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.

Preventive effects of kilohertz frequency electrical stimulation on sepsis-induced muscle atrophy.

OBJECTIVES: The present study sought to evaluate the effect of electrical stimulation (ES) by using kilohertz frequency on muscle atrophy induced by sepsis. METHODS: Seventeen male ICR mice were randomly divided into 3 groups: control, lipopolysaccharide (LPS)-injected for 4 days, LPS plus ES (LPS+ES). Sepsis was induced by 4 days of an intraperitoneal LPS injection (10 µg/g body weight/day). LPS+ES animals received the LPS injections and ES twice a day for 4 days. ELISA and western blot analysis determined the plasma levels of inflammatory cytokines and ubiquitinated proteins, while the tibialis anterior muscles were weighed and muscle fiber cross-sectional area (CSA) were measured to assess muscle atrophy, which were analyzed by Student's t-test and ANOVA. RESULTS: LPS induced increased plasma levels of inflammatory cytokines, significant muscle mass loss (LPS: -29.0%, LPS+ES: -23.1%), decreased fiber cross-sectional area, and an up-regulation of atrogin-1 and ubiquitinated proteins in the tibialis anterior muscle compared with the control. ES attenuated the sepsis-induced loss of muscle mass and decreased fiber CSA, as well as attenuated the atrogin-1 and ubiquitinated protein up-regulation. CONCLUSIONS: Electrical stimulation may prevent sepsis-induced muscle atrophy through ubiquitin-proteasome pathway inhibition.

Different expression patterns of hepatic cytochrome P450 s during anaphylactic or lipopolysaccharide-induced inflammation.

Certain physiological states and diseases can alter the expression and activity of cytochrome P450 s (CYPs), which have the potential to cause unexpected adverse effects. We previously demonstrated that lipopolysaccharide (LPS)-induced inflammation attenuates the induction of CYPs by xenobiotics in mouse liver. In this study, to investigate whether anaphylaxis-induced inflammation affects the hepatic CYPs' expression, we examined the effects of ovalbumin (OVA)-induced anaphylaxis on constitutive CYP mRNA and protein expressions. We also compared these effects with those obtained with LPS treatment. In addition, we examined the tumor necrosis factor (TNF) alpha and interleukin (IL)-113 mRNA levels, because these cytokines are known to be induced by LPS treatment and anaphylactic reactions. LPS treatment decreased the constitutively expressed Cyp1a2, Cyp2c29, and Cyp3al 1 mRNAs, and increased the TNFalpha and IL-1beta mRNAs. LPS treatment also decreased the CYP1A2 and CYP3A protein levels. Anaphylaxis, on the other hand, did not change the levels of the constitutively expressed Cyp1a2, Cyp2c29, or Cyp3a1 1 mRNAs, although it increased the TNFalpha and IL-1beta mRNAs, as observed in the LPS-treated mice. These results suggest that anaphylaxis-induced inflammation had less effect than LPS-induced inflammation on these CYPs in the liver. In contrast, we observed that the expressions of Cyp2b10 mRNA and its protein were quite different from those of the other CYPs in both the anaphylactic and LPS-treated mice. Our findings strongly suggest that the alteration of the constitutive CYPs' expression levels during inflammation varies according to the immunostimulation pathway.

Efficacy of gamma knife surgery for control of peritumoral oedema associated with metastatic brain tumours.

OBJECTIVES: To evaluate the efficacy of gamma knife surgery (GKS) for the control of peritumoral oedema associated with metastatic brain tumours. METHODS: A retrospective study of 280 consecutive metastatic brain tumours-100 from lung cancers, 100 from breast cancers and 80 from renal-cell carcinomas, associated with peritumoral oedema. The peritumoral oedema index was measured as A*B*C, where A (cm) was the maximum diameter of peritumoral oedema on the axial image, B (cm) was the maximum diameter perpendicular to A, and C (cm) was the maximum diameter on the coronal image. RESULTS: The oedema index of the renal cancer metastases was significantly larger than those of lung and breast cancer metastases (p<0.01). The oedema index of the renal cancer metastases at final imaging was also larger than those of lung (p<0.05) and breast (p<0.01) cancer metastases. The delivered marginal dose (22 Gy or more) was significantly correlated with tumour growth control by multivariate analysis (p = 0.03). Primary site (renal or not renal: p<0.01) and delivered marginal dose (25Gy or more: p = 0.04) were significantly correlated with control of peritumoral oedema by multivariate analysis. CONCLUSIONS: Brain oedema around metastatic brain tumours from renal-cell carcinomas was more extensive at the time of GKS and at final imaging compared with lung and breast cancer metastases. This paper suggests that the optimal doses for tumour growth control and brain oedema control may differ for metastatic brain tumours from renal-cell carcinomas.

Microsurgery for vestibular schwannoma after gamma knife radiosurgery.

BACKGROUND: We evaluated the clinical characteristics of microsurgery for vestibular schwannoma (VS) after failed gamma knife radiosurgery (GKS). METHOD: Twelve patients, 5 men and 7 women aged 19 to 70 years (mean 54.5 years), who underwent microsurgery after failed GKS for VS were studied retrospectively. FINDINGS: The median interval between GKS and microsurgery was 28.8 months (range, 6.6-120 months) and 4 patients had undergone previous microsurgery. The mean volume of tumour at GKS was 6.9 cm(3) (range, 0.5-19.7 cm(3)) and the mean prescription dose to the tumour margin was 12.3 Gy. Microsurgery involved the lateral suboccipital approach in all patients. Tumour expansion involved solid enlargement in 7 patients, cystic enlargement in 3, and central necrosis in 2. Bleeding was slight in all patients except in one, probably because of the previous irradiation. Adhesion to the brain stem was severe in 7 patients. Identification of the facial nerve was easy in 5 operations and difficult in 7. Dissection of the tumour from the facial nerve was difficult in most interventions because of severe adhesions or colour change. Severe adhesions between the trigeminal nerve and the tumour was observed in 2 patients. The tumour was subtotally removed except around the internal auditory canal in most patients. Only one residual tumour increased in size and needed second GKS. The function of the facial nerve deteriorated in 3 patients, was unchanged in 7, and improved in 2. All patients had lost hearing on the affected side at the time of microsurgery. CONCLUSIONS: Microsurgery for VS after failed GKS presents some technical difficulties. Dissection of the tumour from the facial nerve or brain stem is likely to be difficult. We recommend subtotal resection without dissection of the facial nerve and tumour, because growth of the residual tumour was rare in our series.

Lack of exercise, via hindlimb suspension, impedes endogenous neurogenesis.

Bedridden patients who receive good physical rehabilitation are able to exhibit clinical improvement. Accumulating evidence demonstrates that exercise increases endogenous neurogenesis and may even protect against central nervous system (CNS) disorders. Here, we explored the effects of lack of exercise on neurogenesis in rats by employing a routine hindlimb suspension (HS) model over a 2-week period, which consists of elevating their tails, thereby raising their hindlimbs above the ground and unloading the weights in these extremities. In addition, the effects of exercise and recovery time with normal caging after HS were also explored. BrdU (50 mg/kg, i.p.) was injected every 8 h over the last 4 days of each paradigm to label proliferative cells. Immunohistochemical results revealed that HS significantly reduced the number of BrdU/Doublecortin double-positive cells in the subventricular zone and dentate gyrus. Exercise and recovery time significantly improved atrophy of the soleus muscle, but did not attenuate the HS-induced decrement in BrdU/Dcx-positive cells. A separate cohort of animals was exposed to the same HS paradigm and enzyme-linked immunosorbent assay (ELISA) of neurotrophic factors was performed on brain tissue samples harvested at the end of the HS period, as well as plasma samples from all animals. ELISA results revealed that HS reduced the levels of brain-derived neurotrophic factor in the hippocampus and vascular endothelial growth factor plasma levels. This study revealed that lack of exercise reduced neurogenesis with downregulation of neurotrophic factors. The use of the HS model in conjunction with CNS disease models should further elucidate the role of exercise in neurogenesis and neurotrophic factors in neurologic disorders.

Gamma knife radiosurgery for intracranial haemangioblastomas.

BACKGROUND: The results of gamma knife radiosurgery for haemangioblastomas were retrospectively studied to assess the efficacy for tumour growth control and clarify the clinical indications for gamma knife radiosurgery in these tumours. METHODS: The medical records of 22 patients with 67 tumours, 12 men and 10 women aged 20-73 years (mean 51.9 years), who underwent gamma knife radiosurgery for haemangioblastomas between January 1993 and January 2006, were retrospectively reviewed. Ten patients with 54 lesions had von Hippel-Lindau disease. The mean tumour volume was 1.69 cm(3) (range 0.0097-16.4 cm(3)). Nineteen patients had undergone 1-4 open surgery procedures (mean 1.5) before gamma knife radiosurgery. Tumours without a cystic component, (the solid type), were found in 54 lesions and tumours associated with cyst, (the mural nodule with cyst type), in 13 lesions. The marginal dose was 8-30 Gy (mean 14.0 Gy). FINDINGS: Follow-up magnetic resonance (MR) imaging was performed at 9-146 months (mean 63 months). The control rate for tumour growth was 83.6%. The only factor affecting tumour growth control was the presence of a cystic component at the time of gamma knife radiosurgery in both univariate and multivariate analysis. No complication such as radiation-induced peritumoural oedema or radiation necrosis occurred. CONCLUSION: The presence of cystic components at the time of gamma knife radiosurgery was the only factor significantly correlated with unfavourable tumour growth control by gamma knife radiosurgery for haemangioblastomas. Gamma knife radiosurgery is effective for solid type tumours, even if the marginal dose is relatively low. Surgical removal is recommended for mural nodule with cyst type tumours, when possible.

Suppression of mediastinal metastasis by uracil-tegafur or cis-diamminedichloroplatinum(II) using a lymphogenous metastatic model in a human lung cancer cell line.

PURPOSE AND EXPERIMENTAL DESIGN: The extent of lymphatic metastasis is the most important factor in the prognosis for non-small cell lung cancer (NSCLC). Therefore, suppression of lymphatic metastasis provides an improvement in survival time in lung cancer patients. We established a new patient-like model for lung cancer metastasis by orthotopic implantation in severe combined immunodeficiency (SCID) mice and demonstrated the lymphogenous spread histologically using human NSCLC cell lines. The cardinal features of this model are a simple procedure and a similarity to the metastatic form of human lung cancer. The purpose of this study is to assess the inhibitory action of uracil-tegafur (UFT) and cis-diamminedichloroplatinum(II) (CDDP) on lymphatic metastasis and life span prolongation in our lymphogenous metastatic model system using SCID mice. RESULTS: The inhibition ratios of mediastinal lymph node metastasis were 86.2, 94, and 92.1% for 12 mg/kg body UFT, 17 mg/kg body UFT, and 10 mg/kg body CDDP, respectively. The administration of anticancer drugs prolonged the life span by 4.6 days (17 mg/kg body UFT) and 8 days (10 mg/kg body CDDP) in MST. CONCLUSION: We demonstrated that UFT alone and CDDP alone suppressed mediastinal metastasis and prolonged the life span in our lymphogenous metastatic model. Regardless of the administration route and characteristics of anticancer drugs, cytostatic or cytotoxic, our model is capable of evaluating the inhibitory effect of drugs on lymphatic metastasis. This model should make an important contribution to our understanding of the mechanism and selection of drugs for antilymphatic metastasis in lung cancer.

Serious cardiac and pulmonary calcification in a young peritoneal dialysis patient: potential role of continuous correction of acidosis.

We describe a 40-month-old male infant with renal failure, treated with peritoneal dialysis, who developed massive calcification of soft tissues including the heart and lungs with subsequent cardiopulmonary insufficiency. A diagnosis of Jeune syndrome was made. After starting peritoneal dialysis, the patient exhibited an intractable metabolic acidosis of unknown etiology necessitating treatment with intravenous or oral sodium bicarbonate. Myocardial calcification was first detected by 2-dimensional echocardiography performed 3 months after starting dialysis. The patient was not suitable for renal transplantation because of his cardiac dysfunction and died of cardiac and respiratory failure at the age of 6 years. Although the patient exhibited a variety of risk factors for ectopic calcification including hyperphosphatemia, hyperparathyroidism, high calcium-phosphate product and treatment with vitamin D, the early and massive soft tissue calcification may have been accelerated by correction of the metabolic acidosis. Therefore, the use of sodium bicarbonate may be involved in the etiology of the myocardial calcification.

Two patients treated with simeprevir plus pegylated-interferon and ribavirin triple therapy for recurrent hepatitis C after living donor liver transplantation: case report.

We previously reported our data on telaprevir (TVR) used in combination with pegylated-interferon and ribavirin (PEG-IFN/RBV) for the treatment of recurrent hepatitis C virus (HCV) genotype 1 infection after liver transplantation (LT). TVR substantially increases the blood levels of immunosuppressive agents such as cyclosporine and tacrolimus for drug-drug interactions. On the other hand, the effect of simeprevir (SMV) on the blood levels of these immunosuppressive agents is unclear. We report 2 patients who achieved viral responses with little effect on the blood levels of cyclosporine and tacrolimus using SMV plus PEG-IFN/RBV treatment. The first was a 71-year-old woman with HCV-related liver cirrhosis and hepatocellular carcinoma who failed to respond to PEG-IFN/RBV after living donor LT. She was treated with 40 mg/d of cyclosporine, and received SMV plus PEG-IFN/RBV treatment. The second was a 65-year-old man with HCV-related liver cirrhosis who failed to respond to PEG-IFN/RBV after living donor LT. He was treated with 3 mg/d of tacrolimus, and received SMV plus PEG-IFN/RBV treatment. Serum HCV RNA became undetectable using TaqMan polymerase chain reaction (PCR) test after 4 weeks of treatment in both patients, and no remarkable fluctuation in blood concentration was observed either in cyclosporine or tacrolimus during the 12 weeks of SMV treatment. Completion of 12-week SMV triple therapy was followed by PEG-IFNα2b plus RBV, and both patients achieved sustained virological response 12 weeks after the end of treatment. SMV plus PEG-IFNRBV treatment showed a remarkable viral response with little effect on blood levels of immunosuppressive agents for recurrent HCV genotype 1 infection after LT.

Bernard-Soulier syndrome associated with 22q11.2 microdeletion.

We describe a Japanese girl with Bernard-Soulier syndrome and 22q11.2 microdeletion. She had viral infections and recurrent thrombocytopenia and hemorrhagic diathesis after cardiac surgery. As congenital heart defects and abnormal immunity are the most common clinical manifestations associated with 22q11.2 deletion, patients with this association may have a greater risk of developing a severe bleeding disorder.

Esophageal actinomycosis after allogeneic peripheral blood stem cell transplantation for extranodal natural killer/T cell lymphoma, nasal type.

We report a 19-year-old man with extranodal natural killer (NK)/T cell lymphoma, nasal type treated by allogeneic peripheral blood stem cell transplantation (allo-PBSCT). His lymphoma was chemoresistant, and disseminated during local radiotherapy. The patient received allo-PBSCT from his HLA-1 locus mismatched sister using busulfan (BU), cyclophosphamide (CY) and VP-16 as the conditioning regimen. His course was complicated by esophageal actinomycosis 9 months after transplantation, which resulted in the rupture of the right common carotid artery. These observations suggest that actinomycosis should be monitored carefully after transplantation in patients who have received local radiation therapy before the procedure.

A new approach to gene mutation analysis using "GFP-Display".

The unique behavior of green fluorescent protein (GFP) on SDS-PAGE was applied to the detection of a single amino acid substitution in GFP-tagged polypeptides. This simple detection method using SDS/urea gels was designated GFP-display. The N-terminal 18 or 37 amino acids of K-Ras was used as a model GFP-tagged polypeptide. K-ras exon 1 was fused to a gfp cDNA at each end and expressed in Escherichia coli. Amino acid number 12 of K-Ras (wild type; Gly) was changed to Ser, Arg, Cys, Asp, Ala, or Val, and the mobility shift of the greenish fluorescent bands in the SDS/urea gel was analyzed. These mutants were easily detected by GFP-display; however, detection depended strongly on the urea concentration and electrophoresis temperature. Subsequently, GFP-display was applied to the 36 amino acids encoding human p53 exon 7. Amino acid number 248 (wild type; Arg) was changed to Gly, Trp, Gln, Pro, or Leu, and similar mobility shifts were observed. GFP-display could be coupled with an in vitro translation system. Fluorescent active GFP and GFP-Ras fusion proteins were synthesized within a few hours. GFP-display shows potential as a modern approach to gene mutation analysis at the protein level, and is a useful method for protein engineering studies.

Genetic vulnerability of cortical neurons isolated from stroke-prone spontaneously hypertensive rats in hypoxia and oxygen reperfusion.

Severe hypertension and cerebrovascular diseases develop in stroke-prone spontaneously hypertensive rats (SHRSP). Cortical neurons from SHRSP are more vulnerable than those from Wistar Kyoto rats (WKY) to the effects of nitric oxide (NO)- and N-methyl-D-aspartate (NMDA)-mediated neurotoxic agents. Growth factors, idebenone, and nilvadipine (a Ca2+ channel blocker) can reduce neuronal damage caused by hypoxia or neurotoxic agents. This study was designed to determine 1) whether cortical neurons from SHRSP are more vulnerable than those from WKY and 2) whether neuronal damage is minimized by the so-called neuroprotective agents in cells exposed to hypoxia and oxygen reperfusion. We demonstrated that 6 to 24 h of hypoxia did not increase cell death in either WKY or SHRSP, whereas 36 h of hypoxia significantly increased cell death in SHRSP (p < 0.01). Furthermore, 6 to 36 h of hypoxia and 1.5 to 5 h of reperfusion heavily damaged cells from both strains of rats, and most cells became apoptotic or necrotic. We also verified that the ability to protect neurons in hypoxia and oxygen reperfusion was as follows: idebenone > insulin-like growth factor-1 (IGF-1) > nilvadipine. These data indicate that oxygen radical generation occurs and the free radicals heavily damage neurons in hypoxia and oxygen reperfusion. SHRSP neurons are weaker than WKY neurons in these conditions. Furthermore, we surmise that idebenone, an antioxidant, decreases free radicals, and IGF-I attenuates p53-mediated apoptosis and thereby prevents cell death. We conclude that antioxidants are more potent than IGF-1 in protecting cortical neurons from damage caused by hypoxia and oxygen reperfusion, although both are very useful in minimizing damage to cortical neurons.

Onset of diabetes with high titer anti-GAD antibody after IFN therapy for chronic hepatitis.

A case of hyperglycemia induced by the injection of interferon-alpha was experienced in our hospital. This patient showed a sustained high titer of anti-GAD antibody after the onset of diabetes, suggesting that the involvement of immunological disturbance by IFN induces the onset of the disease. However, the susceptibility and the response of the immune system differs from patient to patient, and only limited destruction of beta-cells in the islet of Langerhans and normalization of glucose tolerance by CSII was induced in this patient.

Subdural tension pneumocephalus following surgery for chronic subdural hematoma.

The computerized tomography (CT) findings were analyzed in five cases of subdural tension pneumocephalus following surgery for chronic subdural hematoma. They were compared with CT scans in 14 cases of asymptomatic subdural pneumocephalus. In this study, two new CT findings were identified that suggest increased tension of the subdural air. Subdural air separates and compresses the frontal lobes, creating a widened interhemispheric space between the tips of the frontal lobes that mimics the silhouette of Mt. Fuji. The presence of air between the frontal tips associated with massive air inclusion over the frontal lobes presumably indicates increased tension of the subdural air. The "Mt. Fuji sign" was seen in four of the five cases with subdural tension pneumocephalus. The other finding was the presence of multiple small air bubbles scattered through several cisterns ("air bubble sign"). It is postulated that these air bubbles enter the subarachnoid space through a tear in the arachnoid membrane caused by increased tension of air in the subdural space. This finding was seen in four cases with subdural tension pneumocephalus. These two CT findings are helpful in making a diagnosis of subdural tension pneumocephalus following surgery for chronic subdural hematoma.

A new intracranial Silastic encircling clip for hemostasis. Technical note.

A new encircling clip made of a silicone tube has been designed for treating accidentally injured cerebral vessels. No special holders are necessary. This clip can be tailored depending on the shape of the injured vessel. The clip is a simple and effective tool for achieving complete hemostasis.

Globin digest, acidic protease hydrolysate, inhibits dietary hypertriglyceridemia and Val-Val-Tyr-Pro, one of its constituents, possesses most superior effect.

Globin digest (GD), prepared from globin by acidic protease treatment, suppressed the elevation of serum triglyceride level in not only total but also chylomicron fraction after oral administration of olive oil. By screening with this lowering activity, we concluded that Val-Val-Tyr-Pro (VVYP) would be most effective constituent having hypotriglyceridemic action in GD. The mode of their action was dose dependent and did not show species specificity. Neither the repression of peristaltic movement of intestine nor the delaying of gastric emptying was caused by intake of GD or VVYP, however, the excretion of administered lipid was much more than that of control. Furthermore, administration of GD caused more prominent activation of hepatic triglyceride lipase (HTGL) and the increase of hepatic free fatty acid (FFA) concentration in early phase after administration of fat. From these results, it could be elucidated that GD, and also VVYP, inhibited fat absorption from digestive tract and enhanced activity of HTGL, so that more rapid clearance of dietary hypertriglyceridemia was caused.

Doppler echocardiographic evaluation of the hemodynamics in absent aortic valve.

Hemodynamics were estimated by Doppler echocardiography in a neonate with an absent aortic valve and absent or extremely hypoplastic mitral valve. The coronary blood flow depended on the increased end-diastolic pressure of the left ventricle. Pulmonary venous congestion, which was also due to the increased end-diastolic pressure of the left ventricle, may induce decreased oxygen saturation and, subsequently, further myocardial hypoxia, poor contraction and increased end-diastolic pressure of the left ventricle. Finally, hypoxic blood was supplied to each organ from the pulmonary artery through the ductus arteriosus, which induced severe acidosis and differential cyanosis after birth.

T-cell lymphoma presenting with pericardial and pleural effusion as the initial and primary lesion: cytogenetic and molecular evidence.

A 90-year-old woman was admitted with progressive dyspnea. Chest roentgenogram and computed tomography revealed a massive pericardial effusion and bilateral pleural effusion, but no lymphomatous lesion was seen. A diagnosis of malignant lymphoma was made by cytological and immunological studies of the cells obtained from the pericardial effusion. Chromosome analysis showed a clonal abnormality and T-lineage clonality was determined by the rearrangement of the T-cell receptor gamma gene. The patient achieved remission with chemotherapy, but she later relapsed, with right pleural effusion, and died. She exhibited no lymphomatous features throughout the clinical course, indicating the possibility of malignant lymphoma originating from the pericardium and/or pleura.