Assessment of myocardial perfusion with MRI using a modified dual bolus method.

Quantification of regional myocardial blood flow (rMBF) with first-pass magnetic resonance imaging (FP-MRI) requires two contrast agent injections (dual bolus technique), inducing error in the determined rMBF if the injections differ. We hypothesize that using input and residue curves of the same injection would be more reliable. We aim to introduce and evaluate a novel method to correct the high concentration arterial input function (AIF) for determination of rMBF. Sixteen patients with non-Hodgkin's lymphoma were examined before and after chemotherapy. The input function was solved by correcting initial high concentration AIF using the ratio of low and high contrast AIF areas, normalized by corresponding heart rates (modified dual bolus method). For comparison, the scaled low contrast AIF was used as an input function (dual bolus method). Unidirectional transfer coefficient K(trans) was calculated using both methods. K(trans)-values determined with the dual bolus (0.81 ± 0.32 ml g(-1) min(-1)) and modified dual bolus (0.77 ± 0.42 ml g(-1) min(-1)) methods were in agreement (p = 0.21). Mean K(trans)-values increased from 0.76 ± 0.43 to 0.89 ± 0.55 ml g(-1) min(-1) after chemotherapy (p = 0.17). The modified dual bolus technique agrees with the dual bolus technique (R2 = 0.899) when the low and high contrast injections are similar. However, when this is not the case, the modified dual bolus technique may be more reliable.

Chemically modified tetracycline (CMT)-3 inhibits histamine release and cytokine production in mast cells: possible involvement of protein kinase C.

OBJECTIVE: To find novel inhibitors of mast cell function we have studied the effect of a potent, non-antimicrobial, chemically modified tetracycline, CMT-3 or COL-3, on key functions of mast cells. METHODS AND RESULTS: In the presence of 25 microM CMT-3, the 48/80-induced histamine release from rat serosal mast cells was inhibited significantly, to 43.0 +/- 7.3% of control. Similarly, the activation-induced secretion of TNF-alpha and IL-8 by HMC-1 cells were decreased in the presence of 25 microM CMT-3 to 13.5 +/- 4.1% and 9.7 +/- 1.1% of control, respectively. CMT-3 did not cause intracellular accumulation of TNF-alpha but instead it reduced the expression of TNF-alpha mRNA in HMC-1 cells. Moreover, CMT-3 was found to significantly inhibit the protein kinase C (PKC) activity with IC(50) value of 31 microM. CMT-3 inhibited effectively both human recombinant PKCalpha and PKCdelta isoforms. In comparison to doxycycline, CMT-3 was more effective as an inhibitor of both cytokine production and PKC activity. CONCLUSIONS: Considering the central role of PKC in mast cell activation, PKC inhibition could, at least partially, explain the observed inhibitory effects of CMT-3. The inhibition of the key proinflammatory functions of mast cells by CMT-3 suggests its potential clinical usefulness in the treatment of allergic and inflammatory disorders.

Three-dimensional respiratory-gated coronary MR angiography with reference to X-ray coronary angiography.

PURPOSE: To assess the clinical value of three-dimensional coronary MR angiography (CMRA) in the detection of significant coronary artery stenosis using conventional X-ray angiography as the standard reference. MATERIAL AND METHODS: Sixty-nine patients underwent X-ray coronary angiography and CMRA because of suspected or previously diagnosed coronary artery disease. MRI was performed with a 1.5-T whole body imaging system using ECG-triggered 3D gradient echo sequence with retrospective navigator echo respiratory gating and fat suppression. RESULTS: A total of 276 coronary artery segments were analyzed. The X-ray coronary angiography was normal in 22 patients. Significant proximal stenoses (exceeding 50%) or occlusions were present in 102 coronary artery segments. In all, 120 stenoses or occlusions were identified in CMRA. Sixteen percent of the coronary artery segments had to be excluded because of poor image quality. The overall sensitivity and specificity for MRA for identification of significant stenosis were 75% and 62%, respectively. CMRA correctly detected 89% of patients with at least one vessel disease, but 6 patients with coronary artery disease would have been missed. CONCLUSIONS: Because of the high data exclusion and false- negative case rate, CMRA with retrospective navigator echo triggering is at present not suitable as a clinical screening method in coronary artery disease.

Detecting the subregion proceeding to infarction in hypoperfused cerebral tissue: a study with diffusion and perfusion weighted MRI.

Diffusion and perfusion weighted MRI have been widely used in ischaemic stroke. We studied 17 patients in whom ischaemic areas showed an ischaemic core, an area of infarct growth and hypoperfused but ultimately surviving tissue. Apparent diffusion coefficients (ADC) were measured on days 1, 2, and 8 in the three subregions and in contralateral control areas. Cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT) were measured in these regions on day 1 perfusion maps. On day 1, the ischaemic core had very low ADC and CBF and increased MTT. The ADC in the ischaemic core gradually increased during the week. The area of infarct growth on day 1 had slightly but significantly decreased ADC (96% of control, P=0.028), moderately decreased CBF and increased MTT. On day 1 the hypoperfused but surviving tissue had slightly but significantly increased ADC (103% of control, P=0.001), mildly decreased CBF and increased CBV and MTT. The ADC of the area of infarct growth decreased to the same level as in the ischaemic core on days 2 and 8. That of surviving tissue was still above normal on day 2 (103% of control), but had returned to the normal level by day 8. Measurement of ADC combined with perfusion MRI may help distinguish different subregions in acutely hypoperfused brain.

MR volumetry of the entorhinal, perirhinal, and temporopolar cortices in drug-refractory temporal lobe epilepsy.

BACKGROUND AND PURPOSE: The occurrence of damage in the entorhinal, perirhinal, and temporopolar cortices in unilateral drug-refractory temporal lobe epilepsy (TLE) was investigated with quantitative MR imaging. METHODS: Volumes of the entorhinal, perirhinal, and temporopolar cortices were measured in 27 patients with unilateral drug-refractory TLE, 10 patients with extratemporal partial epilepsy, and 20 healthy control subjects. All patients with TLE were evaluated for epilepsy surgery and underwent operations. RESULTS: In left TLE, the mean volume of the ipsilateral entorhinal cortex was reduced by 17% (P <.001 compared with control subjects) and that of the ipsilateral temporopolar cortex by 17% (P <.05). In right TLE, the mean ipsilateral entorhinal volume was reduced by 13% (P < or =.01), but only in patients with hippocampal atrophy. Asymmetry ratios also indicated ipsilateral cortical atrophy. When each patient was analyzed individually, the volume of the ipsilateral hippocampus was reduced (> or = 2 SD from the mean of controls) in 63% and that of the entorhinal cortex in 52% of patients with TLE. Furthermore, ipsilateral entorhinal (left: r = 0.625, P <.001; right: r = 0.524, P < or =.01), perirhinal (left: r = 0.471, P <.05), and temporopolar (right: r = 0.556, P <.01) volumes correlated with ipsilateral hippocampal volumes. There was no association, however, with clinically or pathologically identified causes of epilepsy, duration of epilepsy, or age at onset of epilepsy. Mean cortical volumes were unaffected in extratemporal partial epilepsy. CONCLUSION: Subpopulations of patients with unilateral TLE have ipsilateral damage in the entorhinal and temporopolar cortices. The damage is associated with hippocampal damage.

Cotinine binding to nicotinic acetylcholine receptors in bovine chromaffin cell and rat brain membranes.

Cotinine is the major metabolite of nicotine. It has nicotine-like biological activity, but its potency is low. We studied cotinine binding to nicotinic receptors labelled with [3H]epibatidine. In membranes from cultured bovine chromaffin cells [3H]epibatidine bound to two apparent sites with K(d) values of 93 and 1400 pM. The low-affinity binding represented two-thirds of the binding sites. In rat frontal cortex and hippocampus homogenate membranes, only one apparent binding site was detected. The Kd values were 40 and 62 pM, in frontal cortex and hippocampus, respectively. Nicotine displaced [3H]epibatidine 10 times more potently from the brain than from the chromaffin cell membranes, and cotinine had over two orders of magnitude lower affinity than nicotine. In addition, the competitive nicotinic receptor antagonists methyllycaconitine and dihydro beta-erythroidine displaced [3H]epibatidine (100 pM and 1 nM) from the chromaffin cell membranes. Alpha-bungarotoxin did not affect the binding of 100 pM [3H]epibatidine. However, upon labelling with 1 nM [3H]epibatidine alpha-bungarotoxin (10 nM to 10 microM) displaced one-sixth of the bound radioligand. Our results demonstrate that 100 pM to 1 nM [3H]epibatidine labels mostly neuronal heteropentameric nicotinic receptors in bovine chromaffin cell membranes, and that cotinine is a low-affinity nicotinic ligand both in the adrenal chromaffin cell and in the brain receptors.

Diffusion and perfusion MR imaging in acute ischemic stroke: a comparison to SPECT.

Diffusion (DWI) and perfusion (PWI) magnetic resonance imaging are relatively new methods of clinical imaging that probably can detect infarcted (DWI) and hypoperfused but still salvageable tissue (PWI) in acute human stroke. Forty-six acute stroke patients were imaged within 24 h of ictus, on the second day and after a week. SPECT was also performed on 23 patients in the acute phase (first or second day). On the first day, mean volume of hypoperfused tissue was significantly greater (P<0.001) than the infarcted tissue. The initial hypoperfusion volume correlated significantly with the final infarct size (P<0.001). The initial perfusion-diffusion mismatch correlated significantly with the infarct growth (P< or =0.001). The hypoperfusion volumes measured from PWI and SPECT correlated significantly (P<0.001). In conclusion, combined DWI and PWI is a powerful tool in evaluating the hemodynamics of acute ischemic stroke and can predict the infarct growth during 1 week.

Evolution of MR contrast enhancement patterns during the first week after acute ischemic stroke.

BACKGROUND AND PURPOSE: Intravascular and parenchymal enhancement have been detected with contrast-enhanced T1-weighted MR imaging in patients with ischemic stroke. Diffusion-weighted MR imaging depicts infarct within minutes after the onset of symptoms. The aims of this study were to study the different MR enhancement findings during the first week after stroke and to ascertain whether the presence of intravascular enhancement over a larger area than the infarct on diffusion-weighted images on day 1 is able to predict substantial infarct growth during the first week. METHODS: Forty-eight patients were imaged on the first and second days and again 1 week after the onset of ischemic stroke. T1-weighted spin-echo imaging was performed before and after a 0.2 mmol/kg bolus of gadolinium chelate. Diffusion-weighted imaging was performed at the same slice positions. Enhancement findings were categorized as intravascular and parenchymal, with further categorization of parenchymal enhancement as cortical, subcortical, and deep; these findings were then compared with diffusion-weighted imaging findings. RESULTS: Intravascular enhancement in the infarcted area was detected on day 1 in 78% of the cases, on day 2 in 78% of the cases, and at 1 week in 30% of the cases. Parenchymal enhancement was detected in 26%, 56%, and 100% of the cases, respectively. Intravascular enhancement over a larger area than the infarct on diffusion-weighted images on day 1 was not associated with the extent of infarct growth. CONCLUSION: Detection of different patterns of contrast enhancement can help in determining the age of infarct. Parenchymal enhancement may be intense and can cause diagnostic uncertainty in cases in which the clinical history is obscure.

MR urography in evaluation of acute flank pain: T2-weighted sequences and gadolinium-enhanced three-dimensional FLASH compared with urography. Fast low-angle shot.

OBJECTIVE: The aim of this study was to compare the usefulness of breath-hold heavily T2-weighted sequences with gadolinium-enhanced three-dimensional fast low-angle shot (3D FLASH) MR urography in the evaluation of patients with acute flank pain. SUBJECTS AND METHODS: Forty consecutive patients with symptoms of acute flank pain underwent MR urography followed immediately by excretory urography. Heavily T2-weighted (combined thin-slice half-Fourier acquisition single-shot turbo spin-echo [HASTE] and thick-slab single-shot turbo spin-echo) and 3D FLASH sequences were evaluated separately and independently by two experienced radiologists for the presence, cause, level, and degree of obstruction. Interobserver agreement was calculated using the kappa statistic. Excretory urography and the final clinical diagnosis were used as reference. RESULTS: Twenty-six patients were found to have unilateral obstruction caused by ureteral stones. Both MR urography methods were excellent for detecting obstruction. In the detection of stones 3D FLASH was superior, with a sensitivity of 96.2% and 100% and specificity of 100% and 100% for observers A and B, respectively, compared with a sensitivity of 57.7% and 53.8% and a specificity of 100% and 100%, respectively, for T2-weighted sequences. The best degree of obstruction was seen with 3D FLASH, and the interobserver agreement was excellent for stone detection (kappa = 0.97). CONCLUSION: T2-weighted sequences alone are not sufficient for examining patients with acute flank pain. However, the combined use of both T2-weighted and 3D FLASH sequences will ensure better confidence in the evaluation of acute suspected renal colic. MR urography can replace conventional excretory urography when the latter is contraindicated or undesirable.

Transthoracic three-dimensional echocardiography is as good as magnetic resonance imaging in measuring dynamic changes in left ventricular volume during the heart cycle in children.

AIMS: The purpose of the study was to assess the dynamic changes in left ventricular (LV) volume by transthoracic three-dimensional echocardiography (3DE) and to compare the results with those obtained by magnetic resonance imaging (MRI). METHODS AND RESULTS: Thirty healthy children were studied by digitized 3DE and Doppler, and by MRI. Three-dimensional echocardiography of LV was performed by using rotational acquisition from the transthoracic apical view with ECG gating and without respiratory gating. The acquisition of 3DE data took 10-15s. Three-dimensional echocardiography gave similar values to MRI for EDV, ESV and LVM measurements, and the results correlated well. Peak emptying rates by 3DE and MRI were -236.6 and -169.6ml/s and peak filling rates were 215.0 and 215.9ml/s, respectively. Dynamic changes of LV volumes during the heart cycle were detectable with both methods. CONCLUSION: Digitized 3DE performed in the outpatient clinic and MRI were both useful methods for studying the physiological volume changes in left ventricle in children. These methods may be used for further study of the systolic and diastolic function of the left ventricle in various clinical conditions.

Midazolam 12 mg is moderately counteracted by 250 mg caffeine in man.

OBJECTIVE: Caffeine (Caf) counteracts various effects of benzodiazepines (BZDs). Since the effects of zolpidem, a short-acting atypical GABA(A)-BZD agonist, were not antagonized by Caf, we studied an interaction between Caf and midazolam (Mid) in healthy volunteers. SUBJECTS, MATERIALS AND METHODS: In Study 1, 108 healthy students divided to 6 parallel groups were given Mid 12 mg (capsule) and Caf 125 and 250 mg (in decaffeinated coffee), alone and in combinations in the double-blind placebo-controlled manner. Objective and subjective tests were done before and at 45 and 90 min after intake. Ranked delta-values (changes from baseline) were analyzed by one-way contrast ANOVA and Scheffe's tests. In Study 2, six healthy subjects took Mid 15 mg (tablet) with and without Caf 300 mg. The dynamic effects were analyzed as in Study 1 and the plasma concentrations were assayed. RESULTS: In Study 1, learn effects after placebo (ad + 15%) were seen for letter cancellation and digit symbol substitution tests. Midazolam alone significantly (p < 0.05 vs. delta-placebo) reduced letter cancellation and digit symbol substitution, lowered flicker fusion, impaired digit learning and caused subjective calmness on VAS. Caffeine alone did not differ from placebo objectively, yet improved quick-wittedness and contentedness on VAS. In the combinations, Mid + Caf 125 mg differed from placebo objectively as Mid alone, whereas Mid + Caf 250 mg did not. Mid + Caf 250 mg differed from Mid on digit substitution, but did not differ from Mid+Caf 150 mg in impairing memory and causing subjective sedation. In Study 2, Mid 15 mg caused sedation and Caf 300 mg increased plasma Mid at 45 min. Mid + Caf did not differ from Mid alone objectively, but did so subjectively on VAS (p > 0.05). CONCLUSION: In conclusion, in a parallel group study, sedative effects of Mid 12 mg were only moderately antagonized by Caf 250 mg but not by Caf 125 mg. In a cross-over study, a weak interaction was found subjectively but not in objective measures.

Interrelations of T(1) and diffusion of water in acute cerebral ischemia of the rat.

Interrelation of T(1) and diffusion of water was studied in rat models of acute global and focal cerebral ischemia. Cortical T(1), as quantified with an inversion recovery method, increased by 4-7% within a few minutes of global ischemia at 4.7 and 9.4 T, but a significantly smaller change was detected at 1.5 T. The initial T(1) change occurred within seconds of cardiac arrest, much earlier than the extensive diffusion drop after 1-2 min. Thus, the initial increase in T(1) upon acute cerebral ischemia is directly caused by cessation of blood flow. In transient middle cerebral artery occlusion (MCAO), prolonged T(1) relaxation was detected within 10 min, with a subsequent increase during the course of ischemia. Spin density did not change during the first hour, showing that T(1) increase was not caused by net accumulation of water. Interestingly, partial recovery of T(1) upon release of MCAO, occurring independent of long-term tissue outcome, was observed only in concert with diffusion recovery.

Combined perfusion- and diffusion-weighted MR imaging in acute ischemic stroke during the 1st week: a longitudinal study.

PURPOSE: To compare findings with different magnetic resonance (MR) perfusion maps in acute ischemic stroke. MATERIALS AND METHODS: Combined diffusion-weighted (DW) and perfusion-weighted (PW) MR imaging was performed in 49 patients with acute (<24 hours) stroke, on the 1st and 2nd days and 1 week after stroke. Volumes of hypoperfused tissue on maps of relative cerebral blood volume (rCBV), relative cerebral blood flow (rCBF), and mean transit time (MTT) were compared with the volume of infarcted tissue at DW imaging. RESULTS: The mean infarct volume increased from 41 to 65 cm(3) between the 1st and 2nd days (P: <.001; n = 49). On the 1st day, all perfusion maps on average showed hypoperfusion lesions larger than the infarct at DW imaging (P: <.001; n = 49). MTT maps showed significantly (P: <.001) larger hypoperfusion lesions than did rCBF maps, which showed significantly (P: <.001) larger hypoperfusion lesions than did rCBV maps. The sizes of the initial perfusion-diffusion mismatches correlated significantly with the extent of infarct growth (0.479 < r < 0.657; P:

Hydrogen peroxide attenuates store-operated calcium entry and enhances calcium extrusion in thyroid FRTL-5 cells.

Redox modulation participates in the regulation of intracellular free calcium concentration ([Ca(2+)](i)) in several cell types. In thyroid cells, including FRTL-5 cells, changes in [Ca(2+)](i) regulate several important functions, including the production of H(2)O(2) (hydrogen peroxide). As H(2)O(2) is of crucial importance for the production of thyroid hormones, we investigated the effects of H(2)O(2) on [Ca(2+)](i) in thyroid FRTL-5 cells. H(2)O(2) itself did not modulate basal [Ca(2+)](i). However, H(2)O(2) attenuated store-operated calcium entry evoked by thapsigargin, both in a sodium-containing buffer and in a sodium-free buffer. The effect of H(2)O(2) was abrogated by the reducing agent beta-mercaptoethanol. H(2)O(2) also attenuated the thapsigargin-evoked entry of barium and manganese. The effect of H(2)O(2) was, at least in part, mediated by activation of protein kinase C (PKC), as H(2)O(2) enhanced the binding of [(3)H]phorbol 12,13-dibutyrate. H(2)O(2) also stimulated the translocation of the isoenzyme PKCepsilon from the cytosolic fraction to the particulate fraction. Furthermore, H(2)O(2) did not attenuate store-operated calcium entry in cells treated with staurosporine or calphostin C, or in cells with down-regulated PKC. H(2)O(2) depolarized the membrane potential in bisoxonol-loaded cells and when patch-clamp in the whole-cell mode was used. The depolarization was attenuated in cells with down-regulated PKC. This depolarization, at least in part, explained the H(2)O(2)-evoked inhibition of calcium entry. In addition, H(2)O(2) enhanced the extrusion of calcium from cells stimulated with thapsigargin and this effect was abolished in cells with down-regulated PKC and after treatment of the cells with the reducing agent beta-mercaptoethanol. In conclusion H(2)O(2) attenuates an increase in [Ca(2+)](i). As H(2)O(2) is produced in thyroid cells in a calcium-dependent manner, our results suggest that H(2)O(2) may participate in the regulation of [Ca(2+)](i) in these cells via a negative-feedback mechanism involving activation of PKC.

[11 C]Flumazenil binding in the medial temporal lobe in patients with temporal lobe epilepsy: correlation with hippocampal MR volumetry, T2 relaxometry, and neuropathology.

OBJECTIVE: To detect reduced [11C]flumazenil in patients with temporal lobe epilepsy (TLE) and to relate binding to histopathology. METHODS: The authors studied 16 patients who underwent epilepsy surgery because of drug-resistant TLE using [11C]flumazenil PET and quantitative MRI. In 12 patients, resected hippocampus was available for histologic analysis. [11C]Flumazenil binding potential (fitted BP) was assessed with the simplified reference tissue model. RESULTS: [11C]Flumazenil fitted BP in the medial temporal lobe was reduced in all patients with abnormal hippocampal volumetry or T2 relaxometry on MRI. Fitted BP was also reduced in 46% of the patients with hippocampal volume within the normal range and in 38% of patients with less than 2 SD T2 prolongation. In all MRI-negative/PET-positive patients, the histologic analysis verified hippocampal damage. Also, [11C]flumazenil fitted BP correlated with the severity of reduced hippocampal volume, T2 prolongation, and histologically assessed neuronal loss and astrogliosis. CONCLUSION: [11C]Flumazenil PET provides a useful tool for investigating the hippocampal damage in vivo even in patients with no remarkable hippocampal abnormalities on quantitative MRI.

Repeated 3D coronary MR angiography with navigator echo gating: technical quality and consistency of image interpretation.

The purpose of this study was to evaluate the technical quality of 3D coronary MR angiography (CMRA) with navigator echo and the consistency of image interpretation in repeated imaging sessions. Fourteen subjects underwent CMRA, 10 of whom were imaged twice. The coronary arteries (96 segments) were analyzed twice for hemodynamically significant stenoses. Signal-to-noise and contrast-to-noise ratios varied considerably between the two imagings. Fat saturation was poor or satisfactory in 37%; in 15% of the slabs, the severity of artifacts was moderate; and the overall quality was good to excellent in only 42% of the imagings. The intraobserver reproducibility was good (kappa = 0.54), but the consistency of interpretation for repeated CMRA was only satisfactory (kappa = 0.43). Sensitivities of 84 and 84% and specificities of 70 and 62% were obtained for the two readings. Although the reproducibility of image reading is good, 3D CMRA with navigator echo provides only fair technical consistency, and the frequently compromised image quality impairs the clinical utility of this technique.

Combined SPECT and diffusion-weighted MRI as a predictor of infarct growth in acute ischemic stroke.

UNLABELLED: In acute ischemic stroke, the infarcted core is surrounded by a zone of tissue that has decreased perfusion. Some of this tissue may be salvaged by prompt, effective treatment. Diffusion-weighted MRI is sensitive in detecting the infarcted tissue, whereas SPECT also detects the hypoperfused tissue around the infarcted core. We studied the potential of combined diffusion-weighted MRI and SPECT to predict infarct growth and clinical outcome in patients not receiving thrombolytic treatment. METHODS: Sixteen patients with acute stroke were examined consecutively with diffusion-weighted MRI and 99mTc-ethyl cysteinate dimer (99mTc-ECD) SPECT within 24 h of the onset of symptoms. Follow-up diffusion-weighted MRI was performed on the second day and after 1 wk. The volumes of infarcted and hypoperfused brain tissue were measured from diffusion-weighted MRI and SPECT, respectively. The volume difference between the hypoperfused and infarcted tissue on the first day was compared with the possible increase in infarct volume during the follow-up. Each patient's neurologic status was assessed with the National Institutes of Health Stroke Scale (NIHSS). RESULTS: The volume of infarcted tissue increased from 48 +/- 54 cm3 (mean +/- SD) on the first day to 88 +/- 93 cm3 on the second day (P = 0.001) and to 110 +/- 121 cm3 at 1 wk (P = 0.001). The volume of hypoperfused tissue on the first day was significantly greater than the infarct volume (102 +/- 135 cm3; P = 0.001). The volume difference between the hypoperfused and infarcted tissue on the first day correlated significantly with the infarct growth between the first day and 1 wk (r = 0.71; P < 0.01). Between the first day and 1 wk, the increase of the infarct volume correlated significantly with the change in the NIHSS (r = 0.54; P < 0.05). CONCLUSION: A large hypoperfusion zone around the infarct core in the acute phase of ischemic stroke predicts the infarct growth during the first week, and this correlates significantly with the change in the neurologic status of the patient. Combined diffusion-weighted MRI and SPECT performed within 24 h after the onset of symptoms can be useful in the evaluation of acute stroke to predict infarct growth.

Herpes simplex virus thymidine kinase gene therapy in experimental rat BT4C glioma model: effect of the percentage of thymidine kinase-positive glioma cells on treatment effect, survival time, and tissue reactions.

Herpes simplex virus thymidine kinase (HSV-tk) gene transfer and ganciclovir (GCV) administration have been suggested for the treatment of malignant gliomas. To understand tissue responses and possible ways to improve the treatment effect, we studied tumor growth, tissue reactions, and survival time after HSV-tk/GCV treatment in a syngeneic BT4C rat glioma model by mixing various ratios of stably transfected HSV-tk-expressing BT4C-tk glioma cells with wild-type BT4C glioma cells (percentage of BT4C-tk cells: 0%, 1%, 10%, 30%, 50%, and 100%), followed by injection into BDIX rat brains (n = 79). With the exception of some animals with end-stage tumors, very little astroglia or microglia reactivity was detected in the wild-type tumors as analyzed by immunocytochemistry using glial fibrillary acid protein (GFAP)-, vimentin-, human histocompatibility leukocyte antigen-DR-, OX-42-, and CD68-specific monoclonal antibodies. After 14 days of GCV treatment, tumors induced with > or = 10% BT4C-tk cells showed a significant reduction in tumor size (P < .05) and prolonged survival time (P < .01). Astrogliosis, as indicated by a strong GFAP and vimentin immunoreactivity, was seen in the tumor scar area. GFAP and vimentin reactivity was already present after the GCV treatment in tumors induced with 1% BT4C-tk cells. Much less human histocompatibility leukocyte antigen-DR-positive microglia was seen in the treated animals, indicating low microglia reactivity and immunoactivation against the tumor. However, GCV-treated tumors were positive for apoptosis, indicating that apoptosis is an important mechanism for cell death in the BT4C-tk glioma model. Our results suggest that > or = 10% transfection efficiency is required for a successful reduction in BT4C glioma tumor size with HSV-tk/GCV treatment in vivo. Tissue reactions after 14 days of GCV treatment are characterized by astrogliosis and apoptosis, whereas microglia response and immunoactivation of the brain cells appear to play a minor role. Stimulation of the microglia response by gene transfer or other means might improve the efficacy of the HSV-tk/GCV treatment in vivo.

Left atrial volume assessed by transthoracic three dimensional echocardiography and magnetic resonance imaging: dynamic changes during the heart cycle in children.

OBJECTIVE: To assess the dynamic changes in left atrial volume by transthoracic three dimensional echocardiography and compare the results with those obtained by magnetic resonance imaging (MRI). DESIGN AND PATIENTS: 30 healthy children (15 boys and 15 girls, aged 8 to 13 years) underwent examination by three dimensional echocardiography and MRI. METHODS: Three dimensional echocardiography of the left atrium was performed using rotational acquisition of planes at 18 degrees intervals from the parasternal window with ECG gating and without respiratory gating. Volume estimation by MRI was performed with a slice thickness of 4-8 mm and ECG triggering during breath holding in deep inspiration. A left atrial time-volume curve was reconstructed in each child. RESULTS: Left atrial maximum and minimum volumes averaged 24.0 ml/m(2) and 7. 6 ml/m(2) by three dimensional echocardiography, and 22.1 ml/m(2) and 11.9 ml/m(2) by MRI. The greater left atrial minimum volume in the latter was at least in part a result of breath holding. Dynamic changes in left atrial volume during the heart cycle were detectable by both methods. The higher temporal resolution of three dimensional echocardiography allowed a more precise evaluation of different phases. CONCLUSIONS: Three dimensional echocardiography and MRI were both useful methods for studying the physiological volume changes in the left atrium in children. These methods may be used for further study of the systolic and diastolic function of the heart.

Cotinine and nicotine inhibit each other's calcium responses in bovine chromaffin cells.

Cotinine is the major metabolite of nicotine. It has some biological activity, but its pathophysiological effects are largely unclear. We studied whether cotinine initiates calcium transients or affects those induced by nicotine. In bovine adrenal chromaffin cells labeled with the fluorescent calcium indicator Fura 2, cotinine (0. 32-3.2 mM) concentration-dependently increased the intracellular Ca(2+) concentration ([Ca(2+)](i)). The effect was abolished by omitting extracellular Ca(2+) during the stimulations. Also nicotinic receptor channel blockers hexamethonium (10 microM-1 mM) and chlorisondamine (100 microM), as well as a competitive nicotinic receptor antagonist dihydro-beta-erythroidine (10-100 microM), inhibited the response. Cotinine (0.32-3.2 mM) preincubation for 2 min inhibited both the nicotine-induced and the cotinine-induced increases in [Ca(2+)](i). Also nicotine (3.2-10 microM) inhibited the cotinine-induced increase in [Ca(2+)](i). Tetrodotoxin (1 microM) and thapsigargin (1 microM) pretreatments did not affect the responses to cotinine, while 300 nM nimodipine partially inhibited the cotinine-induced increase in [Ca(2+)](i). The results indicate that cotinine has nicotine-like effects on chromaffin cells. It may also desensitize the nicotinic cholinergic receptors, possibly by acting as a low-affinity agonist at these receptors.