RESUMEN
OBJECTIVES: Analyse alternative methods of intrathecal antibody detection by comparing chemiluminescent immunoassay (CLIA) and enzyme-linked immunosorbent assay (ELISA) techniques to determine if CLIA can replace ELISA in the diagnosis of CNS infections. METHODS: A panel of 280 paired samples-cerebrospinal fluid (CSF) and serum-with known antibody reactivities (Varicella, n = 60; Measles, n = 120) and negative samples (n = 100) were used to evaluate the performance of six serological test kits (Enzygnost, VirClia®, and Serion ELISA (Measles and Variella). RESULTS: For Measles virus IgG, the VirClia® IgG monotest revealed 97% and 94% positive and negative agreement to the Enzygnost as reference test, respectively. In contrast, Serion ELISA kits yielded values of 18% and 90%. For the Varicella Zoster virus (VZV) IgG, the VirClia® IgG monotest showed 97% and 90% positive and negative agreement compared to Enzygnost. The Serion ELISA kits showed values of 55% and 86%, respectively. ROC analysis revealed that the areas under the curve for Measles and VZV IgGs were 0.7 and 0.852, respectively, using the Serion kit, and 0.963 and 0.955, for Vircell S.L CLIA technique. VirClia® monotest values were calculated using an antibody index cut-off of 1.3. CONCLUSION: The findings indicate that CLIA testing can improve antibody detection in CSF samples, aiding the diagnosis of infectious neurological impairments.
Asunto(s)
Anticuerpos Antivirales , Varicela , Ensayo de Inmunoadsorción Enzimática , Inmunoglobulina G , Mediciones Luminiscentes , Virus del Sarampión , Sarampión , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina G/líquido cefalorraquídeo , Sarampión/diagnóstico , Sarampión/inmunología , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/líquido cefalorraquídeo , Mediciones Luminiscentes/métodos , Ensayo de Inmunoadsorción Enzimática/métodos , Niño , Masculino , Femenino , Adulto , Adolescente , Varicela/diagnóstico , Varicela/inmunología , Virus del Sarampión/inmunología , Preescolar , Adulto Joven , Persona de Mediana Edad , Herpesvirus Humano 3/inmunología , Sensibilidad y Especificidad , Lactante , Anciano , Inmunoensayo/métodos , Juego de Reactivos para Diagnóstico/normasRESUMEN
Neuroinflammation is involved in a wide range of brain disorders, thus there is great interest in identifying novel anti-inflammatory agents to include in therapeutic strategies. Our previous in vitro studies revealed that beta-funaltrexamine (ß-FNA), a well-characterized selective mu-opioid receptor (MOR) antagonist, inhibits inflammatory signaling in human astroglial cells, albeit through an apparent MOR-independent mechanism. We also previously determined that lipopolysaccharide (LPS)-induced sickness behavior and neuroinflammation in mice are prevented by pretreatment with ß-FNA. Herein we investigated the temporal importance of ß-FNA treatment in this pre-clinical model of LPS-induced neuroinflammation. Adult, male C57BL/6J mice were administered an i.p. injection of LPS followed by treatment (i.p. injection) with ß-FNA immediately or 4 h post-LPS. Sickness behavior was assessed using an open-field test, followed by assessment of inflammatory signaling in the brain, spleen, and plasma. Levels of inflammatory chemokines/cytokines (interferon γ-induced protein, CXCL10; monocyte chemotactic protein 1, CCL2; and interleukin-6, IL-6) in tissues were measured using an enzyme-linked immunosorbent assay and nuclear factor-kappa B (NFκB), p38 mitogen activated kinase (p38 MAPK), and glial fibrillary acidic protein (GFAP) expression were measured by western blot. LPS-induced sickness behavior and chemokine expression were inhibited more effectively when ß-FNA treatment occurred immediately after LPS administration, as opposed to 4 h post-LPS; and ß-FNA-mediated effects were time-dependent as evidenced by inhibition at 24 h, but not at 8 h. The inhibitory effects of ß-FNA on chemokine expression were more evident in the brain versus the spleen or plasma. LPS-induced NFκB-p65 and p38 MAPK expression in the brain and spleen were inhibited at 8 and 24 h post-LPS. These findings extend our understanding of the anti-inflammatory effects of ß-FNA and warrant further investigation into its therapeutic potential.
Asunto(s)
Lipopolisacáridos , Enfermedades Neuroinflamatorias , Masculino , Humanos , Animales , Ratones , Lipopolisacáridos/farmacología , Ratones Endogámicos C57BL , Antagonistas de Narcóticos/farmacología , FN-kappa B/metabolismo , Quimiocinas/metabolismo , Inflamación , Antiinflamatorios/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Systemic inflammation is present in obesity and emerging evidence, primarily from studies using male rodents fed high-fat diets, suggests neuroimmune signaling also is involved. We investigated early changes in neuroimmune signaling during the weight gain that follows ovariectomy in rats. Ovariectomized (OVX) rats were given standard rat chow and terminated 5 days (baseline), 4 or 8 weeks after ovariectomy. Levels of interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) in plasma and periuterine adipose were not affected by ovariectomy. In contrast, compared to baseline levels, IL-6 expression in the arcuate nucleus (ARC) and dorsal vagal complex (DVC) decreased by 4 weeks after OVX, but was not affected in the paraventricular nucleus (PVN). MCP-1 expression decreased by 4 weeks in the ARC and by 8 weeks in the PVN, but was not affected in the DVC. Increased glial fibrillary acidic protein (GFAP) expression in the PVN indicated astrocyte activation; decreased toll-like receptor 4 (TLR4) expression in the ARC, but not other regions, suggested early effects on innate immune factors. Importantly, in reproductively intact rats, IL-6 and MCP-1 levels in plasma, periuterine adipose, and brain regions were not affected after 8 weeks. Unlike OVX rats, GFAP expression in the DVC of intact rats was decreased at 8 weeks, and TLR4 expression in the ARC was increased at 8 weeks. Taken together, these dynamic and selective changes in neuroimmune factors co-incident with post-ovariectomy weight gain provide insight into the role of neuroimmune signaling in obesity, particularly in females.
Asunto(s)
Encéfalo/inmunología , Obesidad/etiología , Ovariectomía/efectos adversos , Núcleo Hipotalámico Paraventricular/metabolismo , Aumento de Peso/inmunología , Animales , Encéfalo/metabolismo , Estradiol/metabolismo , Femenino , Proteína Ácida Fibrilar de la Glía/metabolismo , Inflamación/inmunología , Obesidad/inmunología , Núcleo Hipotalámico Paraventricular/inmunología , ARN Mensajero/metabolismo , Ratas Sprague-DawleyRESUMEN
PURPOSE: A minimally invasive endoscopic treatment that utilizes radio-frequency energy (RFE) has received increased attention as an appropriate middle-ground approach in the treatment of refractory gastroesophageal reflux disease (GERD) and as an alternative to complicated and invasive surgical procedures. The objective of this study was to develop a longitudinal budget impact analysis from the payer perspective to estimate the direct medical costs of treatment for the refractory GERD patient population and to estimate the budgetary impact of further extending the RFE treatment option to other target populations. DESIGN AND METHODOLOGY: A retrospective analysis of claims designed to assess the longitudinal costs and budget impact on payer expenditures associated with managing and treating GERD surgically (Nissen fundoplication [NF]), endoscopically (RFE), or medically was performed. Both Medicare and commercially insured claims databases were interrogated for such population-level analyses. RESULTS: At current adoption rates (less than 1% of procedures), RFE demonstrated overall cost savings ranging from 7.3% to 50.5% in the 12-month time period following the index procedure (inclusive of procedure costs) when compared to medical management and fundoplication across the commercial and Medicare patient populations. Increasing the total number of RFE procedures to 2% of total cases performed generated per-member, per-month (PMPM) savings of $0.28 in the Medicare population and $0.37 in the commercially insured population. Further increases yielded higher PMPM savings. CONCLUSION: Adding to the clinical importance of RFE in filling the gap between medical and surgical management, this economic analysis demonstrates to payers that the adoption of RFE can create notable savings to their plans when compared to surgery or medical management.
Asunto(s)
Presupuestos , Costos y Análisis de Costo , Reflujo Gastroesofágico/radioterapia , Radioterapia/economía , Humanos , Cobertura del Seguro/economía , Medicare/economía , Estudios Retrospectivos , Estados UnidosRESUMEN
PURPOSE: Reducing hospital readmissions for critically ill patients is of concern to payers and providers alike. Patients in cardiogenic shock are often treated with devices to help support the functions of the heart while the patient undergoes treatment. This study compares the readmission experience of Medicare beneficiaries treated for cardiogenic shock (CS) using percutaneous ventricular assist devices (pVADs) vs. extracorporeal membrane oxygenation (ECMO), two types of advanced cardiac support devices. Hospital readmission is a surrogate for quality and cost. DESIGN AND METHODOLOGY: A retrospective comparison of readmission patterns of patients treated for CS using two advanced cardiac support devices during calendar years 2011 and 2012 was captured via the Medicare Inpatient Standard Analytic File (100% census file). A total of 649 eligible cases (pVAD, 517; ECMO, 132) with 90 days of follow-up documentation were included in this analysis. Baseline characteristics were compared, including demographics, admission type, and severity of illness, with the 2 groups generating clinically similar baseline profiles. Primary outcomes include 30- and 90-day readmissions, associated length of stay (LOS), and costs. RESULTS: At 90 days after initial hospitalization, the readmission rates in the pVAD and ECMO cohorts were 38.7% (200/517) and 53.0% (70/132), respectively. Overall, pVAD was associated with a 27.1% reduction in readmission (P = .004). With the use of pVAD, 90-day readmission costs were lower by $12,294 ($32,736 vs $20,442, a reduction of 37.6%, P=.02) and readmission LOS was shorter by approximately 8 days, (20.5 vs. 12.7 days, a 37.9% reduction, P = .002). Similar trends were observed at 30 days; however, only LOS was significantly reduced, by 7.0 days (P < .001). CONCLUSION: In clinically comparable cohorts, pVADs were associated with reduced risk of rehospitalization, lower cost, and shorter LOS, resulting in cost savings for payers and providers. Increased adoption of pVAD, as a technology to support patients in cardiogenic shock, may help hospitals deliver greater value to both government and commercial payers.
Asunto(s)
Tecnología Biomédica , Hemodinámica , Readmisión del Paciente , Choque Cardiogénico/terapia , Anciano , Bases de Datos Factuales , Humanos , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , Estudios RetrospectivosRESUMEN
BACKGROUND: Inflammation is present in neurological and peripheral disorders. Thus, targeting inflammation has emerged as a viable option for treating these disorders. Previous work indicated pretreatment with beta-funaltrexamine (ß-FNA), a selective mu-opioid receptor (MOR) antagonist, inhibited inflammatory signaling in vitro in human astroglial cells, as well as lipopolysaccharide (LPS)-induced neuroinflammation and sickness-like-behavior in mice. This study explores the protective effects of ß-FNA when treatment occurs 10 h after LPS administration and is the first-ever investigation of the sex-dependent effects of ß-FNA on LPS-induced inflammation in the brain and peripheral tissues, including the intestines. RESULTS: Male and female C57BL/6J mice were administered LPS followed by treatment with ß-FNA-immediately or 10 h post-LPS. Sickness- and anxiety-like behavior were assessed using an open-field test and an elevated-plus-maze test, followed by the collection of whole brain, hippocampus, prefrontal cortex, cerebellum/brain stem, plasma, spleen, liver, large intestine (colon), proximal small intestine, and distal small intestine. Levels of inflammatory chemokines/cytokines (interferon γ-induced-protein, IP-10 (CXCL10); monocyte-chemotactic-protein 1, MCP-1 (CCL2); interleukin-6, IL-6; interleukin-1ß, IL-1ß; and tumor necrosis factor-alpha, TNF-α) in tissues were measured using an enzyme-linked immunosorbent assay. Western blot analysis was used to assess nuclear factor-kappa B (NF-κB) expression. There were sex-dependent differences in LPS-induced inflammation across brain regions and peripheral tissues. Overall, LPS-induced CXCL10, CCL2, TNF-α, and NF-κB were most effectively downregulated by ß-FNA; and ß-FNA effects differed across brain regions, peripheral tissues, timing of the dose, and in some instances, in a sex-dependent manner. ß-FNA reduced LPS-induced anxiety-like behavior most effectively in female mice. CONCLUSION: These findings provide novel insights into the sex-dependent anti-inflammatory effects of ß-FNA and advance this agent as a potential therapeutic option for reducing both neuroinflammation an intestinal inflammation.
RESUMEN
We studied, using a combination of animal and cellular models, the glial mechanisms underlying the anti-neuropathic and anti-inflammatory properties of PAM-2 [(E)-3-furan-2-yl-N-p-tolyl-acrylamide], a positive allosteric modulator of α7 nicotinic acetylcholine receptors (nAChRs). In mice, PAM-2 decreased the inflammatory process induced by the combination of oxaliplatin (OXA), a chemotherapeutic agent, and interleukin-1ß (IL-1ß), a pro-inflammatory molecule. In the brain and spinal cord of treated animals, PAM-2 reduced pro-inflammatory cytokines/chemokines by mechanisms involving mRNA downregulation of factors in the toll-like receptor 4 (TLR4)/nuclear factor (NF)-κB pathway, and increased the precursor of brain-derived neurotrophic factor (proBDNF). To determine the molecular mechanisms underlying the anti-inflammatory activity of PAM-2, both human C20 microglia and normal human astrocytes (NHA) were used. The results showed that PAM-2-induced potentiation of glial α7 nAChRs decreases OXA/IL-1ß-induced overexpression of inflammatory molecules by different mechanisms, including mRNA downregulation of factors in the NF-κB pathway (in microglia and astrocyte) and ERK (only in microglia). The OXA/IL-1ß-mediated reduction in proBDNF was prevented by PAM-2 in microglia, but not in astrocytes. Our findings also indicate that OXA/IL-1ß-induced organic cation transporter 1 (OCT1) expression is decreased by PAM-2, suggesting that decreased OXA influx may be involved in the protective effects of PAM-2. The α7-selective antagonist methyllycaconitine blocked the most important effects mediated by PAM-2 at both animal and cellular levels, supporting a mechanism involving α7 nAChRs. In conclusion, glial α7 nAChR stimulation/potentiation downregulates neuroinflammatory targets, and thereby remains a promising therapeutic option for cancer chemotherapy-induced neuroinflammation and neuropathic pain.
Asunto(s)
Antineoplásicos , Receptor Nicotínico de Acetilcolina alfa 7 , Animales , Humanos , Ratones , Antiinflamatorios , Neuroglía/metabolismo , FN-kappa B/metabolismoRESUMEN
Although increasing research focuses on the phenomenon of body weight gain in women after menopause, the complexity of body weight regulation and the array of models used to investigate it has proven to be challenging. Here, we used ovariectomized (OVX) rats, which rapidly gain weight, to determine if receptors for ghrelin, insulin, or leptin in the dorsal vagal complex (DVC), arcuate nucleus (ARC), or paraventricular nucleus (PVN) change during post-ovariectomy weight gain. Female Sprague-Dawley rats with ad libitum access to standard laboratory chow were bilaterally OVX or sham OVX. Subgroups were weighed and then terminated on day 5, 33, or 54 post-operatively; blood and brains were collected. ELISA kits were used to measure receptors for ghrelin, insulin, and leptin in the DVC, ARC, and PVN, as well as plasma ghrelin, insulin, and leptin. As expected, body weight increased rapidly after ovariectomy. However, ghrelin receptors did not change in any of the areas for either group, nor did circulating ghrelin. Thus, the receptor:hormone ratio indicated comparable ghrelin signaling in these CNS areas for both groups. Insulin receptors in the DVC and PVN decreased in the OVX group over time, increased in the PVN of the Sham group, and were unchanged in the ARC. These changes were accompanied by elevated circulating insulin in the OVX group. Thus, the receptor:hormone ratio indicated reduced insulin signaling in the DVC and PVN of OVX rats. Leptin receptors were unchanged in the DVC and ARC, but increased over time in the PVN of the Sham group. These changes were accompanied by elevated circulating leptin in both groups that was more pronounced in the OVX group. Thus, the receptor:hormone ratio indicated reduced leptin signaling in the DVC and PVN of both groups, but only in the OVX group for the ARC. Together, these data suggest that weight gain that occurs after removal of ovarian hormones by ovariectomy is associated with selective changes in metabolic hormone signaling in the CNS. While these changes may reflect behavioral or physiological alterations, it remains to be determined whether they cause post-ovariectomy weight gain or result from it.
RESUMEN
BACKGROUND: Lifestyle therapy with resistance training is a potent measure to counteract age-related loss in muscle strength and mass. Unfortunately, many individuals fail to respond in the expected manner. This phenomenon is particularly common among older adults and those with chronic diseases (e.g. chronic obstructive pulmonary disease, COPD) and may involve endocrine variables such as vitamin D. At present, the effects of vitamin D supplementation on responses to resistance training remain largely unexplored. METHODS: Ninety-five male and female participants (healthy, n = 71; COPD, n = 24; age 68 ± 5 years) were randomly assigned to receive either vitamin D3 or placebo supplementation for 28 weeks in a double-blinded manner (latitude 61°N, September-May). Seventy-eight participants completed the RCT, which was initiated by 12 weeks of supplementation-only (two weeks with 10 000 IU/day, followed by 2000 IU/day), followed by 13 weeks of combined supplementation (2000 IU/day) and supervised whole-body resistance training (twice weekly), interspersed with testing and measurements. Outcome measures included multiple assessments of muscle strength (nvariables = 7), endurance performance (n = 6), and muscle mass (n = 3, legs, primary), as well as muscle quality (legs), muscle biology (m. vastus lateralis; muscle fibre characteristics, transcriptome), and health-related variables (e.g. visceral fat mass and blood lipid profile). For main outcome domains such as muscle strength and muscle mass, weighted combined factors were calculated from the range of singular assessments. RESULTS: Overall, 13 weeks of resistance training increased muscle strength (13% ± 8%), muscle mass (9% ± 8%), and endurance performance (one-legged, 23% ± 15%; whole-body, 8% ± 7%), assessed as weighted combined factors, and were associated with changes in health variables (e.g. visceral fat, -6% ± 21%; [LDL]serum , -4% ± 14%) and muscle tissue characteristics such as fibre type proportions (e.g. IIX, -3% points), myonuclei per fibre (30% ± 65%), total RNA/rRNA abundances (15%/6-19%), and transcriptome profiles (e.g. 312 differentially expressed genes). Vitamin D3 supplementation did not affect training-associated changes for any of the main outcome domains, despite robust increases in [25(OH)D]serum (∆49% vs. placebo). No conditional effects were observed for COPD vs. healthy or pre-RCT [25(OH)D]serum . In secondary analyses, vitamin D3 affected expression of gene sets involved in vascular functions in muscle tissue and strength gains in participants with high fat mass, which advocates further study. CONCLUSIONS: Vitamin D3 supplementation did not affect muscular responses to resistance training in older adults with or without COPD.
Asunto(s)
Colecalciferol , Entrenamiento de Fuerza , Anciano , Colecalciferol/uso terapéutico , Suplementos Dietéticos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Vitamina D , VitaminasRESUMEN
Microorganisms living inside plants can promote plant growth and health, but their genomic and functional diversity remain largely elusive. Here, metagenomics and network inference show that fungal infection of plant roots enriched for Chitinophagaceae and Flavobacteriaceae in the root endosphere and for chitinase genes and various unknown biosynthetic gene clusters encoding the production of nonribosomal peptide synthetases (NRPSs) and polyketide synthases (PKSs). After strain-level genome reconstruction, a consortium of Chitinophaga and Flavobacterium was designed that consistently suppressed fungal root disease. Site-directed mutagenesis then revealed that a previously unidentified NRPS-PKS gene cluster from Flavobacterium was essential for disease suppression by the endophytic consortium. Our results highlight that endophytic root microbiomes harbor a wealth of as yet unknown functional traits that, in concert, can protect the plant inside out.
Asunto(s)
Beta vulgaris/microbiología , Endófitos/fisiología , Microbiota , Enfermedades de las Plantas/microbiología , Raíces de Plantas/microbiología , Rhizoctonia/patogenicidad , Bacterias/clasificación , Fenómenos Fisiológicos Bacterianos , Bacteroidetes/fisiología , Biodiversidad , Quitinasas/genética , Resistencia a la Enfermedad , Flavobacterium/fisiología , Genes Bacterianos , Genoma Bacteriano , Metagenoma , Mutagénesis Sitio-Dirigida , Péptido Sintasas/genética , Sintasas Poliquetidas/genética , Microbiología del SueloRESUMEN
Pancreatic islet transplantation is a promising treatment for type 1 diabetes mellitus offering improved glycaemic control by restoring insulin production. Improved human pancreatic islet isolation has led to higher islet transplantation success. However, as many as 50% of islets are lost after transplantation due to immune responses and cellular injury, gene therapy presents a novel strategy to protect pancreatic islets for improved survival post-transplantation. To date, most of the vectors used in clinical trials and gene therapy studies have been derived from mammalian viruses such as adeno-associated or retrovirus. However, baculovirus BacMam vectors provide an attractive and safe alternative. Here, a novel BacMam was constructed containing a frameshift mutation within fp25, which results in virus stocks with higher infectious titres. This improved in vitro transduction when compared to control BacMams. Additionally, incorporating a truncated vesicular stomatitis virus G protein increased transduction efficacy and production of EGFP and BCL2 in human kidney (HK-2) and pancreatic islet ß cells (EndoC ßH3). Lastly, we have shown that our optimized BacMam vector can deliver and express egfp in intact pancreatic islet cells from human cadaveric donors. These results confirm that BacMam vectors are a viable choice for providing delivery of transgenes to pancreatic islet cells.
Asunto(s)
Baculoviridae/genética , Diabetes Mellitus Tipo 1/terapia , Terapia Genética/instrumentación , Células Secretoras de Insulina/virología , Transducción Genética , Baculoviridae/fisiología , Técnicas de Transferencia de Gen , Terapia Genética/métodos , Vectores Genéticos/genética , Vectores Genéticos/fisiología , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Humanos , Islotes Pancreáticos/virologíaRESUMEN
Emerging evidence indicates that neuroinflammatory responses in astroglia, including chemokine expression, are altered by opioids. Astroglial chemokines, such as CXCL10, are instrumental in response to many neuropathological insults. Opioid mediated disruption of astroglial CXCL10 expression may be detrimental in opioid abusers or patients receiving acute opioid therapy. We have characterized the in vitro effects of opioids on CXCL10 protein expression in human astroglial (A172) cells. The proinflammatory cytokine, tumor necrosis factor (TNF)alpha induced CXCL10 expression in A172 cells. Using MG-132, helenalin and SN50 [inhibitors of the transcription factor, nuclear factor (NF)-kappaB], we determined that NF-kappaB activation is instrumental in TNFalpha-induced CXCL10 expression in A172 astroglia. Morphine exposure during the 24 h TNFalpha stimulation period did not alter CXCL10 expression. However, fentanyl, a more potent mu-opioid receptor (MOR) agonist, inhibited TNFalpha-induced CXCL10 expression. Interestingly, neither the non-selective opioid receptor antagonist, naltrexone nor beta-funaltrexamine (beta-FNA), a highly selective MOR antagonist, blocked fentanyl mediated inhibition of TNFalpha-induced CXCL10 expression. Rather, beta-FNA dose-dependently inhibited TNFalpha-induced CXCL10 expression with a greater potency than that observed for fentanyl. Immunoblot analysis indicated that morphine, fentanyl and beta-FNA each reduced TNFalpha-induced nuclear translocation of NF-kappaB p65. These data show that beta-FNA and fentanyl inhibit TNFalpha-induced CXCL10 expression via a MOR-independent mechanism. Data also suggest that inhibition of TNFalpha-induced CXCL10 expression by fentanyl and beta-FNA is not directly related to a reduction in NF-kappaB p65 nuclear translocation. Further investigation is necessary in order to fully elucidate the mechanism through which these two opioid compounds inhibit CXCL10 expression. Understanding the mechanism by which chemokine expression is suppressed, particularly by the opioid antagonist, beta-FNA, may provide insights into the development of safe and effective treatments for neuroinflammation.
Asunto(s)
Astrocitos/efectos de los fármacos , Quimiocinas/metabolismo , Naltrexona/análogos & derivados , Antagonistas de Narcóticos/farmacología , Análisis de Varianza , Astrocitos/metabolismo , Astrocitoma , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Quimiocina CXCL10 , Quimiocinas CXC/metabolismo , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Activación Enzimática/efectos de los fármacos , Ensayo de Inmunoadsorción Enzimática/métodos , Fentanilo/farmacología , Humanos , Morfina/farmacología , Naltrexona/farmacología , Narcóticos/farmacologíaRESUMEN
This study was designed to assess the effectiveness of mental imagery supplemented with video-modeling on self-efficacy and front squat strength (three repetition maximum; 3RM). Subjects (13 male, 7 female) who had at least 6 months of front squat experience were assigned to either an experimental (n = 10) or a control (n = 10) group. Subjects' 3RM and self-efficacy for the 3RM were measured at baseline. Following this, subjects in the experimental group followed a structured imagery protocol, incorporating video recordings of both their own 3RM performance and a model lifter with excellent technique, twice a day for three days. Subjects in the control group spent the same amount of time viewing a placebo video. Following three days with no physical training, measurements of front squat 3RM and self-efficacy for the 3RM were repeated. Subjects in the experimental group increased in self-efficacy following the intervention, and showed greater 3RM improvement than those in the control group. Self-efficacy was found to significantly mediate the relationship between imagery and front squat 3RM. These findings point to the importance of mental skills training for the enhancement of self-efficacy and front squat performance.
RESUMEN
Neuroinflammation is an integral component of neurodegenerative disorders, CNS infection and trauma. Astroglial chemokines, such as CXCL10, are instrumental in neuroinflammatory signaling as well as neurotoxicity. We have utilized proinflammatory-induced CXCL10 expression in normal human astrocytes (NHA) as a model in which to assess the anti-inflammatory actions of the selective, mu-opioid receptor (MOR) antagonist, ß-funaltrexamine (ß-FNA). Interferon (IFN)γ+HIV-1 Tat-induced CXCL10 expression (secreted protein and mRNA) was inhibited by co-treatment with ß-FNA. Neither the MOR-selective antagonist, D-Phe-Cys-Tyr-D-Trp-Arg-Pen-Thr-NH2 (CTAP) nor the nonselective opioid receptor antagonist, naltrexone inhibited IFNγ+HIV-1 Tat-induced CXCL10 expression. Furthermore, co-treatment with excess CTAP or naltrexone did not prevent ß-FNA mediated inhibition of IFNγ+HIV-1 Tat-induced CXCL10 expression. Additionally, we utilized an inhibitor of NF-κB activation (SN50) to demonstrate that IFNγ+HIV-1 Tat-induced CXCL10 expression is NF-κB-dependent in NHA. Subsequent experiments revealed that ß-FNA did not significantly affect NF-κB activation. Interestingly, we discovered that ß-FNA inhibited p38 activation as indicated by decreased expression of phospho-p38. Together, these findings suggest that the inhibitory actions of ß-FNA are MOR-independent and mediated, in part, via a transcriptional mechanism. These findings add to our understanding of the mechanism by which chemokine expression is inhibited by ß-FNA. In conjunction with future investigations, these novel findings are expected to provide insights into the development of safe and effective treatments for neuroinflammation.
Asunto(s)
Astrocitos/efectos de los fármacos , Quimiocina CXCL10/metabolismo , Naltrexona/análogos & derivados , Astrocitos/metabolismo , Secuencia de Bases , Células Cultivadas , Cartilla de ADN , Activación Enzimática , Productos del Gen tat/metabolismo , Humanos , Interferón gamma/metabolismo , FN-kappa B/metabolismo , Naltrexona/farmacología , Reacción en Cadena en Tiempo Real de la Polimerasa , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Neuroinflammation and neuronal degeneration observed in Parkinson's disease (PD) has been attributed in part to glial-mediated events. Increased expression of proinflammatory cytokines and abnormal accumulation of the neuronal protein, α-synuclein in the brain are also characteristic of PD. While increasing evidence suggests that astrocytes contribute to neuroinflammation and dopaminergic neuronal degeneration associated with PD, there remains much to learn about these astroglial-mediated events. Therefore, we investigated the in vitro effects of interleukin-1ß (IL-1ß) and α-synuclein on astroglial expression of interferon-γ inducible protein-10 (CXCL10), a proinflammatory and neurotoxic chemokine. IL-1ß-induced CXCL10 protein expression was potentiated by co-exposure to α-synuclein. α-Synuclein did not significantly affect IL-1ß-induced CXCL10 mRNA expression, but did mediate increased CXCL10 mRNA stability, which may explain, in part, the increased levels of secreted CXCL10 protein. Future investigations are warranted to more fully define the mechanism by which α-synuclein enhances IL-1ß-induced astroglial CXCL10 expression. These findings highlight the importance of α-synuclein in modulating inflammatory events in astroglia. These events may be particularly relevant to the pathology of CNS disorders involving α-synuclein accumulation, including PD and HIV-1 associated dementia.
Asunto(s)
Astrocitos/metabolismo , Quimiocina CXCL10/biosíntesis , Interleucina-1beta/metabolismo , alfa-Sinucleína/metabolismo , Línea Celular Tumoral , Ensayo de Inmunoadsorción Enzimática , Humanos , FN-kappa B/metabolismo , Enfermedad de Parkinson/metabolismo , ARN Mensajero/análisis , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
BACKGROUND: Adherence to medical treatment among women with ulcerative colitis (UC) prior to and during pregnancy has never been investigated. The aim was to examine predictors for and prevalence rates of nonadherence to maintenance treatment among women with UC prior to and during pregnancy. METHODS: We identified 115 women with UC having given birth during 2000-2005 within a population of 1.6 million. They received a questionnaire about predictors and adherence and relapses were registered. We retrieved information on medical treatment from prescription databases and used logistic regression to estimate prevalence odds ratios (POR) for nonadherence by different predictors. RESULTS: Among 93 (81%) respondents, 63 (68%) reported taking medication, 53 of whom had filled prescriptions for relevant medication, yielding a positive predictive value of self-reported use of medical treatment of 84.1% (95% confidence interval [CI] 72.7-92.1). Approximately 60% reported adhering to medical treatment. Those who received counseling regarding medical treatment were less likely to be nonadherent compared with no counseling, especially during pregnancy (POR 0.2, 95% CI 0.04-0.94). Of those who were nonadherent, fear of a negative effect on fertility/fetus was stated as the reason by 23% prior to and by 50% during pregnancy. Notably, 40.3% reported an episode of relapse during the pregnancy period, compared with 13.6% in the period 6 months prior to pregnancy. CONCLUSIONS: Adherence was high despite fear of a negative effect on fertility or the fetus. Counseling predicted higher adherence. This may be important because our study suggests an increase in UC activity during pregnancy.
Asunto(s)
Colitis Ulcerosa/tratamiento farmacológico , Cumplimiento de la Medicación , Complicaciones del Embarazo/prevención & control , Prevención Secundaria , Autoinforme , Adulto , Colitis Ulcerosa/epidemiología , Dinamarca/epidemiología , Femenino , Humanos , Persona de Mediana Edad , Embarazo , Complicaciones del Embarazo/epidemiología , Prevalencia , Pronóstico , Encuestas y Cuestionarios , Adulto JovenRESUMEN
Mercury is neurotoxic and increasing evidence suggests that environmental exposure to mercury may contribute to neuropathologies including Alzheimer's disease and autism spectrum disorders. Mercury is known to disrupt immunocompetence in the periphery, however, little is known about the effects of mercury on neuroimmune signaling. Mercury-induced effects on central immune function are potentially very important given that mercury exposure and neuroinflammation both are implicated in certain neuropathologies (i.e., autism). Furthermore, mounting evidence points to the involvement of glial activation in autism. Therefore, we utilized an in vivo model to assess the effects of mercury exposure on neuroimmune signaling. In prairie voles, 10 week mercury exposure (60ppm HgCl(2) in drinking water) resulted in a male-specific increase in TNFα protein expression in the cerebellum and hippocampus. These findings are consistent with our previously reported male-specific mercury-induced deficits in social behavior and further support a role for heavy metals exposure in neuropathologies such as autism. Subsequent studies should further evaluate the mechanism of action and biological consequences of heavy metals exposure. Additionally, these observations highlight the potential of neuroimmune markers in male voles as biomarkers of environmental mercury toxicity.
Asunto(s)
Trastorno Autístico/inducido químicamente , Cerebelo/metabolismo , Hipocampo/metabolismo , Intoxicación del Sistema Nervioso por Mercurio/metabolismo , Factor de Necrosis Tumoral alfa/biosíntesis , Animales , Arvicolinae , Quimiocina CCL2/biosíntesis , Quimiocina CXCL10/biosíntesis , Femenino , Masculino , Modelos Animales , Caracteres SexualesRESUMEN
INTRODUCTION: We examined the positive predictive value of diagnoses of acute exacerbation of chronic obstructive pulmonary disease (COPD) in the Danish National Patient Registry. We also examined the negative predictive value of acute pneumonia or respiratory failure discharge diagnoses for absence of underlying COPD. METHODS: We identified all patients aged 30 years or older with acute hospital admission in Denmark from January 1st to December 31st 2008. Physicians at 34 Danish hospitals retrieved and reviewed medical records for 1581 patients with a discharge diagnosis of COPD, and for 1546 patients with a discharge diagnosis of either pneumonia or respiratory failure but no COPD diagnosis. Presence of COPD was assessed based on medical history, clinical symptoms and findings, and spirometry results. RESULTS: The overall positive predictive value for COPD was 92% (95% confidence interval [CI] = 91-93%). Among patients coded with pneumonia or respiratory failure but not COPD, 19% (95% CI = 17-21%) had COPD, corresponding to a negative predictive value for COPD of 81% (95% CI = 79-83%). CONCLUSIONS: The positive predictive value of acute COPD discharge diagnoses in the Danish National Patient Registry is high. At the same time, there is a substantial underrecording of COPD during hospitalizations with other acute respiratory disorders like pneumonia and respiratory failure.
Asunto(s)
Hospitalización/estadística & datos numéricos , Alta del Paciente/estadística & datos numéricos , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Adulto , Anciano , Dinamarca/epidemiología , Femenino , Humanos , Masculino , Registros Médicos , Persona de Mediana Edad , Neumonía/diagnóstico , Neumonía/epidemiología , Estudios Prospectivos , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Sistema de Registros , Reproducibilidad de los Resultados , Insuficiencia Respiratoria/diagnóstico , Insuficiencia Respiratoria/epidemiología , EspirometríaRESUMEN
Increasing evidence indicates neuroinflammation is instrumental in the pathogenesis of Parkinson's disease (PD). In PD, there is selective degeneration of neuromelanin (NM)-containing dopamine neurons. Neuromelanin is predominantly cytoprotective within dopaminergic neurons, whereas, NM released from damaged neurons activates microglia. However, the effects of NM on astroglial cells remain largely unknown. Astroglia are essential to neuronal homeostasis and responsive to injury, in part, through secretion of chemokines, including interferon γ inducible protein-10 (CXCL10). Thus, we used an in vitro approach to identify the effects of NM on TNFα-induced CXCL10 expression in human astroglial cells. TNFα-induced CXCL10 expression was inhibited in NM exposed cells. Additionally, TNFα-induced NF-кB activation was inhibited by NM. Given that CXCL10 expression is NF-кB-dependent in human astroglial cells, these findings suggest that NM may inhibit CXCL10 expression, in part, through an NF-кB-dependent mechanism. While the in vivo consequences of NM mediated effects on astroglial CXCL10 expression remain to be fully elucidated, insights obtained in this study further our understanding of the effects of NM on inflammatory signaling in human astroglial cells.
Asunto(s)
Antiinflamatorios/farmacología , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Quimiocina CXCL10/biosíntesis , Melaninas/farmacología , Línea Celular , Humanos , FN-kappa B/biosíntesis , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
The inducible isoform of nitric-oxide synthase (iNOS) is involved in neuropathogenesis associated with infection and disease in the brain. Hence, there is considerable interest in the identification of therapeutic interventions to prevent iNOS-mediated pathology. Astroglia are a major site of iNOS expression during neuropathogenesis. To mimic a key component of neuroinflammation, human A172 astroglial cells were exposed in vitro to a cytokine mixture containing interferon gamma, tumor necrosis factor alpha, and interleukin-1beta, resulting in significant iNOS expression. Next, we assessed the effects of the mu opioid receptor antagonist, beta-funaltrexamine (beta-FNA), on cytokine induced iNOS expression in human astroglia. beta-FNA dose-dependently inhibited iNOS expression. beta-FNA transcriptionally (or pre-transcriptionally) inhibited cytokine-induced iNOS activation as indicated by a significant decrease in NOS2 messenger RNA expression. Further characterization of the novel, anti-inflammatory actions of beta-FNA may provide insights for pharmacologic strategies to treat or prevent brain pathologies associated with neuroinflammation.