Abnormal asymmetries in subcortical brain volume in schizophrenia.

Subcortical structures, which include the basal ganglia and parts of the limbic system, have key roles in learning, motor control and emotion, but also contribute to higher-order executive functions. Prior studies have reported volumetric alterations in subcortical regions in schizophrenia. Reported results have sometimes been heterogeneous, and few large-scale investigations have been conducted. Moreover, few large-scale studies have assessed asymmetries of subcortical volumes in schizophrenia. Here, as a work completely independent of a study performed by the ENIGMA consortium, we conducted a large-scale multisite study of subcortical volumetric differences between patients with schizophrenia and controls. We also explored the laterality of subcortical regions to identify characteristic similarities and differences between them. T1-weighted images from 1680 healthy individuals and 884 patients with schizophrenia, obtained with 15 imaging protocols at 11 sites, were processed with FreeSurfer. Group differences were calculated for each protocol and meta-analyzed. Compared with controls, patients with schizophrenia demonstrated smaller bilateral hippocampus, amygdala, thalamus and accumbens volumes as well as intracranial volume, but larger bilateral caudate, putamen, pallidum and lateral ventricle volumes. We replicated the rank order of effect sizes for subcortical volumetric changes in schizophrenia reported by the ENIGMA consortium. Further, we revealed leftward asymmetry for thalamus, lateral ventricle, caudate and putamen volumes, and rightward asymmetry for amygdala and hippocampal volumes in both controls and patients with schizophrenia. Also, we demonstrated a schizophrenia-specific leftward asymmetry for pallidum volume. These findings suggest the possibility of aberrant laterality in neural pathways and connectivity patterns related to the pallidum in schizophrenia.

Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin compared with α-glucosidase inhibitor in Japanese patients with type 2 diabetes inadequately controlled on sulfonylurea alone (SUCCESS-2): a multicenter, randomized, open-label, non-inferiority trial.

We assessed the efficacy and safety of sitagliptin compared with α-glucosidase inhibitor (αGI) in 120 of Japanese patients with type 2 diabetes mellitus (T2DM) inadequately controlled on stable ≤2 mg/day glimepiride alone [mean hemoglobin A1c (HbA1c) 7.7%] by the randomized, active-controlled, non-inferiority trial. Patients were randomly assigned to receive additional sitagliptin or αGI for 24 weeks. The primary endpoint was change in HbA1c from baseline to week 12. After 12 weeks, sitagliptin reduced HbA1c by -0.44% (p < 0.001) relative to αGI. At 24 weeks, the reduction was almost identical between the groups (-0.091%, p = 0.47). Gastrointestinal disorders were more common with αGI than with sitagliptin, but only minor hypoglycaemia occurred in both groups at similar frequency. These data suggested that sitagliptin was not inferior to αGI for reduction of HbA1c in Japanese T2DM patients receiving glimepiride alone, and well tolerated with minimum risk of gastrointestinal symptoms and hypoglycaemia.

Equivocal colonic carcinogenicity of Aloe arborescens Miller var. natalensis berger at high-dose level in a Wistar Hannover rat 2-y study.

A 2-y carcinogenicity study of Aloe, Aloe arborescens Miller var. natalensis Berger, a food additive, was conducted for assessment of toxicity and carcinogenic potential in the diet at doses of 4% or 0.8% in groups of male and female Wistar Hannover rats. Both sexes receiving 4% showed diarrhea, with loss of body weight gain. The survival rate in the 4% female group was significantly increased compared with control females after 2 y. Hematological and biochemical examination showed increase of RBC, Hb, and Alb in the 4% males. The cause of these increases could conceivably have been dehydration through diarrhea. AST and Na were significantly decreased in the males receiving 4%, and Cl was significantly decreased in both 4% and 0.8% males. A/G was significantly increased in the 4% females, and Cl was significantly decreased (0.8%) in the female group. Histopathologically, both sexes receiving 4% showed severe sinus dilatation of ileocecal lymph nodes, and yellowish pigmentation of ileocecal lymph nodes and renal tubules. Adenomas or adenocarcinomas in the cecum, colon, and rectum were observed in 4% males but not in the 0.8% and control male groups. Similarly, in females, adenomas in the colon were also observed in the 4% but not 0.8% and control groups. In conclusion, Aloe, used as a food additive, exerted equivocal carcinogenic potential at 4% high-dose level on colon in the 2-y carcinogenicity study in rats. Aloe is not carcinogenic at nontoxic-dose levels and that carcinogenic potential in at 4% high-dose level on colon is probably due to irritation of the intestinal tract by diarrhea.

Radical resection for intrinsic midbrain pilocytic astrocytoma: report of two cases.

BACKGROUND: Intrinsic midbrain glioma has been one of the most challenging therapeutic tasks in neurosurgery due to its prognosis and risks associated with surgical procedures. It is known that the prognosis of pilocytic astrocytoma is relatively good if radical resection can be achieved without severe complications. In order to remove pilocytic astrocytoma within the midbrain radically, we used microsurgical techniques. METHOD: Two patients with intrinsic pilocytic astrocytomas located at the midbrain were operated on. The subtemporal approach was used with a point of entry on the lateral surface of the midbrain just behind the cerebral peduncle. Major vessels were preserved, followed by resection of the intrinsic tumor making the cleavage between tumour and midbrain. FINDINGS: In both patients, intrinsic pilocytic astrocytoma was grossly totally removed with minimal permanent morbidity. They have been able to maintain independent activities in their daily lives without tumor recurrance. CONCLUSIONS: Surgical cure can be accomplished in some cases of midbrain pilocytic astrocytoma, even if the lesions are intrinsic to the midbrain. To remove the tumor totally without further neurological deficits, it is necessary to select a safe access or entrance point to the tumor, and to demarcate the gliotic plane between tumour and midbrain. A long-term follow up with a larger number of patients is needed to establish the significance of radical resection for intrinsic midbrain pilocytic astrocytoma.

Serial changes in cerebral blood flow and flow-metabolism uncoupling in primates with acute thromboembolic stroke.

The authors recently developed a primate thromboembolic stroke model. To characterize the primate model, the authors determined serial changes in cerebral blood flow (CBF) and the relation between CBF and cerebral metabolic rate of glucose (CMRglc) using high-resolution positron emission tomography. Thromboembolic stroke was produced in male cynomolgus monkeys (n = 4). Acute obstruction of the left middle cerebral artery was achieved by injecting an autologous blood clot into the left internal carotid artery. Cerebral blood flow was measured with [15O]H2O before and 1, 2, 4, 6, and 24 hours after embolization. CMRglc was measured with 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) 24 hours after embolization. Lesion size and location 24 hours after embolization was determined by the 2,3,5-triphenyltetrazolium chloride (TTC) staining method. The results are summarized as follows: (1) 1 hour after embolization, CBF in the temporal cortex and the basal ganglia decreased to < 40% of the contralateral values. In these regions, regarded as an ischemic core, CBF decreased further with time and CMRglc at 24 hours also decreased. Infarcted lesions as indicated by being unstained with TTC were consistently observed in these regions. (2) In the parietal cortex and several regions surrounding the ischemic core, CBF was > 40% of the contralateral values 1 hour after embolization and recovered gradually with time (ischemic penumbra). In these regions, CMRglc at 24 hours increased compared with that in the contralateral regions, indicating an uncoupling of CBF and CMRglc. No obvious TTC-unstained lesions were detected in these regions. The authors demonstrated a gradual recovery of reduced CBF, an elevated CMRglc and a CBF-CMRglc uncoupling in the penumbra regions of the primate model. Positron emission tomography investigations using this model will provide better understanding of the pathophysiology of thromboembolic stroke in humans.

Development of anti-influenza drugs: II. Improvement of oral and intranasal absorption and the anti-influenza activity of stachyflin derivatives.

The in-vivo anti-influenza-virus activity of Stachyflin derivatives (III and its phosphate ester, III-Phos), a new class of haemagglutinin fusion inhibitor, and the improvement of their absorption after oral or intranasal administration were studied in mice, rats, and ferrets. The absorption of III in PEG 4000 and III-Phos aqueous solution increased about three and four fold in AUC after oral administration to uninfected mice compared with that of 0.5% HPMC (hydroxypropyl-methylcellulose) suspension. Using a mouse influenza virus infection model, significant anti-influenza-virus activity was observed in infected mice treated orally with these compounds dissolved in PEG 4000 or distilled water, respectively, but not in mice treated with 0.5% HPMC. The in-vivo anti-influenza-virus activity in ferrets, a good model for influenza virus infection in man, was also studied. Although the concentration of III in plasma was above the IC50 against the influenza virus strain used for 6h after the oral administration of III in PEG 400 to uninfected ferrets, no in-vivo anti-influenza-virus activity was observed at the same dosage given 4 times daily for 3 days. The intranasal administration of III-Phos, which was expected to have a more notable in-vivo anti-influenza-virus activity, was examined. III-Phos, whose intranasal absorption had been improved by the modification of III with phosphate ester in rats, inhibited viral replication in the nasal cavity and suppressed influenza-virus-induced fever when administered intranasally to infected ferrets. This study demonstrates that intranasally administered compounds with anti-influenza-virus activity must permeate the nasal membranes to produce their anti-influenza-virus effect.

Selenium and glutathione peroxidase mRNA in rat glioma.

The purpose of current study was to determine the step at which dietary selenium (Se) regulates the transcriptional expression of the gene for Se-glutathione peroxidase (Se-GPx) in rat brain and transplanted glioma tissue. Wistar rats were fed a Se-free diet or the same diet supplemented with 0.5, 2.0, and 4.0 mg Se/kg as sodium selenite for at least 3 wk. Then, the rats were transplanted with C6 rat glioma cells into the right frontal lobe parenchyma. All rats were observed for 30 d, then tumor and contralateral brain tissue were excised and divided into three portions for purification of selenium content, for the assay of Se concentration, Se-GPx activity, and for Se-GPx mRNA. Se concentration and Se-GPx activity are increased with Se supplementation both in tumor tissue and contralateral brain tissue, and Se concentration in tumor is higher than that in contralateral brain tissue at each dietary Se content. Se-GPx mRNA of brain and tumor were probed with fragments from a rat Se-GPx cDNA in Northern blot analysis. There was significant differences of Se-GPx mRNA transcription in brain tumor tissue among each dietary group of the Se content, and the steady-state level of Se-GPx mRNA was markedly reduced by Se deficiency. These results suggest that dietary Se exerts its augmenting effect on Se-GPx gene transcription.

Primary systemic carnitine deficiency is caused by mutations in a gene encoding sodium ion-dependent carnitine transporter.

Primary systemic carnitine deficiency (SCD; OMIM 212140) is an autosomal recessive disorder characterized by progressive cardiomyopathy, skeletal myopathy, hypoglycaemia and hyperammonaemia. SCD has also been linked to sudden infant death syndrome. Membrane-physiological studies have suggested a defect of the carnitine transport system in the plasma membrane in SCD patients and in the mouse model, juvenile visceral steatosis. Although the responsible loci have been mapped in both human and mouse, the underlying gene has not yet been identified. Recently, we cloned and analysed the function of a novel transporter protein termed OCTN2. Our observation that OCTN2 has the ability to transport carnitine in a sodium-dependent manner prompted us to search for mutations in the gene encoding OCTN2, SLC22A5. Initially, we analysed the mouse gene and found a missense mutation in Slc22a5 in jvs mice. Biochemical analysis revealed that this mutation abrogates carnitine transport. Subsequent analysis of the human gene identified four mutations in three SCD pedigrees. Affected individuals in one family were homozygous for the deletion of a 113-bp region containing the start codon. In the second pedigree, the affected individual was shown to be a compound heterozygote for two mutations that cause a frameshift and a premature stop codon, respectively. In an affected individual belonging to a third family, we found a homozygous splice-site mutation also resulting in a premature stop codon. These mutations provide the first evidence that loss of OCTN2 function causes SCD.

Intra-arterial infusion of papaverine combined with intravenous administration of high-dose nicardipine for cerebral vasospasm.

The clinical effect of combination therapy with high doses of intravenous nicardipine and intra-arterial infusion of papaverine on symptomatic vasospasm after subarachnoid haemorrhage (SAH) was analysed retrospectively. In 66 of 122 patients who underwent early aneurysm surgery between 1990 and 1993, the intracranial haemodynamics were documented by transcranial Doppler (TCD) ultrasonography. 33 of these 66 patients received high dose nicardipine intravenously (Group I); the other 33 patients were not treated with calcium antagonists (Group II). Symptomatic vasospasm occurred in 6 Group I patients (18%) and in 13 (39%) in Group II patients. All 19 symptomatic patients received an intra-arterial infusion of papaverine; 15 patients (79%) responded well to this therapy and the symptoms were reversed quickly. Although the mean flow velocity (MFV) was not different between the two groups, it was reduced significantly after papverine infusion. Our retrospective analysis suggests that symptomatic vasospasm can be treated effectively with the combination of intravenous high dose nicardipine and intra-arterial infusion of papaverine, and that the correct timing of the infusions is crucial.

Molecular cloning and expression of a unique receptor-like protein-tyrosine-phosphatase in the leucocyte-common-antigen-related phosphate family.

Protein-tyrosine-phosphatases (PTPases) have been implicated in the regulation of certain tyrosine kinase growth factor receptors in that they dephosphorylate the activated (autophosphorylated) form of the receptors. In order to identify PTPases that potentially act on receptor targets in liver, we used the human leucocyte common antigen-related PTPase (LAR) cDNA [Streuli, Krueger, Hall, Schlossman and Saito (1988) J. Exp. Med. 168, 1523-1530] and isolated two closely related transmembrane PTPase homologues from a rat hepatic cDNA library. Both PTPases had large extracellular domains that contained three immunoglobulin-like repeats and eight type-III fibronectin repeats. Both enzymes had tandem homologous PTPase domains following a single hydrophobic transmembrane domain. One sequence encoded the rat homologue of LAR. The second PTPase, designated LAR-PTP2, had 79 and 90% identity with rat LAR in the respective cytoplasmic PTPase domains, with only 57% sequence similarity in the extracellular domain. The catalytic domains of LAR and LAR-PTP2 prepared by bacterial expression were active in dephosphorylating a variety of phosphotyrosyl substrates but did not hydrolyse phosphoserine or phosphothreonine residues of labelled casein. Both enzymes exhibited rapid turnover numbers of 4-7 s-1 for myelin basic protein and 78-150 s-1 for derivatized lysozyme. LAR and LAR-PTP2 displayed similar PTPase activity towards the simultaneous dephosphorylation of receptors of intact insulin and epidermal growth factor from liver membranes. These data indicate that there is a family of LAR-related PTPases that may regulate the phosphorylation state of receptor tyrosine kinases in liver and other tissues.

Effects of transcatheter arterial chemoembolization with oral chemotherapy on hepatic neoplasms.

An investigation was carried out into the effects of lipiodol-transcatheter arterial chemoembolization (L-TACE) therapy on hepatocellular carcinoma (HCC) and metastatic liver cancer, as well as the effects of oral 5-fluorouracil administration after L-TACE. For L-TACE, lipiodol mixed with adriamycin (doxorubicin) was injected through a catheter inserted into the tumor feeding artery and this was followed by embolization with a gelatin sponge. Twenty national hospitals throughout Japan participated in this multicenter co-operative open trial. A total of 102 patients became the subjects of study, including 75 HCC patients, 12 metastatic liver cancer patients treated with L-TACE, and 15 HCC patients who had hepatectomy after L-TACE. In 22% of the HCC patients and in 42% of the metastatic liver cancer patients, the tumor size was reduced by more than 50% after L-TACE. 73% of the 63 HCC patients showed a more than 50% reduction of the levels of serum alpha-fetoprotein. Although the survival rates of the HCC patients who had a hepatic resection were better than those who had not, there was no statistically significant difference between the survival rates of the HCC patients and those of the metastatic liver cancer patients treated with L-TACE. The survival rates of the HCC patients after L-TACE did not change as a result of oral 5-fluorouracil administration. It was therefore concluded that L-TACE is an effective way of treating both HCC patients and metastatic liver cancer patients, and that repeated L-TACE should be considered for some patients whose serum levels of alpha-fetoprotein rose again after L-TACE. Further follow-up studies will be needed to discover the effects of oral chemotherapy after L-TACE.

Bovine high molecular weight kininogen. The amino acid sequence, positions of carbohydrate chains and disulfide bridges in the heavy chain portion.

The existence of two types of circulating bovine plasma high molecular weight kininogen (HMWK) was predicted from analyses of complementary DNAs coding for this protein (Kitamura, N., Takagaki, Y., Furuto, S., Tanaka, T., Nawa, H., and Nakanishi, S. (1983) Nature 305, 545-549). The present protein-based study provided evidence in support of the proposed amino acid sequence derived from analysis of the cDNA clone, and the results confirm the existence of two types of circulating HMWK. Type I HMWK contains a heavy chain composed of 361 residues, while the heavy chain of type II HMWK contains 359 residues. The amino acid sequences of type I and type II HMWK determined in this study were identical to that inferred from the cDNA sequence with the exception of microheterogeneity observed in the cDNA at position 87 (Glu/Gln) and 168 (Lys/Arg). The heavy chain of type I HMWK contains 4 asparagine-linked carbohydrate chains at Asn-69, -150 (or -151), -179, and -186, while the heavy chain of type II HMWK contains these and an additional carbohydrate chain at Asn-264. In addition, a carbohydrate chain was found to be O-glycosidically linked to Thr-118 in both chains. Among nine disulfide linkages found in HMWK, eight intrachain disulfide pairs were established in the heavy chain. One interchain disulfide bridge occurs between the heavy chain and the light chain. This disulfide pairing, as well as repeating amino acid sequences observed in the heavy chain, provides strong evidence for the existence of three homologous domains in the heavy chain of bovine HMWK.

[Anti-anoxic effect of 4-(o-benzlphenoxy)-N-methylbutylamine hydrochloride (MCI-2016)].

Anti-anoxic effects of MCI-2016 were compared with those of drugs for cerebrovascular diseases, tricyclic antidepressants and physostigmine in mice. Minimal effective doses of MCI-2016 which significantly increased the survival time or gasping duration were 12.5 mg/kg, p.o. for hypoxia, 50 mg/kg, p.o. for KCN-induced anoxia, and 100 mg/kg, p.o. for decapitation-induced gasping. As a whole, these effects of MCI-2016 were superior to those of reference drugs for cerebrovascular diseases. MCI-2016 was also shown to be effective under a consecutive administration schedule. In marked contrast to the effect of MCI-2016, tricyclic antidepressants significantly shortened the survival time under hypoxia. Considering that atropine shortened and physostigmine markedly increased the survival time under hypoxia, involvement of anti-cholinergic action may be postulated for the shortening effect of tricyclic antidepressants. The anti-hypoxic effect of MCI-2016 as well as physostigmine was diminished by atropine treatment. Furthermore, MCI-2016 exhibited a combination effect with physostigmine at optimal doses. Although the influence of norepinephrine uptake inhibitory action on the hypoxic condition are not clear in the present study, these results may suggest that activation of CNS cholinergic system is involved as one of the causative mechanisms for anti-anoxic effect of MCI-2016.