Iodine contrast volume reduction in preoperative transcatheter aortic valve implantation computed tomography: Comparison with 64- and 256-multidetector row computed tomography.

INTRODUCTION: This study aimed to compare the vascular enhancement and radiation dose in preoperative transcatheter aortic valve implantation (TAVI) computed tomography (CT) with a reduced contrast medium (CM) using volume scans in 256-multidetector row CT (MDCT) with a standard CM using 64-MDCT. METHODS: This study included 78 patients with preoperative TAVI CT with either 64- or 256-MDCT. The CM was injected at 1.5 mL/kg in the 64-MDCT group and 1.0 mL/kg in the 256-MDCT group. We compared vascular enhancement of the aortic root and access routes, image quality (IQ) scores, and radiation dose in both groups. RESULTS: Despite the reduced CM (by 33 %) in the 256-MDCT group, the mean vascular enhancement of the right and left subclavian arteries was significantly higher than that in the 64-MDCT group [284 and 267 Hounsfield units (HU) vs. 376 and 359 HU; p < 0.05]; however, no significant differences in the mean vascular enhancement in the ascending aorta, abdominal aorta at the celiac level, and bilateral common femoral arteries were observed between the two groups (p > 0.05 for all). The median IQ scores at the aortic root were higher in the 256-MDCT group than in the 64-MDCT group (3 vs. 4; p < 0.05), and those at the femoral access routes were comparable (4 vs. 4; p = 0.33). The mean effective dose was significantly reduced by 30 % in the 256-MDCT group (23.6 vs. 16.3 mSv; p < 0.05). CONCLUSION: In preoperative TAVI CT, volume scans using 256-MDCT provide comparable or better vascular enhancement and IQ with a 30 % reduction in CM and radiation dose than those using 64-MDCT. IMPLICATIONS FOR PRACTICE: Volume scan using 256-MDCT for preoperative TAVI CT may reduce CM and radiation dose in TAVI patients with renal dysfunction.

A double three-step theory of brain metastasis in mice: the role of the pia mater and matrix metalloproteinases.

The brain is frequently affected by the spread of lung cancer, and haematogenous metastasis is a common route to brain metastasis. We therefore developed an isogenic brain metastasis model of lung cancer to use the Lewis lung carcinoma cell line and analysed dynamics of neoplastic cells after extravasation. Histological analysis revealed two characteristic patterns: metastatic foci exhibiting an angiocentric pattern were designated 'perivascular proliferations'; neoplastic cells infiltrating the brain parenchyma were designated 'invasive proliferations'. Electron microscopic observation of perivascular proliferations showed that neoplastic cells were confined to the perivascular space. In invasive proliferations, however, fragments of collagen fibre were observed in the gaps between neoplastic cells, indicating that the neoplastic cells had disintegrated the pia-glial membrane. We analysed the expressions of matrix metalloproteinase-2 (MMP-2) and MMP-9 by using both immunohistochemical analysis and real-time polymerase chain reaction analysis. MMP-2 expression was significantly higher in invasive proliferations. MMP-9 expression was significantly higher in day 7, but there was no significant difference in day 11. The pia-glial membrane and perivascular space are the barriers that neoplastic cells must overcome to infiltrate the brain. In conclusion, our findings suggest that brain metastasis requires two distinct processes.

Progress in pursuit of therapeutic A2A antagonists: the adenosine A2A receptor selective antagonist KW6002: research and development toward a novel nondopaminergic therapy for Parkinson's disease.

Research and development of the adenosine A2A receptor selective antagonist KW6002 have focused on developing a novel nondopaminergic therapy for Parkinson's disease (PD). Salient pharmacologic features of KW6002 were investigated in several animal models of PD. In rodent and primate models, KW6002 provides symptomatic relief from parkinsonian motor deficits without provoking dyskinesia or exacerbating existing dyskinesias. The major target neurons of the A2A receptor antagonist were identified as GABAergic striatopallidal medium spiny neurons. A possible mechanism of A2A receptor antagonist action in PD has been proposed based on the involvement of striatal and pallidal presynaptic A2A receptors in the "dual" modulation of GABAergic synaptic transmission. Experiments with dopamine D2 receptor knockout mice showed that A2A receptors can function and anti-PD activities of A2A antagonists can occur independent of the dopaminergic system. Clinical studies of KW6002 in patients with advanced PD with L-dopa-related motor complications yielded promising results with regard to motor symptom relief without motor side effects. The development of KW6002 represents the first time that a concept gleaned from A2A biologic research has been applied successfully to "proof of concept" clinical studies. The selective A2A antagonist should provide a novel nondopaminergic approach to PD therapy.

Angiotensin II induces circadian gene expression of clock genes in cultured vascular smooth muscle cells.

BACKGROUND: Daily rhythms of mammalian physiology and endocrinology are regulated by circadian pacemakers. The master circadian pacemaker resides in the suprachiasmatic nucleus, which is located in the hypothalamus of the brain, but circadian oscillators also exist in peripheral tissues. Because many studies have demonstrated apparent circadian variations in the frequency of cardiovascular disorders, it is of great interest to investigate a possible relation between circadian gene expression and cardiovascular function. We examined whether a circadian oscillation system exists in the aorta and/or in cultured vascular smooth muscle cells (VSMCs). METHODS AND RESULTS: The mRNA levels of clock genes were assayed by northern blot analysis. The mouse aorta showed a clear circadian oscillation in the expression of mPer2, dbp, and Bmal1. Brief treatment of VSMCs with angiotensin II induced a robust increase in mPer2 gene expression, followed by a marked reduction in mPer2 mRNA levels and subsequent synchronous cycling of mPer2, dbp, and Bmal1 mRNAs. The induction of mPer2 in VSMCs by angiotensin II was completely abolished by treatment with CV11947, a specific angiotensin II type1 receptor antagonist. CONCLUSIONS: The present results demonstrate that the aorta and VSMCs possess a circadian oscillation system which is comparable to that of the suprachiasmatic nucleus and that the circadian gene expression in VSMCs is induced by angiotensin II through the angiotensin II type1 receptor. Our in vitro system will provide a useful tool to further analyze the physiological significance of the peripheral clock in cardiovascular function.

Circulatory disturbance of rat spinal cord induced by occluding ligation of the dorsal spinal vein.

Spinal cord infarction can be caused by venous disturbances due to trauma or cancer invasion. However, the precise mechanism of venous infarction is not fully understood. To characterize disorders associated with spinal venous occlusion, we performed time-kinetic pathological analyses of rat spinal cord infarction induced by transdural ligation of the dorsal spinal vein at the levels of the T10-T13 vertebrae. One day after ligation congestion, edema and hemorrhage were observed mainly in the dorsal funiculus. Axons were well preserved, but on the 3rd day axonal degeneration became evident. On the 7th day, the necrotic lesion was confined to the dorsal funiculus and was round in shape with foamy macrophage infiltration and astrocytic gliosis. On the 14th day, the involved cord became atrophic, and infiltration of foamy macrophages and astrocytosis became more prominent. After 21-28 days, the infarction focus decreased in size due to gliosis, and residual macrophages were observed. The main lesion was confined to the dorsal funiculus at all times. However, the severity of the softening varied among rats. Thus, we conclude that the disturbance of venous drainage actually results in spinal cord softening. The variability in the lesions is probably due to the presence of unexpected anastomoses of the spinal venous system.

The secretion of amelogenins is associated with the induction of enamel and dentinoid in an ameloblastic fibro-odontoma.

Ameloblastic fibro-odontoma is the unique entity of epithelial-ectomesenchymal odontogenic tumors, which is characterized by enamel formation in addition to dentine. We examined immunohistochemically a case of this tumor in which enamel having prism structures was developed in the absence of odontoblast differentiation but was in contact with mesenchymal matrices. Histological examination showed diverse morphological features of epithelial tumor cells, e.g., cuboidal cells comprising tooth bud-like projections, ameloblast- and stellate reticulum-like cells, and residual cells in forms of extended cords or islands of odontogenic epithelium. Immunostaining with anti-amelogenin sera proved that the intracellular production of amelogenins was initiated at the tooth bud-like stage. The secreted amelogenins were detected almost exclusively in the induced enamel and dentinoid areas, as well as in the core region of cementicle-like spheres deposited in the encapsulating stroma. The results obtained indicate that the odontogenic tumor epithelia and its products, i.e., amelogenins, participate in multifaceted aspects of dental hard tissue formation that takes place during oncogenesis.

Taurine prevents the decrease in expression and secretion of extracellular superoxide dismutase induced by homocysteine: amelioration of homocysteine-induced endoplasmic reticulum stress by taurine.

BACKGROUND: Hyperhomocysteinemia is an independent risk factor for atherosclerosis. Homocysteine has been shown to induce endoplasmic reticulum (ER) stress in vascular endothelial cells. ER stress is a condition in which glycoprotein trafficking is disrupted and unfolded proteins accumulate in the ER. ER molecular chaperons, such as GRP78, are induced and an ER resident kinase, PERK, is activated when cells are subjected to ER stress. Conversely, taurine is reported to have antiatherogenic effects by unknown mechanisms. To elucidate the mechanisms by which homocysteine induces atherosclerosis and taurine prevents it, we examined whether homocysteine and taurine affect the expression and secretion of extracellular superoxide dismutase (EC-SOD), a glycoprotein secreted from vascular smooth muscle cells (VSMCs) that protects the vascular wall from oxidative stress. METHODS AND RESULTS: We assessed the expression of EC-SOD and GRP78 mRNA in cultured rat VSMCs by Northern blot analysis. The EC-SOD protein secreted into the culture medium was examined by Western blot analysis. Homocysteine (5 mmol/L) and other ER stress inducers, including A23187, were found to decrease EC-SOD mRNA expression and protein secretion. Furthermore, they upregulated GRP78 mRNA expression and activated PERK. Taurine (0.5 to 10 mmol/L), conversely, prevented these actions induced by homocysteine. CONCLUSIONS: Homocysteine induces ER stress and reduces the secretion and expression of EC-SOD in VSMCs, leading to increased oxidative stress in the vascular wall. Taurine restores the secretion and expression of EC-SOD by ameliorating ER stress induced by homocysteine.

Heterochronous development of intrahepatic cholangiocellular carcinoma following hepatocellular carcinoma in a hepatitis B virus carrier.

A 68-year-old Japanese woman was admitted to our hospital in September 1995, because of a mass detected by ultrasonography during a follow-up examination for chronic hepatitis B. Hepatocellular carcinoma (HCC) in the right liver lobe was diagnosed based on imaging studies and elevated alpha-fetoprotein (AFP). Percutaneous ethanol injection therapy (PEIT) was performed. PEIT was repeated in November 1998, because the tumor had enlarged and serum AFP was re-elevated. Follow-up ultrasonography (US) demonstrated low echoic mass in the left liver lobe in August 1999; serum AFP was normal, but serum carbohydrate antigen 19-9 (CA19-9) was elevated to 420 U/ml. In October 1999, radiofrequency interstitial tissue ablation (RITA) was performed after tumor biopsy. Pathological findings revealed adenocarcinoma and pathological diagnosis was made as intrahepatic cholangiocellular carcinoma (ICC). Three weeks later, her serum CA19-9 was remarkably decreased (180 U/ml). The patient has been well for 5 months. Her latest AFP and CA19-9 in the serum were 2 ng/ml and 89 U/ml, respectively. The incidence of double cancer in the liver is rare. This is also the first case report to discuss ICC treated with RITA.

Corpora amylacea replace the hippocampal pyramidal cell layer in a patient with temporal lobe epilepsy.

A 39-year-old woman, with a 23-year history of medically intractable seizures of the complex partial type, underwent a left anterior temporal lobectomy and hippocampectomy. Histologic examinations revealed a massive occurrence of corpora amylacea, neuronal loss, and gliosis in the pyramidal cell layer of the hippocampus. The distribution of corpora amylacea in this case was quite distinctive and unlike the patterns of "nonspecific" corpora amylacea formation seen in aging or other neurodegenerative conditions. The pathogenetic aspects of the accumulation of these peculiar bodies are discussed in relation to hippocampal sclerosis.

Mammary duct ectasia in children presenting bloody nipple discharge: a case in a pubertal girl.

Mammary duct ectasia occurs rarely in childhood. The authors report on the case of a pubertal girl who was operated on for duct ectasia with bloody nipple discharge. Duct ectasia is regarded as a primary lesion; it is considered to be a cause of bloody secretion, and it has a mechanism similar to that of mammary duct papilloma.

Synthesis and preliminary evaluation of a carbon-11-labeled adenosine transporter blocker [(11)C]KF21562 .

We prepared an (11)C-labeled adenosine transporter blocker, [1-methyl-(11)C]-3-[1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl]-1,6-dimethyl-2,4(1H, 3H)-quinazolinedione ([(11)C]KF21652) and examined its potential as a positron emission tomography (PET) ligand for mapping adenosine transporters in the brain and peripheral organs. The log P(7.4) value of KF21652 was 3.14, and the K(i) value was 13 nM for adenosine transporters using [(3)H]nitrobenzylthioinosine as a radioligand. In mice, the highest initial uptake was found in the liver, followed by the kidney and small intestine. The brain uptake was very low. The radioactivity level slightly increased with time in the liver and small intestine, but decreased in the other organs. Coinjection of carrier KF21652 slightly decreased the uptake of [(11)C]KF21562 only in the liver, but not in any other organs. Ex vivo autoradiography of the rat brain showed that [(11)C]KF21652 was scarcely incorporated into the brain. On the other hand, in vitro autoradiography showed the binding of [(11)C]KF21562 to adenosine transporters with high nonspecific binding. These results show that the compound is not a suitable PET ligand for mapping adenosine transporters.

[An operated case of medial temporal lobe epilepsy associated with schizencephaly].

A 24-year-old male of medial temporal lobe epilepsy associated with schizencephaly was presented. He developed complex partial seizure after head trauma at the age of a year and 7 months, which became intractable at the age of 13 year. MRI demonstrated a schizencephalic cleft in the right peri-Rolandic area, cortical dysplasia in the right medical parietal and occipital lobes, and right hippocampal atrophy. Scalp-recorded EEG failed to localize the ictal onset zone. Interictal FDG-PET and ECD-SPECT indicated hypometabolism and hypoperfusion of the right entire temporal lobe, and ictal ECD-SPECT increased perfusion of this area. Chronic subdural electrode recording clearly demonstrated that ictal onset zone was located not on the schizencephalic cleft or its surrounding cortex but on the right medial temporal lobe. Following right anterior temporal lobectomy with hipppocampectomy, seizure control became easy. For the identification of the epileptogenic zone in patients with schizencephaly, chronic subdural electrode recording is mandatory.

De novo acute myeloid leukemia in the elderly; a consistent fraction of long-term survivors by standard-dose chemotherapy.

To clarify the characteristics of de novo acute myeloid leukemia (AML) among the elderly, we reviewed 112 patients over 60 years old (median age 72 years) who were treated at hospitals in Nagasaki Prefecture with a population of 1.5 million between 1987 and 1994. Reclassification of morphological diagnosis revealed that the proportion of M3 was lower but that of M6 and the incidence of cases with trilineage dysplasia (TLD), known as poor prognostic features, were higher in the elderly than in patients less than 60 years old. Similarly, chromosomal data showed a lower frequency of favorable karyotypes such as t(8;21) and t(15;17) in the elderly. The overall survival of all 112 patients was 10.3% at 5 years. Multivariate analysis indicated that good performance status (PS), low WBC at diagnosis, standard dose multi-drug chemotherapy and all-trans retinoic acid (ATRA) treatment for M3 patients, and morphological findings without TLD were significantly correlated with longer survival. Most of the long-term survivors were found among those who received standard dose therapy in this series, although no consensus has been established how to treat elderly AML patients. We propose that a prospective controlled trial is necessary to confirm the role of standard dose chemotherapy for elderly patients with de novo AML.

[A case of asymptomatic urachal cyst in autopsy--histopathological study of urachal cyst and review of the literature of 99 cases during a 10 year period in Japan].

Disorders of urachal remnants are common. While urachal cysts are usually asymptomatic, infection may mimic a variety of acute abdomen. Here we report a very rare case of urachal cyst that protruded in the urinary bladder cavity and among 99 accumulated cases, only 4 cases have been reported similar to this case characterized by intravesical development from 1990 to 1999. An uninfected urachal cyst was found in a 79-year-old male who had died of bile duct carcinoma. The cyst showed ovoid protrusion into urinary bladder cavity from the dome (3.5 x 2.0 x 2.0 cm in size). Histopathologically, the cyst wall was thin and consisted of fibrous connective tissue with muscular tissue and peripheral nerve, and lined by cuboidal epithelium but no inflammatory cells could be seen. Urachal cysts occur in both sexes are affected with equal frequency, and frequently occur in a younger population. In clinical symptoms the umbilical manifestations are predominant in patients younger than 30 years old, while the bladder manifestations are predominant in those older than 30.

Double cancer consisting of adenosquamous and hepatocellular carcinomas of the liver.

A very rare case of a double cancer consisting of adenosquamous and hepatocellular carcinomas of the liver in a 65-year-old-man is discussed. The patient was hospitalized with epigastralgia in May 1997. Abdominal computed axial tomography revealed a tumor located in the left lobe of the liver and a left hepatic lobectomy was performed. The tumor recurred several months after surgery and the patient died on 4 June 1999. At autopsy, both a major tumor mass with extensive involvement, located in the surgical margin, and a small mass located in S7 were discovered. Microscopically, the major tumor was diagnosed as adenosquamous carcinoma and the small one in S7 as hepatocellular carcinoma. To our knowledge, this is the first case of a double cancer consisting of adenosquamous and hepatocellular carcinomas of the liver. The pathological findings support the hypothesis that this tumor developed as a squamous transformation of adenocarcinoma.

Carbon-11-labeled KF21213: a highly selective ligand for mapping CNS adenosine A(2A) receptors with positron emission tomography.

In vivo assessment of the adenosine A(2A) receptors localized in the striatum with positron emission tomography (PET) may offers us a new diagnostic tool for neurological disorders. We evaluated the potential of [7-methyl-(11)C](E)-8-(2,3-dimethyl-4-methoxystyryl)-1, 3,7-trimethylxanthine ([(11)C]KF21213) as a PET ligand for mapping adenosine A(2A) receptors in the central nervous system. KF21213 showed a high affinity for the adenosine A(2A) receptors in vitro (Ki = 3.0 nM) and a very low affinity for the A(1) receptors (Ki > 10,000 nM). In mice, the striatal uptake of [(11)C]KF21213 increased for the first 15 min and then gradually decreased, whereas the uptake in the reference regions such as the cortex and cerebellum rapidly decreased. The uptake ratio of striatum to cortex and striatum to cerebellum increased to 8.6 and 10.5, respectively, at 60 min postinjection. The striatal uptake was significantly blocked by co-injection of carrier KF21213 or each of three other A(2A) antagonists, but not by co-injection of A(1) antagonist. The specific uptake was not detected in the cortex or in the cerebellum. Ex vivo autoradiography and PET clearly visualized adenosine A(2A) receptors in the rat striatum. [(11)C]KF21213 was the most selective tracer for mapping adenosine A(2A) in the central nervous system by PET among the tracers proposed to date.

Mechanomyographic investigation of muscle contractile properties in preadolescent boys.

The aim of the present study was to elucidate the muscle contractile properties of preadolescent boys using the mechanomyogram (MMG) and electromyogram (EMG). In 8 preadolescent boys and 10 male young adults, the EMG and MMG were recorded from quadriceps muscles during isometric knee extension contractions at levels of 10 to 80% MVC. The relationship of EMG and MMG to absolute force was approximated by a regression line (r > 0.8). The regression line of the EMG in preadolescent was located above that of the adults, whereas the MMG in both subject groups was fitted by virtually the same regression line. Thus, the MMG seems to be indicative of absolute force in preadolescents as well as young adults. Both groups showed a non-linear increase in the EMG and MMG with relative force (%MVC). The EMG and %MVC relationship was not significantly different between the two groups, whereas the MMG in preadolescents was smaller than that of adults over the range of force studied. The MMG increment with %MVC was more remarkable above 30 or 40% MVC in both groups; however, the rate of the increment in preadolescents was smaller than that in adults. The MMG and %MVC relationship suggests that the muscle contractile properties in preadolescent boys are characterized by immaturity of the fast twitch fibers.

Further characterization of a CNS adenosine A2a receptor ligand [11C]KF18446 with in vitro autoradiography and in vivo tissue uptake.

PET assessment of the adenosine A2a receptors localized in the striatum offers us a potential new diagnostic tool for neurological disorders. In the present study, we carried out in vitro receptor autoradiography of a newly developed PET ligand [11C]KF18446 ([7-methyl-11C]-(E)-8-(3,4,5-trimethoxystyryl)-1,3,7-trimethylxanthin e) with rat brain sections. [11C]KF18446 showed a high striatum/cortex binding ratio (5.0) and low nonspecific binding (<10%), suggesting that [11C]KF18446 has characteristics comparable or slightly superior to [3H]CGS 21680 or [3H]SCH 58261, which are currently available representative A2a receptor ligands. Scatchard analysis indicated a Kd of 9.8 nM and a Bmax of 170 fmol/mm3 tissue in the striatum and a Kd of 16.4 nM and a Bmax of 33 fmol/mm3 tissue in the cortex. Seven xanthine-type and four nonxanthine-type adenosine receptor ligands with an affinity for the adenosine A2a receptors significantly reduced the in vitro binding of [11C]KF18446 to the brain section. The blocking effects were much stronger in the striatum than in the cortex, but did not necessarily parallel their affinity. On the other hand, four xanthine-type ligands and one nonxanthine-type ligand (SCH 58261) of the 11 ligands studied reduced the in vivo uptake of [11C]KF18446 in mice, but other ligands, including A1-selective and nonselective ligands and three nonxanthine-type A2a-selective antagonists did not. We conclude that [11C]KF18446 is a promising adenosine A2a receptor ligand for PET study.

Oral taurine supplementation prevents the development of ethanol-induced hypertension in rats.

Taurine is known to lower blood pressure in essential hypertension and some experimental hypertensive models. Taurine has also been reported to activate aldehyde dehydrogenase and to inhibit the elevation of plasma acetaldehyde concentration after ethanol intake. Because acetaldehyde, the first metabolite of ethanol, is suspected to be responsible for many adverse effects of alcohol consumption, we examined the effect of taurine supplementation on ethanol-induced hypertension and abnormalities in the intracellular cation metabolism in Witar-Kyoto rats. In Study 1, systolic blood pressure and intraplatelet free calcium were significantly higher in rats who received 15% ethanol in drinking water than in control rats. Oral taurine supplementation (1% taurine and 15% ethanol in drinking water) completely prevented the development of ethanol-induced hypertension. Intraerythrocyte sodium and intraplatelet free calcium were significantly decreased in taurine-supplemented rats as compared with rats who received 15% ethanol only. In Study 2, hemoglobin-associated acetaldehyde (HbAA) was measured as a marker of protein-bound acetaldehyde. HbAA was significantly elevated in rats who received 5% ethanol in drinking water as compared with control rats. Taurine supplementation (1% taurine and 5% ethanol in drinking water) significantly decreased HbAA. Our findings suggest that the oral supplementation of taurine prevents ethanol-induced hypertension by decreasing protein bound acetaldehyde and altering the cation handling by the membrane.