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Today, there is a real political urge to see the sharing of ballistic data intensify across Europe mostly due to recent events such as terrorist attacks. However, technical constraints remain and two main options are being discussed. The first one relies on a centralized common database, implying a vendor monopoly for all Europe and a unified protocol among member states. The second one advocates for a distributed framework relying on existing national infrastructures and leaving each country responsible for its own protocols. This article describes a prototype network linking Switzerland and France using the Evofinder® system by ScannBI. We will first focus on how this network was set up, and then report some results from tests conducted to assess the viability of the concept. These results demonstrate that the second option cannot be discarded and pave the way for a distributed network. This solution appears to be cheaper, more adaptable and answers the practical needs of member states.
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The aim of this study was to compare three gunshot residue (GSR) collection methods used in conjunction with chemographic detection applied by different regional Swiss police services. The specimens were collected from the hands of a shooter with either filter paper (Filter method) or adhesive foil. The adhesive foil was then either applied against photographic paper during visualisation (AF Photo method) or coated with a layer of polyvinyl alcohol (AF PVAL method). The experiments involved two conditions of the examined hands, i.e. dry and humidified. The residues were revealed using the sodium rhodizonate test (SRT). Preliminary tests assessing the possibility of conducting a confirmatory Scanning Electron Microscopy coupled to Energy Dispersive X-ray spectroscopy (SEM/EDX) analysis after the chemographic test were performed on a number of specimens by cutting positive spots and mounting them on stubs. Obtained results were compared in terms of effectiveness - number of positive spots, time requirements, quality of subsequent SEM-EDX analysis, ease of use and cost. The Filter method generally yielded a high-quality detection with both dry and humidified hands, as well as a simple, quick and efficient confirmation by SEM/EDX. The AF Photo performed well on dry hands, but not on humidified hands. The AF PVAL method performance was lower compared to the other methods in both examined conditions of the hands. The SEM/EDX analysis showed that the Filter and AF PVAL method provided satisfactory results when a sufficient carbon coating thickness was applied to the cuttings. It was also observed that the thinner the PVAL layer, the better the quality of the spectra and obtained images in SEM/EDX. Furthermore, the surface of the photographic paper did not seem to be conductive, even after the application of a thick layer of carbon. In conclusion, the Filter method gave the best overall results, but its application required slightly more time and expertise than the two other methods.
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Balística Forense/métodos , Medicina Legal/métodos , Mano , Manejo de Especímenes/métodos , Heridas por Arma de Fuego , Ciclohexanonas/análisis , Humanos , Aplicación de la Ley , Microscopía Electrónica de Rastreo , Piel/química , Espectrometría por Rayos X , SuizaRESUMEN
The Glock company's newest generation of pistols (G42/43, Gen5) is equipped with so-called "Glock Marksman Barrels" (GMB). These barrels feature an enhanced polygonal profile with right-hand twist and a small rifled profile on either side of the main polygonal field impression (Hernandez et al., 2016). Up until now, using the usual methods of comparison (automatic ballistic identification systems, ABIS and comparison microscope) it was difficult to assign bullets fired from a polygonal barrel to their origin with a high evidentiary value (Murdock et al., 1990) [5] (Northcutt, 2010). In this study, test shots from 18 Glock Gen5 pistols (9 Glock 17 pistols and 9 Glock 19 pistols) were compared to examine their differentiability. In addition, a Gen5 Glock 17 pistol was used to shoot 500 cartridges to determine to what degree the first projectile could be matched with the 500th (Zhang and Luo, 2018) [10]. This study was able to demonstrate that the new "Glock Marksman Barrel" (GMB) leaves marks of sufficient quality on projectiles to make high evidentiary value assignments of those projectiles to an individual firearm, both by using the comparison microscope as well as with an ABIS (Evofinder®). Further, it was possible to assign the cartridge casings to an individual pristine firearm.
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Unburned propellant powder particles in gunshot residue (GSR) were detected at near infrared by optical excitation in the visible wavelength range. A series of ammunition (different brands and different manufacturers) was analyzed concerning the luminescence of their propellant. Shooting target samples with different shooting distances were produced on standard textile tissue and analyzed with this optical infrared inspection. The number of luminescent GSR particles per area was measured and curves with particle density vs. shooting distance were drawn. The method was applied on three ammunition types with different particle morphology shot with a pistol and one ammunition type shot with a revolver. The shooting series performed with the revolver showed a large particle density variation within the samples of identical shooting distances. In this case, the ratio of the amount of particles within the area around the bullet hole and within a ring with a defined distance from the bullet hole was calculated. These data resulted in measures with much lower standard deviations, which is a prove that the distribution pattern depends on the shooting distance and not on the amount of GSR particles. It has been shown, that imaging of target tissue with the aid of infrared luminescence is an easy, fast, reproducible and non-destructive method for shooting-distance determination.
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Calcium and iron overload participate in the mechanisms of ischemia/reperfusion (I/R) injury during myocardial infarction (MI). Calcium overload induces cardiomyocyte death by hypercontraction, while iron catalyses generation of reactive oxygen species (ROS). We therefore hypothesized that dexrazoxane, an intracellular metal chelator, would attenuate I/R injury. MI was induced in pigs by occlusion of the left anterior descending artery for 1 hour followed by 2 hours reperfusion. Thirty minutes before reperfusion either 5 mg/ml dexrazoxane (n = 5) or saline (n = 5) was infused intravenously. Myocardial necrosis as percentage of the area at ischemic risk was found to be similar in both groups (77.2 ± 18% for dexrazoxane and 76.4 ± 14% for saline group) as determined by triphenyl tetrazolium chloride staining of the ischemic myocardium. Also, serum levels of troponin-I were similar in both groups. A conductance catheter was used to measure left ventricular pressure and volume at all times. Markers for tissue damage due to ROS (HNE), endothelial cell activation (CD31) and inflammation (IgG, C3b/c, C5b9, MCP-1) were assessed on tissue and/or in serum. No significant differences were observed between the groups for the parameters analyzed. To conclude, in this clinically relevant model of early reperfusion after acute myocardial ischemia, dexrazoxane lacked attenuating effects on I/R injury as shown by the measured parameters.
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Dexrazoxano/uso terapéutico , Infarto del Miocardio/etiología , Daño por Reperfusión Miocárdica/prevención & control , Enfermedad Aguda , Administración Intravenosa , Animales , Quimiocina CCL2/metabolismo , Complemento C3c/metabolismo , Complejo de Ataque a Membrana del Sistema Complemento/metabolismo , Dexrazoxano/farmacología , Modelos Animales de Enfermedad , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/patología , Daño por Reperfusión Miocárdica/complicaciones , Miocardio/patología , Necrosis , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Factores de Riesgo , Porcinos , Troponina I/sangre , Función Ventricular Izquierda/efectos de los fármacosRESUMEN
Serotype 19A strains have emerged as a cause of invasive pneumococcal disease after the introduction of the 7-valent pneumococcal conjugate vaccine (PCV7), and serotype 19A has now been included in the recent 13-valent vaccine (PCV13). Genetic analysis has revealed at least three different capsular serotype 19A subtypes, and nutritional environment-dependent variation of the 19A capsule structure has been reported. Pneumococcal vaccine effectiveness and serotyping accuracy might be impaired by structural differences in serotype 19A capsules. We therefore analyzed the distribution of 19A subtypes collected within a Swiss national surveillance program and determined capsule composition under different nutritional conditions with high-performance liquid chromatography (HPLC), gas chromatography-mass spectrometry (GC-MS), and nuclear magnetic resonance (NMR) spectroscopy. After the introduction of PCV7, a significant relative increase of subtype 19A-II and decrease of 19A-I occurred. Chemical analyses showed no difference in the composition as well as the linkage of 19A subtype capsular saccharides grown in defined and undefined growth media, which is consistent with a trisaccharide repeat unit composed of rhamnose, N-acetyl-mannosamine, and glucose. In summary, our study suggests that no structural variance dependent of the nutritional environment or the subtype exists. The serotype 19A subtype shift observed after the introduction of the PCV7 can therefore not be explained by selection of a capsule structure variant. However, capsule composition analysis of emerging 19A clones is recommended in cases where there is no other explanation for a selective advantage, such as antibiotic resistance or loss or acquisition of other virulence factors.
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Cápsulas Bacterianas/química , Infecciones Neumocócicas/microbiología , Polisacáridos/química , Streptococcus pneumoniae/fisiología , Cromatografía Liquida , Cromatografía de Gases y Espectrometría de Masas , Humanos , Espectroscopía de Resonancia Magnética , Vigilancia de la Población , Análisis de Regresión , Serogrupo , Serotipificación , Streptococcus pneumoniae/clasificaciónRESUMEN
BACKGROUND: Bacterial meningitis (BM) is characterized by an intense host inflammatory reaction, which contributes to the development of brain damage and neuronal sequelae. Activation of the kynurenine (KYN) pathway (KP) has been reported in various neurological diseases as a consequence of inflammation. Previously, the KP was shown to be activated in animal models of BM, and the association of the SNP AADAT + 401C/T (kynurenine aminotransferase II - KAT II) with the host immune response to BM has been described. The aim of this study was to investigate the involvement of the KP during BM in humans by assessing the concentrations of KYN metabolites in the cerebrospinal fluid (CSF) of BM patients and their relationship with the inflammatory response compared to aseptic meningitis (AM) and non-meningitis (NM) groups. METHODS: The concentrations of tryptophan (TRP), KYN, kynurenic acid (KYNA) and anthranilic acid (AA) were assessed by HPLC from CSF samples of patients hospitalized in the Giselda Trigueiro Hospital in Natal (Rio Grande do Norte, Brazil). The KYN/TRP ratio was used as an index of indoleamine 2,3-dioxygenase (IDO) activity, and cytokines were measured using a multiplex cytokine assay. The KYNA level was also analyzed in relation to AADAT + 401C/T genotypes. RESULTS: In CSF from patients with BM, elevated levels of KYN, KYNA, AA, IDO activity and cytokines were observed. The cytokines INF-γ and IL-1Ra showed a positive correlation with IDO activity, and TNF-α and IL-10 were positively correlated with KYN and KYNA, respectively. Furthermore, the highest levels of KYNA were associated with the AADAT + 401 C/T variant allele. CONCLUSION: This study suggests a downward modulatory effect of the KP on CSF inflammation during BM.
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Citocinas/líquido cefalorraquídeo , Inflamación/líquido cefalorraquídeo , Quinurenina/líquido cefalorraquídeo , Meningitis Bacterianas/líquido cefalorraquídeo , Adolescente , Adulto , Cromatografía Líquida de Alta Presión , Femenino , Humanos , Masculino , Adulto JovenRESUMEN
Clostridium perfringens ß-toxin (CPB) is a ß-barrel pore-forming toxin and an essential virulence factor of C. perfringens type C strains, which cause fatal hemorrhagic enteritis in animals and humans. We have previously shown that CPB is bound to endothelial cells within the intestine of affected pigs and humans, and that CPB is highly toxic to primary porcine endothelial cells (pEC) in vitro. The objective of the present study was to investigate the type of cell death induced by CPB in these cells, and to study potential host cell mechanisms involved in this process. CPB rapidly induced lactate dehydrogenase (LDH) release, propidium iodide uptake, ATP depletion, potassium efflux, a marked rise in intracellular calcium [Ca(2+)]i, release of high-mobility group protein B1 (HMGB1), and caused ultrastructural changes characteristic of necrotic cell death. Despite a certain level of caspase-3 activation, no appreciable DNA fragmentation was detected. CPB-induced LDH release and propidium iodide uptake were inhibited by necrostatin-1 and the two dissimilar calpain inhibitors PD150606 and calpeptin. Likewise, inhibition of potassium efflux, chelation of intracellular calcium and treatment of pEC with cyclosporin A also significantly inhibited CPB-induced LDH release. Our results demonstrate that rCPB primarily induces necrotic cell death in pEC, and that necrotic cell death is not merely a passive event caused by toxin-induced membrane disruption, but is propagated by host cell-dependent biochemical pathways activated by the rise in intracellular calcium and inhibitable by necrostatin-1, consistent with the emerging concept of programmed necrosis ("necroptosis").
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Toxinas Bacterianas/farmacología , Calpaína/metabolismo , Células Endoteliales/efectos de los fármacos , Imidazoles/farmacología , Indoles/farmacología , Acrilatos/farmacología , Animales , Western Blotting , Calcio/metabolismo , Calpaína/antagonistas & inhibidores , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Membrana Celular/ultraestructura , Células Cultivadas , Inhibidores de Cisteína Proteinasa/farmacología , Fragmentación del ADN/efectos de los fármacos , Dipéptidos/farmacología , Células Endoteliales/metabolismo , Células Endoteliales/patología , Citometría de Flujo , Proteína HMGB1/metabolismo , Espacio Intracelular/efectos de los fármacos , Espacio Intracelular/metabolismo , Transporte Iónico/efectos de los fármacos , L-Lactato Deshidrogenasa , Microscopía Electrónica de Transmisión , Necrosis , Potasio/metabolismo , PorcinosRESUMEN
While having the highest vitamin C (VitC) concentrations in the body, specific functions of VitC in the brain have only recently been acknowledged. We have shown that postnatal VitC deficiency in guinea pigs causes impairment of hippocampal memory function and leads to 30% less neurons. This study investigates how prenatal VitC deficiency affects postnatal hippocampal development and if any such effect can be reversed by postnatal VitC repletion. Eighty pregnant Dunkin Hartley guinea pig dams were randomized into weight stratified groups receiving High (900 mg) or Low (100 mg) VitC per kg diet. Newborn pups (n = 157) were randomized into a total of four postnatal feeding regimens: High/High (Control); High/Low (Depleted), Low/Low (Deficient); and Low/High (Repleted). Proliferation and migration of newborn cells in the dentate gyrus was assessed by BrdU labeling and hippocampal volumes were determined by stereology. Prenatal VitC deficiency resulted in a significant reduction in postnatal hippocampal volume (P<0.001) which was not reversed by postnatal repletion. There was no difference in postnatal cellular proliferation and survival rates in the hippocampus between dietary groups, however, migration of newborn cells into the granular layer of the hippocampus dentate gyrus was significantly reduced in prenatally deficient animals (P<0.01). We conclude that a prenatal VitC deficiency in guinea pigs leads to persistent impairment of postnatal hippocampal development which is not alleviated by postnatal repletion. Our findings place attention on a yet unrecognized consequence of marginal VitC deficiency during pregnancy.
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Deficiencia de Ácido Ascórbico , Hipocampo/metabolismo , Exposición Materna , Neurogénesis/fisiología , Efectos Tardíos de la Exposición Prenatal , Animales , Animales Recién Nacidos , Peso Corporal , Encéfalo/metabolismo , Encéfalo/patología , Movimiento Celular , Proliferación Celular , Supervivencia Celular , Giro Dentado/metabolismo , Giro Dentado/patología , Femenino , Cobayas , Hipocampo/patología , Aprendizaje por Laberinto , Tamaño de los Órganos , EmbarazoRESUMEN
BACKGROUND: Preconditioning of neonatal mice with nonlethal hypoxia (HPC) protects the brain from hypoxic-ischemic (HI) injury. Overexpression of human glutathione peroxidase 1 (GPx1), which normally protects the developing murine brain from HI injury, reverses HPC protection, suggesting that a certain threshold of hydrogen peroxide concentration is required for activation of HPC signaling. METHODS: Activation (phosphorylation) of extracellular-regulated kinase (ERK) 1/2 and Akt, and induction of hypoxia-inducible factor (HIF)-1α were assessed in the cortex, one of the main structures affected by HI and protected by HPC, at different time points after reoxygenation in wild-type (WT) and GPx1-overexpressing animals. RESULTS: GPx1 overexpression prevented both the global and nuclear increase in activated ERK at 0.5 h after HPC and caused a significant decrease in phospho-ERK (pERK)/ERK levels at 24 h after HPC. In contrast, HIF-1α induction at the end of hypoxia was unaffected by GPx1 overexpression. In the cortex of preconditioned WT animals, enhanced pERK staining was primarily observed in neurons and to a lower extent in astrocytes and endothelial cells, with a nuclear prominence. CONCLUSION: Aberrant activation of ERK probably explains the paradoxical reversal of HPC protection by GPx1 overexpression. The results identify hydrogen peroxide as an important mediator of neuroprotective ERK signaling.
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Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Glutatión Peroxidasa/metabolismo , Animales , Animales Recién Nacidos , Activación Enzimática , Ratones , FosforilaciónRESUMEN
QUESTIONS UNDER STUDY: To gain insight into the determinants of radiologists' professional satisfaction in Switzerland. METHODS: Data from 254 members of the Swiss Society of Radiology (76% men) obtained in a questionnaire survey were analysed by logistic regression analysis using socio-demographic, person- and workplace-related factors as independent variables (determinants) and satisfaction at work as the outcome variable. RESULTS: In terms of person-related factors within a complex logistical regression model, radiologists with low occupational self-efficacy and especially those with low mental wellbeing were at elevated risk for low professional satisfaction, with the latter determinant being the strongest predictor in the whole model. Regarding work-related determinants, low career satisfaction and high workload increased the risk of low job satisfaction while working in a university hospital was a protection factor against low job satisfaction with private practice being the reference. A total of 42% of the respondents enjoyed their job more, and 19% enjoyed it less compared to five years previously, while 39% experienced no change. CONCLUSION: Despite high workload, time and economic pressure, the majority of radiologists were professionally satisfied at a high level, which had even increased within the last five years. However, to keep this level of job satisfaction, career possibilities, especially in private practices, have to be improved. Furthermore, the radiologists' important contribution to the diagnostic and therapeutic process has to be recognised professionally as well as economically.
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Satisfacción en el Trabajo , Servicio de Radiología en Hospital , Adulto , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Encuestas y Cuestionarios , Suiza , Recursos HumanosRESUMEN
CONTEXT: The decreased incidence of cardiovascular disease in premenopausal women has been attributed, at least partially, to protective effects of estrogens. However, premenopausal women with diabetes mellitus are no longer selectively protected. High-glucose (HG) conditions have previously been shown to abolish the antimitogenic effects of 17ß-estradiol (E(2)) in vascular smooth muscle cells (VSMCs). OBJECTIVE: Because E(2) mediates its action via different estrogen receptor (ER) subtypes, we hypothesized that different subtypes may have different, if not opposing, effects on HG-induced VSMC proliferation. METHODS AND RESULTS: Treatment of human aortic VSMCs isolated from premenopausal women with the selective ERα agonist, 4,4',4'-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol, but not with E(2), the selective ERß agonist 2,3-bis(4-hydroxyphenyl)-propionitrile, or the selective G protein-coupled ER agonist G-1 completely prevented increased HG-induced VSMC proliferation. Under these conditions, ERα activation selectively prevented increased hydrogen peroxide (H(2)O(2)) and total intracellular reactive oxygen species (ROS) production, caused up-regulation of manganese superoxide dismutase protein and activity, and inhibited prolonged ERK phosphorylation. The latter was mediated by ROS, and ROS inhibition reversed HG-induced ERK-dependent VSMC proliferation. The selective coactivation of ERß reversed the antimitogenic and antioxidative effects of ERα as well as the up-regulation of manganese superoxide dismutase protein expression. CONCLUSION: Selective activation of ERα is required for reducing oxidative stress and the consequent hyperproliferation of VSMCs under HG. Our results may further suggest that ERα activation inhibits HG-induced proliferation by down-regulating ROS-mediated ERK activation and may explain why antimitogenic effects of E(2) are abolished under HG. Pharmacological activation of ERα may thus have therapeutic potential for treating cardiovascular dysregulation associated with diabetes.
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Aorta/metabolismo , Proliferación Celular/efectos de los fármacos , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Glucosa/metabolismo , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Análisis de Varianza , Aorta/citología , Aorta/efectos de los fármacos , Western Blotting , Células Cultivadas , Femenino , Humanos , Músculo Liso Vascular/citología , Músculo Liso Vascular/efectos de los fármacos , Miocitos del Músculo Liso/citología , Miocitos del Músculo Liso/efectos de los fármacos , Nitrilos/farmacología , Fenoles/farmacología , Fosforilación/efectos de los fármacos , Pirazoles/farmacología , Estadísticas no Paramétricas , Superóxido Dismutasa/metabolismoRESUMEN
Pneumococcal meningitis causes apoptosis of developing neurons in the dentate gyrus of the hippocampus. The death of these cells is accompanied with long-term learning and memory deficits in meningitis survivors. Here, we studied the role of the PI3K/Akt (protein kinase B) survival pathway in hippocampal apoptosis in a well-characterized infant rat model of pneumococcal meningitis. Meningitis was accompanied by a significant decrease of the PI3K product phosphatidylinositol 3,4,5-trisphosphate (PIP(3)) and of phosphorylated (i.e., activated) Akt in the hippocampus. At the cellular level, phosphorylated Akt was decreased in both the granular layer and the subgranular zone of the dentate gyrus, the region where the developing neurons undergo apoptosis. Protein levels and activity of PTEN, the major antagonist of PI3K, were unaltered by infection, suggesting that the observed decrease in PIP(3) and Akt phosphorylation is a result of decreased PI3K signaling. Treatment with the PTEN inhibitor bpV(pic) restored Akt activity and significantly attenuated hippocampal apoptosis. Co-treatment with the specific PI3K inhibitor LY294002 reversed the restoration of Akt activity and attenuation of hippocampal apoptosis, while it had no significant effect on these parameters on its own. These results indicate that the inhibitory effect of bpV(pic) on apoptosis was mediated by PI3K-dependent activation of Akt, strongly suggesting that bpV(pic) acted on PTEN. Treatment with bpV(pic) also partially inhibited the concentration of bacteria and cytokines in the CSF, but this effect was not reversed by LY294002, indicating that the effect of bpV(pic) on apoptosis was independent of its effect on CSF bacterial burden and cytokine levels. These results indicate that the PI3K/Akt pathway plays an important role in the death and survival of developing hippocampal neurons during the acute phase of pneumococcal meningitis.
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Apoptosis/efectos de los fármacos , Hipocampo/efectos de los fármacos , Meningitis Neumocócica/tratamiento farmacológico , Degeneración Nerviosa/tratamiento farmacológico , Compuestos Organometálicos/farmacología , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Animales , Animales Recién Nacidos , Apoptosis/fisiología , Modelos Animales de Enfermedad , Hipocampo/enzimología , Hipocampo/patología , Meningitis Neumocócica/enzimología , Meningitis Neumocócica/patología , Degeneración Nerviosa/enzimología , Degeneración Nerviosa/microbiología , Compuestos Organometálicos/uso terapéutico , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas WistarRESUMEN
Pneumococcal meningitis causes neurological sequelae, including learning and memory deficits in up to half of the survivors. In both humans and in animal models of the disease, there is apoptotic cell death in the hippocampus, a brain region involved in learning and memory function. We previously demonstrated that in an infant rat model of pneumococcal meningitis, there is activation of the kynurenine (KYN) pathway in the hippocampus, and that there was a positive correlation between the concentration of 3-hydroxykynurenine and the extent of hippocampal apoptosis. To clarify the role of the KYN pathway in the pathogenesis of hippocampal apoptosis in pneumococcal meningitis, we specifically inhibited 2 key enzymes of the KYN pathway and assessed hippocampal apoptosis, KYN pathway metabolites, and nicotinamide adenine dinucleotide (NAD) concentrations by high-performance liquid chromatography. Pharmacological inhibition of kynurenine 3-hydroxylase and kynureninase led to decreased cellular NAD levels and increased apoptosis in the hippocampus. The cerebrospinal fluid levels of tumor necrosis factor and interleukin-1α and -ß were not affected. Our data suggest that activation of the KYN pathway in pneumococcal meningitis is neuroprotective by compensating for an increased NAD demand caused by infection and inflammation;this mechanism may prevent energy failure and apoptosis in the hippocampus.
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Apoptosis/fisiología , Metabolismo Energético/fisiología , Quinurenina/metabolismo , Meningitis Neumocócica/patología , NAD/metabolismo , Transducción de Señal/fisiología , Animales , Animales Recién Nacidos , Apoptosis/efectos de los fármacos , Cromatografía Líquida de Alta Presión/métodos , Citocinas/líquido cefalorraquídeo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Metabolismo Energético/efectos de los fármacos , Hipocampo/metabolismo , Meningitis Neumocócica/metabolismo , Meningitis Neumocócica/fisiopatología , Proteína Básica de Mielina/farmacología , Ratas , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Sulfonamidas/farmacología , Tiazoles/farmacologíaRESUMEN
The aim of this exploratory study was to examine the possible mechanisms of behavioral change in a cognitive-behavioral intervention supporting medication adherence in HIV-infected persons. A total of 60 persons currently under medical treatment were randomized to psychotherapy or usual care and were compared with a sociodemographically matched group of general psychotherapy clients. Outcome measures included therapy adherence using medication event-monitoring system psychotherapeutic processes and changes of experience and behavior. The general psychotherapy group was initially more distressed than HIV psychotherapy patients and reached higher levels of psychotherapeutic effect. In the HIV psychotherapy patients, a significant effect was found for maintaining adherence to medical treatment (Weber et al., 2004). These findings show that psychotherapy is a beneficial intervention for HIV-infected persons, and therapeutic alliance and activation of resources do not differ from a general psychotherapy treatment. Differential effects were detected for specific process variables, namely problem actuation.
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Antivirales/uso terapéutico , Terapia Cognitivo-Conductual/métodos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/terapia , Promoción de la Salud , Cooperación del Paciente , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
Pneumococcal meningitis is associated with caspase 3-dependent apoptosis of recently post-mitotic immature neurons in the dentate gyrus of the hippocampus. The death of these cells is implicated in the learning and memory deficits in patients surviving the disease. The stress-activated protein kinase c-Jun N-terminal kinase (JNK) has been shown to be an important mediator of caspase 3-dependent neuronal apoptosis. However, whether JNK is involved in hippocampal apoptosis caused by pneumococcal meningitis has so far not been investigated. Here we show in a neonatal rat model of pneumococcal meningitis that JNK3 but not JNK1 or JNK2 is activated in the hippocampus during the acute phase of infection. At the cellular level, JNK3 activation was accompanied in the dentate gyrus by markedly increased phosphorylation of its major downstream target c-Jun in early immature (Hu-positive) neurons, but not in migrating (doublecortin-positive) neurons, the cells that do undergo apoptosis. These findings suggested that JNK may not be involved in pneumococcal meningitis-induced hippocampal apoptosis. Indeed, although intracerebroventricular administration of D-JNKI-1 or AS601245 (two highly specific JNK inhibitors) inhibited c-Jun phosphorylation and protein expression in the hippocampus, hippocampal apoptosis was unaffected. Collectively, these results demonstrate that JNK does not mediate hippocampal apoptosis in pneumococcal meningitis, and that JNK may be involved in processes unrelated to apoptosis in this disease.
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Apoptosis/fisiología , Hipocampo/enzimología , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Meningitis Neumocócica/enzimología , Neuronas/enzimología , Animales , Animales Recién Nacidos , Proteína Doblecortina , Activación Enzimática/fisiología , Hipocampo/patología , Proteínas Quinasas JNK Activadas por Mitógenos/fisiología , Meningitis Neumocócica/patología , Proteína Quinasa 10 Activada por Mitógenos/metabolismo , Neuronas/patología , Ratas , Ratas WistarRESUMEN
Oxidative stress is a critical component of the injury response to hypoxia-ischemia (HI) in the neonatal brain, and this response is unique and at times paradoxical to that seen in the mature brain. Previously, we showed that copper-zinc superoxide-dismutase (SOD1) over-expression is not beneficial to the neonatal mouse brain with HI injury, unlike the adult brain with ischemic injury. However, glutathione peroxidase 1 (GPx1) over-expression is protective to the neonatal mouse brain with HI injury. To further test the hypothesis that an adequate supply of GPx is critical to protection from HI injury, we crossed SOD1 over-expressing mice (hSOD-tg) with GPx1 over-expressing mice (hGPx-tg). Resulting litters contained wild-type (wt), hGPx-tg, hSOD-tg and hybrid hGPx-tg/hSOD-tg pups, which were subjected to HI at P7. Confirming previous results, the hGPx-tg mice had reduced injury compared to both Wt and hSOD-tg littermates. Neonatal mice over-expressing both GPx1 and SOD1 also had less injury compared to wt or hSOD-tg alone. A result of oxidative stress after neonatal HI is a decrease in the concentration of reduced (i.e. antioxidant-active) glutathione (GSH). In this study, we tested the effect of systemic administration of alpha-lipoic acid on levels of GSH in the cortex after HI. Although GSH levels were restored by 24h after HI, injury was not reduced compared to vehicle-treated mice. We also tested two other pharmacological approaches to reducing oxidative stress in hSOD-tg and wild-type littermates. Both the specific inhibitor of neuronal nitric oxide synthase, 7-nitroindazole (7NI), and the spin-trapping agent alpha-phenyl-tert-butyl-nitrone (PBN) did not reduce HI injury, however. Taken together, these results imply that H2O2 is a critical component of neonatal HI injury, and GPx1 plays an important role in the defense against this H2O2 and is thereby neuroprotective.
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Antioxidantes/farmacología , Hipoxia-Isquemia Encefálica/tratamiento farmacológico , Hipoxia-Isquemia Encefálica/fisiopatología , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/genética , Ácido Tióctico/farmacología , Factores de Edad , Análisis de Varianza , Animales , Animales Recién Nacidos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Glutatión/metabolismo , Glutatión Peroxidasa/genética , Hipoxia-Isquemia Encefálica/genética , Hipoxia-Isquemia Encefálica/metabolismo , Ratones , Ratones Transgénicos , Estrés Oxidativo/fisiología , Superóxido Dismutasa/genética , Superóxido Dismutasa-1 , Glutatión Peroxidasa GPX1RESUMEN
Accumulation of iron probably predisposes the aging brain to progressive neuronal loss. We examined various markers of oxidative stress and damage in the brain and liver of 3- and 24-month-old rats following supplementation with the lipophilic iron derivative [(3,5,5-trimethylhexanoyl)ferrocene] (TMHF), which is capable of crossing the blood-brain barrier. At both ages, iron concentration increased markedly in the liver but failed to increase in the brain. In the liver of TMHF-treated young rats, levels of alpha- and gamma-tocopherols and glutathione (GSH) were also higher. In contrast, the brain displayed unaltered levels of the tocopherols and GSH. Malondialdehyde (MDA) level was also higher in the cerebrospinal fluid (CSF) and the liver but not in the brain. In old rats, the absence of an increase in iron concentration in the brain was reflected by unaltered concentrations of GSH, tocopherols, and MDA as compared to that in untreated rats. In the aging liver, concentrations of GSH and MDA increased with TMHF treatment. Morphological studies revealed unaltered levels of iron, ferritin, heme oxygenase-1 (HO-1), nitrotyrosine (NT), or MDA in the brains of both young and old rats treated with TMHF. In contrast, TMHF treatment increased the level of HO-1 in Kupffer cells, NT in hepatic endothelial cells, and MDA and ferritin in hepatocytes. Although these results demonstrated an increase in the biochemical markers of oxidative stress and damage in response to increasing concentrations of iron in the liver, they also demonstrated that the brain is well protected against dietary iron overload by using iron in a lipid-soluble formulation.
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Compuestos Ferrosos/química , Compuestos Ferrosos/toxicidad , Hierro/toxicidad , Lípidos/química , Hígado/efectos de los fármacos , Hígado/patología , Estrés Oxidativo/efectos de los fármacos , Alimentación Animal , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Suplementos Dietéticos , Hierro/farmacocinética , Hígado/metabolismo , Metalocenos , Ratas , Ratas Endogámicas F344 , SolubilidadRESUMEN
The effect of hypoxic preconditioning (PC) on hypoxic-ischemic (HI) injury was explored in glutathione peroxidase (GPx)-overexpressing mice (human GPx-transgenic [hGPx-tg]) mice. Six-day-old hGPx-tg mice and wild-type (Wt) littermates were pre-conditioned with hypoxia for 30 min and subjected to the Vannucci procedure of HI 24 h after the PC stimulus. Histopathological injury was determined 5 d later (P12). Additional animals were killed 2 h or 24 h after HI and ipsilateral cerebral cortices assayed for GPx activity, glutathione (GSH), and hydrogen peroxide (H2O2). In line with previous studies, hypoxic PC reduced injury in the Wt brain. Preconditioned Wt brain had increased GPx activity, but reduced GSH, relative to naive 24 h after HI. Hypoxic PC did not reduce injury to hGPx-tg brain and even reversed the protection previously reported in the hGPx-tg. GPx activity and GSH in hGPx-tg cortices did not change. Without PC, hGPx-tg cortex had less H2O2 accumulation than Wt at both 2 h and 24 h. With PC, H2O2 remained low in hGPx-tg compared with Wt at 2 h, but at 24 h, there was no longer a difference between hGPx-tg and Wt cortices. Accumulation of H2O2 may be a mediator of injury, but may also induce protective mechanisms.
Asunto(s)
Glutatión Peroxidasa/fisiología , Hipoxia-Isquemia Encefálica/prevención & control , Precondicionamiento Isquémico , Animales , Encéfalo/enzimología , Glutatión/análisis , Glutatión Peroxidasa/análisis , Glutatión Peroxidasa/genética , Humanos , Peróxido de Hidrógeno/análisis , Hipoxia-Isquemia Encefálica/enzimología , Hipoxia-Isquemia Encefálica/patología , Ratones , Ratones TransgénicosRESUMEN
Natural vitamin E consists of four different tocopherol and four different tocotrienol homologues (alpha,beta, gamma, delta) that all have antioxidant activity. However, recent data indicate that the different vitamin E homologues also have biological activity unrelated to their antioxidant activity. In this review, we discuss the anti-inflammatory properties of the two major forms of vitamin E, alpha-tocopherol (alphaT) and gamma-tocopherol (gammaT), and discuss the potential molecular mechanisms involved in these effects. While both tocopherols exhibit anti-inflammatory activity in vitro and in vivo, supplementation with mixed (gammaT-enriched) tocopherols seems to be more potent than supplementation with alphaT alone. This may explain the mostly negative outcomes of the recent large-scale interventional chronic disease prevention trials with alphaT only and thus warrants further investigation.