RESUMEN
Type III phosphatidylinositol-4-kinase beta (PI4KIIIß) was previously implicated in hepatitis C virus (HCV) replication by small interfering RNA (siRNA) depletion and was therefore proposed as a novel cellular target for the treatment of hepatitis C. Medicinal chemistry efforts identified highly selective PI4KIIIß inhibitors that potently inhibited the replication of genotype 1a and 1b HCV replicons and genotype 2a virus in vitro. Replicon cells required more than 5 weeks to reach low levels of 3- to 5-fold resistance, suggesting a high resistance barrier to these cellular targets. Extensive in vitro profiling of the compounds revealed a role of PI4KIIIß in lymphocyte proliferation. Previously proposed functions of PI4KIIIß in insulin secretion and the regulation of several ion channels were not perturbed with these inhibitors. Moreover, PI4KIIIß inhibitors were not generally cytotoxic as demonstrated across hundreds of cell lines and primary cells. However, an unexpected antiproliferative effect in lymphocytes precluded their further development for the treatment of hepatitis C.
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1-Fosfatidilinositol 4-Quinasa/antagonistas & inhibidores , Antivirales/farmacología , Hepacivirus/efectos de los fármacos , Animales , Antivirales/efectos adversos , Células de la Médula Ósea/citología , Células de la Médula Ósea/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Humanos , Masculino , Ratones , Ratas , Ratas Sprague-DawleyRESUMEN
LFF571 is a novel semisynthetic thiopeptide and potent inhibitor of Gram-positive bacteria. We report that the antibacterial activity of LFF571 against Clostridium difficile is due to inhibition of translation. Single-step mutants of C. difficile with reduced susceptibility to LFF571 were selected at frequencies of <4.5 × 10(-11) to 1.2 × 10(-9). Sequencing revealed a G260E substitution in the thiopeptide-binding pocket of elongation factor Tu. Importantly, this mutation did not confer cross-resistance to clinically used antimicrobials. These results support the development of LFF571 as a treatment for C. difficile infection.
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Clostridioides difficile/efectos de los fármacos , Clostridioides difficile/genética , Extensión de la Cadena Peptídica de Translación/efectos de los fármacos , Factor Tu de Elongación Peptídica/genética , Tiazoles/farmacología , Antibacterianos/química , Antibacterianos/farmacología , Sitios de Unión/genética , Farmacorresistencia Bacteriana/genética , Enterocolitis Seudomembranosa/tratamiento farmacológico , Enterocolitis Seudomembranosa/microbiología , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Terciaria de ProteínaRESUMEN
Recently, we identified aminothiazole derivatives of GE2270 A. These novel semisynthetic congeners, like GE2270 A, target the essential bacterial protein elongation factor Tu (EF-Tu). Medicinal chemistry optimization of lead molecules led to the identification of preclinical development candidates 1 and 2. These cycloalklycarboxylic acid derivatives show activity against difficult to treat Gram-positive pathogens and demonstrate increased aqueous solubility compared to GE2270 A. We describe here the in vitro and in vivo activities of compounds 1 and 2 compared to marketed antibiotics. Compounds 1 and 2 were potent against clinical isolates of methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci (MIC(90) ≤ 0.25 µg/ml) but weaker against the streptococci (MIC(90) ≥ 4 µg/ml). Like GE2270 A, the derivatives inhibited bacterial protein synthesis and selected for spontaneous loss of susceptibility via mutations in the tuf gene, encoding EF-Tu. The mutants were not cross-resistant to other antibiotic classes. In a mouse systemic infection model, compounds 1 and 2 protected mice from lethal S. aureus infections with 50% effective doses (ED(50)) of 5.2 and 4.3 mg/kg, respectively. Similarly, compounds 1 and 2 protected mice from lethal systemic E. faecalis infections with ED(50) of 0.56 and 0.23 mg/kg, respectively. In summary, compounds 1 and 2 are active in vitro and in vivo activity against difficult-to-treat Gram-positive bacterial infections and represent a promising new class of antibacterials for use in human therapy.
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Antibacterianos/uso terapéutico , Factor Tu de Elongación Peptídica/antagonistas & inhibidores , Tiazoles/uso terapéutico , Animales , Antibacterianos/efectos adversos , Antibacterianos/química , Antibacterianos/farmacología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Femenino , Células Hep G2 , Humanos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Ratones , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Péptidos Cíclicos/química , Infecciones Estafilocócicas/tratamiento farmacológico , Tiazoles/efectos adversos , Tiazoles/química , Tiazoles/farmacologíaRESUMEN
AIM: Type 2 diabetes is characterized by hyperglycaemia, delayed gastric emptying and a blunted response of gut hormones during feeding that may modulate satiety. We hypothesized that it is associated with more hunger when treated by medication. METHODS: We studied nine type 2 diabetic men (A1C: 6.7+/-0.3%, waist circumference: 104+/-4 cm) after an overnight fast, during 5 h in response to a 2.88 MJ breakfast, twice, in a crossover design, with or without antihyperglycaemic agents. Satiety ratings, thermic effect of meal, gastric emptying, plasma concentrations of gut peptides, leptin, insulin and substrates and intake from a subsequent buffet were determined. RESULTS: With medication, fasting and postprandial plasma glucose levels were lower but area under the curve (AUC) did not vary vs. without medication. Gastric emptying was shortened, branched chain amino acids (BCAA) AUC and thermic effect were lower, and postprandial glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY3-36) were maintained at higher levels beyond 4 h. Correlations were significant between duration of diabetes and fasting ghrelin (r=0.779, p=0.013) and peak insulin (r=-0.769, p=0.016), 5-h postmeal ghrelin and peak glucose (r=0.822, p=0.007), 5-h glucose and GLP-1 (r=-0.788, p=0.012), and 5-h hunger scores and energy intake at buffet (r=0.828, p=0.006). Without medication, fullness scores correlated with BCAA levels. Visual analogue scale scores, ghrelin and leptin levels did not differ between studies. CONCLUSIONS: The decrease in factors associated with postprandial satiety with treatment is counterbalanced by higher GLP-1 and PYY3-36. Medication may normalize the link between perception of hunger and subsequent food intake.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hambre/fisiología , Hipoglucemiantes/farmacología , Saciedad/efectos de los fármacos , Anciano , Aminoácidos/sangre , Área Bajo la Curva , Glucemia/análisis , Estudios Cruzados , Dipéptidos/sangre , Ayuno , Vaciamiento Gástrico/efectos de los fármacos , Péptido 1 Similar al Glucagón/sangre , Gliburida/farmacología , Humanos , Insulina/sangre , Leptina/sangre , Masculino , Metformina/farmacología , Persona de Mediana Edad , Periodo Posprandial/efectos de los fármacos , Saciedad/fisiología , Tiazolidinedionas/farmacologíaRESUMEN
AIMS/HYPOTHESIS: Increased circulating methylarginines (MA) have been linked to the metabolic syndrome to explain endothelial dysfunction and cardiovascular disease risk. Proteins that contain MA are regulatory and release them during catabolism. We hypothesised that increased protein turnover in insulin-resistant states contributes to an increase in circulating MA. MATWERIALS AND METHODS: We performed hyperinsulinaemic, euglycaemic, and isoaminoacidaemic experiments on 49 lean, obese and elderly subjects, with measurements of the kinetics of glucose and protein metabolism. Plasma MA, i.e. asymmetrical dimethylarginine (ADMA), symmetrical dimethylarginine (SDMA), and N -monomethyl-L-arginine (NMMA), lipids and body composition were measured. RESULTS: Insulin resistance of glucose and protein metabolism occurred in obese and elderly subjects. ADMA concentrations were 29 to 120% higher in obese and 34% higher in elderly than in lean subjects. SDMA were 34 and 20% higher in obese than in lean and than in elderly subjects, respectively. NMMA were 32% higher in obese than in lean subjects. ADMA differed by sex, being higher in men, namely by 1.75x in obese men and by 1.27x in elderly men. Postabsorptive ADMA (r=0.71), SDMA (r=0.46), and NMMA (r=0.31) correlated (all p<0.05) with rates of protein flux. All three MA correlated negatively with clamp glucose infusion rates and uptake (p<0.001). ADMA and SDMA correlated negatively with net protein synthesis and clamp amino acid infusion rates (p<0.05). All MA also correlated with adiposity indices and fasting insulin and triglycerides (p<0.05). CONCLUSIONS/INTERPRETATION: Obesity, sex and ageing affect MA. Elevations of the three MA in obese, and of ADMA in elderly men, are related to increased protein turnover and to lesser insulin sensitivity of protein metabolism. These interrelationships might amplify insulin resistance and endothelial dysfunction.
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Envejecimiento/sangre , Arginina/sangre , Resistencia a la Insulina/fisiología , Insulina/fisiología , Obesidad/sangre , Proteínas/metabolismo , omega-N-Metilarginina/sangre , Adulto , Anciano , Anciano de 80 o más Años , Envejecimiento/fisiología , Arginina/análogos & derivados , Glucemia/metabolismo , Composición Corporal/fisiología , Femenino , Glucosa/farmacología , Técnica de Clampeo de la Glucosa , Humanos , Insulina/sangre , Lípidos/sangre , Masculino , Síndrome Metabólico/etiología , Síndrome Metabólico/fisiopatología , Persona de Mediana Edad , Obesidad/fisiopatología , Análisis de Regresión , Caracteres SexualesRESUMEN
BACKGROUND: Predictive equations have been reported to overestimate resting energy expenditure (REE) for obese persons. The presence of hyperglycemia results in elevated REE in obese persons with type 2 diabetes, and its effect on the validity of these equations is unknown. OBJECTIVE: We tested whether (1) indicators of diabetes control were independent associates of REE in type 2 diabetes and (2) their inclusion would improve predictive equations. DESIGN: A cross-sectional study of 65 (25 men, 40 women) obese type 2 diabetic subjects. Variables measured were: REE by ventilated-hood indirect calorimetry, body composition by bioimpedance analysis, body circumferences, fasting plasma glucose (FPG) and hemoglobin A(1c). Data were analyzed using stepwise multiple linear regression. RESULTS: REE, corrected for weight, fat-free mass, age and gender, was significantly greater with FPG>10 mmol/l (P=0.017) and correlated with FPG (P=0.013) and hemoglobin A(1c) as percentage upper limit of normal (P=0.02). Weight was the main determinant of REE. Together with hip circumference and FPG, it explained 81% of the variation. FPG improved the predictability of the equation by >3%. With poor glycemic control, it can represent an increase in REE of up to 8%. CONCLUSION: Our data indicate that in a population of obese subjects with type 2 diabetes mellitus, REE is better predicted when fasting plasma glucose is included as a variable.
Asunto(s)
Metabolismo Basal , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus/metabolismo , Hiperglucemia/metabolismo , Obesidad , Adulto , Anciano , Glucemia/metabolismo , Composición Corporal , Calorimetría Indirecta , Estudios Transversales , Impedancia Eléctrica , Metabolismo Energético , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Hiperglucemia/prevención & control , Masculino , Persona de Mediana Edad , Valor Predictivo de las PruebasRESUMEN
Intracranial recordings were obtained from three patients with intractable chronic pain who underwent analgesic electrical stimulation of the contralateral thalamus. Multilead electrode made it possible to record from several thalamic nuclei. The electrode was targeted into the ventroposterolateral (VPL) nucleus of the thalamus. During separate recording sessions, the following tests were performed: somatosensory evoked potentials (SEP) of the median or posterior tibial nerve, event-related cognitive potentials (auditory oddball P3 wave), readiness potential (RP) and contingent negative variation (CNV) using auditory warning (S1) and visual imperative (S2) stimuli. The movement accompanying potential (MAP), which was present in the VPL in all but one of the recordings, behaved as a far-field potential. Recordings obtained from the VPL confirmed its established role as a relay nucleus, processing somatosensory information to the primary somatosensory cortex. The VPL generated the 'thalamic' SEP, which was the only potential regularly recorded in this nucleus. In the recordings from one patient (No. 3), auditory and visual evoked potentials of the CNV protocol, peaking at approximately 300 ms, were obtained from the VPL and appeared to be generated in situ. Neither RP, CNV nor 'oddball' ERPs appeared in the VPL. From the pulvinar, only a visually evoked potential was recorded. Oddball P3, RP, CNV, and middle and long latency auditory and visual potentials (evoked in the CNV paradigm) appeared to be generated 'dorsally' to the VPL, probably in the nucleus posterolateralis (PL). This structure may therefore be involved in both the processing of afferent information and in cognitive operations.
Asunto(s)
Electroencefalografía , Potenciales Relacionados con Evento P300/fisiología , Movimiento/fisiología , Tálamo/fisiología , Anciano , Estimulación Eléctrica , Terapia por Estimulación Eléctrica , Electrodos Implantados , Electromiografía , Potenciales Evocados Somatosensoriales/fisiología , Humanos , Masculino , Persona de Mediana Edad , Manejo del Dolor , Núcleos Talámicos Posteriores/fisiologíaRESUMEN
OBJECTIVES: Description of 6-9 Hz rhythmic electrical activity observed on recordings from electrodes implanted in the cortex of epileptic patients undergoing presurgical evaluation. METHODS: Recordings were obtained from 74 patients with multilead electrodes in the frontal, parietal and temporal cortex. The motor task consisted of a self-paced fist clenching movement at approximately 10 s intervals. Events within a window extending from 4 s before to 1 s after movement EMG onset were analyzed. RESULTS: (i) Spindle-like rhythmic activity at 6-9 Hz was observed in 29 patients. (ii) This activity was located in the inferior parietal and superior temporal areas. (iii) Enhancement of rhythmic activity occurred when patients were asked to perform the motor task. (iv) A striking tendency to phase-locking of rhythmic oscillations on consecutive trials was noted during the 3-2 s epoch before movement EMG onset. CONCLUSION: Whether this intracerebrally recorded 6-9 Hz rhythmic activity belongs to the mu-alpha class or is a special type of theta, and if it is related to the epileptic process or to drug treatment remain open to discussion. Motor-task related enhancement and phase-locking suggest that this activity may be one more indicator of movement preparation.
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Epilepsia/fisiopatología , Lóbulo Parietal/fisiopatología , Periodicidad , Lóbulo Temporal/fisiopatología , Electrodos Implantados , Electroencefalografía , Electromiografía , Fuerza de la Mano/fisiología , Humanos , Oscilometría , Factores de TiempoRESUMEN
BACKGROUND: During the past decade, Taxol has assumed an important role in cancer chemotherapy. The search for novel compounds with a mechanism of action similar to that of Taxol, but with greater efficacy particularly in Taxol-resistant cells, has led to the isolation of new natural products. One such compound, (+)-discodermolide, although structurally distinct from Taxol, has a similar ability to stabilize microtubules. In addition, (+)-discodermolide is active in Taxol-resistant cell lines that overexpress P-glycoprotein, the multidrug-resistant transporter. Interestingly, (+)-discodermolide demonstrates a profound enhancement of the initiation process of microtubule polymerization compared to Taxol. RESULTS: The synthesis of (+)-discodermolide analogs exploiting our highly efficient, triply convergent approach has permitted structure-activity relationship (SAR) studies. Small changes to the (+)-discodermolide structure resulted in a dramatic decrease in the ability of all four discodermolide analogs to initiate tubulin polymerization. Two of the analogs also demonstrated a decrease in total tubulin polymerization, while a change in the olefin geometry at the C8 position produced a significant decrease in cytotoxic activity. CONCLUSIONS: The availability of (+)-discodermolide and the analogs, and the resultant SAR analysis, have permitted an exploration of the similarities and differences between (+)-discodermolide and Taxol. Docking of the X-ray/solution structure of (+)-discodermolide into the Taxol binding site of beta-tubulin revealed two possible binding modes (models I and II). The preferred pharmacophore model (I), in which the C19 side chain of (+)-discodermolide matches with the C2 benzoyl group of Taxol and the delta-lactone ring of (+)-discodermolide overlays with the C13 side chain of Taxol, concurred with the results of the SAR analysis.
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Alcanos , Antineoplásicos Fitogénicos/farmacología , Carbamatos , Lactonas/farmacología , Paclitaxel/farmacología , Antineoplásicos Fitogénicos/síntesis química , Antineoplásicos Fitogénicos/química , Unión Competitiva , Citometría de Flujo , Humanos , Concentración 50 Inhibidora , Lactonas/síntesis química , Lactonas/química , Microscopía Electrónica , Microscopía Fluorescente , Microtúbulos/efectos de los fármacos , Modelos Moleculares , Paclitaxel/química , Pironas , Estereoisomerismo , Relación Estructura-Actividad , Tubulina (Proteína)/efectos de los fármacos , Células Tumorales CultivadasRESUMEN
OBJECTIVES: The study presents data suggesting that the classic bereitschaftspotential hides in its early component (BP1) steep increases of negativity which precede the movement at varying intervals in repeated trials. METHODS: In 12 volunteers, surface EEG from Fz, Cz, C3, C4, and Pz electrodes and EMG from the flexor digitorum communis were recorded during self-paced wrist flexions. Two hundred trials were collected from each subject. The single trials were grouped for averaging in two different ways. In the first one, single trials for each subject were used to create individual averages. In the second, all single trials were divided into groups according to the point in time of small steep negative shift from the baseline detected on sweeps before the movement and time group averages were created. The identification of small shifts was based on the comparison of calculated mean amplitudes in the first and the second half of the 1 s time window moved along the time axis. RESULTS: The small negative shifts were identified in 97.2% of analyzed records. In each subject, their position on the time axis varied considerably. Individual averages exhibited the characteristics of classical readiness potential, i.e. slow early component, steep late component, laterality over motor cortices. On the other hand, all time group averages (26) displayed an early steep negative shift followed by plateau which, about 0.5 s before the movement, gave rise to the second, late steep negative shift. The slope values calculated in the definite segments of averaged curves were used as a measure of the amplitude of these shifts over various brain areas. MANOVA showed a significant effect of the electrode position both in the case of early slopes (F(4,115)=9.7; P<0.000) and in the case of late slopes (F(4,115)=22.5; P<0.000). In both cases, the largest value was demonstrated under Cz electrode. In contrast to the late slopes, the values of early slopes did not exhibit laterality and suggested greater importance of pre-frontal regions in their formation. CONCLUSION: We have suggested that the formation of steep early negative shifts from the baseline in time group averages was due to synchronization of a mental process which, under classical averaging procedure, was dispersed uniformly throughout the pre-movement period.
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Variación Contingente Negativa/fisiología , Movimiento/fisiología , Adulto , Electroencefalografía , Electromiografía , Femenino , Lateralidad Funcional , Humanos , Masculino , Corteza Motora/fisiología , Tiempo de Reacción/fisiología , Factores de TiempoRESUMEN
[structure: see text]. The solution structure of (+)-discodermolide (1) has been determined via 1- and 2-D NMR techniques in conjunction with Monte Carlo conformational analysis. Taken together, the results demonstrate that in solution (+)-discodermolide occupies a helical conformation remarkably similar to the solid state conformation.
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Alcanos , Carbamatos , Inmunosupresores/química , Lactonas/química , Poríferos/química , Animales , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Modelos Moleculares , Método de Montecarlo , Pironas , Soluciones , Tubulina (Proteína)/químicaRESUMEN
In 13 volunteers, surface EEGs from F(z), C(z), C(3), C(4), and P(z) electrodes and EMG from the flexor digitorum communis were recorded during an experimental task in which the performance of wrist flexion was linked with the selection of a clock sound. In the epoch from 4 to 1 s before movement, more than 95% of the records exhibited a small negative shift from the baseline. The position of these shifts on the time axis made it possible to create groups of time trials. The average EEG curves from these groups showed one prominent negative shift from the baseline, which could be related to the position of particular clock sounds. The slope values of these shifts were highest under the F(z) and C(z) electrodes. We suggested that these negative shifts coincided with 'when to move' decisions, which preceded the execution of the movement at varying intervals.
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Toma de Decisiones/fisiología , Electroencefalografía/psicología , Movimiento/fisiología , Sonido , Adulto , Análisis de Varianza , Electromiografía/psicología , Femenino , Humanos , Masculino , Análisis y Desempeño de Tareas , Muñeca/fisiologíaAsunto(s)
Cateterismo Venoso Central/efectos adversos , Oclusión de Injerto Vascular/etiología , Oclusión de Injerto Vascular/prevención & control , Fallo Renal Crónico/terapia , Diálisis Renal/instrumentación , Vena Subclavia/patología , Anciano , Constricción Patológica , Femenino , Humanos , Planificación de Atención al Paciente , Diálisis Renal/enfermeríaAsunto(s)
Organizaciones de Beneficencia , Bienestar Social , Viudez , Boston/etnología , Organizaciones de Beneficencia/economía , Organizaciones de Beneficencia/historia , Organizaciones de Beneficencia/métodos , Organizaciones de Beneficencia/organización & administración , Femenino , Historia del Siglo XIX , Humanos , Control Social Formal/métodos , Bienestar Social/economía , Bienestar Social/historia , Viudez/economía , Viudez/etnología , Viudez/historia , Mujeres Trabajadoras/historiaAsunto(s)
Amalgama Dental/farmacocinética , Intoxicación por Mercurio/orina , Mercurio/orina , Carga Corporal (Radioterapia) , Exposición a Riesgos Ambientales , Femenino , Humanos , Mercurio/farmacocinética , Intoxicación por Mercurio/diagnóstico , Modelos Biológicos , Porfirinas/orina , Distribución TisularRESUMEN
STATEMENT OF PROBLEM: Previous studies have identified focal areas of alveolar tenderness, elevated mucosal temperature, radiographic abnormality, and increased radioisotope uptake or "hot spots" within the quadrant of pain in most patients with chronic, idiopathic facial pain (phantom pain, atypical facial neuralgia, and atypical facial pain). PURPOSE: This retrospective investigation radiographically and microscopically evaluated intramedullary bone in a certain subset of patients with histories of endodontics, extraction, and fixed partial denture placement in an area of "idiopathic" pain. MATERIAL AND METHODS: Patients from 12 of the United States were identified through tissue samples, histories, and radiographs submitted to a national biopsy service. Imaging tests, coagulation tests, and microscopic features were reviewed. Of 38 consecutive idiopathic facial pain patients, 32 were women. RESULTS: Approximately 90% of subpontic bone demonstrated either ischemic osteonecrosis (68%), chronic osteomyelitis (21%), or a combination (11%). More than 84% of the patients had abnormal radiographic changes in subpontic bone, and 5 of 9 (56%) patients who underwent radioisotope bone scan revealed hot spots in the region. Of the 14 patients who had laboratory testing for coagulation disorders, 71% were positive for thrombophilia, hypofibrinolysis, or both (normal: 2% to 7%). Ten pain-free patients with abnormal subpontic bone on radiographs were also reviewed. CONCLUSIONS: Intraosseous ischemia and chronic inflammation were suggested as a pathoetiologic mechanism for at least some patients with atypical facial pain. These conditions were also offered as an explanation for poor healing of extraction sockets and positive radioisotope scans.
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Dentadura Parcial Fija , Dolor Facial/diagnóstico por imagen , Isquemia/diagnóstico por imagen , Mandíbula/irrigación sanguínea , Enfermedades Mandibulares/diagnóstico por imagen , Maxilar/irrigación sanguínea , Enfermedades Maxilares/diagnóstico por imagen , Osteonecrosis/diagnóstico por imagen , Adulto , Anciano , Biopsia , Pruebas de Coagulación Sanguínea , Enfermedad Crónica , Dentadura Parcial Fija/efectos adversos , Dolor Facial/patología , Femenino , Fibrinólisis , Humanos , Isquemia/patología , Masculino , Enfermedades Mandibulares/patología , Enfermedades Maxilares/patología , Persona de Mediana Edad , Neuralgia/diagnóstico por imagen , Neuralgia/patología , Osteomielitis/diagnóstico por imagen , Osteomielitis/patología , Osteonecrosis/patología , Radiografía , Radiofármacos , Estudios Retrospectivos , Tratamiento del Conducto Radicular/efectos adversos , Medronato de Tecnecio Tc 99m , Trombofilia/diagnóstico por imagen , Trombofilia/patología , Extracción Dental/efectos adversos , Cicatrización de HeridasRESUMEN
[formula: see text] A triply convergent, highly efficient second-generation synthesis of the potent antimitotic agent (+)-discodermolide (1) has been achieved on a 1-g scale.
Asunto(s)
Alcanos , Antineoplásicos/síntesis química , Carbamatos , Lactonas/síntesis química , Animales , Indicadores y Reactivos , Poríferos/química , Pironas , EstereoisomerismoRESUMEN
In epileptic patients explored with depth electrodes kept within the brain for several days ("chronic conditions") to localize their focus, recordings were taken from the less perturbed deep brain areas, before and during the execution of self-paced movements. A few deep leads (some of which were located in areas which did not display a classical readiness potential) showed that phasic paroxystic events very often occurred 2,000 ms and, sometimes, even about 3,000 ms before the movement (movement-related events, MREs). This finding suggests that the preparation of a "voluntary" self-paced movement may begin well before the appearance of the readiness potential or, alternatively, that intracerebral paroxystic spikes delay the decision making. This type of phasic process may be undetectable in scalp recording from normal subjects and only be revealed when some brain structures have become hyper-reactive due to the epileptic process.
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Encéfalo/fisiopatología , Epilepsia/fisiopatología , Movimiento/fisiología , Variación Contingente Negativa/fisiología , Electroencefalografía/métodos , Electromiografía , Electrooculografía , HumanosRESUMEN
Fifteen healthy subjects were asked to randomly select a tick of a mechanical clock which was operating throughout the experiment and to flex their wrist at the chosen tick. The individual averages of EEG recordings collected during the period of the putative decision to begin the task exhibited steep slopes of negativity followed by plateaus. These slopes preceded the selection of the signal sound at varying intervals, the longest interval was 3 s. The grand average of individual averages depicted a waveform whose shape was identical to the early component of the classical readiness potential. Another interesting finding came from experiments with mental counting of clock sounds, which demonstrated that the generation of the first mentally-counted number is preceded by a distinct negative potential shift.
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Variación Contingente Negativa , Probabilidad , Desempeño Psicomotor/fisiología , Estimulación Acústica , Adulto , Análisis de Varianza , Electroencefalografía , Electromiografía , Electrooculografía , Femenino , Humanos , Masculino , Factores de TiempoRESUMEN
OBJECTIVES: Slow potentials appearing during simple repetitive acral limb movement were investigated. Twenty-six patients suffering from drug resistant partial epilepsies and explored with implanted intracerebral electrodes were examined using two protocols. METHODS: In 18 patients, readiness potential (RP), in 13 patients contingent negative variation (CNV), and in 7 patients both protocols, were tested. The recordings from leads with evident pathological EEG activity were excluded from evaluation. The results concerning the slow potentials preceding the movements in RP and CNV protocols have already been published. RESULTS: The movement-accompanying slow potentials (MASP) were polyphasic or monophasic, started before or during the movement. In the primary motor cortex they followed the pre-movement potentials depending on the protocol: in the RP paradigm they were present only contralateral to the movement, but were bilateral in the CNV protocol. In other areas they either followed the potentials preceding the movement, in some cases with opposite polarity, or they occurred alone. MASP was recorded in motor and supplementary motor, premotor and prefrontal, midtemporal, somatosensory, superior parietal and cingular cortices. The cingular cortex was heavily involved in the self-paced movements but rarely in the cued movements. CONCLUSION: The major involvement of the cingular gyrus contrasted with the absence of slow potentials in temporal limbic structures. MASP is evidently a heterogenic phenomenon. Its genesis could be involved in a spread of information through the relevant structures.