Anatase and rutile titanium oxide nanoparticles induce acute kidney injury by coadministration with paraquat, cisplatin or 5-aminosalicylic acid.

Nanoparticles are used in a variety of fields; for example, titanium oxide nanoparticles are used in paints, food additives, cosmetics, and sunscreen materials. Although the use of titanium oxide nanoparticles is regulated, their safety has not been established. Furthermore, the interaction between titanium oxide nanoparticles and various chemical substances and pharmaceuticals is unknown. We co-administered rutile-type titanium oxide nanoparticles (nTR) or anatase-type titanium oxide nanoparticles (nTA) to mice together with paraquat (PQ), cisplatin (CDDP), or anti-5-aminosalicylic acid (5-ASA), and investigated the extent, if any, of liver and kidney injury. As a result, when nTA and nTR were administered alone, no increases were observed in aspartate aminotransferase (AST) and alanine aminotransferase (ALT), which are indicators of liver damage, or urea nitrogen (BUN), which is an indicator of kidney damage. Next, nTA and nTR were co-administered with PQ, CDDP or 5-ASA. Although no increase in ALT or AST was observed, BUN levels increased significantly and acute kidney injury was induced. The findings suggested that titanium oxide nanoparticles induce acute kidney injury through their interaction with chemicals and drugs.

"Bonnet" bypass to proximal trunk of middle cerebral artery with a radial artery interposition graft: technical note.

BACKGROUND: Anastomosis of the superficial temporal artery (STA) to the middle cerebral artery (MCA) is useful for treating certain patients with internal carotid artery occlusion or MCA occlusion. However, in the case of common carotid artery (CCA) occlusion, since the blood flow in the STA is insufficient, another artery should be used as the donor artery. The cortical branches of the MCA are usually selected as recipients in the STA-MCA bypass. However, the intracranial vascular filling gradually increases over a few months after conventional cortical MCA bypass grafting, while early or even immediate vascular filling is observed after proximal MCA bypass grafting. This study aims to develop an elongation technique of the contralateral STA to reach the proximal segment of the ipsilateral MCA. METHODS: Anastomosis of the contralateral STA to the secondary trunk of the ipsilateral MCA was performed in 2 patients with occlusion of the CCA and ipsilateral vertebral artery (VA). The contralateral STA was extended with a radial artery (RA) graft in order to supply blood to the ischemic area. Elongation of the STA by using an RA interposition graft sufficiently lengthens the graft to enable its anastomosis with the contralateral M2 segment. Postoperative imaging revealed good bypass patency even at 1 year after the surgery. CONCLUSION: This novel technique of performing the "bonnet" bypass was effective in treating both CCA and ipsilateral VA occlusion; moreover, this procedure of elongation of the STA can increase candidates of the recipient, and enables one to perform a double bypass to the anterior cerebral artery (ACA) or posterior cerebral artery (PCA).

Promoter hypermethylation of tumor-related genes in sporadic colorectal cancer in young patients.

Sporadic colorectal cancer (SCRC) occurring in young patients represent a subset with a higher proportion of advanced tumors and a poor prognosis, however, the genetic basis of SCRCs has not yet been sufficiently studied. We assigned 16 SCRC patients aged 40 years or less to group 1, and 30 SCRCs patients aged 65 years or more to group 2. The methylation status in the promoter of 7 tumor suppressor genes regarding these two groups was then examined. The average number of hypermethylated tumor-related genes per sample in group 1 was 1.50 +/- 0.07, which was significantly lower than that in group 2 of 2.73 +/- 1.24 (p = 0.0040). The frequencies of the promoter hypermethylation of hMLH1, p15INK4b, p16INK4a, and RASSF1A in group 1 were 12.5%, 12.5%, 12.5%, 6.3%, and 0.0%, which were substantially less frequent than those same rates observed in group 2. In contrast, the frequencies of the promoter hypermethylation of APC, MGMT, p14ARF, in group 1 were 43.8%, 37.5%, and 31.3%, which were as frequent as those seen in group 2. The promoter hypermethylation of APC, MGMT, and pl4ARF is therefore considered to be closely related to the development of SCRCs in young patients, regardless of aging.

Wavelength-sensitive photocatalytic degradation of methyl orange in aqueous suspension over iron(III)-doped TiO2 nanopowders under UV and visible light irradiation.

Well-crystallized iron(III)-doped TiO2 nanopowders with controlled Fe3+ doping concentration and uniform dopant distribution, have been synthesized with plasma oxidative pyrolysis. The photocatalytic reactivity of the synthesized TiO2 nanopowders with a mean particle size of 50-70 nm was quantified in terms of the degradation rates of methyl orange (MO) in aqueous TiO2 suspension under UV (mainly 365 and 316 nm) and visible light irradiation (mainly 405 and 436 nm). The photodecomposition of MO over TiO2 nanopowders followed a distinct two-stage pseudo first order kinetics. Interestingly, the photocatalytic reactivity depends not only on the iron doping concentration but also on the wavelength of the irradiating light. Under UV irradiation, nominally undoped TiO2 had much higher reactivity than Fe3+ -doped TiO2, suggesting that Fe3+ doping (> 0.05 at. %) in TiO2 with a mean particle size of approximately 60 nm was detrimental to the photocatalytic decomposition of methyl orange. Whereas, under visible light irradiation, the Fe3+ -doped TiO2 with an intermediate iron doping concentration of approximately 1 at. % had the highest photocatalytic reactivity due to the narrowing of band gap so that it could effectively absorb the light with longer wavelength. A strategy for improving the photocatalytic reactivity of Fe3+ -doped TiO2 used in the visible light region is also proposed.

Genomic copy-number aberrations related to lymph-node metastasis of colon cancer.

Lymph-node metastasis is an important indicator in the diagnosis of colon cancer. In order to determine the genes involved in metastasis, genomic copy-number aberrations in the primary tumours and lymph-node metastases were analysed in 12 patients using comparative genomic hybridization. This method detects genomic copy-number changes at the chromosomal level and the identification of the regions of aberration on any chromosome. Copy-number gains at 6p12 and losses at 8p12 were observed in a greater number of the primary tumours than in the metastases. These aberrations appear to be involved in lymph-node metastasis of colon cancer, and may allow measurement of the risk of lymph-node metastasis from a given colon cancer.

Analysis of the relationship between sex and chromosomal aberrations in colorectal cancer by comparative genomic hybridization.

Colorectal cancer is thought to be more common in men than in women. The chromosomal locations of DNA gains and losses in surgical specimens of colorectal tumours were detected by comparative genomic hybridization and were compared by gender. Five chromosomal regions, 7p, 8p, 8q, Xp and Xq, contained multiple gains that were significantly more common in males than in females, and within these regions, the differences were significant for Xp21, Xp11.3, Xp11.4 and Xq26. Regions 1p, 3q, 11q, 12p, 12q and 15q contained multiple sites of gain that were significantly more common in females than in males. Tumours from male and female patients showed significantly more losses at 11p and 15q, and at 4q and Xq, respectively. The fact that gains in X-chromosomal regions were detected with a significantly higher frequency in tumours from male patients suggests that the difference between the genders might be explained by X-chromosomal inactivation.

Long-term prognosis of medically treated patients with internal carotid or middle cerebral artery occlusion: can acetazolamide test predict it?

BACKGROUND AND PURPOSE: The importance of hemodynamic parameters for predicting outcome in patients with occlusive carotid disease remains controversial. The present study was aimed at testing the hypothesis that regional cerebrovascular reactivity (rCVR) to acetazolamide can be a reliable predictor of subsequent ischemic stroke in medically treated patients with internal carotid artery or middle cerebral artery occlusion. METHODS: Seventy-seven symptomatic patients were enrolled in this prospective, longitudinal cohort study. All patients met inclusion criteria of cerebral angiography, no or localized cerebral infarction on MRI or CT, and no or minimal neurological deficit. Regional cerebral blood flow (rCBF) and rCVR to acetazolamide were quantitatively determined by (133)Xe SEPCT. All patients were categorized into 4 types on the basis of SPECT studies. RESULTS: During an average follow-up period of 42.7 months, 16 total and 7 ipsilateral ischemic strokes occurred. The annual risks of total and ipsilateral stroke in patients with decreased rCBF and rCVR were 35.6% and 23.7%, respectively, risks that are higher than those in other types of patients. When strokes were categorized into patients with and without decreased rCBF and rCVR, Kaplan-Meier analysis revealed that the risks of total and ipsilateral stroke in patients with decreased rCBF and rCVR were significantly higher than in those without (P<0.0001 and P=0.0001, respectively, log-rank test). Relative risk conferred by decreased rCBF and rCVR was 8.0 (95% CI, 1.9 to 34.4) for ipsilateral stroke and 3.6 (95% CI, 1.4 to 9.3) for total stroke. CONCLUSIONS: Decreased rCBF and rCVR to acetazolamide may identify a subgroup of patients who have a higher risk of subsequent ischemic stroke when treated medically.

A Na+-H+ exchange inhibitor (SM-20550) protects from microvascular deterioration and myocardial injury after reperfusion.

Na+-H+ exchange inhibitors may reduce myocardial damage after reperfusion. However, their effects on microvascular deterioration are not known. We examined the potency of a novel Na+-H+ exchange inhibitor, SM-20550 [ N-(Aminoiminomethyl)-1,4-dimethyl-1H-indole-2-carboxamide methanesulfonate], and its effects on microvascular damage after reperfusion. In an in vitro study, the Na+-H+ exchange inhibiting activity of SM-20550 was about 10 times greater than that of ethylisopropyl amiloride. In in vivo experiments, we occluded the left circumflex coronary artery in 29 dogs for 2 h and then reperfused for 5 h. SM-20550 was administered either before ischemia (n = 11) or before reperfusion (n = 7). Another 11 dogs served as controls. We found that SM-20550 not only improved coronary vasodilator responses to acetylcholine and adenosine after reperfusion, but also reduced infarct size (P < 0.01). Intramyocardial bleeding, which should reflect microvascular damage, was not found in dogs with SM-20550 treatment. Infarct size was correlated inversely with collateral blood flow in control (both, P < 0.01) but not in SM-20550-treated animals. Furthermore, SM-20550 significantly suppressed ventricular fibrillation during both ischemia and reperfusion. These results suggest that protective effects of Na+-H+ exchange inhibitors on reperfused myocardium are due at least in part to microvascular protection.

The cerebrospinal fluid in patients with moyamoya disease (spontaneous occlusion of the circle of Willis) contains high level of basic fibroblast growth factor.

The level of basic fibroblast growth factor (bFGF) in cerebrospinal fluid (CF) was measured by an EIA in 15 patients with moyamoya disease, in 11 patients with atherosclerotic occlusive disease, and in 8 patients with spinal disc disease. In the moyamoya patients, bFGF was found in 13 out of 15 CF samples with a mean value of 101 pg/ml. However, bFGF was detected in only 4 out of 11 patients with atherosclerotic disease with a mean of 8 pg/ml. In all the patients with disc disease, bFGF was not detected. The elevated level of bFGF may play a crucial role in the pathogenesis of moyamoya disease.

Distal aneurysms of the superior cerebellar artery and posterior inferior cerebellar artery feeding an associated arteriovenous malformation: case report.

The authors report a case of two distal aneurysms of the cerebellar arteries, one arising from the vermian branch of the posterior inferior cerebellar artery, the other arising from the hemispheric branch of the superior cerebellar artery, and both feeding an associated arteriovenous malformation (AVM). The aneurysm of the distal posterior inferior cerebellar artery was considered the source of a cerebellar hemorrhage because of the location of a hematoma in the cerebellar vermis. The life-threatening hematoma was evacuated in an emergency operation 6 hours after the acute onset of symptoms. The cerebellar aneurysms and the AVM were clipped or extirpated successfully after the patient's condition improved. The association of two rare types of aneurysms with an AVM strongly supports the theory that increased hemodynamic stress derived from the AVM plays an important role in aneurysm formation. The authors think that one should operate on the symptomatic lesion first or both the aneurysm and the AVM in the same operative procedure.

Effects of surgical revascularization on peripheral artery aneurysms in moyamoya disease: report of three cases.

OBJECTIVE AND IMPORTANCE: The beneficial effects of surgical revascularization on rebleeding in moyamoya disease remain unclear. This report is intended to clarify the effects of surgical revascularization on peripheral artery aneurysms, which represent one of the causes of intracranial bleeding in moyamoya disease. CLINICAL PRESENTATION: Findings for three female patients who experienced intracranial bleeding are presented. Cerebral angiography revealed that intracranial bleeding resulted from the rupture of peripheral artery aneurysms arising from dilated collateral vessels such as the lenticulostriate artery. INTERVENTION: The patients successfully underwent superficial temporal artery-middle cerebral artery anastomosis combined with encephaloduromyoarteriosynangiosis. Angiography demonstrated obliteration of the peripheral artery aneurysms, together with the disappearance or decrease in caliber of the parent collateral arteries, after surgery. None of the patients experienced rebleeding during the follow-up period (up to 52 mo). CONCLUSION: The results strongly suggest that surgical revascularization potentially improves cerebral circulation and decreases hemodynamic stress on collateral vessels, obliterating peripheral artery aneurysms.

Surgical approaches for the treatment of aneurysms on the P2 segment of the posterior cerebral artery.

OBJECTIVE: The P2 segment of the posterior cerebral artery has remained a challenging region to expose surgically. We establish a surgical strategy for P2-segment aneurysms. METHODS: Each segment of the posterior cerebral artery was classified according to Zeal and Rhoton's classification. Fourteen of 18 P2-segment aneurysms were surgically treated. The patient's outcome, the aneurysm location, and the surgical procedures were evaluated. A cadaveric study was performed to clarify the surgical view obtained via three different surgical approaches. RESULTS: Nine aneurysms were clipped, two were trapped, one was coated, and one was excised with parent artery reconstruction. Cerebral revascularization techniques were used for three patients. The pterional approach exposed the anterior half of the P2a segment. The subtemporal approach revealed the P2a segment, but its exposure was restricted by its localization in the ambient cistern. Via the occipital interhemispheric transtentorial approach, the P2p segment was visible and could be manipulated. When the posterior half of P2a segment was high on a coronal view of magnetic resonance imaging, it was extremely hard to access via any approach. CONCLUSION: A surgical strategy for the P2 aneurysm can be planned with accurate prediction of the aneurysm location. When the localization of an aneurysm on the posterior half of P2a segment is high, a resection of brain tissue may be required.

Visualization of the ostium of an arteriotomy in bypass surgery.

Visualization of the ostium of an arteriotomy by staining it blue with methylrosaniline chloride (pyoctaninum blue) in anastomotic bypass surgery for children with moyamoya disease is described. This technique enables surgeons to create an anastomosis more precisely and quickly. No adverse effects were observed.

Acetazolamide test in detecting reduced cerebral perfusion reserve and predicting long-term prognosis in patients with internal carotid artery occlusion.

In a series of 32 patients with internal carotid artery occlusion, regional cerebral blood flow (rCBF) and regional cerebral vasoreactivity (rCVR) were measured by xenon-133 single photon emission computed tomography and the acetazolamide test. We evaluated its usefulness in detecting the reduced cerebral perfusion reserve and predicting long-term prognosis. All Type 1 patients (normal rCBF and rCVR) were medically treated and experienced no recurrent ischemic attack. Cerebral hemodynamics remained unchanged. Type 2, 3, and 4 patients underwent superficial temporal artery-middle cerebral artery double anastomosis, if they consented to surgery. All Type 2 (normal rCBF and reduced rCVR) and Type 3 (reduced rCBF and rCVR) patients, who underwent surgery, showed no further ischemic attacks, as well as long-term normalization of rCVR, although long-term rCBF normalization was obtained in only three of seven Type 3 patients. Cerebral hemodynamics remained unchanged in Type 4 patients after surgery. In follow-up periods, major completed stroke occurred in all 3 Type 2 and Type 3 patients who were medically treated. These results suggest that the acetazolamide test is valuable in assessing the cerebral perfusion reserve and predicting long-term prognosis in patients with internal carotid artery occlusion, although further long-term or randomized studies are needed.

Establishment and characterization of a novel malignant astrocytoma cell line derived from a tumor removed in a patient with neurofibromatosis type 1.

OBJECT: Patients with neurofibromatosis Type 1 (NF1) have a predisposition to development of a variety of benign and malignant tumors including neurofibromas, astrocytomas, pheochromocytomas, and malignant peripheral nerve sheath tumors. The availability of an astrocytoma cell line derived from NF1 would be useful in studies in which sporadic astrocytomas could be compared with NF1-derived astrocytomas. In this article the authors describe a novel astrocytoma cell line, TM-31, that they established from a tumor removed in a 42-year-old woman with NF1. METHODS: The TM-31 cell line was prepared from a surgical specimen of malignant astrocytoma and was serially subcultured over 250 times throughout a 6-year period without showing any sign of cell senescence. Immunocytochemical analyses demonstrated that TM-31 cells are negative for glial fibrillary acidic protein but positive for vimentin and S-100 protein. The TM-31 cells display little neurofibromin expression when subjected to immunoblotting, indicating that there is an NF1 gene mutation. Polymerase chain reaction-single-strand conformational polymorphism analysis revealed that TM-31 cells harbor a p53 point mutation in exon 7, codon 238. Chemosensitivity testing of TM-31 cells revealed a resistance to 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea, although they are sensitive to cisplatin and etoposide. In addition, TM-31 cells displayed no morphological differentiation after all-transretinoic acid and dibutyryl cyclic adenosine monophosphate treatments. Pharmacological inhibition of farnesyltransferase of the Ras oncoprotein led to decreased proliferative activity and inhibition of anchorage-independent growth of TM-31 cells in soft agar. CONCLUSIONS: The TM-31 cell line is an immortalized astrocytoma cell line derived from a tumor obtained in a patient with NF1. Ras activation may be the major event of proliferative activity and of the transformed phenotype of TM-31 cells, and the farnesyltransferase inhibitor may be potentially important as a novel antiproliferative therapy for NF1-derived astrocytomas.

Long-term patency of radial artery graft bypass for reconstruction of the internal carotid artery. Technical note.

Reconstruction of the carotid artery by using a radial artery graft is a useful option that can produce reliable long-term patency for the surgical treatment of giant and/or large aneurysms of the cavernous and paraclinoid internal carotid artery (ICA). During the past 10 years, 43 patients with intracavernous and paraclinoid giant aneurysms of the ICA have been treated by reconstruction of the ICA with radial artery grafts after ligation of the cervical ICA. The long-term patency of the grafted radial artery was evaluated over more than a 5-year period (mean 7.2 years) in 20 of these patients by using magnetic resonance angiography or conventional angiography. There was no late occlusion of the graft in any of these cases. Stenotic graft changes were observed in two cases.

Revascularization surgery for moyamoya disease.

Moyamoya disease is a disease characterized by chronic occlusion of the circle of Willis with subsequent development of fine vascular networks in the ganglionic region, which is common in Japanese people. The term of 'moyamoya' means puff of smoke in the Japanese language and represents the characteristic angiographic findings of subsequent development of fine vascular networks in the ganglionic region. Although reconstructive surgery for moyamoya disease has been widely accepted nowadays, there is still no definite consensus as to a surgical indication for patients with an haemorrhagic attack and as to the selection of an operative method for each individual patient. This paper presents our overall surgical results and introduces a new operation, devised by Y. Nakagawa (i.e. EMAS). It refers also to surgical intervention for patients with haemorrhagic attacks.

Pharmacokinetics of nicorandil, a new coronary vasodilator, in dogs.

The kinetic disposition of nicorandil, N-[2-( nitroxy )ethyl]-3- pyridinecarboxamide (1), and its main metabolic product, N-[2-(hydroxy)-ethyl]-3- pyridinecarboxamide (II), was studied after administering intravenous and oral doses (2.5 mg/kg) of nicorandil to the same beagle dogs. The plasma concentrations were measured using a high-performance liquid chromatographic method. The pharmacokinetic data derived from intravenous administration of nicorandil were: t1/2, 0.73 plus/minus 0.11 h; Vdarea , 0.67 plus/minus 0.04 L/kg; and total plasma clearance, 13.50 plus/minus 1.05 mL/min/kg. After oral administration, nicorandil was rapidly absorbed (tmax, 0.58 plus/minus 0.11 h). The oral bioavailability was calculated as 0.72 plus/minus 0.07. The metabolic formation of the corresponding alcohol after intravenous and oral administration of the parent compound appeared to occur quite efficiently, and its elimination half-life (3.09 plus/minus 0.25 and 3.69 plus/minus 0.88 h after intravenous and oral administration of nicorandil, respectively) was longer than that of the parent compound. Since the dose employed in this study was much higher than the expected therapeutic doses, whether such a good bioavailability after a lower dose of the drug would be obtained in humans remains unanswered.

Antitumor activity of orally administered streptococcal preparation, OK-432 on murine solid tumors and its absorption from the gut.

OK-432 is an immunopotentiator which is normally administered by injection. In the present study, the antitumor activity of orally administered OK-432 on various solid tumors and the absorption of OK-432 from the gut were studied. Orally administered OK-432 inhibited the growth of Meth-A and BAMC-1 fibrosarcomas which had been subcutaneously transplanted in BALB/c mice. Autoradiograms of mice which had been administered 14C-labelled OK-432 orally demonstrated the absorption of OK-432 from the gut, and about 6% of orally administered OK-432 was absorbed 24 hrs after its administration. Moreover, an immunofluorescent study using an anti-OK-432 antibody revealed specific fluorescence in the mesenteric lymph node of mice which had been orally administered with OK-432. These results suggest that oral administration of OK-432 may be a beneficial immunotherapy.