RESUMEN
Severe burn injury is an acute inflammatory state with massive alterations in gene expression and levels of growth factors, cytokines and free radicals. During the catabolic processes, changes in insulin sensitivity and skeletal muscle wasting (unintended loss of 5-15% of lean body mass) are observed clinically. Here, we reveal a novel molecular mechanism of Akt1/protein kinase Bα (Akt1/PKBα) regulated via cross-talking between dephosphorylation of Thr308 and S-nitrosylation of Cys296 post severe burn injury, which were characterized using nano-LC interfaced with tandem quadrupole time-of-fight mass spectrometry (Q-TOF)micro tandem mass spectrometry in both in vitro and in vivo studies. For the in vitro studies, Akt1/PKBα was S-nitrosylated with S-nitrosoglutathione and derivatized by three methods. The derivatives were isolated by SDS-PAGE, trypsinized and analyzed by the tandem MS. For the in vivo studies, Akt1/PKBα in muscle lysates from burned rats was immunoprecipitated, derivatized with HPDP-Biotin and analyzed as above. The studies demonstrated that the NO free radical reacts with the free thiol of Cys296 to produce a Cys296-SNO intermediate which accelerates interaction with Cys310 to form Cys296-Cys310 in the kinase loop. MS/MS sequence analysis indicated that the dipeptide, linked via Cys296-Cys310, underwent dephosphorylation at Thr308. These effects were not observed in lysates from sham animals. As a result of this dual effect of burn injury, the loose conformation that is slightly stabilized by the Lys297-Thr308 salt bridge may be replaced by a more rigid structure which may block substrate access. Together with the findings of our previous report concerning mild IRS-1 integrity changes post burn, it is reasonable to conclude that the impaired Akt1/PKBα has a major impact on FOXO3 subcellular distribution and activities.
Asunto(s)
Quemaduras/metabolismo , Músculo Esquelético/metabolismo , Óxido Nítrico/metabolismo , Proteínas Proto-Oncogénicas c-akt/química , Animales , Cisteína/química , Disulfuros/química , Proteína Forkhead Box O3 , Factores de Transcripción Forkhead/metabolismo , Expresión Génica , Inflamación , Proteínas Sustrato del Receptor de Insulina/metabolismo , Cinética , Músculo Esquelético/lesiones , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , S-Nitrosoglutatión/química , S-Nitrosoglutatión/farmacologíaRESUMEN
Psychosocial neglect during childhood severely impairs both behavioral and physical health. The isolation rearing model in rodents has been employed by our group and others to study this clinical problem at a basic level. We previously showed that immediate early gene (IEG) expression in the hippocampus and medial prefrontal cortex (mPFC) is decreased in isolation-reared (IR) compared to group-reared (GR) rats. In the current study, we sought to evaluate: (1) whether these changes in IEG expression would be detected by the measurement of brain glucose metabolism using positron emission tomography (PET) with fluorodeoxyglucose (FDG) and (2) whether PET FDG could illuminate other brain regions with different glucose metabolism in IR compared to GR rats. We found that there were significant differences in FDG uptake in the hippocampus that were consistent with our findings for IEG expression (decreased mean FDG uptake in IR rats). In contrast, in the mPFC, the FDG uptake between IR and GR rats did not differ. Finally, we found decreased mean FDG uptake in the thalamus of the IR rats, a region we had not previously examined. The results suggest that PET FDG has the potential to be utilized as a biomarker of molecular changes in the hippocampus. Further, the differences found in thalamic brain FDG uptake suggest that further investigation of this region at the molecular and cellular levels may provide an important insight into the neurobiological basis of the adverse clinical outcomes found in children exposed to psychosocial deprivation.
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Mapeo Encefálico , Hipocampo/metabolismo , Aislamiento Social , Tálamo/metabolismo , Animales , Animales Recién Nacidos , Fluorodesoxiglucosa F18 , Hipocampo/diagnóstico por imagen , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Masculino , Tomografía de Emisión de Positrones , Ratas , Ratas Sprague-Dawley , Tálamo/diagnóstico por imagenRESUMEN
Presently, there are no effective treatments for several diseases involving the central nervous system (CNS). While several novel molecular approaches are being developed, many of them require delivery of macromolecular or supramolecular agents to the CNS tissues protected by the blood-brain and blood-arachnoid barriers. A variety of approaches that are being developed for overcoming or bypassing the barriers are based on complex transfer processes. The delivery of biopharmaceuticals and other macromolecules and particulates to the CNS, especially through the leptomeningeal (intrathecal) route, includes a variety of stages, such as leptomeningeal propagation, drainage to the systemic circulation, and penetration into the CNS. The investigation of complex pharmacokinetics that includes convective, as well as diffusional and active transfer processes, greatly benefit from real-time non-invasive in vivo monitoring of the drug transport. Pharmacological positron emission tomography (PET) imaging, which enables such monitoring, plays an increasingly significant role in drug delivery and biopharmacology. PET is a powerful tool for quantitative in vivo tracking of molecules labeled with positron-emitting radionuclides. The high sensitivity, format, and accuracy of the data (similar to those of conventional tissue sampling biodistribution studies) make PET a readily adoptable pharmacological technique. In contrast to the conventional studies, PET also allows for longitudinal nonterminal same-animal studies. The latter may not only improve the data statistics, but also enable preclinical studies (especially in large and/or rare animals) not feasible under the conventional approach. This paper is intended to demonstrate the character of data that can be obtained by PET and to demonstrate how the main patterns of the leptomeningeal route pharmacokinetics can be investigated using this method. Examples of data processing are taken from our recent studies of five model proteins in rats and nonhuman primates.
RESUMEN
Presently, there are no effective treatments for conditions characterized by protein misfolding, such as Alzheimer's, Parkinson's, and other diseases involving CNS. Since misfolding occurs at the earliest stage of the disease, it is likely to be involved in subsequent pathological developments. It has been found that NPT002 (bacteriophage M13) directly dissociates aggregates of misfolded proteins that form amyloid, including amyloid-ß, tau and α-synuclein. For CNS applications, NPT002 requires delivery to the brain parenchyma, the target tissue. NPT002 is an elongated ~950 nm particle that cannot penetrate into the brain from the blood. Furthermore, phage particles, due to their size, cannot be effectively transported in vivo by diffusion. Considering the physiology of the leptomeningeal space, intrathecal administration appears to be a promising convection-driven avenue for NPT002 delivery. In this paper, we use positron emission tomography to investigate the transport of NPT002 in Macaca fascicularis. The data suggest that approximately 50 % of the administered dose can reach the cerebral leptomeningeal space after a single lumbar intrathecal injection. A biologically significant fraction of the phage then enters the brain, resulting in potentially therapeutic cortical and subcortical exposure.
RESUMEN
Akt1/protein kinase Bα (Akt1/PKBα) is a downstream mediator of the insulin signaling system. In this study we explored mechanism(s) for its role in burn injury. Akt1/PKBα in liver extracts from mice with burn injury fed with (2H7)-L-Leu was immunoprecipitated and isolated with SDS-PAGE. Two tryptic peptides, one in the kinase loop and a control peptide just outside of the loop were sequenced via nano-LC interfaced with quadruple time-of-flight tandem mass spectrometry (Q-TOF tandem MS). Their relative isotopologue abundances were determined by stable isotope labeling by amino acids in mammalians (SILAM). Relative quantifications based on paired heavy/light peptides were obtained in 3 steps. The first step included homogenization of mixtures of equal amounts of tissue from burned and sham-treated animals (i.e., isotope dilution) and acquisition of uncorrected data based on parent monoisotopic MS ion ratios. The second step included determination of isotopic enrichment of the kinase from burned mice on Day 7 and the third step enrichment correction of partially labeled heavy and light monoisotopic MS ion ratios for relative quantification of bioactivity (loop peptide) and expression level (control peptide). Protein synthesis and enrichment after injury were found to be dependent on tissue and turnover of individual proteins. Three heavy and light monoisotopic ion ratios for albumin peptides from burned mice indicated ~55% enrichment and ~16.7-fold downregulation. In contract, serum amyloid P had ~66% enrichment and was significantly upregulated. Akt1/PKBα had ~56% enrichment and kinase level in response to the burn injury was upregulated compared with the control peptide. However, kinase bioactivity, represented by the Cys296 peptide, was significantly reduced. Overall, we demonstrated that i) quantitative proteomics can be performed without completely labeled mice; ii) measurement of enrichment of acyl-tRNAs is unnecessary and iii) Cys296 plays an important role in kinase activity after burn injury.
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Aminoácidos/metabolismo , Quemaduras/enzimología , Marcaje Isotópico/métodos , Hígado/enzimología , Proteómica/métodos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Aminoácidos/análisis , Animales , Masculino , Espectrometría de Masas , Ratones , Proteínas Proto-Oncogénicas c-akt/análisis , Albúmina Sérica/análisis , Componente Amiloide P Sérico/análisisRESUMEN
BACKGROUND: Neuroimaging research has demonstrated medial prefrontal cortex (mPFC) hyporesponsivity and amygdala hyperresponsivity to trauma-related or emotional stimuli in post-traumatic stress disorder (PTSD). Relatively few studies have examined brain responses to the recollection of stressful, but trauma-unrelated, personal events in PTSD. In the current study, we sought to determine whether regional cerebral blood flow (rCBF) abnormalities in mPFC and amygdala in PTSD could be observed during the recollection of trauma-unrelated stressful personal events. METHOD: Participants were 35 right-handed male combat veterans (MCVs) and female nurse veterans (FNVs) who served in Vietnam: 17 (seven male, 10 female) with current military-related PTSD and 18 (nine male, nine female) with no current or lifetime PTSD. We used positron emission tomography (PET) and script-driven imagery to study rCBF during the recollection of trauma-unrelated stressful versus neutral and traumatic events. RESULTS: Voxelwise tests revealed significant between-group differences for the trauma-unrelated stressful versus neutral comparison in mPFC, specifically in the anterior cingulate cortex (ACC). Functional region of interest (ROI) analyses demonstrated that this interaction in mPFC represented greater rCBF decreases in the PTSD group during trauma-unrelated stressful imagery relative to neutral imagery compared to the non-PTSD group. No differential amygdala activation was observed between groups or in either group separately. CONCLUSIONS: Veterans with PTSD, compared to those without PTSD, exhibited decreased rCBF in mPFC during mental imagery of trauma-unrelated stressful personal experiences. Functional neuroanatomical models of PTSD must account for diminished mPFC responses that extend to emotional stimuli, including stressful personal experiences that are not directly related to PTSD.
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Corteza Prefrontal/irrigación sanguínea , Trastornos por Estrés Postraumático/fisiopatología , Estrés Psicológico/fisiopatología , Veteranos/psicología , Guerra de Vietnam , Anciano , Circulación Cerebrovascular/fisiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Corteza Prefrontal/fisiopatología , Estados UnidosRESUMEN
BACKGROUND: Extrapyramidal motor symptoms precede dementia in Parkinson disease (PDD) by many years, whereas dementia occurs early in dementia with Lewy bodies (DLB). Despite this clinical distinction, the neuropsychological and neuropathologic features of these conditions overlap. In addition to widespread distribution of Lewy bodies, both diseases have variable burdens of neuritic plaques and neurofibrillary tangles characteristic of Alzheimer disease (AD). OBJECTIVES: To determine whether amyloid deposition, as assessed by PET imaging with the beta-amyloid-binding compound Pittsburgh Compound B (PiB), can distinguish DLB from PDD, and to assess whether regional patterns of amyloid deposition correlate with specific motor or cognitive features. METHODS: Eight DLB, 7 PDD, 11 Parkinson disease (PD), 15 AD, and 37 normal control (NC) subjects underwent PiB-PET imaging and neuropsychological assessment. Amyloid burden was quantified using the PiB distribution volume ratio. RESULTS: Cortical amyloid burden was higher in the DLB group than in the PDD group, comparable to the AD group. Amyloid deposition in the PDD group was low, comparable to the PD and NC groups. Relative to global cortical retention, occipital PiB retention was lower in the AD group than in the other groups. For the DLB, PDD, and PD groups, amyloid deposition in the parietal (lateral and precuneus)/posterior cingulate region was related to visuospatial impairment. Striatal PiB retention in the DLB and PDD groups was associated with less impaired motor function. CONCLUSIONS: Global cortical amyloid burden is high in dementia with Lewy bodies (DLB) but low in Parkinson disease dementia. These data suggest that beta-amyloid may contribute selectively to the cognitive impairment of DLB and may contribute to the timing of dementia relative to the motor signs of parkinsonism.
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Péptidos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Demencia/metabolismo , Enfermedad por Cuerpos de Lewy/psicología , Enfermedad de Parkinson/psicología , Tomografía de Emisión de Positrones , Anciano , Compuestos de Anilina , Encéfalo/diagnóstico por imagen , Cognición , Demencia/diagnóstico , Demencia/diagnóstico por imagen , Demencia/etiología , Diagnóstico Diferencial , Femenino , Humanos , Enfermedad por Cuerpos de Lewy/fisiopatología , Masculino , Persona de Mediana Edad , Movimiento , Pruebas Neuropsicológicas , Enfermedad de Parkinson/fisiopatología , Tiazoles , Distribución TisularRESUMEN
We sought to determine whether the presence of psychotic symptoms in patients with Alzheimer's disease is associated with abnormal regional cerebral function. Perfusion single photon emission computed tomography images from 51 AD patients with psychotic symptoms were compared to images of 52 AD patients without such symptoms. Group comparisons were made with a voxel-based method, Statistical Parametric Mapping. We found that perfusion was lower in female patients with psychotic symptoms in right infero-lateral prefrontal cortex and in inferior temporal regions compared to female patients without such symptoms. In contrast, perfusion was higher in male patients with psychotic symptoms in the right striatum compared to male patients without such symptoms. Comparison groups did not differ in age or in dementia severity, as estimated by the Mini-Mental State Examination (MMSE). These results support the role of right hemisphere prefrontal and lateral temporal cortex in the psychosis of AD in women but not in men, and raise the possibility that these dysfunctional processes have a gender-specific regional pathophysiology in AD.
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Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/epidemiología , Encéfalo/irrigación sanguínea , Encéfalo/diagnóstico por imagen , Circulación Cerebrovascular , Trastornos Psicóticos/diagnóstico por imagen , Trastornos Psicóticos/epidemiología , Anciano , Comorbilidad , Femenino , Humanos , Masculino , Cintigrafía , Distribución por Sexo , Factores Sexuales , Virginia/epidemiologíaRESUMEN
OBJECTIVE: To relate cerebral perfusion abnormalities to subsequent changes in clinical status among patients with mild cognitive impairment (MCI). METHODS: Perfusion single photon emission computed tomography (SPECT) images were acquired in 105 elderly patients without dementia with MCI, using 99mTc-HMPAO. Clinical outcome after a 5-year follow-up period was heterogeneous. RESULTS: Baseline SPECT data differed in those patients with MCI who were later diagnosed with Alzheimer's disease (the converter group) from those patients with MCI who experienced clinically evident decline but did not progress to a diagnosis of Alzheimer's disease within the follow-up period (the decliner group), from patients with MCI who had no clinical evidence of progression (the stable group), and from a group of 19 normal subjects (the control group). The most consistent decreases in relative perfusion in converters compared with the normal, stable and decliner groups were observed in the caudal anterior cingulate, and in the posterior cingulate. In addition, converters showed increased relative perfusion in the rostral anterior cingulate in comparison to the stable and decliner groups. A group of patients with Alzheimer's disease were also included for purposes of comparison. The group of patients with Alzheimer's disease at baseline differed from each of the other groups, with temporoparietal regions showing the most significant reductions in perfusion. CONCLUSIONS: These results suggest that clinical heterogeneity in MCI is reflected in SPECT perfusion differences, and that the pattern of perfusion abnormalities evolves with increasing clinical severity.
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Enfermedad de Alzheimer/diagnóstico por imagen , Trastornos del Conocimiento/diagnóstico por imagen , Tomografía Computarizada de Emisión de Fotón Único , Anciano , Anciano de 80 o más Años , Encéfalo/irrigación sanguínea , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Escala del Estado Mental , Radiofármacos , Flujo Sanguíneo Regional , Exametazima de Tecnecio Tc 99mRESUMEN
Diadenosine-5',5'''-P(1),P(4)-tetraphosphate (Ap(4)A) and its analog P(2),P(3)-monochloromethylene diadenosine-5',5'''-P(1),P(4)-tetraphosphate (AppCHClppA) are competitive inhibitors of adenosine diphosphate-induced platelet aggregation, which plays a central role in arterial thrombosis and plaque formation. In this study, we evaluate the imaging capabilities of positron-emission tomography (PET) with P(2),P(3)-[(18)F]monofluoromethylene diadenosine-5',5'''-P(1),P(4)-tetraphosphate ([(18)F]AppCHFppA) to detect atherosclerotic lesions in male New Zealand White rabbits. Three to six months after balloon injury to the aorta, the rabbits were injected with [(18)F]AppCHFppA, and microPET imaging showed rapid accumulation of this radiopharmaceutical in the atherosclerotic abdominal aorta, with lesions clearly visible 30 min after injection. Computed tomographic images were coregistered with PET images to improve delineation of aortoiliac tracer activity. Plaque macrophage density, quantified by immunostaining with RAM11 against rabbit macrophages, correlated with PET measurements of [(18)F]AppCHFppA uptake (r = 0.87, P < 0.0001), whereas smooth-muscle cell density, quantified by immunostaining with 1A4 against smooth muscle actin, did not. Biodistribution studies of [(18)F]AppCHFppA in normal rats indicated typical adenosine dinucleotide behavior with insignificant myocardial uptake and fast kidney clearance. The accumulation of [(18)F]AppCHFppA in macrophage-rich atherosclerotic plaques can be quantified noninvasively with PET. Hence, [(18)F]AppCHFppA holds promise for the noninvasive characterization of vascular inflammation.
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Aterosclerosis/diagnóstico , Fosfatos de Dinucleósidos , Tomografía de Emisión de Positrones/métodos , Animales , Fosfatos de Dinucleósidos/química , Fosfatos de Dinucleósidos/farmacocinética , Modelos Animales de Enfermedad , Masculino , Estructura Molecular , Conejos , RatasRESUMEN
A 60-year-old male was referred for a positron emission tomography (PET) scan using F-18 fluoro-2-deoxyglucose (F-18 FDG) for evaluation of a right lung opacity identified on a computed tomography (CT) scan. The patient also had a history of idiopathic myelofibrosis. The PET scan revealed markedly increased uptake throughout the spleen and liver, which were massively enlarged. There was also significantly increased uptake diffusely throughout the bone marrow. These findings are a reflection of the patient's myelofibrosis.
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Fluorodesoxiglucosa F18 , Hígado/diagnóstico por imagen , Tomografía de Emisión de Positrones/métodos , Mielofibrosis Primaria/diagnóstico por imagen , Bazo/diagnóstico por imagen , Humanos , Masculino , Persona de Mediana Edad , RadiofármacosRESUMEN
Lymph nodes are primary germination and proliferation sites for many types of pathogens. Maintaining therapeutic levels of appropriate chemotherapeutic agents in the lymph node tissue is critical for the treatment of both infection and cancer. This study was intended to develop a systemic route for loading lymph node phagocytes with drugs, using a lymph node specific nanocarrier. The latter is assembled as a 10-15 nm particle with a drug-carrying core and a phagocyte-homing poly(1-->6)-alpha-d-glucose based interface. Biokinetics and microdistribution of the model carrier were investigated in vivo. Nanocarrier accumulation in lymph nodes reached 30-35% dose/g in central lymph nodes, with deposition in various phagocytic cell populations. The latter included cells harboring inhaled microparticles translocated to lymph nodes from the lungs. In view of the nanocarrier ability to transport and release significant amounts of various drug substances, the data suggests feasibility of systemic drug loading to lymphatic phagocytes and, through drug release, to the neighboring cells.
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Glucosa/análogos & derivados , Glucosa/metabolismo , Ganglios Linfáticos/metabolismo , Nanotecnología/métodos , Fagocitos/metabolismo , Animales , Antineoplásicos/farmacocinética , Vías de Administración de Medicamentos , Sistemas de Liberación de Medicamentos , Estudios de Factibilidad , Femenino , Cinética , Ganglios Linfáticos/citología , Sistema Linfático/metabolismo , Masculino , Tamaño de la Partícula , Fagocitos/citología , Conejos , Ratas , Ratas Endogámicas F344 , Ratas Sprague-DawleyRESUMEN
A water soluble macromolecular conjugate of camptothecin (CPT) with a new, dual phase hydrolytic drug release mechanism was prepared on the basis of a 60 kDa biodegradable hydrophilic "stealth" polyacetal, poly(1-hydroxymethylethylene hydroxy-methyl formal). Succinamido-glycinate was used as a prodrug releasing group. A model preparation with 7.5% CPT content w/w was water soluble. The lipophilic camptothecin prodrug, camptothecin-(O20)-succinimidoglycinate, was released from the conjugate with t(1/2) = 2.2 +/- 0.1 h in rodent plasma. The blood clearance in a rodent model as measured by CPT was release limited, t(1/2) = 2.1 +/- 0.2 h, while the conjugate half-life was 14.2 +/- 1.7 h. In a xenograft tumor model, the conjugate demonstrated higher antineoplastic efficacy than CPT at a less than equitoxic dose. This improved therapeutic window is in line with the modified drug pharmacokinetics and with camptothecin release in a stabilized lipophilic prodrug form. Regulation of prodrug release and hydrolysis rates through linker structure modification will open the way to further improve both pharmacokinetics and pharmacodynamics.
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Adenocarcinoma/tratamiento farmacológico , Antineoplásicos/síntesis química , Camptotecina/síntesis química , Neoplasias del Colon/tratamiento farmacológico , Glicina/síntesis química , Adenocarcinoma/metabolismo , Animales , Antineoplásicos/uso terapéutico , Camptotecina/análogos & derivados , Camptotecina/uso terapéutico , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Neoplasias del Colon/metabolismo , Preparaciones de Acción Retardada/síntesis química , Preparaciones de Acción Retardada/uso terapéutico , Estabilidad de Medicamentos , Glicina/análogos & derivados , Glicina/uso terapéutico , Humanos , Sustancias Macromoleculares/síntesis química , Sustancias Macromoleculares/uso terapéutico , Masculino , Ratones , Ratones Desnudos , Estructura Molecular , Factores de Tiempo , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
BACKGROUND: Positron emission tomography (PET) cameras are expensive and scarce, and the tests are non-reimbursable. A less costly and more available test such as a single photon emission computed tomography (SPECT) may be helpful in the diagnosis of early or atypical Parkinson's disease (PD) if its sensitivity is comparable to a PET scan. Altropane is an iodinated form of the N-allyl analog of WIN 35,428 which acts as a dopamine transport inhibitor. When radiolabeled with the gamma emitting isotope [123I], altropane serves as a SPECT ligand with high affinity and selectivity for the dopamine transporter. It is a good marker for dopamine neurons and is useful in detecting PD. MATERIAL AND METHODS: We describe 2 patients with typical, early PD and their [123I]-altropane SPECT and [18F]-6-flouroDOPA PET scan results which were performed within a three-month interval. PET studies were performed using a PC-4096 scanner (Scanditronix AB, Sweden) with 15 axial slices and resolution of 6 mm FWHM. The SPECT acquisitions were performed on a MultiSPECT gamma camera (Siemens, Hoffman Estates, IL) equipped with fan-beam collimators with an intrinsic resolution of 4.6 FWHM (for Case 1) and a DSI Ceraspect camera with an annular crystal, with resolution of approximately 6.4 mm FWHM (for Case 2). RESULTS: Both patients, aged 54 and 38 years, had a one-year history of intermittent right hand tremor with right arm rigidity and hypokinesia and bradykinesia on fine finger movements. A significant and sustained improvement of their parkinsonian symptoms was noted using a dopamine agonist. SPECT and PET scans showed non-diagnostic fluoroDOPA PET scans with clear unilateral striatal reduction of tracer uptake contralateral to their parkinsonian side on altropane SPECT scans. CONCLUSIONS: Altropane SPECT may be an accessible and sensitive imaging modality for detecting early PD. Further and more controlled studies are needed to define its potential role in detecting presymptomatic, early and atypical PD cases.
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Cocaína/análogos & derivados , Dihidroxifenilalanina/análogos & derivados , Enfermedad de Parkinson/diagnóstico por imagen , Tomografía Computarizada de Emisión de Fotón Único/métodos , Tomografía Computarizada de Emisión/métodos , Adulto , Cuerpo Estriado/diagnóstico por imagen , Humanos , Masculino , Persona de Mediana Edad , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: As interventions for severe, treatment-refractory obsessive compulsive disorder (OCD), neurosurgical procedures are associated with only modest efficacy. The purpose of this study was to identify cerebral metabolic correlates as potential predictors of treatment response to anterior cingulotomy for OCD. METHODS: Clinical data were analyzed in the context of a retrospective design. Subjects were 11 patients who underwent stereotactic anterior cingulotomy for OCD. Symptom severity was measured using the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) before and at approximately 6 months postoperative. Preoperative F-18-fluorodeoxyglucose-positron emission tomography (FDG-PET) data were available. Statistical parametric mapping methods were used to identify loci of significant correlation between preoperative regional cerebral metabolism and postoperative reduction in Y-BOCS scores. RESULTS: One locus within right posterior cingulate cortex was identified, where preoperative metabolism was significantly correlated with improvement in OCD symptom severity following cingulotomy. Specifically, higher preoperative rates of metabolism at that locus were associated with better postoperative outcome. CONCLUSIONS: A possible predictor of treatment response was identified for patients with OCD undergoing anterior cingulotomy. Further research, utilizing a prospective design, is indicated to determine the validity and reliability of this finding. If confirmed, an index for noninvasively predicting response to cingulotomy for OCD would be of great value.
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Giro del Cíngulo/metabolismo , Giro del Cíngulo/cirugía , Procedimientos Neuroquirúrgicos/métodos , Trastorno Obsesivo Compulsivo/diagnóstico , Trastorno Obsesivo Compulsivo/cirugía , Adulto , Femenino , Fluorodesoxiglucosa F18/farmacocinética , Giro del Cíngulo/anatomía & histología , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Periodo Posoperatorio , Cuidados Preoperatorios , Radiofármacos/farmacocinética , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Técnicas Estereotáxicas , Encuestas y Cuestionarios , Tomografía Computarizada de Emisión , Resultado del TratamientoAsunto(s)
Péptido Natriurético Encefálico/sangre , Resistencia Física/fisiología , Carrera/fisiología , Troponina I/sangre , Troponina T/sangre , Adulto , Creatina Quinasa/sangre , Forma MB de la Creatina-Quinasa , Cardiopatías/sangre , Humanos , Isoenzimas/sangre , Persona de Mediana Edad , Mioglobina/sangre , Tomografía Computarizada de Emisión de Fotón Único , Disfunción Ventricular Izquierda/diagnósticoRESUMEN
OBJECTIVE: To delineate functional brain abnormalities associated with anorexia nervosa (AN). STUDY DESIGN: Positron emission tomographic measurements of regional cerebral blood flow (rCBF) were performed on 8 female patients with AN and 8 healthy female control subjects during exposure to 3 types of stimuli: high-calorie foods, low-calorie foods, and non-food items. Heart rate and internal state analog scale scores were also obtained. Stereotactic transformation and statistical parametric mapping techniques were used to analyze imaging data. RESULTS: During the high-calorie condition, control subjects reported a significant desire to eat, whereas subjects with AN reported elevated anxiety and exhibited increases in heart rate. Patients with AN had elevated bilateral medial temporal lobe rCBF compared with control subjects. Planned comparisons for group-by-condition interactions demonstrated greater activation within left occipital cortex and right temporo-occipital cortex for the high-calorie versus low-calorie contrast in patients with AN compared with control subjects. CONCLUSIONS: Our finding of elevated rCBF within bilateral medial temporal lobes is similar to published results in patients with psychotic disorders and may be related to the body image distortion common to AN. The high-calorie food phobia exhibited by patients with AN appears to be associated with exaggerated responses in visual association cortex, as has been previously observed in studies of specific phobias.
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Anorexia Nerviosa/diagnóstico por imagen , Anorexia Nerviosa/psicología , Encéfalo/diagnóstico por imagen , Adulto , Anorexia Nerviosa/fisiopatología , Encéfalo/fisiopatología , Estudios de Casos y Controles , Corteza Cerebral/fisiopatología , Circulación Cerebrovascular , Femenino , Alimentos , Frecuencia Cardíaca , Humanos , CintigrafíaRESUMEN
BACKGROUND: To assess the diagnostic usefulness and clinical impact of positron emission tomography with [F-18]fluorodeoxyglucose (FDG PET) on the management of patients with known or suspected pancreatic carcinoma. METHODS: Attenuation-corrected FDG PET was performed in 20 patients (12 male, eight female) with pancreatic carcinoma at the time of initial diagnosis (n = 7), for tumor surveillance after Whipple surgery (n = 11), and for reevaluation after chemoradiation therapy (n = 2). Visual analysis of PET images were correlated with the results of abdominal computed tomography (CT) and carbohydrate antigen (CA) 19-9 serum tumor marker level that were obtained within 1 month of the PET study. Diagnostic validation was by histology in nine patients and by clinical or radiologic follow-up (5-48 months) in 11 patients. Changes in therapeutic management that were prompted by PET were tabulated. RESULTS: PET was concordant with the findings of abdominal CT in 14 patients (13 true positive, 1 true negative). PET detected clinically unsuspected lung lesions, confirmed subsequently by a chest CT, in one of these 14 patients. PET was discordant with CT in six patients. PET detected tumor recurrence in three patients in this group (15% of total) with nondiagnostic CT findings and elevated CA 19-9 serology. In two of these three patients, chemotherapy with gemcitabine was initiated based on PET localization of disease. Tumor was confirmed in the remaining one of the three patients at autopsy shortly after the PET study. FDG localization in a displaced loop of bowel resulted in an apparent false-positive hepatic lesion in one of six patients in the discordant group. PET underestimated the extent of metastatic disease in the remaining two of six patients due to hyperglycemia. CONCLUSION: In patients with suspected pancreatic carcinoma at the time of initial presentation, PET is complementary to abdominal CT and allows detection of unsuspected distant metastases. In patients with suspected recurrent pancreatic carcinoma, based on elevated or rising CA 19-9 serology, PET can localize the disease when abdominal CT is nondiagnostic as a result of posttherapy anatomic alteration. Imaging evaluation with PET may impact the clinical management of patients with pancreatic carcinoma.
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Carcinoma Ductal Pancreático/diagnóstico por imagen , Carcinoma Ductal Pancreático/diagnóstico , Fluorodesoxiglucosa F18 , Neoplasias Pancreáticas/diagnóstico por imagen , Neoplasias Pancreáticas/diagnóstico , Radiofármacos , Tomografía Computarizada de Emisión/métodos , Adulto , Anciano , Antígenos de Carbohidratos Asociados a Tumores , Diagnóstico Diferencial , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tomografía Computarizada por Rayos X/métodosRESUMEN
Ecteinascidin 743 (ET-743) is a cytotoxic tetrahydroisoquinoline alkaloid that covalently binds to DNA in the minor groove. The in vitro chemosensitivity of cancer cells to ET-743 is markedly enhanced by prolonging the duration of exposure to the drug. A Phase I study of ET-743 given as a 72-h continuous i.v. infusion every 21 days was performed. Characteristics of the 21 adult patients with refractory solid tumors enrolled in the study were as follows: (a) 12 men; (b) 9 women; (c) median age, 59 years; (d) Eastern Cooperative Oncology Group performance status < or = 1, 20 patients; and (e) two prior regimens of chemotherapy, 7 patients. Dose limiting toxicity (DLT) was defined by typical criteria, except that grade 3 transaminitis did not constitute a DLT. There were no DLTs in the six patients evaluated at the first two dose levels of 600 and 900 microg/m2. Reversible grade 4 transaminitis occurred in two of nine patients after treatment with the first cycle of therapy at the third dose level of 1200 microg/m2. Another patient experienced grade 4 rhabdomyolysis, renal failure requiring hemodialysis, grade 4 neutropenia, and grade 3 thrombocytopenia during the second cycle of therapy with this dose. The maximum tolerated dose was 1200 microg/m2, and an additional six patients were enrolled at an intermediate dose level of 1050 microg/m2. This well-tolerated dose was established as the recommended Phase II dose. The disposition of ET-743 was distinctly biexponential, and a departure from linear pharmacokinetic behavior was evident at the 1200-microg/m2 dose level. Pharmacokinetic parameters determined at 1050 microg/m2 were (mean +/- SD): maximum plasma concentration, 318 +/- 147 pg/ml; initial disposition phase half-life, 9.0 +/- 10.3 min; terminal phase half-life, 69.0 +/- 56.7 h; and total plasma clearance, 28.4 +/- 22.5 liters/h/m2. Prolonged systemic exposure to concentrations of the agent that are cytotoxic in vitro were achieved. Toxicity of the drug is clearly schedule-dependent, because increasing the duration of infusion from 3 or 24 h to 72 h results in decreased myelosuppression and comparable hepatotoxicity. Although there were no objective responses to therapy, clear evidence of antitumor activity was observed in a patient with epithelioid mesothelioma, as confirmed by positron emission tomography studies. A Phase II trial to assess the efficacy of ET-743 against this highly refractory neoplasm has been initiated on the basis of this observation. The therapeutically optimal administration schedule remains to be established, inasmuch as there have been indications of activity against a variety of tumors during Phase I studies when the drug was infused over times ranging from 1 to 72 h. Characterizing the pharmacokinetics of ET-743 during the course of Phase II trials and Phase I combination studies is recommended to assure that this promising new anticancer drug can be used with an acceptable margin of safety.
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Antineoplásicos Alquilantes/farmacocinética , Dioxoles/farmacocinética , Isoquinolinas/farmacocinética , Neoplasias/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Alanina Transaminasa/metabolismo , Área Bajo la Curva , Aspartato Aminotransferasas/metabolismo , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Infusiones Intravenosas , Hígado/efectos de los fármacos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Modelos Químicos , Tetrahidroisoquinolinas , Factores de Tiempo , Pruebas de Toxicidad , TrabectedinaRESUMEN
The E isomer of (123)I-2beta-carbomethoxy-3beta-(4-fluorophenyl)-N-(1-iodoprop-1-en-3-yl)nortropane (Altropane(R)) shows high affinity (IC(50) = 6.62 +/- 0.78 nmol) and selectivity (DA/5-HT = 25) for DAT sites in the striatum. Recently, dynamic SPECT studies in healthy volunteers and patients with Parkinson disease demonstrated that the kinetics of striatal accumulation followed a pattern that is characteristic of a reversible tracer with maximal accumulation within 30 min after injection. These findings suggested that radiolabeling Altropane with [(11)C] might provide an equivalent and complementary tracer for PET studies. [(127)I] Altropane was treated with HCl to hydrolyze the methyl ester bond and yield a precursor for [(11)C] labeling. Introduction of an [(11)C] methyl ester group was achieved by treatment with [(11)C] CH(3)I followed by HPLC purification. Five healthy rhesus monkeys were injected with approximately 10 mCi of [(127)I,(11)C] Altropane and dynamic PET images were acquired over 90 min. Arterial blood samples were collected in parallel with imaging and metabolite analysis was performed by HPLC. The PET and metabolite corrected arterial blood data were to calculate k(3)/k(4) by two methods: 1) nonlinear least-squares fitting, and 2) a linear graphical method for reversible ligands. The synthetic procedure yielded high specific activity tracer, >1,000 mCi/micro mole, with radiochemical purity >95%. Synthesis time was approximately 30 min. The PET images revealed excellent striatal definition, with clear separation of caudate nucleus and putamen and minimal accumulation in brain regions with high 5HT transporter density. Metabolite analysis demonstrated that at 60 min after injection, approximately 80% of circulating tracer was intact [(127)I,(11)C] Altropane and the remainder was converted to polar metabolites. Values for k(3)/k(4) calculated by two analysis methods were remarkably similar: Method 1, 3.48 +/- 0.41; Method 2, 3.77 +/- 0.45 (mean +/- SEM, t = 2.31, df = 8, P = 0.64). These results establish that Altropane has the important characteristics of: 1) rapid and specific striatal binding; 2) high selectivity for DA vs. 5-HT transporter sites; 3) reversible binding kinetics; 4) potential for multiple injection studies; 5) high efficiency labeling with either [(11)C] or [(123)I]; 6) applicability for both PET and SPECT. These properties make Altropane an important DAT ligand for both research and clinical applications.