RESUMEN
The resistance-nodulation-division (RND) family efflux pumps are important in the antibiotic resistance of Gram-negative bacteria. However, although a number of bacterial RND efflux pump inhibitors have been developed, there has been no clinically available RND efflux pump inhibitor to date. A set of BSN-coded 2-substituted benzothiazoles were tested alone and in combinations with ciprofloxacin (CIP) against the AcrAB-TolC overexpressor Escherichia coli AG102 clinical strain. The results indicated that the BSN compounds did not show intrinsic antimicrobial activity when tested alone. However, when used in combinations with CIP, a reversal in the antibacterial activity of CIP with up to 10-fold better MIC values was observed. In order to describe the binding site features of these BSN compounds with AcrB, docking studies were performed using the CDocker method. The performed docking poses and the calculated binding energy scores revealed that the tested compounds BSN-006, BSN-023, and BSN-004 showed significant binding interactions with the phenylalanine-rich region in the distal binding site of the AcrB binding monomer. Moreover, the tested compounds BSN-006 and BSN-023 possessed stronger binding energies than CIP, verifying that BSN compounds are acting as the putative substrates of AcrB.
Asunto(s)
Antibacterianos/farmacología , Benzotiazoles/farmacología , Ciprofloxacina/farmacología , Proteínas de Escherichia coli/antagonistas & inhibidores , Escherichia coli/efectos de los fármacos , Antibacterianos/química , Benzotiazoles/química , Sitios de Unión , Ciprofloxacina/química , Farmacorresistencia Bacteriana , Escherichia coli/aislamiento & purificación , Escherichia coli/metabolismo , Proteínas de Escherichia coli/metabolismo , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Unión Proteica , Relación Estructura-Actividad CuantitativaRESUMEN
RND family efflux pumps are important for multidrug resistance in Gram-negative bacteria. To date no efflux pump inhibitors for clinical use have been found, so developing the specific inhibitors of this pump system will be beneficial for the treatment of infections caused by these multidrug-resistant pathogens. A set of BSN-coded 2-substituted benzothiazoles were tested alone and in combination with ciprofloxacin (CIP) against the RND family efflux pump AdeABC overexpressor Acinetobacter baumannii SbMox-2 strain. The results indicated that the BSN compounds did not have antimicrobial activity when tested alone. However, if they were applied in combination with CIP, it was observed that the antibiotic had antimicrobial activity against the tested pathogen, possessing a minimum inhibitory concentration value that could be utilized in clinical treatment. A 3D-common features pharmacophore model was applied by using the HipHop method and the generated pharmacophore hypothesis revealed that the hydrogen bond acceptor property of nitrogen in the thiazole ring and the oxygen of the amide substituted at the second position of the benzothiazole ring system were significant for binding to the target protein. Moreover, three hydrophobic aromatic features were found to be essential for inhibitory activity.
Asunto(s)
Acinetobacter baumannii/efectos de los fármacos , Benzotiazoles/farmacología , Ciprofloxacina/farmacología , Farmacorresistencia Bacteriana Múltiple/fisiología , Acinetobacter baumannii/metabolismo , Antibacterianos/farmacología , Proteínas Bacterianas/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Pruebas de Sensibilidad MicrobianaRESUMEN
BACKGROUND: Vagus nerve stimulation (VNS) therapy is associated with a decrease in seizure frequency in partial-onset seizure patients. Initial trials suggest that it may be an effective treatment, with few side-effects, for intractable depression. METHOD: An open, uncontrolled European multi-centre study (D03) of VNS therapy was conducted, in addition to stable pharmacotherapy, in 74 patients with treatment-resistant depression (TRD). Treatment remained unchanged for the first 3 months; in the subsequent 9 months, medications and VNS dosing parameters were altered as indicated clinically. RESULTS: The baseline 28-item Hamilton Depression Rating Scale (HAMD-28) score averaged 34. After 3 months of VNS, response rates (> or = 50% reduction in baseline scores) reached 37% and remission rates (HAMD-28 score <10) 17%. Response rates increased to 53% after 1 year of VNS, and remission rates reached 33%. Response was defined as sustained if no relapse occurred during the first year of VNS after response onset; 44% of patients met these criteria. Median time to response was 9 months. Most frequent side-effects were voice alteration (63% at 3 months of stimulation) and coughing (23%). CONCLUSIONS: VNS therapy was effective in reducing severity of depression; efficacy increased over time. Efficacy ratings were in the same range as those previously reported from a USA study using a similar protocol; at 12 months, reduction of symptom severity was significantly higher in the European sample. This might be explained by a small but significant difference in the baseline HAMD-28 score and the lower number of treatments in the current episode in the European study.
Asunto(s)
Trastorno Bipolar/terapia , Trastorno Depresivo Mayor/terapia , Terapia por Estimulación Eléctrica/métodos , Nervio Vago/fisiopatología , Adulto , Anticonvulsivantes/uso terapéutico , Antidepresivos/uso terapéutico , Antimaníacos/uso terapéutico , Trastorno Bipolar/diagnóstico , Trastorno Bipolar/fisiopatología , Terapia Combinada , Trastorno Depresivo Mayor/diagnóstico , Trastorno Depresivo Mayor/fisiopatología , Terapia por Estimulación Eléctrica/efectos adversos , Europa (Continente) , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Inventario de Personalidad , Seguridad , Resultado del TratamientoRESUMEN
BACKGROUND: The effects of thoracolumbal spinal cord stimulation (SCS) are confined to restricted microcirculatory areas. This limitation is generally attributed to a predominantly segmental mode of action on the autonomic nervous system. The goal of this study was to determine whether SCS applied close to supraspinal autonomic centers would induce generalized hemodynamic changes that could explain its alleged antianginal properties. METHODS: Invasive hemodynamic tests were performed in 15 anesthetized Göttingen minipigs submitted to iterative cervical SCS of various duration and intensity. RESULTS: Hemodynamic changes exceeding 10% were observed in 59 of 68 SCS sessions (87%). Their extent and time to peak varied with SCS intensity. At 2, 5, and 10 V, significant (t test p < 0.05) peak changes occurred in cardiac output (+34%, +29%, and +28%, respectively), stroke volume (+19%, +16%, +15%), mean pressure (+9%, +27%, +40%), heart rate (+14%, +23%, +14%), systemic (-17%, NS, NS), and pulmonary vascular (25%, NS, NS) resistances. Strikingly, at 2 V, the increase in cardiac output (+34%) was higher than the synchronous rise in rate pressure product (+22%), indicating efficient cardiac work. At 10 V, however, the cardiac work was inefficient (rate pressure product + 53%/cardiac output + 28%). CONCLUSIONS: Low-voltage cervical neuromodulation reduces the postcharge and improves cardiac work efficiency. The resulting reduction in oxygen myocardial demand may account for decreased anginal pain.
Asunto(s)
Angina de Pecho/terapia , Terapia por Estimulación Eléctrica , Angina de Pecho/fisiopatología , Animales , Electrocardiografía , Electrodos Implantados , Hemodinámica , Médula Espinal , Porcinos EnanosRESUMEN
The authors report the first case of chronic globus pallidus internus (GPi) stimulation for treatment of medically intractable hemidystonia for which long-term follow-up data are available. The patient had developed left-sided low-frequency tremor and hemidystonia after a severe head trauma sustained at 15 years of age. He experienced relief of the tremor but not of the hemidystonia after a thalamotomy was performed in the right hemisphere 3 years postinjury. When the patient was 24 years old, the authors performed a magnetic resonance-guided stereotactic implantation of a monopolar electrode in the right-sided posteroventral GPi. Chronic deep brain stimulation resulted in remarkable improvement of dystonia-associated pain, phasic dystonic movements, and dystonic posture, which was accompanied by functional gain. Postoperative improvement was sustained after 4 years of follow up. Chronic GPi stimulation appears to be a valuable treatment option for posttraumatic dystonia.
Asunto(s)
Lesión Encefálica Crónica/terapia , Dominancia Cerebral/fisiología , Distonía/terapia , Terapia por Estimulación Eléctrica , Globo Pálido/fisiopatología , Adulto , Lesión Encefálica Crónica/fisiopatología , Distonía/etiología , Distonía/fisiopatología , Estudios de Seguimiento , Humanos , Imagen por Resonancia Magnética , Masculino , Técnicas Estereotáxicas , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
OBJECTIVES: (1) To determine the proportion of patients with critical limb ischaemia refractory to invasive treatment that can be successfully treated by dorsal column stimulation (DCS), and (2) to identify potential responders to DCS by a simple test that is sufficiently predictive to limit the need for a prolonged trial stimulation period. PATIENTS AND METHODS: Twenty patients with chronic limb-threatening ischaemia were assessed by a battery of macro- and microcirculatory tests and a DCS trial of 1 week. Favourable response during the trial determined selection for long-term stimulation. RESULTS: During a mean observation period of 14 months, limb salvage rate (LSR) was 63% overall and 83% among patients selected after a favourable trial. Of the tests performed preoperatively, digital subtraction angiography, Doppler assessment, oscillometry, capillaroscopy, foot temperature, and transcutaneous partial pressure of oxygen (tcpO2) in the supine or sitting position did not adequately predict DCS response. The supine-sitting tcpO2 gradient (delta tcpO2) was a good predictor of DCS outcome, with an 88% LSR when delta tcpO2 > 15 Torr, dropping to 12% when delta tcpO2 < or = 15 Torr. CONCLUSIONS: DCS is a rewarding therapeutic option in selected patients with critical limb ischaemia. delta tcpO2 appears to reliably predict response to DCS and may obviate trial stimulation in most cases.
Asunto(s)
Terapia por Estimulación Eléctrica , Isquemia/diagnóstico , Pierna/irrigación sanguínea , Adulto , Anciano , Anciano de 80 o más Años , Angiografía de Substracción Digital , Monitoreo de Gas Sanguíneo Transcutáneo , Temperatura Corporal , Enfermedad Crónica , Terapia por Estimulación Eléctrica/instrumentación , Terapia por Estimulación Eléctrica/métodos , Estudios de Evaluación como Asunto , Femenino , Estudios de Seguimiento , Pie/fisiología , Predicción , Humanos , Isquemia/terapia , Masculino , Microcirculación , Persona de Mediana Edad , Oscilometría , Selección de Paciente , Postura , Valor Predictivo de las Pruebas , Flujo Sanguíneo Regional , Reproducibilidad de los Resultados , Posición Supina , Factores de Tiempo , Resultado del Tratamiento , Ultrasonografía DopplerRESUMEN
A total of 33 patients presenting with various cerebral lesions were operated on with stereotactic guided craniotomy. In all cases the lesion could be totally removed and only one patient suffered from a recurrent metastasis. The survival time of patients with malignant brain tumors was in the range of the generally reported data. All the six patients with malignant gliomas developed a recurrence, four of them have since died. Three of the four patients with brain metastases died from systemic progression of their disease, and one patient died from a recurrence of a centrally located metastasis. A new neurological deficit occurred in only two patients. Despite the often deep or central localization of the lesions, major complications were rare. Stereotactic guidance and preoperative selection of the entry point allow a safer surgical procedure, a larger indication for open surgery in cases considered as not removable, and reduce surgical morbidity.
Asunto(s)
Encefalopatías/cirugía , Microcirugia/métodos , Adulto , Anciano , Absceso Encefálico/cirugía , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/cirugía , Craneotomía/métodos , Femenino , Glioma/cirugía , Humanos , Masculino , Meningioma/cirugía , Persona de Mediana Edad , Estudios Prospectivos , Técnicas EstereotáxicasRESUMEN
There is still a lack of prospective randomised studies; at the present we know of only one by Jivegard et al. on a relatively small number of 51 patients. Their results are encouraging, tissue loss being reduced significantly and a trend towards increased limb salvage. The results of ongoing Dutch and American studies are awaited. It has however been shown in convincing microcirculatory studies by Jacobs et al. and others that SCS has a positive effect. Wide clinical experience has also substantiated this; were this not the case it would be hard to understand why elaborate studies by Augustinsson, Meyerson and the prolific work of Linderoth should ever have been designed. Recent communications by Lo Gerfo and others have shown that it is important to visualise the arterial tree all the way down to the foot by selective angiography before pronouncing a leg as non-reconstructible. The 3- and 5-year patency results of femoro- and popliteo-pedal bypass surgery presented by Lo Gerfo are so extraordinary--albeit probably unreproducible by all vascular surgeons--that SCS must be restricted to the truly unoperable or unreconstructable cases of CLI. SCS therefore is definitely not meant to be an alternative to reconstructive techniques!(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Terapia por Estimulación Eléctrica , Isquemia/terapia , Pierna/irrigación sanguínea , Cuidados Paliativos , Médula Espinal/fisiología , Endorfinas/fisiología , Humanos , Neurotransmisores/fisiologíaAsunto(s)
Desplazamiento del Disco Intervertebral/cirugía , Vértebras Lumbares/cirugía , Complicaciones Posoperatorias/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Desplazamiento del Disco Intervertebral/diagnóstico por imagen , Laminectomía/métodos , Vértebras Lumbares/diagnóstico por imagen , Masculino , Microcirugia/métodos , Persona de Mediana Edad , Examen Neurológico , Dimensión del Dolor , Recurrencia , Estudios Retrospectivos , Resultado del TratamientoAsunto(s)
Desplazamiento del Disco Intervertebral/diagnóstico , Vértebras Lumbares , Estudios Transversales , Humanos , Incidencia , Desplazamiento del Disco Intervertebral/clasificación , Desplazamiento del Disco Intervertebral/cirugía , Vértebras Lumbares/cirugía , Síndromes de Compresión Nerviosa/clasificación , Síndromes de Compresión Nerviosa/diagnóstico , Síndromes de Compresión Nerviosa/cirugía , Raíces Nerviosas Espinales/cirugíaRESUMEN
Stereotaxy-guided microsurgery offers significant advantages in the treatment of deep-seated cerebral lesions, or in lesions that cannot reliably be localized because of their small size or lack of evident landmarks. We report our experience with 16 stereotaxy-guided microsurgical procedures performed with the Leksell or the Lerch stereotactic system. Small superficial lesions were operated on in 6 patients and deep-seated subcortical lesions in 10 patients. The lesion size ranged from 10 to 50 mm and the depth of the lesions varied between 5 and 65 mm. A trans-sulcus approach was chosen in patients with cavernomas and a transcortical or transtumoral one in patients presenting with cerebral tumors. In no patient was a new postoperative neurologic deficit found, i.e. 12 patients had neither a pre- nor a postoperative deficit. 2 patients (with central lesions) of 4 presenting with preoperative deficits showed an impressive recovery, while in the other 2 patients with lesions in the dominant temporal lobe the neurologic deficit remained unchanged. Stereotaxy-guided microsurgery allows safe resection of small or deep-seated cerebral lesions without postoperative morbidity in our series.
Asunto(s)
Neoplasias Encefálicas/cirugía , Técnicas Estereotáxicas , Adulto , Anciano , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/secundario , Craneotomía/métodos , Femenino , Hemangioma Cavernoso/cirugía , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Tomografía Computarizada por Rayos XRESUMEN
The present study reports our experience with stereotactic puncture, aspiration and drainage of brain abscesses in 24 patients from a series of 34 consecutive cases. In all patients an intracavitary catheter was left in place for external drainage and daily irrigation with antibiotics. The patients received pre- and postoperatively triple broad spectrum antibiotic treatment, associated with low dose steroids and anti-epileptic drugs. Follow-up CT scans showed immediate reduction of the abscess size and gradual diameter diminution of the enhancing ring structure until its disappearance. The clinical presentation, risk factors, aetiology, outcome, bacteriological and CT findings were analysed. Mortality in this series was 4%. The majority of patients (96%) had no or minimal disability according to the Glasgow Outcome Scale. Our results confirm the value of this treatment policy and suggest that the stereotactic technique is a simple and safe method with minimal mortality and morbidity in the treatment of the majority of chronic brain abscesses.