Aging in the CNS: comparison of gray/white matter volume and diffusion tensor data

This study investigated the global and regional effects of aging on brain volume, mean diffusivity (MD), and fractional anisotropy (FA) in 73 normal female subjects using voxel-based analysis. On a global scale, gray matter volume and FA were negatively correlated, whereas MD was positively correlated with age. Voxel-wise analyses showed brain volume and FA were negatively correlated predominantly in anterior structures, whereas MD was positively correlated in the cortical gray matter and periventricular white matter. Volume preservation was observed in the cingulate gyrus and subjacent white matter. FA increase was observed in the putamen. Voxel-based direct comparisons of volume and diffusion properties showed FA was more strongly negatively correlated in the fronto-temporal white matter, compared with volume and MD. Stronger positive correlation of MD was observed in the thalamus, caudate nucleus, and midbrain and stronger negative correlation of brain volume was observed in the frontal lobe and basal ganglia, compared with the other. These results indicate that diffusion properties and brain volume are complementary markers to the effects of aging.     

Induction of fibroblast-like cells from CD34(+) progenitor cells of the bone marrow in rheumatoid arthritis

To assess the role of bone marrow in the pathogenesis of rheumatoid arthritis (RA), we examined the capacity of CD34(+) cells from bone marrow to generate fibroblast-like type B synoviocytes. CD34(+) cells from the bone marrow of 22 RA patients differentiated into cells with fibroblast-like morphology, which expressed prolyl 4-hydroxylase, in the presence of stem cell factor (SCF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor alpha (TNF-alpha), much more effectively than CD34(+) cells from bone marrow of 15 control subjects (10 patients with osteoarthritis and 5 healthy individuals). The generation of fibroblast-like cells was not at all observed in cultures with SCF, GM-CSF, and interleukin 4 (IL-4) with or without TNF-alpha. Generation of fibroblast-like cells was correlated with matrix metalloproteinase (MMP)-1 levels in culture supernatants. Thus, MMP-1 levels were significantly higher in TNF-alpha-stimulated cultures of bone marrow CD34(+) cells from patients with RA than in those from the control group. These results indicate that bone marrow CD34(+) cells from patients with RA have abnormal capacities to respond to TNF-alpha and to differentiate into fibroblast-like cells producing MMP-1, suggesting that bone marrow CD34(+) progenitor cells might generate type B synoviocytes and thus could play an important role in the pathogenesis of RA.     

Differences between T-cell reactivities to major myelin protein-derived peptides in opticospinal and conventional forms of multiple sclerosis and healthy controls

In Japanese, susceptibility to the conventional form of multiple sclerosis (C-MS) is associated with the HLA-DRB1*1501-DRB5*0101 haplotype while susceptibility to the opticospinal form of MS (OS-MS) is associated with HLA-DPA1*0202-DPB1*0501. To clarify the characteristics of T cells autoreactive to myelin proteins in each MS subtype, we established T-cell lines reactive to such myelin antigens as myelin basic protein (MBP), proteolipid protein (PLP) and myelin oligodendrocyte glycoprotein (MOG) from 5 of 10 OS-MS patients, 6 of 11 C-MS patients and 7 of 13 healthy controls (HCs), and T-cell epitopes and their restriction molecules were determined. We found that (a) intermolecular epitope spreading was found to be significantly more frequent in MS patients than in HCs (P=0.0128), (b) intramolecular epitope spreading also tended to occur more frequently in MS patients than in HCs (P=0.0584), (c) in OS-MS, HLA-DR-restricted and MOG-autoreactive T cells were more frequently established as compared with those reactive to MBP or PLP epitopes and (d) in C-MS, HLA-DQ-restricted and PLP-autoreactive T cells dominated those autoreactive to MBP or MOG epitopes. A DPB1*0501-restricted MBP-reactive T-cell clone from a patient with OS-MS provided evidence that the first HLA class II anchor amino acid of peptide bound to disease-susceptible DP5 molecule was distinct from that for the DR2 molecule. Taken together, these differences in specificities of myelin-autoreactive T cells between C-MS and OS-MS as well as the difference in the anchor motif of the binding peptides between each MS subtype-susceptible HLA class II molecule may contribute to the development of distinct clinical phenotypes.     

Overexpression of the human angiotensin II type 1 receptor in the rat heart augments load induced cardiac hypertrophy

Angiotensin II is known to stimulate cardiac hypertrophy and contractility. Most angiotensin II effects are mediated via membrane bound AT1 receptors. However, the role of myocardial AT1 receptors in cardiac hypertrophy and contractility is still rarely defined. To address the hypothesis that increased myocardial AT1 receptor density causes cardiac hypertrophy apart from high blood pressure we developed a transgenic rat model which expresses the human AT1 receptor under the control of the alpha-myosin heavy-chain promoter specifically in the myocardium. Expression was identified and quantified by northern blot analysis and radioligand binding assays, demonstrating overexpression of angiotensin II receptors in the transgenic rats up to 46 times the amount seen in nontransgenic rats. Coupling of the human AT1 receptor to rat G proteins and signal transduction cascade was verified by sensitivity to GTP-gamma-S and increased sensitivity of intracellular Ca2+ [Ca2+]i to angiotensin II in fluo-3 loaded transgenic cardiomyocytes. Transgenic rats exhibited normal cardiac growth and function under baseline conditions. Pronounced hypertrophic growth and contractile responses to angiotensin II, however, were noted in transgenic rats challenged by volume and pressure overload. In summary, we generated a new transgenic rat model that exhibits an upregulated myocardial AT1 receptor density and demonstrates augmented cardiac hypertrophy and contractile response to angiotensin II after volume and pressure overload, but not under baseline conditions.     

Design and performance evaluation of a master controller for endovascular catheterization

Purpose

It is difficult to manipulate a flexible catheter to target a position within a patient’s complicated and delicate vessels. However, few researchers focused on the controller designs with much consideration of the natural catheter manipulation skills obtained from manual catheterization. Also, the existing catheter motion measurement methods probably lead to the difficulties in designing the force feedback device. Additionally, the commercially available systems are too expensive which makes them cost prohibitive to most hospitals. This paper presents a simple and cost-effective master controller for endovascular catheterization that can allow the interventionalists to apply the conventional pull, push and twist of the catheter used in current practice.

Methods

A catheter-sensing unit (used to measure the motion of the catheter) and a force feedback unit (used to provide a sense of resistance force) are both presented. A camera was used to allow a contactless measurement avoiding additional friction, and the force feedback in the axial direction was provided by the magnetic force generated between the permanent magnets and the powered coil.

Results

Performance evaluation of the controller was evaluated by first conducting comparison experiments to quantify the accuracy of the catheter-sensing unit, and then conducting several experiments to evaluate the force feedback unit. From the experimental results, the minimum and the maximum errors of translational displacement were 0.003 mm (0.01 %) and 0.425 mm (1.06 %), respectively. The average error was 0.113 mm (0.28 %). In terms of rotational angles, the minimum and the maximum errors were \(0.39^{\circ }\) (0.33 %) and \(7.2^{\circ }\) (6 %), respectively. The average error was \(3.61^{\circ }\) (3.01 %). The force resolution was approximately 25 mN and a maximum current of 3A generated an approximately 1.5 N force.

Conclusion

Based on analysis of requirements and state-of-the-art computer-assisted and robot-assisted training systems for endovascular catheterization, a new master controller with force feedback interface was proposed to maintain the natural endovascular catheterization skills of the interventionalists.

     

Imaging of early hepatocellular carcinoma and adenomatous hyperplasia (dysplastic nodules) with dynamic ct and a combination of CT and angiography: experience with resected liver specimens

Early hepatocellular carcinoma (HCC) as defined by the Liver Cancer Study Group of Japan would correspond to high-grade dysplastic nodules with small foci of HCC in the majority of cases, using the classification system proposed by the International Working Party. A large number of early HCCs were revealed to be hypo- or isovascular in the arterial phase of dynamic CT. Only 5% of the lesions evaluated were hypervascular, which contrasted with advanced small HCCs, of which 94% were hypervascular. CT arterial portography (CTAP) showed hypoattenuation in 66% of early HCCs and isoattenuation in 34%. CT hepatic arteriography (CTHA) demonstrated hypoattenuation in 55% of early HCC, isoattenuation in 30% and hyperattenuation in 15%. These findings suggest that most early HCCs receive equal or reduced blood supply from both portal and arterial flow compared with surrounding noncancerous parenchyma. In contrast, 97% of small HCCs are hypoattenuated on CTAP, and 93% are hyperattenuated on CTHA. For nodule-in-nodule type HCC (advanced HCC within early HCC), the CT attenuation of the central and peripheral portions revealed areas of isolated advanced HCC and isolated early HCC, respectively. Adenomatous hyperplasia (low-grade dysplastic nodules) was not readily differentiated using the various imaging modalities, mainly due to the smaller size of these lesions compared to early HCC and/or a portal and arterial blood supply very similar to that of the surrounding parenchyma. Hemodynamic changes in cirrhotic liver were similarly evaluated using CTAP and CTHA, and the treatment of early HCC is briefly discussed herein.     

The art of separation and adsorption: Historical review of apheresis in Japan

Apheresis therapy was first introduced into Japan from the United State as plasmapheresis by a centrifuge method. However, the invention of hollow fiber has subsequently lead to a membrane plasma separation. Selective removal of the plasma or cell component has been improved and matured in clinical application. Therapeutic apheresis has progressed and diversified with the development of technology for membrane separation by hollow fiber and adsorption with a physicochemical adsorbent in Japan.     

72-Week Safety and Tolerability of Dimethyl Fumarate in Japanese Patients with Relapsing-remitting Multiple Sclerosis: Analysis of the Randomised,Double Blind,Placebo-Controlled,Phase III APEX Study and its Open-Label Extension

Introduction

The long-term safety of dimethyl fumarate (DMF) in patients with relapsing-remitting multiple sclerosis (RRMS) has been studied in mainly Caucasian patients. The present interim analysis aimed to evaluate the 72-week safety of DMF in Japanese patients with RRMS.

Methods

Safety data of Japanese subjects enrolled in the 24-week randomised, double-blind, placebo-controlled APEX study (Part I) and its following open-label extension (Part II) were analysed at 72 weeks from the beginning of Part I. In Part I, subjects were randomised to DMF treatment or matching placebo while all subjects received DMF treatment during Part II. Adverse events (AEs) reported throughout the study period were recorded.

Results

Overall, 109 Japanese subjects completed 72 weeks of treatment. The incidence of AEs and serious AEs was 95% and 19%, respectively, in the DMF group compared with 84% and 18%, respectively, in the placebo group at 24 weeks. Common AEs (at least 5%) reported with treatment included nasopharyngitis, flushing, hot flush, gastrointestinal events, pruritus, rash, headache, increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST). AEs led to discontinuation of DMF in 5% of patients and included MS relapse, flushing, abdominal pain, liver disorder and increased ALT/AST. After an initial decrease from baseline of 17% in the DMF group at week 24, the mean lymphocyte counts stabilised and were maintained until week 72. No opportunistic/serious infections nor malignancies were reported with DMF treatment. The incidences of AEs, serious AEs, and discontinuation due to AEs were similar between the DMF and the placebo groups.

Conclusion

The 72-week safety profile of DMF in Japanese patients with RRMS was consistent with previous studies that enrolled mostly Caucasian patients, with a lower incidence of flushing and related symptoms and a lower reduction in the lymphocyte count compared with previous reports.

Trial Registration

ClinicalTrials.gov identifier NCT01838668.

Funding

Biogen Japan Ltd.

     

Analysis and Distribution of Etoposide in Rat Brain Tumor Model: Intracarotid Versus Intracarotid with Angiotensin II—Induced Hypertension

The brain tissue distribution of etoposide has been investigated in 9L gliosarcoma-bearing rats with or without hypertension induced by angiotensin II (AT II). The rat brain tumor models were divided into the following two groups according to etoposide administration route: intracarotid injection (IC) group and intracarotid injection with hypertension induced by AT II (IHIC) group. Ten mg/kg of etoposide was given, and 30 min and 2, 4, 8, and 24 hr later the rats were sacrificed. The drug concentrations in the serum, tumor, and normal brain tissue were analyzed by high-pressure liquid chromatography. The etoposide concentration in the serum, tumor, and normal brain tissue peaked at 30 min in both groups. The serum concentration was similar between the two groups. The etoposide concentration in the tumor was at least 2.2 times higher in the IHIC group than in the IC group at 30 min and 2 hr. The area under drug concentration curve (AUC) in the tumor in the IHIC group was about 2.2 times higher than that in the IC group. The etoposide concentration in the normal brain on the drug injection side changed only slightly from 0.5 hr to 4 hr and was about 3 times higher in the IHIC group than in the IC group. The etoposide concentration in the contralateral normal brain was very low in both groups at 30 min and disappeared thereafter.

Intracarotid injection of anticancer drugs with AT II-induced hypertension further increases the drug concentration and AUC in the tumor compared with intracarotid injection alone and can be useful in treatment of malignant brain tumors.     

Lung cancer screening--comparison of computed tomography and X-ray

Recent studies on lung cancer screening with CT disclosed a discrepancy between its efficiency in detecting early lung cancer and a lack of proof for decreasing mortality from lung cancer. The present study, in a city in Japan where an X-ray screening program is provided, bi-annual CT screening was performed for X-ray screening negative subjects for 4 years. Ten patients with lung cancer were detected among 22,720 person-year subjects (0.044%) through the X-ray screening. Among the X-ray screening-negative subjects, 3305 subjects participated in a CT screening program resulting in the detection of 15 patients with lung cancer (0.454%). All 15 cases detected by CT screening and 5 of the 10 cases detected by X-ray screening were at stage IA. In respect of gender, histological type and CT findings, patients detected by CT screening had a better prognostic profile than those detected by X-ray screening. Survival was significantly better in the former than the latter, both in its entirety comparison and in a comparison limited to patients who underwent surgery. In conclusion, CT screening might have the potential to detect lung cancer with good prognostic factors not limited to early detection. Sufficiently long follow-up time, therefore, would be required to evaluate the efficacy for decreasing lung cancer mortality with CT screening.