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Pharmacokinetics and consistency of pericardial delivery directed to coronary arteries: direct comparison with endoluminal delivery.

BACKGROUND AND HYPOTHESIS: Pharmacologic modulation of the contents of the pericardial space has been shown to influence the response of coronary arteries to balloon injury. Endoluminal (EL) local delivery of various drugs into coronaries has been found to be limited by short residence time, as well as by highly variable deposited agent concentration. We hypothesized that compounds placed into the pericardial space (P) would penetrate into coronary tissue with greater consistency than seen after EL delivery and provide for prolonged coronary exposure to agents. METHODS AND RESULTS: 125I-labeled basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), albumin, or 131I-labeled diazeniumdiolated albumin (NONO-albumin) were delivered as model/therapeutic proteins into the porcine pericardial space (n = 15 pigs) or into coronaries using an EL delivery catheter (n = 48 arteries). In subjects receiving 125I-labeled proteins, the delivery target or mid-regions of the left anterior descending (LAD) and left circumflex (LCx) arteries were harvested at 1 h or 24 h for gamma-counting and autoradiography, and fractional intramural delivery (FID) or retention measured as percent agent in 100 mg artery/agent in infusate for both time points. In the animals receiving 131I-labeled NONO-albumin, serial gamma imaging was employed to evaluate the rate of redistribution in individual animals following either pericardial or endoluminal delivery. At 1 h, FID values ranged from 0.00064 to 0.0052% for P delivery (median 0.0022%), and from 0.00021 to 6.7 for EL delivery (median 0.27%). At 24 h, FID values ranged from 0.00011 to 0.003 for P delivery (median 0.0013), and from 0.0002 to 1.4 for EL delivery. The estimated T1/2 for bFGF redistribution from the vascular tissue was 22 h (P) and 7 h (EL), respectively, while the directly determined T1/2 values for NONO-albumin redistribution from the delivery region were 22.2 h (P) and 2.5 h (EL). CONCLUSIONS: These data show that pericardial fluid contents can access coronary arteries with intramural concentrations which typically vary by 10-15-fold, while EL delivery results in a remarkably wide intramural concentration range with up to 33,000-fold variability. The apparent redistribution rate is more rapid following EL delivery, possibly due to sustained diffusive tissue loading from the pericardial space. Pericardial delivery appears to offer substantial advantages over EL administration with respect to residence time and reproducibility.

Albumins↗

A voxel-based morphometry study of temporal lobe gray matter reductions in Alzheimer's disease.

Several MRI studies have reported reductions in temporal lobe volumes in Alzheimer's disease (AD). Measures have been usually obtained with regions-of-interest (ROI) drawn manually on selected medial and lateral portions of the temporal lobes, with variable choices of anatomical borders across different studies. We used the fully automated voxel-based morphometry (VBM) approach to investigate gray matter abnormalities over the entire extension of the temporal lobe in 14 AD patients (MMSE 14-25) and 14 healthy controls. Foci of significantly reduced gray matter volume in AD patients were detected in both medial and lateral temporal regions, most significantly in the right and left posterior parahippocampal gyri and the left posterior inferior temporal gyrus/fusiform gyrus (P<0.05, corrected for multiple comparisons). At a more flexible statistical threshold (P<0.001, uncorrected for multiple comparisons), circumscribed foci of significant gray matter reduction were also detected in the right amygdala/enthorinal cortex, the anterior and posterior borders of the superior temporal gyrus bilaterally, and the anterior portion of the left middle temporal gyrus. These VBM results confirm previous findings of temporal lobe atrophic changes in AD, and suggest that these abnormalities may be confined to specific sites within that lobe, rather than showing a widespread distribution.

Aged↗

A morphological study of the thoracic duct at the jugulo-subclavian junction.

Chylous fistulae are uncommon but serious complications of neck surgery, occurring with an incidence of 1-3% after radical neck dissection. The majority occur on the left side (75-92%) and are due to damage to the terminal segment of the thoracic duct as it drains into the great veins of the neck in the region of the venous angle. The risk of trauma to the terminal thoracic duct may be influenced by anatomical variations. The macroscopic arrangement of the termination of the thoracic duct in the left neck was examined in 24 UK cadavers. Twenty-one ducts terminated as a single vessel, two ducts showed a bifid termination and one duct had three terminal branches. The precise site of termination was variable. Five thoracic ducts showed branching and reanastamosing patterns prior to their termination, irrespective of the number of terminal branches. Subsidiary cervical lymph trunks were identified in four dissections. These variations are described and their relevance to surgery involving the left side of the neck is discussed.

Adult↗

Giant cell angiofibroma of the inguinal region.

Giant cell angiofibroma is a rare mesenchymal neoplasm most commonly arising in the soft tissues near the orbit. Recently, several cases of extraorbital giant cell angiofibroma have been reported. We report the light microscopic and immunohistochemical features of an additional case of extraorbital giant cell angiofibroma arising in the inguinal region that was clinically mistaken for an inguinal hernia. The patient was a 50-year-old woman who presented with a mobile, nonreducible, left inguinal mass. The tumor was 10.8 cm in greatest diameter, was well circumscribed, and appeared to be encapsulated. Histologically, the tumor was composed of a mixture of cytologically bland spindle-shaped cells and ovoid cells of varying cellularity with deposition in a variably collagenous and myxoid stroma. The tumor had prominent, various-sized blood vessels, often with perivascular hyalinization. In addition, scattered pseudovascular spaces filled with an amorphous eosinophilic material were present and lined by spindle-shaped and ovoid cells similar to those found throughout the neoplasm. Rare multinucleated floret-like giant cells were seen. Immunohistochemically, the tumor cells stained strongly and diffusely for both CD34 and bcl-2 while immunostains for S-100 protein, desmin, smooth muscle actin, and muscle-specific actin were negative. There is no evidence of local recurrence or metastasis 3 months following excision of the mass. This report emphasizes the recognition of this unusual tumor in extraorbital sites. We discuss the overlapping histologic and immunophenotypic features with giant cell fibroblastoma and solitary fibrous tumor and raise the possibility that these tumors could represent a histologic spectrum of CD34-positive dendritic interstitial cell neoplasms.

Abdominal Neoplasms↗

Dyslexia: cultural diversity and biological unity.

The recognition of dyslexia as a neurodevelopmental disorder has been hampered by the belief that it is not a specific diagnostic entity because it has variable and culture-specific manifestations. In line with this belief, we found that Italian dyslexics, using a shallow orthography which facilitates reading, performed better on reading tasks than did English and French dyslexics. However, all dyslexics were equally impaired relative to their controls on reading and phonological tasks. Positron emission tomography scans during explicit and implicit reading showed the same reduced activity in a region of the left hemisphere in dyslexics from all three countries, with the maximum peak in the middle temporal gyrus and additional peaks in the inferior and superior temporal gyri and middle occipital gyrus. We conclude that there is a universal neurocognitive basis for dyslexia and that differences in reading performance among dyslexics of different countries are due to different orthographies.

Adult↗

Imbalances in regional lung ventilation: a validation study on electrical impedance tomography.

Imbalances in regional lung ventilation, with gravity-dependent collapse and overdistention of nondependent zones, are likely associated to ventilator-induced lung injury. Electric impedance tomography is a new imaging technique that is potentially capable of monitoring those imbalances. The aim of this study was to validate electrical impedance tomography measurements of ventilation distribution, by comparison with dynamic computerized tomography in a heterogeneous population of critically ill patients under mechanical ventilation. Multiple scans with both devices were collected during slow-inflation breaths. Six repeated breaths were monitored by impedance tomography, showing acceptable reproducibility. We observed acceptable agreement between both technologies in detecting right-left ventilation imbalances (bias = 0% and limits of agreement = -10 to +10%). Relative distribution of ventilation into regions or layers representing one-fourth of the thoracic section could also be assessed with good precision. Depending on electrode positioning, impedance tomography slightly overestimated ventilation imbalances along gravitational axis. Ventilation was gravitationally dependent in all patients, with some transient blockages in dependent regions synchronously detected by both scanning techniques. Among variables derived from computerized tomography, changes in absolute air content best explained the integral of impedance changes inside regions of interest (r(2) > or = 0.92). Impedance tomography can reliably assess ventilation distribution during mechanical ventilation.

Adult↗

Dimensional complexity of EEG waveforms in neuroleptic-free schizophrenic patients and normal control subjects.

Dimensional complexity reflects the number of independent variables contributing to a dynamic process. EEG epochs recorded from 12 neuroleptic-free schizophrenic patients and 11 normal control subjects were Laplacian-filtered to highlight activity specific to prefrontal and parietal areas, and dimensional complexity measures of the resulting signals were then derived. Complexity of EEG waveforms generated by schizophrenic patients was depressed relative to that of normal subjects, especially in left frontal and right parietal regions. These data suggest that complexity of underlying is also reduced.

Adult↗

Lateralized cortical perfusion in women with Alzheimer's disease.

OBJECTIVE: To define the pathophysiologic substrate of gender differences in cognition and behavior in Alzheimer's disease (AD). DESIGN: Hemispheric regional cerebral blood flow (rCBF) was studied in a consecutive series of dementia patients using single photon emission computed tomography (SPECT). PARTICIPANTS: Subjects included 300 outpatients who were studied with SPECT as part of a diagnostic evaluation for degenerative dementia or memory disorder. METHOD: Based on qualitative descriptions by a radiologist, subjects were classified as having unilateral left, unilateral right, bilateral, or no perfusion defects. Semiquantitative analysis of SPECT images was also performed using region of interest radionuclide counts normalized to the cerebellum. RESULTS: Among 174 females and 126 males, unilateral left hemisphere defects were found more commonly in women than men (24% vs 10%; chi 2 = 9.4; P = .009). This observation was most significant for the 103 females and 62 males regarded as having probable AD (26% vs 8%; chi 2 = 9.3; P = .01). In a multiple regression model of clinical variables, shorter duration of disease and female gender were significant independent predictors of the unilateral left hemisphere pattern among those with probable AD. Age, family history, education, handedness, and severity of cognitive impairment were not significant contributors. CONCLUSIONS: Women with AD exhibit greater heterogeneity in rCBF than men. Asymmetry in rCBF occurs more often in women. In some cases, this is related to relative preservation of right hemisphere function in women.

Aged↗

Cardiovascular and metabolic responses to anesthetic-induced malignant hyperthermia in swine.

BACKGROUND: Several cardiovascular disturbances, such as tachycardia and hypotension, are observed during human and porcine malignant hyperthermic (MH) crises. However, the pathophysiologic mechanisms responsible for the deterioration of cardiovascular function during MH are not completely known. The purpose of this study was to elucidate the changes in left ventricular (LV) function and metabolism and the systemic and regional hemodynamics during anesthetic-induced MH in swine. METHODS: The study was carried out in 12 open-chest MH-susceptible pigs and in 8 healthy control (non-MH-susceptible) pigs under the same conditions. The cardiovascular and metabolic responses to halothane (1% inspired) and succinylcholine (3 mg.kg-1 intravenously 15 min after the start of halothane administration) were studied. Global hemodynamic and LV variables (expressed as means +/- SEM) were determined over a period of 90 min after the beginning of halothane exposure. Simultaneous investigations were performed on hindleg and cardiac muscle to compare the regional functional and metabolic changes in these tissues. RESULTS: MH was triggered in all MH-susceptible pigs. Early (10-30 min) cardiovascular changes during the development of MH consisted of a rapid increase in heart rate (from 86 +/- 4 to 204 +/- 8 beats.min-1), cardiac index (+84%), and peak rate of change in LV pressure (+150%); stroke volume index (-24%) and mean aortic pressure (-13%) decreased progressively even in the early stage of MH. These alterations were accompanied by an early and persistent reduction in systemic vascular resistance (maximally -57%) with an increase in aortic pressure amplitude. Early changes in coronary and peripheral hemodynamics during the development of MH consisted of a three-fold increase in coronary blood flow in conjunction with a marked decrease (-77%) in coronary vascular resistance. The early circulatory changes were associated with a fourfold increase in myocardial and a 2.5-fold increase in peripheral O2 consumption. The ratio of the LV stroke work index (LVWI) to myocardial O2 consumption (MVO2) was significantly decreased, by a factor of 5. Increased catecholamine concentrations and myocardial lactate and H+ production could be demonstrated throughout the MH crisis. In the late stage of MH (> 30 min), pronounced hypotension and a subsequent decrease in cardiac index were noted. These changes were associated with a significant reduction in LV end-diastolic pressure, from 9 +/- 1 to 6 +/- 1 mmHg (P < 0.05), and in the rate of change in LV pressure, by a maximum of -25%. Coronary vascular resistance remained reduced while coronary blood flow decreased. Peripheral (hind-leg) blood flow initially increased by 48% while peripheral vascular resistance decreased by 42%, followed by a fivefold increase in peripheral vascular resistance with a marked decrease in peripheral blood flow (-88%) in the late phase of MH. CONCLUSIONS: The current findings indicate that metabolic status during MH is characterized by a demand ischemia of the heart and of the skeletal muscle. Insufficient coronary blood flow and increased metabolism as a result of tachycardia and increased concentrations of catecholamines are the dominant factors contributing to the dramatic alteration in cardiac performance during porcine MH. Acidosis, hypovolemia, and hyperkalemia, especially in the late phase of MH, are additional essential factors responsible for the progressive cardiovascular deterioration and cardiac death.

Animals↗

Correction of spillover radioactivities for estimation of the blood time-activity curve from the imaged LV chamber in cardiac dynamic FDG PET studies.

In dynamic cardiac PET FDG studies for measurement of myocardial metabolic rate of glucose (MMRGlc), the plasma FDG time-activity curve (input function) is commonly obtained from the left ventricular (LV) region on the PET images. The input function is contaminated by spillover of radioactivity from the surrounding myocardium and this could cause significant error in the estimated MMRGlc. In this study, we determined the effect of myocardial to blood pool spillover on MMRGlc and developed a method to correct for this spillover of activity. The method is based on a reformulation of the FDG model equation in terms of the spillover contaminated input function that includes both the myocardium to blood pool and blood pool to myocardium spillover fractions as variable parameters (Fmb and Fbm). The reformulated model equation can be used to fit the global myocardial tissue activity curve to estimate Fmb and thus yields a spillover corrected input function. The MMRGlc estimate with the corrected input function was within 95% of the true value (compared to 85% using the uncorrected input function) in a set of computer simulation studies. Dynamic PET FDG data were obtained in eight human studies and blood samples were obtained during the study. As compared to the results with the uncorrected input function, the estimates of k4 by the new method were reduced by 69% into a range consistent with in vitro results. The method is effective in correcting Fmb spillover and leads to more accurate estimates of MMRGlc. The method also allows larger regions of interest (up to 150 mm2) to be drawn over the LV in dynamic PET images, thereby reducing the noise level in the input function.

Computer Simulation↗

Flow field mapping in the anesthetized rat.

This study measured the hemodynamics of peripheral arterial sites in the rat, using 20 MHz pulsed ultrasonic Doppler velocimeter (PUDVM) methods. The lower extremities of 14 male Sprague-Dawley rats were studied. The targeted sites included the abdominal aorta, external iliac, proximal femoral, mid-femoral, and saphenous arteries. The hemodynamic variables of pulse period, maximum centerline velocity, lumen diameter, and mean volumetric flow were calculated interactively from temporal-spatial plots of local velocity distributions. An analysis of variance revealed significant differences between right and left sides for lumen diameter (P = 0.028) and mean volumetric flow (P less than 0.0001). The analysis showed no statistical difference for pulse period (P = 0.0836) among sites. However, three distinct groupings of sites: 1) abdominal aorta, 2) external iliac, proximal femoral, and mid-femoral arteries, and 3) saphenous artery were noted for the remaining hemodynamic variables (P less than 0.05). These results indicate that three hemodynamically distinct regions are available for microvascular research in the rat lower extremity arterial tree.

Anesthesia, General↗

The role of central venous oximetry, lactic acid concentration and shock index in the evaluation of clinical shock: a review.

Initial therapy of shock in the emergency department emphasizes the normalization of hemodynamic variables e.g. heart rate (HR), mean arterial pressure (MAP), central venous pressure (CVP) rather than optimization of systemic and regional oxygenation. Central venous oximetry (ScvO2), arterial lactic acid concentrations (Lact) and the shock index (SI) were examined during initial hemodynamic stabilization of clinical shock in the emergency room. Although initial therapy normalized MAP, CVP and HR; ScvO2, Lact and SI continued to be abnormal indicating inadequate systemic oxygenation and left ventricular (LV) performance. Measurement of ScvO2, Lact and SI may provide valuable additional information on the adequacy of systemic oxygenation and LV function during initial therapy of shock. This may identify patients who require further monitoring and intervention to optimize systemic oxygen transport and cardiac performance and reduce their morbidity and mortality.

Blood Pressure↗

Neuroanatomically separable effects of imageability and grammatical class during single-word comprehension.

The present study characterizes the neural correlates of noun and verb imageability and addresses the question of whether components of the neural network supporting word recognition can be separately modified by variations in grammatical class and imageability. We examined the effect of imageability on BOLD signal during single-word comprehension of nouns and verbs. Subjects made semantic similarity judgments while undergoing functional magnetic resonance imaging (fMRI). Nouns and verbs were matched on imageability, and imageability varied continuously within a grammatical category. We observed three anatomically separable effects: a main effect of grammatical class, a main effect of imageability, and an imageability by grammatical class cross-over interaction. The left superior parietal lobule and a region in the left fusiform responded similarly to increases in noun and verb imageability; the left superior temporal gyrus showed greater activity for verbs than nouns after imageability was matched across grammatical class; and, in both the left middle temporal gyrus and the left inferior frontal lobe, a decrease in noun but not verb imageability resulted in higher BOLD signal. The presence of reliable and anatomically separable main effects of both imageability and grammatical class renders unlikely the hypothesis that previously reported dissociations between nouns and verbs can be dismissed as imageability effects. However, some regions previously thought to respond to grammatical class or imageability instead respond to the interaction of these variables.

Acoustic Stimulation↗

Simultaneous mapping of activation and motion timing in the healthy and chronically ischemic heart.

BACKGROUND: Experimental data of simultaneous acquired activation and motion (AM) propagation from human subjects are not available. OBJECTIVES: The purpose of this study was to demonstrate the feasibility of a novel mapping technique allowing combined analysis of AM timing in vivo and to delineate the influence of chronically ischemic tissue on cardiac AM propagation. METHODS: Ten patients with remote myocardial infarction and 4 control patients were studied during sinus rhythm using electroanatomic mapping (CARTO). Maps of the left ventricle were obtained via the retrograde aortic approach. Real-time catheter positions were extracted using custom-made software. Catheter motion was analyzed along a static line connecting the catheter tip with the apex. Tissue Doppler measurements in all patients provided data for validation. RESULTS: Four shapes of catheter motion curves were identified and correlated to healthy tissue with variable degrees of preloading, scar tissue and dyskinetic regions, e.g. aneurysms. An analysis of the AM-delay revealed areas of delayed activation in 7, and slow motion onset in 4 patients. Tissue Doppler data correlated well with local onset of motion (correlation coefficient 0,99). CONCLUSION: Activation delays as well as long AM-intervals that can be differentiated with the described mapping technique are responsible for asynchronous contraction in the ischemic heart. Myocardial wall motion abnormalities can be derived from catheter motion curves.

Adult↗

Changing cortical excitability with low-frequency transcranial magnetic stimulation can induce sustained disruption of tactile perception.

Transcranial magnetic stimulation (TMS) is promising as a therapeutic tool, and TMS of the motor system has served as a model for regionally specific modulations of cortical excitability. It is unclear, however, to what extent response characteristics of the motor cortex are representative of other brain systems. We wanted to determine whether TMS could induce a sustained disruption of somatosensory processing beyond the stimulation duration, similar to observations in the motor system. We applied 1-Hz TMS at 110% of subjects' motor thresholds for a variable duration over the right and left somatosensory cortex before subjects performed a tactile frequency discrimination task with the left hand. Tactile discrimination was impaired only after TMS over the right somatosensory cortex (analysis of variance: p <.01). The duration of this impairment correlated with the duration of the preceding TMS; the effect lasted approximately 2 min after 5 min of TMS, 4 min after 10 min of TMS, and 8 min after 20 min of TMS. Two conclusions arise: 1) low-frequency TMS can interfere with tactile perception in a robust and sustained way, and 2) TMS dosing parameters effective in the motor system are also effective in the somatosensory system and may reflect a modality-independent response characteristic of the cerebral cortex.

Adult↗

Lateral nasal proboscis: antenatal diagnosis and counseling.

BACKGROUND: Lateral nasal proboscis is a rare anomaly resulting in incomplete formation of one side of the nose and other variable abnormalities in the adjoining regions of the face, without associated brain malformations. We report a case diagnosed antenatally and confirmed after birth of the infant. CASE: A 32-year-old white gravida 2 para 1 was referred for a comprehensive fetal ultrasound at 30.5 weeks to evaluate a facial anomaly seen on an ultrasound done to evaluate decreased fetal movements. A fingerlike projection was seen in the left inner eye area with visualization of one nostril and a small nose. After a spontaneous delivery at term, a 3845-g healthy female infant with lateral nasal proboscis and other locally associated anomalies was born and is doing well at 9 months. Reconstructive surgery was done at 3 and 6 months. CONCLUSION: Accurate antenatal diagnosis of lateral nasal proboscis is possible with ultrasound, which is important because its prognosis and management are different from other types of proboscides.

Adult↗

Reduced brain functional reserve and altered functional connectivity in patients with multiple sclerosis.

Cognitive dysfunction (affecting particularly attention and working memory) occurs early in patients with multiple sclerosis. Previous studies have focused on identifying potentially adaptive functional reorganization through recruitment of new brain regions that could limit expression of these deficits. However, lesion studies remind us that functional specializations in the brain make certain brain regions necessary for a given task. We therefore have asked whether altered functional interactions between regions normally recruited provide an alternative adaptive mechanism with multiple sclerosis pathology. We used a version of the n-back task to probe working memory in patients with early multiple sclerosis. We applied a functional connectivity analysis to test whether relationships between relative activations in different brain regions change in potentially adaptive ways with multiple sclerosis. We studied 21 patients with relapsing-remitting multiple sclerosis and 16 age- and sex-matched healthy controls with 3T functional MRI. The two groups performed equally well on the task. Task-related activations were found in similar regions for patients and controls. However, patients showed relatively reduced activation in the superior frontal and anterior cingulate gyri (P > 0.01). Patients also showed a variable, but generally substantially smaller increase in activation than healthy controls with greater task complexity, depending on the specific brain region assessed (P < 0.001). Functional connectivity analysis defined further differences not apparent from the univariate contrast of the task-associated activation patterns. Control subjects showed significantly greater correlations between right dorsolateral prefrontal and superior frontal/anterior cingulate activations (P < 0.05). Patients showed correlations between activations in the right and left prefrontal cortices, although this relationship was not significant in healthy controls (P < 0.05). We interpret these results as showing that, while cognitive processing in the task appears to be performed using similar brain regions in patients and controls, the patients have reduced functional reserve for cognition relevant to memory. Functional connectivity analysis suggests that altered inter-hemispheric interactions between dorsal and lateral prefrontal regions may provide an adaptive mechanism that could limit clinical expression of the disease distinct from recruitment of novel processing regions. Together, these results suggest that therapeutic enhancement of the coherence of interactions between brain regions normally recruited (functional enhancement), as well as recruitment of alternative areas or use of complementary cognitive strategies (both forms of adaptive functional change), may limit expression of cognitive impairments in multiple sclerosis.

Adaptation, Psychological↗

An anatomical landmark for the supplementary eye fields in human revealed with functional magnetic resonance imaging.

Together with the frontal and parietal eye fields, the supplementary eye field (SEF) is involved in the performance and control of voluntary and reflexive saccades and of ocular pursuit. This region was first described in non-human primates and is rather well localized on the dorsal surface of the medial frontal cortex. In humans the site of the SEF is still ill-defined. Functional imaging techniques have allowed investigation of the location and function of the SEF. However, there is great variability with regard to the published standardized coordinates of this area. We used here the spatial precision of functional magnetic resonance imaging (fMRI) in order to better localize the SEF in individuals. We identified as the SEF a region on the medial wall that was significantly activated when subjects executed self-paced horizontal saccades in darkness as compared to rest. This region appeared to be predominantly activated in the left hemisphere. We found that, despite a discrepancy of >2 cm found in the standardized Talairach coordinates, the location of this SEF-region could be precisely and reliably described by referring to a sulcal landmark found in each individual: the upper part of the paracentral sulcus.

Adult↗