Synthesis of 68Ga-Labeled Biopolymer-based Nanoparticle Imaging Agents for Positron-emission Tomography.

AIM: The purpose of this study was to develop a folate receptor-targeted 68Ga-labeled agent for the detection of cancer cells in mouse models of ovarian cancer by dual positron-emission tomography (PET) and magnetic resonance imaging (MRI). Moreover, we aimed to develop a controlled biopolymer-based chemistry that enables linking metal-binding (here Ga-68) chelators. MATERIALS AND METHODS: The nanoparticle (NP) agent was created by self-assembling of folic acid-modified polyglutamic acid and chelator-modified chitosan followed by radiolabeling with 68Ga (III) ions (68Ga-NODAGA-FA). The structure of modified biopolymers was characterized by spectroscopy. Particle size and mobility were determined. RESULTS: Significant selective binding of NPs was established in vitro using folate receptor-positive KB and - negative MDA-MB-231 cell lines. In vivo tumor uptake of folate-targeted 68Ga3+-radiolabeled NPs was tested using subcutaneous tumor-bearing CB17 SCID mice models. PET/MR dual modalities showed high tumor uptake with 6.5 tumor-to-muscle ratio and NP localization. CONCLUSION: In vivo results supporting the preliminary in vitro tests demonstrated considerably higher 68Ga-NODAGA-FA nanoparticle accumulation in KB tumors than in MDA-MB-231 tumors, thereby confirming the folate receptor-mediated uptake of this novel potential PET imaging agent.

Accuracy of computed tomography angiography in the detection of pulmonary embolism in patients with high body weight.

BACKGROUND: The accuracy of CT pulmonary angiography (CTPA) in detecting or excluding pulmonary embolism has not yet been assessed in patients with high body weight (BW). METHODS: This retrospective study involved CTPAs of 114 patients weighing 75-99 kg and those of 123 consecutive patients weighing 100-150 kg. Three independent blinded radiologists analyzed all examinations in randomized order. Readers' data on pulmonary emboli were compared with a composite reference standard, comprising clinical probability, reference CTPA result, additional imaging when performed and 90-day follow-up. Results in both BW groups and in two body mass index (BMI) groups (BMI <30 kg/m(2) and BMI ≥ 30 kg/m(2), i.e., non-obese and obese patients) were compared. RESULTS: The prevalence of pulmonary embolism was not significantly different in the BW groups (P=1.0). The reference CTPA result was positive in 23 of 114 patients in the 75-99 kg group and in 25 of 123 patients in the ≥ 100 kg group, respectively (odds ratio, 0.991; 95% confidence interval, 0.501 to 1.957; P=1.0). No pulmonary embolism-related death or venous thromboembolism occurred during follow-up. The mean accuracy of three readers was 91.5% in the 75-99 kg group and 89.9% in the ≥ 100 kg group (odds ratio, 1.207; 95% confidence interval, 0.451 to 3.255; P=0.495), and 89.9% in non-obese patients and 91.2% in obese patients (odds ratio, 0.853; 95% confidence interval, 0.317 to 2.319; P=0.816). CONCLUSION: The diagnostic accuracy of CTPA in patients weighing 75-99 kg or 100-150 kg proved not to be significantly different.

Tumor-specific localization of self-assembled nanoparticle PET/MR modalities.

AIM: The aim of this work was to synthesize and study in vitro and in vivo nanocarriers used as magnetic resonance imaging (MRI) contrast agents that accumulate in tumor cells specifically overexpressing folate receptors. MATERIALS AND METHODS: Nanoparticles were prepared by self-assembly of poly-γ-glutamic acid and chitosan biopolymers and were complexed with gadolinium ions. Folic acid served as a targeting molecule. Rat hepatocellular carcinoma (HeDe) cells overexpressing folate receptors were used as a model system. For in vivo experiments, HeDe cells were transplanted under the renal capsule of F344 rats. RESULTS: In vitro results showed the significant internalization of nanoparticles into HeDe cells. MRI measurements revealed that targeting nanocarriers accumulated in tumors. The MRI/PET fusion images resulted in the exact localization of tumors. CONCLUSION: The nanocarrier provides a suitable means for the early diagnosis of tumors based on their overexpression of folate receptors.

Cancer cell targeting and imaging with biopolymer-based nanodevices.

We report here the synthesis, in vitro and in vivo investigation of magnetic resonance imaging (MRI) active nanoparticles, which target folate receptor overexpressing tumor cells. Self-assembled nanoparticles with a hydrodynamic size of 50-200 nm were prepared from poly-γ-glutamic acid and chitosan biopolymers with Gd-ions. The nanoparticles are biocompatible, non-toxic and stable for several months in aqueous media. In vitro assays using confocal microscopy, flow cytometry and MR imaging on HeLa human cervix carcinoma tumor cells showed that folic acid targeted nanoparticles were internalized specifically in a folate receptor dependent manner. In vivo study confirmed, that, considerable accumulation of nanosystems was found compared with the control animal represented by the MR images. Relaxometry measurements demonstrated that the nanoparticle-Gd complexes drastically change the signal intensity of the tumor cells. Because of the contrast enhancement, they are attractive candidates as potential contrast agents for a variety of diagnostic applications including early diagnosis of tumors.

Clinical experience with a new endobrochial blocker: the EZ-blocker.

PURPOSE: In some thoracic surgical procedures, the insertion of a double-lumen tube (DLT) is not feasible, or the altered use of a DLT and a single-lumen tube (SLT) is justified during the surgery. In the present article we report our experience with a new bronchial blocker, the EZ-blocker, in clinical use. METHODS: Data were obtained from ten patients undergoing thoracic surgery necessitating one-lung ventilation. For lung isolation, a combination of an SLT and an EZ-blocker was used. The time of insertion and positioning of the EZ-blocker, the lung deflation time with the EZ-blocker cuff inflated and deflated, and the cuff's minimal occlusion volume were recorded. Based on the CT scan, the diameter of the main bronchi and the angle of the bifurcation were measured offline. RESULTS: The insertion duration of the EZ-blocker was 76 ± 15 s. Two malpositionings were caused by the too-deep positioning of the SLT used for introducing the EZ-blocker, which could be corrected within 65 ± 7 s. The use of the EZ-blocker allowed a short deflation time of the lung without (9.4 ± 0.7 s) and with (4.1 ± 0.7 s) administration of suctioning. The proper block was only dependent on the diameter of the main bronchi and was independent of the bifurcation angle. CONCLUSIONS: Use of the EZ-blocker is easy and safe. The short insertion time and short lung deflation time through the lumen of the SLT allows its use in emergency situations or in cases of a difficult airway.

Visualization of the ischemic core on native human brain slices by potassium staining method.

The potassium staining method is based on the formation of potassium cobaltnitrite crystals after the treatment by sodium cobaltnitrite of brain tissue. The degree of staining correlates with the distinct potassium content of infracted and non-infarcted brain areas. The aim of the present study was to prove that potassium staining technique is a reliable method for localization of ischemic core on native whole hemisphere cryosections of stroke patients. Furthermore, potassium stained sections have been compared with appropriate postmortem MRI images of respective brains. Brains of stroke patients were removed within 24h after death and postmortem MRI scanning was performed. Horizontal cryosections of frozen brains were taken and potassium staining was performed. Using the stained whole hemisphere sections as "map" tissue sampling has been made in order to determine water and potassium content. Potassium content of infarcted samples was significantly decreased in comparison with intact regions (0.7346+/-0.2142 mg/L and 1.928+/-0.447 mg/L, respectively, p<0.01) (mean values+/-SD). Water content of affected areas (expressed in percents) has been found to be above non-infarcted regions (81.657%+/-4.07 and 72.96%+/-6.37, respectively, p<0.01). According to our results the potassium staining method of human whole hemisphere brain sections reliably differentiates focal ischemic areas from intact brain regions. In conclusion, the postmortem examination of ischemic brain could be started with making the potassium map of infarcted whole hemisphere cryosections providing guidance for targeted tissue sampling and base of comparison for further examinations.

Carotid intima-media thickness and cerebrovascular reactivity in long-term type 1 diabetes mellitus.

PURPOSE: Diabetes mellitus (DM) is one of the leading risk factors for cerebrovascular diseases. Both macro- and microvascular damage may occur. The aim of the present work was to assess intima-media thickness as well as cerebral vasoreactivity in patients suffering from type 1 diabetes mellitus (IDDM). METHODS: Intima-media thickness and resting middle cerebral artery blood flow velocity was measured in 33 IDDM patients and 31 healthy controls. After baseline investigations, 30 seconds of breath holding (BH) and 60 seconds of voluntary hyperventilation (HV) were performed by the subjects. Transcranial Doppler measurements were performed in each case after vasodilatory (BH) and vasoconstrictor (HV) stimuli. Cerebrovascular reactivity was expressed as the percentage of change of the middle cerebral mean blood flow velocity after BH or HV. RESULTS: IDDM patients showed a significantly larger intima-media thickness (0.1 +/- 0.02 mm) than healthy controls (0.06 +/- 0.006 mm, p < 0.001). Cerebrovascular reactivity after BH was less intensive in diabetic patients (19.3 +/- 16.1%) than that of the control subjects (38.7 +/- 22.8%, p < 0.01). Similarly, HV induced a less-pronounced decrease of cerebral blood flow velocity in diabetic subjects (-30.1 +/- 13.2%) than in nondiabetics (-37.6 +/- 17.0%, p < 0.05). CONCLUSION: Our results refer to early macro- and microangiopathic involvement of the cerebral vessels, which develop in parallel with angiopathies of the other organs, such as nephropathy and retinopathy. Further prospective studies are needed to clarify the role of these macro- and microangiopathic changes in the development of cerebrovascular complications in patients suffering from DM.

Cortical spreading edema in persistent visual migraine aura.

We present imaging evidence of the spreading of cortical edema with reversibly restricted water diffusion from the left occipital to the temporoparietal cortex in persistent visual migraine aura in a 58-year-old man. The right-sided visual field defect lasting for 15 days was associated with discoupling of glucose metabolism and blood flow and the decreased apparent diffusion coefficient also suggested cytotoxic edema. At 8 weeks no signs were present, and magnetic resonance imaging became normal; therefore, long-lasting restricted cortical water diffusion, even if coupled with hypometabolism and edema, can be reversible in persistent visual migraine aura.

Pattern of increased cerebral FDG uptake in Down syndrome patients.

Resting cerebral glucose metabolism was assessed by 18[F]-fluorodeoxyglucose in 11 Down syndrome patients. Standardized uptake values were determined on a pixel-by-pixel basis from the measured tissue-activity data. The results revealed a mean overall 18[F]-fluorodeoxyglucose uptake in the Down syndrome patients close to that observed in the control group, consisting of children and young adults. However, the standard deviation of the standardized uptake values was much higher in the Down syndrome group in almost all voxels relating to the gray matter. The statistical parametric mapping method was applied to compare the cerebral 18[F]-fluorodeoxyglucose accumulation patterns of the Down syndrome and control groups. Six regions (clusters) were found for which the glucose uptake was higher in the Down syndrome patients than in the control group. The anatomic localization of these clusters was based on magnetic resonance investigations and a brain-atlas technique. The localization of the identified clusters with an increased glucose metabolism in the Down syndrome patients suggests that these subjects have an enhanced resting neuronal activity in cortical areas involved in reasoning, cognition, and speech as compared with normal subjects.

[Primary cerebral angiitis: a case history and literature review of its diagnosis]. / Primer cerebralis angiitis: esetismertetés és irodalmi összefoglalás.

The authors present a case history of primary cerebral angiitis with four years of follow-up. The early diagnosis was based on typical clinical symptoms, brain MRI, intracerebral MRA and histology of sural nerve biopsy. Electroneurography suggested peripheral involvement, although the patient did not have clinical signs of peripheral neuropathy. Glucocorticoid and immunosuppressive treatment resulted in remission. The diagnostic difficulties of primary cerebral vasculitis are also summarized in the discussion.

Volume changes in intra- and extraorbital compartments in patients with Graves' ophthalmopathy: effect of smoking.

The objective of this study was to demonstrate the effect of smoking history on soft tissue expansion in specific orbital compartments in patients with Graves' ophthalmopathy. The volumes of the rectus muscles, intra and extraorbital connective, and soft tissues were measured in 110 orbits of 35 patients and 20 control subjects. Data sets from current smokers, ex-smokers, and non-smokers were compared. The total number of cigarettes smoked was calculated, and it was used as an estimate for the severity of smoking (cumulative smoking). The volume measurements were performed on T1-weighted contiguous transversal magnetic resonance images of the orbits. Connective tissue volumes were influenced by smoking history, while muscle volumes were not affected. Ex-smokers had larger amount of extraorbital connective tissue than current smokers (p = 0.012), and this volume showed a good correlation with the number of cigarettes smoked (r = 0.539, p < 0.05). In current smokers, the amount of intraorbital connective tissue correlated well with the cumulative smoking (r = 0.635, p < 0.001). We conclude that connective tissue volumes in certain orbital compartments correlate well with cumulative smoking. Extraocular muscle volumes are not influenced by smoking in patients with Graves' ophthalmopathy.

Angiotensin-converting enzyme gene polymorphism, carotid intima-media thickness, and left ventricular mass index in adolescent hypertension.

PURPOSE: The aim of this study was to determine whether a positive correlation exists between the DD genotype of angiotensin-converting enzyme (ACE) and the carotid intima-media thickness (IMT) or left ventricular mass index (LVMI) in adolescents with hypertension. METHODS: We studied 120 hypertensive and 58 normotensive (control) adolescents. ACE gene polymorphism was determined by a standardized method. The IMT was measured in the common carotid arteries, and the LVMI was calculated on transthoracic echocardiography. The severity of hypertension was graded according to the results of ambulatory blood pressure monitoring as white coat, borderline, or proven hypertension. The association between ACE gene polymorphism and the obtained parameters was analyzed using analysis of variance and chi-square testing. RESULTS: Both the IMT and LVMI were higher in hypertensive than in control adolescents. In hypertensive subjects, no relationship was found between the different ACE genotypes and the IMT: the mean (+/- standard deviation) IMT in patients with the DD genotype was 0.57 +/- 0.11 mm; in those with the DI genotype, 0.53 +/- 0.01 mm; and in those with the II genotype, 0.55 +/- 0.01 mm. The LVMI was also similar in all 3 ACE genotypes: DD, 106.7 +/- 32.3 g/m(2); DI, 102.2 +/- 38.1 g/m(2); and II, 103.2 +/- 26.3 g/m(2). The severity of hypertension as assessed by ambulatory blood pressure monitoring was independent of the ACE genotype. CONCLUSIONS: Target-organ damage (left ventricular hypertrophy and carotid atherosclerosis) is detectable in adolescents with hypertension and, in those subjects, ACE genotype polymorphism is not correlated with the severity of target-organ damage as measured by IMT and LVMI.

Image quality of the temporal bone window examined by transcranial Doppler sonography and correlation with postmortem computed tomography measurements.

BACKGROUND AND PURPOSE: The major limitation of native transcranial colour-coded duplex sonography (TCCS) in older stroke patients is the relatively frequent occurrence of an insufficient temporal window. Our goal was to investigate the relationship between the in vivo Doppler ultrasound image quality of the temporal bone, and computed tomography (CT)-determined thickness, density, and homogeneity of cadaver temporal bone. METHODS: Thirty-three moribund neurological patients who eventually died were examined by TCCS using the transtemporal approach. The sonographer categorized the quality of the TCCS image (excellent, intermediate, and poor). During autopsy, a rectangular sample of the temporal squama was removed, which corresponded to the area of the in vivo acoustic window. The thickness of the whole temporal bone, cortical, and cancellous (= diploe) bone as well as the density and homogeneity were determined by high-resolution CT. RESULTS: Thirty-seven temporal bones were obtained. The quality of the acoustic window was classified as excellent in 13, intermediate in 6 and poor in 18 cases. A significant correlation between the complete bone thickness, as well as between the absolute thickness of the diploe and the quality of the acoustic window was found: the thinner the bone/diploe, the better the colour Doppler signal. The thickness of the cortical plates and the homogeneity of the bones were identical in the three image quality categories. CONCLUSION: The transtemporal TCCS image quality depends mainly on the thickness of the cancellous component of the temporal bone.

MRI findings in central nervous system systemic lupus erythematosus are associated with immunoserological parameters and hypertension.

Involvement of the brain is one of the most important complications of systemic lupus erythematosus (SLE). To investigate the correlation between abnormal cranial MRI findings and age, duration of SLE, neuropsychiatric (NP) manifestations, hypertensive status, and the presence of antiphospholipid antibodies (PA) in patients with SLE we evaluated the MRI results of 81 SLE patients in nine NP clinical subgroups.Immunoserological status was described by the presence of lupus anticoagulant (LA), and anticardiolipin antibodies (aCL). The MRI findings were categorized as normal [41], cerebral atrophy [15], small subcortical hyperintensity [7], and infarct larger than 10mm [18]. Mean age differed among the clinical subgroups (ANOVA, p = 0.002), whereas there was no age difference among the subgroups based on MRI and immunoserological results. Patients with hypertension (33/81) were a mean of 6 years older at the time of examination (p = 0.033) and had stroke more frequently, than normotensive ones (p = 0.0015). MRI abnormalities were more frequent in patients with LA positivity (p < 0.01) than in those without these antibodies, and in the hypertensive than in the normotensive subgroup (p = 0.00041). The presence of PA was associated with abnormal MRI even after controlling for the effect of age and hypertensive status (p = 0.011). In our study the MRI findings in central nervous system SLE were independent of the age of patients and the age at the diagnosis of SLE, and were not influenced by the duration of SLE; however, they were associated with immunoserological parameters and hypertension.

Detection of carotid artery stenosis by in vivo duplex ultrasound: correlation with planimetric measurements of the corresponding postmortem specimens.

BACKGROUND AND PURPOSE: The correct detection and quantification of carotid artery disease are of decisive impact on patient prognosis and adequate treatment. In this study, we evaluated the ability of ultrasonography to detect and to grade carotid artery stenosis through a comparison of the in vivo ultrasound findings with the planimetric analysis of the corresponding postmortem specimens. METHODS: Shortly before their death, 59 critically ill neurological patients (mean age, 70 years) were prospectively examined by extracranial and intracranial Doppler sonography and color-coded duplex ultrasound. Carotid stenosis was classified by hemodynamic and morphological ultrasound criteria. Carotid specimens were removed in toto during autopsy. Under standardized conditions, specimens were redistended, sectioned, and histologically processed. Computerized planimetric measurements of the arteries were carried out and compared with the ultrasound findings. Correlation of the ultrasound and postmortem planimetric findings was available in 93 carotid bifurcations. RESULTS: Through both techniques, 46 carotid arteries were found to be normal. Steno-occlusive carotid lesions ranged from 8.5% to 100% lumen reduction. Overall, r=0.96 and adjusted R(2)=0.90. For the steno-occlusive carotid lesions, r=0.91. CONCLUSIONS: Extracranial and intracranial Doppler and color-coded duplex ultrasound permits reliable detection and quantification of carotid artery stenoses and occlusions even under difficult examination conditions in critically ill patients.

Assessment of cerebrovascular reserve capacity in asymptomatic and symptomatic hemodynamically significant carotid stenoses and occlusions.

BACKGROUND: Cerebrovascular reactivity measurements are believed to be a helpful tool for selecting patients who are at higher risk for hemodynamic strokes. The aim of this study was to compare cerebral vasoreactivity among patients suffering from internal carotid artery stenosis of different severity (asymptomatic stenosis, asymptomatic occlusion, symptomatic stenosis, symptomatic occlusion). METHODS: Sixty-two patients with asymptomatic and symptomatic internal carotid artery stenoses and occlusions underwent transcranial Doppler-acetazolamide tests. Absolute velocities of the middle cerebral arteries (MCAV), percent increases of the MCAV at different time points of the test (cerebrovascular reactivity, CVR) and maximal percent increase after administration of acetazolamide (cerebrovascular reserve, CRC) were compared on the affected and non-affected sides. Asymmetry indices (CRC (affected side)/CRC (non-affected side)) were compared between the groups of different severity of obstructive lesion. RESULTS: Resting MCAV was similar on both sides in all groups. A significant side-difference of the MCAV values after acetazolamide was observed only in the symptomatic groups. Difference of cerebrovascular reserve capacity between the affected and non-affected side was statistically significant only in the symptomatic groups (CRC symptomatic stenosis 36.6 +/- 20.9% vs. 71.1 +/- 27.9%, CRC symptomatic occlusion: 31.2 +/- 24.6% vs. 64.5 +/- 29.7%). Asymmetry index of the CRC was near to 1 in the asymptomatic stenosis group only, while in all the other groups this index referred to a significant hemispheric asymmetry of the vasoreactivity. CONCLUSIONS: Although in general cerebrovascular reserve capacity is compromised in cases of hemodynamically significant carotid lesions, there is a large individual variability within the subgroups. Further randomized studies are needed to clarify whether the clinical efficiency of carotid endarterectomy and extra-intracranial bypass may be improved by selecting the patients using hemodynamic criteria.

[PET and SPECT scans in autistic children]. / PET- és SPECT-vizsgálatok autista gyermekeken.

The authors have analyzed and compared the results of the 99mTc-ECD-SPECT and FDG-PET examinations, performed in alert state, of 12 children suffering from infantile (9 subjects) or atypical (3 subjects) autism. In addition to frontally increased FDG metabolism, a decreased blood flow with left-sided dominance was found bifrontally and bitemporally in the infantile form (perfusion-metabolism mismatch). The regional differences in cortical FDG uptake were not significant in atypical autism, although both the blood flow and the metabolism of the thalami were decreased. Based on the results, the authors suggest that, beyond the usually inconclusive structural (CT or MR) examinations, cerebral blood flow SPECT and metabolic FDG-PET investigations may be useful in classifying the disease.

[Cerebral glucose metabolism in Down syndrome using positron emission tomography]. / Az agyi glükózanyagcsere vizsgálata Down-kórban pozitronemissziós tomográfiával.

Resting cerebral glucose metabolism was assessed by PET using FDG in eleven Down syndrome (DS) patients. Standardized uptake values (SUV) were determined on a pixel by pixel basis from the measured tissue FDG-activity data. The results showed that the mean value of the global FDG-uptake in the DS patients was not significantly different from the one obtained in the control group consisting of children and young adults. The standard deviation of SUV, however, was much higher in the DS group in almost all regions. The statistical parametric mapping (SPM) method was applied to compare the relative cerebral FDG accumulation pattern of the populations. Six regions (clusters) were found in which the glucose-uptake was higher in the DS patients than in the control group. The anatomical localization of these clusters was based on MRI investigations and brain-atlas technique.

[Effect of flumazenil on the regional cerebral blood flow measured by [15O]-butanol PET scan and transcranial Doppler ultrasonography]. / Flumazenil hatása a regionális agyi perfusióra [15O]-butanol-PET- és transcranialis Doppler-UH-vizsgálatok alapján.

The authors investigated the role of the cBZD/GABA-A receptor-complex in the regulation of rCBF by simultaneously applying [15O]-butanol-PET and TCD in therapy-resistant TLE patients. It is known that the density of the cBZD/GABA-A-receptors is reduced in the epileptogenic area of the temporal lobe, but there are no data available about the impact of this phenomenon on rCBF. FMZ is a well-known BZD-receptor antagonist which can be used to inhibit the effect mediated by cBZD/GABA-A-receptors, offering a way to study the contribution of these receptors in the determination of rCBF. The authors examined the possible correlation between the rCBF values obtained by PET and the blood flow speed readings measured by TCD in MCAs. The results show that FMZ does not cause any change in rCBF on the side of the epileptogenic focus but it significantly raises rCBF (p < 0.001) in the intact brain tissue on the other side. The TCD measurements showed no significant differences between the blood flow in the MCAs supplying the affected and the contralateral lobe.