia; Duarte, Danilo Antônio; Leite, Mariana Ferreira; de Sant' Anna, Giselle Rodrigues

    2014-01-01

    Conservation of deciduous teeth with pulp alterations caused by caries and trauma is a major therapeutic challenge in pediatric dentistry as a result of the internal anatomy and life cycle characteristic. It is essential that the root canal procedures sanitizers have a performance in eliminating bacterial. In this context, antimicrobial photodynamic therapy (PAT) is promising and emerging as adjuvant therapy in an attempt to eliminate the microorganisms persistent to chemi-mechanical preparation. Since there is presence of oxygen in cells, photosensitizer activated by light can react with molecules in its vicinity by electrons' or hydrogen's transfer, leading to microorganism death. This paper reports the case of 4-year-old patient, female, with early childhood caries. The proposed endodontic treatment incuded chemomechanical treatment allied to PAT in the decontamination of root canals using methylene blue dye 50 μg/mL during 3–5 minutes and 40 J/cm2 as energy density, taking into account the need for tissue penetration and effectiveness of PAT inside the dentinal tubules. PMID:25371829

  3. The structure of the cyanobactin domain of unknown function from PatG in the patellamide gene cluster

    PubMed Central

    Mann, Greg; Koehnke, Jesko; Bent, Andrew F.; Graham, Rachael; Houssen, Wael; Jaspars, Marcel; Schwarz-Linek, Uli; Naismith, James H.

    2014-01-01

    Patellamides are members of the cyanobactin family of ribosomally synthesized and post-translationally modified cyclic peptide natural products, many of which, including some patellamides, are biologically active. A detailed mechanistic understanding of the biosynthetic pathway would enable the construction of a biotechnological ‘toolkit’ to make novel analogues of patellamides that are not found in nature. All but two of the protein domains involved in patellamide biosynthesis have been characterized. The two domains of unknown function (DUFs) are homologous to each other and are found at the C-termini of the multi-domain proteins PatA and PatG. The domain sequence is found in all cyanobactin-biosynthetic pathways characterized to date, implying a functional role in cyanobactin biosynthesis. Here, the crystal structure of the PatG DUF domain is reported and its binding interactions with plausible substrates are investigated. PMID:25484206

  4. PAT-2 (Plutonium Air-Transportable Model 2) safety analysis report

    SciTech Connect

    Andersen, J.A.; Davis, E.J.; Duffey, T.A.; Dupree, S.A.; George, O.L. Jr.; Ortiz, Z.

    1981-07-01

    The PAT-2 package is designed for the safe transport of plutonium and/or uranium in small quantities. The PAT-2 package is resistant to severe accidents, including that of a high-speed jet aircraft crash, and is designed to withstand such environments as extreme impact, crushing, puncturing and slashing loads, severe hydrocarbon-fueled fires, and deep underwater immersion, with no escape of contents. The package meets the requirements of 10 CFR 71 for Fissile Class I packages with a cargo of 15 grams of Pu-239, or other isotopic forms described herein, not to exceed 2 watts of thermal activity. This SAR presents design and oprational information including evaluations and analyses, test results, operating procedures, maintenance, and quality assurance information.

  5. Fine mapping of the parthenocarpic fruit ( pat) mutation in tomato.

    PubMed

    Beraldi, D; Picarella, M E; Soressi, G P; Mazzucato, A

    2004-01-01

    The parthenocarpic fruit ( pat) gene of tomato is a recessive mutation conferring parthenocarpy, which is the capability of a plant to set seedless fruits in the absence of pollination and fertilization. Parthenocarpic mutants offer a useful method to regulate fruit production and a suitable experimental system to study ovary and fruit development. In order to map the Pat locus, two populations segregating from the interspecific cross Lycopersicon esculentum x Lycopersicon pennellii were grown, and progeny plants were classified as parthenocarpic or wild-type by taking into account some characteristic aberrations affecting mutant anthers and ovules. Through bulk segregant analysis, we searched for both random and mapped AFLPs linked to the target gene. In this way, the Pat locus was assigned to the long arm of chromosome 3, as also confirmed by the analysis of a set of L. pennellii substitution and introgression lines. Afterwards, the Pat position was refined by using simple sequence repeats (SSRs) and conserved ortholog set (COS) markers mapping in the target region. The tightest COSs were converted into CAPS or SCAR markers. At present, two co-dominant SCAR markers encompassing a genetic window of 1.2 cM flank the Pat locus. Considering that these markers are orthologous to Arabidopsis genes, a positional cloning exploiting the tomato- Arabidopsis microsynteny seems to be a short-term objective. PMID:14564391

  6. Extreme Nonresponse in Cognitive Therapy: Can Behavioral Activation Succeed where Cognitive Therapy Fails?

    ERIC Educational Resources Information Center

    Coffman, Sandra J.; Martell, Christopher R.; Dimidjian, Sona; Gallop, Robert; Hollon, Steven D.

    2007-01-01

    In a recent placebo-controlled comparison, behavioral activation was superior to cognitive therapy in the treatment of moderate to severely depressed adults. Moreover, a subset of patients exhibited a pattern of extreme nonresponse to cognitive therapy on self-reports of depression not evident on the clinician ratings. These patients were severely…

  7. Exercise in Treating Hypertension: Tailoring Therapies for Active Patients.

    ERIC Educational Resources Information Center

    Chintanadilok, Jirayos

    2002-01-01

    Exercise can be definitive therapy for some, and adjunctive therapy for many, people with hypertension, though people with secondary hypertension may not derive as much benefit. Low-to- moderate-intensity aerobic exercise can help with mild hypertension and reduce drug dosages in more severe cases. For active patients requiring medication,…

  8. Multivariate PAT solutions for biopharmaceutical cultivation: current progress and limitations.

    PubMed

    Mercier, Sarah M; Diepenbroek, Bas; Wijffels, Rene H; Streefland, Mathieu

    2014-06-01

    Increasingly elaborate and voluminous datasets are generated by the (bio)pharmaceutical industry and are a major challenge for application of PAT and QbD principles. Multivariate data analysis (MVDA) is required to delineate relevant process information from large multi-factorial and multi-collinear datasets. Here the key role of MVDA for industrial (bio)process data is discussed, with a focus on progress and limitations of MVDA as a PAT solution for biopharmaceutical cultivation processes. MVDA based models were proven useful and should be routinely implemented for bioprocesses. It is concluded that although the highest level of PAT with process control within its design space in real-time during manufacturing is not reached yet, MVDA will be central to reach this ultimate objective for cell cultivations. PMID:24732022

  9. Multivariate PAT solutions for biopharmaceutical cultivation: current progress and limitations.

    PubMed

    Mercier, Sarah M; Diepenbroek, Bas; Wijffels, Rene H; Streefland, Mathieu

    2014-06-01

    Increasingly elaborate and voluminous datasets are generated by the (bio)pharmaceutical industry and are a major challenge for application of PAT and QbD principles. Multivariate data analysis (MVDA) is required to delineate relevant process information from large multi-factorial and multi-collinear datasets. Here the key role of MVDA for industrial (bio)process data is discussed, with a focus on progress and limitations of MVDA as a PAT solution for biopharmaceutical cultivation processes. MVDA based models were proven useful and should be routinely implemented for bioprocesses. It is concluded that although the highest level of PAT with process control within its design space in real-time during manufacturing is not reached yet, MVDA will be central to reach this ultimate objective for cell cultivations.

  10. Ion Dynamic Capture Experiments With The High Performance Antiproton Trap (HiPAT)

    NASA Technical Reports Server (NTRS)

    Martin, James; Lewis, Raymond; Chakrabarti, Suman; Sims, William H.; Pearson, J. Boise; Fant, Wallace E.

    2002-01-01

    To take the first step towards using the energy produced from the matter-antimatter annihilation for propulsion applications, the NASA Marshall Space Flight Center (MSFC) Propulsion Research Center (PRC) has initiated a research activity examining the storage of low energy antiprotons. The High Performance Antiproton Trap (HiPAT) is an electromagnetic system (Penning-Malmberg design) consisting of a 4 Tesla superconductor, a high voltage electrode confinement system, and an ultra high vacuum test section. It has been designed with an ultimate goal of maintaining 10(exp 12) charged particles with a half-life of 18 days. Currently, this system is being evaluated experimentally using normal matter ions that are cheap to produce, relatively easy to handle, and provide a good indication of overall trap behavior (with the exception of assessing annihilation losses). The ions are produced via a positive hydrogen ion source and transported to HiPAT in a beam line equipped with electrostatic optics. The optics serve to both focus and gate the incoming ions, providing microsecond-timed beam pulses that are dynamically captured by cycling the HiPAT forward containment field like a "trap door". Initial dynamic capture experiments have been successfully performed with beam energy and currents set to 1.9 kV and 23 micro-amps, respectively. At these settings up to 2x10(exp 9) ions have been trapped during a single dynamic cycle.

  11. Activity Group Therapy for Emotionally Disturbed Pre-School Children.

    ERIC Educational Resources Information Center

    Plenk, Agnes M.

    1978-01-01

    The article discusses the comprehensive services offered emotionally disturbed preschool children by a voluntary social agency (the Childrens Center in Salt Lake City, Utah), focusing on activity group therapy, the major therapeutic tool used there. (Author/DLS)

  12. Stable phantoms for characterization of photoacoustic tomography (PAT) systems

    NASA Astrophysics Data System (ADS)

    Bohndiek, Sarah E.; Van de Sompel, Dominique; Bodapati, Sandhya; Kothapalli, Sri Rajasekhar; Gambhir, Sanjiv S.

    2013-02-01

    Photoacoustic tomography (PAT) is an emerging modality that combines the high contrast of optical imaging, with the spatial resolution and penetration depth of ultrasound, by exploiting the photoacoustic effect. As with any new imaging modality, reliable physical phantoms are needed to: calibrate instruments; validate performance; optimize signal-to-noise; perform routine quality control; and compare systems. Phantom materials for testing small animal PAT systems should also mimic both the optical and acoustic properties of soft tissue, while for calibration purposes should be resistant to degradation over long time periods. We show here that polyvinyl chloride plastisol (PVCP) phantoms enable calibration and performance validation using two PAT systems with distinct designs (Visualsonics Vevo LAZR and Endra Nexus 128) across a wavelength range of 680 nm - 950 nm. Inclusions between 2 and 3.2 mm in diameter were fabricated from PVCP using a range of dye concentrations (0 % to 0.256 % Black Plastic Color, BPC) in a custom mold. A calibration phantom was imaged repeatedly on both systems, over time scales of minutes, hours and days, to assess system stability. Both systems demonstrated good reproducibility over time, with the coefficient of variation in the measured signal-to-noise ratio (SNR) being less than 15% over the course of 30 days. Imaging performance was optimized by plotting SNR as a function of different system parameters. The visualization of objects embedded in optically absorbing and scattering backgrounds was also assessed. PVCP is easy to work with and provides stable phantoms for assessing PAT system performance.

  13. The PATS Project: A State of Tennessee School Reform Initiative.

    ERIC Educational Resources Information Center

    Butler, E. Dean; And Others

    The first-year results of a Tennessee college-school partnership program to implement a data-based school improvement change model--the Positive Attitudes in Tennessee Schools Project (PATS)--are summarized in this report. Two major goals of the first year (1989-90) included assessing and improving school climate and enhancing student and teacher…

  14. Project Achieve Transition Services (PATS), 1993-94. OER Report.

    ERIC Educational Resources Information Center

    Goldberg, Phyllis

    Project Achieve Transition Services (PATS) is a four-year high school attendance improvement, dropout prevention project which targets late-entry students consisting primarily of immigrants, transfers, and long-term absentees. The program uses a case management approach to provide support services, instructional enhancements, and family outreach…

  15. 10. GLASS, SCHNEIDER & REZNER BRIDGE PATENT MODEL, PAT. NO. ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    10. GLASS, SCHNEIDER & REZNER BRIDGE PATENT MODEL, PAT. NO. 71, 868, DECEMBER 10, 1867. THIS MODEL IS ONE OF A FEW THAT SURVIVED THE PATENT OFFICE FIRE OF 1877. IF REPRODUCED, CREDIT SHOULD BE GIVEN TO THE SMITHSONIAN INSTITUTION, NEGATIVE NO. 48660-D. - White Bowstring Arch Truss Bridge, Spanning Yellow Creek at Cemetery Drive (Riverside Drive), Poland, Mahoning County, OH

  16. Pat Thiel talks about attending the Nobel Prize Award Ceremony

    ScienceCinema

    Thiel, Pat

    2016-07-12

    Pat Thiel, Ames Laboratory senior scientist and Iowa State University Distinguished Professor of Chemistry, was invited to be a guest at the ceremony on December 10th, in Stockholm, Sweden, where Danny Shechtman, Ames Laboratory scientist, received the 2011 Nobel Prize in Chemistry. Following her return to the Lab, Thiel shared some of her recollections of the momentous event.

  17. Horticulture Therapy Activities for Exceptional Children.

    ERIC Educational Resources Information Center

    Doutt, Kathleen M.; And Others

    1989-01-01

    The Tennessee Technological University offers an enrichment program (consisting of a summer session and three Saturdays) in which gifted children and children with learning disabilities are grouped together for activities. Horticulture is one of the few enrichment activities adaptable to both groups. Children are allowed to engage in the same…

  18. Photon activation therapy of RG2 glioma carrying Fischer rats using stable thallium and monochromatic synchrotron radiation.

    PubMed

    Ceberg, Crister; Jönsson, Bo-Anders; Prezado, Yolanda; Pommer, Tobias; Nittby, Henrietta; Englund, Elisabet; Grafström, Gustav; Edvardsson, Anneli; Stenvall, Anna; Strömblad, Susanne; Wingårdh, Karin; Persson, Bertil; Elleaume, Hélène; Baldetorp, Bo; Salford, Leif G; Strand, Sven-Erik

    2012-12-21

    75 RG2 glioma-carrying Fischer rats were treated by photon activation therapy (PAT) with monochromatic synchrotron radiation and stable thallium. Three groups were treated with thallium in combination with radiation at different energy; immediately below and above the thallium K-edge, and at 50 keV. Three control groups were given irradiation only, thallium only, or no treatment at all. For animals receiving thallium in combination with radiation to 15 Gy at 50 keV, the median survival time was 30 days, which was 67% longer than for the untreated controls (p = 0.0020) and 36% longer than for the group treated with radiation alone (not significant). Treatment with thallium and radiation at the higher energy levels were not effective at the given absorbed dose and thallium concentration. In the groups treated at 50 keV and above the K-edge, several animals exhibited extensive and sometimes contra-lateral edema, neuronal death and frank tissue necrosis. No such marked changes were seen in the other groups. The results were discussed with reference to Monte Carlo calculated electron energy spectra and dose enhancement factors.

  19. Photon activation therapy of RG2 glioma carrying Fischer rats using stable thallium and monochromatic synchrotron radiation

    NASA Astrophysics Data System (ADS)

    Ceberg, Crister; Jönsson, Bo-Anders; Prezado, Yolanda; Pommer, Tobias; Nittby, Henrietta; Englund, Elisabet; Grafström, Gustav; Edvardsson, Anneli; Stenvall, Anna; Strömblad, Susanne; Wingårdh, Karin; Persson, Bertil; Elleaume, Hélène; Baldetorp, Bo; Salford, Leif G.; Strand, Sven-Erik

    2012-12-01

    75 RG2 glioma-carrying Fischer rats were treated by photon activation therapy (PAT) with monochromatic synchrotron radiation and stable thallium. Three groups were treated with thallium in combination with radiation at different energy; immediately below and above the thallium K-edge, and at 50 keV. Three control groups were given irradiation only, thallium only, or no treatment at all. For animals receiving thallium in combination with radiation to 15 Gy at 50 keV, the median survival time was 30 days, which was 67% longer than for the untreated controls (p = 0.0020) and 36% longer than for the group treated with radiation alone (not significant). Treatment with thallium and radiation at the higher energy levels were not effective at the given absorbed dose and thallium concentration. In the groups treated at 50 keV and above the K-edge, several animals exhibited extensive and sometimes contra-lateral edema, neuronal death and frank tissue necrosis. No such marked changes were seen in the other groups. The results were discussed with reference to Monte Carlo calculated electron energy spectra and dose enhancement factors.

  20. HW 03-4 CAROTID BAROREFLEX ACTIVATION THERAPY.

    PubMed

    Alnima, Teba

    2016-09-01

    Electrical carotid baroreflex activation therapy is an emerging device-based treatment for patients with treatment-resistant hypertension. Its blood pressure lowering effect has been demonstrated in several animal and human studies. In addition, this treatment has showed its prolonged effect over the long-term. The main mechanism of the blood pressure reduction during this therapy is by inhibition of the sympathetic outflow. Yet the question arises whether the inhibition of central sympathetic activity is sufficient to be the sole mechanism behind the sustained reduction in blood pressure. In this lecture, we will present the latest data on the effect of baroreflex activation therapy on blood pressure, the mechanisms of action that account for the persistent blood pressure lowering, the most suitable candidates for this treatment and future developments on the field of baropacing. PMID:27643277

  1. Bioluminescence-activated deep-tissue photodynamic therapy of cancer.

    PubMed

    Kim, Yi Rang; Kim, Seonghoon; Choi, Jin Woo; Choi, Sung Yong; Lee, Sang-Hee; Kim, Homin; Hahn, Sei Kwang; Koh, Gou Young; Yun, Seok Hyun

    2015-01-01

    Optical energy can trigger a variety of photochemical processes useful for therapies. Owing to the shallow penetration of light in tissues, however, the clinical applications of light-activated therapies have been limited. Bioluminescence resonant energy transfer (BRET) may provide a new way of inducing photochemical activation. Here, we show that efficient bioluminescence energy-induced photodynamic therapy (PDT) of macroscopic tumors and metastases in deep tissue. For monolayer cell culture in vitro incubated with Chlorin e6, BRET energy of about 1 nJ per cell generated as strong cytotoxicity as red laser light irradiation at 2.2 mW/cm(2) for 180 s. Regional delivery of bioluminescence agents via draining lymphatic vessels killed tumor cells spread to the sentinel and secondary lymph nodes, reduced distant metastases in the lung and improved animal survival. Our results show the promising potential of novel bioluminescence-activated PDT.

  2. Bioluminescence-Activated Deep-Tissue Photodynamic Therapy of Cancer

    PubMed Central

    Kim, Yi Rang; Kim, Seonghoon; Choi, Jin Woo; Choi, Sung Yong; Lee, Sang-Hee; Kim, Homin; Hahn, Sei Kwang; Koh, Gou Young; Yun, Seok Hyun

    2015-01-01

    Optical energy can trigger a variety of photochemical processes useful for therapies. Owing to the shallow penetration of light in tissues, however, the clinical applications of light-activated therapies have been limited. Bioluminescence resonant energy transfer (BRET) may provide a new way of inducing photochemical activation. Here, we show that efficient bioluminescence energy-induced photodynamic therapy (PDT) of macroscopic tumors and metastases in deep tissue. For monolayer cell culture in vitro incubated with Chlorin e6, BRET energy of about 1 nJ per cell generated as strong cytotoxicity as red laser light irradiation at 2.2 mW/cm2 for 180 s. Regional delivery of bioluminescence agents via draining lymphatic vessels killed tumor cells spread to the sentinel and secondary lymph nodes, reduced distant metastases in the lung and improved animal survival. Our results show the promising potential of novel bioluminescence-activated PDT. PMID:26000054

  3. Use of creative activities in occupational therapy practice in Sweden.

    PubMed

    Müllersdorf, Maria; Ivarsson, Ann Britt

    2012-09-01

    The aim of this study was to describe the prevalence of creative activities in occupational therapy in Sweden and how often Swedish occupational therapists use creative activities as a means of intervention. A web-mail survey was sent to 2975 Swedish occupational therapists working in health care at regional, county council or primary health care level, and those working in vocational rehabilitation. A total of 1867 (63%) answered the questionnaire and showed that 44% did use creative activities as a means of intervention and most often by practitioners working in psychiatric health care. The most commonly used form of creative activity was arts and crafts followed by gardening. This web-mail survey was based on a limited amount of items regarding creative activities. Further research should focus on in-depth inquiries about how occupational therapists and their patients perceive the use of creative activities as a means of treatment in occupational therapy. PMID:22489029

  4. Lifestyle intervention: nutrition therapy and physical activity.

    PubMed

    Evert, Alison B; Riddell, Michael C

    2015-01-01

    Diabetes now affects more than 29 million Americans, and more than 9 million of these people do not know they have diabetes. In adults, type 2 diabetes accounts for about 90% to 95% of all diagnosed cases of diabetes and is the focus of this article. Lifestyle intervention is part of the initial treatment as well as the ongoing management of type 2 diabetes. Lifestyle intervention encompasses a healthful eating plan, physical activity, and often medication to assist in achievement of glucose, lipid, and blood pressure goals. Patient education and self-care practices are also important aspects of disease management.

  5. The mRNA decay factor PAT1 functions in a pathway including MAP kinase 4 and immune receptor SUMM2

    PubMed Central

    Roux, Milena Edna; Rasmussen, Magnus Wohlfahrt; Palma, Kristoffer; Lolle, Signe; Regué, Àngels Mateu; Bethke, Gerit; Glazebrook, Jane; Zhang, Weiping; Sieburth, Leslie; Larsen, Martin R; Mundy, John; Petersen, Morten

    2015-01-01

    Multi-layered defense responses are activated in plants upon recognition of invading pathogens. Transmembrane receptors recognize conserved pathogen-associated molecular patterns (PAMPs) and activate MAP kinase cascades, which regulate changes in gene expression to produce appropriate immune responses. For example, Arabidopsis MAP kinase 4 (MPK4) regulates the expression of a subset of defense genes via at least one WRKY transcription factor. We report here that MPK4 is found in complexes in vivo with PAT1, a component of the mRNA decapping machinery. PAT1 is also phosphorylated by MPK4 and, upon flagellin PAMP treatment, PAT1 accumulates and localizes to cytoplasmic processing (P) bodies which are sites for mRNA decay. Pat1 mutants exhibit dwarfism and de-repressed immunity dependent on the immune receptor SUMM2. Since mRNA decapping is a critical step in mRNA turnover, linking MPK4 to mRNA decay via PAT1 provides another mechanism by which MPK4 may rapidly instigate immune responses. PMID:25603932

  6. Active Interventions in Clinical Practice: Contributions of Gestalt Therapy.

    ERIC Educational Resources Information Center

    Lammert, Marilyn; Dolan, Mary M.

    1983-01-01

    Describes two dimensions of Gestalt therapy that can enhance clinical practice--orientation to the present and active-experimental style--and examines them in relation to some traditional principles of practice. Gestalt theory offers a method of discovery that is a combination of phenomenology and behaviorism. (JAC)

  7. Behavioural activation therapy for adolescents 'at risk' for psychosis?

    PubMed

    Welsh, Patrick; Kitchen, Charlotte E W; Ekers, David; Webster, Lisa; Tiffin, Paul A

    2016-04-01

    The following hypothesis explores the possibility of using behavioural activation therapy for adolescents with an at-risk mental state for psychosis. Support is drawn from psychosis-related survey and pilot data as well as a robust evidence base for adult depression. However, we acknowledge that extensive feasibility work is required before exploring this hypothesis further.

  8. Family Therapy: A Phenomenological and Active Directive Approach

    ERIC Educational Resources Information Center

    Ellis, Albert

    1978-01-01

    A "third force" in family therapy is outlined in this paper, which combines a phenomenological-humanistic approach with a highly active-directive attempt to help family members surrender their misperceptions of themselves and others and to make profound philosophic changes in their intrapersonal and interpersonal attitudes and behaviors. (Author)

  9. Use of Music Activities in Speech-Language Therapy.

    ERIC Educational Resources Information Center

    Zoller, Mary B.

    1991-01-01

    Music activities for use in public school speech-language therapy are described in theory and practice. Client, space and implementation considerations are discussed, as are uses of songs and more specific applications such as exercises for relaxation, body image, breathing, vocalization, articulation, and vocabulary/concept development.…

  10. Stacking Multiple Ion Captures in The High Performance Antiproton Trap (HiPAT)

    NASA Technical Reports Server (NTRS)

    Martin, James J.; Lewis, Raymond A.; Sims, William H.; Chakrabarti, Suman; Pearson, Boise; Fant, Wallace E.

    2004-01-01

    The High performance Antiproton Trap (HiPAT) research project was initiated by the Marshall Space Flight Center's propulsion Research Center to examining the fundamental behavior of low energy antiprotons. Stored antiproton would ultimately be used for experimental demonstration of basic propulsive concepts. Matter-antimatter annihilation produces approximately 10(exp 8) MJ/g nearly 10 orders of magnitude more energy per unit mass than chemical based combustion, hence NASA's interest. To achieve containment, HiPAT utilizes a type of electromagnetic bottle know as a Penning trap positioned within an ultrahigh vacuum test section. Recently, the HiPAT hardware configuration has been enhanced to facilitate the capture of multiple normal matter ion burst. This endeavor is often referred to as "stacking" and used to increasing the number of captured particles. A prior normal matter experimental effort, successfully demonstrated the effectiveness of single burst capture. The stacking process is accomplished by manipulating the electric field generated by the confinement electrodes i.e. adjusting the well potential depth. These potential well values are initially configured to maximize the quantity of captured ions per burst; shallow wells with a depth of 100 volt or less (referenced to the incoming ion beam energy) are typically selected. Once captured, a cooling interval is required to reduce the energy of trapped particles below the lower extent of the "trap door" (or leading electrode) ion emitting potential. This is necessary such that a new burst of hot ions can be introduced while preventing those already inside from escaping. The cooling time is driven by a combination of mechanisms such as synchrotron radiation, background gas scattering, and resistive damping in a time scale on the order of minutes. A potential for reducing this hold period is to actively manipulate the electric field shape, using the power supply control system, to produce a deeper potential

  11. Selective glucocorticoid receptor-activating adjuvant therapy in cancer treatments

    PubMed Central

    Sundahl, Nora; Clarisse, Dorien; Bracke, Marc; Offner, Fritz; Berghe, Wim Vanden; Beck, Ilse M.

    2016-01-01

    Although adverse effects and glucocorticoid resistance cripple their chronic use, glucocorticoids form the mainstay therapy for acute and chronic inflammatory disorders, and play an important role in treatment protocols of both lymphoid malignancies and as adjuvant to stimulate therapy tolerability in various solid tumors. Glucocorticoid binding to their designate glucocorticoid receptor (GR), sets off a plethora of cell-specific events including therapeutically desirable effects, such as cell death, as well as undesirable effects, including chemotherapy resistance, systemic side effects and glucocorticoid resistance. In this context, selective GR agonists and modulators (SEGRAMs) with a more restricted GR activity profile have been developed, holding promise for further clinical development in anti-inflammatory and potentially in cancer therapies. Thus far, the research into the prospective benefits of selective GR modulators in cancer therapy limped behind. Our review discusses how selective GR agonists and modulators could improve the therapy regimens for lymphoid malignancies, prostate or breast cancer. We summarize our current knowledge and look forward to where the field should move to in the future. Altogether, our review clarifies novel therapeutic perspectives in cancer modulation via selective GR targeting. PMID:27713909

  12. Radiation therapy generates platelet-activating factor agonists

    PubMed Central

    Sahu, Ravi P.; Harrison, Kathleen A.; Weyerbacher, Jonathan; Murphy, Robert C.; Konger, Raymond L.; Garrett, Joy Elizabeth; Chin-Sinex, Helen Jan; Johnston, Michael Edward; Dynlacht, Joseph R.; Mendonca, Marc; McMullen, Kevin; Li, Gengxin; Spandau, Dan F.; Travers, Jeffrey B.

    2016-01-01

    Pro-oxidative stressors can suppress host immunity due to their ability to generate oxidized lipid agonists of the platelet-activating factor-receptor (PAF-R). As radiation therapy also induces reactive oxygen species, the present studies were designed to define whether ionizing radiation could generate PAF-R agonists and if these lipids could subvert host immunity. We demonstrate that radiation exposure of multiple tumor cell lines in-vitro, tumors in-vivo, and human subjects undergoing radiation therapy for skin tumors all generate PAF-R agonists. Structural characterization of radiation-induced PAF-R agonistic activity revealed PAF and multiple oxidized glycerophosphocholines that are produced non-enzymatically. In a murine melanoma tumor model, irradiation of one tumor augmented the growth of the other (non-treated) tumor in a PAF-R-dependent process blocked by a cyclooxygenase-2 inhibitor. These results indicate a novel pathway by which PAF-R agonists produced as a byproduct of radiation therapy could result in tumor treatment failure, and offer important insights into potential therapeutic strategies that could improve the overall antitumor effectiveness of radiation therapy regimens. PMID:26959112

  13. Radiation therapy generates platelet-activating factor agonists.

    PubMed

    Sahu, Ravi P; Harrison, Kathleen A; Weyerbacher, Jonathan; Murphy, Robert C; Konger, Raymond L; Garrett, Joy Elizabeth; Chin-Sinex, Helen Jan; Johnston, Michael Edward; Dynlacht, Joseph R; Mendonca, Marc; McMullen, Kevin; Li, Gengxin; Spandau, Dan F; Travers, Jeffrey B

    2016-04-12

    Pro-oxidative stressors can suppress host immunity due to their ability to generate oxidized lipid agonists of the platelet-activating factor-receptor (PAF-R). As radiation therapy also induces reactive oxygen species, the present studies were designed to define whether ionizing radiation could generate PAF-R agonists and if these lipids could subvert host immunity. We demonstrate that radiation exposure of multiple tumor cell lines in-vitro, tumors in-vivo, and human subjects undergoing radiation therapy for skin tumors all generate PAF-R agonists. Structural characterization of radiation-induced PAF-R agonistic activity revealed PAF and multiple oxidized glycerophosphocholines that are produced non-enzymatically. In a murine melanoma tumor model, irradiation of one tumor augmented the growth of the other (non-treated) tumor in a PAF-R-dependent process blocked by a cyclooxygenase-2 inhibitor. These results indicate a novel pathway by which PAF-R agonists produced as a byproduct of radiation therapy could result in tumor treatment failure, and offer important insights into potential therapeutic strategies that could improve the overall antitumor effectiveness of radiation therapy regimens. PMID:26959112

  14. Development of Process Analytical Technology (PAT) methods for controlled release pellet coating.

    PubMed

    Avalle, P; Pollitt, M J; Bradley, K; Cooper, B; Pearce, G; Djemai, A; Fitzpatrick, S

    2014-07-01

    This work focused on the control of the manufacturing process for a controlled release (CR) pellet product, within a Quality by Design (QbD) framework. The manufacturing process was Wurster coating: firstly layering active pharmaceutical ingredient (API) onto sugar pellet cores and secondly a controlled release (CR) coating. For each of these two steps, development of a Process Analytical Technology (PAT) method is discussed and also a novel application of automated microscopy as the reference method. Ultimately, PAT methods should link to product performance and the two key Critical Quality Attributes (CQAs) for this CR product are assay and release rate, linked to the API and CR coating steps respectively. In this work, the link between near infra-red (NIR) spectra and those attributes was explored by chemometrics over the course of the coating process in a pilot scale industrial environment. Correlations were built between the NIR spectra and coating weight (for API amount), CR coating thickness and dissolution performance. These correlations allow the coating process to be monitored at-line and so better control of the product performance in line with QbD requirements.

  15. Transcriptomic analysis of tomato carpel development reveals alterations in ethylene and gibberellin synthesis during pat3/pat4 parthenocarpic fruit set

    PubMed Central

    Pascual, Laura; Blanca, Jose M; Cañizares, Joaquin; Nuez, Fernado

    2009-01-01

    Background Tomato fruit set is a key process that has a great economic impact on crop production. We employed the Affymetrix GeneChip Tomato Genome Array to compare the transcriptome of a non-parthenocarpic line, UC82, with that of the parthenocarpic line RP75/59 (pat3/pat4 mutant). We analyzed the transcriptome under normal conditions as well as with forced parthenocarpic development in RP75/59, emasculating the flowers 2 days before anthesis. This analysis helps to understand the fruit set in tomato. Results Differentially expressed genes were extracted with maSigPro, which is designed for the analysis of single and multiseries time course microarray experiments. 2842 genes showed changes throughout normal carpel development and fruit set. Most of them showed a change of expression at or after anthesis. The main differences between lines were concentrated at the anthesis stage. We found 758 genes differentially expressed in parthenocarpic fruit set. Among these genes we detected cell cycle-related genes that were still activated at anthesis in the parthenocarpic line, which shows the lack of arrest in the parthenocarpic line at anthesis. Key genes for the synthesis of gibberellins and ethylene, which were up-regulated in the parthenocarpic line were also detected. Conclusion Comparisons between array experiments determined that anthesis was the most different stage and the key point at which most of the genes were modulated. In the parthenocarpic line, anthesis seemed to be a short transitional stage to fruit set. In this line, the high GAs contends leads to the development of a parthenocarpic fruit, and ethylene may mimic pollination signals, inducing auxin synthesis in the ovary and the development of a jelly fruit. PMID:19480705

  16. Unpacking Pat Parker: Intersections and Revolutions in "Movement in Black".

    PubMed

    Washburn, Amy

    2015-01-01

    This article explores Pat Parker's poem "Movement in Black." It examines the ways in which she emblematizes intersectionality and simultaneity as forms of revolution in struggles of self and society. It begins with a theoretical and historical apparatus to contextualize Parker as an artist and activist. Then it offers a literary analysis of the poem, focusing on themes of time and space, marginalization and movement, difference and power, visibility and invisibility, and history and memory. It argues that Parker uses autobiographical writing to fuse personal and political sites of resistance.

  17. Unpacking Pat Parker: Intersections and Revolutions in "Movement in Black".

    PubMed

    Washburn, Amy

    2015-01-01

    This article explores Pat Parker's poem "Movement in Black." It examines the ways in which she emblematizes intersectionality and simultaneity as forms of revolution in struggles of self and society. It begins with a theoretical and historical apparatus to contextualize Parker as an artist and activist. Then it offers a literary analysis of the poem, focusing on themes of time and space, marginalization and movement, difference and power, visibility and invisibility, and history and memory. It argues that Parker uses autobiographical writing to fuse personal and political sites of resistance. PMID:26075685

  18. ARA67/PAT1 Functions as a Repressor To Suppress Androgen Receptor Transactivation

    PubMed Central

    Zhang, Yanqing; Yang, Yue; Yeh, Shuyuan; Chang, Chawnshang

    2004-01-01

    The androgen receptor (AR) may recruit multiple coregulators for proper or optimal transactivation. Here we report the identification and characterization of ARA67/PAT1 as an AR coregulator from a prostate cDNA library. ARA67/PAT1 was screened out as an AR N terminus interacting protein. Interaction mapping shows that the cooperation of multiple domains within ARA67/PAT1 may be required for the maximal interaction with AR. ARA67/PAT1 functions as a repressor with better suppressive effects on AR compared to glucocorticoid receptor and estrogen receptor. Further mechanism dissection reveals that the interrupted AR cytoplasmic-nuclear shuttling may play a major role in ARA67/PAT1 mediated suppression on AR. Together, these results suggest that ARA67/PAT1 may function as a novel repressor that can modulate AR function in prostate cancer. PMID:14729952

  19. The syndrome of continuous muscle fibre activity following gold therapy.

    PubMed

    Grisold, W; Mamoli, B

    1984-01-01

    A 72-year-old man suffering from arthritis received a total dose of 500 mg sodium aurothiomalate during a period of 5 months. His clinical state then deteriorated and he had to be hospitalized. Upon admission he was bedridden, his level of consciousness was slightly impaired, he was confused and respiration was laboured. Continuous muscle activity was noted on all extremities and at first, erroneously, fasciculations were diagnosed. The EMG exhibited continuous muscle fibre activity consisting of duplets, triplets and multiplets. The discharges occurred in an irregular pattern; when various muscles were examined at the same time no synchronicity could be observed between muscle discharges. In the left m. deltoideus an increased percentage of polyphasic potentials was found, whereas mean duration of motor unit potentials was normal. Spontaneous activity remained unchanged during sleep and administration of intravenous diazepam or phenytoin. Blocking of ulnar nerve at either elbow or wrist level did not stop spontaneous activity in m. abductor digiti quinti. Ischaemia increased the amount of discharges after 7 min. Within 4 months after termination of gold therapy the patient's condition improved and he was discharged from hospital. Regular EMG follow-up after 8 months showed complete cessation of abnormal spontaneous activities. Nerve conduction velocities were normal except for markedly reduced compound action potential in peroneal nerves. Continuous muscle fibre activity as a side-effect of gold therapy is described. PMID:6440953

  20. The Efflux Pump Inhibitor Reserpine Selects Multidrug-Resistant Streptococcus pneumoniae Strains That Overexpress the ABC Transporters PatA and PatB▿ †

    PubMed Central

    Garvey, Mark I.; Piddock, Laura J. V.

    2008-01-01

    One way to combat multidrug-resistant microorganisms is the use of efflux pump inhibitors (EPIs). Spontaneous mutants resistant to the EPI reserpine selected from Streptococcus pneumoniae NCTC 7465 and R6 at a frequency suggestive of a single mutational event were also multidrug resistant. No mutations in pmrA (which encodes the efflux protein PmrA) were detected, and the expression of pmrA was unaltered in all mutants. In the reserpine-resistant multidrug-resistant mutants, the overexpression of both patA and patB, which encode ABC transporters, was associated with accumulation of low concentrations of antibiotics and dyes. The addition of sodium orthovanadate, an inhibitor of ABC efflux pumps, or the insertional inactivation of either gene restored wild-type antibiotic susceptibility and wild-type levels of accumulation. Only when patA was insertionally inactivated were both multidrug resistance and reserpine resistance lost. Strains in which patA was insertionally inactivated grew significantly more slowly than the wild type. These data indicate that the overexpression of both patA and patB confers multidrug resistance in S. pneumoniae but that only patA is involved in reserpine resistance. The selection of reserpine-resistant multidrug-resistant pneumococci has implications for analogous systems in other bacteria or in cancer. PMID:18362193

  1. Cytoprotective-selective activated protein C therapy for ischemic stroke

    PubMed Central

    Mosnier, Laurent O.; Zlokovic, Berislav V.; Griffin, John H.

    2014-01-01

    Summary Despite years of research and efforts to translate stroke research to clinical therapy, ischemic stroke remains a major cause of death, disability, and diminished quality of life. Primary and secondary preventive measures combined with improved quality of care have made significant progress. However, no novel drug for ischemic stroke therapy has been approved in the past decade. Numerous studies have shown beneficial effects of activated protein C (APC) in rodent stroke models. In addition to its natural anticoagulant functions, APC conveys multiple direct cytoprotective effects on many different cell types that involve multiple receptors including protease activated receptor (PAR) 1, PAR3, and the endothelial protein C receptor (EPCR). Application of molecular engineered APC variants with altered selectivity profiles to rodent stroke models demonstrated that the beneficial effects of APC primarily require its cytoprotective activities but not its anticoagulant activities. Extensive basic, preclinical, and clinical research provided a compelling rationale based on strong evidence for translation of APC therapy that has led to the clinical development of the cytoprotective-selective APC variant, 3K3A-APC, for ischemic stroke. Recent identification of non-canonical PAR1 and PAR3 activation by APC that give rise to novel tethered-ligands capable of inducing biased cytoprotective signaling as opposed to the canonical signaling provides a mechanistic explanation for how APC-mediated PAR activation can selectively induce cytoprotective signaling pathways. Collectively, these paradigm-shifting discoveries provide detailed insights into the receptor targets and the molecular mechanisms for neuroprotection by cytoprotective-selective 3K3A-APC, which is currently a biologic drug in clinical trials for ischemic stroke. PMID:25230930

  2. Intrapleural tissue plasminogen activator and deoxyribonuclease therapy for pleural infection.

    PubMed

    Piccolo, Francesco; Popowicz, Natalia; Wong, Donny; Lee, Yun Chor Gary

    2015-06-01

    Pleural infection remains a global health burden associated with significant morbidity. Drainage of the infected pleural fluid is important but can often be hindered by septations and loculations. Intrapleural fibrinolytic therapy alone, to break pleural adhesions, has shown no convincing advantages over placebo in improving clinical outcome. Deoxyribonucleoprotein from degradation of leukocytes contributes significantly to high viscosity of infected pleural fluid. Recombinant deoxyribonuclease (DNase) is effective in reducing pleural fluid viscosity in pre-clinical studies. The combination of tissue plasminogen activator (tPA) and DNase was effective in animal model experiments of empyema. The benefits were established in a randomized clinical trial: those (n=48) treated with tPA/DNase had significantly improved radiological outcomes and reduced need of surgery and duration of hospital stay. A longitudinal observational series of 107 patients further confirmed the effectiveness and safety of tPA/DNase therapy, including its use as 'rescue therapy' when patients failed to respond to antibiotics and chest tube drainage. Overall, a short course of intrapleural tPA (10 mg) and DNase (5 mg) therapy provides a cure in over 90% of patients without requiring surgery. The treatment stimulates pleural fluid formation, enhances radiographic clearance and resolution of systemic inflammation. Serious complications are uncommon; pleural bleeding requiring transfusion occurred in ~2% of cases. Pain can occur, especially with the first dose. Treatment is contraindicated in those with significant bleeding diathesis or a bronchopleural fistula. Future research is required to optimize dosing regimens and in refining patient selection. PMID:26150913

  3. Combination therapies improve the anticancer activities of retinoids in neuroblastoma

    PubMed Central

    Cheung, Belamy B

    2015-01-01

    Most therapeutic protocols for child cancers use cytotoxic agents which have a narrow therapeutic index, and resulting in severe acute and chronic toxicities to normal tissues. Despite the fact that most child cancer patients achieve complete remission after chemotherapy, death still occurs due to relapse of persistent minimal residual disease (MRD) which remaining after initial cytotoxic chemotherapy. Advanced neuroblastoma (NB) is a leading cause of cancer deaths in young children. Retinoids are an important component of advanced NB therapy at the stage of MRD, yet half of all patients treated with 13-cis-retinoic acid still relapse and die. More effective combination therapies, with a lower side-effect profile, are required to improve outcomes for NB. Fenretinide or N-4-hydroxyphenyl retinamide is a synthetic derivative of retinoic acid which works on cancer cells through nuclear receptor-dependent and -independent signalling mechanisms. Moreover, several histone deacetylase inhibitors have entered early phase trials, and, suberoylanilide hydroxamic acid has been approved for use in adult cutaneous T cell lymphoma. A number of studies suggest that retinoid signal activation is necessary for histone deacetylase inhibitor activity. A better understanding of their mechanism of actions will lead to more evidence-based retinoid combination therapies. PMID:26677433

  4. Activation of endogenous neural stem cells for multiple sclerosis therapy.

    PubMed

    Michailidou, Iliana; de Vries, Helga E; Hol, Elly M; van Strien, Miriam E

    2014-01-01

    Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system, leading to severe neurological deficits. Current MS treatment regimens, consist of immunomodulatory agents aiming to reduce the rate of relapses. However, these agents are usually insufficient to treat chronic neurological disability. A promising perspective for future therapy of MS is the regeneration of lesions with replacement of the damaged oligodendrocytes or neurons. Therapies targeting to the enhancement of endogenous remyelination, aim to promote the activation of either the parenchymal oligodendrocyte progenitor cells or the subventricular zone-derived neural stem cells (NSCs). Less studied but highly potent, is the strategy of neuronal regeneration with endogenous NSCs that although being linked to numerous limitations, is anticipated to ameliorate cognitive disability in MS. Focusing on the forebrain, this review highlights the role of NSCs in the regeneration of MS lesions.

  5. The redox-active nanomaterial toolbox for cancer therapy.

    PubMed

    Ibañez, Irene L; Notcovich, Cintia; Catalano, Paolo N; Bellino, Martín G; Durán, Hebe

    2015-04-01

    Advances in nanomaterials science contributed in recent years to develop new devices and systems in the micro and nanoscale for improving the diagnosis and treatment of cancer. Substantial evidences associate cancer cells and tumor microenvironment with reactive oxygen species (ROS), while conventional cancer treatments and particularly radiotherapy, are often mediated by ROS increase. However, the poor selectivity and the toxicity of these therapies encourage researchers to focus efforts in order to enhance delivery and to decrease side effects. Thus, the development of redox-active nanomaterials is an interesting approach to improve selectivity and outcome of cancer treatments. Herein, we describe an overview of recent advances in redox nanomaterials in the context of current and emerging strategies for cancer therapy based on ROS modulation.

  6. Activation of endogenous neural stem cells for multiple sclerosis therapy

    PubMed Central

    Michailidou, Iliana; de Vries, Helga E.; Hol, Elly M.; van Strien, Miriam E.

    2015-01-01

    Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system, leading to severe neurological deficits. Current MS treatment regimens, consist of immunomodulatory agents aiming to reduce the rate of relapses. However, these agents are usually insufficient to treat chronic neurological disability. A promising perspective for future therapy of MS is the regeneration of lesions with replacement of the damaged oligodendrocytes or neurons. Therapies targeting to the enhancement of endogenous remyelination, aim to promote the activation of either the parenchymal oligodendrocyte progenitor cells or the subventricular zone-derived neural stem cells (NSCs). Less studied but highly potent, is the strategy of neuronal regeneration with endogenous NSCs that although being linked to numerous limitations, is anticipated to ameliorate cognitive disability in MS. Focusing on the forebrain, this review highlights the role of NSCs in the regeneration of MS lesions. PMID:25653584

  7. The redox-active nanomaterial toolbox for cancer therapy.

    PubMed

    Ibañez, Irene L; Notcovich, Cintia; Catalano, Paolo N; Bellino, Martín G; Durán, Hebe

    2015-04-01

    Advances in nanomaterials science contributed in recent years to develop new devices and systems in the micro and nanoscale for improving the diagnosis and treatment of cancer. Substantial evidences associate cancer cells and tumor microenvironment with reactive oxygen species (ROS), while conventional cancer treatments and particularly radiotherapy, are often mediated by ROS increase. However, the poor selectivity and the toxicity of these therapies encourage researchers to focus efforts in order to enhance delivery and to decrease side effects. Thus, the development of redox-active nanomaterials is an interesting approach to improve selectivity and outcome of cancer treatments. Herein, we describe an overview of recent advances in redox nanomaterials in the context of current and emerging strategies for cancer therapy based on ROS modulation. PMID:25597786

  8. The structure of the cyanobactin domain of unknown function from PatG in the patellamide gene cluster

    SciTech Connect

    Mann, Greg; Koehnke, Jesko; Bent, Andrew F.; Graham, Rachael; Houssen, Wael; Jaspars, Marcel; Schwarz-Linek, Uli; Naismith, James H.

    2014-11-14

    The highly conserved domain of unknown function in the cyanobactin superfamily has a novel fold. The protein does not appear to bind the most plausible substrates, leaving questions as to its role. Patellamides are members of the cyanobactin family of ribosomally synthesized and post-translationally modified cyclic peptide natural products, many of which, including some patellamides, are biologically active. A detailed mechanistic understanding of the biosynthetic pathway would enable the construction of a biotechnological ‘toolkit’ to make novel analogues of patellamides that are not found in nature. All but two of the protein domains involved in patellamide biosynthesis have been characterized. The two domains of unknown function (DUFs) are homologous to each other and are found at the C-termini of the multi-domain proteins PatA and PatG. The domain sequence is found in all cyanobactin-biosynthetic pathways characterized to date, implying a functional role in cyanobactin biosynthesis. Here, the crystal structure of the PatG DUF domain is reported and its binding interactions with plausible substrates are investigated.

  9. Factor XI and Contact Activation as Targets for Antithrombotic Therapy

    PubMed Central

    Gailani, David; Bane, Charles E.; Gruber, Andras

    2015-01-01

    Summary The most commonly used anticoagulants produce therapeutic antithrombotic effects either by inhibiting thrombin or factor Xa, or by lowering the plasma levels of the precursors of these key enzymes, prothrombin and factor X. These drugs do not distinguish between thrombin generation contributing to thrombosis from thrombin generation required for hemostasis. Thus, anticoagulants increase bleeding risk, and many patients who would benefit from therapy go untreated because of comorbidities that place them at unacceptable risk for hemorrhage. Studies in animals demonstrate that components of the plasma contact activation system contribute to experimentally-induced thrombosis, despite playing little or no role in hemostasis. Attention has focused on factor XII, the zymogen of a protease (factor XIIa) that initiates contact activation when blood is exposed to foreign surfaces; and factor XI, the zymogen of the protease factor XIa, which links contact activation to the thrombin generation mechanism. In the case of factor XI, epidemiologic data indicate this protein contributes to stroke and venous thromboembolism, and perhaps myocardial infarction, in humans. A phase 2 trial showing that reduction of factor XI may be more effective than low-molecular-weight heparin at preventing venous thrombosis during knee replacement surgery provides proof of concept for the premise that an antithrombotic effect can be uncoupled from an anticoagulant effect in humans by targeting components of contact activation. Here we review data on the role of factor XI and factor XII in thrombosis, and results of pre-clinical and human trials for therapies targeting these proteins. PMID:25976012

  10. Mutation of sepJ reduces the intercellular signal range of a hetN-dependent paracrine signal, but not of a patS-dependent signal, in the filamentous cyanobacterium Anabaena sp. strain PCC 7120.

    PubMed

    Rivers, Orion S; Videau, Patrick; Callahan, Sean M

    2014-12-01

    Formation and maintenance of a periodic pattern of nitrogen-fixing cells called heterocysts by the filamentous cyanobacterium Anabaena sp. strain PCC 7120 is dependent on regulators encoded by patS and hetN. In this study, genetic mosaic filaments that consisted of cells engineered to produce one of the developmental regulators flanked by target cells capable of reporting the activity of the developmental regulator were used to investigate the intercellular movement of patS- and hetN-dependent activity. We provide evidence that hetN encodes a paracrine signal with a signal range of several cells. The signal that moved between cells did not include the C-terminus of the annotated HetN protein as indicated by similar signal ranges from source cells expressing either hetN-YFP or hetN alone, despite a lack of intercellular exchange of the HetN-YFP fusion protein. Deletion of sepJ, which has been shown to encode a component of intercellular channels, caused a significant decrease in the signal range of hetN expressed from source cells but not of patS. These results are consistent with symplastic transport of a paracrine hetN-dependent signal between vegetative cells of Anabaena.

  11. The distinct roles of anion transporters Slc26a3 (DRA) and Slc26a6 (PAT-1) in fluid and electrolyte absorption in the murine small intestine.

    PubMed

    Xia, Weiliang; Yu, Qin; Riederer, Brigitte; Singh, Anurag Kumar; Engelhardt, Regina; Yeruva, Sunil; Song, Penghong; Tian, De-An; Soleiman, Manoocher; Seidler, Ursula

    2014-08-01

    The mixing of gastric and pancreatic juice subjects the jejunum to unique ionic conditions with high luminal CO2 tension and HCO3 − concentration. We investigated the role of the small intestinal apical anion exchangers PAT-1 (Slc26a6) and DRA (Slc26a3) in basal and CO2/HCO3 −-stimulated jejunal fluid absorption. Single pass perfusion of jejunal segments was performed in anaesthetised wild type (WT) as well as in mice deficient in DRA, PAT-1, Na+/H+ exchanger 3 (NHE3) or NHE2, and in carbonic anhydrase II (CAII). Unbuffered saline (pH 7.4) perfusion of WT jejunum resulted in fluid absorption and acidification of the effluent. DRA-deficient jejunum absorbed less fluid than WT, and acidified the effluent more strongly, consistent with its action as a Cl−/HCO3 − exchanger. PAT-1-deficient jejunum also absorbed less fluid but resulted in less effluent acidification. Switching the luminal solution to a 5 % CO2/HCO3 − buffered solution (pH 7.4), resulted in a decrease in jejunal enterocyte pHi in all genotypes, an increase in luminal surface pH and a strong increase in fluid absorption in a PAT-1- and NHE3- but not DRA-, CAII, or NHE2-dependent fashion. Even in the absence of luminal Cl−, luminal CO2/HCO3 − augmented fluid absorption in WT, CAII, NHE2- or DRA-deficient, but not in PAT-1- or NHE3-deficient mice, indicating the likelihood that PAT-1 serves to import HCO3 − and NHE3 serves to import Na+ under these circumstances. The results suggest that PAT-1 plays an important role in jejunal Na+HCO3 – reabsorption, while DRA absorbs Cl− and exports HCO3 − in a partly CAII-dependent fashion. Both PAT-1 and DRA significantly contribute to intestinal fluid absorption and enterocyte acid/base balance but are activated by different ion gradients.

  12. Rationale, Design, and Methods of the Preschool ADHD Treatment Study (PATS)

    ERIC Educational Resources Information Center

    Kollins, Scott; Greenhill, Laurence; Swanson, James; Wigal, Sharon; Abikoff, Howard; McCracken, James; Riddle, Mark; McGough, James; Vitiello, Benedetto; Wigal, Tim; Skrobala, Anne; Posner, Kelly; Ghuman, Jaswinder; Davies, Mark; Cunningham, Charles; Bauzo, Audrey

    2006-01-01

    Objective: To describe the rationale and design of the Preschool ADHD Treatment Study (PATS). Method: PATS was a National Institutes of Mental Health-funded, multicenter, randomized, efficacy trial designed to evaluate the short-term (5 weeks) efficacy and long-term (40 weeks) safety of methylphenidate (MPH) in preschoolers with…

  13. A Training Program for Pat Frisking Female Inmates for New York City Department of Correction Officers.

    ERIC Educational Resources Information Center

    Andrews, Brenda M.

    A training program was developed for male correction officers confronted with pat frisking female inmates. The training goal was to have correction officers in women's prisons identify female inmates' contraband and be able to determine alternatives for male correction officers who were confronted with pat frisking female inmates. The Dick and…

  14. The Preschool Attention-Deficit/Hyperactivity Disorder Treatment Study (PATS) 6-Year Follow-Up

    ERIC Educational Resources Information Center

    Riddle, Mark A.; Yershova, Kseniya; Lazzaretto, Deborah; Paykina, Natalya; Yenokyan, Gayane; Greenhill, Laurence; Abikoff, Howard; Vitiello, Benedetto; Wigal, Tim; McCracken, James T.; Kollins, Scott H.; Murray, Desiree W.; Wigal, Sharon; Kastelic, Elizabeth; McGough, James J.; dosReis, Susan; Bauzo-Rosario, Audrey; Stehli, Annamarie; Posner, Kelly

    2013-01-01

    Objective: To describe the clinical course of attention-deficit/hyperactivity disorder (ADHD) symptom severity and diagnosis from ages 3 to 5 up to 9 to 12 years during a 6-year follow-up after the original Preschool ADHD Treatment Study (PATS). Method: A total of 207 participants (75% male) from the original PATS, assessed at baseline (mean age,…

  15. "Anything That Gets Me in My Heart": Pat Parker's Poetry of Justice.

    PubMed

    Green, David B

    2015-01-01

    This article argues that love and justice are interlocking themes that undergird and motivate the poetry and activism of the Black lesbian feminist Pat Parker. Parker was a prolific working-class poet, a committed Black lesbian feminist, and an international trailblazer whose poems, like her famous "Womanslaughter" discussed in this article, document the many injustices that Black women endured in an anti-Black, rabidly homophobic, and patriarchal U.S. during the last decades of the twentieth century. In a political moment where righteous cries of #BlackLivesMatter are heard across the United States I use this article to remind us all of the historical importance that Black lesbians played and continue to play in the struggles of anti-racist justice in America. PMID:26075686

  16. The mechanism of patellamide macrocyclization revealed by the characterization of the PatG macrocyclase domain

    PubMed Central

    Koehnke, Jesko; Bent, Andrew; Houssen, Wael E; Zollman, David; Morawitz, Falk; Shirran, Sally; Vendome, Jeremie; Nneoyiegbe, Ada F; Trembleau, Laurent; Botting, Catherine H; Smith, Margaret C M; Jaspars, Marcel; Naismith, James H

    2012-01-01

    Peptide macrocycles are found in many biologically active natural products. Their versatility, resistance to proteolysis and ability to traverse membranes has made them desirable molecules. Although technologies exist to synthesize such compounds, the full extent of diversity found among natural macrocycles has yet to be achieved synthetically. Cyanobactins are ribosomal peptide macrocycles encompassing an extraordinarily diverse range of ring sizes, amino acids and chemical modifications. We report the structure, biochemical characterization and initial engineering of the PatG macrocyclase domain of Prochloron sp. from the patellamide pathway that catalyzes the macrocyclization of linear peptides. The enzyme contains insertions in the subtilisin fold to allow it to recognize a three-residue signature, bind substrate in a preorganized and unusual conformation, shield an acyl-enzyme intermediate from water and catalyze peptide bond formation. The ability to macrocyclize a broad range of nonactivated substrates has wide biotechnology applications. PMID:22796963

  17. Low level laser therapy reduces inflammation in activated Achilles tendinitis

    NASA Astrophysics Data System (ADS)

    Bjordal, Jan M.; Iversen, Vegard; Lopes-Martins, Rodrigo Alvaro B.

    2006-02-01

    Objective: Low level laser therapy (LLLT) has been forwarded as therapy for osteoarthritis and tendinopathy. Results in animal and cell studies suggest that LLLT may act through a biological mechanism of inflammatory modulation. The current study was designed to investigate if LLLT has an anti-inflammatory effect on activated tendinitis of the Achilles tendon. Methods: Seven patients with bilateral Achilles tendonitis (14 tendons) who had aggravated symptoms by pain-inducing activity immediately prior to the study. LLLT (1.8 Joules for each of three points along the Achilles tendon with 904nm infrared laser) and placebo LLLT were administered to either Achilles tendons in a random order to which patients and therapist were blinded. Inflammation was examined by 1) mini-invasive microdialysis for measuring the concentration of inflammatory marker PGE II in the peritendinous tissue, 2) ultrasound with Doppler measurement of peri- and intratendinous blood flow, 3) pressure pain algometry and 4) single hop test. Results: PGE 2- levels were significantly reduced at 75, 90 and 105 minutes after active LLLT compared both to pre-treatment levels (p=0.026) and to placebo LLLT (p=0.009). Changes in pressure pain threshold (PPT) were significantly different (P=0.012) between groups. PPT increased by a mean value of 0.19 kg/cm2 [95%CI:0.04 to 0.34] after treatment in the active LLLT group, while pressure pain threshold was reduced by -0.20 kg/cm2 [95%CI:-0.45 to 0.05] after placebo LLLT. Conclusion: LLLT can be used to reduce inflammatory musculskeletal pain as it reduces inflammation and increases pressure pain threshold levels in activity-induced pain episodes of Achilles tendinopathy.

  18. Molecular cloning and characterization of oocyte-specific Pat1a in Rana rugosa frogs.

    PubMed

    Nakamura, Yoriko; Iwasaki, Takehiro; Umei, Yosuke; Saotome, Kazuhiro; Nakajima, Yukiko; Kitahara, Shoichi; Uno, Yoshinobu; Matsuda, Yoichi; Oike, Akira; Kodama, Maho; Nakamura, Masahisa

    2015-10-01

    The Pat1 gene is expressed in the immature oocytes of Xenopus, and is reportedly involved in regulating the translation of maternal mRNAs required for oocyte-maturation. However, it is still unknown when Pat1a first appears in the differentiating ovary of amphibians. To address this issue, we isolated the full-length Pat1a cDNA from the frog Rana rugosa and examined its expression in the differentiating ovary of this frog. Among eight different tissues examined, the Pat1a mRNA was detectable in only the ovary. When frozen sections from the ovaries of tadpoles at various stages of development were immunostained for Vasa-a germ cell-specific protein-and Pat1a, Vasa-immunopositive signals were observed in all of the germ cells, whereas Pat1a signals were confined to the growing oocytes (50-200 μm in diameter), and absent from small germ cells (<50 μm in diameter). Forty days after testosterone injection into tadpoles to induce female-to-male sex-reversal, Pat1a-immunoreactive oocytes had disappeared completely from the sex-reversed gonad, but Vasa-positive small germ cells persisted. Thus, Pat1a would be a good marker for identifying the sexual status of the sex-reversing gonad in amphibians. In addition, fluorescence in situ hybridization analysis showed Pat1a to have an autosomal locus, suggesting that Pat1a transcription is probably regulated by a tissue-specific transcription factor in R. rugosa.

  19. Virtual reality exposure therapy for active duty soldiers.

    PubMed

    Reger, Greg M; Gahm, Gregory A

    2008-08-01

    Virtual reality exposure (VRE) therapy is a promising treatment for a variety of anxiety disorders and has recently been extended to the treatment of posttraumatic stress disorder (PTSD). In this article, the authors briefly review the rationale for VRE and its key processes. They illustrate the treatment with an active-duty Army soldier diagnosed with combat-related PTSD. Six sessions of VRE were provided using an immersive simulation of a military convoy in Iraq. Self-reported PTSD symptoms and psychological distress were reduced at posttreatment relative to pretreatment reports, as assessed by the PTSD Checklist-Military Version and the Behavior and Symptom Identification Scale-24. The case outcomes parallel those reported in the research with other disorders and suggest the applicability of VRE in treating active duty soldiers with combat-related PTSD. PMID:18612993

  20. [Practice of Behavioral Activation in Cognitive-behavioral Therapy].

    PubMed

    Kitagawa, Nobuki

    2015-01-01

    An approach focusing on behavioral activation (BA) was adopted in the cognitive therapy of A. T. Beck, and it came to be considered that BA can play an important role in cognitive-behavioral therapy (CBT) for depression. Therefore, in recent years, BA based on clinical behavior analysis has been developed as a new treatment (Martell, et al.). The core characteristics are as follows: 1) focusing attention on context in daily life to promote the behavior control of patients and avoidance of a hatred experience ; 2) breaking the vicious circle; 3) promoting the behavior according to the purpose that the patients originally expect; 4) recognizing a relationship between behavior and the situation (contingency), thereby recovering self-efficacy tied to the long-term results that one originally expects. This does not increase pleasant activity at random when the patient is inactive, or give a sense of accomplishment. We know that depression is maintained by conducting functional analysis of detailed life behavior, and encourage the patients to have healthy behavior according to individual values. We help them to complete schedules regardless of mood and reflect on the results patiently. It is considered that those processes are important. BA may be easy to apply in clinical practice and effective for the chronic cases, or the patients in a convalescent stage. Also, in principle in the CBT for major depression, it may be effective that behavioral activation is provided in an early stage, and cognitive reconstruction in a latter stage. However, an approach to carry out functional analysis by small steps with careful activity monitoring is essential when the symptoms are severe. Furthermore, it should be considered that the way of psychoeducation requires caution because we encourage rest in the treatment of depression in our country. In particular, we must be careful not to take an attitude that an inactive behavior pattern is unproductive only based model cases.

  1. Simulated Medication Therapy Management Activities in a Pharmacotherapy Laboratory Course

    PubMed Central

    Thorpe, Joshua M.; Trapskin, Kari

    2011-01-01

    Objective. To measure the impact of medication therapy management (MTM) learning activities on students’ confidence and intention to provide MTM using the Theory of Planned Behavior. Design. An MTM curriculum combining lecture instruction and active-learning strategies was incorporated into a required pharmacotherapy laboratory course. Assessment. A validated survey instrument was developed to evaluate student confidence and intent to engage in MTM services using the domains comprising the Theory of Planned Behavior. Confidence scores improved significantly from baseline for all items (p < 0.00), including identification of billable services, documentation, and electronic billing. Mean scores improved significantly for all Theory of Planned Behavior items within the constructs of perceived behavioral control and subjective norms (p < 0.05). At baseline, 42% of students agreed or strongly agreed that they had knowledge and skills to provide MTM. This percentage increased to 82% following completion of the laboratory activities. Conclusion. Implementation of simulated MTM activities in a pharmacotherapy laboratory significantly increased knowledge scores, confidence measures, and scores on Theory of Planned Behavior constructs related to perceived behavioral control and subjective norms. Despite these improvements, intention to engage in future MTM services remained unchanged. PMID:21829269

  2. X-Ray Psoralen Activated Cancer Therapy (X-PACT)

    PubMed Central

    Oldham, Mark; Yoon, Paul; Fathi, Zak; Beyer, Wayne F.; Adamson, Justus; Liu, Leihua; Alcorta, David; Xia, Wenle; Osada, Takuya; Liu, Congxiao; Yang, Xiao Y.; Dodd, Rebecca D.; Herndon, James E.; Meng, Boyu; Kirsch, David G.; Lyerly, H. Kim; Dewhirst, Mark W.; Fecci, Peter; Walder, Harold; Spector, Neil L.

    2016-01-01

    This work investigates X-PACT (X-ray Psoralen Activated Cancer Therapy): a new approach for the treatment of solid cancer. X-PACT utilizes psoralen, a potent anti-cancer therapeutic with current application to proliferative disease and extracorporeal photopheresis (ECP) of cutaneous T Cell Lymphoma. An immunogenic role for light-activated psoralen has been reported, contributing to long-term clinical responses. Psoralen therapies have to-date been limited to superficial or extracorporeal scenarios due to the requirement for psoralen activation by UVA light, which has limited penetration in tissue. X-PACT solves this challenge by activating psoralen with UV light emitted from novel non-tethered phosphors (co-incubated with psoralen) that absorb x-rays and re-radiate (phosphoresce) at UV wavelengths. The efficacy of X-PACT was evaluated in both in-vitro and in-vivo settings. In-vitro studies utilized breast (4T1), glioma (CT2A) and sarcoma (KP-B) cell lines. Cells were exposed to X-PACT treatments where the concentrations of drug (psoralen and phosphor) and radiation parameters (energy, dose, and dose rate) were varied. Efficacy was evaluated primarily using flow cell cytometry in combination with complimentary assays, and the in-vivo mouse study. In an in-vitro study, we show that X-PACT induces significant tumor cell apoptosis and cytotoxicity, unlike psoralen or phosphor alone (p<0.0001). We also show that apoptosis increases as doses of phosphor, psoralen, or radiation increase. Finally, in an in-vivo pilot study of BALBc mice with syngeneic 4T1 tumors, we show that the rate of tumor growth is slower with X-PACT than with saline or AMT + X-ray (p<0.0001). Overall these studies demonstrate a potential therapeutic effect for X-PACT, and provide a foundation and rationale for future studies. In summary, X-PACT represents a novel treatment approach in which well-tolerated low doses of x-ray radiation are delivered to a specific tumor site to generate UVA light which

  3. X-Ray Psoralen Activated Cancer Therapy (X-PACT).

    PubMed

    Oldham, Mark; Yoon, Paul; Fathi, Zak; Beyer, Wayne F; Adamson, Justus; Liu, Leihua; Alcorta, David; Xia, Wenle; Osada, Takuya; Liu, Congxiao; Yang, Xiao Y; Dodd, Rebecca D; Herndon, James E; Meng, Boyu; Kirsch, David G; Lyerly, H Kim; Dewhirst, Mark W; Fecci, Peter; Walder, Harold; Spector, Neil L

    2016-01-01

    This work investigates X-PACT (X-ray Psoralen Activated Cancer Therapy): a new approach for the treatment of solid cancer. X-PACT utilizes psoralen, a potent anti-cancer therapeutic with current application to proliferative disease and extracorporeal photopheresis (ECP) of cutaneous T Cell Lymphoma. An immunogenic role for light-activated psoralen has been reported, contributing to long-term clinical responses. Psoralen therapies have to-date been limited to superficial or extracorporeal scenarios due to the requirement for psoralen activation by UVA light, which has limited penetration in tissue. X-PACT solves this challenge by activating psoralen with UV light emitted from novel non-tethered phosphors (co-incubated with psoralen) that absorb x-rays and re-radiate (phosphoresce) at UV wavelengths. The efficacy of X-PACT was evaluated in both in-vitro and in-vivo settings. In-vitro studies utilized breast (4T1), glioma (CT2A) and sarcoma (KP-B) cell lines. Cells were exposed to X-PACT treatments where the concentrations of drug (psoralen and phosphor) and radiation parameters (energy, dose, and dose rate) were varied. Efficacy was evaluated primarily using flow cell cytometry in combination with complimentary assays, and the in-vivo mouse study. In an in-vitro study, we show that X-PACT induces significant tumor cell apoptosis and cytotoxicity, unlike psoralen or phosphor alone (p<0.0001). We also show that apoptosis increases as doses of phosphor, psoralen, or radiation increase. Finally, in an in-vivo pilot study of BALBc mice with syngeneic 4T1 tumors, we show that the rate of tumor growth is slower with X-PACT than with saline or AMT + X-ray (p<0.0001). Overall these studies demonstrate a potential therapeutic effect for X-PACT, and provide a foundation and rationale for future studies. In summary, X-PACT represents a novel treatment approach in which well-tolerated low doses of x-ray radiation are delivered to a specific tumor site to generate UVA light which

  4. Issues in development, evaluation, and use of the NASA Preflight Adaptation Trainer (PAT)

    NASA Technical Reports Server (NTRS)

    Lane, Norman E.; Kennedy, Robert S.

    1988-01-01

    The Preflight Adaptation Trainer (PAT) is intended to reduce or alleviate space adaptation syndrome by providing opportunities for portions of that adaptation to occur under normal gravity conditions prior to space flight. Since the adaptation aspects of the PAT objectives involve modification not only of the behavior of the trainee, but also of sensiomotor skills which underly the behavioral generation, the defining of training objectives of the PAT utilizes four mechanisms: familiarization, demonstration, training and adaptation. These mechanisms serve as structural reference points for evaluation, drive the content and organization of the training procedures, and help to define the roles of the PAT instructors and operators. It was determined that three psychomotor properties are most critical for PAT evaluation: reliability; sensitivity; and relevance. It is cause for concern that the number of measures available to examine PAT effects exceed those that can be properly studied with the available sample sizes; special attention will be required in selection of the candidate measure set. The issues in PAT use and application within a training system context are addressed through linking the three training related mechanisms of familiarization, demonstration and training to the fourth mechanism, adaptation.

  5. Structural insights into HetR-PatS interaction involved in cyanobacterial pattern formation.

    PubMed

    Hu, Hai-Xi; Jiang, Yong-Liang; Zhao, Meng-Xi; Cai, Kun; Liu, Sanling; Wen, Bin; Lv, Pei; Zhang, Yonghui; Peng, Junhui; Zhong, Hui; Yu, Hong-Mei; Ren, Yan-Min; Zhang, Zhiyong; Tian, Changlin; Wu, Qingfa; Oliveberg, Mikael; Zhang, Cheng-Cai; Chen, Yuxing; Zhou, Cong-Zhao

    2015-01-01

    The one-dimensional pattern of heterocyst in the model cyanobacterium Anabaena sp. PCC 7120 is coordinated by the transcription factor HetR and PatS peptide. Here we report the complex structures of HetR binding to DNA, and its hood domain (HetRHood) binding to a PatS-derived hexapeptide (PatS6) at 2.80 and 2.10 Å, respectively. The intertwined HetR dimer possesses a couple of novel HTH motifs, each of which consists of two canonical α-helices in the DNA-binding domain and an auxiliary α-helix from the flap domain of the neighboring subunit. Two PatS6 peptides bind to the lateral clefts of HetRHood, and trigger significant conformational changes of the flap domain, resulting in dissociation of the auxiliary α-helix and eventually release of HetR from the DNA major grove. These findings provide the structural insights into a prokaryotic example of Turing model. PMID:26576507

  6. Structural insights into HetR−PatS interaction involved in cyanobacterial pattern formation

    PubMed Central

    Hu, Hai-Xi; Jiang, Yong-Liang; Zhao, Meng-Xi; Cai, Kun; Liu, Sanling; Wen, Bin; Lv, Pei; Zhang, Yonghui; Peng, Junhui; Zhong, Hui; Yu, Hong-Mei; Ren, Yan-Min; Zhang, Zhiyong; Tian, Changlin; Wu, Qingfa; Oliveberg, Mikael; Zhang, Cheng-Cai; Chen, Yuxing; Zhou, Cong-Zhao

    2015-01-01

    The one-dimensional pattern of heterocyst in the model cyanobacterium Anabaena sp. PCC 7120 is coordinated by the transcription factor HetR and PatS peptide. Here we report the complex structures of HetR binding to DNA, and its hood domain (HetRHood) binding to a PatS-derived hexapeptide (PatS6) at 2.80 and 2.10 Å, respectively. The intertwined HetR dimer possesses a couple of novel HTH motifs, each of which consists of two canonical α-helices in the DNA-binding domain and an auxiliary α-helix from the flap domain of the neighboring subunit. Two PatS6 peptides bind to the lateral clefts of HetRHood, and trigger significant conformational changes of the flap domain, resulting in dissociation of the auxiliary α-helix and eventually release of HetR from the DNA major grove. These findings provide the structural insights into a prokaryotic example of Turing model. PMID:26576507

  7. PAT4 is abundantly expressed in excitatory and inhibitory neurons as well as epithelial cells.

    PubMed

    Roshanbin, Sahar; Hellsten, Sofie V; Tafreshiha, Atieh; Zhu, Yinan; Raine, Amanda; Fredriksson, Robert

    2014-04-01

    PAT4, the fourth member of the SLC36/proton dependent amino acid transporter (PAT) family, is a high-affinity, low capacity electroneutral transporter of neutral amino acids like proline and tryptophan. It has also been associated with the function of mTORC1, a complex in the mammalian target of rapamycin (mTOR) pathway. We performed in situ hybridization and immunohistological analysis to determine the expression profile of PAT4, as well as an RT-PCR study on tissue from mice exposed to leucine. We performed a phylogenetic analysis to determine the evolutionary origin of PAT4. The in situ hybridization and the immunohistochemistry on mouse brain sections and hypothalamic cells showed abundant PAT4 expression in the mouse brain intracellularly in both inhibitory and excitatory neurons, partially co-localizing with lysosomal markers and epithelial cells lining the ventricles. Its location in epithelial cells around the ventricles indicates a transport of substrates across the blood brain barrier. Phylogenetic analysis showed that PAT4 belongs to an evolutionary old family most likely predating animals, and PAT4 is the oldest member of that family. PMID:24530433

  8. Proteinase-activated receptors (PARs) as targets for antiplatelet therapy.

    PubMed

    Cunningham, Margaret; McIntosh, Kathryn; Bushell, Trevor; Sloan, Graeme; Plevin, Robin

    2016-04-15

    Since the identification of the proteinase-activated receptor (PAR) family as mediators of serine protease activity in the 1990s, there has been tremendous progress in the elucidation of their pathophysiological roles. The development of drugs that target PARs has been the focus of many laboratories for the potential treatment of thrombosis, cancer and other inflammatory diseases. Understanding the mechanisms of PAR activation and G protein signalling pathways evoked in response to the growing list of endogenous proteases has yielded great insight into receptor regulation at the molecular level. This has led to the development of new selective modulators of PAR activity, particularly PAR1. The mixed success of targeting PARs has been best exemplified in the context of inhibiting PAR1 as a new antiplatelet therapy. The development of the competitive PAR1 antagonist, vorapaxar (Zontivity), has clearly shown the value in targeting PAR1 in acute coronary syndrome (ACS); however the severity of associated bleeding with this drug has limited its use in the clinic. Due to the efficacy of thrombin acting via PAR1, strategies to selectively inhibit specific PAR1-mediated G protein signalling pathways or to target the second thrombin platelet receptor, PAR4, are being devised. The rationale behind these alternative approaches is to bias downstream thrombin activity via PARs to allow for inhibition of pro-thrombotic pathways but maintain other pathways that may preserve haemostatic balance and improve bleeding profiles for widespread clinical use. This review summarizes the structural determinants that regulate PARs and the modulators of PAR activity developed to date.

  9. Monte Carlo modelling of daylight activated photodynamic therapy.

    PubMed

    Campbell, C L; Wood, K; Valentine, R M; Brown, C T A; Moseley, H

    2015-05-21

    The treatment of superficial skin lesions via daylight activated photodynamic therapy (PDT) has been explored theoretically with three dimensional (3D) Monte Carlo radiation transfer simulations. For similar parameters and conditions, daylight activated PDT was compared to conventional PDT using a commercially available light source. Under reasonable assumptions for the optical properties of the tissue, protoporphyrin IX (PpIX) concentration and a treatment dose of 75 J cm(-2), it was found that during a clear summer day an effective treatment depth of over 2 mm can be achieved after 30 min of daylight illumination at a latitude of 56 degrees North. The same light dose would require 2.5 h of daylight illumination during an overcast summer day where a treatment depth of about 2 mm can be achieved. For conventional PDT the developed model suggests that 15 min of illumination is required to deliver a light dose of 75 J cm(-2), which would result in an effective treatment depth of about 3 mm. The model developed here allows for the determination of photo-toxicity in skin tissue as a function of depth for different weather conditions as well as for conventional light sources. Our theoretical investigation supports clinical studies and shows that daylight activated PDT has the potential for treating superficial skin lesions during different weather conditions.

  10. Monte Carlo modelling of daylight activated photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Campbell, C. L.; Wood, K.; Valentine, R. M.; Brown, C. T. A.; Moseley, H.

    2015-05-01

    The treatment of superficial skin lesions via daylight activated photodynamic therapy (PDT) has been explored theoretically with three dimensional (3D) Monte Carlo radiation transfer simulations. For similar parameters and conditions, daylight activated PDT was compared to conventional PDT using a commercially available light source. Under reasonable assumptions for the optical properties of the tissue, protoporphyrin IX (PpIX) concentration and a treatment dose of 75 J cm-2, it was found that during a clear summer day an effective treatment depth of over 2 mm can be achieved after 30 min of daylight illumination at a latitude of 56 degrees North. The same light dose would require 2.5 h of daylight illumination during an overcast summer day where a treatment depth of about 2 mm can be achieved. For conventional PDT the developed model suggests that 15 min of illumination is required to deliver a light dose of 75 J cm-2, which would result in an effective treatment depth of about 3 mm. The model developed here allows for the determination of photo-toxicity in skin tissue as a function of depth for different weather conditions as well as for conventional light sources. Our theoretical investigation supports clinical studies and shows that daylight activated PDT has the potential for treating superficial skin lesions during different weather conditions.

  11. Pointing, acquisition and tracking (PAT) subsystems and components for optical space communication systems

    NASA Astrophysics Data System (ADS)

    Kern, R. H.; Kugel, U.

    1989-10-01

    The pointing, acquisition, and tracking (PAT) subsystem that will be incorporated by optical space communications transceivers must furnish very precise beam steering due to the highly collimated nature of the laser beams employed. The PAT subsystem must also be able to cover an angular rate of more than a full hemisphere, if it is intended for use on a LEO satellite which communicates with another in GEO. The present PAT is composed of a coarse-pointing assembly, a fine-pointing assembly, and a point-ahead assembly; their interactive operation is managed by a control law electronics unit. A CO2 laser is assumed to be the transmitter.

  12. Oracle Applications Patch Administration Tool (PAT) Beta Version

    2002-01-04

    PAT is a Patch Administration Tool that provides analysis, tracking, and management of Oracle Application patches. This includes capabilities as outlined below: Patch Analysis & Management Tool Outline of capabilities: Administration Patch Data Maintenance -- track Oracle Application patches applied to what database instance & machine Patch Analysis capture text files (readme.txt and driver files) form comparison detail report comparison detail PL/SQL package comparison detail SQL scripts detail JSP module comparison detail Parse and loadmore » the current applptch.txt (10.7) or load patch data from Oracle Application database patch tables (11i) Display Analysis -- Compare patch to be applied with current Oracle Application installed Appl_top code versions Patch Detail Module comparison detail Analyze and display one Oracle Application module patch. Patch Management -- automatic queue and execution of patches Administration Parameter maintenance -- setting for directory structure of Oracle Application appl_top Validation data maintenance -- machine names and instances to patch Operation Patch Data Maintenance Schedule a patch (queue for later execution) Run a patch (queue for immediate execution) Review the patch logs Patch Management Reports« less

  13. Oracle Applications Patch Administration Tool (PAT) Beta Version

    SciTech Connect

    2002-01-04

    PAT is a Patch Administration Tool that provides analysis, tracking, and management of Oracle Application patches. This includes capabilities as outlined below: Patch Analysis & Management Tool Outline of capabilities: Administration Patch Data Maintenance -- track Oracle Application patches applied to what database instance & machine Patch Analysis capture text files (readme.txt and driver files) form comparison detail report comparison detail PL/SQL package comparison detail SQL scripts detail JSP module comparison detail Parse and load the current applptch.txt (10.7) or load patch data from Oracle Application database patch tables (11i) Display Analysis -- Compare patch to be applied with current Oracle Application installed Appl_top code versions Patch Detail Module comparison detail Analyze and display one Oracle Application module patch. Patch Management -- automatic queue and execution of patches Administration Parameter maintenance -- setting for directory structure of Oracle Application appl_top Validation data maintenance -- machine names and instances to patch Operation Patch Data Maintenance Schedule a patch (queue for later execution) Run a patch (queue for immediate execution) Review the patch logs Patch Management Reports

  14. Active Targeted Nanoparticles for Oral Administration of Gastric Cancer Therapy.

    PubMed

    Lin, Yu-Hsin; Chen, Zih-Rou; Lai, Chih-Ho; Hsieh, Chia-Hung; Feng, Chun-Lung

    2015-09-14

    Gastric carcinogenesis is a commonly diagnosed type of cancer and has a dismal prognosis because of the rate at which it aggressively spreads and because of the lack of effective therapies to stop its progression. This study evaluated a type of oral drug delivery system of a potential target-activated nanosizer comprising a fucose-conjugated chitosan and polyethylene glycol-conjugated chitosan complex with gelatin containing encapsulated green tea polyphenol extract epigallocatechin-3-gallate, allowing oral administration of the drug through a site-specific release in gastric cancer cells. The results demonstrated that the nanoparticles effectively reduced drug release within gastric acids and that a controlled epigallocatechin-3-gallate release inhibited gastric cancer cell growth, induced cell apoptosis, and reduced vascular endothelial growth factor protein expression. Furthermore, in vivo assay results indicated that the prepared epigallocatechin-3-gallate-loaded fucose-chitosan/polyethylene glycol-chitosan/gelatin nanoparticles significantly affected gastric tumor activity and reduced gastric and liver tissue inflammatory reaction in an orthotopic gastric tumor mouse model.

  15. Laser light triggered-activated carbon nanosystem for cancer therapy.

    PubMed

    Chu, Maoquan; Peng, Jinliang; Zhao, Jiajia; Liang, Shanlu; Shao, Yuxiang; Wu, Qiang

    2013-02-01

    Among carbon-based nanomaterials, activated carbon (AC) may be an ideal candidate as a carrier for tumor therapeutic agents. Here we found a new property of nanoscale activated carbon (NAC) with narrow size distribution, namely the rapid conversion of light to thermal energy both in vitro and in vivo. An aqueous suspension of 200 μL of NAC (1 mg/mL) exhibited a rapid temperature increase of more than 35 °C after irradiation for 20 min with a 655-nm laser; this was within the temperature range for effective tumor treatment. We demonstrated that lung cancer cells (H-1299) incubated with bamboo nano-AC (BNAC) were killed with high efficiency after laser irradiation. In addition, mouse tumors with sizes smaller than the laser spot that had been injected with BNAC disappeared after irradiation. For tumors larger than the laser spot area, the incorporation of the photosensitizer ZnPc obviously increased the tumor growth inhibition efficiency of BNAC. BNAC-ZnPc was found to exhibit a synergistic effect when photothermal and photodynamic therapies were administered in combination. These results indicated that NAC can be used for high efficiency cancer phototherapy.

  16. Solid state laser communications in space (SOLACOS) position, acquisition, and tracking (PAT) subsystem implementation

    NASA Astrophysics Data System (ADS)

    Flemmig, Joerg; Pribil, Klaus

    1994-09-01

    This paper presents the concept and implementation aspects of the Pointing, Acquisition and Tracking Subsystem (PAT) which is developed in the frame of the SOLACOS (Solid State Laser Communications in Space) program.

  17. Discharge diversion in the Patía River delta, the Colombian Pacific: Geomorphic and ecological consequences for mangrove ecosystems

    NASA Astrophysics Data System (ADS)

    Restrepo, Juan D.; Cantera, Jaime R.

    2013-10-01

    In the Patía River delta, the best-developed delta on the western margin of South America, a major water diversion started in 1972. The diversion of the Patía flow to the Sanquianga River, the latter a small stream draining internal lakes from the Pacific lowlands, shifted the active delta plain from the south to the north and changed the northern estuarine system into an active delta plain. The Sanquianga Mangrove National Park, a mangrove reserve measuring 800 km2, lies in this former estuary, where major hydrologic and sedimentation changes are occurring. Overall, major environmental consequences of this discharge diversion in terms of geomorphic changes along distributary channels and ecological impacts on mangrove ecosystems are evidenced by: (1) distributary channel accretion by operating processes such as sedimentation, overbank flow, increasing width of levees, sedimentation in crevasses, interdistributary channel fill, and colonization of pioneer mangrove; (2) freshening conditions in the Sanquianga distributary channel, a hydrologic change that has shifted the upper estuarine region (salinity <1%) downstream; (3) downstream advance of freshwater vegetation, which is invading channel banks in the lower and mixing estuarine zones; (4) die-off of approximately 5200 ha of mangrove near the delta apex at Bocas de Satinga, where the highest sediment accumulation rates occur; and (5) recurrent periods of mangrove defoliation due to a worm plague. Further analyses indicate strong mangrove erosion along transgressive barrier islands on the former delta plain. Here tectonic-induced subsidence, relative sea-level rise, and sediment starving conditions due to the channel diversion, are the main causes of the observed retreating conditions of mangrove communities. Our data also indicate that the Patía River has the highest sediment load (27 × 106 t yr-1) and basin-wide sediment yield (1500 t km-2 yr-1) on the west coast of South America. Erosion rates from the Pat

  18. Air transport of plutonium metal : content expansion initiative for the Plutonium Air Transportable (PAT-1) packaging.

    SciTech Connect

    Mann, Paul T.; Caviness, Michael L.; Yoshimura, Richard Hiroyuki

    2010-06-01

    The National Nuclear Security Administration (NNSA) has submitted an application to the Nuclear Regulatory Commission (NRC) for the air shipment of plutonium metal within the Plutonium Air Transportable (PAT-1) packaging. The PAT-1 packaging is currently authorized for the air transport of plutonium oxide in solid form only. The INMM presentation will provide a limited overview of the scope of the plutonium metal initiative and provide a status of the NNSA application to the NRC.

  19. Air transport of plutonium metal: content expansion initiative for the plutonium air transportable (PAT01) packaging

    SciTech Connect

    Caviness, Michael L; Mann, Paul T

    2010-01-01

    The National Nuclear Security Administration (NNSA) has submitted an application to the Nuclear Regulatory Commission (NRC) for the air shipment of plutonium metal within the Plutonium Air Transportable (PAT-1) packaging. The PAT-1 packaging is currently authorized for the air transport of plutonium oxide in solid form only. The INMM presentation will provide a limited overview of the scope of the plutonium metal initiative and provide a status of the NNSA application to the NRC.

  20. GeoPAT: A toolbox for pattern-based information retrieval from large geospatial databases

    NASA Astrophysics Data System (ADS)

    Jasiewicz, Jarosław; Netzel, Paweł; Stepinski, Tomasz

    2015-07-01

    Geospatial Pattern Analysis Toolbox (GeoPAT) is a collection of GRASS GIS modules for carrying out pattern-based geospatial analysis of images and other spatial datasets. The need for pattern-based analysis arises when images/rasters contain rich spatial information either because of their very high resolution or their very large spatial extent. Elementary units of pattern-based analysis are scenes - patches of surface consisting of a complex arrangement of individual pixels (patterns). GeoPAT modules implement popular GIS algorithms, such as query, overlay, and segmentation, to operate on the grid of scenes. To achieve these capabilities GeoPAT includes a library of scene signatures - compact numerical descriptors of patterns, and a library of distance functions - providing numerical means of assessing dissimilarity between scenes. Ancillary GeoPAT modules use these functions to construct a grid of scenes or to assign signatures to individual scenes having regular or irregular geometries. Thus GeoPAT combines knowledge retrieval from patterns with mapping tasks within a single integrated GIS environment. GeoPAT is designed to identify and analyze complex, highly generalized classes in spatial datasets. Examples include distinguishing between different styles of urban settlements using VHR images, delineating different landscape types in land cover maps, and mapping physiographic units from DEM. The concept of pattern-based spatial analysis is explained and the roles of all modules and functions are described. A case study example pertaining to delineation of landscape types in a subregion of NLCD is given. Performance evaluation is included to highlight GeoPAT's applicability to very large datasets. The GeoPAT toolbox is available for download from

  1. The Formation and Chronology of the PAT 91501 Impact-Melt L-Chondrite with Vesicle-Metal-Sulfide Assemblages

    NASA Technical Reports Server (NTRS)

    Benedix, G. K.; Ketcham, R. A.; Wilson, L.; McCoy, T. J.; Bogard, D. D.; Garrison, D. H.; Herzog, G. F.; Xue, S.; Klein, J.; Middleton, R.

    2007-01-01

    The L chondrite Patuxent Range (PAT) 41 91501 is an 8.5-kg unshocked, homogeneous, igneous-textured impact melt that cooled slowly compared to other meteoritic impact melts in a crater floor melt sheet or sub-crater dike. We conducted mineralogical and tomographic studies of previously unstudied mm- to cm-sized metal-sulfide-vesicle assemblages and chronologic studies of the silicate host. Metal-sulfide clasts constitute about 1 vol.%, comprise zoned taenite, troilite and pentlandite, and exhibit a consistent orientation between metal and sulfide and of metal-sulfide contacts. Vesicles make up approximately 2 vol.% and exhibit a similar orientation of long axes. Ar-39-Ar-40 measurements date the time of impact at 4.461 +/- 0.008 Gyr B.P. Cosmogenic noble gases and Be-10 and Al-2l activities suggest a pre-atmospheric radius of 40-60 cm and a cosmic ray exposure age of 25-29 Myr, similar to ages of a cluster of L chondrites. PAT 91501 dates the oldest known impact on the L chondrite parent body. The dominant vesicle-forming gas was S2 (approximately 15-20 ppm), which formed in equilibrium with impact-melted sulfides. The meteorite formed in an impact melt dike beneath a crater, as did other impact melted L chondrites, such as Chico. Cooling and solidification occurred over approximately 2 hours. During this time, approximately 90% of metal and sulfide segregated from the local melt. Remaining metal and sulfide grains oriented themselves in the local gravitational field, a feature nearly unique among meteorites. Many of these metal sulfide grains adhered to vesicles to form aggregates that may have been close to neutrally buoyant. These aggregates would have been carried upward with the residual melt, inhibiting further buoyancy-driven segregation. Although similar processes operated individually in other chondritic impact melts, their interaction produced the unique assemblage observed in PAT 91501.

  2. The efficacy of Watch PAT in obstructive sleep apnea syndrome diagnosis.

    PubMed

    Körkuyu, Emine; Düzlü, Mehmet; Karamert, Recep; Tutar, Hakan; Yılmaz, Metin; Çiftçi, Bülent; Güven, Selma Fırat

    2015-01-01

    Polysomnography is currently considered as the gold standard for the diagnosis of obstructive sleep apnea syndrome (OSAS). But high expense and the backlog of the sleep centers have resulted in a search for an alternative method of diagnosis. The aim of this study is to assess the efficacy and reliability of Watch PAT as an alternate option in OSAS diagnosis. The patients have worn a Watch PAT(®) 200 device in the sleep laboratory during a standard polysomnography. The correlation in REM and Non-REM AHI scores, sleep periods and the mean O2 saturation percentage between Watch PAT and PSG sleep studies were assessed. There was a statistically significant very strong correlation between PSG and Watch PAT AHI scores (Spearman's rho = 0.802 p < 0.001). The mean recording time with PSG and Watch PAT was 463.06 ± 37.08 and 469.33 ± 72.81 min, respectively, and there was no statistically significant difference (p = 0.068). However, there was a statistically significant difference between two methods regarding the average sleep time and REM sleep period. No statistically significant difference was revealed in the mean O2 saturation percentage (p < 0.001). Watch PAT is an efficient device and is considered to be an adjunctive diagnostic method for PSG in diagnosis of OSAS.

  3. PAT1, a new member of the GRAS family, is involved in phytochrome A signal transduction

    PubMed Central

    Bolle, Cordelia; Koncz, Csaba; Chua, Nam-Hai

    2000-01-01

    Light signaling via the phytochrome A (phyA) photoreceptor controls basic plant developmental processes including de-etiolation and hypocotyl elongation. We have identified a new Arabidopsis mutant, pat (phytochrome A signal transduction)1-1, which shows strongly reduced responses in continuous far-red light. Physiological and molecular data indicate that this mutant is disrupted at an early step of phyA signal transduction. The PAT1 gene encodes a cytoplasmic protein of 490 amino acids with sequence homologies to the plant-specific GRAS regulatory protein family. In the pat1-1 mutant, a T-DNA insertion introduces a premature stop codon, which likely results in the production of a truncated PAT1 protein of 341 amino acids. The semidominant phenotype of this mutant can be recapitulated by overexpression of an appropriately truncated PAT1 gene in the wild type. The results indicate that the truncated PAT1 protein acts in a dominant-negative fashion to inhibit phyA signaling. PMID:10817761

  4. Isolation of the patC gene encoding the cystathionine beta-lyase of Lactobacillus delbrueckii subsp. bulgaricus and molecular analysis of inter-strain variability in enzyme biosynthesis.

    PubMed

    Aubel, Dominique; Germond, Jacques Edouard; Gilbert, Christophe; Atlan, Danièle

    2002-07-01

    The patC gene encoding the cystathionine beta-lyase (CBL) of Lactobacillus delbrueckii subsp. bulgaricus NCDO 1489 was cloned and expressed in Escherichia coli. Overexpression of CBL complemented the methionine auxotrophy of an E. coli metC mutant, demonstrating in vivo that this enzyme functions as a CBL. However, PatC is distinguishable from the MetC CBLs by a low identity in amino acid sequence, a sensitivity to iodoacetic acid, greater thermostability and a lower substrate affinity. Homologues of patC were detected in the 13 Lb. delbrueckii strains studied, but only seven of them showed CBL activity. In constrast to CBL(+) strains, all CBL-deficient strains analysed were auxotrophic for methionine. This supports the hypothesis that CBLs from lactobacilli are probably involved in methionine biosynthesis. Moreover, the results of this study suggest that post-transcriptional mechanisms account for the differences in CBL activities observed between strains of Lb. delbrueckii.

  5. Integrating Therapy Dog Teams in a Physical Activity Program for Children with Autism Spectrum Disorders

    ERIC Educational Resources Information Center

    Obrusnikova, Iva; Bibik, Janice M.; Cavalier, Albert R.; Manley, Kyle

    2012-01-01

    The use of therapy-dog teams in programs for children with disabilities is becoming increasingly popular in school and therapeutic settings and has been shown to provide physical, social, and emotional benefits for the children. This article describes the basic steps for implementing therapy dog-assisted activities in physical activity programs…

  6. Enfermedad diarreica aguda por Escherichia coli patógenas en Colombia

    PubMed Central

    Gómez-Duarte, Oscar G.

    2014-01-01

    Resumen Las cepas de E. coli patógenas intestinales son causas importantes de la enfermedad diarreica aguda (EDA) en niños menores de 5 años en América Latina, África y Asia y están asociadas a alta mortalidad en niños en las comunidades más pobres de África y el Sudeste Asiático. Estudios sobre el papel de las E. coli patógenas intestinales en la EDA infantil en Colombia y otros países de América Latina son limitados debido a la carencia de ensayos para detección de estos patógenos en los laboratorios clínicos de centros de salud. Estudios recientes han reportado la detección de E. coli patógenas intestinales en Colombia, siendo la E. coli enterotoxigénica la cepa más frecuentemente asociada a diarrea en niños menores de 5 años. Otros patógenos detectados en estos pacientes incluyen las E. coli enteroagregativa, enteropatógena, productora de toxina Shiga, y de adherencia difusa. Con base en estudios que reportan la presencia de E. coli productora de toxina Shiga y E. coli enteroagregativa en carnes y vegetales en supermercados, se cree que productos alimentarios contaminados contribuyen a la transmisión de estos patógenos y a la infección del huésped susceptible. Más estudios son necesarios para evaluar los mecanismos de transmisión, el impacto en la epidemiologia de la EDA, y las pautas de manejo y prevención de estos patógenos que afectan la población pediátrica en Colombia. PMID:25491457

  7. Effects of Active Versus Passive Group Music Therapy on Preadolescents with Emotional, Learning, and Behavioral Disorders.

    PubMed

    Montello; Coons

    1999-01-01

    This study attempted to compare the behavioral effects of active, rhythm-based group music therapy vs. those of passive, listening-based group music therapy on preadolescents with emotional, learning, and behavioral disorders. It was hypothesized that preadolescents who participated in active music therapy would more significantly improve target behaviors than those involved in passive music therapy. Achenbach's Teacher Report Form (TRF) was used to confirm changes among subjects in attention, motivation, and hostility as rated by homeroom teachers. Twelve music therapy sessions were conducted over a 4-month period with three different groups of subjects (n = 16), with two groups participating in active music therapy and the other receiving passive music therapy. Results indicate that subjects improved significantly after receiving both music therapy interventions. The most significant change in subjects was found on the aggression/hostility scale. These results suggest that group music therapy can facilitate the process of serf-expression in emotionally disturbed/learning disabled adolescents and provide a channel for transforming frustration, anger, and aggression into the experience of creativity and self-mastery. Discussion of results also includes recommendations for chousing one music therapy approach over another based on personality types and/or clinical diagnoses of subjects.

  8. Structural basis for selective recognition of acyl chains by the membrane-associated acyltransferase PatA

    PubMed Central

    Albesa-Jové, David; Svetlíková, Zuzana; Tersa, Montse; Sancho-Vaello, Enea; Carreras-González, Ana; Bonnet, Pascal; Arrasate, Pedro; Eguskiza, Ander; Angala, Shiva K.; Cifuente, Javier O.; Korduláková, Jana; Jackson, Mary; Mikušová, Katarína; Guerin, Marcelo E.

    2016-01-01

    The biosynthesis of phospholipids and glycolipids are critical pathways for virtually all cell membranes. PatA is an essential membrane associated acyltransferase involved in the biosynthesis of mycobacterial phosphatidyl-myo-inositol mannosides (PIMs). The enzyme transfers a palmitoyl moiety from palmitoyl–CoA to the 6-position of the mannose ring linked to 2-position of inositol in PIM1/PIM2. We report here the crystal structures of PatA from Mycobacterium smegmatis in the presence of its naturally occurring acyl donor palmitate and a nonhydrolyzable palmitoyl–CoA analog. The structures reveal an α/β architecture, with the acyl chain deeply buried into a hydrophobic pocket that runs perpendicular to a long groove where the active site is located. Enzyme catalysis is mediated by an unprecedented charge relay system, which markedly diverges from the canonical HX4D motif. Our studies establish the mechanistic basis of substrate/membrane recognition and catalysis for an important family of acyltransferases, providing exciting possibilities for inhibitor design. PMID:26965057

  9. Structural basis for selective recognition of acyl chains by the membrane-associated acyltransferase PatA.

    PubMed

    Albesa-Jové, David; Svetlíková, Zuzana; Tersa, Montse; Sancho-Vaello, Enea; Carreras-González, Ana; Bonnet, Pascal; Arrasate, Pedro; Eguskiza, Ander; Angala, Shiva K; Cifuente, Javier O; Korduláková, Jana; Jackson, Mary; Mikušová, Katarína; Guerin, Marcelo E

    2016-01-01

    The biosynthesis of phospholipids and glycolipids are critical pathways for virtually all cell membranes. PatA is an essential membrane associated acyltransferase involved in the biosynthesis of mycobacterial phosphatidyl-myo-inositol mannosides (PIMs). The enzyme transfers a palmitoyl moiety from palmitoyl-CoA to the 6-position of the mannose ring linked to 2-position of inositol in PIM1/PIM2. We report here the crystal structures of PatA from Mycobacterium smegmatis in the presence of its naturally occurring acyl donor palmitate and a nonhydrolyzable palmitoyl-CoA analog. The structures reveal an α/β architecture, with the acyl chain deeply buried into a hydrophobic pocket that runs perpendicular to a long groove where the active site is located. Enzyme catalysis is mediated by an unprecedented charge relay system, which markedly diverges from the canonical HX4D motif. Our studies establish the mechanistic basis of substrate/membrane recognition and catalysis for an important family of acyltransferases, providing exciting possibilities for inhibitor design. PMID:26965057

  10. Multifunctional Gold Nanostars for Molecular Imaging and Cancer Therapy

    NASA Astrophysics Data System (ADS)

    Liu, Yang; Yuan, Hsiangkuo; Fales, Andrew; Register, Janna; Vo-Dinh, Tuan

    2015-08-01

    Plasmonics-active gold nanoparticles offer excellent potential in molecular imaging and cancer therapy. Among them, gold nanostars (AuNS) exhibit cross-platform flexibility as multimodal contrast agents for macroscopic X-ray computer tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), as well as nanoprobes for photoacoustic tomography (PAT), two-photon photoluminescence (TPL) and surface-enhanced Raman spectroscopy (SERS). Their surfactant-free surface enables versatile functionalization to enhance cancer targeting, and allow triggered drug release. AuNS can also be used as an efficient platform for drug carrying, photothermal therapy, and photodynamic therapy. This review paper presents the latest progress regarding AuNS as a promising nanoplatform for cancer nanotheranostics. Future research directions with AuNS for biomedical applications will also be discussed.

  11. Multifunctional gold nanostars for molecular imaging and cancer therapy

    PubMed Central

    Liu, Yang; Yuan, Hsiangkuo; Fales, Andrew M.; Register, Janna K.; Vo-Dinh, Tuan

    2015-01-01

    Plasmonics-active gold nanoparticles offer excellent potential in molecular imaging and cancer therapy. Among them, gold nanostars (AuNS) exhibit cross-platform flexibility as multimodal contrast agents for macroscopic X-ray computer tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), as well as nanoprobes for photoacoustic tomography (PAT), two-photon photoluminescence (TPL), and surface-enhanced Raman spectroscopy (SERS). Their surfactant-free surface enables versatile functionalization to enhance cancer targeting, and allow triggered drug release. AuNS can also be used as an efficient platform for drug carrying, photothermal therapy, and photodynamic therapy (PDT). This review paper presents the latest progress regarding AuNS as a promising nanoplatform for cancer nanotheranostics. Future research directions with AuNS for biomedical applications will also be discussed. PMID:26322306

  12. Human induced discharge diversion in a tropical delta and its environmental implications: The Patía River, Colombia

    NASA Astrophysics Data System (ADS)

    Restrepo, Juan D.; Kettner, Albert

    2012-03-01

    SummaryThe Patía River, the number one in terms of sediment yield ˜1500 t km-2 yr-1 draining the western South America, has the most extensive and well developed delta on the Pacific coast, measuring 1700 km2. During the Holocene, nature forced the Patía delta to the south; however, a major water diversion, starting in 1972, diverted the Patía flow to the Sanguianga River, the latter, a small stream draining internal lakes from the Pacific lowlands. This human induced discharge diversion shifted the active delta plain back to the north and changed the northern estuarine system into an active delta plain. Overall, major environmental consequences of this discharge diversion in terms of morphological changes along the delta coast and distributary channels, are evidenced by: (1) coastal retreat along the abandoned delta lobe; 63% of the southern shoreline is retreating at maximum rates of 7 m yr-1, with a corresponding coastal land loss of 106 m yr-1; (2) transgressive barrier islands with exposed peat soils in the surf zone; (3) abandonment of former active distributaries in the southern delta plain with associated closing of inlets and formation of ebb tidal deltas; (4) breaching events on barrier islands; and (5) distributary channel accretion in the northern delta plain by morphological processes such as sedimentation (also in crevasses), overbank flow, increasing width of levees, interdistributary channel fill, and colonization of pioneer mangrove. The Sanguianga Mangrove National Park (SMNP), the largest mangrove reserve in Colombia, measuring 800 km2, lies in this former estuary, where major hydrologic and sedimentation changes are occurring. Observed environmental changes in the SMNP, include (1) seaward advance of the sub-aqueous delta front at the Sanquianga inlet evidenced by an increase in tidal flat area from 5.4 Mm2 in 1986 to 14 Mm2 in 2001; (2) freshening conditions in the Sanguianga distributary channel, a hydrologic change that has shifted the

  13. The Catalytic Mechanism of the Marine-Derived Macrocyclase PatGmac.

    PubMed

    Brás, Natércia F; Ferreira, Pedro; Calixto, Ana R; Jaspars, Marcel; Houssen, Wael; Naismith, James H; Fernandes, Pedro A; Ramos, Maria J

    2016-09-01

    Cyclic peptides are a class of compounds with high therapeutic potential, possessing bioactivities including antitumor and antiviral (including anti-HIV). Despite their desirability, efficient design and production of these compounds has not been achieved to date. The catalytic mechanism of patellamide macrocyclization by the PatG macrocyclase domain has been computationally investigated by using quantum mechanics/molecular mechanics methodology, specifically ONIOM(M06/6-311++G(2d,2p):ff94//B3LYP/6-31G(d):ff94). The mechanism proposed herein begins with a proton transfer from Ser783 to His 618 and from the latter to Asp548. Nucleophilic attack of Ser783 on the substrate leads to the formation of an acyl-enzyme covalent complex. The leaving group Ala-Tyr-Asp-Gly (AYDG) of the substrate is protonated by the substrate's N terminus, leading to the breakage of the P1-P1' bond. Finally, the substrate's N terminus attacks the P1 residue, decomposing the acyl-enzyme complex forming the macrocycle. The formation and decomposition of the acyl-enzyme complex have the highest activation free energies (21.1 kcal mol(-1) and 19.8 kcal mol(-1) respectively), typical of serine proteases. Understanding the mechanism behind the macrocyclization of patellamides will be important to the application of the enzymes in the pharmaceutical and biotechnological industries. PMID:27389424

  14. Process analytical technology (PAT): quantification approaches in terahertz spectroscopy for pharmaceutical application.

    PubMed

    Wu, Huiquan; Heilweil, Edwin J; Hussain, Ajaz S; Khan, Mansoor A

    2008-02-01

    Terahertz (THz) spectroscopy and chemometric analysis of resultant absorption spectra in the 30-500 cm(-1) range has been applied to perform quantitative determination of both active ingredient and excipient concentrations of tablets. Tests were performed on a series of tablets composed of various concentrations and processes of theophylline formulated with lactose, magnesium stearate, starch or Avicel, and as a function of tablet hardness. Transmission spectra of polyethylene pellets derived from each of the samples were analyzed using three approaches. Spectral superposition method was used as an indirect measure to examine whether and when the interaction among various pharmaceutical components and the tableting history could be considered insignificant for quantification purpose. Spectral characteristic peak method was able to correlate peak maxima with correction for tablets having the same hardness. Multivariate analysis (PCR and PLS 1) was capable of correlating THz spectra with tablet concentrations. The predicted concentrations of independent samples using multivariate models agreed well with nominal concentrations. The best correlations were obtained using multivariate analysis. With these studies, the advantage of using multivariate approach was demonstrated for process analytical technology (PAT) application. Further, the feasibility of integrating THz spectroscopy and chemometrics for the purpose of quantifying pharmaceutical tablet concentrations was demonstrated. PMID:17722101

  15. Investigating 3-body Decays of Cluster States with the PAT-TPC

    NASA Astrophysics Data System (ADS)

    Carpenter, Lisa; Ayyad Limonge, Y.; Bazin, D.; Beceiro-Novo, S.; Bradt, J.; Cortesi, M.; Mittig, W.; Ahn, T.; Kolata, J. J.; Meisel, Z.; Bechetti, F. D.; Fritsch, A.; Howard, A.

    2016-03-01

    Recent model calculations with most advanced methods for cluster states have shown the need of experimental data to probe the structure of light exotic nuclei, including those with α-clustering, such as 14C. The Prototype Active Target Time Projection Chamber (PAT-TPC) allows us to investigate these types of structures, giving access to the full excitation function with a single beam energy. This type of experiment measures resonances in 14C that can be compared to the models. With an improved Micromegas pad plane with a circular backgammon design we are able to investigate 3-body decays in addition to 2-body scattering. The measurements were carried out by resonant alpha-scattering on 10Be beam delivered by the TwinSol facility at the University of Notre Dame. We also observed the 3-body decay of the Hoyle State in 12C from a 12N or 12B beam with the same device. Preliminary results will be presented. This work is supported by the National Science Foundation.

  16. Clinical Usefulness of Watch-PAT for Assessing the Surgical Results of Obstructive Sleep Apnea Syndrome

    PubMed Central

    Park, Chong Yoon; Hong, Joon Hyeong; Lee, Jae Heon; Lee, Kyu Eun; Cho, Hyun Sang; Lim, Su Jin; Kwak, Jin Wook; Kim, Kyung Soo; Kim, Hyun Jik

    2014-01-01

    Objective: This study aimed to assess the accuracy and clinical efficacy of a wrist-worn device that is based on peripheral arterial tonometry (watch-PAT) to evaluate the surgical results of obstructive sleep apnea (OSA) syndrome subjects. Study Design and Method: Thirty-five subjects who were diagnosed with OSA and underwent sleep surgeries such as septoplasty, tonsillectomy, or uvuloplasty to correct their airway collapse, participated in this study; the watch-PAT-derived respiratory disturbance index (RDI), apnea and hypopnea index (AHI), lowest oxygen saturation, and valid sleep time were measured after the sleep surgery. Results: The present study showed that RDI (32.8 ± 10.7 vs 14.8 ± 7.5), AHI (30.3 ± 8.6 vs 13.4 ± 8.2 events/h), lowest oxygen saturation (78.2% ± 8.4% vs 90.5% ± 7.1%), and valid sleep time (329.1 ± 47.2 min and a postoperative value of 389.1 ± 50.1 min) recovered to within a normal range after surgery in 28 subjects. In addition, good agreement was found between watch-PAT-derived factors and visual analogue scales for changes in subjective symptoms, such as snoring, apnea, and daytime somnolence. Seven of the 35 subjects showed no improvement for their subjective symptoms and complained of snoring and apnea after surgery. We found that the RDI and AHI of those 7 subjects were not reduced, and the changes between pre- and postoperative values which were measured with watch-PAT were minimal. Their postoperative lowest oxygen saturation and valid sleep time were not elevated per the watch-PAT. The results support a strong correlation between the findings from watch-PAT and improved symptoms after surgical correction of an airway collapse. Conclusions: Our study provides evidence that the factors measured by the watch-PAT might be reliable indicators of symptomatic changes in OSA subjects after sleep surgery and also shows that the watch-PAT is a highly sensitive portable device for estimating treatment results in OSA. Citation: Park CY

  17. A thermostable α-galactosidase from Lenzites elegans (Spreng.) ex Pat. MB445947: purification and properties.

    PubMed

    Sampietro, Diego; Quiroga, Emma; Sgariglia, Melina; Soberón, José; Vattuone, Marta A

    2012-08-01

    An α-galactosidase was isolated from a culture filtrate of Lenzites elegans (Spreng.) ex Pat. MB445947 grown on citric pectin as carbon source. It was purified to electrophoretic homogeneity by ammonium sulfate precipitation, gel filtration chromatography and anion-exchange chromatography. The relative molecular mass of the native purified enzyme was 158 kDa determined by gel filtration and it is a homodimer (Mr subunits = 61 kDa). The optimal temperature for enzyme activity was in the range 60-80 °C. This α-galactosidase showed a high thermostability, retaining 94 % of its activity after preincubation at 60 °C for 2 h. The optimal pH for the enzyme was 4.5 and it was stable from pH 3 to 7.5 when the preincubation took place at 60 °C for 2 h. It was active against several α-galactosides such as p-nitrophenyl-α-D-galactopyranoside, α-D-melibiose, raffinose and stachyose. The α-galactosidase is a glycoprotein with 26 % of structural sugars. Galactose was a non-competitive inhibitor with a Ki = 22 mM versus p-nitrophenyl-α-D-galactoside and 12 mM versus α-D-melibiose as substrates. Glucose was a simple competitive inhibitor with a Ki = 10 mM. Cations such as Hg(2+) and p-chloromercuribenzoate were also inhibitors of this activity, suggesting the presence of -SH groups in the active site of the enzyme. On the basis of the sequence of the N-terminus (SPDTIVLDGTNFALN) the studied α-galactosidase would be a member of glycosyl hydrolase family 36 (GH 36). Given the high optimum temperature and heat stability of L. elegans α-galactosidase, this fungus may become a useful source of α-galactosidase production for multiple applications.

  18. PAT: a protein analysis toolkit for integrated biocomputing on the web

    PubMed Central

    Gracy, Jérôme; Chiche, Laurent

    2005-01-01

    PAT, for Protein Analysis Toolkit, is an integrated biocomputing server. The main goal of its design was to facilitate the combination of different processing tools for complex protein analyses and to simplify the automation of repetitive tasks. The PAT server provides a standardized web interface to a wide range of protein analysis tools. It is designed as a streamlined analysis environment that implements many features which strongly simplify studies dealing with protein sequences and structures and improve productivity. PAT is able to read and write data in many bioinformatics formats and to create any desired pipeline by seamlessly sending the output of a tool to the input of another tool. PAT can retrieve protein entries from identifier-based queries by using pre-computed database indexes. Users can easily formulate complex queries combining different analysis tools with few mouse clicks, or via a dedicated macro language, and a web session manager provides direct access to any temporary file generated during the user session. PAT is freely accessible on the Internet at . PMID:15980554

  19. Monitoring granulation rate processes using three PAT tools in a pilot-scale fluidized bed.

    PubMed

    Tok, Ai Tee; Goh, Xueping; Ng, Wai Kiong; Tan, Reginald B H

    2008-01-01

    The purpose of this research was to analyze and compare the responses of three Process Analytical Technology (PAT) techniques applied simultaneously to monitor a pilot-scale fluidized bed granulation process. Real-time measurements using focused beam reflectance measurement (Lasentec FBRM) and near-infra red spectroscopy (Bruker NIR) were taken by inserting in-line probes into the fluidized bed. Non-intrusive acoustic emission measurements (Physical Acoustic AE) were performed by attaching piezoelectric sensors on the external wall of the fluidized bed. Powder samples were collected at regular intervals during the granulation process and characterized offline using laser diffraction, scanning electron microscopy, stereo-optical microscopy and loss on drying method. PAT data comprising chord length distribution and chord count (from FBRM), absorption spectra (from NIR) and average signal levels and counts (from AE) were compared with the particle properties measured using offline samples. All three PAT techniques were able to detect the three granulation regimes or rate processes (wetting and nucleation, consolidation and growth, breakage) to varying degrees of sensitivity. Being dependent on optical signals, the sensitivities of the FBRM and NIR techniques were susceptible to fouling on probe windows. The AE technique was sensitive to background fluidizing air flows and external interferences. The sensitivity, strengths and weaknesses of the PAT techniques examined may facilitate the selection of suitable PAT tools for process development and scale-up studies.

  20. PAT proteins, an ancient family of lipid droplet proteins that regulate cellular lipid stores

    PubMed Central

    Bickel, Perry E.; Tansey, John T.; Welte, Michael A.

    2009-01-01

    Summary The PAT family of lipid droplet proteins includes 5 members in mammals: perilipin, adipose differentiation-related protein (ADRP), tail-interacting protein of 47 kiloDaltons (TIP47), S3-12, and OXPAT. Members of this family are also present in evolutionarily distant organisms, including insects, slime molds and fungi. All PAT proteins share sequence similarity and the ability to bind intracellular lipid droplets, either constitutively or in response to metabolic stimuli, such as increased lipid flux into or out of lipid droplets. Positioned at the lipid droplet surface, PAT proteins manage access of other proteins (lipases) to the lipid esters within the lipid droplet core and can interact with cellular machinery important for lipid droplet biogenesis. Genetic variations in the gene for the best characterized of the mammalian PAT proteins, perilipin, have been associated with metabolic phenotypes, including type 2 diabetes mellitus and obesity. In this review, we discuss how the PAT proteins regulate cellular lipid metabolism both in mammals and in model organisms. PMID:19375517

  1. Simulation model and on-ground performances validation of the PAT system for SILEX program

    NASA Astrophysics Data System (ADS)

    Cosson, Francois; Doubrere, Patrick; Perez, Eric

    1991-06-01

    A description of the simulation model and the on-ground performances validation of the Acquisition and Tracking (PAT) subsystem and of the European SILEX program is presented. The SILEX scenario is composed of two terminals mounted on LEO orbit (SPOT 4) and geostationary orbit (ARTEMIS) spacecrafts. The PAT subsystem is in charge of the initialization of the link, of the tracking of the incoming beam and of the pointing of the emitted laser beam. A short description of the retained strategies (phases of the PAT mission and operating modes) and functional architecture (control laws and sampling frequencies) is presented. In order to validate the PAT performance assessment, a complete simulation software is developed. The model (equipment modeling, dynamical simulation of the terminal structure, and operating modes management) and the associated outputs are examined in detail. The chosen design and architecture of the PAT validation on a system testbed (STB) are described. The validation of a pointing system for optical intersatellite communication, thanks to the combination of simulations and STB measurements, is shown.

  2. PAT proteins, an ancient family of lipid droplet proteins that regulate cellular lipid stores.

    PubMed

    Bickel, Perry E; Tansey, John T; Welte, Michael A

    2009-06-01

    The PAT family of lipid droplet proteins includes 5 members in mammals: perilipin, adipose differentiation-related protein (ADRP), tail-interacting protein of 47 kDa (TIP47), S3-12, and OXPAT. Members of this family are also present in evolutionarily distant organisms, including insects, slime molds and fungi. All PAT proteins share sequence similarity and the ability to bind intracellular lipid droplets, either constitutively or in response to metabolic stimuli, such as increased lipid flux into or out of lipid droplets. Positioned at the lipid droplet surface, PAT proteins manage access of other proteins (lipases) to the lipid esters within the lipid droplet core and can interact with cellular machinery important for lipid droplet biogenesis. Genetic variations in the gene for the best-characterized of the mammalian PAT proteins, perilipin, have been associated with metabolic phenotypes, including type 2 diabetes mellitus and obesity. In this review, we discuss how the PAT proteins regulate cellular lipid metabolism both in mammals and in model organisms. PMID:19375517

  3. A Novel Gene Amplification Causes Upregulation of the PatAB ABC Transporter and Fluoroquinolone Resistance in Streptococcus pneumoniae

    PubMed Central

    Baylay, Alison J.; Ivens, Alasdair

    2015-01-01

    Overexpression of the ABC transporter genes patA and patB confers efflux-mediated fluoroquinolone resistance in Streptococcus pneumoniae and is also linked to pneumococcal stress responses. Although upregulation of patAB has been observed in many laboratory mutants and clinical isolates, the regulatory mechanisms controlling expression of these genes are unknown. In this study, we aimed to identify the cause of high-level constitutive overexpression of patAB in M184, a multidrug-resistant mutant of S. pneumoniae R6. Using a whole-genome transformation and sequencing approach, we identified a novel duplication of a 9.2-kb region of the M184 genome which included the patAB genes. This duplication did not affect growth and was semistable with a low segregation rate. The expression levels of patAB in M184 were much higher than those that could be fully explained by doubling of the gene dosage alone, and inactivation of the first copy of patA had no effect on multidrug resistance. Using a green fluorescent protein reporter system, increased patAB expression was ascribed to transcriptional read-through from a tRNA gene upstream of the second copy of patAB. This is the first report of a large genomic duplication causing antibiotic resistance in S. pneumoniae and also of a genomic duplication causing antibiotic resistance by a promoter switching mechanism. PMID:25779578

  4. Pivotal role of tissue plasminogen activator in the mechanism of action of electroconvulsive therapy.

    PubMed

    Hoirisch-Clapauch, Silvia; Mezzasalma, Marco A U; Nardi, Antonio E

    2014-02-01

    Electroconvulsive therapy is an important treatment option for major depressive disorders, acute mania, mood disorders with psychotic features, and catatonia. Several hypotheses have been proposed as electroconvulsive therapy's mechanism of action. Our hypothesis involves many converging pathways facilitated by increased synthesis and release of tissue-plasminogen activator. Human and animal experiments have shown that tissue-plasminogen activator participates in many mechanisms of action of electroconvulsive therapy or its animal variant, electroconvulsive stimulus, including improved N-methyl-D-aspartate receptor-mediated signaling, activation of both brain-derived neurotrophic factor and vascular endothelial growth factor, increased bioavailability of zinc, purinergic release, and increased mobility of dendritic spines. As a result, tissue-plasminogen activator helps promote neurogenesis in limbic structures, modulates synaptic transmission and plasticity, improves cognitive function, and mediates antidepressant effects. Notably, electroconvulsive therapy seems to influence tissue-plasminogen activator metabolism. For example, electroconvulsive stimulus increases the expression of glutamate decarboxylase 65 isoform in γ-aminobutyric acid-releasing neurons, which enhances the release of tissue-plasminogen activator, and the expression of p11, a protein involved in plasminogen and tissue-plasminogen activator assembling. This paper reviews how electroconvulsive therapy correlates with tissue-plasminogen activator. We suggest that interventions aiming at increasing tissue-plasminogen activator levels or its bioavailability - such as daily aerobic exercises together with a carbohydrate-restricted diet, or normalization of homocysteine levels - be evaluated in controlled studies assessing response and remission duration in patients who undergo electroconvulsive therapy.

  5. Mreg Activity in Tumor Response to Photodynamic Therapy and Photodynamic Therapy-Generated Cancer Vaccines

    PubMed Central

    Korbelik, Mladen; Banáth, Judith; Zhang, Wei

    2016-01-01

    Myeloid regulatory cells (Mregs) are, together with regulatory T cells (Tregs), a dominant effector population responsible for restriction of the duration and strength of antitumor immune response. Photodynamic therapy (PDT) and cancer vaccines generated by PDT are modalities whose effectiveness in tumor destruction is closely dependent on the associated antitumor immune response. The present study investigated whether the immunodepletion of granulocytic Mregs in host mice by anti-GR1 antibody would improve the response of tumors to PDT or PDT vaccines in these animals. Anti-GR1 administration immediately after Temoporfin-PDT of mouse SCCVII tumors abrogated curative effect of PDT. The opposite effect, increasing PDT-mediated tumor cure-rates was attained by delaying anti-GR1 treatment to 1 h post PDT. With PDT vaccines, multiple anti-GR1 administrations (days 0, 4, and 8 post vaccination) improved the therapy response with SCCVII tumors. The results with PDT suggest that neutrophils (boosting antitumor effect of this therapy) that are engaged immediately after photodynamic light treatment are within one hour replaced with a different myeloid population, presumably Mregs that hampers the therapy-mediated antitumor effect. Anti-GR1 antibody, when used with optimal timing, can improve the efficacy of both PDT of tumors in situ and PDT-generated cancer vaccines. PMID:27754452

  6. PAATCH: Program of Auditory Articulation Therapy for Children. Expanded Version. New Carryover Home Activities.

    ERIC Educational Resources Information Center

    Hill, Diane Pagnotto

    This program of auditory articulation therapy de-emphasizes production-oriented therapy in working with unintelligible 3-to-6-year-old children. It proposes auditory training activities, which train the child's ears on all sounds in error in order to facilitate readiness for correct production of sounds. Production training is then suggested for…

  7. Overview of the High Performance Antiproton Trap (HiPAT) Experiment

    NASA Technical Reports Server (NTRS)

    Martin, James; Chakrabarti, Suman; Pearson, Boise; Sims, W. Herbert; Lewis, Raymond; Fant, Wallace; Rodgers, Stephen (Technical Monitor)

    2002-01-01

    A general overview of the High Performance Antiproton Trap (HiPAT) Experiment is presented. The topics include: 1) Why Antimatter? 2) HiPAT Applicability; 3) Approach-Goals; 4) HiPAT General Layout; 5) Sizing For Containment; 6) Laboratory Operations; 7) Vacuum System Cleaning; 8) Ion Production Via Electron Gun; 9) Particle Capture Via Ion Sources; 10) Ion Beam Steering/Focusing; 11) Ideal Ion Stacking Sequence; 12) Setup For Dynamic Capture; 13) Dynamic Capture of H(+) Ions; 14) Dynamic Capture; 15) Radio Frequency Particle Detection; 16) Radio Frequency Antenna Modeling; and 17) R.F. Stabilization-Low Frequencies. A short presentation of propulsion applications of Antimatter is also given. This paper is in viewgraph form.

  8. RF Manipulation and Detection of Protons in the High Performance Antiproton Trap (HiPAT) Experiment

    NASA Technical Reports Server (NTRS)

    Martin, James; Lewis, Raymond A.; Pearson, J. Boise; Sims, W. Herb; Chakrabarti, Suman; Fant, Wallace E.; Stan McDonald

    2003-01-01

    HiPAT is a Penning-Malmberg trap designed to contain 10(exp 12) particles diagnostics of the plasma. Destructive particle detection is performed by extracting trapped ions from HiPAT and colliding them with a microchannel plate detector (providing number and energy information). The improved RF system has been used to detect various plasma modes for both electron and ion plasmas in the two traps at MSFC, including axd, cyclotron, and diocotron modes. New diagnostics are also being added to HiPAT to measure the axial density distribution of the trapped cloud to match measured RF plasma modes to plasma conditions. In addition, plasma modeling efforts have been started using the XOOPIC code.

  9. ePAT: a simple method to tag adenylated RNA to measure poly(A)-tail length and other 3' RACE applications.

    PubMed

    Jänicke, Amrei; Vancuylenberg, John; Boag, Peter R; Traven, Ana; Beilharz, Traude H

    2012-06-01

    The addition of a poly(A)-tail to the 3' termini of RNA molecules influences stability, nuclear export, and efficiency of translation. In the cytoplasm, dynamic changes in the length of the poly(A)-tail have long been recognized as reflective of the switch between translational silence and activation. Thus, measurement of the poly(A)-tail associated with any given mRNA at steady-state can serve as a surrogate readout of its translation-state. Here, we describe a simple new method to 3'-tag adenylated RNA in total RNA samples using the intrinsic property of Escherichia coli DNA polymerase I to extend an RNA primer using a DNA template. This tag can serve as an anchor for cDNA synthesis and subsequent gene-specific PCR to assess poly(A)-tail length. We call this method extension Poly(A) Test (ePAT). The ePAT approach is as efficient as traditional Ligation-Mediated Poly(A) Test (LM-PAT) assays, avoids problems of internal priming associated with oligo-dT-based methods, and allows for the accurate analysis of both the poly(A)-tail length and alternate 3' UTR usage in 3' RACE applications.

  10. Occurrence of Postictal α/β Activity During Maintenance Course of Electroconvulsive Therapy.

    PubMed

    Schultz, Krista; Tham, Joseph; Chan, Peter; Brenner, Colleen; Northcott, Colleen; Vila-Rodriguez, Fidel

    2015-12-01

    We are aware of a report of postictal α activity after seizures in Epilepsy and Behavior. We would like to report another case of a similar phenomenon in a woman receiving maintenance electroconvulsive therapy. PMID:25764162

  11. The Effects of Constraint-Induced Movement Therapy on Activities Important to Independent School Participation of Children with Hemiparesis

    ERIC Educational Resources Information Center

    Carney, Joan

    2012-01-01

    This study investigated the efficacy of constraint-induced movement therapy (CI therapy) on activities important to school participation in children with hemiparesis. Four children, ages 4-0 to 7-10 participated in an intensive CI therapy program in a clinical setting. Constraining casts were worn 24 hours daily. Therapy was delivered 6 hours…

  12. Methylprednisolone pulse therapy induced fall in natural killer cell activity in rheumatoid arthritis.

    PubMed

    Pedersen, B K; Beyer, J M; Rasmussen, A; Klarlund, K; Pedersen, B N; Helin, P

    1984-10-01

    Natural killer (NK) cell activity was studied in 8 patients with classic or definite rheumatoid arthritis (RA) by investigating the killing of K 562 cells by peripheral blood lymphocytes before, during, and after intravenous methylprednisolone pulse therapy (MPPT). MPPT produced a considerable fall in NK activity and after 3 months NK activity was less than half that before MPPT. PMID:6516854

  13. The PATS Peer Support Program: Prevention/Early Intervention for Adolescents Who Have a Parent with Mental Illness

    ERIC Educational Resources Information Center

    Hargreaves, John; Bond, Lyndal; O'Brien, Matt; Forer, Danielle; Davies, Liz

    2008-01-01

    PATS (Paying Attention to Self) is a peer support program for adolescent children of parents with a diagnosed mental illness. The program aims to promote positive mental health, reduce the likelihood of mental health difficulties, increase young people's coping skills and empower them to meet their own and their families' needs. PATS combines peer…

  14. RNA-related nuclear functions of human Pat1b, the P-body mRNA decay factor.

    PubMed

    Marnef, Aline; Weil, Dominique; Standart, Nancy

    2012-01-01

    The evolutionarily conserved Pat1 proteins are P-body components recently shown to play important roles in cytoplasmic gene expression control. Using human cell lines, we demonstrate that human Pat1b is a shuttling protein whose nuclear export is mediated via a consensus NES sequence and Crm1, as evidenced by leptomycin B (LMB) treatment. However, not all P-body components are nucleocytoplasmic proteins; rck/p54, Dcp1a, Edc3, Ge-1, and Xrn1 are insensitive to LMB and remain cytoplasmic in its presence. Nuclear Pat1b localizes to PML-associated foci and SC35-containing splicing speckles in a transcription-dependent manner, whereas in the absence of RNA synthesis, Pat1b redistributes to crescent-shaped nucleolar caps. Furthermore, inhibition of splicing by spliceostatin A leads to the reorganization of SC35 speckles, which is closely mirrored by Pat1b, indicating that it may also be involved in splicing processes. Of interest, Pat1b retention in these three nuclear compartments is mediated via distinct regions of the protein. Examination of the nuclear distribution of 4E-T(ransporter), an additional P-body nucleocytoplasmic protein, revealed that 4E-T colocalizes with Pat1b in PML-associated foci but not in nucleolar caps. Taken together, our findings strongly suggest that Pat1b participates in several RNA-related nuclear processes in addition to its multiple regulatory roles in the cytoplasm.

  15. The formation and chronology of the PAT 91501 impact-melt L chondrite with vesicle metal sulfide assemblages

    NASA Astrophysics Data System (ADS)

    Benedix, G. K.; Ketcham, R. A.; Wilson, L.; McCoy, T. J.; Bogard, D. D.; Garrison, D. H.; Herzog, G. F.; Xue, S.; Klein, J.; Middleton, R.

    2008-05-01

    The L chondrite Patuxent Range (PAT) 91501 is an 8.5-kg unshocked, homogeneous, igneous-textured impact melt that cooled slowly compared to other meteoritic impact melts in a crater floor melt sheet or sub-crater dike [Mittlefehldt D. W. and Lindstrom M. M. (2001) Petrology and geochemistry of Patuxent Range 91501 and Lewis Cliff 88663. Meteoritics Planet. Sci. 36, 439-457]. We conducted mineralogical and tomographic studies of previously unstudied mm- to cm-sized metal-sulfide-vesicle assemblages and chronologic studies of the silicate host. Metal-sulfide clasts constitute about 1 vol.%, comprise zoned taenite, troilite, and pentlandite, and exhibit a consistent orientation between metal and sulfide and of metal-sulfide contacts. Vesicles make up ˜2 vol.% and exhibit a similar orientation of long axes. 39Ar- 40Ar measurements probably date the time of impact at 4.461 ± 0.008 Gyr B.P. Cosmogenic noble gases and 10Be and 26Al activities suggest a pre-atmospheric radius of 40-60 cm and a cosmic ray exposure age of 25-29 Myr, similar to ages of a cluster of L chondrites. PAT 91501 dates the oldest known impact on the L chondrite parent body. The dominant vesicle-forming gas was S 2 (˜15-20 ppm), which formed in equilibrium with impact-melted sulfides. The meteorite formed in an impact melt dike beneath a crater, as did other impact melted L chondrites, such as Chico. Cooling and solidification occurred over ˜2 h. During this time, ˜90% of metal and sulfide segregated from the local melt. Remaining metal and sulfide grains oriented themselves in the local gravitational field, a feature nearly unique among meteorites. Many of these metal-sulfide grains adhered to vesicles to form aggregates that may have been close to neutrally buoyant. These aggregates would have been carried upward with the residual melt, inhibiting further buoyancy-driven segregation. Although similar processes operated individually in other chondritic impact melts, their interaction produced

  16. Design and Fabrication of Cryostat Interface and Electronics for High Performance Antimatter Trap (HI-PAT)

    NASA Technical Reports Server (NTRS)

    Smith, Gerald A.

    1999-01-01

    Included in Appendix I to this report is a complete set of design and assembly schematics for the high vacuum inner trap assembly, cryostat interfaces and electronic components for the MSFC HI-PAT. Also included in the final report are summaries of vacuum tests, and electronic tests performed upon completion of the assembly.

  17. Comparing EndoPAT and BIOPAC measurement of vascular responses to mental stress.

    PubMed

    Martin, Elizabeth A; Nelson, Rebecca E; Felmlee-Devine, M Donna; Brown, Troy E; Lerman, Amir

    2011-06-01

    There are currently no comparison measurements of stress-induced changes in vascular function during acute mental stress tests to measurements made by BIOPAC MP150 systems technology, a standard polygraph device used to detect deception during polygraph examinations in military or law enforcement applications. Vascular responses to reactive hyperaemia and acute mental stress in 25 healthy subjects were measured by both peripheral arterial tonometry (EndoPAT) and a blood pressure cuff attached to a pressure transducer (BIOPAC) and compared. Reactive hyperaemia was performed at baseline and following three acute mental stress tests. There was no difference in vascular reactivity at baseline and following acute mental stress, as measured by EndoPAT or BIOPAC systems (p > 0·05). Mental stress ratios measured by EndoPAT were significantly different than those measured by BIOPAC (p < 0·01). These data suggest that EndoPAT measurements of vascular responses to acute mental stress may be more specific and sensitive than measurements using the BIOPAC system. PMID:21671245

  18. Reconstruction of undersampled radial PatLoc imaging using Total Generalized Variation

    PubMed Central

    Knoll, Florian; Schultz, Gerrit; Bredies, Kristian; Gallichan, Daniel; Zaitsev, Maxim; Hennig, Jürgen; Stollberger, Rudolf

    2016-01-01

    In the case of radial imaging with nonlinear spatial encoding fields, a prominent star-shaped artifact has been observed if a spin distribution is encoded with an undersampled trajectory. This work presents a new iterative reconstruction method based on the total generalized variation (TGV), which reduces this artifact. For this approach, a sampling operator (as well as its adjoint) is needed that maps data from PatLoc k-space to the final image space. It is shown that this can be realized as a Type-3 non-uniform FFT, which is implemented by a combination of a Type-1 and Type-2 non-uniform FFT. Using this operator, it is also possible to implement an iterative conjugate gradient (CG) SENSE based method for PatLoc reconstruction, which leads to a significant reduction of computation time in comparison to conventional PatLoc image reconstruction methods. Results from numerical simulations and in-vivo PatLoc measurements with as few as 16 radial projections are presented, which demonstrate significant improvements in image quality with the TGV based approach. PMID:22847824

  19. Quantifying beetle-mediated effects on gas fluxes from dung pats.

    PubMed

    Penttilä, Atte; Slade, Eleanor M; Simojoki, Asko; Riutta, Terhi; Minkkinen, Kari; Roslin, Tomas

    2013-01-01

    Agriculture is one of the largest contributors of the anthropogenic greenhouse gases (GHGs) responsible for global warming. Measurements of gas fluxes from dung pats suggest that dung is a source of GHGs, but whether these emissions are modified by arthropods has not been studied. A closed chamber system was used to measure the fluxes of carbon dioxide (CO2), methane (CH4) and nitrous oxide (N2O) from dung pats with and without dung beetles on a grass sward. The presence of dung beetles significantly affected the fluxes of GHGs from dung pats. Most importantly, fresh dung pats emitted higher amounts of CO2 and lower amounts of CH4 per day in the presence than absence of beetles. Emissions of N2O showed a distinct peak three weeks after the start of the experiment--a pattern detected only in the presence of beetles. When summed over the main grazing season (June-July), total emissions of CH4 proved significantly lower, and total emissions of N2O significantly higher in the presence than absence of beetles. While clearly conditional on the experimental conditions, the patterns observed here reveal a potential impact of dung beetles on gas fluxes realized at a small spatial scale, and thereby suggest that arthropods may have an overall effect on gas fluxes from agriculture. Dissecting the exact mechanisms behind these effects, mapping out the range of conditions under which they occur, and quantifying effect sizes under variable environmental conditions emerge as key priorities for further research.

  20. Teacher's PAT? Multiple-Role Principal-Agent Theory, Education Politics, and Bureaucrat Power

    ERIC Educational Resources Information Center

    Vanhuysse, Pieter; Sulitzeanu-Kenan, Raanan

    2009-01-01

    This article aims to contribute to current debates about political power and agency relationships in education and other public sectors. In a recent clarion call for a major redirection of political principal-agent theories (PAT), Terry Moe has argued that standard information asymmetries ought no longer to be regarded as the sole foundation of…

  1. Draft Genome Sequence of the Beer Spoilage Bacterium Megasphaera cerevisiae Strain PAT 1T

    PubMed Central

    Kutumbaka, Kirthi K.; Pasmowitz, Joshua; Mategko, James; Reyes, Dindo; Friedrich, Alex; Han, Sukkyun; Martens-Habbena, Willm; Neal-McKinney, Jason; Janagama, Harish K.; Nadala, Cesar

    2015-01-01

    The genus Megasphaera harbors important spoilage organisms that cause beer spoilage by producing off flavors, undesirable aroma, and turbidity. Megasphaera cerevisiae is mainly found in nonpasteurized low-alcohol beer. In this study, we report the draft genome of the type strain of the genus, M. cerevisiae strain PAT 1T. PMID:26358606

  2. Draft Genome Sequence of the Beer Spoilage Bacterium Megasphaera cerevisiae Strain PAT 1T.

    PubMed

    Kutumbaka, Kirthi K; Pasmowitz, Joshua; Mategko, James; Reyes, Dindo; Friedrich, Alex; Han, Sukkyun; Martens-Habbena, Willm; Neal-McKinney, Jason; Janagama, Harish K; Nadala, Cesar; Samadpour, Mansour

    2015-01-01

    The genus Megasphaera harbors important spoilage organisms that cause beer spoilage by producing off flavors, undesirable aroma, and turbidity. Megasphaera cerevisiae is mainly found in nonpasteurized low-alcohol beer. In this study, we report the draft genome of the type strain of the genus, M. cerevisiae strain PAT 1(T). PMID:26358606

  3. PhyloPat: an updated version of the phylogenetic pattern database contains gene neighborhood.

    PubMed

    Hulsen, Tim; Groenen, Peter M A; de Vlieg, Jacob; Alkema, Wynand

    2009-01-01

    Phylogenetic patterns show the presence or absence of certain genes in a set of full genomes derived from different species. They can also be used to determine sets of genes that occur only in certain evolutionary branches. Previously, we presented a database named PhyloPat which allows the complete Ensembl gene database to be queried using phylogenetic patterns. Here, we describe an updated version of PhyloPat which can be queried by an improved web server. We used a single linkage clustering algorithm to create 241,697 phylogenetic lineages, using all the orthologies provided by Ensembl v49. PhyloPat offers the possibility of querying with binary phylogenetic patterns or regular expressions, or through a phylogenetic tree of the 39 included species. Users can also input a list of Ensembl, EMBL, EntrezGene or HGNC IDs to check which phylogenetic lineage any gene belongs to. A link to the FatiGO web interface has been incorporated in the HTML output. For each gene, the surrounding genes on the chromosome, color coded according to their phylogenetic lineage can be viewed, as well as FASTA files of the peptide sequences of each lineage. Furthermore, lists of omnipresent, polypresent, oligopresent and anticorrelating genes have been included. PhyloPat is freely available at http://www.cmbi.ru.nl/phylopat.

  4. Aptamers: Active Targeting Ligands for Cancer Diagnosis and Therapy

    PubMed Central

    Wu, Xu; Chen, Jiao; Wu, Min; Zhao, Julia Xiaojun

    2015-01-01

    Aptamers, including DNA, RNA and peptide aptamers, are a group of promising recognition units that can specifically bind to target molecules and cells. Due to their excellent specificity and high affinity to targets, aptamers have attracted great attention in various fields in which selective recognition units are required. They have been used in biosensing, drug delivery, disease diagnosis and therapy (especially for cancer treatment). In this review, we summarized recent applications of DNA and RNA aptamers in cancer theranostics. The specific binding ability of aptamers to cancer-related markers and cancer cells ensured their high performance for early diagnosis of cancer. Meanwhile, the efficient targeting ability of aptamers to cancer cells and tissues provided a promising way to deliver imaging agents and drugs for cancer imaging and therapy. Furthermore, with the development of nanoscience and nanotechnology, the conjugation of aptamers with functional nanomaterials paved an exciting way for the fabrication of theranostic agents for different types of cancers, which might be a powerful tool for cancer treatment. PMID:25699094

  5. Baroreflex activation therapy lowers arterial pressure without apparent stimulation of the carotid bodies.

    PubMed

    Alnima, Teba; Goedhart, Emilie J B M; Seelen, Randy; van der Grinten, Chris P M; de Leeuw, Peter W; Kroon, Abraham A

    2015-06-01

    Carotid baroreflex activation therapy produces a sustained fall in blood pressure in patients with resistant hypertension. Because the activation electrodes are implanted at the level of the carotid sinus, it is conceivable that the nearby located carotid body chemoreceptors are stimulated as well. Physiological stimulation of the carotid chemoreceptors not only stimulates respiration but also increases sympathetic activity, which may counteract the effects of baroreflex activation. The aim of this exploratory study is to investigate whether there is concomitant carotid chemoreflex activation during baroreflex activation therapy. Fifteen participants with the Rheos system were included in this single-center study. At arrival at the clinic, the device was switched off for 2 hours while patients were at rest. Subsequently, the device was switched on at 6 electric settings of high and low frequencies and amplitudes. Respiration and blood pressure measurements were performed during all device activation settings. Multilevel statistical models were adjusted for age, sex, body mass index, antihypertensive therapeutic index, sleep apnea, coronary artery disease, systolic blood pressure, and heart rate. There was no change in end-tidal carbon dioxide, partial pressure of carbon dioxide, breath duration, and breathing frequency during any of the electric settings with the device. Nevertheless, mean arterial pressure showed a highly significant decrease during electric activation (P<0.001). Carotid baroreflex activation therapy using the Rheos system did not stimulate respiration at several electric device activation energies, which suggests that there is no appreciable coactivation of carotid body chemoreceptors during device therapy.

  6. Impact of preoperative antithrombotic therapy on blood management after implantation of primary total knee arthroplasty

    PubMed Central

    Leitner, Lukas; Musser, Ewald; Kastner, Norbert; Friesenbichler, Jörg; Hirzberger, Daniela; Radl, Roman; Leithner, Andreas; Sadoghi, Patrick

    2016-01-01

    Red blood cell concentrates (RCC) substitution after total knee arthroplasty (TKA) is correlated with multifold of complications and an independent predictor for higher postoperative mortality. TKA is mainly performed in elderly patients with pre-existing polymorbidity, often requiring permanent preoperative antithrombotic therapy (PAT). The aim of this retrospective analysis was to investigate the impact of demand for PAT on inpatient blood management in patients undergoing TKA. In this study 200 patients were retrospectively evaluated after TKA for differences between PAT and non-PAT regarding demographic parameters, preoperative ASA score > 2, duration of operation, pre-, and intraoperative hemoglobin level, and postoperative parameters including amount of wound drainage, RCC requirement, and inpatient time. In a multivariate logistic regression analysis the independent influences of PAT, demographic parameters, ASA score > 2, and duration of the operation on RCC demand following TKA were analyzed. Patients with PAT were significantly older, more often had an ASA > 2 at surgery, needed a higher number of RCCs units and more frequently and had lower perioperative hemoglobin levels. Multivariate logistic regression revealed PAT was an independent predictor for RCC requirement. PAT patients are more likely to require RCC following TKA and should be accurately monitored with respect to postoperative blood loss. PMID:27488941

  7. Impact of preoperative antithrombotic therapy on blood management after implantation of primary total knee arthroplasty.

    PubMed

    Leitner, Lukas; Musser, Ewald; Kastner, Norbert; Friesenbichler, Jörg; Hirzberger, Daniela; Radl, Roman; Leithner, Andreas; Sadoghi, Patrick

    2016-01-01

    Red blood cell concentrates (RCC) substitution after total knee arthroplasty (TKA) is correlated with multifold of complications and an independent predictor for higher postoperative mortality. TKA is mainly performed in elderly patients with pre-existing polymorbidity, often requiring permanent preoperative antithrombotic therapy (PAT). The aim of this retrospective analysis was to investigate the impact of demand for PAT on inpatient blood management in patients undergoing TKA. In this study 200 patients were retrospectively evaluated after TKA for differences between PAT and non-PAT regarding demographic parameters, preoperative ASA score > 2, duration of operation, pre-, and intraoperative hemoglobin level, and postoperative parameters including amount of wound drainage, RCC requirement, and inpatient time. In a multivariate logistic regression analysis the independent influences of PAT, demographic parameters, ASA score > 2, and duration of the operation on RCC demand following TKA were analyzed. Patients with PAT were significantly older, more often had an ASA > 2 at surgery, needed a higher number of RCCs units and more frequently and had lower perioperative hemoglobin levels. Multivariate logistic regression revealed PAT was an independent predictor for RCC requirement. PAT patients are more likely to require RCC following TKA and should be accurately monitored with respect to postoperative blood loss. PMID:27488941

  8. A Process Analytical Technology (PAT) approach to control a new API manufacturing process: development, validation and implementation.

    PubMed

    Schaefer, Cédric; Clicq, David; Lecomte, Clémence; Merschaert, Alain; Norrant, Edith; Fotiadu, Frédéric

    2014-03-01

    Pharmaceutical companies are progressively adopting and introducing Process Analytical Technology (PAT) and Quality-by-Design (QbD) concepts promoted by the regulatory agencies, aiming the building of the quality directly into the product by combining thorough scientific understanding and quality risk management. An analytical method based on near infrared (NIR) spectroscopy was developed as a PAT tool to control on-line an API (active pharmaceutical ingredient) manufacturing crystallization step during which the API and residual solvent contents need to be precisely determined to reach the predefined seeding point. An original methodology based on the QbD principles was designed to conduct the development and validation of the NIR method and to ensure that it is fitted for its intended use. On this basis, Partial least squares (PLS) models were developed and optimized using chemometrics methods. The method was fully validated according to the ICH Q2(R1) guideline and using the accuracy profile approach. The dosing ranges were evaluated to 9.0-12.0% w/w for the API and 0.18-1.50% w/w for the residual methanol. As by nature the variability of the sampling method and the reference method are included in the variability obtained for the NIR method during the validation phase, a real-time process monitoring exercise was performed to prove its fit for purpose. The implementation of this in-process control (IPC) method on the industrial plant from the launch of the new API synthesis process will enable automatic control of the final crystallization step in order to ensure a predefined quality level of the API. In addition, several valuable benefits are expected including reduction of the process time, suppression of a rather difficult sampling and tedious off-line analyses.

  9. A Process Analytical Technology (PAT) approach to control a new API manufacturing process: development, validation and implementation.

    PubMed

    Schaefer, Cédric; Clicq, David; Lecomte, Clémence; Merschaert, Alain; Norrant, Edith; Fotiadu, Frédéric

    2014-03-01

    Pharmaceutical companies are progressively adopting and introducing Process Analytical Technology (PAT) and Quality-by-Design (QbD) concepts promoted by the regulatory agencies, aiming the building of the quality directly into the product by combining thorough scientific understanding and quality risk management. An analytical method based on near infrared (NIR) spectroscopy was developed as a PAT tool to control on-line an API (active pharmaceutical ingredient) manufacturing crystallization step during which the API and residual solvent contents need to be precisely determined to reach the predefined seeding point. An original methodology based on the QbD principles was designed to conduct the development and validation of the NIR method and to ensure that it is fitted for its intended use. On this basis, Partial least squares (PLS) models were developed and optimized using chemometrics methods. The method was fully validated according to the ICH Q2(R1) guideline and using the accuracy profile approach. The dosing ranges were evaluated to 9.0-12.0% w/w for the API and 0.18-1.50% w/w for the residual methanol. As by nature the variability of the sampling method and the reference method are included in the variability obtained for the NIR method during the validation phase, a real-time process monitoring exercise was performed to prove its fit for purpose. The implementation of this in-process control (IPC) method on the industrial plant from the launch of the new API synthesis process will enable automatic control of the final crystallization step in order to ensure a predefined quality level of the API. In addition, several valuable benefits are expected including reduction of the process time, suppression of a rather difficult sampling and tedious off-line analyses. PMID:24468350

  10. Constitutive expression of McCHIT1-PAT enhances resistance to rice blast and herbicide, but does not affect grain yield in transgenic glutinous rice.

    PubMed

    Zeng, Xiao-Fang; Li, Lei; Li, Jian-Rong; Zhao, De-Gang

    2016-01-01

    To produce new rice blast- and herbicide-resistant transgenic rice lines, the McCHIT1 gene encoding the class I chitinase from Momordica charantia and the herbicide resistance gene PAT were introduced into Lailong (Oryza sativa L. ssp. Japonica), a glutinous local rice variety from Guizhou Province, People's Republic of China. Transgenic lines were identified by ß-glucuronidase (GUS) histochemical staining, PCR, and Southern blot analyses. Agronomic traits, resistance to rice blast and herbicide, chitinase activities, and transcript levels of McCHIT1 were assessed in the T2 progeny of three transgenic lines (L1, L8, and L10). The results showed that the introduction of McCHIT1-PAT into Lailong significantly enhanced herbicide and blast resistance. After infection with the blast fungus Magnaporthe oryzae, all of the T2 progeny exhibited less severe lesion symptoms than those of wild type. The disease indices were 100% for wild type, 65.66% for T2 transgenic line L1, 59.69% for T2 transgenic line L8, and 79.80% for T2 transgenic line L10. Transgenic lines expressing McCHIT1-PAT did not show a significant difference from wild type in terms of malondialdehyde (MDA) content, polyphenol oxidase (PPO) activity, and superoxide dismutase (SOD) activity in the leaves. However, after inoculation with M. oryzae, transgenic plants showed significantly higher SOD and PPO activities and lower MDA contents in leaves, compared with those in wild-type leaves. The transgenic and the wild-type plants did not show significant differences in grain yield parameters including plant height, panicles per plant, seeds per panicle, and 1000-grain weight. Therefore, the transgenic plants showed increased herbicide and blast resistance, with no yield penalty.

  11. Adventure Therapy with Girls At-Risk: Responses to Outdoor Experiential Activities.

    ERIC Educational Resources Information Center

    Autry, Cari E.

    2001-01-01

    Explored the feelings, attitudes, and perceptions of at- risk adolescent girls from a psychiatric rehabilitation facility following their participation in adventure therapy that involved outdoor experiential activities. Interview data indicated that participants found positive meaning within various activities. The resulting themes were…

  12. Occupational, Physical, and Speech Therapy Treatment Activities during Inpatient Rehabilitation for Traumatic Brain Injury

    PubMed Central

    Beaulieu, Cynthia L.; Dijkers, Marcel P.; Barrett, Ryan S.; Horn, Susan D.; Giuffrida, Clare G.; Timpson, Misti L.; Carroll, Deborah M.; Smout, Randy J.; Hammond, Flora M.

    2015-01-01

    Objective To describe use of Occupational Therapy (OT), Physical Therapy (PT) and Speech Therapy (ST) treatment activities throughout the acute rehabilitation stay of patients with traumatic brain injuries (TBI). Design Multi-site prospective observational cohort study. Setting 9 U.S. and 1 Canadian inpatient rehabilitation settings. Participants 2130 patients admitted for initial acute rehabilitation following TBI. Patients were categorized based on admission FIM cognitive scores, resulting in 5 fairly homogenous groups. Interventions Not applicable. Main Outcome Measures Percentage of patients engaged in specific activities and mean time patients engaged in the activities, per 10-hour block of time for OT, PT, and ST combined. Results Therapy activities in OT, PT, and ST across all 5 cognitive groups had a primary focus on basic activities. While advanced activities occurred in each discipline and within each cognitive group, these advanced activities occurred with fewer patients and usually only toward the end of the rehabilitation stay. Conclusions The pattern of activities engaged in was both similar to and different from patterns seen in previous PBE studies with different rehabilitation diagnostic groups. PMID:26212399

  13. Nuclear microprobe determination of platinum quantitative distribution in rat brain tumors after cisplatin or carboplatin injection for PAT treatment of glioma

    NASA Astrophysics Data System (ADS)

    Ortega, R.; Biston, M.-C.; Devès, G.; Bohic, S.; Carmona, A.

    2005-04-01

    Conventional radiotherapy of high-grade glioma is unsuccessful since less than 50% of patients survive at 6 months, therefore glioma treatment is still challenging. A new radiotherapy procedure has been recently proposed, the photoactivation therapy (PAT), associating synchrotron radiation with a chemotherapy agent, such as cisplatin. PAT aims at using the monochromaticity and the very high brilliance of the synchrotron radiation for selective excitation of a high-Z compound introduced in tumor cell DNA to maximize the photoelectric effect probability, thus increasing local toxicity. Synchrotron irradiation of cisplatin at the platinum absorption K-edge resulted in a dramatic increase in life span relative to median survival time in the F98 glioma model in Fisher rat. In the purpose to optimize the platinum concentration into the tumor, the platinum content of irradiated target needs to be quantified. These results will enable to correlate injected dose to cellular platinum content in the tumor at the time of irradiation, and to study the spatial diffusion and distribution of the platinum into the tumor and the surrounding healthy tissues from the point of injection. Male Fisher 344 rats were inoculated with 103 F98 glioma cells. Thirteen days after stereotactic inoculation, intracerebral injection at the tumor site of 40 μg of carboplatin and 3 or 5 μg of cisplatin was performed. Platinum quantitative distribution in tumors and adjacent brain tissues was determined using μ-PIXE and μ-RBS analysis.

  14. Effectiveness of virtual reality exposure therapy for active duty soldiers in a military mental health clinic.

    PubMed

    Reger, Greg M; Holloway, Kevin M; Candy, Colette; Rothbaum, Barbara O; Difede, JoAnn; Rizzo, Albert A; Gahm, Gregory A

    2011-02-01

    Exposure therapy is an evidence-based treatment for posttraumatic stress disorder (PTSD), but research evaluating its effectiveness with active duty service members is limited. This report examines the effectiveness of virtual reality exposure therapy (VRE) for active duty soldiers (N = 24) seeking treatment following a deployment to Iraq or Afghanistan. Relative to their pretreatment self-reported symptoms on the PTSD Checklist, Military Version (M = 60.92; SD = 11.03), patients reported a significant reduction at posttreatment (M = 47.08; SD = 12.70; p < .001). Sixty-two percent of patients (n = 15) reported a reliable change of 11 points or more. This study supports the effectiveness of exposure therapy for active duty soldiers and extends previous research on VRE to this population. PMID:21294166

  15. Physical activity, physical fitness, and exercise therapy in children with juvenile idiopathic arthritis.

    PubMed

    Houghton, Kristin

    2012-09-01

    Arthritis in childhood can be associated with low levels of physical activity and poor physical fitness. Children with arthritis may have decreased aerobic and anaerobic fitness, muscle weakness, low bone mass, and low bone strength. Suboptimal physical activity and exercise capacity may contribute to further deconditioning and disability, placing children with arthritis at risk for poor health outcomes. Recent studies suggest that exercise therapy is safe and does not worsen arthritis. Exercise therapy may improve function, quality of life, and physical fitness. However, little is known about the exercise prescription that is most effective to improve clinical outcomes in children with arthritis. This article reviews the current literature on physical activity, physical fitness, and exercise therapy in children with juvenile idiopathic arthritis.

  16. Motor programme activating therapy influences adaptive brain functions in multiple sclerosis: clinical and MRI study.

    PubMed

    Rasova, Kamila; Prochazkova, Marie; Tintera, Jaroslav; Ibrahim, Ibrahim; Zimova, Denisa; Stetkarova, Ivana

    2015-03-01

    There is still little scientific evidence for the efficacy of neurofacilitation approaches and their possible influence on brain plasticity and adaptability. In this study, the outcome of a new kind of neurofacilitation approach, motor programme activating therapy (MPAT), was evaluated on the basis of a set of clinical functions and with MRI. Eighteen patients were examined four times with standardized clinical tests and diffusion tensor imaging to monitor changes without therapy, immediately after therapy and 1 month after therapy. Moreover, the strength of effective connectivity was analysed before and after therapy. Patients underwent a 1-h session of MPAT twice a week for 2 months. The data were analysed by nonparametric tests of association and were subsequently statistically evaluated. The therapy led to significant improvement in clinical functions, significant increment of fractional anisotropy and significant decrement of mean diffusivity, and decrement of effective connectivity at supplementary motor areas was observed immediately after the therapy. Changes in clinical functions and diffusion tensor images persisted 1 month after completing the programme. No statistically significant changes in clinical functions and no differences in MRI-diffusion tensor images were observed without physiotherapy. Positive immediate and long-term effects of MPAT on clinical and brain functions, as well as brain microstructure, were confirmed.

  17. Statement--fundamental concepts of occupational therapy: occupation, purposeful activity, and function.

    PubMed

    Hinojosa, J; Kramer, P

    1997-01-01

    Deriving from the philosophical basis of the profession, occupation is the core concept of the profession of occupational therapy. However, in the occupational therapy literature, the term occupation is used in a variety of ways. Occupation, a collection of activities that people use to fill their time and give life meaning, is organized around roles or in terms of activities of daily living, work and productive activities, or pleasure, for survival, for necessity, and for their personal meaning. It is the individualized, unique combination of activities that comprises an individual's occupations. Purposeful activities have been described in many different ways: as something all people engage in; as tools or media that therapists use to enhance or facilitate performance; and vehicles for bringing about change. Purposeful activities are seen as part of the process of occupational therapy. Purposeful activities are subset of occupations in that they are goal directed and serve as a major tool in the process of occupational therapy. The term function, viewed as the ability to perform activities required in one's occupations has become increasingly important to society in describing the performance or change in individuals. This societal shift in ideas has prompted the concept of function, viewed as a product, to become more important than the process of bringing about change. Occupational therapy practitioners typically have viewed the process as being just as important as the product. When working to improve function, occupational therapy practitioners use purposeful activities that are meaningful to the person in relation to his or her occupational history, preferences, personal goals, and needs. Occupational therapy practitioners need to keep the individual's occupations in the forefront of their thoughts when using any purposeful activity and to plan interventions toward improving the individual's ability to function within his or her occupations. In the interest

  18. [Evaluating influence of Captopril therapy on occupational activity of engine operators with hypertension].

    PubMed

    Serikov, V V; Kolyagin, V Ya; Bogdanova, V E

    2016-01-01

    The article covers results of study concerning influence of Captopril (25 mg) therapy on occupational activity of locomotive crew workers in real night travels model on training complex "EP1M locomotive operator cabin". Findings are that single use of Captopril (25 mg) in modelled railway activity enabled to increase reliability of occupational activity, that manifested in lower number of errors in locomotive operators' actions at night, and in psychophysiologic regulation of various psychic acts. PMID:27396147

  19. [Evaluating influence of Captopril therapy on occupational activity of engine operators with hypertension].

    PubMed

    Serikov, V V; Kolyagin, V Ya; Bogdanova, V E

    2016-01-01

    The article covers results of study concerning influence of Captopril (25 mg) therapy on occupational activity of locomotive crew workers in real night travels model on training complex "EP1M locomotive operator cabin". Findings are that single use of Captopril (25 mg) in modelled railway activity enabled to increase reliability of occupational activity, that manifested in lower number of errors in locomotive operators' actions at night, and in psychophysiologic regulation of various psychic acts.

  20. [Ergotism due to simultaneous use of ergot alkaloids and high activity antiretroviral therapy].

    PubMed

    Cifuentes M, Daniel; Blanco L, Sergio; Ramírez F, Camila

    2016-06-01

    High activity antiretroviral therapy may exacerbate the activity of ergot alkaloids due to an inhibition of cytochrome P450. We report a 57 years old female with AIDS treated with lamivudine, zidovudine, atazanavir, ritonavir and cotrimoxazole presenting with ischemic signs in the four limbs. There was acrocyanosis and weak radial and ulnar pulses. A family member referred that the patient used ergot alkaloids for headaches. An ergotism due to the simultaneous use of ergot alkaloids and antiretroviral therapy was suspected. The latter was discontinued and intravenous nitroglycerin, nifedipine and pentoxifyline were started with good results. PMID:27598502

  1. Effects of mirror therapy combined with motor tasks on upper extremity function and activities daily living of stroke patients

    PubMed Central

    Kim, Kyunghoon; Lee, Sukmin; Kim, Donghoon; Lee, Kyoungbo; Kim, Youlim

    2016-01-01

    [Purpose] The objective of this study was to investigate the effects of mirror therapy combined with exercise tasks on the function of the upper limbs and activities of daily living. [Subjects and Methods] Twenty-five stroke patients who were receiving physical therapy at K Hospital in Gyeonggi-do, South Korea, were classified into a mirror therapy group (n=12) and a conventional therapy group (n=13). The therapies were applied for 30 minutes per day, five times per week, for a total of four weeks. Upper limb function was measured with the Action Research Arm test, the Fugl-Meyer Assessment, and the Box and Block test, and activities of daily living were measured with the Functional Independence Measure. A paired test was performed to compare the intragroup differences between before training and after four weeks of therapy, and an independent t-test was performed to compare the differences between the two groups before and after four weeks of therapy. [Results] In the intragroup comparison, both groups showed significant differences between measurements taken before and after four weeks of therapy. In the intergroup comparison, the mirror therapy group showed significant improvements compared with the conventional therapy group, both in upper limb function and activities of daily living. [Conclusion] The findings of this study demonstrated that mirror therapy is more effective than conventional therapy for the training of stroke patients to improve their upper limb function and activities of daily living. PMID:27065534

  2. PAT-1 safety analysis report addendum author responses to request for additional information.

    SciTech Connect

    Weiner, Ruth F.; Schmale, David T.; Kalan, Robert J.; Akin, Lili A.; Miller, David Russell; Knorovsky, Gerald Albert; Yoshimura, Richard Hiroyuki; Lopez, Carlos; Harding, David Cameron; Jones, Perry L.; Morrow, Charles W.

    2010-09-01

    The Plutonium Air Transportable Package, Model PAT-1, is certified under Title 10, Code of Federal Regulations Part 71 by the U.S. Nuclear Regulatory Commission (NRC) per Certificate of Compliance (CoC) USA/0361B(U)F-96 (currently Revision 9). The National Nuclear Security Administration (NNSA) submitted SAND Report SAND2009-5822 to NRC that documented the incorporation of plutonium (Pu) metal as a new payload for the PAT-1 package. NRC responded with a Request for Additional Information (RAI), identifying information needed in connection with its review of the application. The purpose of this SAND report is to provide the authors responses to each RAI. SAND Report SAND2010-6106 containing the proposed changes to the Addendum is provided separately.

  3. Review of the High Performance Antiproton Trap (HiPAT) Experiment

    NASA Technical Reports Server (NTRS)

    Martin, James J.; Lewis, Raymond A.; Pearson, J. Boise; Sims, W. Herb; Chakrabarti, Suman; Fant, Wallace E.; McDonald, Stan

    2003-01-01

    Many space propulsion concepts exist that use matter-antimatter reactions. Current antiproton production rates are enough to conduct proof-of-principle evaluation of these concepts. One enabling technology for such experiments is portable storage of low energy antiprotons, to transport antiprotons to experimental facilities. To address this need, HiPAT is being developed, with a design goal of containing 10(exp 12) particles for up to 18 days. HiPAT is a Penning-Malmberg trap with a 4 Tesla superconductor, 20kV electrodes, radio frequency (RF) network, and 10(exp -13) Torr vacuum. 'Normal' matter is being used to evaluate the system. An electron beam ionizes background gas in situ, and particle beams are captured dynamically. The experiment examines ion storage lifetimes, RF plasma diagnostics, charge exchange with background gases, and dynamic ion beam capture.

  4. Bicalutamide Activated Oncolytic Adenovirus for the Adjuvant Therapy of High Risk Prostate Cancer

    PubMed Central

    Johnson, Tamara Jane; Hoti, Naser Uddin; Liu, Chunyan; Chowdhury, Wasim H.; Li, Ying; Zhang, Yonggang; Lupold, Shawn E.; DeWeese, Theodore; Rodriguez, Ronald

    2013-01-01

    Conditionally replicating adenoviruses (CRAds) utilize tissue specific promoters to control the expression of the early genes, E1A and E1B, to preferentially replicate and lyse tumor cells (oncolysis). Previous CRAds used in prostate cancer gene therapy require androgens to activate prostate specific promoters and induce viral replication. Unfortunately, these CRAds have reduced activity in patients on androgen suppressive therapy. We describe a novel prostate specific CRAd generated by fusing the E1A gene to the androgen receptor (AR) cDNA with a point mutation in codon 685 (C685Y). The E1A-AR fusion neutralizes the previously described mutual inhibition of E1A & AR, and the C685Y point mutation alters specificity of steroid ligand binding to the AR, such that both androgens and non-steroidal anti-androgens can activate viral replication. We demonstrate that the mutated E1A-AR retained the ability to function in regulating AR responsive genes and E1A responsive viral genes. In combination therapy of virus, bicalutamide (anti-androgen) and radiation, a profound impact on cell death by viral oncolysis was seen both in vitro and tumor xenografts. To our knowledge, this is the first gene therapy engineered to be enhanced by anti-androgens, and a particularly attractive adjuvant strategy for intensity modulated radiation therapy (IMRT) of high-risk prostate cancers. PMID:23764901

  5. Photodynamic therapy for cancer and activation of immune response

    NASA Astrophysics Data System (ADS)

    Mroz, Pawel; Huang, Ying-Ying; Hamblin, Michael R.

    2010-02-01

    Anti-tumor immunity is stimulated after PDT for cancer due to the acute inflammatory response, exposure and presentation of tumor-specific antigens, and induction of heat-shock proteins and other danger signals. Nevertheless effective, powerful tumor-specific immune response in both animal models and also in patients treated with PDT for cancer, is the exception rather than the rule. Research in our laboratory and also in others is geared towards identifying reasons for this sub-optimal immune response and discovering ways of maximizing it. Reasons why the immune response after PDT is less than optimal include the fact that tumor-antigens are considered to be self-like and poorly immunogenic, the tumor-mediated induction of CD4+CD25+foxP3+ regulatory T-cells (T-regs), that are able to inhibit both the priming and the effector phases of the cytotoxic CD8 T-cell anti-tumor response and the defects in dendritic cell maturation, activation and antigen-presentation that may also occur. Alternatively-activated macrophages (M2) have also been implicated. Strategies to overcome these immune escape mechanisms employed by different tumors include combination regimens using PDT and immunostimulating treatments such as products obtained from pathogenic microorganisms against which mammals have evolved recognition systems such as PAMPs and toll-like receptors (TLR). This paper will cover the use of CpG oligonucleotides (a TLR9 agonist found in bacterial DNA) to reverse dendritic cell dysfunction and methods to remove the immune suppressor effects of T-regs that are under active study.

  6. Chlorotoxin: Structure, activity, and potential uses in cancer therapy.

    PubMed

    Ojeda, Paola G; Wang, Conan K; Craik, David J

    2016-01-01

    Chlorotoxin is a disulfide-rich stable peptide from the venom of the Israeli scorpion Leiurus quinquestriatus, which has potential therapeutic applications in the treatment of cancer. Its ability to preferentially bind to tumor cells has been harnessed to develop an imaging agent to help visualize tumors during surgical resection. In addition, chlorotoxin has attracted interest as a vehicle to deliver anti-cancer drugs specifically to cancer cells. Given its interesting structural and biological properties, chlorotoxin also has the potential to be used in a variety of other biotechnology and biomedical applications. Here, we review the structure, activity and potential applications of chlorotoxin as a drug design scaffold.

  7. Prevalence of oral candidiasis in HIV/AIDS children in highly active antiretroviral therapy era. A literature analysis.

    PubMed

    Gaitán-Cepeda, Luis Alberto; Sánchez-Vargas, Octavio; Castillo, Nydia

    2015-08-01

    SummaryHighly active antiretroviral therapy has decreased the morbidity and mortality related to HIV infection, including oral opportunistic infections. This paper offers an analysis of the scientific literature on the epidemiological aspects of oral candidiasis in HIV-positive children in the combination antiretroviral therapy era. An electronic databases search was made covering the highly active antiretroviral therapy era (1998 onwards). The terms used were oral lesions, oral candidiasis and their combination with highly active antiretroviral therapy and HIV/AIDS children. The following data were collected from each paper: year and country in which the investigation was conducted, antiretroviral treatment, oral candidiasis prevalence and diagnostic parameters (clinical or microbiological). Prevalence of oral candidiasis varied from 2.9% in American HIV-positive children undergoing highly active antiretroviral therapy to 88% in Chilean HIV-positive children without antiretroviral therapy. With respect to geographical location and antiretroviral treatment, higher oral candidiasis prevalence in HIV-positive children on combination antiretroviral therapy/antiretroviral therapy was reported in African children (79.1%) followed by 45.9% reported in Hindu children. In HIV-positive Chilean children on no antiretroviral therapy, high oral candidiasis prevalence was reported (88%) followed by Nigerian children (80%). Oral candidiasis is still frequent in HIV-positive children in the highly active antiretroviral therapy era irrespective of geographical location, race and use of antiretroviral therapy.

  8. Influence of nitric oxide on antitumor activity of photodynamic therapy: laser systems for PDT

    NASA Astrophysics Data System (ADS)

    Evtushenko, V. A.; Zagrebelnaya, G. V.; Soldatov, Anatoly N.; Kondakova, I. V.; Shumeiko, Alexei S.

    2004-05-01

    Photodynamic therapy (PDT) is a promising therapeutic modality used for the cancer treatment. The principle of PDT is based on the formation of singlet oxygen and other activated oxygen metabolites that result in apoptotic tumor cell death. However, the resistance of some tumors to radiation therapy is recorded. The search for the chemical agents, therefore, which are able to enhance the antitumor activity of radiation therapy and induce the tumor cell apoptosis is of great importance. The use of pharmacologic agents such as donors of nitric oxide (NO) or modulators of NO-synthase may be one of the approaches to improve the therapeutic efficiency of PDT. The aim of our study was to evaluate the feasibility of using nitric oxide in combination with PDT for enhancing the induction of tumor cell apoptosis.

  9. X-PAT: a multiplatform patient referral data management system for small healthcare institution requirements.

    PubMed

    Masseroli, Marco; Marchente, Mario

    2008-07-01

    We present X-PAT, a platform-independent software prototype that is able to manage patient referral multimedia data in an intranet network scenario according to the specific control procedures of a healthcare institution. It is a self-developed storage framework based on a file system, implemented in eXtensible Markup Language (XML) and PHP Hypertext Preprocessor Language, and addressed to the requirements of limited-dimension healthcare entities (small hospitals, private medical centers, outpatient clinics, and laboratories). In X-PAT, healthcare data descriptions, stored in a novel Referral Base Management System (RBMS) according to Health Level 7 Clinical Document Architecture Release 2 (CDA R2) standard, can be easily applied to the specific data and organizational procedures of a particular healthcare working environment thanks also to the use of standard clinical terminology. Managed data, centralized on a server, are structured in the RBMS schema using a flexible patient record and CDA healthcare referral document structures based on XML technology. A novel search engine allows defining and performing queries on stored data, whose rapid execution is ensured by expandable RBMS indexing structures. Healthcare personnel can interface the X-PAT system, according to applied state-of-the-art privacy and security measures, through friendly and intuitive Web pages that facilitate user acceptance. PMID:18632322

  10. Community-based treatment of advanced HIV disease: introducing DOT-HAART (directly observed therapy with highly active antiretroviral therapy).

    PubMed Central

    Farmer, P.; Léandre, F.; Mukherjee, J.; Gupta, R.; Tarter, L.; Kim, J. Y.

    2001-01-01

    In 2000, acquired immunodeficiency syndrome (AIDS) overtook tuberculosis (TB) as the world's leading infectious cause of adult deaths. In affluent countries, however, AIDS mortality has dropped sharply, largely because of the use of highly active antiretroviral therapy (HAART). Antiretroviral agents are not yet considered essential medications by international public health experts and are not widely used in the poor countries where human immunodeficiency virus (HIV) takes its greatest toll. Arguments against the use of HAART have mainly been based on the high cost of medications and the lack of the infrastructure necessary for using them wisely. We re- examine these arguments in the setting of rising AIDS mortality in developing countries and falling drug prices, and describe a small community-based treatment programme based on lessons gained in TB control. With the collaboration of Haitian community health workers experienced in the delivery of home-based and directly observed treatment for TB, an AIDS-prevention project was expanded to deliver HAART to a subset of HIV patients deemed most likely to benefit. The inclusion criteria and preliminary results are presented. We conclude that directly observed therapy (DOT) with HAART, "DOT-HAART", can be delivered effectively in poor settings if there is an uninterrupted supply of high-quality drugs. PMID:11799447

  11. Adoptive T-Cell Therapy for Cancer in the United Kingdom: A Review of Activity for the British Society of Gene and Cell Therapy Annual Meeting 2015

    PubMed Central

    Anderson, John; Bridgeman, John Stephen; Hawkins, Robert Edward; Exley, Mark Adrian; Stauss, Hans; Maher, John; Pule, Martin; Sewell, Andrew Kelvin; Bendle, Gavin; Lee, Steven; Qasim, Waseem; Thrasher, Adrian; Morris, Emma

    2015-01-01

    Abstract Adoptive T-cell therapy is delivering objective clinical responses across a number of cancer indications in the early phase clinical setting. Much of this clinical activity is taking place at major clinical academic centers across the United States. This review focuses upon cancer-focused cell therapy activity within the United Kingdom as a contribution to the 2015 British Society of Gene and Cell Therapy annual general meeting. This overview reflects the diversity and expansion of clinical and preclinical studies within the United Kingdom while considering the background context of this work against new infrastructural developments and the requirements of nationalized healthcare delivery within the UK National Health Service. PMID:25860661

  12. Health Occupations--Respiration Therapy Technician. Kit No. 66. Instructor's Manual [and] Student Learning Activity Guide.

    ERIC Educational Resources Information Center

    Jackson, Janette

    An instructor's manual and student activity guide on respiration therapy technician are provided in this set of prevocational education materials which focuses on the vocational area of health occupations. (This set of materials is one of ninety-two prevocational education sets arranged around a cluster of seven vocational offerings: agriculture,…

  13. [Analysis of antibacterial activity of a new antiseptic for therapy of maxillofacial inflammations].

    PubMed

    Leont'ev, V K; Kuznetsova, L I; Leshchankina, E L; Kuznetsov, V L

    2002-01-01

    Clinical and experimental studies of polydimethyldiallylammonium chloride (PDMDAAC) experimentally validated the choice of optimal concentration and composition of this agent. The results indicate a high antiseptic activity of 1% PDMDAAC and the possibility of using it in local therapy of periodontitis and posttraumatic infection.

  14. Ion Storage Tests with the High Performance Antimatter Trap (HiPAT)

    NASA Technical Reports Server (NTRS)

    Martin, James J.; Lewis, Raymond A.; Chakrabarti, Suman; Pearson, Boise; Schafer, Charles (Technical Monitor)

    2002-01-01

    The NASA/Marshall Space Flight Centers (NASA/MSFC) Propulsion Research Center (PRC) is evaluating an antiproton storage system, referred to as the High Performance Antiproton Trap (HiPAT). This interest stems from the sheer energy represented by matter/antimatter annihilation process with has an energy density approximately 10 order of magnitude above that of chemical propellants. In other terms, one gram of antiprotons contains the equivalent energy of approximately 23 space shuttle external tanks or ET's (each ET contains roughly 740,000 kgs of fuel and oxidizer). This incredible source of stored energy, if harnessed, would be an enabling technology for deep space mission where both spacecraft weight and propulsion performance are key to satisfying aggressive mission requirements. The HiPAT hardware consists of a 4 Tesla superconductor system, an ultra high vacuum test section (vacuum approaching 10(exp -12) torr), and a high voltage confinement electrode system (up to 20 kvolts operation). The current laboratory layout is illustrated. The HiPAT designed objectives included storage of up to 1 trillion antiprotons with corresponding lifetimes approaching 18 days. To date, testing has centered on the storage of positive hydrogen ions produced in situ by a stream of high-energy electrons that passes through the trapping region. However, due to space charge issues and electron beam compression as it passes through the HiPAT central field, current ion production is limited to less then 50,000 ions. Ion lifetime was determined by counting particle populations at the end of various storage time intervals. Particle detection was accomplished by destructively expelling the ions against a micro-channel plate located just outside the traps magnetic field. The effect of radio frequency (RF) stabilization on the lifetime of trapped particles was also examined. This technique, referred to as a rotating wall, made use of a segmented electrode located near the center of the trap

  15. Expression of PAT and NPT II proteins during the developmental stages of a genetically modified pepper developed in Korea.

    PubMed

    Kim, Hyo Jin; Lee, Si Myung; Kim, Jae Kwang; Ryu, Tae Hun; Suh, Seok Cheol; Cho, Hyun Suk

    2010-10-27

    Estimation of the protein levels introduced in a biotechnology-derived product is conducted as part of an overall safety assessment. An enzyme-linked immunosorbent assay (ELISA) was used to analyze phosphinothricin acetyltransferase (PAT) and neomycin phosphotransferase II (NPT II) protein expression in a genetically modified (GM) pepper plant developed in Korea. PAT and NPT II expression levels, based on both dry weight and fresh weight, were variable among different plant generations and plant sections from isolated genetically modified organism (GMO) fields at four developmental stages. PAT expression was highest in leaves at anthesis (11.44 μg/gdw and 2.17 μg/gfw) and lowest in roots (0.12 μg/gdw and 0.01 μg/gfw). NPT II expression was also highest in leaves at anthesis (17.31 μg/gdw and 3.41 μg/gfw) and lowest in red pepper (0.65 μg/gdw and 0.12 μg/gfw). In pollen, PAT expression was 0.59-0.62 μg/gdw, while NPT II was not detected. Both PAT and NPT II showed a general pattern of decreased expression with progression of the growing season. As expected, PAT and NPT II protein expression was not detectable in control pepper plants.

  16. The Lsm1-7-Pat1 complex promotes viral RNA translation and replication by differential mechanisms

    PubMed Central

    Jungfleisch, Jennifer; Chowdhury, Ashis; Alves-Rodrigues, Isabel; Tharun, Sundaresan; Díez, Juana

    2015-01-01

    The Lsm1-7-Pat1 complex binds to the 3′ end of cellular mRNAs and promotes 3′ end protection and 5′–3′ decay. Interestingly, this complex also specifically binds to cis-acting regulatory sequences of viral positive-strand RNA genomes promoting their translation and subsequent recruitment from translation to replication. Yet, how the Lsm1-7-Pat1 complex regulates these two processes remains elusive. Here, we show that Lsm1-7-Pat1 complex acts differentially in these processes. By using a collection of well-characterized lsm1 mutant alleles and a system that allows the replication of Brome mosaic virus (BMV) in yeast we show that the Lsm1-7-Pat1 complex integrity is essential for both, translation and recruitment. However, the intrinsic RNA-binding ability of the complex is only required for translation. Consistent with an RNA-binding-independent function of the Lsm1-7-Pat1 complex on BMV RNA recruitment, we show that the BMV 1a protein, the sole viral protein required for recruitment, interacts with this complex in an RNA-independent manner. Together, these results support a model wherein Lsm1-7-Pat1 complex binds consecutively to BMV RNA regulatory sequences and the 1a protein to promote viral RNA translation and later recruitment out of the host translation machinery to the viral replication complexes. PMID:26092942

  17. The Lsm1-7-Pat1 complex promotes viral RNA translation and replication by differential mechanisms.

    PubMed

    Jungfleisch, Jennifer; Chowdhury, Ashis; Alves-Rodrigues, Isabel; Tharun, Sundaresan; Díez, Juana

    2015-08-01

    The Lsm1-7-Pat1 complex binds to the 3' end of cellular mRNAs and promotes 3' end protection and 5'-3' decay. Interestingly, this complex also specifically binds to cis-acting regulatory sequences of viral positive-strand RNA genomes promoting their translation and subsequent recruitment from translation to replication. Yet, how the Lsm1-7-Pat1 complex regulates these two processes remains elusive. Here, we show that Lsm1-7-Pat1 complex acts differentially in these processes. By using a collection of well-characterized lsm1 mutant alleles and a system that allows the replication of Brome mosaic virus (BMV) in yeast we show that the Lsm1-7-Pat1 complex integrity is essential for both, translation and recruitment. However, the intrinsic RNA-binding ability of the complex is only required for translation. Consistent with an RNA-binding-independent function of the Lsm1-7-Pat1 complex on BMV RNA recruitment, we show that the BMV 1a protein, the sole viral protein required for recruitment, interacts with this complex in an RNA-independent manner. Together, these results support a model wherein Lsm1-7-Pat1 complex binds consecutively to BMV RNA regulatory sequences and the 1a protein to promote viral RNA translation and later recruitment out of the host translation machinery to the viral replication complexes.

  18. Comparison of Tc-99m labeled liver and liver paté as markers for solid-phase gastric emptying.

    PubMed

    Christian, P E; Moore, J G; Datz, F L

    1984-03-01

    A radionuclide marker for studies of solid-phase gastric emptying should have a high labeling efficiency and remain relatively stable during gastric emptying. The availability of materials and the ease of preparation are also considerations in selecting radionuclide markers. We have compared the stability of intracellularly labeled chicken liver, surface-labeled chicken liver, and labeled puréed meat (liver paté) incubated with hydrochloric acid solution or gastric juice. Intracellularly labeled chicken liver and labeled liver paté were also compared in gastric emptying studies in humans. Our in vitro results demonstrated labeling efficiencies greater than 92% for both intracellularly labeled liver and labeled liver paté. The paté labeled with Tc-99m sulfur colloid was more stable than Tc-99m surface-labeled liver in vitro and its preparation was easier than with the intracellular labeling technique. Gastric emptying studies on normal subjects demonstrated equal performance of the intracellularly labeled liver and the labeled liver paté. Labeled liver paté is thus an alternative to intracellularly labeled chicken liver in measuring solid-phase gastric emptying.

  19. Real-Time Assessment of Autonomic Nerve Activity During Adaptive Servo-Ventilation Support or Waon Therapy.

    PubMed

    Imamura, Teruhiko; Kinugawa, Koichiro; Nitta, Daisuke; Komuro, Issei

    2016-07-27

    Adaptive servo-ventilation support and Waon therapy are recently developed non-pharmacological and noninvasive therapies for patients with heart failure refractory to guideline-directed medical therapy. These therapies decrease both preload and afterload, increase cardiac output, and appear to ameliorate autonomic nerve activity. However, the time course of autonomic nerve activity during these therapies remains unclear. We performed heart rate variability analysis using the MemCalc power spectral density method (MemCalc system; Suwa Trust Co, Tokyo) to assess autonomic nerve activity during adaptive servo-ventilation support and Waon therapy in two different cases and determined the time course of autonomic nerve activity during these therapies. During both therapies, we found a drastic increase in parasympathetic nerve activity and continuous suppression of sympathetic nerve activity. Heart rate variability analysis using the MemCalc method may be promising for the assessment of the efficacy of various treatments, including adaptive servo-ventilation support and Waon therapy, from the viewpoint of autonomic nerve activity. PMID:27385607

  20. Antitumor activity of combined endostatin and thymidine kinase gene therapy in C6 glioma models.

    PubMed

    Chen, Yan; Huang, Honglan; Yao, Chunshan; Su, Fengbo; Guan, Wenming; Yan, Shijun; Ni, Zhaohui

    2016-09-01

    The combination of Endostatin (ES) and Herpes Simplex Virus thymidine kinase (HSV-TK) gene therapy is known to have antitumor activity in bladder cancer. The potential effect of ES and TK therapy in glioma has not yet been investigated. In this study, pTK-internal ribosome entry site (IRES), pIRES-ES, and pTK-IRES-ES plasmids were constructed; pIRES empty vector served as the negative control. The recombinant constructs were transfected into human umbilical vein endothelial cells (HUVECs) ECV304 and C6 rat glioma cell line. Ganciclovir (GCV) was used to induce cell death in transfected C6 cells. We found that ECV304 cells expressing either ES or TK-ES showed reduced proliferation, decreased migration capacity, and increased apoptosis, as compared to untransfected cells or controls. pTK-IRES-ES/GCV or pTK-IRES/GCV significantly suppressed cell proliferation and induced cell apoptosis in C6 cells, as compared to the control. In addition, the administration of pIRES-ES, pTK-IRES/GCV, or pTK-IRES-ES/GCV therapy improved animal activity and behavior; was associated with prolonged animal survival, and a lower microvessel density (MVD) value in tumor tissues of C6 glioma rats. In comparison to others, dual gene therapy in form of pTK-IRES-ES/GCV had a significant antitumor activity against C6 glioma. These findings indicate combined TK and ES gene therapy was associated with a superior antitumor efficacy as compared to single gene therapy in C6 glioma. PMID:27366865

  1. Antioxidative enzymes activity and malondialdehyde concentration during mitoxantrone therapy in multiple sclerosis patients.

    PubMed

    Adamczyk-Sowa, M; Sowa, P; Pierzchala, K; Polaniak, R; Labuz-Roszak, B

    2012-12-01

    Mitoxantrone (MX) is approved for the treatment of aggressive relapsing-remitting, secondary-progressive and progressive-relapsing form of multiple sclerosis (MS). The mechanism of its action is multiaxial, however, it is not free from side effects. The causes of the side effects are still unknown and require further investigation. The aim of this study was to investigate the influence of MX therapy on enzymatic parameters of endogenous antioxidative status: manganese and copper/zinc superoxide dismutase (MnSOD, Cu/ZnSOD), catalase (CAT), glutathione peroxidase (GSH-Px) and lipid peroxidation marker--malondialdehyde (MDA) in blood serum and cerebrospinal fluid (CSF) in patients suffering from MS. After the MX therapy serum and the CSF MDA concentrations increased significantly. We reported that MnSOD activities decrease in serum and the CSF, while, surprisingly, the serum Cu/ZnSOD activity increases after the MX therapy. We also noted a marked decrease in CSF CAT and GSH-Px activity after the MX treatment. Our results strongly suggest the influence of MX therapy on oxidation/antioxidation status of serum and the CSF. These findings open up new opportunities for a better understanding of underlying physiopathological events in MS and provide a new insight into MX's mechanisms of action, especially its potent side effects.

  2. Interdisciplinary therapy changes superoxide dismutase activity and adiponectin in obese adolescents: a randomised controlled trial.

    PubMed

    Nunes, João Elias Dias; Cunha, Heitor Santos; Freitas, Zulmária Rezende; Nogueira, Ana Maria Caixeta; Dâmaso, Ana Raimunda; Espindola, Foued Salmen; Cheik, Nadia Carla

    2016-01-01

    The objective of this study is to evaluate the effect of interdisciplinary therapy in the parameters of the oxidative stress and the anti-inflammatory responses of obese adolescents. We selected 57 participants, who were randomly divided into 2 groups: interdisciplinary therapy group and a control group. After 6 months of intervention, 17 participants of the interdisciplinary therapy group and 8 of the control group returned for re-evaluation. The interdisciplinary therapy group participated in a treatment with 4 weekly sessions of exercise, a weekly group therapy session and a weekly nutritional education session. Blood parameters of oxidative stress and anti-inflammatory response were evaluated. The results demonstrated that there were significant increases in the interdisciplinary therapy group for superoxide dismutase activity (6.56 ± 3.22 to 11.40 ± 7.49) and ferric-reducing antioxidant potential concentration (532.91 ± 106.48 to 573.25 ± 112.57), although adiponectin levels did not reduce (40.9 ± 29.34 to 49.05 ± 41.22). A significant decrease in nitrite levels was also found (14.23 ± 8.48 to 11.45 ± 6.05). In the control group, significant reduction was found in adiponectin (31.56 ± 18.88 to 18.01 ± 11.66). This study suggests that interdisciplinary therapy for 6 months was effective in improving the anti-inflammatory responses and the antioxidant defences in obese adolescents. PMID:26367325

  3. Activation of photodynamic therapy in vitro with Cerenkov luminescence generated from Yttrium-90 (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Hartl, Brad A.; Hirschberg, Henry; Marcu, Laura; Cherry, Simon R.

    2016-03-01

    Translation of photodynamic therapy to the clinical setting has primarily been limited to easily accessible and/or superficial diseases where traditional light delivery can be performed noninvasively. Cerenkov luminescence, as generated from medically relevant radionuclides, has been suggested as a means to deliver light to deeper tissues noninvasively in order to overcome this depth limitation. We report on the use of Cerenkov luminescence generated from Yttrium-90 as a means to active the photodynamic therapy process in monolayer tumor cell cultures. The current study investigates the utility of Cerenkov luminescence for activating both the clinically relevant aminolevulinic acid at 1.0 mM and also the more efficient photosensitizer TPPS2a at 1.2 µM. Cells were incubated with aminolevulinic acid for 6 hours prior to radionuclide addition, as well as additional daily treatments for three days. TPPS2a was delivered as a single treatment with an 18 hour incubation time before radionuclide addition. Experiments were completed for both C6 glioma cells and MDA-MB-231 breast tumor cells. Although aminolevulinic acid proved ineffective for generating a therapeutic effect at any activity for either cell line, TPPS2a produced at least a 20% therapeutic effect at activities ranging from 6 to 60 µCi/well for the C6 cell line. Current results demonstrate that it may be possible to generate a therapeutic effect in vivo using Cerenkov luminescence to activate the photodynamic therapy process with clinically relevant photosensitizers.

  4. The influence of statin therapy on platelet activity markers in hyperlipidemic patients after ischemic stroke

    PubMed Central

    Chmielewski, Henryk; Kaczorowska, Beata; Przybyła, Monika; Baj, Zbigniew

    2015-01-01

    Introduction Low-density lipoprotein cholesterol (LDL-C) has been reported to increase platelet activation. Reducing the level of LDL-C with statins induces important pleiotropic effects such as platelet inhibition. This association between platelet activity and statin therapy may be clinically important in reducing the risk of ischemic stroke. We investigated the effect of simvastatin therapy on platelet activation markers (platelet CD62P, sP-selectin, and platelet-derived microparticles (PDMPs)) in hyperlipidemic patients after ischemic stroke. Material and methods The study group consisted of 21 hyperlipidemic patients after ischemic stroke confirmed by CT, and 20 healthy subjects served as controls. We assessed the CD62P expression on resting and thrombin-activated blood platelets. CD62P and PDMPs were analyzed by the use of monoclonal antibodies anti-CD61 and anti-CD62 on a flow cytometer. The level of sP-selectin in serum was measured by the ELISA (enzyme-linked immunosorbent assay) method. All markers were re-analyzed after 6 months of treatment with simvastatin (20 mg/day). Results Hyperlipidemic patients presented a significantly higher percentage of CD62+ platelets and higher reactivity to thrombin compared to control subjects. After simvastatin therapy hyperlipidemic patients showed a reduction of the percentage of resting CD62P(+) platelets (p = 0.005) and a reduction of expression and percentage of CD62P(+) platelets after activation by thrombin (median p < 0.05; percentage: p = 0.001). A decrease of sP-selectin levels (p = 0.001) and percentage of PDMPs (p < 0.05) in this group was also observed. Conclusions HMG-CoA reductase inhibitor therapy in stroke patients with hyperlipidemia may be useful not only due to the lipid-lowering effect but also because of a significant role in reduction of platelet activation and reactivity. PMID:25861297

  5. Exercise Therapy for Management of Type 2 Diabetes Mellitus: Superior Efficacy of Activity Monitors over Pedometers

    PubMed Central

    Umezono, Tomoya; Fukagawa, Masafumi

    2016-01-01

    We compared the efficacy of activity monitor (which displays exercise intensity and number of steps) versus that of pedometer in exercise therapy for patients with type 2 diabetes. The study subjects were divided into the activity monitor group (n = 92) and pedometer group (n = 95). The primary goal was improvement in hemoglobin A1c (HbA1c). The exercise target was set at 8,000 steps/day and 20 minutes of moderate-intensity exercise (≥3.5 metabolic equivalents). The activity monitor is equipped with a triple-axis accelerometer sensor capable of measuring medium-intensity walking duration, number of steps, walking distance, calorie consumption, and total calorie consumption. The pedometer counts the number of steps. Blood samples for laboratory tests were obtained during the visits. The first examination was conducted at the start of the study and repeated at 2 and 6 months. A significant difference in the decrease in HbA1c level was observed between the two groups at 2 months. The results suggest that the use of activity level monitor that displays information on exercise intensity, in addition to the number of steps, is useful in exercise therapy as it enhances the concept of exercise therapy and promotes lowering of HbA1c in diabetic patients. PMID:27761471

  6. Dispersion and Transport of Cryptosporidium Oocysts from Fecal Pats under Simulated Rainfall Events

    PubMed Central

    Davies, Cheryl M.; Ferguson, Christobel M.; Kaucner, Christine; Krogh, Martin; Altavilla, Nanda; Deere, Daniel A.; Ashbolt, Nicholas J.

    2004-01-01

    The dispersion and initial transport of Cryptosporidium oocysts from fecal pats were investigated during artificial rainfall events on intact soil blocks (1,500 by 900 by 300 mm). Rainfall events of 55 mm h−1 for 30 min and 25 mm h−1 for 180 min were applied to soil plots with artificial fecal pats seeded with approximately 107 oocysts. The soil plots were divided in two, with one side devoid of vegetation and the other left with natural vegetation cover. Each combination of event intensity and duration, vegetation status, and degree of slope (5° and 10°) was evaluated twice. Generally, a fivefold increase (P < 0.05) in runoff volume was generated on bare soil compared to vegetated soil, and significantly more infiltration, although highly variable, occurred through the vegetated soil blocks (P < 0.05). Runoff volume, event conditions (intensity and duration), vegetation status, degree of slope, and their interactions significantly affected the load of oocysts in the runoff. Surface runoff transported from 100.2 oocysts from vegetated loam soil (25-mm h−1, 180-min event on 10° slope) to up to 104.5 oocysts from unvegetated soil (55-mm h−1, 30-min event on 10° slope) over a 1-m distance. Surface soil samples downhill of the fecal pat contained significantly higher concentrations of oocysts on devegetated blocks than on vegetated blocks. Based on these results, there is a need to account for surface soil vegetation coverage as well as slope and rainfall runoff in future assessments of Cryptosporidium transport and when managing pathogen loads from stock grazing near streams within drinking water watersheds. PMID:14766600

  7. Monocyte Activation in Immunopathology: Cellular Test for Development of Diagnostics and Therapy

    PubMed Central

    Ivanova, Ekaterina A.; Orekhov, Alexander N.

    2016-01-01

    Several highly prevalent human diseases are associated with immunopathology. Alterations in the immune system are found in such life-threatening disorders as cancer and atherosclerosis. Monocyte activation followed by macrophage polarization is an important step in normal immune response to pathogens and other relevant stimuli. Depending on the nature of the activation signal, macrophages can acquire pro- or anti-inflammatory phenotypes that are characterized by the expression of distinct patterns of secreted cytokines and surface antigens. This process is disturbed in immunopathologies resulting in abnormal monocyte activation and/or bias of macrophage polarization towards one or the other phenotype. Such alterations could be used as important diagnostic markers and also as possible targets for the development of immunomodulating therapy. Recently developed cellular tests are designed to analyze the phenotype and activity of living cells circulating in patient's bloodstream. Monocyte/macrophage activation test is a successful example of cellular test relevant for atherosclerosis and oncopathology. This test demonstrated changes in macrophage activation in subclinical atherosclerosis and breast cancer and could also be used for screening a panel of natural agents with immunomodulatory activity. Further development of cellular tests will allow broadening the scope of their clinical implication. Such tests may become useful tools for drug research and therapy optimization. PMID:26885534

  8. The relative merits of therapies being developed to tackle inappropriate ('self'-directed) complement activation.

    PubMed

    Antwi-Baffour, Samuel; Kyeremeh, Ransford; Adjei, Jonathan Kofi; Aryeh, Claudia; Kpentey, George

    2016-12-01

    The complement system is an enzyme cascade that helps defend against infection. Many complement proteins occur in serum as inactive enzyme precursors or reside on cell surfaces. Complement components have many biologic functions and their activation can eventually damage the plasma membranes of cells and some bacteria. Although a direct link between complement activation and autoimmune diseases has not been found, there is increasing evidence that complement activation significantly contributes to the pathogenesis of a large number of inflammatory diseases that may have autoimmune linkage. The inhibition of complement may therefore be very important in a variety of autoimmune diseases since their activation may be detrimental to the individual involved. However, a complete and long-term inhibition of complement may have some contra side effects such as increased susceptibility to infection. The site of complement activation will, however, determine the type of inhibitor to be used, its route of application and dosage level. Compared with conventional drugs, complement inhibitors may be the best option for treatment of autoimmune diseases. The review takes a critical look at the relative merits of therapies being developed to tackle inappropriate complement activation that are likely to result in sporadic autoimmune diseases or worsen already existing one. It covers the complement system, general aspects of complement inhibition therapy, therapeutic strategies and examples of complement inhibitors. It concludes by highlighting on the possibility that a better inhibitor of complement activation when found will help provide a formidable treatment for autoimmune diseases as well as preventing one.

  9. Photo-activated porphyrin in combination with antibiotics: therapies against Staphylococci.

    PubMed

    Dastgheyb, Sana S; Eckmann, David M; Composto, Russell J; Hickok, Noreen J

    2013-12-01

    Staphylococcal infections have become difficult to treat due to antibiotic insensitivity and resistance. Antimicrobial combination therapies may minimize acquisition of resistance and photodynamic therapy is an attractive candidate for these combinations. In this manuscript, we explore combined use of antibiotics and meso-tetra (4-aminophenyl) porphine (TAPP), a cationic porphyrin, for treatment of Staphylococcus aureus contamination. We characterize the antimicrobial activity of photoactivated TAPP and show that activity is largely lost in the presence of a radical scavenger. Importantly, TAPP can be reactivated with continued, albeit attenuated, antibacterial activity. We then show that the antimicrobial activity of illuminated TAPP is additive with chloramphenicol and tobramycin for S. aureus and Escherichia coli, and synergistic for MRSA and Staphylococcus epidermidis. Chloramphenicol+methylene blue, another photosensitizer, also show additivity against S. aureus. In contrast, ceftriaxone and vancomycin do not strongly augment the low level effects of TAPP against S. aureus. Eukaryotic cells exhibit a dose-dependent toxicity with illuminated TAPP. Our results suggest that even sub-minimum inhibitory concentrations of photo-activated TAPP could be used to boost the activity of waning antibiotics. This may play an important role in treatments reliant on antibiotic controlled release systems where augmentation with photo-active agents could extend their efficacy.

  10. The Killer Will Remain Free: On Pat Parker and the Poetics of Madness.

    PubMed

    Ali, Kazim

    2015-01-01

    Poet and scholar Kazim Ali reads Pat Parker's Movement in Black intimately, one poet to another, uncovering the shadow-fact of the lives of most people of color: not only the anger that is somehow sublimated into every part of our lives but also the issue that carrying this feeling around has on our mental health itself-that "anger" and "madness" might have sources in one another. Ali concludes that Parker offers a brutal and clear-eyed and ultimately hopeful assessment of the conditions that were faced at the time, and even now, by communities of color. PMID:26075690

  11. EARLY IMPACT MELTING AND SPACE EXPOSURE HISTORY OF THE PAT91501 LCHONDRITE

    NASA Technical Reports Server (NTRS)

    Bogard, Donald D.; Garrison, D. H.; Herzog, G. F.; Xue, S.; Klein, J.; Middleton, R.

    2004-01-01

    Collisions probably occurred frequently in the early history of the asteroid belt. Their effects, which should be recorded in meteorites, must have included heating and melting along with shock alteration of mineral textures. Some non-chondritic meteorite types e.g., eucrites and IIE and IAB irons - do indeed give evidence of extensive impact heating more than 3.4 Gyr ago. The ordinary chondrites, in contrast, show little evidence of early impact heating. The Ar-Ar and Rb-Sr ages of ordinary chondrites that experienced intense shock are for the most part relatively young, many less than 1.5 Gyr. The numerous L-chondrites with Ar- Ar ages clustering near 0.5 Gy are a well-known example. One of them, the 105-kg Chico Lchondrite, shows the effects of unusually intense heating. It is approximately 60% impact melt and likely formed as a dyke beneath a large crater when the L-chondrite parent body underwent a very large impact approximately 0.5 Gyr ago. In rare instances, older shock dates are indicated for ordinary chondrites. Dixon et al show early impact resetting of Ar-Ar ages of a few LL-chondrites including MIL 99301 at 4.23 0.03 Gyr, but in none of these stones did shock lead to extensive melting. As of 2003, searches for chondritic melts attributable to early shock had turned up only the Shaw L-chondrite, which has an Ar-Ar age of approximately 4.42 Gyr. PAT91501 is an 8.55-kg L-chondrite containing vesicles and metal-troilite nodules. It is a unique, near-total impact melt, unshocked, depleted in siderophile and chalcophile elements, and contains only approximately 10% relic chondritic material. The authors conclude that PAT91501 crystallized rapidly and from a much more homogeneous melt than did Shaw. They suggest that PAT resembles Chico and likely formed as an impact melt vein within an impact crater. To define the history of PAT, we have determined its Ar-39-Ar-40 age and measured several radioactive and stable nuclides produced during its space exposure to

  12. Petrology and Geochemistry of LEW 88663 and PAT 91501: High Petrologic L Chondrites

    NASA Astrophysics Data System (ADS)

    Mittlefehldt, D. W.; Lindstrom, M. M.; Field, S. W.

    1993-07-01

    Primitive achondrites (e.g., Acapulco, Lodran) are believed to be highly metamorphosed chondritic materials, perhaps up to the point of anatexis in some types. Low petrologic grade equivalents of these achondrites are unknown, so the petrologic transition from chondritic to achondritic material cannot be documented. However, there are rare L chondrites of petrologic grade 7 that may have experienced igneous processes, and study of these may yield information relevant to the formation of primitive achondrites, and perhaps basaltic achondrites, from chondritic precursors. We have begun the study of the L7 chondrites LEW 88663 and PAT 91501 as part of our broader study of primitive achondrites. Here, we present our preliminary petrologic and geochemical data on these meteorites. Petrology and Mineral Compositions: LEW 88663 is a granular achondrite composed of equant, subhedral to anhedral olivine grains poikilitically enclosed in networks of orthopyroxene and plagioclase. Small grains of clinopyroxene are spatially associated with orthopyroxene. Troilite occurs as large anhedral and small rounded grains. The smaller troilite grains are associated with the orthopyroxene-plagioclase networks. PAT 91501 is a vesicular stone containing centimeter-sized troilite +/- metal nodules. Its texture consists of anhedral to euhedral olivine grains, anhedral orthopyroxene grains (some with euhedral clinopyroxene overgrowths), anhedral to euhedral clinopyroxene, and interstitial plagioclase and SiO2-Al2O3-K2O- rich glass. In some areas, olivine is poikilitically enclosed in orthopyroxene. Fine-grained troilite, metal, and euhedral chromite occur interstitial to the silicates. Average mineral compositions for LEW 88663 are olivine Fo(sub)75.8, orthopyroxene Wo(sub)3.4En(sub)76.2Fs(sub)20.4, clinopyroxene Wo(sub)42.6En(sub)47.8Fs(sub)9.6, plagioclase Ab(sub)75.0An(sub)21.6Or(sub)3.4. Mineral compositions for PAT 91501 are olivine Fo(sub)73.8, orthopyroxene Wo(sub)4.5En(sub)74.8Fs

  13. [Immunosuppressive therapy in patients with HBeAg-positive chronic active hepatitis B?].

    PubMed

    Maier, K P; Lepiorz, H; Berthold, H; Gerok, W

    1982-08-01

    The course of HBsAg-positive chronic active hepatitis was followed in 36 patients who were treated by immunosuppression and in 45 controls by means of serial determinations of HBeAg titers and by repeated biopsies of the liver. In the treated group remission occurred in 52% (HBeAg negative) resp. 48% (HBeAg positive); in the control group these percentages were almost identical, that is to say 61% resp. 41%. During therapy 5 out of 9 HBeAg positive patients and 7 out of 12 HBeAg negative patients developed cirrhosis of the liver as compared to 5 resp. 10, and 2 resp. 12 patients in the control group. Judging from these results it seems unlikely, that the course of HBsAg positive, chronic-active hepatitis in patients, whose serum shows a positive HBeAg titer by immunodiffusion, might be influenced in a positive way by immunosuppressive therapy.

  14. Targeted Aucore-Agshell nanorods as a dual-functional contrast agent for photoacoustic imaging and photothermal therapy

    PubMed Central

    Shi, Yiwen; Peng, Dong; Wang, Kun; Chai, Xinyu; Ren, Qiushi; Tian, Jie; Zhou, Chuanqing

    2016-01-01

    Optimizing contrast enhancement is essential for producing specific signals in biomedical imaging and therapy. The potential of using Aucore-Agshell nanorods (Au@Ag NRs) as a dual-functional theranostic contrast agent is demonstrated for effective cancer imaging and treatments. Due to its strong NIR absorption and high efficiency of photothermal conversion, effects of both photoacoustic tomography (PAT) and photothermal therapy (PTT) are enhanced significantly. The PAT signal grows by 45.3% and 82% in the phantom and in vivo experiments, respectively, when compared to those using Au NRs. In PTT, The maximum increase of tissue temperature treated with Au@Ag NRs is 22.8 °C, twice that with Au NRs. Results of the current study show the feasibility of using Au@Ag NRs for synergetic PAT with PTT. And it will enhance the potential application on real-time PAT guided PTT, which will greatly benefit the customized PTT treatment of cancer. PMID:27231624

  15. Pharmacodynamic monitoring of immunosuppressive effects indicates reduced cyclosporine activity during telaprevir therapy.

    PubMed

    Roos, Katja; Gotthardt, Daniel; Giese, Thomas; Schnitzler, Paul; Stremmel, Wolfgang; Czock, David; Eisenbach, Christoph

    2014-09-01

    Drug interactions with immunosuppressive drugs are a major problem associated with protease inhibitor-based antiviral triple therapy for hepatitis C virus (HCV) reinfection after liver transplantation. In this retrospective cohort study, we analyzed biomarkers of the immunosuppressive effects of cyclosporine A (CSA) by quantifying nuclear factor of activated T cells (NFAT)-regulated gene expression during telaprevir (TVR) therapy in 5 liver transplant patients. Furthermore, dose adjustments and blood concentrations of CSA as well as the clinical course were analyzed. We observed a clear impact of TVR not only on doses and blood concentrations but also on the immunosuppressive effects of CSA. Despite apparently adequate CSA trough concentrations, the CSA peak concentration decreased to 68% (range = 44%-90%). This was associated with a 1.9-fold (1.6- to 4.1-fold) increase in the residual gene activity of NFAT-regulated genes, which indicated reduced immunosuppressive activity of CSA with TVR co-medication. The median dose of CSA was reduced to 25% (range = 16%-48%) and 31% (range = 22%-64%) after 1 and 2 weeks, respectively. The CSA drug clearance was reduced to 38.7% (range = 31.0%-49.4%). We report excellent antiviral efficacy. At the end of the observation period, all patients were HCV RNA-negative (1 patient at 18 weeks, 1 patient at 12 weeks, and 3 patients at 4 weeks after the end of therapy). Safety was acceptable, with mild acute rejection and reactivation of cytomegalovirus being the most serious adverse events. One patient with histologically proven recurrent cholestatic hepatitis before therapy underwent retransplantation during the course of antiviral therapy. In conclusion, the immunomonitoring of NFAT-regulated gene expression indicated reduced immunosuppressive activity of CSA during antiviral therapy with TVR in our cohort of liver transplant patients. Thus, the immunosuppressive effects of CSA may be overestimated if one is looking

  16. A PAT approach for the on-line monitoring of pharmaceutical co-crystals formation with near infrared spectroscopy.

    PubMed

    Sarraguça, Mafalda C; Ribeiro, Paulo R S; Santos, Adenilson O; Silva, Marta C D; Lopes, João A

    2014-08-25

    Cocrystals represent a class of crystalline solids consisting of two or more molecular species usually held together by non-covalent bonds. Pharmaceutical cocrystals can alter the physicochemical properties of the active pharmaceutical ingredient to improve solubility, dissolution rate, particle properties and stability. This work presents a process analytical technology (PAT) approach to monitor on-line the cocrystallization of furosemide and adenine by solvent evaporation using near infrared spectroscopy (NIRS). Furosemide and adenine were added to a small volume of methanol in a beaker and stirred on an orbital stirring table during 8h at room temperature. The on-line monitoring was performed with a FT-NIR spectrometer fitted with a reflectance fiber optic probe. Monitoring was performed with the probe tip placed 1cm above the cocrystallization medium to avoid interference with the cocrystallization process. Cocrystals were vacuum dried to remove residual solvent and characterized off-line by NIRS, MIRS, DSC and XRPD. Results demonstrate that it was possible to follow the main cocrystallization events on-line. PMID:24907598

  17. Stem cell-based gene therapy activated using magnetic hyperthermia to enhance the treatment of cancer.

    PubMed

    Yin, Perry T; Shah, Shreyas; Pasquale, Nicholas J; Garbuzenko, Olga B; Minko, Tamara; Lee, Ki-Bum

    2016-03-01

    Stem cell-based gene therapies, wherein stem cells are genetically engineered to express therapeutic molecules, have shown tremendous potential for cancer applications owing to their innate ability to home to tumors. However, traditional stem cell-based gene therapies are hampered by our current inability to control when the therapeutic genes are actually turned on, thereby resulting in detrimental side effects. Here, we report the novel application of magnetic core-shell nanoparticles for the dual purpose of delivering and activating a heat-inducible gene vector that encodes TNF-related apoptosis-inducing ligand (TRAIL) in adipose-derived mesenchymal stem cells (AD-MSCs). By combining the tumor tropism of the AD-MSCs with the spatiotemporal MCNP-based delivery and activation of TRAIL expression, this platform provides an attractive means with which to enhance our control over the activation of stem cell-based gene therapies. In particular, we found that these engineered AD-MSCs retained their innate ability to proliferate, differentiate, and, most importantly, home to tumors, making them ideal cellular carriers. Moreover, exposure of the engineered AD-MSCS to mild magnetic hyperthermia resulted in the selective expression of TRAIL from the engineered AD-MSCs and, as a result, induced significant ovarian cancer cell death in vitro and in vivo.

  18. Enhanced antitumoral efficacy by intratumoral perfusion of activated macrophages associated with photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Dima, Vasile F.; Vasiliu, Virgil V.; Laky, Dezideriu; Ionescu, Paul; Dima, Stefan V.

    1996-01-01

    Experiments were performed on five batches of Wistar inbred rats with Walker-256 carcinosarcoma receiving photodynamic therapy (PDT), rMuIFN-gamma activated macrophages (AM(Phi) ) or associated therapy (PDT-AM(Phi) -A; PDT-AM(Phi) -B); the control batch (HBSS) consisted of animals with untreated Walker-256 tumors. The results were as follows: the sole treatment (PDT, AM(Phi) ) gave survival rates between 57.2 and 57.7% and cure rates ranging from 23.1 to 34.3%. The 'combined' therapy in multiple doses increased significantly (87.9%) the survival rate of tumor bearing rats as well as the rate of complete tumor regression (72.7%). Cell-mediated immunity test values in batches III and IV exposed to multiple doses of PDT-AM(Phi) showed higher values as compared to the values noticed in batches I - II and the control batch V, performed at 12 and 21 days post-treatment. Summing up, these results demonstrate that 'combined' photodynamic treatment and biotherapy with interferon activated macrophages stimulate cell-mediated antitumoral activity, increase survival rates and reduce incidence of Walker-256 carcinosarcoma in rat model.

  19. The parthenocarpic fruit (pat) mutant of tomato (Lycopersicon esculentum Mill.) sets seedless fruits and has aberrant anther and ovule development.

    PubMed

    Mazzucato, A; Taddei, A R; Soressi, G P

    1998-01-01

    Among the different sources of genetic parthenocarpy described in tomato, the mutation referred to as parthenocarpic fruit (pat) is of particular interest because of its strong expressivity and because it confers earlier ripening, higher fruit set and enhanced fruit quality. As a pleiotropic effect, pat flowers have aberrantly developing androecia and reduced male and female fertility. In this work we extend the early description of the pat phenotype by investigating the expression of parthenocarpy in three different environments and by using light and scanning electron microscopy to analyse the development of male and female floral organs. The degree of parthenocarpy was high in the three experimental environments and was characterised by a precocious initiation of ovary growth to pre-anthesis floral stages. Aberrations in anther development were evident at flower bud stages and resulted in shorter, irregular and teratoid organs. Ectopic production of carpel-like structures bearing external ovules was evident in the most severely altered androecia. Analysis of ovule development revealed that a fraction of pat ovules becomes aberrant from very early stages, having defective integument growth. Meiosis was irregular in aberrant ovules and megaspore or gamete production was severely hampered. The described pat syndrome suggests that parthenocarpy in this mutant could be a secondary effect of a gene controlling, at early stages, organ identity and development. PMID:9389668

  20. Activity of matrix metalloproteinases during antimycobacterial therapy in mice with simulated tuberculous inflammation.

    PubMed

    Sumenkova, D V; Russkikh, G S; Poteryaeva, O N; Polyakov, L M; Panin, L E

    2013-05-01

    Matrix metalloproteinases are shown to be involved in the pathogenesis of tuberculosis inflammation. In the early stages of BCG-granuloma formation in mouse liver and lungs, the serum levels of matrix metalloproteinases 2 and 7 increased by 4.5 times and remained unchanged while the pathology developed. Antimycobacterial therapy with isoniazid reduced enzyme activity almost to the level of intact control. The decrease in activity of matrix metalloproteinases 2 and 7 that play the most prominent role in the development of destructive forms of tuberculosis is of great therapeutic importance.

  1. Active theater as a complementary therapy for Parkinson's disease rehabilitation: a pilot study.

    PubMed

    Modugno, Nicola; Iaconelli, Sara; Fiorlli, Mariagrazia; Lena, Francesco; Kusch, Imogen; Mirabella, Giovanni

    2010-01-01

    Most medical treatments of Parkinson's disease (PD) are aimed at the reduction of motor symptoms. However, even when motor improvements are evident, patients often report a deterioration of their daily lives. Thus, to achieve a global improvement in personal well-being, not only drugs, but also complementary therapies, such as physical exercise, occupational and speech therapy, and active music therapy, have been used. We hypothesized that theater could reduce clinical disability and improve the quality of life of PD patients (primary end points) more efficiently than other complementary therapies because (1) in order to impersonate a character, patients are forced to regain the control of their bodies; and (2) while being part of a group, patients have a high degree of social interaction. The need to regain the control of their bodies and their social functioning is very likely to deeply motivate patients. To assess this hypothesis, we ran a randomized, controlled, and single-blinded study that lasted 3 years, on 20 subjects affected by a moderate form of idiopathic PD, in stable treatment with L-dopa and L-dopa agonists, and without severe sensory deficits. Ten patients were randomly assigned to an active theater program (in which patients were required to participate), while the others underwent physiotherapy (control group), the most common nonpharmacological treatment for PD rehabilitation. Patients of both groups were evaluated at the beginning of each year, using five clinical rating scales (Unified Parkinson's Disease Rating Scale [UPDRS], Schwab and England Scale, Parkinson's Disease Quality of Life [PDQ39] Scale, Epworth Sleepiness Scale, and Hamilton Depression Rating Scale). The theater patients showed progressive improvements and, at the end of the third year, they showed significant improvements in all clinical scales. Conversely, the control patients did not exhibit significant ameliorations with time. Thus, the present study provides the first

  2. Transatlantic Consensus Group on active surveillance and focal therapy for prostate cancer

    PubMed Central

    Ahmed, Hashim U.; Akin, Oguz; Coleman, Jonathan A.; Crane, Sarah; Emberton, Mark; Goldenberg, Larry; Hricak, Hedvig; Kattan, Mike W.; Kurhanewicz, John; Moore, Caroline M.; Parker, Chris; Polascik, Thomas J.; Scardino, Peter; van As, Nicholas; Villers, Arnauld

    2013-01-01

    OBJECTIVE To reach consensus on key issues for clinical practice and future research in active surveillance and focal therapy in managing localized prostate cancer. PATIENTS AND METHODS A group of expert urologists, oncologists, radiologists, pathologists and computer scientists from North America and Europe met to discuss issues in patient population, interventions, comparators and outcome measures to use in both tissue-preserving strategies of active surveillance and focal therapy. Break-out sessions were formed to provide agreement or highlight areas of disagreement on individual topics which were then collated by a writing group into statements that formed the basis of this report and agreed upon by the whole Transatlantic Consensus Group. RESULTS The Transatlantic group propose that emerging diagnostic tools such as precision imaging and transperineal prostate mapping biopsy can improve prostate cancer care. These tools should be integrated into prostate cancer management and research so that better risk stratification and more effective treatment allocation can be applied. The group envisaged a process of care in which active surveillance, focal therapy, and radical treatments lie on a continuum of complementary therapies for men with a range of disease grades and burdens, rather than being applied in the mutually exclusive and competitive way they are now. CONCLUSION The changing landscape of prostate cancer epidemiology requires the medical community to re-evaluate the entire prostate cancer diagnostic and treatment pathway in order to minimize harms resulting from over-diagnosis and over-treatment. Precise risk stratification at every point in this pathway is required alongside paradigm shifts in our thinking about what constitutes cancer in the prostate. PMID:22077593

  3. [Morita Therapy to Treat Depression: When and How to Encourage Patients to Join Activities].

    PubMed

    Nakamura, Kei

    2015-01-01

    The author discusses how Morita therapy is used to treat depression, illustrated with a clinical case, and makes comparisons between Morita therapy and behavioral activation (BA). The author further examines the issue of when and how to encourage patients to join activities in clinical practice in Japan. Both Morita therapy and BA share at least a common view that it is effective to activate patients' constructive behavior at a certain point in depression treatment. However, BA therapists, compared to Morita therapists, seem to pay less attention to the necessity of resting and the appropriate timing for introducing behavioral activation. There may be some contextual differences between depressive patients in Japan and those in North America. In the case of Japanese patients, exhaustion from overwork is often considered a factor triggering the development of depression. At the same time, the Morita-based pathogenic model of depression seems different from BA's model of the same disorder. BA's approach to understanding depression may be considered a psychological (behavioristic) model. In this model, the cause of depression lies in: (a) a lack of positive reinforcement, and (b) negative reinforcement resulting from avoidance of the experience of discomfort. Therefore, the basic strategy of BA is to release depressive patients from an avoidant lifestyle, which serves as a basis for negative reinforcement, and to redirect the patients toward activities which offer the experience of positive reinforcement BA is primarily practiced by clinical psychologists in the U. S. while psychiatrists prescribe medication as a medical service. On the other hand, the clinical practice of treating depression in Japan is based primarily on medical models of depression. This is also true of Morita therapy, but in a broad sense. While those who follow medical models in a narrow sense try to identify the cause of illness and then remove it, Morita therapists pay more attention to the

  4. [Morita Therapy to Treat Depression: When and How to Encourage Patients to Join Activities].

    PubMed

    Nakamura, Kei

    2015-01-01

    The author discusses how Morita therapy is used to treat depression, illustrated with a clinical case, and makes comparisons between Morita therapy and behavioral activation (BA). The author further examines the issue of when and how to encourage patients to join activities in clinical practice in Japan. Both Morita therapy and BA share at least a common view that it is effective to activate patients' constructive behavior at a certain point in depression treatment. However, BA therapists, compared to Morita therapists, seem to pay less attention to the necessity of resting and the appropriate timing for introducing behavioral activation. There may be some contextual differences between depressive patients in Japan and those in North America. In the case of Japanese patients, exhaustion from overwork is often considered a factor triggering the development of depression. At the same time, the Morita-based pathogenic model of depression seems different from BA's model of the same disorder. BA's approach to understanding depression may be considered a psychological (behavioristic) model. In this model, the cause of depression lies in: (a) a lack of positive reinforcement, and (b) negative reinforcement resulting from avoidance of the experience of discomfort. Therefore, the basic strategy of BA is to release depressive patients from an avoidant lifestyle, which serves as a basis for negative reinforcement, and to redirect the patients toward activities which offer the experience of positive reinforcement BA is primarily practiced by clinical psychologists in the U. S. while psychiatrists prescribe medication as a medical service. On the other hand, the clinical practice of treating depression in Japan is based primarily on medical models of depression. This is also true of Morita therapy, but in a broad sense. While those who follow medical models in a narrow sense try to identify the cause of illness and then remove it, Morita therapists pay more attention to the

  5. Bridging the gap between PAT concepts and implementation: An integrated software platform for fermentation.

    PubMed

    Chopda, Viki R; Gomes, James; Rathore, Anurag S

    2016-01-01

    Bioreactor control significantly impacts both the amount and quality of the product being manufactured. The complexity of the control strategy that is implemented increases with reactor size, which may vary from thousands to tens of thousands of litres in commercial manufacturing. The Process Analytical Technology (PAT) initiative has highlighted the need for having robust monitoring tools and effective control schemes that are capable of taking real time information about the critical quality attributes (CQA) and the critical process parameters (CPP) and executing immediate response as soon as a deviation occurs. However, the limited flexibility that present commercial software packages offer creates a hurdle. Visual programming environments have gradually emerged as potential alternatives to the available text based languages. This paper showcases development of an integrated programme using a visual programming environment for a Sartorius BIOSTAT® B Plus 5L bioreactor through which various peripheral devices are interfaced. The proposed programme facilitates real-time access to data and allows for execution of control actions to follow the desired trajectory. Major benefits of such integrated software system include: (i) improved real time monitoring and control; (ii) reduced variability; (iii) improved performance; (iv) reduced operator-training time; (v) enhanced knowledge management; and (vi) easier PAT implementation. PMID:26647285

  6. Bridging the gap between PAT concepts and implementation: An integrated software platform for fermentation.

    PubMed

    Chopda, Viki R; Gomes, James; Rathore, Anurag S

    2016-01-01

    Bioreactor control significantly impacts both the amount and quality of the product being manufactured. The complexity of the control strategy that is implemented increases with reactor size, which may vary from thousands to tens of thousands of litres in commercial manufacturing. The Process Analytical Technology (PAT) initiative has highlighted the need for having robust monitoring tools and effective control schemes that are capable of taking real time information about the critical quality attributes (CQA) and the critical process parameters (CPP) and executing immediate response as soon as a deviation occurs. However, the limited flexibility that present commercial software packages offer creates a hurdle. Visual programming environments have gradually emerged as potential alternatives to the available text based languages. This paper showcases development of an integrated programme using a visual programming environment for a Sartorius BIOSTAT® B Plus 5L bioreactor through which various peripheral devices are interfaced. The proposed programme facilitates real-time access to data and allows for execution of control actions to follow the desired trajectory. Major benefits of such integrated software system include: (i) improved real time monitoring and control; (ii) reduced variability; (iii) improved performance; (iv) reduced operator-training time; (v) enhanced knowledge management; and (vi) easier PAT implementation.

  7. Disease-modifying therapeutic concepts for HIV in the era of highly active antiretroviral therapy.

    PubMed

    Butler, Scott L; Valdez, Hernan; Westby, Michael; Perros, Manos; June, Carl H; Jacobson, Jeffrey M; Levy, Yves; Cooper, David A; Douek, Daniel; Lederman, Michael M; Tebas, Pablo

    2011-11-01

    Chronic HIV infection is associated with persistent immune activation and inflammation even among patients virologically suppressed on antiretroviral therapy for years. Chronic immune activation has been associated with poor outcomes--both AIDS-defining and non-AIDS-defining clinical events--and persistent CD4 T-cell depletion. The cause of chronic immune activation in well-controlled HIV infection is unknown. Proposed drivers include residual viral replication, microbial translocation, and coinfecting pathogens. Therapeutic interventions targeting immune activation are emerging, from approaches that interfere directly with activation and inflammatory pathways to those that prevent microbial translocation or decrease the availability of host target cells for the virus. In the context of the disappointing results of the interleukin-2 trials, the main challenges to developing these disease-modifying therapies include identifying an adequate target population and choosing surrogate endpoints that will provide positive proof-of-concept that the interventions will translate into long-term clinical benefit before embarking on large clinical endpoint trials. PMID:21792065

  8. The effect of mirror therapy on upper-extremity function and activities of daily living in stroke patients

    PubMed Central

    Park, Jin-Young; Chang, Moonyoung; Kim, Kyeong-Mi; Kim, Hee-Jung

    2015-01-01

    The purpose of this study was to examine the effects of mirror therapy on upper-extremity function and activities of daily living in chronic stroke patients. [Subjects and Methods] Fifteen subjects were each assigned to a mirror therapy group and a sham therapy group. The Fugl-Meyer Motor Function Assessment and the Box and Block Test were performed to compare paretic upper-extremity function and hand coordination abilities. The functional independence measurement was conducted to compare abilities to perform activities of daily living. [Results] Paretic upper-extremity function and hand coordination abilities were significantly different between the mirror therapy and sham therapy groups. Intervention in the mirror therapy group was more effective than in the sham therapy group for improving the ability to perform activities of daily living. Self-care showed statistically significant differences between the two groups. [Conclusion] Mirror therapy is effective in improving paretic upper-extremity function and activities of daily living in chronic stroke patients. PMID:26180297

  9. Monitoring the autonomic nervous activity as the objective evaluation of music therapy for severely and multiply disabled children.

    PubMed

    Orita, Makiko; Hayashida, Naomi; Shinkawa, Tetsuko; Kudo, Takashi; Koga, Mikitoshi; Togo, Michita; Katayama, Sotetsu; Hiramatsu, Kozaburo; Mori, Shunsuke; Takamura, Noboru

    2012-01-01

    Severely and multiply disabled children (SMDC) are frequently affected in more than one area of development, resulting in multiple disabilities. The aim of the study was to evaluate the efficacy of music therapy in SMDC using monitoring changes in the autonomic nervous system, by the frequency domain analysis of heart rate variability. We studied six patients with SMDC (3 patients with cerebral palsy, 1 patient with posttraumatic syndrome after head injury, 1 patient with herpes encephalitis sequelae, and 1 patient with Lennox-Gastaut syndrome characterized by frequent seizures, developmental delay and psychological and behavioral problems), aged 18-26 (mean 22.5 ± 3.5). By frequency domain method using electrocardiography, we measured the high frequency (HF; with a frequency ranging from 0.15 to 0.4 Hz), which represents parasympathetic activity, the low frequency/high frequency ratio, which represents sympathetic activity between the sympathetic and parasympathetic activities, and heart rate. A music therapist performed therapy to all patients through the piano playing for 50 min. We monitored each study participant for 150 min before therapy, 50 min during therapy, and 10 min after therapy. Interestingly, four of 6 patients showed significantly lower HF components during music therapy than before therapy, suggesting that these four patients might react to music therapy through the suppression of parasympathetic nervous activities. Thus, music therapy can suppress parasympathetic nervous activities in some patients with SMDC. The monitoring changes in the autonomic nervous activities could be a powerful tool for the objective evaluation of music therapy in patients with SMDC.

  10. Combination therapy for KIT-mutant mast cells: targeting constitutive NFAT and KIT activity.

    PubMed

    Macleod, Alison C; Klug, Lillian R; Patterson, Janice; Griffith, Diana J; Beadling, Carol; Town, Ajia; Heinrich, Michael C

    2014-12-01

    Resistant KIT mutations have hindered the development of KIT kinase inhibitors for treatment of patients with systemic mastocytosis. The goal of this research was to characterize the synergistic effects of a novel combination therapy involving inhibition of KIT and calcineurin phosphatase, a nuclear factor of activated T cells (NFAT) regulator, using a panel of KIT-mutant mast cell lines. The effects of monotherapy or combination therapy on the cellular viability/survival of KIT-mutant mast cells were evaluated. In addition, NFAT-dependent transcriptional activity was monitored in a representative cell line to evaluate the mechanisms responsible for the efficacy of combination therapy. Finally, shRNA was used to stably knockdown calcineurin expression to confirm the role of calcineurin in the observed synergy. The combination of a KIT inhibitor and a calcineurin phosphatase inhibitor (CNPI) synergized to reduce cell viability and induce apoptosis in six distinct KIT-mutant mast cell lines. Both KIT inhibitors and CNPIs were found to decrease NFAT-dependent transcriptional activity. NFAT-specific inhibitors induced similar synergistic apoptosis induction as CNPIs when combined with a KIT inhibitor. Notably, NFAT was constitutively active in each KIT-mutant cell line tested. Knockdown of calcineurin subunit PPP3R1 sensitized cells to KIT inhibition and increased NFAT phosphorylation and cytoplasmic localization. Constitutive activation of NFAT appears to represent a novel and targetable characteristic of KIT-mutant mast cell disease. Our studies suggest that combining KIT inhibition with NFAT inhibition might represent a new treatment strategy for mast cell disease.

  11. Plasminogen Activator System and Breast Cancer: Potential Role in Therapy Decision Making and Precision Medicine

    PubMed Central

    Gouri, Adel; Dekaken, Aoulia; El Bairi, Khalid; Aissaoui, Arifa; Laabed, Nihad; Chefrour, Mohamed; Ciccolini, Joseph; Milano, Gérard; Benharkat, Sadek

    2016-01-01

    Shifting from the historical TNM paradigm to the determination of molecular and genetic subtypes of tumors has been a major improvement to better picture cancerous diseases. The sharper the picture is, the better will be the possibility to develop subsequent strategies, thus achieving higher efficacy and prolonged survival eventually. Recent studies suggest that urokinase-type plasminogen activator (uPA), uPA Receptor (uPAR), and plasmino-gen activator inhibitor-1 (PAI-1) may play a critical role in cancer invasion and metastasis. Consistent with their role in cancer dissemination, high levels of uPA, PAI-1, and uPAR in multiple cancer types correlate with dismal prognosis. In this respect, upfront determination of uPA and PAI-1 as invasion markers has further opened up the possibilities for individualized therapy of breast cancer. Indeed, uPA and PAI-1 could help to classify patients on their risk for metastatic spreading and subsequent relapse, thus helping clinicians in their decision-making process to propose, or not propose, adjuvant therapy. This review covers the implications for cancer diagnosis, prognosis, and therapy of uPA and PAI-1, and therefore how they could be major actors in the development of a precision medicine in breast cancer. PMID:27578963

  12. Plasminogen Activator System and Breast Cancer: Potential Role in Therapy Decision Making and Precision Medicine.

    PubMed

    Gouri, Adel; Dekaken, Aoulia; El Bairi, Khalid; Aissaoui, Arifa; Laabed, Nihad; Chefrour, Mohamed; Ciccolini, Joseph; Milano, Gérard; Benharkat, Sadek

    2016-01-01

    Shifting from the historical TNM paradigm to the determination of molecular and genetic subtypes of tumors has been a major improvement to better picture cancerous diseases. The sharper the picture is, the better will be the possibility to develop subsequent strategies, thus achieving higher efficacy and prolonged survival eventually. Recent studies suggest that urokinase-type plasminogen activator (uPA), uPA Receptor (uPAR), and plasmino-gen activator inhibitor-1 (PAI-1) may play a critical role in cancer invasion and metastasis. Consistent with their role in cancer dissemination, high levels of uPA, PAI-1, and uPAR in multiple cancer types correlate with dismal prognosis. In this respect, upfront determination of uPA and PAI-1 as invasion markers has further opened up the possibilities for individualized therapy of breast cancer. Indeed, uPA and PAI-1 could help to classify patients on their risk for metastatic spreading and subsequent relapse, thus helping clinicians in their decision-making process to propose, or not propose, adjuvant therapy. This review covers the implications for cancer diagnosis, prognosis, and therapy of uPA and PAI-1, and therefore how they could be major actors in the development of a precision medicine in breast cancer. PMID:27578963

  13. Acceptance and Commitment Therapy and Behavioral Activation for the Treatment of Depression: Description and Comparison

    PubMed Central

    Kanter, Jonathan W; Baruch, David E; Gaynor, Scott T

    2006-01-01

    The field of clinical behavior analysis is growing rapidly and has the potential to affect and transform mainstream cognitive behavior therapy. To have such an impact, the field must provide a formulation of and intervention strategies for clinical depression, the “common cold” of outpatient populations. Two treatments for depression have emerged: acceptance and commitment therapy (ACT) and behavioral activation (BA). At times ACT and BA may suggest largely redundant intervention strategies. However, at other times the two treatments differ dramatically and may present opposing conceptualizations. This paper will compare and contrast these two important treatment approaches. Then, the relevant data will be presented and discussed. We will end with some thoughts on how and when ACT or BA should be employed clinically in the treatment of depression. PMID:22478462

  14. Glucocorticoid Receptor Activity Contributes to Resistance to Androgen-Targeted Therapy in Prostate Cancer

    PubMed Central

    Isikbay, Masis; Otto, Kristen; Kregel, Steven; Kach, Jacob; Cai, Yi; Vander Griend, Donald J.; Conzen, Suzanne D.

    2015-01-01

    Despite new treatments for castrate-resistant prostate cancer (CRPC), the prognosis of patients with CRPC remains bleak due to acquired resistance to androgen receptor (AR)-directed therapy. The glucocorticoid receptor (GR) and AR share several transcriptional targets, including the anti-apoptotic genes serum and glucocorticoid-regulated kinase 1 (SGK1) and Map kinase phosphatase 1 (MKP1)/dual specificity phosphatase 1 (DUSP1). Because GR expression increases in a subset of primary prostate cancer (PC) following androgen deprivation therapy, we sought to determine whether GR activation can contribute to resistance to AR-directed therapy. We studied CWR-22Rv1 and LAPC4 AR/GR-expressing PC cell lines following treatment with combinations of the androgen R1881, AR antagonist MDV3100, GR agonist dexamethasone, GR antagonists mifepristone and CORT 122928, or the SGK1 inhibitor GSK650394. Cell lines stably expressing GR (NR3C1)-targeted shRNA or ectopic SGK1-Flag were also studied in vivo. GR activation diminished the effects of the AR antagonist MDV3100 on tumor cell viability. In addition, GR activation increased prostate-specific antigen (PSA) secretion and induced SGKI and MKP1/DUSP gene expression. Glucocorticoid-mediated cell viability was diminished by a GR antagonist or by co-treatment with the SGK1 inhibitor GSK650394. In vivo, GR depletion delayed castrate-resistant tumor formation, while SGK1-Flag-overexpressing PC xenografts displayed accelerated castrate-resistant tumor initiation, supporting a role for SGK1 in GR-mediated CRPC progression. We studied several PC models before and following treatment with androgen blockade and found that increased GR expression and activity contributed to tumor-promoting PC cell viability. Increased GR-regulated SGK1 expression appears, at least in part, to mediate enhanced PC cell survival. Therefore, GR and/or SGK1 inhibition may be useful adjuncts to AR blockade for treating CRPC. PMID:24615402

  15. Effect of low-level laser therapy on the modulation of the mitochondrial activity of macrophages

    PubMed Central

    Souza, Nadhia H. C.; Ferrari, Raquel A. M.; Silva, Daniela F. T.; Nunes, Fabio D.; Bussadori, Sandra K.; Fernandes, Kristianne P. S.

    2014-01-01

    BACKGROUND: Macrophages play a major role among the inflammatory cells that invade muscle tissue following an injury. Low-level laser therapy (LLLT) has long been used in clinical practice to accelerate the muscle repair process. However, little is known regarding its effect on macrophages. OBJECTIVE: This study evaluated the effect of LLLT on the mitochondrial activity (MA) of macrophages. METHOD: J774 macrophages were treated with lipopolysaccharide (LPS) and interferon - gamma (IFN-γ) (activation) for 24 h to simulate an inflammatory process, then irradiated with LLLT using two sets of parameters (780 nm; 70 mW; 3 J/cm2 and 660 nm; 15 mW; 7.5 J/cm2). Non-activated/non-irradiated cells composed the control group. MA was evaluated by the cell mitochondrial activity (MTT) assay (after 1, 3 and 5 days) in three independent experiments. The data were analyzed statistically. RESULTS: After 1 day of culture, activated and 780 nm irradiated macrophages showed lower MA than activated macrophages, but activated and 660 nm irradiated macrophages showed MA similar to activated cells. After 3 days, activated and irradiated (660 nm and 780 nm) macrophages showed greater MA than activated macrophages, and after 5 days, the activated and irradiated (660 nm and 780 nm) macrophages showed similar MA to the activated macrophages. CONCLUSIONS: These results show that 660 nm and 780 nm LLLT can modulate the cellular activation status of macrophages in inflammation, highlighting the importance of this resource and of the correct determination of its parameters in the repair process of skeletal muscle. PMID:25076002

  16. Constitutive STAT5 Activation Correlates With Better Survival in Cervical Cancer Patients Treated With Radiation Therapy

    SciTech Connect

    Chen, Helen H.W.; Chou, Cheng-Yang; Wu, Yuan-Hua; Hsueh, Wei-Ting; Hsu, Chiung-Hui; Guo, How-Ran; Lee, Wen-Ying; Su, Wu-Chou

    2012-02-01

    Purpose: Constitutively activated signal transducers and activators of transcription (STAT) factors, in particular STAT1, STAT3, and STAT5, have been detected in a wide variety of human primary tumors and have been demonstrated to directly contribute to oncogenesis. However, the expression pattern of these STATs in cervical carcinoma is still unknown, as is whether or not they have prognostic significance. This study investigated the expression patterns of STAT1, STAT3, and STAT5 in cervical cancer and their associations with clinical outcomes in patients treated with radical radiation therapy. Methods and Materials: A total of 165 consecutive patients with International Federation of Gynecology and Obstetrics (FIGO) Stages IB to IVA cervical cancer underwent radical radiation therapy, including external beam and/or high-dose-rate brachytherapy between 1989 and 2002. Immunohistochemical studies of their formalin-fixed, paraffin-embedded tissues were performed. Univariate and multivariate analyses were performed to identify and to evaluate the effects of these factors affecting patient survival. Results: Constitutive activations of STAT1, STAT3, and STAT5 were observed in 11%, 22%, and 61% of the participants, respectively. While STAT5 activation was associated with significantly better metastasis-free survival (p < 0.01) and overall survival (p = 0.04), STAT1 and STAT3 activation were not. Multivariate analyses showed that STAT5 activation, bulky tumor ({>=}4 cm), advanced stage (FIGO Stages III and IV), and brachytherapy (yes vs. no) were independent prognostic factors for cause-specific overall survival. None of the STATs was associated with local relapse. STAT5 activation (odds ratio = 0.29, 95% confidence interval = 0.13-0.63) and advanced stage (odds ratio = 2.54; 95% confidence interval = 1.03-6.26) were independent predictors of distant metastasis. Conclusions: This is the first report to provide the overall expression patterns and prognostic significance of

  17. Highly active antiretroviral therapy and tuberculosis control in Africa: synergies and potential.

    PubMed Central

    Harries, Anthony D.; Hargreaves, Nicola J.; Chimzizi, Rehab; Salaniponi, Felix M.

    2002-01-01

    HIV/AIDS (human immunodeficiency virus/acquired immunodeficiency syndrome) and TB (tuberculosis) are two of the world's major pandemics, the brunt of which falls on sub-Saharan Africa. Efforts aimed at controlling HIV/AIDS have largely focused on prevention, little attention having been paid to care. Work on TB control has concentrated on case detection and treatment. HIV infection has complicated the control of tuberculosis. There is unlikely to be a decline in the number of cases of TB unless additional strategies are developed to control both this disease and HIV simultaneously. Such strategies would include active case-finding in situations where TB transmission is high, the provision of a package of care for HIV-related illness, and the application of highly active antiretroviral therapy. The latter is likely to have the greatest impact, but for this therapy to become more accessible in Africa the drugs would have to be made available through international support and a programme structure would have to be developed for its administration. It could be delivered by means of a structure based on the five-point strategy called DOTS, which has been adopted for TB control. However, it may be unrealistic to give TB control programmes the responsibility for running such a programme. A better approach might be to deliver highly active antiretroviral therapy within a comprehensive HIV/AIDS management strategy complementing the preventive work already being undertaken by AIDS control programmes. TB programmes could contribute towards the development and implementation of this strategy. PMID:12132003

  18. TLR3 agonist and Sorafenib combinatorial therapy promotes immune activation and controls hepatocellular carcinoma progression.

    PubMed

    Ho, Victor; Lim, Tong Seng; Lee, Justin; Steinberg, Jeffrey; Szmyd, Radoslaw; Tham, Muly; Yaligar, Jadegoud; Kaldis, Philipp; Abastado, Jean-Pierre; Chew, Valerie

    2015-09-29

    Hepatocellular carcinoma (HCC) is associated with high mortality and the current therapy for advanced HCC, Sorafenib, offers limited survival benefits. Here we assessed whether combining the TLR3 agonist: lysine-stabilized polyinosinic-polycytidylic-acid (poly-ICLC) with Sorafenib could enhance tumor control in HCC. Combinatorial therapy with poly-ICLC and Sorafenib increased apoptosis and reduced proliferation of HCC cell lines in vitro, in association with impaired phosphorylation of AKT, MEK and ERK. In vivo, the combinatorial treatment enhanced control of tumor growth in two mouse models: one transplanted with Hepa 1-6 cells, and the other with liver tumors induced using the Sleeping beauty transposon. Tumor cell apoptosis and host immune responses in the tumor microenvironment were enhanced. Particularly, the activation of local NK cells, T cells, macrophages and dendritic cells was enhanced. Decreased expression of the inhibitory signaling molecules PD-1 and PD-L1 was observed in tumor-infiltrating CD8+ T cells and tumor cells, respectively. Tumor infiltration by monocytic-myeloid derived suppressor cells (Mo-MDSC) was also reduced indicating the reversion of the immunosuppressive tumor microenvironment. Our data demonstrated that the combinatorial therapy with poly-ICLC and Sorafenib enhances tumor control and local immune response hence providing a rationale for future clinical studies.

  19. TLR3 agonist and Sorafenib combinatorial therapy promotes immune activation and controls hepatocellular carcinoma progression.

    PubMed

    Ho, Victor; Lim, Tong Seng; Lee, Justin; Steinberg, Jeffrey; Szmyd, Radoslaw; Tham, Muly; Yaligar, Jadegoud; Kaldis, Philipp; Abastado, Jean-Pierre; Chew, Valerie

    2015-09-29

    Hepatocellular carcinoma (HCC) is associated with high mortality and the current therapy for advanced HCC, Sorafenib, offers limited survival benefits. Here we assessed whether combining the TLR3 agonist: lysine-stabilized polyinosinic-polycytidylic-acid (poly-ICLC) with Sorafenib could enhance tumor control in HCC. Combinatorial therapy with poly-ICLC and Sorafenib increased apoptosis and reduced proliferation of HCC cell lines in vitro, in association with impaired phosphorylation of AKT, MEK and ERK. In vivo, the combinatorial treatment enhanced control of tumor growth in two mouse models: one transplanted with Hepa 1-6 cells, and the other with liver tumors induced using the Sleeping beauty transposon. Tumor cell apoptosis and host immune responses in the tumor microenvironment were enhanced. Particularly, the activation of local NK cells, T cells, macrophages and dendritic cells was enhanced. Decreased expression of the inhibitory signaling molecules PD-1 and PD-L1 was observed in tumor-infiltrating CD8+ T cells and tumor cells, respectively. Tumor infiltration by monocytic-myeloid derived suppressor cells (Mo-MDSC) was also reduced indicating the reversion of the immunosuppressive tumor microenvironment. Our data demonstrated that the combinatorial therapy with poly-ICLC and Sorafenib enhances tumor control and local immune response hence providing a rationale for future clinical studies. PMID:26287667

  20. Combination therapy of orally administered glycyrrhizin and UVB improved active-stage generalized vitiligo.

    PubMed

    Mou, K H; Han, D; Liu, W L; Li, P

    2016-07-25

    Glycyrrhizin has been used clinically for several years due to its beneficial effect on immunoglobulin E (IgE)-induced allergic diseases, alopecia areata and psoriasis. In this study, glycyrrhizin, ultraviolet B light (UVB) or a combination of both were used to treat active-stage generalized vitiligo. One hundred and forty-four patients between the ages of 3 and 48 years were divided into three groups: group A received oral compound glycyrrhizin (OCG); group B received UVB applications twice weekly, and group C received OCG+UVB. Follow-ups were performed at 2, 4, and 6 months after the treatment was initiated. The Vitiligo Area Scoring Index (VASI) and the Vitiligo Disease Activity (VIDA) instrument were used to assess the affected body surface, at each follow-up. Results showed that 77.1, 75.0 and 87.5% in groups A, B and C, respectively, presented repigmentation of lesions. Responsiveness to therapy seemed to be associated with lesion location and patient compliance. Adverse events were limited and transient. This study showed that, although the three treatment protocols had positive results, OCG and UVB combination therapy was the most effective and led to improvement in disease stage from active to stable. PMID:27464024

  1. Baroreflex Activation Therapy in Congestive Heart Failure: Novel Findings and Future Insights.

    PubMed

    Grassi, Guido; Brambilla, GianMaria; Pizzalla, Daniela Prata; Seravalle, Gino

    2016-08-01

    Congestive heart failure is characterized by hemodynamic and non-hemodynamic abnormalities, the latter including an activation of the sympathetic influences to the heart and peripheral circulation coupled with an impairment of baroreceptor control of autonomic function. Evidence has been provided that both these alterations are hallmark features of the disease with a specific relevance for the disease progression as well as for the development of life-threatening cardiac arrhythmias. In addition, a number of studies have documented in heart failure the adverse prognostic role of the sympathetic and baroreflex alterations, which both are regarded as major independent determinants of cardiovascular morbidity and mortality. This represents the pathophysiological and clinical background for the use of carotid baroreceptor activation therapy in the treatment of congestive heart failure. Promising data collected in experimental animal models of heart failure have supported the recent performance of pilot small-scale clinical studies, aimed at providing initial information in this area. The results of these studies demonstrated the clinical safety and efficacy of the intervention which has been tested in large-scale clinical studies. The present paper will critically review the background and main results of the published studies designed at defining the clinical impact of baroreflex activation therapy in congestive heart failure patients. Emphasis will be given to the strengths and limitations of such studies, which represent the background for the ongoing clinical trials testing the long-term effects of the device in heart failure patients. PMID:27334011

  2. Successful Interferon Therapy Reverses Enhanced Hepatic Progenitor Cell Activation in Patients with Chronic Hepatitis C.

    PubMed

    Noritake, Hidenao; Kobayashi, Yoshimasa; Ooba, Yukimasa; Matsunaga, Erika; Ohta, Kazuyoshi; Shimoyama, Shin; Yamazaki, Satoru; Chida, Takeshi; Kawata, Kazuhito; Sakaguchi, Takanori; Suda, Takafumi

    2015-12-01

    The enhanced accumulation of hepatic progenitor cells (HPCs) is related to the risk of progression to hepatocellular carcinoma (HCC). Interferon (IFN) treatment reduces HCC risk in patients with chronic hepatitis C virus (HCV) infection. However, the underlying mechanisms remain unclear. The aim of this study was to examine the effects of IFN treatment on HPC activation in HCV patients. Immunohistochemical detection and computer-assisted quantitative image analyses of cytokeratin 7 (CK7) were performed to evaluate HPC activation in paired pre- and post-treatment liver biopsies from 18 HCV patients with sustained virological response (SVR) to IFN-based therapy and from 23 patients without SVR, as well as normal liver tissues obtained from surgical resection specimens of 10 patients. Pretreatment HCV livers showed increased CK7 immunoreactivity, compared with normal livers (HCV: median, 1.38%; normal: median, 0.69%, P=0.006). IFN treatment reduced hepatic CK7 immunoreactivity (median, 1.57% pre-IFN vs. 0.69% post-IFN, P=0.006) in SVR patients, but not in non-SVR patients. The development of HCC following IFN treatment was encountered in 3 non-SVR patients who showed high post-IFN treatment CK7 immunoreactivity (>4%). Successful IFN therapy can reverse enhanced HPC activation in HCV patients, which may contribute to the reduced risk of HCC development in these patients.

  3. Baroreflex Activation Therapy in Congestive Heart Failure: Novel Findings and Future Insights.

    PubMed

    Grassi, Guido; Brambilla, GianMaria; Pizzalla, Daniela Prata; Seravalle, Gino

    2016-08-01

    Congestive heart failure is characterized by hemodynamic and non-hemodynamic abnormalities, the latter including an activation of the sympathetic influences to the heart and peripheral circulation coupled with an impairment of baroreceptor control of autonomic function. Evidence has been provided that both these alterations are hallmark features of the disease with a specific relevance for the disease progression as well as for the development of life-threatening cardiac arrhythmias. In addition, a number of studies have documented in heart failure the adverse prognostic role of the sympathetic and baroreflex alterations, which both are regarded as major independent determinants of cardiovascular morbidity and mortality. This represents the pathophysiological and clinical background for the use of carotid baroreceptor activation therapy in the treatment of congestive heart failure. Promising data collected in experimental animal models of heart failure have supported the recent performance of pilot small-scale clinical studies, aimed at providing initial information in this area. The results of these studies demonstrated the clinical safety and efficacy of the intervention which has been tested in large-scale clinical studies. The present paper will critically review the background and main results of the published studies designed at defining the clinical impact of baroreflex activation therapy in congestive heart failure patients. Emphasis will be given to the strengths and limitations of such studies, which represent the background for the ongoing clinical trials testing the long-term effects of the device in heart failure patients.

  4. Combination therapy of orally administered glycyrrhizin and UVB improved active-stage generalized vitiligo

    PubMed Central

    Mou, K.H.; Han, D.; Liu, W.L.; Li, P.

    2016-01-01

    Glycyrrhizin has been used clinically for several years due to its beneficial effect on immunoglobulin E (IgE)-induced allergic diseases, alopecia areata and psoriasis. In this study, glycyrrhizin, ultraviolet B light (UVB) or a combination of both were used to treat active-stage generalized vitiligo. One hundred and forty-four patients between the ages of 3 and 48 years were divided into three groups: group A received oral compound glycyrrhizin (OCG); group B received UVB applications twice weekly, and group C received OCG+UVB. Follow-ups were performed at 2, 4, and 6 months after the treatment was initiated. The Vitiligo Area Scoring Index (VASI) and the Vitiligo Disease Activity (VIDA) instrument were used to assess the affected body surface, at each follow-up. Results showed that 77.1, 75.0 and 87.5% in groups A, B and C, respectively, presented repigmentation of lesions. Responsiveness to therapy seemed to be associated with lesion location and patient compliance. Adverse events were limited and transient. This study showed that, although the three treatment protocols had positive results, OCG and UVB combination therapy was the most effective and led to improvement in disease stage from active to stable. PMID:27464024

  5. Acidity-Activated Shielding Strategies of Cationic Gene Delivery for Cancer Therapy.

    PubMed

    Xia, Jialiang; Feng, Zongcai; Yang, Hongyan; Lin, Sanqing; Han, Bing

    2016-01-01

    Cationic gene vectors increased attractive for gene therapy. However, unstable systemic circulation due to the interaction of gene delivery system with blood cells limited the further application. Therefore, pH sensitive shielding systems were exploited, by which, the positive surface charge density of polyplexes was reduced, circulation time was improved and pH-triggered targeting delivery was promised. This mini review mainly focuses on the development of solid tumors pH environment activated shielding systems for cationic gene vectors. This shielding strategy shows great potential for enhancing efficient gene transporting and achieving better therapeutic effects in acidic tumor treatment.

  6. PAT: From Western solid dosage forms to Chinese materia medica preparations using NIR-CI.

    PubMed

    Zhou, Luwei; Xu, Manfei; Wu, Zhisheng; Shi, Xinyuan; Qiao, Yanjiang

    2016-01-01

    Near-infrared chemical imaging (NIR-CI) is an emerging technology that combines traditional near-infrared spectroscopy with chemical imaging. Therefore, NIR-CI can extract spectral information from pharmaceutical products and simultaneously visualize the spatial distribution of chemical components. The rapid and non-destructive features of NIR-CI make it an attractive process analytical technology (PAT) for identifying and monitoring critical control parameters during the pharmaceutical manufacturing process. This review mainly focuses on the pharmaceutical applications of NIR-CI in each unit operation during the manufacturing processes, from the Western solid dosage forms to the Chinese materia medica preparations. Finally, future applications of chemical imaging in the pharmaceutical industry are discussed.

  7. PAT1.1; Pinellas Action Tracking System; Tracks Audit Findings and Corrective Actions

    SciTech Connect

    Mellican, P.L.

    1993-04-09

    PAT was derived from a system that began at the Rocky Flats Plant and was further enhanced at the Mound Plant. Pinellas Plant obtained this system in 1990 to track Tiger Team Findings; it has been expanded to include new modules which encompass a wide range of related functions. Functionality includes tracking of findings and associated corrective actions from various sources such as line operations, self-assessments, oversight assessments, and external organizations. Other functionality includes Management Walk-About tracking, NEPA prioritization, Occurrence/incident Report corrective action tracking, and Management Action Item Tracking. The system utilizes state of the art relational database technology with pop-up windows for table lookups and entry of descriptive text. Standards such as assessment identification numbers, area designations, and finding category codes have been developed to provide enhanced query capabilities and the ability to group findings for trending purposes on a plant-wide basis.

  8. RF Manipulation of Ions in the High Performance Antiproton Trap (HiPAT)

    NASA Technical Reports Server (NTRS)

    Pearson, J. Boise; Martin, James J.; Sims, William H.; Chakrabarti, Suman; Lewis, Raymond A.; Rodgers, Stephen L. (Technical Monitor)

    2002-01-01

    The annihilation of antimatter provides the highest mass specific energy of any other known reaction. Proper harnessing of this energy holds great promise for future space propulsion systems. Many different propulsion concepts have been proposed that take advantage of antimatter, either using matter-antimatter as the primary fuel, or as a 'spark plug' for fusion and fission systems. In order to begin to address these concepts experimentally, a method of storing and transporting antimatter must be developed. The High Performance Antiproton Trap (HiPAT) is a first-generation storage and transportation device designed to store and transport 10(exp 12) antiprotons with a storage half-life of 18 days. It uses a Penning-Malmberg ion trap with a 4T magnetic field and 20 kV potential. This will enable researchers much more flexibility in the design of antimatter experiments related to propulsion. Ions cannot be stored indefinitely in a real trap, as ion cloud instabilities develop from imperfections in manufacturing and misalignments in assembly. Previous work has been done at both the National Institute of Standards and University of California in San Diego in using RF (radio frequency) signals to both diagnose and confine the ion cloud. Two electrodes in the trap have been segmented to allow both reception and transmission of RF waves in the ion cloud. Experiments are underway to determine the number of ions and density in the cloud by "listening" to protons contained in the HiPAT. Currently we believe the density of ions stored in the trap is roughly 10(exp 15) m(exp -3). Development of non-destructive techniques is vital to the project goals, enabling continuous monitoring of the quantities stored in the system. Experimental work is also being done in identifying RF transmission frequencies that can manipulate the density of the cloud, by exchanging energy and momentum between the RF wave and the ions. Preliminary experiments have demonstrated this interaction.

  9. A Chaperone Enhances Blood α-Glucosidase Activity in Pompe Disease Patients Treated With Enzyme Replacement Therapy

    PubMed Central

    Parenti, Giancarlo; Fecarotta, Simona; la Marca, Giancarlo; Rossi, Barbara; Ascione, Serena; Donati, Maria Alice; Morandi, Lucia Ovidia; Ravaglia, Sabrina; Pichiecchio, Anna; Ombrone, Daniela; Sacchini, Michele; Pasanisi, Maria Barbara; De Filippi, Paola; Danesino, Cesare; Della Casa, Roberto; Romano, Alfonso; Mollica, Carmine; Rosa, Margherita; Agovino, Teresa; Nusco, Edoardo; Porto, Caterina; Andria, Generoso

    2014-01-01

    Enzyme replacement therapy is currently the only approved treatment for Pompe disease, due to acid α-glucosidase deficiency. Clinical efficacy of this approach is variable, and more effective therapies are needed. We showed in preclinical studies that chaperones stabilize the recombinant enzyme used for enzyme replacement therapy. Here, we evaluated the effects of a combination of enzyme therapy and a chaperone on α-glucosidase activity in Pompe disease patients. α-Glucosidase activity was analyzed by tandem-mass spectrometry in dried blood spots from patients treated with enzyme replacement therapy, either alone or in combination with the chaperone N-butyldeoxynojirimycin given at the time of the enzyme infusion. Thirteen patients with different presentations (3 infantile-onset, 10 late-onset) were enrolled. In 11 patients, the combination treatment resulted in α-glucosidase activities greater than 1.85-fold the activities with enzyme replacement therapy alone. In the whole patient population, α-glucosidase activity was significantly increased at 12 hours (2.19-fold, P = 0.002), 24 hours (6.07-fold, P = 0.001), and 36 hours (3.95-fold, P = 0.003). The areas under the curve were also significantly increased (6.78-fold, P = 0.002). These results suggest improved stability of recombinant α-glucosidase in blood in the presence of the chaperone. PMID:25052852

  10. mini-PAT (Peer Assessment Tool): A Valid Component of a National Assessment Programme in the UK?

    ERIC Educational Resources Information Center

    Archer, Julian; Norcini, John; Southgate, Lesley; Heard, Shelley; Davies, Helena

    2008-01-01

    Purpose: To design, implement and evaluate a multisource feedback instrument to assess Foundation trainees across the UK. Methods: mini-PAT (Peer Assessment Tool) was modified from SPRAT (Sheffield Peer Review Assessment Tool), an established multisource feedback (360 [degree]) instrument to assess more senior doctors, as part of a blueprinting…

  11. Use of a highly sensitive immunomarking system to characterize face fly (Diptera: Muscidae) dispersal from cow pats.

    PubMed

    Peck, George W; Ferguson, Holly J; Jones, Vincent P; O'Neal, Sally D; Walsh, Douglas B

    2014-02-01

    We tested an immunomarking system that used egg white as marker and enzyme-linked immunosorbent assay as a detection assay to characterize face fly (Musca autumnalis DeGeer) dispersal from cow pats in a pastured beef cattle operation. In microcage assays, adult flies acquired marker after contact with cow pats that were treated with marker and field aged up to 11 d. In arena assays on sprayed full-size cow pats, 77% of eclosed face flies acquired the marker. In a field-marking study, four applications of egg white marker were applied on freshly deposited cow pats over a summer at two peripheral paddocks to a main grazing pasture of ≍50 head of beef cattle. Of the 663 face flies captured, 108 were positive for the egg white marker (16.3%). Of the marked flies, ≍ twofold more male than female flies were captured. Sex-specific dispersal distances were roughly equal up to 450 m, with 11% of female flies dispersing >450 m. Dispersal capability of face flies is discussed in relation to efficacy of rotational grazing and other IPM strategies.

  12. Spatiotemporally synchronized cancer combination therapy using photo-activated nanoparticle drug delivery systems (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Hasan, Tayyaba

    2016-03-01

    This talk will introduce a new nanotechnology platform for cancer combination therapy that utilizes near infrared light activation not only for photodynamic damage but also as an extrinsic mechanism to initiate release of complimentary drugs to suppress dynamic bursts in molecular signaling networks that promote tumor cell survival and treatment escape. The goal is to achieve co-delivery with concomitant activity of photodynamic, molecular inhibitor and chemotherapeutic agents, selectively within the tumor. This approach overcomes challenges in achieving synergistic interactions using sequential drug delivery. Conventional drug delivery is compromised by the differential pharmacokinetics of individual agents and potentially antagonistic effects—such as vascular shutdown by one agent that limits delivery of the second. Here, photodynamic damage—which efficiently kills drug-resistant cells via damage of common proteins involved in drug-resistance (such as anti-apoptosis factors and drug-efflux transporters)—is synchronized spatially and temporally with the photo-initiated release of complimentary agents—to enable full interaction amongst the individual therapies. This spatiotemporal synchronization offers new prospects for exploiting time-sensitive synergistic interactions. Specific implementations of these concepts will be presented in preclinical models of cancer. Strategies to enable molecular-targeting of cancer cells via site-specific attachment of targeting moieties to the outer lipid shell of these nanovehicles will also be discussed. If successful in humans, this new paradigm for synchronized, tumor-focused combination therapy will ultimately supersede the present use of chronic drug injection by increasing efficacy per cycle whilst reducing systemic exposure to toxic drugs.

  13. Ophthalmic manifestations of HIV in the highly active anti-retroviral therapy era.

    PubMed

    Mowatt, L

    2013-01-01

    HIV-related eye disease can be classified as retinal HIV microangiopathy, opportunistic infections, neuro-ophthalmic manifestations and unusual malignancies. There is a 52-100% lifetime accumulative risk of HIV patients developing eye problems. Seventy-seven per cent of patients with ocular manifestations of HIV had CD4 counts < 200 cells/μL. Cytomegalovirus (CMV) is the most prevalent opportunistic infection, however, Africa has a low incidence of this, and more commonly squamous cell carcinoma, compared to the western hemisphere. Due to highly active antiretroviral therapy (HAART), the anti-CMV therapy may be discontinued if the CD4+ T cell count is > 100 cells/μL for a minimum of three months. Despite HAART, patients with a CD4 count < 50 cells/μL have a similar risk of developing CMV retinitis as compared to the pre-HAART era. Opportunistic infections include CMV, herpetic retinopathy (progressive outer retinal necrosis - PORN), less commonly toxoplasmosis, pneumocystis and cryptococcus. Malignancies associated with HIV include Kaposi's sarcoma and conjunctival squamous cell carcinoma. Cranial nerve palsies, optic disc swelling and atrophy are characteristic neuro-ophthalmic features. They usually occur secondary to meningitis/encephalitis (from cryptococcus and tuberculosis). With the advent of HAART, new complications have developed in CMV retinitis: immune recovery uveitis (IRU) and cystoid macula oedema (CMO). Immune recovery uveitis occurs in 71% of patients if HAART is started before the induction of the anti-CMV treatment. However, this is reduced to 31% if HAART is started after the induction treatment. Molluscum contagiosum and Kaposi's sarcoma can spontaneously resolve on HAART. Highly active anti-retroviral therapy has reduced the frequencies of opportunistic infections and improved the remission duration in HIV patients. PMID:24756590

  14. Atorvastatin Therapy Modulates Telomerase Activity in Patients Free of Atherosclerotic Cardiovascular Diseases

    PubMed Central

    Strazhesko, Irina D.; Tkacheva, Olga N.; Akasheva, Dariga U.; Dudinskaya, Ekaterina N.; Plokhova, Ekaterina V.; Pykhtina, Valentina S.; Kruglikova, Anna S.; Kokshagina, Natalia V.; Sharashkina, Natalia V.; Agaltsov, Mikhail V.; Kashtanova, Daria A.; Vygodin, Vladimir A.; Ozerova, Irina N.; Skvortsov, Dmitry A.; Vasilkova, Daria; Boytsov, Sergey A.

    2016-01-01

    Background: Telomerase activity (TA) is considered as the biomarker for cardiovascular aging and cardiovascular diseases (CVDs). Recent studies suggest a link between statins and telomere biology that may be explained by anti-inflammatory actions of statins and their positive effect on TA. Until now, this effect has not been investigated in prospective randomized studies. We hypothesized that 12 months of atorvastatin therapy increased TA in peripheral blood mononuclear cells. Methods: In a randomized, placebo-controlled study 100 hypercholesterolemic patients, aged 35–75 years, free of known CVDs and diabetes mellitus type 2 received 20 mg of atorvastatin daily or placebo for 12 months. TA was measured by quantitative polymerase chain reaction. Results: At study end, 82 patients had sufficient peripheral blood mononuclear cells needed for longitudinal analysis. TA expressed as natural logarithms changed from 0.46 ± 0.05 to 0.68 ± 0.06 (p = 0.004) in the atorvastatin group and from 0.67 ± 0.06 to 0.60 ± 0.07 (p = 0.477) in the control group. In multiple regression analysis, atorvastatin therapy was the only independent predictor (p = 0.05) of the changes in TA independently of markers of chronic inflammation and oxidative stress. Atorvastatin therapy was associated with increases in interleukin-6 within the normal range and a tendency toward reduction in blood urea. Conclusion: These initial observations suggest atorvastatin can act as telomerase activator and potentially as effective geroprotector. Trial registration: The trial was registered in ISRCTN registry ISRCTN55050065. PMID:27746733

  15. Mesenchymal Stem Cell Therapy Alleviates Interstitial Cystitis by Activating Wnt Signaling Pathway

    PubMed Central

    Song, Miho; Lim, Jisun; Yu, Hwan Yeul; Park, Junsoo; Chun, Ji-Youn; Jeong, Jaeho; Heo, Jinbeom; Kang, Hyunsook; Kim, YongHwan; Cho, Yong Mee; Kim, Seong Who; Oh, Wonil; Choi, Soo Jin; Jang, Sung-Wuk; Park, Sanghyeok

    2015-01-01

    Interstitial cystitis (IC) is a syndrome characterized by urinary urgency, frequency, pelvic pain, and nocturia in the absence of bacterial infection or identifiable pathology. IC is a devastating disease that certainly decreases quality of life. However, the causes of IC remain unknown and no effective treatments or cures have been developed. This study evaluated the therapeutic potency of using human umbilical cord-blood-derived mesenchymal stem cells (UCB-MSCs) to treat IC in a rat model and to investigate its responsible molecular mechanism. IC was induced in 10-week-old female Sprague–Dawley rats via the instillation of 0.1 M HCl or phosphate-buffered saline (PBS; sham). After 1 week, human UCB-MSC (IC+MSC) or PBS (IC) was directly injected into the submucosal layer of the bladder. A single injection of human UCB-MSCs significantly attenuated the irregular and decreased voiding interval in the IC group. Accordingly, denudation of the epithelium and increased inflammatory responses, mast cell infiltration, neurofilament production, and angiogenesis observed in the IC bladders were prevented in the IC+MSC group. The injected UCB-MSCs successfully engrafted to the stromal and epithelial tissues and activated Wnt signaling cascade. Interference with Wnt and epidermal growth factor receptor activity by small molecules abrogated the benefits of MSC therapy. This is the first report that provides an experimental evidence of the therapeutic effects and molecular mechanisms of MSC therapy to IC using an orthodox rat animal model. Our findings not only provide the basis for clinical trials of MSC therapy to IC but also advance our understanding of IC pathophysiology. PMID:25745847

  16. Ophthalmic manifestations of HIV in the highly active anti-retroviral therapy era.

    PubMed

    Mowatt, L

    2013-01-01

    HIV-related eye disease can be classified as retinal HIV microangiopathy, opportunistic infections, neuro-ophthalmic manifestations and unusual malignancies. There is a 52-100% lifetime accumulative risk of HIV patients developing eye problems. Seventy-seven per cent of patients with ocular manifestations of HIV had CD4 counts < 200 cells/μL. Cytomegalovirus (CMV) is the most prevalent opportunistic infection, however, Africa has a low incidence of this, and more commonly squamous cell carcinoma, compared to the western hemisphere. Due to highly active antiretroviral therapy (HAART), the anti-CMV therapy may be discontinued if the CD4+ T cell count is > 100 cells/μL for a minimum of three months. Despite HAART, patients with a CD4 count < 50 cells/μL have a similar risk of developing CMV retinitis as compared to the pre-HAART era. Opportunistic infections include CMV, herpetic retinopathy (progressive outer retinal necrosis - PORN), less commonly toxoplasmosis, pneumocystis and cryptococcus. Malignancies associated with HIV include Kaposi's sarcoma and conjunctival squamous cell carcinoma. Cranial nerve palsies, optic disc swelling and atrophy are characteristic neuro-ophthalmic features. They usually occur secondary to meningitis/encephalitis (from cryptococcus and tuberculosis). With the advent of HAART, new complications have developed in CMV retinitis: immune recovery uveitis (IRU) and cystoid macula oedema (CMO). Immune recovery uveitis occurs in 71% of patients if HAART is started before the induction of the anti-CMV treatment. However, this is reduced to 31% if HAART is started after the induction treatment. Molluscum contagiosum and Kaposi's sarcoma can spontaneously resolve on HAART. Highly active anti-retroviral therapy has reduced the frequencies of opportunistic infections and improved the remission duration in HIV patients.

  17. JNK Pathway Activation Modulates Acquired Resistance to EGFR/HER2-Targeted Therapies.

    PubMed

    Manole, Simin; Richards, Edward J; Meyer, Aaron S

    2016-09-15

    Resistance limits the effectiveness of receptor tyrosine kinase (RTK)-targeted therapies. Combination therapies targeting resistance mechanisms can considerably improve response, but will require an improved understanding of when particular combinations will be effective. One common form of resistance is bypass signaling, wherein RTKs not targeted by an inhibitor can direct reactivation of pathways essential for survival. Although this mechanism of resistance is well appreciated, it is unclear which downstream signaling events are responsible. Here, we apply a combined experimental- and statistical modeling-based approach to identify a set of pathway reactivation essential for RTK-mediated bypass resistance. Differences in the downstream pathway activation provided by particular RTKs lead to qualitative differences in the capacity of each receptor to drive therapeutic resistance. We identify and validate that the JNK pathway is activated during and strongly modulates bypass resistance. These results identify effective therapeutic combinations that block bypass-mediated resistance and provide a basic understanding of this network-level change in kinase dependence that will inform the design of prognostic assays for identifying effective therapeutic combinations in individual patients. Cancer Res; 76(18); 5219-28. ©2016 AACR. PMID:27450453

  18. A double-blind placebo-controlled trial of methylprednisolone pulse therapy in active rheumatoid disease.

    PubMed

    Williams, I A; Baylis, E M; Shipley, M E

    1982-07-31

    To confirm the findings of uncontrolled trials that methylprednisolone pulse therapy (MPPT) is a safe treatment for active rheumatoid disease, a double-blind trial was conducted in which 20 patients with active rheumatoid disease were randomly allocated to receive an infusion of either 1 g methylprednisolone or placebo. Methylprednisolone produced significant improvement in all clinical variables measured, a benefit which was sustained for at least 6 weeks. The placebo produced only transient improvement in some of the clinical variables measured. when the 10 placebo groups patients were later given an infusion of 1 g methylprednisolone, they too showed significant clinical benefit. The methylprednisolone also gave rise to improvements in some haematological and biochemical variables. PMID:6124671

  19. The role and regulation of complement activation as part of the thromboinflammation elicited in cell therapies.

    PubMed

    Nilsson, Bo; Teramura, Yuji; Ekdahl, Kristina N

    2014-10-01

    Cell therapies in which the cells come into direct contact with blood and other body fluids are emerging treatment procedures for patients with various diseases, such as diabetes mellitus, liver insufficiency, and graft-versus-host disease. However, despite recent progress, these procedures are associated with tissue loss caused by thromboinflammatory reactions. These deleterious reactions involve the activation of the complement and coagulation cascades and platelet and leukocyte activation, ultimately resulting in clot formation and damage to the implanted cells. In this concept review, we discuss the basic mechanisms underlying the thrombininflammatory process, with special reference to the engagement of complement and emerging strategies for the therapeutic regulation of these reactions that include the use of selective systemic inhibitors and various procedures to coat the surfaces of the cells. The coating procedures may also be applied to other treatment modalities in which similar mechanisms are involved, including whole organ transplantation, treatment with biomaterials in contact with blood, and extracorporeal procedures.

  20. A novel approach to the antimicrobial activity of maggot debridement therapy

    PubMed Central

    Andersen, Anders S.; Sandvang, Dorthe; Schnorr, Kirk M.; Kruse, Thomas; Neve, Søren; Joergensen, Bo; Karlsmark, Tonny; Krogfelt, Karen A.

    2010-01-01

    Objectives Commercially produced sterile green bottle fly Lucilia sericata maggots are successfully employed by practitioners worldwide to clean a multitude of chronic necrotic wounds and reduce wound bacterial burdens during maggot debridement therapy (MDT). Secretions from the maggots exhibit antimicrobial activity along with other activities beneficial for wound healing. With the rise of multidrug-resistant bacteria, new approaches to identifying the active compounds responsible for the antimicrobial activity within this treatment are imperative. Therefore, the aim of this study was to use a novel approach to investigate the output of secreted proteins from the maggots under conditions mimicking clinical treatments. Methods cDNA libraries constructed from microdissected salivary glands and whole maggots, respectively, were treated with transposon-assisted signal trapping (TAST), a technique selecting for the identification of secreted proteins. Several putative secreted components of insect immunity were identified, including a defensin named lucifensin, which was produced recombinantly as a Trx-fusion protein in Escherichia coli, purified using immobilized metal affinity chromatography and reverse-phase HPLC, and tested in vitro against Gram-positive and Gram-negative bacterial strains. Results Lucifensin was active against Staphylococcus carnosus, Streptococcus pyogenes and Streptococcus pneumoniae (MIC 2 mg/L), as well as Staphylococcus aureus (MIC 16 mg/L). The peptide did not show antimicrobial activity towards Gram-negative bacteria. The MIC of lucifensin for the methicillin-resistant S. aureus and glycopeptide-intermediate S. aureus isolates tested ranged from 8 to >128 mg/L. Conclusions The TAST results did not reveal any highly secreted compounds with putative antimicrobial activity, implying an alternative antimicrobial activity of MDT. Lucifensin showed antimicrobial activities comparable to other defensins and could have potential as a future drug

  1. Radioiodine therapy in patients with hyperthyroid disorder: standard versus dosimetric activity application.

    PubMed

    Reinartz, P; Zimny, M; Schaefer, W; Mueller, B; Buell, U; Sabri, O

    2003-12-01

    Due to its high success rate and non-invasive character, an increasing demand for radioiodine therapy can be seen. This study was conducted to determine whether standardized 131I activities can be used to facilitate management of patients with hyperthyroid disorder or whether a pre-therapeutic radioiodine test is advisable to determine an adequate therapeutic activity. The therapeutic uptake of 218 patients with benign thyroid disorders were determined and compared with 24 h and 48 h test uptake measurements as well as with calculated standard uptake values. Since there is a linear relationship between iodine uptake and delivered radiation dose, the effect of the different therapeutic approaches on the latter parameter was analysed. Special care was taken to assess possible differences between the various thyroid disorders. A mean deviation between pre-therapeutic test uptake and actual therapeutic uptake of 14.7% was observed in contrast to one of 29.1% when using disease specific standard values per millilitre of thyroid tissue. Furthermore, the proportion of patients with large deviations of more than 40% increased drastically when using standard uptake values (with radioiodine test, 4.1%; with standard values, 18.8%). In conclusion, the dosimetric approach with a pre-therapeutic radioiodine test proved to be the most accurate therapeutic procedure. Both the 24 h and 48 h test uptake measurements gave analogous results and yielded a correlation coefficient of 0.91 when compared with the therapeutic uptake. While it may be tempting to use standard activities to facilitate patient management, the findings of this study confirm that, for precise therapy planning, a pre-therapeutic radioiodine test is advised. Since no significant difference could be found between the 24 h and 48 h test uptake values, an early measurement 24 h after administration of the test activity is recommended. PMID:14627852

  2. Photodynamic quenched cathepsin activity based probes for cancer detection and macrophage targeted therapy.

    PubMed

    Ben-Nun, Yael; Merquiol, Emmanuelle; Brandis, Alexander; Turk, Boris; Scherz, Avigdor; Blum, Galia

    2015-01-01

    Elevated cathepsins levels and activities are found in several types of human cancer, making them valuable biomarkers for detection and targeting therapeutics. We designed small molecule quenched activity-based probes (qABPs) that fluoresce upon activity-dependent covalent modification, yielding cell killing by Photodynamic Therapy (PDT). These novel molecules are highly selective theranostic probes that enable both detection and treatment of cancer with minimal side effects. Our qABPs carry a photosensitizer (PS), which is activated by light, resulting in oxidative stress and subsequent cell ablation, and a quencher that when removed by active cathepsins allow the PS to fluoresce and demonstrate PD properties. Our most powerful and stable PS-qABP, YBN14, consists of a selective cathepsin recognition sequence, a QC-1 quencher and a new bacteriochlorin derivative as a PS. YBN14 allowed rapid and selective non-invasive in vivo imaging of subcutaneous tumors and induced specific tumor macrophage apoptosis by light treatment, resulting in a substantial tumor shrinkage in an aggressive breast cancer mouse model. These results demonstrate for the first time that the PS-qABPs technology offers a functional theranostic tool, which can be applied to numerous tumor types and other inflammation-associated diseases.

  3. Hybrid-Actuating Macrophage-Based Microrobots for Active Cancer Therapy.

    PubMed

    Han, Jiwon; Zhen, Jin; Du Nguyen, Van; Go, Gwangjun; Choi, Youngjin; Ko, Seong Young; Park, Jong-Oh; Park, Sukho

    2016-01-01

    Using macrophage recruitment in tumors, we develop active, transportable, cancer theragnostic macrophage-based microrobots as vector to deliver therapeutic agents to tumor regions. The macrophage-based microrobots contain docetaxel (DTX)-loaded poly-lactic-co-glycolic-acid (PLGA) nanoparticles (NPs) for chemotherapy and Fe3O4 magnetic NPs (MNPs) for active targeting using an electromagnetic actuation (EMA) system. And, the macrophage-based microrobots are synthesized through the phagocytosis of the drug NPs and MNPs in the macrophages. The anticancer effects of the microrobots on tumor cell lines (CT-26 and 4T1) are evaluated in vitro by cytotoxic assay. In addition, the active tumor targeting by the EMA system and macrophage recruitment, and the chemotherapeutic effect of the microrobots are evaluated using three-dimensional (3D) tumor spheroids. The microrobots exhibited clear cytotoxicity toward tumor cells, with a low survivability rate (<50%). The 3D tumor spheroid assay showed that the microrobots demonstrated hybrid actuation through active tumor targeting by the EMA system and infiltration into the tumor spheroid by macrophage recruitment, resulting in tumor cell death caused by the delivered antitumor drug. Thus, the active, transportable, macrophage-based theragnostic microrobots can be considered to be biocompatible vectors for cancer therapy. PMID:27346486

  4. Hybrid-Actuating Macrophage-Based Microrobots for Active Cancer Therapy

    PubMed Central

    Han, Jiwon; Zhen, Jin; Du Nguyen, Van; Go, Gwangjun; Choi, Youngjin; Ko, Seong Young; Park, Jong-Oh; Park, Sukho

    2016-01-01

    Using macrophage recruitment in tumors, we develop active, transportable, cancer theragnostic macrophage-based microrobots as vector to deliver therapeutic agents to tumor regions. The macrophage-based microrobots contain docetaxel (DTX)-loaded poly-lactic-co-glycolic-acid (PLGA) nanoparticles (NPs) for chemotherapy and Fe3O4 magnetic NPs (MNPs) for active targeting using an electromagnetic actuation (EMA) system. And, the macrophage-based microrobots are synthesized through the phagocytosis of the drug NPs and MNPs in the macrophages. The anticancer effects of the microrobots on tumor cell lines (CT-26 and 4T1) are evaluated in vitro by cytotoxic assay. In addition, the active tumor targeting by the EMA system and macrophage recruitment, and the chemotherapeutic effect of the microrobots are evaluated using three-dimensional (3D) tumor spheroids. The microrobots exhibited clear cytotoxicity toward tumor cells, with a low survivability rate (<50%). The 3D tumor spheroid assay showed that the microrobots demonstrated hybrid actuation through active tumor targeting by the EMA system and infiltration into the tumor spheroid by macrophage recruitment, resulting in tumor cell death caused by the delivered antitumor drug. Thus, the active, transportable, macrophage-based theragnostic microrobots can be considered to be biocompatible vectors for cancer therapy. PMID:27346486

  5. Photodynamic Quenched Cathepsin Activity Based Probes for Cancer Detection and Macrophage Targeted Therapy

    PubMed Central

    Ben-Nun, Yael; Merquiol, Emmanuelle; Brandis, Alexander; Turk, Boris; Scherz, Avigdor; Blum, Galia

    2015-01-01

    Elevated cathepsins levels and activities are found in several types of human cancer, making them valuable biomarkers for detection and targeting therapeutics. We designed small molecule quenched activity-based probes (qABPs) that fluoresce upon activity-dependent covalent modification, yielding cell killing by Photodynamic Therapy (PDT). These novel molecules are highly selective theranostic probes that enable both detection and treatment of cancer with minimal side effects. Our qABPs carry a photosensitizer (PS), which is activated by light, resulting in oxidative stress and subsequent cell ablation, and a quencher that when removed by active cathepsins allow the PS to fluoresce and demonstrate PD properties. Our most powerful and stable PS-qABP, YBN14, consists of a selective cathepsin recognition sequence, a QC-1 quencher and a new bacteriochlorin derivative as a PS. YBN14 allowed rapid and selective non-invasive in vivo imaging of subcutaneous tumors and induced specific tumor macrophage apoptosis by light treatment, resulting in a substantial tumor shrinkage in an aggressive breast cancer mouse model. These results demonstrate for the first time that the PS-qABPs technology offers a functional theranostic tool, which can be applied to numerous tumor types and other inflammation-associated diseases. PMID:26000057

  6. Cognitive therapy for irritable bowel syndrome is associated with reduced limbic activity, GI symptoms, and anxiety.

    PubMed

    Lackner, Jeffrey M; Lou Coad, Mary; Mertz, Howard R; Wack, David S; Katz, Leonard A; Krasner, Susan S; Firth, Rebecca; Mahl, Thomas C; Lockwood, Alan H

    2006-05-01

    This study sought to identify brain regions that underlie symptom changes in severely affected IBS patients undergoing cognitive therapy (CT). Five healthy controls and 6 Rome II diagnosed IBS patients underwent psychological testing followed by rectal balloon distention while brain neural activity was measured with O-15 water positron emission tomography (PET) before and after a brief regimen of CT. Pre-treatment resting state scans, without distention, were compared to post-treatment scans using statistical parametric mapping (SPM). Neural activity in the parahippocampal gyrus and inferior portion of the right cortex cingulate were reduced in the post-treatment scan, compared to pre-treatment (x, y, z coordinates in MNI standard space were -30, -12, -30, P=0.017; 6, 34, -8, P=0.023, respectively). Blood flow values at these two sites in the controls were intermediate between those in the pre- and post-treatment IBS patients. Limbic activity changes were accompanied by significant improvements in GI symptoms (e.g., pain, bowel dysfunction) and psychological functioning (e.g., anxiety, worry). The left pons (-2, -26, -28, P=0.04) showed decreased neural activity which was correlated with post-treatment anxiety scores. Changes in neural activity of cortical-limbic regions that subserve hypervigilance and emotion regulation may represent biologically oriented change mechanisms that mediate symptom improvement of CT for IBS.

  7. Resistance of Cancer Cells to Targeted Therapies Through the Activation of Compensating Signaling Loops.

    PubMed

    von Manstein, Viktoria; Yang, Chul Min; Richter, Diane; Delis, Natalia; Vafaizadeh, Vida; Groner, Bernd

    2013-12-01

    The emergence of low molecular weight kinase inhibitors as "targeted" drugs has led to remarkable advances in the treatment of cancer patients. The clinical benefits of these tumor therapies, however, vary widely in patient populations and with duration of treatment. Intrinsic and acquired resistance against such drugs limits their efficacy. In addition to the well studied mechanisms of resistance based upon drug transport and metabolism, genetic alterations in drug target structures and the activation of compensatory cell signaling have received recent attention. Adaptive responses can be triggered which counteract the initial dependence of tumor cells upon a particular signaling molecule and allow only a transient inhibition of tumor cell growth. These compensating signaling mechanisms are often based upon the relief of repression of regulatory feedback loops. They might involve cell autonomous, intracellular events or they can be mediated via the secretion of growth factor receptor ligands into the tumor microenvironment and signal induction in an auto- or paracrine fashion. The transcription factors Stat3 and Stat5 mediate the biological functions of cytokines, interleukins and growth factors and can be considered as endpoints of multiple signaling pathways. In normal cells this activation is transient and the Stat molecules return to their non-phosphorylated state within a short time period. In tumor cells the balance between activating and de-activating signals is disturbed resulting in the persistent activation of Stat3 or Stat5. The constant activation of Stat3 induces the expression of target genes, which cause the proliferation and survival of cancer cells, as well as their migration and invasive behavior. Activating components of the Jak-Stat pathway have been recognized as potentially valuable drug targets and important principles of compensatory signaling circuit induction during targeted drug treatment have been discovered in the context of kinase

  8. ROS-Responsive Activatable Photosensitizing Agent for Imaging and Photodynamic Therapy of Activated Macrophages

    PubMed Central

    Kim, Hyunjin; Kim, Youngmi; Kim, In-Hoo; Kim, Kyungtae; Choi, Yongdoo

    2014-01-01

    The optical properties of macrophage-targeted theranostic nanoparticles (MacTNP) prepared from a Chlorin e6 (Ce6)-hyaluronic acid (HA) conjugate can be activated by reactive oxygen species (ROS) in macrophage cells. MacTNP are nonfluorescent and nonphototoxic in their native state. However, when treated with ROS, especially peroxynitrite, they become highly fluorescent and phototoxic. In vitro cell studies show that MacTNP emit near-infrared (NIR) fluorescence inside activated macrophages. The NIR fluorescence is quenched in the extracellular environment. MacTNP are nontoxic in macrophages up to a Ce6 concentration of 10 μM in the absence of light. However, MacTNP become phototoxic upon illumination in a light dose-dependent manner. In particular, significantly higher phototoxic effect is observed in the activated macrophage cells compared to human dermal fibroblasts and non-activated macrophages. The ROS-responsive MacTNP, with their high target-to-background ratio, may have a significant potential in selective NIR fluorescence imaging and in subsequent photodynamic therapy of atherosclerosis with minimum side effects. PMID:24396511

  9. Reduced serum hydroxyl radical scavenging activity in erythropoietin therapy resistant renal anemia.

    PubMed

    Hirayama, Aki; Nagase, Sohji; Gotoh, Michihiro; Ueda, Atsushi; Ishizu, Takashi; Yoh, Keigyou; Aoyagi, Kazumasa; Terao, Junji; Koyama, Akio

    2002-11-01

    Relation between anemia resistant to recombinant human erythropoietin (rHuEPO) therapy and the oxidative stress in hemodialysis (HD) patients was investigated. Stable HD patients who had consistent hemoglobin concentrations on a constant dose of rHuEPO were studied. Patients were excluded if there were factors that might affect hemopoiesis or administration of antioxidant supplements. Patients were classified into three groups: High (9000 U/week), Low (1500-4500 U/week) and No rHuEPO group. Thiobarbituric acid reactive substances (TBARS) of sera and erythrocyte were examined. Serum superoxide and hydroxyl radical scavenging activities were measured using electron spin resonance. TBARS in the erythrocyte was higher in High rHuEPO group compared with No rHuEPO group, though the serum TBARS were similar. A diminution of serum hydroxyl radical scavenging activity was observed in High rHuEPO group. Hydroxyl radical signal intensity showed a strong correlation with the serum ferritin in High rHuEPO group, although ferritin concentrations were not different among the 3 groups. Superoxide scavenging activity showed no differences. These results indicate that increased lipid peroxidation in erythrocyte, raised by decreased serum hydroxyl radical scavenging activity, is one cause of rHuEPO resistant anemia. Serum ferritin may be involved in this hydroxyl radical production.

  10. Activating Photodynamic Therapy in vitro with Cerenkov Radiation Generated from Yttrium-90.

    PubMed

    Hartl, Brad A; Hirschberg, Henry; Marcu, Laura; Cherry, Simon R

    2016-01-01

    The translation of photodynamic therapy (PDT) to the clinical setting has primarily been limited to easily accessible and/or superficial diseases, for which traditional light delivery can be performed noninvasively. Cerenkov radiation, as generated from medically relevant radionuclides, has been suggested as a means to deliver light to deeper tissues noninvasively to overcome this depth limitation. This article investigates the utility of Cerenkov radiation, as generated from the radionuclide yttrium-90, for activating the PDT process using clinically approved aminolevulinic acid at 1.0 mm and also the more efficient porphyrin-based photosensitizer mesotetraphenylporphine with two sulfonate groups on adjacent phenyl rings (TPPS2a) at 1.2 µm. Experiments were conducted with monolayer cultured glioma and breast tumor cell lines. Although aminolevulinic acid proved to be ineffective for generating a therapeutic effect at all but the highest activity levels, TPPS2a produced at least a 20% therapeutic effect at activities ranging from 6 to 60 µCi/well for the C6 glioma cell line. Importantly, these results demonstrate for the first time, to our knowledge, that Cerenkov radiation generated from a radionuclide can be used to activate PDT using clinically relevant photosensitizers. These results therefore provide evidence that it may be possible to generate a phototherapeutic effect in vivo using Cerenkov radiation and clinically relevant photosensitizers. PMID:27481495

  11. Activity-Based Restorative Therapies after Spinal Cord Injury: Inter-institutional conceptions and perceptions

    PubMed Central

    Dolbow, David R.; Gorgey, Ashraf S.; Recio, Albert C.; Stiens, Steven A.; Curry, Amanda C.; Sadowsky, Cristina L.; Gater, David R.; Martin, Rebecca; McDonald, John W.

    2015-01-01

    This manuscript is a review of the theoretical and clinical concepts provided during an inter-institutional training program on Activity-Based Restorative Therapies (ABRT) and the perceptions of those in attendance. ABRT is a relatively recent high volume and intensity approach toward the restoration of neurological deficits and decreasing the risk of secondary conditions associated with paralysis after spinal cord injury (SCI). ABRT is guided by the principle of neuroplasticity and the belief that even those with chronic SCI can benefit from repeated activation of the spinal cord pathways located both above and below the level of injury. ABRT can be defined as repetitive-task specific training using weight-bearing and external facilitation of neuromuscular activation. The five key components of ABRT are weight-bearing activities, functional electrical stimulation, task-specific practice, massed practice and locomotor training which includes body weight supported treadmill walking and water treadmill training. The various components of ABRT have been shown to improve functional mobility, and reverse negative body composition changes after SCI leading to the reduction of cardiovascular and other metabolic disease risk factors. The consensus of those who received the ABRT training was that ABRT has much potential for enhancement of recovery of those with SCI. Although various institutions have their own strengths and challenges, each institution was able to initiate a modified ABRT program. PMID:26236547

  12. Treatment of primary HIV-1 infection with cyclosporin A coupled with highly active antiretroviral therapy

    PubMed Central

    Rizzardi, G. Paolo; Harari, Alexandre; Capiluppi, Brunella; Tambussi, Giuseppe; Ellefsen, Kim; Ciuffreda, Donatella; Champagne, Patrick; Bart, Pierre-Alexandre; Chave, Jean-Philippe; Lazzarin, Adriano; Pantaleo, Giuseppe

    2002-01-01

    Primary HIV-1 infection causes extensive immune activation, during which CD4+ T cell activation supports massive HIV-1 production. We tested the safety and the immune-modulating effects of combining cyclosporin A (CsA) treatment with highly active antiretroviral therapy (HAART) during primary HIV-1 infection. Nine adults with primary HIV-1 infection were treated with CsA along with HAART. At week 8, all patients discontinued CsA but maintained HAART. Viral replication was suppressed to a comparable extent in the CsA + HAART cohort and in 29 control patients whose primary infection was treated with HAART alone. CsA restored normal CD4+ T cell levels, both in terms of percentage and absolute numbers. The increase in CD4+ T cells was apparent within a week and persisted throughout the study period. CsA was not detrimental to virus-specific CD8+ or CD4+ T cell responses. At week 48, the proportion of IFN-γ–secreting CD4+ and CD4+CCR7– T cells was significantly higher in the CsA + HAART cohort than in the HAART-alone cohort. In conclusion, rapid shutdown of T cell activation in the early phases of primary HIV-1 infection can have long-term beneficial effects and establish a more favorable immunologic set-point. Appropriate, immune-based therapeutic interventions may represent a valuable complement to HAART for treating HIV infection. PMID:11877476

  13. Uncoupling RARA transcriptional activation and degradation clarifies the bases for APL response to therapies.

    PubMed

    Ablain, Julien; Leiva, Magdalena; Peres, Laurent; Fonsart, Julien; Anthony, Elodie; de Thé, Hugues

    2013-04-01

    In PML/RARA-driven acute promyelocytic leukemia (APL), retinoic acid (RA) induces leukemia cell differentiation and transiently clears the disease. Molecularly, RA activates PML/RARA-dependent transcription and also initiates its proteasome-mediated degradation. In contrast, arsenic, the other potent anti-APL therapy, only induces PML/RARA degradation by specifically targeting its PML moiety. The respective contributions of RA-triggered transcriptional activation and proteolysis to clinical response remain disputed. Here, we identify synthetic retinoids that potently activate RARA- or PML/RARA-dependent transcription, but fail to down-regulate RARA or PML/RARA protein levels. Similar to RA, these uncoupled retinoids elicit terminal differentiation, but unexpectedly fail to impair leukemia-initiating activity of PML/RARA-transformed cells ex vivo or in vivo. Accordingly, the survival benefit conferred by uncoupled retinoids in APL mice is dramatically lower than the one provided by RA. Differentiated APL blasts sorted from uncoupled retinoid-treated mice retain PML/RARA expression and reinitiate APL in secondary transplants. Thus, differentiation is insufficient for APL eradication, whereas PML/RARA loss is essential. These observations unify the modes of action of RA and arsenic and shed light on the potency of their combination in mice or patients.

  14. Activity-Based Restorative Therapies after Spinal Cord Injury: Inter-institutional conceptions and perceptions.

    PubMed

    Dolbow, David R; Gorgey, Ashraf S; Recio, Albert C; Stiens, Steven A; Curry, Amanda C; Sadowsky, Cristina L; Gater, David R; Martin, Rebecca; McDonald, John W

    2015-08-01

    This manuscript is a review of the theoretical and clinical concepts provided during an inter-institutional training program on Activity-Based Restorative Therapies (ABRT) and the perceptions of those in attendance. ABRT is a relatively recent high volume and intensity approach toward the restoration of neurological deficits and decreasing the risk of secondary conditions associated with paralysis after spinal cord injury (SCI). ABRT is guided by the principle of neuroplasticity and the belief that even those with chronic SCI can benefit from repeated activation of the spinal cord pathways located both above and below the level of injury. ABRT can be defined as repetitive-task specific training using weight-bearing and external facilitation of neuromuscular activation. The five key components of ABRT are weight-bearing activities, functional electrical stimulation, task-specific practice, massed practice and locomotor training which includes body weight supported treadmill walking and water treadmill training. The various components of ABRT have been shown to improve functional mobility, and reverse negative body composition changes after SCI leading to the reduction of cardiovascular and other metabolic disease risk factors. The consensus of those who received the ABRT training was that ABRT has much potential for enhancement of recovery of those with SCI. Although various institutions have their own strengths and challenges, each institution was able to initiate a modified ABRT program. PMID:26236547

  15. SU-E-J-49: Distal Edge Activity Fall Off Of Proton Therapy Beams

    SciTech Connect

    Elmekawy, A; Ewell, L; Butuceanu, C; Zhu, L

    2014-06-01

    Purpose: To characterize and quantify the distal edge activity fall off, created in a phantom by a proton therapy beam Method and Materials: A 30x30x10cm polymethylmethacrylate phantom was irradiated with a proton therapy beam using different ranges and beams. The irradiation volume is approximated by a right circular cylinder of diameter 7.6cm and varying lengths. After irradiation, the phantom was scanned via a Philips Gemini Big Bore™ PET-CT for isotope activation. Varian Eclipse™ treatment planning system as well as ImageJ™ were used to analyze the resulting PET and CT scans. The region of activity within the phantom was longitudinally measured as a function of PET slice number. Dose estimations were made via Monte Carlo (GATE) simulation. Results: For both the spread out Bragg peak (SOBP) and the mono-energetic pristine Bragg peak proton beams, the proximal activation rise was steep: average slope −0.735 (average intensity/slice number) ± 0.091 (standard deviation) for the pristine beams and −1.149 ± 0.117 for the SOBP beams. In contrast, the distal fall offs were dissimilar. The distal fall off in activity for the pristine beams was fit well by a linear curve: R{sup 2} (Pierson Product) was 0.9968, 0.9955 and 0.9909 for the 13.5, 17.0 and 21.0cm range beams respectively. The good fit allows for a slope comparison between the different ranges. The slope varied as a function of range from 1.021 for the 13.5cm beam to 0.8407 (average intensity/slice number) for the 21.0cm beam. This dependence can be characterized: −0.0234(average intensity/slice number/cm range). For the SOBP beams, the slopes were significantly less and were also less linear: average slope 0.2628 ± 0.0474, average R{sup 2}=0.9236. Conclusion: The distal activation fall off edge for pristine proton beams was linear and steep. The corresponding quantities for SOBP beams were shallower and less linear. Philips has provided support for this work.

  16. [Baroreflex activation therapy. A novel interventional approach to treat heart failure with reduced ejection fraction].

    PubMed

    Halbach, M; Fritz, T; Madershahian, N; Pfister, R; Reuter, H

    2015-11-01

    Sympathovagal imbalance plays an important role in the progression of heart failure with reduced ejection fraction. Baroreflex activation therapy (BAT), i. e. electrical stimulation of baroreceptors located at the carotid sinus, can reduce sympathetic and enhance parasympathetic tone. Large animal studies on BAT demonstrated improvements in cardiac function, arrhythmogenic risk and a survival benefit compared to untreated controls. The recently published Neo Randomized Heart Failure Study, the first multicenter, randomized and controlled trial of optimal medical and device therapy alone or plus BAT in patients with a left ventricular ejection fraction ≤ 35 %, demonstrated a reasonable safety profile of BAT in this severely ill patient population and no relevant interactions with other devices. The study found significant improvements in the New York Heart Association (NYHA) class of heart failure, quality of life as well as 6 min walking distance and data pointed to a reduction in hospitalization rates. Moreover, N-terminal pro-brain natriuretic peptide (NT-proBNP) levels were significantly reduced. This review gives an overview on BAT for the treatment of heart failure with reduced ejection fraction, from the rationale and animal experiments to the most recent clinical data and future perspectives.

  17. VR PTSD exposure therapy results with active duty OIF/OEF combatants.

    PubMed

    Rizzo, Albert A; Difede, Joann; Rothbaum, Barbara O; Johnston, Scott; McLay, Robert N; Reger, Greg; Gahm, Greg; Parsons, Thomas; Graap, Ken; Pair, Jarrell

    2009-01-01

    Post Traumatic Stress Disorder (PTSD) is reported to be caused by traumatic events that are outside the range of usual human experience including military combat, violent personal assault, being kidnapped or taken hostage and terrorist attacks. Reports indicate that at least 1 out of 6 Iraq War veterans are exhibiting symptoms of depression, anxiety and PTSD. Virtual Reality exposure therapy has been previously used for PTSD with reports of positive outcomes. This paper will present a brief description of the USC/ICT Virtual Iraq/Afghanistan PTSD therapy application and present clinical outcome data from active duty patients treated at the Naval Medical Center-San Diego (NMCSD) as of October 2009. Initial outcomes from the first twenty patients to complete treatment indicate that 16 no longer meet diagnostic criteria for PTSD at post treatment. Research and clinical tests using the Virtual Iraq/Afghanistan software are also currently underway at Weill Cornell Medical College, Emory University, Fort Lewis and WRAMC along with 20 other test sites. PMID:19377167

  18. Decline in HIV infectivity following the introduction of highly active antiretroviral therapy

    PubMed Central

    Porco, Travis C.; Martin, Jeffrey N.; Page-Shafer, Kimberly A.; Cheng, Amber; Charlebois, Edwin; Grant, Robert M.; Osmond, Dennis H.

    2008-01-01

    Objective Little is known about the degree to which widespread use of antiretroviral therapy in a community reduces uninfected individuals’ risk of acquiring HIV. We estimated the degree to which the probability of HIV infection from an infected partner (the infectivity) declined following the introduction of highly active antiretroviral therapy (HAART) in San Francisco. Design Homosexual men from the San Francisco Young Men’s Health Study, who were initially uninfected with HIV, were asked about sexual practices, and tested for HIV antibodies at each of four follow-up visits during a 6-year period spanning the advent of widespread use of HAART (1994 to 1999). Methods We estimated the infectivity of HIV (per-partnership probability of transmission from an infected partner) using a probabilistic risk model based on observed incident infections and self-reported sexual risk behavior, and tested the hypothesis that infectivity was the same before and after HAART was introduced. Results A total of 534 homosexual men were evaluated. Decreasing trends in HIV seroincidence were observed despite increases in reported number of unprotected receptive anal intercourse partners. Conservatively assuming a constant prevalence of HIV infection between 1994 and 1999, HIV infectivity decreased from 0.120 prior to widespread use of HAART, to 0.048 after the widespread use of HAART – a decline of 60% (P = 0.028). Conclusions Use of HAART by infected persons in a community appears to reduce their infectiousness and therefore may provide an important HIV prevention tool. PMID:15090833

  19. Disseminated rhodococcus equi infection in HIV infection despite highly active antiretroviral therapy

    PubMed Central

    2011-01-01

    Background Rhodococcus equi (R.equi) is an acid fast, GRAM + coccobacillus, which is widespread in the soil and causes pulmonary and extrapulmonary infections in immunocompromised people. In the context of HIV infection, R.equi infection (rhodococcosis) is regarded as an opportunistic disease, and its outcome is influenced by highly active antiretroviral therapy (HAART). Case presentation We report two cases of HIV-related rhodococcosis that disseminated despite suppressive HAART and anti-rhodococcal treatment; in both cases there was no immunological recovery, with CD4+ cells count below 200/μL. In the first case, pulmonary rhodococcosis presented 6 months after initiation of HAART, and was followed by an extracerebral intracranial and a cerebral rhodococcal abscess 1 and 8 months, respectively, after onset of pulmonary infection. The second case was characterized by a protracted course with spread of infection to various organs, including subcutaneous tissue, skin, colon and other intra-abdominal tissues, and central nervous system; the spread started 4 years after clinical resolution of a first pulmonary manifestation and progressed over a period of 2 years. Conclusions Our report highlights the importance of an effective immune recovery, despite fully suppressive HAART, along with anti-rhodococcal therapy, in order to clear rhodococcal infection. PMID:22168333

  20. Highly active antiretroviral therapy potently suppresses HIV infection in humanized Rag2-/-gammac-/- mice.

    PubMed

    Sango, Kaori; Joseph, Aviva; Patel, Mahesh; Osiecki, Kristin; Dutta, Monica; Goldstein, Harris

    2010-07-01

    Humanized Rag2(-/-)gamma(c)(-/-) mice (Hu-DKO mice) become populated with functional human T cells, B cells, and dendritic cells following transplantation with human hematopoietic stem cells (HSC) and represent an improved model for studying HIV infection in vivo. In the current study we demonstrated that intrasplenic inoculation of hu-DKO mice with HIV-1 initiated a higher level of HIV infection than intravenous or intraperitoneal inoculation, associated with a reciprocal decrease in peripheral CD4(+) T cells and increase in peripheral CD8(+) T cells. HIV infection by intrasplenic injection increased serum levels of human IgG and IgM including human IgM and IgG specific for HIV-1 gp120. There was a significant inverse correlation between the level of HIV-1 infection and the extent of CD4(+) T cell depletion. Highly active antiretroviral therapy (HAART) initiated 1 week after HIV-1 inoculation markedly suppressed HIV-1 infection and prevented CD4(+) T cell depletion. Taken together, these findings demonstrate that intrasplenic injection of hu-DKO mice with HIV is a more efficient route of HIV infection than intravenous or intraperitoneal injection and generates increased infection associated with an increased anti-HIV humoral response. This animal model can serve as a valuable in vivo model to study the efficacy of anti-HIV therapies.

  1. Natural healers: a review of animal assisted therapy and activities as complementary treatment for chronic conditions.

    PubMed

    Reed, Reiley; Ferrer, Lilian; Villegas, Natalia

    2012-01-01

    The primary objective of this review is to synthesize the existing literature on the use of animal-assisted therapy and activity (AAT/A) as complementary treatment among people living with chronic disease and to discuss the possible application of this practice among children living with HIV. Relevant databases were searched between March 10 and April 11, 2011, using the words: animal assisted therapy or treatment and chronic conditions or diseases. Thirty-one articles were found and 18 followed the inclusion and exclusion criteria. Research suggests that AAT/A is effective for different patient profiles, particularly children. Interaction with dogs has been found to increase positive behaviors, such as sensitivity and focus, in children with social disabilities. Decreased levels of pain have also been reported among child patients as a result of AAT/A. More research should be done in the area of children living with chronic diseases that require strict adherence to treatment, such as HIV, and on AAT/A's prospective use as an educational tool to teach children about the importance of self-care for their medical conditions.

  2. Magnetic field activated drug release system based on magnetic PLGA microspheres for chemo-thermal therapy.

    PubMed

    Fang, Kun; Song, Lina; Gu, Zhuxiao; Yang, Fang; Zhang, Yu; Gu, Ning

    2015-12-01

    Controlled drug delivery systems have been extensively investigated for cancer therapy in order to obtain better specific targeting and therapeutic efficiency. Herein, we developed doxorubicin-loaded magnetic PLGA microspheres (DOX-MMS), in which DOX was encapsulated in the core and high contents (28.3 wt%) of γ-Fe2O3 nanoparticles (IOs) were electrostatically assembled on the surface of microsphere to ensure the high sensitivity to response of an external alternating current magnetic field (ACMF). The IOs in PLGA shell can both induce the heat effect and trigger shell permeability enhancement to release drugs when DOX-MMs was activated by ACMF. Results show that the cumulative drug release from DOX-MMs exposed to ACMF for 30 min (21.6%) was significantly higher (approximately 7 times higher) than that not exposed to ACMF (2.8%). The combination of hyperthermia and enhanced DOX release from DOX-MMS is beneficial for in vitro 4T1 breast cancer cell apoptosis as well as effective inhibition of tumor growth in 4T1 tumor xenografts. Therefore, the DOX-MMS can be optimized as powerful delivery system for efficient magnetic responsive drug release and chemo-thermal therapy.

  3. Seasonal migration and environmental conditions of Pacific halibut Hippoglossus stenolepis, elucidated from pop-up archival transmitting (PAT) tags

    USGS Publications Warehouse

    Loher, T.; Seitz, A.

    2006-01-01

    Pop-up archival transmitting (PAT) tags were used to study the fall migration of halibut in the Gulf of Alaska (GOA). We tagged 6 Pacific halibut Hippoglossus stenolepis on summer feeding grounds in the eastern GOA and another 6 in the western GOA from June 13 to August 6, 2002. The tags were programed to be released from the fish on January 15, 2003, at the height of the winter spawning season: 10 tags successfully detached, transmitted archived environmental data (depth and temperature), and generated accurate latitude-longitude coordinates shortly after pop-up; 2 tags deployed off SE Alaska were lost. The tags revealed that 6 fish had moved a considerable distance (>200 km) between tagging and pop-up, and all of these had moved northward to some extent. The longest of the observed migrations was from the southern Alaska Peninsula to Yakutat Bay, a linear displacement of 1153 km; 4 fish showed little evidence of geographic displacement, exhibiting migrations that ranged only from 30 to 69 km. Although 2 fish had moved inshore by the end of the tagging period, all other fish had moved offshore regardless of their overall migration distance. The precise timing of offshore movements varied, beginning as early as August and as late as January. These observations generally corroborate conventional tagging, indicating migration of halibut toward winter spawning grounds in the northern GOA, and movement of fish to deep water in fall. However, no single stereotypic migration behavior was apparent, and a variety of vertical movement patterns and temperature profiles were observed. Halibut spent most time in waters of 5 to 7??C, but experienced temperatures ranging from 2.6 to 11.6??C. Depth observations ranged from 0 to 736 m, with summertime activity concentrated in depths from 0 to 400 m, and halibut that exhibited offshore movement were typically observed at 300 to 700 m by mid-winter. Vertical movement (short-period changes in depth) varied among fish and over time

  4. Activism today: the Coalition for Salvage Therapy. Interview with Linda Grinberg. Interview by John S. James.

    PubMed

    Grinberg, L

    1999-11-01

    The article details an interview with activist Linda Grinberg of Foundation for AIDS and Immune Research (FAIR) on the activities of the Coalition for Salvage Therapy (CST), advocates for persons with advanced HIV infection and multiple treatment failures; CST seeks to improve research, and promote the earliest possible access to drugs for patients who urgently need new treatments. Although heavily pre-treated or multi-drug resistant patients appear to be the most realistic test for new drugs, companies often recruit treatment-naive patients, where success may be more easily shown. By working with pharmaceutical companies to persuade them to conduct trials such as "proof of concept" studies, CST and other groups are trying to improve treatment for persons with HIV infection. Contact information is provided.

  5. A case of atypical progressive outer retinal necrosis after highly active antiretroviral therapy.

    PubMed

    Woo, Se Joon; Yu, Hyeong Gon; Chung, Hum

    2004-06-01

    This is a report of an atypical case of progressive outer retinal necrosis (PORN) and the effect of highly active antiretroviral therapy (HAART) on the clinical course of viral retinitis in an acquired immunodeficiency syndrome (AIDS) patient. A 22-year-old male patient infected with human immunodeficiency virus (HIV) presented with unilaterally reduced visual acuity and a dense cataract. After cataract extraction, retinal lesions involving the peripheral and macular areas were found with perivascular sparing and the mud-cracked, characteristic appearance of PORN. He was diagnosed as having PORN based on clinical features and was given combined antiviral treatment. With concurrent HAART, the retinal lesions regressed, with the regression being accelerated by further treatment with intravenous acyclovir and ganciclovir. This case suggests that HAART may change the clinical course of PORN in AIDS patients by improving host immunity. PORN should be included in the differential diagnosis of acute unilateral cataract in AIDS patients. PMID:15255240

  6. A case of atypical progressive outer retinal necrosis after highly active antiretroviral therapy.

    PubMed

    Woo, Se Joon; Yu, Hyeong Gon; Chung, Hum

    2004-06-01

    This is a report of an atypical case of progressive outer retinal necrosis (PORN) and the effect of highly active antiretroviral therapy (HAART) on the clinical course of viral retinitis in an acquired immunodeficiency syndrome (AIDS) patient. A 22-year-old male patient infected with human immunodeficiency virus (HIV) presented with unilaterally reduced visual acuity and a dense cataract. After cataract extraction, retinal lesions involving the peripheral and macular areas were found with perivascular sparing and the mud-cracked, characteristic appearance of PORN. He was diagnosed as having PORN based on clinical features and was given combined antiviral treatment. With concurrent HAART, the retinal lesions regressed, with the regression being accelerated by further treatment with intravenous acyclovir and ganciclovir. This case suggests that HAART may change the clinical course of PORN in AIDS patients by improving host immunity. PORN should be included in the differential diagnosis of acute unilateral cataract in AIDS patients.

  7. Maggot debridement therapy promotes diabetic foot wound healing by up-regulating endothelial cell activity.

    PubMed

    Sun, Xinjuan; Chen, Jin'an; Zhang, Jie; Wang, Wei; Sun, Jinshan; Wang, Aiping

    2016-03-01

    To determine the role of maggot debridement therapy (MDT) on diabetic foot wound healing, we compared growth related factors in wounds before and after treatment. Furthermore, we utilized human umbilical vein endothelial cells (HUVECs) to explore responses to maggot excretions/secretions on markers of angiogenesis and proliferation. The results showed that there was neo-granulation and angiogenesis in diabetic foot wounds after MDT. Moreover, significant elevation in CD34 and CD68 levels was also observed in treated wounds. In vitro, ES increased HUVEC proliferation, improved tube formation, and increased expression of vascular endothelial growth factor receptor 2 in a dose dependent manner. These results demonstrate that MDT and maggot ES can promote diabetic foot wound healing by up-regulating endothelial cell activity.

  8. Perceptions of Equine Assisted Activities and Therapies by Parents and Children with Spinal Muscular Atrophy

    PubMed Central

    Lemke, Danielle; Rothwell, Erin; Newcomb, Tara M.; Swoboda, Kathryn J.

    2014-01-01

    Purpose To identify the physical and psychosocial effects of equine assisted activities and therapies (EAAT) on children with Spinal Muscular Atrophy (SMA) from the perspective of the child and their parents. Methods The families of all eligible children with SMA, who reported participation in EAAT, from a western metropolitan academic center were contacted and invited to participate. This study implemented qualitative, semi-structured interviews of children with SMA and their parents. Results Three themes emerged from the qualitative content analysis: physical/psychosocial benefits; relationship development with the horses, instructors, and children; and barriers to continued EAAT engagement. Conclusions The data suggest the overall EAAT experience was a source of enjoyment, self-confidence, and normalcy for the children with SMA. The results of this study provide preliminary support for the use of EAAT among children with SMA. PMID:24675128

  9. Highly active antiretroviral therapy-related mechanisms of endothelial and platelet function alterations.

    PubMed

    Gresele, Paolo; Falcinelli, Emanuela; Momi, Stefania; Francisci, Daniela; Baldelli, Franco

    2014-01-01

    Highly active antiretroviral therapy (HAART) has transformed human immunodeficiency virus (HIV) infection into a chronic condition, which has allowed the infected population to age and become prone to chronic degenerative diseases common to the general population, including atherosclerotic cardiovascular disease, and coronary artery disease (CAD). Possible causative mechanisms of HIV-associated CAD are related to classic cardiovascular risk factors, such as dyslipidemia, insulin resistance, and fat redistribution, which may be due to either HIV infection or to HAART-associated toxicity. However, other mechanisms are emerging as crucial for the cardiovascular complication of HIV and HAART. This article analyzes the effects of HIV and HAART on endothelial function, endothelium-leukocyte interactions, and platelets as possible mechanisms of enhanced cardiovascular risk.

  10. Hybrid data capture for monitoring patients on highly active antiretroviral therapy (HAART) in urban Botswana.

    PubMed Central

    Bussmann, Hermann; Wester, C. William; Ndwapi, Ndwapi; Vanderwarker, Chris; Gaolathe, Tendani; Tirelo, Geoffrey; Avalos, Ava; Moffat, Howard; Marlink, Richard G.

    2006-01-01

    Individual patient care and programme evaluation are pivotal for the success of antiretroviral treatment programmes in resource-limited countries. While computer-aided documentation and data storage are indispensable for any large programme, several important issues need to be addressed including which data are to be collected, who collects it and how it is entered into an electronic database. We describe a patient-monitoring approach, which uses patient encounter forms (in hybrid paper + electronic format) based on optical character recognition, piloted at Princess Marina Hospital in Gaborone, Botswana's first public highly active antiretroviral therapy (HAART) outpatient clinic. Our novel data capture approach collects "key" data for tracking patient and programme outcomes. It saves physician time and does not detract from clinical care. PMID:16501730

  11. Complement activation and choriocapillaris loss in early AMD: implications for pathophysiology and therapy.

    PubMed

    Whitmore, S Scott; Sohn, Elliott H; Chirco, Kathleen R; Drack, Arlene V; Stone, Edwin M; Tucker, Budd A; Mullins, Robert F

    2015-03-01

    Age-related macular degeneration (AMD) is a common and devastating disease that can result in severe visual dysfunction. Over the last decade, great progress has been made in identifying genetic variants that contribute to AMD, many of which lie in genes involved in the complement cascade. In this review we discuss the significance of complement activation in AMD, particularly with respect to the formation of the membrane attack complex in the aging choriocapillaris. We review the clinical, histological and biochemical data that indicate that vascular loss in the choroid occurs very early in the pathogenesis of AMD, and discuss the potential impact of vascular dropout on the retinal pigment epithelium, Bruch's membrane and the photoreceptor cells. Finally, we present a hypothesis for the pathogenesis of early AMD and consider the implications of this model on the development of new therapies.

  12. Complement activation and choriocapillaris loss in early AMD: Implications for pathophysiology and therapy

    PubMed Central

    Whitmore, S.Scott; Sohn, Elliott H.; Chirco, Kathleen R.; Drack, Arlene V.; Stone, Edwin M.; Tucker, Budd A.; Mullins, Robert F.

    2015-01-01

    Age-related macular degeneration (AMD) is a common and devastating disease that can result in severe visual dysfunction. Over the last decade, great progress has been made in identifying genetic variants that contribute to AMD, many of which lie in genes involved in the complement cascade. In this review we discuss the significance of complement activation in AMD, particularly with respect to the formation of the membrane attack complex in the aging choriocapillaris. We review the clinical, histological and biochemical data that indicate that vascular loss in the choroid occurs very early in the pathogenesis of AMD, and discuss the potential impact of vascular dropout on the retinal pigment epithelium, Bruch's membrane and the photoreceptor cells. Finally, we present a hypothesis for the pathogenesis of early AMD and consider the implications of this model on the development of new therapies. PMID:25486088

  13. Impediments to enhancement of CPT-11 anticancer activity by E. coli directed beta-glucuronidase therapy.

    PubMed

    Hsieh, Yuan-Ting; Chen, Kai-Chuan; Cheng, Chiu-Min; Cheng, Tian-Lu; Tao, Mi-Hua; Roffler, Steve R

    2015-01-01

    CPT-11 is a camptothecin analog used for the clinical treatment of colorectal adenocarcinoma. CPT-11 is converted into the therapeutic anti-cancer agent SN-38 by liver enzymes and can be further metabolized to a non-toxic glucuronide SN-38G, resulting in low SN-38 but high SN-38G concentrations in the circulation. We previously demonstrated that adenoviral expression of membrane-anchored beta-glucuronidase could promote conversion of SN-38G to SN-38 in tumors and increase the anticancer activity of CPT-11. Here, we identified impediments to effective tumor therapy with E. coli that were engineered to constitutively express highly active E. coli beta-glucuronidase intracellularly to enhance the anticancer activity of CPT-11. The engineered bacteria, E. coli (lux/βG), could hydrolyze SN-38G to SN-38, increased the sensitivity of cultured tumor cells to SN-38G by about 100 fold and selectively accumulated in tumors. However, E. coli (lux/βG) did not more effectively increase CPT-11 anticancer activity in human tumor xenografts as compared to non-engineered E. coli. SN-38G conversion to SN-38 by E. coli (lux/βG) appeared to be limited by slow uptake into bacteria as well as by segregation of E. coli in necrotic regions of tumors that may be relatively inaccessible to systemically-administered drug molecules. Studies using a fluorescent glucuronide probe showed that significantly greater glucuronide hydrolysis could be achieved in mice pretreated with E. coli (lux/βG) by direct intratumoral injection of the glucuronide probe or by intratumoral lysis of bacteria to release intracellular beta-glucuronidase. Our study suggests that the distribution of beta-glucuronidase, and possibly other therapeutic proteins, in the tumor microenvironment might be an important barrier for effective bacterial-based tumor therapy. Expression of secreted therapeutic proteins or induction of therapeutic protein release from bacteria might therefore be a promising strategy to enhance anti

  14. Impediments to Enhancement of CPT-11 Anticancer Activity by E. coli Directed Beta-Glucuronidase Therapy

    PubMed Central

    Hsieh, Yuan-Ting; Chen, Kai-Chuan; Cheng, Chiu-Min; Cheng, Tian-Lu; Tao, Mi-Hua; Roffler, Steve R.

    2015-01-01

    CPT-11 is a camptothecin analog used for the clinical treatment of colorectal adenocarcinoma. CPT-11 is converted into the therapeutic anti-cancer agent SN-38 by liver enzymes and can be further metabolized to a non-toxic glucuronide SN-38G, resulting in low SN-38 but high SN-38G concentrations in the circulation. We previously demonstrated that adenoviral expression of membrane-anchored beta-glucuronidase could promote conversion of SN-38G to SN-38 in tumors and increase the anticancer activity of CPT-11. Here, we identified impediments to effective tumor therapy with E. coli that were engineered to constitutively express highly active E. coli beta-glucuronidase intracellularly to enhance the anticancer activity of CPT-11. The engineered bacteria, E. coli (lux/βG), could hydrolyze SN-38G to SN-38, increased the sensitivity of cultured tumor cells to SN-38G by about 100 fold and selectively accumulated in tumors. However, E. coli (lux/βG) did not more effectively increase CPT-11 anticancer activity in human tumor xenografts as compared to non-engineered E. coli. SN-38G conversion to SN-38 by E. coli (lux/βG) appeared to be limited by slow uptake into bacteria as well as by segregation of E. coli in necrotic regions of tumors that may be relatively inaccessible to systemically-administered drug molecules. Studies using a fluorescent glucuronide probe showed that significantly greater glucuronide hydrolysis could be achieved in mice pretreated with E. coli (lux/βG) by direct intratumoral injection of the glucuronide probe or by intratumoral lysis of bacteria to release intracellular beta-glucuronidase. Our study suggests that the distribution of beta-glucuronidase, and possibly other therapeutic proteins, in the tumor microenvironment might be an important barrier for effective bacterial-based tumor therapy. Expression of secreted therapeutic proteins or induction of therapeutic protein release from bacteria might therefore be a promising strategy to enhance anti

  15. Beneficial effects of postmenopausal hormone replacement therapy with transdermal estradiol on sensitivity to activated protein C.

    PubMed

    De Mitrio, V; Marino, R; Cicinelli, E; Galantino, P; Di Bari, L; Giannoccaro, F; De Pergola, G; Lapecorella, M; Schonauer, S; Schiraldi, O

    2000-03-01

    Many hemostatic and fibrinolytic parameters have been evaluated following hormone replacement therapy (HRT) but little is known about its influence on the anticoagulant response to activated protein C (APC-sensitivity). For this purpose, we studied the effect of transdermal 17-beta-estradiol (50 microg/24 h) by a continuous regimen on the APC-sensitivity, in 28 postmenopausal hysterectomized women (mean age, 47 years; range, 44-65 years). We also measured the plasma proteins directly involved in the protein C anticoagulant pathway, such as activities of factor VIII (VIII:C), factor V and free protein S. Von Willebrand factor (vWF) antigen, the carrier protein of factor VIII, was also determined. Blood sampling was done at baseline and after 16-week therapy. A significant increase in the normalized APC-sensitivity ratio (n-APC-SR) values (mean +/- SD: pre-trial, 0.88 +/- 0.14; post-trial, 1.01 +/- 0.12; P < 0.001) and a significant decrease of factor VIII:C plasma levels (pre-trial, 1.13 +/- 0.29 IU/ml; post-trial, 0.98 +/- 0.20 IU/ ml; P = 0.001) were found. No difference was observed in factor V, protein S and vWF plasma levels. Correlation studies demonstrated only a significant negative correlation between the percent change in n-APC-SR and the percent change in factor VIII:C (r = -0.574; P = 0.001). Our findings clearly show that HRT with transdermal estradiol improves the anticoagulant response to APC, probably as a result of a decreased factor VIII:C. We also suggest that a similar but opposite mechanism may occur for perorally administered estrogens used in the HRT. These results may have some clinical implications about the reported increase of the risk for venous thromboembolism following HRT.

  16. Antitumor activity of photodynamic therapy performed with nanospheres containing zinc-phthalocyanine

    PubMed Central

    2013-01-01

    Background The increasing incidence of cancer and the search for more effective therapies with minimal collateral effects have prompted studies to find alternative new treatments. Among these, photodynamic therapy (PDT) has been proposed as a very promising new modality in cancer treatment with the lowest rates of side effects, revealing itself to be particularly successful when the photosensitizer is associated with nanoscaled carriers. This study aimed to design and develop a new formulation based on albumin nanospheres containing zinc-phthalocyanine tetrasulfonate (ZnPcS4-AN) for use in the PDT protocol and to investigate its antitumor activity in Swiss albino mice using the Ehrlich solid tumor as an experimental model for breast cancer. Methods Ehrlich tumor’s volume, histopathology and morphometry were used to assess the efficacy of intratumoral injection of ZnPcS4-AN in containing tumor aggressiveness and promoting its regression, while the toxicity of possible treatments was assessed by animal weight, morphological analysis of the liver and kidneys, hemogram, and serum levels of total bilirubin, direct bilirubin, indirect bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl transferase (GGT), alkaline phosphatase, creatinine and urea. In order to evaluate the efficacy of PDT, groups of animals treated with intratumoral injection of doxorubicin (Dox) were also investigated. Results Intratumoral injection of ZnPcS4-AN was found to be efficient in mediating PDT to refrain tumor aggressiveness and to induce its regression. Although tumor volume reduction was not significant, PDT induced a remarkable increase in the necrosis area seen in the tumor’s central region, as in other experimental groups, including tumor and Dox treated groups, but also in the tumor’s peripheral region. Further, PDT showed minimal adverse effects. Indeed, the use of ZnPcS4-AN in mediating PDT revealed anti-neoplastic activity similar to that

  17. Prognostic Significance of Estimation of Pseudocholinesterase Activity and Role of Pralidoxime Therapy in Organophosphorous Poisoning

    PubMed Central

    Chaudhary, Shyam Chand; Singh, Khemraj; Sawlani, Kamal Kumar; Jain, Nirdesh; Vaish, Arvind Kumar; Atam, Virendra; Patel, Munna Lal; Agarwal, Avinash

    2013-01-01

    Background: Organophosphorous (OP) poisoning is one of the most common poisonings seen in India. OP compounds act through inhibition of enzyme acetylcholinesterase and estimation of pseudocholinesterase (PCE) activity strengthens the diagnosis in clinically uncertain cases of OP poisoning. The role of pralidoxime (PAM) therapy in OP poisoning has been controversial. Study Objectives: This study was aimed to determine the prognostic significance of estimation of PCE activity and also to assess the role of PAM therapy in OP poisoning. Materials and Methods: Patients of suspected OP poisoning of age >12 years admitted to emergency unit at a tertiary healthcare center of north India were enrolled. Patients were categorized into two groups; group A who were given intravenous atropine and group B who were given injectable PAM along with atropine. Serum PCE level was estimated at the time of admission in all patients and severity of OP poisoning was assessed according to PCE level. Requirement of atropine, oxygen inhalation, intubation and ventilatory support, total hospital stay, and mortality were compared between different classes of severity and also between Groups A and B. Results: This study included a total of 70 subjects, 35 in each group with mean age of 24.99 ± 8.7 years. Out of 70 subjects 49 (70%) were male and 21 (30%) were female. Forty nine patients (70%) of OP poisoning were with suicidal intent while 21 (30%) cases were accidentally poisoned. In all suicidal cases route of poisoning was ingestion whereas in all the accidental cases route of exposure was inhalational. PCE levels were reduced in all the cases and the mean level was 3,154.16 ± 2,562.40 IU/L. The total dose of atropine required, need for oxygen inhalation and need for intubation and ventilatory support, mean duration of hospital stay and mortality rate (P = 0.003) were higher in moderate to severe cases and did not have significant difference between Groups A and B. Conclusion: The study

  18. Bcl-2 overexpression blocks caspase activation and downstream apoptotic events instigated by photodynamic therapy

    PubMed Central

    Granville, D J; Jiang, H; An, M T; Levy, J G; McManus, B M; Hunt, D W C

    1999-01-01

    Treatment with the photosensitizer benzoporphyrin derivative monoacid ring A (BPD-MA, verteporfin) followed by irradiation with visible light induces apoptosis in human acute myelogenous leukaemia HL-60 cells. Photoactivation of BPD-MA induces procaspase 3 (CPP32/Yama/apopain) and procaspase 6 (Mch2) cleavage into their proteolytically active subunits in these cells. The Bcl-2 proto-oncogene product has been shown to protect cells from a number of proapoptotic stimuli. In the present study, the influence of Bcl-2 overexpression on cellular resistance to photoactivation of BPD-MA was studied. Overexpression of Bcl-2 in HL-60 cells prevented apoptosis-related events including caspase 3 and 6 activation, poly(ADP-ribose) polymerase cleavage and the formation of hypodiploid DNA produced by BPD-MA (0–200 ng ml−1) and light. However, Bcl-2 overexpression was less effective at preventing cell death that occurred after photoactivation at high levels (50–100 ng ml−1) compared with lower doses (10–25 ng ml−1) of BPD-MA. These results indicate that caspase 3 and 6 activation and their regulation by Bcl-2 may play important roles in photodynamic therapy (PDT)-induced cell killing. © 1999 Cancer Research Campaign PMID:10408699

  19. Activation of mechanosensitive ion channel TRPV4 normalizes tumor vasculature and improves cancer therapy

    PubMed Central

    Adapala, Ravi K.; Thoppil, Roslin J.; Ghosh, Kaustabh; Cappelli, Holly; Dudley, Andrew C.; Paruchuri, Sailaja; Keshamouni, Venkateshwar; Klagsbrun, Michael; Meszaros, J. Gary; Chilian, William M.; Ingber, Donald E.; Thodeti, Charles K.

    2016-01-01

    Tumor vessels are characterized by abnormal morphology and hyper-permeability that together cause inefficient delivery of chemotherapeutic agents. Although VEGF has been established as a critical regulator of tumor angiogenesis, the role of mechanical signaling in the regulation of tumor vasculature or tumor endothelial cell (TEC) function is not known. Here, we show that the mechanosensitive ion channel TRPV4 regulates tumor angiogenesis and tumor vessel maturation via modulation of TEC mechanosensitivity. We found that TEC exhibit reduced TRPV4 expression and function, which is correlated with aberrant mechanosensitivity towards ECM stiffness, increased migration and abnormal angiogenesis by TEC. Further, syngeneic tumor experiments revealed that the absence of TRPV4 induced increased vascular density, vessel diameter and reduced pericyte coverage resulting in enhanced tumor growth in TRPV4 KO mice. Importantly, overexpression or pharmacological activation of TRPV4 restored aberrant TEC mechanosensitivity, migration and normalized abnormal angiogenesis in vitro by modulating Rho activity. Finally, a small molecule activator of TRPV4, GSK1016790A, in combination with anti-cancer drug Cisplatin, significantly reduced tumor growth in WT mice by inducing vessel maturation. Our findings demonstrate TRPV4 channels to be critical regulators of tumor angiogenesis and represent a novel target for anti-angiogenic and vascular normalization therapies. PMID:25867067

  20. Cognitive milieu therapy and physical activity: experiences of mastery and learning among patients with dual diagnosis.

    PubMed

    Borge, L; Røssberg, J I; Sverdrup, S

    2013-12-01

    During the last decade, there has been a growing interest in implementing cognitive milieu therapy (CMT) in psychiatric institutions. However, there is a lack of systematic evaluations from patients' point of view. The aim of this study was to explore and describe patient perceptions of essential experiences of mastery, learning alternative ways of thinking, and acquiring new skills through CMT and physical activity in an inpatient setting. Qualitative interviews were carried out with 20 patients with dual diagnosis. A hermeneutic - phenomenological approach was used in the data collection and analysis. The results showed that the learning climate in the unit was important. This included a proactive attitude from the staff, focusing on cooperation on equal terms between patients and staff, and a professional methodological approach through CMT. The optimal balance between staff-induced activities and patient initiatives was not easy to obtain. Patients appreciated both the education provided by the staff and learning from other patients. The cognitive method was sometimes experienced as too theoretical and difficult to understand. Physical activity, however, was experienced as 'concrete' and providing practical knowledge. It motivated patients to establish new habits and provided opportunities for the development of mastery together with other patients.

  1. Effects of active music therapy on the normal brain: fMRI based evidence.

    PubMed

    Raglio, Alfredo; Galandra, Caterina; Sibilla, Luisella; Esposito, Fabrizio; Gaeta, Francesca; Di Salle, Francesco; Moro, Luca; Carne, Irene; Bastianello, Stefano; Baldi, Maurizia; Imbriani, Marcello

    2016-03-01

    The aim of this study was to investigate the neurophysiological bases of Active Music Therapy (AMT) and its effects on the normal brain. Twelve right-handed, healthy, non-musician volunteers were recruited. The subjects underwent 2 AMT sessions based on the free sonorous-music improvisation using rhythmic and melodic instruments. After these sessions, each subject underwent 2 fMRI scan acquisitions while listening to a Syntonic (SP) and an A-Syntonic (AP) Production from the AMT sessions. A 3 T Discovery MR750 scanner with a 16-channel phased array head coil was used, and the image analysis was performed with Brain Voyager QX 2.8. The listening to SP vs AP excerpts mainly activated: (1) the right middle temporal gyrus and right superior temporal sulcus, (2) the right middle frontal gyrus and in particular the right precentral gyrus, (3) the bilateral precuneus, (4) the left superior temporal sulcus and (5) the left middle temporal gyrus. These results are consistent with the psychological bases of the AMT approach and with the activation of brain areas involved in memory and autobiographical processes, and also in personal or interpersonal significant experiences. Further studies are required to confirm these findings and to explain possible effects of AMT in clinical settings.

  2. Targeting Microglial Activation in Stroke Therapy: Pharmacological Tools and Gender Effects

    PubMed Central

    Chen, Y.; Won, S.J.; Xu, Y.; Swanson, R.A.

    2014-01-01

    Ischemic stroke is caused by critical reductions in blood flow to brain or spinal cord. Microglia are the resident immune cells of the central nervous system, and they respond to stroke by assuming an activated phenotype that releases cytotoxic cytokines, reactive oxygen species, proteases, and other factors. This acute, innate immune response may be teleologically adapted to limit infection, but in stroke this response can exacerbate injury by further damaging or killing nearby neurons and other cell types, and by recruiting infiltration of circulating cytotoxic immune cells. The microglial response requires hours to days to fully develop, and this time interval presents a clinically accessible time window for initiating therapy. Because of redundancy in cytotoxic microglial responses, the most effective therapeutic approach may be to target the global gene expression changes involved in microglial activation. Several classes of drugs can do this, including histone deacetylase inhibitors, minocycline and other PARP inhibitors, corticosteroids, and inhibitors of TNFα and scavenger receptor signaling. Here we review the pre-clinical studies in which these drugs have been used to suppress microglial activation after stroke. We also review recent advances in the understanding of sex differences in the CNS inflammatory response, as these differences are likely to influence the efficacy of drugs targeting post-stroke brain inflammation. PMID:24372213

  3. Effects of active music therapy on the normal brain: fMRI based evidence.

    PubMed

    Raglio, Alfredo; Galandra, Caterina; Sibilla, Luisella; Esposito, Fabrizio; Gaeta, Francesca; Di Salle, Francesco; Moro, Luca; Carne, Irene; Bastianello, Stefano; Baldi, Maurizia; Imbriani, Marcello

    2016-03-01

    The aim of this study was to investigate the neurophysiological bases of Active Music Therapy (AMT) and its effects on the normal brain. Twelve right-handed, healthy, non-musician volunteers were recruited. The subjects underwent 2 AMT sessions based on the free sonorous-music improvisation using rhythmic and melodic instruments. After these sessions, each subject underwent 2 fMRI scan acquisitions while listening to a Syntonic (SP) and an A-Syntonic (AP) Production from the AMT sessions. A 3 T Discovery MR750 scanner with a 16-channel phased array head coil was used, and the image analysis was performed with Brain Voyager QX 2.8. The listening to SP vs AP excerpts mainly activated: (1) the right middle temporal gyrus and right superior temporal sulcus, (2) the right middle frontal gyrus and in particular the right precentral gyrus, (3) the bilateral precuneus, (4) the left superior temporal sulcus and (5) the left middle temporal gyrus. These results are consistent with the psychological bases of the AMT approach and with the activation of brain areas involved in memory and autobiographical processes, and also in personal or interpersonal significant experiences. Further studies are required to confirm these findings and to explain possible effects of AMT in clinical settings. PMID:25847861

  4. Cancer therapies activate RIG-I-like receptor pathway through endogenous non-coding RNAs.

    PubMed

    Ranoa, Diana Rose E; Parekh, Akash D; Pitroda, Sean P; Huang, Xiaona; Darga, Thomas; Wong, Anthony C; Huang, Lei; Andrade, Jorge; Staley, Jonathan P; Satoh, Takashi; Akira, Shizuo; Weichselbaum, Ralph R; Khodarev, Nikolai N

    2016-05-01

    Emerging evidence indicates that ionizing radiation (IR) and chemotherapy activate Type I interferon (IFN) signaling in tumor and host cells. However, the mechanism of induction is poorly understood. We identified a novel radioprotective role for the DEXH box RNA helicase LGP2 (DHX58) through its suppression of IR-induced cytotoxic IFN-beta [1]. LGP2 inhibits activation of the RIG-I-like receptor (RLR) pathway upon binding of viral RNA to the cytoplasmic sensors RIG-I (DDX58) and MDA5 (IFIH1) and subsequent IFN signaling via the mitochondrial adaptor protein MAVS (IPS1). Here we show that MAVS is necessary for IFN-beta induction and interferon-stimulated gene expression in the response to IR. Suppression of MAVS conferred radioresistance in normal and cancer cells. Germline deletion of RIG-I, but not MDA5, protected mice from death following total body irradiation, while deletion of LGP2 accelerated the death of irradiated animals. In human tumors depletion of RIG-I conferred resistance to IR and different classes of chemotherapy drugs. Mechanistically, IR stimulated the binding of cytoplasmic RIG-I with small endogenous non-coding RNAs (sncRNAs), which triggered IFN-beta activity. We demonstrate that the small nuclear RNAs U1 and U2 translocate to the cytoplasm after IR treatment, thus stimulating the formation of RIG-I: RNA complexes and initiating downstream signaling events. Taken together, these findings suggest that the physiologic responses to radio-/chemo-therapy converge on an antiviral program in recruitment of the RLR pathway by a sncRNA-dependent activation of RIG-I which commences cytotoxic IFN signaling. Importantly, activation of interferon genes by radiation or chemotherapy is associated with a favorable outcome in patients undergoing treatment for cancer. To our knowledge, this is the first demonstration of a cell-intrinsic response to clinically relevant genotoxic treatments mediated by an RNA-dependent mechanism.

  5. Cancer therapies activate RIG-I-like receptor pathway through endogenous non-coding RNAs

    PubMed Central

    Ranoa, Diana Rose E.; Parekh, Akash D.; Pitroda, Sean P.; Huang, Xiaona; Darga, Thomas; Wong, Anthony C.; Huang, Lei; Andrade, Jorge; Staley, Jonathan P.; Satoh, Takashi; Akira, Shizuo

    2016-01-01

    Emerging evidence indicates that ionizing radiation (IR) and chemotherapy activate Type I interferon (IFN) signaling in tumor and host cells. However, the mechanism of induction is poorly understood. We identified a novel radioprotective role for the DEXH box RNA helicase LGP2 (DHX58) through its suppression of IR-induced cytotoxic IFN-beta [1]. LGP2 inhibits activation of the RIG-I-like receptor (RLR) pathway upon binding of viral RNA to the cytoplasmic sensors RIG-I (DDX58) and MDA5 (IFIH1) and subsequent IFN signaling via the mitochondrial adaptor protein MAVS (IPS1). Here we show that MAVS is necessary for IFN-beta induction and interferon-stimulated gene expression in the response to IR. Suppression of MAVS conferred radioresistance in normal and cancer cells. Germline deletion of RIG-I, but not MDA5, protected mice from death following total body irradiation, while deletion of LGP2 accelerated the death of irradiated animals. In human tumors depletion of RIG-I conferred resistance to IR and different classes of chemotherapy drugs. Mechanistically, IR stimulated the binding of cytoplasmic RIG-I with small endogenous non-coding RNAs (sncRNAs), which triggered IFN-beta activity. We demonstrate that the small nuclear RNAs U1 and U2 translocate to the cytoplasm after IR treatment, thus stimulating the formation of RIG-I: RNA complexes and initiating downstream signaling events. Taken together, these findings suggest that the physiologic responses to radio-/chemo-therapy converge on an antiviral program in recruitment of the RLR pathway by a sncRNA-dependent activation of RIG-I which commences cytotoxic IFN signaling. Importantly, activation of interferon genes by radiation or chemotherapy is associated with a favorable outcome in patients undergoing treatment for cancer. To our knowledge, this is the first demonstration of a cell-intrinsic response to clinically relevant genotoxic treatments mediated by an RNA-dependent mechanism. PMID:27034163

  6. Effect of Antiviral Therapy on Serum Activity of Angiotensin Converting Enzyme in Patients with Chronic Hepatitis C

    PubMed Central

    Husic-Selimovic, Azra; Sofic, Amela; Huskic, Jasminko; Bulja, Deniz

    2016-01-01

    Introduction: Renin-angiotenzin system (RAS) is frequently activated in patients with chronic liver disease. Angiotenzin - II (AT-II), produced by angiotenzin converting enzyme (ACE), has many physiological effects, including an important role in liver fibrogenesis. Combined antiviral therapy with PEG-IFN and ribavirin besides its antiviral effect also leads to a reduction in liver parenchyma fibrosis. Aim of the study: Determining the value of ACE in serum of patients with chronic hepatitis C before and after combined antiviral therapy, as well as the value of ACE activities in sera of the control group. Materials and methods: We studied 50 patients treated at Gastroenterohepatology Department, in the time-period of four years. Value of ACE in serum was determined by Olympus AU 400 device, with application of kit “Infinity TN ACE Liquid Stable Reagent”. HCV RNA levels in sera were measured by real time PCR. HCV RNA test was performed with modular analysis of AMPLICOR and COBAS AMPLICOR HCV MONITOR test v2.0, which has proved infection and was used for quantification of the viruses and monitoring of the patients’ response to therapy. Liver histology was evaluated in accordance with the level of necroinflammation activity and stage of fibrosis. Results: Serum activities of ACE in chronic hepatitis C patients is statistically higher than the values in the control group (p=0.02). Antiviral therapy in chronic hepatitis C patients statistically decreases serum activities of ACE (p= 0.02) and indirectly affects fibrogenesis of the liver parenchyma. Correlation between ACE and ALT activity after the therapy was proved (0.3934). Conclusion: Our findings suggest that the activity of ACE in serum is a good indirect parameter of the liver damage, and could be used as an indirect prognostic factor of the level of liver parenchyma damage. Serum activity of ACE can be used as a parameter for non-invasive assessment of intensity of liver damage. PMID:27147779

  7. Ion Storage with the High Performance Antiproton Trap (HiPAT)

    NASA Technical Reports Server (NTRS)

    Martin, James; Lewis, Raymond; Chakrabarti, Suman; Pearson, Boise

    2002-01-01

    The matter antimatter reaction represents the densest form of energy storage/release known to modern physics: as such it offers one of the most compact sources of power for future deep space exploration. To take the first steps along this path, NASA-Marshall Space Flight Center is developing a storage system referred to as the High Performance Antiproton Trap (HiPAT) with a goal of maintaining 10(exp 12) particles for up to 18 days. Experiments have been performed with this hardware using normal matter (positive hydrogen ions) to assess the device's ability to hold charged particles. These ions are currently created using an electron gun method to ionize background gas; however, this technique is limited by the quantity that can be captured. To circumvent this issue, an ion source is currently being commissioned which will greatly increase the number of ions captured and more closely simulate actual operations expected at an antiproton production facility. Ions have been produced, stored for various time intervals, and then extracted against detectors to measure species, quantity and energy. Radio frequency stabilization has been tested as a method to prolong ion lifetime: results show an increase in the baseline 1/e lifetime of trapped particles from hours to days. Impurities in the residual background gas (typically carbon-containing species CH4, CO, CO2, etc.) present a continuing problem by reducing the trapped hydrogen population through the mechanism of ion charge exchange.

  8. Network and user interface for PAT DOME virtual motion environment system

    NASA Technical Reports Server (NTRS)

    Worthington, J. W.; Duncan, K. M.; Crosier, W. G.

    1993-01-01

    The Device for Orientation and Motion Environments Preflight Adaptation Trainer (DOME PAT) provides astronauts a virtual microgravity sensory environment designed to help alleviate tye symptoms of space motion sickness (SMS). The system consists of four microcomputers networked to provide real time control, and an image generator (IG) driving a wide angle video display inside a dome structure. The spherical display demands distortion correction. The system is currently being modified with a new graphical user interface (GUI) and a new Silicon Graphics IG. This paper will concentrate on the new GUI and the networking scheme. The new GUI eliminates proprietary graphics hardware and software, and instead makes use of standard and low cost PC video (CGA) and off the shelf software (Microsoft's Quick C). Mouse selection for user input is supported. The new Silicon Graphics IG requires an Ethernet interface. The microcomputer known as the Real Time Controller (RTC), which has overall control of the system and is written in Ada, was modified to use the free public domain NCSA Telnet software for Ethernet communications with the Silicon Graphics IG. The RTC also maintains the original ARCNET communications through Novell Netware IPX with the rest of the system. The Telnet TCP/IP protocol was first used for real-time communication, but because of buffering problems the Telnet datagram (UDP) protocol needed to be implemented. Since the Telnet modules are written in C, the Adap pragma 'Interface' was used to interface with the network calls.

  9. Implementation of transmission NIR as a PAT tool for monitoring drug transformation during HME processing.

    PubMed

    Islam, Muhammad T; Scoutaris, Nikolaos; Maniruzzaman, Mohammed; Moradiya, Hiren G; Halsey, Sheelagh A; Bradley, Michael S A; Chowdhry, Babur Z; Snowden, Martin J; Douroumis, Dennis

    2015-10-01

    The aim of the work reported herein was to implement process analytical technology (PAT) tools during hot melt extrusion (HME) in order to obtain a better understanding of the relationship between HME processing parameters and the extruded formulations. For the first time two in-line NIR probes (transmission and reflectance) have been coupled with HME to monitor the extrusion of the water insoluble drug indomethacin (IND) in the presence of Soluplus (SOL) or Kollidon VA64 hydrophilic polymers. In-line extrusion monitoring of sheets, produced via a specially designed die, was conducted at various drug/polymer ratios and processing parameters. Characterisation of the extruded transparent sheets was also undertaken by using DSC, XRPD and Raman mapping. Analysis of the experimental findings revealed the production of molecular solutions where IND is homogeneously blended (ascertained by Raman mapping) in the polymer matrices, as it acts as a plasticizer for both hydrophilic polymers. PCA analysis of the recorded NIR signals showed that the screw speed used in HME affects the recorded spectra but not the homogeneity of the embedded drug in the polymer sheets. The IND/VA64 and IND/SOL extruded sheets displayed rapid dissolution rates with 80% and 30% of the IND being released, respectively within the first 20min.

  10. Dog-assisted therapies and activities in rehabilitation of children with cerebral palsy and physical and mental disabilities.

    PubMed

    Elmacı, Dilek Tunçay; Cevizci, Sibel

    2015-05-12

    The aim of the present study was to evaluate dog-assisted therapies and activities in the rehabilitation of children with cerebral palsy and physical and mental disabilities who have difficulties in benefiting from well-being and health-improving services. This descriptive-explanatory study was conducted in disabled children of various ages between 2008 and 2011 by an experienced team in a private training and rehabilitation center in Antalya (Turkey). In this study, five study groups were formed among the children with physical and mental disabilities. During the therapy studies, three dogs were used. For each therapy group, the goals for the children and therapist were defined, and the activities were determined according to these goals. The entire study process was followed using audio-records and photographs of patients. The expected targets were reached in all study groups. The children who experienced fear, anxiety and difficulties due to their disabilities in daily life learned to cope with their anxieties and fears, set goals and make plans to achieve their aims. During this study, the children improved their abilities to use their bodies according to their capabilities. Accordingly, they improved their ability to develop empathy between themselves and a therapy dog, to receive and present help, and to communicate. The results of the present study revealed that dog-assisted therapies and activities can be a supportive method for routine treatment procedures in the rehabilitation of children with cerebral palsy and physical and mental disabilities.

  11. Dog-Assisted Therapies and Activities in Rehabilitation of Children with Cerebral Palsy and Physical and Mental Disabilities

    PubMed Central

    Tunçay Elmacı, Dilek; Cevizci, Sibel

    2015-01-01

    The aim of the present study was to evaluate dog-assisted therapies and activities in the rehabilitation of children with cerebral palsy and physical and mental disabilities who have difficulties in benefiting from well-being and health-improving services. This descriptive-explanatory study was conducted in disabled children of various ages between 2008 and 2011 by an experienced team in a private training and rehabilitation center in Antalya (Turkey). In this study, five study groups were formed among the children with physical and mental disabilities. During the therapy studies, three dogs were used. For each therapy group, the goals for the children and therapist were defined, and the activities were determined according to these goals. The entire study process was followed using audio-records and photographs of patients. The expected targets were reached in all study groups. The children who experienced fear, anxiety and difficulties due to their disabilities in daily life learned to cope with their anxieties and fears, set goals and make plans to achieve their aims. During this study, the children improved their abilities to use their bodies according to their capabilities. Accordingly, they improved their ability to develop empathy between themselves and a therapy dog, to receive and present help, and to communicate. The results of the present study revealed that dog-assisted therapies and activities can be a supportive method for routine treatment procedures in the rehabilitation of children with cerebral palsy and physical and mental disabilities. PMID:25985307

  12. Comprehensive clinical studies in 34 patients with molecularly defined UPD(14)pat and related conditions (Kagami-Ogata syndrome).

    PubMed

    Kagami, Masayo; Kurosawa, Kenji; Miyazaki, Osamu; Ishino, Fumitoshi; Matsuoka, Kentaro; Ogata, Tsutomu

    2015-11-01

    Paternal uniparental disomy 14 (UPD(14)pat) and epimutations and microdeletions affecting the maternally derived 14q32.2 imprinted region lead to a unique constellation of clinical features such as facial abnormalities, small bell-shaped thorax with a coat-hanger appearance of the ribs, abdominal wall defects, placentomegaly, and polyhydramnios. In this study, we performed comprehensive clinical studies in patients with UPD(14)pat (n=23), epimutations (n=5), and microdeletions (n=6), and revealed several notable findings. First, a unique facial appearance with full cheeks and a protruding philtrum and distinctive chest roentgenograms with increased coat-hanger angles to the ribs constituted the pathognomonic features from infancy through childhood. Second, birth size was well preserved, with a median birth length of ±0 SD (range, -1.7 to +3.0 SD) and a median birth weight of +2.3 SD (range, +0.1 to +8.8 SD). Third, developmental delay and/or intellectual disability was invariably present, with a median developmental/intellectual quotient of 55 (range, 29-70). Fourth, hepatoblastoma was identified in three infantile patients (8.8%), and histological examination in two patients showed a poorly differentiated embryonal hepatoblastoma with focal macrotrabecular lesions and well-differentiated hepatoblastoma, respectively. These findings suggest the necessity of an adequate support for developmental delay and periodical screening for hepatoblastoma in the affected patients, and some phenotypic overlap between UPD(14)pat and related conditions and Beckwith-Wiedemann syndrome. On the basis of our previous and present studies that have made a significant contribution to the clarification of underlying (epi)genetic factors and the definition of clinical findings, we propose the name 'Kagami-Ogata syndrome' for UPD(14)pat and related conditions.

  13. Comprehensive clinical studies in 34 patients with molecularly defined UPD(14)pat and related conditions (Kagami-Ogata syndrome).

    PubMed

    Kagami, Masayo; Kurosawa, Kenji; Miyazaki, Osamu; Ishino, Fumitoshi; Matsuoka, Kentaro; Ogata, Tsutomu

    2015-11-01

    Paternal uniparental disomy 14 (UPD(14)pat) and epimutations and microdeletions affecting the maternally derived 14q32.2 imprinted region lead to a unique constellation of clinical features such as facial abnormalities, small bell-shaped thorax with a coat-hanger appearance of the ribs, abdominal wall defects, placentomegaly, and polyhydramnios. In this study, we performed comprehensive clinical studies in patients with UPD(14)pat (n=23), epimutations (n=5), and microdeletions (n=6), and revealed several notable findings. First, a unique facial appearance with full cheeks and a protruding philtrum and distinctive chest roentgenograms with increased coat-hanger angles to the ribs constituted the pathognomonic features from infancy through childhood. Second, birth size was well preserved, with a median birth length of ±0 SD (range, -1.7 to +3.0 SD) and a median birth weight of +2.3 SD (range, +0.1 to +8.8 SD). Third, developmental delay and/or intellectual disability was invariably present, with a median developmental/intellectual quotient of 55 (range, 29-70). Fourth, hepatoblastoma was identified in three infantile patients (8.8%), and histological examination in two patients showed a poorly differentiated embryonal hepatoblastoma with focal macrotrabecular lesions and well-differentiated hepatoblastoma, respectively. These findings suggest the necessity of an adequate support for developmental delay and periodical screening for hepatoblastoma in the affected patients, and some phenotypic overlap between UPD(14)pat and related conditions and Beckwith-Wiedemann syndrome. On the basis of our previous and present studies that have made a significant contribution to the clarification of underlying (epi)genetic factors and the definition of clinical findings, we propose the name 'Kagami-Ogata syndrome' for UPD(14)pat and related conditions. PMID:25689926

  14. Regorafenib: Antitumor Activity upon Mono and Combination Therapy in Preclinical Pediatric Malignancy Models.

    PubMed

    Daudigeos-Dubus, Estelle; Le Dret, Ludivine; Lanvers-Kaminsky, Claudia; Bawa, Olivia; Opolon, Paule; Vievard, Albane; Villa, Irène; Pagès, Mélanie; Bosq, Jacques; Vassal, Gilles; Zopf, Dieter; Geoerger, Birgit

    2015-01-01

    The multikinase inhibitor regorafenib (BAY 73-4506) exerts both anti-angiogenic and anti-tumorigenic activity in adult solid malignancies mainly advanced colorectal cancer and gastrointestinal stromal tumors. We intended to explore preclinically the potential of regorafenib against solid pediatric malignancies alone and in combination with anticancer agents to guide the pediatric development plan. In vitro effects on cell proliferation were screened against 33 solid tumor cell lines of the Innovative Therapies for Children with Cancer (ITCC) panel covering five pediatric solid malignancies. Regorafenib inhibited cell proliferation with a mean half maximal growth inhibition of 12.5 μmol/L (range 0.7 μmol/L to 28 μmol/L). In vivo, regorafenib was evaluated alone at 10 or 30 mg/kg/d or in combination with radiation, irinotecan or the mitogen-activated protein kinase kinase (MEK) inhibitor refametinib against various tumor types, including patient-derived brain tumor models with an amplified platelet-derived growth factor receptor A (PDGFRA) gene. Regorafenib alone significantly inhibited tumor growth in all xenografts derived from nervous system and connective tissue tumors. Enhanced effects were observed when regorafenib was combined with irradiation and irinotecan against PDGFRA amplified IGRG93 glioma and IGRM57 medulloblastoma respectively, resulting in 100% tumor regressions. Antitumor activity was associated with decreased tumor vascularization, inhibition of PDGFR signaling, and induction of apoptotic cell death. Our work demonstrates that regorafenib exhibits significant antitumor activity in a wide spectrum of preclinical pediatric models through inhibition of angiogenesis and induction of apoptosis. Furthermore, radio- and chemosensitizing effects were observed with DNA damaging agents in PDGFR amplified tumors. PMID:26599335

  15. Regorafenib: Antitumor Activity upon Mono and Combination Therapy in Preclinical Pediatric Malignancy Models

    PubMed Central

    Daudigeos-Dubus, Estelle; Le Dret, Ludivine; Lanvers-Kaminsky, Claudia; Bawa, Olivia; Opolon, Paule; Vievard, Albane; Villa, Irène; Pagès, Mélanie; Bosq, Jacques; Vassal, Gilles; Zopf, Dieter; Geoerger, Birgit

    2015-01-01

    The multikinase inhibitor regorafenib (BAY 73–4506) exerts both anti-angiogenic and anti-tumorigenic activity in adult solid malignancies mainly advanced colorectal cancer and gastrointestinal stromal tumors. We intended to explore preclinically the potential of regorafenib against solid pediatric malignancies alone and in combination with anticancer agents to guide the pediatric development plan. In vitro effects on cell proliferation were screened against 33 solid tumor cell lines of the Innovative Therapies for Children with Cancer (ITCC) panel covering five pediatric solid malignancies. Regorafenib inhibited cell proliferation with a mean half maximal growth inhibition of 12.5 μmol/L (range 0.7 μmol/L to 28 μmol/L). In vivo, regorafenib was evaluated alone at 10 or 30 mg/kg/d or in combination with radiation, irinotecan or the mitogen-activated protein kinase kinase (MEK) inhibitor refametinib against various tumor types, including patient-derived brain tumor models with an amplified platelet-derived growth factor receptor A (PDGFRA) gene. Regorafenib alone significantly inhibited tumor growth in all xenografts derived from nervous system and connective tissue tumors. Enhanced effects were observed when regorafenib was combined with irradiation and irinotecan against PDGFRA amplified IGRG93 glioma and IGRM57 medulloblastoma respectively, resulting in 100% tumor regressions. Antitumor activity was associated with decreased tumor vascularization, inhibition of PDGFR signaling, and induction of apoptotic cell death. Our work demonstrates that regorafenib exhibits significant antitumor activity in a wide spectrum of preclinical pediatric models through inhibition of angiogenesis and induction of apoptosis. Furthermore, radio- and chemosensitizing effects were observed with DNA damaging agents in PDGFR amplified tumors. PMID:26599335

  16. Hypertension among HIV-Infected Adults Receiving Highly Active Antiretroviral Therapy (HAART) in Malaysia

    PubMed Central

    Hejazi, Nazisa; MSL, Huang; Lin, Khor Geok; Choong, Lee Christopher Kwok

    2014-01-01

    There are increasing researches about non-communicable disease such as elevated blood pressure among people living with HIV before and after initiation of highly active antiretroviral therapy (HAART). This cross-sectional study was designed to determine the prevalence of hypertension and associated risk factors among 340 HIV-infected patients on antiretroviral therapy at a Malaysian public hospital providing HIV-related treatment. Data on socioeconomic background, anthropometry, medical history and dietary intake of the patients were collected. Hypertension is defined as blood pressure ≥130/85 (mm Hg). Prevalence of hypertension was 45.60% (n=155) of which 86.5% of the hypertensive group were male (n=134). The results showed that increase in age (OR 1.051, 95% confidence interval (CI) 1.024-1.078), higher body mass index (OR 1.18, 95% CI 1.106-2.71), bigger waist circumference (OR 1.18, 95%CI 1.106-2.71), higher waist-hip ratio (OR 1.070, 95%CI 1.034-1.106), higher fasting plasma glucose (OR 1.332, 95% CI 0.845-2.100) and percentage energy intake from protein >15 (OR 2.519, 95%CI 1.391-4.561) were significant risk factors for hypertension (p<0.001). After adjusting for other variables, increasing age (adjusted odds ratio (aOR) 1.069 95%CI 1.016-1.124, p=0.010), being male (aOR 3.026, 95%CI 1.175-7.794, p=0.022) and higher body mass index (aOR 1.26, 95%CI 1.032-1.551, p=0.024) were independently associated with hypertension. None of the antiretroviral therapy and immunologic factors was linked to hypertension. In conclusion hypertension among PLHIV was linked to the well-known risk factors such as age, gender and body mass index. With HAART, people can live longer by making monitoring and control of some reversible factors, especially excessive weight gain for maintaining quality of life. PMID:24576366

  17. Renal responses to long-term carotid baroreflex activation therapy in patients with drug-resistant hypertension.

    PubMed

    Alnima, Teba; de Leeuw, Peter W; Tan, Frans E S; Kroon, Abraham A

    2013-06-01

    Carotid baroreflex activation has been demonstrated to provide enduring reductions in arterial blood pressure. The aim of this study was to investigate the effect of long-term therapy on renal function. A total of 322 patients were enrolled in the Rheos Pivotal Trial. Group 1 consisted of 236 patients who started baroreflex activation therapy 1 month after device implantation, whereas in the 86 patients from group 2 the device was activated 6 months later. Serum creatinine and urine albumin/creatinine ratio were collected at screening (before device activation), and at months 6 and 12. Multilevel statistical analyses were adjusted for various covariables. Serum creatinine increased from 78 to 84 μmol/L, and glomerular filtration rate decreased from 92 to 87 mL/min per 1.73 m(2) in group 1 at month 6 (P<0.05). These values did not change any further after 12 months of therapy. Patients with highest glomerular filtration rate showed the greatest decrease in glomerular filtration. Group 2 showed the same trends as group 1 even before device activation at month 6. Systolic blood pressure reduction seemed to be significantly related to the change in glomerular filtration rate in both groups. Albumin/creatinine ratio did not change in both groups during follow-up. In conclusion, baroreflex activation therapy in hypertensive patients is associated with an initial mild decrease in glomerular filtration rate, which may be considered as a normal hemodynamic response to the drop in blood pressure. Long-term treatment does not result in further decrease in renal function, indicating baroreflex activation as a safe and effective therapy.

  18. Anti-TNF-α therapy reduces endothelial cell activation in non-diabetic ankylosing spondylitis patients.

    PubMed

    Genre, Fernanda; López-Mejías, Raquel; Miranda-Filloy, José A; Ubilla, Begoña; Mijares, Verónica; Carnero-López, Beatriz; Gómez-Acebo, Inés; Dierssen-Sotos, Trinidad; Remuzgo-Martínez, Sara; Blanco, Ricardo; Pina, Trinitario; González-Juanatey, Carlos; Llorca, Javier; González-Gay, Miguel A

    2015-12-01

    Endothelial dysfunction can be detected by the presence of elevated levels of biomarkers of endothelial cell activation. In this study, we aimed to establish whether correlations of these biomarkers with characteristics of patients with ankylosing spondylitis (AS) exist. We also studied the effect of anti-TNF-α therapy on these biomarkers. Serum sE-selectin, MCP-1 and sVCAM-1 levels were measured by ELISA in 30 non-diabetic AS patients undergoing anti-TNF-α therapy, immediately before and after an infusion of infliximab. Correlations of these biomarkers with clinical features, systemic inflammation, metabolic syndrome and other serum and plasma biomarkers of cardiovascular risk were studied. Potential changes in the concentration of these biomarkers following an infliximab infusion were also assessed. sE-selectin showed a positive correlation with CRP (p = 0.02) and with other endothelial cell activation biomarkers such as sVCAM-1 (p = 0.019) and apelin (p = 0.008). sVCAM-1 negatively correlated with BMI (p = 0.018), diastolic blood pressure (p = 0.008) and serum glucose (p = 0.04). sVCAM-1 also showed a positive correlation with VAS spinal pain (p = 0.014) and apelin (p < 0.001). MCP-1 had a negative correlation with LDL cholesterol (p = 0.026) and ESR (p = 0.017). Patients with hip involvement and synovitis and/or enthesitis in other peripheral joints showed higher levels of MCP-1 (p = 0.004 and 0.02, respectively). A single infliximab infusion led to a significant reduction in sE-selectin (p = 0.0015) and sVCAM-1 (p = 0.04). Endothelial dysfunction correlates with inflammation and metabolic syndrome features in patients with AS. A beneficial effect of the anti-TNF-α blockade on endothelial dysfunction, manifested by a reduction in levels of biomarkers of endothelial cell activation, was observed.

  19. Cognitive functioning during highly active antiretroviral therapy interruption in human immunodeficiency virus type 1 infection.

    PubMed

    Childers, Meredith E; Woods, Steven Paul; Letendre, Scott; McCutchan, J Allen; Rosario, Debralee; Grant, Igor; Mindt, Monica Rivera; Ellis, Ronald J

    2008-11-01

    Although no longer considered therapeutically beneficial, antiretroviral treatment interruptions (TIs) still occur frequently among patients with human immunodeficiency virus (HIV) infection for a variety of reasons. TIs typically result in viral rebound and worsening immunosuppression, which in turn are risk factors for neurocognitive decline and dementia. We sought to determine the extent of neurocognitive risk with TIs and subsequent reintroduction of highly active antiretroviral therapy (HAART) by using a comprehensive, sensitive neuropsychological assessment and by concurrently determining changes in plasma and cerebrospinal fluid (CSF) viral load and CD4 counts. Prospective, serial, clinical evaluations including neuropsychological (NP) testing and measurement of plasma HIV RNA and CD4 count and mood state were performed on HIV-1-infected individuals (N=11) at three time points: (1) prior to a TI, while on HAART; (2) after TIs averaging 6 months; and (3) after reinitiating HAART therapy. During TI, plasma HIV RNA increased and CD4 counts declined significantly, but NP performance did not change. Following reinitiation of HAART, viral loads fell below pre-TI levels, and CD4 counts rose. Improved viral suppression and immune restoration with reinitiation of HAART resulted in significant improvement in neurocognitive performance. No changes on comprehensive questionnaires of mood state were observed in relation to TI.NP performance and mood state remained stable during TIs despite worsened viral loads and CD4 counts. Because "practice effects" are generally greatest between the first and second NP testing sessions, improvement at the third, post-TI time point was unlikely to be accounted for by practice. TIs of up to 6 months appear to be neurocognitively and psychiatrically safe for most patients.

  20. Highly Active Antiretroviral Therapy and Adverse Birth Outcomes Among HIV-Infected Women in Botswana

    PubMed Central

    Chen, Jennifer Y.; Ribaudo, Heather J.; Souda, Sajini; Parekh, Natasha; Ogwu, Anthony; Lockman, Shahin; Powis, Kathleen; Dryden-Peterson, Scott; Creek, Tracy; Jimbo, William; Madidimalo, Tebogo; Makhema, Joseph; Essex, Max; Shapiro, Roger L

    2012-01-01

    Background. It is unknown whether adverse birth outcomes are associated with maternal highly active antiretroviral therapy (HAART) in pregnancy, particularly in resource-limited settings. Methods. We abstracted obstetrical records at 6 sites in Botswana for 24 months. Outcomes included stillbirths (SBs), preterm delivery (PTD), small for gestational age (SGA), and neonatal death (NND). Among human immunodeficiency virus (HIV)–infected women, comparisons were limited to HAART exposure status at conception, and those with similar opportunities for outcomes. Comparisons were adjusted for CD4+ lymphocyte cell count. Results. Of 33 148 women, 32 113 (97%) were tested for HIV, of whom 9504 (30%) were HIV infected. Maternal HIV was significantly associated with SB, PTD, SGA, and NND. Compared with all other HIV-infected women, those continuing HAART from before pregnancy had higher odds of PTD (adjusted odds ratio [AOR], 1.2; 95% confidence interval [CI], 1.1, 1.4), SGA (AOR, 1.8; 95% CI, 1.6, 2.1) and SB (AOR, 1.5; 95% CI, 1.2, 1.8). Among women initiating antiretroviral therapy in pregnancy, HAART use (vs zidovudine) was associated with higher odds of PTD (AOR, 1.4; 95% CI, 1.2, 1.8), SGA (AOR, 1.5; 95% CI, 1.2, 1.9), and SB (AOR, 2.5; 95% CI, 1.6, 3.9). Low CD4+ was independently associated with SB and SGA, and maternal hypertension during pregnancy with PTD, SGA, and SB. Conclusions. HAART receipt during pregnancy was associated with increased PTD, SGA, and SB. PMID:23066160

  1. HIV-Associated Lung Cancer in the Era of Highly Active Antiretroviral Therapy (HAART)

    PubMed Central

    Pakkala, Suchita; Chen, Zhengjia; Rimland, David; Owonikoko, Taofeek K.; Gunthel, Clifford; Brandes, Johann R.; Saba, Nabil R.; Shin, Dong M.; Curran, Walter J.; Khuri, Fadlo R.; Ramalingam, Suresh S.

    2011-01-01

    Background Lung cancer is the leading cause of death among non-acquired immunodeficiency syndrome (AIDS) defining malignancies. Since highly active anti-retroviral therapy (HAART) has improved survival for human immunodeficiency virus (HIV) patients, we evaluated lung cancer outcomes in the HAART era. Methods HIV-positive patients diagnosed with lung cancer in our institution during the HAART era (1995-2008) were analyzed. Patient charts were reviewed for clinical and laboratory data. CD4 count at diagnosis was treated as a continuous variable and subcategorized into distinct variables with 3 cut-off points (50, 200, & 500 μl). Pearson’s correlation coefficients were estimated for each covariate studied. Survival was determined by the Kaplan-Meier method. Results Out of 80 patients, 73 had non-small cell lung cancer. Baseline characteristics were: median age-52 yrs; male-80%; African American-84%; injection drug use-25%; smokers-100%; and prior exposure to antiretroviral agents-55%. Mean CD4 count and viral load were 304 μL and 82,420 copies/ml, respectively at cancer diagnosis. The latency between diagnosis of HIV and lung cancer was significantly shorter in women (4.1 yrs vs. 7.7 yrs, P=0.02) and 71% of the patients received anti-cancer therapy. The 1- and 3-year survival rates were 31% and 4% overall. Grade 3/4 toxicities occurred in 60% with chemo-radiation vs. 36% with chemotherapy. Cancer-related survival was better for patients with CD4 count >200 (P=0.0298) and >500 (P=0.0076). Conclusions The latency from diagnosis of HIV to lung cancer was significantly shorter for women. Although outcomes for lung cancer patients with HIV remain poor, high CD4 count is associated with an improved lung cancer-related survival. PMID:21713759

  2. Natural Xanthones from Garcinia mangostana with Multifunctional Activities for the Therapy of Alzheimer's Disease.

    PubMed

    Wang, Sheng-Nan; Li, Qian; Jing, Ming-Hua; Alba, Espargaró; Yang, Xiao-Hong; Sabaté, Raimon; Han, Yi-Fan; Pi, Rong-Biao; Lan, Wen-Jian; Yang, Xiao-Bo; Chen, Jing-Kao

    2016-07-01

    Natural xanthones have diversity pharmacological activities. Here, a series of xanthones isolated from the pericarps of Garcinia mangostana Linn, named α-Mangostin, 8-Deoxygartanin, Gartanin, Garciniafuran, Garcinone C, Garcinone D, and γ-Mangostin were investigated. Biological screening performed in vitro and in Escherichia coli cells indicated that most of the xanthones exhibited significant inhibition of self-induced β-amyloid (Aβ) aggregation and also β-site amyloid precursor protein-cleaving enzyme 1, acted as potential antioxidants and biometal chelators. Among these compounds, α-Mangostin, Gartanin, Garcinone C and γ-Mangostin showed better antioxidant properties to scavenge Diphenyl-1-(2,4,6-trinitrophenyl) hydrazyl (DPPH) free radical than Trolox, and potent neuroprotective effects against glutamate-induced HT22 cell death partly by up-regulating HO-1 protein level and then scavenging reactive oxygen species. Moreover, Gartanin, Garcinone C and γ-Mangostin could be able to penetrate the blood-brain barrier (BBB) in vitro. These findings suggest that the natural xanthones have multifunctional activities against Alzheimer's disease (AD) and could be promising compounds for the therapy of AD.

  3. Natural Xanthones from Garcinia mangostana with Multifunctional Activities for the Therapy of Alzheimer's Disease.

    PubMed

    Wang, Sheng-Nan; Li, Qian; Jing, Ming-Hua; Alba, Espargaró; Yang, Xiao-Hong; Sabaté, Raimon; Han, Yi-Fan; Pi, Rong-Biao; Lan, Wen-Jian; Yang, Xiao-Bo; Chen, Jing-Kao

    2016-07-01

    Natural xanthones have diversity pharmacological activities. Here, a series of xanthones isolated from the pericarps of Garcinia mangostana Linn, named α-Mangostin, 8-Deoxygartanin, Gartanin, Garciniafuran, Garcinone C, Garcinone D, and γ-Mangostin were investigated. Biological screening performed in vitro and in Escherichia coli cells indicated that most of the xanthones exhibited significant inhibition of self-induced β-amyloid (Aβ) aggregation and also β-site amyloid precursor protein-cleaving enzyme 1, acted as potential antioxidants and biometal chelators. Among these compounds, α-Mangostin, Gartanin, Garcinone C and γ-Mangostin showed better antioxidant properties to scavenge Diphenyl-1-(2,4,6-trinitrophenyl) hydrazyl (DPPH) free radical than Trolox, and potent neuroprotective effects against glutamate-induced HT22 cell death partly by up-regulating HO-1 protein level and then scavenging reactive oxygen species. Moreover, Gartanin, Garcinone C and γ-Mangostin could be able to penetrate the blood-brain barrier (BBB) in vitro. These findings suggest that the natural xanthones have multifunctional activities against Alzheimer's disease (AD) and could be promising compounds for the therapy of AD. PMID:27038926

  4. Silent left ventricular dysfunction during routine activity after thrombolytic therapy for acute myocardial infarction

    SciTech Connect

    Kayden, D.S.; Wackers, F.J.; Zaret, B.L. )

    1990-06-01

    To investigate prospectively the occurrence and significance of postinfarction transient left ventricular dysfunction, 33 ambulatory patients who underwent thrombolytic therapy after myocardial infarction were monitored continuously for 187 +/- 56 min during normal activity with a radionuclide left ventricular function detector at the time of hospital discharge. Twelve patients demonstrated 19 episodes of transient left ventricular dysfunction (greater than 0.05 decrease in ejection fraction, lasting greater than or equal to 1 min), with no change in heart rate. Only two episodes in one patient were associated with chest pain and electrocardiographic changes. The baseline ejection fraction was 0.52 +/- 0.12 in patients with transient left ventricular dysfunction and 0.51 +/- 0.13 in patients without dysfunction (p = NS). At follow-up study (19.2 +/- 5.4 months), cardiac events (unstable angina, myocardial infarction or death) occurred in 8 of 12 patients with but in only 3 of 21 patients without transient left ventricular dysfunction (p less than 0.01). During submaximal supine bicycle exercise, only two patients demonstrated a decrease in ejection fraction greater than or equal to 0.05 at peak exercise; neither had a subsequent cardiac event. These data suggest that transient episodes of silent left ventricular dysfunction at hospital discharge in patients treated with thrombolysis after myocardial infarction are common and associated with a poor outcome. Continuous left ventricular function monitoring during normal activity may provide prognostic information not available from submaximal exercise test results.

  5. Smart hyaluronidase-actived theranostic micelles for dual-modal imaging guided photodynamic therapy.

    PubMed

    Li, Wenjun; Zheng, Cuifang; Pan, Zhengyin; Chen, Chi; Hu, Dehong; Gao, Guanhui; Kang, Shendong; Cui, Haodong; Gong, Ping; Cai, Lintao

    2016-09-01

    We here report smart hyaluronidase-actived theranostic nanoparticles based on hyaluronic acid (HA) coupled with chlorin e6 (Ce6) via adipic dihydrazide (ADH) forming HA-ADH-Ce6 conjugates and self-assembling into HACE NPs. The resulting nanoparticles showed stable nano-structure in aqueous condition with uniform size distribution and can be actively disassembled in the presence of hyaluronidase (over-expressed in tumor cells), exhibiting hyaluronidase-responsive "OFF/ON" behavior of fluorescence signal. The HACE NPs were rapidly taken up to human lung cancer cells A549 via CD44 (the HA receptor on the surface of tumor cells) receptor mediated endocytosis. Upon laser irradiation, the HACE NPs realized good near-infrared fluorescence imaging and photoacoustic imaging in the tumor bearing mice, which showed 5-fold higher fluorescence intensity and 3-fold higher photoacoustic (PA) intensity than free Ce6, respectively. In addition, under low dose of laser power, the HACE NPs presented more effective photodynamic therapy to suppression of tumor growth than free Ce6 in vitro and in vivo. Overall, these results suggest that the well-defined HACE NPs is a biocompatible theranostic nanoplatform for in vivo dual-modal tumor imaging and phototherapy simultaneously. PMID:27262027

  6. Efficacy of physical activity counseling plus sleep restriction therapy on the patients with chronic insomnia

    PubMed Central

    Wang, Jihui; Yin, Guangxia; Li, Guanying; Liang, Wenjing; Wei, Qinling

    2015-01-01

    Objective Lack of physical activity (PA) is common in patients with chronic insomnia. Studies to increase PA and decrease sedentary behavior in those patients are limited. Therefore, we investigated the efficacy of “PA counseling combined with sleep restriction (SR) therapy (PASR)” vs only SR in the patients with chronic insomnia. Methods Seventy-one outpatients were assigned to either PASR (n=35), consisting of four weekly PA counseling sessions based on 5A model (assess, advise, agree, assist, and arrange) + SR, or SR (n=36), consisting of four weekly SR. International Physical Activity Questionnaire (Chinese version) and pedometer-based daily steps were evaluated as the primary endpoints. Insomnia Severity Index, Epworth Sleepiness Scale, Fatigue Scale-14, and Sleep Diary were evaluated as the secondary endpoints. Results The results showed that the patients in the PASR group gained more benefits than the SR group in terms of PA level and pedometer-based daily steps (all P<0.05). Better improvements of the study group were also shown in Epworth Sleepiness Scale, Fatigue Scale-14, and Sleep efficiency (all P<0.05). Conclusion We conclude that PA counseling based on 5A model combined with SR cannot only effectively increase the PA levels but also improve the sleep quality for patients with chronic insomnia. PMID:26566369

  7. High-speed pre-clinical brain imaging using pulsed laser diode based photoacoustic tomography (PLD-PAT) system

    NASA Astrophysics Data System (ADS)

    Upputuri, Paul Kumar; Pramanik, Manojit

    2016-03-01

    Photoacoustic tomography (PAT) is a promising biomedical imaging modality for small animal imaging, breast cancer imaging, monitoring of vascularisation, tumor angiogenesis, blood oxygenation, total haemoglobin concentration etc. The existing PAT systems that uses Q-switched Nd:YAG and OPO nanosecond lasers have limitations in clinical applications because they are expensive, non-potable and not suitable for real-time imaging due to their low pulse repetition rate. Low-energy pulsed near-infrared diode laser which are low-cost, compact, and light-weight (<200 grams), can be used as an alternate. In this work, we present a photoacoustic tomography system with a pulsed laser diode (PLD) that can nanosecond pulses with pulse energy 1.3 mJ/pulse at ~803 nm wavelength and 7000 Hz repetition rate. The PLD is integrated inside a single-detector circular scanning geometric system. To verify the high speed imaging capabilities of the PLD-PAT system, we performed in vivo experimental results on small animal brain imaging using this system. The proposed system is portable, low-cost and can provide real-time imaging.

  8. PAT-seq: a method to study the integration of 3'-UTR dynamics with gene expression in the eukaryotic transcriptome.

    PubMed

    Harrison, Paul F; Powell, David R; Clancy, Jennifer L; Preiss, Thomas; Boag, Peter R; Traven, Ana; Seemann, Torsten; Beilharz, Traude H

    2015-08-01

    A major objective of systems biology is to quantitatively integrate multiple parameters from genome-wide measurements. To integrate gene expression with dynamics in poly(A) tail length and adenylation site, we developed a targeted next-generation sequencing approach, Poly(A)-Test RNA-sequencing. PAT-seq returns (i) digital gene expression, (ii) polyadenylation site/s, and (iii) the polyadenylation-state within and between eukaryotic transcriptomes. PAT-seq differs from previous 3' focused RNA-seq methods in that it depends strictly on 3' adenylation within total RNA samples and that the full-native poly(A) tail is included in the sequencing libraries. Here, total RNA samples from budding yeast cells were analyzed to identify the intersect between adenylation state and gene expression in response to loss of the major cytoplasmic deadenylase Ccr4. Furthermore, concordant changes to gene expression and adenylation-state were demonstrated in the classic Crabtree-Warburg metabolic shift. Because all polyadenylated RNA is interrogated by the approach, alternative adenylation sites, noncoding RNA and RNA-decay intermediates were also identified. Most important, the PAT-seq approach uses standard sequencing procedures, supports significant multiplexing, and thus replication and rigorous statistical analyses can for the first time be brought to the measure of 3'-UTR dynamics genome wide. PMID:26092945

  9. PAT-seq: a method to study the integration of 3'-UTR dynamics with gene expression in the eukaryotic transcriptome.

    PubMed

    Harrison, Paul F; Powell, David R; Clancy, Jennifer L; Preiss, Thomas; Boag, Peter R; Traven, Ana; Seemann, Torsten; Beilharz, Traude H

    2015-08-01

    A major objective of systems biology is to quantitatively integrate multiple parameters from genome-wide measurements. To integrate gene expression with dynamics in poly(A) tail length and adenylation site, we developed a targeted next-generation sequencing approach, Poly(A)-Test RNA-sequencing. PAT-seq returns (i) digital gene expression, (ii) polyadenylation site/s, and (iii) the polyadenylation-state within and between eukaryotic transcriptomes. PAT-seq differs from previous 3' focused RNA-seq methods in that it depends strictly on 3' adenylation within total RNA samples and that the full-native poly(A) tail is included in the sequencing libraries. Here, total RNA samples from budding yeast cells were analyzed to identify the intersect between adenylation state and gene expression in response to loss of the major cytoplasmic deadenylase Ccr4. Furthermore, concordant changes to gene expression and adenylation-state were demonstrated in the classic Crabtree-Warburg metabolic shift. Because all polyadenylated RNA is interrogated by the approach, alternative adenylation sites, noncoding RNA and RNA-decay intermediates were also identified. Most important, the PAT-seq approach uses standard sequencing procedures, supports significant multiplexing, and thus replication and rigorous statistical analyses can for the first time be brought to the measure of 3'-UTR dynamics genome wide.

  10. The physical activity levels among people living with human immunodeficiency virus/acquired immunodeficiency syndrome receiving high active antiretroviral therapy in Rwanda.

    PubMed

    Frantz, J M; Murenzi, A

    2013-01-01

    The accessibility of high active antiretroviral therapy (HAART) for local human immunodeficiency virus (HIV) patients is improving in Rwanda. It is well known that this therapy is associated with serious adverse effects, such as metabolic and morphologic changes. One of the recommended preventive modalities for these complications is participation in physical activity. The current study aims to determine the anthropometric profile and physical activity levels among people living with HIV and receiving HAART in Kigali, Rwanda. The study was a cross-sectional, descriptive quantitative survey. The participant's levels of physical activity participation and their association with anthropometric profiles were measured, using a structured self-administered questionnaire for 407 clients passing through the clinics. Of the participants, approximately 70% were inactive and in addition, 40% were obese and 43% overweight. Obesity was found to be strongly associated with inactivity. Lack of motivation, and time as well as fear of worsening the disease were found to be barriers to participation in physical activity.

  11. Successful Tocilizumab Therapy for Macrophage Activation Syndrome Associated with Adult-Onset Still's Disease: A Case-Based Review.

    PubMed

    Watanabe, Eri; Sugawara, Hitoshi; Yamashita, Takeshi; Ishii, Akira; Oda, Aya; Terai, Chihiro

    2016-01-01

    We report the case of a 71-year-old Japanese woman with adult-onset Still's disease (AOSD) in whom macrophage activation syndrome (MAS) developed despite therapy with oral high-dose prednisolone and intravenous methylprednisolone pulse therapy twice. She was successfully treated with tocilizumab (TCZ). Soon afterward, her fever ceased and high levels of both ferritin and C-reactive protein levels decreased. Her course was complicated by disseminated intravascular coagulation, cytomegalovirus infection, and Pneumocystis jirovecii pneumonia. After these were resolved, AOSD-associated MAS was well controlled. She was discharged on hospital day 87. Although biologics such as TCZ are becoming established for the treatment of AOSD, there is no recommended therapy for AOSD-associated MAS. Several biologics have been tried for this complication, but their efficacy and safety remain controversial. We reviewed reported cases of AOSD-associated MAS successfully treated with various biologics. TCZ initiation after adequate nonselective immunosuppressive therapy, such as methylprednisolone pulse therapy or a prednisolone-based combination of immunosuppressants, can be an effective treatment for AOSD-associated MAS. On the other hand, biologics given after insufficient immunosuppressive therapy may cause MAS. A strategy combining adequate immunosuppression and a biologic could be safe if special attention is given to adverse events such as opportunistic infections or biologic-associated MAS. PMID:27688774

  12. Successful Tocilizumab Therapy for Macrophage Activation Syndrome Associated with Adult-Onset Still's Disease: A Case-Based Review

    PubMed Central

    Watanabe, Eri; Yamashita, Takeshi; Ishii, Akira; Oda, Aya; Terai, Chihiro

    2016-01-01

    We report the case of a 71-year-old Japanese woman with adult-onset Still's disease (AOSD) in whom macrophage activation syndrome (MAS) developed despite therapy with oral high-dose prednisolone and intravenous methylprednisolone pulse therapy twice. She was successfully treated with tocilizumab (TCZ). Soon afterward, her fever ceased and high levels of both ferritin and C-reactive protein levels decreased. Her course was complicated by disseminated intravascular coagulation, cytomegalovirus infection, and Pneumocystis jirovecii pneumonia. After these were resolved, AOSD-associated MAS was well controlled. She was discharged on hospital day 87. Although biologics such as TCZ are becoming established for the treatment of AOSD, there is no recommended therapy for AOSD-associated MAS. Several biologics have been tried for this complication, but their efficacy and safety remain controversial. We reviewed reported cases of AOSD-associated MAS successfully treated with various biologics. TCZ initiation after adequate nonselective immunosuppressive therapy, such as methylprednisolone pulse therapy or a prednisolone-based combination of immunosuppressants, can be an effective treatment for AOSD-associated MAS. On the other hand, biologics given after insufficient immunosuppressive therapy may cause MAS. A strategy combining adequate immunosuppression and a biologic could be safe if special attention is given to adverse events such as opportunistic infections or biologic-associated MAS. PMID:27688774

  13. Successful Tocilizumab Therapy for Macrophage Activation Syndrome Associated with Adult-Onset Still's Disease: A Case-Based Review

    PubMed Central

    Watanabe, Eri; Yamashita, Takeshi; Ishii, Akira; Oda, Aya; Terai, Chihiro

    2016-01-01

    We report the case of a 71-year-old Japanese woman with adult-onset Still's disease (AOSD) in whom macrophage activation syndrome (MAS) developed despite therapy with oral high-dose prednisolone and intravenous methylprednisolone pulse therapy twice. She was successfully treated with tocilizumab (TCZ). Soon afterward, her fever ceased and high levels of both ferritin and C-reactive protein levels decreased. Her course was complicated by disseminated intravascular coagulation, cytomegalovirus infection, and Pneumocystis jirovecii pneumonia. After these were resolved, AOSD-associated MAS was well controlled. She was discharged on hospital day 87. Although biologics such as TCZ are becoming established for the treatment of AOSD, there is no recommended therapy for AOSD-associated MAS. Several biologics have been tried for this complication, but their efficacy and safety remain controversial. We reviewed reported cases of AOSD-associated MAS successfully treated with various biologics. TCZ initiation after adequate nonselective immunosuppressive therapy, such as methylprednisolone pulse therapy or a prednisolone-based combination of immunosuppressants, can be an effective treatment for AOSD-associated MAS. On the other hand, biologics given after insufficient immunosuppressive therapy may cause MAS. A strategy combining adequate immunosuppression and a biologic could be safe if special attention is given to adverse events such as opportunistic infections or biologic-associated MAS.

  14. Systemic Cyclosporine Therapy for Scleritis: A Proposal of a Novel System to Assess the Activity of Scleritis.

    PubMed

    Aoki, Haruka; Hiraoka, Miki; Hashimoto, Masato; Ohguro, Hiroshi

    2015-01-01

    In the present study, two female patients with unilateral scleritis without systemic complications were examined. Both patients were suffering from ocular pain and received corticosteroid therapy. The first patient, a 45-year-old woman, was diagnosed with scleritis and iritis in her right eye. Topical corticosteroid treatment could eradicate the iritis but not the scleritis. Oral corticosteroid administration and corticosteroid pulse therapy were applied with little effect. The application of systemic cyclosporine had a satisfactory effect in controlling the scleritis. The other patient, a 60-year-old woman, was suffering from scleritis and lid swelling in her right eye. Not only did topical and systemic corticosteroid therapy prove insufficient, they also resulted in the elevation of her intraocular pressure. After termination of corticosteroid therapy, the systemic cyclosporine was applied orally. Subsequently, the patient's scleritis improved without any severe side effects. Scleritis is a painful and destructive inflammatory disease of the sclera that causes congestion of the scleral venous plexus. In this study, we have established a new grading system for assessing activity in scleritis that can score the extent of ocular pain and the area of congestion. This system provides a practical method for following the clinical course and monitoring the outcome of therapy. We report two cases of unilateral scleritis that were resistant to corticosteroid therapy but responsive to systemic administration of cyclosporine. Findings from these cases indicate that cyclosporine is an effective drug for controlling severe scleritis.

  15. Photodynamic-therapy Activates Immune Response by disrupting Immunity Homeostasis of Tumor Cells, which Generates Vaccine for Cancer Therapy

    PubMed Central

    Zheng, Yuanhong; Yin, Guifang; Le, Vanminh; Zhang, Anle; Chen, Siyu; Liang, Xin; Liu, Jianwen

    2016-01-01

    Photodynamic therapy (PDT), a regulatory approved cancer treatment, is reported to be capable of causing immunogenic apoptosis. The current data reveal PDT can cause the dysregulation of “eat me” and “don't eat me” signal by generating reactive oxygen species (ROS) -mediated endoplasmic reticulum (ER) stress. This dysregulation probably contribute to the increased uptake of PDT-killed Lewis lung carcinoma (LLC) cells by homologous dendritic cells (DCs), accompanied by phenotypic maturation (CD80high, CD86high, and CD40high) and functional stimulation (NOhigh, IL-10absent) of dendritic cells as well as subsequent T-cell responses. Morevover, C57BL/6 mice vaccinated with dendritic cells (DCs) pulsed with PDT-treated LLCs (PDT-DCs) or PDT-treated LLCs alone (PDT-LLCs) exhibited potent immunity against LLC tumors. In the current study, the PDT-induced immune response was characterized as a process related with the dysregulation of “eat me” signal and “don't eat me” signal, revealing the possibility for developing PDT into an antitumor vaccination strategy for personalized cancer immunotherapy. PMID:26722223

  16. p53 activated by AND gate genetic circuit under radiation and hypoxia for targeted cancer gene therapy.

    PubMed

    Ding, Miao; Li, Rong; He, Rong; Wang, Xingyong; Yi, Qijian; Wang, Weidong

    2015-09-01

    Radio-activated gene therapy has been developed as a novel therapeutic strategy against cancer; however, expression of therapeutic gene in peritumoral tissues will result in unacceptable toxicity to normal cells. To restrict gene expression in targeted tumor mass, we used hypoxia and radiation tolerance features of tumor cells to develop a synthetic AND gate genetic circuit through connecting radiation sensitivity promoter cArG6 , heat shock response elements SNF1, HSF1 and HSE4 with retroviral vector plxsn. Their construction and dynamic activity process were identified through downstream enhanced green fluorescent protein and wtp53 expression in non-small cell lung cancer A549 cells and in a nude mice model. The result showed that AND gate genetic circuit could be activated by lower required radiation dose (6 Gy) and after activated, AND gate could induce significant apoptosis effects and growth inhibition of cancer cells in vitro and in vivo. The radiation- and hypoxia-activated AND gate genetic circuit, which could lead to more powerful target tumoricidal activity represented a promising strategy for both targeted and effective gene therapy of human lung adenocarcinoma and low dose activation character of the AND gate genetic circuit implied that this model could be further exploited to decrease side-effects of clinical radiation therapy.

  17. Effectiveness of Group Activity Play Therapy on Internalizing and Externalizing Behavior Problems of Preadolescent Orphans in Uganda

    ERIC Educational Resources Information Center

    Ojiambo, Deborah

    2011-01-01

    This pilot study investigated the impact of group activity play therapy (GAPT) on displaced orphans aged 10 to 12 years living in a large children's village in Uganda. Teachers and housemothers identified 60 preadolescents exhibiting clinical levels of internalizing and externalizing behavior problems. The participants' ethnicity was…

  18. Randomized Trial of Behavioral Activation, Cognitive Therapy, and Antidepressant Medication in the Prevention of Relapse and Recurrence in Major Depression

    ERIC Educational Resources Information Center

    Dobson, Keith S.; Hollon, Steven D.; Dimidjian, Sona; Schmaling, Karen B.; Kohlenberg, Robert J.; Gallop, Robert J.; Rizvi, Shireen L.; Gollan, Jackie K.; Dunner, David L.; Jacobson, Neil S.

    2008-01-01

    This study followed treatment responders from a randomized controlled trial of adults with major depression. Patients treated with medication but withdrawn onto pill-placebo had more relapse through 1 year of follow-up compared to patients who received prior behavioral activation, prior cognitive therapy, or continued medication. Prior…

  19. Strategies To Assess Hypoxic/HIF-1-Active Cancer Cells for the Development of Innovative Radiation Therapy

    PubMed Central

    Yeom, Chan Joo; Zeng, Lihua; Zhu, Yuxi; Hiraoka, Masahiro; Harada, Hiroshi

    2011-01-01

    Local tumor recurrence and distant tumor metastasis frequently occur after radiation therapy and result in the death of cancer patients. These problems are caused, at least in part, by a tumor-specific oxygen-poor microenvironment, hypoxia. Oxygen-deprivation is known to inhibit the chemical ionization of both intracellular macro-molecules and water, etc., and thus reduce the cytotoxic effects of radiation. Moreover, DNA damage produced by free radicals is known to be more repairable under hypoxia than normoxia. Hypoxia is also known to induce biological tumor radioresistance through the activation of a transcription factor, hypoxia-inducible factor 1 (HIF-1). Several potential strategies have been devised in radiation therapy to overcome these problems; however, they have not yet achieved a complete remission. It is essential to reveal the intratumoral localization and dynamics of hypoxic/HIF-1-active tumor cells during tumor growth and after radiation therapy, then exploit the information to develop innovative therapeutic strategies, and finally damage radioresistant cells. In this review, we overview problems caused by hypoxia/HIF-1-active cells in radiation therapy for cancer and introduce strategies to assess intratumoral hypoxia/HIF-1 activity. PMID:24212970

  20. Task Lists for Health Occupations. Radiologic Aide. Activity Aide. Optometric Assistant. Physical Therapy Aide. Education for Employment Task Lists.

    ERIC Educational Resources Information Center

    Lathrop, Janice

    These task lists contain employability skills and tasks for the following health occupations: radiologic aide, activity aide, physical therapy aide, and optometric assistant. The duties and tasks found in these lists form the basis of instructional content for secondary, postsecondary, and adult occupational training programs. Employability skills…

  1. Relapse Prevention in Major Depressive Disorder: Mindfulness-Based Cognitive Therapy Versus an Active Control Condition

    PubMed Central

    Shallcross, Amanda J.; Gross, James J.; Visvanathan, Pallavi D.; Kumar, Niketa; Palfrey, Amy; Ford, Brett Q.; Dimidjian, Sona; Shirk, Stephen; Holm-Denoma, Jill; Goode, Kari M.; Cox, Erica; Chaplin, William; Mauss, Iris B.

    2015-01-01

    Objective We evaluated the comparative effectiveness of Mindfulness-based cognitive therapy (MBCT) versus an active control condition (ACC) for depression relapse prevention, depressive symptom reduction, and improvement in life satisfaction. Method Ninety-two participants in remission from Major Depressive Disorder with residual depressive symptoms were randomized to either an 8-week MBCT or a validated ACC that is structurally equivalent to MBCT and controls for non-specific effects (e.g., interaction with a facilitator, perceived social support, treatment outcome expectations). Both interventions were delivered according to their published manuals. Results Intention-to-treat analyses indicated no differences between MBCT and ACC in depression relapse rates or time to relapse over a 60-week follow-up. Both groups experienced significant and equal reductions in depressive symptoms and improvements in life satisfaction. A significant quadratic interaction (group x time) indicated that the pattern of depressive symptom reduction differed between groups. The ACC experienced immediate symptom reduction post-intervention and then a gradual increase over the 60-week follow-up. The MBCT group experienced a gradual linear symptom reduction. The pattern for life satisfaction was identical but only marginally significant. Conclusions MBCT did not differ from an ACC on rates of depression relapse, symptom reduction, or life satisfaction, suggesting that MBCT is no more effective for preventing depression relapse and reducing depressive symptoms than the active components of the ACC. Differences in trajectory of depressive symptom improvement suggest that the intervention-specific skills acquired may be associated with differential rates of therapeutic benefit. This study demonstrates the importance of comparing psychotherapeutic interventions to active control conditions. PMID:26371618

  2. New compounds for neutron capture therapy (NCT) and their significance

    SciTech Connect

    Fairchild, R.G.; Bond, V.P.

    1982-01-01

    Clearly the most effective tumor therapy would be obtained by the selective targeting of cytotoxic agents to tumor cells. Although many biomolecules are known to be taken up in tumors, the targeting of cytotoxic agents to tumors is limited by the fact that other essential cell pools compete with equal or even greater effectiveness. The approach of delivering stable non-toxic isotopes to tumor, with activation by means of an external radiation beam, is advantageous for two reasons: (1) it obviates problems associated with high uptake of isotopes in normal tissues, as these cell pools can be excluded from the radiation field, and (2) the general tumor area can be included in the activating beam field; thus, the possibility exists that all microscopic tumor extensions can be irradiated. As long as range of reaction products is short, dose will be restricted to the tumor, with a resultant high therapeutic ratio. This method can be accomplished with either photon activation therapy (PAT) or Neutron Capture Therapy (NCT), the latter will be emphasized here. The range of the high LET, low OER particles from the /sup 10/B(n,..cap alpha..)/sup 7/Li reaction is approx. 10 ..mu..m, or one cell diameter; hence this reaction is optimal for cell killing. A number of biomolecules have been investigated as possible vehicles for transport of boron to tumors, including phenothiazines, thiouracils, porphyrins, nucleosides, and amino acids. Biodistributions of these compounds show selective concentration in tumor adequate for therapy. The biological halflives are in the order of days, allowing the possibility of fractionated or protracted irradiations. The radiobiological and physical implication of these parameters on NCT are discussed. The possibility of using an approximately-monoenergetic, scandium-filtered beam of about 2 keV, to reduce the dose from background radiations by about 85%, is also discussed. (ERB)

  3. patGPCR: A Multitemplate Approach for Improving 3D Structure Prediction of Transmembrane Helices of G-Protein-Coupled Receptors

    PubMed Central

    Wu, Hongjie; Lü, Qiang; Quan, Lijun; Qian, Peide; Xia, Xiaoyan

    2013-01-01

    The structures of the seven transmembrane helices of G-protein-coupled receptors are critically involved in many aspects of these receptors, such as receptor stability, ligand docking, and molecular function. Most of the previous multitemplate approaches have built a “super” template with very little merging of aligned fragments from different templates. Here, we present a parallelized multitemplate approach, patGPCR, to predict the 3D structures of transmembrane helices of G-protein-coupled receptors. patGPCR, which employs a bundle-packing related energy function that extends on the RosettaMem energy, parallelizes eight pipelines for transmembrane helix refinement and exchanges the optimized helix structures from multiple templates. We have investigated the performance of patGPCR on a test set containing eight determined G-protein-coupled receptors. The results indicate that patGPCR improves the TM RMSD of the predicted models by 33.64% on average against a single-template method. Compared with other homology approaches, the best models for five of the eight targets built by patGPCR had a lower TM RMSD than that obtained from SWISS-MODEL; patGPCR also showed lower average TM RMSD than single-template and multiple-template MODELLER. PMID:23554839

  4. Anti-TNFα therapy for inflammatory bowel diseases is associated with Epstein-Barr virus lytic activation.

    PubMed

    Lapsia, Sameer; Koganti, Siva; Spadaro, Salvatore; Rajapakse, Ramona; Chawla, Anupama; Bhaduri-McIntosh, Sumita

    2016-02-01

    Anti-TNFα therapy, known to suppress T-cell immunity, is increasingly gaining popularity for treatment of autoimmune diseases including inflammatory bowel diseases (IBD). T-cell suppression increases the risk of B-cell EBV-lymphoproliferative diseases and lymphomas. Since EBV-lytic activation is essential for development of EBV-lymphomas and there have been reports of EBV-lymphomas in patients treated with anti-TNFα therapy, we investigated if patients treated with anti-TNFα antibodies demonstrate greater EBV-lytic activity in blood. Peripheral blood mononuclear cells from 10 IBD patients solely on anti-TNFα therapy compared to 3 control groups (10 IBD patients not on immunosuppressive therapy, 10 patients with abdominal pain but without IBD, and 10 healthy subjects) were examined for the percentage of T-cells, EBV load and EBV-lytic transcripts. Patients on anti-TNFα therapy had significantly fewer T-cells, greater EBV load, and increased levels of transcripts from EBV-lytic genes of all kinetic classes compared to controls. Furthermore, exposure of EBV-infected B-cell lines to anti-TNFα antibodies resulted in increased levels of BZLF1 mRNA; BZLF1 encodes for ZEBRA, the viral latency-to-lytic cycle switch. Thus, IBD patients treated with anti-TNFα antibodies have greater EBV loads likely due to enhanced EBV-lytic gene expression and anti-TNFα antibodies may be sufficient to activate the EBV lytic cycle. Findings from this pilot study lay the groundwork for additional scientific and clinical investigation into the effects of anti-TNFα therapy on the life cycle of EBV, a ubiquitous oncovirus that causes lymphomas in the setting of immunocompromise. PMID:26307954

  5. Anti-TNFα therapy for inflammatory bowel diseases is associated with Epstein-Barr virus lytic activation.

    PubMed

    Lapsia, Sameer; Koganti, Siva; Spadaro, Salvatore; Rajapakse, Ramona; Chawla, Anupama; Bhaduri-McIntosh, Sumita

    2016-02-01

    Anti-TNFα therapy, known to suppress T-cell immunity, is increasingly gaining popularity for treatment of autoimmune diseases including inflammatory bowel diseases (IBD). T-cell suppression increases the risk of B-cell EBV-lymphoproliferative diseases and lymphomas. Since EBV-lytic activation is essential for development of EBV-lymphomas and there have been reports of EBV-lymphomas in patients treated with anti-TNFα therapy, we investigated if patients treated with anti-TNFα antibodies demonstrate greater EBV-lytic activity in blood. Peripheral blood mononuclear cells from 10 IBD patients solely on anti-TNFα therapy compared to 3 control groups (10 IBD patients not on immunosuppressive therapy, 10 patients with abdominal pain but without IBD, and 10 healthy subjects) were examined for the percentage of T-cells, EBV load and EBV-lytic transcripts. Patients on anti-TNFα therapy had significantly fewer T-cells, greater EBV load, and increased levels of transcripts from EBV-lytic genes of all kinetic classes compared to controls. Furthermore, exposure of EBV-infected B-cell lines to anti-TNFα antibodies resulted in increased levels of BZLF1 mRNA; BZLF1 encodes for ZEBRA, the viral latency-to-lytic cycle switch. Thus, IBD patients treated with anti-TNFα antibodies have greater EBV loads likely due to enhanced EBV-lytic gene expression and anti-TNFα antibodies may be sufficient to activate the EBV lytic cycle. Findings from this pilot study lay the groundwork for additional scientific and clinical investigation into the effects of anti-TNFα therapy on the life cycle of EBV, a ubiquitous oncovirus that causes lymphomas in the setting of immunocompromise.

  6. Magnetic resonance imaging evaluation of lipodystrophy in HIV-positive patients receiving highly active antiretroviral therapy.

    PubMed

    Eichler, K; Bickel, T M; Klauke, S; Eisen, J; Vogl, T J; Zangos, S

    2015-07-01

    We evaluated retrospectively an automated method for the separate detection of subcutaneous and visceral fat in the abdominal region by magnetic resonance studies in HIV-positive patients on highly active antiretroviral therapy. The patients were divided into four different groups: lipoatrophy, lipohypertrophy, mixed and the control group. The use of software for the automated detection of abdominal compartment visceral adipose tissue (VAT), total adipose tissue (TAT) and subcutaneous adipose tissue (SAT) was compared to manual evaluation methods (fuzzy C-mean). The results of ROC analysis showed that the parameters, particularly the VAT, are better than the VAT/TAT and at identifying patients with the symptoms of abdominal fat accumulation. A sensitivity of 80.3% and a specificity of 79.5% resulted from a threshold VAT value of >87 cm(2). Moreover, the manual evaluation method was shown to provide greater values for VAT and the VAT/TAT ratio than those given by the automated method. In the present study, a rapid MRI protocol for the detection and assessment of the course of lipodystrophy was presented and tested on a group of patients with signs of HALS, as well as on an antiretroviral naïve control group.

  7. Body mass index changes during highly active antiretroviral therapy in Nigeria.

    PubMed

    Denue, B A; Ikunaiye, P N Y; Denue, C B A

    2014-01-09

    Wasting remains an important condition in HIV-infected patients receiving highly active antiretroviral therapy (HAART). In this study, 120 patients with newly diagnosed HIV infection were prospectively evaluated to determine the effect of HAART on body mass index (BMI). Eighty-nine (83.1%) patients gained weight, 5 (4.7%) had no weight change, and 13 (12.2%) lost weight. There was a significant increase in overweight and obese patients. On multivariate analysis, time-updated CD4 count and higher baseline BMI were associated with a greater increase in BMI. Anaemia at diagnosis was associated with a significant increase in BMI. There were no significant effects of age, sex, disease severity, viral load or educational status on BMI changes. About 27% of the HIV patients presented with weight loss, which emphasizes that weight loss and wasting remain important AIDS-defining conditions, despite the advent of HAART. A linear association was observed between time-updated CD4 count and increase in BMI. The association between time-updated CD4 count and greater increase in BMI suggests that BMI could be a surrogate for CD4 count in monitoring treatment response in resource-limited settings.

  8. A Systematic Review of Cognitive Behavioral Therapy and Behavioral Activation Apps for Depression.

    PubMed

    Huguet, Anna; Rao, Sanjay; McGrath, Patrick J; Wozney, Lori; Wheaton, Mike; Conrod, Jill; Rozario, Sharlene

    2016-01-01

    Depression is a common mental health condition for which many mobile apps aim to provide support. This review aims to identify self-help apps available exclusively for people with depression and evaluate those that offer cognitive behavioural therapy (CBT) or behavioural activation (BA). One hundred and seventeen apps have been identified after searching both the scientific literature and the commercial market. 10.26% (n = 12) of these apps identified through our search offer support that seems to be consistent with evidence-based principles of CBT or BA. Taking into account the non existence of effectiveness/efficacy studies, and the low level of adherence to the core ingredients of the CBT/BA models, the utility of these CBT/BA apps are questionable. The usability of reviewed apps is highly variable and they rarely are accompanied by explicit privacy or safety policies. Despite the growing public demand, there is a concerning lack of appropiate CBT or BA apps, especially from a clinical and legal point of view. The application of superior scientific, technological, and legal knowledge is needed to improve the development, testing, and accessibility of apps for people with depression. PMID:27135410

  9. A Systematic Review of Cognitive Behavioral Therapy and Behavioral Activation Apps for Depression

    PubMed Central

    McGrath, Patrick J.; Wozney, Lori; Wheaton, Mike; Conrod, Jill; Rozario, Sharlene

    2016-01-01

    Depression is a common mental health condition for which many mobile apps aim to provide support. This review aims to identify self-help apps available exclusively for people with depression and evaluate those that offer cognitive behavioural therapy (CBT) or behavioural activation (BA). One hundred and seventeen apps have been identified after searching both the scientific literature and the commercial market. 10.26% (n = 12) of these apps identified through our search offer support that seems to be consistent with evidence-based principles of CBT or BA. Taking into account the non existence of effectiveness/efficacy studies, and the low level of adherence to the core ingredients of the CBT/BA models, the utility of these CBT/BA apps are questionable. The usability of reviewed apps is highly variable and they rarely are accompanied by explicit privacy or safety policies. Despite the growing public demand, there is a concerning lack of appropiate CBT or BA apps, especially from a clinical and legal point of view. The application of superior scientific, technological, and legal knowledge is needed to improve the development, testing, and accessibility of apps for people with depression. PMID:27135410

  10. Access to highly active antiretroviral therapy for injection drug users: adherence, resistance, and death.

    PubMed

    Vlahov, David; Celentano, David D

    2006-04-01

    Injection drug users (IDUs) continue to comprise a major risk group for HIV infection throughout the world and represent the focal population for HIV epidemics in Asia and Eastern Europe/Russia. HIV prevention programs have ranged from HIV testing and counseling, education, behavioral and network interventions, drug abuse treatment, bleach disinfection of needles, needle exchange and expanded syringe access, as well as reducing transition to injection and primary substance abuse prevention. With the advent of highly active antiretroviral therapy (HAART) in 1996, dramatic clinical improvements have been seen. In addition, the treatment's impact on reducing HIV viral load (and therefore transmission by all routes) provides a stronger rationale for an expansion of the focus on prevention to emphasize early identification and treatment of HIV infected individuals. However, treatment of IDUs has many challenges including adherence, resistance and relapse to high risk behaviors, all of which impact issues of access and ultimately effectiveness of potent antiretroviral treatment. A major current challenge in addressing the HIV epidemic revolves around an appropriate approach to HIV treatment for IDUs.

  11. VEGF neutralizing aerosol therapy in primary pulmonary adenocarcinoma with K-ras activating-mutations.

    PubMed

    Hervé, Virginie; Rabbe, Nathalie; Guilleminault, Laurent; Paul, Flora; Schlick, Laurène; Azzopardi, Nicolas; Duruisseaux, Michael; Fouquenet, Delphine; Montharu, Jérôme; Redini, Françoise; Paintaud, Gilles; Lemarié, Etienne; Cadranel, Jacques; Wislez, Marie; Heuzé-Vourc'h, Nathalie

    2014-01-01

    K-ras mutations promote angiogenesis in lung cancer and contribute to the drug resistance of cancer cells. It is not clear whether K-ras mutated adenocarcinomas are sensitive to anti-angiogenic therapy with monoclonal antibodies (mAbs) that target vascular endothelial growth factor (VEGF). Anti-angiogenic mAbs are usually delivered systemically, but only a small proportion reaches the lung after intravenous injection. We investigated the relevance of a non-invasive pulmonary route for the delivery of anti-VEGF mAbs in the mouse K-ras(LA1) model. We found that pulmonary delivery of these mAbs significantly reduced the number of tumor lesions and inhibited malignant progression. The antitumor effect involves the VEGFR2-dependent inhibition of blood vessel growth, which impairs tumor proliferation. Pharmacokinetic analysis of aerosolized anti-VEGF showed its low rate of passage into the bloodstream, suggesting that this delivery route is associated with reduced systemic side effects. Our findings highlight the value of the aerosol route for administration of anti-angiogenic mAbs in pulmonary adenocarcinoma with K-ras activating-mutations. PMID:25484066

  12. Alemtuzumab: A new therapy for active relapsing–remitting multiple sclerosis

    PubMed Central

    Aktas, Orhan; Boyko, Alexey N

    2015-01-01

    Alemtuzumab is a humanized monoclonal antibody directed against CD52 to deplete circulating T and B lymphocytes; lymphocyte depletion is followed by a distinctive pattern of T- and B-cell repopulation, changing the balance of the immune system. This review reports the efficacy and safety findings of the phase 2 CAMMS223 trial and the phase 3 CARE-MS I and II trials investigating alemtuzumab for the treatment of active relapsing–remitting MS. Alemtuzumab, administered intravenously, was shown to improve relapse rate versus subcutaneous interferon beta-1a in patients who were treatment-naive (CAMMS223 and CARE-MS I) or had relapsed on prior therapy (CARE-MS II), and to reduce sustained accumulation of disability (CAMMS223 and CARE-MS II). Important adverse events were infusion-associated reactions, serious infections and autoimmune events. A safety monitoring program allowed for early detection and management of autoimmune events. Recommendations for the monitoring of adverse events are made. Alemtuzumab’s mechanism of action, pharmacodynamics and opportunities for future research are discussed. PMID:25344374

  13. Music therapy modulates fronto-temporal activity in rest-EEG in depressed clients.

    PubMed

    Fachner, Jörg; Gold, Christian; Erkkilä, Jaakko

    2013-04-01

    Fronto-temporal areas process shared elements of speech and music. Improvisational psychodynamic music therapy (MT) utilizes verbal and musical reflection on emotions and images arising from clinical improvisation. Music listening is shifting frontal alpha asymmetries (FAA) in depression, and increases frontal midline theta (FMT). In a two-armed randomized controlled trial (RCT) with 79 depressed clients (with comorbid anxiety), we compared standard care (SC) versus MT added to SC at intake and after 3 months. We found that MT significantly reduced depression and anxiety symptoms. The purpose of this study is to test whether or not MT has an impact on anterior fronto-temporal resting state alpha and theta oscillations. Correlations between anterior EEG, Montgomery-Åsberg Depression Rating Scale (MADRS) and the Hospital Anxiety and Depression Scale-Anxiety Subscale (HADS-A), power spectral analysis (topography, means, asymmetry) and normative EEG database comparisons were explored. After 3 month of MT, lasting changes in resting EEG were observed, i.e., significant absolute power increases at left fronto-temporal alpha, but most distinct for theta (also at left fronto-central and right temporoparietal leads). MT differed to SC at F7-F8 (z scored FAA, p < .03) and T3-T4 (theta, p < .005) asymmetry scores, pointing towards decreased relative left-sided brain activity after MT; pre/post increased FMT and decreased HADS-A scores (r = .42, p < .05) indicate reduced anxiety after MT. Verbal reflection and improvising on emotions in MT may induce neural reorganization in fronto-temporal areas. Alpha and theta changes in fronto-temporal and temporoparietal areas indicate MT action and treatment effects on cortical activity in depression, suggesting an impact of MT on anxiety reduction.

  14. Clinical evidence on high flow oxygen therapy and active humidification in adults.

    PubMed

    Gotera, C; Díaz Lobato, S; Pinto, T; Winck, J C

    2013-01-01

    Recently there has been growing interest in an alternative to conventional oxygen therapy: the heated, humidified high flow nasal cannula oxygen therapy (HFNC). A number of physiological effects have been described with HFNC: pharyngeal dead space washout, reduction of nasopharyngeal resistance, a positive expiratory pressure effect, an alveolar recruitment, greater humidification, more comfort and better tolerance by the patient, better control of FiO2 and mucociliary clearance. There is limited experience of HFNC in adults. There are no established guidelines or decision-making pathways to guide use of the HFNC therapy for adults. In this article we review the existing evidence of HFNC oxygen therapy in adult patients, its advantages, limitations and the current literature on clinical applications. Further research is required to determine the long-term effect of this therapy and identify the adult patient population to whom it is most beneficial.

  15. [Media use and physical activity patterns of adolescent participants in obesity therapy: Analysis of the impact of selected sociodemographic factors].

    PubMed

    Wulff, Hagen; Wagner, Petra

    2016-02-01

    To meet the challenge of obesity, effective therapeutic concepts for adolescents focusing on lifestyle changes are necessary. Particularly relevant are nutrition and physical activity patterns associated with media use, which can be influenced by sociodemographic factors. For the optimization of obesity therapy approaches, it is essential to analyze these sociodemographic factors to adjust the aims, content, and methods of interventions, and to use the potential of media in treatment concepts. Thus, the research question is: what are the media and physical activity patterns of 11- to 17-year-old participants in obesity therapy, depending on sociodemographic factors? The national multicenter study was conducted from 2012 to 2013. A questionnaire was administered to 564 participants aged 13.4 ± 1.6 (mean ± standard deviation) years. Standardized instruments were used to assess the variables physical activity, media use, and sociodemographic factors. Participants were physically active for 1 h on 3.3 ± 1.8 days per week, 8.5 % daily. Televisions, mobile phones, and computers were available in all sociodemographic groups and were used for 2 h per day. Sociodemographic differences can be seen in the extent of media usage (h/day). These differences can be found between girls and boys concerning their usage of mobile phones (2.49 vs. 1.90; p  < 0.001), between 11- to 13- and 14- to 17-year-old children concerning their usage of game consoles (0.55 vs. 1.65; p  = 0.007), and in the correlation analysis of media usage and physical activity. Compared with existing literature, the survey results reveal reduced activity and increased media use, which vary among the groups. Thus, differentiated therapy approaches appear to be reasonable. Future research needs to evaluate to what extent media, despite the risks, can contribute to the methodological support of therapy, training, and aftercare concepts.

  16. Brachyury as a potential modulator of androgen receptor activity and a key player in therapy resistance in prostate cancer

    PubMed Central

    Pinto, Filipe; Pértega-Gomes, Nelma; Vizcaíno, José R.; Andrade, Raquel P.; Cárcano, Flavio M.; Reis, Rui Manuel

    2016-01-01

    Prostate cancer (PCa) is the most commonly diagnosed neoplasm and the second leading cause of cancer-related deaths in men. Acquisition of resistance to conventional therapy is a major problem for PCa patient management. Several mechanisms have been described to promote therapy resistance in PCa, such as androgen receptor (AR) activation, epithelial-to-mesenchymal transition (EMT), acquisition of stem cell properties and neuroendocrine transdifferentiation (NEtD). Recently, we identified Brachyury as a new biomarker of PCa aggressiveness and poor prognosis. In the present study we aimed to assess the role of Brachyury in PCa therapy resistance. We showed that Brachyury overexpression in prostate cancer cells lines increased resistance to docetaxel and cabazitaxel drugs, whereas Brachyury abrogation induced decrease in therapy resistance. Through ChiP-qPCR assays we further demonstrated that Brachyury is a direct regulator of AR expression as well as of the biomarker AMACR and the mesenchymal markers Snail and Fibronectin. Furthermore, in vitro Brachyury was also able to increase EMT and stem properties. By in silico analysis, clinically human Brachyury-positive PCa samples were associated with biomarkers of PCa aggressiveness and therapy resistance, including PTEN loss, and expression of NEtD markers, ERG and Bcl-2. Taken together, our results indicate that Brachyury contributes to tumor chemotherapy resistance, constituting an attractive target for advanced PCa patients. PMID:27049720

  17. Up-regulation of BRAF activated non-coding RNA is associated with radiation therapy for lung cancer.

    PubMed

    Chen, Jian-xiang; Chen, Ming; Zheng, Yuan-da; Wang, Sheng-ye; Shen, Zhu-ping

    2015-04-01

    Radiation therapy has become more effective in treating primary tumors, such as lung cancer. Recent evidence suggested that BRAF activated non-coding RNAs (BANCR) play a critical role in cellular processes and are found to be dysregulated in a variety of cancers. The clinical significance of BANCR in radiation therapy, and its molecular mechanisms controlling tumor growth are unclear. In the present study, C57BL/6 mice were inoculated Lewis lung cancer cells and exposed to radiation therapy, then BANCR expression was analyzed using qPCR. Chromatin immunoprecipitation and western blot were performed to calculate the enrichment of histone acetylation and HDAC3 protein levels in Lewis lung cancer cells, respectively. MTT assay was used to evaluate the effects of BANCR on Lewis lung cancer cell viability. Finally, we found that BANCR expression was significantly increased in C57BL/6 mice receiving radiation therapy (P<0.05) compared with control group. Additionally, knockdown of BANCR expression was associated with larger tumor size in C57BL/6 mice inoculated Lewis lung cancer cells. Histone deacetylation was observed to involve in the regulation of BANCR in Lewis lung cancer cells. Moreover, over expression HDAC3 reversed the effect of rays on BANCR expression. MTT assay showed that knockdown of BANCR expression promoted cell viability surviving from radiation. In conclusion, these findings indicated that radiation therapy was an effective treatment for lung cancer, and it may exert function through up-regulation BANCR expression.

  18. Assessing play-based activities, child talk, and single session outcome in family therapy with young children.

    PubMed

    Willis, Amber B; Walters, Lynda H; Crane, D Russell

    2014-07-01

    This exploratory, observational study was designed to reveal descriptive information regarding therapists' actual practices with preschool- and school-aged children in a single session of family therapy and to investigate change mechanisms in family play therapy that have been proposed to make this approach effective. A purposive sample of 30 families receiving family therapy was recruited and video-taped during a family session where at least one child between the ages of 4 and 12 was present. Following the session, the therapist and parent(s) completed questionnaires while one of the children (aged 4-12) was interviewed. Session recordings were coded, minute-by-minute, for participant talk time, visual aids or props used, and therapy technique type (e.g., play-based/activity vs. talk-only techniques). Hierarchical regression and canonical correlational analyses revealed evidence supporting the theory that play-based techniques promote young children's participation, enhance the quality of the child-therapist relationship, and build positive emotional experiences in family therapy.

  19. Long-term warfarin therapy and biomarkers for osteoporosis and atherosclerosis

    PubMed Central

    Namba, Sayaka; Yamaoka-Tojo, Minako; Hashikata, Takehiro; Ikeda, Yuki; Kitasato, Lisa; Hashimoto, Takuya; Shimohama, Takao; Tojo, Taiki; Takahira, Naonobu; Masuda, Takashi; Ako, Junya

    2015-01-01

    Background Stroke prevention by warfarin, a vitamin K antagonist, has been an integral part in the management of atrial fibrillation. Vitamin K-dependent matrix Gla protein (MGP) has been known as a potent inhibitor of arterial calcification and osteoporosis. Therefore, we hypothesized that warfarin therapy affects bone mineral metabolism, vascular calcification, and vascular endothelial dysfunction. Methods We studied 42 atrial fibrillation patients at high-risk for atherosclerosis having one or more coronary risk factors. Twenty-four patients had been treated with warfarin for at least 12 months (WF group), and 18 patients without warfarin (non-WF group). Bone alkaline phosphatase (BAP) and under carboxylated osteocalcin (ucOC) and receptor activator of nuclear factor-kappa B ligand (RANKL) were measured as bone metabolism markers. Reactive hyperemia-peripheral arterial tonometry (RH-PAT) index measured by Endo-PAT2000 was used as an indicator of vascular endothelial function. Results There were no significant differences in patient background characteristics and other clinical indicators between the two groups. In WF group, the ucOC levels were significantly higher than those in the non-WF group (10.3 ± 0.8 vs. 3.4 ± 0.9 ng/mL; P < 0.01), similarly, the RANKL levels in the WF group were higher than those in the non-WF group (0.60 ± 0.06 vs. 0.37 ± 0.05 ng/mL; P = 0.007). Moreover, RH-PAT index was significantly lower in the WF group compared to those in the non-WF group (1.48 ± 0.11 vs. 1.88 ± 0.12; P = 0.017). Conclusions Long-term warfarin therapy may be associated with bone mineral loss and vascular calcification in 60–80 year old hypertensive patients. PMID:26674156

  20. Group cognitive behavioural therapy and group recreational activity for adults with autism spectrum disorders: A preliminary randomized controlled trial

    PubMed Central

    Plenty, Stephanie; Bejerot, Susanne

    2014-01-01

    Although adults with autism spectrum disorder are an increasingly identified patient population, few treatment options are available. This preliminary randomized controlled open trial with a parallel design developed two group interventions for adults with autism spectrum disorders and intelligence within the normal range: cognitive behavioural therapy and recreational activity. Both interventions comprised 36 weekly 3-h sessions led by two therapists in groups of 6–8 patients. A total of 68 psychiatric patients with autism spectrum disorders participated in the study. Outcome measures were Quality of Life Inventory, Sense of Coherence Scale, Rosenberg Self-Esteem Scale and an exploratory analysis on measures of psychiatric health. Participants in both treatment conditions reported an increased quality of life at post-treatment (d = 0.39, p < 0.001), with no difference between interventions. No amelioration of psychiatric symptoms was observed. The dropout rate was lower with cognitive behavioural therapy than with recreational activity, and participants in cognitive behavioural therapy rated themselves as more generally improved, as well as more improved regarding expression of needs and understanding of difficulties. Both interventions appear to be promising treatment options for adults with autism spectrum disorder. The interventions’ similar efficacy may be due to the common elements, structure and group setting. Cognitive behavioural therapy may be additionally beneficial in terms of increasing specific skills and minimizing dropout. PMID:24089423

  1. Group cognitive behavioural therapy and group recreational activity for adults with autism spectrum disorders: a preliminary randomized controlled trial.

    PubMed

    Hesselmark, Eva; Plenty, Stephanie; Bejerot, Susanne

    2014-08-01

    Although adults with autism spectrum disorder are an increasingly identified patient population, few treatment options are available. This preliminary randomized controlled open trial with a parallel design developed two group interventions for adults with autism spectrum disorders and intelligence within the normal range: cognitive behavioural therapy and recreational activity. Both interventions comprised 36 weekly 3-h sessions led by two therapists in groups of 6-8 patients. A total of 68 psychiatric patients with autism spectrum disorders participated in the study. Outcome measures were Quality of Life Inventory, Sense of Coherence Scale, Rosenberg Self-Esteem Scale and an exploratory analysis on measures of psychiatric health. Participants in both treatment conditions reported an increased quality of life at post-treatment (d = 0.39, p < 0.001), with no difference between interventions. No amelioration of psychiatric symptoms was observed. The dropout rate was lower with cognitive behavioural therapy than with recreational activity, and participants in cognitive behavioural therapy rated themselves as more generally improved, as well as more improved regarding expression of needs and understanding of difficulties. Both interventions appear to be promising treatment options for adults with autism spectrum disorder. The interventions' similar efficacy may be due to the common elements, structure and group setting. Cognitive behavioural therapy may be additionally beneficial in terms of increasing specific skills and minimizing dropout.

  2. The Effect of Reminiscence Therapy on Cognition, Depression, and Activities of Daily Living for Patients With Alzheimer Disease.

    PubMed

    Duru Aşiret, Güler; Kapucu, Sevgisun

    2016-01-01

    The purpose of this study was, conducted with experimental design, to investigate the effect of reminiscence therapy on cognition, depression, activities of daily living of institutionalized mild and moderate Alzheimer patients. The study was conducted with a total of 62 patients (31 intervention group and 31 control group) in four home care in Ankara, Turkey. Study was done between the July 1, 2013 and December 20, 2014. Reminiscence therapy sessions were held with groups consists of 4-5 patients, once a week with 30-35 minute duration for 12 weeks. Standardized Mini Mental Test was used in sample selection. Patients were listed through their mini mental test scores, and randomized as odd numbers to control group and even numbers to intervention group. Data were collected with forms developed by researcher 'Data Sheet' and 'Activities of Daily Living Follow-up Form' as well as scales 'Standardized Mini Mental Test' and 'Geriatric Depression Scale'. Chi-square, Mann Whitney-U test, variance analyses in repeated measures and Bonferroni tests were used for analysis. The increase in mean Standardized Mini Mental Test score and the decrease in mean Geriatric Depression Scale score of the individuals in the intervention group compared to the control group at the end of the reminiscence therapy was statistically significant (P < 0.05). At the end of reminiscence therapy sessions, increase in cognition and decrease in depression were found statistically significant in intervention group.

  3. Immune reconstitution but persistent activation after 48 weeks of antiretroviral therapy in youth with pre-therapy CD4 >350 in ATN 061

    PubMed Central

    Rudy, Bret J.; Kapogiannis, Bill G.; Worrell, Carol; Squires, Kathleen; Bethel, James; Li, Su; Wilson, Craig M.; Agwu, Allison; Emmanuel, Patricia; Price, Georgine; Hudey, Stephanie; Goodenow, Maureen M.; Sleasman, John W.

    2015-01-01

    Measures of immune outcomes in youth who initiate combination antiretroviral therapy (cART) early in HIV infection are limited. Design Adolescent Trials Network 061 examined changes over 48 weeks of cART in T cell subsets and markers of T cell and macrophage activation in subjects with pre-therapy CD4>350. All subjects had optimal viral suppression from weeks 24 through 48. Methods Subjects (n=48) initiated cART with tenofovir/emtricitabine plus ritonavir-boosted atazanavir. Data were collected at baseline and weeks 12, 24, and 48. Trends were compared to uninfected controls. Results Significant increases over 48 weeks were noted in all CD4 populations including total, naïve, central memory (CM), and effector memory RO (EM RO) and effector memory RA (EM RA) while numbers of CM and EMRO CD8 cells declined significantly. By week 48, CD4 naïve cells were similar to controls while CM CD4 cells remained significantly lower and EM RO and EM RA subsets were significantly higher. CD38 and HLA DR expression, both individually and when co-expressed, decreased over 48 weeks of cART on CD8 cells but remained significantly higher than controls at week 48. In contrast, markers of macrophage activation measured by sCD14 and sCD163 in plasma did not change with cART and were significantly higher than controls. Conclusion In youth initiating early cART, CD4 cell reconstitution is robust with decreases in CD8 cells. However CD8 T cell and macrophage activation persists at higher levels than uninfected controls. PMID:25942459

  4. Speed of sound estimation with active PZT element for thermal monitoring during ablation therapy: feasibility study

    NASA Astrophysics Data System (ADS)

    Kim, Younsu; Guo, Xiaoyu; Cheng, Alexis; Boctor, Emad M.

    2016-04-01

    Controlling the thermal dose during ablation therapy is instrumental to successfully removing the tumor while preserving the surrounding healthy tissue. In the practical scenario, surgeons must be able to determine the ablation completeness in the tumor region. Various methods have been proposed to monitor it, one of which uses ultrasound since it is a common intraoperative imaging modality due to its non-invasive, cost-effective, and convenient natures. In our approach, we propose to use time of flight (ToF) information to estimate speed of sound changes. Accurate speed of sound estimation is crucial because it is directly correlated with temperature change and subsequent determination of ablation completeness. We divide the region of interest in a circular fashion with a variable radius from the ablator tip. We introduce the concept of effective speed of sound in each of the sub-regions. Our active PZT element control system facilitates this unique approach by allowing us to acquire one-way ToF information between the PZT element and each of the ultrasound elements. We performed a simulation and an experiment to verify feasibility of this method. The simulation result showed that we could compute the effective speed of sound within 0.02m/s error in our discrete model. We also perform a sensitivity analysis for this model. Most of the experimental results had less than 1% error. Simulation using a Gaussian continuous model with multiple PZT elements is also demonstrated. We simulate the effect of the element location one the optimization result.

  5. Effects of Baroreflex Activation Therapy on Ambulatory Blood Pressure in Patients With Resistant Hypertension.

    PubMed

    Wallbach, Manuel; Lehnig, Luca-Yves; Schroer, Charlotte; Lüders, Stephan; Böhning, Enrico; Müller, Gerhard A; Wachter, Rolf; Koziolek, Michael J

    2016-04-01

    Baroreflex activation therapy (BAT) has been demonstrated to decrease office blood pressure (BP) in the randomized, double-blind Rheos trial. There are limited data on 24-hour BP changes measured by ambulatory BP measurements (ABPMs) using the first generation rheos BAT system suggesting a significant reduction but there are no information about the effect of the currently used, unilateral BAT neo device on ABPM. Patients treated with the BAT neo device for uncontrolled resistant hypertension were prospectively included into this study. ABPM was performed before BAT implantation and 6 months after initiation of BAT. A total of 51 patients were included into this study, 7 dropped out from analysis because of missing or insufficient follow-up. After 6 months, 24-hour ambulatory systolic (from 148 ± 17 mm Hg to 140 ± 23 mm Hg, P<0.01), diastolic (from 82 ± 13 mm Hg to 77 ± 15 mm Hg, P<0.01), day- and night-time systolic and diastolic BP (all P ≤ 0.01) significantly decreased while the number of prescribed antihypertensive classes could be reduced from 6.5 ± 1.5 to 6.0 ± 1.8 (P=0.03). Heart rate and pulse pressure remained unchanged. BAT was equally effective in reducing ambulatory BP in all subgroups of patients. This is the first study demonstrating a significant BP reduction in ABPM in patients undergoing chronically stimulation of the carotid sinus using the BAT neo device. About that BAT-reduced office BP and improved relevant aspects of ABPM, BAT might be considered as a new therapeutic option to reduce cardiovascular risk in patients with resistant hypertension. Randomized controlled trials are needed to evaluate BAT effects on ABPM in patients with resistant hypertension accurately.

  6. Neural activity based biofeedback therapy for Autism spectrum disorder through wearable wireless textile EEG monitoring system

    NASA Astrophysics Data System (ADS)

    Sahi, Ahna; Rai, Pratyush; Oh, Sechang; Ramasamy, Mouli; Harbaugh, Robert E.; Varadan, Vijay K.

    2014-04-01

    Mu waves, also known as mu rhythms, comb or wicket rhythms are synchronized patterns of electrical activity involving large numbers of neurons, in the part of the brain that controls voluntary functions. Controlling, manipulating, or gaining greater awareness of these functions can be done through the process of Biofeedback. Biofeedback is a process that enables an individual to learn how to change voluntary movements for purposes of improving health and performance through the means of instruments such as EEG which rapidly and accurately 'feedback' information to the user. Biofeedback is used for therapeutic purpose for Autism Spectrum Disorder (ASD) by focusing on Mu waves for detecting anomalies in brain wave patterns of mirror neurons. Conventional EEG measurement systems use gel based gold cup electrodes, attached to the scalp with adhesive. It is obtrusive and wires sticking out of the electrodes to signal acquisition system make them impractical for use in sensitive subjects like infants and children with ASD. To remedy this, sensors can be incorporated with skull cap and baseball cap that are commonly used for infants and children. Feasibility of Textile based Sensor system has been investigated here. Textile based multi-electrode EEG, EOG and EMG monitoring system with embedded electronics for data acquisition and wireless transmission has been seamlessly integrated into fabric of these items for continuous detection of Mu waves. Textile electrodes were placed on positions C3, CZ, C4 according to 10-20 international system and their capability to detect Mu waves was tested. The system is ergonomic and can potentially be used for early diagnosis in infants and planning therapy for ASD patients.

  7. CLEFT PALATE IN HIV-EXPOSED NEWBORNS OF MOTHERS ON HIGHLY ACTIVE ANTIRETROVIRAL THERAPY

    PubMed Central

    James, Ayotunde; Oluwatosin, Babatunde; Njideka, Georgina; Babafemi; Benjamin, Onyekwere George; Olufemi, David; Leo, Robert; Folorunso, Isaac; Phylis; Olusina, Olusegun

    2014-01-01

    Aims Cleft lip/palate, though rare, is the commonest head and neck congenital malformation. Both genetic and environmental factors have been implicated in the aetiopathogenesis but the role of in-utero exposure to human immunodeficiency virus (HIV) and highly active antiretroviral therapy (HAART) is still being investigated. This short communication reports the occurrence of cleft palate in three newborns exposed in-utero to HIV and HAART. Material and methods This is a case series of HIV-exposed newborns observed to have cleft palate among a larger cohort of HIV-exposed and unexposed newborns in a study evaluating the effect of HIV infection and HAART on newborn hearing. The Risk Ratio (RR) was calculated to detect a potential association between in-utero exposure to Efavirenz containing ART and cleft palate. Results Three HIV-exposed newborns with cleft palate were identified during hearing screening performed on 126 HIV-exposed and 121 HIV unexposed newborns. Two had exposure to tenofovir+lamivudine+efavirenz (TDF+3TC+EFV) while the third had exposure to zidovudine+lamivudine+nevirapine (ZDV+3TC+NVP) during the first trimester. There was no statistically significant association between presence of cleft palate and exposure to an EFV containing HAART regimen (p=0.07, RR=10.95 [0.94-126.84]). Conclusions This communication highlights the possible aetiologic role of HAART in cleft palate, the need for further prospective follow-up studies and establishment of antiretroviral pregnancy, birth and neonatal registries. PMID:25653715

  8. Repurposing the NRF2 Activator Dimethyl Fumarate as Therapy Against Synucleinopathy in Parkinson's Disease

    PubMed Central

    García-Yagüe, Angel J.; Scannevin, Robert H.; Casarejos, María J.; Kügler, Sebastian; Rábano, Alberto

    2016-01-01

    Abstract Aims: This preclinical study was aimed at determining whether pharmacological targeting of transcription factor NRF2, a master controller of many homeostatic genes, might provide a disease-modifying therapy in the animal model of Parkinson's disease (PD) that best reproduces the main hallmark of this pathology, that is, α-synucleinopathy, and associated events, including nigral dopaminergic cell death, oxidative stress, and neuroinflammation. Results: Pharmacological activation of NRF2 was achieved at the basal ganglia by repurposing dimethyl fumarate (DMF), a drug already in use for the treatment of multiple sclerosis. Daily oral gavage of DMF protected nigral dopaminergic neurons against α-SYN toxicity and decreased astrocytosis and microgliosis after 1, 3, and 8 weeks from stereotaxic delivery to the ventral midbrain of recombinant adeno-associated viral vector expressing human α-synuclein. This protective effect was not observed in Nrf2-knockout mice. In vitro studies indicated that this neuroprotective effect was correlated with altered regulation of autophagy markers SQTSM1/p62 and LC3 in MN9D, BV2, and IMA 2.1 and with a shift in microglial dynamics toward a less pro-inflammatory and a more wound-healing phenotype. In postmortem samples of PD patients, the cytoprotective proteins associated with NRF2 expression, NQO1 and p62, were partly sequestered in Lewy bodies, suggesting impaired neuroprotective capacity of the NRF2 signature. Innovation: These experiments provide a compelling rationale for targeting NRF2 with DMF as a therapeutic strategy to reinforce endogenous brain defense mechanisms against PD-associated synucleinopathy. Conclusion: DMF is ready for clinical validation in PD. Antioxid. Redox Signal. 25, 61–77. PMID:27009601

  9. Polyomavirus JCV excretion and genotype analysis in HIV-infected patients receiving highly active antiretroviral therapy

    NASA Technical Reports Server (NTRS)

    Lednicky, John A.; Vilchez, Regis A.; Keitel, Wendy A.; Visnegarwala, Fehmida; White, Zoe S.; Kozinetz, Claudia A.; Lewis, Dorothy E.; Butel, Janet S.

    2003-01-01

    OBJECTIVE: To assess the frequency of shedding of polyomavirus JC virus (JCV) genotypes in urine of HIV-infected patients receiving highly active antiretroviral therapy (HAART). METHODS: Single samples of urine and blood were collected prospectively from 70 adult HIV-infected patients and 68 uninfected volunteers. Inclusion criteria for HIV-infected patients included an HIV RNA viral load < 1000 copies, CD4 cell count of 200-700 x 106 cells/l, and stable HAART regimen. PCR assays and sequence analysis were carried out using JCV-specific primers against different regions of the virus genome. RESULTS: JCV excretion in urine was more common in HIV-positive patients but not significantly different from that of the HIV-negative group [22/70 (31%) versus 13/68 (19%); P = 0.09]. HIV-positive patients lost the age-related pattern of JCV shedding (P = 0.13) displayed by uninfected subjects (P = 0.01). Among HIV-infected patients significant differences in JCV shedding were related to CD4 cell counts (P = 0.03). Sequence analysis of the JCV regulatory region from both HIV-infected patients and uninfected volunteers revealed all to be JCV archetypal strains. JCV genotypes 1 (36%) and 4 (36%) were the most common among HIV-infected patients, whereas type 2 (77%) was the most frequently detected among HIV-uninfected volunteers. CONCLUSION: These results suggest that JCV shedding is enhanced by modest depressions in immune function during HIV infection. JCV shedding occurred in younger HIV-positive persons than in the healthy controls. As the common types of JCV excreted varied among ethnic groups, JCV genotypes associated with progressive multifocal leukoencephalopathy may reflect demographics of those infected patient populations.

  10. Erectile Dysfunction Among HIV Patients Undergoing Highly Active Antiretroviral Therapy: Dyslipidemia as a Main Risk Factor

    PubMed Central

    Romero-Velez, Gustavo; Lisker-Cervantes, Andrés; Villeda-Sandoval, Christian I; Sotomayor de Zavaleta, Mariano; Olvera-Posada, Daniel; Sierra-Madero, Juan Gerardo; Arreguin-Camacho, Lucrecia O; Castillejos-Molina, Ricardo A

    2014-01-01

    Objective To assess the prevalence and risk factors of erectile dysfunction (ED) in HIV patients from the HIV clinic of a tertiary referral center in Mexico City. Design Prevalence was obtained from cross-sectional studies, and the International Index of Erectile Function (IIEF), a standardized method, was used to assess ED. Methods A cross-sectional study was performed in the HIV clinic. Participants completed the IIEF to allow ED assessment. Information on demographics, clinical and HIV-related variables was retrieved from their medical records. Results One hundred and nine patients were included, with a mean age of 39.9 ± 8.8 years. ED was present in 65.1% of the individuals. Patients had been diagnosed with HIV for a mean of 92.7 ± 70.3 months and had undergone a mean 56.4 ± 45.5 months of HAART. The only variable associated with ED in the univariate analysis was dyslipidemia, and this association was also found in the multivariate analysis (P = 0.01). Conclusions ED is highly prevalent in HIV patients. Dyslipidemia should be considered as a risk factor for ED in HIV patients. Romero-Velez G, Lisker-Cervantes A, Villeda-Sandoval CI, Sotomayor de Zavaleta M, Olvera-Posada D, Sierra-Madero JG, Arreguin-Camacho LO, and Castillejos-Molina RA. Erectile dysfunction among HIV patients undergoing highly active antiretroviral therapy: Dyslipidemia as a main risk factor. Sex Med 2014;2:24–30. PMID:25356298

  11. Importance of Baseline Prognostic Factors With Increasing Time Since Initiation of Highly Active Antiretroviral Therapy

    PubMed Central

    2012-01-01

    Background The extent to which the prognosis for AIDS and death of patients initiating highly active antiretroviral therapy (HAART) continues to be affected by their characteristics at the time of initiation (baseline) is unclear. Methods We analyzed data on 20,379 treatment-naive HIV-1–infected adults who started HAART in 1 of 12 cohort studies in Europe and North America (61,798 person-years of follow-up, 1844 AIDS events, and 1005 deaths). Results Although baseline CD4 cell count became less prognostic with time, individuals with a baseline CD4 count <25 cells/µL had persistently higher progression rates than individuals with a baseline CD4 count >350 cells/µL (hazard ratio for AIDS = 2.3, 95% confidence interval [CI]: 1.0 to 2.3; mortality hazard ratio = 2.5, 95% CI: 1.2 to 5.5, 4 to 6 years after starting HAART). Rates of AIDS were persistently higher in individuals who had experienced an AIDS event before starting HAART. Individuals with presumed transmission by means of injection drug use experienced substantially higher rates of AIDS and death than other individuals throughout follow-up (AIDS hazard ratio = 1.6, 95% CI: 0.8 to 3.0; mortality hazard ratio = 3.5, 95% CI: 2.2 to 5.5, 4 to 6 years after starting HAART). Conclusions Compared with other patient groups, injection drug users and patients with advanced immunodeficiency at baseline experience substantially increased rates of AIDS and death up to 6 years after starting HAART. PMID:18043315

  12. Viral Decay Kinetics in the Highly Active Antiretroviral Therapy-Treated Rhesus Macaque Model of AIDS

    PubMed Central

    Deere, Jesse D.; Higgins, Joanne; Cannavo, Elda; Villalobos, Andradi; Adamson, Lourdes; Fromentin, Emilie; Schinazi, Raymond F.; Luciw, Paul A.; North, Thomas W.

    2010-01-01

    To prevent progression to AIDS, persons infected with human immunodeficiency virus type 1 (HIV-1) must remain on highly active antiretroviral therapy (HAART) indefinitely since this modality does not eradicate the virus. The mechanisms involved in viral persistence during HAART are poorly understood, but an animal model of HAART could help elucidate these mechanisms and enable studies of HIV-1 eradication strategies. Due to the specificity of non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) for HIV-1, we have used RT-SHIV, a chimeric virus of simian immunodeficiency virus with RT from HIV-1. This virus is susceptible to NNRTIs and causes an AIDS-like disease in rhesus macaques. In this study, two groups of HAART-treated, RT-SHIV-infected macaques were analyzed to determine viral decay kinetics. In the first group, viral loads were monitored with a standard TaqMan RT-PCR assay with a limit of detection of 50 viral RNA copies per mL. Upon initiation of HAART, viremia decayed in a bi-phasic manner with half-lives of 1.7 and 8.5 days, respectively. A third phase was observed with little further decay. In the second group, the macaques were followed longitudinally with a more sensitive assay utilizing ultracentrifugation to concentrate virus from plasma. Bi-phasic decay of viral RNA was also observed in these animals with half-lives of 1.8 and 5.8 days. Viral loads in these animals during a third phase ranged from 2–58 RNA copies/mL, with little decay over time. The viral decay kinetics observed in these macaques are similar to those reported for HIV-1 infected humans. These results demonstrate that low-level viremia persists in RT-SHIV-infected macaques despite a HAART regimen commonly used in humans. PMID:20668516

  13. A Scintillation Counter System Design To Detect Antiproton Annihilation using the High Performance Antiproton Trap(HiPAT)

    NASA Technical Reports Server (NTRS)

    Martin, James J.; Lewis, Raymond A.; Stanojev, Boris

    2003-01-01

    The High Performance Antiproton Trap (HiPAT), a system designed to hold up to l0(exp 12) charge particles with a storage half-life of approximately 18 days, is a tool to support basic antimatter research. NASA's interest stems from the energy density represented by the annihilation of matter with antimatter, 10(exp 2)MJ/g. The HiPAT is configured with a Penning-Malmberg style electromagnetic confinement region with field strengths up to 4 Tesla, and 20kV. To date a series of normal matter experiments, using positive and negative ions, have been performed evaluating the designs performance prior to operations with antiprotons. The primary methods of detecting and monitoring stored normal matter ions and antiprotons within the trap includes a destructive extraction technique that makes use of a micro channel plate (MCP) device and a non-destractive radio frequency scheme tuned to key particle frequencies. However, an independent means of detecting stored antiprotons is possible by making use of the actual annihilation products as a unique indicator. The immediate yield of the annihilation event includes photons and pie mesons, emanating spherically from the point of annihilation. To "count" these events, a hardware system of scintillators, discriminators, coincident meters and multi channel scalars (MCS) have been configured to surround much of the HiPAT. Signal coincidence with voting logic is an essential part of this system, necessary to weed out the single cosmic ray events from the multi-particle annihilation shower. This system can be operated in a variety of modes accommodating various conditions. The first is a low-speed sampling interval that monitors the background loss or "evaporation" rate of antiprotons held in the trap during long storage periods; provides an independent method of validating particle lifetimes. The second is a high-speed sample rate accumulating information on a microseconds time-scale; useful when trapped antiparticles are extracted

  14. Review of the High Performance Antiproton Trap (HiPAT) Experiment at the Marshall Space Flight Center

    NASA Technical Reports Server (NTRS)

    Pearson, J. B.; Sims, Herb; Martin, James; Chakrabarti, Suman; Lewis, Raymond; Fant, Wallace

    2003-01-01

    The significant energy density of matter-antimatter annihilation is attractive to the designers of future space propulsion systems, with the potential to offer a highly compact source of power. Many propulsion concepts exist that could take advantage of matter-antimatter reactions, and current antiproton production rates are sufficient to support basic proof-of-principle evaluation of technology associated with antimatter- derived propulsion. One enabling technology for such experiments is portable storage of low energy antiprotons, allowing antiprotons to be trapped, stored, and transported for use at an experimental facility. To address this need, the Marshall Space Flight Center's Propulsion Research Center is developing a storage system referred to as the High Performance Antiproton Trap (HiPAT) with a design goal of containing 10(exp 12) particles for up to 18 days. The HiPAT makes use of an electromagnetic system (Penning- Malmberg design) consisting of a 4 Telsa superconductor, high voltage electrode structure, radio frequency (RF) network, and ultra high vacuum system. To evaluate the system normal matter sources (both electron guns and ion sources) are used to generate charged particles. The electron beams ionize gas within the trapping region producing ions in situ, whereas the ion sources produce the particles external to the trapping region and required dynamic capture. A wide range of experiments has been performed examining factors such as ion storage lifetimes, effect of RF energy on storage lifetime, and ability to routinely perform dynamic ion capture. Current efforts have been focused on improving the FW rotating wall system to permit longer storage times and non-destructive diagnostics of stored ions. Typical particle detection is performed by extracting trapped ions from HiPAT and destructively colliding them with a micro-channel plate detector (providing number and energy information). This improved RF system has been used to detect various

  15. Role of mitogen activated protein kinases in skin tumorigenicity of Patulin

    SciTech Connect

    Saxena, Neha; Ansari, Kausar M.; Kumar, Rahul; Chaudhari, Bhushan P.; Dwivedi, Premendra D.; Das, Mukul

    2011-12-15

    WHO has highlighted the need to evaluate dermal toxicity of mycotoxins including Patulin (PAT), detected in several fruits. In this study the skin carcinogenic potential of topically applied PAT was investigated. Single topical application of PAT (400 nmol) showed enhanced cell proliferation ({approx} 2 fold), along with increased generation of ROS and activation of ERK, p38 and JNK MAPKs, in mouse skin. PAT exposure also showed activation of downstream target proteins, c-fos, c-Jun and NF-{kappa}B transcription factors. Further, single topical application of PAT (400 nmol) followed by twice weekly application of TPA resulted in tumor formation after 14 weeks, indicating the tumor initiating activity of PAT. However no tumors were observed when PAT was used either as a complete carcinogen (80 nmol) or as a tumor promoter (20 nmol and 40 nmol) for 25 weeks. Histopathological findings of tumors found in PAT/TPA treated mice showed that these tumors were of squamous cell carcinoma type and similar to those found in the positive control group (DMBA/TPA) along with significant increase of lipid peroxidation and decrease in free sulfydryls, catalase, superoxide dismutase and glutathione reductase activities. The results suggest the possible role of free radicals in PAT mediated dermal tumorigenicity involving MAPKs. -- Highlights: Black-Right-Pointing-Pointer Single topical application of Patulin showed enhanced cell proliferation. Black-Right-Pointing-Pointer Patulin activate MAPKs, c-fos, c-Jun and NF-{kappa}B transcription factors. Black-Right-Pointing-Pointer Patulin showed skin tumor initiating potential. Black-Right-Pointing-Pointer We could not detect skin tumor promoting potential of Patulin at the tested dose. Black-Right-Pointing-Pointer However prolonged exposure of Patulin at a higher dose may promote tumor.

  16. The Study of External Dose Rate and Retained Body Activity of Patients Receiving 131I Therapy for Differentiated Thyroid Carcinoma

    PubMed Central

    Zhang, Haiying; Jiao, Ling; Cui, Songye; Wang, Liang; Tan, Jian; Zhang, Guizhi; He, Yajing; Ruan, Shuzhou; Fan, Saijun; Zhang, Wenyi

    2014-01-01

    Radiation safety is an integral part of targeted radionuclide therapy. The aim of this work was to study the external dose rate and retained body activity as functions of time in differentiated thyroid carcinoma patients receiving 131I therapy. Seventy patients were stratified into two groups: the ablation group (A) and the follow-up group (FU). The patients’ external dose rate was measured, and simultaneously, their retained body radiation activity was monitored at various time points. The equations of the external dose rate and the retained body activity, described as a function of hours post administration, were fitted. Additionally, the release time for patients was calculated. The reduction in activity in the group receiving a second or subsequent treatment was more rapid than the group receiving only the initial treatment. Most important, an expeditious method was established to indirectly evaluate the retained body activity of patients by measuring the external dose rate with a portable radiation survey meter. By this method, the calculated external dose rate limits are 19.2, 8.85, 5.08 and 2.32 μSv·h−1 at 1, 1.5, 2 and 3 m, respectively, according to a patient’s released threshold level of retained body activity <400 MBq. This study is beneficial for radiation safety decision-making. PMID:25337944

  17. Safety evaluation of the phosphinothricin acetyltransferase proteins encoded by the pat and bar sequences that confer tolerance to glufosinate-ammonium herbicide in transgenic plants.

    PubMed

    Hérouet, Corinne; Esdaile, David J; Mallyon, Bryan A; Debruyne, Eric; Schulz, Arno; Currier, Thomas; Hendrickx, Koen; van der Klis, Robert-Jan; Rouan, Dominique

    2005-03-01

    Transgenic plant varieties, which are tolerant to glufosinate-ammonium, were developed. The herbicide tolerance is based upon the presence of either the bar or the pat gene, which encode for two homologous phosphinothricin acetyltransferases (PAT), in the plant genome. Based on both a review of published literature and experimental studies, the safety assessment reviews the first step of a two-step-approach for the evaluation of the safety of the proteins expressed in plants. It can be used to support the safety of food or feed products derived from any crop that contains and expresses these PAT proteins. The safety evaluation supports the conclusion that the genes and the donor microorganisms (Streptomyces) are innocuous. The PAT enzymes are highly specific and do not possess the characteristics associated with food toxins or allergens, i.e., they have no sequence homology with any known allergens or toxins, they have no N-glycosylation sites, they are rapidly degraded in gastric and intestinal fluids, and they are devoid of adverse effects in mice after intravenous administration at a high dose level. In conclusion, there is a reasonable certainty of no harm resulting from the inclusion of the PAT proteins in human food or in animal feed.

  18. Self-shielding effects in neutron spectra measurements for neutron capture therapy by means of activation foils.

    PubMed

    Pytel, Krzysztof; Józefowicz, Krystyna; Pytel, Beatrycze; Koziel, Alina

    2004-01-01

    The design and optimisation of a neutron beam for neutron capture therapy (NCT) is accompanied by the neutron spectra measurements at the target position. The method of activation detectors was applied for the neutron spectra measurements. Epithermal neutron energy region imposes the resonance structure of activation cross sections resulting in strong self-shielding effects. The neutron self-shielding correction factor was calculated using a simple analytical model of a single absorption event. Such a procedure has been applied to individual cross sections from pointwise ENDF/B-VI library and new corrected activation cross sections were introduced to a spectra unfolding algorithm. The method has been verified experimentally both for isotropic and for parallel neutron beams. Two sets of diluted and non-diluted activation foils covered with cadmium were irradiated in the neutron field. The comparison of activation rates of diluted and non-diluted foils has demonstrated the correctness of the applied self-shielding model.

  19. In vitro and in vivo antimicrobial activity of combined therapy of silver nanoparticles and visible blue light against Pseudomonas aeruginosa.

    PubMed

    Nour El Din, Suzanne; El-Tayeb, Tarek A; Abou-Aisha, Khaled; El-Azizi, Mohamed

    2016-01-01

    Silver nanoparticles (AgNPs) have been used as potential antimicrobial agents against resistant pathogens. We investigated the possible therapeutic use of AgNPs in combination with visible blue light against a multidrug resistant clinical isolate of Pseudomonas aeruginosa in vitro and in vivo. The antibacterial activity of AgNPs against P. aeruginosa (1×10(5) colony forming unit/mL) was investigated at its minimal inhibitory concentration (MIC) and sub-MIC, alone and in combination with blue light at 460 nm and 250 mW for 2 hours. The effect of this combined therapy on the treated bacteria was then visualized using transmission electron microscope. The therapy was also assessed in the prevention of biofilm formation by P. aeruginosa on AgNP-impregnated gelatin biopolymer discs. Further, in vivo investigations were performed to evaluate the efficacy of the combined therapy to prevent burn-wound colonization and sepsis in mice and, finally, to treat a real infected horse with antibiotic-unresponsive chronic wound. The antimicrobial activity of AgNPs and visible blue light was significantly enhanced (P<0.001) when both agents were combined compared to each agent alone when AgNPs were tested at MIC, 1/2, or 1/4 MIC. Transmission electron microscope showed significant damage to the cells that were treated with the combined therapy compared to other cells that received either the AgNPs or blue light. In addition, the combined treatment significantly (P<0.001) inhibited biofilm formation by P. aeruginosa on gelatin discs compared to each agent individually. Finally, the combined therapy effectively treated a horse suffering from a chronic wound caused by mixed infection, where signs of improvement were observed after 1 week, and the wound completely healed after 4 weeks. To our knowledge, this combinatorial therapy has not been investigated before. It was proved efficient and promising in managing infections caused by multidrug resistant bacteria and could be used as an

  20. In vitro and in vivo antimicrobial activity of combined therapy of silver nanoparticles and visible blue light against Pseudomonas aeruginosa

    PubMed Central

    Nour El Din, Suzanne; El-Tayeb, Tarek A; Abou-Aisha, Khaled; El-Azizi, Mohamed

    2016-01-01

    Silver nanoparticles (AgNPs) have been used as potential antimicrobial agents against resistant pathogens. We investigated the possible therapeutic use of AgNPs in combination with visible blue light against a multidrug resistant clinical isolate of Pseudomonas aeruginosa in vitro and in vivo. The antibacterial activity of AgNPs against P. aeruginosa (1×105 colony forming unit/mL) was investigated at its minimal inhibitory concentration (MIC) and sub-MIC, alone and in combination with blue light at 460 nm and 250 mW for 2 hours. The effect of this combined therapy on the treated bacteria was then visualized using transmission electron microscope. The therapy was also assessed in the prevention of biofilm formation by P. aeruginosa on AgNP-impregnated gelatin biopolymer discs. Further, in vivo investigations were performed to evaluate the efficacy of the combined therapy to prevent burn-wound colonization and sepsis in mice and, finally, to treat a real infected horse with antibiotic-unresponsive chronic wound. The antimicrobial activity of AgNPs and visible blue light was significantly enhanced (P<0.001) when both agents were combined compared to each agent alone when AgNPs were tested at MIC, 1/2, or 1/4 MIC. Transmission electron microscope showed significant damage to the cells that were treated with the combined therapy compared to other cells that received either the AgNPs or blue light. In addition, the combined treatment significantly (P<0.001) inhibited biofilm formation by P. aeruginosa on gelatin discs compared to each agent individually. Finally, the combined therapy effectively treated a horse suffering from a chronic wound caused by mixed infection, where signs of improvement were observed after 1 week, and the wound completely healed after 4 weeks. To our knowledge, this combinatorial therapy has not been investigated before. It was proved efficient and promising in managing infections caused by multidrug resistant bacteria and could be used as an

  1. In vitro and in vivo antimicrobial activity of combined therapy of silver nanoparticles and visible blue light against Pseudomonas aeruginosa.

    PubMed

    Nour El Din, Suzanne; El-Tayeb, Tarek A; Abou-Aisha, Khaled; El-Azizi, Mohamed

    2016-01-01

    Silver nanoparticles (AgNPs) have been used as potential antimicrobial agents against resistant pathogens. We investigated the possible therapeutic use of AgNPs in combination with visible blue light against a multidrug resistant clinical isolate of Pseudomonas aeruginosa in vitro and in vivo. The antibacterial activity of AgNPs against P. aeruginosa (1×10(5) colony forming unit/mL) was investigated at its minimal inhibitory concentration (MIC) and sub-MIC, alone and in combination with blue light at 460 nm and 250 mW for 2 hours. The effect of this combined therapy on the treated bacteria was then visualized using transmission electron microscope. The therapy was also assessed in the prevention of biofilm formation by P. aeruginosa on AgNP-impregnated gelatin biopolymer discs. Further, in vivo investigations were performed to evaluate the efficacy of the combined therapy to prevent burn-wound colonization and sepsis in mice and, finally, to treat a real infected horse with antibiotic-unresponsive chronic wound. The antimicrobial activity of AgNPs and visible blue light was significantly enhanced (P<0.001) when both agents were combined compared to each agent alone when AgNPs were tested at MIC, 1/2, or 1/4 MIC. Transmission electron microscope showed significant damage to the cells that were treated with the combined therapy compared to other cells that received either the AgNPs or blue light. In addition, the combined treatment significantly (P<0.001) inhibited biofilm formation by P. aeruginosa on gelatin discs compared to each agent individually. Finally, the combined therapy effectively treated a horse suffering from a chronic wound caused by mixed infection, where signs of improvement were observed after 1 week, and the wound completely healed after 4 weeks. To our knowledge, this combinatorial therapy has not been investigated before. It was proved efficient and promising in managing infections caused by multidrug resistant bacteria and could be used as an

  2. Insulin activates glycerol-3-phosphate acyltransferase (de novo phosphatidic acid synthesis) through a phospholipid-derived mediator. Apparent involvement of Gi alpha and activation of a phospholipase C.

    PubMed

    Vila, M C; Milligan, G; Standaert, M L; Farese, R V

    1990-09-18

    We studied the mechanism whereby insulin activates de novo phosphatidic acid synthesis in BC3H-1 myocytes. Insulin rapidly activated glycerol-3-phosphate acyltransferase (G3PAT) in intact and cell-free preparations of myocytes in a dose-related manner. The apparent Km of the enzyme was decreased by treatment with insulin, whereas the Vmax was unaffected. No activation was found by ACTH, insulin-like growth factor-I, angiotensin II, or phenylephrine, but epidermal growth factor, which, like insulin, is known to activate de novo phosphatidic acid synthesis in intact myocytes, also stimulated G3PAT activity. In homogenates or membrane fractions, the effect of insulin on G3PAT was fully mimicked by nonspecific or phosphatidylinositol (PI)-specific phospholipase C (PLC). An antiserum raised against PI-glycan-PLC completely blocked the effect of insulin on G3PAT. Although the above findings suggested involvement of a PLC in insulin-induced activation of G3PAT, neither diacylglycerol nor protein kinase C activation appeared to be involved. On the other hand, insulin stimulated the release of a cytosolic factor, which activated membrane-associated G3PAT. This cytosolic factor had a molecular weight of less than 5K as determined by Sephadex G-25 chromatography. NaF, a phosphatase inhibitor, blocked the activation of G3PAT by insulin, suggesting involvement of a phosphatase. Insulin-induced activation of G3PAT was also blocked by pretreatment of intact myocytes with pertussis toxin and by prior addition, to homogenates, of an antiserum that recognizes the C-terminal decapeptide of Gi alpha.(ABSTRACT TRUNCATED AT 250 WORDS)

  3. Exploration of the effect and mechanism of activating blood circulation and stasis-removing therapy on tumor metastasis.

    PubMed

    Lu, Xiang; Li, Bai

    2009-10-01

    Metastasis is one of the specificities of late stage tumor and also a lethal factor often encountered. The study of tumor metastasis has important meaning for prolonging patients' survival and elevating their quality of life, but no really ideal prevention and treatment method has been found so far. Recent researches showed that tumor metastasis is correlated with platelet aggregation and blood hyperviscosity manner. Therefore, the early application of surgery, radiotherapy, chemotherapy and biological therapies, in combination with Chinese medicine therapy for activating blood circulation and removing stasis (ABCRS) may be, after all, an effective approach. ABCRS therapy is an important therapy of Chinese medicine, which, composed of several methods like smoothening blood flow in vessels, promoting blood circulation and dispersing stagnant blood, could influence tumor metastasis to different extents, and could coordinate with some other Chinese medicine therapeutic methods like supplementing qi, promoting qi, clearing heat, removing toxic substances, warming meridian, dispelling wind, eliminating dampness, nourishing yin, dissolving sputum, relieving stagnancy, emptying viscerals, etc. The effect and acting mechanism of ABCRS on tumor metastasis is summarized in this paper and its bi-directional regulatory effects discussed as well.

  4. SU-C-303-01: Activation-Induced Cytidine Deaminase Confers Cancer Resistance to Radiation Therapy

    SciTech Connect

    Yi, S; La Count, S; Liu, J; Bai, X; Lu, L

    2015-06-15

    Purpose: To study the role of activation-induced cytidine deaminase (AID) in malignant cell resistance to radiation therapy. Methods: We first developed several small devices that could be used to adopt radiation beams from clinical high dose rate brachy therapy (HDR) or linac-based megavoltage machines to perform pre-clinical cell and mouse experiments. Then we used these devices to deliver radiation to AID-positive and AID-silenced cancer cells or tumors formed by these cells in mice. Cells and mice bearing tumors received the same dose under the same experimental conditions. For cells, we observed the apoptosis and the cell survival rate over time. For mice bearing tumors, we measured and recorded the tumor sizes every other day for 4 weeks. Results: For cell experiments, we found that the AID-positive cells underwent much less apoptosis compared with AID-silenced cells upon radiation. And for mouse experiments, we found that AID-positive tumors grew significantly faster than the AID-silenced tumors despite of receiving the same doses of radiation. Conclusion: Our study suggests that AID may confer cancer resistance to radiation therapy, and AID may be a significant biomarker predicting cancer resistance to radiation therapy for certain cancer types.

  5. Prediction of acute and late responses to light therapy from vocal (pitch) and self-rated activation in seasonal affective disorder.

    PubMed

    Boenink, A D; Bouhuys, A L; Beersma, D G; Meesters, Y

    1997-02-01

    It was hypothesized that pre-treatment activation plays a role in the response to light therapy in Seasonal Affective Disorder (SAD). In 55 SAD patients (DSMIII-R) energetic and tense activation was assessed before light therapy via self-rating (AD-ACL) and voice sound characteristics (mean pitch and variation in pitch). These variables were studied in relation to the "acute" response to 4 days of light therapy (30 min, 10000 lux) and to a "late" response (11 (10) days after light therapy had stopped). Acute response was defined as the percent change in 3 times daily self-rated depressed mood (AMS) with respect to the average of 4 baseline days. "Late" response was defined as the percent change in HRSD or AMS scores between baseline and 11 (10) days after light therapy. It was found that patients having high pitched voices with small variation in this pitch benefitted more from light therapy than the patients with low pitch and large variation in pitch levels. This effect was only significant after the first day of light exposure. No other significant relations were found between baseline activation and acute or late responses to light therapy. Hence, light therapy seems to give extra comfort in "tense" patients, who become rapid responders to light therapy.

  6. [Foetal therapy for Down syndrome: a pro-active ethical reflection].

    PubMed

    de Wert, G M W R; Dondorp, W J

    2016-01-01

    Prenatal screening for Down syndrome has to date focused on facilitating the informed choice to continue or not with a pregnancy. The non-invasive prenatal test (NIPT) for Down syndrome does potentially offer the option to apply foetal neurocognitive therapy for Down syndrome (FTDS). Current research in animal models looks promising and therefore a proactive ethical reflection in relation to clinical trials is urgently needed. This discussion includes an exploration of the ethical aspects of FTDS. There seem to be no convincing a priori objections on the basis of the social model of disability. Arguments in terms of (respect for) autonomy, wellbeing and justice seem to in principle support such therapy. Still, both the conditions for sound clinical trials and the implications of possible effective therapy for current prenatal screening need further scrutiny. PMID:27334087

  7. [The dilemma between the functional deficits of obese people and recommended physical activity: what part can dance therapy play?].

    PubMed

    Muller-Pinget, Solange; Pataky, Zoltan; Golay, Alain; Armand, Stéphane; Allet, Lara

    2012-03-28

    Obese people may have trouble with walking and may present reduced postural control. Medical doctors or therapists should guide the patient to restart doing physical activities that are gentle and progressive. Exercise should take into account walking difficulties. Thus, the first challenge is to help obese individuals start exercising without risk, or excessive strain on the joints. The second stage should encourage individuals to persevere in the chosen activity. Enjoyment is a key factor for attaining these objectives. Dance therapy, with its psychological and physiological impact, could help individuals take on the challenge.

  8. Lipodystrophy in Human Immunodeficiency Virus (HIV) Patients on Highly Active Antiretroviral Therapy (HAART)

    PubMed Central

    Kumar, N. Sunil; Shashibhushan, J.; Venugopal, K.; Vishwanatha, Huggi; Menon, Mahesh

    2015-01-01

    Background In recent years, abnormal lipid deposition (both lipoatrophy and fat redistribution) and its related complications have changed from an anecdotal issue into a major problem for HIV (Human Immunodeficiency Virus) infected patients on HAART (Highly Active Anti-Retroviral Therapy). Lipoatrophy and fat redistribution are potentially stigmatizing complications of HAART and leads to poor adherence among patients. Hence we conducted this study to determine the pattern and to assess various risk factors for maldeposition of lipids in HIV patients. Materials and Methods A cross-sectional case series study was conducted in ART PLUS centre, Bellary over a period of 8 months from January to August 2014 in HIV patients on ART to determine risk factors associated with and epidemiological pattern of fat redistribution or atrophy. Results A total of 50 patients with LD {lipodystrophy} (26 with fat redestribution and 24 with lipoatrophy {LA} were diagnosed in this period. Most of them belonged to younger age and was commonly seen in females (76%). Patients with LA had a significantly lower BMI (18.73 ± 7.4), {the p-value being 0.19} compared to LH group (21.54 ± 7.62). The duration of disease was comparable among both groups (6.96 years in LH and 5.79 years in LA group) {p-value is 0.29}. There was a relatively good immunity among these patients with mean CD4 count was 509.23 in LH and 545.91 in LA group {single CD4 count was taken and the p-value was 0.001}. Most of the patients were in TLN (Tenofovir, Lamivudine, Nevirapine) regimen (58%).The duration that patient was on ART before commencement of study varied from patient to patient, but the mean duration was approximately five years in fat redistribution group and 4.5 years in LA group. There were no derangements in lipid and sugar levels among them. Conclusion This study shows the need to identify and impact of LD with respect to treatment adherence in young patients especially female patients. Early community

  9. Small GTPase CDC-42 promotes apoptotic cell corpse clearance in response to PAT-2 and CED-1 in C. elegans.

    PubMed

    Neukomm, L J; Zeng, S; Frei, A P; Huegli, P A; Hengartner, M O

    2014-06-01

    The rapid clearance of dying cells is important for the well-being of multicellular organisms. In C. elegans, cell corpse removal is mainly mediated by three parallel engulfment signaling cascades. These pathways include two small GTPases, MIG-2/RhoG and CED-10/Rac1. Here we present the identification and characterization of CDC-42 as a third GTPase involved in the regulation of cell corpse clearance. Genetic analyses performed by both loss of cdc-42 function and cdc-42 overexpression place cdc-42 in parallel to the ced-2/5/12 signaling module, in parallel to or upstream of the ced-10 module, and downstream of the ced-1/6/7 module. CDC-42 accumulates in engulfing cells at membranes surrounding apoptotic corpses. The formation of such halos depends on the integrins PAT-2/PAT-3, UNC-112 and the GEF protein UIG-1, but not on the canonical ced-1/6/7 or ced-2/5/12 signaling modules. Together, our results suggest that the small GTPase CDC-42 regulates apoptotic cell engulfment possibly upstream of the canonical Rac GTPase CED-10, by polarizing the engulfing cell toward the apoptotic corpse in response to integrin signaling and ced-1/6/7 signaling in C. elegans.

  10. ASC-1, PAT2, and P2RX5 are cell surface markers for white, beige, and brown adipocytes.

    PubMed

    Ussar, Siegfried; Lee, Kevin Y; Dankel, Simon N; Boucher, Jeremie; Haering, Max-Felix; Kleinridders, Andre; Thomou, Thomas; Xue, Ruidan; Macotela, Yazmin; Cypess, Aaron M; Tseng, Yu-Hua; Mellgren, Gunnar; Kahn, C Ronald

    2014-07-30

    White, beige, and brown adipocytes are developmentally and functionally distinct but often occur mixed together within individual depots. To target white, beige, and brown adipocytes for diagnostic or therapeutic purposes, a better understanding of the cell surface properties of these cell types is essential. Using a combination of in silico, in vitro, and in vivo methods, we have identified three new cell surface markers of adipose cell types. The amino acid transporter ASC-1 is a white adipocyte-specific cell surface protein, with little or no expression in brown adipocytes, whereas the amino acid transporter PAT2 and the purinergic receptor P2RX5 are cell surface markers expressed in classical brown and beige adipocytes in mice. These markers also selectively mark brown/beige and white adipocytes in human tissue. Thus, ASC-1, PAT2, and P2RX5 are membrane surface proteins that may serve as tools to identify and target white and brown/beige adipocytes for therapeutic purposes.

  11. Mass-spectrometry analysis of histone post-translational modifications in pathology tissue using the PAT-H-MS approach.

    PubMed

    Noberini, Roberta; Pruneri, Giancarlo; Minucci, Saverio; Bonaldi, Tiziana

    2016-06-01

    Aberrant histone post-translational modifications (hPTMs) have been implicated with various pathologies, including cancer, and may represent useful epigenetic biomarkers. The data described here provide a mass spectrometry-based quantitative analysis of hPTMs from formalin-fixed paraffin-embedded (FFPE) tissues, from which histones were extracted through the recently developed PAT-H-MS method. First, we analyzed FFPE samples from mouse spleen and liver or human breast cancer up to six years old, together with their corresponding fresh frozen tissue. We then combined the PAT-H-MS approach with a histone-focused version of the super-SILAC strategy-using a mix of histones from four breast cancer cell lines as a spike-in standard- to accurately quantify hPTMs from breast cancer specimens belonging to different subtypes. The data, which are associated with a recent publication (Pathology tissue-quantitative mass spectrometry analysis to profile histone post-translational modification patterns in patient samples (Noberini, 2015) [1]), are deposited at the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD002669. PMID:27408908

  12. Asc-1, PAT2 and P2RX5 are novel cell surface markers for white, beige and brown adipocytes

    PubMed Central

    Ussar, Siegfried; Lee, Kevin Y.; Dankel, Simon N.; Boucher, Jeremie; Haering, Max-Felix; Kleinridders, Andre; Thomou, Thomas; Xue, Ruidan; Macotela, Yazmin; Cypess, Aaron M.; Tseng, Yu-Hua; Mellgren, Gunnar; Kahn, C. Ronald

    2015-01-01

    White, beige and brown adipocytes are developmentally and functionally distinct but often occur mixed together within individual depots. To target white, beige and brown adipocytes for diagnostic or therapeutic purposes, a better understanding of the cell surface properties of these cell types is essential. Using a combination of in silico, in vitro and in vivo methods, we have identified three new cell surface markers of adipose cell types. The amino acid transporter Asc-1 is a white adipocyte-specific cell surface protein, with little or no expression in brown adipocytes, whereas the amino acid transporter PAT2 and the purinergic receptor P2RX5 are cell surface markers expressed in classical brown and beige adipocytes in mice. These markers also selectively mark brown/beige and white adipocytes in human tissue. Thus, Asc-1, PAT2 and P2RX5 are membrane surface proteins that may serve as tools to identify and target white and brown/beige adipocytes for therapeutic purposes. PMID:25080478

  13. Strategic funding priorities in the pharmaceutical sciences allied to Quality by Design (QbD) and Process Analytical Technology (PAT).

    PubMed

    Aksu, Buket; De Beer, Thomas; Folestad, Staffan; Ketolainen, Jarkko; Lindén, Hans; Lopes, Joao Almeida; de Matas, Marcel; Oostra, Wim; Rantanen, Jukka; Weimer, Marco

    2012-09-29

    Substantial changes in Pharmaceutical R&D strategy are required to address existing issues of low productivity, imminent patent expirations and pressures on pricing. Moves towards personalized healthcare and increasing diversity in the nature of portfolios including the rise of biopharmaceuticals however have the potential to provide considerable challenges to the establishment of cost effective and robust supply chains. To guarantee product quality and surety of supply for essential medicines it is necessary that manufacturing science keeps pace with advances in pharmaceutical R&D. In this position paper, the EUFEPS QbD and PAT Sciences network make recommendations that European industry, academia and health agencies focus attention on delivering step changes in science and technology in a number of key themes. These subject areas, all underpinned by the sciences allied to QbD and PAT, include product design and development for personalized healthcare, continuous-processing in pharmaceutical product manufacture, quantitative quality risk assessment for pharmaceutical development including life cycle management and the downstream processing of biopharmaceutical products. Plans are being established to gain commitment for inclusion of these themes into future funding priorities for the Innovative Medicines Initiative (IMI).

  14. In vivo and protease-activated receptor-1-mediated platelet activation but not response to antiplatelet therapy predict two-year outcomes after peripheral angioplasty with stent implantation.

    PubMed

    Gremmel, T; Steiner, S; Seidinger, D; Koppensteiner, R; Panzer, S; Kopp, C W

    2014-03-01

    Data linking the response to antiplatelet therapy with clinical outcomes after angioplasty and stenting for lower extremity artery disease (LEAD) are scarce. Moreover, associations of in vivo and thrombin-inducible platelet activation with the occurrence of adverse events have not been investigated in these patients, so far. We therefore assessed clinical outcomes and on-treatment platelet reactivity by four test systems in 108 patients receiving dual antiplatelet therapy after infrainguinal angioplasty and stenting for LEAD. Further, in vivo and thrombin receptor-activating peptide (TRAP)-6-inducible glycoprotein (GP) IIb/IIIa activation and P-selectin expression were measured as sensitive parameters of platelet activation. The primary endpoint was defined as the composite of atherothrombotic events and target vessel restenosis or reocclusion. Residual platelet reactivity to adenosine diphosphate and arachidonic acid was similar between patients without and with adverse outcomes within two-year follow-up (all p>0.05). Further, the occurrence of clinical endpoints did not differ significantly between patients without and with high on-treatment residual platelet reactivity by all test systems (all p>0.05). In contrast, in vivo and TRAP-6-inducible platelet activation were significantly more pronounced in patients with subsequent adverse events (all p<0.05), and high levels of platelet activation were independent predictors of the primary endpoint (adjusted hazard ratios: 3.5 for high in vivo activated GPIIb/IIIa, 2.9 for high TRAP-6-inducible activated GPIIb/IIIa, 2.3 for high in vivo P-selectin, and 3 for high TRAP-6-inducible P-selectin; all p<0.05). In conclusion, in vivo and protease-activated receptor-1-mediated platelet activation predict two-year clinical outcomes in stable patients undergoing angioplasty and stenting for LEAD.

  15. Cognitive Behavior Therapy for Relatively Active and for Passive Chronic Fatigue Syndrome Patients

    ERIC Educational Resources Information Center

    Bazelmans, Ellen; Prins, Judith; Bleijenberg, Gijs

    2006-01-01

    In chronic fatigue syndrome (CFS), facilitating, initiating, and perpetuating factors are distinguished. Although somatic factors might have initiated symptoms in CFS, they do not explain the persistence of fatigue. Cognitive behavior therapy (CBT) for CFS focuses on factors that perpetuate and prolong symptoms. Recently it has been shown that,…

  16. Effects of Drawing on Alpha Activity: A Quantitative EEG Study with Implications for Art Therapy

    ERIC Educational Resources Information Center

    Belkofer, Christopher M.; Van Hecke, Amy Vaughan; Konopka, Lukasz M.

    2014-01-01

    Little empirical evidence exists as to how materials used in art therapy affect the brain and its neurobiological functioning. This pre/post within-groups study utilized the quantitative electroencephalogram (qEEG) to measure residual effects in the brain after 20 minutes of drawing. EEG recordings were conducted before and after participants (N =…

  17. Acceptance and Commitment Therapy and Behavioral Activation for the Treatment of Depression: Description and Comparison

    ERIC Educational Resources Information Center

    Kanter, Jonathan W.; Baruch, David E.; Gaynor, Scott T.

    2006-01-01

    The field of clinical behavior analysis is growing rapidly and has the potential to affect and transform mainstream cognitive behavior therapy. To have such an impact, the field must provide a formulation of and intervention strategies for clinical depression, the "common cold" of outpatient populations. Two treatments for depression have emerged:…

  18. Brief Behavioral Activation and Problem-Solving Therapy for Depressed Breast Cancer Patients: Randomized Trial

    ERIC Educational Resources Information Center

    Hopko, Derek R.; Armento, Maria E. A.; Robertson, Sarah M. C.; Ryba, Marlena M.; Carvalho, John P.; Colman, Lindsey K.; Mullane, Christen; Gawrysiak, Michael; Bell, John L.; McNulty, James K.; Lejuez, Carl W.

    2011-01-01

    Objective: Major depression is the most common psychiatric disorder among breast cancer patients and is associated with substantial impairment. Although some research has explored the utility of psychotherapy with breast cancer patients, only 2 small trials have investigated the potential benefits of behavior therapy among patients with…

  19. High mitochondrial redox potential may promote induction and activation of UCP2 in hepatocytes during hepatothermic therapy.

    PubMed

    McCarty, Mark F

    2005-01-01

    Although uncoupling protein-1 is a key mediator of thermogenesis in activated brown fat, the more recently characterized uncoupling proteins-2 and -3 do not appear to influence basal metabolism, but rather may function to diminish excessive mitochondrial superoxide production when mitochondrial redox potential is high. Under these circumstances, superoxide within the mitochondrial matrix directly activates uncoupling protein-2 (UCP2), and may also promote induction of this protein. Normal healthy hepatocytes do not express UCP2, but this protein is induced in hepatocytes that are steatotic or that are treated with agents that boost superoxide production. It is proposed that induction and activation of UCP2 may play a role in the thermogenesis evoked by hepatothermic therapy, a strategy designed to decrease body fat by maximizing hepatic fatty acid oxidation. Under these conditions, high mitochondrial redox potential would be expected, and induction of UCP2's uncoupling activity would represent a homeostatically appropriate antioxidant response. PMID:15823721

  20. The use of craft activities as an occupational therapy treatment modality in Norway during 1952-1960.

    PubMed

    Horghagen, Sissel; Josephsson, Staffan; Alsaker, Sissel

    2007-01-01

    The purpose of the present study was to explore the use of craft activities as occupational therapy treatment modalities in Norway during the period 1952-1960. Data were obtained through in-depth interviews with six retired occupational therapists on their experiences in using crafts. Data were analysed through textual analysis and this resulted in four themes: craft activities identified as a therapeutic tool; ambivalence in how to frame the intervention; practice relative to power relationships; and occupational therapists and patients as equals. A limitation of the present study was that participants drew on their screened memories in the context of contemporary practice, which may omit or distort the historical truth. Further research is needed to document the effect of contemporary therapeutic use of craft activities, and to bring forward how occupational therapists and clients value the craft activities of today in the context of their lives. PMID:17623378

  1. Induction by interleukin-7 of lymphokine-activated killer activity in lymphocytes from autologous and syngeneic marrow transplant recipients before and after systemic interleukin-2 therapy.

    PubMed

    Pavletic, Z; Benyunes, M C; Thompson, J A; Lindgren, C G; Massumoto, C; Alderson, M R; Buckner, C D; Fefer, A

    1993-09-01

    Therapy with recombinant lymphokines after autologous bone marrow transplantation (ABMT) is being explored as a way to prevent relapse. Lymphokine therapy may exert an antitumor effect through a variety of mechanisms, including the induction of lymphokine-activated killer (LAK) cell cytotoxicity. We tested the ability of interleukin-7 (IL-7) to induce LAK cytotoxicity in peripheral blood mononuclear cells (PBMC) from healthy subjects and from patients early after ABMT. LAK activity was defined as lysis of Daudi by PBMC after incubation with IL-7 at 10 to 100 ng/mL or IL-2 at 1000 U/mL. PBMC from four healthy subjects were cultured with either IL-7 or IL-2. IL-7 induced LAK activity in two of the four, whereas IL-2 induced LAK activity in all four. The median percent lysis (effector-to-target ratio [E:T] 40:1) with IL-7 (23%) was lower than with IL-2 (67%). PBMC were obtained from 15 patients 27 to 84 days after autologous (n = 13) or syngeneic (n = 2) bone marrow transplantation (BMT) and tested for IL-7-induced LAK activity. Eleven exhibited significant activity (10% to 77% lysis at E:T 40:1). In contrast to the results in PBMC from normal subjects, in PBMC from ABMT patients IL-7 induced LAK activity of a magnitude similar to that induced by IL-2. Studies were also performed on PBMC from eight patients who had received IL-2 after ABMT (3.0 x 10(6) U/m2/d) for 4 days by continuous intravenous (IV) infusion. In seven of the eight patients, IL-7 induced significant LAK activity, which was higher than that seen in PBMC from ABMT patients who had not received IL-2. Thus, IL-7 reproducibly induced significant LAK activity in cells obtained early after autologous or syngeneic BMT. Indeed, such LAK activity was comparable quantitatively to that induced by IL-2. Finally, IL-7 induced an even greater LAK activity in vitro in PBMC obtained after ABMT and preactivated in vivo by IL-2 therapy. The results suggest that IL-7 may have a potential immunotherapeutic role, alone or

  2. Simultaneous Enrichment of Cysteine-containing Peptides and Phosphopeptides Using a Cysteine-specific Phosphonate Adaptable Tag (CysPAT) in Combination with titanium dioxide (TiO2) Chromatography*

    PubMed Central

    Huang, Honggang; Haar Petersen, Martin; Ibañez-Vea, Maria; Lassen, Pernille S.; Larsen, Martin R.; Palmisano, Giuseppe

    2016-01-01

    Cysteine is a rare and conserved amino acid involved in most cellular functions. The thiol group of cysteine can be subjected to diverse oxidative modifications that regulate many physio-pathological states. In the present work, a Cysteine-specific Phosphonate Adaptable Tag (CysPAT) was synthesized to selectively label cysteine-containing peptides (Cys peptides) followed by their enrichment with titanium dioxide (TiO2) and subsequent mass spectrometric analysis. The CysPAT strategy was developed using a synthetic peptide, a standard protein and subsequently the strategy was applied to protein lysates from Hela cells, achieving high specificity and enrichment efficiency. In particular, for Cys proteome analysis, the method led to the identification of 7509 unique Cys peptides from 500 μg of HeLa cell lysate starting material. Furthermore, the method was developed to simultaneously enrich Cys peptides and phosphorylated peptides. This strategy was applied to SILAC labeled Hela cells subjected to 5 min epidermal growth factor (EGF) stimulation. In total, 10440 unique reversibly modified Cys peptides (3855 proteins) and 7339 unique phosphopeptides (2234 proteins) were simultaneously identified from 250 μg starting material. Significant regulation was observed in both phosphorylation and reversible Cys modification of proteins involved in EGFR signaling. Our data indicates that EGF stimulation can activate the well-known phosphorylation of EGFR and downstream signaling molecules, such as mitogen-activated protein kinases (MAPK1 and MAPK3), however, it also leads to substantial modulation of reversible cysteine modifications in numerous proteins. Several protein tyrosine phosphatases (PTPs) showed a reduction of the catalytic Cys site in the conserved putative phosphatase HC(X)5R motif indicating an activation and subsequent de-phosphorylation of proteins involved in the EGF signaling pathway. Overall, the CysPAT strategy is a straight forward, easy and promising

  3. The Effects of Brief Behavioral Activation Therapy for Depression on Cognitive Control in Affective Contexts: an fMRI investigation

    PubMed Central

    Dichter, Gabriel S.; Felder, Jennifer N.; Smoski, Moria J.

    2010-01-01

    Background Unipolar major depressive disorder (MDD) is characterized by impaired cognitive control in affective contexts, but the potential for psychotherapy to affect the neural correlates of these functions has not been evaluated. Method Twelve adults with and 15 adults without MDD participated in two identical functional magnetic resonance imaging (fMRI) scans that utilized a task requiring cognitive control in both sad and neutral contexts. Between scans, MDD outpatients received Behavioral Activation Therapy for Depression, a psychotherapy modality designed to increase engagement with positive stimuli and reduce avoidance behaviors. Results Seventy-five percent of adults with MDD were treatment responders, achieving post-treatment Hamilton Rating Scale for Depression score of six or below. Consistent with predictions, psychotherapy resulted in decreased activation in response to cognitive control stimuli presented within a sad context in prefrontal structures, including the paracingulate gyrus, the right orbital frontal cortex, and the right frontal pole. Furthermore, the magnitude of pretreatment activation in the paracingulate gyrus cluster responsive to psychotherapy predicted the magnitude of depressive symptom change after psychotherapy. Limitations Replication with larger samples is needed, as are follow-up studies that involve placebo control groups, wait-list control groups, and alternative forms of antidepressant intervention. Conclusions Behavioral Activation Therapy for Depression improves depressive symptoms and concomitantly influences brain systems mediating cognitive control in affective contexts. PMID:20421135

  4. Detection of cocaine induced rat brain activation by photoacoustic tomography

    PubMed Central

    Jo, Janggun; Yang, Xinmai

    2011-01-01

    Photoacoustic tomography (PAT) was used to detect the progressive changes on the cerebral cortex of Sprague Dawley rats after the administration of cocaine hydrochloride. Different concentrations (0, 2.5, and 5.0 mg per kg body) of cocaine hydrochloride in saline solution were injected into Sprague Dawley rats through tail veins. Cerebral cortex images of the animals were continuously acquired by PAT. For continuous observation, PAT system used multi-transducers to reduce the scanning time and maintain a good signal-to-noise ratio (SNR). The obtained photoacoustic images were compared with each other and confirmed that changes in blood volume were induced by cocaine hydrochloride injection. The results demonstrate that PAT may be used to detect the effects of drug abuse-induced brain activation. PMID:21163301

  5. An iontophoretic fentanyl patient-activated analgesic delivery system for postoperative pain: a double-blind, placebo-controlled trial.

    PubMed

    Viscusi, Eugene R; Reynolds, Lowell; Tait, Stacy; Melson, Timothy; Atkinson, Linda E

    2006-01-01

    An iontophoretic fentanyl HCl patient-activated transdermal system (fentanyl HCl PATS) is under development for the treatment of acute postoperative pain. The fentanyl HCl PATS is a needle-free, credit card-sized, preprogrammed system that is applied to the patient's upper outer arm or chest. The fentanyl HCl PATS was demonstrated to be superior to placebo in a previous trial; however, the randomization scheme used and the lack of control of entry pain level may have contributed to the lack of robust findings. We compared the fentanyl HCl PATS with placebo for acute postoperative pain management in a larger trial that addressed the limitations of the previous study. Adult patients admitted to the postanesthesia care unit after major surgery were titrated to comfort with opioids and randomized 1:1 to receive the fentanyl HCl PATS 40 microg or placebo for 24 hours. Supplemental IV fentanyl was available to patients upon request in both treatment groups for the first 3 hours after enrollment. The primary efficacy end-point was the percentage of patients who discontinued participation in the study because of inadequate analgesia. Pain intensity scores, patient global assessments (PGA), and investigator global assessments (IGA) were collected. Four-hundred-eighty-four patients (PATS, n = 244; placebo, n = 240) were enrolled. Fewer patients receiving the fentanyl HCl PATS discontinued because of inadequate analgesia compared with placebo (28.7% versus 60.0%; P < 0.0001). Mean last pain intensity scores were 3.5 and 5.4 for the fentanyl HCl PATS and placebo groups, respectively. Patients (73.4%, PGA) and investigators (72.1%, IGA) considered the fentanyl HCl PATS a good or excellent method of pain control. Treatment-related adverse events were similar between groups. This study demonstrated the superiority of the iontophoretic fentanyl HCl PATS over placebo for acute postoperative pain management. PMID:16368828

  6. Improving therapeutic activity of anti-CD20 antibody therapy through immunomodulation in lymphoid malignancies.

    PubMed

    Lipowska-Bhalla, Grazyna; Fagnano, Ester; Illidge, Timothy M; Cheadle, Eleanor J

    2016-01-01

    Nearly two decades ago rituximab heralded a new era in management of B cell malignancies significantly increasing response rates and survival. However, despite clear therapeutic advantage, significant numbers of patients become refractory to anti-CD20 mAb therapy, suggesting urgent improvements are required. It is now well recognized that the suppressive tumor microenvironment plays an important role in the outcome of anti-CD20 mAb therapy and that manipulation of this environment may improve the efficacy and produce long-term tumor control. The past few years have seen a surge of interest in immunomodulatory agents capable of overwriting immune suppressive networks into favorable clinical outcome. Currently, a number of such combinations with anti-CD20 mAb is under evaluation and some have produced encouraging outcomes in rituximab refractory disease. In this review, we give an outline of anti-CD20 mAbs and explore the combinations with immunomodulatory agents that enhance antitumor immunity through targeting stimulatory or inhibitory pathways and have proven potential to synergize with anti-CD20 mAb therapy. These agents, primarily mAbs, target CTLA-4, PD-1/PD-L1, and CD40. PMID:27050042

  7. Photo-activated Cancer Therapy: Potential for Treatment of Brain Tumors

    NASA Astrophysics Data System (ADS)

    Hirschberg, Henry

    The diffuse and infiltrative nature of high grade gliomas, such as glioblastoma multiforme (GBM), makes complete surgical resection virtually impossible. The propensity of glioma cells to migrate along white matter tracts suggests that a cure is possible only if these migratory cells can be eradicated. Approximately 80% of GBMs recur within 2 cm of the resection margin, suggesting that a reasonable approach for improving the prognosis of GBM patients would be the development of improved local therapies capable of eradicating glioma cells in the brain-adjacent-to-tumor (BAT). An additional complicating factor for the development of successful therapies is the presence of the blood-brain barrier (BBB) which is highly variable throughout the BAT—it is intact in some regions, while leaky in others. This variance in BBB patency has significant implications for the delivery of therapeutic agents. The results of a number of studies have shown that experimental light-based therapeutic modalities such as photochemical internalization (PCI) and photothermal therapy (PTT) may be useful in the treatment of gliomas. This chapter summarizes recent findings illustrating the potential of: (1) PCI for the delivery of therapeutic macromolecules such as chemotherapeutic agents and tumor suppressor genes, and (2) nanoshell-mediated PTT, including nanoparticle delivery approaches via macrophages.

  8. Plasmonic Vesicles of Amphiphilic Nanocrystals: Optically Active Multifunctional Platform for Cancer Diagnosis and Therapy.

    PubMed

    Song, Jibin; Huang, Peng; Duan, Hongwei; Chen, Xiaoyuan

    2015-09-15

    Vesicular structures with compartmentalized, water-filled cavities, such as liposomes of natural and synthetic amphiphiles, have tremendous potential applications in nanomedicine. When block copolymers self-assemble, the result is polymersomes with tailored structural properties and built-in releasing mechanisms, controlled by stimuli-responsive polymer building blocks. More recently, chemists are becoming interested in multifunctional hybrid vesicles containing inorganic nanocrystals with unique optical, electronic, and magnetic properties. In this Account, we review our recent progress in assembling amphiphilic plasmonic nanostructures to create a new class of multifunctional hybrid vesicles and applying them towards cancer diagnosis and therapy. Localized surface plasmon resonance (LSPR) gives plasmonic nanomaterials a unique set of optical properties that are potentially useful for both biosensing and nanomedicine. For instance, the strong light scattering at their LSPR wavelength opens up the applications of plasmonic nanostructures in single particle plasmonic imaging. Their superior photothermal conversion properties, on the other hand, make them excellent transducers for photothermal ablation and contrast agents for photoacoustic imaging. Of particular note for ultrasensitive detection is that the confined electromagnetic field resulting from excitation of LSPR can give rise to highly efficient surface enhanced Raman scattering (SERS) for molecules in close proximity. We have explored several ways to combine well-defined plasmonic nanocrystals with amphiphilic polymer brushes of diverse chemical functionalities. In multiple systems, we have shown that the polymer grafts impart amphiphilicity-driven self-assembly to the hybrid nanoparticles. This has allowed us to synthesize well-defined vesicles in which we have embedded plasmonic nanocrystals in the shell of collapsed hydrophobic polymers. The hydrophilic brushes extend into external and interior aqueous

  9. Plasmonic Vesicles of Amphiphilic Nanocrystals: Optically Active Multifunctional Platform for Cancer Diagnosis and Therapy.

    PubMed

    Song, Jibin; Huang, Peng; Duan, Hongwei; Chen, Xiaoyuan

    2015-09-15

    Vesicular structures with compartmentalized, water-filled cavities, such as liposomes of natural and synthetic amphiphiles, have tremendous potential applications in nanomedicine. When block copolymers self-assemble, the result is polymersomes with tailored structural properties and built-in releasing mechanisms, controlled by stimuli-responsive polymer building blocks. More recently, chemists are becoming interested in multifunctional hybrid vesicles containing inorganic nanocrystals with unique optical, electronic, and magnetic properties. In this Account, we review our recent progress in assembling amphiphilic plasmonic nanostructures to create a new class of multifunctional hybrid vesicles and applying them towards cancer diagnosis and therapy. Localized surface plasmon resonance (LSPR) gives plasmonic nanomaterials a unique set of optical properties that are potentially useful for both biosensing and nanomedicine. For instance, the strong light scattering at their LSPR wavelength opens up the applications of plasmonic nanostructures in single particle plasmonic imaging. Their superior photothermal conversion properties, on the other hand, make them excellent transducers for photothermal ablation and contrast agents for photoacoustic imaging. Of particular note for ultrasensitive detection is that the confined electromagnetic field resulting from excitation of LSPR can give rise to highly efficient surface enhanced Raman scattering (SERS) for molecules in close proximity. We have explored several ways to combine well-defined plasmonic nanocrystals with amphiphilic polymer brushes of diverse chemical functionalities. In multiple systems, we have shown that the polymer grafts impart amphiphilicity-driven self-assembly to the hybrid nanoparticles. This has allowed us to synthesize well-defined vesicles in which we have embedded plasmonic nanocrystals in the shell of collapsed hydrophobic polymers. The hydrophilic brushes extend into external and interior aqueous

  10. Opportunistic diseases in HIV-infected patients in Gabon following the administration of highly active antiretroviral therapy: a retrospective study.

    PubMed

    Okome-Nkoumou, Madeleine; Guiyedi, Vincent; Ondounda, Magloire; Efire, Nora; Clevenbergh, Philippe; Dibo, Mireille; Dzeing-Ella, Arnaud

    2014-02-01

    Opportunistic diseases cause substantial morbidity and mortality to human immunodeficiency virus (HIV)-infected patients. Highly active antiretroviral therapy (HAART) leading to immune reconstitution is the most effective treatment of preventing opportunistic diseases. This retrospective study established an epidemiologic profile of opportunistic diseases 10 years after the introduction of HAART. The HIV antiretroviral therapy-naive patients matching inclusion criteria were included. The primary outcome was the prevalence of opportunistic diseases. From January 1, 2002 to September 30, 2010, 654 opportunistic diseases were identified in 458 patients. Pulmonary tuberculosis, herpes zoster, cerebral toxoplasmosis, oral candidiasis, and severe pneumonia accounted for 22.05%, 15.94%, 14.19%, 14.19%, and 9.39%, respectively. Cryptococcal meningitis and pneumocystosis accounted for 0.44% and 0.21%, respectively. The prevalence of opportunistic diseases in Gabon remains high. New guidelines emphasize the importance of initiating antiretroviral therapy early to reconstitute the immune system, and reduce disease risk, and treat the primary opportunistic infection of pulmonary tuberculosis.

  11. Modifications to the INSM1 promoter to preserve specificity and activity for use in adenoviral gene therapy of neuroendocrine carcinomas.

    PubMed

    Akerstrom, V; Chen, C; Lan, M S; Breslin, M B

    2012-12-01

    The INSM1 gene encodes a transcriptional repressor that is exclusively expressed in neuronal and neuroendocrine tissue during embryonic development that is re-activated in neuroendocrine tumors. Using the 1.7 kbp INSM1 promoter, an adenoviral HSV thymidine kinase gene therapy was tested for the treatment of neuroendocrine tumors. An unforeseen interference on the INSM1 promoter specificity from the adenoviral genome was observed. Attempts were made to protect the INSM1 promoter from the influence of essential adenoviral sequences and to further enhance the tissue specificity of the INSM1 promoter region. Using the chicken β-globin HS4 insulator sequence, we eliminated off-target tissue expression from the Ad-INSM1 promoter-luciferase2 constructs in vivo. In addition, inclusion of two copies of the mouse nicotinic acetylcholine receptor (n(AchR)) neuronal-restrictive silencer element (NRSE) reduced nonspecific activation of the INSM1 promoter both in vitro and in vivo. Further, inclusion of both the HS4 insulator with the n(AchR) 2 × NRSE modification showed a two log increase in luciferase activity measured from the NCI-H1155 xenograft tumors compared with the original adenovirus construct. The alterations increase the therapeutic potential of adenoviral INSM1 promoter-driven suicide gene therapy for the treatment of a variety of neuroendocrine tumors. PMID:23079673

  12. Mutants of lymphotoxin-α with augmented cytotoxic activity via TNFR1 for use in cancer therapy.

    PubMed

    Morishige, Tomohiro; Yoshioka, Yasuo; Narimatsu, Shogo; Ikemizu, Shinji; Tsunoda, Shin-ichi; Tsutsumi, Yasuo; Mukai, Yohei; Okada, Naoki; Nakagawa, Shinsaku

    2013-02-01

    The cytokine lymphotoxin-α (LTα) is a promising candidate for use in cancer therapy. However, the instability of LTαin vivo and the insufficient levels of tumor necrosis factor receptor 1 (TNFR1)-mediated bioactivity of LTα limit its therapeutic potential. Here, we created LTα mutants with increased TNFR1-mediated bioactivity by using a phage display technique. We constructed a phage library displaying lysine-deficient structural variants of LTα with randomized amino acid residues. After affinity panning, we screened three clones of lysine-deficient LTα mutant, and identified a LTα mutant with TNFR1-mediated bioactivity that was 32 times that of the wild-type LTα (wtLTα). When compared with wtLTα, the selected clone showed augmented affinity to TNFR1 due to slow dissociation rather than rapid association. In contrast, the mutant showed only 4 times the TNFR2-mediated activity of wtLTα. In addition, the LTα mutant strongly and rapidly activated caspases that induce TNFR1-mediated cell death, whereas the mutant and wtLTα activated nuclear factor-kappa B to a similar extent. Our data suggest that the kinetics of LTα binding to TNFR1 play an important role in signal transduction patterns, and a TNFR1-selective LTα mutant with augmented bioactivity would be a superior candidate for cancer therapy. PMID:23246116

  13. Active co-infection with HBV and/or HCV in South African HIV positive patients due for cancer therapy.

    PubMed

    Musyoki, Andrew M; Msibi, Thembeni L; Motswaledi, Mojakgomo H; Selabe, Selokela G; Monokoane, Tshweu S; Mphahlele, M Jeffrey

    2015-02-01

    Human immunodeficiency virus (HIV), Hepatitis B virus (HBV) and Hepatitis C virus (HCV) share routes of transmission. There is limited data on the incidence of active co-infection with HBV and/or HCV in cancer patients infected with HIV in Africa. This was a prospective study based on 34 patients with varied cancer diagnosis, infected with HIV and awaiting cancer therapy in South Africa. HIV viral load, CD4+ cell counts, Alanine-aminotransferase and aspartate aminotransferase levels were tested. Exposure to HBV and HCV was assessed serologically using commercial kits. Active HBV and/or HCV co-infection was detected using viral specific nested PCR assays. HCV 5'-UTR PCR products were sequenced to confirm active HCV infection. Active viral infection was detected in 64.7% of patients for HBV, 38.2% for HCV, and 29.4% for both HBV and HCV. Occult HBV infection was observed in 63.6% of the patients, while seronegative HCV infection was found in 30.8% of patients. In addition, CD4+ cell count < 350 cells/µl was not a risk factor for increased active HBV, HCV or both HBV and HCV co-infections. A total of 72.7%, 18.2% and 9.1% of the HCV sequences were assigned genotype 5, 1 and 4 respectively.The study revealed for the first time a high active HBV and/or HCV co-infection rate in cancer patients infected with HIV. The findings call for HBV and HCV testing in such patients, and where feasible, appropriate antiviral treatment be indicated, as chemotherapy or radiotherapy has been associated with reactivation of viral hepatitis and termination of cancer therapy. PMID:25156907

  14. Concurrent Intervention With Exercises and Stabilized Tumor Necrosis Factor Inhibitor Therapy Reduced the Disease Activity in Patients With Ankylosing Spondylitis

    PubMed Central

    Liang, Hui; Li, Wen-Rong; Zhang, Hua; Tian, Xu; Wei, Wei; Wang, Chun-Mei

    2015-01-01

    Abstract Since the use of tumor necrosis factor (TNF) inhibitor therapy is becoming wider, the effects of concurrent intervention with exercises and stabilized TNF inhibitors therapy in patients with ankylosing spondylitis (AS) are different. The study aimed to objectively evaluate whether concurrent intervention with exercises and stabilized TNF inhibitors can reduce the disease activity in patients with AS. A search from PubMed, Web of Science, EMBASE, and the Cochrane Library was electronically performed to collect studies which compared concurrent intervention with exercise and TNF inhibitor to conventional approach in terms of disease activity in patients with AS published from their inception to June 2015. Studies that measured the Bath Ankylosing Spondylitis Functional Index (BASFI), the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), the Bath Ankylosing Spondylitis Metrology Index (BASMI), and chest expansion as outcomes were included. Two independent investigators screened the identified articles, extracted the data, and assessed the methodological quality of the included studies. Quantitative analysis was performed with Review Manager (RevMan) software (version 5.3.0). A total of 5 studies comprising 221 participants were included in the study. Meta-analyses showed that concurrent intervention with exercises and stabilized TNF inhibitors therapy significantly reduced the BASMI scores (MD, −0.99; 95% CI, −1.61 to −0.38) and BASDAI scores (MD, −0.58; 95% CI, −1.10 to −0.06), but the BASFI scores (MD, −0.31; 95% CI, −0.76 to 0.15) was not reduced, and chest expansion (MD, 0.80; 95% CI, −0.18 to 1.78) was not increased. Concurrent intervention with exercises and stabilized TNF inhibitors therapy can reduce the disease activity in patients with AS. More randomized controlled trials (RCTs) with high-quality, large-scale, and appropriate follow-up are warranted to further establish the benefit of concurrent intervention with

  15. In vitro and in vivo studies on laser-activated gold nanorods for applications in photothermal therapies

    NASA Astrophysics Data System (ADS)

    Pini, Roberto; Ratto, Fulvio; Matteini, Paolo; Centi, Sonia; Rossi, Francesca

    2010-04-01

    We review our experimental studies on near infrared laser-activated gold nanoparticles in the direct welding of connective tissues. In particular, we discuss the use of gold nanorods excited by diode laser radiation at 810 nm to mediate functional photothermal effects and weld eye's lens capsules and arteries. The preparation of biopolymeric matrices including gold nanorods is described as well, together with preliminary tests for their application in the closure of wounds in vessels and tendons. Finally we mention future perspectives on the use of these nanoparticles for applications in the therapy of cancer.

  16. A dual function theranostic agent for near-infrared photoacoustic imaging and photothermal therapy

    NASA Astrophysics Data System (ADS)

    Upputuri, Paul Kumar; Huang, Shuo; Wang, Mingfeng; Pramanik, Manojit

    2016-03-01

    Theranostic, defined as combining diagnostic and therapeutic agents, has attracted more attention in biomedical application. It is essential to monitor diseased tissue before treatment. Photothermal therapy (PTT) is a promising treatment of cancer tissue due to minimal invasion, unharmful to normal tissue and high efficiency. Photoacoustic tomography (PAT) is a hybrid nonionizing biomedical imaging modality that combines rich optical contrast and high ultrasonic resolution in a single imaging modality. The near infra-red (NIR) wavelengths, usually used in PAT, can provide deep penetration at the expense of reduced contrast, as the blood absorption drops in the NIR range. Exogenous contrast agents with strong absorption in the NIR wavelength range can enhance the photoacoustic imaging contrast as well as imaging depth. Most theranostic agents incorporating PAT and PTT are inorganic nanomaterials that suffer from poor biocompatibility and biodegradability. Herein, we present an benzo[1,2-c;4,5-c'] bis[1,2,5] thiadiazole (BBT), based theranostic agent which not only acts as photoacoustic contrast agent but also a photothermal therapy agent. Experiments were performed on animal blood and organic nanoparticles embedded in a chicken breast tissue using PAT imaging system at ~803 nm wavelengths. Almost ten time contrast enhancement was observed from the nanoparticle in suspension. More than 6.5 time PA signal enhancement was observed in tissue at 3 cm depth. HeLa cell lines was used to test photothermal effect showing 90% cells were killed after 10 min laser irradiation. Our results indicate that the BBT - based naoparticles are promising theranostic agents for PAT imaging and cancer treatment by photothermal therapy.

  17. Hybrid modeling for quality by design and PAT-benefits and challenges of applications in biopharmaceutical industry.

    PubMed

    von Stosch, Moritz; Davy, Steven; Francois, Kjell; Galvanauskas, Vytautas; Hamelink, Jan-Martijn; Luebbert, Andreas; Mayer, Martin; Oliveira, Rui; O'Kennedy, Ronan; Rice, Paul; Glassey, Jarka

    2014-06-01

    This report highlights the drivers, challenges, and enablers of the hybrid modeling applications in biopharmaceutical industry. It is a summary of an expert panel discussion of European academics and industrialists with relevant scientific and engineering backgrounds. Hybrid modeling is viewed in its broader sense, namely as the integration of different knowledge sources in form of parametric and nonparametric models into a hybrid semi-parametric model, for instance the integration of fundamental and data-driven models. A brief description of the current state-of-the-art and industrial uptake of the methodology is provided. The report concludes with a number of recommendations to facilitate further developments and a wider industrial application of this modeling approach. These recommendations are limited to further exploiting the benefits of this methodology within process analytical technology (PAT) applications in biopharmaceutical industry.

  18. Strategic framework for education and training in Quality by Design (QbD) and process analytical technology (PAT).

    PubMed

    de Matas, Marcel; De Beer, Thomas; Folestad, Staffan; Ketolainen, Jarkko; Lindén, Hans; Lopes, João Almeida; Oostra, Wim; Weimer, Marco; Öhrngren, Per; Rantanen, Jukka

    2016-07-30

    The regulatory and technical landscape of the pharmaceutical field is rapidly evolving from one focused predominantly on development of small molecules, using well established manufacturing technologies towards an environment in which biologicals and complex modalities are being developed using advanced science and technology coupled with the application of modern Quality by Design (QbD) principles. In order that Europe keeps pace with these changes and sustains its position as major player in the development and commercialization of medicines, it is essential that measures are put in place to maintain a highly skilled workforce. A number of challenges however exist to equipping academic, industrial and health agency staff with the requisite knowledge, skills and experience to develop the next generation of medicines. In this regard, the EUFEPS QbD and PAT Sciences Network has proposed a structured framework for education, training and continued professional development, which comprises a number of pillars covering the fundamental principles of modern pharmaceutical development including the underpinning aspects of science, engineering and technology innovation. The framework is not prescriptive and is not aimed at describing specific course content in detail. It should however be used as a point of reference for those institutions delivering pharmaceutical based educational courses, to ensure that the necessary skills, knowledge and experience for successful pharmaceutical development are maintained. A positive start has been made and a number of examples of formal higher education courses and short training programs containing elements of this framework have been described. The ultimate vision for this framework however, is to see widespread adoption and proliferation of this curriculum with it forming the backbone of QbD and PAT science based skills development. PMID:27112991

  19. A double-focus collimator system for full PAT performance testing of inter-satellite laser communication terminals

    NASA Astrophysics Data System (ADS)

    Wang, Lijuan; Luan, Zhu; Sun, Jianfeng; Zhou, Yu; Liu, De'an; Liu, Liren

    2006-08-01

    A laser collimator is necessary for the testing and verification of the PAT performance of inter-satellite laser communication terminals. However, the terminals mostly have a large field of view for the acquisition and a high angular accuracy for the fine tracking needed to be examined. A single collimator has the conflict to reach at both a large field of view and a fine resolution. To compromise, a double-focus laser collimator is proposed. The collimator is mainly composed of a primary lens, a beam splitter, a secondary lens and some reflectors. The primary lens with a 9.9m focal length directly forms the long focal length arm of the collimator. The combination of the primary lens and the secondary lens has a new focal length of 1.3m and constructs the short focal length arm of the collimator. With two CMOS imaging sensors, the collimator can realize a 1.1mrad field of view with a <1μrad resolution in the focal plane of the long focal length arm and a 8.3mrad field of view with a 8.2μrad resolution in the focal plane of the short focal length arm. In combination with a coarse beam scanner (+/-15°) and a fine beam scanner (1mrad) to simulate the mutual angular movement between two satellites, the united system is capable to test the full PAT performance of inter-satellite laser communication terminals. The optical layouts of the collimator and two detecting units are illustrated. The optical design of the collimator is detailed. The mechanical design of the collimator is given.

  20. Decay of Fecal Indicator Bacterial Populations and Bovine-Associated Source-Tracking Markers in Freshly Deposited Cow Pats

    PubMed Central

    Oladeinde, Adelumola; Bohrmann, Thomas; Wong, Kelvin; Purucker, S. T.; Bradshaw, Ken; Brown, Reid; Snyder, Blake

    2014-01-01

    Understanding the survival of fecal indicator bacteria (FIB) and microbial source-tracking (MST) markers is critical to developing pathogen fate and transport models. Although pathogen survival in water microcosms and manure-amended soils is well documented, little is known about their survival in intact cow pats deposited on pastures. We conducted a study to determine decay rates of fecal indicator bacteria (Escherichia coli and enterococci) and bovine-associated MST markers (CowM3, Rum-2-bac, and GenBac) in 18 freshly deposited cattle feces from three farms in northern Georgia. Samples were randomly assigned to shaded or unshaded treatment in order to determine the effects of sunlight, moisture, and temperature on decay rates. A general linear model (GLM) framework was used to determine decay rates. Shading significantly decreased the decay rate of the E. coli population (P < 0.0001), with a rate of −0.176 day−1 for the shaded treatment and −0.297 day−1 for the unshaded treatment. Shading had no significant effect on decay rates of enterococci, CowM3, Rum-2-bac, and GenBac (P > 0.05). In addition, E. coli populations showed a significant growth rate (0.881 day−1) in the unshaded samples during the first 5 days after deposition. UV-B was the most important parameter explaining the decay rate of E. coli populations. A comparison of the decay behaviors among all markers indicated that enterococcus concentrations exhibit a better correlation with the MST markers than E. coli concentrations. Our results indicate that bovine-associated MST markers can survive in cow pats for at least 1 month after excretion, and although their decay dynamic differs from the decay dynamic of E. coli populations, they seem to be reliable markers to use in combination with enterococci to monitor fecal pollution from pasture lands. PMID:24141130

  1. Strategic framework for education and training in Quality by Design (QbD) and process analytical technology (PAT).

    PubMed

    de Matas, Marcel; De Beer, Thomas; Folestad, Staffan; Ketolainen, Jarkko; Lindén, Hans; Lopes, João Almeida; Oostra, Wim; Weimer, Marco; Öhrngren, Per; Rantanen, Jukka

    2016-07-30

    The regulatory and technical landscape of the pharmaceutical field is rapidly evolving from one focused predominantly on development of small molecules, using well established manufacturing technologies towards an environment in which biologicals and complex modalities are being developed using advanced science and technology coupled with the application of modern Quality by Design (QbD) principles. In order that Europe keeps pace with these changes and sustains its position as major player in the development and commercialization of medicines, it is essential that measures are put in place to maintain a highly skilled workforce. A number of challenges however exist to equipping academic, industrial and health agency staff with the requisite knowledge, skills and experience to develop the next generation of medicines. In this regard, the EUFEPS QbD and PAT Sciences Network has proposed a structured framework for education, training and continued professional development, which comprises a number of pillars covering the fundamental principles of modern pharmaceutical development including the underpinning aspects of science, engineering and technology innovation. The framework is not prescriptive and is not aimed at describing specific course content in detail. It should however be used as a point of reference for those institutions delivering pharmaceutical based educational courses, to ensure that the necessary skills, knowledge and experience for successful pharmaceutical development are maintained. A positive start has been made and a number of examples of formal higher education courses and short training programs containing elements of this framework have been described. The ultimate vision for this framework however, is to see widespread adoption and proliferation of this curriculum with it forming the backbone of QbD and PAT science based skills development.

  2. Decay of fecal indicator bacterial populations and bovine-associated source-tracking markers in freshly deposited cow pats.

    PubMed

    Oladeinde, Adelumola; Bohrmann, Thomas; Wong, Kelvin; Purucker, S T; Bradshaw, Ken; Brown, Reid; Snyder, Blake; Molina, Marirosa

    2014-01-01

    Understanding the survival of fecal indicator bacteria (FIB) and microbial source-tracking (MST) markers is critical to developing pathogen fate and transport models. Although pathogen survival in water microcosms and manure-amended soils is well documented, little is known about their survival in intact cow pats deposited on pastures. We conducted a study to determine decay rates of fecal indicator bacteria (Escherichia coli and enterococci) and bovine-associated MST markers (CowM3, Rum-2-bac, and GenBac) in 18 freshly deposited cattle feces from three farms in northern Georgia. Samples were randomly assigned to shaded or unshaded treatment in order to determine the effects of sunlight, moisture, and temperature on decay rates. A general linear model (GLM) framework was used to determine decay rates. Shading significantly decreased the decay rate of the E. coli population (P < 0.0001), with a rate of -0.176 day(-1) for the shaded treatment and -0.297 day(-1) for the unshaded treatment. Shading had no significant effect on decay rates of enterococci, CowM3, Rum-2-bac, and GenBac (P > 0.05). In addition, E. coli populations showed a significant growth rate (0.881 day(-1)) in the unshaded samples during the first 5 days after deposition. UV-B was the most important parameter explaining the decay rate of E. coli populations. A comparison of the decay behaviors among all markers indicated that enterococcus concentrations exhibit a better correlation with the MST markers than E. coli concentrations. Our results indicate that bovine-associated MST markers can survive in cow pats for at least 1 month after excretion, and although their decay dynamic differs from the decay dynamic of E. coli populations, they seem to be reliable markers to use in combination with enterococci to monitor fecal pollution from pasture lands.

  3. Enhanced risk of thromboembolic disease in hypertension from platelet hyperfunction and decreased fibrinolytic activity: has antihypertensive therapy any influence?

    PubMed

    Winther, K; Gleerup, G; Hedner, T

    1992-01-01

    Enhanced platelet function and a decrease in fibrinolytic activity have been reported in patients with mild hypertension after treatment with various nonselective beta-blockers. Until now, such changes have not been reported during treatment with beta 1-selective drugs or with agents that have intrinsic sympathomimetic activity. The impact of angiotensin-converting enzyme inhibitors and diuretics on platelet function and fibrinolytic activity has not been fully elucidated. Calcium antagonists of various types, however, are known to decrease platelet release in vivo whereas their effects on platelet aggregation and fibrinolytic activity are less clear. The new dihydropyridine calcium antagonist isradipine, when tested in a group of patients with mild hypertension, resulted in a decrease in platelet aggregation, a shortened euglobulin clot-lysis time, and a dramatic increase in t-PA (tissue-plasminogen activator) activity after 14 days of treatment. These changes remained stable throughout the 1-year study period. The fact that antihypertensive therapy does not always result in the hoped-for prolongation of life, despite satisfactory blood pressure reduction, may be in part due to an unfavorable impact on various components of the blood-clotting system.

  4. Inhibition of NF-κB in Tumor Cells Exacerbates Immune Cell Activation Following Photodynamic Therapy

    PubMed Central

    Broekgaarden, Mans; Kos, Milan; Jurg, Freek A.; van Beek, Adriaan A.; van Gulik, Thomas M.; Heger, Michal

    2015-01-01

    Although photodynamic therapy (PDT) yields very good outcomes in numerous types of superficial solid cancers, some tumors respond suboptimally to PDT. Novel treatment strategies are therefore needed to enhance the efficacy in these therapy-resistant tumors. One of these strategies is to combine PDT with inhibitors of PDT-induced survival pathways. In this respect, the transcription factor nuclear factor κB (NF-κB) has been identified as a potential pharmacological target, albeit inhibition of NF-κB may concurrently dampen the subsequent anti-tumor immune response required for complete tumor eradication and abscopal effects. In contrast to these postulations, this study demonstrated that siRNA knockdown of NF-κB in murine breast carcinoma (EMT-6) cells increased survival signaling in these cells and exacerbated the inflammatory response in murine RAW 264.7 macrophages. These results suggest a pro-death and immunosuppressive role of NF-κB in PDT-treated cells that concurs with a hyperstimulated immune response in innate immune cells. PMID:26307977

  5. [Open questions in the drug therapy of tumors with new active substances].

    PubMed

    Ludwig, Wolf-Dieter; Schott, Gisela

    2010-01-01

    At the time of market authorization and/or the expansion of indication of new oncology drugs, it is often not possible to reliably measure the relevant benefit for the patient. The conception of the clinical studies, on which the market authorization and/or expansion of indication is based, orients itself primarily at the regulatory requirements of the regulatory authorities. In addition, their results are frequently published only incompletely or some time after the end of the clinical study. To clarify these outstanding questions regarding the individual treatment of patients, independent,science-initiated clinical studies after the market authorization are required. However, the execution of these studies is obstructed due to insufficient financial means as well as by regulations and the low evaluation of such studies by the academia. Further challenges result from the high costs of innovative oncologic therapies, which burden the resources of the statutory and private health insurance providers(GKV, PKV) who are confronted with an aging population and a rising prevalence of tumor cases. Independent post-market authorization clinical studies need to be completed in order to ensure a need-oriented and efficient treatment with new oncologic substances. New perspectives result by connecting the reimbursement of the costs of innovative therapies by the GKV and PKV to the generation of evidence in the context of clinical studies, thus improving the medical care of tumor patients as well as the efficient handling of limited health resources. PMID:20926907

  6. A new bifunctional hybrid nanostructure as an active platform for photothermal therapy and MR imaging.

    PubMed

    Khafaji, Mona; Vossoughi, Manouchehr; Hormozi-Nezhad, M Reza; Dinarvand, Rassoul; Börrnert, Felix; Irajizad, Azam

    2016-01-01

    As a bi-functional cancer treatment agent, a new hybrid nanostructure is presented which can be used for photothermal therapy by exposure to one order of magnitude lower laser powers compared to similar nanostructures in addition to substantial enhancment in magnetic resonance imaging (MRI) contrast. This gold-iron oxide hybrid nanostructure (GIHN) is synthesized by a cost-effective and high yield water-based approach. The GIHN is sheilded by PEG. Therefore, it shows high hemo and biocompatibility and more than six month stability. Alongside earlier nanostructures, the heat generation rate of GIHN is compareable with surfactnat-capped gold nanorods (GNRs). Two reasons are behind this enhancement: Firstly the distance between GNRs and SPIONs is adjusted in a way that the surface plasmon resonance of the new nanostructure is similar to bare GNRs and secondly the fraction of GNRs is raised in the hybrid nanostructure. GIHN is then applied as a photothermal agent using laser irradiation with power as low as 0.5 W.cm(-2) and only 32% of human breast adenocarcinoma cells could survive. The GIHN also acts as a dose-dependent transvers relaxation time (T2) MRI contrast agent. The results show that the GINH can be considered as a good candidate for multimodal photothermal therapy and MRI. PMID:27297588

  7. A new bifunctional hybrid nanostructure as an active platform for photothermal therapy and MR imaging

    PubMed Central

    Khafaji, Mona; Vossoughi, Manouchehr; Hormozi-Nezhad, M. Reza; Dinarvand, Rassoul; Börrnert, Felix; Irajizad, Azam

    2016-01-01

    As a bi-functional cancer treatment agent, a new hybrid nanostructure is presented which can be used for photothermal therapy by exposure to one order of magnitude lower laser powers compared to similar nanostructures in addition to substantial enhancment in magnetic resonance imaging (MRI) contrast. This gold-iron oxide hybrid nanostructure (GIHN) is synthesized by a cost-effective and high yield water-based approach. The GIHN is sheilded by PEG. Therefore, it shows high hemo and biocompatibility and more than six month stability. Alongside earlier nanostructures, the heat generation rate of GIHN is compareable with surfactnat-capped gold nanorods (GNRs). Two reasons are behind this enhancement: Firstly the distance between GNRs and SPIONs is adjusted in a way that the surface plasmon resonance of the new nanostructure is similar to bare GNRs and secondly the fraction of GNRs is raised in the hybrid nanostructure. GIHN is then applied as a photothermal agent using laser irradiation with power as low as 0.5 W.cm−2 and only 32% of human breast adenocarcinoma cells could survive. The GIHN also acts as a dose-dependent transvers relaxation time (T2) MRI contrast agent. The results show that the GINH can be considered as a good candidate for multimodal photothermal therapy and MRI. PMID:27297588

  8. Remission of progressive multifocal leukoencephalopathy following highly active antiretroviral therapy in a man with AIDS.

    PubMed

    Yoganathan, Katie; Brown, David; Yoganathan, Kathir

    2012-01-01

    A 43-year-old Caucasian homosexual man with AIDS presented with blurring of vision, change of personality, and memory loss in March 1999. He had first been admitted 2 months previously for treatment of Pneumocystis jiroveci pneumonia. A magnetic resonance imaging scan on admission showed multiple white matter lesions involving both subcortical cerebral hemispheres and cerebellar regions, with no mass effect or surrounding edema. JC virus was detected by nested polymerase chain reaction in the cerebrospinal fluid. These findings were diagnostic of progressive multifocal leukoencephalopathy (PML). His CD4 count was 34 cells/mL, and his HIV ribonucleic acid level was 800,789 copies/mL. He was treated with a combination antiretroviral therapy. He was last reviewed in October 2011. He was fully independent socially and mentally, but he still had some residual neurologic signs with right-sided homonymous hemianopia and visual agnosia. His HIV ribonucleic acid level was undetectable, and his CD4 count was 574 cells/mm(3). Although the median survival of patients with PML was poor before the antiretroviral therapy era, our patient, who is now aged 55 years, is still alive 12 years after the diagnosis. The diagnosis of PML and differential diagnosis of focal neurologic signs in HIV-positive patients are discussed in this case report. PMID:22536089

  9. Myosin7a Deficiency Results in Reduced Retinal Activity Which Is Improved by Gene Therapy

    PubMed Central

    Colella, Pasqualina; Sommella, Andrea; Marrocco, Elena; Di Vicino, Umberto; Polishchuk, Elena; Garrido, Marina Garcia; Seeliger, Mathias W.; Polishchuk, Roman; Auricchio, Alberto

    2013-01-01

    Mutations in MYO7A cause autosomal recessive Usher syndrome type IB (USH1B), one of the most frequent conditions that combine severe congenital hearing impairment and retinitis pigmentosa. A promising therapeutic strategy for retinitis pigmentosa is gene therapy, however its pre-clinical development is limited by the mild retinal phenotype of the shaker1 (sh1−/−) murine model of USH1B which lacks both retinal functional abnormalities and degeneration. Here we report a significant, early-onset delay of sh1−/− photoreceptor ability to recover from light desensitization as well as a progressive reduction of both b-wave electroretinogram amplitude and light sensitivity, in the absence of significant loss of photoreceptors up to 12 months of age. We additionally show that subretinal delivery to the sh1−/− retina of AAV vectors encoding the large MYO7A protein results in significant improvement of sh1−/− photoreceptor and retinal pigment epithelium ultrastructural anomalies which is associated with improvement of recovery from light desensitization. These findings provide new tools to evaluate the efficacy of experimental therapies for USH1B. In addition, although AAV vectors expressing large genes might have limited clinical applications due to their genome heterogeneity, our data show that AAV-mediated MYO7A gene transfer to the sh1−/− retina is effective. PMID:23991031

  10. Targeting chromatin binding regulation of constitutively active AR variants to overcome prostate cancer resistance to endocrine-based therapies

    PubMed Central

    Chan, Siu Chiu; Selth, Luke A.; Li, Yingming; Nyquist, Michael D.; Miao, Lu; Bradner, James E.; Raj, Ganesh V.; Tilley, Wayne D.; Dehm, Scott M.

    2015-01-01

    Androgen receptor (AR) variants (AR-Vs) expressed in prostate cancer (PCa) lack the AR ligand binding domain (LBD) and function as constitutively active transcription factors. AR-V expression in patient tissues or circulating tumor cells is associated with resistance to AR-targeting endocrine therapies and poor outcomes. Here, we investigated the mechanisms governing chromatin binding of AR-Vs with the goal of identifying therapeutic vulnerabilities. By chromatin immunoprecipitation and sequencing (ChIP-seq) and complementary biochemical experiments, we show that AR-Vs display a binding preference for the same canonical high-affinity androgen response elements (AREs) that are preferentially engaged by AR, albeit with lower affinity. Dimerization was an absolute requirement for constitutive AR-V DNA binding and transcriptional activation. Treatment with the bromodomain and extraterminal (BET) inhibitor JQ1 resulted in inhibition of AR-V chromatin binding and impaired AR-V driven PCa cell growth in vitro and in vivo. Importantly, this was associated with a novel JQ1 action of down-regulating AR-V transcript and protein expression. Overall, this study demonstrates that AR-Vs broadly restore AR chromatin binding events that are otherwise suppressed during endocrine therapy, and provides pre-clinical rationale for BET inhibition as a strategy for inhibiting expression and chromatin binding of AR-Vs in PCa. PMID:25908785

  11. Association between immune activation and early depressive symptoms in cancer patients treated with interleukin-2-based therapy.

    PubMed

    Capuron, L; Ravaud, A; Gualde, N; Bosmans, E; Dantzer, R; Maes, M; Neveu, P J

    2001-11-01

    The relationship between immune activation and the development of early depressive symptoms were studied in 33 cancer patients undergoing cytokine therapy. Patients were treated either with subcutaneous IL-2 administered alone (n=13) or in association with IFN-alpha (n=5), or with IFN-alpha alone administered subcutaneously at low doses (n=5) or intravenously at high doses (n=10). The intensity of depressive symptoms was assessed during a clinical interview carried out before the start of cytokine therapy and five days later using the Montgomery and Asberg Depression Rating Scale (MADRS). On the same days, blood samples were collected for each patient to measure serum concentrations of cytokines (IL-6, IL-10, IL-1ra) and cytokine-receptors (sIL-2R, LIF-R). Results showed that patients treated with IL-2 or IL-2+IFN-alpha displayed concomitant mood symptoms and increased serum cytokine levels during treatment. In these patients, the intensity of depressive symptoms at endpoint was positively correlated with the increases measured in serum levels of IL-10 between baseline and endpoint. IL-10 is an anti-inflammatory cytokine that is produced in response to the production of pro-inflammatory cytokines, and thereby reflects an inflammatory response. These results support the hypothesis of close relationship between depressive symptoms and the activation of the cytokine network.

  12. Targeting chromatin binding regulation of constitutively active AR variants to overcome prostate cancer resistance to endocrine-based therapies.

    PubMed

    Chan, Siu Chiu; Selth, Luke A; Li, Yingming; Nyquist, Michael D; Miao, Lu; Bradner, James E; Raj, Ganesh V; Tilley, Wayne D; Dehm, Scott M

    2015-07-13

    Androgen receptor (AR) variants (AR-Vs) expressed in prostate cancer (PCa) lack the AR ligand binding domain (LBD) and function as constitutively active transcription factors. AR-V expression in patient tissues or circulating tumor cells is associated with resistance to AR-targeting endocrine therapies and poor outcomes. Here, we investigated the mechanisms governing chromatin binding of AR-Vs with the goal of identifying therapeutic vulnerabilities. By chromatin immunoprecipitation and sequencing (ChIP-seq) and complementary biochemical experiments, we show that AR-Vs display a binding preference for the same canonical high-affinity androgen response elements (AREs) that are preferentially engaged by AR, albeit with lower affinity. Dimerization was an absolute requirement for constitutive AR-V DNA binding and transcriptional activation. Treatment with the bromodomain and extraterminal (BET) inhibitor JQ1 resulted in inhibition of AR-V chromatin binding and impaired AR-V driven PCa cell growth in vitro and in vivo. Importantly, this was associated with a novel JQ1 action of down-regulating AR-V transcript and protein expression. Overall, this study demonstrates that AR-Vs broadly restore AR chromatin binding events that are otherwise suppressed during endocrine therapy, and provides pre-clinical rationale for BET inhibition as a strategy for inhibiting expression and chromatin binding of AR-Vs in PCa.

  13. A Tale of Two Melt Rocks: Equilibration and Metal/Sulfide-Silicate Segregation in the L7 Chondrites PAT 91501 and LEW 88663

    NASA Astrophysics Data System (ADS)

    Harvey, R. P.

    1993-07-01

    Type 7 ordinary chondrites have experienced temperatures near or beyond those necessary for partial melting. Two recently collected Antarctic specimens, PAT91501 (PAT) and LEW88663 (LEW), have been tentatively identified as L7 chondrites based on mineral and oxygen isotope compositions [1,2]. The petrology and mineralogy of these meteorites suggests that they have undergone significant metal/sulfide-silicate segregation, with implications for meteorite parent bodies. PAT consists of an equigranular contact-framework of nearly euhedral olivine grains, with interstitial spaces filled by plagioclase, pyroxenes, and several minor phases. Ortho- and clinopyroxene occur in an exsolution relationship. Olivine and pyroxene are highly equilibrated, varying <<1% in Fe-endmember content. Pyroxene equilibration temperatures calculated for PAT using the methods of [3] are self-consistent at about 1180 degrees C. In thin section, PAT contains only traces of metal, as tiny isolated blebs in sulfide grains; large (>1 cm) globular sulfide inclusions are seen in hand-sample [1], but are not present in the section examined. LEW was originally classified as an achondrite with olivine and pyroxene compositions similar to those in L chondrites [2]. Metal is absent in LEW, although the specimen is small and heavily rusted, making it impossible to gauge the original metal content. Olivine grains are commonly rounded in shape and seldom in contact with more than a few other grains. LEW olivine and pyroxene are also highly equilibrated. Veins of Ni-bearing metal oxides and sulfides are common. Both low- and high-Ca pyroxene occur as discrete grains, orthopyroxene often poikilitically enclosing olivine. Pyroxene equilibration temperatures for LEW are more variable than those for PAT and consistently lower, with an average around 900 degrees C. The various textural and compositional characteristics of PAT and LEW suggest they have experienced partial melting to varying degrees. Both visually

  14. Levodopa replacement therapy alters enzyme activities in striatum and neuropeptide content in striatal output regions of 6-hydroxydopamine lesioned rats.

    PubMed

    Engber, T M; Susel, Z; Kuo, S; Gerfen, C R; Chase, T N

    1991-06-21

    The effects of striatal dopamine denervation and levodopa replacement therapy on neuronal populations in the rat striatum were assessed by measurement of glutamic acid decarboxylase (GAD) and choline acetyltransferase (CAT) activities in the striatum, dynorphin and substance P concentrations in the substantia nigra, and enkephalin concentration in the globus pallidus. Rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal pathway were treated for 21 days with levodopa (100 mg/kg/day, i.p., with 25 mg/kg benserazide) on either an intermittent (b.i.d.) or continuous (osmotic pump infusion) regimen and sacrificed following a three day drug washout. In saline-treated control rats, striatal GAD activity and globus pallidus enkephalin content were elevated and nigral substance P content was reduced ipsilateral to the 6-OHDA lesion. Intermittent levodopa treatment further increased GAD activity, decreased CAT activity, restored substance P to control levels, markedly increased dynorphin content, and had no effect on enkephalin. In contrast, continuous levodopa elevated globus pallidus enkephalin beyond the levels occurring with denervation, but had no effect on any of the other neurochemical measures. These results indicate that striatal neuronal populations are differentially affected by chronic levodopa therapy and by the continuous or intermittent nature of the treatment regimen. With the exception of substance P, levodopa did not reverse the effects of the 6-OHDA lesion but, rather, either exacerbated the lesion-induced changes (e.g. GAD and enkephalin) or altered neurochemical markers which had been unaffected by the lesion (e.g. CAT and dynorphin).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1717109

  15. Natural Killer Cell-Based Therapies Targeting Cancer: Possible Strategies to Gain and Sustain Anti-Tumor Activity

    PubMed Central

    Dahlberg, Carin I. M.; Sarhan, Dhifaf; Chrobok, Michael; Duru, Adil D.; Alici, Evren

    2015-01-01

    Natural killer (NK) cells were discovered 40 years ago, by their ability to recognize and kill tumor cells without the requirement of prior antigen exposure. Since then, NK cells have been seen as promising agents for cell-based cancer therapies. However, NK cells represent only a minor fraction of the human lymphocyte population. Their skewed phenotype and impaired functionality during cancer progression necessitates the development of clinical protocols to activate and expand to high numbers ex vivo to be able to infuse sufficient numbers of functional NK cells to the cancer patients. Initial NK cell-based clinical trials suggested that NK cell-infusion is safe and feasible with almost no NK cell-related toxicity, including graft-versus-host disease. Complete remission and increased disease-free survival is shown in a small number of patients with hematological malignances. Furthermore, successful adoptive NK cell-based therapies from haploidentical donors have been demonstrated. Disappointingly, only limited anti-tumor effects have been demonstrated following NK cell infusion in patients with solid tumors. While NK cells have great potential in targeting tumor cells, the efficiency of NK cell functions in the tumor microenvironment is yet unclear. The failure of immune surveillance may in part be due to sustained immunological pressure on tumor cells resulting in the development of tumor escape variants that are invisible to the immune system. Alternatively, this could be due to the complex network of immune-suppressive compartments in the tumor microenvironment, including myeloid-derived suppressor cells, tumor-associated macrophages, and regulatory T cells. Although the negative effect of the tumor microenvironment on NK cells can be transiently reverted by ex vivo expansion and long-term activation, the aforementioned NK cell/tumor microenvironment interactions upon reinfusion are not fully elucidated. Within this context, genetic modification of NK cells

  16. Natural Killer Cell-Based Therapies Targeting Cancer: Possible Strategies to Gain and Sustain Anti-Tumor Activity.

    PubMed

    Dahlberg, Carin I M; Sarhan, Dhifaf; Chrobok, Michael; Duru, Adil D; Alici, Evren

    2015-01-01

    Natural killer (NK) cells were discovered 40 years ago, by their ability to recognize and kill tumor cells without the requirement of prior antigen exposure. Since then, NK cells have been seen as promising agents for cell-based cancer therapies. However, NK cells represent only a minor fraction of the human lymphocyte population. Their skewed phenotype and impaired functionality during cancer progression necessitates the development of clinical protocols to activate and expand to high numbers ex vivo to be able to infuse sufficient numbers of functional NK cells to the cancer patients. Initial NK cell-based clinical trials suggested that NK cell-infusion is safe and feasible with almost no NK cell-related toxicity, including graft-versus-host disease. Complete remission and increased disease-free survival is shown in a small number of patients with hematological malignances. Furthermore, successful adoptive NK cell-based therapies from haploidentical donors have been demonstrated. Disappointingly, only limited anti-tumor effects have been demonstrated following NK cell infusion in patients with solid tumors. While NK cells have great potential in targeting tumor cells, the efficiency of NK cell functions in the tumor microenvironment is yet unclear. The failure of immune surveillance may in part be due to sustained immunological pressure on tumor cells resulting in the development of tumor escape variants that are invisible to the immune system. Alternatively, this could be due to the complex network of immune-suppressive compartments in the tumor microenvironment, including myeloid-derived suppressor cells, tumor-associated macrophages, and regulatory T cells. Although the negative effect of the tumor microenvironment on NK cells can be transiently reverted by ex vivo expansion and long-term activation, the aforementioned NK cell/tumor microenvironment interactions upon reinfusion are not fully elucidated. Within this context, genetic modification of NK cells

  17. Impact of antiretroviral therapy (ART) timing on chronic immune activation/inflammation and end-organ damage

    PubMed Central

    Rajasuriar, Reena; Wright, Edwina; Lewin, Sharon R.

    2015-01-01

    Purpose of review The purpose of this review was to summarize recent studies on the effect of early antiretroviral therapy (ART) in HIV-infected patients on markers of immune activation/inflammation, viral persistence and serious non-AIDS events. Recent findings Early ART, initiated within days to months of HIV infection, was associated with marked reduction in T-cell activation often reaching levels observed in HIV-uninfected individuals. However, the impact of early ART on markers of innate immune activation, microbial translocation and inflammation/coagulation was less clear. Early ART has also been associated with a significant reduction in the frequency of latently infected cells, which was greater if ART was initiated within days to weeks rather than months following infection. However, few studies have evaluated the relationship between immune activation and viral reservoirs, specifically following early ART. Early ART may potentially reduce serious non-AIDS events and associated mortality, but most of these studies have extrapolated from changes in surrogate markers, such as CD4 : CD8 ratio. Summary Early ART was associated with beneficial effects on multiple markers of immune activation, inflammation and viral persistence. Longer term prospective studies are still needed to determine whether early ART translates to a significant reduction in serious non-AIDS events and mortality. PMID:25415420

  18. Developing a Manualized Occupational Therapy Diabetes Management Intervention: Resilient, Empowered, Active Living With Diabetes

    PubMed Central

    Pyatak, Elizabeth A.; Carandang, Kristine; Davis, Shain

    2016-01-01

    This article reports on the development of a manualized occupational therapy intervention for diabetes management. An initial theoretical framework and core content areas for a Stage 1 intervention manual were developed based on an in-depth needs assessment and review of existing literature. After evaluation by a panel of experts and completion of a feasibility study, the intervention was revised into a Stage 2 manual in preparation for a randomized study evaluating the intervention’s efficacy. In developing the initial manual, we delineated core theoretical principles to allow for flexible application and tailoring of the intervention’s content areas. Expert panel feedback and feasibility study results led to changes to the intervention structure and content as we developed the Stage 2 manual. Through describing this process, we illustrate the dynamic evolution of intervention manuals, which undergo revisions due to both theoretical and practical considerations at each stage of the research-to-clinical practice pipeline. PMID:26594741

  19. Developing a Manualized Occupational Therapy Diabetes Management Intervention: Resilient, Empowered, Active Living With Diabetes.

    PubMed

    Pyatak, Elizabeth A; Carandang, Kristine; Davis, Shain

    2015-07-01

    This article reports on the development of a manualized occupational therapy intervention for diabetes management. An initial theoretical framework and core content areas for a Stage I intervention manual were developed based on an in-depth needs assessment and review of existing literature. After evaluation by a panel of experts and completion of a feasibility study, the intervention was revised into a Stage 2 manual in preparation for a randomized study evaluating the intervention's efficacy. In developing the initial manual, we delineated core theoretical principles to allow for flexible application and tailoring of the intervention's content areas. Expert panel feedback and feasibility study results led to changes to the intervention structure and content as we developed the Stage 2 manual. Through describing this process, we illustrate the dynamic evolution of intervention manuals, which undergo revisions due to both theoretical and practical considerations at each stage of the research-to-clinical practice pipeline. PMID:26594741

  20. Activating human genes with zinc finger proteins, transcription activator-like effectors and CRISPR/Cas9 for gene therapy and regenerative medicine.

    PubMed

    Gersbach, Charles A; Perez-Pinera, Pablo

    2014-08-01

    New technologies have recently been developed to control the expression of human genes in their native genomic context by engineering synthetic transcription factors that can be targeted to any DNA sequence. The ability to precisely regulate any gene as it occurs naturally in the genome provides a means to address a variety of diseases and disorders. This approach also circumvents some of the traditional challenges of gene therapy. In this editorial, we review the technologies that have enabled targeted human gene activation, including the engineering of transcription factors based on zinc finger proteins, transcription activator-like effectors and the CRISPR/Cas9 system. Additionally, we highlight examples in which these methods have been developed for therapeutic applications and discuss challenges and opportunities.

  1. [Effect of components and some protocols of anti-ulcer therapy on content and activity of monooxigenase system enzymes of the stomach mucosa in experimental stomach ulcer].

    PubMed

    Iakubov, A V; Pattakhova, M Kh

    2009-01-01

    The influence of components and some schemata of antiulcerous therapy on content and activity of monooxigenase system's enzymes in mucous membrane of stomach are studied on the model of experimental stomach ulcer in rats. It is established, that among components of antiulcerous therapy such as omeprazole, clarithromycin and metronidazole inhibit content and activity of MOS enzymes. Tinidazol, amoxicillin and azithromycin do not affect the function of MOS. Rifampicin and pantoprazole induce enzyme system of monooxigenase. In triple therapy with omeprazole, clarithromycin and metronidazole the inhibit effect of preparations to system of MOS is exponentiated and it leads to suppression of mucous cytoprotaction of gastro duodenal zone. Triple therapy of ulcerous disease with pantoprazole, rifampicin and azithromycin is effective planning to stimulate defense mechanisms of the organism.

  2. Effects of combined fine motor skill and cognitive therapy to cognition, degree of dementia, depression, and activities of daily living in the elderly with Alzheimer’s disease

    PubMed Central

    Lee, Jin; Lee, ByoungHee; Park, YuHyung; Kim, Yumi

    2015-01-01

    [Purpose] This study evaluated the effects of combined fine motor skill and cognitive therapies on cognition, depression, and activities of daily living in elderly patients with Alzheimer’s disease (AD). [Subjects and Methods] Twenty-six participants comprised 2 groups. The experimental group (n=13) received combined fine motor skill and cognitive therapy, and the control group (n=13) received only general medical care. [Results] The experimental group showed improvements in cognition, degree of dementia, depression, and activities of daily living compared to the control group. However, there were no significant differences between the two groups. [Conclusion] These results suggest that combined fine motor skill and cognitive therapy improves cognition, degree of dementia, depression, and daily living in elderly patients with AD. These therapies would therefore be effective as general medical care strategies. PMID:26644663

  3. Low level laser therapy activates NF-kB via generation of reactive oxygen species in mouse embryonic fibroblasts

    NASA Astrophysics Data System (ADS)

    Chen, Aaron Chih-Hao; Arany, Praveen R.; Huang, Ying-Ying; Tomkinson, Elizabeth M.; Saleem, Taimur; Yull, Fiona E.; Blackwell, Timothy S.; Hamblin, Michael R.

    2009-02-01

    Despite over forty years of investigation on low-level light therapy (LLLT), the fundamental mechanisms underlying photobiomodulation remain unclear. In this study, we isolated murine embryonic fibroblasts (MEF) from transgenic NF-kB luciferase reporter mice and studied their response to 810-nm laser radiation. Significant activation of NFkB was observed for fluences higher than 0.003 J/cm2. NF-kB activation by laser was detectable at 1-hour time point. Moreover, we demonstrated that laser phosphorylated both IKK α/β and NF-kB 15 minutes after irradiation, which implied that laser activates NF-kB via phosphorylation of IKK α/β. Suspecting mitochondria as the source of NF-kB activation signaling pathway, we demonstrated that laser increased both intracellular reactive oxygen species (ROS) by fluorescence microscopy with dichlorodihydrofluorescein and ATP synthesis by luciferase assay. Mitochondrial inhibitors, such as antimycin A, rotenone and paraquat increased ROS and NF-kB activation but had no effect on ATP. The ROS quenchers N-acetyl-L-cysteine and ascorbic acid abrogated laser-induced NF-kB and ROS but not ATP. These results suggested that ROS might play an important role in the signaling pathway of laser induced NF-kB activation. However, the western blot showed that antimycin A, a mitochondrial inhibitor, did not activate NF-kB via serine phosphorylation of IKK α/β as the laser did. On the other hand, LLLT, unlike mitochondrial inhibitors, induced increased cellular ATP levels, which indicates that light also upregulates mitochondrial respiration. ATP upregulation reached a maximum at 0.3 J/cm2 or higher. We conclude that LLLT not only enhances mitochondrial respiration, but also activates the redox-sensitive transcription factor NF-kB by generating ROS as signaling molecules.

  4. Activation of PI3K/Akt/mTOR signaling in the tumor stroma drives endocrine therapy-dependent breast tumor regression

    PubMed Central

    Polo, María Laura; Riggio, Marina; May, María; Rodríguez, María Jimena; Perrone, María Cecilia; Stallings-Mann, Melody; Kaen, Diego; Frost, Marlene; Goetz, Matthew; Boughey, Judy; Lanari, Claudia; Radisky, Derek; Novaro, Virginia

    2015-01-01

    Improved efficacy of neoadjuvant endocrine-targeting therapies in luminal breast carcinomas could be achieved with optimal use of pathway targeting agents. In a mouse model of ductal breast carcinoma we identify a tumor regressive stromal reaction that is induced by neoadjuvant endocrine therapy. This reparative reaction is characterized by tumor neovascularization accompanied by infiltration of immune cells and carcinoma-associated fibroblasts that stain for phosphorylated ribosomal protein S6 (pS6), downstream the PI3K/Akt/mTOR pathway. While tumor variants with higher PI3K/Akt/mTOR activity respond well to a combination of endocrine and PI3K/Akt/mTOR inhibitors, tumor variants with lower PI3K/Akt/mTOR activity respond more poorly to the combination therapy than to the endocrine therapy alone, associated with inhibition of stromal pS6 and the reparative reaction. In human breast cancer xenografts we confirm that such differential sensitivity to therapy is primarily determined by the level of PI3K/Akt/mTOR in tumor cells. We further show that the clinical response of breast cancer patients undergoing neoadjuvant endocrine therapy is associated with the reparative stromal reaction. We conclude that tumor level and localization of pS6 are associated with therapeutic response in breast cancer and represent biomarkers to distinguish which tumors will benefit from the incorporation of PI3K/Akt/mTOR inhibitors with neoadjuvant endocrine therapy. PMID:26098779

  5. Synthesis, Structure-Activity Relationship, and Mechanistic Investigation of Lithocholic Acid Amphiphiles for Colon Cancer Therapy

    PubMed Central

    Bhargava, Priyanshu; Singh, Ashima; Motiani, Rajender K.; Shyam, Radhey; Sreekanth, Vedagopuram; Sengupta, Sagar; Bajaj, Avinash

    2014-01-01

    We report a structure-activity relationship of lithocholic acid amphiphiles for their anticancer activities against colon cancer. We synthesized ten cationic amphiphiles differing in nature of cationic charged head groups using lithocholic acid. We observed that anticancer activities of these amphiphiles against colon cancer cell lines are contingent on nature of charged head group. Lithocholic acid based amphiphile possessing piperidine head group (LCA-PIP1) is ~10 times more cytotoxic as compared to its precursor. Biochemical studies revealed that enhanced activity of LCA-PIP1 as compared to lithocholic acid is due to greater activation of apoptosis.LCA-PIP1 induces sub G0 arrest and causes cleavage of caspases. A single dose of lithocholic acid-piperidine derivative is enough to reduce the tumor burden by 75% in tumor xenograft model. PMID:25685308

  6. Impact of DCS-facilitated cue exposure therapy on brain activation to cocaine cues in cocaine dependence

    PubMed Central

    Prisciandaro, James J.; Myrick, Hugh; Henderson, Scott; McRae-Clark, Aimee L.; Ana, Elizabeth J. Santa; Saladin, Michael E.; Brady, Kathleen T.

    2013-01-01

    Background The development of addiction is marked by a pathological associative learning process that imbues incentive salience to stimuli associated with drug use. Recent efforts to treat addiction have targeted this learning process using cue exposure therapy augmented with D-cycloserine (DCS), a glutamatergic agent hypothesized to enhance extinction learning. To better understand the impact of DCS-facilitated extinction on neural reactivity to drug cues, the present study reports fMRI findings from a randomized, double-blind, placebo-controlled trial of DCS-facilitated cue exposure for cocaine dependence. Methods Twenty-five participants completed two MRI sessions (before and after intervention), with a cocaine-cue reactivity fMRI task. The intervention consisted of 50mg of DCS or placebo, combined with two sessions of cocaine cue exposure and skills training. Results Participants demonstrated cocaine cue activation in a variety of brain regions at baseline. From the pre- to post-study scan, participants experienced decreased activation to cues in a number of regions (e.g., accumbens, caudate, frontal poles). Unexpectedly, placebo participants experienced decreases in activation to cues in the left angular and middle temporal gyri and the lateral occipital cortex, while DCS participants did not. Conclusions Three trials of DCS-facilitated cue exposure therapy for cocaine dependence have found that DCS either increases or does not significantly impact response to cocaine cues. The present study adds to this literature by demonstrating that DCS may prevent extinction to cocaine cues in temporal and occipital brain regions. Although consistent with past research, results from the present study should be considered preliminary until replicated in larger samples. PMID:23497788

  7. Effect of antiangiogenic therapy on luciferase activity in a cytomegalovirus- or HSP70-promoter-transfected M21 tumor model

    NASA Astrophysics Data System (ADS)

    Hundt, Walter; Schink, Christian; Steinbach, Silke; O'Connell-Rodwell, Caitlin E.; Kiessling, Andreas; Librizzi, Damiano; Burbelko, Mykhaylo; Guccione, Samira

    2012-06-01

    We investigated the effect of targeted gene therapy on heat shock protein 70 expression (Hsp70) and protein production (HSP70) in a melanoma tumor model (M21; M21-L). M21 and M21-L cells transfected with a plasmid containing the Hsp70 (Hspa1b) or the cytomegalovirus (CMV) promoter and the luciferase reporter gene were injected into mice; the resulting tumors grew to a size of 650 mm3. Mice (five per group) were intravenously treated with an Arg-Gly-Asp peptide-nanoparticle/Raf-1 kinase inhibitor protein complex [RGD-NP/RAF(-)] or with a nanoparticle control. Bioluminescence imaging (IVIS®, Xenogen, USA) was performed at 12, 24, 48, and 72 h after the treatment cycle. Western blot analysis of HSP70 protein was performed to monitor protein expression. The size of the treated M21 tumors remained fairly constant (647.8+/-103.4 mm2 at the beginning versus 704.8+/-94.4 mm3 at the end of the experiment). The size of the M21-L tumors increased, similar to the untreated control tumors. Bioluminescent imaging demonstrated that when transcription was controlled by the CMV promoter, luciferase activity decreased to 17.9%+/-4.3% of baseline values in the treated M21 tumors. When transcription was controlled by the Hsp70 promoter, the highest luciferase activity (4.5+/-0.7-fold increase over base-line values) was seen 24 h after injection in the M21 tumors; however, no luciferase activity was seen in the M21-L tumors. In accordance with bioluminescent imaging, western blot analysis showed a peak in HSP70 production at 24 h after the injection of the RGD-NP/RAF(-) complex in the M21 tumors; however, no HSP70 protein induction was seen in the M21-L tumors. Thus, targeted antiangiogenic therapy can induce Hsp70 expression and HSP70 protein in melanoma tumors.

  8. Acidic extracellular pH neutralizes the autophagy-inhibiting activity of chloroquine: implications for cancer therapies.

    PubMed

    Pellegrini, Paola; Strambi, Angela; Zipoli, Chiara; Hägg-Olofsson, Maria; Buoncervello, Maria; Linder, Stig; De Milito, Angelo

    2014-04-01

    Acidic pH is an important feature of tumor microenvironment and a major determinant of tumor progression. We reported that cancer cells upregulate autophagy as a survival mechanism to acidic stress. Inhibition of autophagy by administration of chloroquine (CQ) in combination anticancer therapies is currently evaluated in clinical trials. We observed in 3 different human cancer cell lines cultured at acidic pH that autophagic flux is not blocked by CQ. This was consistent with a complete resistance to CQ toxicity in cells cultured in acidic conditions. Conversely, the autophagy-inhibiting activity of Lys-01, a novel CQ derivative, was still detectable at low pH. The lack of CQ activity was likely dependent on a dramatically reduced cellular uptake at acidic pH. Using cell lines stably adapted to chronic acidosis we could confirm that CQ lack of activity was merely caused by acidic pH. Moreover, unlike CQ, Lys-01 was able to kill low pH-adapted cell lines, although higher concentrations were required as compared with cells cultured at normal pH conditions. Notably, buffering medium pH in low pH-adapted cell lines reverted CQ resistance. In vivo analysis of tumors treated with CQ showed that accumulation of strong LC3 signals was observed only in normoxic areas but not in hypoxic/acidic regions. Our observations suggest that targeting autophagy in the tumor environment by CQ may be limited to well-perfused regions but not achieved in acidic regions, predicting possible limitations in efficacy of CQ in antitumor therapies. PMID:24492472

  9. Rehabilitation Program for the Quality of Life for Individuals on Highly Active Antiretroviral Therapy in KwaZulu-Natal, South Africa: A Short Report

    ERIC Educational Resources Information Center

    Maharaj, Sonill S.; Chetty, Verusia

    2011-01-01

    Patients on highly active antiretroviral therapy (HAART) spend less time on vigorous activities due to lower aerobic capacity with functional limitations that can be attributed to a detraining effect, resulting in a poor quality of life (QoL). The overall aims of rehabilitation are to restore, to maintain, and to enhance the QoL and this…

  10. Immunoglobulin G kappa [IgG kappa] and IgG lambda paraproteinemia in a child with AIDS and response to highly active antiretroviral therapy.

    PubMed

    Seeborg, Filiz Odabasi; Gay, Hannah; Schmiege, Lorenz M; Bernard, David; Shearer, William T

    2005-11-01

    We report an 8-year-old boy with AIDS, extremely elevated serum immunoglobulin G (IgG) concentration and IgG kappa [IgG(kappa)] and IgG lambda [IgG(lambda)] paraproteinemia. This paraproteinemia partially responded to highly active antiretroviral therapy. This case emphasizes the importance of controlling B-cell activation. PMID:16275950

  11. The Alfred Hospital experience of resumption of cardiac activity after withdrawal of life-sustaining therapy.

    PubMed

    Sa, Yong; S, D'Souza; S, Philpot; Dv, Pilcher

    2016-09-01

    With the advent of donation after circulatory death programs in Australia and New Zealand, greater knowledge is needed about physiologic variation in haemodynamic activity following withdrawal of cardiorespiratory support. The ANZICS Statement on Death and Organ Donation allows provision for variation in the observation times between two and five minutes after cessation of the circulation prior to declaration of death. We report our experience of two cases, the first where electrical activity and pulse returned after a 102 second pause and the second where electrical activity returned after a three minute pause; both longer than previously reported cases. PMID:27608344

  12. The Alfred Hospital experience of resumption of cardiac activity after withdrawal of life-sustaining therapy.

    PubMed

    Yong, S A; D'Souza, S; Philpot, S; Pilcher, D V

    2016-09-01

    With the advent of donation after circulatory death programs in Australia and New Zealand, greater knowledge is needed about physiologic variation in haemodynamic activity following withdrawal of cardiorespiratory support. The ANZICS Statement on Death and Organ Donation allows provision for variation in the observation times between two and five minutes after cessation of the circulation prior to declaration of death. We report our experience of two cases, the first where electrical activity and pulse returned after a 102 second pause and the second where electrical activity returned after a three minute pause; both longer than previously reported cases.

  13. The advantages of PD1 activating chimeric receptor (PD1-ACR) engineered lymphocytes for PDL1(+) cancer therapy.

    PubMed

    Tang, Xiaolong; Li, Qingguo; Zhu, Yongqiang; Zheng, Donghui; Dai, Jingjing; Ni, Wenxuan; Wei, Jia; Xue, Yubao; Chen, Ke; Hou, Wei; Zhang, Chao; Feng, Xiaojun; Liang, Yong

    2015-01-01

    Tumors exploit immunoregulatory checkpoints to attenuate T cell responses as a means of circumventing immunologic rejection. By activating the inhibitory costimulatory pathway of Programmed Death 1 (PD1)/PDL1 which provides tumor cells an escape mechanism from immune surveillance, Programmed Death Ligand1 (PDL1)(+) tumors hamper activated tumor-specific T cell functions and render them functionally exhausted. To overcome the inhibitory costimulatory effects of PDL1 on the adoptively transferred T cells, we sought to convert PD1 to a T cell costimulatory receptor by exchanging its transmembrane and cytoplasmic tail with CD28 and 4-1BB signaling domains (PD1-CD28-4-1BB, PD1-ACR), anticipating the genetically modified effector T lymphocytes expressing PD1-ACR would exhibit enhanced functional attributes. And the results showed that PD1-ACR expressed T cells retained the ability to bind PDL1, resulting in T cell activation as evidenced by the elevated activity of phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), the augmentation of cytokine secretion and the increased proliferative capacity. Moreover, when systemically administered in the mouse model of glioblastoma metastases, PD1-ACR T cells localized at the area of U87 invasive tumor, which results in suppressed tumor growth and enhanced survival of mice with established U87 glioblastoma. Together, these data demonstrated that PD1-ACR has a high potential to serve as a novel strategy to overcome PDL1 mediated immunosuppression of T cells for cancer therapy. PMID:26045887

  14. Use of Percutaneous Aspiration Thrombectomy vs. Anticoagulation Therapy to Treat Acute Iliofemoral Venous Thrombosis: 1-year Follow-up Results of a Randomised, Clinical Trial

    SciTech Connect

    Cakir, Volkan; Gulcu, Aytac; Akay, Emrah; Capar, Ahmet E.; Gencpinar, Tugra; Kucuk, Banu; Karabay, Ozalp; Goktay, A. Yigit

    2014-08-15

    PurposeThe purpose of this study was to compare the efficacy of percutaneous aspiration thrombectomy (PAT) followed by standard anticoagulant therapy, with anticoagulation therapy alone, for the treatment of acute proximal lower extremity deep vein thrombosis.MethodsIn this randomised, prospective study, 42 patients with acute proximal iliofemoral deep vein thrombosis documented via Doppler ultrasound examination, were separated into an interventional treatment group (16 males, 5 females, average age 51 years) and a medical treatment group (13 males, 8 females, average age 59 years). In the interventional group, PAT with large-lumen 9-F diameter catheterisation was applied, after initiation of standard anticoagulant therapy. Balloon angioplasty (n 19) and stent implementation (n: 14) were used to treat patients with residual stenosis (>50 %) after PAT. Prophylactic IVC filters were placed in two patients. The thrombus clearance status of the venous system was evaluated by venography. In both the medical and interventional groups, venous patency rates and clinical symptom scores were evaluated at months 1, 3, and 12 after treatment.ResultsDeep venous systems became totally cleared of thrombi in 12 patients treated with PAT. The venous patency rates in month 12 were 57.1 and 4.76 % in the interventional and medical treatment groups, respectively. A statistically significant improvement was observed in clinical symptom scores of the interventional group (PAT) with or without stenting (4.23 ± 0.51 before treatment; 0.81 ± 0.92 at month 12) compared with the medical treatment group (4.00 ± 0.63 before treatment; 2.43 ± 0.67 at month 12). During follow-up, four patients in the medical treatment and one in the interventional group developed pulmonary embolisms.ConclusionsFor treatment of acute deep vein thrombosis, PAT with or without stenting is superior to anticoagulant therapy alone in terms of both ensuring venous patency and improving clinical

  15. [Myeloperoxidase activity in blood plasma as a criterion of therapy for patients with cardiovascular disease].

    PubMed

    Grigorieva, D V; Gorudko, I V; Kostevich, V A; Sokolov, A V; Buko, I V; Vasilyev, V B; Polonetsky, L Z; Panasenko, O M; Cherenkevich, S N

    2016-03-01

    A significant increase in the myeloperoxidase (MPO) activity has been found in plasma of patients with stable angina and with acute coronary syndrome (ACS) in comparison with the control group. MPO concentration was significantly increased in plasma of ACS patients. Reduced MPO activity in the treated ACS patients correlated with a favorable outcome of the disease. Generally, changes in plasma MPO concentration coincided with changes in lactoferrin concentration thus confirming the role of neutrophil degranulation in the increase of plasma concentrations of these proteins. The increase in MPO activity was obviously determined by modification of the MPO protein caused by reactive oxygen species and halogen in the molar ratio of 1 : 25 and 1 : 50. The decrease in plasma MPO activity may be associated with increased plasma concentrations of the physiological inhibitor of its activity, ceruloplasmin, and also with modification of the MPO protein with reactive oxygen species and halogen at their molar ratio of 1 : 100 and higher. Thus, MPO activity may be used for evaluation of effectiveness of the treatment of cardiovascular diseases. PMID:27420626

  16. Alterations in thigh subcutaneous adipose tissue gene expression in protease inhibitor-based highly active antiretroviral therapy

    PubMed Central

    Chaparro, Juan; Reeds, Dominic N.; Wen, Weidong; Xueping, E.; Klein, Samuel; Semenkovich, Clay F.; Bae, Kyongtae T.; Quirk, Erin K.; Powderly, William G.; Yarasheski, Kevin E.; Li, Ellen

    2006-01-01

    Use of protease inhibitor (PI)–based highly active antiretroviral therapy (HAART) has been associated with altered regional fat distribution, insulin resistance, and dyslipidemias. To assess how PI-based HAART affects adipocyte gene expression in male HIV-1–infected patients, reverse transcription–polymerase chain reaction was used to quantify messenger RNA expression of adipocyte transcription factors and adipocytokines in thigh and abdominal subcutaneous adipose tissue from male (1) HIV-1 seronegative subjects (control, n = 9), (2) asymptomatic treatment-naive HIV-1–infected patients (naive, n = 6), (3) HIV-1–infected patients who were receiving antiretroviral agents but never received PIs (PI naive, n = 5), (4) HIV-1–infected patients who were receiving PI-based HAART (PI, n = 7), and (5) HIV-1–infected patients who discontinued the PI component of their antiviral therapy more than 6 months before enrollment (past PI, n =7). In the PI group, the messenger RNA expression levels of the CCAAT/enhancer–binding protein α, leptin, and adiponectin (18%, P < .01; 23%, P < .05; and 13%, P < .05, respectively) were significantly lower than the levels measured in the PI-naive group. These results are consistent with previous studies on the effects of PIs on cultured adipocytes. Prospective longitudinal studies of thigh fat adipose tissue gene expression could provide further insights on the pathogenesis of metabolic complications associated with PI-based HAART. PMID:15877283

  17. Behavioral activation and problem-solving therapy for depressed breast cancer patients: preliminary support for decreased suicidal ideation.

    PubMed

    Hopko, D R; Funderburk, J S; Shorey, R C; McIndoo, C C; Ryba, M M; File, A A; Benson, K; Vitulano, M

    2013-11-01

    Major depressive disorder (MDD) is the most common psychiatric disorder in breast cancer patients. The prevalence of suicidal ideation in breast cancer patients is considerable, and relative to the general population, the prevalence of completed suicide is elevated, particularly in cancer patients with MDD. A major component of suicide prevention is effective treatment of MDD. Although some research has explored the utility of psychotherapy with breast cancer patients, only three trials have explored the benefits of behavior therapy in patients with well-diagnosed MDD and there has been no systematic investigation of the potential benefits of psychotherapy toward reducing suicidal ideation in breast cancer patients. As a follow-up to a recently completed randomized trial, this study examined the efficacy of 8 weeks of behavioral activation treatment for depression (BATD) and problem-solving therapy (PST) in reducing depression and suicidal ideation, as well as increasing hopefulness in breast cancer patients with MDD (n = 80). Across both treatments, GEE analyses revealed decreased depression and suicidal ideation and increased hopefulness at posttreatment, results that were maintained at 12-month follow-up. Moreover, follow-up patient contact at approximately 2 years posttreatment yielded no indication of completed suicide. Although these data are preliminary, BATD and PST may represent practical approaches to decrease suicidal ideation in depressed breast cancer patients.

  18. Tailored Synthesis of Octopus-type Janus Nanoparticles for Synergistic Actively-Targeted and Chemo-Photothermal Therapy.

    PubMed

    Zhang, Lingyu; Chen, Yinyin; Li, Zilu; Li, Lu; Saint-Cricq, Philippe; Li, Chunxia; Lin, Jun; Wang, Chungang; Su, Zhongmin; Zink, Jeffrey I

    2016-02-01

    A facile, reproducible, and scalable method was explored to construct uniform Au@poly(acrylic acid) (PAA) Janus nanoparticles (JNPs). The as-prepared JNPs were used as templates to preferentially grow a mesoporous silica (mSiO2 ) shell and Au branches separately modified with methoxy-poly(ethylene glycol)-thiol (PEG) to improve their stability, and lactobionic acid (LA) for tumor-specific targeting. The obtained octopus-type PEG-Au-PAA/mSiO2 -LA Janus NPs (PEG-OJNP-LA) possess pH and NIR dual-responsive release properties. Moreover, DOX-loaded PEG-OJNP-LA, upon 808 nm NIR light irradiation, exhibit obviously higher toxicity at the cellular and animal levels compared with chemotherapy or photothermal therapy alone, indicating the PEG-OJNP-LA could be utilized as a multifunctional nanoplatform for in vitro and in vivo actively-targeted and chemo-photothermal cancer therapy. PMID:26732130

  19. Endorphins in male impotence: evidence for naltrexone stimulation of erectile activity in patient therapy.

    PubMed

    Fabbri, A; Jannini, E A; Gnessi, L; Moretti, C; Ulisse, S; Franzese, A; Lazzari, R; Fraioli, F; Frajese, G; Isidori, A

    1989-01-01

    In the present study we evaluated whether naltrexone administration could stimulate sexual function in 30 male patients, ages 25 to 50 years, with idiopathic impotence of at least one year's duration and not of organic etiology. The patients received naltrexone (50 mg/day) or placebo, on a random basis for two weeks. Sexual performance, expressed as the number of full coitus/week, was assessed before (time 0) and during (on days 7 and 15) each treatment. The naltrexone therapy significantly increased the number of successful coitus compared to placebo after 7 and 15 days of treatment: improvement of sexual performance was evident in 11 out of the 15 treated patients. All the patients experienced a significant increase in morning and spontaneous full penile erections/week. No significant side effects were reported. Endocrine studies revealed no significant modification of plasma LH, FSH or testosterone by naltrexone, suggesting that the positive effect of the drug on sexual behavior was exerted at a central level. A two-month follow-up, at which time patients were off treatment, erectile capacity had returned to baseline in 10 patients, while five reported complete recovery of their sexual ability. We hypothesize that an alteration in central opioid tone is present in idiopathic impotence and is involved in the impairment of sexual behavior. PMID:2543996

  20. The care home activity project: does introducing an occupational therapy programme reduce depression in care homes?

    PubMed

    Mozley, C G; Schneider, J; Cordingley, L; Molineux, M; Duggan, S; Hart, C; Stoker, B; Williamson, R; Lovegrove, R; Cruickshank, A

    2007-01-01

    The primary aim of the study was to test the hypothesis that depression severity in care homes for older people would be reduced by an occupational therapy programme. This was a feasibility study for a cluster randomised controlled trial and involved four intervention and four control homes in northern England. In each intervention home a registered occupational therapist worked full-time for one year delivering an individualised programme to participants. Pre- and post-intervention data for the Geriatric Mental State-Depression Scale (primary outcome measure) were obtained for 143 participants. Secondary outcomes included dependency and quality of life. No significant intervention effects were found in any of the quantitative outcome measures, though qualitative interviews showed the intervention was valued by many participants, staff and relatives. Therapist ratings and qualitative interviews suggested that the intervention was beneficial to some participants but no distinctive characteristics were found that might enable prediction of likely benefit on initial assessment. This exploratory study provides no evidence that this intervention produced benefits in terms of depression, dependency or quality of life. Lack of prior power calculations means these are not definitive findings; but numbers were sufficient to perform the required analyses and data did not suggest effects that would have reached statistical significance with a larger sample. This study highlights issues for consideration in providing such services in care homes.

  1. Synergistic activity of combination therapy with PEGylated pemetrexed and gemcitabine for an effective cancer treatment.

    PubMed

    Vandana, Mallaredy; Sahoo, Sanjeeb K

    2015-08-01

    Combination therapy in cancer is now opted as a potential therapeutic strategy for cancer treatment. However, effective delivery of drugs in combination at the tumor site is marred by low bioavailability and systemic toxicity of individual drugs. Polymer therapeutics is indeed an upcoming approach for the combinational drug delivery in favor of better cancer management. Hence, the objective of our investigation was to develop a dual drug PEGylated system that carries two chemotherapeutic drugs simultaneously for effective treatment of cancer. In this regard, we have synthesized Pem-PEG-Gem, wherein pemetrexed (Pem) and gemcitabine (Gem) are conjugated to a heterobifunctional polyethylene glycol (PEG) polymer for the effective treatment of Non-Small Cell Lung Cancer (NSCLC). Our results demonstrate enhanced bioavailability of the individual drugs in Pem-PEG-Gem in comparison with the drugs in their native form. The developed Pem-PEG-Gem showed enhanced cell death with respect to their native counterparts when treated singly or in combination against NSCLC cells. This might be attributed to better cellular internalization through the process of macropinocytosis and synergistic cytotoxic action of Pem-PEG-Gem in NSCLC cells. Hence, we propose the above dual drug based polymer therapeutic approach suitable for better clinical application in the treatment of NSCLC.

  2. Stress-activated signaling responses leading to apoptosis following photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Oleinick, Nancy L.; He, Jin; Xue, Liang-yan; Separovic, Duska

    1998-05-01

    Photodynamic treatment with the phthalocyanine Pc 4, a mitochondrially localizing photosensitizer, is an efficient inducer of cell death by apoptosis, a cell suicide pathway that can be triggered by physiological stimuli as well as by various types of cellular damage. Upon exposure of the dye- loaded cells to red light, several stress signalling pathways are rapidly activated. In murine L5178Y-R lymphoblasts, caspase activation and other hallmarks of the final phase of apoptosis are observed within a few minutes post-PDT. In Chinese hamster CHO-K1 cells, the first signs of apoptosis are not observed for 1 - 2 hours. The possible involvement of three parallel mitogen-activated protein kinase (MAPK) signalling pathways has been investigated. The extracellular- regulated kinases (ERK-1 and ERK-2), that are thought to promote cell growth, are not appreciably altered by PDT. However, PDT causes marked activation of the stress-activated protein kinase (SAPK) cascade in both cell types and of the p38/HOG-type kinase in CHO cells. Both of these latter pathways have been demonstrated to be associated with apoptosis. A specific inhibitor of the ERK pathway did not alter PDT-induced apoptosis; however, an inhibitor of the p38 pathway partially blocked PDT-induced apoptosis. Blockage of the SAPK pathway is being pursued by a genetic approach. It appears that the SAPK and p38 pathways may participate in signaling apoptosis in response to PDT with Pc 4.

  3. Cytochrome P450 2D6 Activity Predicts Discontinuation of Tamoxifen Therapy in Breast Cancer Patients

    PubMed Central

    Rae, James M.; Sikora, Matthew J.; Henry, N. Lynn; Li, Lang; Kim, Seongho; Oesterreich, Steffi; Skaar, Todd; Nguyen, Anne T.; Desta, Zeruesenay; Storniolo, Anna Maria; Flockhart, David A.; Hayes, Daniel F.; Stearns, Vered

    2009-01-01

    The selective estrogen receptor modulator tamoxifen is routinely used for treatment and prevention of estrogen receptor positive breast cancer. Studies of tamoxifen adherence suggest that over half of patients discontinue treatment before the recommended 5 years. We hypothesized that polymorphisms in CYP2D6, the enzyme responsible for tamoxifen activation, predict for tamoxifen discontinuation. Tamoxifen-treated women (n = 297) were genotyped for CYP2D6 variants and assigned a “score” based on predicted allele activities from 0 (no activity) to 2 (high activity). Correlation between CYP2D6 score and discontinuation rates at 4 months were tested. We observed a strong non-linear correlation between higher CYP2D6 score and increased rates of discontinuation (r2 = 0.935, p = 0.018). These data suggest that presence of active CYP2D6 alleles may predict for higher likelihood of tamoxifen discontinuation. Therefore, patients who may be most likely to benefit from tamoxifen may paradoxically be most likely to discontinue treatment prematurely. PMID:19421167

  4. Evolution of Surface Motor Activation Zones in Hemiplegic Patients During 20 Sessions of FES Therapy with Multi-pad Electrodes

    PubMed Central

    Malešević, Jovana; Štrbac, Matija; Isaković, Milica; Kojić, Vladimir; Konstantinović, Ljubica; Vidaković, Aleksandra; Dedijer, Suzana; Kostić, Miloš; Keller, Thierry

    2016-01-01

    The purpose of this study was to examine surface motor activation zones for wrist, fingers and thumb extension movements and their temporal change during 20 therapy sessions using advanced multi-pad functional electrical stimulation system. Results from four hemiplegic patients indicate that certain zones have higher probability of eliciting each of the target movements. However, mutual overlap and variations of the zones are present not just between the subjects, but also on the intrasubject level, reflected through these session to session transformations of the selected virtual electrodes. The obtained results could be used as a priori knowledge for semi-automated optimization algorithm and could shorten the time required for calibration of the multi-pad electrode. PMID:27478575

  5. The Wolbachia endosymbiont of Brugia malayi has an active phosphoglycerate mutase: a candidate target for anti-filarial therapies.

    PubMed

    Foster, Jeremy M; Raverdy, Sylvine; Ganatra, Mehul B; Colussi, Paul A; Taron, Christopher H; Carlow, Clotilde K S

    2009-04-01

    Phosphoglycerate mutases (PGM) interconvert 2- and 3-phosphoglycerate in the glycolytic and gluconeogenic pathways. A putative cofactor-independent phosphoglycerate mutase gene (iPGM) was identified in the genome sequence of the Wolbachia endosymbiont from the filarial nematode, Brugia malayi (wBm). Since iPGM has no sequence or structural similarity to the cofactor-dependent phosphoglycerate mutase (dPGM) found in mammals, it may represent an attractive Wolbachia drug target. In the present study, wBm-iPGM cloned and expressed in Escherichia coli was mostly insoluble and inactive. However, the protein was successfully produced in the yeast Kluyveromyces lactis and the purified recombinant wBm-iPGM showed typical PGM activity. Our results provide a foundation for further development of wBm-iPGM as a promising new drug target for novel anti-filarial therapies that selectively target the endosymbiont.

  6. Transformable Peptide Nanocarriers for Expeditious Drug Release and Effective Cancer Therapy via Cancer‐Associated Fibroblast Activation

    PubMed Central

    Ji, Tianjiao; Zhao, Ying; Ding, Yanping; Wang, Jing; Zhao, Ruifang; Lang, Jiayan; Qin, Hao; Liu, Xiaoman; Shi, Jian; Tao, Ning; Qin, Zhihai; Nie, Guangjun

    2015-01-01

    Abstract A novel cleavable amphiphilic peptide (CAP) was designed to be specifically responsive to fibroblast activation protein‐α (FAP‐α), a protease specifically expressed on the surface of cancer‐associated fibroblasts. The CAP self‐assembled into fiber‐like nanostructures in solution, while the presence of hydrophobic chemotherapeutic drugs readily transformed the assemblies into drug‐loaded spherical nanoparticles. The disassembly of these nanoparticles (CAP‐NPs) upon FAP‐α cleavage resulted in rapid and efficient release of the encapsulated drugs specifically at tumor sites. This Transformers‐like drug delivery strategy could allow them to disrupt the stromal barrier and enhance local drug accumulation. Therapeutic results suggested that drug‐loaded CAP‐NPs hold promising tumor specificity and therapeutic efficacy for various solid tumor models, confirming its potential utility and versatility in antitumor therapy. PMID:26283097

  7. Evolution of drug resistance after virologic failure of a first highly active antiretroviral therapy regimen in Uganda

    PubMed Central

    Reynolds, Steven J.; Kityo, Cissy; Mbamanya, Frank; Dewar, Robin; Ssali, Francis; Quinn, Thomas C.; Mugyenyi, Peter; Dybul, Mark

    2009-01-01

    Objective To determine the extent of viral resistance over time among non-clade B HIV-1 infected patients in Uganda maintained on first line highly active antiretroviral therapy (HAART) following virologic failure. Methods Genotyping was performed on sixteen patients with virologic failure who were enrolled in an open label randomized clinical trial of short-cycle treatment interruption. Results All patients receiving efavirenz containing HAART had at least 1 efavirenz resistance mutation develop during follow-up. The majority 13/15 (86%) developed lamivudine resistance during follow-up but no thymidine analogue mutations (TAMS) developed during a median duration of virologic failure of 325.5 days. Conclusions Genotypic resistance to both efavirenz and lamivudine developed early during the course of treatment after virologic failure. TAMs did not emerge early despite moderate exposure time to thymidine analogs during virologic failure. PMID:19430104

  8. Is physical activity possible and beneficial for patients with hepatitis C receiving pegylated interferon and ribavirin therapy?

    PubMed

    Payen, J-L; Pillard, F; Mascarell, V; Rivière, D; Couzigou, P; Kharlov, N

    2009-01-01

    The great majority of patients with chronic viral hepatitis C are treated with pegylated interferon-ribavirin therapy. The aim of this study was to demonstrate that these patients were able to have some form of physical exercise, and that this activity can lead to an improvement in their quality-of-life. Twelve volunteer patients with hepatitis C, who were either sedentary or had become sedentary and who had been treated by combination therapy for the past few weeks, were recruited at hepatology clinics in the Midi-Pyrénées region of France early in 2006. All patients attended a sports medicine consultation for an initial evaluation: maximal aerobic power and maximal oxygen consumption tests, maximum heart rate (MHR), search for contraindications for participation in the proposed program of physical exercise. The patients were given a heart rate monitor so they could measure their heart rate during physical exercise and check that they exercised under safe conditions and remained within the so-called "endurance" zone. The patients came to a sports facility daily for 5 days for the exercise program. The activities were divided into four sessions each day: an individual physical exercise selected by the patient, team physical exercise, recreational physical exercise, lectures on the different types of hepatitis and their treatment, on nutrition and on sports medicine assessments. Data on hepatitis, results of the cardiorespiratory examination and personal history and record of past physical activity were collected for each patient. Quality-of-life (SF36) was assessed at enrollment in the study and one month after the training sessions. At the initial sports medicine consultation, all patients reached their MHR and were found capable of participating in the proposed physical exercise program. One enrolled patient was excluded from the analysis because of the presence of sinusitis on arrival. Seven men and four women, mean age of 46 years completed the full course of

  9. Effect of chronic activity-based therapy on bone mineral density and bone turnover in persons with spinal cord injury

    PubMed Central

    Harness, Eric T.; Witzke, Kara A.

    2014-01-01

    Purpose Osteoporosis is a severe complication of spinal cord injury (SCI). Many exercise modalities are used to slow bone loss, yet their efficacy is equivocal. This study examined the effect of activity-based therapy (ABT) targeting the lower extremities on bone health in individuals with SCI. Methods Thirteen men and women with SCI (age and injury duration = 29.7 ± 7.8 and 1.9 ± 2.7 years) underwent 6 months of ABT. At baseline and after 3 and 6 months of training, blood samples were obtained to assess bone formation (serum procollagen type 1 N propeptide (PINP) and bone resorption (serum C-terminal telopeptide of type I collagen (CTX), and participants underwent dual-energy X-ray absorptiometry scans to obtain total body and regional estimates of bone mineral density (BMD). Results Results demonstrated significant increases (p < 0.05) in spine BMD (+4.8 %; 1.27 ± 0.22–1.33 ± 0.24 g/cm2) and decreases (p < 0.01) in total hip BMD (−6.1 %; 0.98 ± 0.18–0.91 ± 0.16 g/cm2) from 0 to 6 months of training. BMD at the bilateral distal femur (−7.5 to −11.0 %) and proximal tibia (− 8.0 to −11.2 %) declined but was not different (p > 0.05) versus baseline. Neither PINP nor CTX was altered (p> 0.05) with training. Conclusions Chronic activity-based therapy did not reverse bone loss typically observed soon after injury, yet reductions in BMD were less than the expected magnitude of decline in lower extremity BMD in persons with recent SCI. PMID:24097172

  10. 808-nm laser therapy with a flat-top handpiece photobiomodulates mitochondria activities of Paramecium primaurelia (Protozoa).

    PubMed

    Amaroli, Andrea; Ravera, Silvia; Parker, Steven; Panfoli, Isabella; Benedicenti, Alberico; Benedicenti, Stefano

    2016-05-01

    Photobiomodulation is proposed as a non-linear process, and only low-level laser therapy (LLLT) is assumed to stimulate exposed cells, whereas high powered laser and fluences can cause negative effects, exhausting the cell's energy reserve as a consequence of excessive photon-based stimulation. In our work, we investigated and compared the effects of 808-nm diode laser (CW) with a new flat-top handpiece. To this purpose, we tested the photobiomodulation effects of 1 and 3 J/cm(2) fluence, both generated by 100 mW or 1 W of laser power and of 64 J/cm(2) of fluence generated by 100 mW, 1 W, 1.5 W or 2 W, as expressed through oxygen consumption and ATP synthesis of Paramecium. Data collected indicates the incremental consumption of oxygen through irradiation with 3 J/cm(2)-100 mW or 64 J/cm(2)-1 W correlates with an increase in Paramecium ATP synthesis. The Paramecium respiration was inhibited by fluences 64 J/cm(2)-100 mW or 64 J/cm(2)-2 W and was followed by a decrease in the endogenous ATP concentration. The 1 J/cm(2)-100 mW or 1 W and 3 J/cm(2)-1 W did not affect mitochondrial activity. The results show that the fluence of 64 J/cm(2)-1 W more than the 3 J/cm(2)-100 mW causes greater efficiency in Paramecium mitochondria respiratory chain activity. Our results suggest that thanks to flat-top handpiece we used, high fluences by high-powered laser have to be reconsidered as an effective and non-invasive therapy. Possible associated benefits of deeper tissue penetration would increase treatment effectiveness and reduced irradiation time. PMID:26984347

  11. Long-term gene therapy with thrombospondin 2 inhibits TGF-β activation, inflammation and angiogenesis in chronic allograft nephropathy.

    PubMed

    Daniel, Christoph; Vogelbacher, Regina; Stief, Andrea; Grigo, Christina; Hugo, Christian

    2013-01-01

    We recently identified Thrombospondin-2 (TSP-2) as a regulator of matrix remodelling and inflammation in experimental kidney disease by using TSP-2 null mice and successfully proved TSP-2 overexpression as a therapeutic concept in a short term glomerulonephritis model in the rat. In this current study, we investigated if long-term TSP-2 overexpression is also capable to ameliorate the progression of chronic kidney disease in the setting of the chronic allograft nephropathy F344-Lewis model in the rat. Two weeks after renal transplantation, two rat thigh muscles were transfected once only with either a TSP-2 overexpressing plasmid (n = 8) or a luciferase-expressing plasmid as control (n = 8). Rats were monitored for renal function, histological changes and gene expression in the graft for up to 30 weeks after transplantation. Unexpectedly, only in the TSP-2 treated group 2 rats died before the end of the experiment and renal function tended to be worsened in the TSP-2 group compared to the luciferase-treated controls. In addition, glomerular sclerosis and tubular interstitial injury as well as cortical fibronectin deposition was significantly increased in the TSP-2 treated kidneys despite reduced TGF-β activation and marked anti-inflammatory (macrophages, T-cells and B-cells) effects in this group. Long-term TSP-2 therapy impaired repair of renal endothelium, as demonstrated by significant higher glomerular and peritubular endothelial rarefaction and reduced endothelial cell proliferation in the transplanted kidneys from TSP-2 treated rats compared to controls. This TSP-2 effect was associated with decreased levels of renal VEGF but not VEGF1 receptor. In conclusion, despite its anti-inflammatory and TGF-β activation blocking effects, TSP-2 gene therapy did not ameliorate but rather worsened experimental chronic allograft nephropathy most likely via its anti-angiogenic properties on the renal microvasculature.

  12. Long-Term Gene Therapy with Thrombospondin 2 Inhibits TGF-β Activation, Inflammation and Angiogenesis in Chronic Allograft Nephropathy

    PubMed Central

    Daniel, Christoph; Vogelbacher, Regina; Stief, Andrea; Grigo, Christina; Hugo, Christian

    2013-01-01

    We recently identified Thrombospondin-2 (TSP-2) as a regulator of matrix remodelling and inflammation in experimental kidney disease by using TSP-2 null mice and successfully proved TSP-2 overexpression as a therapeutic concept in a short term glomerulonephritis model in the rat. In this current study, we investigated if long-term TSP-2 overexpression is also capable to ameliorate the progression of chronic kidney disease in the setting of the chronic allograft nephropathy F344-Lewis model in the rat. Two weeks after renal transplantation, two rat thigh muscles were transfected once only with either a TSP-2 overexpressing plasmid (n = 8) or a luciferase-expressing plasmid as control (n = 8). Rats were monitored for renal function, histological changes and gene expression in the graft for up to 30 weeks after transplantation. Unexpectedly, only in the TSP-2 treated group 2 rats died before the end of the experiment and renal function tended to be worsened in the TSP-2 group compared to the luciferase-treated controls. In addition, glomerular sclerosis and tubular interstitial injury as well as cortical fibronectin deposition was significantly increased in the TSP-2 treated kidneys despite reduced TGF-β activation and marked anti-inflammatory (macrophages, T-cells and B-cells) effects in this group. Long-term TSP-2 therapy impaired repair of renal endothelium, as demonstrated by significant higher glomerular and peritubular endothelial rarefaction and reduced endothelial cell proliferation in the transplanted kidneys from TSP-2 treated rats compared to controls. This TSP-2 effect was associated with decreased levels of renal VEGF but not VEGF1 receptor. In conclusion, despite its anti-inflammatory and TGF-β activation blocking effects, TSP-2 gene therapy did not ameliorate but rather worsened experimental chronic allograft nephropathy most likely via its anti-angiogenic properties on the renal microvasculature. PMID:24376766

  13. Adverse Drug Reaction Profile in Patients on Anti-tubercular Treatment Alone and in Combination with Highly Active Antiretroviral Therapy

    PubMed Central

    Sadiq, Shamiya; Khajuria, Vijay; Mahajan, Annil; Singh, Jang B.

    2015-01-01

    Background and Objectives Adverse drug reactions are very common among patients on anti-tubercular treatment alone or in combination with highly active antiretroviral therapy but comparatively studied very less. Hence, the current study was done to evalaute the adverse drug reaction (ADR) profile in patients receiving anti-tubercular treatment (ATT) and ATT with highly active antiretroviral therapy (HAART). Materials and Methods A one year prospective, cross-sectional observational study was undertaken using suspected adverse drug data collection form available under Pharmacovigilance Programme of India. Results Seventy four patients receiving ATT & 32 patients on both ATT & HAART presented with 74 and 45 adverse drug events (ADE) respectively. Males were more affected than females in both the groups. DOTS category- 1 regimen was mostly responsible for ADE in both the groups. Epigastric pain was the most common ADE in TB patients, while anaemia was the most common presentation in TB with HIV group. On comparison, ADE rate of TB with HIV co-morbid patients was more (55.8%) than TB patients (0.36%) (p < 0.001). Urban population presented more with ADR in TB/HIV group unlike rural population in TB group (p<0.0001). Whereas, illiterate were more involved in TB group unlike literate in TB/HIV group (p<0.05). Type A reactions were more common in TB group (p < 0.001). Addition of drugs for the management of ADR events was more in TB/HIV group (p < 0.001) as compared to TB group. Rest all the parameters were comparable. Conclusion The study underscores that concomitant HAART and ATT, result in more ADRs in comparison to ATT alone demanding collaboration & integration of National AIDS Control programme and PvPI to enhance drug safety in this field. PMID:26557538

  14. 808-nm laser therapy with a flat-top handpiece photobiomodulates mitochondria activities of Paramecium primaurelia (Protozoa).

    PubMed

    Amaroli, Andrea; Ravera, Silvia; Parker, Steven; Panfoli, Isabella; Benedicenti, Alberico; Benedicenti, Stefano

    2016-05-01

    Photobiomodulation is proposed as a non-linear process, and only low-level laser therapy (LLLT) is assumed to stimulate exposed cells, whereas high powered laser and fluences can cause negative effects, exhausting the cell's energy reserve as a consequence of excessive photon-based stimulation. In our work, we investigated and compared the effects of 808-nm diode laser (CW) with a new flat-top handpiece. To this purpose, we tested the photobiomodulation effects of 1 and 3 J/cm(2) fluence, both generated by 100 mW or 1 W of laser power and of 64 J/cm(2) of fluence generated by 100 mW, 1 W, 1.5 W or 2 W, as expressed through oxygen consumption and ATP synthesis of Paramecium. Data collected indicates the incremental consumption of oxygen through irradiation with 3 J/cm(2)-100 mW or 64 J/cm(2)-1 W correlates with an increase in Paramecium ATP synthesis. The Paramecium respiration was inhibited by fluences 64 J/cm(2)-100 mW or 64 J/cm(2)-2 W and was followed by a decrease in the endogenous ATP concentration. The 1 J/cm(2)-100 mW or 1 W and 3 J/cm(2)-1 W did not affect mitochondrial activity. The results show that the fluence of 64 J/cm(2)-1 W more than the 3 J/cm(2)-100 mW causes greater efficiency in Paramecium mitochondria respiratory chain activity. Our results suggest that thanks to flat-top handpiece we used, high fluences by high-powered laser have to be reconsidered as an effective and non-invasive therapy. Possible associated benefits of deeper tissue penetration would increase treatment effectiveness and reduced irradiation time.

  15. Extra-corporeal pulsed-activated therapy ("EPAT" sound wave) for Achilles tendinopathy: a prospective study.

    PubMed

    Saxena, Amol; Ramdath, Sona; O'Halloran, Patrick; Gerdesmeyer, Ludger; Gollwitzer, Hans

    2011-01-01

    Achilles tendinopathy is common and extracorporeal shockwaves have become a popular treatment for this condition, even though previous research has not provided conclusive results regarding its efficacy in cases of Achilles tendinopathy. Our aim was to evaluate 3 weekly shockwave treatments in patients with Achilles tendinopathy, as quantified by the Roles and Maudsley score. A total of 74 tendons in 60 patients were assessed at baseline and at least 1 year posttreatment, including 32 (43.24%) paratendinoses, 23 (31.08%) proximal tendinoses, and 19 (25.68%) insertional tendinoses. The mean age of the participants was 48.6 ± 12.94 years, and patients with paratendinosis (41.44 ± 14.01 years) were statistically significantly younger than those with proximal (53 ± 8.9 years) and insertional (54.26 ± 9.74 years) tendinopathy, and these differences were statistically significant (P = .0012 and P = .0063, respectively). Overall, 58 (78.38%) tendons improved by at least 1 year posttreatment, including 75% in the paratendinosis, 78.26% in the proximal tendinosis, and 84.21% in the insertional tendinosis groups, and no adverse effects were observed. The Roles and Maudsley score improved from 3.22 ± 0.55 to 1.84 ± 1.05 (P < .0001) in the paratendinosis group, 3.39 ± 0.5 to 1.57 ± 0.66 (P < .0001) in the proximal tendinopathy group, and 3.32 ± 0.58 to 1.47 ± 0.7 (P = .0001) in the insertional tendinopathy group. Based on these results, we believe that shockwave therapy serves as a safe, viable, and effective option for the treatment of Achilles tendinopathy.

  16. Exercise-Induced Release of Pharmacologically Active Substances and Their Relevance for Therapy of Hepatic Injury

    PubMed Central

    Schon, Hans-Theo; Weiskirchen, Ralf

    2016-01-01

    Chronic liver disease (CLD) features constant parenchymal injury and repair together with an increasing hepatic impairment, finally leading to fibrosis and cirrhosis and a heightened risk of hepatocellular carcinoma (HCC). Closely related to the rise in obesity, the worldwide prevalence of nonalcoholic fatty liver disease, the most common form of CLD, has reached an epidemic dimension and is estimated to afflict up to 46% of the general population, including more than one out of three U.S. citizens. Up to now there is no effective drug treatment available, which is why recommendations encompass both exercise programs and changes in dietary habits. Exercise is well-known for unleashing potent anti-inflammatory effects, which can principally counteract liver inflammation and chronic low-grade inflammation. This review article summarizes the underlying mechanisms responsible for the exercise-mediated anti-inflammatory effects, illustrates the application in animal models as well as in humans, and highlights the therapeutic value when possible. Based on the available results there is no doubt that exercise can even be beneficial in an advanced stage of liver disease and it is the goal of this review article to provide evidence for the therapeutic impact on fibrosis, cirrhosis, and HCC and to assess whether exercise might be of value as adjuvant therapy in the treatment of CLD. In principle, all exercise programs carried out in these high-risk patients should be guided and observed by qualified healthcare professionals to guarantee the patients’ safety. Nevertheless, it is also necessary to additionally determine the optimal amount and intensity of exercise to maximize its value, which is why further studies are essential. PMID:27625607

  17. Hormone therapy effects on social behavior and activity levels of surgically postmenopausal cynomolgus monkeys.

    PubMed

    Shively, Carol A; Wood, Charles E; Register, Thomas C; Willard, Stephanie L; Lees, Cynthia J; Chen, Haiying; Sitruk-Ware, Regine L; Tsong, Yun-Yen; Cline, J Mark

    2007-01-01

    The purpose of the experiments reported here was to investigate central nervous system effects of commonly prescribed postmenopausal hormone therapies in a primate model, the cynomolgus monkey (Macaca fascicularis). The results of two experiments are reported. In the first, ovariectomized adult cynomolgus monkeys were treated for eight weeks each with oral micronized 17beta-estradiol (E2) (n=23), E2+medroxyprogesterone acetate (MPA) (n=23), E2+progesterone (P4) (n=23), and placebo (n=23) using a crossover design. In the second, ovariectomized adult cynomolgus monkeys were treated for eight weeks with oral micronized E2+oral micronized P4 (n=10), or E2+intravaginal micronized P4 delivered via a Silastic ring (n=8), or oral placebo and intravaginal placebo (n=5), using a parallel arm design. Behavior was recorded during weeks two through four. Cerebrospinal fluid (CSF) and blood were sampled, and 24h heart rate recorded by telemetry during weeks five through seven. Monoaminergic metabolites were assayed in CSF, and cortisol was assayed in serum. There were no significant effects of treatment on CSF monoaminergic metabolites or heart rate. E2+MPA increased cortisol concentrations. While there were some differences in effects between experiments, both progestogens and both routes of administration increased time spent resting, particularly resting in body contact, resulting in increased passive affiliative interaction. Thus, synthetic progestogens appear to be as sedating as progesterone, and the ring delivery system does not appear to protect the central nervous system from effects of progestogens. Further research is needed to explore social context as an important feature of behavioral response to steroid hormone regimens and to verify and extend knowledge of systemic effects of vaginal ring-delivered progestogens.

  18. Exercise-Induced Release of Pharmacologically Active Substances and Their Relevance for Therapy of Hepatic Injury.

    PubMed

    Schon, Hans-Theo; Weiskirchen, Ralf

    2016-01-01

    Chronic liver disease (CLD) features constant parenchymal injury and repair together with an increasing hepatic impairment, finally leading to fibrosis and cirrhosis and a heightened risk of hepatocellular carcinoma (HCC). Closely related to the rise in obesity, the worldwide prevalence of nonalcoholic fatty liver disease, the most common form of CLD, has reached an epidemic dimension and is estimated to afflict up to 46% of the general population, including more than one out of three U.S. citizens. Up to now there is no effective drug treatment available, which is why recommendations encompass both exercise programs and changes in dietary habits. Exercise is well-known for unleashing potent anti-inflammatory effects, which can principally counteract liver inflammation and chronic low-grade inflammation. This review article summarizes the underlying mechanisms responsible for the exercise-mediated anti-inflammatory effects, illustrates the application in animal models as well as in humans, and highlights the therapeutic value when possible. Based on the available results there is no doubt that exercise can even be beneficial in an advanced stage of liver disease and it is the goal of this review article to provide evidence for the therapeutic impact on fibrosis, cirrhosis, and HCC and to assess whether exercise might be of value as adjuvant therapy in the treatment of CLD. In principle, all exercise programs carried out in these high-risk patients should be guided and observed by qualified healthcare professionals to guarantee the patients' safety. Nevertheless, it is also necessary to additionally determine the optimal amount and intensity of exercise to maximize its value, which is why further studies are essential. PMID:27625607

  19. Exercise-Induced Release of Pharmacologically Active Substances and Their Relevance for Therapy of Hepatic Injury

    PubMed Central

    Schon, Hans-Theo; Weiskirchen, Ralf

    2016-01-01

    Chronic liver disease (CLD) features constant parenchymal injury and repair together with an increasing hepatic impairment, finally leading to fibrosis and cirrhosis and a heightened risk of hepatocellular carcinoma (HCC). Closely related to the rise in obesity, the worldwide prevalence of nonalcoholic fatty liver disease, the most common form of CLD, has reached an epidemic dimension and is estimated to afflict up to 46% of the general population, including more than one out of three U.S. citizens. Up to now there is no effective drug treatment available, which is why recommendations encompass both exercise programs and changes in dietary habits. Exercise is well-known for unleashing potent anti-inflammatory effects, which can principally counteract liver inflammation and chronic low-grade inflammation. This review article summarizes the underlying mechanisms responsible for the exercise-mediated anti-inflammatory effects, illustrates the application in animal models as well as in humans, and highlights the therapeutic value when possible. Based on the available results there is no doubt that exercise can even be beneficial in an advanced stage of liver disease and it is the goal of this review article to provide evidence for the therapeutic impact on fibrosis, cirrhosis, and HCC and to assess whether exercise might be of value as adjuvant therapy in the treatment of CLD. In principle, all exercise programs carried out in these high-risk patients should be guided and observed by qualified healthcare professionals to guarantee the patients’ safety. Nevertheless, it is