[Respiratory muscle disorders in chest wall diseases].
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Adult↗
Biomedical subjects
J Pavía
Publications and source records attributed to J Pavía.
Double-blind olanzapine vs. haloperidol D2 dopamine receptor blockade in schizophrenic patients: a baseline-endpoint.
The aim of this study was to compare in vivo striatal D2 dopamine receptor occupancy induced by olanzapine and haloperidol in schizophrenic patients using a baseline-endpoint [(123)I]IBZM single photon computed emission tomography (SPECT) design. The relationships of striatal D2 receptor occupancy with clinical efficacy and extrapyramidal symptoms (EPS) were also assessed. Twenty-seven inpatients with schizophrenia or schizophreniform disorder were included in a 4-week prospective, randomized, double-blind, parallel and comparative clinical trial. Thirteen patients were treated with haloperidol (10 mg/day) and 14 with olanzapine (10 mg/day). Ratings of clinical status and EPS were obtained weekly. The percentage of D2 receptor occupancy was estimated by using basal ganglia (striatum)/frontal cortex IBZM uptake ratios obtained from each patient before and after 4 weeks of maintained antipsychotic treatment. Olanzapine led to a mean striatal D2 receptor occupancy of 49% (range 28-69%), which was significantly lower than that induced by haloperidol (mean 64%, range 46-90%). The baseline-endpoint SPECT design used in this study revealed lower antipsychotic D2 occupancy percentage values than those reported in the literature, using other approaches. The degree of striatal D2 receptor occupancy correlated to the EPS, which predominantly appeared in patients on haloperidol. No relationship was found between the striatal D2 receptor occupancy and clinical improvement. Olanzapine induced a lower striatal D2 occupancy than haloperidol. This low striatal D2 occupancy, together with the lower incidence of EPS in olanzapine-treated patients, contributed to confirm the atypical behavior of this new antipsychotic drug. Nevertheless, conclusions based on SPECT-estimated percentages of antipsychotic D2 occupancy should be cautious, since the SPECT design could influence the results. In this regard, SPECT studies including baseline and endpoint examinations should be encouraged.
Adult↗
Muscarinic receptor subtypes and calcium signaling in Fischer rat thyroid cells.
A specific and saturable binding site for [3H]N-methyl-scopolamine ([3H]NMS) was observed in plasma membrane of Fischer rat thyroid (FRT) cells with an equilibrium dissociation constant (K(d)) of 0.11 +/- 0.02 nM and a concentration of receptor sites (B(max)) of 14.1 +/- 3.9 fmol/mg protein. Pharmacological characterization of this binding site using pirenzepine, himbacine, (11(2-diethyl-amino)methyl)-1-piperidinylacetyl-5-11-dihydro-6H-pyrido(14) benzodiazepine (AF-DX 116), dicyclomine, 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP), and hexahydro-sila-difenidol (HHSD) showed clear differences, in terms of affinities, between these muscarinic receptor antagonists. The order of potency for inhibiting [3H]NMS binding was HHSD = dicyclomine > 4-DAMP > pirenzepine = himbacine > AF-DX 116. These findings suggest that the muscarinic receptors found in FRT cells belong to the M3 subtype. Stimulation of FRT cells with carbachol produced a biphasic and dose-dependent increase in the intracellular calcium concentration ([Ca2+]i), which was blocked in pretreated cells with atropine and almost abolished by a low concentration of 4-DAMP and HHSD. Removal of extracellular Ca2+ from the incubation medium reduced the initial transient peak and completely abolished the plateau phase, while the transient phase was markedly reduced by the phospholipase C inhibitor U73122. These data indicate that [Ca2+]i results from both Ca2+ influx across Ca2+ channels and mobilization of Ca2+ from intracellular Ca2+ stores. The present data showed the presence of the M3 muscarinic acetylcholine receptor subtype in plasma membrane of FRT cells, which may influence cellular function via modulation of [Ca2+]i.
Animals↗
Characterisation of fan-beam collimators.
Fan-beam collimators offer a good balance between resolution and noise. The collimator response may be included in iterative reconstruction algorithms in order to improve single-photon emission tomography (SPET) resolution. To this end, accurate determination of the focal region and characterisation of the collimator response as a function of the source co-ordinates must be performed. In this paper, a method to characterise fanbeam collimators is evaluated. First, we calculated the real focal region and the accuracy of the collimator convergence. Then, we confirmed the hypothesis that Gaussian distributions adequately fit the collimator responses, although no individualised treatment was performed for the tails of detector response which are associated with scattering and septal penetration. Finally, analytical functions were used to model the resolution and sensitivity. The parameter values in these functions were obtained from experimental measures by non-linear regression fitting. Our findings show differences of 1.43% between nominal and real focal length and standard deviations of 2.5 mm in the x-direction and 7.1 mm in the y-direction for the focal convergence. The correlation coefficients between experimental and predicted values were 0.994 for resolution and 0.991 for sensitivity. As a consequence, the proposed method can be used to characterise the collimator response.
Algorithms↗
[Tomographic studies of myocardial perfusion normality with 99m Tc-Tetrofosmin. Spanish multicenter study].
As a first phase in a nationwide multicenter study to obtain myocardial perfusion normality patterns, this work presents the study design and quality control methodology used to guarantee that the gammacameras fulfilled some minimum quality requirements. The following aspects were considered in the study design in order to guarantee the homogeneity and interchangeability of the results: creation and structure of the work group, data interchange system, data selection and acquisition, centralized archiving and processing, assessment system, study acceptance criteria and distribution of the results. To carry out the instrumental quality control, three phantom studies were established, one to control the rotation center, another to verify tomographic uniformity and a third to simulate the shape and orientation of the left ventricle. The three phantoms circulated through all of the 18 participating centers in this project, which corresponded to 19 gammacameras. Very strict guidelines had to be followed in the acquisition and processing of these phantom studies. If any camera and/or center did not fulfill the criteria established, it was advised of the problem detected in order to correct it. Once the defect was repaired, all the phantoms were sent again for verification. Uniformity of the rotation center was quantified by means of the eccentricity of a 360 degrees orbit, admitting up to a maximum of 10%. Tomographic uniformity was visually assessed, taking in account the number of slices with rings and their contrast and finally no artifacts could be present in the reconstructed study of the ventricle. The center of rotation was within limits in all the cameras except one case while the tomographic uniformity was incorrect in 6 cases. All the departments, except one, corrected the defects detected, and passed the acceptance test. The results made it possible to guarantee adequate homogeneity and instrumental quality in this multicenter study.
Coronary Circulation↗
[Tomographic studies of myocardial perfusion normality with 99m Tc-Tetrofosmin. Spanish multicenter study].
This objective of this study was to obtain a pool of Myocardial Perfusion SPECTs with a 99mTetrofosmin stress/rest one day protocol in normal volunteers having a less than or equal to 5% likelihood of coronary artery disease that represents normalcy in the Spanish population. A total of 169 volunteers from 15 hospitals were studied. The volunteers were divided into 5 groups: Groups 1, 2 or 3 corresponding to men < 30 years (n = 33), men between 30 and 50 years (n = 32), or men > 50 years (n = 31); Groups 4 or 5: premenopausal (n = 38) or postmenopausal women (n = 35). A clinical history, physical examination, clinical laboratory parameters, echocardiography and a symptom limited exercise stress test were performed in all of them and had to be normal. The mean likelihood of coronary artery disease was 1.15 +/- 1.07%.Twenty-four segments were analyzed in each study and were classified into 5 grades of uptake (1 = normal, 2, 3, 4 = mild, moderate or severe defect and 5 = no uptake). Defects were then analyzed according to sex and location. Considering the stress and rest studies separately (8,112 segments), only 19 moderate and 75 mild defects were found, these corresponding to 16 volunteers, with more inferior defects in men and anterior defects in women. These data validate the normalcy of our population. A pool of Myocardial Perfusion SPECTs with a 99mTetrofosmin stress/rest one day protocol in normal volunteers that represents Spanish normal values was obtained.
Adult↗
Activation of muscarinic acetylcholine receptors induces Ca(2+) mobilization in FRT cells.
The effect of the muscarinic receptors agonist carbachol (Cch) on intracellular calcium concentration ([Ca(2+)](i)) and cAMP level was studied in polarized Fischer rat thyroid (FRT) epithelial cells. Cch provoked a transient increase in [Ca(2+)](i), followed by a lower sustained phase. Thapsigargin, a specific microsomal Ca(2+)-ATPase inhibitor, caused a rapid rise in [Ca(2+)](i) and subsequent addition of Cch was without effect. Removal of extracellular Ca(2+) reduced the initial transient response and completely abolished the plateau phase. Ryanodine, an agent that depletes intracellular Ca(2+) stores through stimulation of ryanodine receptors (RyRs), had no effect on [Ca(2+)](i). However, the transitory activation of [Ca(2+)](i) was dose-dependently attenuated in cells pretreated with U73122, a specific inhibitor of phospholipase C (PLC). These data suggest that the Cch-stimulated increment of [Ca(2+)](i) required IP(3) formation and binding to its specific receptors in Ca(2+) stores. Further studies were performed to investigate whether the effect of Cch on Ca(2+) entry into FRT cells was via L-type voltage-dependent Ca(2+) channels (L-VDCCs). Nicardipine, a nonspecific L-type Ca(2+) channel blocker, decreased Cch-induced increase on [Ca(2+)](i), while Bay K-8644, an L-type Ca(2+) channel agonist, slightly increased [Ca(2+)](i) in FRT cells. These data indicate that Ca(2+) entry into these nondifferentiated thyroid cells occurs through an L-VDCC, and probably through another mechanism such as a capacitative pathway. Cch did not affect the intracellular cAMP levels, but its effects on [Ca(2+)](i) were significantly reduced when cells were pretreated with forskolin, suggesting the existence of an intracellular cross-talk between PLC and cAMP mechanisms in the regulation of intracellular Ca(2+) mobilization in neoplastic FRT cells.
Animals↗
Brain perfusion and neuropsychological changes in schizophrenic patients after cognitive rehabilitation.
The role of cognitive variables was compared in two single cases of schizophrenia hypofrontality. SPECT procedures and neuropsychological tests were used to study frontal brain function. After cognitive rehabilitation, neuropsychological performance were enhanced in both patients, but only one of them showed enhanced the frontal blood flow. The brain perfusion changes after cognitive rehabilitation could be associated with the cognitive-dependent hypofrontality.
Adult↗
Repeated intracerebroventricular administration of beta-amyloid(25-35) to rats decreases muscarinic receptors in cerebral cortex.
The effects of repeated in vivo administration to rats of beta-amyloid(25-35) (betaA(25-35)) on several cholinergic markers have been studied and compared with those of a peptide with a scrambled sequence. Rats received intracerebroventricular injections of betaA(25-35) (5 or 20 microg/day) for 7 days and they were sacrificed at 2 or 3 weeks survival. The density of total muscarinic receptors labeled with [3H]N-methyl-scopolamine was dose-dependently decreased by betaA(25-35) in the cerebral cortex at 3 weeks survival. No changes were observed at 2 weeks survival in cerebral cortex or in the hippocampus, at any time. BetaA(25-35) administration did not modify choline acetyltranferase activity in cerebral cortex. However, in betaA(25-35)-treated rats hypertrophic/hyperactive positive acetylcholinesterase nucleus basalis cholinergic neurons were observed at 2 weeks survival, while the density of acetylcholinesterase-positive fibers of cerebral cortex was increased along with the number of cortical positive neurons at 3 weeks survival. These results suggest that increased cholinergic function may be responsible of muscarinic receptor down-regulation. Given the involvement of cholinergic systems in memory and learning, repeated administration of betaA(25-35) may represent a good approach to explore the role of betaA in Alzheimer's disease and to develop therapeutic strategies relevant to it.
Acetylcholinesterase↗
Effects of chronic administration of S-adenosyl-L-methionine on brain oxidative stress in rats.
S-adenosyl-L-methionine (SAM), used to treat liver diseases and as a coadjuvant in antidepressive medication, has neuroprotective effects in animal models. The aim of this study was to discover whether SAM has antioxidant effects in rat brain tissue. Ten male Wistar rats were killed by decapitation and the forebrains incubated with SAM for in vitro experiments. To study the effects of long-term administration, animals in four groups of ten rats each were given 10 mg SAM/kg per day s.c., and 40 other rats were given an equivalent volume of L-lysine (the commercial solvent for SAM). Treatment was started at the end of lactation, and animals were killed by decapitation after 15 days or 1, 6 or 22 months of treatment. The forebrain of each animal was used to test membrane lipid peroxidation by determining thiobarbituric acid-reactive substances (TBARS), glutathione level and enzyme activities related to glutathione (reduced form GSH, oxidized form GSSG) metabolism: GSH-peroxidase (GSHpx), GSSD-reductase (GSSGrd) and GSH-transferase (GSHtf). Chronic treatment with SAM decreased maximum forebrain production of TBARS by 46% compared with animals given L-lysine and increased glutathione levels by 50%, GSHpx activity by 115% and GSHtf activity by 81.4%. The results of in vitro experiments were qualitatively similar: lipid peroxidation was inhibited (13.1+/-1.3 nmol/mg protein in controls vs. 5.9+/-0.8 nmol/mg protein in samples incubated with 1000 micromol/l SAM) and glutathione levels were stimulated (0.97+/-0.06 micromol/g tissue in control samples vs. 1.55+/-0.08 micromol/g tissue in samples incubated with 1000 micromol/l SAM), as were GSHpx and GSHtf. No significant effect was seen in any of the experiments with L-lysine. We conclude that SAM has antioxidant effects in rat brain tissue both in vitro and ex vivo. The effect is seen both as inhibition of lipid peroxide production and as an enhancement of the endogenous glutathione antioxidant system.
Animals↗
Migration pathways of hypodermically injected technetium-99m in dogs.
Hypodermic injection of technetium-99m (99mTc-pertechnetate) at points of low electrical resistance give rise to rapid, longitudinal, and progressive diffusion of the radioactive tracer. We assessed the effect of cutaneous incisions that did not intersect the migration trajectory of 99mTc-pertechnetate and the re-establishment of pathways after the suture of incisions that intersected the migration trajectory. Linear and rapid migration of 99mTc-pertechnetate was not altered or prevented by incisions that did not intersect the migration pathway. Different patterns of 99mTc-pertechnetate spread were found when incisions intersected the radioactive pathways until restoration of the normal migration pathway observed in undamaged skin occurred. In all experiments in which migration of 99mTc-pertechnetate was observed, lavage of surgical wounds was followed by disappearance of the 99mTc-pertechnetate migration observed around the suture. Linear migration of the tracer was not observed when the incision was left uncovered, filled with petroleum jelly, or with a solid silicone sheet, but it was seen when non-sutured incisions were filled with transonic or silicone gel or covered with a solid silicone sheet parallel to the cutaneous plane. These data show that after a cutaneous incision that intersected the diffusion trajectory of the radioactive tracer, linear migration of 99mTc-pertechnetate hypodermically injected at points of low electrical resistance was restored before healing of the cutaneous incision and was independent of incisions made on the skin not overlying the radioactive pathway. A mechanism similar to that of capillary electrophoresis is suggested to explain the hypodermic diffusion of inert particles through specific and constant linear pathways.
Animals↗
Evaluation of algorithms for the registration of 99Tcm-HMPAO brain SPET studies.
Five functions of merit were used for the registration of 99Tcm-HMPAO brain SPET studies. The correlation coefficient (COR), the stochastic sign change (SSC), the standard deviation of ratios (SDR), the sum of the absolute differences (SAD) and a new function based on a local correlation coefficient (LOC) were tested in the registration of photic neuroactivation (ACT), epilepsy (EPL) and Wada (WAD) SPET studies. The comparison included simulated and real studies. The translation error in registration was 0.1 +/- 0.1 pixels (mean +/- S.D.) for all functions of merit for the complete set of simulated studies (10 runs for each ACT, EPL and WAD). For rotation, LOC yielded the best results with a mean error of 0.3 +/- 0.2 degree and a maximum error of 0.6 degree. Slightly higher errors were found with SAD (0.4 +/- 0.2 degree, maximum 1.0 degree) and COR (0.5 +/- 1.0 degree, maximum 1.0 degree). The highest errors were found with SDR (0.8 +/- 1.0 degree, maximum 4.8 degrees) and SSC (0.8 +/- 1.1 degrees, maximum 4.7 degrees). The results obtained from five real studies of ACT, of EPL and of WAD were in agreement with the findings from the simulated studies, thus confirming the robustness of LOC, SAD and COR for the registration of 99Tcm-HMPAO brain SPET studies.
Algorithms↗
Quantitative evaluation of bone scintigraphy in the assessment of Paget's disease activity.
Interest in the assessment of activity of Paget's disease has increased since the advent of effective therapies. The aim of this study was to develop a quantitative method for the scintigraphic assessment of Paget's disease activity in bone. Twenty patients with Paget's disease were studied prospectively. A scintigraphic visual activity index, together with a quantitative activity index that reflects both the extent and activity of the disease, was obtained for each patient. The quantitative activity index is calculated as the sum of the activity (geometric mean measured from the anterior and posterior views) for all affected bones divided by a reference obtained in non-affected bone. To evaluate the validity of the scintigraphic methods, several biochemical markers of bone turnover were assessed: serum total alkaline phosphatase and serum propeptide aminoterminal of type I procollagen (PINP) as markers of bone formation; urinary hydroxyproline and urinary N-terminal cross-linked telopeptide of type I collagen (NTx) as markers of bone resorption. The visual and quantitative scintigraphic indices were highly correlated (r = 0.78, P < 0.0001). The highest correlations between the biochemical markers and the quantitative activity index were found for PINP (r = 0.69, P < 0.001), which was the most sensitive marker of bone formation, and for urinary NTx (r = 0.63, P < 0.005), which was the most sensitive marker of bone resorption. In conclusion, quantitative evaluation of bone scintigraphy allows easy and objective assessment of Paget's disease activity and it may be useful in evaluating the effectiveness of therapies.
Adult↗
[Myocardial perfusion scintigraphy with 99mTC-sestamibi and gated SPECT and myocardial perfusion scintigraphy with reinjection of 201Tl at 24 hours. Are the techniques comparable?].
AIM: To compare the results obtained with 99mTc-sestamibi and gated-SPECT (gated SPECT in stress and rest) with 201Tl (stress, redistribution, and 24 hour reinjection SPECT). METHODS: Twenty patients underwent two SPECT studies, one with 201Tl and the other with 99mTc-sestamibi. RESULTS: Using 201Tl as a reference, 177 segments were considered normal, 31 viable and 32 with myocardial necrosis. The overall concordance with 99mTc-sestamibi was 84.2%. In the subgroup of defects that improved after reinjection of 201Tl, it was much less (45%), even after wall thickness and movement (55%) were analyzed. CONCLUSION: The overall concordance between 201Tl scintigraphy compared to 99mTc-sestamibi is acceptable. Correlation is low in the viable segments with 99mTc-sestamibi, even after analyzing the Gated-SPECT.
Adult↗
Role of the cingulate gyrus during the Wisconsin Card Sorting Test: a single photon emission computed tomography study in normal volunteers.
The purpose of this study was to investigate the effect of the Wisconsin Card Sorting Test (WCST) on frontal regional cerebral blood flow (rCBF) in normal subjects, separating the cingulate gyrus from the prefrontal cortex. Two technetium-99m-hexamethyl-propylene-amine-oxime brain single photon emission computed tomography (SPECT) scans, at rest and during WCST performance, were performed in randomized order on 13 right-handed normal volunteers. A statistically significant rCBF increase was found in the left inferior cingulate and the left posterior frontal region, although rCBF ratios in the left and right prefrontal cortex, and in the right inferior cingulate, were slightly higher during WCST performance in nine of the 13 subjects studied. No differences in activation scores (activated-resting rCBF ratios) were found between subjects who had the resting SPECT first and subjects who had the resting condition second. These results suggest that the inferior cingulate cortex, a limbic region that has been implicated in attentional mechanisms, plays a significant role in WCST performance. Furthermore, the motor component of the WCST may account for the activation of the left posterior frontal region. In addition, no order effect was found in this study. These findings illustrate the advantage of independently evaluating the cingulate gyrus and the prefrontal cortex in SPECT studies of frontal cognitive function.
Adult↗
Evaluation of a cross-validation stopping rule in MLE SPECT reconstruction.
One of the problems in the routine use of the maximum-likelihood estimator method-expectation maximization (MLE-EM) algorithm is to decide when the iterative process should be stopped. We studied a cross-validation stopping rule to assess its usefulness in SPECT. We tested this stopping rule criterion in the MLE-EM algorithm without acceleration as well as in two accelerating algorithms, the successive substitutions algorithm (SSA) and the additive algorithm (AA). Different values of an acceleration factor were tested in SSA and AA. Our results from numerical and physical phantoms show that the stopping rule based on the cross-validation ratio (CVR) takes into account the similarity of the reconstructed image to the ideal image, noise and the contrast of the image. CVR yields reconstructed images with balanced values of the figures of merit (FOM) employed to assess the image quality. The CVR criterion can be used in the original MLE-EM algorithm as well as in SSA and AA. The reconstructed images obtained with SSA and AA showed FOM values that were very similar. These results were justified by considering AA to be an approximate form of SSA. The range of validity for the acceleration factor in SSA and AA was found to be [1, 2]. In this range, an inverse function connects the acceleration factor to the number of iterations needed to attain prefixed values of FOMs.
Algorithms↗
Predictive value of 99Tcm-sestamibi gated SPET for long-term myocardial perfusion and functional recovery after an acute myocardial infarction.
We assessed the predictive value of 99Tcm-sestamibi gated single photon emission tomography (SPET) for changes in perfusion and functional outcome after an acute myocardial infarction and compared the findings on functional recovery with echocardiography using low-dose dobutamine. Gated 99Tcm-sestamibi SPET and radionuclide angiocardiography were performed in 17 patients 4-10 days after an acute myocardial infarction. Six months later, both isotopic studies and rest-dobutamine echocardiography were performed to assess outcome. Perfusion improved in six of seven severely hypoperfused segments (positive predictive value = 85.7%) that showed wall thickening but not in any of 28 segments (negative predictive value = 100%) without wall thickening. The mean ejection fraction improved from 47.7 to 52.3% (P = 0.018). Furthermore, there was a greater improvement in ejection fraction in the group of patients in whom wall thickening predicted a recovery in perfusion (9.0 vs 3.7%, P = 0.01). A comparison of the assessment of functional recovery between gated SPET and dobutamine echocardiography showed good agreement (81.4%). We conclude that the presence of wall thickening in severely hypoperfused segments on 99Tcm-sestamibi gated SPET is predictive of changes in perfusion and functional recovery after acute myocardial infarction, thus identifying the presence of viable myocardium. In contrast, segments showing hypoperfusion and dysfunction after an acute myocardial infarction probably contain scar tissue only.
Adult↗
Alzheimer's disease: relationship between muscarinic cholinergic receptors, beta-amyloid and tau proteins.
Senile dementia is one of the most important health problems in developed countries. The main disease causing dementia is Alzheimer's disease that is characterized by the progressive deterioration of the cholinergic system, beta-amyloid production and deposition, and neurofibrillary tangle formation. Most of the reviewed data, along with data from experiments performed in our laboratory, suggest that there are no changes in the number of muscarinic receptors between Alzheimer and control brains, although the receptors expressed in Alzheimer's disease brains can be anomalous in their function. The muscarinic receptor-G-protein interaction also seems to be impaired in Alzheimer's disease compared with control brains, as well as the G-protein system, with an important decrease in the function of the Gq/11, the most important G-protein stimulating phosphoinositide hydrolysis in human brain; in addition, the second messenger system is also impaired, with a decrease in the synthesis of phosphoinositides and in the number of IP3 receptors. Muscarinic cholinergic receptors are also linked to beta-amyloid production, stimulation of the M1 subtype with agonists results in the processing of the beta-amyloid precursor protein to non-amyloidogenic products and administration of a fraction of the beta-amyloid (beta-amyloid 25-35) to rats, results in a decrease in the number of muscarinic receptors in brain. M1 agonists also decrease the phosphorylation of tau proteins, playing again a modulatory role in the pathogenesis of Alzheimer's disease. The existence of a link between beta-amyloid and tau proteins also has been reported; treatment of hippocampal neurones with beta-amyloid, or the 25-35 residue fragment, resulted in an increase in tau protein phosphorylation. The particular contribution of muscarinic receptors, beta-amyloid and tau proteins in the pathogenesis of Alzheimer's disease remains still unclear. Probably Alzheimer's disease could be due to a progressive degeneration in the relationship between the three components covered in this review.
Alzheimer Disease↗