Lateral Asymmetry and Spatial Difference of Iron Deposition in the Substantia Nigra of Patients with Parkinson Disease Measured with Quantitative Susceptibility Mapping.

BACKGROUND AND PURPOSE: Quantitative susceptibility mapping is useful for assessing iron deposition in the substantia nigra of patients with Parkinson disease. We aimed to determine whether quantitative susceptibility mapping is useful for assessing the lateral asymmetry and spatial difference in iron deposits in the substantia nigra of patients with Parkinson disease. MATERIALS AND METHODS: Our study population comprised 24 patients with Parkinson disease and 24 age- and sex-matched healthy controls. They underwent 3T MR imaging by using a 3D multiecho gradient-echo sequence. On reconstructed quantitative susceptibility mapping, we measured the susceptibility values in the anterior, middle, and posterior parts of the substantia nigra, the whole substantia nigra, and other deep gray matter structures in both hemibrains. To identify the more and less affected hemibrains in patients with Parkinson disease, we assessed the severity of movement symptoms for each hemibrain by using the Unified Parkinson's Disease Rating Scale. RESULTS: In the posterior substantia nigra of patients with Parkinson disease, the mean susceptibility value was significantly higher in the more than the less affected hemibrain substantia nigra (P < .05). This value was significantly higher in both the more and less affected hemibrains of patients with Parkinson disease than in controls (P < .05). Asymmetry of the mean susceptibility values was significantly greater for patients than controls (P < .05). Receiver operating characteristic analysis showed that quantitative susceptibility mapping of the posterior substantia nigra in the more affected hemibrain provided the highest power for discriminating patients with Parkinson disease from the controls. CONCLUSIONS: Quantitative susceptibility mapping is useful for assessing the lateral asymmetry and spatial difference of iron deposition in the substantia nigra of patients with Parkinson disease.

Visualization of the Medial and Lateral Geniculate Nucleus on Phase Difference Enhanced Imaging.

BACKGROUND AND PURPOSE: The precise identification and measurement of the medial geniculate nucleus and lateral geniculate nucleus on MR imaging remain technically challenging because the thalamic nuclei are small structures. We compared the visualization of the medial geniculate nucleus and lateral geniculate nucleus on phase difference enhanced imaging with 3D high-resolution phase imaging, 2D-T2WI, STIR, proton attenuation-weighted imaging, and DTI acquired at 3T. We also measured the volume and height of the medial geniculate nucleus and lateral geniculate nucleus on phase difference enhanced imaging. MATERIALS AND METHODS: Phase difference enhanced, 2D-T2-weighted, STIR, proton attenuation-weighted, and DTI were acquired on a 3T MR imaging unit in 10 healthy volunteers. Two neuroradiologists recorded the qualitative visualization scores of the medial geniculate nucleus and lateral geniculate nucleus, specifically the identification of their boundaries, for all images. Measurement differences were assessed with the Wilcoxon signed rank test. The volume and height of the medial geniculate nucleus and lateral geniculate nucleus were measured on phase difference enhanced imaging and compared with previously reported values. RESULTS: The qualitative visualization scores of the lateral geniculate nucleus and medial geniculate nucleus were significantly higher on phase difference enhanced images than on T2-weighted, proton attenuation-weighted, STIR, or DTI (P < .05). On phase difference enhanced imaging, the medial geniculate nucleus and lateral geniculate nucleus were bordered by low-intensity structures: the cerebral peduncle, the origin of the optic radiation, and the superior and inferior quadrigeminal brachia. The volume of the medial geniculate nucleus and lateral geniculate nucleus varied from 74.0 to 183.75 mm(3) (mean, 129.0 ± 34.7 mm(3)) and from 96.5 to 173.75 mm(3) (mean, 135.2 ± 28.0 mm(3)), respectively. CONCLUSIONS: For the depiction of the medial geniculate nucleus and lateral geniculate nucleus on 3T MR imaging, phase difference enhanced imaging is superior to conventional MR imaging. The medial geniculate nucleus and lateral geniculate nucleus volumes vary among individuals.

Distinguishing imaging features between spinal hyperplastic hematopoietic bone marrow and bone metastasis.

BACKGROUND AND PURPOSE: Systematic investigations of the distinguishing imaging features between spinal hyperplastic hematopoietic bone marrow and bone metastasis have not been reported, to our knowledge. The purpose of this study was to determine the distinguishing imaging features of the 2 entities. MATERIALS AND METHODS: We retrospectively reviewed the radiologic images of 8 consecutive male patients (age range, 52-78 years; mean, 64 years) with suspected spinal metastasis on MR imaging and FDG-PET, which was later confirmed as hyperplastic hematopoietic bone marrow. MR imaging, FDG-PET, CT, and bone scintigraphy images were qualitatively and/or quantitatively evaluated. Imaging findings in 24 patients with spinal metastasis were compared, and differences were statistically analyzed. RESULTS: All 8 vertebral hyperplastic hematopoietic bone marrow lesions were hypointense on T1- and T2-weighted images; lesions contiguous with the adjacent vertebra were significantly more often seen in hyperplastic hematopoietic bone marrow than in metastasis (P = .035). T2 signal intensity of the lesion was significantly different between the 2 entities (P = .033). FDG-PET showed slightly higher uptake in all hyperplastic hematopoietic bone marrow lesions; their maximum standard uptake value was significantly lower than that of metastatic lesions (P = .037). CT attenuation of hyperplastic hematopoietic bone marrow was equal to or slightly higher than that of adjacent normal-appearing vertebra; the CT appearances of hyperplastic hematopoietic bone marrow and metastasis were significantly different (P < .01). Bone scintigraphy showed normal uptake for all vertebrae with hyperplastic hematopoietic bone marrow; the uptake was significantly different from that of metastasis (P < .01). CONCLUSIONS: If a lesion was isointense to hyperintense to normal-appearing marrow on MR imaging or had a maximum standard uptake value of >3.6, the lesion was considered metastatic. A normal appearance on CT or bone scintigraphy excluded metastasis.

Comparison of dynamic contrast-enhanced 3T MR and 64-row multidetector CT angiography for the localization of spinal dural arteriovenous fistulas.

BACKGROUND AND PURPOSE: For the localization of spinal dural arteriovenous fistulas, it is not determined whether dynamic contrast-enhanced MRA is more reliable than multidetector CTA. The aim of this study was to compare the agreement between intra-arterial DSA, dynamic contrast-enhanced MRA at 3T, and 64-row multidetector CTA for the localization of spinal dural arteriovenous fistulas. MATERIALS AND METHODS: We enrolled 12 consecutive patients (11 men, 1 woman; age range, 46-83 years; mean, 65 years) who underwent preoperative dynamic contrast-enhanced MRA at 3T and 64-row multidetector CTA. The spinal dural arteriovenous fistula location was confirmed by intra-arterial DSA as the reference standard. Two reviewers independently evaluated the level of the artery feeding the spinal dural arteriovenous fistula on the basis of continuity between the feeder and abnormal spinal vessels on 3T dynamic contrast-enhanced MRA and 64-row multidetector CTA images. Interobserver and intermodality agreement was determined by calculation of the κ coefficient. RESULTS: On DSA, the vessel feeding the spinal dural arteriovenous fistula was the intercostal artery (7 cases), the lumbar artery (3 cases), and the internal iliac artery or the ascending pharyngeal artery (1 case each). For the fistula level, interobserver agreement was excellent for 3T dynamic contrast-enhanced MRA (κ = 0.97; 95% CI, 0.92-1.00) and very good for 64-row multidetector CTA (κ = 0.84; 95% CI, 0.72-0.96). Intermodality agreement with DSA was good for 3T dynamic contrast-enhanced MRA (κ = 0.78; 95% CI, 0.49-1.00) and moderate for 64-row multidetector CTA (κ = 0.41; 95% CI, 0.020-0.84). CONCLUSIONS: For the localization of spinal dural arteriovenous fistulas, 3T dynamic contrast-enhanced MRA may be more reliable than 64-row multidetector CTA.

Ultraselective transcatheter infusion of epirubicin in water-in-oil-in-water emulsion for small hepatocellular carcinoma.

OBJECTIVE: We have previously reported the clinical efficacy of water-in-oil-in-water (W/O/W) emulsions, particularly for non-selective transcatheter arterial infusion (TAI) therapy. W/O/W emulsions limit damage to normal hepatic parenchyma, because of their minimal embolic effect on peripheral arteries and slow release of anticancer agent. The purpose of this study was to evaluate the safety and effectiveness of ultraselective TAI (UTI) of a W/O/W emulsion for hepatocellular carcinoma (HCC). METHODS: 11 patients with Stage I-III small HCCs (<5 cm) underwent UTI with a W/O/W emulsion at our institute. Response was assessed using the Response Evaluation Criteria in Solid Tumors. Disease-free survival time was estimated using the Kaplan-Meier method. RESULTS: All 10 patients, excluding a patient who underwent a hepatectomy after UTI, achieved complete response. The 6, 12 and 30 month cumulative disease-free survival rates for the 10 patients were 100%, 90% and 60%, respectively. The patient who underwent hepatectomy after UTI developed complete necrosis of the HCC and peritumoral non-tumorous liver parenchyma. CONCLUSION: UTI therapy using a W/O/W emulsion for patients with small HCCs results in a good local response.

Transcatheter infusion of epirubicin in water-in-oil-in-water emulsion via a cystic artery for the treatment of hepatocellular carcinoma.

PURPOSE: We have previously reported the clinical efficacy of water-in-oil-in-water (W/O/W) emulsion containing anticancer agent. The purpose of this study was to evaluate the safety and effectiveness of transcatheter arterial infusion (TAI) of W/O/W emulsion via a cystic artery for hepatocellular carcinoma (HCC). METHODS: TAI of a W/O/W emulsion was performed at our institute in five patients with Stage III or IV HCC with blood supply from the cystic artery. In all patients, 2-12 ml/O/W emulsion was infused via a cystic artery. Therapeutic effects and complications were evaluated in these patients. RESULTS: Of the five patients treated, one achieved a complete response and two achieved a partial response. After treatment, acute cholecystitis or gallbladder ischemia that required treatment was not encountered in any patient. CONCLUSIONS: W/O/W emulsion can be safely infused via a cystic artery without major complications; it is a good therapeutic option for the patients with advanced HCC fed by a cystic artery.

Involvement of the extracellular signal-regulated protein kinase (ERK) pathway in the induction of apoptosis by cadmium chloride in CCRF-CEM cells.

When CCRF-CEM cells were incubated with 5-40 microM CdCl(2,) apoptosis was observed most clearly at 10 microM. Prior to the development of apoptosis, mitogen-activated protein kinases (MAPKs), i.e. extracellular signal-regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 MAPK, were activated with different sensitivity to CdCl(2) exposure. ERK and p38 MAPK were phosphorylated with incubation of 1 microM CdCl(2,) but higher than 20 microM CdCl(2) was required for the clear phosphorylation of JNK. In the time-course study, ERK and p38 MAPK were phosphorylated earlier than JNK after CdCl(2) exposure. The in vitro activities of MAPKs also increased in response to CdCl(2) exposure. Pretreatment with an intracellular Ca(2+) chelator, 1, 2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetra(acetoxymethyl) ester (BAPTA/AM), suppressed almost completely CdCl(2)-induced phosphorylation of JNK and p38 MAPK, but not ERK phosphorylation, indicating that the activation of JNK and p38 MAPK depends on the intracellular Ca(2+) but that of ERK does not. On the other hand, treatment with a MAPK/ERK kinase (MEK) inhibitor, U0126 (1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene ), suppressed CdCl(2)-induced ERK activation and the apoptosis as well. The inhibition of p38 MAPK activity with SB203580 (4-[4-fluorophenyl]-2-[4-methylsulfinylphenyl]-5-[4-pyridyl]1H- imidaz ole) did not protect cells from apoptosis. The present results showed that the activation of ERK, JNK, and p38 MAPK is differently regulated in CCRF-CEM cells exposed to CdCl(2,) and that the ERK pathway seems to be responsible for the induction of apoptosis by CdCl(2) exposure in this human T cell line.

Inhibition of HgCl2-induced mitogen-activated protein kinase activation by LL-Z1640-2 in CCRF-CEM cells.

Exposure of HgCl2 to CCRF-CEM human lymphoblastoid cells induced phosphorylation of mitogen-activated protein kinases (MAPKs); extracellular signal-regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK) and p38. LL-Z1640-2, a macrocyclic nonaketide, inhibited HgCl2-induced JNK phosphorylation at 5-100 ng/ml. It also inhibited phosphorylation of ERK and p38 but only at 100 ng/ml. The same doses of radicicol did not suppress MAPKs activation. LL-Z1640-2 (at 100 ng/ml) inhibited HgCl2-induced JNK phosphorylation in NIH 3T3 fibroblasts but not in LLC-PK(1) renal epithelial cells. Thus, LL-Z1640-2 is a potent inhibitor of HgCl2-induced MAPKs activation, especially that of JNK, in CCRF-CEM cells.

Activation of mitogen-activated protein kinases by tributyltin in CCRF-CEM cells: role of intracellular Ca(2+).

Effects of tributyltin chloride (TBT) and other organotin compounds on mitogen-activated protein kinases (MAPKs) were examined in CCRF-CEM human T lymphoblastoid cells. In response to the incubation with 0.25-2 microM TBT for 1 h, the levels of the phosphorylated form of extracellular signal-regulated protein kinase (ERK), c-Jun NH(2)-terminal kinase (JNK), and p38 MAPK increased in a dose-dependent manner. The phosphorylation was observed after 15 min and lasted for 4 h following exposure to 1 microM TBT, while the cell viability was not lowered significantly within 6 h. On the other hand, no clear changes were found in the total protein levels of ERK, JNK, and p38 MAPK. The in vitro activities of MAPKs also increased in response to TBT exposure. The potentials of MAPKs phosphorylation and of cellular damage were TBT > dibutyltin dichloride (DBT) > monobutyltin trichloride (MBT). When compared to other triorganotin compounds such as trimethyltin chloride (TMT), triphenyltin chloride (TPT), and triethyltin bromide (TET), TBT exposure induced the most marked phosphorylation of MAPKs. Chelation of intracellular Ca(2+) suppressed TBT-induced MAPKs phosphorylation almost completely, but removal of external Ca(2+) did not. The present results showed that tributyltin is a potent activator of ERK, JNK, and p38 MAPK pathways, and Ca(2+) mobilized from intracellular stores plays an important role for the phosphorylation of MAPKs in this human T cell line.

Mercury chloride activates c-Jun N-terminal kinase and induces c-jun expression in LLC-PK1 cells.

In response to various environmental stresses including heavy metals, the c-Jun N-terminal kinase (JNK) is phosphorylated and then it phosphorylates c-Jun protein. In the present study, effects of mercury chloride (HgCl2) on JNK signalling pathway were examined in LLC-PK1 cells. When exposed to 10 or 20 microM HgCl2, the level of phosphorylated JNK and the activity of JNK assayed in vitro using glutathione-S-transferase-c-Jun as substrate increased markedly. The level of phosphorylated JNK increased 30 min after HgCl2 exposure and remained elevated even at 8 h. On the other hand, no changes were found in the total amount of JNK protein. Consistent with the activation of JNK, c-Jun proteins phosphorylated on Ser63 and Ser73 were accumulated in cells exposed to HgCl2. Concomitantly, the levels of c-jun mRNA and c-Jun protein were elevated. When compared to other heavy metal compounds such as manganese chloride, zinc chloride, cadmium chloride, and lead chloride, HgCl2 could phosphorylate JNK more markedly. Neither intracellular Ca2+ nor sulfhydryl groups appeared to play a major role in the activation of JNK by HgCl2 exposure in this porcine renal epithelial cell line.

Effects of pentachlorophenol, pentylenetetrazol and carnitine on mitochondria.

Pentachlorophenol (PCP) increased oxygen consumption and lowered the respiratory control ratio (RCR) in mitochondria from rat liver. These effects of PCP were lessened by 1 mM L-carnitine but not by D-carnitine. In contrast, up to 150 mM of pentylenetetrazol (PTZ) added at state 4 of respiration did not accelerate oxygen consumption. When mitochondria were incubated with 3.3 mM of PTZ, oxygen consumption, RCR and ADP/O ratio were all decreased. Moreover, these could not be suppressed even by high concentrations (-20 mM) of L-carnitine. Thus, while L-carnitine could suppress effects of PCP, it could not counteract PTZ in mitochondria. It appears that anticonvulsive effects of carnitine in PTZ-induced seizures may not be due to mitochondrial protection.

Suppression of pentylenetetrazol-induced seizures by carnitine in mice.

When ddY mice were pretreated with L-carnitine (5, 10 or 20 mmol/kg), clonic as well as tonic seizures induced by pentylenetetrazol (PTZ) were dose-dependently suppressed. A time/response study (PTZ was injected 1, 5, 15 or 30 min after L-carnitine) showed that the anticonvulsive effects were apparent when the interval between L-carnitine and PTZ administration was 15-30 min. Saline containing 43% sucrose prolonged the latency to the first clonic seizure but was less effective than 20 mmol/kg L-carnitine and did not suppress clonic or tonic seizures. Alterations in brain energy metabolites caused by PTZ including increase of lactate and decrease of ATP and phosphocreatine were also suppressed by L-carnitine. L-carnitine was more potent than D-carnitine in prolonging the latency to the first clonic seizure and in decreasing the frequency of clonic as well as tonic seizures. The anticonvulsive effects of L-carnitine in PTZ-induced seizures may be unrelated to the transport of long-chain acyl CoA since they were not interfered with by D-carnitine.

Protection of the brain by carnitine.

Carnitine (beta-hydroxy-gamma-trimethylammonium butyrate) is widely distributed in the body including the nervous system. Its physiological function, viz. a carrier of long-chain fatty acids through the inner mitochondrial membrane, has been well established. In this review, mainly based on our experiments, we discuss the possibility that carnitine may have effects other than the "physiological" function and that it may be a potent protector of the brain. When mice were exposed to ammonia (intraperitoneal injection of ammonium acetate), they developed seizures and concentrations of brain energy metabolites were altered; ATP and phosphocreatine decreased while ADP, AMP, pyruvate and lactate increased. The seizures and changes in brain energy metabolites were clearly suppressed when the mice were pre-treated with carnitine. Furthermore, changes in energy metabolites in the brain caused by severe ischemia (decapitation) were also suppressed by carnitine. Since D-carnitine showed similar effects as those of L-carnitine, the effects seem due to function(s) of carnitine yet to be defined. Intrinsic substances including carnitine appear to deserve further studies for possible use in protecting the brain.